Title of Invention

AQUEOUS COMPOSITITIONS CONTAINING METRONIDAZOLE

Abstract An aqueous solution of metronidazole in which the concentration of metronidazole is higher than 0.75%. The solution contains a combination of solubility-enhancing agents, one of which is a cyclodextrin such as beta-cyclodextrin and the second is a compound other than a cyclodextrin. Methods of manufacture and therapeutic use of the solution are disclosed. (FIG. - 1)
Full Text AQUEOUS COMPOSITIONS CONTAINING METRONIDAZOLE
The invention pertains to the field of topically applied
medications for treatment of skin and mucosal disorders. In
particular, the invention pertains to aqueous compositions
containing metronidazole as the active ingredient.
BACKGROUND OF THE INVENTION
Metronidazole, 1-(2-hydroxyethyl)-2-methyl-5-
nitroimidazole, has long been known as an effective drug to
treat a variety of disorders, and is especially well known for
the treatment of various protozoal diseases. As a topical
therapy, metronidazole has also been shown to be useful in
treating various skin disorders, including acne rosacea,
bacterial ulcers, and perioral dermatitis. See, Borgman, U.S.
Patent No. 4,837,378. Metronidazole has been found to have an
anti-inflammatory activity when used topically to treat
dermatologic disorders. See, Czernielewski, et al., U.S.
Patent No. 5,849,776. Metronidazole may also be used as an
intravaginal therapeutic agent for the treatment of bacterial
vaginosis. See, Borgman, U.S. Patent No. 5,536,743.
Compositions containing metronidazole for treatment of
dermatologic disorders are available in cream, lotion and gel
forms. One commercially available metronidazole cream
product, NORITATEJ (Dermik Laboratories, Inc., Collegeville,
PA 19426 USA) contains 1% metronidazole in which the insoluble
drug is suspended in the opaque cream. A commercially
available metronidazole gel product, METROGEL7 (Galderma
Laboratories, Inc. Fort Worth, Texas, 76133 USA), contains
0.75% metronidazole which is solubilized to produce a clear
gel.
For the treatment of many dermatologic and mucosal
disorders, it is often preferable to use a solubilized water-
based formulation, such as a gel, rather than a cream, lotion
or an ointment. Creams, lotions (typically oil in water
emulsions) and ointments (typically petroleum jelly based
compositions) are often comedogenic, acnegenic, or not
cosmetically appealing to patients. Solubilized topical
products are generally more bioavailable than products in
which the active ingredient is insoluble.
The oil-based cream and ointment metronidazole
formulations have an advantage over presently available gel-
based formulations in that oil-based formulations may contain
a concentration of metronidazole of 1%. Aqueous-based gel
compositions are limited to a concentration of metronidazole
of 0.75% because of the poor solubility of metronidazole in
water.
Cyclodextrins have been shown to enhance the solubility
of various drugs in aqueous solutions. An amphiphilic or
lipophilic drug, such as metronidazole, is partially or
completely enclosed within this cage structure, thereby
increasing the solubility of the drug in aqueous media.
Cyclodextrins have certain disadvantages, however, including
expense, limitations of cyclodextrin solubility,
incompatibility in certain vehicles, and potential for local
and systemic toxicity.
Several authors have described the use of beta-
cyclodextrin (BCD) in combination with metronidazole. Kata
and Antal, Acta Pharmaceutica Hungarica, 54:116-122 (1984),
disclose a marked increase in the rate of dissolution of
metronidazole when dissolved in a solution containing BCD at
37°C. The stability of the BCD/metronidazole solutions is not
addressed. Major problems with the use of BCD to solubilize
drugs such as metronidazole is that BCD has a relatively low
solubility in water and is a relatively inefficient
solubilizer, particularly for lipophilic or amphiphilic drugs
such as metronidazole. Additionally, cyclodextrins, such as
BCD and its derivatives, are expensive and the drug
formulations containing BCD as a solubilizing agent likewise
become expensive. A need exists for a way to increase the
solubility of drugs which requires a reduced concentration of
BCD.
Solubility enhancing agents other than cyclodextrins have
been described. Yie W. Chien, Journal of Parenteral Science
and Technology, 38(l):32-36 (Jan. 1984), discloses that
niacinamide is a solubility enhancing agent that can increase
the water solubility of MTZ. Chien further discloses that the
water soluble vitamins ascorbic acid, and pyridoxine are
solubility enhancing agents for aqueous solutions. Chien
discloses that the solubility of metronidazole in water
increases linearly with relation to the concentration of these
water soluble vitamins in the solution. The Chien article is
incorporated herein by reference. The prior art does not
address the combination of cyclodextrins, such as BCD, with
other solubility enhancing agents, such as niacinamide or
other water soluble vitamins.
SUMMARY OF THE INVENTION
It has been surprisingly discovered that the combination
of a cyclodextrin and a second solubility enhancing agent,
such as niacinamide or niacin, has a synergistic effect on the
aqueous solubility of amphiphilic or lipophilic chemical
compounds such as metronidazole. The second solubility
enhancing agent may be other than niacinamide or niacin. The
synergistic effect provided by the combination of cyclodextrin
and the second solubility enhancing agent permits the use of
lower concentrations of cyclodextrins than would be necessary
o obtain a desired level of solubility of the chemical
compound in the absence of the second solubility enhancing
agent. Because cyclodextrins are expensive, has limited
aqueous solubility, and is not entirely free of toxicity, the
invention provides an important way to greatly reduce costs in
the formulation and preparation of pharmaceutical
preparations, as well as to increase the solubilizing
capability of cyclodextrins such as BCD, and to obtain desired
concentrations of pharmacologic compounds while minimizing the
amount of cyclodextrins used..
As used herein, the term Asolubility enhancing [email protected] or
Asolubility enhancer means a chemical compound that, when
present in solution in a solvent, increases the solubility of
a second chemical compound, such as an active ingredient, in
the solvent, but which chemical compound is not itself a
solvent for the second chemical compound.
All concentrations referred to in this specification are
% w/w, unless indicated otherwise.
The invention is described below with reference to a
particular cyclodextrin, BCD, and a particular chemical
compound, metronidazole. It is conceived, however, that the
invention is applicable to other cyclodextrins, both
crystalline and non-crystalline, including alpha and gamma
cyclodextrins, and crystalline and non-crystalline derivatives
thereof, and other amphiphilic and lipophilic chemical
compounds besides metronidazole.
Physically stable aqueous solutions of higher than 0.75%
metronidazole (MTZ) may be obtained by combining in the
solution a first solubility enhancing agent which is a
cyclodextrin, such as beta-cyclodextrin (BCD),. and a second
solubility enhancing agent, such as niacinamide or niacin.
The combination of the cyclodextrin and the second solubility
enhancing agent provides a synergistic effect in increasing
the solubility of MTZ in water. These discoveries permit the
production of aqueous MTZ solutions, including solutions that
are gels, at levels of 1% MTZ or higher. At such levels, MTZ
may be effectively used as a topical medicament.
In one embodiment, the invention is an aqueous solution
having a concentration of MTZ higher than 0.75% w/w,
preferably about 1% or higher. The aqueous solution contains
a cyclodextrin, such as BCD, as a first solubility enhancing
agent and a second solubility enhancing agent, such as niacin
or niacinamide. Preferably, the level of each of the
cyclodextrin and the second solubility enhancing agent is less
than that which, in the absence of the other solubility
enhancing agent, would provide for a dissolved concentration
of the MTZ to the level of that present in the aqueous
solution. If desired, however, the solution may contain an
excess of the second solubility enhancing agent. Most
preferably, the enhanced solubility of MTZ in the combination
solution is higher than the sum of the enhanced solubilities
of MTZ in two solutions, each of which contains a single
solubility enhancer at the concentration present in the
combination solution. Preferably, the solution is
substantially free of aqueous solubility-enhancing agents
other than a cyclodextrin and the second solubility enhancing
agent. Preferably, the solution is an aqueous gel.
In another embodiment, the invention is a method for the
manufacture of an aqueous solution of MTZ having a
concentration greater than 0.75%, preferably about 1.0% or
higher. The method includes combining MTZ and two solubility
enhancing agents, one of which is a cyclodextrin such as BCD,
in a water based solution wherein the concentration of the
final aqueous solution of MTZ is higher than 0.75%.
Preferably, the level of each of the cyclodextrin and the
second solubility enhancing agent is less than that which, in
the absence of the other solubility enhancing agent, would
provide for a dissolved concentration of the MTZ to the level
of that present in the aqueous solution. If desired, however,
an excess of the second solubility enhancing agent may be
used. Most preferably, the enhanced solubility of MTZ in the
combination solution is higher than the sum of the enhanced
solubilities of MTZ in two solutions, each of which contains a
single solubility enhancer at the concentration present in the
combination solution. Preferably, a gelling agent is further
combined in the solution, preferably after addition of the MTZ
and the solubility-enhancing agents.
In another embodiment, the invention is a method for the
treatment of a dermatologic or mucosal disorder. The method
includes topically applying to affected areas an aqueous
solution of MTZ and a cyclodextrin, such as BCD, and a second
solubility enhancing agent, such as niacin or niacinamide.,
which solution has a concentration of MTZ higher than 0.75%,
preferably about 1.0% or higher. Preferably, the level of
each of the cyclodextrin and the second solubility enhancing
agent is less than that which, in the absence of the other
solubility enhancing agent, would provide for a dissolved
concentration of the MTZ to the level of that present in the
aqueous solution. If desired, however, the solution may
contain an excess of the second solubility enhancing agent.
Most preferably, the enhanced solubility of MTZ in the
combination solution is higher than the sum of the enhanced
solubilities of MTZ in two solutions, each of which contains a
single solubility enhancer at the concentration present in the
combination solution. Preferably, the aqueous solution is a
gel.
In another embodiment, the invention is a kit for the
treatment of a dermatologic or mucosal disorder. The kit of
the invention includes a container that contains an aqueous
solution of MTZ and which aqueous solution contains a first
solubility enhancing agent which is a cyclodextrin, such as
BCD, and a second solubility enhancing agent such as niacin or
niacinamide. Preferably, the level of each of the
cyclodextrin and the second solubility enhancing agent is less
than that which, in the absence of the other solubility
enhancing agent, would provide for a dissolved concentration
of the MTZ to the level of that present in the aqueous
solution. If desired, however, the solution may contain an
excess of the second solubility enhancing agent. Most
preferably, the enhanced solubility of MTZ in the combination
solution is higher than the sum of the enhanced solubilities
of MTZ in two solutions, each of which contains a single
solubility enhancer at the concentration present in the
combination solution. Preferably, the aqueous solution is a
gel.
BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 shows a diagrammatic representation of a
preferred embodiment of the kit of the invention.
DETAILED DESCRIPTION OF THE INVENTION
It has been unexpectedly discovered that stable aqueous
solutions of metronidazole (MTZ) of greater than 0.75% w/w,
and even about 1.0% or higher, are able to be obtained by
using a combination of solubility-enhancing agents, wherein
one of the solubility enhancing agents is a cyclodextrin, such
as BCD, and the second solubility enhancing agent is other
than a cyclodextrin. Examples of suitable second enhancing
agents include niacin and niacinamide.
As used in this specification, the term Astable refers
to physical, rather than chemical, stability. In accordance
with the invention, the metronidazole solutions of the
invention are physically stable, that is substantially no
crystal or precipitate from solution, when stored at
refrigerated temperatures of 5EC for at least 7 days.
The physically stable aqueous solutions of metronidazole
at concentrations greater than 0.75% are obtained without the
substantial presence of water-miscible organic solvents, such
as ethyl alcohol or propylene glycol, which may be irritating
to intact or damaged skin or mucosal surfaces. The
elimination of these organic solvents provides a therapeutic
solution that has decreased potential for irritation and makes
the solutions especially good for treating topical
dermatologic conditions, such as rosacea, that may be worsened
by irritating chemicals present in a therapeutic formulation.
However, if desired, such organic solvents may be included in
the solution, up to a concentration of about 10%. In a most
preferred embodiment, the aqueous solutions are substantially
free of organic solvents for MTZ.
The stable aqueous MTZ solutions of the invention have a
concentration of MTZ greater than 0.75% w/w. Preferably, the
concentration of MTZ in the solution of the invention is about
1.0%. In accordance with the invention, the concentration of
MTZ in aqueous solution may be even higher, such as 1.25%,
1.5%, 2.0%, or 2.5%, or more. At a level of 1% or higher of
MTZ, the aqueous solution may be effectively used
therapeutically as a topical formulation.
The solution is preferably in the form of a gel.
Therefore, the aqueous MTZ solution preferably contains a
gelling agent. Any gelling agent that is water-dispersible
and forms an aqueous gel of substantially uniform consistency
is suitable for use in the solution of the invention so long
as the gelling agent does not substantially interfere with the
water solubility of MTZ or with the therapeutic efficacy of
the solution. ASubstantially interferes means that the
inclusion of the gelling agent decreases the solubility of MTZ
to 0.75% w/w or less in aqueous solution. A preferred gelling
agent is hydroxyethylcellulose (NATROSOLJ, Hercules Inc.,
Wilmington, DE, USA). Examples of other suitable gelling
agents include carboxyvinyl polymers, such as CARBOPOL7 934,
940, and 941 (Noveon, Inc., Akron, OH, USA).
The level of the cyclodextrin in the solution may be
varied depending upon the desired dissolved concentration of
MTZ. In general, it is preferable to use as low a
concentration of cyclodextrin as possible to obtain the
desired concentration of MTZ because cyclodextrins are
expensive, of limited aqueous solubility, not entirely free of
toxicity, and the presence of cyclodextrin may be irritating
to certain intact and diseased skin and mucosal surfaces. In
accordance with the invention, the concentration of
cyclodextrin in aqueous solution may be between 0.1% and 20%,
or higher. Preferably, the concentration of cyclodextrin in
the solution is no more than about 5% w/w. In the case of
beta-cyclodextrin, the concentration in aqueous solution is
limited by its solubility in water. An aqueous solution,
such as a gel, of beta-cyclodextrin is saturated at a
concentration of about 0.5% at 5EC (refrigerator temperature).
The solutions, especially in gel formulation, are non-
tacky, fast-drying, and cosmetically elegant. The solutions,
including the gel formulations, are physically stable at 5EC
(refrigerator temperature) or room temperature conditions for
at least 7 days. No crystal formation or precipitation is
observed after one week at 5°C.
It is preferred that the aqueous solution of the
invention be substantially free of pharmacologically active -
compounds other than MTZ having a water-solubility which is
increased by the presence of cyclodextrins. These other
compounds may act as competitors for the sequestration sites
within the cyclodextrin cage structure and reduce the MTZ
solubility enhancement by the cyclodextrin. Multiple solutes
that are increased in solubility by cyclodextrins may be
utilized in the solutions so long as the level of cyclodextrin
and the second solubility enhancer in the solution is
sufficiently high to result in the desired dissolved
concentration of MTZ, even in the presence of the competitor
solute.
In a preferred embodiment of the invention, the amount of
cyclodextrin in the solution is at a level below that which
enhances the solubilization of MTZ to the level desired, and a
second solubility enhancer, such as niacinamide or niacin, is
included in the solution at a level that permits the desired
concentration of MTZ in aqueous solution to be attained. For
example, if a stable 1% MTZ aqueous solution is desired, 0.1%
to 1.0% BCD may be used and an amount of niacinamide or niacin
may be combined in the solution to bring the solubility of MTZ
to 1%. The amount of niacinamide to be combined in the
solution is less than that which, without the presence of BCD
in the solution, can enhance the solubility of MTZ
sufficiently to obtain a 1% solution of MTZ, or whatever level
of MTZ is desired. In accordance with this embodiment of the
invention for a 1% aqueous solution of MTZ, the concentration
of BCD % w/w in the solution is preferably at a level of 1.0%
or less and the concentration of niacinamide or niacin equal
to or more than that of BCD.
The aqueous solutions, including the aqueous gels, of the
invention may be made in any way that results in a stable MTZ
concentration of greater than 0.75%, preferably of 1.0% or
higher. Preferably, the solubility enhancers and the MTZ are
combined in water, or a water-based solution, before the
addition of a gelling agent, or at least before gelling of the
solution occurs. Preferably, the solubility enhancers are
dissolved in water before addition of the MTZ.
In a preferred method of manufacture of the aqueous
solution of the invention, an aqueous solution of BCD and
niacinamide or niacin is prepared, wherein the levels of BCD
and niacinamide or niacin are as described above.
Metronidazole is then added to the solution. The amount of
metronidazole added to the solution may be an amount
calculated to provide the desired concentration of MTZ or it
may be an excess amount of MTZ. The solution is preferably
stirred or agitated at an elevated temperature and then
permitted to cool to room or refrigerator temperature. A
gelling agent, if desired, is preferably added at any time
after the addition of MTZ to the solution. Most preferably,
the gelling agent is added to the solution after the agitation
of the solution, during the cooling of the solution, or
following cooling of the solution.
The solutions of the invention, including gels, may be
used for the topical treatment of dermatologic or mucosal
disorders that are responsive to therapy with metronidazole.
In accordance with the method of treatment of the invention, a
stable aqueous solution containing metronidazole at a
concentration higher than 0.75% w/w, preferably about 1% or
higher, is topically applied to skin or mucosal surfaces in
need of such therapy. The applied solution preferably
contains a cyclodextrin like BCD, as described above, in
combination with niacin or niacinamide, as described above.
The therapeutic method of the invention may be used to
treat any disorder that is responsive, or potentially
responsive, to metronidazole therapy. Examples of disorders
that are suitably treated in accordance with the invention
include inflammatory lesions on the skin, oral mucosa, or
vaginal mucosa, diabetic foot ulcers, and certain infectious
diseases that may be treated topically. In a preferred
embodiment, the method of the invention is used to treat
rosacea.
At concentrations of about 1% or higher, the application
of the metronidazole solution is preferably only once daily.
The solution is applied on a daily basis, one or more times
per day, for a time sufficient to produce an amelioration or a
cure of the disorder. In certain chronic disorders, the
solution may be applied one or more times daily for a
prolonged period to prevent worsening of the disorder.
In another embodiment of the invention, a kit (Figure 1)
is provided for the topical treatment of skin or mucosal
disorders. The kit contains a jar 101 or other container
suitable for holding an aqueous metronidazole solution as
described herein, and instructions (not illustrated) for
applying the solution topically to affected areas of the skin
or mucosal surface. Preferably, the metronidazole solution
has a concentration of metronidazole of about 1% or higher and
the instructions call for applying the metronidazole solution
to affected areas once daily. The jar 101 is preferably
packaged within a box 102, upon which additional information,
such as instructions, may be written.
The following non-limiting examples provide a further
description of the invention.
Example 1
All solutions in the following examples contain the
components listed as the generic formula or gel vehicle shown
in Table 1.
Table 1
Different solutions according to Table 1 were made with
varying concentrations of beta-cyclodextrin (BCD). The
solutions of BCD were maintained at 5EC monitored weekly for
two weeks for signs of crystal or precipitate formation. The
results are shown in Table 2. The data show that the
saturated BCD solubility in the aqueous solutions at 5EC is
about 0.5%.
Table 2
Example 2
Different concentrations of metronidazole were prepared
with the gel vehicle of Example 1 containing 0.5% BCD. The
metronidazole (MTZ)/BCD solutions were maintained at 5EC for
one week. The results are shown in Table 3.
Table 3
From this study, the stable solubility of metronidazole
in the gel vehicle containing 0.5% BCD at 5°C was determined to
be about 0.8% w/w.
Example 3
A similar study using various concentrations of
niacinamide showed that the concentration of niacinamide
required to obtain a stable aqueous gel solution of 1.0%
metronidazole is about 3%. Various gel solutions of Table 1
were prepared with a concentration of 1.0% metronidazole and
containing either 0.5% or 1.0% BCD and differing
concentrations of niacinamide. The gels were maintained at
5EC for one week to observe for precipitate or crystal
formation. The results are shown in Table 4.
Table 4
The results in Table 4 show that concentrations of BCD
and niacinamide as low as 0.5% and 1.0%, respectively, may be
used together to obtain a physically stable aqueous gel
solution of 1.0% metronidazole.
Example 4
Various gel solutions of Table 1 were prepared with a
concentration of 1.0% metronidazole and various concentrations
of niacin. The pH was adjusted to 5.0 +/- 0.15 with
trolamine. The solutions were maintained at 5EC for one week
to observe evidence of precipitation or crystal formation.
The results are shown in Table 5.
* - seven out of eight samples showed crystal formation
Table 5
The results in Table 5 show that the minimum
concentration of niacin required to obtain a stable 1.0%
metronidazole gel solution is greater than 0.5% and preferably
about 0.75%.
Example 5
Various solutions according to Table 1 with 1%
metronidazole, 0.5% niacin, pH adjusted to 5.0+/-0.15 and
varying concentrations of BCD. The solutions were maintained
at 5EC for one week to observe for crystal or precipitate
formation. The results are shown in Table 6.
Table 6
As shown in Table 6, using a combination of 0.5% niacin
and 0.5% BCD, a stable 1.0% aqueous gel solution of
metronidazole was produced.
The above data in Examples 1 to 5 show that BCD at its
maximum soluble aqueous concentration raises the stable
solubility of MTZ in aqueous solution, such as a gel, at 5°C by
0.1%, that is from 0.7% to 0.8%. A 3% concentration of
niacinamide is needed to increase MTZ aqueous solubility by
0.3% to 1%. Thus, niacinamide at about 3% raises the
physically stable solubility of MTZ in aqueous gel by an
amount that is about 3 times the increase provided by the
maximum soluble concentration of BCD.
When BCD and niacinamide are both utilized in the
solution, the two compounds act synergistically to increase
the solubility of MTZ in water. The data in Examples 1 to 5
show that when BCD is added to an aqueous solution at an
amount expected to yield an increase of 0.1% and niacinamide
is added at a level that is one third the amount of
niacinamide that is able to raise the solubility of MTZ by
0.3%, this combination results in a solubility of MTZ that is
0.3% above its unaided solubility.
Similar results were obtained using a 0.5% concentration
of niacin, a concentration which is below that which produces
a stable 1% solution of metronidazole. When this
concentration of niacin was combined with 0.5% BCD, a
concentration that provides only a 0.1% increase in MTZ
aqueous solubility to 0.8%, the solubility of MTZ was
synergistically increased to 1% at a pH of about 5.
Various modifications of the above described
invention will be evident to those skilled in the art. For
example, more than one cyclodextrin may be used, such as beta-
cyclodextrin and hydroxypropyl-beta-cyclodextrin. Similarly,
the second solubility enhancing agent may be a multiplicity of
solubility enhancing agents, such as both niacin and
niacinamide. It is intended that such modifications are
included within the scope of the following claims.
WE CLAIM :
1. An aqueous solution that is physically stable for at
least one week at 5°C comprising metronidazole, a first
solubility enhancing agent which is betacyclodextrin, and a
second solubility enhancing agent which is niacin or
niacinamide, wherein in the solution, the concentration of
metronidazole is higher than 0.75% w/w.
2. The aqueous solution as claimed in claim 1 wherein
the concentration of metronidazole is 1.0 % w/w or higher.
3. The aqueous solution as claimed in claim 1 wherein
the concentration of betacyclodextrin is about 0.5% w/w or
higher and the concentration of niacinamide or niacin is about
0.5% w/w or higher.
4. The aqueous solution as claimed in claim 1 wherein
the second solubility enhancing agent is niacinamide.
5. The aqueous solution as claimed in claim 1 wherein
the second solubility enhancing agent is niacin.
6. The aqueous solution as claimed in claim 1 wherein
the concentration of niacinamide or niacin is about 1.0% w/w
or higher.
7. The aqueous solution as claimed in claim 1 which is
a gel.
8. A method for making an aqueous solution of
metronidazole greater than 0.75% w/w comprising combining
metronidazole, beta-cyclodextrin (BCD), and niacin or
niacinamide in an aqueous fluid.
9. The method as claimed in claim 8 wherein the amount
of BCD that is combined in the aqueous fluid is sufficient to
provide a concentration of BCD in the solution of 0.5% w/w or
higher and wherein the aqueous solution is physically stable
when stored for one week at 5°C.
10. The method as claimed in claim 8 wherein the
metronidazole is added to the aqueous fluid after the BCD and
the niacin or niacinamide are dissolved in the aqueous fluid.
11. The method as claimed in claim 8 which further
comprises, after the combination of metronidazole, BCD, and
the niacin or niacinamide, adding a gelling agent.
12. The method as claimed in claim 8 wherein niacinamide
is combined.
13. The method as claimed in claim 8 wherein niacin is
combined.
14. An aqueous solution made by the method as claimed in
claims 8 to 13.
15. A method for increasing the solubility of
metronidazole in aqueous solution comprising combining
metronidazole, betacyclodextrin, and niacinamide or niacin in
an aqueous fluid.
16. The method as claimed in claim 15 wherein the
concentration of betacyclodextrin in the fluid is about 0.5%
w/w or more and the concentration of niacinamide or niacin in
the fluid is about 1.0% or higher.
17. The method as claimed in claim 15 wherein the
aqueous solution is a gel.
18. The method as claimed in claim 15 which comprises
combining niacinamide in the fluid.
19. The method as claimed in claim 15 which comprises
combining niacin in the fluid.
20. The method as claimed in claim 15 wherein the
solubility of metronidazole is increased to 0.75% w/w or more.
21. The method as claimed in claim 15 wherein the
solubility of metronidazole is increased to about 1.0% w/w or
more.
22. A method for increasing the enhancing effect of
betacyclodextrin on the solubility of metronidazole in aqueous
fluid comprising combining niacin or niacinamide with the
betacyclodextrin in the aqueous fluid.
23. The method as claimed in claim 22 wherein the
concentration of betacyclodextrin in the fluid is about 0.5%
or more and the concentration of niacin or niacinamide is
about 1.0% w/w or more.
24. The method as claimed in claim 22 wherein niacin is
combined with the betacyclodextrin in the aqueous fluid.
25. The method as claimed in claim 22 wherein
niacinamide is combined with the betacyclodextrin in the
aqueous fluid.
26. An aqueous solution comprising metronidazole,
betacyclodextrin, and niacinamide, wherein the solution is
free of crystal or precipitate formation when stored for one
week at 5°C.
27. The aqueous solution as claimed in claim 26 wherein
the concentration of betacyclodextrin in the solution is 0.5%
w/w or higher.
28. The aqueous solution as claimed in claim 26 wherein
the concentration of betacyclodextrin is about 1% w/w or
higher.
29. The aqueous solution as claimed in claim 26 which is
an aqueous gel solution.
30. A method for obtaining an aqueous solution
containing metronidazole comprising combining in an aqueous
fluid metronidazole, betacyclodextrin, and niacinamide or
niacin, wherein the amount of the niacinamide or niacin
combined in the aqueous fluid is sufficient to provide a
dissolved concentration of betacyclodextrin greater than 0.5%
w/w at a temperature of 5°C.
31. The method as claimed in claim 30 wherein the
aqueous solution contains betacyclodextrin at a concentration
greater than 0.5% w/w.
32. The method as claimed in claim 30 wherein the
aqueous solution containing betacyclodextrin at a
concentration greater than 0.5% w/w and niacinamide is
physically stable for one week at 5°C.
33. The method as claimed in claim 30 wherein the
aqueous solution is an aqueous gel solution.
34. A kit for the topical treatment of dermatologic or
mucosal disorders comprising a container and the aqueous
solution as claimed in claim 1 within said container.
35. The kit as claimed in claim 34 wherein the
concentration of beta-cyclodextrin is 0.5% w/w or higher and
the concentration of niacin or niacinamide is about 1.0% w/w
or higher.
36. The kit as claimed in claim 34 wherein the
concentration of metronidazole is about 1% w/w or higher.
37. The kit as claimed in claim 34 wherein the aqueous
solution is a gel.
38. A method for obtaining an aqueous solution
containing betacyclodextrin at a concentration greater than
0.5% w/w comprising combining in an aqueous fluid
betacyclodextrin and niacinamide or niacin wherein the amount
of the niacinamide or niacin combined in the aqueous fluid is
sufficient to provide a dissolved concentration of
betacyclodextrin greater than 0.5%w/w at a temperature of 5°C.
39. The method as claimed in claim 38 wherein the
aqueous solution containing betacyclodextrin at a
concentration greater than 0.5% w/w and niacinamide or niacin
is physically stable for one week at 5°C.
40. The method as claimed in claim 38 wherein the
aqueous solution is an aqueous gel solution.
41. The method as claimed in claim 38 wherein the
concentration of niacin or niacinamide in the aqueous solution
is 0.5% w/w or higher.
42. The method as claimed in claim 38 wherein the
concentration of niacin or niacinamide in the aqueous solution
is 1.0% w/w or higher.
43. An aqueous solution as claimed in claim 1, for the
topical treatment of a dermatologic or mucosal disorder.
44. The aqueous solution as claimed in claim 43 wherein
the dermatologic disorder is rosacea.
45. The aqueous solution as claimed in claim 43 or 44,
wherein the solution is effective in the treatment of the
dermatologic disorder when applied once daily.
An aqueous solution of metronidazole in which the
concentration of metronidazole is higher than 0.75%. The
solution contains a combination of solubility-enhancing
agents, one of which is a cyclodextrin such as beta-
cyclodextrin and the second is a compound other than a
cyclodextrin. Methods of manufacture and therapeutic use of
the solution are disclosed.

Documents:

882-kolnp-2004-granted-abstract.pdf

882-kolnp-2004-granted-assignment.pdf

882-kolnp-2004-granted-claims.pdf

882-kolnp-2004-granted-correspondence.pdf

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

882-kolnp-2004-granted-drawings.pdf

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

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

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

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

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

882-kolnp-2004-granted-gpa.pdf

882-kolnp-2004-granted-letter patent.pdf

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

882-kolnp-2004-granted-specification.pdf


Patent Number 215521
Indian Patent Application Number 00882/KOLNP/2004
PG Journal Number 09/2008
Publication Date 29-Feb-2008
Grant Date 27-Feb-2008
Date of Filing 24-Jun-2004
Name of Patentee DOW PHARMACEUTICAL SCIENCES
Applicant Address 1330A REDWOOD SAY, PETALUMA CA 94954-6542 USA.
Inventors:
# Inventor's Name Inventor's Address
1 CHANG YUNIK 814 THIRD STREET WEST, SONOMA, CA-94476 USA
2 DOW GORDON J 4189 CHAPARRAL COUIRTY , US CITIZEN SANTA ROSA. CA 95409 USA
PCT International Classification Number A61K
PCT International Application Number PCT/US02/36063
PCT International Filing date 2002-11-07
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 10/033,835 2001-12-24 U.S.A.