PCT
`INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
`wo 95/03319
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`WORLD INTEllECTUAL PROPERTY ORGANIZATION
`International Bureau
`
`(51) International Patent Classification 6 :
`C07J 53/00, A61K 31/57
`
`Al
`
`(11) International Publication Number:
`
`(43) International Publication Date:
`
`2 February 1995 (02.02.95)
`
`(21) International Application Number:
`
`PCr/US94/07827
`
`(22) International Filing Date:
`
`13 July 1994 (13.07.94)
`
`(81) Designated States: CA, CN, JP, European patent (AT, BE, CH,
`DE, DK, ES, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE).
`
`(30) Priority Data:
`08/096,086
`
`23 July 1993 (23.07.93)
`
`us
`
`Published
`With international search report.
`
`(71) Applicant: TilE PROCIER & GAMBLE COMPANY
`[US/US]; One Procter & Gamble Plaza, Cincinnati, OH
`45202 (US).
`
`(72) Inventors: SCHWEN, Richard, John; 8741 Apalachie Drive,
`Cincinnati, OH 45249 (US). SINE, Mark, Richard; 2731
`East U.S. 22 & 3, Morrow, OH 45152 (US). WARREN,
`Raphael; 6258 Robison Road, Cincinnati, OH 45213 (US).
`
`(74) Agents: REED, T., David et al.; The Procter & Gamble
`Company, 5299 Spring Grove Avenue, Cincinnati, OH
`45217 (US).
`
`(54) Title: CYPR01ERONE ACETA1E THIOACETA1E
`
`(57) Abstract
`
`The present invention relates to the compound cyproterone acetate thioacetate (CATA) and compositions comprising CATA. The
`present invention further relates to methods of treating acne and/or sebaceous gland activity comprising topical application of CAT A. The
`present invention additionally relates to methods of regulating hair growth comprising application of compositions comprising CAT A.
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`FOR THE PURPOSES OF INFORMATION ONLY
`
`Codes used to identify States party to the PCr on the front pages of pamphlets publishing international
`applications under the PCr.
`
`AT
`AU
`BB
`BE
`BF
`BG
`BJ
`BR
`BY
`CA
`CF
`CG
`CH
`CI
`CM
`CN
`cs
`cz
`DE
`DK
`ES
`FI
`FR
`GA
`
`Austria
`Alllllralia
`Barbados
`Belgium
`BurkinA Faso
`Bulgaria
`Benin
`Brazil
`Belarus
`Canada
`Central African Republic
`Congo
`Switzerland
`COte d'Ivoire
`Cameroon
`Olioa
`Czechoslovakia
`Czech Republic
`Germany
`Deoow:k
`Spain
`Finland
`France
`Gabon
`
`GB
`GE
`GN
`GR
`BU
`IE
`IT
`JP
`KE
`KG
`KP
`
`KR
`KZ
`u
`LK
`LU
`LV
`MC
`MD
`MG
`ML
`MN
`
`United Kingdom
`Georgia
`Guioe4
`Greece
`Hungary
`In: land
`Italy
`Japan
`Kenya
`Kyrgystan
`Democratic People's Republic
`of Korea
`Republic of Korea
`Kazakhstan
`Liechtenstein
`Sri Lanka
`Luxembourg
`Latvia
`Monaco
`Republic of Moldova
`Madagascar
`Mali
`Mongolia
`
`MR
`Mauritania
`MW Malawi
`NE
`Niger
`Netherlands
`NL
`NO
`Norway
`NewZealaod
`NZ
`PL
`Poland
`Portugal
`PT
`RO
`Romania
`RU
`Russian Fedc:ration
`SD
`Sudan
`SE
`Sweden
`SI
`Slovenia
`SK
`Slovakia
`Senegal
`SN
`TD
`Chad
`Togo
`TG
`Tajikistan
`TJ
`TT
`Trinidad and Tobago.
`Ulaaioe
`UA
`us
`United States of America
`UZ
`Uzbekistan
`VN
`VietNam
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`wo 95/03319
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`PCT /US94/07827
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`CYPROTERONE ACETATE TIDOACETATE
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`TECHNICAL FIELD
`The present invention relates to the field of sebum control and treatment of
`acne in mammalian skin and scalp. The present invention also relates to the field
`of regulating hair growth.
`
`BACKGROUND
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`The pilosebaceous gland is a principal source of oil on mammalian skin
`and scalp. Therefore, a benefit of controlling sebaceous gland activity (sebum
`secretion) includes a reduction in the level of oil found in skin and hair.
`Sebum secretion is also related to acne. Acne is a pilosebaceous disease
`characterized by comedo, papules, inflamed nodules and superficial pus-filled
`cysts. The course and severity of acne is determined by the interaction between
`hormones, keratinization, sebum formation and bacteria. Acne usually begins at
`puberty, when circulating levels of androgens increase. The pilosebaceous glands
`increase in size and sebum synthetic activity is elevated due to this increase in
`circulating levels of androgens. Follicular hyperkeratosis can also occur, causing
`restriction of pilosebaceous follicles and, consequently, comedo or plug formation.
`The comedo contains sebum, protein debris, and anaerobic microorganisms
`including propionibacterium (corynebacterium) acnes (P. acnes). P. acnes
`thrives on the sebum and generates inflammatory free tatty acids (FF A). The FF A
`cause irritation in the follicular wall and can lead to rupture of the follicular wall,
`inducing an inflamed lesion. In severe cases, this lesion will heal with scarring.
`Existing treatments for acne include from general topical application of
`lotions and salves to affected skin areas, to localized (spot) topical treatment.
`30 Products used for such treatments include benzoyl peroxide, sulfur resorcino~
`salicylic acid and trans-retinoic acid. The therapeutic value is limited because of
`poor efficacy, poor aesthetics, and lack of effect on sebum production.
`Other effective therapies for acne which reduce sebum production, include
`the use of antiandrogens, and cis-retinoic acid. However, because of undesirable
`systemic side effects, such as teratogenecity, pituitary dysfunction, and male
`sterility, current use is restricted to the more severe cases of acne. Antimicrobials
`are also somewhat effective in treating acne because they control the growth of P.
`acnes. The effectiveness of antimicrobials is limited because they do not affect
`sebum production.
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`For the foregoing reasons, there is a need for an efficacious, easily
`administered, agent for treating acne and/or reducing sebaceous gland activity in a
`mammal, having little or no undesirable side effects.
`Hair Growth
`Society in general continues to attach a stigma to hair loss. Men and
`women suffer from hair loss, often resulting in self-consciousness relating to the
`hair loss. Domestic animals, such as cats and dogs, also suffer from hair loss.
`While the animal is not likely to be emotionally affected by such hair loss, its
`owner may be, particularly if such an animal is to be shown in various
`competitions. Additionally, increased hair growth in livestock such as sheep,
`thereby resulting in increased wool production, is also desirable. The desire for a
`healthy full head (or body, in the case of animals) of hair has resulted in a variety
`of approaches to the "curing" of hair Joss.
`One such approach involves the much publicized use of minoxidil (6-(1-
`piperidinyl)-2,4-pyrimidinediamine 3-oxide), a potent antihypertensive agent, as a
`hair growth promoting agent (see US Patent Nos., 3,461,461; 3,973,061;
`3,464,987; and 4,139,619). Unfortunately, not all people respond to minoxidil
`and the efficacy level is limited in those individuals exhibiting a response.
`Another approach for "curing" hair Joss involves a procedure of weaving
`synthetic or natural hair strands into the remaining hair strands of the subject.
`Such a procedure is time consuming, expensive and requires follow-up re(cid:173)
`weavings as the weaves loosen and/or the subject's existing hair strands grow.
`Furthermore, such a procedure does not cure hair loss, but merely masks the
`condition.
`Another approach for treating hair Joss is the use of hair plugs. This
`procedure involves the transplantation of terminal hair follicles from regions of
`normal hair growth on the subject's scalp to regions of thinning or no hair growth
`on the scalp. The procedure is time consuming, expensive and can be painful.
`Furthermore, the transplanted plugs, at least in the early stages following
`transplantation, produce an unnatural look to the scalp.
`For the foregoing reasons, there is a need for an easily administered,
`efficacious agent for treating hair Joss in a mammal having little or no undesirable
`side effects.
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`Objects of the Present Invention
`It is an object of the present ~vention to provide compounds useful for
`treating acne and/or sebaceous gland activity and/or regulating hair growth.
`It is also an object of the present invention to provide compositions useful
`for treating acne and/or sebaceous gland activity and/or regulating hair growth.
`It is also an object of the present invention to provide methods for treating
`acne and/or sebaceous gland activity.
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`It is also an object of the present invention to provide methods for
`regulating hair growth.
`
`SUMMARY
`The present invention is directed to cyproterone acetate thioacetate
`(hereinafter "CATA") and compositions comprising CATA Such a compound
`and compositions satisfy the need for an efficacious, easily administered agent for
`treating acne and/or sebaceous gland activity, having little or no undesirable side
`effects. Such a compound and compositions also satisfy the need for an
`efficacious, easily administered agent for regulating hair growth, having little or no
`undesirable side effects. The present invention is further directed to a method of
`treating acne and/or sebaceous gland activity in the skin of a mammal susceptible
`to or having acne, comprising application of a composition of the present
`invention. The present invention is further directed to a method of regulating hair
`growth in a mammal (e.g., humans and domestic animals) susceptible to or
`suffering from hair loss, comprising application of a composition of the present
`invention.
`The compositions of the present invention relating to the acne treatment or
`hair growth regulation embodiments comprise a safe and effective amount of
`CATA and a pharmaceutically-acceptable or cosmetically-acceptable carrier.
`These and other features, aspects and advantages of the present invention
`will become better understood with reference to the following description and
`· appended claims.
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`DETAILED DESCRIPTION
`As used herein, "cyproterone acetate thioacetate• and "CATA" mean a
`compound having the structure:
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`Cl
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`As used herein, "topical application" means directly laying on or spreading
`on outer skin.
`As used herein, "cutaneous injection" means introduction of a substance
`beneath or within the skin by a hypodennic needle; preferably proximate to the
`site of desired response.
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`As used herein, "safe and effective amount• means a sufficient amount of a
`composition to provide a desired hair growth regulating or acne and/or sebaceous
`gland activity treating effect (whichever the case may be).
`As used herein, "comprising" means that other steps and other ingredients
`5 which do not affect the end result can be added. This tenn encompasses the tenns
`"consisting of' and "consisting essentially or'.
`As used herein, "pharmaceutically-acceptable" means
`that drugs,
`medicaments or inert ingredients which the tenn describes are suitable for use in
`contact with the tissues of humans and lower animals without undue toxicity,
`incompatibility, instability, irritation, allergic response, and the like.
`As used herein, "cosmetically-acceptable" means that ingredients which the
`term descn'bes are suitable for use in contact with the skin of humans and lower
`animals without undue toxicity, incompatibility, instability, irritation, allergic
`response, and the like.
`15 Acne
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`As used herein "treating sebaceous gland activity" means preventing,
`retarding and/or arresting the production of sebum.
`As used herein "treating acne" means preventing, retarding and/or arresting
`the process of acne formation.
`It has been unexpectedly discovered that CAT A, when administered to a
`mammal, in a safe and effective amount, can treat acne and/or sebaceous gland
`activity.
`Compositions useful for treating acne and/or sebaceous gland activity
`preferably comprise from about 0.0001% to about 10% of CATA, more
`preferably from about 0.001% to about 5%, more preferably still from about
`0.01% to about 2%, more preferably still from about 0.1% to about 1%.
`Hair Growth
`As used herein, "regulating hair growth" means increasing the rate of hair
`growth and/or inducing the formation of a greater number of hair strands, and/or
`increasing the diameter of the hair strand, and/or lengthening the hair strand,
`and/or changing the hair follicle from vellus to tenninal, and/or converting follicles
`from telogen to anagen phase (thereby increasing the overall ratio of anagen phase
`follicles relative to telogen phase follicles) and/or preventing, retarding, or
`arresting the process of hair loss, and/or treating alopecias.
`As used herein, "vellus hair follicle" means a hair follicle which produces a
`soft, short, and often colorless hair fiber. The size of the vellus follicle is
`considerably smaller than the terminal hair follicle. In an adult, veUus follicles can
`be found on the forehead (i.e., receding hair line area) and bald scalp.
`As used herein, "terminal follicle" means a hair follicle whicl1 produces a
`coarse, long, and often pigmented hair follicle. The size of the terminal follicle is
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`considerably larger, thicker in diameter and longer than the vellus follicle. In the
`adult, tenninal follicles can be found on the scalp, axilla and pubic areas.
`As used herein, "anagen phase" refers to the period in the hair follicle
`growth cycle wherein the follicle is actively growing and producing new hair.
`As used herein, "telogen phase• refers to the period in the hair follicle
`growth cycle wherein the follicle is resting and not producing new hair.
`It has been unexpectedly discovered that CATA, when administered to a
`mammal (e.g., human or domestic animal), in a safe and effective amount, can
`regulate hair growth.
`Compositions useful for regulating hair growth preferably comprise from
`about 0.0001% to about 100/o ofCATA, more preferably from about 0.001% to
`about 5%, more preferably still from about 0.01% to about 2%, more preferably
`still from about 0.1% to about 1%.
`The Carrier
`The compositions of the present invention comprise a solid, semi-solid or
`liquid cosmetically and/or physiologically acceptable and/or phannaceutically(cid:173)
`acceptable carrier to enable CATA to be delivered to the desired target at an
`appropriate concentration. The carrier can itself be inert or it can possess
`cosmetic, physiological or pharmaceutical benefits of its own. The nature of the
`carrier will be dictated by the method chosen for administration of the
`composition. The method of administration of CATA composition may range
`from internal methods such as injection to external topical methods.
`A preferred method of administration of CATA is by cutaneous injection.
`The carrier for facilitation of such administration would preferably comprise water
`or a saline solution, preferably an isotonic saline solution.
`A more preferred m~thod of administration of CATA is by topical
`application. Topical application is preferably achieved with compositions in the
`forms of lotions, solutions, ointments, sprays, tonics, creams, bars, shampoos,
`cream rinses, gels, sticks, mousse, pastes and the like.
`Topical compositions of the present invention can be formulated as liquids,
`for example as a lotion, cream, shampoo, conditioner, gel, mousse or milk. Such
`liquid compositions may be formulated for use in conjunction with an applicator
`such as a roll-ball applicator, a tined applicator, a pad applicator, or a spray device
`such as an aerosol can containing propellant, or a container fitted with a pump to
`dispense the liquid product.
`Alternatively, the compositions ofthe invention can be solid or semi-solid,
`for example sticks, creams or gels. Such solid or semi-solid compositions may be
`formulated for use in conjunction with a suitable applicator or simply a tube, or
`bottle, or as a liquid-impregnated fabric, such as a tissue wipe.
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`The selection of a carrier for this purpose presents a wide range of
`possibilities depending on the required product fonn of the composition. Suitable
`vehicles can be classified as described hereinafter.
`The tenn "topical carrier" refers to substances which can act as diluents,
`dispersants, or solvents for CATA which therefore ensure that it can be applied to
`and distributed evenly over the selected target at an appropriate concentration.
`The carrier is preferably one which can aid penetration of CATA into the skin to
`reach the immediate environment of the hair follicle and/or sebaceous glands.
`Topical carriers useful in compositions ofthe subject invention can include water
`as a vehicle, and/or at least one cosmetically-acceptable vehicle other than water.
`Carriers useful in topical compositions according to the invention may include
`liposomes, latex latices, microspheres, cyclodextrans and various fonns of
`microencapsulation of CATA
`Generally, the carrier is either organic in nature or an aqueous emulsion
`and capable of having CATA dispersed or dissolved therein. The carrier may
`include phannaceutically-acceptable emollients, skin penetration enhancers,
`coloring agents, fragrances, emulsifiers, thickening agents, and solvents.
`Topical compositions of the present invention may be formulated as a
`composition comprising an emollient. Such compositions typically comprise from
`about 1% to about 50%, preferably from about S% to about 20% of a topical
`phannaceutically-acceptable emollient; and a safe and effective amount of CAT A
`As used herein, "emollients• refer to materials used for the prevention or
`relief of dryness, as well as for the protection of the skin. A wide variety of
`suitable emollients are known and may be used herein. Such emollients include,
`but are not limited to, hydrocarbon oils and waxes, silicon oils, triglyceride fats
`and oils, acetoglyceride esters, ethoxylated glycerides alkyl esters of fatty acids
`having 10 to 20 carbon atoms, alkenyl esters of fatty acids having 10 to 20 carbon
`atoms, fatty acids having 8-22 carbon atoms, fatty alcohols having 8-22 carbon
`atoms, fatty alcohol ethers, ether-esters, lanolin and derivatives, polyhydric
`alcohols and polyether derivatives, polyhydric alcohol ethers, wax esters, beeswax
`derivatives, vegetable waxes, phospholipids, sterols, and amides.
`SAGARIN,
`COSMETICS, SCIENCE AND TEcHNOLOOY, 2nd Edition, Vol. 1, pp. 32-43 (1972),
`incorporated herein by reference, contains numerous examples of suitable
`materials.
`Preferably the lotions of the present invention comprise a safe and
`effective amount of CAT A; and from 1% to SO%, preferably from 3% to 15%, of
`an emollient.
`Preferably the creams of the present invention comprise a safe and
`effective amount ofCATA; from 5% to SO%, preferably from 100..4 to 25%, of an
`emollient; and the balance being water. The emollients described above can also
`be used in the cream compositions. Optionally the cream form contains a suitable
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`emulsifier. When an emulsifier is included, it is in the composition at a level from
`3% to 50%, preferably from 5% to 200/e.
`Preferably the solution form of the present invention comprises a safe and
`effective amount of CATA, the balance being water and/or a suitable organic
`solvent. Suitable organic materials useful as the solvent or a part of a solvent
`system are as follows: dimethyl isosorbide, N-octyl pyrrolidone, propylene glyco~
`glycerine, polyethylene glycol (M.W. 200-600), polypropylene glycol (M. W. 425-
`2025), glycerine, sorbitol esters, 1,2,6-hexanetrio~ ethano~ isopropanoL diethyl
`tartrate, butanediol and mixtures thereof. Such solvent systems can also contain
`10 water.
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`Gel compositions of the present invention can be formulated by simply
`admixing a suitable thickening agent to the previously descn"bed solution
`compositions. The gel compositions preferably comprise a safe and effective
`amount of CAT A; from 5% to 75%, preferably from 100/o to 500/o, of an organic
`solvent as previously described; and from 0.5% to 200/o, preferably from 1% to
`10% ofthe thickening agent.
`Compositions of solid forms of the present invention have use as stick(cid:173)
`type compositions intended for application to the scalp or other parts of the body.
`Such compositions preferably comprise a safe and effective amount of CAT A, and
`from 50% to 98%, preferably from 60% to 900/o, of the previously descnbed
`emollients. This composition can further comprise from 1% to 200/o, preferably
`from 5% to 15%, of a suitable thickening agent, and optionally emulsifiers and
`water. Thickening agents previously descnbed with respect to lotions are suitable
`herein.
`
`Skin cleaning compositions (preferably for use in the acne treatmem
`and/or sebaceous gland activity treatment embodiment of the present invention)
`and scalp cleaning compositions (useful in both the acne and/or sebaceous gland
`treatment, and hair growth regulation embodiments of the present invention),
`comprise, in addition to CAT A, a cosmetically-acceptable surfactant.
`The cleaning compositions useful in the subject invention preferably
`contain a safe and effective amount of CATA and preferably from about 1% to
`from about 5%
`to about 10%, of a
`about 900/o, more preferably
`cosmetically-acceptable surfactant.
`The physical form of the cleansing compositions is not critical. The
`compositions can be, for example, formulated as toilet bars, liquids, shampoos,
`pastes, or mousses. Toilet bars are most preferred since this is the form of
`cleansing agent most commonly used to wash the skin. Rinse-off cleansing
`compositions, such as shampoos, require a delivery system adequate to deposit
`sufficient levels of CATA on the skin and scalp. A preferred delive.y system
`involves the use of insoluble complexes. For a more complete disclosure, see U.S.
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`Patent 4, 835,148, Barford et al., issued May 30, 1989; incorporated herein by
`reference in its entirety.
`The surfactant component of the compositions useful in the subject
`invention are selected from anionic, nonionic, zwitterionic, amphoteric and
`ampholytic surfactants, as weD as mixtures of these surfactants. Such surfactants
`are weD-known to those skilled in the detergency art.
`The cleaning compositions useful in the subject invention can optionally
`contain, at their art-established levels, materials which are conventionally used in
`cleansing compositions. Nonlimiting examples of possible surfactants include
`isoceteth-20, sodium methyl cocoyl taurate, sodium methyl oleoyl taurate, and
`sodium Iaury) sulfate. See U.S. Patent No. 4,800,197, to Kowcz et al., issued
`January 24, 1989, which is incorporated herein by reference in its entirety.
`Examples of a broad variety of additional surfactants useful herein are descnl>ed in
`McCutcheon's, DETERGENTS AND EMuLsiFIERS, North American Edition (1986),
`published by Allured Publishing Corporation, which is incorporated herein by
`reference in its entirety.
`Acne - Combination Actives
`The compositions of the present invention useful for treating acne or
`sebaceous gland activity can also comprise, in addition to CAT A, actives such as
`anti-inflammatory agents, retinoids, antimicrobial agents, antiandrogens, and/or
`comedolytic agents, for the treatment of acne and/or sebaceous gland activity.
`A Anti-inflammatoty agents
`An anti-inflammatory agent may be included as an active along with CAT A,
`for treatment of acne and/or sebaceous gland activity. A safe and effective
`amount of an anti-inflammatory agent may be added to the compositions useful in
`the subject invention, preferably from about 0.1% to about 1 00/e, more preferably
`from about 0.5% to about 5%, of the composition. The exact amount of
`anti-inftammatory agent to be used in the compositions will depend on the
`particular anti-inflammatory agent utilized since such agents vary widely in
`potency.
`to,
`limited
`including but not
`Steroidal anti-inflammatory agents,
`corticosteroids such as hydrocortisone, hydroxyltriamcinolone, alpha-methyl
`dexamethasone, dexamethasone-phosphate,
`beclomethasone dipropionates,
`clobetasol valerate, desonide, desoxymethasone, desoxycorticosterone acetat~.
`dexamethasone, dichlorisone, diflorasone diacetate, ditlucortolone valerate,
`tluadrenolone, tluclorolone acetonide, tludrocortisone, tlumethasone pivalate,
`tluosinolone acetonide,
`tluocinonide,
`flucortine butylesters,
`fluocortolone,
`tluprednidene
`(fluprednylidene)
`acetate,
`flurandrenolone,
`halcinonide,
`hydrocortisone acetate, hydrocortisone butyrate, methylprednisolone, -triam-
`cinolone acetonide, cortisone, cortodoxone,
`tlucetonide,
`fludrocortisone,
`difluorosone diacetate, tluradrenolone, fludrocortisone, diflurosone diacetate,
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`fluradrenolone acetonide, medrysone, amcinafel, amcinafide, betamethasone and
`the balance of its esters, chloroprednisone, chlorprednisone acetate, clocortelone,
`clescinolone,
`dichlorisone,
`diflurprednate,
`flucloronide,
`flunisolide,
`fluoromethalone,
`fluperolone,
`fluprednisolone,
`hydrocortisone
`valerate,
`hydrocortisone
`cyclopentylpropionate,
`hydrocortamate,
`meprednisone,
`paramethasone,
`prednisolone,
`prednisone,
`beclomethasone
`dipropionate,
`triamcinolone, and mixtures thereof may be used. The preferred steroidal anti(cid:173)
`-inflammatory for use is hydrocortisone.
`A second class of anti-inflammatory agents which is useful in the
`compositions includes the non-steroidal anti-inflammatory agents. The variety of
`compounds encompassed by this group are weD-known to those skilled in the art.
`For detailed disclosure of the chemical structure, synthesis, side effects, etc. of
`non-steroidal anti-inflammatory agents, reference may be had to standard texts,
`including ANn-INFLAMMATORY AND ANn-RHEUMATIC DRUGS, K.D. Rainsford,
`15 Vol. l-ID, CRC Press, Boca Raton, (1985), and ANn-INFLAMMATORY AGENTS,
`CHEMISTRY AND PHARMACOLOOY, 1, RA Scherrer, et al., Academic Press, New
`York (1974), both of which are incorporated herein by reference.
`Specific non-steroidal anti-inflammatory agents useful in compositions of
`the present invention include, but are not limited to:
`1)
`the oxicams, such as piroxicam, isoxicam, tenoxicam, sudoxicam, and
`CP-14,304;
`the salicylates, such as aspirin, disalcid, benorylate, trilisate, safapryn,
`solprin, diflunisal, and fendosal;
`fenclofenac,
`the acetic acid derivatives, such as diclofenac,
`indomethacin, sulindac, tolmetin,
`isoxepac, furofenac,
`tiopinac,
`zidometacin, acematacin, fentiazac, zomepirac, clindanac, oxepinac,
`felbinac, and ketorolac;
`the fenamates, such as mefenamic, meclofenamic, fluofenamic,
`niflumic, and tolfenamic acids;
`ibuprofen, naproxen,
`the propionic acid derivatives, such as
`fenoprofen,
`fenbufen,
`benoxaprofen,
`flurbiprofen, ketoprofen,
`indopropfen,
`pirprofen,
`carprofen,
`oxaprozin,
`pranoprofen,
`miroprofen, tioxaprofen, suprofen, alminoprofen, and tiaprofenic; and
`the pyrazoles, such as phenylbutazone, oxyphenbutazone, feprazone,
`azapropazone, and trimethazone.
`Mixtures of these non-steroidal anti-inflammatory agents may also be
`employed, as well as the pharmaceuticaUy-acceptable salts and esters of these
`agents. For example, etofenamate, a flufenamic acid derivative, is particularly
`useful for topical application. Of the non-steroidal anti-inflamrria\ory ·agents,
`ibuprofen, naproxen, flufenamic acid, mefenamic acid, meclofenamic acid,
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`piroxicam and felbinac are preferred; ibuprofen, naproxen, and flufenamic acid are
`most preferred.
`Fmally, so-called "natural" anti-inflammatory agents are useful in methods
`of the subject invention. For example, candelilla wax, alpha bisabolol, aloe vera,
`5 Manjistha (extracted from plants in the genus Rubia, particularly Rubia
`Cordifolia), and Guggal (extracted from plants in the genus Commiphora,
`particularly Commiphora Mukul), may be used.
`B. Retinoids
`In a preferred acne and/or sebaceous gland treating composition useful in
`the subject invention, a retinoid, preferably retinoic acid, is included as an active
`along with CATA The inclusion of a retinoid increases the acne and/or
`sebaceous gland treating benefits of the composition. A safe and effective amount
`of a retinoid may be added to the compositions useful in the subject invention,
`preferably from about 0.001% to about 0.5%, more preferably from about 0.01%
`to about 0.1% of the composition. As used herein, •retinoid" includes all natural
`and/or synthetic analogs of Vitamin A or retinol-like compounds which possess
`the biological activity of Vitamin A in the skin as well as the geometric isomers
`and stereoisomers of these compounds, such as all-trans retinoic acid and
`13-cis-retinoic acid.
`20 C. Antimicrobial agents
`In a preferred acne and/or sebaceous gland treating composition useful in
`the subject invention, an antimicrobial agent is included as an active along with
`CATA The inclusion of an antimicrobial agent increases the acne-treating
`benefits of the composition. As used herein, "antimicrobial agent" means a
`compound capable of destroying microbes, preventing the development of
`microbes or preventing the pathogenic action of microbes.
`A safe and effective amount of an antimicrobial agent may be added to
`compositions useful in the subject invention, preferably from about 0.001% to
`about 5%, more preferably from about 0.01% to about 2%, more preferably still
`from about 0.05% to about 1% of the compositions. Preferred antimicrobial
`agents useful in the subject invention are benzoyl peroxide, erythromycin, tetra(cid:173)
`cycline, clindamycin, azelaic acid, and sulfur resorcinol.
`D. Comedolytic agents
`In a preferred acne and/or sebaceous gland treating composition useful in
`the subject invention, a comedolytic agent is included as an active along with
`CATA
`As used herein, the term "comedolytic agent" refers to any compound
`capable of rupturing a comedo.
`A safe and effective amount of a comedolytic agent may be added. to the
`compositions useful in the subject invention, preferably from about 0.05% to
`about 100/o, more preferably from about 0.1% about 5%.
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`A preferred comedolytic agent useful in the subject invention is salicylic
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`acid.
`Hair Growth - Combination Actives
`The compositions of the present invention useful for regulating hair
`growth can also optionally comprise other hair growth stimulants capable of
`functioning in different ways to enhance the benefit of CATA An example of
`such a substance includes, but is not limited to rninoxidil, and derivatives thereof:
`as disclosed in U.S. Patent Nos., 3,461,461; 3,973,061; 3,464,987; and
`4,139,619; incorporated herein by reference.
`Additional hair growth stimulants useful in compositions of the present
`invention comprising CATA include the agents disclosed by the following, which
`are all incorporated herein by reference: U.S. Patent 5,215,760, Kauvossi and
`Kauvossi, issued June 1, 1993; U.S. Patent 5,192,534, Grollier and Richoux,
`issued March 9, 1993; U.S. Patent 5,178,883, Knighton, issued January 12, 1993;
`15 U.S. Patent 5,177,061, Pickart, issued January 5, 1993; U.S. Patent 5,130,142,
`Wong and Warren, issued July 14, 1992; U.S. Patent 5,068,315, Buultjens, Colin,
`Jahoda and Oliver, issued November 26, 1991; U.S. Patent 5,091,173, Buultjens,
`Hellens, Oliver and Withers, issued February 25, 1992; U.S. Patent 5,037,643,
`Green, issued August 6, 1991; U.S. Patent 4,975,441, Gibson, issued December
`4, 1990; U.S. Patent 4,871,839, Gtbson, issued October 3, 1989; U.S. Patent
`4,832,946, Green, issued May 23, 1989; U.S. Patent 4,761,401, Couchman,
`issued August 2, 1988; U.S. Patent 4,139,619, Chidsey, issued February 13,
`1979; U.S. Patent 3,466,364, Takahashi, issued September 9, 1969; and U.S.
`Patent 1,732,120, Christen, issued October 15, 1929; and PROSCAR.,. (a.k.a.,
`finasteride
`or
`(Sa,
`17f3)-1-1-Dimethylethyl)-3 -oxo-4-aza.androst-1-ene-17-
`carboxarnide; Merck & Co.) see 1HE MERCK INDEX, 11th Ed., p. 1250, entry
`7888.
`Delivery Methods for Topical Compositions
`The topical compositions useful for the methods of the instant invention can
`be delivered from a variety of delivery devices. The following are two nonlimiting
`examples.
`A Medicated cleansing pads
`The compositions useful herein can be incorporated into a medicated
`cleansing pad. Preferably these