U.S. patent application number 13/258114 was filed with the patent office on 2013-01-10 for antimycotic pharmaceutical composition.
This patent application is currently assigned to Pola Pharma Inc.. Invention is credited to Hirokazu Kobayashi, Eiko Kosugi, Nobuo Kubota.
Application Number | 20130011351 13/258114 |
Document ID | / |
Family ID | 42735580 |
Filed Date | 2013-01-10 |
United States Patent
Application |
20130011351 |
Kind Code |
A2 |
Kobayashi; Hirokazu ; et
al. |
January 10, 2013 |
ANTIMYCOTIC PHARMACEUTICAL COMPOSITION
Abstract
In a pharmaceutical composition for external use containing a
compound such as luliconazole and/or a salt thereof in an amount of
5% by mass or more, comprised is/are acetone, a polyoxyethylene
alkyl (having 8 to 30 carbon atoms) ether, and/or a polyoxyethylene
alkenyl (having 8 to 30 carbon atoms) ether. Provided is a
preparation using a solvent other than crotamiton, propylene
carbonate, and N-methyl-2-pyrrolidone as a solvent for
solubilization and steric stabilization and having the following
properties: 1) when a compound represented by the general formula
(1) and/or a salt thereof has a stereoisomer, the amount of the
stereoisomer of the compound and/or a salt thereof produced under a
preservation condition of 60.degree. C. for 3 weeks is 1% by mass
or less with respect to the total mass of the compound and/or a
salt thereof at the beginning of preservation; 2) the preparation
is in a clear liquid state when preserved at a constant temperature
of 20.degree. C. immediately after manufacture; and 3) no crystal
is deposited when the preparation is preserved at 5.degree. C. for
2 weeks after manufacture.
Inventors: |
Kobayashi; Hirokazu;
(Yokohama-shi, Kanagawa, JP) ; Kosugi; Eiko;
(Yokohama-shi, Kanagawa, JP) ; Kubota; Nobuo;
(Yokohama-shi, Kanagawa, JP) |
Assignee: |
Pola Pharma Inc.
Shinagawa-ku, Tokyo
JP
141-0031
Nihon Nohyaku Co., Ltd.
Chuo-ku, Tokyo
JP
103-8236
|
Prior
Publication: |
|
Document Identifier |
Publication Date |
|
US 20120014893 A1 |
January 19, 2012 |
|
|
Family ID: |
42735580 |
Appl. No.: |
13/258114 |
Filed: |
April 9, 2010 |
PCT Filed: |
April 9, 2010 |
PCT NO: |
PCT/JP2010/056881 |
371 Date: |
September 21, 2011 |
Current U.S.
Class: |
424/61;
514/397 |
Current CPC
Class: |
A61P 31/04 20180101;
A61P 31/10 20180101; A61K 9/7015 20130101; A61K 9/08 20130101; A61K
47/10 20130101; A61K 31/4178 20130101; A61K 47/08 20130101; A61K
47/14 20130101; A61K 9/0014 20130101 |
Class at
Publication: |
424/061;
514/397 |
International
Class: |
A61K 31/4178 20060101
A61K031/4178; A61P 31/10 20060101 A61P031/10 |
Foreign Application Data
Date |
Code |
Application Number |
Apr 9, 2009 |
JP |
2009-111551 |
Apr 9, 2009 |
JP |
2009-111552 |
Claims
1. A pharmaceutical composition for external use, comprising: 1) a
compound represented by the following general formula (1) and/or a
salt thereof in an amount of 5 to 15% by mass with respect to a
total amount of the pharmaceutical composition; and 2) one kind or
two or more kinds selected from the following group: acetone in an
amount of 1 to 30% by mass with respect to a total amount of the
pharmaceutical composition; a polyoxyethylene alkyl (having 8 to 30
carbon atoms) ether in an amount of 1 to 10% by mass with respect
to a total amount of the pharmaceutical composition; and a
polyoxyethylene alkenyl (having 8 to 30 carbon atoms) ether in an
amount of 1 to 10% by mass with respect to a total amount of the
pharmaceutical composition; ##STR5## wherein R.sub.1 and R.sub.2
each independently represent a hydrogen atom or a halogen atom, and
at least one of R.sub.1 and R.sub.2 represent a halogen atom.
2. The pharmaceutical composition for external use according to
claim 1, wherein the compound represented by the general formula
(1) is luliconazole. ##STR6##
3. The pharmaceutical composition for external use according to
claim 1, which has the following properties: 1) when the compound
represented by the general formula (1) and/or a salt thereof has a
stereoisomer, an amount of the stereoisomer of the compound and/or
a salt thereof produced under a preservation condition of
60.degree. C. for 3 weeks is 1% by mass or less with respect to a
total mass of the compound and/or a salt thereof at beginning of
preservation; 2) the composition is in a clear liquid state when
preserved at a constant temperature of 20.degree. C. immediately
after manufacture; and 3) no crystal is deposited when the
composition is preserved at 5.degree. C. for 2 weeks after
manufacture.
4. The pharmaceutical composition for external use according to
claim 1, further comprising one kind or two or more kinds selected
from a diester carbonate, an aromatic alcohol, and a diester of a
dibasic acid, provided that carbonic acid is excluded, in an amount
of 1 to 30% by mass with respect to a total amount of the
pharmaceutical composition.
5. The pharmaceutical composition for external use according to
claim 1, wherein the pharmaceutical composition is a medicament for
treatment of tinea unguium.
6. A method of manufacturing the pharmaceutical composition for
external use according to claim 1, comprising the steps of: mixing
a compound represented by the general formula (1) and/or a salt
thereof with a part of a solvent; after the previous step, adding
components except acetone, a polyoxyethylene alkyl (having 8 to 30
carbon atoms) ether, and a polyoxyethylene alkenyl (having 8 to 30
carbon atoms) ether; and after the previous step, adding one kind
or two or more kinds selected from acetone, a polyoxyethylene alkyl
(having 8 to 30 carbon atoms) ether, and a polyoxyethylene alkenyl
(having 8 to 30 carbon atoms) ether under a heating condition.
7. The pharmaceutical composition for external use according to
claim 2, which has the following properties: 1) when the compound
represented by the general formula (1) and/or a salt thereof has a
stereoisomer, an amount of the stereoisomer of the compound and/or
a salt thereof produced under a preservation condition of
60.degree. C. for 3 weeks is 1% by mass or less with respect to a
total mass of the compound and/or a salt thereof at beginning of
preservation; 2) the composition is in a clear liquid state when
preserved at a constant temperature of 20.degree. C. immediately
after manufacture; and 3) no crystal is deposited.
8. The pharmaceutical composition for external use according to
claim 2, further comprising one kind or two or more kinds selected
from a diester carbonate, an aromatic alcohol, and a diester of a
dibasic acid, provided that carbonic acid is excluded, in an amount
of 1 to 30% by mass with respect to a total amount of the
pharmaceutical composition.
9. The pharmaceutical composition for external use according to
claim 2, wherein the pharmaceutical composition is a medicament for
treatment of tinea unguium.
10. A method of manufacturing the pharmaceutical composition for
external use according to claim 2, comprising the steps of: mixing
a compound represented by the general formula (1) and/or a salt
thereof with a part of a solvent; after the previous step, adding
components except acetone, a polyoxyethylene alkyl (having 8 to 30
carbon atoms) ether, and a polyoxyethylene alkenyl (having 8 to 30
carbon atoms) ether; and after the previous step, adding one kind
or two or more kinds selected from acetone, a polyoxyethylene alkyl
(having 8 to 30 carbon atoms) ether, and a polyoxyethylene alkenyl
(having 8 to 30 carbon atoms) ether under a heating condition.
11. A method for treatment of tinea unguium comprising
administering the pharmaceutical composition of claim 1 in an
effective amount to an individual in need thereof.
12. A method for treatment of tinea unguium comprising
administering the pharmaceutical composition of claim 2 in an
effective amount to an individual in need thereof.
13. The method according to claim 11, wherein the pharmaceutical
composition further comprises one kind or two or more kinds
selected from a diester carbonate, an aromatic alcohol, and a
diester of a dibasic acid, provided that carbonic acid is excluded,
in an amount of 1 to 30% by mass with respect to a total amount of
the pharmaceutical composition.
14. The method according to claim 12, wherein the pharmaceutical
composition further comprises one kind or two or more kinds
selected from a diester carbonate, an aromatic alcohol, and a
diester of a dibasic acid, provided that carbonic acid is excluded,
in an amount of 1 to 30% by mass with respect to a total amount of
the pharmaceutical composition.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is the U.S. National Phase under 35 U.S.C.
.sctn.371 of International Application PCT/JP2010/056881, filed
Apr. 9, 2010, which claims priority to JP Application No.
2009-111551, filed Apr. 9, 2009 and JP 2009-111552, filed Apr. 9,
2009.
TECHNICAL FIELD
[0002] The present invention relates to a pharmaceutical
composition, and more specifically, to an antimycotic
pharmaceutical composition for external use useful for treatment of
mycoses.
BACKGROUND ART
[0003] A compound represented by the general formula (1) as
typified by, for example, luliconazole has an excellent antimycotic
activity, and it has been pointed out that the compound may be
applied to treatment of onychomycosis, which could not be treated
by external administration hitherto (for example, see Patent
document 1). However, in the case of producing such formulation for
treatment of onychomycosis, there is a demand to further increase
the content of the compound represented by the general formula (1)
solubilized in the formulation. In particular, in a formulation for
treatment of tinea unguium, it has been desired to solubilize the
compound represented by the general formula (1) as typified by
luliconazole in an amount twice or more that of a general
formulation used for treatment of dermatomycosis, specifically, in
an amount of 5% by mass or more, and it has been desired to develop
a solvent for solubilizing and formulating the compound represented
by the general formula (1) in a high concentration. However, there
was a situation in which only a few solvents could be used for
producing a formulation containing such compound in a high
concentration because of its high crystallinity. That is, some
kinds of solvents caused deficiency including crystal deposition
when a low temperature condition such as 5.degree. C. and crystal
deposition during application.
[0004] In addition, in a solution of luliconazole or the like,
there exists a situation in which stereoisomers are easily
produced. Only crotamiton, propylene carbonate, and
N-methyl-2-pyrroridone have been known as a solvent for preventing
production of such stereoisomers (for example, see Patent document
2). However, such solvents may also be blended in a limited amount
because of medicinal effects such as anti-inflammatory effects
inherently possessed by the solvents, and it has been desired to
develop a novel solvent for a formulation of luliconazole or the
like as an alternative of the solvents. ##STR1## where R.sub.1 and
R.sub.2 each independently represent a hydrogen atom or a halogen
atom, and at least one of R.sub.1 and R.sub.2 represent a halogen
atom. ##STR2##
[0005] That is, there has been a demand to develop a solvent that
enables a preparation having the following properties by means
independent of solvent properties of crotamiton, propylene
carbonate, and N-methyl-2-pyrrolidone (solubilization and steric
stabilization properties of luliconazole or the like), in a
pharmaceutical composition for external use containing luliconazole
or the like in an amount of 5% by mass or more:
1) the amount of a stereoisomer of luliconazole or the like
produced under a preservation condition of 60.degree. C. for 3
weeks is 1% by mass or less with respect to the total mass of
luliconazole or the like at the beginning of preservation;
2) the preparation is in a clear liquid state when preserved at a
constant temperature of 20.degree. C. immediately after
manufacture.
3) no crystal is deposited when the preparation is preserved at
5.degree. C. for 2 weeks after manufacture.
[0006] Meanwhile, acetone has been already used in an antimycotic
pharmaceutical for external use, especially a pharmaceutical for
external use for tinea unguium (for example, see Patent documents
3, 4 and 5). However, there has been no finding that acetone serves
as a solvent for stably solubilizing luliconazole or the like while
maintaining a steric structure of luliconazole or the like, in the
pharmaceutical composition for external use containing luliconazole
or the like. [0007] [Patent document 1] WO/2007/102241 [0008]
[Patent document 2] WO/2007/102242 [0009] [Patent document 3] JP
08-291049 A [0010] [Patent document 4] JP 2009-511553 A [0011]
[Patent document 5] JP 2001-316247 A
SUMMARY OF INVENTION
Technical Problem
[0012] The present invention has been made under such
circumstances, and an object of the present invention is to provide
a preparation having the following properties 2) and 3) by means
independent of solvent properties of crotamiton, propylene
carbonate, and N-methyl-2-pyrrolidone (solubilization and steric
stabilization properties of a compound represented by the general
formula (1) and/or a salt thereof) in a pharmaceutical composition
for external use containing the compound represented by the general
formula (1) and/or a salt thereof such as luliconazole in an amount
of 5% by mass or more. Further, when the compound represented by
the general formula (1) and/or a salt thereof has a stereoisomer,
an object of the present invention is to provide a preparation
having the following properties 1) to 3):
[0013] 1) the amount of a stereoisomer of the compound represented
by the general formula (1) and a salt thereof produced under a
preservation condition of 60.degree. C. for 3 weeks is 1% by mass
or less with respect to the total mass of the compound represented
by the general formula (1) and/or a salt thereof at the beginning
of preservation;
2) the preparation is in a clear liquid state when preserved at a
constant temperature of 20.degree. C. immediately after
manufacture; and
3) no crystal is deposited when the preparation is preserved at
5.degree. C. for 2 weeks after manufacture.
Solution to Problems
[0014] In view of such circumstances, the inventors of the present
invention have intensively studied to seek a preparation having
stable solubilizing properties by means independent of solvent
properties of crotamiton, propylene carbonate, and
N-methyl-2-pyrrolidone (solubilization and steric stabilization
properties of a compound represented by the general formula (1)
and/or a salt thereof) in a pharmaceutical composition for external
use containing a compound represented by the general formula (1)
and/or a salt thereof in an amount of 5% by mass or more. As a
result, the inventors have found that such preparation is obtained
by using acetone and/or a polyoxyethylene alkyl (or alkenyl) ether
(note that the alkyl group and the alkenyl group have 8 to 30
carbon atoms) in place of crotamiton, propylene carbonate, and
N-methyl-2-pyrrolidone. Thus, the present invention has been
completed. That is, the present invention is as described below.
[1] A pharmaceutical composition for external use, comprising: 1) a
compound represented by the following general formula (1) and/or a
salt thereof in an amount of 5 to 15% by mass with respect to a
total amount of the pharmaceutical composition; and 2) one kind or
two or more kinds selected from the following group: acetone in an
amount of 1 to 30% by mass with respect to a total amount of the
pharmaceutical composition; a polyoxyethylene alkyl (having 8 to 30
carbon atoms) ether in an amount of 1 to 10% by mass with respect
to a total amount of the pharmaceutical composition; and a
polyoxyethylene alkenyl (having 8 to 30 carbon atoms) ether in an
amount of 1 to 10% by mass with respect to a total amount of the
pharmaceutical composition; ##STR3## where R.sub.1 and R.sub.2 each
independently represent a hydrogen atom or a halogen atom, and at
least one of R.sub.1 and R.sub.2 represent a halogen atom. [2] The
pharmaceutical composition for external use according to the item
[1], wherein the compound represented by the general formula (1) is
luliconazole. ##STR4## [3] The pharmaceutical composition for
external use according to the item [1] or [2], which has the
following properties: 1) when the compound represented by the
general formula (1) and/or a salt thereof has a stereoisomer, the
amount of the stereoisomer of the compound and/or a salt thereof
produced under a preservation condition of 60.degree. C. for 3
weeks is 1% by mass or less with respect to the total mass of the
compound and/or a salt thereof at the beginning of preservation; 2)
the composition is in a clear liquid state when preserved at a
constant temperature of 20.degree. C. immediately after
manufacture; and 3) no crystal is deposited when the composition is
preserved at 5.degree. C. for 2 weeks after manufacture. [4] The
pharmaceutical composition for external use according to any one of
the items [1] to [3], further comprising one kind or two or more
kinds selected from a diester carbonate, an aromatic alcohol, and a
diester of a dibasic acid, provided that a carbonic acid is
excluded, in an amount of 1 to 30% by mass with respect to a total
amount of the pharmaceutical composition. [5] The pharmaceutical
composition for external use according to any one of the items [1]
to [4], in which the pharmaceutical composition is a medicament for
treatment of tinea unguium. [6] A method of manufacturing the
pharmaceutical composition for external use according to any one of
the items [1] to [5], comprising the steps of: mixing a compound
represented by the general formula (1) and/or a salt thereof with
apart of a solvent; after the previous process, adding components
except acetone, a polyoxyethylene alkyl (having 8 to 30 carbon
atoms) ether, and a polyoxyethylene alkenyl (having 8 to 30 carbon
atoms) ether; and after the previous process, adding one kind or
two or more kinds selected from acetone, a polyoxyethylene alkyl
(having 8 to 30 carbon atoms) ether, and a polyoxyethylene alkenyl
(having 8 to 30 carbon atoms) ether under a heating condition.
Advantageous Effects of Invention
[0015] According to the present invention, in the pharmaceutical
composition for external use containing a compound represented by
the general formula (1) and/or a salt thereof such as luliconazole
in an amount of 5% by mass or more, there can be provided a
preparation having the following properties 2) and 3) by means
independent of solvent properties of crotamiton, propylene
carbonate, and N-methyl-2-pyrrolidone (solubilization and steric
stabilization properties of the compound represented by the general
formula (1) and/or a salt thereof). Further, when the compound
represented by the general formula (1) has a stereoisomer, an
object of the present invention is to provide a preparation having
the following properties 1) to 3):
[0016] 1) the amount of a stereoisomer of the compound and/or a
salt thereof represented by the general formula (1) and/or a salt
thereof produced under a preservation condition of 60.degree. C.
for 3 weeks is 1% by mass or less with respect to the total mass of
the compound and/or a salt thereof at the beginning of
preservation;
2) the preparation is in a clear liquid state when preserved at a
constant temperature of 20.degree. C. immediately after
manufacture; and
3) no crystal is deposited when the preparation is preserved at
5.degree. C. for 2 weeks after manufacture.
DESCRIPTION OF EMBODIMENTS
<1> Compound Represented by the General Formula (1) and/or
Salt Thereof as Essential Component of Pharmaceutical Composition
for External Use of the Present Invention
[0017] The pharmaceutical composition for external use of the
present invention is characterized by including a compound
represented by the general formula (1) and/or a salt thereof such
as luliconazole and lanoconazole. Luliconazole is a compound
represented by the chemical name
(R)-(-)-(E)-[4-(2,4-dichlorophenyl)-1,3-dithiolan-2-ylidene]-1-imidazolyl-
acetonitrile, and lanoconazole is a compound represented by the
chemical name
(.+-.)-(E)-[4-(2-chlorophenyl)-1,3-dithiolan-2-ylidene]-1-imidazolyl-
acetonitrile. Methods of manufacturing such compounds have already
been known (see, for example, Japanese Patent Application Laid-open
No. 09-100279).
[0018] The pharmaceutical composition for external use of the
present invention is characterized by containing a compound
represented by the general formula (1) and/or a salt thereof in an
amount of generally 5 to 15% by mass, or preferably 8 to 13% by
mass with respect to the total amount of the pharmaceutical
composition. Luliconazole has excellent crystallinity, and thus,
may cause crystal deposition in a content of 1% by mass or more
when preserved using some kinds of solvents at a low temperature
such as 5.degree. C., even in a state where crystallization is
suppressed by adding a hydroxycarboxylic acid such as lactic acid.
In the present invention, such deposition is suppressed by using a
combination of solvents of acetone and/or a polyoxyethylene alkyl
(or alkenyl) ether as described below, thereby the bioavailability,
in particular, transfer into the nail is enhanced and as a result a
therapeutic effect for tinea unguium is enhanced. The nail is an
organ where the transfer into the tissue is difficult, and in order
to transfer an effective amount of a compound, the content is
preferably 5% by mass or more, or more preferably 8% by mass or
more with respect to the total amount of the pharmaceutical
composition. Further, in view of the upper limit for suppressing
crystal deposition at a low temperature, the content is preferably
15% by mass or less, or more preferably 13% by mass or less with
respect to the total amount of the pharmaceutical composition. From
the foregoing, the content is more preferably about 8 to 13% by
mass.
[0019] The above-mentioned "salt thereof" is not particularly
limited as long as it is physiologically acceptable. For example,
there may be suitably given: mineral acid salts such as a
hydrochloride, a nitrate, a sulfate, and a phosphate; organic acid
salts such as a citrate, an oxalate, a lactate, and an acetate; and
sulfate-containing salts such as a mesilate and a tosilate. In
terms of safety and solubility, a hydrochloride is more
preferred.
<2> Acetone and Polyoxyethylene Alkyl (or Alkenyl) Ether as
Essential Components in Pharmaceutical Composition for External Use
of the Present Invention
[0020] The pharmaceutical composition for external use of the
present invention is characterized by including acetone and/or a
polyoxyethylene alkyl (or alkenyl) ether as essential components.
The pharmaceutical composition is characterized by containing
acetone in an amount of generally 1 to 30% by mass, or preferably 3
to 20% by mass with respect to the total amount of the
pharmaceutical composition, a polyoxyethylene alkyl (or alkenyl)
ether having an alkyl group or an alkenyl group with 8 to 30 carbon
atoms, or preferably an alkyl group or an alkenyl group with 10 to
18 carbon atoms, or one kind or two or more kinds selected from
respectively from a polyoxyethylene alkyl ether or a
polyoxyethylene alkenyl ether in an amount of generally 1 to 10% by
mass, or preferably 2 to 5% by mass with respect to the total
amount of the pharmaceutical composition. That is, for such
components, any one kind of the acetone and/or polyoxyethylene
alkyl (or alkenyl) ether may be contained, or two kinds thereof
(acetone and polyoxyethylene alkyl ether, or acetone and
polyoxyethylene alkenyl ether) may be contained. The preferred
content in the case where two kinds are contained may be understood
as the sum of preferred contents of the respective components. This
is because the effects thereof are independent of each other.
[0021] For an alkyl group or an alkenyl group of which the
polyoxyethylene alkyl (or alkenyl) ether is formed, the group has 8
to 30 carbon atoms, or preferably 10 to 18 carbon atoms. To be
specific, there may be particularly suitably exemplified a lauryl
group, a cetyl group, an isostearyl group, and an oleyl group. In
addition, the polymerization degree of oxyethylene in a
polyoxyethylene group is preferably 1 to 30, or more preferably 2
to 25. For the properties, it is preferred that the polyoxyethylene
alkyl (alkenyl) ether be in a liquid state under a condition of 1
atm and 25.degree. C. For specific examples of the polyoxyethylene
alkyl (or alkenyl) ether, there may be suitably given
polyoxyethylene (POE) (4.2) laurylether, POE (10) cetylether, POE
(30) cetylether, POE (10) oleyl ether, and POE (20) isostearyl
ether.
[0022] Such components have effects of stably maintaining the
solubilized state of the compound represented by the general
formula (1) and/or a salt thereof in a high concentration region of
5% by mass or more even in a low temperature region of about
5.degree. C. or less without impairing the steric stability in the
dissolved state. In particular, in the case where the content of
the compound represented by the general formula (1) and/or a salt
thereof is about 10% by mass, the effects are remarkably exerted by
blending the components in an amount equal to or more than the mass
of the compound represented by the general formula (1) and/or a
salt thereof. Therefore, it is preferred to satisfy such blending
condition. Under such condition, the pharmaceutical composition for
external use of the present invention shows no change in
solubilizing properties when preserved for 2 weeks, preferably 1
month or more, or more preferably 3 months or more at a wide range
of temperatures, including a low temperature region of about
5.degree. C., a room temperature condition of about 20.degree. C.,
and a high temperature region of about 40.degree. C. Substantially
no stereoisomer is produced, and even after preservation at
60.degree. C. for 3 weeks, the amount of the stereoisomers is 1% by
mass or less with respect to the total mass of the compound and/or
a salt thereof at the beginning of preservation. Therefore, the
composition is suitable for a formulation to be applied to an organ
with low absorbability such as the nail. In particular, because it
is rare that crystal deposition occurs through, for example,
enrichment of the compound of the general formula (1) or change in
solvent constitution due to evaporation after application or
absorption of only a solvent into a living body, or an interfacial
effect on a contact area, the absorption into the nail is not
inhibited. Such effect may remarkably improve the
bioavailability.
<3> Pharmaceutical Composition for External Use of the
Present Invention
[0023] The pharmaceutical composition for external use of the
present invention contains the above-mentioned essential components
and may contain an optional component which is generally used for
formulation.
[0024] For such optional component, there may be preferably
exemplified: oils and waxes such as macadamia nut oil, avocado oil,
corn oil, olive oil, rapeseed oil, sesame oil, castor oil,
safflower oil, cottonseed oil, jojoba oil, coconut oil, palm oil,
liquid lanolin, hydrogenated coconut oil, hydrogenated oil, haze
wax, hydrogenated castor oil, beeswax, candelilla wax, carnauba
wax, insect wax, lanolin, reduced lanolin, hard lanolin, and jojoba
wax; hydrocarbons such as liquid paraffin, squalane, pristane,
ozokerite, paraffin, ceresin, vaseline, and microcrystalline wax;
higher fatty acids such as oleic acid, isostearic acid, lauric
acid, myristic acid, palmitic acid, stearic acid, behenic acid, and
undecylenic acid; lower alcohols such as ethanol and isopropanol;
higher alcohols such as oleyl alcohol, cetyl alcohol, stearyl
alcohol, isostearyl alcohol, behenyl alcohol, octyldodecanol,
myristyl alcohol, and cetostearyl alcohol; synthetic ester oils
such as cetyl isooctanoate, isopropyl myristate, hexyldecyl
isostearate, cetyl lactate, diisostearyl malate, ethylene glycol
di-2-ethyl hexanoate, neopentyl glycol dicaprate, glycerin
di-2-heptyl undecanoate, glycerin tri-2-ethylhexanoate,
trimethylolpropane tri-2-ethyl hexanoate, trimethylolpropane
triisostearate, and pentane erythrite tetra-2-ethylhexanoate; oils
such as silicone oils which are not classified into silicones,
including dimethyl polysiloxane, methylphenyl polysiloxane, and
modified polysiloxanes such as amino-modified polysiloxane,
polyether-modified polysiloxane, alkyl-modified polysiloxane, and
fluorine-modified polysiloxane; anionic surfactants such as fatty
acid soaps (including sodium laurate and sodium palmitate),
potassium lauryl sulfate, triethanolamine alkyl sulfate, and sodium
polyoxyethylene lauryl phosphate; cationic surfactants such as
stearyltrimethylammonium chloride, benzalkonium chloride, and
laurylamine oxide; amphoteric surfactants such as imidazoline-based
amphoteric surfactants (including a 2-cocoyl-2-imidazolinium
hydroxide-1-carboxyethyloxy-2-sodium salt), betaine-based
surfactants (including alkylbetaine, amidobetaine, and
sulfobetaine), and acylmethyl taurine; nonionic surfactants such as
sorbitan fatty acid esters (including sorbitan monostearate,
sorbitan monolaurate, and sorbitan sesquioleate), glycerin fatty
acids (including glycerin monostearate), propylene glycol fatty
acid esters (including propylene glycol monostearate), hydrogenated
castor oil derivatives, glycerin alkyl ethers, POE sorbitan fatty
acid esters (including POE sorbitan monooleate, polyoxyethylene
sorbitan monostearate, and polyoxyethylene sorbitan monolaurate),
POE sorbit fatty acid esters (including POE-sorbit monolaurate),
POE glycerin fatty acid esters (including POE-glycerin
monoisostearate), POE fatty acid esters (including polyethylene
glycol monooleate and POE distearate), POE alkylphenyl ethers
(including POE octylphenyl ether and POE nonylphenyl ether),
Pluronics, POE.POP alkyl ethers (including POE.POP 2-decyl
tetradecyl ether), Tetronics, POE castor oil-hydrogenated castor
oil derivatives (including POE castor oil and POE hydrogenated
castor oil), sucrose fatty acid esters, and alkylglucosides;
polyalcohols such as polyethylene glycol, glycerin, 1,3-butylene
glycol, erythritol, sorbitol, xylitol, maltitol, gluconolactone,
propylene glycol, dipropylene glycol, diglycerin, isoprene glycol,
1,2-pentanediol, 2,4-hexanediol, 1,2-hexanediol, 1,2-octanediol,
polypropylene glycol, and 2-ethyl-1,3-hexanediol; moisturizing
components such as sodium pyrrolidone carboxylate, lactic acid, and
sodium lactate; pH adjusters such as phosphoric acid and citric
acid; powders such as mica, talc, kaolin, synthetic mica, and
barium sulfate which may have treated surfaces; inorganic pigments
such as colcothar, yellow iron oxide, black iron oxide, cobalt
oxide, ultramarine blue pigment, iron blue pigment, titanium oxide,
and zinc oxide which may have treated surfaces; pearls such as mica
titanium, fish scale guanine, and bismuth oxychloride which may
have treated surfaces; organic pigments such as Red 202, Red 228,
Red 226, Yellow 4, Blue 404, Yellow 5, Red 505, Red 230, Red 223,
Orange 201, Red 213, Yellow 204, Yellow 203, Blue 1, Green 201,
Violet 201, and Red 204 which may be laked; organic powders such as
polyethylene powder, polymethyl methacrylate powder, nylon powder,
and organopolysiloxane elastomer; UV absorbers such as
p-aminobenzoic acid-based UV absorber, anthranilic acid-based UV
absorber, salicylic acid-based UV absorber, cinnamic acid-based UV
absorber, benzophenone-based UV absorber, sugar-based UV absorber,
2-(2'-hydroxy-5'-t-octylphenyl)benzotriazole, and
4-methoxy-4'-t-butyl dibenzoylmethane; vitamins such as vitamin A
or derivatives thereof, vitamin B's including vitamin B.sub.6
hydrochloride, vitamin B.sub.6 tripalmitate, vitamin B.sub.6
dioctanoate, vitamin B.sub.2 or derivatives thereof, vitamin
B.sub.12, and vitamin B.sub.15 or derivatives thereof, vitamin E's
including .alpha.-tocopherol, .beta.-tocopherol,
.gamma.-tocopherol, and vitamin E acetate, vitamin D's, vitamin H,
pantothenic acid, pantethine, and pyrroloquinoline quinone;
solvents such as aromatic alcohols such as phenylethyl alcohol,
phenylpropyl alcohol, and benzyl alcohol, crotamiton,
N-methyl-2-pyrrolidone, alkylene carbonates such as ethylene
carbonate and propylene carbonate, diester carbonates such as
diethyl carbonate and dicapryl carbonate, diesters of dibasic
acids, such as diethyl sebacate, diisopropyl sebacate, diethyl
adipate, and diisopropyl adipate, triacetin, and ethylene glycol
salicylate; stabilizers such as hydroxy acids such as lactic acid,
glycolic acid, and citric acid, and mineral acids such as
phosphoric acid.
[0025] For particularly preferred components out of those optional
components, there may be preferably exemplified a solvent selected
from an alkylene carbonate having a cyclic structure, such as
propylene carbonate, a diester carbonate typified by a dialkyl
carbonate such as dicapryl carbonate in which two linear
hydrocarbon groups are bonded, an aromatic alcohol such as benzyl
alcohol, and a diester of a dibasic acid (provided that carbonic
acid is excluded) such as adipic acid and sebacic acid, and the
like.
[0026] In order to improve the stability, the pharmaceutical
composition for external use of the present invention preferably
contains a diester carbonate such as a dialkyl carbonate or an
alkylene carbonate, preferably an alkylene carbonate, or more
preferably propylene carbonate in an amount of preferably 1 to 10%
by mass, more preferably 2 to 8% by mass, or particularly
preferably 3 to 5% by mass with respect to the total amount of the
pharmaceutical composition. Such diester carbonate has preferably 5
to 30 carbon atoms, or more preferably 6 to 25 carbon atoms in
total. Such component has an effect of improving solubilization
stability of luliconazole or the like at a low temperature, and
also has effects of suppressing crystal deposition during
preservation at 5.degree. C. for 2 weeks, preferably 4 weeks or
more and improving stability at a high temperature. The component
prevents stereoisomerization even during preservation at 60.degree.
C. for 3 weeks and suppresses production of stereoisomers to 1% by
mass or less. Such component is preferably contained at a mass
ratio almost equal to or almost half of that of luliconazole or the
like. Propylene carbonate is one of the alkylene carbonates, and
other alkylene carbonates such as ethylene carbonate or diester
carbonates such as diethyl carbonate and dicapryl carbonate also
fall within the technical scope of the present invention because
they have the same effects as that of propylene carbonate. In the
case of using two or more kinds of components, the amount of the
diester carbonate may be construed as the total amount of the
diester carbonates.
[0027] In order to improve the solubility and stability, the
pharmaceutical composition for external use of the present
invention contains an aromatic alcohol, or preferably benzyl
alcohol in an amount of preferably 1 to 10% by mass, more
preferably 1 to 8% by mass, or particularly preferably 1 to 5% by
mass with respect to the total amount of pharmaceutical
composition. Such component is useful as an aid for solubilizing
the compound represented by the general formula (1) and/or a salt
thereof during manufacture, and has an effect of suppressing
crystal deposition of the compound represented by the general
formula (1) and/or a salt thereof in preservation at low
temperatures. Such effect is exerted when the amount is in the
above-mentioned range. Other aromatic alcohols such as phenylethyl
alcohol and phenylpropyl alcohol also exert similar effects,
although the effects are smaller than that of benzyl alcohol, and
hence may be handled in the same way as benzyl alcohol. That is,
such aromatic alcohols fall within the technical scope of the
present invention.
[0028] The pharmaceutical composition for external use of the
present invention contains, as a preferred component, a diester of
a dibasic acid, or preferably diethyl adipate or diisopropyl
adipate in an amount of preferably 1 to 20% by mass, more
preferably 2 to 18% by mass, or particularly preferably 3 to 15% by
mass with respect to the total amount of the pharmaceutical
composition. Here, the dibasic acid means a collective name
including dicarboxylic acids having two carboxyl groups but
excluding carbonic acid. For such dibasic acid, adipic acid,
tartaric acid, succinic acid, and sebacic acid may be suitably
exemplified. For an ester moiety of which the diester of a dibasic
acid is formed, there may be exemplified an alkyl group or an
alkenyl group having a linear or branched structure with 1 to 20
carbon atoms, or more preferably 1 to 5 carbon atoms. To be
specific, there may be suitably exemplified a methyl group, an
ethyl group, an ethoxyethyl group, a propyl group, an isopropyl
group, an isoprenyl group, a butyl group, a sec-butyl group, a
tert-butyl group, a hexyl group, an octyl group, an isooctyl group,
a decanyl group, a lauryl group, a cetyl group, a stearyl group, an
isostearyl group, and an oleyl group. Such component has an action
of, in the range of the above-mentioned amount, dissolving a
compound represented by the general formula (1) and/or a salt
thereof solvated with benzyl alcohol or the like to form a
homogeneous solution system. Such action may be observed in a wide
range of diesters of dibasic acids, such as diethyl sebacate and
diisopropyl sebacate, although being weaker than that of diethyl
adipate and diisopropyl adipate. That is, those fall within the
technological scope of the present invention. For the diester of a
dibasic acid, which enhances the effect of the present invention,
as described above, there may be particularly preferably
exemplified one having, as an acid residue, an adipic acid residue,
a sebacic acid residue, or a succinic acid residue, and having, as
an aliphatic group, a methyl group, an ethyl group, an ethoxyethyl
group, a propyl group, an isopropyl group, a butyl group, a
sec-butyl group, a tert-butyl group, an octyl group, an isooctyl
group, or a lauryl group.
[0029] For the diester carbonate, and aromatic alcohol, and diester
of a dibasic acid, one kind chosen therefrom may be selected, or a
combination of two or more kinds may be selected. For the amount
range, preferred amount ranges may be independently selected for
the respective components, and those three kinds of components are
preferably blended so that the total mass would be 1 to 30% by
mass, or more preferably 2 to 25% by mass with respect to the total
amount of the pharmaceutical composition.
[0030] Further, in order to improve the stability of the
pharmaceutical composition for external use of the present
invention and the effect of suppressing crystal deposition after
application, a stabilizer such as a hydroxy acid including lactic
acid, glycolic acid, and citric acid or a mineral acid including
phosphoric acid is preferably incorporated in an amount of
preferably 0.1 to 20% by mass, or more preferably 1 to 10% by mass
with respect to the total amount of the pharmaceutical composition.
In addition, in order to improve the solubility and stability, it
is also preferred to contain a higher alcohol in a liquid state at
1 atom at 25.degree. C., such as isostearyl alcohol, in an amount
of preferably 10 to 30% by mass, or more preferably 15 to 25% by
mass with respect to the total amount of the pharmaceutical
composition. In addition, crotamiton or N-methyl-2-pyrroridone
having an effect of maintaining steric stability is preferably
incorporated in an amount of preferably 1 to 30% by mass, or more
preferably 2 to 15% by mass with respect to the total amount of the
pharmaceutical composition. In addition, in order to improve the
solubility, it is also preferred to contain a polyalcohol such as
propylene glycol, in an amount of preferably 1 to 30% by mass, or
more preferably 5 to 20% by mass with respect to the total amount
of the pharmaceutical composition.
[0031] The pharmaceutical composition for external use of the
present invention may be manufactured by using such optional
components and essential components. For a method of manufacturing
the pharmaceutical composition for external use of the present
invention, there may be preferably exemplified a method involving
adding a part of solvent components such as an aliphatic alcohol
and an aromatic alcohol to a compound represented by the general
formula (1) or a salt thereof to solvate the compound or a salt
thereof and adding the remainder of solvents for salvation to
solubilize the compound or a salt thereof. For the above-mentioned
solvents for solvation and soluvilization, there may be suitably
exemplified an aliphatic and aromatic alcohol are preferably used
for solubilization, and a diester of a dibasic acid, acetone and a
diester carbonate are preferably used for improving the
solubilization. In such solubilization process, heating is
preferably performed at 30 to 90.degree. C. The amount of the
above-mentioned solvents for solvation is preferably 10 to 50% by
mass of the total amount of the solvents for salvation. The
pharmaceutical composition for external use of the present
invention may be obtained by performing the above-mentioned
processes and further treatment of the resultant according to a
conventional method.
[0032] The pharmaceutical composition for external use of the
present invention can be formulated into any form without
particular limitation as long as the form is used in a
pharmaceutical composition for external use, and for example, there
may be suitably given a lotion, an emulsion, a gel, a cream, an
aerosol, a nail enamel, and a hydrogel patch. Of those, a lotion is
particularly preferred.
[0033] The pharmaceutical composition for external use of the
present invention is preferably used for treatment of mycotic
diseases or prevention of progression of the diseases by using
characteristics of luliconazole or the like. For the mycotic
diseases, there may be exemplified: tinea pedis such as athlete's
foot; tinea corporis such as candida and pityriasis versicolor; and
tinea on a hard keratin portion, such as tinea unguium. Because of
remarkable effects, it is particularly preferred to use the
pharmaceutical composition for external use of the present
invention for treatment of the hard keratin portion, such as tinea
unguium. The effect of the pharmaceutical composition for external
use of the present invention is particularly suitably expressed on
the nail, and such effect is also expressed on typical
dermatomycosis. Therefore, a pharmaceutical composition for
external use for dermatomycosis, which satisfies the configuration
of the present invention, also falls within the technical scope of
the present invention. For such dermatomycosis, there may be
exemplified tinea such as tinea pedis, or particularly
hyperkeratotic tinea which appears on the heels or the like. It is
preferred to apply the pharmaceutical composition of the present
invention to hyperkeratotic tinea, on which the conventional
medicaments hardly exert their effects, in the above-mentioned
dermatomycosis, because the effect of the present invention is
remarkably expressed.
[0034] With regard to the use mode, for example, the pharmaceutical
composition is applied to a diseased site one or several times a
day at a preferred amount, and the treatment is preferably carried
out day after day. In particular, for tinea unguium, luliconazole
or the like as an effective component may be transferred into the
nail in an amount that cannot be attained by a normal formulation.
As a result, tinea unguium may be treated by simple external
application without taking an antimycotic agent over a long period
of time. In addition, recurrence and reinfection are being a major
problem for tinea unguium. However, the recurrence and reinfection
may 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. The pharmaceutical composition for
external use of the present invention exerts a preventive effect in
such a mode.
[0035] As described above, the pharmaceutical composition for
external use of the present invention may be a preparation having
the following properties 2) and 3). Further, when the compound
represented by the general formula (1) has a stereoisomer, the
pharmaceutical composition may be a preparation having the
following properties 1) to 3):
1) the amount of a stereoisomer of the compound and/or a salt
thereof produced under a preservation condition of 60.degree. C.
for 3 weeks is 1% by mass or less with respect to the total mass of
the compound and/or a salt thereof at the beginning;
2) the preparation is in a clear liquid state when preserved at a
constant temperature of 20.degree. C. immediately after
manufacture; and
3) no crystal is deposited when the preparation is preserved at
5.degree. C. for 2 weeks after manufacture.
[0036] The characteristic 1) may be determined by, for example,
preserving a preparation at 60.degree. C. for 3 weeks after
manufacture, performing liquid chromatography using an
optically-active stationary phase which may separate a compound of
interest from optical isomers thereof to optically resolve the
compound from the optical isomers, and calculating the amount of
the isomers by peak areas of the optical isomers in the resultant
chart.
[0037] The characteristic 2) may be assessed by, for example,
keeping a preparation at a constant temperature of 20.degree. C.
after manufacture, and observing the liquid state of the
preparation with the naked eye and/or under a microscope when/after
the preparation having reached a constant temperature. When white
turbidity, precipitation, or the like is not confirmed, or a
crystal is confirmed only with a microscope or through observation
under a microscope and the time-dependent growth of the crystal is
not confirmed, the assessment of a clear liquid state is given. (It
should be noted that, hereinafter, such state may be referred to as
"a small amount of crystal deposition was confirmed.")
[0038] The characteristic 3) may be assessed by, for example,
preserving a preparation at 5.degree. C. for 2 weeks after
manufacture, and observing the preparation with the naked eye
and/or under a microscope. When no crystal deposition is confirmed
with the naked eye and/or under a microscope, or a crystal is
confirmed only with a microscope or through observation under a
microscope and the time-dependent growth of the crystal is not
confirmed, the assessment of no crystal deposition is given. (It
should be noted that, hereinafter, such state may be referred to as
"a small amount of crystal deposition was confirmed.")
[0039] The thus-obtained pharmaceutical composition for external
use of the present invention has an excellent effect of maintaining
its transparency over a long period of time although the
composition contains a compound represented by the general formula
(1) and/or a salt thereof in a high concentration. In addition,
because crystal deposition after application is suppressed,
inhibition of orientation and transfer of the compound to organs by
the crystal is suppressed. Therefore, the composition has excellent
bioavailability. Meanwhile, a sufficient amount of the compound is
oriented to an organ with low drug orientation such as the nail,
and hence the composition is preferred as a pharmaceutical
composition for external use for the nail.
EXAMPLES
[0040] Hereinafter, the present invention is described in more
detail by way of examples.
Examples 1 to 7
[0041] Pharmaceutical composition for external use of the present
invention was produced in accordance with the formulations shown in
Table 1 below. That is, luliconazole was wetted with a part (10 to
30% by mass) of dehydrated ethanol, lactic acid as a component for
suppressing crystallization was dissolved in the remainder of
dehydrated ethanol, and those were mixed and dissolved with heating
(at 50.degree. C. to 90.degree. C.). To the mixture under heating
(at 80 to 90.degree. C.) successively added were benzyl alcohol and
propylene carbonate. After confirmation of solubilization, acetone
was added, the remainder of components was added, and the whole was
mixed with stirring. After confirmation of solubilization, the
mixture was cooled with stirring to afford Pharmaceutical
compositions 1 to 5 for external use of the present invention.
After preservation at 20.degree. C. for 12 hours of those
compositions, no crystal deposition was confirmed in observation
with the naked eye and under a microscope, and clear solution
properties were exhibited. Table 1 shows the results. Table 1 also
shows observation results with the naked eye and under a microscope
on the presence or absence of crystal deposition under preservation
at 5.degree. C. of those compositions, together with the generation
status of optical isomers immediately after manufacture and under a
preservation condition of 60.degree. C. for 3 weeks.
[0042] A method of quantitatively determining an SE form [(S)-(E)
form] is as follows:
[0043] HPLC (LC-9A manufactured by Shimadzu Corporation, HPLC
conditions: column; CHIRALCEL OD-R 4.6.times.250 mm, column
temperature; 40.degree. C., mobile phase; a sodium perchlorate
mixture (methanol/water (4:1, v/v)) solution (7.fwdarw.500), flow
rate; 0.56 mL/min., detection; 295 nm)
[0044] Meanwhile, a method of quantitatively determining a Z form
is as follows:
[0045] HPLC (LC-10VP manufactured by Shimadzu Corporation, HPLC
conditions: column; Inertsil ODS-2 4.6.times.150 mm, column
temperature; 40.degree. C., mobile phase; a sodium
1-undecanesulfonate mixture (water/acetonitrile/acetic acid (100)
(54:45:1, v/v/v)) solution (13.fwdarw.10000), flow rate; 1.0
mL/min., detection; 295 nm)
[0046] It should be noted that, in both of Example 6 in which
propylene carbonate of Example 1 was replaced by acetone, and
Example 7 in which propylene carbonate of Example 4 was replaced by
acetone, an insoluble matter was confirmed on Day 1 after
preservation at 20.degree. C. after manufacture. TABLE-US-00001
TABLE 1 Formulations (% by mass) Components Example 1 Example 2
Example 3 Example 4 Example 5 Example 6 Example 7 Luliconazole 8 6
8 10 8 8 10 Acetone 10 10 10 10 10 15 15 Propylene carbonate 5 5 5
5 3 -- -- Benzyl alcohol 2 2 2 2 2 2 2 Diisopropyl adipate (DID) --
-- -- -- -- -- -- Lactic acid 4 4 6 6 6 4 6 Propylene glycol 10 10
10 10 10 10 10 Dehydrated ethanol 61 63 59 57 61 61 57 Solution
properties after manufacture 20.degree. C. 12 hr .smallcircle.
.smallcircle. .smallcircle. .smallcircle. .smallcircle.
.smallcircle. .smallcircle. 20.degree. C. 24 hr .smallcircle.
.smallcircle. .smallcircle. .smallcircle. .smallcircle. .DELTA.
.DELTA. Presence or absence of crystal deposition under
preservation 5.degree. C. 5 day .smallcircle. .smallcircle.
.smallcircle. .smallcircle. .smallcircle. 5.degree. C. 1 week
.smallcircle. .smallcircle. .smallcircle. .smallcircle.
.smallcircle. 5.degree. C. 2 week .smallcircle. .smallcircle.
.smallcircle. .smallcircle. .smallcircle. 5.degree. C. 3 week
.smallcircle. .DELTA. .smallcircle. .smallcircle. .smallcircle.
Stability Beginning Quantitative determination (with respect to
beginning) 100 100 100 100 100 Purity SE form 0.44 0.44 0.47 0.48
0.47 Z form 0.02 0.02 0.02 0.01 0.02 Others Total amount 0.037
0.0184 0.0126 0.0061 60.degree. C., 3 week Quantitative
determination (with respect to beginning) 100.1 99.4 101.4 100.9
100 Purity SE form 0.46 0.46 0.48 0.49 0.48 Z form 0.06 0.06 0.07
0.08 0.06 Others Total amount 0.1534 0.1544 0.1814 0.1747 0.121
Indication of solution properties; .smallcircle.: no insoluble
matter was confirmed, .DELTA.: a small amount of insoluble matter
was confirmed, and x: an insoluble matter was confirmed.
Indication of presence or absence of crystal deposition;
.largecircle.: no crystal deposition was confirmed, and .DELTA.: a
small amount of crystal deposition was confirmed.
Comparative Example 1
[0047] Components of Table 2 below were treated, and a
pharmaceutical composition for external use of Comparative Example
1 was obtained in the same method as in Example 1. It was revealed
that the pharmaceutical composition had a problem in its practical
use because crystal deposition was already confirmed under a
constant temperature of 20.degree. C. immediately after
manufacture. TABLE-US-00002 TABLE 2 Formulation (% by mass)
Comparative Components Example 1 Luliconazole 10 Acetone --
Propylene carbonate 5 Benzyl alcohol 2 DID -- Lactic acid 4
Propylene glycol 10 Dehydrated ethanol 69 Presence or absence of
crystal deposition x immediately after manufacture (crystal
deposition)
Example 8
[0048] Components of Table 3 below were treated, and a
pharmaceutical composition for external use of Example 8 was
obtained in the same method as in Example 1. In the pharmaceutical
composition, such crystal deposition that is less than Comparative
Example 1 but was recognized only under a microscope was confirmed
under a constant temperature of 20.degree. C. immediately after
manufacture. It should be noted that, when the pharmaceutical
composition was preserved at 5.degree. C., such a small amount of
crystal deposition that was recognized only under a microscope was
confirmed on Day 1. As long as the solubility is concerned, it was
revealed that the diester of a dibasic acid exhibited a similar
effect to that of diester carbonate. TABLE-US-00003 TABLE 3
Formulation (% by mass) Components Example 8 Luliconazole 10
Acetone 10 Propylene carbonate -- Benzyl alcohol 2 DID 12 Lactic
acid 4 Propylene glycol -- Dehydrated ethanol 62 Presence or
absence of crystal deposition .DELTA. (small amount of immediately
after manufacture crystal deposition) Presence or absence of
crystal deposition under preservation 5.degree. C. 1 day .DELTA.
(small amount of crystal deposition)
Example 9
[0049] Components of Table 4 below were treated, and a
pharmaceutical composition for external use of Example 9 was
obtained. In the pharmaceutical composition, no crystal deposition
was recognized under a microscope under a constant temperature of
20.degree. C. immediately after manufacture. It should be noted
that, when the pharmaceutical composition was preserved at
5.degree. C., there was no change in appearance on Day 1, a trace
amount of crystal deposition was confirmed on Day 4, and a small
amount of crystal deposition which was recognized only under a
microscope was confirmed on Week 1. This revealed that it was
preferred to contain propylene carbonate in terms of not only
stability but also solubility. Further, an effect by addition of
propylene glycol was also confirmed. TABLE-US-00004 TABLE 4
Formulation (% by mass) Components Example 9 Luliconazole 10
Acetone 10 Propylene carbonate 5 Benzyl alcohol 2 DID -- Lactic
acid 4 Propylene glycol -- Dehydrated ethanol 69 Presence or
absence of crystal deposition .smallcircle. (no deposition
immediately after manufacture was confirmed) Presence or absence of
crystal deposition under preservation 5.degree. C. 1 week .DELTA.
(small amount of crystal deposition)
Examples 10 to 14 and Comparative Example 2
[0050] Pharmaceutical compositions for external use of the present
invention were manufactured in accordance with the formulations
shown in Table 5 below. That is, formulation components were heated
to 70.degree. C., luliconazole was wetted with a part (10 to 30% by
mass) of dehydrated ethanol, lactic acid as a component for
suppressing crystallization was dissolved in the remainder of
dehydrated ethanol, and those were mixed and dissolved with
heating. To the mixture successively added were benzyl alcohol and
propylene carbonate. After confirmation of solubilization, to the
mixture under heating, isostearyl alcohol and/or a polyoxyethylene
alkyl ether, which had been mixed in advance, were gradually added
to stabilize solubilizing properties, and after doing that, the
remainder of components were successively added to solubilize
formulation components. The solution was cooled with stirring to
afford Pharmaceutical compositions 10 to 13 for external use of the
present invention. After preservation at 20.degree. C. for 12 hours
of those compositions, no crystal deposition was confirmed in
observation with the naked eye and under a microscope, and clear
solution properties were exhibited. Table 5 shows the results.
Table 5 also shows observation results with the naked eye and under
a microscope on the presence or absence of crystal deposition under
preservation at 5.degree. C. of those compositions, together with
the generation status of optical isomers immediately after
manufacture and under a preservation condition of 60.degree. C. for
3 weeks. A method of quantitatively determining optical isomers is
the same as that as mentioned above.
[0051] It should be noted that, in Example 14 in which propylene
carbonate of Example 10 was replaced by ethanol, a small amount of
crystal deposition that was recognized only under a microscope was
confirmed immediately after manufacture and in Comparative Example
2 in which polyoxyethylene (10) cetyl ether was replaced by
ethanol, a crystal was already confirmed immediately after
manufacture. Thus, it is understood that a constitution of the
present invention exerts an effect of stably solubilizing
luliconazole in as high a concentration as 5% by mass.
TABLE-US-00005 TABLE 5 Formulations (% by mass) Example Example
Example Example Components 10 11 12 13 Luliconazole 5 5 5 5
Polyoxyethylene (10) 2.5 -- -- -- cetyl ether (Nikkol BC-10)
Polyoxyethylene (10) -- 5 5 5 lauryl ether (Nikkol BL-4.2)
Polyethylene glycol -- -- -- 20 (PEG) 400 Propylene carbonate 5 5 5
5 Benzyl alcohol 2 2 2 2 DID -- -- -- -- Lactic acid 4 4 4 4
Propylene glycol 10 10 10 10 Isostearyl alcohol -- -- 20 20
Dehydrated ethanol 71.5 69 49 29 Solution properties after
manufacture 20.degree. C. 12 hr .largecircle. .largecircle.
.largecircle. .largecircle. 20.degree. C. 24 hr .largecircle.
.largecircle. .largecircle. .largecircle. Presence or absence of
crystal deposition under preservation 5.degree. C. 1 week
.largecircle. .largecircle. .largecircle. .largecircle. 5.degree.
C. 2 week .largecircle. .largecircle. .largecircle. .largecircle.
5.degree. C. 3 week .largecircle. .largecircle. .largecircle.
.largecircle. 5.degree. C. 4 week .largecircle. .largecircle.
.largecircle. .largecircle. 5.degree. C. 8 week .largecircle.
.largecircle. .largecircle. .largecircle. 5.degree. C. 10 week
.largecircle. .largecircle. .largecircle. .largecircle. Stability
Beginning Quantitative 100% 100% 100% 100% determination (with
respect to beginning) Purity SE form 0.3 0.33 0.32 0.32 Z form 0.01
0.02 0.01 0.01 Others 5.4 mm -- -- -- -- 6.6 mm -- -- -- -- 9.8 mm
-- -- -- -- 60.degree. C., 3 week Quantitative 99.5% 99.6% 98.6%
97.6% determination (with respect to beginning) Purity SE form 0.4
0.41 0.39 0.4 Z form 0.06 0.06 0.05 0.09 Others Total amount 0.21
0.21 0.292 0.3 Indication of solution properties; .largecircle.: no
insoluble matter was confirmed, .DELTA.: a small amount of
insoluble matter was confirmed, and x: insoluble matter was
confirmed.
Indication of presence or absence of crystal deposition;
.largecircle.: no crystal deposition was confirmed, and .DELTA.: a
small amount of crystal deposition was confirmed.
INDUSTRIAL APPLICABILITY
[0052] The present invention can be applied to a pharmaceutical
composition for external use useful for treatment of
onychomycosis.
* * * * *