U.S. patent application number 12/338096 was filed with the patent office on 2009-04-16 for external preparation for athlete's foot treatment.
Invention is credited to Youichi Kawamura, Hiroki Kawatsura, Toshihiro Shirouzu, Mitsuhiko Tokunaga.
Application Number | 20090099202 12/338096 |
Document ID | / |
Family ID | 33554443 |
Filed Date | 2009-04-16 |
United States Patent
Application |
20090099202 |
Kind Code |
A1 |
Shirouzu; Toshihiro ; et
al. |
April 16, 2009 |
External Preparation for Athlete's Foot Treatment
Abstract
External preparations for athlete's foot treatment capable of
enhancing patient's compliance and capable of reducing the symptom
of rubefaction, comprising an anti-trichophyton drug mixed with at
least one compound selected from among 1-menthol, menthol analogue
compounds and bactericidal compounds.
Inventors: |
Shirouzu; Toshihiro;
(Tosu-shi, JP) ; Kawamura; Youichi; (Tosu-shi,
JP) ; Kawatsura; Hiroki; (Tosu-shi, JP) ;
Tokunaga; Mitsuhiko; (Tosu-shi, JP) |
Correspondence
Address: |
Jane Massey Licata;Licata & Tyrrell P.C.
66 East Main Street
Marlton
NJ
08053
US
|
Family ID: |
33554443 |
Appl. No.: |
12/338096 |
Filed: |
December 18, 2008 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10561499 |
Dec 19, 2005 |
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PCT/JP2004/008992 |
Jun 25, 2004 |
|
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12338096 |
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Current U.S.
Class: |
514/254.07 ;
514/312; 514/396; 514/399; 514/488; 514/557; 514/649; 514/655;
514/738 |
Current CPC
Class: |
A61P 31/10 20180101;
A61P 31/00 20180101; A61K 31/05 20130101; A61P 23/00 20180101; A61K
31/185 20130101; A61P 43/00 20180101; A61K 31/47 20130101; A61K
31/137 20130101; A61P 17/00 20180101; A61K 31/185 20130101; A61K
31/27 20130101; A61P 29/00 20180101; A61K 31/045 20130101; A61K
31/167 20130101; A61K 31/137 20130101; A61K 31/4402 20130101; A61K
31/47 20130101; A61K 9/0014 20130101; A61K 45/06 20130101; A61K
31/4402 20130101; A61K 31/047 20130101; A61K 31/56 20130101; A61K
31/047 20130101; A61K 31/56 20130101; A61P 23/02 20180101; A61K
31/05 20130101; A61K 31/167 20130101; A61K 2300/00 20130101; A61K
2300/00 20130101; A61K 2300/00 20130101; A61K 2300/00 20130101;
A61K 2300/00 20130101; A61K 2300/00 20130101; A61K 2300/00
20130101; A61K 2300/00 20130101; A61K 2300/00 20130101; A61K
2300/00 20130101; A61K 31/045 20130101; A61K 31/27 20130101; A61K
47/22 20130101 |
Class at
Publication: |
514/254.07 ;
514/738; 514/649; 514/655; 514/488; 514/396; 514/399; 514/312;
514/557 |
International
Class: |
A61K 31/047 20060101
A61K031/047; A61K 31/135 20060101 A61K031/135; A61K 31/27 20060101
A61K031/27; A61K 31/4164 20060101 A61K031/4164; A61K 31/496
20060101 A61K031/496; A61K 31/47 20060101 A61K031/47; A61K 31/19
20060101 A61K031/19; A61P 31/10 20060101 A61P031/10 |
Foreign Application Data
Date |
Code |
Application Number |
Jun 25, 2003 |
JP |
2003/181264 |
Dec 5, 2003 |
JP |
2003/407136 |
Claims
1. An external preparation for athlete's foot treatment, comprising
an anti-trichophyton drug mixed with
3-1-menthoxypropane-1,2-diol.
2. The external preparation for athlete's foot treatment of claim
1, wherein the anti-trichophyton drug and
3-1-menthoxypropane-1,2-diol are blended in 0.1-10% by mass and
0.5-5% by mass respectively.
3. The external preparation for athlete's foot treatment of claim
1, wherein the anti-trichophyton drug is selected from benzylamine
type, allylamine type, thiocarbamic acid type and imidazole type
antifungal agents.
4. The external preparation for athlete's foot treatment of claim
1, wherein the anti-trichophyton drug is one kind selected from
butenafine hydrochloride, terbinafine hydrochloride, tolnaftate,
bifonazole, ketoconazole, neticonazole hydrochloride and
lanoconazole.
5. The external preparation for athlete's foot treatment of claim 4
wherein butenafine hydrochloride and 3-1-menthoxypropane-1,2-diol
are blended.
6. The external preparation for athlete's foot treatment of claim 1
further comprising at least one kind of a local anesthetic, an
antihistamine and an anti-inflammatory drug.
7. The external preparation for athlete's foot treatment of claim
6, wherein the local anesthetic is dibucaine hydrochloride, or
lidocaine or its salt.
8. The external preparation for athlete's foot treatment of claim
6, wherein the antihistamine is chlorpheniramine maleate, or
diphenhydramine or its salt.
9. The external preparation for athlete's foot treatment of claim
6, wherein the anti-inflammatory drug is glycyrrhetinic acid or its
salt, or allantoin.
10. The external preparation for athlete's foot treatment of claim
6 wherein butenafine hydrochloride, 3-1-menthoxypropane-1,2-diol,
dibucaine hydrochloride, chlorpheniramine maleate and
glycyrrhetinic acid are blended.
Description
[0001] This patent application is a continuation of U.S.
application Ser. No. 10/561,499, filed Dec. 19, 2005, which is the
National Stage of International Application No. PCT/JP2004/008992,
filed Jun. 25, 2004, which claims the benefit of priority from
Japanese Application No. 2003-407136, filed Dec. 5, 2003 and
Japanese Application No. 2003-181264, filed Jun. 25, 2003,
teachings of each of which are herein incorporated by reference in
their entirety.
TECHNICAL FIELD
[0002] The invention relates to an external preparation for
athlete's foot treatment, comprising an anti-trichophyton drug and
at least one compound, which is selected from l-menthol, menthol
analogue compounds and bactericidal compounds, as an essential
ingredient.
BACKGROUND ART
[0003] As an anti-fungal agent used for an external preparation for
athlete's foot treatment, various antifungal agents such as
imidazole, triazole, thiocarbamic acid, benzylamine, allylamine and
morpholine types have been developed and have been on the
market.
[0004] However, each of anti-fungal agents has a difference in its
width of the antifungal spectrum and the antifungal activity, and
there is no antifungal agent which shows a strong antibacterial
activity over Trychophyton and other fungi, for example, Candida
albicans and the like, fungi in general, whereby an external
preparation and the like, in which an antifungal activity or the
like are strengthened by a combination of two or more of antifungal
agents, are reported (ex. see Patent documents 1-3).
[0005] In addition, although a composition with a strengthened
antifungal activity is also reported, in which an allylamine type
antifungal agent and menthol are blended, this increases the
activity against so called Trychophyton and does not strengthen the
antifungal activity against other fungi such as Candida albicans
(ex. see Patent document 4).
[0006] Further, although there are a preparation in which a
peripheral vasodilator is added to an antifungal agent (ex. see
Patent document 5) and a preparation in which an antifungal agent
is added with a substance such as methyl salicylate, glycol
salicylate, crotamitone, peppermint oil or l-menthol to improve a
horny layer accumulation of the antifungal agent (ex. see Patent
document 6), they do not show any excellent antifungal property
against Trychophyton and other fungi including Candida albicans and
the like.
[0007] In addition, any external preparation disclosed in the above
documents did not suppress the growth of skin habitual bacteria
such as Staphylococus aureus and did not have effects in a case
that the skin habitual bacteria such as Candida albicans and
Staphylococus aureus, which accelerated the discomfort of athlete's
foot (itch, bad smell, etc.), grew abnormally, therefore, it could
not be said that it satisfactorily enhanced patient's compliance
after applying such external preparation described above.
[0008] Furthermore, in case of using the above substance improving
a horny layer accumulation, a frequency of occurrence of a light
symptom such as rubefaction, which an antifungal agent originally
has in not a serious degree, is enhanced, whereby further
enhancement of patient's compliance has been desired.
[0009] Patent document 1: JP, A1, 3-38522
[0010] Patent document 2: JP, A1, 9-176014
[0011] Patent document 3: JP, A1, 2004-35411
[0012] Patent document 4: JP, A1, 2004-149508
[0013] Patent document 5: JP, A1, 7-233088
[0014] Patent document 6: JP, A1, 8-20527
DISCLOSURE OF THE INVENTION
Problems to be Solved by the Invention
[0015] Although an anti-trichophyton drug such as butenafine
hydrochloride has a very excellent antifungal action even in alone,
the invention provides an external preparation for athlete's foot
treatment, having a more excellent effect in points such as
enhancement of patient's compliance and reduction of the symptom of
rubefaction.
Means to Solve the Invention
[0016] After extensive researches to enhance patient's compliance
on an external preparation for athlete's foot treatment, the
inventors found out that not only Trichophyton but also other fungi
such as Candida albicans and a skin habitual bacteria such as
Staphylococus aureus are effectively reduced by an external
preparation containing an anti-trichophyton drug and at least one
compound selected from l-menthol, menthol analogue compounds and
bactericidal compounds as an essential ingredient.
[0017] Namely, the invention relates to an external preparation for
athlete's foot treatment, comprising an anti-trichophyton drug
mixed with at least one compound selected from l-menthol, menthol
analogue compounds and bactericidal compounds.
[0018] In addition, the invention relates to the external
preparation for athlete's foot treatment, wherein the
anti-trichophyton drug and at least one compound selected from
l-menthol, menthol analogue compounds and bactericidal compounds
are blended in 0.1-10% by mass and 0.5-5% by mass respectively.
[0019] Further, the invention relates to the external preparation
for athlete's foot treatment, wherein the menthol analogue compound
is 3-l-menthoxypropane-1,2-diol.
[0020] The invention relates to an external preparation for
athlete's foot treatment, wherein the bactericidal compound is
isopropylmethylphenol.
[0021] In addition, the invention relates to an external
preparation for athlete's foot treatment, wherein the
anti-trichophyton drug is selected from benzylamine type,
allylamine type, thiocarbamic acid type and imidazole type
antifungal agents.
[0022] Further, the invention relates to an external preparation
for athlete's foot treatment, wherein the anti-trichophyton drug is
one kind selected from butenafine hydrochloride, terbinafine
hydrochloride, tolnaftate, bifonazole, ketoconazole, neticonazole
hydrochloride and lanoconazole.
[0023] Furthermore, the invention relates to an external
preparation for athlete's foot treatment, wherein the
anti-trichophyton drug and l-menthol are blended.
[0024] The invention relates to the external preparation for
athlete's foot treatment, wherein butenafine hydrochloride,
l-menthol and isopropylmethylphenol are blended.
[0025] In addition, the invention relates to the external
preparation for athlete's foot treatment, also comprising at least
one kind of a local anesthetic, an antihistamine and an
anti-inflammatory drug.
[0026] Further, the invention relates to the external preparation
for athlete's foot treatment, wherein the local anesthetic is
dibucaine hydrochloride, or lidocaine or its salt.
[0027] Furthermore, the invention relates to the external
preparation for athlete's foot treatment, wherein the antihistamine
is chlorpheniramine maleate, or diphenhydramine or its salt.
[0028] Further, the invention relates to the external preparation
for athlete's foot treatment, wherein the anti-inflammatory drug is
glycyrrhetinic acid or its salt, or allantoin.
[0029] Further, the invention relates to the external preparation
for athlete's foot treatment, wherein butenafine hydrochloride,
l-menthol, dibucaine hydrochloride, chlorpheniramine maleate and
glycyrrhetinic acid are blended.
[0030] Consequently, in an anti-trichophyton drugs of which
antibacterial action against fungi except Trichophyton is not
necessarily satisfactory, the external preparation for athlete's
foot treatment of the invention suppresses the growth of skin
habitual fungi such as Staphylococus aureus and Candida albicans,
which become a cause of a bad smell of foot due to athlete's foot,
aggravation athlete's foot and the like, without combination of an
antifungal agent, and not only improves a therapeutic effect for
athlete's foot compared with a case simply to reduce Trichophyton
but has effect to enhance patient's compliance.
[0031] In addition, by blending at least one kind of compound,
preferably two kinds of compounds in combination, which were
selected from l-menthol, a menthol analogue compound and a
bactericidal compound, it was found that an anti-trichophyton drug
could synergistically suppress the growth of Staphylococus aureus
and Candida albicans in a lower blend amount.
[0032] Further, if said external preparation for athlete's foot
treatment contains at least one kind among a local anesthetic, an
antihistamine and an anti-inflammatory drug, it suppresses
rubefaction which an anti-trichophyton drug rarely produces even if
in a slight degree, and further favorable enhancement of compliance
can be obtained. Although this effect can be obtained by blending
at least one kind among the local anesthetic, the antihistamine and
the anti-inflammatory drug, it is possible to get further favorable
effect by combination of two or more kinds.
BEST EMBODIMENT FOR CARRYING OUT THE INVENTION
[0033] As described above, in the external preparation for
athlete's foot treatment, an anti-trichophyton drug is blended in a
specific concentration, that is, 0.1-10.0% by mass, preferably 1-5%
by mass, with at least one kind of compound selected from
l-menthol, a menthol analogue compound and a bactericidal compound
in the range of 0.5-5% by mass, preferably 1-3% by mass in
total.
[0034] By making the blend amount of the anti-trichophyton drug not
less than 0.1% by mass, the effect as an anti-trichophyton agent
can easily be obtained, and even if blending not less than 10% by
mass, the effect as the anti-trichophyton agent is hardly
improved.
[0035] The anti-trichophyton drugs used in the invention are
benzylamine type, allylamine type, thiocarbamic acid type and
imidazole type and triazole type antifungal agents, specifically,
include butenafine hydrochloride, terbinafine hydrochloride,
tolnaftate, miconazole, bifonazole, ketoconazole, clotrimazole,
econazole nitrate, neticonazole hydrochloride, lanoconazole,
isoconazole, oxiconazole, sulconazole, tioconazole, fluconazole and
itraconazole, though butenafine hydrochloride, terbinafine
hydrochloride, tolnaftate, bifonazole, ketoconazole, neticonazole
hydrochloride and lanoconazole are preferable, and butenafine
hydrochloride is particularly preferable.
[0036] Although butenafine hydrochloride is high in activity
against Trichophyton, the activity against Candida albicans and
Staphylococus aureus can not be expected much, and therefore, by
using it with at least one kind of compound in combination, which
are selected from l-menthol, a menthol analogue compound and a
bactericidal compound, preferably the activity against Trichophyton
as well as Candida albicans and Staphylococus aureus can
synergistically be enhanced.
[0037] Compounds used together with the anti-trichophyton drug in
the invention include l-menthol, in addition, menthol analogue
compounds such as dl-menthol, 3-l-menthoxypropane-1,2-diol,
isopulegol, neoisopulegol, neomenthol, isomenthol, neo-isomenthol,
citronellol and linallol, and bactericidal compounds such as
isopropylmethylphenol, dequalinium chloride, dequalinium acetate,
benzethonium chloride, benzalkonium chloride, chlorhexidine
chloride, chlorhexidine gluconate, hinokitiol and resorcin, though
3-l-menthoxypropane-1,2-diol, isopropylmethylphenol and the like
are preferably used.
[0038] Further, combined use of l-menthol and
isopropyl-methylphenol are particularly preferable.
[0039] In addition, by blending at least one kind of compound in
not less than 0.5% by mass in total, which are selected from
l-menthol, amenthol analogue compound andabactericidal compound,
the growth of Candida albicans and Staphylococus aureus can
preferably be suppressed, and making it not more than 5% by mass is
preferable because a problem of difficult drying in a liquid
preparation does not occur.
[0040] Although the kinds of antihistamines used in the invention
include cholorpheniramine or its salts, diphenhydramine or its
salts, promethazine, mequitazine and the like, cholorpheniramine,
diphenhydramine or its salts are preferable.
[0041] The concentration of the antihistamine is preferably
0.05-5.0% by mass, more preferably 0.05-2.0% by mass. By making the
blend amount of the antihistamine not less than 0.5% by mass, the
effect as the antihistamine can easily be obtained, and even if
making it not less than 5.0% by mass it does not improve the effect
as the antihistamine.
[0042] Although the kinds of local anesthetics used in the
invention include lidocaine or its salts, dibucaine or its salts,
tetracaine or its salts, procaine or its salts, ethyl aminobenzoate
and the like, dibucaine hydrochloride, or lidocaine or is salts are
preferable.
[0043] The concentration of the local anesthetic is preferably
0.01-5.0% by mass, more preferably 0.05-2.0% by mass. By making the
blend amount of the local anesthetic not less than 0.01% by mass,
the effect as the local anesthetic can easily be obtained, and even
if making it not less than 5.0% by mass it does not improve the
effect as the local anesthetic.
[0044] The kinds of anti-inflammatory drugs used in the invention
include glycyrrhetinic acid or its salts, non-steroidal types such
as methyl salicylate, glycol salicylate, indometacin, diclofenac,
felbinac, piroxicam, ketoprofen, ibuprofen piconol, bufexamac or
allantoin, and steroidal types such as amcinonide, prednisolone
valerate, diflucortolone valerate, dexamethasone valerate,
betamethasone valerate, dexamethasone acetate, hydrocortisone
acetate, dexamethasone, triamcinolone acetonide, halcinonide,
betamethasone dipropionate, fluocinonide, fluocinolone acetonide,
prednisolone, deprodone propionate, clobetasol propionate or
betamethasone, though glycyrrhetinic acid or its salts, or
allantoin are preferable.
[0045] The concentration of the anti-inflammatory drug is
preferably 0.05-10.0% by mass, more preferably 0.05-2.0% by mass.
By making the blend amount of the anti-inflammatory drug not less
than 0.05% by mass, the effect as the anti-inflammatory drug can
easily be obtained, and even if making it not less than 5.0% by
mass it does not improve the effect as the anti-inflammatory
drug.
[0046] The formula in which dibucaine hydrochloride,
cholorpheniramine maleate and glycyrrhetinic acid are blended for
an external preparation for athlete's foot treatment consisting of
butenafine hydrochloride and l-menthol is particularly preferable
because it can synergistically enhance the compliance.
[0047] Further, the external preparation described in the invention
includes a liquid preparation, a cream, a lotion, an aerosol
preparation, a patch and the like.
[0048] The external preparation of the invention may contain a
usual base according to its form, and in the case of the liquid
preparation or the lotion, a lower alcohol, a polyhydric alcohol,
water or the like may be contained.
[0049] In the case of the cream, an oily base, a higher alcohol, a
fatty acid ester, or a polyhydric alcohol or its derivative, a
surfactant, a gellant, water or the like may be contained.
[0050] As the aerosol preparation, a lower alcohol, a polyhydric
alcohol or the like may be contained to dissolve the drug of the
invention.
[0051] As the lower alcohol used in the above formulas, methanol,
ethanol, denatured ethanol, isopropanol and the like may be
illustrated.
[0052] As the oily base, liquid paraffin, vaseline, paraffin-wax
and the like may be illustrated, and the higher alcohol is
C.sub.10-20 alcohol, preferably cetyl alcohol, stearyl alcohol,
cetostearyl alcohol and oleyl alcohol are preferable. As the
polyhydric alcohol and its derivative, there are glycerol, ethylene
glycol. propylene glycol, 1,3-butylene glycol, dipropylene glycol,
polyethylene glycol, polypropylene glycol, and these esters or
ethers. The fatty acid ester is a higher fatty acid ester, and
esters of a higher fatty acid such as myristic acid, palmitic acid,
stearic acid or oleic acid, with a lower alcohol (C.sub.1-6) may be
illustrated.
[0053] The surfactant may be an anionic surfactant such as
polyoxyethylenealkylether phosphate or sodium alkylsulfate, a
sorbitan fatty acid ester such as sorbitan sesquioleate, sorbitan
trioleate, sorbitan monostearate, sorbitan monolaurate,
polyoxyethylene sorbitan stearate, a nonionic surfactant such as
polyoxyethylene nonylether, monooxyethylene cetylether or
monooxyethylene laurylether, in addition, a cationic surfactant
such as benzethonium chloride or benzalkonium chloride, or an
amphoteric surfactant.
[0054] The gel-type vehicle includes carboxyvinyl polymer,
hydroxyethyl cellulose, hydroxypropyl cellulose, methyl-cellulose,
ethylcellulose, carboxymethyl cellulose and the like.
[0055] The external preparation for athlete's foot treatment of the
invention may contain a percutaneous absorption promoter, and if
said percutaneous absorption promoter is one or more compounds in
which a percutaneous absorption promoting action of the
anti-trichophyton drug is recognized, any compound may be used.
[0056] Examples include C.sub.6-C.sub.20 fatty acids, fatty
alcohols, fatty acid esters or fatty acid ethers, aromatic organic
acids, aromatic alcohols, aromatic organic acid esters or aromatic
organic acid ethers, furthermore lactic acid esters, acetic acid
esters, monoterpene compounds, sesquiterpene compounds, Azone or
Azone derivatives, glycerol fatty acid esters, sorbitan fatty acid
esters, polysorbates, polyethylene glycol fatty acid esters,
polyoxyethylene hydrogenated castor oils and sucrose fatty acid
esters. Fatty acid esters and fatty alcohols are preferable, in
particular, isopropyl miristate, isopropyl palmitate, sorbitan
monooleate and oleyl alcohol are preferable.
[0057] Further, the external preparation for athlete's foot
treatment of the invention may contain an antioxidant, an
antiseptic agent, a preservative, a moisturizing agent, a chelate
agent and other additive which are usually blended in a skin
external preparation.
[0058] In the following, the invention is explained in more detail
by the examples. The invention, however, is not limited to these
examples, and various changes may be made without departing from
the spirit of the invention. Further, in the examples, `%` means `%
by mass` unless otherwise specified.
EXAMPLES 1-6
Aerosol Preparations
Preparation Method for Aerosol Preparations
[0059] A solid ingredient was dissolved in ethanol, and to this was
added with other ingredients to prepare a raw solution. The raw
solution and a propellant were filled in an aerosol can to obtain
the aerosol preparations of the examples 1-6.
TABLE-US-00001 TABLE 1 (Examples of aerosol preparations) Examples
Composition 1 2 3 Butenafine hydrochloride 1 0.5 1
Diphenhydraminehydrochloride 0 0.2 0.2 Chlorpheniraminemaleate 0
0.5 0.5 Glycyrrhetinic acid 0 0 0.2 l-Menthol 2 1 3 Ethanol 45 50
55 Isopropyl myristate 4 4 8 1,3-Butylene glycol 16 20 12 Purified
water 32 21.8 20.1 Raw liquid in total 100 100 100 Above raw
liquid's amount 50 30 35 Dimethyl ether 30 50 25 LP gas 20 20 40
Aerosol in total 100 100 100
TABLE-US-00002 TABLE 2 Examples Composition 4 5 6 Butenafine
hydrochloride 5 0.5 1 Lidocaine 0 1.5 0.5
Diphenhydraminehydrochloride 0 0.5 0.5 Dipotassium glycyrrhetinate
0 0 0.2 Allantoin 0.2 1.5 0 l-Menthol 2 1 3 Ethanol 25 60 50
Isopropyl myristate 4 4 8 Polyethylene glycol 200 27 8 13 Purified
water 36.8 23 23.8 Raw liquid in total 100 100 100 Above raw
liquid's amount 50 30 35 Dimethyl ether 30 50 25 LP gas 20 20 40
Aerosol in total 100 100 100
Preparation Method for Creams
[0060] As to a preparation method for a cream, an aqueous phase and
an oil phase were each heated at 80.degree. C., mixed and
emulsified under a sufficient stirring. Then, the emulsion was
cooled under stirring to room temperature to obtain the creams of
the examples 7-9.
TABLE-US-00003 TABLE 3 (Examples of creams) Examples Composition 7
8 9 Oil Butenafine hydrochloride 2 1 1 phase Lidocaine 0.1
Diphenhydramine 5 Glycyrrhetinic acid 5 0.5 l-Menthol 1 3 2 Liquid
paraffin 10 10 8 Isopropyl myristate 10 5 2 Cetanol 2 3 Stearyl
alcohol 2 9 3 Polyoxyethylene cetyl ether 2 4 Polyoxyethylene 5
sorbitan stearate Carboxyvinyl polymer 1.5 Aqueous Lidocaine
hydrochloride 0.5 phase Dibucaine hydrochloride 0.5
Chlorpheniramine hydrochloride 0.05 Chlorpheniramine maleate 0.5
Diethanolamine 0.2 0.2 0.2 Methylparaben 0.2 0.2 0.2 Purified water
balance balance balance Total 100 100
Preparation Method for Liquid Preparations
[0061] As to a preparation method for a liquid preparation, an
active ingredient was dissolved in ethanol, and added to other
ingredients to obtain the liquid preparation of the examples 10-17
and the comparative examples 1-3.
TABLE-US-00004 TABLE 4 Examples of Liquid Preparations Example
Example Example Example Example Example Composition 10 11 12 13 14
15 Butenafine hydrochloride 1.0 1.0 1.0 1.0 1.0 1.0 Dibucaine
hydrochloride 0.5 0.5 0.5 0.5 0.5 0.5 Chlorpheniramine maleate 0.5
0.5 0.5 0.5 0.5 0.5 Glycyrrhetinic acid 0.2 0.2 0.2 0.2 0.2 0.2
Isopropylmethylphenol 0 0 0 0 0 0 l-Menthol 1 2 3 0 0 0 MP20H 0 0 0
0.5 1.0 2.0 Propylene carbonate 10 10 10 10 10 10 Ethanol 30 30 30
30 30 30 Sodium hyaluronate 0.01 0.01 0.01 0.01 0.01 0.01 Purified
water balance balance balance balance balance balance Total 100 100
100 100 100 100 Example Example Comparative Comparative Comparative
Composition 16 17 example 1 example 2 example 3 Butenafine
hydrochloride 1.0 1.0 1.0 1.0 1.0 Dibucaine hydrochloride 0.5 0.5
0.5 0.5 0.5 Chlorpheniramine maleate 0.5 0.5 0.5 0.5 0.5
Glycyrrhetinic acid 0.2 0.2 0.2 0.2 0.2 Isopropylmethylphenol 0 0.5
0 0 0 l-Menthol 0 2 0 0 0 MP20H 4.0 0 0 0.1 0.2 Propylene carbonate
10 10 10 10 10 Ethanol 30 30 30 30 30 Sodium hyaluronate 0.01 0.01
0.01 0.01 0.01 Purified water balance balance balance balance
balance Total 100 100 100 100 100 MP20H:
3-l-Menthoxypropane-1,2-diol
Test Example 1
Sensory Test
[0062] The preparations of the examples 10-12 and the comparative
example 1 were applied to 20 patients with a skin fungus disease,
showing the number of persons who got the refreshing feeling and
the efficacy feeling (in particular, alleviation of itch).
TABLE-US-00005 TABLE 5 Sensory test Comparative Example 10 Example
11 Example 12 example 1 Refreshing 12 persons/ 14 persons/ 17
persons/ 8 persons/ feeling 20 persons 20 persons 20 persons 20
persons Efficacy 5 persons/ 7 persons/ 10 persons/ 2 persons/
feeling 20 persons 20 persons 20 persons 20 persons (alleviation of
itch)
Test Example 2
Evaluation of Antibacterial Action by Halo Test
[0063] Test Method
[0064] 1. The test bacteria (Staphylococus aureus, Candida
albicans) were inoculated to a SCD agar culture medium cooled to an
appropriate temperature after a high-pressure wet sterilization,
adjusting the bacterial count to about 10.sup.6/mL.
[0065] 2. The test bacteria incubated in 1. were thinly applied to
the SCD agar culture medium formed beforehand into a multilayer,
cooled and fixed at room temperature.
[0066] 3. 50 .mu.L of the following samples were applied to a
sterilized paper disc (diameter: 8 mm) for an antibiotic test,
which was placed on the culture medium of 2.
[0067] 4. 3. was incubated at 35.degree. C. for 24-48 hours, and
the presence or the absence of a growth inhibition ring which
occurred around the paper disc was observed.
[0068] Test Samples
[0069] A liquid, in which butenafine hydrochloride as an
anti-trichophyton drug and only l-menthol as an auxiliary agent
were blended, was prepared on an experimental basis (the below
formula), and the antibacterial actions against Staphylococus
aureus, Candida albicans were evaluated. The results are shown in
Table 6.
[0070] The blend amount of l-menthol was set in 7 classes in the
range of 0-4%.
[0071] Test formula of liquid preparation for athlete's foot
treatment
[0072] Butenafine hydrochloride: 1%
[0073] l-Menthol: 0-4%
[0074] Macrogol 400: 20%
[0075] Ethanol: 30%
[0076] Purified water: Residual quantity
TABLE-US-00006 TABLE 6 Results Observation results of inhibition
ring (diameter of inhibition ring in parentheses) Test bacteria:
Test bacteria: Staphylococus aureus Candida albicans Butenafine
Absence of Absence of hydrochloride: 1% inhibition ring inhibition
ring L-Menthol: 0% Butenafine Absence of Absence of hydrochloride:
1% inhibition ring inhibition ring L-Menthol: 0.1% Butenafine
Absence of Absence of hydrochloride: 1% inhibition ring inhibition
ring L-Menthol: 0.2% Butenafine Absence of Presence of
hydrochloride: 1% inhibition ring inhibition L-Menthol: 0.5% ring
(10 mm) Butenafine Presence of Presence of hydrochloride: 1%
inhibition inhibition L-Menthol: 1% ring (9 mm) ring (10 mm)
Butenafine Presence of Presence of hydrochloride: 1% inhibition
inhibition L-Menthol: 2% ring (10 mm) ring (12 mm) Butenafine
Presence of Presence of hydrochloride: 1% inhibition inhibition
L-Menthol: 4% ring (10 mm) ring (14 mm)
[0077] The antibacterial action was confirmed by blend of not less
than 0.5% against Candida albicans and not less than 1% against
Staphylococus aureus.
[0078] The evaluation of the antibacterial action by Halo test was
carried out by the formulas in the examples 13-17 and the
comparative examples 1-3, described in Table 4. The test method is
same with that in the test example 2, and the results are shown as
follows.
TABLE-US-00007 TABLE 7 Results Observation results of inhibition
ring (diameter of inhibition ring in parentheses) Test bacteria:
Test bacteria: Staphylococus aureus Candida albicans Comparative
Absence of Absence of example 1 inhibition ring inhibition ring
Comparative Absence of Absence of example 2 inhibition ring
inhibition ring Comparative Absence of Absence of example 3
inhibition ring inhibition ring Example 13 Presence of Presence of
inhibition inhibition ring (11 mm) ring (11 mm) Example 14 Presence
of Presence of inhibition inhibition ring (13 mm) ring (13 mm)
Example 15 Presence of Presence of inhibition inhibition ring (14
mm) ring (15 mm) Example 16 Presence of Presence of inhibition
inhibition ring (18 mm) ring (16 mm) Example 17 Presence of
Presence of inhibition inhibition ring (14.5 mm) ring (16 mm)
[0079] The antibacterial action against Staphylococus aureus and
Candida albicans was confirmed in the concentration of not less
than 0.5% of 3-l-menthoxypropane-1,2-diol. In addition, in the
formula in which isopropylmethylphenol and l-menthol were blended
in combination, it was also confirmed to be able to carry out
effectively the suppression of Staphylococus aureus and Candida
albicans.
INDUSTRIAL APPLICABILITY
[0080] By using an external preparation for athlete's foot
treatment containing an anti-trichophyton drug and a compound
suppressing the growth of Staphylococus aureus and Candida albicans
as an essential ingredient, it becomes possible to reduce
effectively not only Trichophyton but also other fungi such as
Candida albicans and a skin habitual bacteria such as Staphylococus
aureus, and therefore, the application to a wide-ranging use such a
therapy for a fungus infectious disease or the like can be
made.
* * * * *