U.S. patent application number 13/693987 was filed with the patent office on 2013-04-18 for pharmaceutical composition for external use.
This patent application is currently assigned to POLA PHARMA INC.. The applicant listed for this patent is Nihon Nohyaku Co., Ltd., Pola Pharma Inc.. Invention is credited to Katsumasa Ariyoshi, Hirokazu Kobayashi, Akira Nozawa.
Application Number | 20130096187 13/693987 |
Document ID | / |
Family ID | 38474687 |
Filed Date | 2013-04-18 |
United States Patent
Application |
20130096187 |
Kind Code |
A1 |
Kobayashi; Hirokazu ; et
al. |
April 18, 2013 |
PHARMACEUTICAL COMPOSITION FOR EXTERNAL USE
Abstract
A pharmaceutical composition for external use, including: i)
luliconazole represented by the following structural formula (1)
and/or a salt thereof; and ii) crotamiton.
(-)-(E)-[(4R)-(2,4-dichlorophenyl)-1,3-dithiolan-2-iliden]-1-imidazolyl
acetonitrile ##STR00001##
Inventors: |
Kobayashi; Hirokazu;
(Yokohama-shi, JP) ; Nozawa; Akira; (Yokohama-shi,
JP) ; Ariyoshi; Katsumasa; (Yokohama-shi,
JP) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Nihon Nohyaku Co., Ltd.;
Pola Pharma Inc.; |
Tokyo
Tokyo |
|
JP
JP |
|
|
Assignee: |
POLA PHARMA INC.
Tokyo
JP
NIHON NOHYAKU CO., LTD.
Tokyo
JP
|
Family ID: |
38474687 |
Appl. No.: |
13/693987 |
Filed: |
December 4, 2012 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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12281967 |
Sep 5, 2008 |
8349882 |
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PCT/JP2006/319708 |
Oct 2, 2006 |
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13693987 |
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Current U.S.
Class: |
514/440 |
Current CPC
Class: |
A61K 31/167 20130101;
A61K 47/18 20130101; A61K 9/08 20130101; A61P 17/00 20180101; A61K
31/4178 20130101; A61K 31/4015 20130101; C07D 409/06 20130101; A61P
31/10 20180101; A61K 31/385 20130101; A61K 9/0014 20130101; A61P
31/02 20180101; A61K 47/22 20130101 |
Class at
Publication: |
514/440 |
International
Class: |
A61K 31/385 20060101
A61K031/385; A61K 31/167 20060101 A61K031/167 |
Foreign Application Data
Date |
Code |
Application Number |
Mar 8, 2006 |
JP |
2006-062079 |
Aug 8, 2006 |
JP |
2006-215871 |
Claims
1. A pharmaceutical composition for external use, comprising: i)
(R)-luliconazole represented by the following structural formula
(1) and/or a salt thereof; and ii) crotamiton at a concentration of
0.1 to 40% by mass ##STR00005##
(-)-(E)-[(4R)-(2,4-dichlorophenyl)-1,3-dithiolan-2-iliden]-1-imidazolyl
acetonitrile Structural formula (1).
2. A pharmaceutical composition according to claim 1, wherein the
composition comprises crotamiton in an amount of 1 to 10% by mass
of the composition.
3. A pharmaceutical composition according to claim 1, wherein the
composition comprises (R)-luliconazole in an amount of 0.5 to 15%
by mass of the composition.
4. A pharmaceutical composition according to claim 1, wherein the
composition further comprises ethanol.
5. A pharmaceutical composition according to claim 4, wherein the
composition comprises ethanol in amount of 50 to 90% by mass of the
composition.
6. A method of treating mycotic disease comprising externally
administering the composition of claim 1 to an individual in need
of treatment.
7. A method according to claim 6, wherein the mycotic disease is
foot trichophytosis, trichophytosis corporis or trichophytosis on a
hard keratin portion.
8. A method according to claim 6, wherein the mycotic disease is
athlete's foot.
9. A method according to claim 6, wherein the mycotic disease is
onychomycosis.
10. A method according to claim 6, wherein the mycotic disease is a
mycotic disease of a nail.
11. A method according to claim 6, wherein the mycotic disease is
dermatomycosis.
12. A pharmaceutical composition according to claim 2, wherein the
composition comprises (R)-luliconazole in an amount of 0.5 to 15%
by mass of the composition.
13. A pharmaceutical composition according to claim 2, wherein the
composition further comprises ethanol.
14. A pharmaceutical composition according to claim 13, wherein the
composition comprises ethanol in amount of 50 to 90% by mass of the
composition.
15. A pharmaceutical composition according to claim 3, wherein the
composition further comprises ethanol.
16. A pharmaceutical composition according to claim 15, wherein the
composition comprises ethanol in amount of 50 to 90% by mass of the
composition.
17. A pharmaceutical composition according to claim 12, wherein the
composition further comprises ethanol.
18. A pharmaceutical composition according to claim 17, wherein the
composition comprises ethanol in amount of 50 to 90% by mass of the
composition.
19. A pharmaceutical composition for external use, consisting
essentially of: i)
(R)-(-)-(E)-[4-(2,4-dichlorophenyl)-1,3-dithiolan-2-iliden]-1-imid-
azolyl acetonitrile and/or a salt thereof; and ii) crotamiton at a
concentration of 0.1 to 40% by mass.
20. The pharmaceutical composition of any one of claims 1, 2, 3, 4,
12, or 14, wherein the pharmaceutical composition is formulated as
a lotion.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a divisional of U.S. application Ser.
No. 12/281,967, filed Sep. 5, 2008 which is the U.S. National Phase
under 35 U.S.C. .sctn.371 of International Application
PCT/JP2006/319708, filed Oct. 2, 2006, which was published in a
non-English language, which claims priority to JP Patent
Application No. 2006-062079, filed Mar. 8, 2006 and JP Patent
Application No. 2006-215871 filed Aug. 8, 2006. The above
applications are incorporated herein by reference.
TECHNICAL FIELD
[0002] The present invention relates to a pharmaceutical
composition for external use, and more particularly, to a
pharmaceutical composition for external use, which can be preserved
in a state where a decrease in optical purity is suppressed.
BACKGROUND ART
[0003] The Japanese archipelago extends from a subtropical zone to
a temperate zone and has a warm climate high in humidity, which is
liable to facilitate propagation of fungi such as molds. In
addition, due to westernization of clothes, people are now
accustomed to wearing shoes on feet. Accordingly, afoot serves as a
favorable environment for the propagation of the fungi, leading to
mycotic skin diseases that are serious social issues nowadays. Of
those, onychomycosis has a low complete cure rate and high
relapsing and reinfection rates. Therefore, an effective therapy
has been demanded.
[0004] Conventionally, treatments mainly using tolnaftate
formulations have been conducted on such diseases. In recent years,
imidazole-based antifungal agents, such as bifonazole and
itraconazole, are mainly used.
[0005] As the imidazole-based antifungal agents, there are
commercially available imidazole-based antifungal agents such as
those represented by the general formula (1) described below,
specifically, luliconazole represented by the structural formula
(1) below and lanoconazole represented by the structural formula
(2) below. A commercially available product called "Lulicon"
(registered trademark) is also present (e.g., see Patent Document 1
and Patent Document 2).
[0006] The luliconazole is an imidazole-based antifungal agent
having optical activity with a wide antifungal spectrum, in
particular, shows remarkable antifungal activity against
dermatophytes. In addition, the luliconazole is also characterized
in that its retention in the stratum corneum is extremely high, and
thus is a compound expected to be applied to treatment of
onychomycosis. Like other imidazole-based antifungal agents,
however, luliconazole and lanoconazole are agents having problems
in their solubility, so there is a need of using a solvent for
their preparation. On the other hand, in some cases, the
characteristic features of luliconazole may include a risk of a
decrease in its optical purity when it is stored in a dissolved
state under severe circumstances due to a type of a solvent used
for dissolution, temperature, acid and base, or the like. Besides,
such a decrease in optical purity may relate to a solvent. In other
words, with regard to a pharmaceutical composition for external use
containing luliconazole and/or a salt thereof, it is desirable to
provide means for increasing the solubility thereof while
suppressing a decrease in optical purity even under severe
environment.
[0007] A decrease in optical purity is a common phenomenon, which
sometimes occurs in an optically active compound according to
storage conditions, particularly under severe conditions at high
temperature. However, no means for suppressing the phenomenon is
known.
[0008] Heretofore, in a pharmaceutical technology for antifungal
agents, various studies have been conducted for increasing the
solubility thereof (see, for example, Patent Documents 3 to 5).
However, the antifungal agents to be dissolved show increases
different in their solubility. Therefore, the effect of one of them
cannot be directly applied to the other compounds. Among the
solvents, a solvent that acts to prevent the optically active
compound from a decrease in optical purity has not yet been
known.
[0009] On the other hand, as a pharmaceutical preparation
containing luliconazole and/or a salt thereof, a pharmaceutical
preparation containing a film-forming agent and a
polyoxypropylene/polyoxyethylene copolymer has been known (see, for
example, Patent Document 6), but one containing
N-methyl-2-pyrrolidone, propylene carbonate, or crotamiton has not
been known at all. In addition, a basic process for manufacturing
an imidazole-based compound is also already known in the art (see,
for example, Patent Document 7):
##STR00002##
General formula (1) where X represents a hydrogen atom or a
chloride atom.
##STR00003## [0010] Patent Document 1: JP 10-226686 A [0011] Patent
Document 2: JP 2-275877 A [0012] Patent Document 3: JP 5-306223 A
[0013] Patent Document 4: JP 7-206711 A [0014] Patent Document 5:
WO96/11710 [0015] Patent Document 6: WO03/105841 [0016] Patent
Document 7: JP 62-93227 A
DISCLOSURE OF THE INVENTION
Problem to be Solved by the Invention
[0017] The present invent has been made under such circumstances,
and an object of the present invention is to provide a technique of
dissolving luliconazole and/or a salt thereof (hereinafter, also
referred to as "luliconazole or the like") and preserving the
luliconazole or the like in a state where a decrease in optical
purity is suppressed.
Means for Solving the Problem
[0018] In consideration of such a situation, the inventors of the
present invention have made intensive studies and efforts to obtain
a technique of dissolving luliconazole and/or a salt thereof and
pre serving the luliconazole or the like in a state where a
decrease in optical purity is suppressed and have finally completed
the present invention by finding out that the luliconazole or the
like can be stored in a state where a decrease in optical purity
thereof is suppressed in addition to increase the solubility of the
luliconazole or the like by dissolving the luliconazole or the like
in an organic solvent, such as N-methyl-2-pyrrolidone, propylene
carbonate, or crotamiton. In other words, the present invention is
as follows:
[0019] (1) A pharmaceutical composition for external use,
including: i) luliconazole represented by the following structural
formula (1) and/or a salt thereof; and ii) one or two or more
selected from N-methyl-2-pyrrolidone, propylene carbonate, and
crotamiton.
##STR00004##
[0020] (2) A pharmaceutical composition for external use according
to the item (1), in which the pharmaceutical composition for
external use is provided for treatment or prevention of
onychomycosis.
Effects of the Invention
[0021] According to the present invention, a pharmaceutical
composition for external use to be stored in a state in which
luliconazole or the like is dissolved and prevented from a decrease
in optical purity thereof can be provided.
BEST MODE FOR CARRYING OUT THE INVENTION
[0022] (1) Luliconazole and/or a Salt Thereof as Essential
Components of a Pharmaceutical Composition for External Use
(Hereinafter, Referred to as Pharmaceutical Composition of the
Present Invention)
[0023] The pharmaceutical composition for external use of the
present invention contains as essential components luliconazole
and/or a salt thereof. The above-mentioned luliconazole is
represented by the above-mentioned structural formula (1). The
above-mentioned luliconazole is a known compound represented by
(-)-(E)-[(4R)-(2,4-dichlorophenyl)-1,3-dithiolan-2-iliden]-1-imidazolyl
acetonitrile. Its manufacturing method and the antifungal
properties are already known in the art. JP 62-93227 A (Patent
Document 7 above) can be used as reference.
[0024] In addition, "salt thereof" is not specifically limited as
far as it is physiologically acceptable. Preferable examples
thereof include: mineral acid salts such as hydrochloride, nitrate,
sulfate, and phosphate; organic acid salts such as citrate,
oxalate, lactate, and acetate; and sulfuric acid-containing salts
such as mesilate and tosilate. In terms of safety and solubility,
hydrochloride is more preferable.
[0025] In the pharmaceutical composition for external use of the
present invention, the content of luliconazole or the like is
preferably 0.1 to 30% by mass, more preferably 0.5 to 15% by mass
in total with respect to the total amount of the pharmaceutical
composition. The content of luliconazole or the like can be
determined based on its solubility and formulation
characteristics.
[0026] (2) Essential Component of Pharmaceutical Composition for
external use of the present invention: N-methyl-2-pyrrolidone,
propylene carbonate, or crotamiton
[0027] The pharmaceutical composition for external use of the
present invention contains one or two or more organic solvents
selected from N-methyl-2-pyrrolidone, propylene carbonate, and
crotamiton as an essential component. Obviously, for the organic
solvent, there may be used a single kind thereof or a combination
of two or more kinds thereof. In the pharmaceutical composition of
the present invention, among the above organic solvents, it is
preferable to contain at least N-methyl-2-pyrrolidone, particularly
both N-methyl-2-pyrrolidone and propylene carbonate. The organic
solvent of such a preferable aspect is excellent not only in action
of dissolving luliconazole or a salt thereof but also in action of
suppressing, in a dissolved state, a decrease in optical purity.
For exerting such an action sufficiently, the total content of such
a solvent is preferably 0.1 to 40% by mass, more preferably 1 to
10% by mass with respect to the total amount of the pharmaceutical
composition.
[0028] (3) Pharmaceutical Composition for External Use of the
Present Invention
[0029] The pharmaceutical composition for external use of the
present invention can contain any of components commonly used in
pharmaceutical compositions in addition to those described above,
as far as it does not impair the effects of the present
invention.
[0030] Preferable examples of such components include: hydrocarbons
such as vaseline and microcrystalline wax; esters such as jojoba
oil and cetaceum; triglycerides such as beef tallow and olive oil;
higher alcohols such as cetanol and oleyl alcohol; fatty acids such
as stearic acid and oleic acid; alcohols such as ethanol and
isopropanol; polyalcohols such as glycerin and 1,3-butanediol;
water; non-ionic surfactants; anionic surfactants; cationic
surfactants; amphoteric surfactants; thickeners such as polyvinyl
pyrrolidone and carbopol; preservatives; UV absorbers;
antioxidants; pigments; and powders. Those optional components and
the above-mentioned component are treated by common procedures,
whereby a pharmaceutical composition for external use of the
present invention can be produced. The pharmaceutical composition
for external use of the present invention is not specifically
limited as far as it is formulated into any of forms used for
pharmaceutical composition for external uses, and preferable
examples thereof include lotions, emulsions, gelatinizing agents,
cream pharmaceuticals, aerosols, nail enamel agents, and hide gel
patches. Of those, the lotions are most preferable. For stabilizing
the clarity and color of solution such as luliconazole, 50 to 90%
by mass of ethanol is most preferably contained.
[0031] The pharmaceutical composition for external use of the
present invention is preferably used for treating mycotic diseases
or preventing progression of the diseases by using characteristics
of luliconazole or the like. The mycotic diseases include: foot
trichophytosis such as athlete's foot; trichophytosis corporis such
as candida and pityriasis versicolor; and trichophytosis on a hard
keratin portion, such as onychomycosis. Because of remarkable
effects, it is particularly preferable to use the pharmaceutical
composition for external use of the present invention for treating
the hard keratin portion, such as onychomycosis. In particular, the
pharmaceutical composition for external use of the present
invention exerts preferable effects on the nail and such an effect
is also exerted on typical dermatomycosis. Therefore, the
application of a pharmaceutical composition for external use
against dermatomycosis, which satisfies the configuration of the
present invention, is also within the technical scope of the
present invention. Examples of such dermatomycosis include
trichophytosis such as foot trichophytosis, particularly
horny-outgrowing type hyperkeratotic trichophytosis which appears
on heels or the like. The present invention has a significant
effect on the horny-outgrowing type hyperkeratotic trichophytosis,
on which the conventional agents hardly exert their effects, among
the above-mentioned dermatomycosis, which is preferable.
[0032] With regard to its use, for example, the pharmaceutical
composition is applied on a diseased portion one or several times a
day and the treatment is preferably carried out day after day. In
particular, for onychomycosis, luliconazole or the like, which is
an effective component in an amount that cannot be attained by
normal formulation, can be transferred into the nail. Therefore,
onychomycosis can be treated only by the external application
without having to drink an antifungal agent over a long period of
time. In addition, recurrence and reinfection have been a major
problem for onychomycosis. However, the recurrence and reinfection
can be prevented by application of the pharmaceutical composition
for external use of the present invention for 1 to 2 weeks after
abatement of the symptom. Therefore, the pharmaceutical composition
for external use of the present invention exerts preventive
efficacy in this aspect.
EXAMPLES
[0033] Hereinafter, the present invention will be described in more
detail with reference to examples. However, the present invention
is not limited to those examples.
Examples 1 to 6 and Comparative Examples 1 to 4
[0034] According to the formulation shown in Table 1,
Pharmaceutical Preparations 1 to 6 each containing the
pharmaceutical composition for external use of the present
invention were prepared. That is, formulation components were
stirred at room temperature and components for pharmaceutical
preparation were then dissolved, thereby obtaining a pharmaceutical
preparation of a clear lotion dosage form. Here, the value
represents "% by mass". Likewise, according to Table 2, Comparative
Pharmaceutical Preparations 1 to 4 for the respective comparative
examples were also prepared.
TABLE-US-00001 TABLE 1 Pharmaceutical Preparations 1 2 3 4 5 6
Luliconazole 1 1 1 1 1 1 N-methyl-2-pyrrolidone 5 8 5 8 Propylene
carbonate 5 10 Crotamiton 5 Squalane 5 1,3-butylene glycol 20 25
Concentrated glycerin 3 Cetanol 0.75 POE (10) hydrogenated castor
oil 1 POE (10) lauric acid 0.25 Stearic acid monoglyceride 0.25
Water 10 55.75 Ethanol 94 94 94 81 64
TABLE-US-00002 TABLE 2 Comparative Pharmaceutical Preparations 1 2
3 4 Luliconazole 1 1 1 1 Dimethyl sulfoxide 5 Methyl ethyl ketone 5
Ethyl acetate 5 Ethanol 94 94 94 99
Experimental Examples
[0035] Pharmaceutical Preparations 1 to 6 and Comparative
Pharmaceutical Preparations 1 to 4 as described above were
subjected to two-week storage experiments under conditions of
40.degree. C. and 60.degree. C. Immediately before and after the
storage experiment, the amount of an SE body ((S)-(+)isomer)
produced, which is an enantiomer of luliconazole, was measured by
HPLC and expressed in area percentage to investigate the stability
thereof. The results are shown in Table 3. Consequently, it can be
recognized that any of the pharmaceutical composition for external
uses of the present invention is stored in a state where a decrease
in optical purity is suppressed.
<HPLC Conditions>
[0036] Instrument used: LC-97 system (Shimadzu Corporation) [0037]
Column: CHIRALPACK AD-H 4.6 mm.times.250 mm [0038] Column
temperature: 40.degree. C. [0039] Mobile phase:
Water:acetonitrile=90:11 to 60:40 (30-minute gradient condition)
[0040] Flow rate: 0.8 ml/min [0041] Detection: UV (300 nm in
wavelength) [0042] Quantitative assay: an area-percentage method
using an absolute working curve
TABLE-US-00003 [0042] TABLE 3 Stability (Increased amount of SE
isomer) At start 40.degree., 2 Week 60.degree., 2 Week
Pharmaceutical 0.16 1.11 3.03 preparation 1 Pharmaceutical 0.21
2.13 14.89 preparation 2 Pharmaceutical 0.15 0.55 5.79 preparation
3 Pharmaceutical 0.14 0.18 Not detected preparation 4
Pharmaceutical 0.44 0.52 Not detected preparation 5 Pharmaceutical
0.32 0.43 Not detected preparation 6 Comparative 0.20 5.09 23.01
preparation 1 Comparative 0.23 8.69 32.73 preparation 2 Comparative
0.19 3.30 31.15 preparation 3 Comparative 0.16 8.70 41.68
preparation 4
INDUSTRIAL APPLICABILITY
[0043] According to the present invention, a pharmaceutical
composition for external use to be stored in a state where
luliconazole or the like is dissolved and a decrease in optical
purity thereof is suppressed can be provided.
* * * * *