|Title of Invention||
METHOD FOR MAKING DRY POWDER BLEND PHARMACEUTICAL FORMULATIONS
|Abstract||Methods are provided for making a dry powder blend pharmaceutical formulation comprising (i) forming microparticles which comprise a pharmaceutical agent: (ii) providing at least one excipient in the form of particles having a volume average diameter that is greater than the volume average diameter of the microparticles: (iii) blending the microparticles with the excipient to form a powder blend: and (iv) jet milling the powder blend to deagglomerate at least a portion of any of the microparticles which have agglomerated, while substantially maintaining the size and morphology of the individual microparticles. Jet milling advantageously can eliminate the need for more complicated wet deagglomeration processes, can lower residual moisture and solvent levels in the microparticles (which leads to better stability and handling properties for dry powder formulations) and can improve wettability, suspendability, and content uniformity of dry powder blend formulations.|
|Full Text||METHOD FOR MAKING DRY POWDER BLEND
Background of the Invention
This invention is in the field of pharmaceutical formulation comprising microparticles
and particulary a method for making dry powder blend pharmaceutical formulations.
Microencapsulation of therapeutic and diagnostic agents is known to be a useful
tool for enhancing the controlled delivery of such agents to humans or animals. For
these applications, microparticles having very specific sizes and size ranges are,needed
in order to effectively deliver these agents. Microparticles, however; may tend to
agglomerate during their production and processing, thereby undesirably altering the
effective size of the particles, to the detriment of the microparticle formulation's
performance and/or reproducibility. Agglomeration depends on a variety of factors,
including the temperature, humidity, and compaetion forces to which the microparticles
are exposed, as well as the particular materials and methods used in making the
microparticles. It therefore would be useful to deagglomerate the microparticles. post
production and/or the microparticle dry powder formulations-using a process that do es
not substantially affect the size and morphology of the microparticle as originally
formed. Such a process preferably should be simple and operate af ambient conditions
to minimize equipment and operating costs and to avoid degradation of pharmaceutical
agents, such as thermally labile drugs.
Microparticle production techniques typically require the use of one or more
aqueous or organic solvents. For example, an organic solvent can be combined with,
and then removed from, a polymeric matrix material in the process of forming
polymeric microparticles by spray drying. An undesirable consequence, however, is
that the mi crop articles often retain solvent residue. It is highly desirable to minimize
these solvent residue levels in pharmaceutical formulations." It therefore would be
advantageous to develop a process that enhances solvent removal from microparticle
Similarly, it would be desirable to reduce moisture levels in microparticle-
formulations, irrespective of the source by which the moisture is introduced, in order to
decrease caking, increase flowabiliry, and improve storage stability of the formulation.
For example, an aqueous solvent can be used to dissolve or disperse an excipient to
facilitate mixing of the excipient with microparticles, after which the aqueous solvent is
removed. It therefore would be advantageous to develop a process that enhances
moisture removal from microparticle formulations.
Excipients often are added to the microparticles and pharmaceutical agents in
order to provide the microparticle formulations with certain desirable properties or to
enhance processing of the microparticle formulations. For example, the excipients can
facilitate administration of the microparticles, minimize micropanicle agglomeration
upon storage or upon reconsritution, facilitate appropriate release or retention of the
active agent, and/or enhance shelf life of the product. Representative types of these
excipients include osmotic agents, bulking agents, surfactants, preservatives, wetting
agents, pharmaceutically acceptable carriers, diluents, binders, disintegrants, glidants,
and lubricants. It is important that the process of combining these excipients and
microparticles yield a uniform blend. Combining these excipients with the
microparticles can complicate production and scale-up; it is not a trivial matter to-make
such microparticle pharmaceutical formulations, particularly on a commercial scale.
Laboratory scale methods for producing microparticle pharmaceutical
formulations may require several steps, which may not be readily or efficiently
transferred to larger scale production. Examples of these steps include dispersing the
microparticles, size classification of the microparticles, drying and/or lyophilizing
them, loading them with one or more active agents, and combining them with one or
more excipient materials to form a homogenous product ready for packaging. Some
process steps such as freezing the microparticles (e.g., as part of a solvent removal
process) by the use of liquid nitrogen are expensive and difficult to execute in a clean
room for large volume operations. Other process steps, such as sonication, may require
expensive custom made equipment to perform on larger scales. It would be
advantageous to develop pharmaceutical formulation production methods to eliminate,
combine, or simplify any of these steps.
It therefore would be desirable to provide deagglomerated microparticle
pharmaceutical formulations having low residuals. It would be particularly desirable
for dry forms of the microparticle formulation to disperse and suspend well upon
reconsritution, providing an injectable formulation. It would be desirable for dry forms
of the microparticle formulation to disperse well in the dry form, presiding an inhalable
formulation. It would be desirable for dry forms of the microparticle formulation to
disperse well upon oral administration, providing a solid oral dosage form.
WO 0189492 discloses a blend of formoterol fumanete dehydrate and lactose
monohydrate which is mincronised in a spiral jet mill. This milled blend was then mixed
with micronized budesonide, jet millad to deagglomerate, and then spheronized to
WO 9615814 discloses making of hollow microcapsules that are useful to enhance ultro
sound imaging. WO 9615814 teaches that agglomeration of the microcapsules can be
ninimized by "milling" the microcapsules with or inert excipient using a Fritsch
centrifugal bin mill or air inpact jet mill. However, this reference fails to teach jet milling
the powder blend to deagglomerete while substantially maintaining the size of the
WO 9953501 discloses using a jet mill to micronize particles and reduce their size. Its
examples suggest jet milling to reduce the size of particles.
WO 0243701 discloses a method making composite active particles for use in
pharmaceutical formulations by co-milling active particles with additive particles where
preferably, the milling is not jet milling (micronisation).
There are different approaches in the prior art referred above for either trying to prevent
particles agglomeration in dry powder pharmaceutical formulations and/or for trying to
deagglomerate them once formed.
It would be desirable to provide a method for both deagglomerating
microparticulate pharmaceutical formulations and reducing residual moisture (and/or
solvent) levels in these formulations, using a process that does not substantially affect
the size and morphology of the microparticle as originally formed. It would also be
desirable to provide methods for making uniform blends of deagglomerated
microparticles and excipients, preferably without the use of an excipient solvent. Such
methods desirably would be adaptable for efficient, commercial scale production.
The present invention provides a method of making a dry powder blend pharmaceutical
formulation that enables the deagglomeration of drug microparticles in the blend without
detrimentally impacting the microparticle size. This enables one to enhance content
uniformity of the dry powder pharmaceutical confrontion which is very important in the
production of dry powder drug formulations. The method also advantageously reduces
residual moisture, which improves stability and handling of the dry powder and reduces
the organic solvent levels in the microparticles.
Summary of the Invention
Methods are provided for making a dry powder pharmaceutical formulation
comprising (i) forming microparticles; which comprise a pharmaceutical agent; (ii)
providing at least one excipient (e.g.. a bulking agent, surface active agent, wetting
agent, or osmotic agent) in the form of particles having a volume average diameter that .
is greater than the volume average diameter of the microparticles; (iii) blending the
microparticles with the excipient to form a powder blend; and (iv) jet milling the
powder blend to deagglomerate at least a portion of any of the microparticles which
have agglomerated, while substantially maintaining the size and morphology of the
The excipient particles can have, for example, a volume average size between
10 and 500 µm, between 20 and 200 jam, or between 40 and 100 µm, depending in part
on the particular pharmaceutical formulation and route of administration. Examples of
excipients include lipids, sugars, amino acids, and polyoxyethyjene. sorbitan fatty acid
esters, and combinations thereof, In one embodiment, the excipient is selected from the
group consisting of lactose, mannitol, sorbitol, rrehalose,xylitpl, and combinations
thereof. In another embodiment, the excipient comprises hydrophobic amino acids such
as leucine, isoleucine, alanine, glucine, valine, proline, cysteine, methionine,
phenyla.lanine, or tryptophan. In another embodiment, the excipient comprises binders,
disintegjants, glidants, diluents, coloring agents, flavoring agents,.sweeteners, and
lubricants for a solid oral dosage formulation such as for a tablet, capsule, or wafer.
Two or more different excipients can be blended with the microparticles, in one or
more steps. In one embodiment the microparticles consist essentially of a therapeutic
or prophylactic pharmaceutical agent. In another embodiment, the microparticles
further comprises a shell material (e.g., a polymer, protein, lipid, sugar, or ammo acid).
In another aspect, a method is provided for making a dry powder blend
pharmaceutical formulation comprising two or more different pharmaceutical agents.
In one method, the steps include (a) providing a first quantity of microparticles which
comprise a first pharmaceutical agent; (b) providing a second quantity of microparticles
which comprise a second pharmaceutical agent; (c) blending the first quantity and the
second quantity to form a powder blend; and (d) jet milling the powder blend to
deagglomerate at least a portion of any of the microparticles which have agglomerated,
while substantially maintaining the size and morphology of the individual
microparticles. This method can further comprise blending an excipient material with
the first quantity, the second quantity, the powder blend, or a combination thereof.
In yet another embodiment, a method is provided for making pharmaceutical
formulations comprising microparticles, wherein the method comprises (i) spraying an
emulsion, solution, or suspension which comprises a solvent and a pharmaceutical
agent through an atomizer to form droplets of the solvent and the pharmaceutical agent;
(ii) evaporating a portion of the solvent to solidify the droplets and form microparticles;
and (iii) jet milling the microparticles to deagglomerate at least a portion of
agglomerated microparticles, if any, while substantially maintaining the size and
morphology of the individual microparticles. In one embodiment, the microparticles
consist essentially of a therapeutic or prophylactic pharmaceutical agent. In another
embodiment, the emulsion, solution, or suspension further comprises a shell material
(e.g., a polymer, lipid, sugar, protein, or ammo acid).
In a further embodiment, a method is provided for making pharmaceutical
formulations comprising microparticles, wherein the method comprises: (i) forming
microparticles which comprise a pharmaceutical agent and a shell material; and jet
milling the microparticles to deagglomerate at least a portion of any of the
microparticles which have agglomerated, while substantially maintaining the size and
morphology of the individual microparticles. Spray drying or other methods can be
used in the microparticle-forming step. In one embodiment, the pharmaceutical agent is
dispersed throughout the shell material. In another embodiment, the microparticles
comprise a core of the pharmaceutical agent, which is surrounded by the shell material.
Examples of shell materials include polymers, amino acids, sugars, proteins.
carbohydrates, and lipids. In one embodiment, the shell material comprises a
biocompatible synthetic polymer.
In another embodiment, jet milling is used to increase the percent crystalliniry or
decrease amorphous content of the drug within the microparticles.
In one embodiment of these methods, the jet milling is performed with a feed
gas and or grinding gas supplied to the jet mill at a temperature of less than about SO
°C. more preferably less than about 30 °C. In one embodiment, the feed gas and or
grinding gas supplied to jet mill consists essentially of dry nitrogen gas.
In various embodiments of these methods, the microparticles have a number
average size between 1 and 10 µm. have a volume average size between 2 and 50 µm,
and, or have an aerodynamic diameter between 1 and 30 µm.
In one embodiment, the microparticles comprise microspheres having voids or
pores therein. In a preferred variation of this embodiment, the pharmaceutical agent is a
therapeutic or prophylactic agent, which is hydrophobic.
In one embodiment of these methods, the pharmaceutical agent is a therapeutic
or prophylactic agent. Examples of classes of these agents include non-steroidal anti-
inflammatory agents, corticosteroids, anti-neoplastics, anti-microbial agents, anti-virals.
anti-bacterial agents, anti-fungals, anti-asthmatics, bronchiodilators, antihistamines,
immunosuppressive agents, anti-anxiety agents, sedatives/hypnotics, anti-psychotic
agents, anticonvulsants, and calcium channel blockers. Examples'of therapeutic or
prophylactic agents include celecoxib, rofecoxib, docetaxel, paclitaxel, acyclovir.
alprazolam, amiodaron, amoxicillin. anagrelide, bactrim, beclomethasone dipropionate,
biaxin. budesonide, bulsulfan, carbamazepinc, ccftazidime, cefprozil, ciprofloxcin,
clarithromycin, clozapine, cyclosporine, cstradiol, etodolac, famciclovir, fenofibrate,
fexofenadine, fluticasonc propionate, gemcitabine. ganciclovir, itraconazole,
lamotrigine, loratidine, lorazepam, mcloxicam, mesalamine, minocycline, nabumetone,
nelfinavir, mesylate, olanzapine, oxcarbazepine, phenytoiri, propfol, ritinavir, SN-38,
sulfasalazine, tracrolimus. tiagabine, tizanidinc, valsartan. voriconazole, zafirlukast,
zilueton, and ziprasidone.
In another embodiment, the pharmaceutical agent is a diagnostic agent, such as
an ultrasound contrast agent.
Dry powder pharmaceutical formulations are also provided. These formulations
comprise blended or unblended microparticles that have been deaggiomerated as
described herein, which may provide reduced moisture conteni and residual solvent
levels in the formulation, improved suspendability of the formulation, improved
aerodynamic properties, decreased amorphous drug content, and (for blends) improved
Brief Description of Accompanying
FIG. 1 is a process flow diagram of a preferred process for producing
deagglomerated microparticle formulations.
FIG. 2 illustrates a diagram of a typical jet mill useful in the method of
FIGS. 3A-B are SEM images of microsphcres taken before and after jet milling.
Detailed Description of the Invention
Improved methods have been developed for making pharmaceutical
formulations comprising deagglomerated microparticles and for making blends of
microparticles and excipients that have enhanced content uniformity. Jet milling
advantageously breaks up microparticle agglomerates. The reduction of microparticle
agglomerates leads to improved suspendability for injectable dosage forms, improved
dispcrsibiliry for oral dosage forms, or improved aerodynamic properties for inhalable
dosage forms Moreover, jet milling beneficially lowers residual moisture and solvent
levels in the microparticles, leading to better stability and handling properties for the
dry powder pharmaceutical formulations.
As used herein, the terms "comprise, 'comprising," "include," and "including"
are intended to be open, non-limiting terms, unless the contrary is expressly indicated.
I. The Microparticle Formulations
The formulations include microparticles comprising one or more pharmaceutical
agents such as a therapeutic or a diagnostic agent, and optionally one or more
excipients. In one embodiment, the formulation is a uniform dry powder blend
comprising microparticles of a pharmaceutical agent blended with larger microparticles
of an excipient.
As used herein, the term '"microparticle" includes microspheres and
microcapsuies, as well as microparticies, unless otherwise specified Microparticles
may or may not be spherical in shape. Microcapsuies are defined as microparticles
having an outer shell surrounding a core of another material, in this case, the
pharmaceutical agent. The core can be gas. liquid, gel. or solid. Microsphercs can be
solid spheres, can be porous and include a sponge-like or honeycomb structure formed
by pores or voids in a matrix material or shell, or can include a single internal void in a
matrix material or shell.
In one embodiment, the microparticles is formed entirely of the pharmaceutical
agent. In another embodiment, the microparticle has a core of pharmaceutical agent
encapsulated in a shell. In another embodiment, the pharmaceutical agent is
interspersed within the shell or matrix. In another embodiment, the pharmaceutical
agent is uniformly mixed within the material comprising the shell or matrix.
Optionally, the microparticies can be blended with one or more excipients.
1. Size and Morphology
As used herein, the terms "size" or "diameter" in reference to microparticies
refers to the number average particle size, unless otherwise'specified. An example of
an equation that can be used to describe the number average particle size is shown
where n = number of particles of a given diameter (d).
As used herein, the term "volume average diameter" refers to the volume
weighted diameter average. An example of an equation that can be used to describe the
volume average diameter is shown below:
where n = number of particles of a given diameter (d).
As used herein, the term "aerodynamic diameter" refers to the equivalent
diameter of a sphere with density of 1 g/mL were it to fall under gravity with the same
velocity as the particle analyzed. The values of the aerodynamic average diameter for
the distribution of particles are reported. Aerodynamic diameters can be determined on
the dry powder using an Aerosizer (TSI), which is a time of flight technique, or by
cascade impaction, or liquid impinger techniques.
Particle size analysis can be performed on a Coulter counter, by light
microscopy, scanning electron microscopy, transmission electron microscopy, laser
diffraction methods, light scattering methods or time of flight methods. Where a
Coulter method is described, the powder is dispersed in an electrolyte, and the resulting
suspension analyzed using a Coulter Multisizer II fitted with a 50-um aperture tube.
The jet milling process described herein deagglomerates agglomerated
microparticles, such that the size and morphology of the individual microparticles is
substantially maintained. That is, a comparison of the microparticle size before and
after jet milling should show a volume average size reduction of at least 15% and a
number average size reduction of no more than-75%.
In the formulations, the microparticles preferably have a number average size
between about 1 and 20 µm. It is believed that the jet milling processes will be most
useful in deagglomerating microparticles having a volume average diameter or
aerodynamic average diameter greater than about 2 µm. In one embodiment, the
microparticles have a volume average size between 2 and 50 µm. In another
embodiment, the microparticles have an aerodynamic diameter between 1 and 50 µm.
The microparticles are manufactured to have a size (i.e., diameter) suitable for
the intended route of administration. Particle size also can affect RES uptake. For
intravascular administration, the microparticles preferably have a number average
diameter of between 0.5 and 8 µm. For subcutaneous or intramuscular administration,
the microparticles preferably have a number average diameter of between about 1 and
100 µm. For oral administration for delivery to the gastrointestinal tract and for
application to other lumens or mucosal surfaces (e.g., rectal, vaginal, buccal, or nasal),
the microparticles preferably have a number average diameter of between 0.5 µm and 5
mm. A preferred size for administration to the pulmonary system is an aerodynamic
diameter of between 1 and 5 µm, with an actual volume average diameter (or an
aerodynamic average diameter) of 5 µm or less.
In one embodiment, the microparticles comprise microsphercs having voids
therein. In one embodiment, the microspheres have a number average size between 1
and 3 µm and a volume average size between 3 and 8 µm.
i In another embodiment, jet milling increases the crystallinily or decreases the
amorphous content of the drug within the microspheres as assessed by differential
2. Pharmaceutical Agents
The pharmaceutical agent is a therapeutic, diagnostic, or prophylactic agent.
The pharmaceutical agent is sometimes referred to herein generally as a "drug" or
"active agent." The pharmaceutical agent may be present in an amorphous state, a
crystalline state, or a mixture thereof. The pharmaceutical agent may be labeled with a
detectable label such as a fluorescent label, radioactive label or an enzymatic or
chromatographically detectable agent.
A wide variety of therapeutic, diagnostic and prophylactic agents can be loaded
into the microparticles. These can be proteins or peptides, sugars, oligosaccharides,
nucleic acid molecules, or other synthetic or natural agents. Representative examples
of suitable drugs include the following categories and examples-of drugs and alternative
forms of these drugs such as alternative salt forms, free acid forms, free base forms, and
analgesics/antipyretics (e.g., aspirin, acetaminophen, ibuprofen, naproxen sodium,
buprenorphine, propoxyphene hydrochloride, propoxyphene napsylate, mcperidine
hydrochloride, hydromorphone hydrochloride, morphine, oxycodone, codeine,
dihydrocodeine bitarrrate, pentazocine. hydrocodone bitarrrate, Ievorphanol, diflunisal.
trolamine salicylate, nalbuphine hydrochloride, mefenamic acid, butorphanol, choline
salicylate, butalbital, phenyltoloxamine citrate, and meprobamate);
antiasthmatics (e.g., ketotifen and traxanox);
antibiotics (e.g., neomycin, streptomycin, chloramphenicol, cephalosporin, ampicillin,
penicillin, tetracycline, and ciprofloxacin);
antidepTessants (e.g., nefopam, oxypertine, doxepin, amoxapine, trazodone,
amitriptyline, maprotiline, phenelzine, desipramine, nortriptyline, tranylcypromine,
fluoxetine, imipramine, imipramine pamoate, isocarboxazid, ftimipramine, and
antineoplastics (e.g., cyclophosphamide. actinomycin, bleomycin. daunorubicin,
doxorubicin. epirubicin, mitomycin, methotrexate, fluorouracil, carboplatin, carmustine
(BCNU), methyl-CCNU, cisplatin, etoposide, camptothecin and derivatives thereof,
phenesterine, paclitaxel and derivatives thereof, docetaxel and derivatives thereof,
vinblastine, vincristine, tamoxifen, and piposulfan);
antianxierv agents (e.g., lorazepam, buspirone, prazepam, chlordiazepoxide, oxazepam,
clorazepatc dipotassium, diazeparn", hydroxyzine pamoate, hydroxyzine hydrochioride.
alprazolam, droperidol, halazepam, chlormezanone, and dantrolene);
immunosuppressive agents (e.g., cyclpsporine, azathioprine, mizoribine, and FK506
antimigraine agents (e.g., ergotamine, propanolol, and dichloralphenazone);
sedatives/hypnotics (e.g., barbiturates such as pentobarbital, pentobarbital, and
secobarbital; and benzodiazapincs such as flurazepam hydrochioride. and triazolam);
antianginal agents (e.g., beta-adrenergic blockers; calcium channel blockers such as
nifedipinc, and diltiazem; and nitrates such as nitroglycerin, and erythrityl tetranitrate);
antipsvchotic agents (e.g., haloperidol loxapine succinate, loxapine hydrochioride,
thioridazine. thioridazine hydrochioride, thiothixcne, fluphcnazine, fluplienazine
decanoate, fluphenazine cnanthate, trifluoperazine, lithium citrate, prochlorperazine,
aripiprazole, and risperdione);
antimanic agents (e.g., lithium-carbonate);
antiarrhvthmics (e.g., bretylium tosylate, esmolol, verapamil, amiodarone, encainide,
digoxin. digitoxin, mexiletine, disopyra'mide phosphate, procainamide, quinidine
sulfate. quinidine gluconate, flecainide acetate, tocainidc, and lidocaine);
antiarthritic agents (e.g., phenvlbutazone. sulindaco. penicillamine. salsalale, piroxicam.
azathioprine, indomethacin. meclofenamate, gold sodium thiomalate. ketonrofen.
auranofin, aurothioglucose. and tolmetin sodium);
antigout agents (e.g., colchicine, and allopurinol);
anticoagulants (e.g., heparin, heparin sodium, and warfarin sodium):
thrombolvtic agents (e.g., urokinase, streptokinase, and alteplase);
antifihrinolvtic agents (e.g., aminocaproic acid1):
hemorheologic agents (e.g., pentoxifylline):
antiplatelet agents (e.g., aspirin):
anticonvulsants (e.g., valproic acid, divalproex sodium, phenytoin. phenytoin sodium,
clonazepam. primidone, phenobarbitol, carbamazepine. amobarbital sodium;
methsuximide, tnctharbital, mephobarbital, paramethadione, ethotoin, phenacemide,
secobarbitol sodium, clorazepate dipotassium. oxcarbazepine and trmethadione);
antiparkinson agents (e.g., ethosuximide);
antihistamines/antipruritics (e.g., hydroxyzine, diphenhydramine, chlorpheniramine.
brompheniramine maleate, cyproheptadine hydrochloride, terfenadine, elemastine
fumarate, azatadine, tripelennaminc, dexchlorpheniramine maleate. methdalizine);
agents useful for calcium regulation (e.g., calcitonin, and parathyroid hormonc);
antibacterial agents (e.g., amikacin sulfate, aztreonam, chloramphenicol,
chloramphenicol palmitate, ciprofloxacin, clindamycin. clindamycin palmitate,
clindamycin phosphate, metronidazole. metronidazole hydrochloridc. gentarnicin
sulfate, lincomycin hydrochloride, tobramycin sulfate, vancomycin hydrochloride,
polynyxin B sulfate, colistimethate sodium, clarithromycin and colistin sulfate):
antiviral agents (e.g., interferons, zidov.udine, amantadine hydrochloride. ribavirin. and
antimicrobials (e.g., cephalosporins such as ceftazidime; penicillins: erythromycins; and
tetracyclines such as tetracycline hydrochloride, doxycycline hyclatc. and minocycline
hydrochloride, azithromycin, clarjthromycin);
anti-infectives (e.g., GM-CSF);
bronchodilators (e.g., sympathomimetics such as epinephrine hydrochloride,
metaproterenol sulfate, terbutaline sulfate, isoetharinc. isoetharine mesylate. isoetharine
hydrochloridc, albuterol sulfate, albutcrol, bitolterolmesylatc, isoproterenol
hydrochloride, terbutaline sulfate, epinephrine bitartrate, metaproterenol sulfate,
epinephrine, and cpinephrinc bitartrate; amicholinergic agents such as iprarropium
bromide; xanthines such as aminophylline. dyphylline. metaprotrenol sulfate, and
aminophylline; mast cell stabilizers such as cromolyn sodium: salbutamol: iprarropium
bromide; ketotifen; salmetcrol; xinafoate; terbutaline sulfate; thcopibylline; aedocromil
sodium; metaproterenol sulfate: albuterol);
inhalant corticosteroids (e.g., beclomethasone dipropionate (BDP), beclomethasone
dipropionate monohydrate; budesonide, triamcinolone; flunisolide: fluticasone
steroidal compounds and hormones (e.g., androgens such as danazol, testosterone
cypionate, fluoxymesterone, ethyl testosterone, testosterone enathate.
methyltestostcrone, fluoxymesterone, and testosterone cypionate; estrogens such as
estradiol, cstropipate, and conjugated estrogens; progestins such as
methoxyprogesterone acetate, and norethindrone acetate; corticosteroids such as
triamcinolone, betamethasonc, betamethasone sodium phosphate, dexamethasone.
dexamethasone sodium phosphate, prednisone, methylprednisolone acetate suspension,
tnamcinolone acetonide, methylprednisolone, prednisolone sodium phosphate,
methylprednisolone sodium succinate. hydrocortisonc sodium succinate, triamcinolone
hexacetonide, hydrocortisone., hydrocortisone cypionate. prednisolone, fludrocortisone
acetate, paramethasone acetate, prednisolone tebutate, prednisolone acetate,
prednisolone sodium phosphate, and hydrocortisone sodium succinate; and thyroid
hormones such as levothyroxine sodium);
hvpoelvcemic agents (e.g.,human insulin, purified beef insulin, purified pork.insuhn,
glyburide, chlorpropamide, glipizide, tolbutamide, and tola/amide);
hvpolipidcmic agents (e.g., clofibrate, dexrrothyroxine sodium, probucol, pravastitin.
atorvastatin, lovastatin, and niacin);
proteins (e.g., DNase, alginase, superoxide dismutase, and lipase);
nucleic acids (e.g.. sense or anti-sense nucleic acids encoding any therapeutically useful
protein, including any of the proteins described herein);
agents useful for ervthropoiesis stimulation (e.g., erythropoietin);
antiulcer/antireflux agents (e.g., famotidine, cimetidine, and ranitidine hydrochloride);
antinauseants/antiemetics (e.g., meclizinc hydrochloride, nabilone, prochlorpcrazine,
dimenhydrinate, promethazine hydrochloride, thiethylperazine, and scopoldamine);
oil-soluble vitamins (e.g., vitamins A, D, E, K, and the like);
as well as other drugs such as mitotane, halonitrosoureas, anthrocyclines, and
ellipticine. A description of these and other classes 'of useful drugs and a listing of
species within each class can be found in Martindale, The Extra Pharmacopoeia, 30th
Ed. (The Pharmaceutical Press, London 1993).
Examples of other drugs useful in the compositions and methods described
herein include ceftriaxone, ketoconazole, ceftazidime, oxaprozin, albuteroi,
valacyclovir, urofollitropin, famciclovir, flutamide, enalapril, mefformin, itraconazole,
buspirone, gabapentin, fosinopril, tramadol, acarbose, lorazepan, follitropin, glipizide,
omeprazole, fluoxetine, lisinopril, tramsdol, levofloxacin, zafirlukast, interferon,
growth hormone, interleukin, erythropoietin, granulocyte stimulating factor, nizatidine,
bupropion, perindopril, erbumine, adenosine, alendronate. alprostadil, benazepril,
betaxolol, bleomycin sulfate dexfenfluramine, diltiazem, fentanyl, flecainid,
gemcitabine, glatiramer-acetate, granisetron, lamivudine, mangafodipir trisodium,
mesalamine, metoprolol fumarate, metronidazole, miglitol, moexipril, monteleukast,
octreotide acetate, olopatadine paricalcitol, somatropin, sumatriptan succinate, tacrine,
verapamil, nabumetone, trovafloxacin, dolasetron, zidovudine, finasteride, tobramycin,
isradipine, tolcapone,.enoxaparin, fluconazole, lansoprazole, terbinafine, pamidronate,
- didanosine, diclofenac, cisapride, venlafaxine, troglitazone, fluvastatin, losartan,
imiglucerase, donepezil, olanzapine, valsartan, fexofenadine, calcitonin, and
ipratropium bromide. These drugs are generally considered water-soluble.
Preferred drugs include albuteroi, adapalene, doxazosin mesylate, mometasone
furoate, ursodiol, amphotericin, enalapril maleate, felodipine, nefazodone
hydrochloride, valrubicin, albendazole, conjugated estrogens, medroxj'progesterone
acetate, nicardipine hydrochloride, zolpidem tartrate, amlodipine besylate, ethinyl,
estradiol, omeprazole, rubitecan,-amlodipine besylate/ benazepril hydrochloride,
etodolac, paroxetine hydrochloride, paclitaxel, atovaquone, felodipine, podofilox,
paricalcitol, betamethasone dipropionate, fentanyl, pramipexole dihydrochloride,
Vitamin D3 and related analogues, finasteride, quetiapine fumarate, alprostadil,
candesartan, cilexetil, fluconazole, ritonavir, busulfan, carbamazepine, flumazenil,
risperidone, carbemazepirie, carbidopa, levodopa, ganciclovir, saquinavir, amprenavir,
carboplatin, glyburide, sertraline hydrochloride, rofecoxib carvedilol,
halobetasolproprionate, sildenafil citrate, celecoxib, chlorthalidone, imiquimod,
simvastatin, citalopram, ciprofloxacin, irinotecan hydrochloride, sparfloxacin,
efavirenz, cisapride monohydrate, lansoprazole, tamsulosin hydrochloride, mofafinil.
clarithromycin, letrozole, terbinafine hydrochloride, rosiglitazone maieate, diclofenac
sodium, lomefloxacin hydrochloride, tirofiban hydrochloride. telmisartan. diazapam,
loratadine, toremifene citrate, thalidomide, dinoprostone, mefioquine hydrochloride,
trandolapril, docetaxel, mitoxantrone hydrochloride, tretinoin, etodolac, triamcinolone
acetate, estradiol, ursodiol, nelfinavir mesylate, indinavir, beclomethasone dipropionate,
oxaprozin, flutamide, famotidine, nifedipine, prednisone, cefuroxime, lorazepam,
digoxin, lovastatin, griseofulvin, naproxen, ibuprofen, isorretinoin, tamoxifen citrate,
nimodipine, amiodarone, and alprazolam.
In one embodiment, the pharmaceutical agent is a hydrophobic compound,
particularly a hydrophobic therapeutic agent. Examples of such hydrophobic drugs
include celecoxib, rofecoxib, paclitaxel, docetaxel, acyclovir, alprazolam, amiodaron,
amoxicillin, anagrelide, bactrim, biaxin, budesonide, bulsulfan, carbamazepine,
ceftazidime, cefprozil, ciprofloxicin, clarithromycin, clozapine, cyclosporine, diazepam,
esrradiol, etodolac, famciclovir, fenoflbrate, fexofenadine, gemcitabine, gancicloyir,
itraconazole, lamotrigine,-loratidine, lorazepam, meloxicam, mesalamine, minocycline,
modafinil, nabumetone, nelfinavir mesylate, olanzapine, oxcarbazepine, phenytoin,
propofol, ritinavir, SN-38, sulfamethoxazol, sulfasalazine, tracrolimus, tiagabine,
tizanidine, trimethoprim, valium, valsartan, voriconazole, zafirlukast, zileuton, and
ziprasidone. In this embodiment, the microparticles preferably are porous.
In one embodiment, the pharmaceutical agent is for pulmonary administration.
Examples include corticosteroids such as budesonide, fluticasone propionate,
beclomethasone dipropionate, mometasone, flunisolide, and triamcinolone acetonide,
other steroids such as testosterone, progesterone, and esrradiol, leukolriene inhibitors
such as zafirlukast and zileutbn, antibiotics such as cefprozil, amoxicillin, antifungals
such as ciprofloxacin, and itraconazole, bronchiodilators such as albuterol, fomoterol,
and salmeterol, antineoplastics such as paclitaxel and docetaxel, and peptides or
proteins such as insulin, calcitonin, leuprolide, granulocyte colony-stimulating factor,
parathyroid hormone-related peptide, and somatostatin.
In another embodiment, the pharmaceutical agent is a contrast agent for
diagnostic imaging, -particularly a gas for ultrasound imaging. In a preferred
embodiment, the gas is a biocompatible or pharmacologically acceptable fluorinated
gas, as described, for example, in U.S. Patent No. 5,611,344 to Bernstein et al. The
term "gas" refers to any compound that is a gas or capable of forming a cas at the
temperature at which imaging is being performed. The gas may be composed of a
single compound or a mixture of compounds. Perfluorocjrbon gases are preferred:
examples include CF4, C2F6, C3F8, C4F10, SF6, C2F4, and C3F6. Other imaging agents
can be incorporated in place of a gas, or in combination with the pas. Imaging agents
that may be utilized include commercially available agents used in positron emission
tomography (PET), computer assisted tomograph)1 (CAT), single photon emission
computerized tomography, x-ray, fluoroscopy, and magnetic resonance imaging (MRI).
Micropartioles loaded with these agents can be detected using standard techniques
available in the art and commercially available equipment. Examples of suitable
materials fcr use as contrast agents in MRI include the gadolinium chelates currently
available, such as.diethylene triamine pentacetic acid (DTPA) and gadopentotate
dimcglumine, as well as iron, magnesium, manganese, copper and chromium.
Examples of materials useful for CAT and x-rays include iodine based materials for
intravenous administration, such as ionic monomers typified by diatrizoate and
iothalamate, non-ionic monomers such as iopamidol, isohexol, and ioversol, lion-ionic
dimers, such as iotrol and iodixanol, and ionic dimers, e.g., ioxagalte. Other useful
materials include barium for oral use.
3. The Shell Material
The shell material can be a synthetic material or a natural material. -The Shell
material can be water soluble or water insoluble. The microparticles can be formed of
non-biodegradable or biodegradable materials, although biodegradable materials are
preferred, particularly for parenteral administration. Examples of types of shell
materials include polymers, amino acids, sugars, proteins, carbohydrates, and lipids.
Polymeric shell materials can be degradable or non-degradable, erodible or non-
erodible. natural or synthetic. Non-erodible polymers may be used for oral
administration. In general, synthetic polymers are preferred due to more reproducible
synthesis and degradation. Natural polymers also may be used. Natural biopolymers
that degrade by hydrolysis, such as polyhydroxybutyrate, may be of particular interest.
The polymer is selected based on a variety of performance factors, including the time
required for /';; vivo stability, i.e., the time required for distribution to the site where
delivery is desired, arjd the time desired for delivery. Other selection factors may
include shelf life, degradation rate, mechanical properties, and glass transition
temperature of the polymer.
Representative synthetic polymers are poly(hydroxy acids) such as poly(lactie
acid), poly(glycolic acid), and poly(lactic acid-co-glycolic acid), poly(lactide).
poly(glycolide), poly(lactide-co-glycolide), polyanliydrides, polyorthoesiers.
polyamides, polycarbonates, polyalkylenes such as polyethylene and polypropylene,
polyalkylene glycols such as poly(ethylene glycol), polyalkylene oxides such as
poly(ethylene oxide), polyalkylene terepthalates such as poly(ethylene terephthalate),
polyvinyl alcohols, polyvinyl ethers, polyvinyl esters, polyvinyl halides such as
poly(vinyl chloride), polyvinylpyrrolidone, polysiloxanes, poly(vinyl alcohols).
poly(vinyl acetate), polystyrene, polyurethanes and co-polymers thereof, derivativized
celluloses such as alkyl cellulose, hydroxyalkyl celluloses, cellulose ethers, cellulose
esters, nitro celluloses, methyl cellulose, ethyl cellulose, hydroxypropyl cellulose,
hydroxy-propyl methyl cellulose, hydroxybutyl methyl cellulose, cellulose acetate,
cellulose propionate, cellulose acetate butyrate, cellulose acetate phthalate,
carboxyethyl cellulose, cellulose triacetate, and cellulose sulphate sodium salt jointly"
referred to herein as "synthetic celluloses"), polymers of acrylic acid, methacrylic acid
or copolymers or derivatives thereof including esters, poly(methyl methacrylate),
poly(ethyl methacrylate), poly(butylmethacrylate), poly(isobutyl methacrylate),
poly(hexylmethacrylate), poly(isodecyl methacrylate), poly(lauryl methacrylate)
poly(phenyl methacrylate), poiy(methyl acrylate), poly(isopropyl acrylate),
poly(isobutyl acrylate), and poly(octadecyl acrylate) (jointly referred to her'ein'as
"polyacrylic acids"), poly(butyric acid), poly(valeric acid), and poly(lactide-co-
caprolactone), copolymers and blends thereof. As used herein, "derivatives" include
polymers having substitutions, additions of chemical groups, for example, alky],
alkylene, hydroxylations, oxidations, and other modifications routinely made by those
skilled in the art.
Examples of preferred biodegradable polymers include polymers of hydroxy
acids such as lactic acid and glycolic acid, and copolymers with PEG, polyanhydrides,
poly(ortho)esters, polyurethanes, poly(butyric acid), poly(valeric acid), poly(lactide-co-
caprolactone), blends and copolymers thereof.
Examples of preferred natural polymers include proteins such as albumin and
prolamines, for example, zein, and polysaccharides such as alginate, cellulose and
polyhydroxyalkanoates, for example, polyhydroxybutyrate. The in vivo stability of the
matrix can be adjusted during the production by using polymers such as polylactide-co-
glycolide copolymerized with polyethylene glyco! (PEG). PEG. if exposed or. the
external surface, may extend the time these materials circulate post inrravascular
administration, as it is hydrophilic and has been demonstrated to mask RES
(reticuloendothelial system) recognition.
Examples of preferred non-biodegradable polymers include ethylene vinyl
acetate, poly(meth)acrylic acid, polyamides, copolymers and mixtures thereof.
Bioadhcsive polymers can be of particular interest for use in targeting of
mucosal surfaces (e.g.. in the gastrointestinal tract, mouth, nasal cavity. Inns, vagina,
and eye). Examples of these include polyanhydrides. polyacrylic acid, poly(methyl
methacrylates), poly(ethyl mcthacrylates), poly(butylmethacrylate), poly(isobulyl
methacrylate), poly(hexylmethacrylate). poly(isodecyl methacrylate), poly(lauryl
methacrylate). poly(phenyl methacrylate), poly(methyl acrylate), poly(isopropyl
acrylate), poly(isobutyl acrylate), and poly(octadecyl acrylate).
Representative amino acids that can be used in the shell include both naturally
occurring and non-naturally occurring amino acids. The amino acids can be
hydrophobic or hydrophilic and may be D amino acids, L amino acids or racemic
mixtures. Amino acids that can be used include glycinc. arginine, histidine, threonine,
asparagine, aspartic acid, serine, glutamate, proline, cysteine, methioniue, valine,
leucine, isoleucine, rryptophan, phenylalanine, tyrosine, lysine, alanine, and glutamine.
The amino acid can be used as a bulking agent, or as an anti-crystallization agent for
drugs in the amorphous state, or as a crystal growth inhibitor for drugs in the crystalline
state or as a wetting agent. Hydrophobic amino acids such as leucine, isoleucine,
alanine. glucine, valine, proline. cysteine, methionine, phenylalanine, tryptophan are
more likely to be effective as anticrystallization agents or crystal growth inhibitors. In
addition, amino acids can serve to make the shell have a pH dependency that can be
used to influence the pharmaceutical properties of the shell such as solubility, rate of
dissolution or wetting.
The shell material can be the same or different from the excipient material, if
present. In one embodiment, the excipient can comprise the same classes or types of
material used to form the shell. In another embodiment, the excipient comprises one or
more materials different from the shell material. In this latter embodiment, the
excipient can be a surfactant, wetting agent, salt, bulking agent, etc. In one
embodiment, the formulation comprises (a) microparticles that have a core of a drug
and a shell comprising a sugar or ammo acid, blended with (b) another sugar or amino
acid that functions as a bulking or tonicity agent.
The term "excipient" refers to any non-active ingredient of the formulation
intended to facilitate delivery and administration by the intended route. For example,
the excipient can comprise proteins, amino acids, sugars or other carbohydrates,
starches, lipids, or combinations thereof. The excipient may enhance handling,
stability, aerodynamic properties, and dispersibility of the active agent.
In preferred embodiments, the excipient is a dry powder (e.g., in the form of
microparticles,) which is blended with drug microparticles. Preferably, the excipient
microparticles are larger in size than the pharmaceutical microparticles. In one
embodiment, the excipient microparticles have a volume average size between about 10
and 500. µm, preferably between 20 and 200 µm, more preferably between 40 and 100
Representative amino acids that can be used in the drug matrices include both
naturally occurring and non-naturally occurring amino acids. The amino acids-can be
hydrophobic or hydrophilic and may be D amino acids, L amino acids or racemic
mixtures. Amino acids that can be used include glycine, arginine, histidine, threonine,
asparagine, aspartic acid, serine, glutamate, proline, cysteine, methionine, valine,
leucine. isoleucine, tryptophan, phenylalanine, tyrosine, lysine, alanine, glutamine. The
amino acid can be used as a bulking agent, as a wetting agent, or as a crystal growth
inhibitor for drugs in the crystalline state. Hydrophobic amino acids such as leucine,
isoleucine, alanine, glucine, valine, proline, cysteine, methionine, phenylalanine,
tryptophan are more likely to be effective as crystal growth inhibitors. In addition,
amino acids can serve to make the matrix have a pH dependency that can be used to
influence the pharmaceutical properties of the matrix, such as solubility, rate of
dissolution, or wetting.
Examples of excipients include pharmaceutically acceptable carriers and
bulking agents, including sugars such as lactose, mannitol, trehalose, xylitol, sorbitol,
dextran, sucrose, and fructose. These sugars may also serve as wetting agents. Other
suitable excipients include surface active agents, dispersants, osmotic agents, binders,
disintegrants, glidants, diluents, color agents, flavoring agents, sweeteners, and
lubricants. Examples include sodium desoxycholate; sodium dodecylsulfate;
polyoxyethylene sorbitan fatty acid esters, e.g., potyoxyethylene 20 sorbitan
monolaurate (TWEEN™ 20), polyoxyethylene 4 sorbitan monolaurate (TWEEN™ 21),
polyoxyethylene 20 sorbitan monopalmitate (TWEEN™ 40), polyoxyethylene 20
sorbitan monooleate (TWEEN™ 80); polyoxyethylene alkyl ethers, e.g.,
polyoxyethylene 4 lauryl ether (BRIJ™ 30), polyoxyethylene 23 lauryl ether (BRII™
35), polyoxyethylene 10 oleyl ether (BRIJ™ 97); polyoxyethylene glycol esters, e.g.,
poloxyethylene 8 stearate (MYRJ™ 45), poloxyethylene 40 stearate (MYRJ™ 52);
Tyloxapol; Spans; and mixtures thereof.
Examples of binders include starch, gelatin, sugars, gums, polyethylene glycol,
ethylcellulose, waxes and polyvinylpyrrolidone. Examples of disintegrants (including
super disintegrants) includes starch, clay, celluloses, croscarmelose, crospovidone and
sodium starch glycolate. Examples of glidants include colloidal silicon dioxide and
talc. Examples of diluents include dicalcium phosphate, calcium sulfate, lactose,
cellulose, kaolin, mannitol, sodium chloride, dry starch and powdered sugar. Examples
of lubricants include talc, magnesium stearate, calcium stearate, stearic acid,
. hydrogenated vegetable oils, and polyethylene glycol.
The amounts of excipient for a particular formulation depend on a variety of
factors and can be selected by one skilled in the art. Examples of these factors include
the choice of excipient, the type and amount of drug, the microparticle size and
morphology, and the desired properties and route of administration of the final
In one embodiment for injectable microparticles, a combination of mannitol and
TWEEN™ 80 is blended with polymeric microspheres. In one case, the mannitol is
provided at between 100 and 200 % w/w, preferably 130 and 170 % w/w,
microparticles, while the TWEEN™ 80 is provided at between 0.1 and 10 % w/w,
preferably 3.0 and 5.1 % w/w microparticles. In another case, the mannitol is provided
with a volume average particle size between 10 and 500 µm.
In another embodiment, the excipient comprises binders, disintegrants, glidants,
diluents, color agents, flavoring agents, sweeteners, lubricants, or combinations thereof
for use in a solid oral dosage form. Examples of solid oral dosage forms include
capsules, tablets, and wafers.
II. Methods of Making the Microparticle Formulations
The pharmaceutical formulations are made by a process that includes forming a
quantity of microparticles comprising a pharmaceutical agent and having a selected size
and morphology; and then jet milling the microparticles effective to deagglomerate the
agglomerated microparticles while substantially maintaining the size and morphology
of the individual microparticles. That is, the jet milling step deagglomerates the
microparticles without significantly fracturing individual microparticles. The jet
milling step can advantageously reduce moisture content and residual solvent levels in
the formulation, can improve the suspendability and wettability of the dry powder
formulation (e.g., for better injectability), and give the dry powder formulation
improved aerodynamic properties (e.g., for better pulmonary deliver}').
In one embodiment, the process further (and optionally) includes blending the
microparticles with one or more excipients, to create uniform blends of microparticles
and excipients in the dry state. Preferably, the blending is conducted before the jet
milling step. If desired, however, some or all of the components of the blended
formulation can be jet milled before being blended together. Additionally, such blends
can be further jet milled again to deagglomerate the blended microparticles.
One specific embodiment of the process is illustrated in FIG. 1. In this
embodiment, microspheres are produced by spray drying in spray dryer 10. The
microspheres are then blended with excipients in blender 20. Finally, the blended
microsphcres/excipients are fed to jet mill 30, where the microspheres are
deagglomerated and residual solvent levels reduced. The moisture level in the
microsphere formulation also can be reduced in the jet milling process. In addition, the
content uniformity of the blended microspheres/excipientscan be improved over that of
the non-jet milled blended microspheres/excipients.
The processes described herein generally can be conducted using batch,
continuous, or semi batch methods.
The microparticles can be made using a variety of techniques known in the art.
Suitable techniques include spray drying, melt extrusion, compression molding, fluid
bed drying, solvent extraction, hot melt encapsulation, phase inversion encapsulation,
and solvent evaporation.
In the most preferred embodiment, the micronarticles arc produced by spray
drying. See. e.g., U.S. Patents No. 5,853.69S to Srraub et al.; No. 5.611.344 to
Bernstein et al.; No. 6.395,300 to Straub et al.; and No. 6.223,455 to ("nickering HI. et
ai. For example, the microparticles can be produced by dissolving a pharmaceutical
agent and/or shell material in an appropriate solvent, (and optionally dispersing a solid
or liquid active agent, pore forming agent (e.g., a volatile salt), or other additive into the
solution containing the pharmaceutical agent and/or shell material) and then spray
drying the solution, to form microparticles. As defined herein, the process of "spray
drying" a solution containing a pharmaceutical agent and or shell material refers to a
process wherein the solution is atomized to form a fine mist and dried by direct contact
with hot carrier gases. Using spray drying equipment available in the art, the solution
containing the pharmaceutical agent and/or shell material may be atomized intoa
drying chamber, dried within the chamber, and then collected via a cyclone at the outlet
of the chamber. Representative examples of types of suitable atomization devices
include ultrasonic, pressure feed, air atomizing, and rotating disk. The temperature may
be varied depending on the solvent or materials.used.. The temperature of the inlet and
outlet ports can be controlled to produce the desired products. The size of the
particulates of pharmaceutical agent and/or shell material is a function of the nozzle
used to spray the solution of pharmaceutical agent and/or shell material, nozzle
pressure, the solution and atomization flow rates, the pharmaceutical agent and/or shell
material used, the concentration of the pharmaceutical agent and/or shell material, the
type of solvent, the temperature of spraying (both inlet and outlet temperature), and the
molecular weight of a shell material such as a polymer or other matrix material.
Generally, the higher the molecular weight, the larger the particle size, assuming the
concentration is the same (because an increase in molecular weight generally increases
the solution viscosity). Microparticles having a target diameter between 0.5 and 500
µm can be obtained. The morphology of these microparticles depends, for example, on
the selection of shell material, concentration, molecular weight of a shell material such
as a polymer or other matrix material, spray flow, and drying conditions.
Solvent evaporation is described by Mathiowitz, et al., J. Scanning Microscopy,
4:329 (1990); Beck, et al., Fertil Steril, 31:545 (1979); and Benita, et al., J. Pltarm.
Sci., 73:1721 (19S4). In this method, a shell material is dissolved in a volatile-organic
solvent such as methylenc chloride. A pore forming agent as a solid or as a liquid may
be added to the solution. The pharmaceutical agent can be added as either a solid or
solution to the shell material solution. The mixture is sonicated or homogenized and
the resulting dispersion or emulsion is added to an aqueous solution that may contain a
surface active agent (such as TWEEN™20, TWEENTM80. polyethylene glycol. or
polyvinyl alcohol), and homogenized to form an emulsion. The resulting emulsion is
stirred until most of the organic solvent evaporates, leaving microparticlcs. Several
different polymer concentrations can be used (e.g., 0.05-0.60 gmL) Micropanicles
with different sizes (1-1000 µm) and morphologies can be obtained by this method.
This method is particularly useful for shell materials comprising relatively stable
polymers such as polyesters.
Hot-melt microencapsulation is described in Mathiowitz, et al., Reactive
Polymers. 6:275 (1987). In this method, a shell material is first melted and then mixed
with a solid or liquid pharmaceutical agent. A pore forming agent as a solid or in
solution may be added to the melt. The mixture is suspended in a non-miscible solvent
(e.g., silicon oil), and, while stirring continuously, heated to 5 °C above the melting
point of the shell material. Once the emulsion is stabilized, it is cooled until the shell
material particles solidify. The resulting microparticles are washed by decantation with
a shell material non-solvent, such as petroleum ether, to give a frre flowing powder.
Generally, microparticles with sizes between 50 and 5000 µn are obtained with this
method. The external surfaces of particles prepared with this technique are usually
smooth and dense. This procedure is used to prepare microparticles made of polyesters
and polyanhydrides. However, this method is limited to shell materials such as
polymers with molecular weights between 1000 and 50,000. Preferred polyanhydrides
include polyanhydrides made of biscarboxyphenoxypropanc and sebacic acid with
molar ratio of 20:80 (P(CPP-SA) 20:80) (MW 20,000) and poly(fumaric-co-sebacic)
(20:80) (MW 15,000).
Solvent removal is a technique primarily designed for shell materials such as
polyanhydrides. In this method, the solid or liquid pharmaceutical agent is dispersed or
dissolved in a solution of a shell material in a volatile organic solvent, such as
mcthylene chloride. This mixture is suspended by stirring in an organic oil (e.g., silicon
oil) to form an emulsion. Unlike solvent evaporation, however, this method can be
used to make microparticles from shell materials such as polymers with high melting
points and different molecular weights. The external morphology of particles produced
with this technique is highly dependent on the type of sheli material used.
Extrusion techniques can be used to make microparticles. In this method,
microparticles made of shell materials such as gel-type polymers, such as
polyphosphazene or polymethylmethacrylate, are produced by dissolving the shell
material in an aqueous solution, suspending if desired a pore forming agent in the
mixture, homogenizing the mixture, and extruding the material through a microdroplet
forming device, producing microdroplets that fall into a slowly stirred hardening bath of
an oppositely charged ion or polyelectrolyte solution. The advantage of these systems
is the ability to further modify the surface of the hydrogel microparticles by coating
them with polycationic polymers, like polylysine, after fabrication. Microparticle size
can be controlled by using various size extruders or atomizing devices.
Phase inversion encapsulation is described in U.S. Patent No. 6,143,211 to.
Mathiowitz, et al. By using relatively low viscosities and/or relatively low shell .
material concentrations, by using solvent and nonsolvent pairs that are miscible and by
using greater than ten fold excess of nonsolvent, a continuous phase of nonsolvent with
dissolved pharmaceutical agent and/or shell material can be rapidly introduced into the
nonsolvent. This causes a phase inversion and spontaneous formation of discreet
microparticles, typically having an average particle size of between 10 nm and 10 urn.
As used herein, the terms "jet mill" and "jet milling" include and refer to the use
of any type of fluid energy impact mills, including spiral jet mills, loop jet mills, and
fluidized bed jet mills, with or without internal air classifiers. As used herein, jet
milling is a teclinique for substantially deagglomerating microparticle agglomerates that
have been produced during or subsequent to formation of the microparticles, by
bombarding the feed particles with high velocity air or other gas, typically in a spiral or
circular flow. The jet milling process conditions are selected so that the microparticles
are substantially deagglomerated while substantially maintaining the size and
morphology of the individual microparticles, which can be quantified as providing a
volume average size reduction of at least 15% and a number average size reduction of
no more than 75%. The process is characterized by the acceleration of particles in a gas
stream to high velocities for impingement on other particles, similarly accelerated.
A typical spiral jet mill is illustrated in FIG. 2. The jet mill 50 is shown in
cross-section. Microparticles (blended or unblended) are fed into feed chute 52, and
injection gas is fed through one or more ports 56. The microparticles are forced
through injector 54 into deagglomeration chamber 58. The microparticles enter an
extremely rapid vortex in the chamber 58, where they collide with one another and with
chamber walls until small enough to be dragged out of a central discharge port 62 in the
mill by the gas stream (against centrifugal forces experienced in the vortex). Grinding
gas is fed from port 60 into gas supply ring 61. The grinding gas then is fed into the
chamber 58 via a plurality of apertures; only two 63a and 63b are shown.
Deagglomerated, uniformly blended, microparticles are discharged from the mill 50.
The selection of the material forming the bulk of the microparticles and the
temperature of the microparticles in the mill are among the factors that affect
deagglomeration. Therefore, the mill optionally can be provided with a temperature
control system. For example, the control system may heat the microparticlesy rendering
the material less brittle and thus less easily fractured in the mill, thereby minimizing
unwanted size reduction. Alternatively, the control system may need to cool the
microparticles to below the glass transition or melting temperature of the material, so
that deagglomeration is possible.
In one embodiment, a hopper and feeder are used to control introduction of dry
powder materials into the jet mill, providing a constant flow of material to the mill.
Examples of suitable feeders include vibratory feeders and screw feeders. Other means
known in the art also can be used for introducing the dry powder materials into the jet
In one operation method, the microparticles are aseptically fed to the jet mill via
a feeder, and a suitable gas, preferably dry nitrogen, is used to feed and grind the
microparticles through the mill. Grinding and feed gas pressures can be adjusted based
on the material characteristics. Preferably, these gas pressures are between 0 and 10
bar, more preferably between 2 and 8 bar. Microparticle throughput depends on the
size and capacity of the mill. The milled microparticles can be collected by filtration
or, more preferably, cyclone.
It was discovered that jet milling the microparticles not only deagglomerates the
microparticles, but also can lower the residual solvent and moisture levels in the
microparticles. Thus, a single process step was found to provide both deagglomeration
and moisture/solvent reduction. To achieve reduced residual levels, the
injection/grinding gas preferably is a low humidity gas, such as dry nitrogen. In one
embodiment, the injection/grinding gas is at a temperature less than 100 oC (e.g, less
than 75 °C, less than 50 °C. less than 25 °C etc.).
It was also found that by jet milling the microparticles (or a microparlicle-
comprising dry powder blend) to deagglomerate them.it improved the dispersibility of
the niicroparticles. As used herein, the term "dispcrsibility includes the suspendability
of a powder (e.g.. a quantity or dose of microparticles) within a liquid, as well as the
aerodynamic properties of such a powder or such microparticles. Accordingly, the term
'improved dispersibility" refers to a reduction of particle-particle interactions of the
micropaiticles of a powder within a liquid or a gas.
In another embodiment, jet milling the microparticles can induce transformation •
of the drug within the microparticles from an at least partially amorphous Term to a less
amorphous form (i.e., a more crystalline form). This advantageously provides the drug
in a more stable form.
In a preferred embodiment, dry uniform microparticle blends are produced.
. That is, the dcagglomerated microparticles can be blended with another material, such
as an excipient material, a (second) pharmaceutical agent, or a combination thereof. Jet
milling can advantageously enhance the content uniformity of a dry powder blend.
In a preferred embodiment, the excipient or pharmaceutical agent is in the form
of a dry powder. In one embodiment, the methods for deagglomerating further include
blending microparticles with one or more other materials having a larger particle size
than that of the microparticles.
In one embodiment, a blend is made by deagglomerating microparticles
comprising a first pharmaceutical agent, and then blending these microparticles (in one
or more steps) with one or more excipient materials and with a second pharmaceutical
agent. In a second embodiment, a blend is made of two or more pharmaceutical agents,
without an excipient material. For example, the method could include deagglomerating
microparticles comprising a first pharmaceutical agent, and then blending these
microparticles with a second pharmaceutical agent. Alternatively, niicroparticles
comprising the first pharmaceutical agent could be blended with microparticles
comprising the second pharmaceutical agent, and the resulting blend could then be
The blending can be conducted in one or more steps, in a continuous, batch, or
semi-batch process. For example, if two or more cxeipients are used, they can be
blended together before, or at the same time as. being blended with the microparticles
Generally, there arc two approaches for adding excipients to micropaarticles: wet
addition and dry addition. Wet addition typically involves adding an aqueous solution
of the excipient to the microparticles. The microparticles are then dispersed by mixing
and may require additional processing such as sonication to fully disperse the
microparticles. To create the dry dispersion, the water must be removed, for example,
using methods such as lyophilization. It would be desirable to eliminate the wet
processing, and thus use dry addition. In dry addition, the excipients are added to the
microparticles in the dry state and the components are blended using standard dry. solid
mixing techniques. Dry blending advantageously eliminates the need to dissolve or
disperse the excipient in a solvent before combining the excipient with the
microparticles and thus eliminates the need to subsequently remove that solvent. This
is particularly advantageous when the solvent removal step would otherwise require
lyophilization, freezing, distillation, or vacuum drying steps.
Content uniformity of solid-solid pharmaceutical blends is critical. Jet milling
can be conducted on the microparticles either before and/or after blending, to enhance
content uniformity. In a preferred embodiment, the microparticles are Wended with one
or more excipients of interest, and the resulting blend is then jet milled to yield a
uniform mixture of deagglomerated microparticles and excipient.
Jet-milling advantageously can provide improved wetting and dispersibility
upon reconstitution. In addition, the resulting microparticle formulation can provide
improved injectability, passing through the needle of a syringe more easily.
Jet-milling advantageously can provide improved dispersibility of the dry
powder, which provides for improved aerodynamic properties for pulmonary,
In another embodiment, the jet-milled microparticles or jet-milled blends of
microparticles/excipient can be further processed into a solid oral dosage form, such as
a power-filled capsule, a wafer, or a tablet. Jet-milling advantageously can provide
improved wetting and dispersibility upon oral dosing as a solid oral dosage form
formed from jet-milled microparticles or jet-milled microparticle/excipient blend.
The blending can be carried out using essentially any technique or device
suitable for combining the microparticles with one or more other materials (e.g.,
excipients), preferably to achieve uniformity of blend. For example, the blending
process can be performed using a variety of blenders. Representative examples of
suitable blenders include V-blenders, slant-cone blenders, cube blenders, bin blenders,
static continuous blenders, dynamic continuous blenders, orbital screw blenders,
planetary blenders, Forberg blenders, horizontal double-arm blenders, horizontal high
intensity mixers, vertical high intensity mixers, stirring vane mixers, twin cone mixers,
drum mixers, and tumble blenders. The blender preferably is of a strict sanitary design
required for pharmaceutical products.
Tumble blenders are preferred for batch operation. In one embodiment,
blending is accomplished by aseptically combining two or more components -(which
can include both dry components and small portions of liquid components) in a suitable
container. The container may, for example, be a polished, stainless steel or a glass
container. The container is then sealed and placed (i.e., secured) into the tumble
blender (e.g., TURBULA™, distributed by Glen Mills Inc., Clifton, NJ, USA, .and
made by Willy A. Bachofen AG, Maschinenfabrik, Basel, Switzerland) and then mixed
at a specific speed for an appropriate duration. (TURBULA™ lists speeds of 22, 32,
46, 67, and 96 rpm for its model T2F, which has a 2L basket and a maximum load of 10
kg.) Durations preferably are between about five minutes and.six hours, more
preferably between about 5 and 60 minutes. Actual operating parameters will depend,
for example, on the particular formulation, size of the mixing vessel, andquantity of
material being blended.
For continuous or semi-continuous operation, the blender optionally may be
provided with a rotary feeder, screw conveyor, or other feeder mechanism for controlled
introduction of one or more of the dry powder components into the blender.
Other Steps in the Formulation Process
The blended and jet milled product may undergo additional processing.
Representative examples of such processes include lyophilization or vacuum drying to
further remove residual solvents, temperature conditioning to anneal materials, size
classification to recover or remove certain fractions of the particles (i.e., to optimize the
size distribution), compression molding to form a tablet or other geometry, and
packaging. In one embodiment, oversized (e.g., 20 µm or larger, preferably 10 µm or
larger) microparticles are separated from the microparricles of interest. Some
formulations also may undergo sterilization, such as by gamma irradiation.
III. Applications for Using the Microparticle Formulations
In preferred embodiments, the microparticle formulations are administered to a
human or animal in need thereof, for the delivery of a therapeutic, diagnostic, or
prophylactic agent in an effective amount. The formulations can be administered in dry
form or dispersed in a physiological solution for injection or oral administration. The
dry form can be aerosolized and inhaled for pulmonary administration. The route of
administration depends on the pharmaceutical agent being delivered.
The microparticle formulations containing an encapsulated imaging agent may
be used in vascular imaging, as well as in applications to detect liver and renal diseases,
in cardiology applications, in detecting and characterizing tumor masses and tissues,
and in measuring peripheral blood velocity. The microparticles also can be linked with
ligands that minimize tissue adhesion or that target the microparticles to specific
regions of the body in vivo as known in the art.
The invention can further be understood with reference to the following non-
Blending and jet milling experiments were carried out, combining PLGA
microspheres, TWEEN™ 80 (Spectrum Chemicals, New Brunswick, NJ), and mannitol
(Spectrum Chemicals). TWEEN™ 80 is hereinafter referred to as "TweenSO." Dry
blending was carried out based on the following relative amounts of each material: 39
mg of PLGA microspheres, 54.6 mg of mannitol, and 0.16 mg of TweenSO.
A TURBULA™ inversion mixer (model: T2F) was used for blending. An
Alpine Aeroplex Spiral Jet Mill (model: 50AS), with dry nitrogen gas as the injector
and grinding gases, was used for de-agglomeration. Four blending processes were
tested, and three different jet mill operating conditions were tested for each of the four
blending processes, as described in Examples 1-4.
In all of the studies, the dry powder was fed manually into the jet mill and hence
the powder feed rate was not constant. It should be noted that although the powder
feeding was manual, the feed rate was calculated to be approximately 1.0 g/min. for all
of the studies. Feed rate is the ratio of total material processed in one batch to the total
batch time. Particle size measurement of the jet milled samples, unless otherwise
indicated, was conducted using a Coulter Multisizer II with a 50 µm aperture. Where
aerodynamic particle size is reported, the analysis was performed using an Aerosizer
The PLGA microspheres used in Examples I -4 originated from the same batch
("Lot A"). The microspheres were prepared as follows: A polymer emulsion was
prepared, composed of droplets of an aqueous phase suspended in a continuous
polymer/organic solvent phase. The polymer was a commercially obtained
poly(lactide-co-glycolide) (PLGA) (50:50), and the organic solvent was methylene
chloride. The resulting emulsion was spray dried at a flow rate of 150 mL/min with an
outlet temperature of 12 °C on a custom spray dryer with a drying chamber.
The PLGA microspheres used in Example 5 were from Lot A as described
above and from Lot B and Lot C, which were prepared as follows: Lot B: An emulsion
was created as for Lot A, except that the polymer was provided from a different
commercial source. The resulting emulsion was spray dried at a flow rate of 200
mL/min with an outlet temperature of 12 °C on a custom spray dryer with a drying
chamber. Lot C: An emulsion was created in the same manner as for Lot B, except that
the resulting emulsion was spray dried at a flow rate of 150 mL/min. Table A below
provides information describing the spray drying conditions and bulk microspheres
Example 1: Jet Milling of PLGA Microspheres/Excipienr Blend
(Made by Dry/Dry Two-Step Blending)
Blending was conducted in two dry steps. In the first step, 5.46 g of mannitol
and 0.16 g of Tween80 were added into a 125 mL glass jar. The jar was then set in the
TURBULA™ mixer for 15 minutes at 46 min-1. In the second step, 3.9 g of PLGA
microspheres were added into the glass jar containing the blended mannitol and
Tween80. The jar was then set in the TURBULA™ mixer for 30 minutes at 46 min-1.
A dry blended powder was produced. The dry blended powder was then fed manually
into a jet mill for particle deagglomeration. Three sets of operating conditions for the
jet mill were used, as described in Table 1.
The resulting jet milled samples were analyzed for particle size. For comparison, a
representative sample of mannitol (pre blending and jet milling), and a control sample
(blended but not jet milled) were analyzed. The Coulter Multisizer II results are shown
in Table 2.
By comparing the data of the control sample and jet milled.samples, it can be inferred
that the jet milling provides significant particle deagglomeralion. As the grinding air
pressure was increased, Xn stayed nearly constant, but Xv decreased.
Example 2: Jet Milling of PLGA Microspheres/Excipient Blend
Made by Wet/Dry Two-Step Blending
Blending was conducted in two steps: one wet and one dry. In the first, step,
mannitol and Tween80 were blended in liquid form. A 500 mL quantity of
Tween80/mannitol vehicle was prepared from TweenSO, mannitol, and water. The
vehicle had concentrations of 0.16 % Tween80 and 54.6 mg/mL mannitol. The vehicle
was transferred into a 1200 mL Virtis glass jar and then frozen'with liquid nitrogen.
The vehicle was frozen as a shell aTound the inside of the jar in 3.0 minutes, and then
subjected to vacuum drying in a Virtis dryer (model: FreezeMobile 8EL) at 31 mTorr
for 115 hours. At the end of vacuum drying, the vehicle was in the form of a powder,
believed to be the Tween80 homogeneously dispersed with the mannitol. In the second
step, 3.9 g of PLGA microspheres were added into the glass jar containing (the blended
mannitol and TweenSO. The jar was then set in the TURBUL.A™ mixer for 30 minutes
at 46 min-1 A dry blended powder was produced. The dry blended powdet was then
fed manually into a jet mill for particle deagglomeration. Three sets of operating
conditions for the jet mill were used, as described in Table 3.
The resulting jet milled samples were analyzed for particle size. For comparison, a
control sample (blended but not jet milled) was similarly analyzed. The Coulter
Multisi/er II results are shown in Table 4.
Again, by comparing the data of the control sample and jet milled samples, it can be
inferred that the jet milling provides significant panicle deagglomcration.
Example 3: Jet Milling of PLGA Microsphercs/Excipient Blend
Made by One-Step Dry Blending
In an attempt to reduce the blending time even further, a single blending step
was tested. First, 5.46 g of mannitol was added into a 125 mL glass jar. Then 0.16 g of
Tween80 and 3.9 g of PLGA microspheres were added iuto the jar. The jar was then
set in the TURBULA™ mixer for 30 minutes at 46 min-1. A dry blended powder was
produced. The dry blended powder was fed manually into a jet mill for particle
deagglomeration. Three sets of operating conditions for the jet mill were used, as
described in Table 5.
The resulting jet milled samples were analyzed for particle size. For comparison, a
control sample (blended but not jet milled) was similarly analyzed. The Coulter
Multisizer II values are shown in Table 6.
Again, by comparing the data of the control sample and jet milled samples, it can be
inferred that the jet milling provides significant particle deagglomcration.
Example 4: Jet Milling of PLGA Microspheres/Excipient Blend
(Made by One-Step Dry Blending - Higher Speed)
In an attempt to reduce the blending time even further, a single blending step
was tested using an increased blending speed for the TURBULA™ mixer as compared
to the speed used in Example 3. First, 5.46 g of mannitol was added into a 125 mL
glass jar. Then 0.16 g of Tween80 and 3.9 g of PLGA microspheres were added into
the jar. The jar was then set in the TURBULA™ mixer for 30 minutes, with the
blending speed was set at 96 min-1. A dry blended powder was produced. The dry
blended powder was fed manually into a jet mill for panicle deagglomeration. Three
sets of operating conditions for the jet mill were used, as described in Table 7.
The resulting jet milled samples were analyzed for particle size. For comparison, a
control sample (blended but not jet milled) was similarly analyzed. The Coulter
Mulrisizer II results are shown in Table S.
Again, by comparing the data of the control sample and jet milled samples, it can be
inferred that the jet milling provides significant particle deagglomeration.
Example 5: Effect of Jet Milling on Microsphere Residual Moisture Level
and Microsphere Morphology
Moisture content of PLGA microspheres was measured by Karl Fischer
titration, before and after jet milling. A Brinkman Metrohm 701 KF Titrinio titrator
was used, with chloroform-methanol (70:30) as the solvent and Hydranl-Componsite 1
as the titrant. The PLGA microspheres all were produced by spray drying as described
in the introduction portion of the examples, and then jet milled using the conditions
shown in Table 9. The grinding pressure was provided by ambient nitrogen at a
temperature of approximately 18 to 20 °C. The results are shown in Table 10.
The data in Table 10 show that a substantial reduction in moisture level occurred.
Because moisture levels in excess of 10% can render the powder formulation unstable
and not easily handled, jet milling appears to provide a highly useful and unexpected
ancillary benefit. That is, along with the deagglomeration, jet milling converted the
material into one that is more useable, more stable, and more easily handled.
FIGS. 3A-B show SEM images taken before and after jet milling (3.6 bar
injection pressure, 3.1 bar grinding pressure, sample 5.1 from Table 9), which indicate
that the microsphere morphology remains intact. In particular, FIG. 3 A is an SEM of
pre-milled microspheres, which clearly shows aggregates of individual particles, while
FIG. 3B is an SEM of post-milled microspheres, which do not exhibit similar
aggregated: clumps. In addition, the overall microsphere structure remains intact, with
no signs of milling or fracturing of individual spheres. This indicates that the jet milling
is deagglomerating or deaggregating the microparticles, and is not actually fracturing
and reducing the size of the individual microparticles.
Example 6: Effect of Jet Milling on Blend Residual Moisture Level
Blends were prepared as described in Example 1, and moisture levels were
measured as described in Example 5. Table 11 shows the moisture level of the dry
blend of microspheres (Lot A), mannitol, and TweenSO, as measured before jet milling
(control) and after jet milling, with grinding gas at a temperature of 24 °C.
The results demonstrate that the moisture content of the dry blended material was
reduced by jet milling, by about 80%. Increasing the grinding pressures did not
significantly decrease the moisture content further.
Example 7: Effect of Jet Milling on Residual Organic Solvent Level.
Residual methylene chloride content of PLGA microspheres was measured by
gas chromatography before blending and jet milling and then after jet milling.. The
porous PLGA microspheres (from Lot A described in Example 1) were blended with
mannitol at 46 rpm for 30 minutes and then jet milled (injection pressure 3.9 bar,
grinding pressure 3.0 bar, and air temperature 24 °C). The assay was run on a Hewlett
Packard model 5890 gas chromatograph equipped with a head space autosampler and
an electron capture detector. The column used was a DBWa as column (30 m x 0.25 mm
ED, 0.5 µm film thickness). Samples were weighed into a head space vial, which was
then heated to 40 °C. The head space gas was transferred to the column at a column
flowrate of 5 mL min, and then subjected to a 40 °C to 180 °C thermal gradient. The
results are shown in Table 12.
The results demonstrate that a substantial reduction in the level of residual methylene
chloride can be achieved by jet milling the microparticle dry blend formulations.
Publications cited herein and the materials for which they are cited are.
specifically incorporated by reference. Modifications and variations of the methods and
devices described herein will be obvious to those skilled in the art from the foregoing
detailed description. Such modifications and Variations are intended to come within the
scope of the appended claims.
1. A method for making a dry powder blend pharmaceutical formulation comprising:
forming microparticles which comprise a pharmaceutical agent;
blending the microparticles with at least one excipient, which is in the form of
particles having a volume average diameter that is greater than the volume average diameter of
the microparticles, to form a powder blend; and
jet milling the powder blend to deagglomerate at least a portion of any of the
microparticles which have agglomerated, while substantially maintaining the size and
morphology of the individual microparticles.
2. The method as claimed in claim 1, wherein the jet milling step reduces the residual
solvent or moisture content of the dry powder blend relative to the solvent or moisture content of
the non-jet milled dry powder blend, and/or improves the dispersability of the dry powder blend,
and/or reduces the amount of amorphous content of the pharmaceutical agent within the dry
3. The method as claimed in claim 1 or 2, wherein the excipient particles have a volume
average size between 10 and 500 microns.
4. The method as claimed in any of claims 1 to 3, wherein the excipient is selected from
bulking agents, preservatives, wetting agents, surface active agents, osmotic agents,
pharmaceutically acceptable carriers, diluents, binders, disintegrants, glidants, lubricants, and
5. The method as claimed in any of claims 1 to 3, wherein the excipient is selected from
lipids, sugars, amino acids, and polyoxyethylene sorbitan fatty acid esters, and combinations
6. The method as claimed in any of claims 1 to 3, wherein the excipient is selected from
lactose, mannitol, sorbitol, trehalose, xylitol, and combinations thereof.
7. The method as claimed in any of claims 1 to 3, wherein the excipient is selected from
binders, disintegrants, glidants, diluents, coloring agents, flavoring agents, sweeteners, lubricants,
and combinations thereof, which are suitable for use in a solid oral dosage form.
8. The method as claimed in any of claims 1 to 7, wherein two or more excipients are
blended with the microparticles.
9. The method as claimed in claim 8, wherein the two or more excipients are blended
together in a wet or dry blending step to form an excipient blend, which is then blended with the
10. The method as claimed in claim 8, wherein the two or more excipients and the
microparticles are blended together in a single step.
11. The method as claimed in any of claims 1 to 10, wherein the microparticles optionally
comprise a biocompatible polymer.
12. A method for making the pharmaceutical formulation as claimed in claim 1, wherein said
microparticles are formed by a spray drying process which comprises: (a) spraying an emulsion,
solution, or suspension which comprises a solvent and a pharmaceutical agent through an
atomizer to form droplets of the solvent and the pharmaceutical agent; and (b) evaporating a
portion of the solvent to solidify the droplets and form microparticles.
13. The method as claimed in claim 12, wherein the emulsion, solution, or suspension
further comprises a biocompatible polymer.
14. The method as claimed in claim 13, wherein the biocompatible polymer is a synthetic
polymer selected from poly(hydroxy acids), polyanhydrides, poly(ortho)esters, polyurethanes,
poly(butyric acid), poly(valeric acid), poly(lactide-co-caprolactone), blends and copolymers
15. The method as claimed in claim 1, wherein the microparticles comprise a shell material
surrounding a core of the pharmaceutical agent.
16. The method as claimed in claim 15, wherein the shell material is selected from polymers,
amino acids, sugars, proteins, carbohydrates, and lipids.
17. The method as claimed in claim 1, wherein the jet milling is performed with a feed gas
and/or grinding gas supplied to the jet mill at a temperature of less than 100 °C.
18. The method as claimed in claim 1, wherein the microparticles have a number average
size between 1 and 10 µm.
19. The method as claimed in claim 1, wherein the microparticles have a volume average size
between 2 and 50 µm.
20. The method as claimed in claim 1, wherein the microparticles have an aerodynamic
diameter between 1 and 50 µm.
21. The method as claimed in claim 1, wherein the microparticles comprise microspheres
having voids or pores therein.
22. The method as claimed in claim 1, wherein the pharmaceutical agent is a therapeutic or
23. The method as claimed in claim 22, wherein the therapeutic or prophylactic agent is
hydrophobic and the microparticles comprise microspheres having voids or pores therein.
24. The method as claimed in claim 22, wherein the therapeutic or prophylactic agent is
selected from non-steroidal anti-inflammatory agents, corticosteroids, anti-neoplasties, anti-
microbial agents, anti-virals, anti-bacterial agents, anti-fungals, anti-asthmatics, bronchiodilators,
antihistamines, immunosuppressive agents, anti-anxiety agents, sedatives/hypnotics, anti-
psychotic agents, anti-convulsants, and calcium channel blockers.
25. The method as claimed in claim 22, wherein the therapeutic or prophylactic agent is
selected from celecoxib, rofecoxib, docetaxel, paclitaxel, acyclovir, albuterol, alprazolam,
amiodaron, amoxicillin, anagrelide, bactrim, beclomethasone dipropionate, biaxin, budesonide,
bulsulfan, calcitonin, carbamazepine, ceftazidime, cefprozil, ciprofloxacin, clarithromycin,
clozapine, cyclosporine, diazepam, estradiol, etodolac, famciclovir, fenofibrate, fexofenadine,
fomoterol, flunisolide, fluticasone propionate, gemcitabine, ganciclovir, , granulocyte colony-
stimulating factor, insulin, itraconazole, lamotrigine, leuprolide, loratidine, lorazepam,
meloxicam, mesalamine, minocycline, modafinil, mometasone, nabumetone, nelfinavir
mesylate, olanzapine, oxcarbazepine, parathyroid hormone-related peptide, phenytoin,
progesterone, propfol, ritinavir, salmeterol, sirolimus, SN-38, somatostatin, sulfamethoxazole,
sulfasalazine, testosterone, tacrolimus, tiagabine, tizanidine, triamcinolone acetonide,
trimethoprim, valsartan, voriconazole, zafirlukast, zileuton, and ziprasidone.
26. The method as claimed in claim 1, wherein the pharmaceutical agent comprises a
Methods are provided for making a dry powder blend pharmaceutical formulation
comprising (i) forming microparticles which comprise a pharmaceutical agent: (ii)
providing at least one excipient in the form of particles having a volume average diameter
that is greater than the volume average diameter of the microparticles: (iii) blending the
microparticles with the excipient to form a powder blend: and (iv) jet milling the powder
blend to deagglomerate at least a portion of any of the microparticles which have
agglomerated, while substantially maintaining the size and morphology of the individual
microparticles. Jet milling advantageously can eliminate the need for more complicated
wet deagglomeration processes, can lower residual moisture and solvent levels in the
microparticles (which leads to better stability and handling properties for dry powder
formulations) and can improve wettability, suspendability, and content uniformity of dry
powder blend formulations.
|Indian Patent Application Number||01037/KOLNP/2005|
|PG Journal Number||10/2008|
|Date of Filing||31-May-2005|
|Name of Patentee||ACUSPHERE, INC.|
|Applicant Address||500 ARSENAL STREET WATERTOWN, MA 02472-2806|
|PCT International Classification Number||A61K 9/00|
|PCT International Application Number||PCT/US2003/037100|
|PCT International Filing date||2003-11-20|