Note: Descriptions are shown in the official language in which they were submitted.
2241~
24205-572
A Pharmaceutical Composition
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This invention relates to a preparation for topical
application intended for the treatment of acne.
Acne is a common inflammatory disease of the sebaceous
glands that occurs frequently during adolescence, being more spec-
ifically named acne vulgaris, and clinically defined as "a chronic
inflammatory lesion occurxing in the hair follicle, principally in
the pilosebaceous gland system". Acne, for which the mechanism has
not yetbeensatisfactorilyestablished, is a skin disease caused by
different complicated factors, whereby excessive excretion of sebum,
; cornification of the hair follicle and bacteria in the hair follicle
are generally considered to play an important role. As the topical
medication for the treatment of acne, therefore, frequent use has
normally been made of creams or ointments having sebum excretion
depressants and/or antimicrobial substances incorporated into them~
However, none of the commercially available preparations for the
treatment of acne are completely free from a wide variety of defects.
For example, hormones of the female type, which act as a sebum
excretion depressant, suppress the growth of the epidermis and
reduce excretion of the sebaceous gland, but the side-effects (e.g.
estrogenic ef~ect) brought about by the hormone of the female type
are not desirable to males and females at puberty; andf the anti-
microbial agents, such as h~xachlorophene, trichlorocarbanilide
and benzalkonium chloride, demonstrate in vitro exceedingly~ high
antimicrobial activity against Propionibacterium acnes, an acne
bacterium ordinarily found on the skin, but when incorporated into
creams, ointments, etc. and used for the treatmen~ of acne, mostly
fail to produce the expected therapeutic effect.
541232
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The present inventors, after intensive research to obtain
a pharmaceutical preparation free from side-effects, while being
mild to the skin and being superior in therapeutic e~fect against
acne, have found that a composition which contains (1) a compound
of the formula: ~H
, ~ ~ y CH2CH3
0~
wherein the dotted line at the 9(10~ position indicates a satur-
ated bond or an unsaturated double bond, or its ester or ether
(hereinaf-ter referred to briefly as "Compound ~I~"), (2) keratoly-
tic agent and (3) pharmaceutically acceptable carrier, attains an
unexp~ctedly enhanced therapeutic effect through the combination
or synergistic effect of the Compound ~I~ and the keratolytic
agent. Furthermore, the present inventors have also unexpectedly
found that a composition comprising Compound rI~ , keratolytic
agent, gelling agent and alcohol shows further enhancement of the
therapeutic effect in a shorter period of time in the treatment
of acne through the increased adsorption of the Compound rI~ into
the lesion. The present invention is a culmination of these
unexpected findings.
The Compound ~I~ which is used in the present invention
possesses excellent inhibitory activity against hormones of ths
male type ~the United States Patent Specification No. 3856829, the
Japanese Unexamined Patent Publication No. 53499/1982 and the
Japanese Patent Application No. 57227~1983~ . The dotted line at
9(10) position of Compound [I~ indica-tes a saturated bond or an
unsaturated double bond. Therefore,
,
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Compound [I] consists of the following two compounds tIa and
Ib) and their esters and ethers.
OH OH
,CH2CH3 ~ C}l2C~3
Ia Ib
The Compound ~Ia] is oxedolone (16 ~-ethyl-17 ~-hydroxy-4-
estren-3-on) and has been put on the market as a therapeutic
agent for prostatomegaly ~Tradename of "Prostetln",
produced by Takeda Chemical Industries, Ltd., in Japan).
The esters and ethers which are included in the Compound
[I~ mean the compounds of ~I] where the hydroxy portion at
the 17-position is esterified and etherified, respectively.
As the ester at the 17-position, there may be mentioned
esters with Cl_l8 alkanoyl groups and C2_18 alkenoyl groups 7
wherein these groups may be substituted. Specific examples
of the Cl 18 alkanoyl groups include formyl, acetyl,
propionyl, butyryl, isobutyryl, valeryl, pivaloyl, caproyl,
enanthoyl, capryloyl, lauroyl, myristoyl, palmitoyl,
stearoyl, etc. Specific examples of the C2 18 alkenoyl
groups include crotonoyl, oleoyl, linoleoyl, linolenoyl,
etc. As the substituents on these alkanoyl and alkenoyl
groups, there may be mentioned halogen atoms (e.g. fluorine,
chlorine, etc.), hydroxyl group, mercapto group, oxo group,
thioxo group, Cl 6 alkoxy groups (e.g., methoxy, ethoxy,
etc.), Cl 6 alkylthio groups (e.g., methylthio, ethylthio,
etc.), Cl 1~ alkanoyloxy groups (Cl 18 alkanoyls include
for example those as mentioned above), C2 18 alkenoyloxy
groups (alkenoyls include for example those as mentioned
above), C6 12 aryl groups (e.g., phenyl, naphthyl, etc.),
C6 12 aryloxy groups (e.g., phenoxy, naphthyloxyJ etc.~, and
so forth. Among more specific examples of the substituted
alkanoyl groups are chloroacetyl, phenylacetyl, phenoxyacetyl,
. ... . . .. .. .
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~L224~
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benzoyl, caproyloxyacetyl, enanthoyloxyacetyl, (2-ethylbutyryloxy)
acetyl, etc. As the ether at the 17-position, there may be mentioned
ethers with Cl_6 alkyl groups such as methyl, ethyl, propyl, butyl
and pentyl, and ethers with Cl 6 alkoxy-Cl 6 alkyl groups such as
methoxymethyl, methoxyethyl, ethoxymethyl and ethoxyethyl as well as
ethers with groups such as tetrahydropyranyl, tetrahydrofuryl and
tetrahydrothienyl. The above-mentioned esters and ethers are easily
produced by the known method or a per se known method.
The amount of the Compound [I~ to be incorporated into the
composition of the present invention is preferably at a ratio of
about 0.001 to about 2 W/V %.
The keratolytic agent which is used in the present inven-
tion denotes a compound which exhibits the action of suppressing the
hypercornification of ducts of the sebaceous gland, and specifically
includes sulfur, selenium disulfide, urea, benzoyl peroxide, resor-
cinol, salicylic acid, vitamin A acid, etc., with preferably exam-
ples being urea and resorcinol.
The amount of the keratolytic agent to be incorporated into
the composition of the present invention is preferably at a ratio
of about 0.001 to about 15 W/V %, and preferably is about 1.0 to
a~out 15 W/V % in the case of sulfur, selenium disulfide and benzoyl
peroxide, about 0.005 to about 0.1 W/V % in the case of vitamin A
acid and about 0.05 to about 5 W/V % in the case of other keratolytic
agents~
As the pharmaceutically acceptable carrier which is used
in the present inventionl there may be mentioned qelling aqent,
alcohol, sebum excretion depressant, antimicrobial agent, surface
active agent, thickening agent, humidifying agent, astringent, p~I
.
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adjustlng agent, perfume, colorant, watex, etc. The carrier
can be incorporated into the preparation for topical appl-cation
according to the present invention to such an extent as may
not impair the effect of the preparation. Among others, a
gelling agent and/or
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~24~52
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an alcohol are preferably used as carriers. A gelling agent
and an alcohol improves poor solubility being so far
regarded as the defect of the Compound ~I] from the stand-
point of processing it into preparations.
As the gelling agent which is used in the present
invention, specifically, there may be mentioned carboxyvinyl
polymers ~hereinafter abbreviated as CVP, with the average
molecular weight of 10 millions to 500 millions, preferably,
100 millions to 300 millions, such as Carbopol ~ 940 and
941, produced by Goodrich Chemical Co., in U.S.A., Hivis
Wako~ 103r 104 and 105 produced by Wako Pure Chemical
Industries, Ltd., in Japan,and so forth), carboxymethyl-
cellulose, sodium carboxymethylcellulose, methylcellulose,
hydroxyethylcellulose hydroxypropylcellulose, polyvinyl
alcohol (with a degree of polymerization of about 500 to
about 2000), etc., with the preferred example being CVP.
These gelling agents exhibit gelling action and in some
instances act as a thickening agent and stabilizer, as well.
The amount of the gelling agent to be incorporated
into the composition of the present invention is generally
at a ratio of about 0.001 to about 20 W/V ~ or CVP
mentioned above as the preferred example, the pre~erable
amount incorporated is about 0.01 to about 5 W/V %.
As the alcohols which are used in the present inven-
tion, there may be mentioned monohydric alcohols and
polyhydric alcohols, and the above-mentioned alcohols may
be used singly or in combinationr Examples o the
monohydric alcohols include aliphatic Cl 18 alcohols such
as ethanol, n-propanol, i-propanol, n-butanol, i-butanol,
sec-butanol, tert-butanol, n-pentanol, n-hexanol, lauryl
alcohol and ce~yl alcohol; alicyclic C3 7 alcohols such as
cyclopropanol and cyclobutanol; and phenyl-Cl 6 alkanols
such as benzyl alcohol ~nd phenetyl alcohol. Amon~ others,
ethanol and benzyl alcohol are ~requently used, and these
alcohols~ making up for low solubility o~ the Compound [I}~
function to increase absorption and penetration o~ the
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composition of the present invention. As examples of the poly-
hydric alcohols, there may be mentioned aliphatic C2 6 polyhydric
alcohols (with a number of hydroxyl groups of 2 to 6), such as
ethylene glycol, propylene glycol, trimethylene glycol, 1,3-
butanediol, glycerol and sorbitol, as well as diethylene glycol,
polyethylene glycols (with an average molecular weight~f 200 to
2000), dipropylene glycol, polypropylene glycols (with an average
molecular weight of 200 to 2000), and so forth. Like the mono-
hydric alcohols, these polyhydric alcohols act as a solvent, and
in some instances function as a humidifying agent.
The amount of the alcohols to be incorporated into the
composition of the present invention is preferably at a ratio of
about 5 to about 70 W/V %.
As the sebum secretion depressant, there may be mentioned
hormones of the female type such as estradiol. Examples of the
antimicrobial agents include hexachlorophene, trichlorocarbanilide,
benzalkonium chloride, ph~nol, cetyl pyridinium chloride, undecy-
lenic acid and bithionol. As the surface active agent, there may
be mentioned nonionic surface active agents, anionic surface
active agents, amphoteric surface active agents, etc., and the
preferred examples are nonionic surface active agents and anionic
surface active agents. Examples of the nonionic surface active
agents include polyoxyethylene aliphatic alcohol ethers (with a
degree of ethylene oxide polymerization of 5 to 50, in which the
aliphatic alcohol residues have 12 to 18 carbon atoms; for example
Brij~ 35, 78 and 98, etc., produced by Kao Atlas Co., in Japan;
hereinafter "ethyleneoxide" is abbreviated as "EO"), polyoxyethy-
lene fatty acid esters tWith a degree of EO polymerization of 8 to
: :
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50, in which the fatty acid residues have 12 to 18 carbon atoms;
for example Myrj@~ 45, 52 and 53, etc., produced by Kao Atlas
Co., in Japan), fatty acid esters of sorbitan (with a degree
of EO polymerization of 0 to 40, in which the fatty acid
residues have lZ to 18 carbon atoms; for example Tween~ 20,
40, 60 and 80, Span~ 20, 40, 60 and 80, etc., produced by Kao
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Atlas Co.,in Jap~n), polyoxyethylene h~^ogenated castor oils (with
a degree of E0 polymerization of 5 to 60, for example
Nikkol R HC0-50, HC0-60 and HC0-100~ etc., produced by Nikko
Chemicals Co., Ltd.,in Japan), and so forth. In the abo~-e nonionic
surface active agents, examples of ~12-18 aliphati
residues are lauryl, cetyl and so forth and examples of
C12 18 fatty acid residues are lauroyl, palmitoyl, stearoyl
and so forth. As examples of the anionic surface active
ayents, there may be mentioned sodium soaps (haviny 12 to 18
carbon atoms, for example sodium lauroate, sodium stearoate),
potassium soaps (having 12 to 18 carbon atoms, for example
potassium lauroate, potassium stearate), etc. Examples of
the astringents include tannin and so forth. Examples of
the humidifying agents include hyaluronic acid, sodium
hyaluronate, chondroitin sulfate, pyrrolidonecarboxylic acid,
sodium pyrrolidonecarboxylate and so forth. As the pH adjust-
ing agent, there may be mentioned acids and bases which are
usually employed in this field. Thus, examples of acids used
as the pH adjusting agent are hydrochloric acid, citric acid,
etc. and examples of bases used as the pH adjusting agent
are sodium hydroxide, potassium hydroxide, triethanolamine,
diisopropanolamine, etc.
The composition of the present invention can be
prepared by mixing, by a per se known method, (1) the 25 Compound [I], (2) keratolytic agent and (3) pharmaceutically
acceptable carrier.
As the pH value of the composition of the present
invention is normally within the range of 4 to 8 and
preferably 6 to 8, pH adjusting agents as described above
can be used to adjust the pH value.
The most preferable composition comprises oxendolone,
a keratolytic agent (urea or resorcinol), carbaxyvinyl
polymer, ethyl alcohol and benzyl alcohol. This composition
may contain further additional carrier(s) as mentioned above.
The composition which comprises oxendolone, a keratolytic
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agent (urea or resorcinol), carboxyvinyl polymer, ethyl
alcohol and benzyl alcohol shows especially high therapeutic
effect to acne and causes no irritation to the skin.
The properties of the preparation for topical appli-
cation according to the present invention may be those ofany kind being applicable to the external skin, such as
cream, ointment and lotion. Methods for producing cream,
ointment, lotion and other type of preparations for topical
use are per se known and well established in the phar-
maceutical field. Also in the present invention, such
known technique can be applied to producing the composition
of the present invention in the form of cream, ointment,
lotion, etc. The formulation examples for ointment are
described in the Example.
Action
The preparation for topical application according to
the present invention may be applied to the affected part
normally once to several times daily in the single dose
within the range of 0.1 mg to 0.5 g, depending upon its
symptoms. This method normally permits mild
acne to clear up within several days and even severe acne to
disappear in two to three weeks. In addition, the present
therapy can be applied without any side-effect observed.
Example:
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Gel ointments containing 0.2 to 2.0 W/V % of exendolone
were prepared as the following Examples and Table.
Formulation Example l
In a mixed solution consisting of 5.0 g of benzyl
alcohol and 20.0 g of ethanol was dissolved 0.2 g of oxen-
dolone, and 15.0 g of polyethylene glycol (PEG-600) wa~
added, for dissolution, to the solution, followed by the
addition of a solution of 1.0 g of urea in lO.0 g of purified
water. Then, a solution of 0.8 g of a carboxyvinyl polymer
(Carbopol 940) and 0.1 g of hyaluronic acid in 20.0 g of
purified water was added~ and after stirring and mixing,
27.7 g of purified water was added, followed by the
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~22415~
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neutralization with 0.2 g of triethanolamine to produce a
gel-like ointment for topical application.
Formulation Examples 2 and 3
Gel-like ointments containing the same ingredients as
in Example 1 were produced in the similar manner to Example 1.
Formulation Examiples 4 to 8
In a mixed solution of benzyl alcohol and ethanol
further containing or not containing 1,3-butanediol was
dissolved oxendolone, and polyethylene glycol (PEG-300) was
added, for dissolution, to the solution, followed by the
addition of a solution of a keratolytic agent (urea,
resorcinol or benzoyl peroxide) or mixture of keratolytic
agents in a part of purified water. Then, a solution of a
carboxyvinyl polymer and polyoxyethylene hydrogenated castor
oil (further containing or not containing hydroxypropyl-
cellulose or polyvinyl alcohol) and hyaluronic acid in
purified water was added, and after stirring and mixing rest
of water was added, followed by the neutralization with
diisopropanolamine.
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Clinical test:
The clinical tests are described in the following
to illustrate the phramaceutical effect of the present
invention in more detail.
Medicament preparation used
-
The gel ointment-type preparation for topical application
as produced in the Formulation Example 1 was used.
Patients applied with the pre~aration and duration OL observation
15 to 30 year aged, males and females in total
of 15 patients.
Method of aPplication
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~ fter the patients washed thoroughly their faces with
use of toilet soap, the above mentioned ointment-type
preparation was applied for topical application only
onto the efflorescence once to three times a day.
Items of observation and duration of observation
The patients were observed for three symptomsti,e., comedo,
papule and pustule, and the severity of each
symptom observed was rated on a scale divided into five grades
ofin~ense (4), moderate (3), slight ~2), little (1) and none (0).
By putting the severities of these three symptoms together,
the degree of kefore-treatment seriousness of acne vulgaris was divided into
three grades of severe, mild and minor acne. The observations
for progress were made at the times of before treatment(O) and
one week(I), tWD weeks(II), three weeks(III) and four weeks(IV) after treatment.Dearee of overall improvement
The degree of improvement in symptoms brought about
by the medicament preparation use~ over the before-treatment
symptoms was divided into five grades of marked relief (+~+),
fair relief (++), slight relief (+~, no relief ~ and
aggravation (-~.
Usefulness
On the basis of the degree of overall improvement~
the effect of the me~icament preparation used was rated as
greatly useful (+++), fairly useful ~++1, s1ightly useful (+~
and useless (_).
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Results
Case Serious~ Comedo Papule Pustule DOI* Useful-
Age Sex . . .
No. ness 0 I I[ m 15~ 0 I Il~ 7 0 I ~ rcc ~7 I lI m ~7 ness
__ _
16 Female Mild 222 2 2 222 1 2 111 1 1 + + + + +
2 20 Male .. 322 1 0 210 0 0 110 0 0 .+~ * *+ *t
3 30 Female ... 222 1 0 221 1 1 221 1 1 + .~ +~ J,+ +~
4 21 " Severe 443 2 1 433 2 1 322 1 0 + +~ *1 +~ +1+
., " 44 ~ 3 2 332 1 1 332 1 0 + + +~ +'+ +~
6 24 Male Mild 311 0 0 322 1 0 321 1 0 +~ ~ +~ ++ +'+
7 26 Female ... 33222 2121 1 21111 ++ + + +
8 19 1. Severe 3 21 0 0 4 32 2 1 31000 ttt~*~+ +H
9 15 " Mild 3 2 1 0 0 311 0 0 3 2100 .+~+~+~ +.+
23 ll ll 100 0 0 331 0 0 310 0 0 +~+ ~+ +~ ++
11 20 ~, ., 100 0 0 210 0 0 100 0 0 ~*t+~ *~
12 18 Male Severe 321 0 0 42110 20000 ~t~+~+~+ +
13 24 Female Mild 322 1 1 3310 0 100 0 0 + t+ +~ +~ +~
14 20 .. ~. ~ 311 1 1 31111 11000 -H++~ ~ +~ :
27 ~- ll 210 3 21 OOOOO +-+1+~1+~+ *~
Note: *), the degree of overall improvement.
~ ~As being clear from the above results, the clinical
: test resuIts on these 15 cases consisting of 3 males and 12 females,
in which ~ (.useless) accounted for l case ~7%), ~ (slightly
useful) l case (7%), ~ (fairly usefuI) 4 cases (26~) and -H~
(greatly useful) 9 cases (60%), demonstrate th~ good effect produced
by the preparation for topical application according ~o the
present invention.
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