Title of Invention

A MEDICAL IMPLANT, METHOD OF MAKING IT AND COMPOSITION FOR THE SAME

Abstract The invention discloses a medical implant which comprises a fluoropyrimidine or a composition that comprises a fluoropyridimine, wherein the fluoropyrimidine is in an amount effective to reduce or inhibit infection associated with the medical implant. The invention further discloses the making of said medical implant and composition for the same.
Full Text A MEDICAL IMPLANT, METHOD OF MAKING IT AND
COMPOSITION FOR THE SAME
BACKGROUND OF THE INVENTION
Field of the Invention
The present invention relates generally to pharmaceutical
compositions, methods, and devices, and more specifically, to compositions and
methods which reduce the likelihood of an infection associated with a medical
implant.
Description of the Related Art
Infections associated with medical implants represent a major
healthcare problem. For example, 5% of patients admitted to an acute care facility
develop a hospital acquired infection. Hospital acquired infections (nosocomial
infections) are the 11th leading cause of death in the US and cost over $2 billion
annually. Nosocomial infections directly cause 19,000 deaths per year in the US
and contribute to over 58,000 others.
The four most common causes of nosocomial infections are: urinary
tract infection (28%); surgical site infection (19%); respiratory tract infection (17%);
and bloodstream infection (16% and rising). A significant percentage of these
infections are related to bacterial colonization of implanted medical implants such
as Foley catheters (urinary tract infections); surgical drains, meshes, sutures,
artificial joints, vascular grafts (wound infections); endotracheal and tracheostomy
tubes (respiratory tract infection); and vascular infusion catheters (bloodstream
infections). Although any infectious agent can infect medical implant.
Staphylococci (S. aureus, S. epidermidis, S. pyogenes), Enterococci (E. coif).
Gram Negative Aerobic Bacilli, and Pseudomonas aeruginosa are common
causes. Once a medical implant becomes colonized by bacteria, it must frequently
be replaced resulting in increased morbidity for the patient and increased cost to
the healthcare system. Often the infected device serves as a source for a
disseminated infection which can lead to significant morbidity or even death.
In an attempt to combat this important clinical problem, devices have
been coated with antimicrobial drugs. Representative examples include U.S.
Patent No. 5,520,664 ("Catheter Having a Long-Lasting Antimicrobial Surface
Treatment"), U.S. Patent No. 5,709,672 ("Silastic and Polymer-Based Catheters
with Improved Antimicrobial/Antifungal Properties"), U.S. Patent No. 6,361,526
("Antimicrobial Tympanostomy Tubes"), U.S. Patent No. 6,261,271 ("Anti-infective
and antithrombogenic medical articles and method for their preparation"), U.S.
Patent No. 5,902,283 ("Antimicrobial impregnated catheters and other medical
implants") U.S. Patent No. 5,624,704 ("Antimicrobial impregnated catheters and
other medical implants and method for impregnating catheters and other medical
implants with an antimicrobial agent") and U.S. Patent No. 5,709,672 ("Silastic and
Polymer-Based Catheters with Improved Antimicrobial/Antifungal Properties").
One difficulty with these devices, however, is that they can become
colonized by bacteria resistant to the antibiotic coating. This can result in at least
two distinct clinical problems. First, the device serves as a source of infection in
the body with the resulting development of a local or disseminated infection.
Secondly, if an infection develops, it cannot be treated with the antibiotic(s) used in
the device coating. The development of antibiotic-resistant strains of microbes
remains a significant healthcare problem, not just for the infected patient, but also
for the healthcare institution in which it develops.
Thus, there is a need in the art for medical implants which have a
reduced likelihood of an associated infection. The present invention discloses
such devices (as well as compositions and methods for making such devices)
which reduce the likelihood of infections in medical implants, and further, provides
other, related advantages.
ACCOMPANYING
BRIEF DESCRIPTION OF THEjDRAWING
Figure 1 shows the effect of palmitic acid on the release profile of
5-fluorouracil from a polyurethane sample.
BRIEF SUMMARY OF THE INVENTION
Briefly stated, the present invention provides compositions and
methods for preventing, reducing or inhibiting the likelihood of infections
associated with medical implants. More specifically, within one aspect of the
invention medical implants or devices are provided which release a
chemotherapeutic agent, wherein the chemotherapeutic agent reduces, inhibits, or
prevents the growth or transmission of foreign organisms (e.g., bacteria, fungi, or
viruses) which are on or are associated with the medical device or implant. For
example, within one aspect of the invention medical implant or devices are
provided which release an anthracycline, fluoropyrimidine, folic acid antagonist,
podophylotoxin, camptothecin, hydroxyurea, or platinum complex. Within various
embodiments, the implant is coated in whole or in part with a composition
comprising an anthracycline, fluoropyrimidine, folic acid antagonist,
podophylotoxin, camptothecin, hydroxyurea, or platinum complex.
Other aspects of the present invention provide methods for making
medical implants, comprising adapting a medical implant (e.g., coating the implant)
with an anthracycline, fluoropyrimidine, folic acid antagonist, podophylotoxin,
camptothecin, hydroxyurea, or platinum complex. Within certain embodiments, the
desired therapeutic agent is coated on and/or released from the medical implant at
a dosage and/or concentration which is less than the typical dosage and/or
concentration of the agent when used in the treatment of cancer.
A wide variety of medical implants can be generated using the
methods provided herein, including for example, catheters (e.g., vascular and
dialysis catheters), heart valves, cardiac pacemakers, implantable cardioverter
defibrillators, grafts (e.g., vascular grafts), ear, nose, or throat implants, urological
implants, endotracheal or tracheostomy tubes, CNS shunts, orthopedic implants,
and ocular implants. Within certain embodiments, the catheter (e.g., vascular and
dialysis catheters), heart valve, cardiac pacemaker, implantable cardioverter
defibrillator, graft (e.g., vascular grafts), ear, nose, or throat implant, urological
implant, endotracheal or tracheostomy tube, CNS shunt, orthopedic implant, or
ocular implant releases a fluoropyrimide (e.g., 5-FU) at a dosage and/or
concentration which is less than a typical dosage and/or concentration which is
used for the treatment of cancer.
Within further aspects of the invention, there is provided a catheter
which releases an agent selected from the group consisting of an anthracycline,
fluoropyrimidine, folic acid antagonist, podophylotoxin, camptothecin, hydroxyurea,
or platinum complex. In one embodiment, the catheter releases a fluoropyrimidine
and in still another embodiment the fluoropyrimidine is 5-FU. In other
embodiments, the catheter further comprises a polymer wherein the agent is
released from a polymer on the catheter. In certain embodiments, the catheter has
a polymer that is polyurethane or poly(lactide-co-glycolide) (PLG). In related
embodiments, the catheter is a vascular catheter or a dialysis catheter. In still
other embodiments, the catheter relaeases an agent that is present on the catheter
at a concentration which is less than the typical dosage and/or concentration that
is used in the treatment of cancer.
Within further aspects of the invention, there is provided a heart valve
which releases an agent selected from the group consisting of an anthracycline,
fluoropyrimidine, folic acid antagonist, podophylotoxin, camptothecin, hydroxyurea,
or platinum complex. In one embodiment, the heart valve releases a
fluoropyrimidine and in still another embodiment the fluoropyrimidine is 5-FU. In
other embodiments, the heart valve further comprises a polymer wherein the agent
is released from a polymer on the heart valve. In certain embodiments, the heart
valve has a polymer that is polyurethane or PLG. In related embodiments, the
heart valve is a prosthetic heart valve. In still other embodiments, the heart valve
relaeases an agent that is present on the heart valve at a concentration which is
less than the typical dosage and/or concentration that is used in the treatment of
cancer.
Within further aspects of the invention, there is provided a cardiac
pacemaker which releases an agent selected from the group consisting of an
anthracycline, fluoropyrimidine, folic acid antagonist, podophylotoxin,
camptothecin, hydroxyurea, or platinum complex. In one embodiment, the cardiac
pacemaker releases a fluoropyrimidine and in still another embodiment the
fluoropyrimidine is 5-FU. In other embodiments, the cardiac pacemaker further
comprises a polymer wherein the agent is released from a polymer on the cardiac
pacemaker. In certain embodiments, the cardiac pacemaker has a polymer that is
polyurethane or PLG. In still other embodiments, the cardiac pacemaker relaeases
an agent that is present on the cardiac pacemaker at a concentration which is less
than the typical dosage and/or concentration that is used in the treatment of
cancer.
Within further aspects of the invention, there is provided a
implantable cardioverter defibrillator which releases an agent selected from the
group consisting of an anthracycline, fluoropyrimidine, folic acid antagonist,
podophylotoxin, camptothecin, hydroxyurea, or platinum complex. In one
embodiment, the implantable cardioverter defibrillator releases a fluoropyrimidine
and in still another embodiment the fluoropyrimidine is 5-FU. In other
embodiments, the implantable cardioverter defibrillator further comprises a polymer
wherein the agent is released from a polymer on the implantable cardioverter
defibrillator. In certain embodiments, the implantable cardioverter defibrillator has
a polymer that is polyurethane or PLG. In still other embodiments, the implantable
cardioverter defibrillator relaeases an agent that is present on the implantable
cardioverter defibrillator at a concentration which is less than the typical dosage
and/or concentration that is used in the treatment of cancer.
Within further aspects of the invention, there is provided a graft which
releases an agent selected from the group consisting of an anthracycline,
fluoropyrimidine, folic acid antagonist, podophylotoxin, camptothecin, hydroxyurea,
or platinum complex. In one embodiment, the graft releases a fluoropyrimidine
and in still another embodiment the fluoropyrimidine is 5-FU. In other
embodiments, the graft further comprises a polymer wherein the agent is released
from a polymer on the graft. In certain embodiments, the graft has a polymer that
is polyurethane or PLG. In related embodiments, the graft is a vascular graft or a
hemodialysis access graft. In still other embodiments, the graft relaeases an agent
that is present on the graft at a concentration which is less than the typical dosage
and/or concentration that is used in the treatment of cancer.
Within further aspects of the invention, there is provided a ear, nose,
or throat implant which releases an agent selected from the group consisting of an
anthracycline, fluoropyrimidine, folic acid antagonist, podophylotoxin,
camptothecin, hydroxyurea, or platinum complex. In one embodiment, the ear,
nose, or throat implant releases a fluoropyrimidine and in still another embodiment
the fluoropyrimidine is 5-FU. In other embodiments, the ear, nose, or throat
implant further comprises a polymer wherein the agent is released from a polymer
on the ear, nose, or throat implant. In certain embodiments, the ear, nose, or
throat implant has a polymer that is polyurethane or PLG. In related embodiments,
the ear, nose, or throat implant is a tympanostomy tube or a sinus stent. In still
other embodiments, the ear, nose, or throat, implant relaeases an agent that is
present on the ear, nose, or throat implant at a concentration which is less than the
typical dosage and/or concentration that is used in the treatment of cancer.
Within further aspects of the invention, there is provided a urological
implant which releases an agent selected from the group consisting of an
anthracycline, fluoropyrimidine, folic acid antagonist, podophylotoxin,
camptothecin, hydroxyurea, or platinum complex. In one embodiment, the
urological implant releases a fluoropyrimidine and in still another embodiment the
fluoropyrimidine is 5-FU. In other embodiments, the urological implant further
comprises a polymer wherein the agent is released from a polymer on the
urological implant. In certain embodiments, the urological implant has a polymer
that is polyurethane or PLG. In related embodiments, the urological implant is a
urinary catheter, ureteral stent, urethral stent, bladder sphincter, or penile implant.
In still other embodiments, the urological implant relaeases an agent that is
present on the urological implant at a concentration which is less than the typical
dosage and/or concentration that is used in the treatment of cancer.
Within further aspects of the invention, there is provided a
endotracheal or tracheostomy tube which releases an agent selected from the
group consisting of an anthracycline, fluoropyrimidine, folic acid antagonist,
podophylotoxin, camptothecin, hydroxyurea, or platinum complex. In one
embodiment, the endotracheal or tracheostomy tube releases a fluoropyrimidine
and in still another embodiment the fluoropyrimidine is 5-FU. In other
embodiments, the endotracheal or tracheostomy tube further comprises a polymer
wherein the agent is released from a polymer on the endotracheal or tracheostomy
tube. In certain embodiments, the endotracheal or tracheostomy tube has a
polymer that is polyurethane or PLG. In still other embodiments, the endotracheal
or tracheostomy tube relaeases an agent that is present on the endotracheal or
tracheostomy tube at a concentration which is less than the typical dosage and/or
concentration that is used in the treatment of cancer.
Within further aspects of the invention, there is provided a CNS shunt
which releases an agent selected from the group consisting of an anthracycline,
fluoropyrimidine, folic acid antagonist, podophylotoxin, camptothecin, hydroxyurea,
or platinum complex. In one embodiment, the CNS shunt releases a
fluoropyrimidine and in still another embodiment the fluoropyrimidine is 5-FU. In
other embodiments, the CNS shunt further comprises a polymer wherein the agent
is released from a polymer on the CNS shunt. In certain embodiments, the CNS
shunt has a polymer that is polyurethane or PLG. In related embodiments, the
CNS shunt is a ventriculopleural shunt, a VA shunt, or a VP shunt. In still other
embodiments, the CNS shunt relaeases an agent that is present on the CNS shunt
at a concentration which is less than the typical dosage and/or concentration that
is used in the treatment of cancer.
Within further aspects of the invention, there is provided a orthopedic
implant which releases an agent selected from the group consisting of an
anthracycline, fluoropyrimidine, folic acid antagonist, podophylotoxin,
camptothecin, hydroxyurea, or platinum complex. In one embodiment, the
orthopedic implant releases a fluoropyrimidine and in still another embodiment the
fluoropyrimidine is 5-FU. In other embodiments, the orthopedic implant further
comprises a polymer wherein the agent is released from a polymer on the
orthopedic implant. In certain embodiments, the orthopedic implant has a polymer
that is polyurethane or PLG. In related embodiments, the orthopedic implant is a
prosthetic joint or fixation device. In still other embodiments, the orthopedic
implant relaeases an agent that is present on the orthopedic implant at a
concentration which is less than the typical dosage and/or concentration that is
used in the treatment of cancer.
Within further aspects of the invention, there is provided a ocular
implant which releases an agent selected from the group consisting of an
anthracycline, fluoropyrimidine, folic acid antagonist, podophylotoxin,
camptothecin, hydroxyurea, or platinum complex. In one embodiment, the ocular
implant releases a fluoropyrimidine and in still another embodiment the
fluoropyrimidine is 5-FU. In other embodiments, the ocular implant further
comprises a polymer wherein the agent is released from a polymer on the ocular
implant. In certain embodiments, the ocular implant has a polymer that is
polyurethane or PLG. In related embodiments, the ocular implant is an intraocular
lens or a contact lens. In still other embodiments, the ocular implant relaeases an
agent that is present on the ocular implant at a concentration which is less than the
typical dosage and/or concentration that is used in the treatment of cancer.
Within other aspects of the invention, compositions are provided
comprising a polymer and an anthracycline, fluoropyrimidine, folic acid antagonist,
podophylotoxin, camptothecin, hydroxyurea, or platinum complex, wherein said
anthracycline, fluoropyrimidine, folic acid antagonist, podophylotoxin,
camptothecin, hydroxyurea, or platinum complex is present in said composition at
a concentration of less than any one of 10-4 M, 10-5 M, 10-6 M, or, 10-7 M.
Also provided methods for reducing or inhibiting infection associated
with a medical implant, comprising the step of introducing a medical implant into a
patient which has been coated with an anthracycline, fluoropyrimidine, folic acid
antagonist, podophylotoxin, camptothecin, hydroxyurea, or platinum complex.
Within various embodiments of the above, the anthracycline is
doxorubicin or mitoxantrone, the fluoropyrimidine is 5-fluorouracil, the folic acid
antagonist is methotrexate, and the podophylotoxin is etoposide. Within further
embodiments the composition further comprises a polymer.
These and other aspects of the present invention will become evident
upon reference to the following detailed description and attached drawings. In
addition, various references are set forth herein which describe in more detail
certain procedures or compositions (e.g., compounds or agents and methods for
making such compounds or agents, etc.), and are therefore incorporated by
reference in their entirety. When PCT applications are referred to it is also
understood that the underlying or cited U.S. applications are also incorporated by
reference herein in their entirety.
DETAILED DESCRIPTION OF THE INVENTION
Prior to setting forth the invention, it may be helpful to an
understanding thereof to set forth definitions of certain terms that will be used
hereinafter.
"Medical implant" refers to devices or objects that are implanted or
inserted into a body. Representative examples include vascular catheters,
prosthetic heart valves, cardiac pacemakers, implantable cardioverter defibrillators,
vascular grafts, ear, nose, or throat implants, urological implants, endotracheal or
tracheostomy tubes, dialysis catheters, CNS shunts, orthopedic implants, and
ocular implants.
As used herein, the term "about" or "consists essentially of refers to
± 15% of any indicated structure, value, or range. Any numerical ranges recited
herein are to be understood to include any integer within the range and, where
applicable (e.g., concentrations), fractions thereof, such as one tenth and one
hundredth of an integer (unless otherwise indicated).
Briefly, as noted above, the present invention discloses medical
implants (as well as compositions and methods for making medical implants) which
reduce the likelihood of infections in medical implants. More specifically, as noted
above, infection is a common complication of the implantation of foreign bodies
such as medical devices. Foreign materials provide an ideal site for micro-
organisms to attach and colonize. It is also hypothesized that there is an
impairment of host defenses to infection in the microenvironment surrounding a
foreign material. These factors make medical implants particularly susceptible to
infection and make eradication of such an infection difficult, if not impossible, in
most cases.
Medical implant failure as a result of infection, with or without the
need to replace the implant, results in significant morbidity, mortality and cost to
the healthcare system. Since there is a wide array of infectious agents capable of
causing medical implant infections, there exists a significant unmet need for
therapies capable of inhibiting the growth of a diverse spectrum of bacteria and
fungi on implantable devices. The present invention meets this need by providing
drugs that can be released from an implantable device, and which have potent
antimicrobial activity at extremely low doses. Further, these agents have the
added advantage that should resistance develop to the chemotherapeutic agent,
the drug utilized in the coating would not be one which would be used to combat
the subsequent infection (i.e., if bacterial resistance developed it would be to an
agent that is not used as an antibiotic).
Discussed in more detail below are (I) Agents; (II) Compositions and
Formulations; (III) Devices, and (IV) Clinical Applications.
I. AGENTS
Briefly, a wide variety of agents (also referred to herein as
'therapeutic agents' or 'drugs') can be utilized within the context of the present
invention, either with or without a carrier (e.g., a polymer; see section II below).
Discussed in more detail below are (A) Anthracyclines (e.g., doxorubicin and
mitoxantrone), (B) Fluoropyrimidines (e.g., 5-FU), (C) Folic acid antagonists (e.g.,
methotrexate), (D) Podophylotoxins (e.g., etoposide), (E) Camptothecins, (F)
Hydroxyureas, and (G) Platinum complexes (e.g., cisplatin).
A. Anthracyclines
Anthracyclines have the following general structure, where the R
groups may be a variety of organic groups:
According to U.S. Patent 5,594,158, suitable R groups are as follows:
R1 is CH3 or CH2OH; R2 is daunosamine or H; R3 and R4 are independently one of
OH, NO2, NH2, F, CI, Br, I, CN, H or groups derived from these; R5 is hydrogen,
hydroxy, or methoxy; and R6-8 are all hydrogen. Alternatively, R5 and R6 are
hydrogen and R7 and R8 are alkyl or halogen, or vice versa.
According to U.S. Patent 5,843,903, R1 may be a conjugated
peptide. According to U.S. Patent 4,296,105, R5 may be an ether linked alkyl
group. According to U.S. Patent 4,215,062, R5 may be OH or an ether linked alkyl
group. R1 may also be linked to the anthracycline ring by a group other than C(O),
such as an alkyl or branched alkyl group having the C(O) linking moiety at its end,
such as -CH2CH(CH2-X)C(O)-R1, wherein X is H or an alkyl group (see, e.g., U.S.
Patent 4,215,062). R2 may alternately be a group linked by the functional group
=N-NHC(O)-Y, where Y is a group such as a phenyl or substituted phenyi ring.
Alternately R3 may have the following structure:
in which R9 is OH either in or out of the plane of the ring, or is a second sugar
moiety such as R3. R10 may be H or form a secondary amine with a group such as
an aromatic group, saturated or partially saturated 5 or 6 membered heterocyclic
having at least one ring nitrogen (see U.S. Patent 5,843,903). Alternately, R10 may
be derived from an amino acid, having the structure -C(O)CH(NHR11)(R12), in
which R11 is H, or forms a C3-4 membered alkylene with R12. R12 may be H, alkyl,
aminoalkyl, amino, hydroxy, mercapto, phenyl, benzyl or methylthio (see U.S.
Patent 4,296,105).
Exemplary anthracyclines are Doxorubicin, Daunorubicin, Idarubicin,
Epirubicin, Pirarubicin, Zorubicin, and Carubicin. Suitable compounds have the
structures:
Other suitable anthracyclines are Anthramycin, Mitoxantrone,
Menogaril, Nogalamycin, Aclacinomycin A, Olivomycin A, Chromomycin A3. and
Plicamycin having the structures:
Other representative anthracyclines include, FCE 23762 doxorubicin
derivative (Quaglia et al., J. Liq. Chromatogr. 17(18):3911-3923,1994), annamycin
(Zou et al., J. Pharm. Sci. 82(11):1151-1154,1993), ruboxyl (Rapoport et al., J.
Controlled Release 58(2): 153-162, 1999), anthracycline disaccharide doxorubicin
analogue (Pratesi et al., Clin. Cancer Res. 4(11):2833-2839, 1998), N-
(trifluoroacetyl)doxorubicin and 4'-O-acetyl-N-(trifluoroacetyl)doxorubicin (Berube &
Lepage, Synth. Commun. 28(6): 1109-1116, 1998), 2-pyrrolinodoxorubicin (Nagy et
a/., Proc. Nat'l Acad. Sci. U.S.A. 95(4): 1794-1799, 1998), disaccharide doxorubicin
analogues (Arcamone et al., J. Nat'l Cancer Inst. 89(16): 1217-1223, 1997), 4-
demethoxy-7-0-[2,6-dideoxy-4-0-(2,3,6-trideoxy-3-amino-a-L-lyxo-
hexopyranosyl)-a-L-lyxo-hexopyranosyl]adriamicinone doxorubicin disaccharide
analog (Monteagudo et al., Carbohydr. Res. 300(1 ):11-16,1997), 2-
pyrrolinodoxorubicin (Nagy et al., Proc. Nat'l Acad. Sci. U. S. A. 94(2):652-656,
1997), morpholinyl doxorubicin analogues (Duran et a/., Cancer Chemother.
Pharmacol. 38(3):210-216, 1996), enaminomalonyl-ß-alanine doxorubicin
derivatives (Seitz et al., Tetrahedron Lett. 36(9):1413-16, 1995), cephalosporin
doxorubicin derivatives (Vrudhula et al., J. Med. Chem. 38(8): 1380-5, 1995),
hydroxyrubicin (Solary et al.. Int. J. Cancer 58(1 ):85-94, 1994), methoxymorpholino
doxorubicin derivative (Kuhl et al.. Cancer Chemother. Pharmacol. 33(1): 10-16,
1993), (6-maleimidocaproyl)hydrazone doxombicin derivative (Willner et al.,
Bioconjugate Chem. 4(6):521-7, 1993), N-(5,5-diacetoxypent-1-yl) doxorubicin
(Cherif & Farquhar, J. Med. Chem. 35(17):3208-14, 1992), FCE 23762
methoxymorpholinyl doxorubicin derivative (Ripamonti et al, Br. J. Cancer
65(5):703-7, 1992), N-hydroxysuccinimide ester doxorubicin derivatives (Demant
et al., Biochim. Biophys. Acta 1118(1 ):83-90, 1991), polydeoxynucleotide
doxorubicin derivatives (Ruggiero et al., Biochim. Biophys. Acta 1129(3):294-302,
1991), morpholinyl doxorubicin derivatives (EPA 434960), mitoxantrone
doxorubicin analogue (Krapcho et al., J. Med. Chem. 34(8):2373-80. 1991), AD198
doxorubicin analogue (Traganos et al., Cancer Res. 57(14):3682-9,1991), 4-
demethoxy-3'-N-trifluoroacetyldoxorubicin (Horton et al., Drug Des. Delivery
6(2):123-9,1990), 4'-epidoxorubicin (Drzewoski et al., Pol. J. Pharmacol. Pharm.
40(2): 159-65, 1988; Weenen et al., Eur. J. Cancer Clin. Oncol. 20(7):919-26,
1984), alkylating cyanomorpholino doxorubicin derivative (Scudder et al., J. Nat'l
Cancer Inst. 80(16): 1294-8, 1988), deoxydihydroiodooxorubicin (EPA 275966),
adriblastin (Kalishevskaya et al., Vestn. Mosk. Univ., 16(Biol. 1):21-7. 1988), 4'-
deoxydoxorubicin (Schoelzel et al., Leuk. Res. 10( 12): 1455-9, 1986), 4-
demethyoxy-4'-o-methyldoxorubicin (Giuliani et al., Proc. Int. Congr. Chemother.
76:285-70-285-77, 1983), 3'-deamino-3'-hydroxydoxorubicin (Horton et al., J.
Antibiot. 37(8):853-8, 1984), 4-demethyoxy doxorubicin analogues (Barbieri et al..
Drugs Exp. Clin. Res. 70(2):85-90, 1984), N-L-leucyl doxorubicin derivatives
(Trouet et al., Anthracyclines (Proc. Int. Symp. Tumor Pharmacother.), 179-81,
1983), 3'-deamino-3'-(4-methoxy-1-piperidinyl) doxorubicin derivatives (U.S.
4,314,054), 3'-deamino-3'-(4-mortholinyl) doxorubicin derivatives (U.S. 4,301,277),
4'-deoxydoxorubicin and 4'-o-methyldoxorubicin (Giuliani et al., Int. J. Cancer
27(1):5-13, 1981), aglycone doxorubicin derivatives (Chan & Watson, J. Pharm.
Sci. 67(12): 1748-52, 1978), SM 5887 (Pharma Japan 1468:20, 1995), MX-2
(Pharma Japan 1420:19, 1994), 4'-deoxy-13(S)-dihydro-4'-iododoxorubicin (EP
275966), morpholinyl doxorubicin derivatives (EPA 434960), 3'-deamino-3'-(4-
methoxy-1-piperidinyl) doxorubicin derivatives (U.S. 4,314,054), doxorubicin-14-
valerate, morpholinodoxorubicin (U.S. 5,004,606), 3'-deamino-3'-(3"-cyano-4"-
morpholinyl doxorubicin; 3'-deamino-3'-(3"-cyano-4"-morpholinyl)-13-
dihydoxorubicin; (3'-deamino-3'-(3"-cyano-4"-morpholinyl) daunorubicin; 3'-
deamino-3'-(3"-cyano-4"-morpholinyl)-3-dihydrodaunorubicin; and 3'-deamino-3'-
(4"-morpholinyl-5-iminodoxorubicin and derivatives (U.S. 4,585,859), 3'-deamino-
3'-(4-methoxy-1-piperidinyl) doxorubicin derivatives (U.S. 4,314,054) and 3-
deamino-3-(4-morpholinyl) doxorubicin derivatives (U.S. 4,301,277).
B. Fluoropyrimidine analogs
In another aspect, the therapeutic agent is a fluoropyrimidine analog,
such as 5-fluorouracil, or an analog or derivative thereof, including Carmofur,
Doxifluridine, Emitefur, Tegafur, and Floxuridine. Exemplary compounds have the
structures:
Other suitable fluoropyrimidine analogs include 5-FudR (5-fluoro-
deoxyuridine), or an analog or derivative thereof, including 5-iododeoxyuridine (5-
ludR), 5-bromodeoxyuridine (5-BudR), Fluorouridine triphosphate (5-FUTP), and
Fluorodeoxyuridine monophosphate (5-dFUMP). Exemplary compounds have the
structures:
Other representative examples of fluoropyrimidine analogs include
N3-alkylated analogues of 5-fluorouracil (Kozai et a/., J. Chem. Soc, Perkin Trans.
1(19):3145-3146, 1998), 5-fluorouracil derivatives with 1,4-oxaheteroepane
moieties (Gomez et al., Tetrahedron 54(43): 13295-13312, 1998), 5-fluorouracil and
nucleoside analogues (Li, Anticancer Res. 17(1A):21-27, 1997), cis- and trans-5-
fluoro-5,6-dihydro-6-alkoxyuracil (Van der Wilt et al., Br. J. Cancer 68(4):702-7,
1993), cyclopentane 5-fluorouracil analogues (Hronowski & Szarek, Can. J. Chem.
70(4):1162-9, 1992), A-OT-fluorouracil (Zhang et at., Zongguo Yiyao Gongye Zazhi
20(11):513-15,1989), N4-trimethoxybenzoyl-5'-deoxy-5-fluorocytidine and 5'-
deoxy-5-fluorouridine (Miwa et al., Chem. Pharm. Bull. 38(4):998-1003,1990), 1-
hexylcarbamoyl-5-fluorouracil (Hoshi et ai, J. Pharmacobio-Dun. 3(9):478-81,
1980; Maehara et al., Chemotherapy (Basel) 34(6):484-9, 1988), B-3839 (Prajda et
al., In Vivo 2(2):151-4, 1988), uracil-1-(2-tetrahydrofuryl)-5-fluorouracil (Anai et al.,
Oncology 45(3):144-7, 1988), 1-(2'-deoxy-2'-fluoro-ß-D-arabinofuranosyl)-5-
fluorouracil (Suzuko et al., Mol. Pharmacol. 37(3):301-6, 1987), doxifluridine
(Matuura et al, Oyo Yakuri 29(5):803-31, 1985), 5'-deoxy-5-fluorouridine (Bollag &
Hartmann, Eur. J. Cancer 16(4):427-32, 1980), 1-acetyl-3-0-toluyl-5-fluorouracil
(Okada, Hiroshima J. Med. Sci. 28(1):49-66, 1979), 5-fluorouracil-m-
formylbenzene-sulfonate (JP 55059173), N'-(2-furanidyl)-5-fluorouracil (JP
53149985) and 1-(2-tetrahydrofuryl)-5-fluorouracil (JP 52089680).
These compounds are believed to function as therapeutic agents by
serving as antimetabolites of pyrimidine.
C. Folic acid antagonists
In another aspect, the therapeutic agent is a folic acid antagonist,
such as Methotrexate or derivatives or analogs thereof, including Edatrexate,
Trimetrexate, Raltitrexed, Piritrexim, Denopterin, Tomudex, and Pteropterin.
Methotrexate analogs have the following general structure:
The identity of the R group may be selected from organic groups, particularly those
groups set forth in U.S. Patent Nos. 5,166,149 and 5,382,582. For example, R1
may be N, R2 may be N or C(CH3), R3 and R3' may H or alkyl, e.g., CH3, R4 may be
a single bond or NR, where R is H or alkyl group. R5,6,8 may be H, OCH3, or
alternately they can be halogens or hydro groups. R7 is a side chain of the general
structure:
wherein n = 1 for methotrexate, n = 3 for pteropterin. The carboxyl groups in the
side chain may be esterified or form a salt such as a Zn2+ salt. R9 and R10 can be
NH2 or may be alkyl substituted.
Exemplary folic acid antagonist compounds have the structures:
Other representative examples include 6-S-aminoacyloxymethyl
mercaptopurine derivatives (Harada et al., Chem. Pharm. Bull. 43(10):793-6,
1995), 6-mercaptopurine (6-MP) (Kashida et al., Biol. Pharm. Bull. 18(11):1492-7,
1995), 7,8-polymethyleneimidazo-1,3,2-diazaphosphorines (Nilov et al.,
Mendeleev Commun. 2:67, 1995), azathioprine (Chifotides et al, J. Inorg.
Biochem. 56(4):249-64, 1994), methyl-D-glucopyranoside mercaptopurine
derivatives (Da Silva et al, Eur. J. Med. Chem. 29(2): 149-52,1994) and s-alkynyl
mercaptopurine derivatives (Ratsino et al, Khim.-Farm. Zh. 75(8):65-7,1981);
indoline ring and a modified ornithine or glutamic acid-bearing methotrexate
derivatives (Matsuoka et al, Chem. Pharm. Bull. 45(7):1146-1150,1997), alkyl-
substituted benzene ring C bearing methotrexate derivatives (Matsuoka et al,
Chem. Pharm. Bull. 44( 12):2287-2293,1996), benzoxazine or benzothiazine
moiety-bearing methotrexate derivatives (Matsuoka et al, J. Med. Chem.
40(1): 105-111, 1997), 10-deazaaminopterin analogues (DeGraw et al, J. Med.
Chem. 40(3):370-376, 1997), 5-deazaaminopterin and 5,10-dideazaaminopterin
methotrexate analogues (Piperet al, J. Med. Chem. 40(3):377-384, 1997),
indoline moiety-bearing methotrexate derivatives (Matsuoka et al, Chem. Pharm.
Bull. 44(7):1332-1337,1996), lipophilic amide methotrexate derivatives (Pignatello
et al, World Meet. Pharm., Biopharm. Pharm. Technol., 563-4, 1995), L-threo-
(2S,4S)-4-fluoroglutamic acid and DL-3,3-difluoroglutamic acid-containing
methotrexate analogues (Hart et al, J. Med. Chem. 39(1):5S-65, 1996),
methotrexate tetrahydroquinazoline analogue (Gangjee, et al, J. Heterocycl
Chem. 32(1):243-8,1995), N-(a-aminoacyl) methotrexate derivatives (Cheung et
al, Pteridines 3(1-2):101-2, 1992), biotin methotrexate derivatives (Fan et al,
Pteridines 3(1-2): 131-2, 1992), D-glutamic acid or D-erythrou, threo-4-
fluoroglutamic acid methotrexate analogues (McGuire et al, Biochem. Pharmacol.
42(12):2400-3,1991), (5,y-methano methotrexate analogues (Rosowsky et al,
Pteridines 2(3): 133-9,1991), 10-deazaaminopterin (10-EDAM) analogue
(Braakhuis et al, Chem. Biol. Pteridines, Proc. Int. Symp. Pteridines Folic Acid
Deriv., 1027-30, 1989), y-tetrazole methotrexate analogue (Kalman et al, Chem.
Biol. Pteridines, Proc. Int. Symp. Pteridines Folic Acid Deriv., 1154-7, 1989), N-(L-
a-aminoacyl) methotrexate derivatives (Cheung et al, Heterocycles 28(2):751-8,
1989), meta and ortho isomers of aminopterin (Rosowsky et al, J. Med. Chem.
32(12):2582, 1989), hydroxymethylmethotrexate (DE 267495), ?-
fluoromethotrexate (McGuire et al., Cancer Res. 49(16):4517-25,1989),
polyglutamyl methotrexate derivatives (Kumar et al., Cancer Res. 46(10):5020-3,
1986). gem-diphosphonate methotrexate analogues (WO 88/06158), a- and ?-
substituted methotrexate analogues (Tsushima et al., Tetrahedron 44(17):5375-87,
1988), 5-methyl-5-deaza methotrexate analogues (4,725,687), Nd-acyl-Na-(4-
amino-4-deoxypteroyl)-L-omithine derivatives (Rosowsky et al., J. Med. Chem.
31(7):1332-7,1988), 8-deaza methotrexate analogues (Kuehl et al., Cancer Res.
48(6): 1481-8, 1988), acivicin methotrexate analogue (Rosowsky et al., J. Med.
Chem. 30(8): 1463-9, 1987), polymeric platinol methotrexate derivative (Carraher et
al., Polym. Sci. Technol. (Plenum), 35(Adv. Biomed. Polym.):311-24, 1987),
methotrexate-?-dimyristoylphophatidylethanolamine (Kinsky et al., Biochim.
Biophys. Acta 977(2):211-18,1987), methotrexate polyglutamate analogues
(Rosowsky et al., Chem. Biol. Pteridines, Pteridines Folid Acid Deriv., Proc. Int.
Symp. Pteridines Folid Acid Deriv.: Chem., Biol. Clin. Aspects: 985-8, 1986), poly-
?-glutamyl methotrexate derivatives (Kisliuk et al., Chem. Biol. Pteridines,
Pteridines Folid Acid Deriv., Proc. Int. Symp. Pteridines Folid Acid Deriv.: Chem.,
Biol. Clin. Aspects: 989-92, 1986), deoxyuridylate methotrexate derivatives
(Webber et al., Chem. Biol. Pteridines, Pteridines Folid Acid Deriv., Proc. Int.
Symp. Pteridines Folid Acid Deriv.: Chem., Biol. Clin. Aspects: 659-62, 1986),
iodoacetyl lysine methotrexate analogue (Delcamp et al., Chem. Biol. Pteridines,
Pteridines Folid Acid Deriv., Proc. Int. Symp. Pteridines Folid Acid Deriv.: Chem.,
Biol. Clin. Aspects: 807-9, 1986), 2,.omega.-diaminoalkanoid acid-containing
methotrexate analogues (McGuire et al., Biochem. Pharmacol. 35(15):2607-13,
1986), polyglutamate methotrexate derivatives (Kamen & Winick, Methods
Enzymol. 722(Vitam. Coenzymes, Pt. G):339-46, 1986), 5-methyl-5-deaza
analogues (Piper et al., J. Med. Chem. 29(6):1080-7, 1986), quinazoline
methotrexate analogue (Mastropaolo et al., J. Med. Chem. 29(1):155-8, 1986),
pyrazine methotrexate analogue (Lever & Vestal, J. Heterocycl. Chem. 22(1):5-6,
1985), cysteic acid and homocysteic acid methotrexate analogues (4,490,529), ?-
tert-butyl methotrexate esters (Rosowsky et al., J. Med. Chem. 28(5):660-7, 1985),
fluorinated methotrexate analogues (Tsushima et al., Heterocycles 23(1):45-9,
1985), folate methotrexate analogue (Trombe, J. Bactenol. 760(3):849-53, 1984),
phosphonoglutamic acid analogues (Sturtz & Guillamot, Eur. J. Med. Chem.-Chim.
Ther. 79(3):267-73,1984), poly (L-lysine) methotrexate conjugates (Rosowsky et
a/., J. Med. Chem. 27(7):888-93, 1984), dilysine and trilysine methotrexate
derivates (Forsch & Rosowsky, J. Org. Chem. 49(7): 1305-9, 1984), 7-
hydroxymethotrexate (Fabre et al., Cancer Res. 43(10):4648-52,1983), poly-?-
glutamyl methotrexate analogues (Piper & Montgomery, Adv. Exp. Med. Biol.,
163(Folyl Antifolyl Polyglutamates):95-100, 1983), 3',5'-dichloromethotrexate
(Rosowsky & Yu, J. Med. Chem. 26(10): 1448-52, 1983), diazoketone and
chloromethylketone methotrexate analogues (Gangjee er al., J. Pharm. Sci.
77(6):717-19, 1982), 10-propargylaminopterin and alkyl methotrexate homologs
(Piper et al., J. Med. Chem. 25(7):877-80,1982), lectin derivatives of methotrexate
(Lin et al., JNCI 66(3):523-8,1981), polyglutamate methotrexate derivatives
(Galivan, Mol. Pharmacol. 17(1): 105-10, 1980), halogentated methotrexate
derivatives (Fox, JNCI 58(4):J955-8, 1977), 8-alkyl-7,8-dihydro analogues
(Chaykovsky et al., J. Med. Chem. 20(10):J1323-7, 1977), 7-methyl methotrexate
derivatives and dichloromethotrexate (Rosowsky & Chen, J. Med. Chem.
17(12):J1308-11,1974), lipophilic methotrexate derivatives and 3',5'-
dichloromethotrexate (Rosowsky, J. Med. Chem. 16(10):J1190-3, 1973), deaza
amethopterin analogues (Montgomery et al., Ann. N.Y. Acad. Sci. 186.J227-34,
1971), MX068 (Pharma Japan, 1658:18, 1999) and cysteic acid and homocysteic
acid methotrexate analogues (EPA 0142220);
These compounds are believed to act as antimetabolites of folic acid.
D. Podophyllotoxins
In another aspect, the therapeutic agent is a Podophyllotoxin, or a
derivative or an analog thereof. Exemplary compounds of this type are Etoposide
or Teniposide, which have the following structures:
Other representative examples of podophyllotoxins include Cu(II)-
VP-16 (etoposide) complex (Tawa et al., Bioorg. Med. Chem. 6X7): 1003-1008,
1998), pyrrolecarboxamidino-bearing etoposide analogues (Ji et al., Bioorg. Med.
Chem. Lett. 7(5):607-612, 1997), 4ß-amino etoposide analogues (Hu, University of
North Carolina Dissertation, 1992), ?-lactone ring-modified arylamino etoposide
analogues (Zhou et al., J. Med. Chem. 37(2):287-92, 1994), N-glucosyl etoposide
analogue (Allevi et al., Tetrahedron Lett. 34(45):7313-16,1993), etoposide A-ring
analogues (Kadow et al., Bioorg. Med. Chem. Lett. 2(1 ):17-22,1992), 4'-
deshydroxy-4'-methyl etoposide (Saulnier et al., Bioorg. Med. Chem. Lett.
2(10):1213-18,1992), pendulum ring etoposide analogues (Sinha et al., Eur. J.
Cancer 26(5):590-3, 1990) and E-ring desoxy etoposide analogues (Saulnier et al.,
J. Med. Chem. 32(7): 1418-20, 1989).
These compounds are believed to act as Topoisomerase II Inhibitors
and/or DNA cleaving agents.
E. Camptothecins
In another aspect, the therapeutic agent is Camptothecin, or an
analog or derivative thereof. Camptothecins have the following general structure.
In this structure, X is typically O, but can be other groups, e.g., NH in
the case of 21-lactam derivatives. R1 is typically H or OH, but may be other
groups, e.g., a terminally hydroxylated C1-3 alkane. R2 is typically H or an amino
containing group such as (CH3)2NHCH2, but may be other groups e.g., NO2, NH2,
halogen (as disclosed in, e.g., U.S. Patent 5,552,156) or a short alkane containing
these groups. R3 is typically H or a short alkyl such as C2H5. R4 is typically H but
may be other groups, e.g., a methylenedioxy group with R1.
Exemplary camptothecin compounds include topotecan, irinotecan
(CPT-11), 9-aminocamptothecin, 21-lactam-20(S)-camptothecin, 10,11-
methylenedioxycamptothecin, SN-38, 9-nitrocamptothecin, 10-
hydroxycamptothecin. Exemplary compounds have the structures:
Camptothecins have the five rings shown here. The ring labeled E
must be intact (the lactone rather than carboxylate form) for maximum activity and
minimum toxicity.
Camptothecins are believed to function as Topoisomerase I Inhibitors
and/or DNA cleavage agents.
F. Hydroxyureas
The therapeutic agent of the present invention may be a
hydroxyurea. Hydroxyureas have the following general structure:
Suitable hydroxyureas are disclosed in, for example, U.S. Patent No.
6,080,874, wherein R1 is:
and R2 is an alkyl group having 1-4 carbons and R3 is one of H, acyl, methyl, ethyl,
and mixtures thereof, such as a methylether.
Other suitable hydroxyureas are disclosed in, e.g., U.S. Patent No.
5,665,768, wherein R1 is a cycloalkenyl group, for example N-[3-[5-(4-
fluorophenylthio)-furyl]-2-cyclopenten-1-yl]N-hydroxyurea; R2 is H or an alkyl group
having 1 to 4 carbons and R3 is H; X is H or a cation.
Other suitable hydroxyureas are disclosed in, e.g., U.S. Patent No.
4,299,778, wherein R1 is a phenyl group substituted with one or more fluorine
atoms; R2 is a cyclopropyl group; and R3 and X is H.
Other suitable hydroxyureas are disclosed in, e.g., U.S. Patent No.
5,066,658, wherein R2 and R3 together with the adjacent nitrogen form:
wherein m is 1 or 2, n is 0-2 and Y is an alkyl group.
In one aspect, the hydroxyurea has the structure:
These compounds are thought to function by inhibiting DNA
synthesis.
G. Platinum complexes
In another aspect, the therapeutic agent is a platinum compound. In
general, suitable platinum complexes may be of Pt(ll) or Pt(IV) and have this basic
structure:
wherein X and Y are anionic leaving groups such as sulfate, phosphate,
carboxylate, and halogen, R1 and R2 are alkyl, amine, amino alkyl any may be
further substituted, and are basically inert or bridging groups. For Pt(ll) complexes
Z1 and Z2 are non-existent. For Pt(IV) Z1 and Z2 may be anionic groups such as
halogen, hydroxy, carboxylate, ester, sulfate or phosphate. See, e.g., U.S. Patent
Nos. 4,588,831 and 4,250,189.
Suitable platinum complexes may contain multiple Pt atoms. See,
e.g., U.S. Patent Nos. 5,409,915 and 5,380,897. For example bisplatinum and
triplatinum complexes of the type:
Exemplary platinum compounds are Cisplatin, Carboplatin,
Oxaliplatin, and Miboplatin having the structures:
Other representative platinum compounds include (CPA)2Pt[DOLYM]
and (DACH)Pt[DOLYM] cisplatin (Choi et al., Arch. Pharmacal Res. 22(2):151-156,
1999), Cis-[PtCI2(4,7-H-5-methyl-7-oxo]1,2,4[triazolo[1,5-a]pyrimidine)2] (Navarro
et a/., J. Med. Chem. 41(3):332-338, 1998), [Pt(cis-1,4-DACH)(trans-
CI2)(CBDCA)]. 1/2MeOH cisplatin (Shamsuddin et a/., Inorg. Chem. 36(25):5969-
5971, 1997), 4-pyridoxate diammine hydroxy platinum (Tokunaga et al., Pharm.
Sci. 3(7):353-356, 1997), Pt(ll) ... Pt(lI) (Pt2[NHCHN(C(CH2)(CH3))]4) (Navarro et
a/., Inorg. Chem. 35(26):7829-7835, 1996), 254-S cisplatin analogue (Koga et al.,
Neurol. Res. 18(3):244-247, 1996), o-phenylenediamine ligand bearing cisplatin
analogues (Koeckerbauer & Bednarski, J. Inorg. Biochem. 62(4):281-298,1996),
trans, cis-[R(OAc)2l2(en)] (Kratochwil et al., J. Med. Chem. 39(13):2499-2507,
1996), estrogenic 1,2-diarylethylenediamine ligand (with sulfur-containing amino
acids and glutathione) bearing cisplatin analogues (Bednarski, J. Inorg. Biochem.
62(1):75,1996), cis-1,4-diaminocyclohexane cisplatin analogues (Shamsuddin et
a/., J. Inorg. Biochem. 67(4):291-301, 1996), 5' orientational isomer of cis-
[Pt(NH3)(4-aminoTEMP-O){d(GpG)}] (Dunham & Lippard, J. Am. Chem. Soc.
117(43):10702-12, 1995), chelating diamine-bearing cisplatin analogues
(Koeckerbauer & Bednarski, J. Pharm. Sci. 84(7):819-23, 1995), 1,2-
diarylethyleneamine ligand-bearing cisplatin analogues (Otto et al., J. Cancer Res.
Clin. Oncol. 121(1):31-8,1995), (ethylenediamine)platinum(lI) complexes (Pasini
et al., J. Chem. Soc, Dalton Trans. 4:579-85, 1995), CI-973 cisplatin analogue
(Yang et al., Int. J. Oncol. 5(3):597-602,1994), cis-diaminedichloroplatinum(ll)and
its analogues cis-1,1-cyclobutanedicarbosylato(2R)-2-methyl-1,4-
butanediamineplatinum(ll) and cis-diammine(glycolato)platinum (Claycamp &
Zimbrick, J. Inorg. Biochem. 26(4):257-67, 1986; Fan et al., Cancer Res.
48(11):3135-9, 1988; Heiger-Bemays et al., Biochemistry 29(36);8461-6, 1990;
Kikkawa et al., J. Exp. Clin. Cancer Res. 72(4):233-40,1993; Murray et al.,
Biochemistry 31 (47)A 1812-17, 1992;Takahashi et al., Cancer Chemother.
Pharmacol. 33(1):31-5, 1993), cis-amine-cyclohexylamine-dichloroplatinum(ll)
(Yoshida et al., Biochem. Pharmacol. 48(4):793-9,1994), gem-diphosphonate
cisplatin analogues (FR 2683529), (meso-1,2-bis(2,6-dichloro-4-
hydroxyplenyl)ethylenediamine) dichloroplatinum(ll) (Bednarski et al., J. Med.
Chem. 35(23):4479-85, 1992), cisplatin analogues containing a tethered dansyl
group (Hartwig et al., J. Am. Chem. Soc. 7 74(21):8292-3,1992), platinum(ll)
polyamines (Siegmann et al., Inorg. Met-Containing Polym. Mater., (Proc. Am.
Chem. Soc. Int. Symp.), 335-61,1990), cis-
(3H)dichloro(ethylenediamine)platinum(ll) (Eastman, Anal. Biochem. 797(2):311-
15,1991), trans-diamminedichloroplatinum(ll) and cis-(Pt(NH3)2(N3-cytosine)CI)
(Bellon & Lippard, Biophys. Chem. 35(2-3): 179-88, 1990), 3H-cis-1,2-
diaminocyclohexanedichloroplatinum(ll) and 3H-cis-1,2-diaminocyclohexane-
malonatoplatinum (II) (Oswald et al., Res. Commun. Chem. Pathol. Pharmacol.
64(1):41-58,1989), diaminocarboxylatoplatinum (EPA 296321), trans-(D,1)-1,2-
diaminocyclohexane carrier ligand-bearing platinum analogues (Wyrick & Chaney,
J. Labelled Compd. Radiopharm. 25(4):349-57, 1988),
aminoalkylaminoanthraquinone-derived cisplatin analogues (Kitov et al., Eur. J.
Med. Chem. 23(4):381-3, 1988), spiroplatin, carboplatin, iproplatin and JM40
platinum analogues (Schroyen et al., Eur. J. Cancer Clin. Oncol. 24(8): 1309-12,
1988), bidentate tertiary diamine-containing cisplatinum derivatives (Orbell et al..
Inorg. Chim. Acta 152(2): 125-34, 1988), platinum(ll), platinum(lV) (Liu & Wang,
Shandong Yike Daxue Xuebao 24(1):35-41, 1986), cis-diammine(1,1-
cyclobutanedicarboxylato-)platinum(ll) (carboplatin, JM8) and ethylenediammine-
malonatoplatinum(ll) (JM40) (Begg et al., Radiother. Oncol. 9(2): 157-65. 1987),
JM8 and JM9 cisplatin analogues (Harstrick et al, Int. J. Androl. 70(1); 139-45,
1987), (NPr4)2((PtCL4).cis-(PtCI2-(NH2Me)2)) (Brammer ef ai, J. Chem. Soc,
Chem. Commun. 6:443-5, 1987), aliphatic tricarboxylic acid platinum complexes
(EPA 185225), and cis-dichloro(amino acid)(tert-butylamine)platinum(ll) complexes
(Pasini & Bersanetti, Inorg. Chim. Acta 107(4):259-67, 1985). These compounds
are thought to function by binding to DNA, i.e., acting as alkylating agents of DNA.
II. COMPOSITIONS AND FORMULATIONS
As noted above, therapeutic agents described herein may be
formulated in a variety of manners, and thus may additionally comprise a carrier. In
this regard, a wide variety of carriers may be selected of either polymeric or non-
polymeric origin. The polymers and non-polymer based carriers and formulations
which are discussed in more detail below are provided merely by way of example,
not by way of limitation.
Within one embodiment of the invention a wide variety of polymers
can be utilized to contain and/or deliver one or more of the agents discussed
above, including for example both biodegradable and non-biodegradable
compositions. Representative examples of biodegradable compositions include
albumin, collagen, gelatin, chitosan, hyaluronic acid, starch, cellulose and
derivatives thereof (e.g., methylcellulose, hydroxypropylcellulose,
hydroxypropylmethylcellulose, carboxymethylcellulose, cellulose acetate phthalate,
cellulose acetate succinate, hydroxypropylmethylcellulose phthalate), alginates,
casein, dextrans, polysaccharides, fibrinogen, poly(L-lactide), poly(D,L lactide),
poly(L-lactide-co-glycolide), poly(D,L-lactide-co-glycolide), poly(glycolide),
poly(trimethylene carbonate), poly(hydroxyvalerate), poly(hydroxybutyrate),
poly(caprolactone), poly(alkylcarbonate) and poly(orthoesters), polyesters,
poly(hydroxyvaleric acid), polydioxanone, poly(malic acid), poly(tartronic acid),
polyanhydrides, polyphosphazenes, poly(amino acids), copolymers of such
polymers and blends of such polymers (see generally. Ilium, L, Davids, S.S. (eds.)
"Polymers in Controlled Drug Delivery" Wright, Bristol, 1987; Arshady, J. Controlled
Release 17:1-22,1991; Pitt, Int. J. Phar. 59:173-196, 1990; Holland et al., J.
Controlled Release 4:155-0180,1986). Representative examples of
nondegradable polymers include poly(ethylene-co-vinyl acetate) ("EVA")
copolymers, silicone rubber, acrylic polymers (e.g., polyacrylic acid,
polymethylacrylic acid, poly(hydroxyethylmethacrylate), polymethylmethacrylate,
polyalkylcyanoacrylate), polyethylene, polyproplene, polyamides (e.g., nylon 6,6),
polyurethane (e.g., poly(ester urethanes), poly(ether urethanes), poly(ester-urea),
poly(carbonate urethanes)), polyethers (e.g., poly(ethylene oxide), poly(propylene
oxide), Pluronics and poly(tetramethylene glycol)) and vinyl polymers [e.g.,
polyvinylpyrrolidone, polyvinyl alcohol), polyvinyl acetate phthalate)]. Polymers
may also be developed which are either anionic (e.g., alginate, carrageenin,
carboxymethyl cellulose and poly(acrylic acid), or cationic (e.g., chitosan, poly-L-
lysine, polyethylenimine, and poly (allyl amine)) (see generally, Dunn et al., J.
Applied Polymer Sci. 50:353-365,1993; Cascone et al., J. Materials Sci.: Materials
in Medicine 5:770-774,1994; Shiraishi et al., Biol. Pharm. Bull. 76(11):1164-1168,
1993; Thacharodi and Rao, Int'l J. Pharm. 720:115-118,1995; Miyazaki et al., Int'l
J. Pharm. 118:257-263,1995). Particularly preferred polymeric carriers include
poly(ethylene-co-vinyl acetate), polyurethane, acid, poly(caprolactone),
poly(valerolactone), polyanhydrides, copolymers of poly(caprolactone) or
poly(lactic acid) with a polyethylene glycol (e.g., MePEG), and blends thereof.
Other representative polymers include carboxylic polymers,
polyacetates, polyacrylamides, polycarbonates, polyethers, polyesters,
polyethylenes, polyvinylbutyrals, polysilanes, polyureas, polyurethanes,
polyoxides, polystyrenes, polysulfides, polysulfones, polysulfonides,
polyvinylhalides, pyrrolidones, rubbers, thermal-setting polymers, cross-linkable
acrylic and methacrylic polymers, ethylene acrylic acid copolymers, styrene acrylic
copolymers, vinyl acetate polymers and copolymers, vinyl acetal polymers and
copolymers, epoxy, melamine, other amino resins, phenolic polymers, and
copolymers thereof, water-insoluble cellulose ester polymers (including cellulose
acetate propionate, cellulose acetate, cellulose acetate butyrate, cellulose nitrate,
cellulose acetate phthalate, and mixtures thereof), polyvinylpyrrolidone,
polyethylene glycols, polyethylene oxide, polyvinyl alcohol, polyethers,
polysaccharides, hydrophilic polyurethane, polyhydroxyacrylate, dextran, xanthan,
hydroxypropyl cellulose, methyl cellulose, and homopolymers and copolymers of
N-vinylpyrrolidone, N-vinyllactam, N-vinyl butyrolactam, N-vinyl caprolactam, other
vinyl compounds having polar pendant groups, acrylate and methacrylate having
hydrophilic esterifying groups, hydroxyacrylate, and acrylic acid, and combinations .
thereof; cellulose esters and ethers, ethyl cellulose, hydroxyethyl cellulose,
cellulose nitrate, cellulose acetate, cellulose acetate butyrate, cellulose acetate
propionate, polyurethane, polyacrylate, natural and synthetic elastomers, rubber,
acetal, nylon, polyester, styrene polybutadiene, acrylic resin, polyvinylidene
chloride, polycarbonate, homopolymers and copolymers of vinyl compounds,
polyvinylchloride, polyvinylchloride acetate.
Representative examples of patents relating to polymers and their
preparation include PCT Publication Nos. W072827, 98/12243, 98/19713,
98/41154, 99/07417, 00/33764, 00/21842, 00/09190, 00/09088, 00/09087,
2001/17575 and 2001/15526 (as well as their corresponding U.S. applications),
and U.S. Patent Nos. 4,500,676, 4,582,865, 4,629,623, 4,636,524, 4,713,448,
4,795,741, 4,913,743, 5,069,899. 5,099,013, 5,128,326, 5,143,724, 5,153,174,
5,246,698, 5,266,563, 5,399,351, 5,525,348, 5,800,412, 5,837,226, 5,942,555,
5,997,517, 6,007,833, 6,071,447, 6,090,995, 6,099,563, 6,106,473, 6,110,483,
6,121,027, 6,156,345, 6,179,817, 6,197,051, 6,214,901, 6,335,029, 6,344,035,
which, as noted above, are all incorporated by reference in their entirety.
Polymers can be fashioned in a variety of forms, with desired release
characteristics and/or with specific desired properties. For example, polymers can
be fashioned to release a therapeutic agent upon exposure to a specific triggering
event such as pH (see, e.g., Heller et al., "Chemically Self-Regulated Drug
Delivery Systems," in Polymers in Medicine III, Elsevier Science Publishers B.V.,
Amsterdam, 1988, pp. 175-188; Kang et al., J. Applied Polymer Sci. 48:343-354,
1993; Dong et al., J. Controlled Release 19:171-178, 1992; Dong and Hoffman, J.
Controlled Release 75:141-152, 1991; Kim et al., J. Controlled Release 28:143-
152, 1994; Cornejo-Bravo et al, J. Controlled Release 33:223-229,1995; Wu and
Lee, Pharm. Res. 70(10):1544-1547,1993; Serres et al., Pharm. Res. )3(2):196-
201,1996; Peppas, "Fundamentals of pH- and Temperature-Sensitive Delivery
Systems," in Gumy et al. (eds.), Pulsatile Drug Delivery, Wissenschaftliche
Veriagsgesellschaft mbH, Stuttgart, 1993, pp. 41-55; Doelker, "Cellulose
Derivatives," 1993, in Peppas and Langer (eds.), Biopolymers I, Springer-Verlag,
Berlin). Representative examples of pH-sensitive polymers include poly(acrylic
acid)-based polymers and derivatives (including, for example, homopolymers such
as poly(aminocarboxylic acid), poly(acrylic acid), poly(methyl acrylic acid),
copolymers of such homopolymers, and copolymers of poly(acrylic acid) and
acrylmonomers such as those discussed above). Other pH sensitive polymers
include polysaccharides such as carboxymethyl cellulose,
hydroxypropylmethylcellulose phthalate, hydroxypropyl-methylcellulose acetate
succinate, cellulose acetate trimellilate, chitosan and alginates. Yet other pH
sensitive polymers include any mixture of a pH sensitive polymer and a water
soluble polymer.
Likewise, polymers can be fashioned which are temperature
sensitive (see, e.g., Chen et al., "Novel Hydrogels of a Temperature-Sensitive
Pluronic Grafted to a Bioadhesive Polyacrylic Acid Backbone for Vaginal Drug
Delivery," in Proceed. Intern. Symp. Control. Rel. Bioact. Mater. 22:167-168,
Controlled Release Society, Inc., 1995, Okano, "Molecular Design of Stimuli-
Responsive Hydrogels for Temporal Controlled Drug Delivery," in Proceed. Intern.
Symp. Control. Rel. Bioact. Mater. 22:111-112, Controlled Release Society, Inc.,
1995; Johnston et al., Pharm. Res. 9(3):425-433, 1992; Tung, Int'l J. Pharm.
107:85-90,1994; Harsh and Gehrke, J. Controlled Release 77:175-186,1991; Bae
et al, Pharm. Res. 8(4):531-537,1991; Dinarvand and D'Emanuele, J. Controlled
Release 36:221-227, 1995; Yu and Grainger, "Novel Thermo-sensitive Amphiphilic
Gels: Poly N-isopropylacrylamide-co-sodium acrylate-co-n-N-alkylacrylamide
Network Synthesis and Physicochemical Characterization," Dept. of Chemical &
Biological Sci., Oregon Graduate Institute of Science & Technology, Beaverton,
OR, pp. 820-821; Zhou and Smid, "Physical Hydrogels of Associative Star
Polymers," Polymer Research Institute, Dept. of Chemistry, College of
Environmental Science and Forestry, State Univ. of New York, Syracuse, NY, pp.
822-823; Hoffman et al., "Characterizing Pore Sizes and Water'Structure' in
Stimuli-Responsive Hydrogels," Center for Bioengineering, Univ. of Washington,
Seattle, WA, p. 828; Yu and Grainger, "Thermo-sensitive Swelling Behavior in
Crosslinked N-isopropylacrylamide Networks: Cationic, Anionic and Ampholytic
Hydrogels," Dept. of Chemical & Biological Sci., Oregon Graduate Institute of
Science & Technology, Beaverton, OR, pp. 829-830; Kim et al., Pharm. Res.
9 Controlled Release 30:69-75,1994; Yoshida et al, J. Controlled Release 32:97-102,
1994; Okano et al, J. Controlled Release 36:125-133, 1995; Chun and Kim, J.
Controlled Release 38:39-47, 1996; D'Emanuele and Dinarvand, Int'l J. Pharm.
118:237-242, 1995; Katono et al., J. Controlled Release 16:215-228,1991; Hoffman,
Thermally Reversible Hydrogels Containing Biologically Active Species," in
Migliaresi et al. (eds), Polymers in Medicine III, Elsevier Science Publishers B.V.,
Amsterdam, 1988, pp. 161-167; Hoffman, "Applications of Thermally Reversible
Polymers and Hydrogels in Therapeutics and Diagnostics," in Third International
Symposium on Recent Advances in Drug Delivery Systems, Salt Lake City, UT, Feb.
24-27, 1987, pp. 297-305; Gutowska et al., J. Controlled Release 22:95-104,1992;
Paiasis and Gehrke, J. Controlled Release 18:1-12, 1992; Paavola et al., Pharm.
Res. 12(12): 1997-2002, 1995).
Representative examples of thermogelling polymers include
homopolymers such as poly(N-methyl-N-n-propylacrylamide), poly(N-n-
propylacrylamide), poly(N-methyl-N-isopropylacrylamide), poly(N-n-
propylmethacrylamide), poly(N-isopropylacrylamide), poly(N, n-diethylacrylamide),
poly(N-isopropylmethacrylamide), poly(N-cyclopropylacrylamide), poly(N-
ethylmethyacrylamide), poly(N-methyl-N-ethylacrylamide), poly(N-
cyclopropylmethacrylamide) and poly(N-ethylacrylamide). Moreover thermogelling
polymers may be made by preparing copolymers between (among) monomers of
the above, or by combining such homopolymers with other water soluble polymers
such as acrylmonomers (e.g., acrylic acid and derivatives thereof such as
methylacrylic acid, acrylate and derivatives thereof such as butyl methacrylate,
acrylamide, and N-n-butyl acrylamide).
Other representative examples of thermogelling cellulose ether
derivatives such as hydroxypropyl cellulose, methyl cellulose, hydroxypropylmethyl
cellulose, ethylhydroxyethyl cellulose, and Pluronics, such as F-127.
A wide variety of forms may be fashioned by the polymers of the
present invention, including for example, rod-shaped devices, pellets, slabs,
particulates, micelles, films, molds, sutures, threads, gels, creams, ointments,
sprays or capsules (see, e.g., Goodell et at. Am. J. Hosp. Pharm. 43:1454-1461,
1986; Langer et al., "Controlled release of macromolecules from polymers", in
Biomedical Polymers, Polymeric Materials and Pharmaceuticals for Biomedical
Use, Goldberg, E.P., Nakagim, A. (eds.) Academic Press, pp. 113-137, 1980;
Rhine et al., J. Pharm. Sci. 69:265-270, 1980; Brown et al., J. Pharm. Sci.
72:1181-1185, 1983; and Bawa et al., J. Controlled Release 1:259-267,1985).
Agents may be incorporated by dissolution in the polymer, occlusion in the
matrices of the polymer, bound by covalent linkages, or encapsulated in
microcapsules. Within certain preferred embodiments of the invention, therapeutic
compositions are provided in non-capsular formulations, such as coatings
microspheres (ranging from nanometers to micrometers in size), pastes, threads or
sutures of various size, films and sprays.
Other compounds which can be utilized to carry and/or deliver the
agents provided herein include vitamin-based compositions (e.g., based on
vitamins A, D, E and/or K, see, e.g., PCT publication Nos. WO 98/30205 and WO
00/71163) and liposomes (see, U.S. Patent Nos. 5,534,499, 5,683,715, 5,776,485,
5,882,679, 6,143,321, 6,146,659, 6,200.598, and PCT Publication Nos. WO
98/34597, WO 99/65466, WO 00/01366, WO 00/53231, WO 99/35162, WO
00/117508, WO 00/125223, WO 00/149,268, WO 00/1565438, and WO'
00/158455).
Preferably, therapeutic compositions of the present invention are
fashioned in a manner appropriate to the intended use. Within certain aspects of
the present invention, the therapeutic composition should be biocompatible, and
release one or more agents over a period of several days to months. Further,
therapeutic compositions of the present invention should preferably be stable for
several months and capable of being produced, and maintained under sterile
conditions.
Within certain aspects of the present invention, therapeutic
compositions may be fashioned in any size ranging from 50 nm to 500 nm,
depending upon the particular use. Alternatively, such compositions may also be
readily applied as a "spray" which solidifies into a film or coating. Such sprays
may be prepared from microspheres of a wide array of sizes, including for
example, from 0.1 µm to 9 µm, from 10 µm to 30 µm and from 30 µm to 100 µm.
Therapeutic compositions of the present invention may also be
prepared in a variety of "paste" or gel forms. For example, within one embodiment of
the invention, therapeutic compositions are provided which are liquid at one
temperature (e.g., temperature greater than 37°C) and solid or semi-solid at another
temperature (e.g., ambient body temperature, or any temperature lower than 37°C).
Also included are polymers, such as Pluronic F-127, which are liquid at a low
temperature (e.g., 4°C) and a gel at body temperature. Such "thermopastes" may be
readily made given the disclosure provided herein.
Within yet other aspects of the invention, the therapeutic
compositions of the present invention may be formed as a film. Preferably, such
films are generally less than 5,4, 3, 2 or 1 mm thick, more preferably less than
0.75 mm or 0.5 mm thick, and most preferably less than 500 µm. Such films are
preferably flexible with a good tensile strength (e.g., greater than 50, preferably
greater than 100, and more preferably greater than 150 or 200 N/cm2), good
adhesive properties (i.e., readily adheres to moist or wet surfaces), and have
controlled permeability.
Within certain embodiments of the invention, the therapeutic
compositions can also comprise additional ingredients such as surfactants (e.g.,
Pluronics such as F-127, L-122, L-92, L-81, and L-61).
Within further aspects of the present invention, polymers are
provided which are adapted to contain and release a hydrophobic compound, the
carrier containing the hydrophobic compound in combination with a carbohydrate,
protein or polypeptide. Within certain embodiments, the polymeric carrier contains
or comprises regions, pockets or granules of one or more hydrophobic
compounds. For example, within one embodiment of the invention, hydrophobic
compounds may be incorporated within a matrix which contains the hydrophobic
compound, followed by incorporation of the matrix within the polymeric carrier. A
variety of matrices can be utilized in this regard, including for example,
carbohydrates and polysaccharides, such as starch, cellulose, dextran,
methylcellulose, and hyaluronic acid, proteins or polypeptides such as albumin,
collagen and gelatin. Within alternative embodiments, hydrophobic compounds
may be contained within a hydrophobic core, and this core contained within a
hydrophilic shell.
Other carriers that may likewise be utilized to contain and deliver the
agents described herein include: hydroxypropyl ß-cyclodextrin (Cserhati and Hollo,
Int. J. Pharm. 108:69-75,1994), liposomes (see, e.g., Sharma et al., Cancer Res.
53:5877-5881, 1993; Sharma and Straubinger, Pharm. Res. 11(60):889-896,1994;
WO 93/18751; U.S. Patent No. 5,242,073), liposome/gel (WO 94/26254),
nanocapsules(Bartoli et al., J. Microencapsulation 7(2):191-197,1990), micelles
(Alkan-Onyuksel et al., Pharm. Res. 11(2):206-212,1994), implants (Jampel et al.,
Invest. Ophthalm. Vis. Science 34(11): 3076-3083,1993; Walter et al., Cancer Res.
54:22017-2212, 1994), nanoparticles (Violante and Lanzafame PAACR),
nanoparticles - modified (U.S. Patent No. 5,145,684), nanoparticles (surface
modified) (U.S. Patent No. 5,399,363), taxol emulsion/solution (U.S. Patent
No. 5,407,683), micelle (surfactant) (U.S. Patent No. 5,403,858), synthetic
phospholipid compounds (U.S. Patent No. 4,534,899), gas borne dispersion (U.S.
Patent No. 5,301,664), foam, spray, gel, lotion, cream, ointment, dispersed vesicles,
particles or droplets solid- or liquid- aerosols, microemulsions (U.S. Patent No.
5,330,756), polymeric shell (nano- and micro- capsule) (U.S. Patent No. 5,439,686),
taxoid-based compositions in a surface-active agent (U.S. Patent No. 5,438,072),
liquid emulsions (Tarr et al., Pharm Res. 4:62-165, 1987), nanospheres (Hagan et
al., Proc. Intern. Symp. Control Rel. Bioact. Mater. 22,1995; Kwon et al., Pharm
Res. 12(2): 192-195; Kwon et al., Pharm Res. 70(7):970-974; Yokoyama et al., J.
Contr. Rel. 32:269-277,1994; Gref et al., Science 263:1600-1603,1994; Bazile et
al, J. Pharm. Sci. 84:493-498, 1994) and implants (U.S. Patent No. 4,882,168).
The agents provided herein can also be formulated as a sterile
composition (e.g., by treating the composition with ethylene oxide or by irradiation),
packaged with preservatives or other suitable excipients suitable for administration
to humans. Similarly, the devices provided herein (e.g., coated catheter) may be
sterilized and prepared suitable for implantation into humans.
III. MEDICAL IMPLANTS
A. Representative Medical Implants
A wide variety of implants or devices can be coated with or otherwise
constructed to contain and/or release the therapeutic agents provided herein.
Representative examples include cardiovascular devices (e.g., implantable venous
catheters, venous ports, tunneled venous catheters, chronic infusion lines or ports,
including hepatic artery infusion catheters, pacemakers and pacesmaker leads
(see, e.g., U.S. Patent Nos. 4,662,382, 4,782,836,4,856,521, 4,860,751,
5,101,824, 5.261,419, 5,284,491, 6,055,454, 6,370,434, and 6,370,434),
implantable defibrillators (see, e.g., U.S. Patent Nos. 3,614,954, 3,614,955,
4,375,817, 5,314,430, 5,405,363, 5,607,385, 5,697,953, 5,776,165, 6,067,471,
6,169,923, and 6,152,955)); neurologic/neurosurgical devices (e.g., ventricular
peritoneal shunts, ventricular atrial shunts, nerve stimulator devices, dural patches
and implants to prevent epidural fibrosis post-laminectomy, devices for continuous
subarachnoid infusions); gastrointestinal devices (e.g., chronic indwelling
catheters, feeding tubes, portosystemic shunts, shunts for ascites, peritoneal
implants for drug delivery, peritoneal dialysis catheters, and suspensions or solid
implants to prevent surgical adhesions); genitourinary devices (e.g., uterine
implants, including intrauterine devices (lUDs) and devices to prevent endometrial
hyperplasia, fallopian tubal implants, including reversible sterilization devices,
fallopian tubal stents, artificial sphincters and periurethral implants for
incontinence, ureteric stents, chronic indwelling catheters, bladder augmentations,
or wraps or splints for vasovasostomy, central venous catheters (see, e.g., U.S.
Patent Nos. 3,995,623, 4,072,146 4,096,860, 4,099,528, 4,134,402, 4,180,068,
4,385,631, 4,406.656,4,568,329, 4,960,409, 5,176,661, 5,916,208), urinary
catheters (see, e.g. U.S. Patent Nos. 2,819,718, 4,227,533, 4,284,459, 4,335,723,
4,701,162, 4,571,241, 4,710,169, and 5,300,022,)); prosthetic heart valves (see,
e.g., U.S. Patent Nos. 3,656,185, 4,106,129,4.892,540, 5,528,023, 5,772,694,
6,096,075, 6,176,877, 6,358,278, and 6,371,983), vascular grafts (see, e.g.
3,096,560, 3,805,301, 3,945,052, 4,140,126, 4,323,525, 4,355,426, 4,475,972,
4,530,113, 4,550,447, 4,562,596, 4,601,718, 4,647,416, 4,878,908, 5,024,671,
5,104,399, 5,116,360, 5,151,105, 5,197,977, 5,282.824, 5,405,379, 5,609,624,
5,693,088, and 5,910,168), ophthalmologic implants (e.g., multino implants and
other implants for neovascular glaucoma, drug eluting contact lenses for
pterygiums, splints for failed dacrocystalrhinostomy, drug eluting contact lenses for
corneal neovascularity, implants for diabetic retinopathy, drug eluting contact
lenses for high risk corneal transplants); otolaryngology devices (e.g., ossicular
implants, Eustachian tube splints or stents for glue ear or chronic otitis as an
alternative to transtempanic drains); plastic surgery implants (e.g., breast implants
or chin implants), catheter cuffs and orthopedic implants (e.g., cemented
orthopedic prostheses).
B. Methods of Making Medical Implants having Therapeutic Agents
Implants and other surgical or medical devices may be covered,
coated, contacted, combined, loaded, filled, associated with, or otherwise adapted
to release therapeutic agents compositions of the present invention in a variety of
manners, including for example: (a) by directly affixing to the implant or device a
therapeutic agent or composition (e.g., by either spraying the implant or device
with a polymer/drug film, or by dipping the implant or device into a polymer/drug
solution, or by other covalent or noncovalent means); (b) by coating the implant or
device with a substance, such as a hydrogel, which will in turn absorb the
therapeutic composition (or therapeutic factor above); (c) by interweaving
therapeutic composition coated thread (or the polymer itself formed into a thread)
into the implant or device; (d) by inserting the implant or device into a sleeve or
mesh which is comprised of or coated with a therapeutic composition; (e)
constructing the implant or device itself with a therapeutic agent or composition; or
(f) by otherwise adapting the implant or device to release the therapeutic agent.
Within preferred embodiments of the invention, the composition should firmly
adhere to the implant or device during storage and at the time of insertion. The
therapeutic agent or composition should also preferably not degrade during
storage, prior to insertion, or when warmed to body temperature after insertion
inside the body (if this is required). In addition, it should preferably coat or cover
the desired areas of the implant or device smoothly and evenly, with a uniform
distribution of therapeutic agent. Within preferred embodiments of the invention,
the therapeutic agent or composition should provide a uniform, predictable,
prolonged release of the therapeutic factor into the tissue surrounding the implant
or device once it has been deployed. For vascular stents, in addition to the above
properties, the composition should not render the stent thrombogenic (causing
blood clots to form), or cause significant turbulence in blood flow (more than the
stent itself would be expected to cause if it was uncoated).
Within certain embodiments of the invention, a therapeutic agent can
be deposited directly onto all or a portion of the device (see, e.g., U S. Patent Nos.
6,096,070 and 6,299,604), or admixed with a delivery system or carrier (e.g., a
polymer, liposome, or vitamin as discussed above) which is applied to all or a
portion of the device (see the patents, patent applications, and references listed
above under "Compositions and Formulations."
Within certain aspects of the invention, therapeutic agents can be
attached to a medical implant using non-covalent attachments. For example, for
compounds that are relatively sparingly water soluble or water insoluble, the
compound can be dissolved in an organic solvent a specified concentration. The
solvent chosen for this application would not result in dissolution or swelling of the
polymeric device surface. The medical implant can then be dipped into the
solution, withdrawn and then dried (air dry and/or vacuum dry). Alternatively, this
drug solution can be sprayed onto the surface of the implant. This can be
accomplished using current spray coating technology. The release duration for this
method of coating would be relatively short and would be a function of the solubility
of the drug in the body fluid in which it was placed.
In another aspect, a therapeutic agent can be dissolved in a solvent
that has the ability to swell or partially dissolve the surface of a polymeric implant.
Depending on the solvent/implant polymer combination, the implant could be
dipped into the drug solution for a period of time such that the drug can diffuse into
the surface layer of the polymeric device. Alternatively the drug solution can be
sprayed onto all or a part of the surface of the implant. The release profile of the
drug depends upon the solubility of the drug in the surface polymeric layer. Using
this approach, one would ensure that the solvent does not result in a significant
distortion or dimensional change of the medical implant.
If the implant is composed of materials that do not allow incorporation
of a therapeutic agent into the surface layer using the above solvent method, one
can treat the surface of the device with a plasma polymerization method such that
a thin polymeric layer is deposited onto the device surface. Examples of such
methods include parylene coating of devices, and the use of various monomers
such hydrocyclosiloxane monomers, acrylic acid, acrylate monomers, methacrylic
acid or methacrylate monomers. One can then use the dip coating or spray
coating methods described above to incorporate the therapeutic agent into the
coated surface of the implant.
For therapeutic agents that have some degree of water solubility, the
retention of these compounds on a device are relatively short-term. For
therapeutic agents that contain ionic groups, it is possible to ionically complex
these agents to oppositely charged compounds that have a hydrophobic
component. For example therapeutic agents containing amine groups can be
complexed with compounds such as sodium dodecyl sulfate (SDS). Compounds
containing carboxylic groups can be complexed with tridodecymethyammonium
chloride (TDMAC). Mitoxantrone, for example, has two secondary amine groups
and comes as a chloride salt. This compound can be added to sodium dodecyl
sulfate in order to form a complex. This complex can be dissolved in an organic
solvent which can then be dip coated or spray coated. Doxorubicin has an amine
group and could thus also be complexed with SDS. This complex could then be
applied to the device by dip coating or spray coating methods. Methotrexate, for
example contains 2 carboxylic acid groups and could thus be complexed with
TDMAC and then coated onto the medical implant.
For therapeutic agents that have the ability to form ionic complexes
or hydrogen bonds, the release of these agents from the device can be modified
by the use of organic compounds that have the ability to form ionic or hydrogen
bonds with the therapeutic agent. As described above, a complex between the
ionically charged therapeutic agent and an oppositely charged hydrophobic
compound can be prepared prior to application of this complex to the medical
implant. In another embodiment, a compound that has the ability to form ionic or
hydrogen bond interactions with the therapeutic agent can be incorporated into the
implant during the manufacture process, or during the coating process.
Alternatively, this compound can be incorporated into a coating polymer that is
applied to the implant or during the process of loading the therapeutic agent into or
onto the implant. These agents can include fatty acids (e.g., palmitic acid, stearic
acid, lauric acid), aliphatic acids, aromatic acids (e.g., benzoic acid, salicylic acid),
cylcoaliphatic acids, aliphatic (stearyl alcohol, lauryl alcohol, cetyl alcohol) and
aromatic alcohols alco multifunctional alcohols (e.g., citric acid, tartaric acid,
pentaerithratol), lipids (e.g., phosphatidyl choline, phosphatidylethanolamine),
carbohydrates, sugars, spermine, spermidine, aliphatic and aromatic amines,
natural and synthetic amino acids, peptides or proteins. For example, a fatty acid
such as palmitic acid can be used to modulate the release of 5-Fluoruracil from the
implant.
For therapeutic agents that have the ability to form ionic complexes
or hydrogen bonds, the release of these agents from the implant can be modified
by the use of polymers that have the ability to form ionic or hydrogen bonds with
the therapeutic agent. For example, therapeutic agents containing amine groups
can form ionic complexes with sulfonic or carboxylic pendant groups or end-groups
of a polymer. Examples of polymers that can be used for this application include,
but are not limited to polymers and copolymers that are prepared using acrylic
acid, methacrylic acid, sodium styrene sulfonate, styrene sulfonic acid, maleic acid
or 2-acrylamido-2-methyl propane sulfonic acid. Polymers that have been
modified by sulfonation post-polymerization can also be used in this application.
The medical implant, for example, can be coated with, or prepared with, a polymer
that comprises nafion, a sulfonated fluoropolymer. This medical device can then
be dipped into a solution that comprises the amine-containing therapeutic agent.
The amine-containing therapeutic agent can also be applied by a spray coating
process. Methotrexate and doxorubicin are examples of therapeutic agents that
can be used in this application.
It is known that the presence of bacteria on the implant surface can
result in a localized decrease in pH. For polymers that comprise ionic exchange
groups, for example, carboxylic groups, these polymers can have a localized
increase in release of the therapeutic agent in response to the localized decrease
in pH as a result of the presence of the bacteria. For therapeutic agents that
contain carboxylic acid groups, polymers with pendant end-groups comprising
primary, secondary, tertiary or quaternary amines can be used to modulate the
release of the therapeutic agent.
Therapeutic agents with available functional groups can be covalently
attached to the medical implant surface using several chemical methods. If the
polymeric material used to manufacture the implant has available surface
functional groups then these can be used for covalent attachment of the agent. For
example, if the implant surface contains carboxylic acid groups, these groups can
be converted to activated carboxylic acid groups (e.g acid chlorides, succinimidyl
derivatives, 4-nitrophenyl ester derivatives etc). These activated carboxylic acid
groups can then be reacted with amine functional groups that are present on the
therapeutic agent (e.g., methotrexate, mitoxantrone).
For surfaces that do not contain appropriate functional groups, these
groups can be introduced to the polymer surface via a plasma treatment regime.
For example, carboxylic acid groups can be introduced via a plasma treatment
process process (e.g., the use of O2 and/or CO2 as a component in the feed gas
mixture). The carboxylic acid groups can also be introduced using acrylic acid or
methacrylic acid in the gas stream. These carboxylic acid groups can then be
converted to activated carboxylic acid groups (e.g., acid chlorides, succinimidyl
derivatives, 4-nitrophenyl ester derivatives, etc.) that can subsequently be reacted
with amine functional groups that are present on the therapeutic agent.
In addition to direct covalent bonding to the implant surface, the
therapeutic agents with available functional groups can be covalently attached to
the medical implant via a linker. These linkers can be degradable or non-
degradabie. Linkers that are hydrolytically or enzymatically cleaved are preferred.
These linkers can comprise azo, ester, amide, thioester, anhydride, or
phosphoester bonds.
To further modulate the release of the therapeutic agent from the
medical implant, portions of or the entire medical implant may be further coated
with a polymer. The polymer coating can comprise the polymers described above.
The polymer coating can be applied by a dip coating process, a spray coating
process or a plasma deposition process. This coating can, if desired, be further
crosslinked using thermal, chemical, or radiation (e.g., visible light, ultraviolet light,
e-beam, gamma radiation, x-ray radiation) techniques in order to further modulate
the release of the therapeutic agent from the medical implant.
This polymer coating can further contain agents that can increase the
flexibility (e.g., plasticizer - glycerol, triethyl citrate), lubricity (e.g., hyaluronic acid),
biocompatibility or hemocompatability (e.g., heparin) of the coating.
The methods above describe methods for incorporation of a
therapeutic agent into or onto a medical implant. Additional antibacterial or
antifungal agents can also be incorporated into or onto the medical implant. These
antibacterial or antifungal agents can be incorporated into or onto the medical
implant prior to, simultaneously or after the incorporation of the therapeutic agents,
described above, into or onto the medical implant. Agents that can be used
include, but are not limited to silver compounds (e.g., silver chloride, silver nitrate,
silver oxide), silver ions, silver particles, iodine, povidone/iodine, chlorhexidine,
2-p-sulfanilyanilinoethanol, 4,4'-sulfinyldianiline, 4-suifanilamidosalicylic acid,
acediasulfone, acetosulfone, amikacin, amoxicillin, amphotericin B, ampiciilin,
apalcillin, apicycline, apramycin, arbekacin, aspoxicillin, azidamfenicol,
azithromycin, aztreonam, bacitracin, bambermycin(s), biapenem, brodimoprim,
butirosin, capreomycin, carbenicillin, carbomycin, carumonam, cefadroxil,
cefamandole, cefatrizine, cefbuperazone, cefclidin, cefdinir, cefditoren, cefepime,
cefetamet, cefixime, cefinenoxime, cefminox, cefodizime, cefonicid, cefoperazone,
ceforanide, cefotaxime, cefotetan, cefotiam, cefozopran, cefpimizole, cefpiramide,
cefpirome, cefprozil, cefroxadine, ceftazidime, cefteram, ceftibuten, ceftriaxone,
cefuzonam, cephalexin, cephaloglycin, cephalosporin C, cephradine,
chloramphenicol, chlortetracycline, ciprofloxacin, clarithromycin, clinafloxacin,
clindamycin, clomocycline, colistin, cyclacillin, dapsone, demeclocycline,
diathymosulfone, dibekacin, dihydrostreptomycin, dirithromycin, doxycycline,
enoxacin, enviomycin, epicillin, erythromycin, flomoxef, fortimicin(s), gentamicin(s),
glucosulfone solasulfone, gramicidin S, gramicidin(s), grepafloxacin,
guamecycline, hetacillin, imipenem, isepamicin, josamycin, kanamycin(s),
leucomycin(s), lincomycin, lomefloxacin, lucensomycin, lymecycline, meclocycline,
meropenem, methacycline, micronomicin, midecamycin(s), minocycline,
moxalactam, mupirocin, nadifloxacin, natamycin, neomycin, netilmicin, norfloxacin,
oleandomycin, oxytetracycline, p-sulfanilylbenzylamine, panipenem, paromomycin,
pazufloxacin, penicillin N, pipacycline, pipemidic acid, polymyxin, primycin,
quinacillin, ribostamycin, rifamide, rifampin, rifamycin SV, rifapentine, rifaximin,
ristocetin, ritipenem, rokitamycin, rolitetracycline, rosaramycin, roxithromycin,
salazosulfadimidine, sancycline, sisomicin, sparfloxacin, spectinomycin,
spiramycin, streptomycin, succisulfone, sulfachrysoidine, sulfaloxic acid,
sulfamidochrysoidine, sulfanilic acid, sulfoxone, teicoplanin, temafloxacin,
temocillin, tetracycline, tetroxoprim, thiamphenicol, thiazoisulfone, thiostrepton,
ticarcillin, tigemonam, tobramycin, tosufloxacin, trimethoprim, trospectomycin,
trovafloxacin, tuberactinomycin, vancomycin, azaserine, candicidin(s),
chlorphenesin, dermostatin(s), filipin, fungichromin, mepartricin, nystatin,
oligomycin(s), ciproflaxacin, norfloxacin, ofloxacin, pefloxacin, enoxacin, rosoxacin,
amifloxacin, fleroxacin, temafloaxcin, lomefloxacin, perimycin A or tubercidin, and
the like.
IV. CLINICAL APPLICATIONS
In order to further the understanding of the invention, discussed in
more detail below are various clinical applications for the compositions, methods
and devices provided herein.
Briefly, as noted above, within one aspect of the invention methods
are provided for preventing, reducing, and/or inhibiting an infection associated with
a medical device or implant, comprising the step of introducing into a patient a
medical implant which releases a chemotherapeutic agent, wherein the
chemotherapeutic agent reduces, inhibits, or prevents the growth or transmission
of foreign organisms (e.g., bacteria, fungi, or viruses). As used herein, agents that
reduce, inhibit, or prevent the growth or transmission of foreign organisms in a
patient means that the growth or transmission of a foreign organism is reduced,
inhibited, or prevented in a statistically significant manner in at least one clinical
outcome, or by any measure routinely used by persons of ordinary skill in the art
as a diagnostic criterion in determining the same. In a preferred embodiment, the
medical implant has been covered or coated with an anthracycline (e.g.,
doxorubicin and mitoxantrone), fluoropyrimidine (e.g., 5-FU), folic acid antagonist
(e.g., methotrexate), podophylotoxin (e.g., etoposide), camptothecin, hydroxyurea,
and/or a platinum complexe (e.g., cisplatin).
Particularly preferred agents which are utilized within the context of
the present invention should have an MIC of less than or equal to any one of
10-4M, 10-5M, 10-6M, or, 10-7M. Furthermore, particularly preferred agents are
suitable for use at concentrations less than that 10%, 5%, or even 1% of the
concentration typically used in chemotherapeutic applications (Goodman and
Gilman's The Pharmacological Basis of Therapeutics. Editors J.G. Hardman, LL.
Limbird. Consulting editor A.Goodman Gilman Tenth Edition. McGraw-Hill Medical
publishing division. 10th edition, 2001, 2148 pp.). Finally, the devices should
preferably be provided sterile, and suitable for use in humans.
A. Vascular Catheter-Associated Infections
More than 30 million patients receive infusion therapy annually in the
United States. In fact, 30% of all hospitalized patients have at least one vascular
catheter in place during their stay in hospital. A variety of medical devices are
used for infusion therapy including, but not restricted to, peripheral intravenous
catheters, central venous catheters, total parenteral nutrition catheters, peripherally
inserted central venous catheters (PIC lines), totally implanted intravascular
access devices, flow-directed balloon-tipped pulmonary artery catheters, arterial
lines, and long-term central venous access catheters (Hickman lines, Broviac
catheters).
Unfortunately, vascular access catheters are prone to infection by a
variety of bacteria and are a common cause of bloodstream infection. Of the
100,000 bloodstream infections in US hospitals each year, many are related to the
presence of an intravascular device. For example, 55,000 cases of bloodstream
infections are caused by central venous catheters, while a significant percentage
of the remaining cases are related to peripheral intravenous catheters and arterial
lines.
Bacteremia related to the presence of intravascular devices is not a
trivial clinical concern: 50% of all patients developing this type of infection will die
as a result (over 23,000 deaths per year) and in those who survive, their
hospitalization will be prolonged by an average of 24 days. Complications related
to bloodstream infections include cellulites, the formation of abscesses, septic
thrombophlebitis, and infective endocarditis. Therefore, there is a tremendous
clinical need to reduce the morbidity and mortality associated with intravascular
catheter infections.
The most common point of entry for the infection-causing bacteria is
tracking along the device from the insertion site in the skin. Skin flora spread
along the outside of the device to ultimately gain access to the bloodstream. Other
possible sources of infection include a contaminated infusate, contamination of the
catheter hub-infusion tubing junction, and hospital personnel. The incidence of
infection increases the longer the catheter remains in place and any device
remaining in situ for more than 72 hours is particularly susceptible. The most
common infectious agents include common skin flora such as coagulase-negative
staphylococci (S. epidermidis, S. saprophyticus) and Staphylococcus aureus
(particularly MRSA - methicillin - resistant S. aureus) which account for 2/3 of all
infections. Coagulase-negative staphylococci (CNS) is the most commonly
isolated organism from the blood of hospitalized patients. CNS infections tend to
be indolent; often occurring after a long latent period between contamination (i.e.
exposure of the medical device to CNS bacteria from the skin during implantation)
and the onset of clinical illness. Unfortunately, most clinically significant CNS
infections are caused by bacterial strains that are resistant to multiple antibiotics,
making them particularly difficult to treat. Other organisms known to cause
vascular access catheter-related infections include Enterococci (e.g. E. coli, VRE -
vancomycin-resistant enterococcci), Gram-negative aerobic bacilli, Pseudomonas
aeruginosa, Klebsiella spp., Serratia marcescens, Burkholderia cepacia,
Citrobacter freundii, Corynebacteria spp. and Candida species.
Most cases of vascular access catheter-related infection require
removal of the catheter and treatment with systemic antibiotics (although few
antibiotics are effective), with vancomycin being the drug of choice. As mentioned
previously, mortality associated with vascular access catheter-related infection is
high, while the morbidity and cost associated with treating survivors is also
extremely significant.
It is therefore extremely important to develop vascular access
catheters capable of reducing the incidence of bloodstream infections. Since it is
impossible to predict in advance which catheters will become infected, any
catheter expected to be in place longer than a couple of days would benefit from a
therapeutic coating capable of reducing the incidence of bacterial colonization of
the device. An ideal therapeutic coating would have one or more of the following
characteristics: (a) the ability to kill, prevent, or inhibit colonization of a wide array
of potential infectious agents including most or all of the species listed above; (b)
the ability to kill, prevent, or inhibit colonization of bacteria (such as CNS and VRE)
that are resistant to multiple antibiotics; (c) utilize a therapeutic agent unlikely to be
used in the treatment of a bloodstream infection should one develop (i.e., one
would not want to coat the device with a broad-acting antibiotic, for if a strain of
bacteria resistant to the antibiotic were to develop on the device it would
jeopardize systemic treatment of the patient since the infecting agent would be
resistant to a potentially useful therapeutic).
Several classes of anticancer agents are particularly suitable for
incorporation into coatings for vascular catheters, namely, anthracyclines (e.g.,
doxorubicin and mitoxantrone), fluoropyrimidines (e.g., 5-FU), folic acid
antagonists (e.g., methotrexate), and podophylotoxins (e.g., etoposide). These
agents have a high degree of antibacterial activity against CNS (S. epidermidis)
and Staphylococcus aureus - the most common causes of vascular catheter
infections. Particularly preferred agents are doxorubicin, mitoxantrone,
5-fluorouracil and analogues and derivatives thereof which also have activity
against Escheridia coli and Pseudomonas aeruginosa. It is important to note that
not all anticancer agents are suitable for the practice of the present invention as
several agents, including 2-mercaptopurine, 6-mercaptopurine, hydroxyurea,
cytarabine, cisplatinum, tubercidin, paclitaxel, and camptothecin did not have
antibacterial activity against the organisms known to cause vascular access
catheter-related infections.
1. Central Venous Catheters
For the purposes of this invention, the term "Central Venous
Catheters" should be understood to include any catheter or line that is used to
deliver fluids to the large (central) veins of the body (e.g., jugular, pulmary, femoral,
iliac, inferior vena cava, superior vena cava, axillary etc.). Examples of such
catheters include central venous catheters, total parenteral nutrition catheters,
peripherally inserted central venous catheters, flow-directed balloon-tipped
pulmonary artery catheters, long-term central venous access catheters (such as
Hickman lines and Broviac catheters). Representative examples of such catheters
are described in U.S. Patent Nos. 3,995,623, 4,072,146 4,096,860, 4,099,528,
4,134,402, 4,180,068, 4,385,631, 4,406,656, 4,568,329, 4,960,409, 5,176,661,
5,916,208.
As described previously, 55,000 cases of bloodstream infections are
caused by central venous catheters every year in the United States resulting in
23,000 deaths. The risk of infection increases the longer the catheter remains in
place, particularly if it is used beyond 72 hours. Severe complications of central
venous catheter infection also include infective endocarditis and suppurative
phlebitis of the great veins. If the device becomes infected, it must be replaced at
a new site (over-the-wire exchange is not acceptable) which puts the patient at
further risk to develop mechanical complications of insertion such as bleeding,
pneumothorax and hemothorax. In addition, systemic antibiotic therapy is also
required. An effective therapy would reduce the incidence of device infection,
reduce the incidence of bloodstream infection, reduce the mortality rate, reduce
the incidence of complications (such as endocarditis or suppurative phlebitis),
prolong the effectiveness of the central venous catheter and/or reduce the need to
replace the catheter. This would result in lower mortality and morbidity for patients
with central venous catheters in place.
In a preferred embodiment, doxorubicin, mitoxantrone, 5-fluorouracil
and/or etoposide are formulated into a coating applied to the surface of the
vascular catheter. The drug(s) can be applied to the central venous catheter
system in several manners: (a) as a coating applied to the exterior surface of the
intravascular portion of the catheter and/or the segment of the catheter that
traverses the skin; (b) as a coating applied to the interior and exterior surface of
the intravascular portion of the catheter and/or the segment of the catheter that
traverses the skin; (c) incorporated into the polymers which comprise the
intravascular portion of the catheter; (d) incorporated into, or applied to the
surface of, a subcutaneous "cuff" around the catheter, (e) in solution in the
infusate; (f) incorporated into, or applied as a coating to, the catheter hub,
junctions and/or infusion tubing; and (g) any combination of the aforementioned.
Drug-coating of, or drug incorporation into, the central venous
catheter will allow bacteriocidal drug levels to be achieved locally on the catheter
surface, thus reducing the incidence of bacterial colonization of the vascular
catheter (and subsequent development of blood borne infection), while producing
negligible systemic exposure to the drugs. Although for some agents polymeric
carriers are not required for attachment of the drug to the catheter surface, several
polymeric carriers are particularly suitable for use in this embodiment. Of particular
interest are polymeric carriers such as polyurethanes (e.g., ChronoFlex AL 85A
[CT Biomaterials], HydroMed640™ [CT Biomaterials], HYDROSLIP C™ [CT
Biomaterials], HYDROTHANE™ [CT Biomaterials]), acrylic or methacrylic
copolymers (e.g., poly(ethylene-co-acrylic acid), cellulose-derived polymers (e.g.
nitrocellulose, Cellulose Acetate Butyrate, Cellulose acetate propionate), acrylate
and methacrylate copolymers (e.g., poly(ethylene-co-vinyl acetate)) as well as
blends thereof.
As central venous catheters are made in a variety of configurations
and sizes, the exact dose administered will vary with device size, surface area and
design. However, certain principles can be applied in the application of this art.
Drug dose can be calculated as a function of dose per unit area (of the portion of
the device being coated), total drug dose administered can be measured and
appropriate surface concentrations of active drug can be determined. Regardless
of the method of application of the drug to the central venous catheter, the
preferred anticancer agents, used alone or in combination, should be administered
under the following dosing guidelines:
(a) Anthracyclines. Utilizing the anthracycline doxorubicin as an
example, whether applied as a polymer coating, incorporated into the polymers
which make up the device, or applied without a polymer carrier, the total dose of
doxorubicin applied to the central venous catheter (and the other components of
the infusion system) should not exceed 25 mg (range of 0.1 µg to 25 mg). In a
particularly preferred embodiment, the total amount of drug applied to the central
venous catheter (and the other components of the infusion system) should be in
the range of 1 µg to 5 mg. The dose per unit area of the device (i.e. the amount of
drug as a function of the surface area of the portion of the device to which drug is
applied and/or incorporated) should fall within the range of 0.01 µg -100 µg per
mm2 of surface area. In a particularly preferred embodiment, doxorubicin should
be applied to the device surface at a dose of 0.1 µg/mm2 - 10 µg/mm2. As
different polymer and non-polymer coatings will release doxorubicin at differing
rates, the above dosing parameters should be utilized in combination with the
release rate of the drug from the device surface such that a minimum
concentration of 10-7-10-4 M of doxorubicin is maintained on the device surface. It
is necessary to insure that drug concentrations on the device surface exceed
concentrations of doxorubicin known to be lethal to multiple species of bacteria
and fungi (i.e., are in excess of 10-4 M; although for some embodiments lower
concentrations are sufficient). In a preferred embodiment, doxorubicin is released
from the surface of the device such that anti-infective activity is maintained for a
period ranging from several hours to several months. In a particularly preferred
embodiment the drug is released in effective concentrations for a period ranging
from 1-30 days. It should be readily evident given the discussions provided
herein that analogues and derivatives of doxorubicin (as described previously) with
similar functional activity can be utilized for the purposes of this invention; the
above dosing parameters are then adjusted according to the relative potency of
the analogue or derivative as compared to the parent compound (e.g. a compound
twice as potent as doxorubicin is administered at half the above parameters, a
compound half as potent as doxorubicin is administered at twice the above
parameters, etc.).
Utilizing mitoxantrone as another example of an anthracycline,
whether applied as a polymer coating, incorporated into the polymers which make
up the device, or applied without a carrier polymer, the total dose of mitoxantrone
applied to the central venous catheter (and the other components of the infusion
system) should not exceed 5 mg (range of 0.01 µg to 5 mg). In a particularly
preferred embodiment, the total amount of drug applied to the central venous
catheter (and the other components of the infusion system) should be in the range
of 0.1 µg to 1 mg. The dose per unit area of the device (i.e. the amount of drug as
a function of the surface area of the portion of the device to which drug is applied
and/or incorporated) should fall within the range of 0.01 µg - 20 µg per mm2 of
surface area. In a particularly preferred embodiment, mitoxantrone should be
applied to the device surface at a dose of 0.05 µg/mm2 - 3 µg/mm2. As different
polymer and non-polymer coatings will release mitoxantrone at differing rates, the
above dosing parameters should be utilized in combination with the release rate of
the drug from the device surface such that a minimum concentration of 10-5-10-6
M of mitoxantrone is maintained on the device surface. It is necessary to insure
that drug concentrations on the device surface exceed concentrations of
mitoxantrone known to be lethal to multiple species of bacteria and fungi (i.e. are in
excess of 10-5 M; although for some embodiments lower drug levels will be
sufficient). In a preferred embodiment, mitoxantrone is released from the surface
of the device such that anti-infective activity is maintained for s period ranging from
several hours to several months. In a particularly preferred embodiment the drug
is released in effective concentrations for a period ranging from 1-30 days. It
should be readily evident given the discussions provided herein that analogues
and derivatives of mitoxantrone (as described previously) with similar functional
activity can be utilized for the purposes of this invention; the above dosing
parameters are then adjusted according to the relative potency of the analogue or
derivative as compared to the parent compound (e.g. a compound twice as potent
as mitoxantrone is administered at half the above parameters, a compound half as
potent as mitoxantrone is administered at twice the above parameters, etc.).
(b) Fluoropyrimidines Utilizing the fluoropyrimidine 5-fluorouracil as
an example, whether applied as a polymer coating, incorporated into the polymers
which make up the device, or applied without a carrier polymer, the total dose of 5-
fluorouracil applied to the central venous catheter (and the other components of
the infusion system) should not exceed 250 mg (range of 1.0 µg to 250 mg). In a
particularly preferred embodiment, the total amount of drug applied to the central
venous catheter (and the other components of the infusion system) should be in
the range of 10 µg to 25 mg. The dose per unit area of the device (i.e. the amount
of drug as a function of the surface area of the portion of the device to which drug
is applied and/or incorporated) should fall within the range of 0.1 µg - 1 mg per
mm2 of surface area. In a particularly preferred embodiment, 5-fluorouracil should
be applied to the device surface at a dose of 1.0 µg/mm2 - 50 µg/mm2. As
different polymer and non-polymer coatings will release 5-fluorouracil at differing
rates, the above dosing parameters should be utilized in combination with the
release rate of the drug from the device surface such that a minimum
concentration of 10-4-10-7 M of 5-fluorouracil is maintained on the device surface.
It is necessary to insure that drug concentrations on the device surface exceed
concentrations of 5-fluorouracil known to be lethal to numerous species of bacteria
and fungi (i.e., are in excess of 10-4 M; although for some embodiments lower drug
levels will be sufficient). In a preferred embodiment, 5-fluorouracil is released from
the surface of the device such that anti-infective activity is maintained for a period
ranging from several hours to several months. In a particularly preferred
embodiment the drug is released in effective concentrations for a period ranging
from 1-30 days. It should be readily evident given the discussions provided
herein that analogues and derivatives of 5-fluorouracil (as described previously)
with similar functional activity can be utilized for the purposes of this invention; the
above dosing parameters are then adjusted according to the relative potency of
the analogue or derivative as compared to the parent compound (e.g. a compound
twice as potent as 5-fluorouracil is administered at half the above parameters, a
compound half as potent as 5-fluorouracil is administered at twice the above
parameters, etc.).
(c) Podophylotoxins Utilizing the podophylotoxin etoposide as an
example, whether applied as a polymer coating, incorporated into the polymers
which make up the device, or applied without a carrier polymer, the total dose of
etoposide applied to the central venous catheter (and the other components of the
infusion system) should not exceed 25 mg (range of 0.1 µg to 25 mg). In a
particularly preferred embodiment, the total amount of drug applied to the central
venous catheter (and the other components of the infusion system) should be in
the range of 1 µg to 5 mg. The dose per unit area of the device (i.e. the amount of
drug as a function of the surface area of the portion of the device to which drug is
applied and/or incorporated) should fall within the range of 0.01 µg - 100 µg per
mm2 of surface area. In a particularly preferred embodiment, etoposide should be
applied to the device surface at a dose of 0.1 µg/mm2 - 10 µg/mm2. As different
polymer and non-polymer coatings will release etoposide at differing rates, the
above dosing parameters should be utilized in combination with the release rate of
the drug from the device surface such that a concentration of 10-5 -10-6 M of
etoposide is maintained on the device surface. It is necessary to insure that drug
concentrations on the device surface exceed concentrations of etoposide known to
be lethal to a variety of bacteria and fungi (i.e., are in excess of 10-5M; although for
some embodiments lower drug levels will be sufficient). In a preferred
embodiment, etoposide is released from the surface of the device such that anti-
infective activity is maintained for a period ranging from several hours to several
months. In a particularly preferred embodiment the drug is released in effective
concentrations for a period ranging from 1-30 days. It should be readily evident
based upon the discussions provided herein that analogues and derivatives of
etoposide (as described previously) with similar functional activity can be utilized
for the purposes of this invention; the above dosing parameters are then adjusted
according to the relative potency of the analogue or derivative as compared to the
parent compound (e.g. a compound twice as potent as etoposide is administered
at half the above parameters, a compound half as potent as etoposide is
administered at twice the above parameters, etc.).
(d) Combination therapy. It should be readily evident based upon
the discussions provided herein that combinations of anthracyclines (e.g.,
doxorubicin or mitoxantrone), fluoropyrimidines (e.g., 5-fluorouracil), folic acid
antagonists (e.g., methotrexate) and podophylotoxins (e.g., etoposide) can be
utilized to enhance the antibacterial activity of the central venous catheter coating.
Similarly an anthracycline (e.g., doxorubicin or mitoxantrone), fluoropyrimidine
(e.g., 5-fluorouracil), folic acid antagonist (e.g., methotrexate) and/or
podophylotoxin (e.g., etoposide) can be combined with traditional antibiotic and/or
antifungal agents to enhance efficacy. Since thrombogenicity of the catheter is
associated with an increased risk of infection, combinations of anthracyclines (e.g.,
doxorubicin or mitoxantrone), fluoropyrimidines (e.g., 5-fluorouracil), folic acid
antagonists (e.g., methotrexate and/or podophylotoxins (e.g., etoposide) can be
combined with antithrombotic and/or antiplatelet agents (for example, heparin,
dextran sulphate, danaparoid, lepirudin, hirudin, AMP, adenosine,
2-chloroadenosine, aspirin, phenylbutazone, indomethacin, meclofenamate,
hydrochloroquine, dipyridamole, iloprost, ticlopidine, clopidogrel, abcixamab,
eptifibatide, tirofiban, streptokinase, and/or tissue plasminogen activator) to
enhance efficacy.
2. Peripheral Intravenous Catheters
For the purposes of this invention, the term "Peripheral Venous
Catheters" should be understood to include any catheter or line that is used to
deliver fluids to the smaller (peripheral) superficial veins of the body.
Peripheral venous catheters have a much lower rate of infection than
do central venous catheters, particularly if they are in place for less than 72 hours.
One exception is peripheral catheters inserted into the femoral vein (so called
"femoral lines") which have a significantly higher rate of infection.. The organisms
that cause infections in a peripheral venous catheter are identical to those
described above (for central venous catheters).
In a preferred embodiment, doxorubicin, mitoxantrone, 5-fluorouracil
and/or etoposide are formulated into a coating applied to the surface of the
peripheral vascular catheter. The drug(s) can be applied to the peripheral venous
catheter system in several manners: (a) as a coating applied to the exterior and/or
interior surface of the intravascular portion of the catheter and/or the segment of
the catheter that traverses the skin; (b) incorporated into the polymers which
comprise the intravascular portion of the catheter; (c) incorporated into, or applied
to the surface of, a subcutaneous "cuff" around the catheter; (e) in solution in the
infusate; (f) incorporated into, or applied as a coating to, the catheter hub,
junctions and/or infusion tubing; and (g) any combination of the aforementioned.
The formulation and closing guidelines for this embodiment are
identical to those described for central venous catheters.
3. Arterial Lines and Transducers
Arterial lines are used to draw arterial blood gasses, obtain accurate
blood pressure readings and to deliver fluids. They are placed in a peripheral
artery (typically the radial artery) and often remain in place for several days.
Arterial lines have a very high rate of infection (12-20% of arterial lines become
infected) and the causative organisms are identical to those described above (for
central venous catheters).
In a preferred embodiment, doxorubicin, mitoxantrone, 5-fluorouracil
and/or etoposide are formulated into a coating applied to the arterial line in several
manners: (a) as a coating applied to the exterior and/or interior surface of the
intravascular portion of the catheter and/or the segment of the catheter that
traverses the skin; (b) incorporated into the polymers which comprise the
intravascular portion of the catheter; (c) incorporated into, or applied to the surface
of, a subcutaneous "cuff" around the catheter; (e) in solution in the infusate; (f)
incorporated into, or applied as a coating to, the catheter hub, junctions and/or
infusion tubing; and (g) any combination of the aforementioned.
The formulation and dosing guidelines for this embodiment are
identical to those described for central venous catheters.
B. Prosthetic Heart Valve Endocarditis (PVE)
Prosthetic heart valves, mechanical and bioprosthetic, are at a
significant risk for developing an infection. In fact, 3-6% of patients develop
valvular infection within 5 years of valve replacement surgery and prosthetic valve
endocarditis accounts for up to 15% of all cases of endocarditis. The risk of
developing an infection is not uniform - the risk is greatest in the first year
following surgery with a peak incidence between the second and third month
postoperatively. Mechanical valves in particular are susceptible to infection in the
3 months following surgery and the microbiology is suggestive of nosocomial
infection. Therefore, a drug coating designed to prevent colonization and infection
of the valves in the months following surgery could be of great benefit in the
prevention of this important medical problem. The incidence of prosthetic valve
endocarditis has not changed in the last 40 years despite significant advances in
surgical and sterilization technique.
Representative examples of prosthetic heart valves include those
described in U.S. Patent Nos. 3,656,185, 4,106,129, 4,892,540, 5,528,023,
5,772,694, 6,096,075, 6,176,877, 6,358,278, and 6,371,983
Early after valve implantation, the prosthetic valve sewing ring and
annulus are not yet endothelialized. The accumulation of platelets and thrombus
at the site provide an excellent location for the adherence and colonization of
microorganisms. Bacteria can be seeded during the surgical procedure itself or as
a result of bacteremia arising in the early postoperative period (usually
contamination from i.v. catheters, catheters to determine cardiac output,
mediastinal tubes, chest tubes or wound infections). Common causes of PVE
include Coagulase Negative Staphylococci (Staphylococcus epidermidis; 30%),
Staphylococcus aureus (23%), Gram Negative Enterococci (Enterobacteriaceae,
Pseudomonas arugenosa; 14%), Fungi (Candida albicans, Aspergillis: 12%), and
Corynebacterium diptheriae. PVE of bioprosthetic valves is largely confined to the
leaflets (and rarely the annulus), whereas the annulus is involved in the majority of
cases of PVE in mechanical valves (82%).
Unfortunately, eradication of the infecting organism with antimicrobial
therapy alone is often difficult or impossible. As a result, many patients who
develop this complication require repeat open-heart surgery to replace the infected
valve resulting in significant morbidity and mortality. Even if the infection is
successfully treated medically, damage to the leaflets in bioprosthetic valves
reduces the lifespan of the valve. Particularly problematic are patients who
develop an infection caused by Staphylococcus aureus, as they have a 50-85%
mortality rate and overall reoperation rate of 50-65%. Infections caused by
Staphylococcus epidermidis are also difficult to treat as the majority are caused by
organisms resistant to all currently available beta-lactam antibiotics. Other
complications of prosthetic valve endocarditis include valve malfunction (stenosis,
regurgitation), abscess formation, embolic complications (such as stroke, CNS
hemorrhage, cerebritis), conduction abnormalities, and death (55-75% of patients
who develop an infection in the first 2 months after surgery).
An effective therapeutic valve coating would reduce the incidence of
prosthetic valve endocarditis, reduce the mortality rate, reduce the incidence of
complications, prolong the effectiveness of the prosthetic valve and/or reduce the
need to replace the valve. This would result in lower mortality and morbidity for
patients with prosthetic heart valves.
In a preferred embodiment, doxorubicin, mitoxantrone, 5-fIuorouracil
and/or etoposide are formulated into a coating applied to the surface of the
bioprosthetic or mechanical valve. The drug(s) can be applied to the prosthetic
valve in several manners: (a) as a coating applied to the surface of the annular ring
(particularly mechanical valves); (b) as a coating applied to the surface of the valve
leaflets (particularly bioprosthetic valves); (c) incorporated into the polymers which
comprise the annular ring; and/or (d) any combination of the aforementioned.
Drug-coating of, or drug incorporation into prosthetic heart valves will
allow bacteriocidal drug levels to be achieved locally on the valvular surface, thus
reducing the incidence of bacterial colonization and subsequent development of
PVE, while producing negligible systemic exposure to the drugs. Although for
some agents polymeric carriers are not required for attachment of the drug to the
valve annular ring and/or leaflets, several polymeric carriers are particularly
suitable for use in this embodiment. Of particular interest are polymeric carriers
such as polyurethanes (e.g., ChronoFlex AL 85A [CT Biomaterials],
HydroMed640™ [CT Biomaterials], HYDROSLIP C™ [CT Biomaterials],
HYDROTHANE [CT Biomaterials]), acrylic or methacrylic copolymers (e.g.
poly(ethylene-co-acrylic acid), cellulose-derived polymers {e.g., nitrocellulose,
Cellulose Acetate Butyrate, Cellulose acetate propionate), acrylate and
methacrylate copolymers (e.g., poly(ethylene-co-vinyl acetate)), as well as blends
thereof.
As prosthetic heart valves are made in a variety of configurations and
sizes, the exact dose administered will vary with device size, surface area and
design. However, certain principles can be applied in the application of this art.
Drug dose can be calculated as a function of dose per unit area (of the portion of
the device being coated), total drug dose administered can be measured and
appropriate surface concentrations of active drug can be determined. Regardless
of the method of application of the drug to the prosthetic heart valve, the preferred
anticancer agents, used alone or in combination, should be administered under the
following dosing guidelines:
(a) Anthracyclines. Utilizing the anthracycline doxorubicin as an
example, whether applied as a polymer coating, incorporated into the polymers
which make up the prosthetic heart valve, or applied without a carrier polymer, the
total dose of doxorubicin applied to the prosthetic heart valve should not exceed 25
mg (range of 0.1 µg to 25 mg). In a particularly preferred embodiment, the total
amount of drug applied to the prosthetic heart valve should be in the range of 1 µg
to 5 mg. The dose per unit area of the valve (i.e., the amount of drug as a function
of the surface area of the portion of the valve to which drug is applied and/or
incorporated) should fall within the range of 0.01 µg -100 µg per mm2 of surface
area. In a particularly preferred embodiment, doxorubicin should be applied to the
valve surface at a dose of 0.1 µg/mm2 - 10 µg/mm2. As different polymer and non-
polymer coatings will release doxorubicin at differing rates, the above dosing
parameters should be utilized in combination with the release rate of the drug from
the valve surface such that a minimum concentration of 107 -104 M of doxorubicin
is maintained on the surface. It is necessary to insure that drug concentrations on
the valve surface exceed concentrations of doxorubicin known to be lethal to
multiple species of bacteria and fungi (i.e., are in excess of 104 M; although for
some embodiments lower concentrations are sufficient). In a preferred
embodiment, doxorubicin is released from the surface of the valve such that anti-
infective activity is maintained for a period ranging from several hours to several
months. In a particularly preferred embodiment the drug is released in effective
concentrations for a period ranging from 1-6 months. It should be readily evident
based upon the discussions provided herein that analogues and derivatives of
doxorubicin (as described previously) with similar functional activity can be utilized
for the purposes of this invention; the above dosing parameters are then adjusted
according to the relative potency of the analogue or derivative as compared to the
parent compound (e.g. a compound twice as potent as doxorubicin is administered
at half the above parameters, a compound half as potent as doxorubicin is
administered at twice the above parameters, etc.).
Utilizing mitoxantrone as another example of an anthracycline,
whether applied as a polymer coating, incorporated into the polymers which make
up the prosthetic heart valve, or applied without a carrier polymer, the total dose of
mitoxantrone applied to the prosthetic heart valve should not exceed 5 mg (range
of 0.01 µg to 5 mg). In a particularly preferred embodiment, the total amount of
drug applied to the prosthetic heart valve should be in the range of 0.1 µg to 1 mg.
The dose per unit area of the valve (i.e. the amount of drug as a function of the
surface area of the portion of the valve to which drug is applied and/or
incorporated) should fall within the range of 0.01 µg - 20 µg per mm2 of surface
area. In a particularly preferred embodiment, mitoxantrone should be applied to
the valve surface at a dose of 0.05 µg/mm2 - 3 µg/mm2. As different polymer and
non-polymer coatings will release mitoxantrone at differing rates, the above dosing
parameters should be utilized in combination with the release rate of the drug from
the valve surface such that a minimum concentration of 105 - 106 M of
mitoxantrone is maintained on the valve surface. It is necessary to insure that
drug concentrations on the valve surface exceed concentrations of mitoxantrone
known to be lethal to multiple species of bacteria and fungi (i.e. are in excess of
105 M; although for some embodiments lower drug levels will be sufficient). In a
preferred embodiment, mitoxantrone is released from the surface of the valve such
that anti-infective activity is maintained for a period ranging from several hours to
several months. In a particularly preferred embodiment the drug is released in
effective concentrations for a period ranging from 1-6 months. It should be
readily evident based upon the discussions provided herein that analogues and
derivatives of mitoxantrone (as described previously) with similar functional activity
can be utilized for the purposes of this invention; the above dosing parameters are
then adjusted according to the relative potency of the analogue or derivative as
compared to the parent compound (e.g. a compound twice as potent as
mitoxantrone is administered at half the above parameters, a compound half as
potent as mitoxantrone is administered at twice the above parameters, etc.).
(b) Fluoropyrimidines Utilizing the fluoropyrimidine 5-fluorouracil as
an example, whether applied as a polymer coating, incorporated into the polymers
which make up the prosthetic heart valve, or applied without a carrier polymer, the
total dose of 5-fluorouracil applied to the prosthetic heart valve should not exceed
250 mg (range of 1.0 µg to 250 mg). In a particularly preferred embodiment, the
total amount of drug applied to the prosthetic heart valve should be in the range of
10 µg to 25 mg. The dose per unit area of the valve (i.e. the amount of drug as a
function of the surface area of the portion of the valve to which drug is applied
and/or incorporated) should fall within the range of 0.1 µg - 1 mg per mm2 of
surface area. In a particularly preferred embodiment, 5-fluorouracil should be
applied to the valve surface at a dose of 1.0 µg/mm2 - 50 µg/mm2. As different
polymer and non-polymer coatings will release 5-fluorouracil at differing rates, the
above dosing parameters should be utilized in combination with the release rate of
the drug from the valve surface such that a minimum concentration of 104 -107 M
of 5-fluorouracil is maintained on the valve surface. It is necessary to insure that
drug concentrations on the prosthetic heart valve surface exceed concentrations of
5-fluorouracil known to be lethal to numerous species of bacteria and fungi (i.e.,
are in excess of 104 M; although for some embodiments lower drug levels will be
sufficient). In a preferred embodiment, 5-fluorouracil is released from the surface
of the valve such that anti-infective activity is maintained for a period ranging from
several hours to several months. In a particularly preferred embodiment the drug
is released in effective concentrations for a period ranging from 1-6 months. It
should be readily evident based upon the discussions provided herein that
analogues and derivatives of 5-fluorouracil (as described previously) with similar
functional activity can be utilized for the purposes of this invention; the above
dosing parameters are then adjusted according to the relative potency of the
analogue or derivative as compared to the parent compound {e.g., a compound
twice as potent as 5-fluorouracil is administered at half the above parameters, a
compound half as potent as 5-fluorouracil is administered at twice the above
parameters, etc.).
(c) Podophylotoxins Utilizing the podophylotoxin etoposide as an
example, whether applied as a polymer coating, incorporated into the polymers
which make up the prosthetic heart valve, or applied without a carrier polymer, the
total dose of etoposide applied to the prosthetic heart valve should not exceed 25
mg (range of 0.1 µg to 25 mg). In a particularly preferred embodiment, the total
amount of drug applied to the prosthetic heart valve should be in the range of 1 µg
to 5 mg. The dose per unit area of the valve (i.e., the amount of drug as a function
of the surface area of the portion of the valve to which drug is applied and/or
incorporated) should fall within the range of 0.01 pg -100 µg per mm2 of surface
area. In a particularly preferred embodiment, etoposide should be applied to the
prosthetic heart valve surface at a dose of 0.1 µg/mm2 - 10 µg/mm2. As different
polymer and non-polymer coatings will release etoposide at differing rates, the
above dosing parameters should be utilized in combination with the release rate of
the drug from the valve surface such that a concentration of 105-106 M of
etoposide is maintained on the valve surface. It is necessary to insure that drug
concentrations on the valve surface exceed concentrations of etoposide known to
be lethal to a variety of bacteria and fungi (i.e., are in excess of 105 M; although for
some embodiments lower drug levels will be sufficient). In a preferred
embodiment, etoposide is released from the surface of the valve such that anti-
infective activity is maintained for a period ranging from several hours to several
months. In a particularly preferred embodiment the drug is released in effective
concentrations for a period ranging from 1-6 months. It should be readily evident
based upon the discussions provided herein that analogues and derivatives of
etoposide (as described previously) with similar functional activity can be utilized
for the purposes of this invention; the above dosing parameters are then adjusted
according to the relative potency of the analogue or derivative as compared to the
parent compound (e.g. a compound twice as potent as etoposide is administered
at half the above parameters, a compound half as potent as etoposide is
administered at twice the above parameters, etc.).
(d) Combination therapy. It should be readily evident based upon
the discussions provided herein that combinations of anthracyclines (e.g.,
doxorubicin or mitoxantrone), fluoropyrimidines (e.g., 5-fluorouracil), folic acid
antagonists (e.g., methotrexate and/or podophylotoxins (e.g., etoposide) can be
utilized to enhance the antibacterial activity of the prosthetic heart valve coating.
Similarly anthracyclines (e.g., doxorubicin or mitoxantrone), fluoropyrimidines (e.g.,
5-fluorouracil), folic acid antagonists (e.g., methotrexate and/or podophylotoxins
(e.g., etoposide) can be combined with traditional antibiotic and/or antifungal
agents to enhance efficacy. Since thrombogenicity of the prosthetic heart valve is
associated with an increased risk of infection, anthracyclines (e.g., doxorubicin or
mitoxantrone), fluoropyrimidines (e.g., 5-fluorouracil), folic acid antagonists (e.g.,
methotrexate and/or podophylotoxins (e.g., etoposide) can be combined with
antithrombotic and/or antiplatelet agents (for example, heparin, dextran sulphate,
danaparoid, lepirudin, hirudin, AMP, adenosine, 2-chloroadenosine, aspirin.
phenylbutazone, indomethacin, meclofenamate, hydrochloroquine, dipyridamole,
iloprost, ticlopidine, clopidogrel, abcixamab, eptifibatide, tirofiban, streptokinase,
and/or tissue plasminogen activator) to enhance efficacy.
C. Cardiac Pacemaker Infections
Overall, slightly greater than 5% of cardiac pacemakers become
infected following implantation. Cardiac pacemakers are subject to infection in two
general manners: (a) infections involving the pulse generator pocket and/or
subcutaneous portion of the lead, and (b) infections involving the transvenous
intravascular electrode and/or the generator unit. Representative examples of
patents which describe pacemakers and pacemaker leads include U.S. Patent
Nos. 4,662,382, 4,782,836, 4,856,521, 4,860,751, 5,101,824, 5,261,419,
5,284,491, 6,055,454, 6,370.434, and 6,370,434.
The most common type of pacemaker infection involves the
subcutaneous generator unit or lead wires in the period shortly after placement.
This type of infection is thought to be the result of contamination of the surgical site
by skin flora at the time of placement. Staphylococcus epidermidis (65-75% of
cases), Stapylococcus aureus, Streptococci, Corynebacterium, Proprionibacterium
acnes, Enterobacteriaceae and Candida species are frequent causes of this type
of infection. Treatment of the infection at this point is relatively straightforward, the
infected portion of the device is removed, the patient is treated with antibiotics and
a new pacemaker is inserted at a different site. Unfortunately, infections of the
generator pocket can subsequently spread to the epicardial electrodes causing
more severe complications such pericarditis, mediastinitis and bacteremia.
Infection of the intravascular portion of the tranvenous electrode
poses a more significant clinical problem. This infection is thought to be caused by
infection of the subcutaneous portion of the pacing apparatus that tracks along the
device into the intravascular and intracardiac portions of the device. This infection
tends to present at a later time (1-6 months post-procedure) and can result in
sepsis, endocarditis, pneumonia, bronchitis, pulmonary embolism, cardiac
vegetations and even death. Coagulase Negative Staphylococci (56% of
infections), Staphylococcus aureus (27%), Enterobacteriaceae (6%),
Pseudomonas arugenosa (3%) and Candida albicans (2%) are the most common
cause of this serious form of pacemaker infection. Treatment of this form of
infection is more complex. The generator and electrodes must be removed (often
surgically), antibiotics are required for prolonged periods and an entire new
pacemaker system must be inserted. Mortality rates associated with this condition
can be quite high -41% if treated with antibiotics alone, 20% if treated with
electrode removal and antibiotics.
An effective cardiac pacemaker coating would reduce the incidence
of subcutaneous infection and subsequent tracking of infection to the pericardial
and endocardial surfaces of the heart. Clinically, this would result in a reduction in
the overall rate of infection and reduce the incidence of more severe complications
such as sepsis, endocarditis, pneumonia, bronchitis, pulmonary embolism, cardiac
vegetations and even death. An effective coating could also prolong the
effectiveness of the pacemaker and decrease the number of pacemakers requiring
replacement, resulting in lower mortality and morbidity for patients with these
implants.
In a preferred embodiment, an anthracycline (e.g., doxorubicin and
mitoxantrone), fluoropyrimidine (e.g., 5-FU), folic acid antagonist (e.g.,
methotrexate), and/or podophylotoxin (e.g., etoposide) is formulated into a coating
applied to the surface of the components of the cardiac pacemaker. The drug(s)
can be applied to the pacemaker in several manners: (a) as a coating applied to
the surface of the generator unit; (b) as a coating applied to the surface of the
subcutaneous portion of the lead wires; (c) incorporated into, or applied to the
surface of, a subcutaneous "cuff around the subcutaneous insertion site; (d) as a
coating applied to the surface of the epicardial electrodes; (e) as a coating applied
to the surface of the transvenous electrode; and/or (f) any combination of the
aforementioned.
Drug-coating of, or drug incorporation into cardiac pacemakers will
allow bacteriocidal drug levels to be achieved locally on the pacemaker surface,
thus reducing the incidence of bacterial colonization and subsequent development
of infectious complications, while producing negligible systemic exposure to the
drugs. Although for some agents polymeric carriers are not required for
attachment of the drug to the generator unit, leads and electrodes, several
polymeric carriers are particularly suitable for use in this embodiment. Of particular
interest are polymeric carriers such as polyurethanes (e.g., ChronoFlex AL 85A
[CT Biomaterials], HydroMed640™ [CT Biomaterials], HYDROSLIP C™ [CT
Biomaterials], HYDROTHANE™ [CT Biomaterials]), acrylic or methacrylic
copolymers (e.g. poly(ethylene-co-acrylic acid), cellulose-derived polymers (e.g.
nitrocellulose, Cellulose Acetate Butyrate, Cellulose acetate propionate), acrylate
and methacrylate copolymers (e.g. poly(ethylene-co-vinyl acetate)) as well as
blends thereof.
As cardiac pacemakers are made in a variety of configurations and
sizes, the exact dose administered will vary with device size, surface area, design
and portions of the pacemaker coated. However, certain principles can be applied
in the application of this art. Drug dose can be calculated as a function of dose per
unit area (of the portion of the device being coated), total drug dose administered
can be measured and appropriate surface concentrations of active drug can be
determined. Regardless of the method of application of the drug to the cardiac
pacemaker, the preferred anticancer agents, used alone or in combination, should
be administered under the following dosing guidelines:
(a) Anthracyclines. Utilizing the anthracycline doxorubicin as an
example, whether applied as a polymer coating, incorporated into the polymers
which make up the pacemaker components, or applied without a carrier polymer,
the total dose of doxorubicin applied to the pacemaker should not exceed 25 mg
(range of 0.1 µg to 25 mg). In a particularly preferred embodiment, the total
amount of drug applied should be in the range of 1 µg to 5 mg. The dose per unit
area (i.e. the amount of drug as a function of the surface area of the portion of the
pacemaker to which drug is applied and/or incorporated) should fall within the
range of 0.01 µg -100 µg per mm2 of surface area. In a particularly preferred
embodiment, doxorubicin should be applied to the pacemaker surface at a dose of
0.1 µg/mm2 - 10 µg/mm2. As different polymer and non-polymer coatings will
release doxorubicin at differing rates, the above dosing parameters should be
utilized in combination with the release rate of the drug from the pacemaker
surface such that a minimum concentration of 10-7 -10-4 M of doxorubicin is
maintained on the surface. It is necessary to insure that surface drug
concentrations exceed concentrations of doxorubicin known to be lethal to multiple
species of bacteria and fungi (i.e., are in excess of 10-4M; although for some
embodiments lower concentrations are sufficient). In a preferred embodiment,
doxorubicin is released from the surface of the pacemaker such that anti-infective
activity is maintained for a period ranging from several hours to several months. In
a particularly preferred embodiment the drug is released in effective concentrations
for a period ranging from 1 week - 6 months. It should be readily evident based
upon the discussions provided herein that analogues and derivatives of
doxorubicin (as described previously) with similar functional activity can be utilized
for the purposes of this invention; the above dosing parameters are then adjusted
according to the relative potency of the analogue or derivative as compared to the
parent compound (e.g. a compound twice as potent as doxorubicin is administered
at half the above parameters, a compound half as potent as doxorubicin is
administered at twice the above parameters, etc.).
Utilizing mitoxantrone as another example of an anthracycline,
whether applied as a polymer coating, incorporated into the polymers which make
up the pacemaker, or applied without a carrier polymer, the total dose of
mitoxantrone applied should not exceed 5 mg (range of 0.01 µg to 5 mg). In a
particularly preferred embodiment, the total amount of drug applied should be in
the range of 0.1 µg to 1 mg. The dose per unit area (i.e. the amount of drug as a
function of the surface area of the portion of the pacemaker to which drug is
applied and/or incorporated) should fall within the range of 0.01 µg - 20 µg per
mm2 of surface area. In a particularly preferred embodiment, mitoxantrone should
be applied to the pacemaker surface at a dose of 0.05 µg/mm2 - 3 µg/mm2. As
different polymer and non-polymer coatings will release mitoxantrone at differing
rates, the above dosing parameters should be utilized in combination with the
release rate of the drug from the pacemaker surface such that a minimum
concentration of 10-5 -10-6 M of mitoxantrone is maintained. It is necessary to
insure that drug concentrations on the pacemaker surface exceed concentrations
of mitoxantrone known to be lethal to multiple species of bacteria and fungi (i.e.
are in excess of 10"5 M; although for some embodiments lower drug levels will be
sufficient). In a preferred embodiment, mitoxantrone is released from the surface
of the pacemaker such that anti-infective activity is maintained for a period ranging
from several hours to several months. In a particularly preferred embodiment the
drug is released in effective concentrations for a period ranging from 1 week - 6
months. It should be readily evident based upon the discussions provided herein
that analogues and derivatives of mitoxantrone (as described previously) with
similar functional activity can be utilized for the purposes of this invention; the
above dosing parameters are then adjusted according to the relative potency of
the analogue or derivative as compared to the parent compound (e.g. a compound
twice as potent as mitoxantrone is administered at half the above parameters, a
compound half as potent as mitoxantrone is administered at twice the above
parameters, etc.).
(b) Fluoropyrimidines Utilizing the fluoropyrimidine 5-fluorouracil as
an example, whether applied as a polymer coating, incorporated into the polymers
which make up the pacemaker, or applied without a carrier polymer, the total dose
of 5-fluorouracil applied should not exceed 250 mg (range of 1.0 µg to 250 mg). In
a particularly preferred embodiment, the total amount of drug applied should be in
the range of 10 µg to 25 mg. The dose per unit area (i.e. the amount of drug as a
function of the surface area of the portion of the pacemaker to which drug is
applied and/or incorporated) should fall within the range of 0.1 µg - 1 mg per mm2
of surface area. In a particularly preferred embodiment, 5-fluorouracil should be
applied to the pacemaker surface at a dose of 1.0 µg/mm2 - 50 µg/mm2. As
different polymer and non-polymer coatings will release 5-fluorouracil at differing
rates, the above dosing parameters should be utilized in combination with the
release rate of the drug from the pacemaker surface such that a minimum
concentration of 10-4 -10-7 M of 5-fluorouracil is maintained. It is necessary to
insure that surface drug concentrations exceed concentrations of 5-fluorouracil
known to be lethal to numerous species of bacteria and fungi (i.e., are in excess of
10-4 M; although for some embodiments lower drug levels will be sufficient). In a
preferred embodiment, 5-fluorouracil is released from the pacemaker surface such
that anti-infective activity is maintained for a period ranging from several hours to
several months. In a particularly preferred embodiment the drug is released in
effective concentrations for a period ranging from 1 week - 6 months. It should be
readily evident based upon the discussions provided herein that analogues and
derivatives of 5-fluorouracil (as described previously) with similar functional activity
can be utilized for the purposes of this invention; the above dosing parameters are
then adjusted according to the relative potency of the analogue or derivative as
compared to the parent compound (e.g. a compound twice as potent as 5-
fluorouracil is administered at half the above parameters, a compound half as
potent as 5-fluorouracil is administered at twice the above parameters, etc.).
(c) Podophylotoxins Utilizing the podophylotoxin etoposide as an
example, whether applied as a polymer coating, incorporated into the polymers
which make up the cardiac pacemaker, or applied without a carrier polymer, the
total dose of etoposide applied should not exceed 25 mg (range of 0.1 µg to 25
mg). In a particularly preferred embodiment, the total amount of drug applied
should be in the range of 1 µg to 5 mg. The dose per unit area (i.e. the amount of
drug as a function of the surface area of the portion of the pacemaker to which
drug is applied and/or incorporated) should fall within the range of 0.01 µg -100 µg
per mm2 of surface area. In a particularly preferred embodiment, etoposide should
be applied to the pacemaker surface at a dose of 0.1 µg/mm2 - 10 µg/mm2. As
different polymer and non-polymer coatings will release etoposide at differing
rates, the above dosing parameters should be utilized in combination with the
release rate of the drug from the pacemaker surface such that a concentration of
10-5-10-6 M of etoposide is maintained. It is necessary to insure that surface drug
concentrations exceed concentrations of etoposide known to be lethal to a variety
of bacteria and fungi (i.e. are in excess of 105 M; although for some embodiments
lower drug levels will be sufficient). In a preferred embodiment, etoposide is
released from the surface of the pacemaker such that anti-infective activity is
maintained for a period ranging from several hours to several months. In a
particularly preferred embodiment the drug is released in effective concentrations
for a period ranging from 1 week - 6 months. It should be readily evident based
upon the discussions provided herein that analogues and derivatives of etoposide
(as described previously) with similar functional activity can be utilized for the
purposes of this invention; the above dosing parameters are then adjusted
according to the relative potency of the analogue or derivative as compared to the
parent compound (e.g. a compound twice as potent as etoposide is administered
at half the above parameters, a compound half as potent as etoposide is
administered at twice the above parameters, etc.).
(d) Combination therapy. It should be readily evident based upon
the discussions provided herein that combinations of anthracyclines (e.g.,
doxorubicin or mitoxantrone), fluoropyrimidines (e.g., 5-fluorouracil), folic acid
antagonists (e.g., methotrexate and/or podophylotoxins (e.g., etoposide) can be
utilized to enhance the antibacterial activity of the pacemaker coating. Similarly
anthracyclines (e.g., doxorubicin or mitoxantrone), fluoropyrimidines (e.g., 5-
fluorouracil), folic acid antagonists (e.g., methotrexate and/or podophylotoxins
(e.g., etoposide) can be combined with traditional antibiotic and/or antifungal
agents to enhance efficacy. Since thrombogenicity of the intravascular portion of
the transvenous electrode is associated with an increased risk of infection,
anthracyclines (e.g., doxorubicin or mitoxantrone), fluoropyrimidines (e.g., 5-
fluorouracil), folic acid antagonists (e.g., methotrexate and/or podophylotoxins
(e.g., etoposide) can be combined with antithrombotic and/or antiplatelet agents
(for example heparin, dextran sulphate, danaparoid, lepirudin, hirudin, AMP,
adenosine, 2-chloroadenosine, aspirin, phenylbutazone, indomethacin,
meclofenamate, hydrochloroquine, dipyridamole, iloprost, ticlopidine, clopidogrel,
abcixamab, eptifibatide, tirofiban, streptokinase, and/or tissue plasminogen
activator) to enhance efficacy.
D. Infections of Implantable Cardioverter-Defibrillators (ICD)
Overall, approximately 5-10% of implantable cardioverter-
defibrillators become infected following implantation (the rate is highest if surgical
placement is required). Like cardiac pacemakers, implantable defibrillators are
subject to infection in two general manners: (a) infections involving the
subcutaneous portion of the device (subcutaneous electrodes and pulse generator
unit, and (b) infections involving the intrathoracic components (rate sensing
electrode, SVC coil electrode and epicardial electrodes). Representative
examples of ICD's and associated components are described in U.S. Patent Nos.
3.614,954, 3,614,955, 4,375,817, 5,314,430, 5,405,363, 5,607,385, 5,697,953,
5,776,165, 6,067,471, 6,169,923, and 6,152,955.
Most infections present period shortly after placement and are
thought to be the result of contamination of the surgical site by skin flora.
Staphylococcus epidermidis, Stapylococcus aureus, Streptococci,
Corynebacterium, Proprionibacterium acnes, Enterobacteriaceae and Candida
species are frequent causes of this type of infection. Unfortunately, treatment
frequently involves removal of the entire system and prolonged antibiotic therapy.
An effective 1CD coating would reduce the incidence of infection-
related side effects such subcutaneous infection, sepsis and pericarditis. An
effective coating could also prolong the effectiveness of the ICD and decrease the
number of patients requiring replacement, resulting in lower mortality and morbidity
associated with these implants.
In a preferred embodiment, doxorubicin, mitoxantrone, 5-fluorouracil
and/or etoposide are formulated into a coating applied to the surface of the
components of the ICD. The drug(s) can be applied in several manners: (a) as a
coating applied to the surface of the pulse generator unit; (b) as a coating applied
to the surface of the subcutaneous portion of the lead wires; (c) incorporated into,
or applied to the surface of, a subcutaneous "cuff" around the subcutaneous
insertion site; (d) as a coating applied to the surface of the SVC coil electrode; (e)
as a coating applied to the surface of the epicardial electrode; and/or (f) any
combination of the aforementioned.
Drug-coating of, or drug incorporation into prosthetic heart valves will
allow bacteriocidal drug levels to be achieved locally on the ICD surface, thus
reducing the incidence of bacterial colonization and subsequent development of
infectious complications, while producing negligible systemic exposure to the
drugs. Although for some agents polymeric carriers are not required for
attachment of the drug to the generator unit, leads and electrodes, several
polymeric carriers are particularly suitable for use in this embodiment. Of particular
interest are polymeric carriers such as polyurethanes (e.g., ChronoFlex AL 85A
[CT Biomaterials], HydroMed640™ [CT Biomaterials], HYDROSLIP C™ [CT
Biomaterials], HYDROTHANE™ [CT Biomaterials)), acrylic or methacrylic
copolymers (e.g. poly(ethylene-co-acrylic acid), cellulose-derived polymers (e.g.
nitrocellulose, Cellulose Acetate Butyrate, Cellulose acetate propionate), acrylate
and methacrylate copolymers (e.g. poly(ethylene-co-vinyl acetate)) as well as
blends thereof.
As implantable cardioverter-defibrillators have many design features
similar to those found in cardiac pacemakers, the dosing guidelines for
doxorubicin, mitoxantrone, 5-fluorouracil and etoposide in coating ICDs are
identical to those described above for cardiac pacemakers.
E. Vascular Graft Infections
Infection rates for synthetic vascular grafts range from 1-5% and are
highest in grafts that traverse the inguinal region (such as aorto-femoral grafts and
femoral-popliteal grafts). Although infection can result from extension of an
infection from an adjacent contaminated tissue or hematogenous seeding, the
most common cause of infection is intraoperative contamination. In fact, more
than half of all cases present within the first 3 months after surgery. The most
common causes of infection include Staphylococcus aureus (25-35% of cases),
Enterobacteriaceae, Pseudomonas aerugenosa, and Coagulase Negative
Staphylococci.
Complications arising from vascular graft infection include sepsis,
subcutaneous infection, false aneurysm formation, graft thrombosis, haemorrhage,
septic or thrombotic emboli and graft thrombosis. Treatment requires removal of
the graft in virtually all cases combined with systemic antibiotics. Often the surgery
must be performed in a staged manner (complete resection of the infected graft,
debridement of adjacent infected tissues, development of a healthy arterial stump,
reperfusion through an uninfected pathway) further adding to the morbidity and
mortality associated with this condition. For example, if an aortic graft becomes
infected there is a 37% mortality rate and a 21% rate of leg amputation in
survivors; for infrainguinal grafts the rates are 18% and 40% respectively.
Representative examples of vascular grafts are described in U.S.
Patent Nos. 3,096,560, 3,805,301, 3,945,052, 4,140,126, 4,323,525, 4,355,426,
4,475,972, 4,530,113, 4,550,447, 4,562,596, 4,601,718, 4,647,416, 4,878,908,
5,024,671, 5,104,399, 5,116,360, 5,151,105, 5,197,977, 5,282,824, 5,405,379,
5,609,624, 5,693,088, and 5,910,168.
An effective vascular graft coating would reduce the incidence of
complications such as sepsis, haemorrhage, thrombosis, embolism, amputation
and even death. An effective coating would also decrease the number of vascular
grafts requiring replacement, resulting in lower mortality and morbidity for patients
with these implants.
In a preferred embodiment, an anthracycline (e.g., doxorubicin and
mitoxantrone), fluoropyrimidine (e.g., 5-FU), folic acid antagonist (e.g.,
methotrexate), and/or podophylotoxin (e.g., etoposide) is formulated into a coating
applied to the surface of the components of the vascular graft. The drug(s) can be
applied in several manners: (a) as a coating applied to the external surface of the
graft; (b) as a coating applied to the internal (luminal) surface of the graft; and/or
(c) as a coating applied to all or parts of both surfaces.
Drug-coating of, or drug incorporation into vascular grafts will allow
bacteriocidal drug levels to be achieved locally on the graft surface, thus reducing
the incidence of bacterial colonization and subsequent development of infectious
complications, while producing negligible systemic exposure to the drugs.
Although for some agents polymeric carriers are not required for attachment of the
drug, several polymeric carriers are particularly suitable for use in this
embodiment. Of particular interest are polymeric carriers such as polyurethanes
(e.g., ChronoFlex AL 85A [CT Biomaterials], HydroMed640™ [CT Biomaterials],
HYDROSLIP C™ [CT Biomaterials], HYDROTHANE™ [CT Biomaterials]), acrylic
or methacrylic copolymers (e.g. poly(ethylene-co-acrylic acid), cellulose-derived
polymers (e.g. nitrocellulose, Cellulose Acetate Butyrate, Cellulose acetate
propionate), acrylate and methacrylate copolymers (e.g. poly(ethylene-co-vinyl
acetate)) collagen as well as blends thereof.
As vascular grafts are made in a variety of configurations and sizes,
the exact dose administered will vary with device size, surface area, design and
portions of the graft coated. However, certain principles can be applied in the
application of this art. Drug dose can be calculated as a function of dose per unit
area (of the portion of the device being coated), total drug dose administered can
be measured and appropriate surface concentrations of active drug can be
determined. Regardless of the method of application of the drug to the vascular
graft, the preferred anticancer agents, used alone or in combination, should be
administered under the following dosing guidelines:
(a) Anthracyclines. Utilizing the anthracycline doxorubicin as an
example, whether applied as a polymer coating, incorporated into the polymers
which make up the vascular graft components (such as Dacron or Teflon), or
applied without a carrier polymer, the total dose of doxorubicin applied should not
exceed 25 mg (range of 0.1 µg to 25 mg). In a particularly preferred embodiment,
the total amount of drug applied should be in the range of 1 µg to 5 mg. The dose
per unit area (i.e. the amount of drug as a function of the surface area of the
portion of the vascular graft to which drug is applied and/or incorporated) should
fall within the range of 0.01 µg -100 µg per mm2 of surface area. In a particularly
preferred embodiment, doxorubicin should be applied to the vascular graft surface
at a dose of 0.1 µg/mm2 - 10 µg/mm2. As different polymer and non-polymer
coatings will release doxorubicin at differing rates, the above dosing parameters
should be utilized in combination with the release rate of the drug from the
vascular graft surface such that a minimum concentration of 10-7-10-4 M of
doxorubicin is maintained on the surface. It is necessary to insure that surface
drug concentrations exceed concentrations of doxorubicin known to be lethal to
multiple species of bacteria and fungi (i.e., are in excess of 10-4 M; although for
some embodiments lower concentrations are sufficient). In a preferred
embodiment, doxorubicin is released from the surface of the vascular graft such
that anti-infective activity is maintained for a period ranging from several hours to
several months. In a particularly preferred embodiment the drug is released in
effective concentrations for a period ranging from 1 week - 6 months. It should be
readily evident based upon the discussions provided herein that analogues and
derivatives of doxorubicin (as described previously) with similar functional activity
can be utilized for the purposes of this invention; the above dosing parameters are
then adjusted according to the relative potency of the analogue or derivative as
compared to the parent compound (e.g. a compound twice as potent as
doxorubicin is administered at half the above parameters, a compound half as
potent as doxorubicin is administered at twice the above parameters, etc.).
Utilizing mitoxantrone as another example of an anthracycline,
whether applied as a polymer coating, incorporated into the polymers which make
up the vascular graft (such as Dacron or Teflon), or applied without a carrier
polymer, the total dose of mitoxantrone applied should not exceed 5 mg (range of
0.01 µg to 5 mg). In a particularly preferred embodiment, the total amount of drug
applied should be in the range of 0.1 µg to 1 mg. The dose per unit area (i.e. the
amount of drug as a function of the surface area of the portion of the vascular graft
to which drug is applied and/or incorporated) should fall within the range of 0.01 µg
- 20 µg per mm2 of surface area. In a particularly preferred embodiment,
mitoxantrone should be applied to the vascular graft surface at a dose of 0.05
µg/mm2 - 3 µg/mm2. As different polymer and non-polymer coatings will release
mitoxantrone at differing rates, the above dosing parameters should be utilized in
combination with the release rate of the drug from the vascular graft surface such
that a minimum concentration of 105 - 10-6 M of mitoxantrone is maintained. It is
necessary to insure that drug concentrations on the surface exceed concentrations
of mitoxantrone known to be lethal to multiple species of bacteria and fungi (i.e.
are in excess of 105 M; although for some embodiments lower drug levels will be
sufficient). In a preferred embodiment, mitoxantrone is released from the vascular
graft surface such that anti-infective activity is maintained for a period ranging from
several hours to several months. In a particularly preferred embodiment the drug
is released in effective concentrations for a period ranging from 1 week - 6
months. It should be readily evident based upon the discussions provided herein
that analogues and derivatives of mitoxantrone (as described previously) with
similar functional activity can be utilized for the purposes of this invention; the
above dosing parameters are then adjusted according to the relative potency of
the analogue or derivative as compared to the parent compound (e.g. a compound
twice as potent as mitoxantrone is administered at half the above parameters, a
compound half as potent as mitoxantrone is administered at twice the above
parameters, etc.).
(b) Fluoropyrimidines Utilizing the fluoropyrimidine 5-fluorouracil as
an example, whether applied as a polymer coating, incorporated into the polymers
which make up the vascular graft (such as Dacron or Teflon), or applied without a
carrier polymer, the total dose of 5-fluorouracil applied should not exceed 250 mg
(range of 1.0 µg to 250 mg). In a particularly preferred embodiment, the total
amount of drug applied should be in the range of 10 µg to 25 mg. The dose per
unit area (i.e. the amount of drug as a function of the surface area of the portion of
the vascular graft to which drug is applied and/or incorporated) should fall within
the range of 0.1 µg - 1 mg per mm2 of surface area. In a particularly preferred
embodiment, 5-fluorouracil should be applied to the vascular graft surface at a
dose of 1.0 µg/mm2 - 50 µg/mm2. As different polymer and non-polymer coatings
will release 5-fluorouracil at differing rates, the above dosing parameters should be
utilized in combination with the release rate of the drug from the vascular graft
surface such that a minimum concentration of 104-107 M of 5-fluorouracil is
maintained. It is necessary to insure that surface drug concentrations exceed
concentrations of 5-fluorouracil known to be lethal to numerous species of bacteria
and fungi (i.e., are in excess of 10-4M; although for some embodiments lower drug
levels will be sufficient). In a preferred embodiment, 5-fluorouracil is released from
the vascular graft surface such that anti-infective activity is maintained for a period
ranging from several hours to several months. In a particuarly preferred
embodiment the drug is released in effective concentrations for a period ranging
from 1 week - 6 months. It should be readily evident based upon the discussions
provided herein that analogues and derivatives of 5-fluorouracil (as described
previously) with similar functional activity can be utilized for the purposes of this
invention; the above dosing parameters are then adjusted according to the relative
potency of the analogue or derivative as compared to the parent compound (e.g. a
compound twice as potent as 5-fluorouracil is administered at half the above
parameters, a compound half as potent as 5-fluorouracil is administered at twice
the above parameters, etc.).
(c) Podophylotoxins Utilizing the podophylotoxin etoposide as an
example, whether applied as a polymer coating, incorporated into the polymers
which make up the vascular graft (such as Dacron or Teflon), or applied without a
carrier polymer, the total dose of etoposide applied should not exceed 25 mg
(range of 0.1 µg to 25 mg). In a particularly preferred embodiment, the total
amount of drug applied should be in the range of 1 µg to 5 mg. The dose per unit
area (i.e. the amount of drug as a function of the surface area of the portion of the
vascular graft to which drug is applied and/or incorporated) should fall within the
range of 0.01 ng -100 µg per mm2 of surface area. In a particularly preferred
embodiment, etoposide should be applied to the vascular graft surface at a dose of
0.1 µg/mm2 - 10 µg/mm2. As different polymer and non-polymer coatings will
release etoposide at differing rates, the above dosing parameters should be
utilized in combination with the release rate of the drug from the vascular graft
surface such that a concentration of 105-106 M of etoposide is maintained. It is
necessary to insure that surface drug concentrations exceed concentrations of
etoposide known to be lethal to a variety of bacteria and fungi (i.e. are in excess of
105 M; although for some embodiments lower drug levels will be sufficient). In a
preferred embodiment, etoposide is released from the surface of the vascular graft
such that anti-infective activity is maintained for a period ranging from several
hours to several months. In a particularly preferred embodiment the drug is
released in effective concentrations for a period ranging from 1 week - 6 months.
It should be readily evident based upon the discussions provided herein that
analogues and derivatives of etoposide (as described previously) with similar
functional activity can be utilized for the purposes of this invention; the above
dosing parameters are then adjusted according to the relative potency of the
analogue or derivative as compared to the parent compound (e.g. a compound
twice as potent as etoposide is administered at half the above parameters, a
compound half as potent as etoposide is administered at twice the above
parameters, etc.).
(d) Combination therapy. It should be readily evident based upon
the discussions provided herein that combinations of anthracyclines (e.g.,
doxorubicin or mitoxantrone), fluoropyrimidines (e.g., 5-fluorouracil), folic acid
antagonists (e.g., methotrexate and podophylotoxins (e.g., etoposide) can be
utilized to enhance the antibacterial activity of the vascular graft coating. Similarly
anthracyclines (e.g., doxorubicin or mitoxantrone), fluoropyrimidines (e.g., 5-
fluorouracil), folic acid antagonists (e.g., methotrexate and/or podophylotoxins
(e.g., etoposide) can be combined with traditional antibiotic and/or antifungal
agents to enhance efficacy. Since thrombogenicity of the vascular graft is
associated with an increased risk of infection, anthracyclines (e.g., doxorubicin or
mitoxantrone), fluoropyrimidines (e.g., 5-fluorouracil), folic acid antagonists (e.g.,
methotrexate and/or podophylotoxins (e.g., etoposide) can be combined with
antithrombotic and/or antiplatelet agents (for example heparin, dextran sulphate,
danaparoid, lepirudin, hirudin, AMP, adenosine, 2-chloroadenosine, aspirin,
phenylbutazone, indomethacin, meclofenamate, hydrochloroquine, dipyridamole,
iloprost, ticlopidine, clopidogrel, abcixamab, eptifibatide, tirofiban, streptokinase,
and/or tissue plasminogen activator) to enhance efficacy.
F. Infections Associated with Ear, Nose and Throat Implants
Bacterial infections involving the ear, nose and throat are common
occurrences in both children and adults. For the management of chronic
obstruction secondary to persistent infection, the use of implanted medical tubes is
a frequent form of treatment. Specifically, chronic otitis media is often treated with
the surgical implantation of tympanostomy tubes and chronic sinusitis is frequently
treated with surgical drainage and the placement of a sinus stent.
Tympanostomy Tubes
Acute otitis media is the most common bacterial infection, the most
frequent indication for surgical therapy, the leading cause of hearing loss and a
common cause of impaired language development in children. The cost of treating
this condition in children under the age of five is estimated at $5 billion annually in
the United States alone. In fact, 85% of all children will have at least one episode
of otitis media and 600,000 will require surgical therapy annually. The prevalence
of otitis media is increasing and for severe cases surgical therapy is more cost
effective than conservative management.
Acute otitis media (bacterial infection of the middle ear) is
characterized by Eustachian tube dysfunction leading to failure of the middle ear
clearance mechanism. The most common causes of otitis media are
Streptococcus pneumoniae (30%), Haemophilus influenza (20%), Branhamella
catarrhalis (12%), Streptococcus pyogenes (3%), and Staphylococcus aureus
(1.5%). The end result is the accumulation of bacteria, white blood cells and fluid
which, in the absence of an ability to drain through the Eustachian tube, results in
increased pressure in the middle ear. For many cases antibiotic therapy is
sufficient treatment and the condition resolves. However, tor a significant number
of patients the condition becomes frequently recurrent or does not resolve
completely. In recurrent otitis media or chronic otitis media with effusion, there is a
continuous build-up of fluid and bacteria that creates a pressure gradient across
the tympanic membrane causing pain and impaired hearing. Fenestration of the
tympanic membrane (typically with placement of a tympanostomy tube) relieves
the pressure gradient and facilitates drainage of the middle ear (through the outer
ear instead of through the Eustachian tube - a form of "Eustachian tube bypass").
Surgical placement of tympanostomy tubes is the most widely used
treatment for chronic otitis media because, although not curative, it improves
hearing (which in turn improves language development) and reduces the incidence
of acute otitis media. Tympanostomy tube placement is one of the most common
surgical procedures in the United States with 1.3 million surgical placements per
year. Nearly all younger children and a large percentage of older children require
general anaesthesia for placement. Since general anaesthesia has a higher
incidence of significant side effects in children (and represents the single greatest
risk and cost associated with the procedure), it is desirable to limit the number of
anaesthetics that the child is exposed to. Common complications of
tympanostomy tube insertion include chronic otorrhea (often due to infection by S.
pneumoniae, H. influenza, Pseudomonas aerugenosa, S.aureus, or Candida),
foreign body reaction with the formation of granulation tissue and infection,
plugging (usually obstructed by granulation tissue, bacteria and/or clot), tympanic
membrane perforation, myringosclerosis, tympanic membrane atrophy (retraction,
atelectasis), and cholesteatoma.
An effective tympanostomy tube coating would allow easy insertion,
remain in place for as long as is required, be easily removed in the office without
anaesthesia, resist infection and prevent the formation of granulation tissue in the
tube (which can not only lead to obstruction, but also "tack down" the tube such
that surgical removal of the tube under anaesthetic becomes necessary). An
effective tympanostomy tube would also reduce the incidence of complications
such as chronic otorrhea (often due to infection by S. pneumoniae, H. influenza,
Pseudomonas aerugenosa, S.aureus, or Candida); maintain patency (prevent
obstruction by granulation tissue, bacteria and/or clot); and/or reduce tympanic
membrane perforation, myringosclerosis, tympanic membrane atrophy and
cholesteatoma. Therefore, development of a tube which does not become
obstructed by granulation tissue, does not scar in place and is less prone to
infection (thereby reducing the need to remove/replace the tube) would be a
significant medical advancement.
In a preferred embodiment, doxorubicin, mitoxantrone, 5-fluorouracil
and/or etoposide are formulated into a coating applied to the surface of the
tympanostomy tube. The drug(s) can be applied in several manners: (a) as a
coating applied to the external surface of the tympanostomy tube; (b) as a coating
applied to the internal (luminal) surface of the tympanostomy tube; (c) as a coating
applied to all or parts of both surfaces; and/or (d) incorporated into the polymers
which comprise the tympanostomy tube.
Drug-coating of, or drug incorporation into, the tympanostomy tube
will allow bacteriocidal drug levels to be achieved locally on the tube surface, thus
reducing the incidence of bacterial colonization (and subsequent development of
middle ear infection), while producing negligible systemic exposure to the drugs.
Although for some agents polymeric carriers are not required for attachment of the
drug to the tympanostomy tube surface, several polymeric carriers are particularly
suitable for use in this embodiment. Of particular interest are polymeric carriers
such as polyurethanes (e.g., ChronoFlex AL 85A [CT Biomaterials],
HydroMed640™ [CT Biomaterials], HYDROSLIP C™ [CT Biomaterials],
HYDROTHANE™ [CT Biomaterials]), acrylic or methacrylic copolymers (e.g.
poly(ethylene-co-acrylic acid), cellulose-derived polymers (e.g. nitrocellulose,
Cellulose Acetate Butyrate, Cellulose acetate propionate), acrylate and
methacrylate copolymers (e.g. poly(ethylene-co-vinyl acetate)) as well as blends
thereof.
There are two general designs of tympanostomy tubes: grommet-
shaped tubes, which tend to stay in place for less than 1 year but have a low
incidence of permanent perforation of the tympanic membrane (1%), and T-tubes,
which stay in place for several years but have a higher rate of permanent
perforation (5%). As tympanostomy tubes are made in a variety of configurations
and sizes, the exact dose administered will vary with device size, surface area and
design. However, certain principles can be applied in the application of this art.
Drug dose can be calculated as a function of dose per unit area (of the portion of
the device being coated), total drug dose administered can be measured and
appropriate surface concentrations of active drug can be determined. Regardless
of the method of application of the drug to the tympanostomy tube, the preferred
anticancer agents, used alone or in combination, should be administered under the
following dosing guidelines:
(a) Anthracyclines. Utilizing the anthracycline doxorubicin as an
example, whether applied as a polymer coating, incorporated into the polymers
which make up the tympanostomy tube components, or applied without a carrier
polymer, the total dose of doxorubicin applied should not exceed 25 mg (range of
0.1 µg to 25 mg). In a particularly preferred embodiment, the total amount of drug
applied should be in the range of 1 µg to 5 mg. The dose per unit area (i.e. the
amount of drug as a function of the surface area of the portion of the
tympanostomy tube to which drug is applied and/or incorporated) should fall within
the range of 0.01 µg -100 µg per mm2 of surface area. In a particularly preferred
embodiment, doxorubicin should be applied to the tympanostomy tube surface at a
dose of 0.1 µg/mm2 - 10 µg/mm2. As different polymer and non-polymer coatings
will release doxorubicin at differing rates, the above dosing parameters should be
utilized in combination with the release rate of the drug from the tympanostomy
tube surface such that a minimum concentration of 107 -104 M of doxorubicin is
maintained on the surface. It is necessary to insure that surface drug
concentrations exceed concentrations of doxorubicin known to be lethal to multiple
species of bacteria and fungi (i.e., are in excess of 10-4 M; although for some
embodiments lower concentrations are sufficient). In a preferred embodiment,
doxorubicin is released from the surface of the tympanostomy tube such that anti-
infective activity is maintained for a period ranging from several hours to several
months. In a particularly preferred embodiment the drug is released in effective
concentrations for a period ranging from 1 week - 6 months. It should be readily
evident based upon the discussions provided herein that analogues and
derivatives of doxorubicin (as described previously) with similar functional activity
can be utilized for the purposes of this invention; the above dosing parameters are
then adjusted according to the relative potency of the analogue or derivative as
compared to the parent compound (e.g. a compound twice as potent as
doxorubicin is administered at half the above parameters, a compound half as
potent as doxorubicin is administered at twice the above parameters, etc.).
Utilizing mitoxantrone as another example of an anthracycline,
whether applied as a polymer coating, incorporated into the polymers which make
up the tympanostomy tube, or applied without a carrier polymer, the total dose of
mitoxantrone applied should not exceed 5 mg (range of 0.01 µg to 5 mg). In a
particularly preferred embodiment, the total amount of drug applied should be in
the range of 0.1 µg to 1 mg. The dose per unit area (i.e. the amount of drug as a
function of the surface area of the portion of the tympanostomy tube to which drug
is applied and/or incorporated) should fall within the range of 0.01 µg - 20 ug per
mm2 of surface area. In a particularly preferred embodiment, mitoxantrone should
be applied to the tympanostomy tube surface at a dose of 0.05 µg/mm2 - 3
µg/mm2. As different polymer and non-polymer coatings will release mitoxantrone
at differing rates, the above dosing parameters should be utilized in combination
with the release rate of the drug from the tympanostomy tube surface such that a
minimum concentration of 105 -106 M of mitoxantrone is maintained. It is
necessary to insure that drug concentrations on the surface exceed concentrations
of mitoxantrone known to be lethal to multiple species of bacteria and fungi (i.e.
are in excess of 105 M; although for some embodiments lower drug levels will be
sufficient). In a preferred embodiment, mitoxantrone is released from the
tympanostomy tube surface such that anti-infective activity is maintained for a
period ranging from several hours to several months. In a particularly preferred
embodiment the drug is released in effective concentrations for a period ranging
from 1 week - 6 months. It should be readily evident based upon the discussions
provided herein that analogues and derivatives of mitoxantrone (as described
previously) with similar functional activity can be utilized for the purposes of this
invention; the above dosing parameters are then adjusted according to the relative
potency of the analogue or derivative as compared to the parent compound (e.g. a
compound twice as potent as mitoxantrone is administered at half the above
parameters, a compound half as potent as mitoxantrone is administered at twice
the above parameters, etc.).
(b) Fluoropyrimidines Utilizing the fluoropyrimidine 5-fluorouracil as
an example, whether applied as a polymer coating, incorporated into the polymers
which make up the tympanostomy tube, or applied without a carrier polymer, the
total dose of 5-fluorouracil applied should not exceed 250 mg (range of 1.0 µg to
250 mg). In a particularly preferred embodiment, the total amount of drug applied
should be in the range of 10 µg to 25 mg. The dose per unit area (i.e. the amount
of drug as a function of the surface area of the portion of the tympanostomy tube to
which drug is applied and/or incorporated) should fall within the range of 0.1 µg - 1
mg per mm2 of surface area. In a particularly preferred embodiment, 5-fluorouracil
should be applied to the tympanostomy tube surface at a dose of 1.0 µg/mm2 - 50
µg/mm2. As different polymer and non-polymer coatings will release 5-fluorouracil
at differing rates, the above dosing parameters should be utilized in combination
with the release rate of the drug from the tympanostomy tube surface such that a
minimum concentration of 10-4-10-7 M of 5-fluorouracil is maintained. It is
necessary to insure that surface drug concentrations exceed concentrations of 5-
fluorouracil known to be lethal to numerous species of bacteria and fungi (i.e., are
in excess of 10-4 M; although for some embodiments lower drug levels will be
sufficient). In a preferred embodiment, 5-fluorouracil is released from the
tympanostomy tube surface such that anti-infective activity is maintained for a
period ranging from several hours to several months. In a particularly preferred
embodiment the drug is released in effective concentrations for a period ranging
from 1 week - 6 months. It should be readily evident given the discussions
provided herein that analogues and derivatives of 5-fluorouracil (as described
previously) with similar functional activity can be utilized for the purposes of this
invention; the above dosing parameters are then adjusted according to the relative
potency of the analogue or derivative as compared to the parent compound (e.g. a
compound twice as potent as 5-fluorouracil is administered at half the above
parameters, a compound half as potent as 5-fluorouracil is administered at twice
the above parameters, etc.).
(c) Podophylotoxins Utilizing the podophylotoxin etoposide as an
example, whether applied as a polymer coating, incorporated into the polymers
which make up the tympanostomy tube, or applied without a carrier polymer, the
total dose of etoposide applied should not exceed 25 mg (range of 0.1 µg to 25
mg). In a particularly preferred embodiment, the total amount of drug applied
should be in the range of 1 µg to 5 mg. The dose per unit area (i.e. the amount of
drug as a function of the surface area of the portion of the tympanostomy tube to
which drug is applied and/or incorporated) should fall within the range of 0.01 µg -
100 µg per mm2 of surface area. In a particularly preferred embodiment, etoposide
should be applied to the tympanostomy tube surface at a dose of 0.1 µg/mm2 - 10
µg/mm2. As different polymer and non-polymer coatings will release etoposide at
differing rates, the above dosing parameters should be utilized in combination with
the release rate of the drug from the tympanostomy tube surface such that a
concentration of 105-106 M of etoposide is maintained. It is necessary to insure
that surface drug concentrations exceed concentrations of etoposide known to be
lethal to a variety of bacteria and fungi (i.e. are in excess of 10-5 M; although for
some embodiments lower drug levels will be sufficient). In a preferred
embodiment, etoposide is released from the surface of the tympanostomy tube
such that anti-infective activity is maintained for a period ranging from several
hours to several months. In a particularly preferred embodiment the drug is
released in effective concentrations for a period ranging from 1 week - 6 months.
It should be readily evident given the discussions provided herein that analogues
and derivatives of etoposide (as described previously) with similar functional
activity can be utilized for the purposes of this invention; the above dosing
parameters are then adjusted according to the relative potency of the analogue or
derivative as compared to the parent compound (e.g. a compound twice as potent
as etoposide is administered at half the above parameters, a compound half as
potent as etoposide is administered at twice the above parameters, etc.).
(d) Combination therapy. It should be readily evident based upon
the discussions provided herein that combinations of anthracyciines (e.g.,
doxorubicin or mitoxantrone), fluoropyrimidines (e.g., 5-fluorouracil), folic acid
antagonists (e.g., methotrexate) and podophylotoxins (e.g., etoposide) can be
utilized to enhance the antibacterial activity of the tympanostomy tube coating.
Similarly anthracyciines (e.g., doxorubicin or mitoxantrone), fluoropyrimidines (e.g.,
5-fluorouracil), folic acid antagonists (e.g., methotrexate) and/or podophylotoxins
(e.g., etoposide) can be combined with traditional antibiotic and/or antifungal
agents to enhance efficacy.
Sinus Stents
The sinuses are four pairs of hollow regions contained in the bones
of the skull named after the bones in which they are located (ethmoid, maxillary,
frontal and sphenoid). All are lined by respiratory mucosa which is directly
attached to the bone. Following an inflammatory insult such as an upper
respiratory tract infection or allergic rhinitis, a purulent form of sinusitis can
develop. Occasionally secretions can be retained in the sinus due to altered ciliary
function or obstruction of the opening (ostea) that drains the sinus. Incomplete
drainage makes the sinus prone to infection typically with Haemophilus influenza,
Streptococcus pneumoniae, Moraxella catarrhalis, Veillonella, Peptococcus,
Corynebacterium acnes and certain species of fungi.
When initial treatment such as antibiotics, intranasal steroid sprays
and decongestants are ineffective, it may become necessary to perform surgical
drainage of the infected sinus. Surgical therapy often involves debridement of the
ostea to remove anatomic obstructions and removal of parts of the mucosa.
Occasionally a stent (a cylindrical tube which physically holds the lumen of the
ostea open) is left in the osta to ensure drainage is maintained even in the
presence of postoperative swelling. Stents, typically made of stainless steel or
plastic, remain in place for several days or several weeks before being removed.
Unfortunately, the stents can become infected or overgrown by
granulation tissue that renders them ineffective. An effective sinus stent coating
would allow easy insertion, remain in place for as long as is required, be easily
removed in the office without anaesthesia, resist infection and prevent the
formation of granulation tissue in the stent (which can not only lead to obstruction,
but also "tack down" the stent such that surgical removal becomes necessary).
Therefore, development of a sinus stent which does not become obstructed by
granulation tissue, does not scar in place and is less prone to infection would be
beneficial.
In a preferred embodiment, doxorubicin, mitoxantrone, 5-fluorouracil
and/or etoposide are formulated into a coating applied to the surface of the sinus
stent. The drug(s) can be applied in several manners: (a) as a coating applied to
the external surface of the sinus stent; (b) as a coating applied to the internal
(luminal) surface of the sinus stent; (c) as a coating applied to all or parts of both
surfaces; and/or (d) incorporated into the polymers which comprise the sinus stent.
Drug-coating of, or drug incorporation into, the sinus stent will allow
bacteriocidal drug levels to be achieved locally on the tube surface, thus reducing
the incidence of bacterial colonization (and subsequent development of sinusitis),
while producing negligible systemic exposure to the drugs. Although for some
agents polymeric carriers are not required for attachment of the drug to the sinus
stent surface, several polymeric carriers are particularly suitable for use in this
embodiment. Of particular interest are polymeric carriers such as polyurethanes
(e.g., ChronoFlex AL 85A [CT Biomaterials], HydroMed640™ [CT Biomaterials],
HYDROSLIP C™ [CT Biomaterials], HYDROTHANE™ [CT Biomaterials]), acrylic
or methacrylic copolymers (e.g. poly(ethylene-co-acrylic acid), cellulose-derived
polymers (e.g. nitrocellulose, Cellulose Acetate Butyrate, Cellulose acetate
propionate), acrylate and methacrylate copolymers (e.g. poly(ethylene-co-vinyl
acetate)) as well as blends thereof.
As sinus stents are prone to the same complications and infections
from the same bacteria, the dosing guidelines for doxorubicin, mitoxantrone, 5-
fluorouracil and etoposide in coating sinus stents are identical to those described
above for tympanostomy tubes.
G. Infections Associated with Urological Implants
Implanted medical devices are used in the urinary tract with greater
frequency than in any other body system and have some of the highest rates of
infection. In fact, the great majority of urinary devices become infected if they
remain in place for a prolonged period of time and are the most common cause of
nosocomial infection.
Urinary (Foley) Catheters
Four-to-five million bladder catheters are inserted into hospitalized
patients every year in the United States. The duration of catheterization is the
important risk factor for patients developing a clinically significant infection - the
rate of infection increases 5-10% per day that the patient is catheterized. Although
simple cystitis can be treated with a short course of antibiotics (with or without
removal of the catheter), serious complications are frequent and can be extremely
serious. The infection can ascend to the kidneys causing acute pyelonephritis
which can result in scarring and long term kidney damage. Perhaps of greatest
concern is the 1-2% risk of developing gram negative sepsis (the risk is 3-times
higher in catheterized patients and accounts for 30% of all cases) which can be
extremely difficult to treat and can result in septic shock and death (up to 50% of
patients). Therefore, there exists a significant medical need to produce improved
urinary catheters capable of reducing the incidence of urinary tract infection in
catheterized patients.
The most common cause of infection is bacteria typically found in the
bowel or perineum that are able to track up the catheter to gain access to the
normally sterile bladder. Bacteria can be carried into the bladder as the catheter is
inserted, gain entry via the sheath of exudates that surrounds the catheter, and/or
travel intraluminally inside the catheter tubing. Several species of bacteria are
able to adhere to the catheter and form a biofilm that provides a protected site for
growth. With short-term catheterization, single organism infections are most
common and are typically due to Escherichia coli, Enterococci, Pseudomonas
aeruginosa, Klebsiella, Proteus, Enterobacter, Staphylococcus epidermidis,
Staphylococcus aureus and Staphylococcus saprophyticus. Patients who are
catheterized for long periods of time are prone to polymicrobial infections caused
by all of the organisms previously mentioned as well as Providencia stuartii,
Morganella morganii and Candida. Antibiotic use either systemically or locally has
been largely proven to be ineffective as it tends to result only in the selection of
drug-resistant bacteria.
An effective urinary catheter coating would allow easy insertion into
the bladder, resist infection and prevent the formation of biofilm in the catheter. An
effective coating would prevent or reduce the incidence of urinary tract infection,
pyelonephritis, and/ or sepsis. In a preferred embodiment, doxorubicin,
mitoxantrone, 5-fluorouracil and/or etoposide are formulated into a coating applied
to the surface of the urinary catheter. The drug(s) can be applied in several
manners: (a) as a coating applied to the external surface of the urinary catheter;
(b) as a coating applied to the internal (luminal) surface of the urinary catheter; (c)
as a coating applied to all or parts of both surfaces; and/or (d) incorporated into the
polymers which comprise the urinary catheter.
Drug-coating of, or drug incorporation into, the urinary catheter will
allow bacteriocidal drug levels to be achieved locally on the catheter surface, thus
reducing the incidence of bacterial colonization (and subsequent development of
urinary tract infection and bacteremia), while producing negligible systemic
exposure to the drugs. Although for some agents polymeric carriers are not
required for attachment of the drug to the urinary catheter surface, several
polymeric carriers are particularly suitable for use in this embodiment. Of particular
interest are polymeric carriers such as polyurethanes (e.g., ChronoFlex AL 85A
[CT Biomaterials], HydroMed640™ [CT Biomaterials], HYDROSLIP C™ [CT
Biomaterials], HYDROTHANE™ [CT Biomaterials]), acrylic or methacrylic
copolymers (e.g. poly(ethylene-co-acrylic acid), cellulose-derived polymers (e.g.
nitrocellulose, Cellulose Acetate Butyrate, Cellulose acetate propionate), acrylate
and methacrylate copolymers {e.g. poly(ethylene-co-vinyl acetate)) as well as
blends thereof.
As urinary catheters (e.g. Foley catheters, suprapubic catheters) are
made in a variety of configurations and sizes, the exact dose administered will vary
with device size, surface area and design. However, certain principles can be
applied in the application of this art. Drug dose can be calculated as a function of
dose per unit area (of the portion of the device being coated), total drug dose
administered can be measured and appropriate surface concentrations of active
drug can be determined. Regardless of the method of application of the drug to
the urinary catheter, the preferred anticancer agents, used alone or in combination,
should be administered under the following dosing guidelines:
(a) Anthracyclines. Utilizing the anthracycline doxorubicin as an
example, whether applied as a polymer coating, incorporated into the polymers
which make up the urinary catheter components, or applied without a carrier
polymer, the total dose of doxorubicin applied should not exceed 25 mg (range of
0.1 µg to 25 mg). In a particularly preferred embodiment, the total amount of drug
applied should be in the range of 1 µg to 5 mg. The dose per unit area (i.e. the
amount of drug as a function of the surface area of the portion of the urinary
catheter to which drug is applied and/or incorporated) should fall within the range
of 0.01 µg -100 µg per mm2 of surface area. In a particularly preferred
embodiment, doxorubicin should be applied to the urinary catheter surface at a
dose of 0.1 µg/mm2 - 10 µg/mm2. As different polymer and non-polymer coatings
will release doxorubicin at differing rates, the above dosing parameters should be
utilized in combination with the release rate of the drug from the urinary catheter
surface such that a minimum concentration of 107 -104 M of doxorubicin is
maintained on the surface. It is necessary to insure that surface drug
concentrations exceed concentrations of doxorubicin known to be lethal to multiple
species of bacteria and fungi (i.e., are in excess of 10-4 M; although for some
embodiments lower concentrations are sufficient). In a preferred embodiment,
doxorubicin is released from the surface of the urinary catheter such that anti-
infective activity is maintained for a period ranging from several hours to several
months. In a particularly preferred embodiment the drug is released in effective
concentrations for a period ranging from 1 hour - 1 month. It should be readily
evident given the discussions provided herein that analogues and derivatives of
doxorubicin (as described previously) with similar functional activity can be utilized
for the purposes of this invention; the above dosing parameters are then adjusted
according to the relative potency of the analogue or derivative as compared to the
parent compound (e.g. a compound twice as potent as doxorubicin is administered
at half the above parameters, a compound half as potent as doxorubicin is
administered at twice the above parameters, etc.).
Utilizing mitoxantrone as another example of an anthracycline,
whether applied as a polymer coating, incorporated into the polymers which make
up the urinary catheter, or applied without a carrier polymer, the total dose of
mitoxantrone applied should not exceed 5 mg (range of 0.01 µg to 5 mg). In a
particularly preferred embodiment, the total amount of drug applied should be in
the range of 0.1 µg to 1 mg. The dose per unit area (i.e. the amount of drug as a
function of the surface area of the portion of the urinary catheter to which drug is
applied and/or incorporated) should fall within the range of 0.01 µg - 20 µg per
mm2 of surface area. In a particularly preferred embodiment, mitoxantrone should
be applied to the urinary catheter surface at a dose of 0.05 µg/mm2..- 3 µg/mm2.
As different polymer and non-polymer coatings will release mitoxantrone at
differing rates, the above dosing parameters should be utilized in combination with
the release rate of the drug from the urinary catheter surface such that a minimum
concentration of 105 -106 M of mitoxantrone is maintained. It is necessary to
insure that drug concentrations on the surface exceed concentrations of
mitoxantrone known to be lethal to multiple species of bacteria and fungi (i.e. are in
excess of 105 M; although for some embodiments lower drug levels will be
sufficient). In a preferred embodiment, mitoxantrone is released from the urinary
catheter surface such that anti-infective activity is maintained for a period ranging
from several hours to several months. In a particularly preferred embodiment the
drug is released in effective concentrations for a period ranging from 1 hour - 1
month. It should be readily evident given the discussions provided herein that
analogues and derivatives of mitoxantrone (as described previously) with similar
functional activity can be utilized for the purposes of this invention; the above
dosing parameters are then adjusted according to the relative potency of the
analogue or derivative as compared to the parent compound (e.g. a compound
twice as potent as mitoxantrone is administered at half the above parameters, a
compound half as potent as mitoxantrone is administered at twice the above
parameters, etc.).
(b) Fluoropyrimidines Utilizing the fluoropyrimidine 5-fluorouracil as
an example, whether applied as a polymer coating, incorporated into the polymers
which make up the urinary catheter, or applied without a carrier polymer, the total
dose of 5-fluorouracil applied should not exceed 250 mg (range of 1.0 µg to 250
mg). In a particularly preferred embodiment, the total amount of drug applied
should be in the range of 10 µg to 25 mg. The dose per unit area (i.e. the amount
of drug as a function of the surface area of the portion of the urinary catheter to
which drug is applied and/or incorporated) should fall within the range of 0.1 µg - 1
mg per mm2 of surface area. In a particularly preferred embodiment, 5-fluorouracil
should be applied to the urinary catheter surface at a dose of 1.0 µg/mm2 - 50
µg/mm2. As different polymer and non-polymer coatings will release 5-fluorouracil
at differing rates, the above dosing parameters should be utilized in combination
with the release rate of the drug from the urinary catheter surface such that a
minimum concentration of 104-107 M of 5-fluorouracil is maintained. It is
necessary to insure that surface drug concentrations exceed concentrations of 5-
fluorouracil known to be lethal to numerous species of bacteria and fungi {i.e., are
in excess of 10-4 M; although for some embodiments lower drug levels will be
sufficient). In a preferred embodiment, 5-fluorouracil is released from the urinary
catheter surface such that anti-infective activity is maintained for a period ranging
from several hours to several months. In a particularly preferred embodiment the
drug is released in effective concentrations for a period ranging from 1 hour - 1
month. It should be readily evident given the discussions provided herein that
analogues and derivatives of 5-fluorouracil (as described previously) with similar
functional activity can be utilized for the purposes of this invention; the above
dosing parameters are then adjusted according to the relative potency of the
analogue or derivative as compared to the parent compound (e.g. a compound
twice as potent as 5-fluorouracil is administered at half the above parameters, a
compound half as potent as 5-fluorouracil is administered at twice the above
parameters, etc.).
(c) Podophylotoxins Utilizing the podophylotoxin etoposide as an
example, whether applied as a polymer coating, incorporated into the polymers
which make up the urinary catheter, or applied without a carrier polymer, the total
dose of etoposide applied should not exceed 25 mg (range of 0.1 µg to 25 mg). In
a particularly preferred embodiment, the total amount of drug applied should be in
the range of 1 µg to 5 mg. The dose per unit area (i.e. the amount of drug as a
function of the surface area of the portion of the urinary catheter to which drug is
applied and/or incorporated) should fall within the range of 0.01 µg - 100 µg per
mm2 of surface area. In a particularly preferred embodiment, etoposide should be
applied to the urinary catheter surface at a dose of 0.1 µg/mm2 - 10 µg/mm2. As
different polymer and non-polymer coatings will release etoposide at differing
rates, the above dosing parameters should be utilized in combination with the
release rate of the drug from the urinary catheter surface such that a concentration
of 105 -106 M of etoposide is maintained. It is necessary to insure that surface
drug concentrations exceed concentrations of etoposide known to be lethal to a
variety of bacteria and fungi (i.e. are in excess of 10-5 M; although for some
embodiments lower drug levels will be sufficient). In a preferred embodiment,
etoposide is released from the surface of the urinary catheter such that anti-
infective activity is maintained for a period ranging from several hours to several
months. In a particularly preferred embodiment the drug is released in effective
concentrations for a period ranging from 1 hour - 1 month. It should be readily
evident given the discussions provided herein that analogues and derivatives of
etoposide (as described previously) with similar functional activity can be utilized
for the purposes of this invention; the above dosing parameters are then adjusted
according to the relative potency of the analogue or derivative as compared to the
parent compound (e.g. a compound twice as potent as etoposide is administered
at half the above parameters, a compound half as potent as etoposide is
administered at twice the above parameters, etc.).
(d) Combination therapy. It should be readily evident based upon
the discussions provided herein that combinations of anthracyclines (e.g.,
doxorubicin or mitoxantrone), fluoropyrimidines (e.g., 5-fluorouracil), folic acid
antagonists (e.g., methotrexate) and podophylotoxins (e.g., etoposide) can be
utilized to enhance the antibacterial activity of the urinary catheter coating.
Similarly anthracyclines (e.g., doxorubicin or mitoxantrone), fluoropyrimidines (e.g.,
5-fluorouracil), folic acid antagonists (e.g., methotrexate) and podophylotoxins
(e.g., etoposide) can be combined with traditional antibiotic and/or antifungal
agents to enhance efficacy.
Ureteral Stents
Ureteral stents are hollow tubes with holes along the sides and coils
at either end to prevent migration. Ureteral stents are used to relieve obstructions
(caused by stones or malignancy), to facilitate the passage of stones, or to allow
healing of ureteral anastomoses or leaks following surgery or trauma. They are
placed endoscopically via the bladder or percutaneously via the kidney. A
microbial biofilm forms on up to 90% of ureteral stents and 30% develop significant
bacteruria with the incidence increasing the longer the stent is in place.
Pseudomonas aeruginosa is the most common pathogen, but Enterococci,
Staphylococcus aureus and Candida also cause infection. Effective treatment
frequently requires stent removal in addition to antibiotic therapy.
Unfortunately, ureteral stents can become infected or encrusted with
urinary salts that render them ineffective. An effective ureteral stent coating would
allow easy insertion, remain in place for as long as is required, be easily removed,
resist infection and prevent the formation of urinary salts. Therefore, development
of a ureteral stent which does not become obstructed by granulation tissue, does
not scar in place and is less prone to infection would be beneficial.
In a preferred embodiment, doxorubicin, mitoxantrone, 5-fluorouracil
and/or etoposide are formulated into a coating applied to the surface of the ureteral
stent. The drug(s) can be applied in several manners: (a) as a coating applied to
the external surface of the ureteral stent; (b) as a coating applied to the internal
(luminal) surface of the ureteral stent; (c) as a coating applied to all or parts of both
surfaces; and/or (d) incorporated into the polymers which comprise the ureteral
stent.
Drug-coating of, or drug incorporation into, the ureteral stent will
allow bacteriocidal drug levels to be achieved locally on the stent surface, thus
reducing the incidence of bacterial colonization (and subsequent development of
pyelonephritis and/or bacteremia), while producing negligible systemic exposure to
the drugs. Although for some agents polymeric carriers are not required for
attachment of the drug to the ureteral stent surface, several polymeric carriers are
particularly suitable for use in this embodiment. Of particular interest are polymeric
carriers such as polyurethanes (e.g., ChronoFlex AL 85A [CT Biomaterials],
HydroMed640™ [CT Biomaterials], HYDROSLIP C™ [CT Biomaterials],
HYDROTHANE™ [CT Biomaterials]), acrylic or methacrylic copolymers (e.g.
poly(ethylene-co-acrylic acid), cellulose-derived polymers (e.g. nitrocellulose,
Cellulose Acetate Butyrate, Cellulose acetate propionate), acrylate and
methacrylate copolymers (e.g. poly(ethylene-co-vinyl acetate)) as well as blends
thereof.
As ureteral stents are prone to the same complications and infections
from the same bacteria, the dosing guidelines for doxorubicin, mitoxantrone, 5-
fluorouracil and etoposide in coating ureteral stents are identical to those
described above for urinary catheters. However, unlike the formulations described
for urinary catheters, drug release should occur over a 2 to 24 week period.
Urethral Stents
Urethral stents are used for the treatment of recurrent urethral
strictures, detruso-external sphincter dyssynergia and bladder outlet obstruction
due to benign prostatic hypertrophy. The stents are typically self-expanding and
composed of metal superalloy, titanium, stainless steel or polyurethane. Infections
are most often due to Coagulase Negative Staphylococci, Pseudomonas
aeruginosa, Enterococci, Staphylococcus aureus, Serratia and Candida.
Treatment of infected stents frequently requires systemic antibiotic therapy and
removal of the device.
An effective urethral stent coating would allow easy insertion, remain
in place for as long as is required, be easily removed, resist infection and prevent
the formation of urinary salts. Therefore, development of a urethral stent which
does not become obstructed by granulation tissue, does not scar in place and is
less prone to infection would be beneficial.
In a preferred embodiment, doxorubicin, mitoxantrone, 5-fluorouracil
and/or etoposide are formulated into a coating applied to the surface of the urethral
stent. The drug(s) can be applied in several manners: (a) as a coating applied to
the external surface of the urethral stent; (b) as a coating applied to the internal
(luminal) surface of the urethral stent; (c) as a coating applied to all or parts of both
surfaces; and/or (d) incorporated into the polymers which comprise the urethral
stent.
Drug-coating of, or drug incorporation into, the urethral stent will
allow bacteriocidal drug levels to be achieved locally on the stent surface, thus
reducing the incidence of bacterial colonization (and subsequent development of
pyelonephritis and/or bacteremia), while producing negligible systemic exposure to
the drugs. Although for some agents polymeric carriers are not required for
attachment of the drug to the ureteral stent surface, several polymeric earners are
particularly suitable for use in this embodiment. Of particular interest are polymeric
carriers such as polyurethanes (e.g., ChronoFlex AL 85A [CT Biomaterials],
HydroMed640™ [CT Biomaterials], HYDROSLIP C™ [CT Biomaterials],
HYDROTHANE™ [CT Biomaterials]), acrylic or methacrylic copolymers (e.g.
poly(ethylene-co-acrylic acid), cellulose-derived polymers (e.g. nitrocellulose,
Cellulose Acetate Butyrate, Cellulose acetate propionate), acrylate and
methacrylate copolymers (e.g. poly(ethylene-co-vinyl acetate)) as well as blends
thereof.
As urethral stents are prone to the same complications and infections
from the same bacteria, the dosing guidelines for doxorubicin, mitoxantrone, 5-
fluorouracil and etoposide in coating ureteral stents are identical to those
described above for urinary catheters. However, unlike the formulations described
for urinary catheters, drug release should occur over a 2 to 24 week period.
Prosthetic Bladder Sphincters
Prosthetic bladder sphincters are used to treat incontinence and
generally consist of a periurethral implant. The placement of prosthetic bladder
sphincters can be complicated by infection (usually in the first 6 months after
surgery) with Coagulase Negative Staphylococci (including Staphylococcus
epidermidis), Staphylococcus aureus, Pseudomonas aeruginosa, Enterococci,
Serratia and Candida. Infection is characterized by fever, erythema, induration
and purulent drainage from the operative site. The usual route of infection is
through the incision at the time of surgery and up to 3% of prosthetic bladder
sphincters become infected despite the best sterile surgical technique. To help
combat this, intraoperative irrigation with antibiotic solutions is often employed.
Treatment of infections of prosthetic bladder sphincters requires
complete removal of the device and antibiotic therapy; replacement of the device
must often be delayed for 3-6 months after the infection has cleared. An effective
prosthetic bladder sphincter coating would resist infection and reduce the
incidence of re-intervention.
In a preferred embodiment, doxorubicin, mitoxantrone, 5-fluorouracil
and/or etoposide are formulated into a coating applied to the surface of the
prosthetic bladder sphincter. The drug(s) can be applied in several manners: (a)
as a coating applied to the external surface of the prosthetic bladder sphincter,
and/or (b) incorporated into the polymers which comprise the prosthetic bladder
sphincter.
Drug-coating of, or drug incorporation into, the prosthetic bladder
sphincter will allow bacteriocidal drug levels to be achieved locally, thus reducing
the incidence of bacterial colonization (and subsequent development of urethritis
and/or wound infection), while producing negligible systemic exposure to the
drugs. Although for some agents polymeric carriers are not required for
attachment of the drug to the prosthetic bladder sphincter surface, several
polymeric carriers are particularly suitable for use in this embodiment. Of particular
interest are polymeric carriers such as polyurethanes (e.g., ChronoFlex AL 85A
[CT Biomaterials], HydroMed640™ [CT Biomaterials], HYDROSLIP C™ [CT
Biomaterials], HYDROTHANE™ [CT Biomaterials]), acrylic or methacrylic
copolymers (e.g. poly(ethylene-co-acrylic acid), cellulose-derived polymers (e.g.
nitrocellulose, Cellulose Acetate Butyrate, Cellulose acetate propionate), acrylate
and methacrylate copolymers (e.g. poly(ethylene-co-vinyl acetate)) as well as
blends thereof.
As prosthetic bladder sphincters are prone to infections caused by
the same bacteria as occur with urinary catheters, the dosing guidelines for
doxorubicin, mitoxantrone, 5-fluorouracil and etoposide in coating prosthetic
bladder sphincters are identical to those described above for urinary catheters.
However, unlike the formulations described for urinary catheters, drug release
should occur over a 2 to 24 week period.
Penile Implants
Penile implants are used to treat erectile dysfunction and are
generally flexible rods, hinged rods or inflatable devices with a pump. The
placement of penile implants can be complicated by infection (usually in the first 6
months after surgery) with Coagulase Negative Staphylococci (including
Staphylococcus epidermidis), Staphylococcus aureus, Pseudomonas aeruginosa,
Enterococci, Serratia and Candida. The type of device or route of insertion does
not affect the incidence of infection. Infection is characterized by fever, erythema,
induration and purulent drainage from the operative site. The usual route of
infection is through the incision at the time of surgery and up to 3% of penile
implants become infected despite the best sterile surgical technique. To help
combat this, intraoperative irrigation with antibiotic solutions is often employed.
Treatment of infections of penile implants requires complete removal
of the device and antibiotic therapy; replacement of the device must often be
delayed for 3-6 months after the infection has cleared. An effective penile implant
coating would resist infection and reduce the incidence of re-intervention.
In a preferred embodiment, doxorubicin, mitoxantrone, 5-fluorouracil
and/or etoposide are formulated into a coating applied to the surface of the penile
implant. The drug(s) can be applied in several manners: (a) as a coating applied
to the external surface of the penile implant; and/or (b) incorporated into the
polymers which comprise the penile implant.
Drug-coating of, or drug incorporation into, the penile implant will
allow bacteriocidal drug levels to be achieved locally, thus reducing the incidence
of bacterial colonization (and subsequent development of local infection and
device failure), while producing negligible systemic exposure to the drugs.
Although for some agents polymeric carriers are not required for attachment of the
drug to the penile implant surface, several polymeric carriers are particularly
suitable for use in this embodiment.
As penile implants are prone to infections caused by the same
bacteria as occur with urinary catheters, the dosing guidelines for doxorubicin,
mitoxantrone, 5-fluorouracil and etoposide in coating penile implants are identical
to those described above for urinary catheters. However, unlike the formulations
described for urinary catheters, drug release should occur over a 2 to 24 week
period.
H. Infections Associated with Endotracheal and Tracheostomy Tubes
Endotracheal tubes and tracheostomy tubes are used to maintain the
airway when ventilatory assistance is required. Endotracheal tubes tend to be
used to establish an airway in the acute setting, while tracheostomy tubes are
used when prolonged ventilation is required or when there is a fixed obstruction in
the upper airway. In hospitalized patients, nosocomial pneumonia occurs 300,000
times per year and is the second most common cause of hospital-acquired
infection (after urinary tract infection) and the most common infection in ICU
patients. In the intensive care unit, nosocomial pneumonia is a frequent cause
death with fatality rates over 50%. Survivors spend on average 2 weeks longer in
hospital and the annual cost of treatment is close to $2 billion.
Bacterial pneumonia is the most common cause of excess morbidity
and mortality in patients who require intubation. In patients who are intubated
electively (i.e. for elective surgery), less than 1 % will develop a nosocomial
pneumonia. However, patients who are severely ill with ARDS (Adult Respiratory
Distress Syndrome) have a greater than 50% chance of developing a nosocomial
pneumonia. It is thought that new organisms colonize the oropharynx in intubated
patients, are swallowed to contaminate the stomach, are aspirated to inoculate the
lower airway and eventually contaminate the endotracheal tube. Bacteria adhere
to the tube, form a biolayer and multiply serving as a source for bacteria that can
aerosolize and be carried distally into the lungs. Chronic tracheostomy tubes also
frequently become colonized with pathogenic bacteria known to cause pneumonia.
The most common causes of pneumonia in ventilated patients are Staphylococcus
aureus (17%), Pseudomonas aeruginosa (18%), Klebsiella pneumoniae (9%),
Enterobacter (9%) and Haemophilus influenza (5%). Treatment requires
aggressive therapy with antibiotics.
An effective endotracheal tube or tracheostomy tube coating would
resist infection and prevent the formation of biofilm in the tube. An effective
coating would prevent or reduce the incidence of pneumonia, sepsis and death. In
a preferred embodiment, doxorubicin, mitoxantrone, 5-fluorouracil and/or
etoposide are formulated into a coating applied to the surface of the endotracheal
tube or tracheostomy tube. Due to its activity against Klebsiella pneumoniae,
methotrexate can also be useful for this embobiment. As cisplatin and
hydroxyurea have some activity against Pseudomonas aeruginosa, they can also
be of some utility in the practice of this embodiment. The drug(s) can be applied in
several manners: (a) as a coating applied to the external surface of the
endotracheal tube or tracheostomy tube; (b) as a coating applied to the internal
(luminal) surface of the endotracheal tube or tracheostomy tube; (c) as a coating
applied to all or parts of both surfaces; and/or (d) incorporated into the polymers
which comprise the endotracheal tube or tracheostomy tube.
Drug-coating of, or drug incorporation into, the endotracheal tube or
tracheostomy tube will allow bacteriocidal drug levels to be achieved locally on the
catheter surface, thus reducing the incidence of bacterial colonization (and
subsequent development of pneumonia and sepsis), while producing negligible
systemic exposure to the drugs. Although for some agents polymeric carriers are
not required for attachment of the drug to the endotracheal tube or tracheostomy
tube surface, several polymeric carriers are particularly suitable for use in this
embodiment. Of particular interest are polymeric carriers such as polyurethanes
(e.g., ChronoFlex AL 85A [CT Biomaterials], HydroMed640™ [CT Biomaterials],
HYDROSLIP C™ [CT Biomaterials], HYDROTHANE™ [CT Biomaterials]), acrylic
or methacrylic copolymers (e.g. poly(ethylene-co-acrylic acid), cellulose-derived
polymers (e.g. nitrocellulose, Cellulose Acetate Butyrate, Cellulose acetate
propionate), acrylate and methacrylate copolymers (e.g. poly(ethylene-co-vinyl
acetate)) as well as blends thereof.
As endotracheal tube and tracheostomy tubes are made in a variety
of configurations and sizes, the exact dose administered will vary with device size,
surface area and design. However, certain principles can be applied in the
application of this art. Drug dose can be calculated as a function of dose per unit
area (of the portion of the device being coated), total drug dose administered can
be measured and appropriate surface concentrations of active drug can be
determined. Regardless of the method of application of the drug to the
endotracheal tube or tracheostomy tube, the preferred anticancer agents, used
alone or in combination, should be administered under the following dosing
guidelines:
(a) Anthracyclines. Utilizing the anthracycline doxorubicin as an
example, whether applied as a polymer coating, incorporated into the polymers
which make up the endotracheal tube or tracheostomy tube components, or
applied without a carrier polymer, the total dose of doxorubicin applied should not
exceed 25 mg (range of 0.1 µg to 25 mg). In a particularly preferred embodiment,
the total amount of drug applied should be in the range of 1 µg to 5 mg. The dose
per unit area (i.e. the amount of drug as a function of the surface area of the
portion of the endotracheal tube or tracheostomy tube to which drug is applied
and/or incorporated) should fall within the range of 0.01 µg -100 µg per mm2 of
surface area. In a particularly preferred embodiment, doxorubicin should be
applied to the endotracheal tube or tracheostomy tube surface at a dose of 0.1
µg/mm2 - 10 µg/mm2. As different polymer and non-polymer coatings will release
doxorubicin at differing rates, the above dosing parameters should be utilized in
combination with the release rate of the drug from the endotracheal tube or
tracheostomy tube surface such that a minimum concentration of 107-104 M of
doxorubicin is maintained on the surface. It is necessary to insure that surface
drug concentrations exceed concentrations of doxorubicin known to be lethal to
multiple species of bacteria and fungi (i.e., are in excess of 10-4 M; although for
some embodiments lower concentrations are sufficient). In a preferred
embodiment, doxorubicin is released from the surface of the endotracheal tube or
tracheostomy tube such that anti-infective activity is maintained for a period
ranging from several hours to several months. In a particularly preferred
embodiment the drug is released in effective concentrations from the endotracheal
tube for a period ranging from 1 hour to 1 month, while release from a
tracheostomy tube would range from 1 day to 3 months. It should be readily
evident given the discussions provided herein that analogues and derivatives of
doxorubicin (as described previously) with similar functional activity can be utilized
for the purposes of this invention; the above dosing parameters are then adjusted
according to the relative potency of the analogue or derivative as compared to the
parent compound (e.g. a compound twice as potent as doxorubicin is administered
at half the above parameters, a compound half as potent as doxorubicin is
administered at twice the above parameters, etc.).
Utilizing mitoxantrone as another example of an anthracycline,
whether applied as a polymer coating, incorporated into the polymers which make
up the endotracheal tube or tracheostomy tube, or applied without a carrier
polymer, the total dose of mitoxantrone applied should not exceed 5 mg (range of
0.01 µg to 5 mg). In a particularly preferred embodiment, the total amount of drug
applied should be in the range of 0.1 µg to 1 mg. The dose per unit area (i.e. the
amount of drug as a function of the surface area of the portion of the endotracheal
tube or tracheostomy tube to which drug is applied and/or incorporated) should fall
within the range of 0.01 µg - 20 µg per mm2 of surface area. In a particularly
preferred embodiment, mitoxantrone should be applied to the endotracheal tube or
tracheostomy tube surface at a dose of 0.05 µg/mm2 - 3 µg/mm2. As different
polymer and non-polymer coatings will release mitoxantrone at differing rates, the
above dosing parameters should be utilized in combination with the release rate of
the drug from the endotracheal tube or tracheostomy tube surface such that a
minimum concentration of 105-106 M of mitoxantrone is maintained. It is
necessary to insure that drug concentrations on the surface exceed concentrations
of mitoxantrone known to be lethal to multiple species of bacteria and fungi (i.e.
are in excess of 105 M; although for some embodiments lower drug levels will be
sufficient). In a preferred embodiment, mitoxantrone is released from the
endotracheal tube or tracheostomy tube surface such that anti-infective activity is
maintained for a period ranging from several hours to several months. In a
particularly preferred embodiment, the drug is released in effective concentrations
from the endotracheal tube for a period ranging from 1 hour to 1 month, while
release from a tracheostomy tube would range from 1 day to 3 months. It should
be readily evident given the discussions provided herein that analogues and
derivatives of mitoxantrone (as described previously) with similar functional activity
can be utilized for the purposes of this invention; the above dosing parameters are
then adjusted according to the relative potency of the analogue or derivative as
compared to the parent compound (e.g. a compound twice as potent as
mitoxantrone is administered at half the above parameters, a compound half as
potent as mitoxantrone is administered at twice the above parameters, etc.).
(b) Fluoropyrimidines Utilizing the fluoropyrimidine 5-fluorouracil as
an example, whether applied as a polymer coating, incorporated into the polymers
which make up the endotracheal tube or tracheostomy tube, or applied without a
carrier polymer, the total dose of 5-fluorouracil applied should not exceed 250 mg
(range of 1.0 µg to 250 mg). In a particularly preferred embodiment, the total
amount of drug applied should be in the range of 10 µg to 25 mg. The dose per
unit area (i.e. the amount of drug as a function of the surface area of the portion of
the endotracheal tube or tracheostomy tube to which drug is applied and/or
incorporated) should fall within the range of 0.1 µg - 1 mg per mm2 of surface
area. In a particularly preferred embodiment, 5-fluorouracil should be applied to
the endotracheal tube or tracheostomy tube surface at a dose of 1.0 µg/mm2 - 50
µg/mm2. As different polymer and non-polymer coatings will release 5-fluorouracil
at differing rates, the above dosing parameters should be utilized in combination
with the release rate of the drug from the endotracheal tube or tracheostomy tube
surface such that a minimum concentration of 104 -107 M of 5-fluorouracil is
maintained. It is necessary to insure that surface drug concentrations exceed
concentrations of 5-fluorouracil known to be lethal to numerous species of bacteria
and fungi (i.e. are in excess of 10-4M; although for some embodiments lower drug
levels will be sufficient). In a preferred embodiment, 5-fluorouracil is released from
the endotracheal tube or tracheostomy tube surface such that anti-infective activity
is maintained for a period ranging from several hours to several months. In a
particularly preferred embodiment, the drug is released in effective concentrations
from the endotracheal tube for a period ranging from 1 hour to 1 month, while
release from a tracheostomy tube would range from 1 day to 3 months. It should
be readily evident given the discussions provided herein that analogues and
derivatives of 5-fluorouracil (as described previously) with similar functional activity
can be utilized for the purposes of this invention; the above dosing parameters are
then adjusted according to the relative potency of the analogue or derivative as
compared to the parent compound (e.g. a compound twice as potent as 5-
fluorouracil is administered at half the above parameters, a compound half as
potent as 5-fluorouracil is administered at twice the above parameters, etc.).
(c) Podophylotoxins Utilizing the podophylotoxin etoposide as an
example, whether applied as a polymer coating, incorporated into the polymers
which make up the endotracheal tube or tracheostomy tube, or applied without a
carrier polymer, the total dose of etoposide applied should not exceed 25 mg
(range of 0.1 µg to 25 mg). In a particularly preferred embodiment, the total
amount of drug applied should be in the range of 1 µg to 5 mg. The dose per unit
area (i.e. the amount of drug as a function of the surface area of the portion of the
endotracheal tube or tracheostomy tube to which drug is applied and/or
incorporated) should fall within the range of 0.01 µg -100 µg per mm2 of surface
area. In a particularly preferred embodiment, etoposide should be applied to the
endotracheal tube or tracheostomy tube surface at a dose of 0.1 µg/mm2 - 10
µg/mm2. As different polymer and non-polymer coatings will release etoposide at
differing rates, the above dosing parameters should be utilized in combination with
the release rate of the drug from the endotracheal tube or tracheostomy tube
surface such that a concentration of 105 -106 M of etoposide is maintained. It is
necessary to insure that surface drug concentrations exceed concentrations of
etoposide known to be lethal to a variety of bacteria and fungi (i.e. are in excess of
105 M; although for some embodiments lower drug levels will be sufficient). In a
preferred embodiment, etoposide is released from the surface of the endotracheal
tube or tracheostomy tube such that anti-infective activity is maintained for a period
ranging from several hours to several months. In a particularly preferred,
embodiment the drug is released in effective concentrations from the endotracheal
tube for a period ranging from 1 hour to 1 month, while release from a
tracheostomy tube would range from 1 day to 3 months. It should be readily
evident given the discussions provided herein that analogues and derivatives of
etoposide (as described previously) with similar functional activity can be utilized
for the purposes of this invention; the above dosing parameters are then adjusted
according to the relative potency of the analogue or derivative as compared to the
parent compound (e.g. a compound twice as potent as etoposide is administered
at half the above parameters, a compound half as potent as etoposide is
administered at twice the above parameters, etc.).
(d) Combination therapy. It should be readily evident based upon
the discussions provided herein that combinations of anthracyclines (e.g.,
doxorubicin or mitoxantrone), fluoropyrimidines (e.g., 5-fluorouracil), folic acid
antagonists (e.g., methotrexate) and podophylotoxins (e.g., etoposide) can be
utilized to enhance the antibacterial activity of the endotracheal tube or
tracheostomy tube coating. Similarly anthracyclines (e.g., doxorubicin or
mitoxantrone), fluoropyrimidines (e.g., 5-fluorouracil), folic acid antagonists (e.g.,
methotrexate) and/or podophylotoxins (e.g., etoposide) can be combined with
traditional antibiotic and/or antifungal agents to enhance efficacy.
I. Infections Associated with Dialysis Catheters
In 1997, there were over 300,000 patients in the United States with
end-stage renal disease. Of these, 63% were treated with hemodialysis, 9% with
peritoneal dialysis and 38% with renal transplantation. Hemodialysis requires
reliable access to the vascular system typically as a surgically created
arteriovenous fistula (AVF; 18%), via a synthetic bridge graft (usually a PTFE
arteriovenous interposition graft in the forearm or leg; 50%) or a central venous
catheter (32%). Peritoneal dialysis requires regular exchange of dialysate through
the peritoneum via a double-cuffed and tunnelled peritoneal dialysis catheter.
Regardless of the form of dialysis employed, infection is the second leading cause
of death in renal failure patients (15.5% of all deaths) after heart disease. A
significant number of those infections are secondary to the dialysis procedure
itself.
Hemodialysis Access Grafts
Kidney failure patients have a dysfunctional immune response that
makes them particularly susceptible to infection. Infections of hemodialysis access
grafts are characterized as either being early (within month; thought to be a
complication of surgery) and late (after 1 month; thought to be related to access
care). Over a 2 year period, approximately 2% of AVF's become infected while 11-
16% of PTFE grafts will become infected on at least one occasion. Although
infection can result from extension of an infection from an adjacent contaminated
tissue or hematogenous seeding, the most common cause of infection is
intraoperative contamination. The most common causes of infection include
Staphylococcus aureus, Enterobacteriaceae, Pseudomonas aerugenosa, and
Coagulase Negative Staphylococci.
Complications arising from hemodialysis access graft infection
include sepsis, subcutaneous infection, false aneurysm formation, endocarditis,
osteomyelitis, septic arthritis, haemorrhage, septic or thrombotic emboli, graft
thrombosis and septic dealth (2-4% of all infections). Treatment often requires
removal of part or all of the graft combined with systemic antibiotics.
In a preferred embodiment, doxorubicin, mitoxantrone, 5-fluorouracil
and/or etoposide are formulated into a coating applied to the surface of the
components of the synthetic hemodialysis access graft. The drug(s) can be
applied in several manners: (a) as a coating applied to the external surface of the
graft; (b) as a coating applied to the internal (luminal) surface of the graft; and/or
(c) as a coating applied to all or parts of both surfaces. For an AVF, the drug would
be formulated into a surgical implant placed around the outside of the fistula at the
time of surgery.
Drug-coating of, or drug incorporation into hemodialysis access grafts
will allow bacteriocidal drug levels to be achieved locally on the graft surface, thus
reducing the incidence of bacterial colonization and subsequent development of
infectious complications, while producing negligible systemic exposure to the
drugs. Although for some agents polymeric carriers are not required for
attachment of the drug, several polymeric carriers are particularly suitable for use
in this embodiment. Of particular interest are polymeric carriers such as
polyurethanes (e.g., ChronoFlex AL 85A [CT Biomaterials], HydroMed640™ [CT
Biomaterials], HYDROSLIP C™ [CT Biomaterials], HYDROTHANE™ [CT
Biomaterials]), acrylic or methacrylic copolymers (e.g. poly(ethylene-co-acrylic
acid), cellulose-derived polymers (e.g. nitrocellulose, Cellulose Acetate Butyrate,
Cellulose acetate propionate), acrylate and methacrylate copolymers (e.g.
poly(ethylene-co-vinyl acetate)), collagen, PLG as well as blends thereof.
An effective hemodialysis access graft coating would reduce the
incidence of complications such as sepsis, haemorrhage, thrombosis, embolism,
endocarditis, osteomyelitis and even death. An effective coating would also
decrease the number of hemodialysis access grafts requiring replacement,
resulting in lower mortality and morbidity for patients with these implants.
As hemodialysis access grafts are made in a variety of configurations
and sizes, the exact dose administered will vary with device size, surface area,
design and portions of the graft coated. However, certain principles can be applied
in the application of this art. Drug dose can be calculated as a function of dose per
unit area (of the portion of the device being coated), total drug dose administered
can be measured and appropriate surface concentrations of active drug can be
determined. Regardless of the method of application of the drug to the
hemodialysis access graft, the preferred anticancer agents, used alone or in
combination, should be administered under the following dosing guidelines:
(a) Anthracyclines. Utilizing the anthracycline doxorubicin as an
example, whether applied as a polymer coating, incorporated into the polymers
which make up the hemodialysis access graft components (such as Dacron or
Teflon), or applied without a carrier polymer, the total dose of doxorubicin applied
should not exceed 25 mg (range of 0.1 µg to 25 mg). In a particularly preferred
embodiment, the total amount of drug applied should be in the range of 1 µg to 5
mg. The dose per unit area (i.e. the amount of drug as a function of the surface
area of the portion of the hemodialysis access graft to which drug is applied and/or
incorporated) should fall within the range of 0.01 µg -100 µg per mm2 of surface
area. In a particularly preferred embodiment, doxorubicin should be applied to the
hemodialysis access graft surface at a dose of 0.1 µg/mm2 - 10 µg/mm2. As
different polymer and non-polymer coatings will release doxorubicin at differing
rates, the above dosing parameters should be utilized in combination with the
release rate of the drug from the hemodialysis access graft surface such that a
minimum concentration of 107-104 M of doxorubicin is maintained on the surface.
It is necessary to insure that surface drug concentrations exceed concentrations of
doxorubicin known to be lethal to multiple species of bacteria and fungi (i.e., are in
excess of 104 M; although for some embodiments lower concentrations are
sufficient). In a preferred embodiment, doxorubicin is released from the surface of
the hemodialysis access graft such that anti-infective activity is maintained for a
period ranging from several hours to several months. In a particularly preferred
embodiment the drug is released in effective concentrations for a period ranging
from 1 week - 6 months. It should be readily evident given the discussions
provided herein that analogues and derivatives of doxorubicin (as described
previously) with similar functional activity can be utilized for the purposes of this
invention; the above dosing parameters are then adjusted according to the relative
potency of the analogue or derivative as compared to the parent compound (e.g. a
compound twice as potent as doxorubicin is administered at half the above
parameters, a compound half as potent as doxorubicin is administered at twice the
above parameters, etc.).
Utilizing mitoxantrone as another example of an anthracycline,
whether applied as a polymer coating, incorporated into the polymers which make
up the hemodialysis access graft (such as Dacron or Teflon), or applied without a
carrier polymer, the total dose of mitoxantrone applied should not exceed 5 mg
(range of 0.01 µg to 5 mg). In a particularly preferred embodiment, the total
amount of drug applied should be in the range of 0.1 µg to 1 mg. The dose per unit
area (i.e. the amount of drug as a function of the surface area of the portion of the
hemodialysis access graft to which drug is applied and/or incorporated) should fall
within the range of 0.01 µg - 20 µg per mm2 of surface area. In a particularly
preferred embodiment, mitoxantrone should be applied to the hemodialysis access
graft surface at a dose of 0.05 µg/mm2 - 3 µg/mm2. As different polymer and non-
polymer coatings will release mitoxantrone at differing rates, the above dosing
parameters should be utilized in combination with the release rate of the drug from
the hemodialysis access graft surface such that a minimum concentration of 105-
106 M of mitoxantrone is maintained. It is necessary to insure that drug
concentrations on the surface exceed concentrations of mitoxantrone known to be
lethal to multiple species of bacteria and fungi (i.e. are in excess of 105M;
although for some embodiments lower drug levels will be sufficient). In a preferred
embodiment, mitoxantrone is released from the hemodialysis access graft surface
such that anti-infective activity is maintained for a period ranging from several
hours to several months. In a particularly preferred embodiment the drug is
released in effective concentrations for a period ranging from 1 week - 6 months.
It should be readily evident given the discussions provided herein that analogues
and derivatives of mitoxantrone (as described previously) with similar functional
activity can be utilized for the purposes of this invention; the above dosing
parameters are then adjusted according to the relative potency of the analogue or
derivative as compared to the parent compound (e.g. a compound twice as potent
as mitoxantrone is administered at half the above parameters, a compound half as
potent as mitoxantrone is administered at twice the above parameters, etc.).
(b) Fluoropyrimidines Utilizing the fluoropyrimidine 5-fluorouracil as
an example, whether applied as a polymer coating, incorporated into the polymers
which make up the hemodialysis access graft (such as Dacron or Teflon), or
applied without a carrier polymer, the total dose of 5-fluorouracil applied should not
exceed 250 mg (range of 1.0 µg to 250 mg). In a particularly preferred
embodiment, the total amount of drug applied should be in the range of 10 µg to 25
mg. The dose per unit area (i.e. the amount of drug as a function of the surface
area of the portion of the hemodialysis access graft to which drug is applied and/or
incorporated) should fall within the range of 0.1 µg - 1 mg per mm2 of surface
area. In a particularly preferred embodiment, 5-fluorouracii should be applied to
the hemodialysis access graft surface at a dose of 1.0 µg/mm2 - 50 µg/mm2. As
different polymer and non-polymer coatings will release 5-fluorouracil at differing
rates, the above dosing parameters should be utilized in combination with the
release rate of the drug from the hemodialysis access graft surface such that a
minimum concentration of 10-4-10-7 M of 5-fluorouracil is maintained. It is
necessary to insure that surface drug concentrations exceed concentrations of 5-
fluorouracil known to be lethal to numerous species of bacteria and fungi (i.e., are
in excess of 104 M; although for some embodiments lower drug levels will be
sufficient). In a preferred embodiment, 5-fluorouracil is released from the
hemodialysis access graft surface such that anti-infective activity is maintained for
a period ranging from several hours to several months. In a particularly preferred
embodiment the drug is released in effective concentrations for a period ranging
from 1 week - 6 months. It should be readily evident given the discussions
provided herein that analogues and derivatives of 5-fluorouracil (as described
previously) with similar functional activity can be utilized for the purposes of this
invention; the above dosing parameters are then adjusted according to the relative
potency of the analogue or derivative as compared to the parent compound (e.g. a
compound twice as potent as 5-fiuorouracil is administered at half the above
parameters, a compound half as potent as 5-fluorouracil is administered at twice
the above parameters, etc.).
(c) Podophylotoxins Utilizing the podophylotoxin etoposide as an
example, whether applied as a polymer coating, incorporated into the polymers
which make up the hemodialysis access graft (such as Dacron or Teflon), or
applied without a carrier polymer, the total dose of etoposide applied should not
exceed 25 mg (range of 0.1 µg to 25 mg). In a particularly preferred embodiment,
the total amount of drug applied should be in the range of 1 µg to 5 mg. The dose
per unit area (i.e. the amount of drug as a function of the surface area of the
portion of the hemodialysis access graft to which drug is applied and/or
incorporated) should fall within the range of 0.01 µg -100 µg per mm2 of surface
area. In a particularly preferred embodiment, etoposide should be applied to the
hemodialysis access graft surface at a dose of 0.1 µg/mm2 - 10 µg/mm2. As
different polymer and non-polymer coatings will release etoposide at differing
rates, the above dosing parameters should be utilized in combination with the
release rate of the drug from the hemodialysis access graft surface such that a
concentration of 105 -106 M of etoposide is maintained. It is necessary to insure
that surface drug concentrations exceed concentrations of etoposide known to be
lethal to a variety of bacteria and fungi (i.e. are in excess of 105 M; although for
some embodiments lower drug levels will be sufficient). In a preferred
embodiment, etoposide is released from the surface of the hemodialysis access
graft such that anti-infective activity is maintained for a period ranging from several
hours to several months. In a particularly preferred embodiment the drug is
released in effective concentrations for a period ranging from 1 week - 6 months.
It should be readily evident given the discussions provided herein that analogues
and derivatives of etoposide (as described previously) with similar functional
activity can be utilized for the purposes of this invention; the above dosing
parameters are then adjusted according to the relative potency of the analogue or
derivative as compared to the parent compound (e.g. a compound twice as potent
as etoposide is administered at half the above parameters, a compound half as
potent as etoposide is administered at twice the above parameters, etc.).
(d) Combination therapy. It should be readily evident based upon
the discussions provided herein that combinations of anthracyclines (e.g.,
doxorubicin or mitoxantrone), fluoropyrimidines (e.g., 5-fluorouracil), folic acid
antagonists (e.g., methotrexate) and podophylotoxins (e.g., etoposide) can be
utilized to enhance the antibacterial activity of the hemodialysis access graft
coating. Similarly anthracyclines (e.g., doxorubicin or mitoxantrone),
fluoropyrimidines (e.g., 5-fluorouracil), folic acid antagonists (e.g., methotrexate)
and/or podophylotoxins (e.g., etoposide) can be combined with traditional antibiotic
and/or antifungal agents to enhance efficacy. Since thrombogenicity of the
hemodialysis access graft is associated with an increased risk of infection,
anthracyclines (e.g., doxorubicin or mitoxantrone), fluoropyrimidines (e.g., 5-
fluorouracil), folic acid antagonists (e.g., methotrexate) and/or podophylotoxins
(e.g., etoposide) can be combined with antithrombotic and/or antiplatelet agents
(for example heparin, dextran sulphate, danaparoid, lepirudin, hirudin, AMP,
adenosine, 2-chloroadenosine, aspirin, phenylbutazone, indomethacin,
meclofenamate, hydrochloroquine, dipyridamole, iloprost, ticlopidine, clopidogrel,
abcixamab, eptifibatide, tirofiban, streptokinase, and/or tissue plasminogen
activator) to enhance efficacy.
Central Venous Catheters
A variety of central venous catheters are available for use in
hemodialysis including, but not restricted to, catheters which are totally implanted
such as the Lifesite (Vasca Inc., Tewksbury, Mass.) and the Dialock (Biolink Corp.,
Middleboro, Mass.). Central venous catheters are prone to infection and
embodiments for that purpose are described above.
Peritoneal Dialysis Catheters
Peritoneal dialysis catheters are typically double-cuffed and tunnelled
catheters that provide access to the peritoneum. The most common peritoneal
dialysis catheter designs are the Tenckhoff catheter, the Swan Neck Missouri
catheter and the Toronto Western catheter. In peritoneal dialysis, the peritoneum
acts as a semipermeable membrane across which solutes can be exchanged
down a concentration gradient.
Peritoneal dialysis infections are typically classified as either
peritonitis or exit-site/tunnel infections (i.e. catheter infections). Exit-site/tunnel
infections are characterized by redness, induration or purulent discharge from the
exit site or subcutaneous portions of the catheter. Peritonitis is more a severe
infection that causes abdominal pain, nausea, fever and systemic evidence of
infection. Unfortunately, the peritoneal dialysis catheter likely plays a role in both
types of infection. In exit-site/tunnel infections, the catheter itself becomes
infected. In peritonitis, the infection is frequently the result of bacteria tracking
from the skin through the catheter lumen or migrating on the outer surface
(pericatheter route) of the catheter into the peritoneum. Peritoneal catheter-related
infections are typically caused by Staphylococcus aureus, Coagulase Negative
Staphylococci, Escherichia coli, Viridans group streptococci, Enterobacteriacae,
Corynebacterium, Branhamella, Actinobacter, Serratia, Proteus, Pseudomonas
aeruginosa and Fungi.
Treatment of peritonitis involves rapid in-and-out exchanges of
dialysate, systemic antibiotics (intravenous and/or intraperitoneal administration)
and often requires removal of the catheter. Complications include hospitalization,
the need to switch to another form of dialysis (30%) and mortality (2%; higher if the
infection is due to Enterococci, S. aureus or polymicrobial).
In a preferred embodiment, doxorubicin, mitoxantrone, 5-fluorouracil
and/or etoposide are formulated into a coating applied to the surface of the
components of the synthetic peritoneal dialysis graft. The drug(s) can be applied
in several manners: (a) as a coating applied to the external surface of the graft; (b)
as a coating applied to the internal (luminal) surface of the graft; (c) as a coating
applied to the superficial cuff; (d) as a coating applied to the deep cuff; (e)
incorporated into the polymers that comprise the graft; and/or (f) as a coating
applied to a combination of these surfaces.
Drug-coating of, or drug incorporation into peritoneal dialysis grafts
will allow bacteriocidal drug levels to be achieved locally on the graft surface, thus
reducing the incidence of bacterial colonization and subsequent development of
infectious complications, while producing negligible systemic exposure to the
drugs. Although for some agents polymeric carriers are not required for
attachment of the drug, several polymeric carriers are particularly suitable for use
in this embodiment. Of particular interest are polymeric carriers such as
polyurethanes (e.g., ChronoFlex AL 85A [CT Biomaterials], HydroMed640™ [CT
Biomaterials], HYDROSLIP C™ [CT Biomaterials], HYDROTHANE™ [CT
Biomaterials]), acrylic or methacrylic copolymers (e.g. poly(ethylene-co-acrylic
acid), cellulose-derived polymers (e.g. nitrocellulose, Cellulose Acetate Butyrate,
Cellulose acetate propionate), acrylate and methacrylate copolymers (e.g.
poly(ethylene-co-vinyl acetate)) as well as blends thereof.
An effective peritoneal dialysis graft coating would reduce the
incidence of complications such as hospitalization, peritonoitis, sepsis, and even
death. An effective coating would also decrease the number of peritoneal dialysis
grafts requiring replacement, resulting in lower mortality and morbidity for patients
with these implants.
As peritoneal dialysis grafts are made in a variety of configurations
and sizes, the exact dose administered will vary with device size, surface area,
design and portions of the graft coated. However, certain principles can be applied
in the application of this art. Drug dose can be calculated as a function of dose per
unit area (of the portion of the device being coated), total drug dose administered
can be measured and appropriate surface concentrations of active drug can be
determined. Regardless of the method of application of the drug to the peritoneal
dialysis graft, the preferred anticancer agents, used alone or in combination,
should be administered under the following dosing guidelines:
(a) Anthracyclines. Utilizing the anthracycline doxorubicin as an
example, whether applied as a polymer coating, incorporated into the polymers
which make up the peritoneal dialysis graft components (such as Dacron or
Teflon), or applied without a carrier polymer, the total dose of doxorubicin applied
should not exceed 25 mg (range of 0.1 µg to 25 mg). In a particularly preferred
embodiment, the total amount of drug applied should be in the range of 1 µg to 5
mg. The dose per unit area (i.e. the amount of drug as a function of the surface
area of the portion of the peritoneal dialysis graft to which drug is applied and/or
incorporated) should fall within the range of 0.01 µg -100 µg per mm2 of surface
area. In a particularly preferred embodiment, doxorubicin should be applied to the
peritoneal dialysis graft surface at a dose of 0.1 µg/mm2 - 10 µg/mm2. As different
polymer and non-polymer coatings will release doxorubicin at differing rates, the
above dosing parameters should be utilized in combination with the release rate of
the drug from the peritoneal dialysis graft surface such that a minimum
concentration of 107 -104 M of doxorubicin is maintained on the surface. It is
necessary to insure that surface drug concentrations exceed concentrations of
doxorubicin known to be lethal to multiple species of bacteria and fungi (i.e., are in
excess of 104 M; although for some embodiments lower concentrations are
sufficient). In a preferred embodiment, doxorubicin is released from the surface of
the peritoneal dialysis graft such that anti-infective activity is maintained for a
period ranging from several hours to several months. In a particularly preferred
embodiment the drug is released in effective concentrations for a period ranging
from 1 week - 6 months. It should be readily evident given the discussions
provided herein that analogues and derivatives of doxorubicin (as described
previously) with similar functional activity can be utilized for the purposes of this
invention; the above dosing parameters are then adjusted according to the relative
potency of the analogue or derivative as compared to the parent compound (e.g. a
compound twice as potent as doxorubicin is administered at half the above
parameters, a compound half as potent as doxorubicin is administered at twice the
above parameters, etc.).
Utilizing mitoxantrone as another example of an anthracycline,
whether applied as a polymer coating, incorporated into the polymers which make
up the peritoneal dialysis graft (such as Dacron or Teflon), or applied without a
carrier polymer, the total dose of mitoxantrone applied should not exceed 5 mg
(range of 0.01 µg to 5 mg). In a particularly preferred embodiment, the total
amount of drug applied should be in the range of 0.1 µg to 1 mg. The dose per unit
area (i.e. the amount of drug as a function of the surface area of the portion of the
peritoneal dialysis graft to which drug is applied and/or incorporated) should fall
within the range of 0.01 µg - 20 µg per mm2 of surface area. In a particularly
preferred embodiment, mitoxantrone should be applied to the peritoneal dialysis
graft surface at a dose of 0.05 µg/mm2 - 3 µg/mm2. As different polymer and non-
polymer coatings will release mitoxantrone at differing rates, the above dosing
parameters should be utilized in combination with the release rate of the drug from
the peritoneal dialysis graft surface such that a minimum concentration of 105-106
M of mitoxantrone is maintained. It is necessary to insure that drug
concentrations on the surface exceed concentrations of mitoxantrone known to be
lethal to multiple species of bacteria and fungi (i.e. are in excess of 105 M;
although for some embodiments lower drug levels will be sufficient). In a preferred
embodiment, mitoxantrone is released from the peritoneal dialysis graft surface
such that anti-infective activity is maintained for a period ranging from several
hours to several months. In a particularly preferred embodiment the drug is
released in effective concentrations for a period ranging from 1 week - 6 months.
It should be readily evident given the discussions provided herein that analogues
and derivatives of mitoxantrone (as described previously) with similar functional
activity can be utilized for the purposes of this invention; the above dosing
parameters are then adjusted according to the relative potency of the analogue or
derivative as compared to the parent compound (e.g. a compound twice as potent
as mitoxantrone is administered at half the above parameters, a compound half as
potent as mitoxantrone is administered at twice the above parameters, etc.).
(b) Fluoropyrimidines Utilizing the fluoropyrimidine 5-fluorouracil as
an example, whether applied as a polymer coating, incorporated into the polymers
which make up the peritoneal dialysis graft (such as Dacron or Teflon), or applied
without a carrier polymer, the total dose of 5-fluorouracil applied should not exceed
250 mg (range of 1.0 µg to 250 mg). In a particularly preferred embodiment, the
total amount of drug applied should be in the range of 10 µg to 25 mg. The dose
per unit area (i.e. the amount of drug as a function of the surface area of the
portion of the peritoneal dialysis graft to which drug is applied and/or incorporated)
should fall within the range of 0.1 µg - 1 mg per mm2 of surface area. In a
particularly preferred embodiment, 5-fluorouracil should be applied to the
peritoneal dialysis graft surface at a dose of 1.0 µg/mm2 - 50 µg/mm2. As different
polymer and non-polymer coatings will release 5-fluorouracil at differing rates, the
above dosing parameters should be utilized in combination with the release rate of
the drug from the peritoneal dialysis graft surface such that a minimum
concentration of 104-107 M of 5-fluorouracil is maintained. It is necessary to
insure that surface drug concentrations exceed concentrations of 5-fluorouracil
known to be lethal to numerous species of bacteria and fungi (i.e., are in excess of
104 M; although for some embodiments lower drug levels will be sufficient). In a
preferred embodiment, 5-fluorouracil is released from the peritoneal dialysis graft
surface such that anti-infective activity is maintained for a period ranging from
several hours to several months. In a particularly preferred embodiment the drug
is released in effective concentrations for a period ranging from 1 week - 6
months. It should be readily evident given the discussions provided herein that
analogues and derivatives of 5-fluorouracil (as described previously) with similar
functional activity can be utilized for the purposes of this invention; the above
dosing parameters are then adjusted according to the relative potency of the
analogue or derivative as compared to the parent compound (e.g. a compound
twice as potent as 5-fluorouracil is administered at half the above parameters, a
compound half as potent as 5-fluorouracil is administered at twice the above
parameters, etc.).
(c) Podophylotoxins Utilizing the podophylotoxin etoposide as an
example, whether applied as a polymer coating, incorporated into the polymers
which make up the peritoneal dialysis graft (such as Dacron or Teflon), or applied
without a carrier polymer, the total dose of etoposide applied should not exceed 25
mg (range of 0.1 µg to 25 mg). In a particularly preferred embodiment, the total
amount of drug applied should be in the range of 1 µg to 5 mg. The dose per unit
area (i.e. the amount of drug as a function of the surface area of the portion of the
peritoneal dialysis graft to which drug is applied and/or incorporated) should fall
within the range of 0.01 µg -100 µg per mm2 of surface area. In a particularly
preferred embodiment, etoposide should be applied to the peritoneal dialysis graft
surface at a dose of 0.1 µg/mm2 - 10 µg/mm2. As different polymer and non-
polymer coatings will release etoposide at differing rates, the above dosing
parameters should be utilized in combination with the release rate of the drug from
the peritoneal dialysis graft surface such that a concentration of 105-106 M of
etoposide is maintained. It is necessary to insure that surface drug concentrations
exceed concentrations of etoposide known to be lethal to a variety of bacteria and
fungi (i.e. are in excess of 105 M; although for some embodiments lower drug
levels will be sufficient). In a preferred embodiment, etoposide is released from
the surface of the peritoneal dialysis graft such that anti-infective activity is
maintained for a period ranging from several hours to several months. In a
particularly preferred embodiment the drug is released in effective concentrations
for a period ranging from 1 week - 6 months. It should be readily evident given the
discussions provided herein that analogues and derivatives of etoposide (as
described previously) with similar functional activity can be utilized for the
purposes of this invention; the above dosing parameters are then adjusted
according to the relative potency of the analogue or derivative as compared to the
parent compound (e.g. a compound twice as potent as etoposide is administered
at half the above parameters, a compound half as potent as etoposide is
administered at twice the above parameters, etc.).
(d) Combination therapy. It should be readily evident based upon
the discussions provided herein that combinations of anthracyclines (e.g.,
doxorubicin or mitoxantrone), fluoropyrimidines (e.g., 5-fluorouracil), folic acid
antagonists (e.g., methotrexate) and podophylotoxins (e.g., etoposide) can be
utilized to enhance the antibacterial activity of the peritoneal dialysis graft coating.
Similarly anthracyclines (e.g., doxorubicin or mitoxantrone), fluoropyrimidines (e.g.,
5-fluorouracil), folic acid antagonists (e.g., methotrexate) and/or podophylotoxins
(e.g., etoposide) can be combined with traditional antibiotic and/or antifungal
agents to enhance efficacy.
J. Infections of Central Nervous System (CNS) Shunts
Hydocephalus, or accumulation of cerebrospinal fluid (CSF) in the
brain, is a frequently encountered neurosurgical condition arising from congenital
malformations, infection, hemmorrhage, or malignancy. The incompressible fluid
exerts pressure on the brain leading to brain damage or even death if untreated.
CNS shunts are conduits placed in the ventricles of the brain to divert the flow of
CSF from the brain to other body compartments and relieve the fluid pressure.
Ventricular CSF is diverted via a prosthetic shunt to a number of drainage locations
including the pleura (ventriculopleural shunt), jugular vein, vena cava (VA shunt),
gallbladder and peritoneum (VP shunt; most common).
Unfortunately, CSF shunts are relatively prone to developing
infection, although the incidence has declined from 25% twenty years ago to 10%
at present as a result of improved surgical technique. Approximately 25% of all
shunt complications are due to the development of infection of the shunt and these
can lead to significant clinical problems such as ventriculitis, ventricular
compartmentalization, meningitis, subdural empyema, nephritis (with VA shunts),
seizures, cortical mantle thinning, mental retardation or death. Most infections
present with fever, nausea, vomiting, malaise, or signs of increased intracranial
pressure such as headache or altered consciousness. The most common
organisms causing CNS shunt infections are Coagulase Negative Staphylococci
(67%; Staphylococcus epidermidis is the most frequently isolated organism),
Staphylococcus aureus (10-20%), viridans streptococci, Streptococcus pyogenes,
Enterococcus, Corynebacterium, Escherichia coli, Klebsiella, Proteus and
Pseudomonas aeruginosa. It is thought that the majority of infections are due to
inoculation of the organism during surgery, or during manipulation of the shunt in
the postoperative period. As a result, most infections present clinically in the first
few weeks following surgery.
Since many of the infections are caused by S. epidermidis, it is not
uncommon to find that the catheter becomes coated with a bacterial-produced
"slime" that protects the organism from the immune system and makes eradication
of the infection difficult. Therefore, the treatments of most infections require shunt
removal (and often placement of a temporary external ventricular shunt to relieve
hydrocephalus) in addition to systemic and/or intraventricular antibiotic therapy.
Poor therapeutic results tend to occur if the shunt is left in place during treatment.
Antibiotic therapy is complicated by the fact that many antibiotics do not cross the
blood-brain barrier effectively.
An effective CNS shunt coating would reduce the incidence of
complications such as ventriculitis, ventricular compartmentaiization, meningitis,
subdural empyema, nephritis (with VA shunts), seizures, cortical mantle thinning,
mental retardation or death. An effective coating would also decrease the number
of CNS shunts requiring replacement, resulting in lower mortality and morbidity for
patients with these implants.
In a preferred embodiment, an anthracycline (e.g., doxorubicin and
mitoxantrone), fluoropyrimidine (e.g., 5-FU), folic acid antagonist (e.g.,
methotrexate), and/or podophylotoxin (e.g., etoposide) is formulated into a coating
applied to the surface of the components of the CNS shunt. The drug(s) can be
applied in several manners: (a) as a coating applied to the external surface of the
shunt; (b) as a coating applied to the internal (luminal) surface of the shunt; and/or
(c) as a coating applied to all or parts of both surfaces.
Drug-coating of, or drug incorporation into CNS shunts will allow
bacteriocidal drug levels to be achieved locally on the shunt surface, thus reducing
the incidence of bacterial colonization and subsequent development of infectious
complications, while producing negligible systemic exposure to the drugs.
Although for some agents polymeric carriers are not required for attachment of the
drug, several polymeric carriers are particularly suitable for use in this
embodiment. Of particular interest are polymeric carriers such as polyurethanes
(e.g., ChronoFlex AL 85A [CT Biomaterials], HydroMed640™ [CT Biomaterials],
HYDROSLIP C™ [CT Biomaterials], HYDROTHANE™ [CT Biomaterials]), acrylic
or methacrylic copolymers (e.g. poly(ethylene-co-acrylic acid), cellulose-derived
polymers (e.g. nitrocellulose, Cellulose Acetate Butyrate, Cellulose acetate
propionate), acrylate and methacrylate copolymers (e.g. poly(ethylene-co-vinyl
acetate)) as well as blends thereof.
As CNS shunts are made in a variety of configurations and sizes, the
exact dose administered will vary with device size, surface area, design and
portions of the shunt coated. However, certain principles can be applied in the
application of this art. Drug dose can be calculated as a function of dose per unit
area (of the portion of the device being coated), total drug dose administered can
be measured and appropriate surface concentrations of active drug can be
determined. Regardless of the method of application of the drug to the CNS shunt,
the preferred anticancer agents, used alone or in combination, should be
administered under the following dosing guidelines:
(a) Anthracyclines. Utilizing the anthracycline doxorubicin as an
example, whether applied as a polymer coating, incorporated into the polymers
which make up the CNS shunt components (such as Dacron or Teflon), or applied
without a carrier polymer, the total dose of doxorubicin applied should not exceed
25 mg (range of 0.1 µg to 25 mg). In a particularly preferred embodiment, the total
amount of drug applied should be in the range of 1 µg to 5 mg. The dose per unit
area (i.e. the amount of drug as a function of the surface area of the portion of the
CNS shunt to which drug is applied and/or incorporated) should fall within the
range of 0.01 µg -100 µg per mm2 of surface area. In a particularly preferred
embodiment, doxorubicin should be applied to the CNS shunt surface at a dose of
0.1 µg/mm2 - 10 µg/mm2. As different polymer and non-polymer coatings will
release doxorubicin at differing rates, the above dosing parameters should be
utilized in combination with the release rate of the drug from the CNS shunt
surface such that a minimum concentration of 107-104 M of doxorubicin is
maintained on the surface. It is necessary to insure that surface drug
concentrations exceed concentrations of doxorubicin known to be lethal to multiple
species of bacteria and fungi (i.e., are in excess of 104 M; although for some
embodiments lower concentrations are sufficient). In a preferred embodiment,
doxorubicin is released from the surface of the CNS shunt such that anti-infective
activity is maintained for a period ranging from several hours to several months. In
a particularly preferred embodiment the drug is released in effective concentrations
for a period ranging from 1 -12 weeks. It should be readily evident given the
discussions provided herein that analogues and derivatives of doxorubicin (as
described previously) with similar functional activity can be utilized for the
purposes of this invention; the above dosing parameters are then adjusted
according to the relative potency of the analogue or derivative as compared to the
parent compound (e.g. a compound twice as potent as doxorubicin is administered
at half the above parameters, a compound half as potent as doxorubicin is
administered at twice the above parameters, etc.).
Utilizing mitoxantrone as another example of an anthracycline,
whether applied as a polymer coating, incorporated into the polymers which make
up the CNS shunt (such as Dacron or Teflon), or applied without a carrier polymer,
the total dose of mitoxantrone applied should not exceed 5 mg (range of 0.01 µg to
5 mg). In a particularly preferred embodiment, the total amount of drug applied
should be in the range of 0.1 µg to 1 mg. The dose per unit area (i.e. the amount of
drug as a function of the surface area of the portion of the CNS shunt to which
drug is applied and/or incorporated) should fall within the range of 0.01 µg - 20 µg
per mm2 of surface area. In a particularly preferred embodiment, mitoxantrone
should be applied to the CNS shunt surface at a dose of 0.05 µg/mm2 - 3 µg/mm2.
As different polymer and non-polymer coatings will release mitoxantrone at
differing rates, the above dosing parameters should be utilized in combination with
the release rate of the drug from the CNS shunt surface such that a minimum
concentration of 105 -106 M of mitoxantrone is maintained. It is necessary to
insure that drug concentrations on the surface exceed concentrations of
mitoxantrone known to be lethal to multiple species of bacteria and fungi (i.e. are in
excess of 105 M; although for some embodiments lower drug levels will be
sufficient). In a preferred embodiment, mitoxantrone is released from the CNS
shunt surface such that anti-infective activity is maintained for a period ranging
from several hours to several months. In a particularly preferred embodiment the
drug is released in effective concentrations for a period ranging from 1-12 weeks.
It should be readily evident based upon the discussion provided herein that
analogues and derivatives of mitoxantrone (as described previously) with similar
functional activity can be utilized for the purposes of this invention; the above
dosing parameters are then adjusted according to the relative potency of the
analogue or derivative as compared to the parent compound (e.g. a compound
twice as potent as mitoxantrone is administered at half the above parameters, a
compound half as potent as mitoxantrone is administered at twice the above
parameters, etc.).
(b) Fluoropyrimidines Utilizing the fluoropyrimidine 5-fluorouracil as
an example, whether applied as a polymer coating, incorporated into the polymers
which make up the CNS shunt (such as Dacron or Teflon), or applied without a
carrier polymer, the total dose of 5-fluorouracil applied should not exceed 250 mg
(range of 1.0 µg to 250 mg). In a particularly preferred embodiment, the total
amount of drug applied should be in the range of 10 µg to 25 mg. The dose per
unit area (i.e. the amount of drug as a function of the surface area of the portion of
the CNS shunt to which drug is applied and/or incorporated) should fall within the
range of 0.1 µg - 1 mg per mm2 of surface area. In a particularly preferred
embodiment, 5-fluorouracil should be applied to the CNS shunt surface at a dose
of 1.0 µg/mm2 - 50 µg/mm2. As different polymer and non-polymer coatings will
release 5-fluorouracil at differing rates, the above dosing parameters should be
utilized in combination with the release rate of the drug from the CNS shunt
surface such that a minimum concentration of 104-107 M of 5-fluorouracil is
maintained. It is necessary to insure that surface drug concentrations exceed
concentrations of 5-fluorouracil known to be lethal to numerous species of bacteria
and fungi (i.e., are in excess of 104 M; although for some embodiments lower drug
levels will be sufficient). In a preferred embodiment, 5-fluorouracil is released from
the CNS shunt surface such that anti-infective activity is maintained for a period
ranging from several hours to several months. In a particularly preferred
embodiment the drug is released in effective concentrations for a period ranging
from 1-12 weeks. It should be readily evident based upon the discussion provided
herein that analogues and derivatives of 5-fluorouracil (as described previously)
with similar functional activity can be utilized for the purposes of this invention; the
above dosing parameters are then adjusted according to the relative potency of
the analogue or derivative as compared to the parent compound (e.g. a compound
twice as potent as 5-fluorouracil is administered at half the above parameters, a
compound half as potent as 5-fluorouracil is administered at twice the above
parameters, etc.).
(c) Podophylotoxins Utilizing the podophylotoxin etoposide as an
example, whether applied as a polymer coating, incorporated into the polymers
which make up the CNS shunt (such as Dacron or Teflon), or applied without a
carrier polymer, the total dose of etoposide applied should not exceed 25 mg
(range of 0.1 µg to 25 mg). In a particularly preferred embodiment, the total
amount of drug applied should be in the range of 1 µg to 5 mg. The dose per unit
area (i.e. the amount of drug as a function of the surface area of the portion of the
CNS shunt to which drug is applied and/or incorporated) should fall within the
range of 0.01 µg -100 µg per mm2 of surface area. In a particularly preferred
embodiment, etoposide should be applied to the CNS shunt surface at a dose of
0.1 µg/mm2 - 10 µg/mm2. As different polymer and non-polymer coatings will
release etoposide at differing rates, the above dosing parameters should be
utilized in combination with the release rate of the drug from the CNS shunt
surface such that a concentration of 105-106 M of etoposide is maintained. It is
necessary to insure that surface drug concentrations exceed concentrations of
etoposide known to be lethal to a variety of bacteria and fungi (i.e. are in excess of
105 M; although for some embodiments lower drug levels will be sufficient). In a
preferred embodiment, etoposide is released from the surface of the CNS shunt
such that anti-infective activity is maintained for a period ranging from several
hours to several months. In a particularly preferred embodiment the drug is
released in effective concentrations for a period ranging from 1-12 weeks. It
should be readily evident based upon the discussion provided herein that
analogues and derivatives of etoposide (as described previously) with similar
functional activity can be utilized for the purposes of this invention; the above
dosing parameters are then adjusted according to the relative potency of the
analogue or derivative as compared to the parent compound (e.g. a compound
twice as potent as etoposide is administered at half the above parameters, a
compound half as potent as etoposide is administered at twice the above
parameters, etc.).
(d) Combination therapy. It should be readily evident based upon
the discussions provided herein that combinations of anthracyclines (e.g.,
doxorubicin or mitoxantrone), fluoropyrimidines (e.g., 5-fluorouracil), folic acid
antagonists (e.g., methotrexate) and podophylotoxins (e.g., etoposide) can be
utilized to enhance the antibacterial activity of the CNS shunt coating. Similarly
anthracyclines (e.g., doxorubicin or mitoxantrone), fluoropyrimidines (e.g., 5-
fluorouracil), folic acid antagonists (e.g., methotrexate) and/or podophylotoxins
(e.g., etoposide) can be combined with traditional antibiotic and/or antifungal
agents to enhance efficacy.
(g) External Ventricular Drainage (EVD) Device and Intracranial
Pressure (ICP) Monitoring Devices
EVD and ICP monitoring devices are also used in the management
of hydrocephalus. The therapeutic agents, doses, coatings and release kinetics for
the development of drug-coated EVD's and drug-coated ICP monitoring devices
are identical to those described for CNS shunts.
K. Infections of Orthopedic Implants
Implanted orthopedic devices such as prosthetic joints such as hip,
knee, elbow, shoulder, wrist, metacarpal, and metatarsal prosthetics are subject to
complications as a result of infection of the implant. Orthopedic implant infection
has a variety of sequela including pain, immobility, failure of the prosthetic itself,
loss/removal the of prosthetic, reoperation, loss of the affected limb or even death.
The cost of treating each infection exceeds the cost of the primary joint
arthroplasty itself by 3 or 4-fold (in excess of $50,0007case). Other orthopedic
implant hardware such as internal and external fixation devices, plates and screws
are also subject to such infection and infection-related complications. The present
treatment includes multiple operations to remove infected prosthetics, with its own
inherent risks, combined with antibiotic use.
The rate of orthopedic prosthetic infection is highest in the first month
post operatively then declines continuously there after. As an example, the
combined incidence of rate of prosthetic joint infection for 2 years is approximately
5.9% per 1,000 joints; the rate then drops to 2.3% per 1,000 joints from year 2 to
10. The rate of infection also varies depending on the joint. Knee prosthetics are
infected twice as frequently as hips. Shoulder prosthetic infections range from
0.5% to 3%, elbows up to 12%, wrists 1.5% to 5.0% and ankles 1.4% to 2.4%.
There are three main mechanisms of infection. The most common is
colonization of the implant (prosthetic, fixation plate, screws - any implantable
orthopedic device) at the time of implant, either directly or through airborne
contamination of the wound. The second method is spread from an adjacent focus
of infection, such as wound infection, abscess or sinus tract. The third is
hematogenous seeding during a systemic bacteremia, likely accounting for
approximately 7% of all implant infections.
Risk factors are multiple. The host may be compromised as a result
of a systemic condition, an illness, a local condition, or as a result of medications
that decrease the host defence capability. There is also a predisposition to
infections if the patient has had prior surgery, perioperative wound compilations, or
rheumatoid arthritis. Repeat surgical procedures increase the likelihood of
infection as there is a reported 8-fold elevated risk of infection as compared to the
primary prosthetic replacement procedure. The presence of a deep infection
increases the risk of prosthetic infection 6-fold. Various diseases also increase the
risk of infection. For example, rheumatoid arthritis patients have a higher risk of
infection possibly as a result of medications that compromising their
immunocompetency, while psoriatic patients have a higher rate possibly mediated
by a compromised skin barrier that allows entry of microbes.
The implant itself, and the cements that secure it in place, can cause
a local immunocompromised condition that is poorly understood. Different implant
materials have their own inherent rate of infection. For example, a metal-to-metal
hinged prosthetic knee has 20-times the risk of infection of a metal-to-plastic knee.
An implanted device is most susceptible to infection early on. Rabbit
models have shown that only a few Staphylococcus aureus inoculated at the time
of implant are required to cause an infection, but bacteremic (hematogenous)
seeding at 3 weeks postoperatively is substantially more difficult and requires
significantly more bacteria. This emphasizes the importance of an antimicrobial
strategy initiated early at the time of implantation.
Sixty five percent of all prosthetic joint infections are caused by gram
positive cocci, (Staphylococcus aureus, Coagulase Negative Staphylococci, Beta-
Hemolytic Streptococcus, Viridans Group Streptococci) and enterococci. Often
multiple strains of staphylococcus can be present in a single prosthetic infection.
Other organisms include aerobic gram negative bacilli, Enterobacteriacea,
Pseudomonas aeruginosa and Anaerobes (such as Peptostreptococcus and
Bacteroides species). Polymicrobial infections account for 12% of infections.
The diagnosis of an infected implant is difficult due to the highly
variable presentation; fever, general malaise, swelling, erythema, joint pain,
loosening of the implant, or even acute septicemia. Fulminate presentations are
typically caused by more virulent organisms such as Stapylococcus arureus and
pyogneic beta-hemolytic streptococci. Chronic indolent courses are more typical of
coagulase-negative staphylococci.
Management of an infected orthopedic implant usually requires
prolonged use of antibiotics and surgery to remove the infected device. Surgery
requires debridement of the infected tissue, soft tissue, bone, cement, and removal
of the infected implant. After a period of prolonged antibiotic use (weeks, months
and sometimes a year to ensure microbial eradication), it is possible to implant a
replacement prosthesis. Some authors advocate the use of antibiotic impregnated
cement, but cite concerns regarding the risk of developing antibiotic resistance;
especially methecillin resistance. If bone loss is extensive, an arthrodesis is often
performed and amputation is necessary in some cases. Even when an infection is
eradicated, the patient can be left severely compromised physically, have
significant pain and carry a high risk of re-infection.
It is therefore extremely clinically important to develop orthopedic
implants capable of resisting or reducing the rate of infection. An effective
orthopedic implant coating would reduce the incidence of joint and hardware
infection; lower the incidence of prosthetic failure, sepsis, amputation and even
death; and also decrease the number of orthopedic implants requiring
replacement, resulting in lower morbidity for patients with these implants.
In a preferred embodiment, doxorubicin, mitoxantrone, 5-fluorouracil
and/or etoposide are formulated into a coating applied to the surface of the
components of the orthopedic implant. The drug(s) can be applied in several
manners: (a) as a coating applied to the external intraosseous surface of the
prosthesis; (b) as a coating applied to the external (articular) surface of the
prosthesis; (c) as a coating applied to all or parts of both surfaces; (d) as a coating
applied to the surface of the orthopedic hardware (plates, screws, etc); (e)
incorporated into the polymers which comprise the prosthetic joints (e.g. articular
surfaces and other surface coatings) and hardware (e.g. polylactic acid screws and
plates); and/or (f) incorporated into the components of the cements used to secure
the orthopedic implants in place.
Drug-coating of, or drug incorporation into orthopedic implant will
allow bacteriocidal drug levels to be achieved locally on the implant surface, thus
reducing the incidence of bacterial colonization and subsequent development of
infectious complications, while producing negligible systemic exposure to the
drugs. Although for some agents polymeric carriers are not required for
attachment of the drug, several polymeric carriers are particularly suitable for use
in this embodiment. Of particular interest are polymeric carriers such as
polyurethanes (e.g., ChronoFlex AL 85A [CT Biomaterials], HydroMed640IM [CT
Biomaterials], HYDROSLIP C™ [CT Biomaterials], HYDROTHANE™ [CT
Biomaterials]), acrylic or methacrylic copolymers (e.g. poly(ethylene-co-acrylic
acid), cellulose-derived polymers (e.g. nitrocellulose, Cellulose Acetate Butyrate,
Cellulose acetate propionate), acrylate and methacrylate copolymers (e.g.
poly(ethylene-co-vinyl acetate)) as well as blends thereof.
The drugs of interest can also be incorporated into calcium
phosphate or hydroxyapatite coatings on the medical devices.
As orthopedic implants are made in a variety of configurations and
sizes, the exact dose administered will vary with implant size, surface area, design
and portions of the implant coated. However, certain principles can be applied in
the application of this art. Drug dose can be calculated as a function of dose per
unit area (of the portion of the implant being coated), total drug dose administered
can be measured and appropriate surface concentrations of active drug can be
determined. Regardless of the method of application of the drug to the orthopedic
implant, the preferred anticancer agents, used alone or in combination, should be
administered under the following dosing guidelines:
(a) Anthracyclines. Utilizing the anthracycline doxorubicin as an
example, whether applied as a polymer coating, incorporated into the polymers
which make up the orthopedic implant components, or applied without a carrier
polymer, the total dose of doxorubicin applied should not exceed 25 mg (range of
0.1 µg to 25 mg). In a particularly preferred embodiment, the total amount of drug
applied should be in the range of 1 µg to 5 mg. The dose per unit area (i.e. the
amount of drug as a function of the surface area of the portion of the orthopedic
implant to which drug is applied and/or incorporated) should fall within the range of
0.01 µg -100 µg per mm2 of surface area. In a particularly preferred embodiment,
doxorubicin should be applied to the orthopedic implant surface at a dose of 0.1
µg/mm2 - 10 µg/mm2. As different polymer and non-polymer coatings will release
doxorubicin at differing rates, the above dosing parameters should be utilized in
combination with the release rate of the drug from the orthopedic implant surface
such that a minimum concentration of 107-104 M of doxorubicin is maintained on
the surface. It is necessary to insure that surface drug concentrations exceed
concentrations of doxorubicin known to be lethal to multiple species of bacteria
and fungi (i.e., are in excess of 10-4 M; although for some embodiments lower
concentrations are sufficient). In a preferred embodiment, doxorubicin is released
from the surface of the orthopedic implant such that anti-infective activity is
maintained for a period ranging from several hours to several months. As
described previously, the risk of infectious contamination of the implant is greatest
over the first 3 days. Therefore, in a particularly preferred embodiment, the
majority (or all) of the drug is released over the first 72 hours to prevent infection
while allowing normal healing to occur thereafter. It should be readily evident
based upon the discussion provided herein that analogues and derivatives of
doxorubicin (as described previously) with similar functional activity can be utilized
for the purposes of this invention; the above dosing parameters are then adjusted
according to the relative potency of the analogue or derivative as compared to the
parent compound (e.g., a compound twice as potent as doxorubicin is
administered at half the above parameters, a compound half as potent as
doxorubicin is administered at twice the above parameters, etc.).
Utilizing mitoxantrone as another example of an anthracycline,
whether applied as a polymer coating, incorporated into the polymers which make
up the orthopedic implant, or applied without a carrier polymer, the total dose of
mitoxantrone applied should not exceed 5 mg (range of 0.01 µg to 5 mg). In a
particularly preferred embodiment, the total amount of drug applied should be in
the range of 0.1 µg to 1 mg. The dose per unit area (i.e. the amount of drug as a
function of the surface area of the portion of the orthopedic implant to which drug is
applied and/or incorporated) should fall within the range of 0.01 µg - 20 µg per
mm2 of surface area. In a particularly preferred embodiment, mitoxantrone should
be applied to the orthopedic implant surface at a dose of 0.05 µg/mm2 - 3 µg/mm2.
As different polymer and non-polymer coatings will release mitoxantrone at
differing rates, the above dosing parameters should be utilized in combination with
the release rate of the drug from the orthopedic implant surface such that a
minimum concentration of 105 -106 M of mitoxantrone is maintained. It is
necessary to insure that drug concentrations on the surface exceed concentrations
of mitoxantrone known to be lethal to multiple species of bacteria and fungi (i.e.
are in excess of 105 M; although for some embodiments lower drug levels will be
sufficient). In a preferred embodiment, mitoxantrone is released from the
orthopedic implant surface such that anti-infective activity is maintained for a
period ranging from several hours to several months. As described previously, the
risk of infectious contamination of the implant is greatest over the first 3 days.
Therefore, in one embodiment, the majority (or all) of the drug is released over the
first 72 hours to prevent infection while allowing normal healing to occur thereafter.
It should be readily evident based upon the discussion provided herein that
analogues and derivatives of mitoxantrone (as described previously) with similar
functional activity can be utilized for the purposes of this invention; the above
dosing parameters are then adjusted according to the relative potency of the
analogue or derivative as compared to the parent compound (e.g. a compound
twice as potent as mitoxantrone is administered at half the above parameters, a
compound half as potent as mitoxantrone is administered at twice the above
parameters, etc.).
(b) Fluoropyrimidines Utilizing the fluoropyrimidine 5-fluorouracil as
an example, whether applied as a polymer coating, incorporated into the polymers
which make up the orthopedic implant, or applied without a carrier polymer, the
total dose of 5-fluorouracil applied should not exceed 250 mg (range of 1.0 µg to
250 mg). In a particularly preferred embodiment, the total amount of drug applied
should be in the range of 10 µg to 25 mg. The dose per unit area (i.e. the amount
of drug as a function of the surface area of the portion of the orthopedic implant to
which drug is applied and/or incorporated) should fall within the range of 0.1 µg - 1
mg per mm2 of surface area. In a particularly preferred embodiment, 5-fluorouracil
should be applied to the orthopedic implant surface at a dose of 1.0 µg/mm2 - 50
µg/mm2. As different polymer and non-polymer coatings will release 5-fluorouracil
at differing rates, the above dosing parameters should be utilized in combination
with the release rate of the drug from the orthopedic implant surface such that a
minimum concentration of 10-4 -10-7 M of 5-fluorouracil is maintained. It is
necessary to insure that surface drug concentrations exceed concentrations of 5-
fluorouracil known to be lethal to numerous species of bacteria and fungi (i.e., are
in excess of 10-4 M; although for some embodiments lower drug levels will be
sufficient). In a preferred embodiment, 5-fluorouracil is released from the
orthopedic implant surface such that anti-infective activity is maintained for a
period ranging from several hours to several months. As described previously, the
risk of infectious contamination of the implant is greatest over the first 3 days.
Therefore, in a particularly preferred embodiment, the majority (or all) of the drug is
released over the first 72 hours to prevent infection while allowing normal healing
to occur thereafter. It should be readily evident based upon the discussion
provided herein that analogues and derivatives of 5-fluorouracil (as described
previously) with similar functional activity can be utilized for the purposes of this
invention; the above dosing parameters are then adjusted according to the relative
potency of the analogue or derivative as compared to the parent compound (e.g. a
compound twice as potent as 5-fluorouracil is administered at half the above
parameters, a compound half as potent as 5-fluorouracil is administered at twice
the above parameters, etc.).
(c) Podophylotoxins Utilizing the podophylotoxin etoposide as an
example, whether applied as a polymer coating, incorporated into the polymers
which make up the orthopedic implant, or applied without a carrier polymer, the
total dose of etoposide applied should not exceed 25 mg (range of 0.1 µg to 25
mg). In a particularly preferred embodiment, the total amount of drug applied
should be in the range of 1 µg to 5 mg. The dose per unit area (i.e. the amount of
drug as a function of the surface area of the portion of the orthopedic implant to
which drug is applied and/or incorporated) should fall within the range of 0.01 µg -
100 µg per mm2 of surface area. In a particularly preferred embodiment, etoposide
should be applied to the orthopedic implant surface at a dose of 0.1 µg/mm2 - 10
µg/mm2. As different polymer and non-polymer coatings will release etoposide at
differing rates, the above dosing parameters should be utilized in combination with
the release rate of the drug from the orthopedic implant surface such that a
concentration of 10-5 -10-6 M of etoposide is maintained. It is necessary to insure
that surface drug concentrations exceed concentrations of etoposide known to be
lethal to a variety of bacteria and fungi (i.e. are in excess of 10-5 M; although for
some embodiments lower drug levels will be sufficient). In a preferred
embodiment, etoposide is released from the surface of the orthopedic implant such
that anti-infective activity is maintained for a period ranging from several hours to
several months. As described previously, the risk of infectious contamination of the
implant is greatest over the first 3 days. Therefore, in a particularly preferred
embodiment, the majority (or all) of the drug is released over the first 72 hours to
prevent infection while allowing normal healing to occur thereafter. It should be
readily evident based upon the discussion provided herein that analogues and
derivatives of etoposide (as described previously) with similar functional activity
can be utilized for the purposes of this invention; the above dosing parameters are
then adjusted according to the relative potency of the analogue or derivative as
compared to the parent compound (e.g. a compound twice as potent as etoposide
is administered at half the above parameters, a compound half as potent as
etoposide is administered at twice the above parameters, etc.).
(d) Combination therapy. It should be readily evident based upon
the discussions provided herein that combinations of anthracyclines (e.g.,
doxorubicin or mitoxantrone), fluoropyrimidines (e.g., 5-fluorouracil), folic acid
antagonists (e.g., methotrexate) and podophylotoxins (e.g., etoposide) can be
utilized to enhance the antibacterial activity of the orthopedic implant coating.
Similarly anthracyclines (e.g., doxorubicin or mitoxantrone), fluoropyrimidines (e.g.,
5-fluorouracil), folic acid antagonists (e.g., methotrexate) and/or podophylotoxins
(e.g., etoposide) can be combined with traditional antibiotic and/or antifungal
agents to enhance efficacy.
L. Infections Associated with Other Medical Devices and Implants
Implants are commonly used in the practice of medicine and surgery
for a wide variety of purposes. These include implants such as drainage tubes,
biliary T-tubes, clips, sutures, meshes, barriers (for the prevention of adhesions),
anastomotic devices, conduits, irrigation fluids, packing agents, stents, staples,
inferior vena cava filters, embolization agents, pumps (for the delivery of
therapeutics), hemostatic implants (sponges), tissue fillers, cosmetic implants
(breast implants, facial implants, prostheses), bone grafts, skin grafts, intrauterine
devices (IUD), ligatures, titanium implants (particularly in dentistry), chest tubes,
nasogastric tubes, percutaneous feeding tubes, colostomy devices, bone wax, and
Penrose drains, hair plugs, ear rings, nose rings, and other piercing-associated
implants, as well as anaesthetic solutions to name a few. Any foreign body when
placed into the body is at risk for developing an infection - particularly in the period
immediately following implantation.
The drug-coating, dosing, surface concentrations and release
kinetics of these implants is identical to the embodiment described above for
orthopedic implants. In addition, doxorubicin, mitoxantrone, 5-fluorouracil and/or
etoposide can be added to solutions used in medicine (storage solutions, irrigation
fluids, saline, mannitol, glucose solutions, lipids, nutritional fluids, and anaesthetic
solutions) to prevent infection transmitted via infected solutions/fluids used in
patient management.
M. Infections Associated with Ocular Implants
The principle infections of medical device implants in the eye are
endophthalmitis associated with intraocular lens implantation for cataract surgery
and corneal infections secondary to contact lens use.
Infections of Intraocular Lenses
The number of intraocular lenses implanted in the United States has
grown exponentially over the last decade. Currently, over 1 million intraocular
lenses are implanted annually, with the vast majority (90%) being placed in the
posterior chamber of the eye. Endophthalmitis is the most common infectious
complication of intraocular lens placement and occurs in approximately 0.3% of
surgeries (3,000 cases per year). The vast majority are due to surgical
contamination and have an onset within 48 hours of the procedure.
The most common causes of endophthalmitis are Coagulase
Negative Staphylococci (principally Staphylococcus epidermidis), Staphylococcus
aureus, Enterococci, and Proteus mirabilis. Symptoms of the condition include
blurred vision, ocular pain, headache, photophobia, and corneal edema. The
treatment of endophthalmitis associated with cataract surgery includes vitrectomy
and treatment with systemic and/or intravitreal antibiotic therapy. Although most
cases do not require removal of the lens, in complicated cases, visual acuity can
be permanently affected and/or the lens must be removed and replaced at a later
date. An effective intraocular lens coating would reduce the incidence of
endophthalmitis and also decrease the number of intraocular lens requiring
replacement, resulting in lower morbidity for patients with these implants.
In a preferred embodiment, doxorubicin, mitoxantrone, 5-fluorouracil
and/or etoposide are formulated into a coating applied to the surface of the
components of the intraocular lens. The drug(s) can be applied in several
manners: (a) as a coating applied to the external surface of the lens; (b) as a
coating applied to the internal (luminal) surface of the lens; (c) as a coating applied
to all or parts of both surfaces of the lens; and/or (d) incorporated into the polymers
which comprise the lens.
Drug-coating of, or drug incorporation into intraocular lenses will
allow bacteriocidal drug levels to be achieved locally on the lens surface, thus
reducing the incidence of bacterial colonization and subsequent development of
infectious complications, while producing negligible systemic exposure to the
drugs. Although for some agents polymeric carriers are noi required for
attachment of the drug, several polymeric carriers are particularly suitable for use
in this embodiment. Of particular interest are polymeric carriers such as
polyurethanes (e.g., ChronoFlex AL 85A [CT Biomaterials], HydroMed640™ [CT
Biomaterials], HYDROSLIP C™ [CT Biomaterials], HYDROTHANE™ [CT
Biomaterials]), acrylic or methacrylic copolymers (e.g. poly(ethylene-co-acrylic
acid), cellulose-derived polymers (e.g. nitrocellulose, Cellulose Acetate Butyrate,
Cellulose acetate propionate), acrylate and methacrylate copolymers (e.g.
poly(ethylene-co-vinyl acetate)) as well as blends thereof.
As intraocular lenses are made in a variety of configurations and
sizes, the exact dose administered will vary with lens size, surface area, design
and portions of the lens coated. However, certain principles can be applied in the
application of this art. Drug dose can be calculated as a function of dose per unit
area (of the portion of the lens being coated), total drug dose administered can be
measured and appropriate surface concentrations of active drug can be
determined. Regardless of the method of application of the drug to the intraocular
lens, the preferred anticancer agents, used alone or in combination, should be
administered under the following dosing guidelines:
(a) Anthracyclines. Utilizing the anthracycline doxorubicin as an
example, whether applied as a polymer coating, incorporated into the polymers
which make up the intraocular lens components, or applied without a carrier
polymer, the total dose of doxorubicin applied should not exceed 25 mg (range of
0.1 µg to 25 mg). In a particularly preferred embodiment, the total amount of drug
applied should be in the range of 1 µg to 5 mg. The dose per unit area (i.e. the
amount of drug as a function of the surface area of the portion of the intraocular
lens to which drug is applied and/or incorporated) should fall within the range of
0.01 µg -100 µg per mm2 of surface area. In a particularly preferred embodiment,
doxorubicin should be applied to the intraocular lens surface at a dose of 0.1
µg/mm2 - 10 fig/mm2. As different polymer and non-polymer coatings will release
doxorubicin at differing rates, the above dosing parameters should be utilized in
combination with the release rate of the drug from the intraocular lens surface such
that a minimum concentration of 10-7-10-4 M of doxorubicin is maintained on the
surface. It is necessary to insure that surface drug concentrations exceed
concentrations of doxorubicin known to be lethal to multiple species of bacteria
and fungi (i.e., are in excess of 10-4 M; although for some embodiments lower
concentrations are sufficient). In a preferred embodiment, doxorubicin is released
from the surface of the intraocular lens such that anti-infective activity is
maintained for a period ranging from several hours to several months. In a
particularly preferred embodiment the drug is released in effective concentrations
for a period ranging from 1-12 weeks. It should be readily evident based upon the
discussion provided herein that analogues and derivatives of doxorubicin (as
described previously) with similar functional activity can be utilized for the
purposes of this invention; the above dosing parameters are then adjusted
according to the relative potency of the analogue or derivative as compared to the
parent compound (e.g. a compound twice as potent as doxorubicin is administered
at half the above parameters, a compound half as potent as doxorubicin is
administered at twice the above parameters, etc.).
Utilizing mitoxantrone as another example of an anthracycline,
whether applied as a polymer coating, incorporated into the polymers which make
up the intraocular lens, or applied without a carrier polymer, the total dose of
mitoxantrone applied should not exceed 5 mg (range of 0.01 µg to 5 mg). In a
particularly preferred embodiment, the total amount of drug applied should be in
the range of 0.1 µg to 1 mg. The dose per unit area (i.e. the amount of drug as a
function of the surface area of the portion of the intraocular lens to which drug is
applied and/or incorporated) should fall within the range of 0.01 µg - 20 µg per
mm2 of surface area. In a particularly preferred embodiment, mitoxantrone should
be applied to the intraocular lens surface at a dose of 0.05 µg/mm2 - 3 µg/mm2.
As different polymer and non-polymer coatings will release mitoxantrone at
differing rates, the above dosing parameters should be utilized in combination with
the release rate of the drug from the intraocular lens surface such that a minimum
concentration of 10-5-10-6 M of mitoxantrone is maintained. It is necessary to
insure that drug concentrations on the surface exceed concentrations of
mitoxantrone known to be lethal to multiple species of bacteria and fungi (i.e. are in
excess of 10-5 M; although for some embodiments lower drug levels will be
sufficient). In a preferred embodiment, mitoxantrone is released from the
intraocular lens surface such that anti-infective activity is maintained for a period
ranging from several hours to several months. In a particularly preferred
embodiment the drug is released in effective concentrations for a period ranging
from 1-12 weeks. It should be readily evident based upon the discussion
provided herein that analogues and derivatives of mitoxantrone (as described
previously) with similar functional activity can be utilized for the purposes of this
invention; the above dosing parameters are then adjusted according to the relative
potency of the analogue or derivative as compared to the parent compound (e.g. a
compound twice as potent as mitoxantrone is administered at half the above
parameters, a compound half as potent as mitoxantrone is administered at twice
the above parameters, etc.).
(b) Fluoropyrimidines Utilizing the fluoroDyrimidine 5-fluorouracil as
an example, whether applied as a polymer coating, incorporated into the polymers
which make up the intraocular lens, or applied without a carrier polymer, the total
dose of 5-fluorouracil applied should not exceed 250 mg (range of 1.0 µg to 250
mg). In a particularly preferred embodiment, the total amount of drug applied
should be in the range of 10 µg to 25 mg. The dose per unit area (i.e. the amount
of drug as a function of the surface area of the portion of the intraocular lens to
which drug is applied and/or incorporated) should fall within the range of 0.1 µg - 1
mg per mm2 of surface area. In a particularly preferred embodiment, 5-fluorouracil
should be applied to the intraocular lens surface at a dose of 1.0 µg/mm2 - 50
µg/mm2. As different polymer and non-polymer coatings will release 5-fluorouracil
at differing rates, the above dosing parameters should be utilized in combination
with the release rate of the drug from the intraocular lens surface such that a
minimum concentration of 10-4-10-7 M of 5-fluorouracil is maintained. It is
necessary to insure that surface drug concentrations exceed concentrations of 5-
fluorouracil known to be lethal to numerous species of bacteria and fungi (i.e., are
in excess of 10-4 M; although for some embodiments lower drug levels will be
sufficient). In a preferred embodiment, 5-fluorouracil is released from the
intraocular lens surface such that anti-infective activity is maintained for a period
ranging from several hours to several months. In a particularly preferred
embodiment the drug is released in effective concentrations for a period ranging
from 1-12 weeks. It should be readily evident based upon the discussion provided
herein that analogues and derivatives of 5-fluorouracil (as described previously)
with similar functional activity can be utilized for the purposes of this invention; the
above dosing parameters are then adjusted according to the relative potency of
the analogue or derivative as compared to the parent compound (e.g. a compound
twice as potent as 5-fluorouracil is administered at half the above parameters, a
compound half as potent as 5-fluorouracil is administered at twice the above
parameters, etc.).
(c) Podophylotoxins Utilizing the podophylotoxin etoposide as an
example, whether applied as a polymer coating, incorporated into the polymers
which make up the intraocular lens, or applied without a carrier polymer, the total
dose of etoposide applied should not exceed 25 mg (range of 0.1 µg to 25 mg). In
a particularly preferred embodiment, the total amount of drug applied should be in
the range of 1 µg to 5 mg. The dose per unit area {i.e. the amount of drug as a
function of the surface area of the portion of the intraocular lens to which drug is
applied and/or incorporated) should fall within the range of 0.01 µg -100 µg per
mm2 of surface area. In a particularly preferred embodiment, etoposide should be
applied to the intraocular lens surface at a dose of 0.1 µg/mm2 - 10 µg/mm2. As
different polymer and non-polymer coatings will release etoposide at differing
rates, the above dosing parameters should be utilized in combination with the
release rate of the drug from the intraocular lens surface such that a concentration
of 105 -106 M of etoposide is maintained. It is necessary to insure that surface
drug concentrations exceed concentrations of etoposide known to be lethal to a
variety of bacteria and fungi (i.e. are in excess of 10-5 M; although for some
embodiments lower drug levels will be sufficient). In a preferred embodiment,
etoposide is released from the surface of the intraocular lens such that anti-
infective activity is maintained for a period ranging from several hours to several
months. In a particularly preferred embodiment the drug is released in effective
concentrations for a period ranging from 1-12 weeks. It should be readily evident
based upon the discussion provided herein that analogues and derivatives of
etoposide (as described previously) with similar functional activity can be utilized
for the purposes of this invention; the above dosing parameters are then adjusted
according to the relative potency of the analogue or derivative as compared to the
parent compound (e.g. a compound twice as potent as etoposide is administered
at half the above parameters, a compound half as potent as etoposide is
administered at twice the above parameters, etc.).
(d) Combination therapy. It should be readily evident based upon
the discussions provided herein that combinations of anthracyclines (e.g.,
doxorubicin or mitoxantrone), fluoropyrimidines (e.g., 5-fluorouracil), folic acid
antagonists (e.g., methotrexate) and podophylotoxins (e.g., etoposide) can be
utilized to enhance the antibacterial activity of the intraocular lens coating.
Similarly anthracyclines (e.g., doxorubicin or mitoxantrone), fluoropyrimidines (e.g.,
5-fluorouracil), folic acid antagonists (e.g., methotrexate) and/or podophylotoxins
(e.g., etoposide) can be combined with traditional antibiotic and/or antifungal
agents to enhance efficacy.
Corneal Infections Secondary to Contact Lens Use
Contact lenses are primarily used for the correction of refractive
errors, but are also used after cataract surgery (Aphakie lenses) and "bandage"
lenses are used following corneal trauma. Over 24 million people wear contact
lenses and many of them will suffer from ulcerative keratitis resulting from contact
lens-associated infection. These infections are typically bacterial in nature, are
secondary to corneal damage/defects, and are caused primarily by Gram Positive
Cocci and Pseudomonas aeruginosa.
The drug-coating of contact lenses is identical to the embodiment
described above for intraocular lenses. In addition, doxorubicin, mitoxantrone, 5-
fluorouracil and/or etoposide can be added to contact lens storage solution to
prevent infection transmitted via infected cleaning/storage solutions.
It should be readily evident to one of skill in the art that any of the
previously mentioned agents, or derivatives and analogues thereof, can be utilized
to create variation of the above compositions without deviating from the spirit and
scope of the invention.
EXAMPLES
EXAMPLE 1
MIC Determination by Microtitre Broth Dilution Method
A. MIC assay of various gram negative and positive bacteria
MIC assays were conducted essentially as described by Amsterdam,
D. 1996. Susceptibility testing of antimicrobials in liquid media, p.52-111. In Loman,
V., ed. Antibiotics in laboratory medicine, 4th ed. Williams and Wilkins, Baltimore,
MD. Briefly, a variety of compounds were tested for antibacterial activity against
isolates of P. aeruginosa, K. pneumoniae, E. coli, S. epidermidus and S. aureus in
the MIC (minimum inhibitory concentration assay under aerobic conditions using
96 well polystyrene microtitre plates (Falcon 1177), and Mueller Hinton broth at
37°C incubated for 24h. (MHB was used for most testing except C721 (S.
pyogenes), which used Todd Hewitt broth, and Haemophilus influenzae, which
used Haemophilus test medium (HTM)) Tests were conducted in triplicate. The
results are provided below in Table 1.
B. MIC of antibiotic-resistant bacteria
Various concentrations of the following compounds, mitoxantrone,
cisplatin, tubercidin, methotrexate, 5-fluorouracil, etoposide, 2-mercaptopurine,
doxorubicin, 6-mercaptopurine, camptothecin, hydroxyurea and cytarabine were
tested for antibacterial activity against clinical isolates of a methicillin resistant S.
aureus and a vancomycin resistant pediocoocus clinical isolate in an MIC assay as
described above. Compounds which showed inhibition of growth (MIC value of
resistant pediococcus), 5-fluorouracil (both strains), etoposide (both strains), and
2-mercaptopurine (vancomycin resistant pediococcus).
EXAMPLE 2
Catheter - Dip coating - Non-degradable polymer
A coating solution is prepared by dissolving 20 g ChronoFlex Al 85A
(CT Biomaterials) in 100 mL DMAC:THF (40:60) at 50°C with stirring. Once
dissolved, the polymer solution is cooled to room temperature. 20 mg
mitoxantrone is added to 2 mL of the polyurethane solution. The solution is stirred
until a homogenious mixture is obtained. Polyurethane 7 French tubing is dipped
into the polymer/drug solution and then withdrawn. The coated tube is air dried
(80°C). The sample is then dried under vacuum to further reduce the residual
solvent in the coating.
EXAMPLE 3
Catheter - Dip coating - Degradable polymer
A coating solution is prepared by dissolving 2 g PLG (50:50) in 10 mL
dichloromethane:methanol (70:30). Once dissolved, 20mg mitoxantrone is added
to the polymer solution. Once the solution is a homogeneous solution,
polyurethane 7 French tubing is dipped into the solution and then withdrawn. The
coated tube is air dried. The sample is then dried under vacuum to further reduce
the residual solvent in the coating.
EXAMPLE 4
Catheter - Dip coating - Drug only
1 mL methanol is added to 20 mg mitoxantrone. Polyurethane 7
French tubing is dipped into the solution and then withdrawn. The coated tube is
air dried. The sample is then dried under vacuum to further reduce the residual
solvent in the coating.
EXAMPLE 5
Catheter - Dip Coating - Drug Impregnation
0.6 mL methanol is added to 20 mg mitoxantrone. 1.4 mL DMAC is
added slowly. Polyurethane 7 French tubing is dipped into the solution. After
various periods of time (2 min, 5 min, 10 min, 20 min, 30 min) the tube was
withdrawn. The coated tube is air dried (80 °C). The sample is then dried under
vacuum to further reduce the residual solvent in the coating.
EXAMPLE 6
Tympanostomy Tubes - Dip Coating - Non-degradable polymer
A coating solution is prepared by dissolving 20 g ChronoFlex Al 85A
(CT Biomaterials) in 100 mL DMAC:THF (50:50) at 50 °C with stirring. Once
dissolved, the polymer solution is cooled to room temperature. 20 mg mitoxantrone
is added to 2 mL of the polyurethane solution. The solution is stirred until a
homogenious mixture is obtained. A stainless steel tympanostomy tube is dipped
into the polymer/drug solution and then withdrawn. The coated tube is air dried
(80 °C). The sample is then dried under vacuum to further reduce the residual
solvent in the coating.
EXAMPLE 7
Catheter- Dip coating - Non-degradable polymer
A coating solution is prepared by dissolving 20 g ChronoFlex Al 85A
(CT Biomaterials) in 100 mL THF at 50 °C with stirring. Once dissolved, the
polymer solution is cooled to room temperature. 20 mg etoposide is added to 2 mL
of the polyurethane solution. The solution is stirred until a homogenious mixture is
obtained. Polyurethane 7 French tubing is dipped into the polymer/drug solution
and then withdrawn. The coated tube is air dried (80 C). The sample is then dried
under vacuum to further reduce the residual solvent in the coating.
EXAMPLE 8
Catheter - Dip coating - Degradable polymer
A coating solution is prepared by dissolving 2 g PLG (50:50) in 10 mL
dichloromethane:methanol (70:30). Once dissolved, 20mg etoposide is added to
the polymer solution. Once the solution is a homogeneous solution, polyurethane
7 French tubing is dipped into the solution and then withdrawn. The coated tube is
air dried. The sample is then dried under vacuum to further reduce the residual
solvent in the coating.
EXAMPLE 9
Catheter - Dip coating - Drug only
1 mL THF is added to 20 mg etoposide. Polyurethane 7 French
tubing is dipped into the solution and then withdrawn. The coated tube is air dried.
The sample is then dried under vacuum to further reduce the residual solvent in
the coating.
EXAMPLE 10
Catheter - Dip Coating - Drug Impregnation
0.6 mL methanol is added to 1.4 mL DMAC which contains 20 mg
etoposide. Polyurethane 7 French tubing is dipped into the solution. After various
periods of time (2 min, 5 min, 10 min, 20 min, 30 min) the tube was withdrawn.
The coated tube is air dried (80 °C). The sample is then dried under vacuum to
further reduce the residual solvent in the coating.
EXAMPLE 11
Tympanostomy Tubes - Dip Coating - Non-degradable polymer
A coating solution is prepared by dissolving 20 g ChronoFlex Al 85A
(CT Biomaterials) in 100 mL DMAC:THF (50:50) at 50°C with stirring. Once
dissolved, the polymer solution is cooled to room temperature. 20 mg etoposide is
added to 2 mL of the polyurethane solution. The solution is stirred until a
homogenious mixture is obtained. A stainless steel tympanostomy tube is dipped
into the polymer/drug solution and then withdrawn. The coated tube is air dried
(80°C). The sample is then dried under vacuum to further reduce the residual
solvent in the coating.
EXAMPLE 12
Covalent attachment of doxorubicin to a polymer coated device
A piece of polyurethane 7 French tubing, with and without an oxygen
plasma pretreatment step, is dipped into a solution of 5% (w/w) poly(ethylene-co
acrylic acid) in THF. The sample was dried at 45 °C for 3 hours. The coated tubing
was then dipped into a water:methanol (30:70) solution that contained 1-(3-
dimethylaminopropyl)-3-ethylcarbodiimide (EDC) and 20 mg/mL Doxorubicin. After
various times (15 min, 30 min, 60 min 120 min) the tubing is removed from the
solution and dried at 60 °C for 2 hours followed by vacuum drying for 24 hours.
EXAMPLE 13
COVALENT ATTACHMENT OF DOXORUBICIN TO A DEVICE SURFACE
A piece of polyurethane 7 French tubing that has undergone a
oxygen plasma pretreatment step is dipped into a water:methanol (30:70) solution
that contained 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDC) and 20
mg/mL Doxorubicin. After various times (15 min, 30 min, 60 min 120 min) the
tubing is removed from the solution and dried at 60 °C for 2 hours followed by
vacuum drying for 24 hours.
EXAMPLE 14
Impregnation of 5-Fluorouracil into Polyurethane Catheter
A solution was prepared by dissolving 100 mg of 5-Fluorouracil into
20 ml anhydrous methanol. Polyurethane catheter tubing was immersed in this
solution for 16 hours. The catheter tubing was vacuum dried at 50°C for 16 hours.
EXAMPLE 15
Impregnation of Mitoxantrone into Polyurethane Catheter
A solution was prepared by dissolving 20 mg of Mitoxantrone-2HCI
into 20 ml anhydrous methanol. Polyurethane catheter tubing was immersed in
this solution for 16 hours. The catheter tubing was vacuum dried at 50°C for 16
hours.
EXAMPLE 16
Impregnation of Doxorubicin into Polyurethane Catheter
A solution was prepared by dissolving 20 mg of Doxorubicin-HCI into
20 ml anhydrous methanol. Polyurethane catheter tubing was immersed in this
solution for 16 hours. The catheter tubing was vacuum dried at 50°C for 16 hours.
EXAMPLE 17
Polyurethane Dip Coating with 5-Fluorouracil
A solution was prepared by dissolving 125 mg 5-Fluorouracil and 2.5
g of Chronoflex AL85A (CT Biomaterials) in 50 ml of THF at 55°C. The solution
was cooled to room temperature. Polyurethane catheters were weighted at one
end and dipped in solution and then removed immediately. This process was
repeated three times with 1 minute drying time interval between each dipping
process. The catheter tubing was vacuum dried at 50°C for 16 hours.
EXAMPLE 18
Polyurethane Dip Coating with 5-Fluorouracil and Palmitic Acid
A solution was prepared by dissolving 125 mg 5-Fluorouracil, 62.5
mg of palmitic acid, and 2.437 g of Chronoflex AL85A (CT Biomaterials) in 50 ml of
THF at 55°C. The solution was cooled to room temperature. Polyurethane
catheters were weighted at one end and dipped in solution and then removed
immediately. This process was repeated three times with a 1 minute drying time
interval between each dipping process. The catheter tubing was vacuum dried at
50°C for 16 hours.
EXAMPLE 19
Catheter Dip Coating with Nafion and Mitoxantrone
Catheters are weighted at one end and dipped into 5% Nafion
solution (Dupont) and then removed immediately. This process was repeated
three times with a 1 minute drying time interval between each dipping process.
The catheter tubing was dried at room temperature for 2 hours. A solution was
prepared with 1 mg of mitoxantrone-2HCI in 40 ml of deionized water. The
catheter tubing was immersed in the solution for 5 minutes, and then was washed
with deionized water and dried at room temperature.
EXAMPLE 20
Catheter Dip Coating with Nafion and Doxorubicin
Catheters are weighted at one end and dipped into 5% Nafion
solution (Dupont) and then removed immediately. This process was repeated
three times with a 1 minute drying time interval between each dipping process.
The catheter tubing was dried at room temperature for 2 hours. A solution was
prepared with 1 mg of doxorubicin-HCI in 40 ml of deionized water. The catheter
tubing was immersed in the solution for 5 minutes, and then was washed with
deionized water and dried at room temperature.
EXAMPLE 21
Preparation of Release Buffer
The release buffer was prepared by adding 8.22 g sodium
chloride, 0.32 g sodium phosphate monobasic (monohydrate) and 2.60 g
sodium phosphate dibasic (anhydrous) to a beaker. 1L HPLC grade water
was added and the solution was stirred until all the salts were dissolved. If
required, the pH of the solution was adjusted to pH 7.4 ± 0.2 using either
0.1N NaOH or 0.1 N phosphoric acid.
EXAMPLE 22
Release study to determine release profile of the therapeutic
agent from a catheter
A sample of the therapeutic agent-loaded catheter was placed
in a 15 mL culture tube. 15 mL release buffer (Example 21) was added to
the culture tube. The tube was sealed with a Teflon lined screw cap and
was placed on a rotating wheel in a 37 °C oven. At various time point, the
buffer is withdrawn from the culture tube and is replaced with fresh buffer.
The withdrawn buffer is then analysed for the amount of therapeutic agent
contained in this buffer solution.
EXAMPLE 23
HPLC ANALYSIS OF THERAPEUTIC AGENTS IN RELEASE BUFFER
The following chromatographic conditions were used to quantify the
amount of the therapeutic agent in the release medium:
EXAMPLE 24
Effect of Palmitic acid on the Release profile of 5-fluorouracil
from a polyurethane film
A 25%(w/v) Chronoflex AL 85A (CT Biomaterials) solution was
prepared in THF. 50 mg 5-fluorouracil was weighed into each of 4 glass scintillation
vials. Various amount of palmitic acid were added to each vial. 20 mL of the
polyurethane solution was added to each scintillation vial. The samples were
rotated at 37°C until the solids had all dissolved. Samples were then cast as films
using a casting knife on a piece of release liner. Samples were air dried and then
dried overnight under vacuum. A portion of these samples were used to perform
release studies (Example 22). Figure 1 show the effect of palmitic acid on the
release profile of 5-fluorouracil.
EXAMPLE 25
Radial Diffusion Assay for Testing Drug Impregnated Catheters
Against Various Strains of Bacteria
An overnight bacterial culture was diluted 1 to 5 to a final volume of 5
mis fresh Mueller Hinton broth. Then 100 µl of the diluted bacterial culture were
spread onto Mueller Hinton agar plates. A test material (e.g., catheter tubing), with
or without drug, was placed on the center of the plate. For example, catheters are
typically 1 cm long and about 3 mm in diameter (which may be made of
polyurethane, silicon or other suitable material) and are loaded with drug either
through dip-coating or through use of a drug-impregnated coating. The plates
were incubated at 37°C for 16-18 hours. The zone of clearing around a test
material was then measured (e.g., the distance from the catheter to where
bacterial growth is inhibited), which indicated the degree of bacterial growth
prevention. Various bacterial strains that may be tested include, but are not limited
to, the following: E.coli C498 UB1005, P. aeruginosa H187, S. aureus C622
ATCC 25923, and S. epidermidis C621.
One cm polyurethane catheters coated with 5-fluorouracil at several
concentrations (2.5 mg/mL and 5.0 mg/mL) were examined for their effect against
S. aureus. The zone of inhibition around the catheters coated in a solution of
2.5 mg/mL 5-Fluorouracil and placed on Mueller Hinton agar plates as described
above was 35x39 mm, and for the catheters coated in a solution of 5.0 mg/mL
5-Fluorouracil was 30x37 mm. Catheters without drug showed no zone of
inhibition. These results demonstrate the efficacy of 5-fluorouracil coated on a
catheter at inhibiting the growth of S. aureus.
From the foregoing, it will be appreciated that, although specific
embodiments of the invention have been described herein for purposes of
illustration, various modifications may be made without deviating from the spirit
and scope of the invention. Accordingly, the invention is not limited except as by
the appended claims.
WE CLAIM:
1. A medical implant which comprises a fluoropyrimidine or a
composition that comprises a fluoropyridimine, wherein the fluoropyrimidine is in
an amount effective to reduce or inhibit infection associated with the medical
implant.
2. The medical implant as claimed in claim 1, wherein said
implant is covered or coated in whole or in part with the composition comprising
the fluoropyrimidine.
3. The medical implant as claimed in claim 1 or claim 2,
wherein the fluoropyrimidine is 5-fluorouracil.
4. The medical implant as claimed in any one of claims 1 to 3,
wherein the implant comprises 1.0 µg to 250 mg fluoropyrimidine.
5. The medical implant as claimed in any one of claims 1 to 3,
wherein the implant comprises 10 µg to 25 mg fluoropyrimidine.
6. The medical implant as claimed in any one of claims 1 to 3,
wherein the implant comprises 0.1 µg to 1 mg fluoropyrimidine per mm2 of
surface area of the portion of the medical implant to which the fluoropyrimidine is
applied or incorporated.
7. The medical implant as claimed in any one of claims 1 to 3,
wherein the implant comprises 1 µg to 50 µg fluoropyrimidine per mm2 of surface
area of the portion of the medical implant to which the fluoropyrimidine is applied
or incorporated.
8. The medical implant as claimed in any one of claims 1 to 7,
wherein the fluoropyrimidine is present in an amount effective to reduce or inhibit
bacterial infection associated with the medical implant.
9. The medical implant as claimed in claim 8, wherein the
bacterial infection is antibiotic resistant.
10. The medical implant as claimed in any one of claims 1 to 7,
wherein the fluoropyrimidine is present in an amount effective to reduce or inhibit
bacterial colonization of the medical implant.
11. The medical implant as claimed in any one of claims 1 to 7,
wherein the fluoropyrimidine is present in an amount effective to reduce or inhibit
fungal growth on the medical implant.
12. The medical implant as claimed in any one of claims 1 to 11,
wherein the medical implant releases the fluoropyrimidine in concentrations
effective to reduce or inhibit infection associated with the medical implant for a
period ranging from 1-30 days.
13. The medical implant as claimed in any one of claims 1 to 12,
wherein the composition further comprises one or more polymers such as herein
described.
14. The medical implant as claimed in claim 13, wherein said
composition comprises a non-biodegradable polymer.
15. The medical implant as claimed in claim 14, wherein the
non-biodegradable polymer is selected from polyurethanes, acrylic or methacrylic
copolymers, cellulose or cellulose-derived polymers, and blends thereof.
16. The medical implant as claimed in claim 15, wherein the
polyurethane is a polycarbonate urethane), poly(ester urethane) or poly(ether
urethane).
17. The medical implant as claimed in claim 15, wherein the
cellulose-derived cellulose is selected from nitrocellulose, cellulose acetate
butyrate, and cellulose acetate propionate.
18. The medical implant as claimed in claim 15, wherein the
non-biodegradable polymer comprises polyurethane and nitrocellulose.
19. The medial implant as claimed in any one of claims 1 to 18,
wherein the medical implant is a catheter.
20. The medical implant as claimed in claim 19, wherein the
catheter is a vascular access catheter.
21. The medical implant as claimed in claim 19, wherein the
catheter is a central venous catheter.
22. The medical implant as claimed in claim 19, wherein the
catheter is a peripheral venous catheter.
23. The medical implant as claimed in claim 19, wherein the
catheter is a vascular infusion catheter.
24. The medical implant as claimed in claim 19, wherein the
catheter is a hemodialysis catheter.
25. The medical implant as claimed in claim 19, wherein the
catheter is a peritoneal dialysis catheter.
26. The medical implant as claimed in claim 19, wherein the
catheter is a chronic dwelling gastrointestinal catheter, chronic dwelling
genitourinary catheter, or urinary catheter.
27. The medical implant as claimed in any one of claims 1 to 18,
wherein the medical implant is an arterial line.
28. The medical implant as claimed in any one of claims 1 to 18,
wherein the medical implant is selected from endotracheal tubes, tracheostomy
tubes, feeding tubes, central nervous shunts, portosystemic shunts, shunts for
ascites, tympanostomy tubes, drainage tubes, biliary tubes, conduits, nasogastric
tubes, and percutaneous feeding tubes.
29. The medical implant as claimed in any one of claims 1 to 18,
wherein the medical implant is a pump, a venous port, a chronic infusion port, a
vascular graft, a cardiac pacemaker, or an implantable cardioverter defibrillator.
30. The medical implant as claimed in any one of claims 1 to 18,
wherein the medical implant is a thread or suture, an orthopedic implant, a
urological implant, a prosthetic heart valve, an ocular implant, an ear, nose, or
throat implant, a cardiac pacemaker lead, a neurological or neurosurgical device,
a gastrointestinal device, a genitourinary device, an ophthalmological implant, a
plastic surgery implant, or a catheter cuff.
31. The medical implant as claimed in claim 19, wherein the
catheter is composed of polyurethane.
32. The medical implant as claimed in claim 28, wherein the
medical implant is composed of polyurethane.
33. The medical implant as claimed in any one of claims 1 to 32,
wherein the medical implant further comprises a second anti-infective agent.
34. The medical implant as claimed in claim 33, wherein the
second anti-infective agent is an antibiotic.
35. The medical implant as claimed in claim 33, wherein the
second anti-infective agent is an antifungal agent.
36. The medical implant as claimed in any one of claims 1 to 32,
wherein the medical implant optionally comprise an antithrombotic agent or an
antiplatelet agent.
37. The medical implant as claimed in claim 36, wherein the
antithrombotic agent or the antiplatelet agent is selected from heparin, dextran
sulphate, danaparoid, lepirudin, hirudin, AMP, adenosine, 2-chloroadenosine,
aspirin, phenylbutazone, indomethacin, meclofenamate, hydrochloroquine,
dipyridamole, iloprost, ticlopidine, clopidogrel, abcixamab, eptifibatide, tirofiban,
streptokinase, and/or tissue plasminogen activator.
38. The medical implant as claimed in claim 1, wherein the
implant is composed of polyurethane and coated with a composition comprising
polyurethane, nitrocellulose and 5-fluorouracil in an amount of 0.1 ug to 1 mg per
mm2 of surface area of the portion of the catheter to which 5-fluorouracil is
applied or incorporated, wherein the medical implant releases 5-fluorouracil in an
amount effective to reduce or inhibit infection associated with the medical
implant.
39. The medical implant as claimed in claim 38, wherein the
medical implant is a catheter.
40. The medical implant as claimed in claim 39, wherein the
catheter is a vascular access catheter.
41. The medical implant as claimed in claim 39, wherein the
catheter is a central venous catheter.
42. The medical implant as claimed in claim 39, wherein the
catheter is a peripheral venous catheter.
43. The medical implant as claimed in claim 39, wherein the
catheter is a vascular infusion catheter.
44. The medical implant as claimed in claim 39, wherein the
catheter is a hemodialysis catheter.
45. The medical implant as claimed in claim 39, wherein the
catheter is a peritoneal dialysis catheter.
46. The medical implant as claimed in claim 39, wherein the
catheter is a chronic dwelling gastrointestinal catheter, chronic dwelling
genitourinary catheter, or urinary catheter.
47. The medical implant as claimed in claim 38, wherein the
medical implant is an arterial line.
48. The medical implant as claimed in claim 38, wherein the
medical implant is selected from endotracheal tubes, tracheostomy tubes,
feeding tubes, central nervous shunts, portosystemic shunts, shunts for ascites,
tympanostomy tubes, drainage tubes, biliary tubes, conduits, nasogastric tubes,
and percutaneous feeding tubes.
49. The medical device as claimed in any one of claims 39-44
and 47, wherein the medical implant comprises an intravascular portion, and
wherein the coating is on the exterior surface of the intravascular portion.
50. A method for making a medical implant of any one of claims
1 to 49, comprising covering, coating, combining, loading, associating, spraying
or impregnating a medical implant with a fluoropyrimidine or a composition that
comprises a fluoropyrimidine such that the medical implant comprises the
fluoropyrimidine in an amount effective to reduce or inhibit infection associated
with the medical implant.
51. The method as claimed in claim 50 wherein said medical
implant is coated by dipping, spraying, or impregnation.
52. A composition, comprising one or more polymers such as
herein described and a fluoropyrimidine, wherein the composition is in the form of
a coating on a medical implant, and wherein the coated medical implant releases
the fluoropyrimidine in an amount effective in reducing or inhibiting bacterial
infection in a radial diffusion assay.
53. The composition as claimed in claim 52 wherein the one or
more polymers comprise a non-biodegradable polymer.
54. The composition as claimed in claim 52 wherein the one or
more polymers comprise a polyurethane.
55. The composition as claimed in claim 54 wherein the
polyurethane is a polycarbonate urethane), poly(ester urethane) or poly(ether
urethane).
56. The composition as claimed in claim 52 wherein the one or
more polymers comprise cellulose or a cellulose-derived polymer.
57. The composition as claimed in claim 56 wherein the
cellulose or cellulose-derived polymer is nitrocellulose, cellulose acetate butyrate,
or cellulose acetate propionate.
58. The composition as claimed in claim 52 wherein the one or
more polymer comprise a polyurethane, acrylic or methacrylic copolymer,
cellulose or a cellulose-derived polymer, or a blend thereof.
59. The composition as claimed in claim 52 wherein the one or
more polymers comprise polyurethane and nitrocellulose.
60. The composition as claimed in any one of claims 52 to 59
wherein said fluoropyrimidine is 5-fluorouracil.
61. The composition as claimed in any one of claims 52 to 60
wherein the medical implant is a catheter.
62. The composition as claimed in claim 61, wherein the
catheter is a vascular access catheter.
63. The composition as claimed in claim 61, wherein the
catheter is a central venous catheter.
64. The composition as claimed in claim 61, wherein the
catheter is a peripheral venous catheter.
65. The composition as claimed in claim 61, wherein the
catheter is a vascular infusion catheter.
66. The composition as claimed in claim 61, wherein the
catheter is a hemodialysis catheter.
67. The composition as claimed in claim 61, wherein the
catheter is a peritoneal dialysis catheter.
68. The composition as claimed in claim 61, wherein the
catheter is a chronic dwelling gastrointestinal catheter, chronic dwelling
genitourinary catheter, or urinary catheter.
69. The composition as claimed in any one of claims 52 to 60,
wherein the medical implant is an arterial line.
70. The composition as claimed in any one of claims 52 to 60,
wherein the medical implant is selected from endotracheal tubes, tracheostomy
tubes, feeding tubes, central nervous shunts, portosystemic shunts, shunts for
ascites, tympanostomy tubes, drainage tubes, biliary tubes, conduits, nasogastric
tubes, and percutaneous feeding tubes.
71. The composition as claimed in any one of claims 52 to 60,
wherein the medical implant is a pump, a venous port, a chronic infusion port, a
vascular graft, a cardiac pacemaker, or an implantable cardioverter defibrillator.
72. The composition as claimed in any one of claims 52 to 60,
wherein the medical implant is a thread or suture, an orthopedic implant, a
urological implant, a prosthetic heart valve, an ocular implant, an ear, nose, or
throat implant, a cardiac pacemaker lead, a neurological or neurosurgical device,
a gastrointestinal device, a genitourinary device, an ophthalmological implant, a
plastic surgery implant, or a catheter cuff.
73. A composition comprising a polyurethane, cellulose or a
cellulose-derived polymer, and a fluoropyrimidine.
74. The composition as claimed in claim 73, wherein the
polyurethane is a polycarbonate urethane), poly(ester urethane) or poly(ether
urethane).
75. The composition as claimed in claim 73 or claim 74, wherein
the cellulose or cellulose-derived polymer is nitrocellulose, cellulose acetate
butyrate, or cellulose acetate propionate.
76. The composition as claimed in any one of claims 73 to 75,
wherein the fluoropyrimidine is 5-fluorouracil.
77. The composition as claimed in claim 73, comprising
polyurethane, nitrocellulose and 5-fluorouracil.

The invention discloses a medical implant which comprises a fluoropyrimidine or a
composition that comprises a fluoropyridimine, wherein the fluoropyrimidine is in an amount
effective to reduce or inhibit infection associated with the medical implant.
The invention further discloses the making of said medical implant and composition for the
same.

Documents:

1731-kolnp-2004-abstract.pdf

1731-kolnp-2004-assignment.pdf

1731-kolnp-2004-claims.pdf

1731-kolnp-2004-correspondence.pdf

1731-kolnp-2004-description (complete).pdf

1731-kolnp-2004-examination report.pdf

1731-kolnp-2004-form 1.pdf

1731-kolnp-2004-form 13.pdf

1731-kolnp-2004-form 18.pdf

1731-KOLNP-2004-FORM 27.pdf

1731-kolnp-2004-form 3.pdf

1731-kolnp-2004-form 5.pdf

1731-kolnp-2004-gpa.pdf

1731-kolnp-2004-granted-abstract.pdf

1731-kolnp-2004-granted-assignment.pdf

1731-kolnp-2004-granted-claims.pdf

1731-kolnp-2004-granted-correspondence.pdf

1731-kolnp-2004-granted-description (complete).pdf

1731-kolnp-2004-granted-drawings.pdf

1731-kolnp-2004-granted-examination report.pdf

1731-kolnp-2004-granted-form 1.pdf

1731-kolnp-2004-granted-form 13.pdf

1731-kolnp-2004-granted-form 18.pdf

1731-kolnp-2004-granted-form 3.pdf

1731-kolnp-2004-granted-form 5.pdf

1731-kolnp-2004-granted-gpa.pdf

1731-kolnp-2004-granted-reply to examination report.pdf

1731-kolnp-2004-granted-specification.pdf

1731-kolnp-2004-reply to examination report.pdf

1731-kolnp-2004-specification.pdf


Patent Number 235907
Indian Patent Application Number 1731/KOLNP/2004
PG Journal Number 36/2009
Publication Date 04-Sep-2009
Grant Date 03-Sep-2009
Date of Filing 16-Nov-2004
Name of Patentee ANGIOTECH INTERNATIONAL AG
Applicant Address BUNDESPLATZ 1, 6304 ZUG
Inventors:
# Inventor's Name Inventor's Address
1 HUNTER WILLIAM L 4444 WEST 15TH AVENUE, VANCOUVER, BRITISH COLUMBIA V6R 3B2
2 TOLEIKIS PHILIP M 8011 LABURNUM STREET, VANCOUVER, BRITISH COLUMBIA V6P 5N8
3 LOSS TROY A.E. #3-1536 EASTERN AVENUE, NORTH VANCOUVER, BRITISH COLUMBIA V7L 3GI
4 LIGGINS RICHARD T 407 LAKEVIEW STREET, COQUITLAM, BRITISH COLUMBIA V3K 5K7
5 GRAVETT DAVID M 616 WEST 21ST AVENUE, VANCOUVER, BRITISH COLUMBIA V5Z 1Y8
6 HUNTER WILLIAM L 4444 WEST 15TH AVENUE, VANCOUVER, BRITISH COLUMBIA V6R 3B2
7 LIGGINS RICHARD T 407 LAKEVIEW STREET, COQUITLAM, BRITISH COLUMBIA V3K 5K7
8 TOLEIKIS PHILIP M 8011 LABURNUM STREET, VANCOUVER, BRITISH COLUMBIA V6P 5N8
9 LOSS TROY A.E. #3-1536 EASTERN AVENUE, NORTH VANCOUVER, BRITISH COLUMBIA V7L 3GI
10 GRAVETT DAVID M 616 WEST 21ST AVENUE, VANCOUVER, BRITISH COLUMBIA V5Z 1Y8
PCT International Classification Number A61L 27/34
PCT International Application Number PCT/US2003/16719
PCT International Filing date 2003-05-27
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 60/383,419 2002-05-24 U.S.A.