CA1224152A - Topical treatment of acne - Google Patents

Abstract

ABSTRACT OF THE DISCLOSURE
The present invention concerns a composition for topical application which is useful for the treatment of acne. The composition contains (1) a compound of the formula:

Description

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A Pharmaceutical Composition .. . ..
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.

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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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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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- 4a -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 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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- 6a -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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12~ S2 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:
-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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g 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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' ~22~l~52 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 -~ 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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Claims (19)

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. A composition for the topical treatment of acne, which comprises:
(1) a compound of the formula:

(I) wherein the dotted line at the 9(10) position indicates a saturated bond or an unsaturated double bond, or its ester or ether, (2) keratolytic agent, and (3) pharmaceutically acceptable carrier.

2. The composition according to Claim 1, wherein the composition comprises at least one member of the group consisting of a gelling agent and an alcohol as the carrier.

3. The composition according to Claim 1 or 2, wherein the content of the compound of the formula I is from about 0.001 W/V% to about 2 W/V% relative to the whole composition.

4. The composition according to Claim 1 or 2, wherein the compound of the formula is oxendolone.

5. The composition according to Claim 1 or 2, wherein the keratolytic agent is urea.

6. The composition according to Claim 1 or 2, wherein the keratolytic agent is resorcinol.

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7. The composition according to Claim 2, wherein the gelling agent is carboxyvinyl polymer.

8. The composition according to Claim 2, wherein the alcohol is ethyl alcohol.

9. The composition according to Claim 2, wherein the alcohol is benzyl alcohol.

10. The composition according to Claim 2, which comprises oxendolone, urea, carboxyvinyl polymer, ethyl alcohol and benzyl alcohol.

11. The composition according to Claim 2, which comprises oxendolone, resorcinol, carbonyvinyl polymer, ethyl alcohol and benzyl alcohol.

12. A process for producing a composition for the topical treatment of acne as defined in claim 1, which Process comprises admixing the compound of formula (I) defined in claim 1 with a keratolytic agent and a pharmaceutically acceptable carrier.

13. The process according to claim 12, wherein at least one member of the group consisting of a gelling agent and an alcohol is employed as the carrier.

14. The process according to claim 13, wherein 0.001 to 2 W/V % of the compound of formula (I) relative to the whole composition is employed.

15. A gel ointment for the topical treatment of acne, which comprises:
(1) about 0.001 to about 2 W/V % of a compound of the formula:

(I) (wherein the dotted line at the 9(10)position indicates a saturated bond or unsaturated double bond) or an ester thereof at the 17-position with a C1-18 alkanoyl or C2-18 alkenoyl group or an ether thereof at the 17-position with a C1-6 alkyl or C1-6 alkoxy-C1-6 alkyl group, (2) about 0.001 to about 15 W/V % of a keratolytic and (3) about 0.001 to about 20 W/V % of a gelling agent, wherein W/V percentage is based on the whole composition.

16. The composition according to claim 15, which comprises (1) 0.2 to 2.0 W/V % of oxendolone as the compound of formula (I), (2) benzoyl peroxide, urea or resorcinol as the keratolytic agent and (3) a carboxyvinyl polymer as the gelling agent.

17. The composition according to claim 16, which further comprises about 5 to about 70 W/V % of an alcohol, the balance of the composition being substantially water.

18. A process for producing a gell ointment composition as defined in claim 17, which process comprises:
admixing an alcoholic-aqueous solution containing oxendolone and the keratolylic agent with an aqueous solution of the carboxyvinyl polymer gelling agent, and neutralizing the resulting solution to a pH value of 6 to 8 by adding a base.

19. A process according to claim 18, wherein as the alcohol one or more alcohols selected from the group consisting of benzyl alcohol, ethanol, polyethylene glycol and 1,3-butanediol are used; and diisopropanolamine or triethanolamine is used as the base.