United States Patent (19)
`Ueda et al.
`
`11
`45
`
`Patent Number:
`Date of Patent:
`
`4,657,901
`Apr. 14, 1987
`
`54 PHARMACEUTICAL COMPOSITION
`75) Inventors: Haruhiko Ueda, Yokohama;
`Hidekazu Toyoda, Urawa; Minoru
`Fukuda, Sagamihara, all of Japan
`73) Assignees: Sheiseido Company, Ltd., Tokyo;
`Takeda Chemical Industries, Ltd.,
`Osaka, both of Japan
`(21) Appl. No.: 648,276
`22 Filed:
`Sep. 7, 1984
`(30)
`Foreign Application Priority Data
`Sep. 7, 1983 JP
`Japan ................................ 58-164356
`Jul. 27, 1984 JP
`Japan ................................ 59-157009
`511 Int. Cl.'.............................................. A61K 31/56
`52 U.S. C. ..................................... 514/171; 514/859
`58) Field of Search .......................... 514/171; 424/81;
`260/.397.4
`
`
`
`56)
`
`References Cited
`U.S. PATENT DOCUMENTS
`3,856,829 12/1974 Hiraga et al. .................... 260/.397.4
`4,514,385 4/1985 Damani et al. ....................... 424/81
`
`OTHER PUBLICATIONS
`Chem. Abstracts vol. 98 (26) Par 221834(a).
`Primary Examiner-Leonard Schenkman
`Assistant Examiner-Joseph A. Lipovsky
`Attorney, Agent, or Firm-Wenderoth, Lind & Ponack
`57
`ABSTRACT
`The present invention concerns a composition for topi
`cal application which is greatly useful for the treatment
`of acne. The composition contains (1) a compound of
`the formula:
`
`or its ester or ether, (2) keratolytic agent and (3) phar
`maceutically acceptable carrier.
`
`18 Claims, No Drawings
`
`AQUESTIVE EXHIBIT 1019 page 0001
`
`

`

`1.
`
`4,657,901
`2
`mones of the male type the U.S. Pat. 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) indicates a saturated bond or an unsatu
`rated double bond. Therefore, Compound I consists of
`the following two compounds (Ia and Ib) and their
`esters and ethers.
`
`10
`
`OH
`
`Ia
`
`CH2CH3
`
`OH
`
`Ib
`
`PHARMACEUTICAL COMPOSITION
`This invention relates to a preparation for topical
`application intended for the treatment of acne.
`Acne is common inflammatory disease of sebaceous
`glands that occurs so frequently during adolescence,
`being more specifically named acne vulgaris, and is
`clinically defined as "a chronic inflammatory lesion
`occurring in the hair follicle, principally in the piloseba
`ceous gland system'. Acne, of which the mechanism
`has not yet been satisfactory established at present, 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 gen
`15
`erally considered to play an important role in causing
`acne. As the topical medication for the treatment of
`acne, therefore, frequent use has been normally made of
`the creams or ointments having the sebum excretion
`depressant, and antimicrobial substances incorporated
`20
`into them. However, none of the commercially avail
`able preparations for the treatment of acne are com
`pletely 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 epider
`25
`mis and reduce excretion of the sebaceous gland, but the
`side-effects (e.g. estrogenic effect) brought about by the
`hormone of the female type are not desirable to males
`and females at puberty; and, the antimicrobial agents,
`such as hexachlorophene, trichlorocarbanilide and
`30
`benzalkonium chloride, demonstrate in vitro exceed
`ingly high antimicrobial activity against Propionibacter
`ium acnes, an acne bacterium ordinarily found on the
`skin, but when being in practice incorporated into
`creams, ointments, etc. and used for the treatment of
`acne, mostly fail to produce the expected therapeutic
`effect.
`The present inventors, after intensive research to
`obtain a pharmaceutical preparation being free from the
`side-effects, being mild to the skin and being superior in
`therapeutic effect against acne, found that a composi
`tion which contains (1) a compound of the formula:
`
`The Compound IIa) is oxedolone (16 (3-ethyl-17 3
`hydroxy-4-estren-3-on) and has been put on the market
`as a therapeutic agent for prostatomegaly (Tradename
`of "Prostetin', produced by Takeda Chemical Indus
`tries, Ltd., in Japan).
`The esters and ethers which are included in the Com
`pound I mean the compounds of I) where the hy
`5 droxy portion at the 17-position is esterified and etheri
`fied, respectively. As the ester at the 17-position, there
`may be mentioned esters with C1-18 alkanoyl groups and
`C2-18 alkenoyl groups, wherein these groups may be
`substituted. Specific examples of the C1-18 alkanoyl
`groups include formyl, acetyl, propionyl, butyryl,
`isobutyryl, valleryl, pivaloyl, caproyl, enanthoyl, cap
`ryloyl, lauroyl, myristoyl, palmitoyl, stearoyl, etc. Spe
`cific examples of the C2-18 alkenoyl groups include cro
`tonoyl, oleoyl, linoleoyl, linolenoyl, etc. As the substitu
`ents 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, C1-6 alkoxy groups (e.g., methoxy, eth
`oxy, etc.), C1-6 alkylthio groups (e.g., methylthio, eth
`ylthio, etc.), C1-18 alkanoyloxy groups (C1-18 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., phe
`noxy, naphthyloxy, etc.), and so forth. Among more
`specific examples of the substituted alkanoyl groups are
`chloroacetyl, phenylacetyl, phenoxyacetyl, benzoyl,
`caproyloxyacetyl,
`enanthoyloxyacetyl,
`(2-ethyl
`butyryloxy)acetyl, etc. As the ether at the 17-position,
`there may be mentioned ethers with C1-6 alkyl groups
`such as methyl, ethyl, propyl, butyl and pentyl, and
`ethers with C1-6 alkoxy-C1-6 alkyl groups such as me
`thoxymethyl, methoxyethyl, ethoxymethyl and ethox
`yethyl as well as ethers with groups such as tetrahydro
`pyranyl, tetrahydrofuryl and tetrahydrothienyl. The
`above-mentioned esters and ethers are easily produced
`by the known method or a perse known method.
`
`OH
`
`CH2CH3
`
`O
`
`45
`
`50
`
`wherein the dotted line at 9(10) position indicates a
`saturated bond or an unsaturated double bond, or its
`ester or ether (hereinafter referred to briefly as "Com
`pound I"), (2) keratolytic agent and (3) pharmaceuti
`55
`cally acceptable carrier, attains an unexpectedly en
`hanced therapeutic effect through the combination ef.
`fect of the Compound I and the keratolytic agent.
`Furthermore, the present inventors have also unexpect
`edly found that a composition comprising Compound
`I), keratolytic agent, gelling agent and alcohol shows
`further enhancement of the therapeutic effect in a
`shorter period in the treatment of acne through the
`increased adsorption of the Compound I into the le
`sion. The present invention is a culmination of these
`unexpected findings.
`The Compound I) which is used in the present inven
`tion possesses excellent inhibitory activity against hor
`
`AQUESTIVE EXHIBIT 1019 page 0002
`
`

`

`5
`
`15
`
`20
`
`4,657,901
`4.
`3.
`present invention. As examples of the polyhydric alco
`The amount of the Compound (I) to be incorporated
`hols, there may be mentioned aliphatic C2-6 polyhydric
`into the composition of the present invention is at a ratio
`alcohols (with a number of hydroxyl groups of 2 to 6),
`of about 0.001 to about 2 W/V 9%.
`such as ethylene glycol, propylene glycol, trimethylene
`The keratolytic agent which is used in the present
`glycol, 1,3-butanediol, glycerol and sorbitol, as well as
`invention denotes a compound which exhibits the ac
`tion of suppressing the hypercornification of ducts of
`diethylene glycol, polyethylene glycols (with an aver
`the sebaceous gland, and specifically includes sulfur,
`age molecular weight of 200 to 2000), dipropylene gly
`selenium disulfide, urea, benzoyl peroxide, resorcinol,
`col, polypropylene glycols (with an average molecular
`salicylic acid, vitamin A acid, etc., with preferable ex
`weight of 200 to 2000), and so forth. Like the monohy
`amples being urea and resorcinol.
`dric alcohols, these polyhydric alcohols act as a solvent,
`10
`The amount of the keratolytic agent to be incorpo
`and in some instances function as a humidifying agent.
`rated into the composition of the present invention is at
`The amount of the alcohols to be incorporated into
`a ratio of about 0.001 to about 15 W/V%, and prefera
`the composition of the present invention is at a ratio of
`bly is about 1.0 to about 15 W/V 9% in the case of sulfur,
`about 5 to about 70 W/V 2.
`selenium disulfide and benzoyl peroxide, about 0.005 to
`As the sebum secretion depressant, there may be
`about 0.1 W/V 9% in the case of vitamin A acid and
`mentioned hormones of the female type such as estra
`about 0.05 to about 5 W/V 9% in the case of other kera
`diol. Examples of the antimicrobial agents include hexa
`tolytic agents.
`chlorophene, trichlorocarbanilide, benzalkonium chlo
`As the pharmaceutically acceptable carrier which is
`ride, phenol, cetyl pyridinium chloride, undecylenic
`used in the present invention, there may be mentioned
`acid and bithionol. As the surface active agent, there
`gelling agents, alcohols, sebum excretion depressants,
`may be mentioned nonionic surface active agents, ani
`antimicrobial agents, surface active agents, thickening
`onic surface active agents, amphoteric surface active
`agents, humidifying agents, astringents, pH adjusting
`agents, etc., and the preferred examples are nonionic
`agents, perfumes, colorants, water, etc. The carrier can
`surface active agents and anionic surface active agents.
`be incorporated into the preparation for topical applica
`25
`Examples of the nonionic surface active agents include
`tion according to the present invention to such an extent
`polyoxyethylene aliphatic alcohol ethers (with a degree
`as may not impair the effect of the preparation. Among
`of ethylene oxide polymerization of 5 to 50, in which
`others, a gelling agent and/or an alcohol are preferably
`the aliphatic alcohol residues have 12 to 18 carbon
`used as carriers. A gelling agent and an alcohol in
`atoms; for example Brij (R)35,78 and 98, etc., produced
`proves poor solubility being so far regarded as the de
`30
`by Kao Atlas Co., in Japan; hereinafter "ethyleneoxide'
`fect of the Compound I from the standpoint of pro
`is abbreviated as "EO”), polyoxyethylene fatty acid
`cessing it into preparations.
`esters (with a degree of EO polymerization of 8 to 50, in
`As the gelling agent which is used in the present
`which the fatty acid residues have 12 to 18 carbon
`invention, specifically, there may be mentioned carbox
`atoms; for example Myrj(E) 45, 52 and 53, etc., pro
`yvinyl polymers (hereinafter abbreviated as CVP, with
`35
`duced by Kao Atlas Co., in Japan), fatty acid esters of
`the average molecular weight of 10 millions to 500
`sorbitan (with a degree of EO polymerization of 0 to 40,
`millions, preferably, 100 millions to 300 millions, such as
`in which the fatty acid residues have 12 to 18 carbon
`. Carbopol (E) 940 and 941, produced by Goodrich
`atoms; for example Tween (E) 20, 40, 60 and 80, Span (R)
`Chemical Co., in U.S.A., Hivis Wako (R) 103, 104 and
`20, 40, 60 and 80, etc., produced by Kao Atlas Co., in
`105 produced by Wako Pure Chemical Industries, Ltd.,
`Japan), polyoxyethylene hydrogenated castor oils (with
`in Japan, and so forth), carboxymethylcellulose, sodium
`a degree of EO polymerization of 5 to 60, for example
`carboxymethylcellulose, methylcellulose, hydroxyeth
`Nikkol(R) HCO-50, HCO-60 and HCO-100, etc., pro
`ylcellulose hydroxypropylcellulose, polyvinyl alcohol
`duced by Nikko Chemicals Co., Ltd., in Japan), and so
`(with a degree of polymerization of about 500 to about
`forth. In the above nonionic surface active agents, ex
`2000), etc., with the preferred example being CVP.
`45
`amples of C12-18 aliphatic alcohol residues are lauryl,
`These gelling agents exhibit gelling action and in some
`cetyl and so forth and examples of C12-18 fatty acid
`instances act as a thickening agent and stabilizer, as
`residues are lauroyl, palmitoyl, stearoyl and so forth. As
`well.
`examples of the anionic surface active agents, there may
`The amount of the gelling agent to be incorporated
`be mentioned sodium soaps (having 12 to 18 carbon
`into the composition of the present invention is gener
`50
`atoms, for example sodium lauroate, sodium stearoate),
`ally at a ratio of about 0.001 to about 20 W/V 9%. For
`potassium soaps (having 12 to 18 carbon atoms, for
`CVP mentioned above as the preferred example, the
`example potassium lauroate, potassium stearate), etc.
`preferable amount incorporated is about 0.01 to about 5
`Examples of the astringents include tannin and so forth.
`W/V 92.
`Examples of the humidifying agents include hyaluronic
`As the alcohols which are used in the present inven
`55
`acid, sodium hyaluronate, chondroitin sulfate, pyr
`tion, there may be mentioned monohydric alcohols and
`rolidonecarboxylic acid, sodium pyrrolidonecarboxy
`polyhydric alcohols, and the above-mentioned alcohols
`late and so forth. As the pH adjusting agent, there may
`may be used singly or in combination. Examples of the
`be mentioned acids and bases which are usually em
`monohydric alcohols include aliphatic C1-18 alcohols
`ployed in this field. Thus, examples of acids used as the
`such as ethanol, n-propanol, i-propanol, n-butanol, i
`pH adjusting agent are hydrochloric acid, citric acid,
`butanol, sec-butanol, tert-butanol, n-pentanol, n-hex
`etc. and examples of bases used as the pH adjusting
`anol, lauryl alcohol and cetyl alcohol; alicyclic C3-7
`agent are sodium hydroxide, potassium hydroxide, tri
`alcohols such as cyclopropanol and cyclobutanol; and
`ethanolamine, diisopropanolamine, etc.
`phenyl-C1-6 alkanols such as benzyl alcohol and phene
`The composition of the present invention can be
`tyl alcohol. Among others, ethanol and benzyl alcohol
`65
`prepared by mixing, by a per se known method, (1) the
`are frequently used, and these alcohols, making up for
`Compound I, (2) keratolytic agent and (3) pharmaceu
`low solubility of the Compound I), function to increase
`absorption and penetration of the composition of the
`tically acceptable carrier.
`
`AQUESTIVE EXHIBIT 1019 page 0003
`
`

`

`4,657,901
`5
`6
`As the pH value of the composition of the present
`addition of a solution of 1.0 g of urea in 100 g of puri
`invention is normally within the range of 4 to 8 and
`fied water. Then, a solution of 0.8 g of a carboxyvinyl
`preferably 6 to 8, pH adjusting agents as described
`polymer (Carbopol 940) and 0.1 g of hyaluronic acid in
`above can be used to adjust the pH value.
`20.0 g of purified water was added, and after stirring
`The most preferable composition comprises oxendo
`and mixing, 27.7 g of purified water was added, fol
`lone, a keratolytic agent (urea or resorcinol), carboxyvi
`lowed by the neutralization with 0.2 g of triethanol
`nyl polymer, ethyl alcohol and benzyl alcohol. This
`amine to produce a gel-like ointment for topical applica
`composition may contain further additional carrier(s) as
`tion.
`mentioned above. The composition which comprises
`oxendolone, a keratolytic 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 applica
`tion according to the present invention may be those of
`15
`any 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 perse known and well established in
`the pharmaceutical field. Also in the present invention,
`20
`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
`
`10
`
`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 Examples 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, fol
`lowed 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 polyoxyethyl
`ene hydrogenated castor oil (further containing or not
`containing hydroxypropylcellulose or polyvinyl alco
`hol) and hyaluronic acid in purified water was added,
`and after stirring and mixing rest of water was added,
`followed by the neutralization with diisopropanol
`amine.
`
`25
`
`
`
`Ingredient
`Oxendolone
`Benzyl alcohol
`Ethanol
`Polyethylene glycol PEG-300
`Polyethylene glycol PEG-600
`1,3-Butanediol
`Carboxyvinyl polymer
`Carbopol 940
`Hydroxypropylcellulose
`Polyvinyl alcohol
`Hyaluronic acid
`Polyoxyethylene hydrogenated
`castor oil, Nikkol HCO-60
`Urea
`Resorcinol
`Salicylic acid
`Benzoyl peroxide
`Triethanolamine
`Diisopropanolamine
`Purified water
`
`TABLE
`Formulation Examples
`
`Formulation
`7
`6
`4
`5
`3
`2
`1
`0.2
`1.0
`2.0
`1.5
`0.2
`0.5
`0.2
`5.0
`0-0
`10.0
`5.0
`S.O.
`5.0 100
`20.0 25.0 200 37.0 35.0 30.0 40.0
`10.0
`10.0
`
`S.0 200 15.0
`
`0.8
`
`0.6
`
`0.2
`
`O.
`
`O.1
`
`0.2
`
`200 5.0 200
`0 (0.8
`1.0
`0.8
`
`0.2
`
`0.2
`
`0.1
`
`20 2.0
`
`2.0
`
`2.0
`
`10
`
`1.0
`
`3.0
`
`1.0 P
`2.0
`
`0.5
`
`15.0
`
`0.2
`
`0.2
`
`0.
`
`0.2
`0.2
`0.2
`0.2
`57.7 42.6 56.3 36.7 33.3 40.3 16.6
`
`Unit:g
`
`8
`2.0
`10.0
`37.0
`0.0
`
`1.0
`
`0.
`
`2.0
`
`1.0
`1.0
`
`0.2
`35.7
`
`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
`55
`present therapy can be applied without any side-effects
`observed.
`
`EXAMPLE
`Gel ointments containing 0.2 to 2.0 W/V % of exen
`dolone were prepared as the following Examples and
`Table.
`
`Formulation Example 1
`In a mixed solution consisting of 5.0 g of benzyl alco
`65
`hol and 20.0 g of ethanol was dissolved 0.2 g of oxendo
`lone, and 15.0 g of polyethylene glycol (PEG-600) was
`added, for dissolution, to the solution, followed by the
`
`Clinical test:
`The clinical tests are described in the following to
`illustrate the phramaceutical effects of the present in
`vention in more detail.
`Medicament preparation used
`The gel ointment-type preparation for topical appli
`cation as produced in the Formulation Example 1 was
`used.
`Patients applied with the preparation and duration of
`observation.
`15 to 30 year old, males and females to a total of 15
`patients.
`Method of application
`After the patients thoroughly washed their faces with
`use of toilet soap, the above mentioned ointment-tvipe
`
`AQUESTIVE EXHIBIT 1019 page 0004
`
`

`

`4,657,901
`8
`7
`5. The composition according to claim 1 wherein the
`preparation was applied for topical application only
`oxendolone is from about 0.001 W/V 26 to about 2
`onto the efflorescence once to three times a day.
`W/V 9% relative to the whole composition and the
`Items of observation and duration of observation
`keratolytic agent is present in an amount of 0.001 to
`The patients were observed for three symptoms, i.e.,
`comedo, papule and pustule, and the severity of each
`about 15 W/V 2.
`6. The composition according to claim 1 which con
`symptom observed was rated on a scale divided into
`tains a gelling agent in an amount of 0.001 to about 20
`five grades of intense (4), moderate (3), slight (2), little
`W/V 9% and an alcohol in an amount of 5 to 70 W/V 9%.
`(1) and none (0). By putting the severities of these three
`7. The composition according to claim 1, wherein the
`symptoms together, the degree of before-treatment
`composition comprises a gelling agent and/or an alco
`seriousness of acne vulgaris was divided into three
`hol.
`grades of severe, mild and minor acne. The observa
`8. The composition according to claim 7, wherein the
`tions for progress were made at the times of before
`gelling agent is carboxyvinyl polymer.
`treatment(O) and one week (I), two weeks (II), three
`9. The composition according to claim 7, wherein the
`weeks (III), and four weeks (IV) after treatment.
`alcohol is ethyl alcohol.
`Degree of overall improvement
`10. The composition according to claim 7, wherein
`The degree of improvement in symptoms brought
`the alcohol is benzyl alcohol.
`about by the medicament preparation used over the
`11. The composition according to claim 7, which
`before-treatment symptoms was divided into five
`comprises oxendolone, urea, carboxyvinyl polymer,
`grades of marked relief (------), fair relief (++), slight
`ethyl alcohol and benzyl alcohol.
`relief (--), no relief (t) and aggravation (-).
`12. The composition according to claim 7, which
`Usefulness
`comprises oxendolone, resorcinol, carboxyvinyl poly
`On the basis of the degree of overall improvement,
`mer, ethyl alcohol and benzyl alcohol.
`the effect of the medicament preparation used was rated
`13. The composition according to claim 7, wherein
`as greatly useful (------), fairly useful (++), slightly
`useful (--) and useless ().
`25 the content of the oxendolone is from about 0.001 W/V
`
`10
`
`15
`
`Serious-
`SS
`Mild
`
`Male
`Female
`F.
`f
`
`Male
`Female
`
`Severe
`Mild
`Af
`v
`Severe
`Mild
`
`1
`
`--
`
`DO
`III
`
`Useful
`ress
`
`IV
`
`II
`
`- -
`--
`-- -
`--
`- - -
`
`- Results -
`Pustule
`Papule
`Comedo
`Case
`I
`IV
`I
`III V 0
`III IV O I
`0
`No. Age Sex
`-
`1
`1
`1
`1
`2 2 2 2 2 2 2 2 1
`2 1
`16
`Female
`------
`------
`- - -
`0 O 0 - - -
`1
`3 2 2 1
`0 2
`1
`0 0 0
`1
`20
`Male
`2
`----
`----
`----
`1
`1
`1
`2
`2.
`2 2 1
`0 2 2
`1
`1
`2
`30
`Female
`3
`- - - -
`- -
`-
`- - - -
`Severe 4 4 3 2
`1
`4 3 3 2
`3 2 2
`1
`0
`21
`t
`4
`- -
`- - -
`-- -
`a
`4 4 4 3 2 3
`3
`2
`1
`3 3 2
`1
`0
`25
`5
`------
`- - -
`- - -
`Mild
`3
`1
`1
`0 0 3 2
`2
`1
`0 3 2
`1
`1
`0 - -
`24
`6
`--
`--
`--
`3
`3 2 2.
`2 2
`2
`1
`2
`1
`1
`1
`--
`26
`7
`------
`------
`------ - - -
`1
`3 2
`1
`0 0 4 3 2 2
`3
`1
`0 0 0
`- -
`19
`8
`------
`- - -
`------ - - -
`3
`2 1
`0 0 3
`1
`1
`0 0 3
`2
`1
`0 0 - -
`5
`9
`1
`0 0 0 0 3 3
`1
`0 0 3
`1
`0 0 0 + + + + + + + + + + + ++--
`23
`10
`1
`0 0 0 0 2
`1
`0 0 0
`1
`0
`0
`0
`0
`---- - - -
`- - - -
`- - -
`------
`20
`11.
`3
`2
`1
`0 0 4 2.
`1
`1
`0 2 0 0 0 0 - - -
`- - -
`- - -
`- - -
`- - -
`18
`12
`3 2 2 1
`1
`3 3
`1
`0 0
`1
`0 0 0 0
`-
`-- -
`------ - - -
`- -
`13 24
`3
`1
`1
`1
`3
`1
`1
`1
`1
`0 0 0 - -
`- -
`- - -
`- -
`----
`14 20
`2
`1
`0
`0
`3 2
`0 0 0 0 0 0 0 - -
`- - -
`- - -
`- - -
`------
`FA
`15 27
`Note: "the degree of overall improvement.
`
`0
`
`1
`
`As being clear from the above results, the clinical test
`results on these 15 cases consisting of 3 males and 12
`females, in which - (useless) accounted for 1 case
`(7%), --(slightly useful) 1 case (7%), ---- (fairly useful)
`4 cases (26%) and ------ (greatly useful) 9 cases (60%),
`demonstrate the good effect produced by the prepara
`50
`tion for topical application according to the present
`invention.
`What we claim is:
`1. A composition for the topical treatment of acne,
`which comprises
`55
`(1) an effective amount for treating acne of oxendo
`lone or its ester or ether, (2) a keratolytic agent,
`and (3) a pharmaceutically acceptable carrier.
`2. The composition according to claim 1, wherein the
`content of oxendolone is from about 0.001 W/V 9% to
`60
`about 2 W/V 9% relative to the whole composition.
`3. The composition according to claim 1, wherein the
`keratolytic agent is urea.
`4. The composition according to claim 1, wherein the
`keratolytic agent is resorcinol.
`
`65
`
`% to about 2 W/V % relative to the whole composi
`tion.
`e
`14. The composition according to claim 7, wherein
`the keratolytic agent is urea.
`15. The composition according to claim 7, wherein
`the heratolytic agent is resorcinol.
`16. A method of treatment of acne which comprises
`administering topically the composition containing
`(1) an effective amount for treating acne of oxendo
`lone, or its ester or ether,
`(2) a keratolytic agent, and
`(3) a pharmaceutically acceptable carrier.
`17. A method according to claim 16 wherein the
`oxendolone is present in an amount of from about 0.001
`W/V 9% to about 2 W/V 2 relative to the whole com
`position and the keratolytic agent is present in an
`amount of 0.001 to about 15 W/V 2.
`18. A method according to claim 17 which contains a
`gelling agent in an amount of 0.001 to about 20 W/V%
`and an alcohol in an amount of 5 to 70 W/V 9%.
`k
`sk
`k
`
`AQUESTIVE EXHIBIT 1019 page 0005
`
`