Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K8/00—Cosmetics or similar toiletry preparations
  • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
  • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
  • A61K8/33—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing oxygen
  • A61K8/38—Percompounds, e.g. peracids
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K8/00—Cosmetics or similar toiletry preparations
  • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
  • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
  • A61K8/40—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing nitrogen
  • A61K8/42—Amides
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K8/00—Cosmetics or similar toiletry preparations
  • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
  • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
  • A61K8/40—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing nitrogen
  • A61K8/44—Aminocarboxylic acids or derivatives thereof, e.g. aminocarboxylic acids containing sulfur; Salts; Esters or N-acylated derivatives thereof
  • A61K8/442—Aminocarboxylic acids or derivatives thereof, e.g. aminocarboxylic acids containing sulfur; Salts; Esters or N-acylated derivatives thereof substituted by amido group(s)
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
  • A61Q19/00—Preparations for care of the skin
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
  • A61Q19/00—Preparations for care of the skin
  • A61Q19/10—Washing or bathing preparations
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K2800/00—Properties of cosmetic compositions or active ingredients thereof or formulation aids used therein and process related aspects
  • A61K2800/40—Chemical, physico-chemical or functional or structural properties of particular ingredients
  • A61K2800/59—Mixtures
  • A61K2800/596—Mixtures of surface active compounds

Definitions

• 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.
• 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 the pilosebaceous glands increase in size, and sebum synthetic activity is elevated due to increased circulating levels of androgens. Follicular hyperkeratosis can also occur, causing restriction of pilo- sebaceous follicles and, consequently, comedo or plug formation. The comedo contains sebum, protein debris, and anaerobic microorganisms including
• Propionibacterium fCorvnebacteriu ⁇ ) acnes (P. acnesY P. acnes thrive on sebum and generate inflammatory free fatty acids (FFA).
• FFA inflammatory free fatty acids
• 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.
• the subject invention involves a combination of benzoyl peroxide and certain zwitterionic surfactants having the structure: II + 1
• R! 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 0 or 1 ;
• R2 and R ⁇ are, independently, saturated, straight chain alkyl having from 1 to about 3 carbon atoms, unsubstituted or mono-substituted with hydroxy;
• R4 is saturated or unsaturated, straight or branched chain alkyl, which is unsubstituted or mono-substituted with hydroxy, having from 1 to about 5 carbon atoms;
• X is CO2, SO3 or SO4.
• compositions of the subject invention comprise a safe and effective .amount of benzoyl peroxide in combination with a safe and effective amount of certain zwitterionic surfactants, and a pharmaceutically-acceptable carrier.
• the subject invention also includes methods of using such compositions for prevention or treatment of acne.
• treating acne means preventing, retarding and/or arresting the process of acne formation in mammalian skin.
• alkyl means carbon-containing chains which may be straight or branched, substituted or unsubstituted, saturated, monounsaturated (i.e. one double bond or triple bond in the carbon chain), or polyunsaturated (i.e. 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.
• zwitterionic surfactant means a compound having the structure:
• R is unsubstituted alkyl having from about 9 to about 22 carbon atoms.
• Preferred R 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.
• m is an integer from 1 to 3, preferably 2 or 3; more preferably 3.
• n is either 0 or 1; n is preferably 1.
• 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 , CH2CH2OH, and CH2CH2CH2OH. More preferred R 2 and R 3 are CH3.
• X is selected from the group consisting of CO2, SO3 and SO 4 .
• R 4 is alkyl unsubstituted or mono-substituted with hydroxy, having from 1 to about 5 carbon atoms.
• R 4 preferably has 1 or 3 carbon atoms, more preferably 1 carbon atom.
• R 4 preferably has from about 2 to about 4 carbon atoms, more preferably 3 carbon atoms.
• Preferred zwitterionic surfactants of the subject invention include the following compounds: a) cetyl betaine:
• R is unsubstituted, saturated, straight chained .alkyl with from about 9 to about 13 carbon atoms; and e) behenyl betaine:
• More preferred zwitterionic surfactants of the subject invention include cetyl betaine, cocoamidopropyl betaine and cetyl propyl hydroxy sultaine. Still more preferred zwitterionic 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.
• topical application means directly laying on or spreading on outer skin.
• 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.
• 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 Joxicity, incompatibility, instability, irritation, allergic response and the like.
• actives or “active agents” means a combination of benzoyl peroxide, and a zwitterionic surfactant according to structure (I) or a mixture of such surfactants.
• compositions useful for treating acne preferably comprise from about 0.1 % to about 10% , more preferably from about 1 % to about 6%, 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 6% , also preferably from about 2 % to about 5 % of zwitterionic surfactant according to structure (I) or a pharmaceutically-acceptable salt thereof.
• Preferred pharmaceutically-acceptable 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 .
• the pharmaceutical compositions of the present invention essentially comprise a pharmaceutically-acceptable carrier.
• pharmaceutically-acceptable carrier means one or more compatible solid or liquid filler diluents which are suitable for administration to a human or lower animal.
• compatible 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.
• Pharmaceutically- acceptable carriers must, of course, be of sufficiently high purity and sufficiently low toxicity to render them suitable for administration to the human or lower animal being treated.
• compositions of the subject invention are administered topically to a biological subject, i.e. , by the direct laying on or spreading of the composition on the skin of the subject.
• 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.
• 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.
• compositions useful in the subject invention formulated as solutions typically include a pharmaceutically-acceptable aqueous or organic solvent.
• 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 (e.g. , irritation and sensitization characteristics). Water is a preferred solvent.
• 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.
• solutions useful in the subject invention preferably contain from about 80% to about 99.99% of an acceptable aqueous or organic solvent.
• a propellant is added to a solution composition. Examples include chloro-fluorinated lower molecular weight hydrocarbons.
• 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.
• emollients refer to materials used for the prevention or relief of dryness, as well as for the protection of the skin.
• suitable emollients are known and may be used herein. Sagarin, Cosmetics. Science and Technology. 2nd Edition, Vol. 1, pp. 32-43 (1972), incorporated 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 10% , of an emollient; and from about 50% to about 90% , preferably from about 60% to about 80% , water.
• a cream typically comprises from about 5 % to about 50%, 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.
• An ointment may comprise a simple base of animal or vegetable oils or semi-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.
• thickening agents useful herein can be found in Sagarin, Cosmetics. Science and Technology. 2nd Edition, Vol. l, pp. 72-73 (1972).
• the carrier is formulated as an emulsion, preferably from about 1 % to about 10%, more preferably from about 2% to about 5 %, of the carrier system comprises an emulsifier.
• Emulsifiers may be nomonic, 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 20, 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.
• 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 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 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 composi ⁇ tions useful in the subject invention, preferably from about 0.1 % to about 10%, more preferably from about 0.5 % to about 5 % , 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, cor
• 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.
• compositions include, but are not limited to:
• the oxicams such as piroxicam, isoxicam, tenoxicam, sudoxicam, and CP-14,304
• the acetic acid derivatives such as diclofenac, fenclofenac, indomethacin, sulindac, tolmetin, isoxepac, furofenac, tiopinac, zidometacin, acematacin, fentiazac, zomepirac, clindanac, oxepinac, felbinac, and ketorolac;
• fenamates such as mefenamic, meclofenamic, flufenamic, niflumic, and tolfenamic acids
• the propionic acid derivatives such as ibuprofen, naproxen, benoxaprofen, flurbiprofen, ketoprofen, fenoprofen, fenbufen, indopropfen, piiprofen, carprofen, oxaprozin, pranoprofen, miroprofen, tioxaprofen, suprofen, alminoprofen, and tiaprofenic; and 5) the pyrazoles, such as phenylbutazone, oxyphenbutazone, feprazone, azapropazone, and trimethazone.
• non-steroidal anti-inflammatory agents may also be * employed, as well as the pharmaceutically-acceptable salts and esters of these agents.
• etofenamate a flufenamic acid derivative
• ibuprofen, naproxen, flufenamic acid, mefenamic acid, meclofenamic acid, piroxicam and felbinac are preferred; ibuprofen, naproxen, and flufenamic acid are most preferred.
• a retinoid preferably retinoic acid
• a retinoid 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 0.5%, more preferably from about 0.01 % to about 0.1 % of the composition.
• 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.
• an antiandrogen is included as an active along with the active agents.
• anti ⁇ androgen 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.
• glycolic acid is included as an active along with the subject anti-acne agents.
• the composition comprises from about 0.1 % to about 10%, more preferably from about 1 % to about 6% , also preferably from about 2% to about 5 % glycolic acid.
• 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.
• the composition comprises from about 0.1 % to about 5 %, more preferably about
• compositions useful for the methods of the instant invention can be delivered from a variety of delivery devices.
• compositions useful herein can be incorporated into a medicated cleansing pad.
• 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.
• 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.
• Examples of applicators useful herein are commercially available from Dab-O-Matic, Mount Vernon, NY.
• 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.
• effective amount means an amount sufficient to provide an anti-acne benefit.
• the composition can be applied for several days, weeks, months 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.
• 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.
• Example I A topical composition is prepared by combining the following components utilizing conventional mixing techniques. Ingredient % Weight
• a cleaning composition is prepared by combining the following ingredients, using conventional mixing techniques: Ingredient % Weight
• the cleaning composition is applied to the face twice a day to treat acne.
• topical gel is prepared by mixing the ingredients according to conventional mixing techniques:
• 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.
• the following lotion is prepared by mixing the ingredients according to conventional mixing techniques:
• the following cleaning solution is prepared by mixing the ingredients according to conventional mixing techniques:
• the following lotion is prepared by mixing the ingredients according to conventional mixing techniques:
• 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.

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• 1995
  • 1995-02-27 KR KR1019960704823A patent/KR970701531A/ko not_active Application Discontinuation
  • 1995-02-27 CN CN95192504A patent/CN1145585A/zh active Pending
  • 1995-02-27 CA CA002184378A patent/CA2184378A1/en not_active Abandoned
  • 1995-02-27 AU AU18841/95A patent/AU699289B2/en not_active Ceased
  • 1995-02-27 CZ CZ962572A patent/CZ257296A3/cs unknown
  • 1995-02-27 MX MX9603850A patent/MX9603850A/es unknown
  • 1995-02-27 EP EP95911129A patent/EP0748209A1/de not_active Withdrawn
  • 1995-02-27 WO PCT/US1995/002489 patent/WO1995023587A1/en not_active Application Discontinuation
  • 1995-02-27 JP JP7522978A patent/JPH09509933A/ja active Pending

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