AU699289B2

AU699289B2 - Anti-acne compositions

Info

Publication number: AU699289B2
Application number: AU18841/95A
Authority: AU
Inventors: Donald Lynn Bissett; Ranjit Chatterjee
Original assignee: Procter and Gamble Co
Current assignee: Procter and Gamble Co
Priority date: 1994-03-03
Filing date: 1995-02-27
Publication date: 1998-11-26
Anticipated expiration: 2015-02-27
Also published as: CZ257296A3; MX9603850A; CA2184378A1; WO1995023587A1; EP0748209A1; AU1884195A; JPH09509933A; CN1145585A; KR970701531A

Description

WO 95/23587 PCTIUS95/02489

I

ANTI-ACNE COMPOSITIONS TECHNICAL FIELD The subject invention relates to the field of treatment of acne in mammalian skin. Specifically, the subject invention relates to methods for treatment of acne in human skin.

BACKGROUND OF THE INVENTION Acne is a pilosebaceous disease characterized by comedo, papules, inflamed to 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 the pilosebaceous glands increase 0 in size, and sebum synthetic activity is elevated due to increased circulating levels of .androgens. Follicular hyperkeratosis can also occur, causing restriction of pilo- 15 sebaceous follicles and, consequently, comedo or plug formation. The comedo contains sebum, protein debris, and anaerobic microorganisms including Propionibacterium (Corvnebacterium) acnes acnes). P. acnes thrive on sebum and generate inflammatory free fatty acids (FFA). The FFA 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 general topical application of lotions and salves to affected skin areas, as well as localized (spot) topical treatment. Products :used for such treatments include anti-bacterial agents, such as benzoyl peroxide.

It would be desirable to provide topical compositions for the treatment of acne in mammalian skin.

It would further be desirable to provide such compositions Swhich disrupt the follicular plug, permitting greater delivery of benzoyl peroxide to P. acnes present .i the come~one,thaan existing compositions.

j It would yet further be desirable to provide methods for treatment of acne in mammalian skin.

It would still further be desirable to provide methods for the treatment of acne in mammalian skin which control P. acnes growth by enhancing Sdelivery of benzoyl peroxide.

SUMMARY OF THE INVENTION The subject invention involves a combination of benzoyl peroxide and certain zwitterionic surfactants having the structure:

I,

2 0 R2 II +1 R1-[C -NH-(CH 2 )mln-N-R4-X

I

R

3 wherein

R

1 is unsubstituted, saturated or unsaturated, straight or branched chain alkyl having from about 9 to about 22 carbon atoms; m is an integer from 1 to 3; n is 0 or 1;

R

2 and R 3 are, independently, saturated, straight chain alkyl having from 1 to about 3 carbon atoms, unsubstituted or mono-substituted with hydroxy;

R

4 is saturated or unsaturated, straight or branched chain alkylene, which is unsubstituted or mono-substituted with hydroxy, having from 1 to about carbon atoms; and 15 X is CO 2

SO

3 or SO4.

The compositions of the subject invention comprise a safe and effective amount of benzoyl peroxide in combination with a safe and effective amount of Scertain zwitterionic surfactants, and a pharmaceutically-acceptable carrier. The subject invention also includes methods of using such compositions for S' 20 prevention or treatment of acne.

The subject invention also provides use of components for the preparation of a topical anti-acne composition according to claim 1 wherein said composition is prepared by combining the following components using conventional mixing techniques: a) a safe and effective amount of zwitterionic surfactant having the structure: O R2 II +1 Ri-(C-NH-(CH2 )m)N-N-R 4

-X

R

3 i wherein R' is unsubstituted, saturated or unsaturated, straight or branched chain alkyl having from 9 to 22 carbon atoms; m is an integer from 1 to U-Q in'( AWWORMTONIUMU SPA bWCS1: \c) __i 3; n is 0 or 1; R 2 and R 3 are, independently, saturated, straight chained alkyl having from 1 to 3 carbon atoms, unsubstituted or mono-substituted with hydroxy;

R

4 is saturated or unsaturated, straight or branched chain alkylene, unsubstituted or mono-substituted with hydroxy, having from 1 to 5 carbon atoms; and X is selected from the group consisting of SO 3 and SO 4 b) a safe and effective amount of benzoyl peroxide, and c) a topical carrier.

The subject invention yet further provides a method of preventing or treating acne in mammalian skin, including topically applying to the skin an effective amount of a composition substantially as herein described.

These and other features, aspects and advantages of the subject invention 9 will become better understood with reference to the following description and appended claims.

DETAILED DESCRIPTION OF THE INVENTION *15 It has been found that a combination of benzoyl peroxide and certain zwitterionic surfactants are unexpectedly useful in the treatment of acne. While :not limited to any specific mechanism, it is believed that the subject compositions io exhibit the ability to disrupt the follicular plug in mammalian comedones. It is believed that the subject combination works by affecting the skin surface's 20 proteolytic enzyme which degrades the protein connections (desmosomes) between cells in the follicular plug, thus causing cell or scale shedding.

As used herein "desquamation" means the shedding or removal of scales from the outermost layer (stratum comeum) of the epidermis. Desquamation is believed to aid in the treatment of acne because it disrupts the comedone in skin with acne.

As used herein "treating acne" means preventing, retarding and/or S CAWINWORDTONIA'MLHtSPECMSP14I.DOC 1.l WO 95/23587 PCT/US95/02489 "pi WO 95/23587 PCT/US95/02489 3 arresting the process of acne formation in mammalian skin.

As used herein, the term "alkyl", unless otherwise indicated, means carbon-containing chains which may be straight or branched, substituted or unsubstituted, saturated, monounsaturated one double bond or triple bond in the carbon chain), or polyunsaturated two or more double bonds in the carbon chain, two or more triple bonds in the carbon chain, one or more double and one or more triple bonds in the carbon chain). Preferred alkyl are straight chain. Preferred alkyl are mono- or di-substituted, or unsubstituted, more preferably unsubstituted. Preferred alkyl are saturated or mono-unsaturated and, if so, preferably with a double bond; more preferably, alkyl are saturated.

Preferred alkyl substituents include halogen, aryl, amino, hydroxy, alkoxy, cyano, nitro and trifluoromethyl. More preferred alkyl substituents are halogen and aryl.

As used herein "zwitterionic surfactant" means a compound having the structure: 0 R2 II

R

1

[C-NH-(CH

2 )mn-N-R4-X 1 (1) R3 In structure R 1 is unsubstituted alkyl having from about 9 to about 22 carbon atoms. Preferred R 1 has from about 11 to about 18 carbon atoms; more preferably from about 12 to about 16 carbon atoms; more preferably still from about 14 to about 16 carbon atoms.

In structure m is an integer from 1 to 3, preferably 2 or 3; more preferably 3.

In structure n is either 0 or 1; n is preferably 1.

In structure R 2 and R 3 are, independently, selected from the group consisting of saturated, straight chain alkyl having from 1 to about 3 carbon atoms, unsubstituted or mono-substituted with hydroxy. Preferred R 2 and R 3 are

CH

3

CH

2

CH

2 OH, and CH 2

CH

2 CH20H. More preferred R 2 and R 3 are CH3.

In structure X is selected from the group consisting of C0 2

SO

3 and S04.

In structure R 4 is alkyl unsubstituted or mono-substituted with hydroxy, having from 1 to about 5 carbon atoms. When X is C0 2

R

4 preferably has 1 or 3 carbon atoms, more preferably 1 carbon atom. When X is S03 or

SO

4

R

4 preferably has from about 2 to about 4 carbon atoms, more preferably 3 carbon atoms.

C

i" WO 95/23587 r'CTIUS95/0248 .9 4 Preferred zwitterionic surfactants of the subject invention include the fol-lowing compounds: a) cetyl betaine:

CH

3

C

16

H

33 -N-CH 2 -C0 2 C; H 3 b) cocoaniidopropylbetaine: 0 CH 3 11 I-

R-C-NH-(CH

2 3 -N-C H 2 -CO2 C H 3 wh e re in R is unsubstituted, saturated, straight chained alclwith f rom about 9 to about 13 carbon atoms;ali 10 c) cetyl propyl hydroxy sultaine:

(CH

3

OH

C

1 6

H

3 T-N~-CHj--CH-C1Hj-SO 3 II

CH

d) cocoamnidopropyl hydroxy sultaine: O 11 +1 1 R-C -NH-(C H 2 3-N-CH 2 -C H-CH 2 -S0 Ut1 3 wherein R is unsubstituted, saturated, straight chained alkyl with from about 9 to about 13 carbon atoms; and e) behenyl betaine: 4

CH

3

C

22

H

4 5

-N-CH

2 -CO2 IMore preferred zwitterionlc surfactants of the subject invention include cetyl betaine, cocoamidopropyl betaine and cetyl propyl hydroxy sultaine. Still 20 more preferred zwitteriomic surfactants of the subject invention include cetyl betaine and cetyl propyl hydroxy sultaine. The most preferred zwitterionic surfactant of the subject invention is cetyl betaine.

As used herein "topical application" means directly laying on or spreading on outer skin.

V 17 4 A nmrr~c~r~r a a

UJ

£r *r 4 r .t a

C

As used herein, "safe and effective amount" means a sufficient amount of a composition to significantly induce a positive modification in the condition being treated, but low enough to avoid serious side effects.

Throughout the description and claims of this specification, the word "comprise" and variations of the word, such as "comprising" and "comprises", is not intended to exclude other additives or components or integers or steps.

As used herein "comprising" means that other steps and ingredients which do not affect the end result can be added. This term encompasses the terms "consisting of' and "consisting essentially of".

As used herein, "pharmaceutically-acceptable" means that drugs, medicaments or inert ingredients which the term 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, "actives" or "active agents" means a combination of benzoyl peroxide, and a zwitterionic surfactant according to structure or a mixture of such surfactants.

As used herein, all percentages are by weight of the composition.

Compositions useful for treating acne preferably comprise from about 0.1% to about 10%, more preferably from about 1% to about also preferably about 2% to about 5% of benzoyl peroxide.

Compositions useful for treating acne also preferably comprise from about 0.1% to about 10%, more preferably from about 1% to about also preferably from about 2% to about 5% of zwitterionic surfactant according to structure or a pharmaceutically-acceptable salt thereof. Preferred pharmaceuticallyacceptable salts include alkali metal salts, such as sodium and potassium; alkaline earth metal salts, such as calcium and magnesium; non-toxic heavy metal salts; ammonium salts; and trialkylammonium salts, such as trimethylammonium and triethylammonium.

Pharmaceutically-Acceptable Carrier In addition to the active agents as described hereinbefore, the pharmaceutical compositions of the present invention essentially comprise a Spharmaceutically-acceptable carrier. The term "pharmaceutically-acceptable

~I

j Ir: i 1U) .I 'a carrier", as used herein, means one or more compatible solid or liquid filler diluents which are suitable for administration to a human or lower animal. The term "compatible", as used herein, means that the components. of the pharmaceutical compositions are capable of being comingled with the compound of the present invention, and with each other, in a manner such that there is no interaction which would substantially reduce the pharmaceutical efficacy of the pharmaceutical composition under ordinary use situations. Pharmaceuticallyacceptable carriers must, of course, be of sufficiently high purity and sufficiently low toxicity to render them suitable for administration to the human or lower 4 4 6 A Rt t a -4 41uAm P Ecsp i i fl t jti 4 '\NT O< m 14

I

i_ li-~ WO 95/23587 PCT/US95102489 animal being treated.

The compositions of the subject invention are administered topically to a biological subject, by the direct laying on or spreading of the composition on the skin of the subject. The topical compositions useful in the subject invention involve compositions suitable for topical application to mammalian skin, the composition comprising a safe and effective amount of the active agents or mixture of such actives as described hereinafter, and a pharmaceutically-acceptable topical carrier.

The topical compositions useful in the subject invention may be made into a wide variety of product types. These include, but are not limited to, lotions, creams, gels, sticks, sprays, ointments, pastes, mousses and cosmetics. These product types may comprise several types of carrier systems including, but not limited to solutions, emulsions, gels, solids, and liposomes.

The topical compositions useful in the subject invention formulated as solutions typically include a pharmaceutically-acceptable aqueous or organic solvent. The terms "pharmaceutically-acceptable organic solvent" refer to a solvent which is capable of having the actives dispersed or dissolved therein, and of possessing acceptable safety properties irritation and sensitization characteristics). Water is a preferred solvent. Examples of suitable organic solvents include: propylene glycol, polyethylene glycol (200-600), polypropylene glycol (425-2025), glycerol, 1,2,4-butanetriol, sorbitol esters, 1,2,6-hexanetriol, ethanol, isopropanol, sorbitol esters, butanediol, and mixtures thereof. These solutions useful in the subject invention preferably contain from about 80% to about 99.99% of an acceptable aqueous or organic solvent.

If the topical compositions useful in the subject invention are formulated as an aerosol and applied to the skin as a spray-on, a propellant is added to a solution composition. Examples include chloro-fluorinated lower molecular weight hydrocarbons. A more complete disclosure of propellants useful herein can be found in Sagarin, Cosmetics Science and Technology, 2nd Edition, Vol. 2, pp.

443-465 (1972) Topical compositions useful in the subject invention may be formulated as a solution comprising an emollient. Such compositions preferably contain from about 2% to about 50% of a topical pharmaceutically-acceptable emollient.

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. Sagarin, Cosmetics, Science and Technology, 2nd Edition, Vol. 1, pp. 32-43 (1972), incorporated I -UCC INTERNATIONAL SEARCH REPORT Inter. Al Application No PCT/US 95/02489 A. CLASSIFICATION OF SUBJECT MATTER IPC 6 A61K7/48 "Vm WO 95/23587 PCT/US95/02489 herein by reference, contains numerous examples of suitable materials.

A lotion can be made from a solution carrier system. Lotions typically comprise from about 1% to about 20%, preferably from about 5% to about of an emollient; and from about 50% to about 90%, preferably from about 60% to about 80%, water.

Another type of product that may be formulated from a solution carrier system is a cream. A cream typically comprises from about 5% to about preferably from about 10% to about 20%, of an emollient, and from about 45% to about 85 preferably from about 50 to about 75 water.

Yet another type of product that may be formulated from a solution carrier system is an ointment. An ointment may comprise a simple base of animal or vegetable oils or s'ni-solid hydrocarbons (oleaginous). Ointments may also comprise absorption ointment bases which absorb water to form emulsions: Ointment carriers may also be water soluble. An ointment may comprise from about 2% to about 10% of an emollient; and from about 0.1% to about 2% of a thickening agent. A more complete disclosure of thickening agents useful herein can be found in Sagarin, Cosmetics, Science and Technology, 2nd Edition, Vol.

1, pp. 72-73 (1972).

If the carrier is formulated as an emulsion, preferably from about 1% to about 10%, more preferably from about 2% to about of the carrier system comprises an emulsifier. Emulsifiers may be nonionic, anionic or cationic.

Suitable emulsifiers are disclosed in, for example, U.S. Patent 3,755,560, issued August 28, 1973, Dickert et al.; U.S. Patent 4,421,769, issued December 1983, Dixon et al.; and McCutcheon's Detergents and Emulsifiers, North American Edition, pages 317-324 (1986); The cleaning compositions useful in the subject invention preferably contain from about 1% to about 90%, more preferably from about 5% to about 10%, of a 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 actives on the skin and scalp. A preferred delivery system involves the use of insoluble complexes. For a more complete disclosure, see U.S. Patent 4, 835,148, Barford et al., issued May 30, 1989; incorporated herein by reference in its entirety.

i i ii

I

"rr~-c 31'" f r i j- 1 WO 95/23587 PCT/US95/02489 8 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 sodium methyl cocoyl taurate, sodium methyl oleoyl taurate, and sodium lauryl 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 described in McCutcheon's, Detergents and Emulsifiers, North American Edition (1986), published by Allured Publishing Corporation, which is incorporated herein by io reference in its entirety.

Combination Actives A. Anti-Inflammatory Agents An anti-inflammatory agent may be included as an active along with the active agents, to reduce the redness and irritation of inflamed acne lesions. 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 more preferably from about 0.5% to about of the composition. The exact amount of anti-inflammatory agent to be used in the compositions will depend on the particular anti-inflammatory agent utilized since such agents vary widely in potency.

Steroidal anti-inflammatory agents, including but not limited to, corticosteroids such as hydrocortisone, hydroxyltriamcinolone, alpha-methyl dexamethasone, dexamethasone-phosphate, beclomethasone dipropionates, clobetasol valerate, desonide, desoxymethasone, desoxycorticosterone acetate, dexamethasone, dichlorisone, diflorasone diacetate, diflucortolone valerate, fluadrenolone, fluclorolone acetonide, fludrocortisone, flumethasone pivalate, fluosinolone acetonide, fluocinonide, flucortine butylesters, fluocortolone, fluprednidene (fluprednylidene) acetate, flurandrenolone, halcinonide, hydrocortisone acetate, hydrocortisone butyrate, methylprednisolone, triamcinolone acetonide, cortisone, cortodoxone, flucetonide, fludrocortisone, difluorosone diacetate, fluradrenolone, fludrocortisone, diflurosone diacetate, fluradrenone acetonide, medrysone, amcinafel, amcinafide, betamethasone and the balance of its esters, chloroprednisone, chlorprednisone acetate, clocortelone, Slescinolone, dichlorisone, diflurprednate, flucloronide, flunisolide, fluoromethalone, fluperolone, fluprednisolone, hydrocortisone valer, -A Shydrocortisone cyclopentylpropionate, hydrocortamate, mepredniso paramethasone, prednisolone, prednisone, beclomethasone dipropionate, 1 t 1 0 d d AJ, WO 95/23587 PCT/US95/02489 9 triamcinolone, and mixtures thereof may be used. The preferred steroidal anti- -inflammatory for use is hydrocortisone.

A second class of anti-inflammatory agents which is useful in the compositions includes the nonsteroidal anti-inflammatory agents. The variety of compounds encompassed by this group are well-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 Anti-inflammatory and Anti-Rheumatic Drugs, K.D. Rainsford, Vol.

I-m, CRC Press, Boca Raton, (1985), and Anti-inflammatory Agents. Chemistry and Pharmacology, 1, R.A. Scherrer, et al., Academic Press, New York (1974).

Specific non-steroidal anti-inflammatory agents useful in the composition invention include, but are not limited to: 1) the oxicams, such as piroxicam, isoxicam, tenoxicam, sudoxicam, and CP-14,304; 2) the acetic acid derivatives, such as diclofenac, fenclofenac, indomethacin, sulindac, tolmetin, isoxepac, furofenac, tiopinac, zidometacin, acematacin, fentiazac, zomepirac, clindanac, oxepinac, felbinac, and ketorolac; 3) the fenamates, such as mefenamic, meclofenamic, flufenamic, niflumic, and tolfenamic acids; 4) the propionic acid derivatives, such as ibuprofen, naproxen, benoxaprofen, flurbiprofen, ketoprofen, fenoprofen, fenbufen, indopropfen, pirprofen, carprofen, oxaprozin, pranoprofen, miroprofen, tioxaprofen, suprofen, alminoprofen, and tiaprofenic; and 5) 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 pharmaceutically-acceptable salts and esters of these agents. For example, etofenamate, a flufenamic acid derivative, is particularly useful for topical application. Of the nonsteroidal anti-inflammatory agents, ibuprofen, naproxen, flufenamic acid, mefenamic acid, meclofenamic acid, piroxicam and felbinac are preferred; ibuprofen, naproxen, and flufenamic acid are most preferred.

Finally, so-called "natural" anti-inflammatory agents are useful in methods of the subject invention. For example, candelilla wax, alpha bisabolol, aloe vera, Manjistha (extracted from plants in the genus Rubia, particularly Rubia Cordifolia), and Guggal (extracted from plants in the genus Commiphora, I I 7 WO 95/23587 PCTIUS95/02489 particularly Commiphora Mukul), may be used.

B. Retinoids In a preferred composition useful in the subject invention, a retinoid, preferably retinoic acid, is included as an active along with the active agents. The inclusion of a retinoid increases the anti-acne benefits of the composition and suppresses sebum production in the skin. 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 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.

C. Antiandrogens In a preferred composition useful in the subject invention, an antiandrogen is included as an active along with the active agents. As used herein, "antiandrogen" means a compound capable of correcting androgen-related disorders by interfering with the action of androgens at their target organs. The target organ for the subject invention is mammalian skin. Preferred antiandrogens include cyproterone thiopivalate and cyproterone acetate thioacetate.

D. Glycolic Acid In a preferred composition of the subject invention, glycolic acid is included as an active along with the subject anti-acne agents. Preferably, the composition comprises from about 0.1% to about 10%, more preferably from about 1% to about also preferably from about 2% to about 5% glycolic acid.

E. Anti-acne Agents In a preferred composition of the subject invention, an additional anti-acne agent is included as an active along with the subject anti-acne agents. Preferred additional anti-acne agents include hesperetin and phloretin. Preferably, the composition comprises from about 0.1% to about more preferably about to about also preferably from about 1% to about 2% of an anti-acne agent.

Delivery Methods for the 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.

Medicated Cleansing Pads

*I

~ili Lu Il-i; iii i- i- I ii ~.iil~31YIIII-L~L--LI WO 95/23587 PCT/US95/02489 The compositions useful herein can be incorporated into a medicated cleansing pad. Preferably these pads comprise from about 50% to about 75% by weight of one or more layers of nonwoven fabric material and from about 20% to about 50% by weight of a liquid composition deliverable from the nonwoven fabric material comprising hydroxy acid comprising salicylic acid and a subject zwitterionic surfactant, or mixture of such surfactants. These pads are described in detail in U. S. Patent No. 4,891,228, to Thaman et al., issued January 2, 1990; and U. S. Patent No. 4,891,227, to Thaman et al., issued January 2, 1990; both of which are incorporated by reference herein in their entirety.

Dispensing Devices The compositions useful herein can also be incorporated into and delivered from a soft-tipped or flexible dispensing device. These devices are useful for the controlled delivery of the compositions to the skin surface and have the advantage that the treatment composition itself never need be directly handled by the user.

Nonlimiting examples of these devices comprise a fluid container including a mouth, an applicator, means for holding the applicator in the mouth of the container, and a normally closed pressure-responsive valve for permitting the flow of fluid from the container to the applicator upon the application of pressure to the valve. The fluid comprises hydroxy acid comprising salicylic acid and a subject zwitterionic surfactant, or mixture of such surfactants.

The valve can include a diaphragm formed from an elastically fluid impermeable material with a plurality of non-intersecting arcuate slits therein, where each slit has a base which is intersected by at least one other slit, and where each slit is out of intersecting relation with its own base, and wherein there is a means for disposing the valve in the container inside of the applicator. Examples of these applicator devices are described in U.S. Patent No. 4,693,623, to Schwartzman, issued September 15, 1987; U.S. Patent No. 4,620,648, to Schwartzman, issued September 15, 1987; U.S. Patent No. 3,669,323, to Harker et al., issued June 13, 1972; U.S. Patent No. 3,418,055, to Schwartzman,. issued December 24, 1968; and U.S. Patent No. 3,410,645, to Schwartzman, issued November 12, 1968; all of which are incorporated herein by reference in their entirety. Examples of applicators useful herein are commercially available from Dab-O-Matic, Mount Vernon, NY.

METHODS FOR TREATMENT OF ACNE The subject invention relates to methods of treating acne in mammalian skin. Such methods comprise topically applying to the skin or scalp an effective amount of the compositions of the subject invention. The term "effective I7 lit WO 95/23587 PCT/US95/02489 amount", as used herein, means an amount sufficient to provide an anti-acne benefit. The composition can be applied for several days, weeks, r.,onths or years at appropriate intervals: from about three times a day to about once every three days, preferably from about twice a day to once every other day, also preferably about once a day until a satisfactory anti-acne benefit has been achieved.

Typically, in each application, an effective coating of the skin or scalp is achieved by applying from about 0.004mg/cm 2 to about 0.1 mg/cm 2 each of benzoyl peroxide and a subject zwitterionic surfactant, or mixture of such surfactants, more preferably from about 0.02mg/cm 2 to about 0.06mg/cm 2 of each agent, also preferably about 0.04 mg/cm 2 of each agent.

Examples The following examples further describe and demonstrate embodiments within the scope of the subject invention. The examples are given solely for the purpose of illustration and are not to be construed as limitations of the subject invention, as many variations thereof are possible without departing from the spirit and scope of the invention.

Example I A topical composition is prepared by combining the following components utilizing conventional mixing techniques.

Ingredient Weight Water 50.67 Triethanolamine 0.66 Cetyl Betaine 6.66 Disodium EDTA 0.01 Ethanol 32.00 Benzoyl Peroxide 10.00 The above composition is applied to the face to treat acne at a dose enough to deposit 2 mg of the composition per cm 2 skin, once a day. As existing acne subsides, application is reduced to once every other day.

Example n A cleaning composition is prepared by combining the following ingredients, using conventional mixing techniques: Ingredient Weight Water 44.75 Tetrasodium EDTA 0.12 Cetyl Betaine 3.33 Sodium methyl cocoyl taurate 41.67 i i j i u i h I. I I_ WO 95/23587 PCT/US95/02489 Cetyl propyl hydroxysultaine 6.00 Benzoyl peroxide 2.00 Cocoamidopropyl betaine 1.43 Hydroxypropyl methylcellulose 0.50 Glycolic Acid 0.20 Perfume 0.12 The cleaning composition is applied to the face twice a day to treat acne.

An amount enough to deposit 3 mg of the composition per cm 2 skin is used. As existant acne subsides, frequency is reduced to once a day.

Example In The following topical gel is prepared by mixing the ingredients according to conventional mixing techniques: Ingredients Weight Alcohol SD-40 (95 40.00 Benzoyl peroxide 2.00 Disodium EDTA 0.005 Cetyl Betaine 6.66 Water 47.335 The gel is applied to the face at a dose of 0.2 mg composition per cm 2 skin three times a day to treat acne. As treatment progresses, application is reduced to once a day.

Example IV The following lotion is prepared by mixing the conventional mixing techniques: Ingredient Water Glycerin Petrolatum Cetyl Alcohol Cyclomethicone and Dimethicone Copolyol Stearyl Alcohol Isopropyl Palmitate Dimethicone Sodium Hydroxide Lanolin Acid Polyethyleneglycol-100 Stearate ingredients according to Weight 69.96 1.8 1.2 1.0 0.34 0.25 0.25 ,i i i i j 1 j- WO 95/23587 PCT/US95/02489 14 Stearic Acid 0.25 Methylparaben 0.2 Titanium Dioxide 0.15 EDTA 0.1 Benzoyl peroxide Cocoamidopropyl Betaine The above lotion is applied to the face once a day at a dose of .75 mg composition per cm 2 skin. As existant acne subsides, frequency of application is reduced to once every two days.

EXAMPLE V The following cleaning solution is prepared by mixing the ingredients according to conventional mixing techniques: Ingredient Weight Water 85.3 Carbopol 980 .9 Cetyl betaine EDTA disodium .1 NaOH solution 9.2 Benzoyl Peroxide The above lotion is applied to the face twice a day at a dose of .90 mg composition per cm 2 skin. As existant acne subsides, frequency of application is reduced to once a day.

EXAMPLE VI The following lotion is prepared by mixing the ingredients according to conventional mixing techniques:

K"

WO 95/23587 PCT/US95/02489 Ingredient Weight Carbopol 980 .9 Water 80.5 EDTA disodium 0.1 Cetyl betaine Dow Coming Anti Foam Cetyl Alcohol Stearyl Alcohol Steareth-2 1 .9 Steareth-21 1 .1 Benzoyl Peroxide Cyclomethicone D4/D5 NaOH solution (5 1 obtained from ICI Americas The above lotion is applied to the face once every other day at a dose of 20 mg composition per cm 2 skin. As existant acne subsides, frequency of application is reduced to once a week.

While particular embodiments of the subject invention have been described, it will be obvious to those skilled in the art that various changes and modifications to the subject invention can be made without departing from the spirit and scope of the invention. It is intended to cover, in the appended claims, all such modifications that are within the scope of the subject invention.

Claims

1. An anti-acne composition useful for topical application wherein said composition comprises; a) a safe and effective amount of zwitterionic surfactant having the structure: 0 R2 II +1 R1-(C-NH-(C H 2 )m)-N-R4-X R 3 wherein R 1 is unsubstituted, saturated or unsaturated, straight or branched chain alkyl having from 9 to 22 carbon atoms; m is an integer from 1 to 3; n is 0 or 1; R 2 and R 3 are, independently, saturated, straight chained alkyl having from 1 to 3 carbon atoms, unsubstituted or mono-substituted with hydroxy; 15 R 4 is saturated or unsaturated, straight or branched chain alkylene, unsubstituted or mono-substituted with hydroxy, having from 1 to 5 carbon atoms; and X is selected from the group consisting of CO 2 SO 3 and SO 4 Sb) a safe and effective amount of benzoyl peroxide; and c) a topical carrier.

2. A composition according to Claim 1 wherein: the concentration of benzoyl peroxide is from 0.1% to 10%; and the concentration of zwitterionic surfactant is from 0.1% to

3. A composition according to any one of the preceding claims wherein: R 2 and R 3 are independently selected from the group CH 3 CH 2 CH 2 OH and CH 2 CH 2 CH 2 OH; X is CO 2 or SO 3 and m is 2 or 3. j CWNWORDTONAMUMMMSECISP184.DOC li ,iR ;I-I~LirLLiC~ V S: 0 so 0000 *000.0 v S S~ S. 5 0 S *SSS S S 17

4. A composition according to Claim 3 wherein R 4 is saturated, straight chained, and has from 1 to 3 carbon atoms when X is CO2, and from 2 to 4 carbon atoms when X is SO 3

5. A composition according to Claim 4 wherein: a) R 1 is a saturated, straight chain alkyl with from 11 to 18 carbon atoms; b) R 2 and R 3 are CH 3 and c) R 4 has 1 carbon atom when X is CO2; and R 4 has 3 carbon atoms when X is SO3. d) m is 3; and e) n is 1.

6. The composition of any one of the preceding claims wherein: 15 the concentration of benzoyl peroxide is from 1% to 6%;and the concentration of zwitterionic surfactant is from 1 to 6%.

7. A composition of any one of the preceding claims wherein the composition further comprises from 1% to 6% of glycolic acid.

8. A composition according to any one of the preceding claims wherein the zwitterionic surfactant is behenyl betaine, cocoamidopropyl betaine, cetyl propyl hydroxy sultaine or cetyl betaine.

9. A composition according to any one of the preceding claims wherein; the amount of benzoyl peroxide when applied topically is from 0.004 mg/cm 2 skin to 0.1 mg/cm 2 skin; and the amount of zwitterionic surfactant when applied topically is from 0.004 mg/cm 2 skin to 0.1 mg/cm 2 skin. i- i: i; i 1 1 y CANWOMflTONtMMAWUPECA'SPl68WOC 18 Use of components for the preparation of a topical anti-acne composition according to claim 1 wherein said composition is prepared by combining the following components using conventional mixing techniques: a) a safe and effective amount of zwitterionic surfactant having the structure: 0 R2 II R1--(C-NH-(C H 2 )m)-N-R 4 X R3 wherein R 1 is unsubstituted, saturated or unsaturated, straight or branched chain alkyl having from 9 to 22 carbon atoms; m is an integer from 1 to 3; n is 0 or 1; R 2 and R 3 are, independently, saturated, straight chained alkyl having from 1 to 3 carbon atoms, unsubstituted or mono-substituted with hydroxy; R 4 is saturated or unsaturated, straight or branched chain alkylene, unsubstituted 15 or mono-substituted with hydroxy, having from 1 to 5 carbon atoms; and X is selected from the group consisting of CO2, SO 3 and SO 4 b) a safe and effective amount of benzoyl peroxide, and c) a topical carrier.

S 20

11. A method of preventing or treating acne in mammalian skin, including topically applying to the skin an effective amount of a composition according to any one of claims 1 to 9.

12. The method according to claim 11 wherein said mammalian skin is human skin including scalp.

13. An anti-acne composition according to claim 1, substantially as hereinbefore described with reference to any one of the examples.

14. Use of components for the preparation of a topical anti-acne composition, according to claim 10 and substantially as hereinbefore described with reference to any one of the examples. 1i CA.WI.oRDTONAML PECrSPlS41M.DOC t 19 A method of treating or preventing acne according to claim 11, substantially as hereinbefore described with reference to any one of the examples. DATED: 14 October 1998 PHILLIPS ORMONDE FITZPATRICK Attorneys for: THE PROCTER GAMBLE COMPANY (CCI C C C C Ci C Ct C C C C CC 4 C C C 9 I C C 4 SC 'CCC C Cf C CC CCC I C CCCI CCC I. C C (*C I i CkVINORTONLAMUKSPECL\P184lDOC is, W.00 1 ,who v INTERNATIONAL SEARCH REPORT Intern. Al Application No PCT/US 95/02489 A. CLASSIFICATION OF SUBJECT MATTER IPC 6 A61K7/48 According to International Patent Classification (IPC) or to both national classification and IPC r n v Tretf fcAnoIui-cr 0. rlzL~ua 0-1lnC Minimum documentation searched (classification system followed by classification symbols) IPC 6 A61K Documentation scarched other than minimum documentation to the extent that such documents are included in the fields searched Electronic data base consulted during the international search (name of data base and, where practical, search terms used) C. DOCUMENTS CONSIDERED TO BE RELEVANT Category" Citation of document, with indication, where appropriate, of the relevant passages Relevant to claim No. X LU,A,68 215 (FLOW PHARMACEUTICALS INC.) 21 1-10 February 1974 see the whole document A EP,A,O 335 115 (L'OREAL) 4 October 1989 1-10 see the whole document A EP,A,O 413 528 (YU RUEY 20 February 1-10 1991 see the whole document A US,A,4 350 681 (JAMES E. FULTON) 21 1-10 September 1982 see the whole document A WO,A,90 00899 (CIRO'S TOUCH LTD) 8 1-10 February 1990 see the whole document E] Further documents are listed in the continuation of box C. Patent family members are listed in annex. Special categories of cited documents later document published after the international filing date or priority date and not in conflict with the application but document defining the general state of the art which is not cited to understand the principle or theory underlying the considered to be of particular relevance invention earlier document but published on or after the internatlonal document of particular relevance; the claimed invention filing date cannot be considered novel or cannot be considered to document which may throw doubts on priority claim(s) or involve an inventive step when the document is taken alone which is cited to establish the publication date of another docrment of particular relevance; the claimed invention citation or other special reason (as specified) cannot be considered to involve an inventive step when the document referring to an oral disclosure, use, exhibition or do.ument is combined with one or more other such docu- other means mcnts, such combination being obvious to a person skilled document published prior to the international filing date but in the art. later than the priority date claimed document member of the same patent family Date of the actual compleof theact compet f the international search Date of mailing of the international search report July 1995 07.08.95 Name and mailing address of the ISA Authorized officer European Patent Office, P.B. 5818 Patentlaan 2 NL 2280 HV Rijswijk Tel. (+31.70) 340-2040, Tx 31 651 eponl, CouRkuyt, P Fax: 31.70) 340-3016 Form PCT/ISA/210 (second sheet) (July 1992) page 1 of 2 I2MERNATIONAL SEARCH REPORT Intern. Al Application No PCT/US 95/02489 C.(Continuation) DOCUMENTS CONSIDERED TO BE RELEVANT Catcgory Ctation of document, wvith indijcation, where appropriate, or the relevant passages Relevant to claim No. US,A,4 228 163 (BLISS) 14 October 1980 see the whole document GB,A,1 465 528 (PETROLITE CORPORATION) 23 February 1977 see page 12, line 15-26; example 24 T~1-10 1-10 J Form PCT/ISA210 (ccftifUutiofl bdseond sheet) (July 1992) page 2 of 2 ERNATIONAL SEARCH REPORT Iti a p~ainN infornmation on patent family members PCT/US 95/02489 Patent document I Publication IPatent fanily I Publicadi'n cited in search report date member(s) date LU-A-68215 21-02-74 US-A- 3852210 03-12-74 AU-B- 470214 04-03-76 AU-A- 5887973 06-02-75 BE-A- 803362 08-02-74 CA-A- 997647 28-09-76 DE-A- 2340568 2 1-02-74 FR-A,B 2328039 13-05-77 GB-A- 1398253 18-06-75 JP-C- 868380 30-06-77 JP-A- 49086275 19-08-74 JP-B- 51041105 08-11-76 NL-A- 7310909 13-02-74 EP-A-335115 04-10-89 FR-A- 2628319 15-09-89 ~JP-A- 1268632 26-10-89 US-A- 4960772 02-10-90 EP-A-413528 20-02-91 US-A- 5091171 25-02-92 AU-B- 660917 13-07-95 AU-A- 5913990 21-02-91 CA-A- 2019273 15-02-91 US-A- 5385938 31-01-95 US-A-4350681 21-09-82 US-A- 4189501 19-02-80 US-A- 4361584 30-11-82 WO-A-9000899 08-02-90 AT-T- 118350 15-03-95 AU-A- 3687489 19-02-90 DE-D- 68921209 23-03-95 EP-A- 0425507 08-05-9 1 JP-T- 3506024 26-12-91 US-A- 5047249 10-09-91 US-A-4228163 14-10-80 NONE GB-A-1465528 23-02-77 NONE I 1 focrm PC?/ISA$21 (patent (euiy ann~ex) (luly 1992)