Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/60—Salicylic acid; Derivatives thereof
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
  • A61K31/07—Retinol compounds, e.g. vitamin A
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
  • A61K31/19—Carboxylic acids, e.g. valproic acid
  • A61K31/20—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids
  • A61K31/203—Retinoic acids ; Salts thereof
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
  • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
  • A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
  • A61K31/23—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin of acids having a carboxyl group bound to a chain of seven or more carbon atoms
  • A61K31/232—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin of acids having a carboxyl group bound to a chain of seven or more carbon atoms having three or more double bonds, e.g. etretinate
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
  • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• • 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
  • A61K8/36—Carboxylic acids; Salts or anhydrides thereof
  • A61K8/368—Carboxylic acids; Salts or anhydrides thereof with carboxyl groups directly bound to carbon atoms of aromatic rings
• • 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
  • A61K8/37—Esters of carboxylic acids
• • 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
  • A61K8/64—Proteins; Peptides; Derivatives or degradation products thereof
• • 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
  • A61K8/67—Vitamins
  • A61K8/671—Vitamin A; Derivatives thereof, e.g. ester of vitamin A acid, ester of retinol, retinol, retinal
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P17/00—Drugs for dermatological disorders
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P17/00—Drugs for dermatological disorders
  • A61P17/06—Antipsoriatics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
  • A61Q17/00—Barrier preparations; Preparations brought into direct contact with the skin for affording protection against external influences, e.g. sunlight, X-rays or other harmful rays, corrosive materials, bacteria or insect stings
  • A61Q17/005—Antimicrobial preparations
• • 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
  • A61Q19/08—Anti-ageing preparations
• • 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
  • A61Q19/02—Preparations for care of the skin for chemically bleaching or whitening the skin

Definitions

• the present invention relates to formulations and kits useful in the treatment of skin conditions.
• the invention further relates to methods of treatment comprising co-administering multiple active ingredients.
• Retinoids are a group of compounds known to include retinol (Vitamin A), retinal, all-trans-retinoic acid, 13-cis-retinoic acid, and 9-cis-retinoic acid, as well as a variety of esters and similar derivatives. Many retinoids have useful skin-treatment properties. Vitamin A, for example, has long been employed for dermal treatments, particularly for the treatment of acne in a variety of its manifestations. The use of Vitamin A itself has been limited because of the toxic character of the compound when administered in excess. Vitamin A esters, such as Vitamin A palmitate, for example, are considered safer, although these materials too have substantial levels of toxicity that limits the concentrations at which the compounds can be administered.
• beta-carotene As a Vitamin A precursor, beta-carotene has also been explored, with the expectation of greater safety. The precursor is less effective, though, since beta-carotene itself is largely inactive and must be cleaved to the active Vitamin A form before the desired effects are produced. Such cleavage, however, is difficult to manage, predict, and control.
• All-trans-retinoic acid is generally recognized as the topical product RETIN A® (Ortho Pharmaceuticals, Inc., a subsidiary of Johnson & Johnson), which has been approved for use in the treatment of acne vulgaris and related forms of acne. A substantial level of administration for other indications has not yet been approved, including anti-wrinkling and antiactinic treatments of the skin. All-trans-retinoic acid has been demonstrated to be irritating to the skin, producing inflammation in a substantial proportion of users.
• retinoids have been identified with antiaging and antiactinic properties, including esters and amides of 13-cis-retinoic acid and all-trans-retinoic acid. In many cases these compounds have activities comparable to the parent acid and comparable inflammatory and irritating characteristics, although some are known to be safer and less irritating than others (sometimes at the expense of reduced effectiveness). Such retinoids have also been shown to be of benefit in the reduction of skin cancers and precancerous lesions of the skin, although to date use for such indications have not been approved by regulatory authorities. Retinol (Vitamin A) and retinoic acid (Vitamin A acid), its isomers, and certain of its analogs are known to have beneficial effects in the treatment of acne and keratinizing skin disorders.
• Complicating side effects complicating administration of tretinoin include skin irritation and dermatitis of several weeks duration.
• a method of dermal therapy that would retain the effectiveness of tretinoin, but which is essentially non-irritating would provide a much needed solution for the treatment of many skin conditions, including acne, psoriasis, photoaging, and the like.
• many retinoids require a 10 to 14 day treatment cycle before noticeable therapeutic results are seen.
• a method of dermal therapy that has a fast onset of treatment effect would be highly desirable.
• the present invention provides a safe and effective combination of active agents characterized by synergistic activity, and which is particularly useful in the treatment of skin disorders, particularly acne.
• the combined active agents include at least one retinoid, particularly selected from a class of retinoids that are non-irritating to skin, and salicylic acid, or an ester, amide, salt, or solvate thereof.
• the combination of these active ingredients provides a skin treatment formulation characterized by rapid onset of activity and lack of skin irritation.
• the invention provides a topical formulation adapted for treatment of a skin condition, the formulation comprising (i) at least one retinoid; and (ii) salicylic acid or an ester, amide, salt, or solvate thereof.
• the invention provides a kit for treatment of a skin condition, the kit comprising (i) at least one retinoid in a topical formulation; (ii) salicylic acid or an ester, amide, salt, or solvate thereof in a topical formulation; and (iii) instructions for usage of the kit to treat a skin condition.
• the retinoid component and the salicylic acid component can be formulated in a single topical formulation or in separate topical formulations.
• the invention provides a method of treating a skin condition in a subject, comprising topically administering to the subject (i) at least one retinoid, and (ii) salicylic acid or an ester, amide, salt, or solvate thereof.
• skin conditions include acne vulgaris, cystic acne, hyper-pigmentation, hypo-pigmentation, dermal and epidermal hypoplasia and keratoses, wrinkles of the skin as an incident of aging and actinic damage, enlarged pores, surface roughness, ichthyoses, follicular disorders, benign epithelial tumors, perforated dematoses, and disorders of keratinization.
• the retinoid component used in the invention comprises one or more compounds derived from 13-cis-retinoic acid, 13-trans retinoic acid, or 9-cis-retinoic acid (e.g., esters and amides thereof), and wherein the retinoid is characterized by an absence of skin irritation, mutagenicity, and teratogenicity.
• the retinoid could have either of the following structures:
• R is:
• R′′′ is the hydrocarbon backbone of fatty acids
• R′′′′ is R′ or the hydrocarbon backbone of fatty acids
• R′′′′′ is the lower alkyls ranging from C 1 to C 6 ; and further, where the are two or more R′, R′′, R′′′, R′′′′, or R′′′′′ groups attached to the same carbon, each R′, R′′, R′′′, R′′′′, or R′′′′′ group may be the same as or different from the other R′, R′′, R′′′, R′′′′, or R′′′′′ groups attached to that carbon.
• the retinoid could have either of the following structures:
• R is:
• X is —H, —F, —Cl, —Br, —I, —OH, —OR, —OR′
• n is a number from 1 to 5; wherein R′ is H or any of the lower alkyls ranging from C 1 to C 6 ; wherein R′′ is
• R′′′ is the hydrocarbon backbone of fatty acids; wherein R′′′′ is R′′ or the hydrocarbon backbone of fatty acids; wherein R′′′′′ is the lower alkyls ranging from C 1 to C 6 ; and further, where the are two or more R′, R′′, R′′′, R′′′′, or R′′′′′ groups attached to the same carbon, each R′, R′′, R′′′, R′′′′, or R′′′′′ group may be the same as or different from the other R′, R′′, R′′′, R′′′′, or R′′′′′ groups attached to that carbon.
• Exemplary retinoid compounds for use in the invention include 13-trans retinoic 1-hydroxy-3,3-dimethyl-2-butanone ester, 2-(13-cis-retinoyloxy)-4′-methoxyacetophenone, 1-(13-cis-retinoyloxy)-2-propanone, 1-(13-cis-retinoyloxy)-3-decanoyloxy-2-propanone, 13-bis-(13-cis-retinoyloxy)-2-propanone, 2-(13-cis-retinoyloxy)-acetophenone, 13-cis-retinoyloxy methyl 2,2-dimethyl propanoate, 2-(13-cis-retinoyloxy)-n-methyl-acetamide, 1-(13-cis-retinoyloxy)-3-hydroxy-2-propanone, 1-(13-cis-retinoyloxy)-2,3-dioleoylpropanone, succinim
• the retinoid is selected from the group consisting of 13-trans retinoic 1-hydroxy-3,3-dimethyl-2-butanone ester, 2-(13-cis-retinoyloxy)-4′-methoxyacetophenone, and pinacoyl 9-cis-retinoate, and the salicylic acid is in the form of an alkali metal salt.
• alkyl as used herein means saturated straight, branched, or cyclic hydrocarbon groups.
• alkyl refers to groups comprising 1 to 10 carbon atoms (“C 1-10 alkyl”).
• alkyl refers to groups comprising 1 to 8 carbon atoms (“C 1-8 alkyl”), 1 to 6 carbon atoms (“C 1-6 alkyl”), or 1 to 4 carbon atoms (“C 1-4 alkyl”).
• alkyl refers to methyl, trifluoromethyl, ethyl, propyl, isopropyl, cyclopropyl, butyl, isobutyl, t-butyl, pentyl, cyclopentyl, isopentyl, neopentyl, hexyl, isohexyl, cyclohexyl, cyclohexylmethyl, 3-methylpentyl, 2,2-dimethylbutyl, and 2,3-dimethylbutyl.
• Substituted alkyl refers to alkyl substituted with one or more moieties selected from the group consisting of halo (e.g., Cl, F, Br, and I); halogenated alkyl (e.g., CF 3 , 2-Br-ethyl, CH 2 F, CH 2 Cl, CH 2 CF 3 , or CF 2 CF 3 ; hydroxyl; amino; carboxylate; carboxamido; alkylamino; arylamino; alkoxy; aryloxy; nitro; azido; cyano; thio; sulfonic acid; sulfate; phosphonic acid; phosphate; and phosphonate.
• halo e.g., Cl, F, Br, and I
• halogenated alkyl e.g., CF 3 , 2-Br-ethyl, CH 2 F, CH 2 Cl, CH 2 CF 3 , or CF 2 CF 3
• hydroxyl
• halo or “halogen” as used herein means fluorine, chlorine, bromine, or iodine.
• aryl as used herein means a stable monocyclic, bicyclic, or tricyclic carbon ring of up to 8 members in each ring, wherein at least one ring is aromatic as defined by the Hückel 4n+2 rule.
• exemplary aryl groups according to the invention include phenyl, naphthyl, tetrahydronaphthyl, and biphenyl.
• the aryl group can be substituted with one or more moieties selected from the group consisting of hydroxyl, amino, alkylamino, arylamino, alkoxy, aryloxy, nitro, cyano, sulfonic acid, sulfate, phosphonic acid, phosphate, or phosphonate.
• amino as used herein means a moiety represented by the structure NR 2 , and includes primary amines, and secondary and tertiary amines substituted by alkyl (i.e., alkylamino).
• R 2 may represent two hydrogen atoms, two alkyl moieties, or one hydrogen atom and one alkyl moiety.
• alkylamino and arylamino as used herein mean an amino group that has one or two alkyl or aryl substituents, respectively.
• the present invention provides useful combinations of compounds beneficial for treating and improving skin conditions and damage to skin.
• the combination of the invention includes at least one retinoid and salicylic acid or an ester, amide, salt, or solvate thereof.
• the present invention provides combinations of two or more active agents and methods of treatment of various conditions using such combinations.
• the combinations are useful in the treatment of damaged skin, such as inflicted wounds (e.g., skin abrasions), acne, photodamage, and age-related skin damage.
• retinoids and retinoid derivatives can be used according to the present invention.
• retinol, retinal, all-trans-retinoic acid, 13-cis-retinoic acid, 13-trans-retinoic acid, and 9-cis-retinoic acid could all be used in the inventive combinations.
• Particularly beneficial according to certain embodiments of the invention are retinoid derivatives, especially derivatives of 13-cis-retinoic acid, 13-trans retinoic acid, and 9-cis-retinoic acid.
• the specific deleterious side effect that negatively impact commercialization of many retinoids is skin irritation. Other side effects include mutagenicity and teratogenicity.
• the preferred retinoids set forth below such as MDI 101 and MDI 403 (and other esters and amides of 13-cis-retinoic acid, 13-trans-retinoic acid, or 9-cis-retinoic acid), are not irritating to skin, and are also not mutagenic or teratogenic.
• the retinoids comprise esters and amides of 13-cis-retinoic acid (Formula I) and 13-trans-retinoic acid (Formula II) having the following structure:
• R is:
• X is —H, —F, —Cl, —Br, —I, —OH, —OR, —OR′
• n is a number from 1 to 5; wherein R′ is H or any of the lower alkyls ranging from C 1 to C 6 ; wherein R′′ is
• R′′′ is the hydrocarbon backbone of fatty acids
• R′′′′ is R′ or the hydrocarbon backbone of fatty acids
• R′′′′′ is the lower alkyls ranging from C 1 to C 6 ; and further, where the are two or more R′, R′′, R′′′, R′′′′, or R′′′′′ groups attached to the same carbon, each R′, R′′, R′′′, R′′′′, or R′′′′′ group may be the same as or different from the other R′, R′′, R′′′, R′′′′, or R′′′′′ groups attached to that carbon.
• R is preferably —CH 2 C(O)R a , wherein R a is optionally substituted C1-C6 alkyl (e.g., optionally substituted with one or more X groups as defined above), or optionally substituted aryl such as phenyl (e.g., optionally substituted with one or more C1-C6 alkyl groups or X groups as defined above).
• R a is optionally substituted C1-C6 alkyl (e.g., optionally substituted with one or more X groups as defined above), or optionally substituted aryl such as phenyl (e.g., optionally substituted with one or more C1-C6 alkyl groups or X groups as defined above).
• the retinoid derivative used according to the invention is 13-trans retinoic 1-hydroxy-3,3-dimethyl-2-butanone ester, which is also known as MDI 101 and has the structure according to Formula (III).
• the retinoid derivative used in the invention is 2-(13-cis-retinoyloxy)-4′-methoxyacetophenone, which is also known as MDI 403 and has the structure according to Formula (IV).
• exemplary compounds within Formulas (I) or (II) include 1-(13-cis-retinoyloxy)-2-propanone, 1-(13-cis-retinoyloxy)-3-decanoyloxy-2-propanone, 1,3-bis-(13-cis-retinoyloxy)-2-propanone, 2-(13-cis-retinoyloxy)-acetophenone, 13-cis-retinoyloxy methyl 2,2-dimethyl propanoate, 2-(13-cis-retinoyloxy)-n-methyl-acetamide, 1-(13-cis-retinoyloxy)-3-hydroxy-2-propanone, 1-(13-cis-retinoyloxy)-2,3-dioleoylpropanone, succinimdyl 13-cis-retinoate, 1-(13-cis-retinoyloxy)methyl phenyl ketone, 1-(13-cis-retino
• the retinoids comprise esters of 9-cis-retinoic acid (Formula V) and amides of 9-cis-retinoic acid (Formula VI) having the following structure:
• R is:
• X is —H, —F, —Cl, —Br, —I, —OH, —OR, —OR′
• n is a number from 1 to 5; wherein R′ is H or any of the lower alkyls ranging from C 1 to C 6 ; wherein R′′ is
• R′′′ is the hydrocarbon backbone of fatty acids; wherein R′′′′ is R′′ or the hydrocarbon backbone of fatty acids; wherein R′′′′′ is the lower alkyls ranging from C 1 to C 6 ; and further, where the are two or more R′, R′′, R′′′, R′′′′, or R′′′′′ groups attached to the same carbon, each R′, R′′, R′′′, R′′′′, or R′′′′′ group may be the same as or different from the other R′, R′′, R′′′, R′′′′, or R′′′′′ groups attached to that carbon.
• the retinoid derivative used according to the invention is pinacoyl 9-cis-retinoate, which is also known as MDI 301 and has the structure according to Formula (VII).
• exemplary compounds within Formulas (V) or (VI) include 1-(9-cis-retinoyloxy)-2-propanone, 1-(9-cis-retinoyloxy)-3-decanoyloxy-2-propanone, 1,3-bis-(9-cis-retinoyloxy)-2-propanone, 2-(9-cis-retinoyloxy)-acetophenone, 9-cis-retinoyloxy methyl 2,2-dimethyl propanoate, 2-(9-cis-retinoyloxy)-n-methyl-acetamide, 1-(9-cis-retinoyloxy)-3-hydroxy-2-propanone, 1-(9-cis-retinoyloxy)-2,3-dioleoylpropanone, and succinimidyl 9-cis-retinoate.
• Retinoids according to the invention are particularly useful in light of their ability to treat acne and similar dermatological disorders. Such compounds are also useful for the non-irritating treatment of skin cancer and photoaging. The use of these compounds also extends to non-irritating treatments involving the retardation and reversal of additional dermatological and cosmetic conditions which are ameliorated by tretinoin such as the effacement of wrinkles, improvement in appearance such as improvement in color or condition of the skin (e.g., reduction in spots caused from exposure to the sun or reduction in surface roughness), as well as other skin disorders such as the decrease or elimination of skin cancers and the retardation of melanoma growth and metastasis.
• tretinoin such as the effacement of wrinkles, improvement in appearance such as improvement in color or condition of the skin (e.g., reduction in spots caused from exposure to the sun or reduction in surface roughness)
• other skin disorders such as the decrease or elimination of skin cancers and the retardation of melanoma growth and metastasis.
• the retinoids of the invention are useful in the treatment of conditions such as acne vulgaris, cystic acne, hyper-pigmentation, hypo-pigmentation, psoriasis, dermal and epidermal hypoplasia and keratoses, the reduction of wrinkling of the skin as an incident of aging and actinic damage, normalization of the production of sebum, the reduction of enlarged pores, promoting the rate of wound healing, limiting of scar tissue formation during healing and the like. They are additionally useful for treatment or amelioration of the same additional classes of skin disorders as is retinoic acid itself and other retinoids.
• ichthyoses e.g., ichthyosis hystrix, epidermolytic hyperkeratosis, and lamellar ichthyosis
• follicular disorders e.g., pseudofolliculites, senile comedones, nevus comidonicas, and trichostatis spinulosa
• benign epithelial tumors e.g., flat warts, trichoepithelioma, and molluscum contagiosum
• perforated dematoses e.g., elastosis perforans seripiginosa and Kyrles disease
• disorders of keratinization e.g., Dariers disease, keratoderma, hyperkeratosis plantaris, pityriasis rubra pilaris, lichen planus acanthosis nigricans, and psoriasis).
• Retinoid derivatives useful according to the invention can be prepared by conventional methods.
• U.S. Pat. No. 4,677,120 and U.S. Pat. No. 5,124,356, both of which are incorporated herein by reference disclose methods of synthesizing 13-cis and 13-trans retinoid derivatives.
• U.S. Pat. No. 5,837,728, which is incorporated herein by reference discloses methods of synthesizing 9-cis retinoid derivatives.
• “retinoid” refers to all of the above compounds, as well as any biologically active variants, including esters, amides, salts, solvates, or other derivatives thereof.
• Salicylic acid also known as 2-hydroxybenzoic acid, is a beta hydroxy acid (BHA) with the formula C 6 H 4 (OH)CO 2 H, where the OH group is adjacent to the carboxyl group.
• BHA beta hydroxy acid
• Salicylic acid has the structure according to Formula (VIII) below.
• Alkali metal salts of salicylic acid, such as the sodium salt, are particularly preferred for use in the present invention.
• Salicylic acid is the key active ingredient in many skin-care products for the treatment of acne, psoriasis, callulses, corns, keratosis pilaris, and warts.
• Sodium salicylate also acts as non-steroidal anti-inflammatory drug (NSAID) and induces apoptosis in cancer cells.
• NSAID non-steroidal anti-inflammatory drug
• This active ingredient treats acne by causing skin cells to slough off more readily, thereby preventing clogged pores.
• This effect on skin cells also makes salicylic acid a useful active ingredient in certain dandruff shampoos. In higher concentrations, salicylic acid is used as a chemical peel.
• the salicylic acid component is replaced with an antimicrobial peptide component.
• an antimicrobial peptide component is present in addition to both the retinoid component and the salicylic acid component.
• This peptide component may be a naturally-occurring or synthetic peptide, or biologically active salt, ester, or other derivative, thereof.
• the peptide may be glycosylated, phosphorylated, amidated, carboxylated, prenylated, farnesylated, or otherwise modified.
• Antimicrobial peptides are produced by numerous organisms, including mammals, birds, reptiles, insects, plants, and microorganisms. Such peptides include cecropins, defensins magainins, cathelicidins, sarcotoxins, and melittin. The peptides tend to be rich in basic amino acids (Lys and Arg) and, therefore, cationic. Some peptides are helical and some amphipathic, having discrete hydrophilic and hydrophobic surfaces. Over 700 different antimicrobial peptide sequences are known. The Department of Biochemistry, Biophysics and Macromolecular Chemistry at the University of Trieste (Italy) maintains a database of antimicrobial peptides. Although widely studied, the mechanism of action of antimicrobial peptides is poorly understood. The peptides appear to cause the formation of pores or channels in membranes, causing membrane depolarization and the loss of essential cellular components.
• U.S. Pat. No. 6,503,881 describes plant and animal-derived cationic peptides that function as indolicidin analogues.
• U.S. Pat. No. 5,912,230 describes anti-fungal and anti-bacterial histatin-based peptides based on portions of naturally occurring human histatins.
• U.S. Pat. No. 5,717,064 describes synthetic methylated lysine-rich lytic peptides.
• U.S. Pat. No. 5,646,014 describes an antimicrobial peptide isolated from silkworm.
• WO 2004/016653 describes a peptide based on amino acid residues 20-44 sequence of azurocidin.
• U.S. Pat. No. 6,495,516 and U.S. Pat. Pub. No. 2005/0148495 describe bactericidal peptides based on the bactericidal 55 kDa protein bactericidal/permeability increasing protein (BPI).
• U.S. Pat. No. 6,875,744 describes short bioactive peptides containing Phe, Leu, Ala, and Lys residue (i.e., FLAK peptides).
• the peptides can be used in antibacterial, antifungal, anticancer, and other biological applications.
• U.S. Pat. Pub. No. 2007/0207112 describes the use of certain FLAK peptides in the preparation of an acne medicament.
• Several U.S. patents owned by Demegen, Inc. (Pittsburgh, Pa.) describe lytic peptides containing Phe, Ala, Val, and Lys residues (e.g., U.S. Pat. Nos. 6,559,281, and 6,084,156).
• U.S. Pat. Pub. No. 2007/0185019 describes antimicrobial peptides derived from endogenous mammalian proteins, and containing at least four amino acid residues selected from Lys, Arg, and His.
• WO/2005/014639 describes “periodic” antimicrobial peptides defined by the general formulae: P2N2, P3N, PN2, P2N, and NP, wherein P is a cationic residue (preferably Lys, Arg, or Orn) and N is a hydrophobic residue (preferably Ala, Phe, Gly, Leu, Ile, Thr, Tyr, Trp, Val, or Met).
• Preferred antimicrobial peptides for use in the present compositions are synthetic, vegetable-derived, and contain primarily Phe, Ala, Leu, and/or Lys.
• the antimicrobial peptide is selected from the peptides described in U.S. Pat. No. 6,875,744 or US 2007/0207112.
• the antimicrobial peptide for use in the invention comprises about 15 to about 20 amino acids and at least about 95% of the amino acids are selected from phenylalanine, alanine, leucine, and lysine. All of the references noted herein as directed to antimicrobial peptides are incorporated by reference herein in their entirety.
• Biologically active variants of the various compounds disclosed herein as active agents are particularly also encompassed by the invention. Such variants should retain the general biological activity of the original compounds; however, the presence of additional activities would not necessarily limit the use thereof in the present invention. Such activity may be evaluated using standard testing methods and bioassays recognizable by the skilled artisan in the field as generally being useful for identifying such activity.
• suitable biologically active variants comprise analogues and derivatives of the compounds described herein.
• a single compound, such as those described herein may give rise to an entire family of analogues or derivatives having similar activity and, therefore, usefulness according to the present invention.
• a single compound, such as those described herein may represent a single family member of a greater class of compounds useful according to the present invention. Accordingly, the present invention fully encompasses not only the compounds described herein, but analogues and derivatives of such compounds, particularly those identifiable by methods commonly known in the art and recognizable to the skilled artisan.
• the compounds disclosed herein as active agents may contain chiral centers, which may be either of the (R) or (S) configuration, or may comprise a mixture thereof. Accordingly, the present invention also includes stereoisomers of the compounds described herein, where applicable, either individually or admixed in any proportions.
• Stereoisomers may include, but are not limited to, enantiomers, diastereomers, racemic mixtures, and combinations thereof. Such stereoisomers can be prepared and separated using conventional techniques, either by reacting enantiomeric starting materials, or by separating isomers of compounds of the present invention.
• Isomers may include geometric isomers. Examples of geometric isomers include, but are not limited to, cis isomers or trans isomers across a double bond. Other isomers are contemplated among the compounds of the present invention. The isomers may be used either in pure form or in admixture with other isomers of the compounds described herein.
• optical isomers of the compounds according to the present invention include the following:
• enzymatic asymmetric synthesis a synthetic technique whereby at least one step of the synthesis uses an enzymatic reaction to obtain an enantiomerically pure or enriched synthetic precursor of the desired enantiomer;
• kinetic resolutions comprising partial or complete resolution of a racemate (or of a further resolution of a partially resolved compound) by virtue of unequal reaction rates of the enantiomers with a chiral, non-racemic reagent or catalyst under kinetic conditions;
• x) chiral liquid chromatography whereby the enantiomers of a racemate are separated in a liquid mobile phase by virtue of their differing interactions with a stationary phase.
• the stationary phase can be made of chiral material or the mobile phase can contain an additional chiral material to provoke the differing interactions;
• xiii) transport across chiral membranes whereby a racemate is placed in contact with a thin membrane barrier.
• the barrier typically separates two miscible fluids, one containing the racemate, and a driving force such as concentration or pressure differential causes preferential transport across the membrane barrier. Separation occurs as a result of the non-racemic chiral nature of the membrane which allows only one enantiomer of the racemate to pass through.
• the compound optionally may be provided in a composition that is enantiomerically enriched, such as a mixture of enantiomers in which one enantiomer is present in excess, in particular to the extent of 95% or more, or 98% or more, including 100%.
• esters, amides, salts, solvates, and other derivatives of the compounds of the present invention may be prepared according to methods generally known in the art, such as, for example, those methods described by J. March, Advanced Organic Chemistry: Reactions, Mechanisms and Structure, 4 th Ed. (New York: Wiley-Interscience, 1992), which is incorporated herein by reference.
• Examples of dermatologically acceptable salts of the compounds useful according to the invention include acid addition salts. Salts of non-dermatologically acceptable acids, however, may be useful, for example, in the preparation and purification of the compounds.
• Suitable acid addition salts according to the present invention include organic and inorganic acids. Preferred salts include those formed from hydrochloric, hydrobromic, sulfuric, phosphoric, citric, tartaric, lactic, pyruvic, acetic, succinic, fumaric, maleic, oxaloacetic, methanesulfonic, ethanesulfonic, p-toluenesulfonic, benzesulfonic, and isethionic acids.
• compositions include propionic acid, glycolic acid, oxalic acid, malic acid, malonic acid, benzoic acid, cinnamic acid, mandelic acid, salicylic acid, and the like.
• dermatologically acceptable salts include, but are not limited to, sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, phosphates, monohydrogenphosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, propionates, decanoates, caprylates, acrylates, formates, isobutyrates, caproates, heptanoates, propiolates, oxalates, malonates, succinates, suberates, sebacates, fumarates, maleates, butyne-1,4-dioates, hexyne-1,6-dioates, be
• An acid addition salt may be reconverted to the free base by treatment with a suitable base.
• Preparation of basic salts of acid moieties which may be present on a compound useful according to the present invention may be prepared in a similar manner using a dermatologically acceptable base, such as sodium hydroxide, potassium hydroxide, ammonium hydroxide, calcium hydroxide, triethylamine, or the like.
• Esters of the active agent compounds according to the present invention may be prepared through functionalization of hydroxyl and/or carboxyl groups that may be present within the molecular structure of the compound.
• Amides may also be prepared using techniques known to those skilled in the art. For example, amides may be prepared from esters, using suitable amine reactants, or they may be prepared from anhydride or an acid chloride by reaction with ammonia or a lower alkyl amine.
• esters and amides of compounds of the invention can be made by reaction with a carbonylating agent (e.g., ethyl formate, acetic anhydride, methoxyacetyl chloride, benzoyl chloride, methyl isocyanate, ethyl chloroformate, methanesulfonyl chloride) and a suitable base (e.g., 4-dimethylaminopyridine, pyridine, triethylamine, potassium carbonate) in a suitable organic solvent (e.g., tetrahydrofuran, acetone, methanol, pyridine, N,N-dimethylformamide) at a temperature of 0° C. to 60° C.
• a carbonylating agent e.g., ethyl formate, acetic anhydride, methoxyacetyl chloride, benzoyl chloride, methyl isocyanate, ethyl chloroformate, methanesul
• the compounds used in the methods of the invention may exist in different forms.
• the compounds may exist in stable and metastable crystalline forms and isotropic and amorphous forms, all of which are intended to be within the scope of the present invention.
• the desired salt may be prepared by any suitable method known to the art, including treatment of the free base with an inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, or with an organic acid, such as acetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, pyranosidyl acids such as glucuronic acid and galacturonic acid, alpha-hydroxy acids such as citric acid and tartaric acid, amino acids such as aspartic acid and glutamic acid, aromatic acids such as benzoic acid and cinnamic acid, sulfonic acids such a p-toluenesulfonic acid or ethanesulfonic acid, or the like.
• an inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,
• the desired salt may be prepared by any suitable method known to the art, including treatment of the free acid with an inorganic or organic base, such as an amine (primary, secondary or tertiary), an alkali metal or alkaline earth metal hydroxide or the like.
• an inorganic or organic base such as an amine (primary, secondary or tertiary), an alkali metal or alkaline earth metal hydroxide or the like.
• suitable salts include organic salts derived from amino acids such as glycine and arginine, ammonia, primary, secondary and tertiary amines, and cyclic amines such as piperidine, morpholine and piperazine, and inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum, and lithium.
• references to any active ingredient herein such as reference to a retinoid or to salicylic acid, is intended to encompass all biologically active variants of the specific compounds noted herein, including esters, amides, salts, solvates, and other derivatives.
• compositions for Topical Administration III. Compositions for Topical Administration
• compositions comprising one or more compounds described herein as active agents.
• the compositions used in the methods of the present invention comprise the active compounds, as described above, or acceptable esters, amides, salts, solvates, analogs, or derivatives thereof.
• the active agent compounds described herein can be prepared and delivered together with one or more cosmetically and/or dermatologically acceptable carriers therefore, and optionally, other therapeutic ingredients.
• Carriers should be acceptable in that they are compatible with any other ingredients of the composition and not harmful to the recipient thereof.
• a carrier may also reduce any undesirable side effects of the agent.
• Such carriers or vehicle ingredients are known in the art. See, Handbook of Cosmetic Science and Technology Taylor & Francis Group, 2006, herein incorporated by reference in its entirety.
• compositions for topical administration according to the invention can be for local and/or systemic use, depending upon the active ingredient provided therein and the area and frequency of administration.
• topical formulations could be viewed as describing systemic formulations to the extent an active agent capable of topical systemic administration is included therein.
• compositions for topical administration used in the combinations of the invention can be incorporated into any pharmaceutical, cosmetic, or dermatological preparation customarily used and which may exist in a variety of forms.
• the composition for topical administration may be a solution, a water-in-oil (W/O) type emulsion, an oil-in-water (O/W) type emulsion, or a multiple emulsion, for example a water-in-oil-in-water (W/O/W) or oil-in-water-in-oil (O/W/O) emulsion, a hydrodispersion or lipodispersion, a gel, a cream, a solid stick, or an aerosol.
• W/O water-in-oil
• O/W oil-in-water
• O/W/O oil-in-water-in-oil
• Emulsions in accordance with the present invention are advantageous and comprise, for example, fats, oils, waxes and/or other lipids, as well as water and one or more emulsifiers as they are usually used for such a type of formulation.
• compositions for topical administration according to the invention may be used, for example, as a protective skin cream, cleansing milk, sun protection lotion, nutrient cream, day cream or night cream and the like, depending on their composition.
• compositions for topical administration may comprise cosmetically active ingredients, cosmetic auxiliaries and/or cosmetic additives conventionally used in such preparations.
• cosmetically active ingredients include, for example, antioxidants, preservatives, bactericides, thickeners, fillers, antifoams, fragrances, essential oils, pigments (e.g., fumed silica, microfine pigments such as oxides and silicates including optionally coated iron oxide, titanium dioxide, boron nitride, and barium sulfate), ceramides (either as natural materials or functional mimics of natural ceramides), surfactants, emulsifiers, phospholipids, cholesterol, phytosphingosines, additional active ingredients such as vitamins or proteins (e.g., retinyl palmitate or acetate, Vitamin B as panthenol and its derivatives, Vitamin E as tocopheryl acetate, Vitamin F as polyunsaturated fatty acid esters such as gamma-linolenic acid esters), sunscreen
• the topical compositions of the invention can also comprise one or more additional active agents or materials providing a beneficial effect.
• the topical compositions can comprise a sun protection product.
• These preferably comprise, in addition to the active ingredient used in accordance with the invention, at least one additional UVA filter and/or at least one UVB filter and/or at least one inorganic pigment.
• the UVB filters may be soluble in oil or in water.
• substances which are soluble in oil are, for example: 3-benzylidenecamphor and its derivatives, for example 3-(4-methylbenzylidene)camphor, 4-aminobenzoic acid derivatives, preferably 2-ethylhexyl 4-dimethylaminobenzoate, amyl 4-dimethylaminobenzoate; cinnamic esters, preferably 2-ethylhexyl 4-methoxycinnamate, isopentyl 4-methoxycinnamate; salicylic esters, preferably 2-ethylhexyl salicylate, 4-isopropylbenzyl salicylate, homomethyl salicylate; benzophenone derivatives, preferably 2-hydroxy-4-methoxybenzophenone, 2-hydroxy-4-methoxy-4′-methylbenzophenone, 2,2′-dihydroxy-4-methoxybenzophenone; benzalmalonic esters, preferably di(2-
• Advantageous substances which are soluble in water are: 2-phenylbenzimidazole-5-sulphonic acid and its salts, for example sodium, potassium or triethanolammonium salts, sulphonic acid derivatives of benzophenones, preferably 2-hydroxy-4-methoxybenzophenone-5sulphonic acid and its salts; sulphonic acid derivatives of 3-benzylidenecamphor such as, for example, 4-(2-oxo-3-bornylidene-methyl)benzenesulphonic acid, 2-methyl-5-(2-oxo-3-bornylidenemethyl)sulphonic acid and their salts.
• UVB filters which may be used according to the invention is not intended to be limiting.
• UVA filters examples include dibenzoylmethane derivatives, in particular 1-(4′-tert-butylphenyl)-3-(4′-methoxyphenyl)propane-1,3-dione and 1-phenyl-3-(4′-isopropylphenyl)propane-1,3-dione.
• inorganic pigments examples include oxides of titanium, zinc, iron, zirconium, silicon, manganese, aluminum, cerium and mixtures of these, and modifications where the oxides are the active agents. Especially preferably, they are pigments based on titanium dioxide.
• antioxidants which may be used in accordance with the invention are all those antioxidants which are suitable or conventional for cosmetic and/or dermatological applications.
• the antioxidants are advantageously selected from the group consisting of amino acids (e.g., glycine, histidine, tyrosine, tryptophan) and their derivatives, imidazoles (e.g., urocaninic acid) and their derivatives, peptides such as D,L-carnosine, D-carnosine, L-carnosine and their derivatives (e.g., anserine), carotenoids, carotenes (e.g., ⁇ -carotene, ⁇ -carotene, lycopene) and their derivatives, aurothioglucose, propylthiouracil and other thiols (e.g., thioredoxin, glutathione, cysteine, cystine, cystamine and their glycosyl, N-acetyl, methyl, ethy
• the compositions for topical administration can comprise solvents exemplified by the following: water or aqueous solutions; oils such as triglycerides of capric or caprylic acid, preferably castor oil; fats, waxes and other natural and synthetic lipids, preferably esters of fatty acids with alcohols of low C number, for example with isopropanol, propylene glycol or glycerol, or esters of fatty alcohols with alkanolic acids of low C number or with fatty acids; alcohols, diols or polyols of low C number and their ethers, preferably ethanol, isopropanol, propylene glycol, glycerol, ethylene glycol, ethylene glycol monoethyl ether or ethylene glycol monobutyl ether, propylene glycol monomethyl ether, propylene glycol monoethyl ether or propylene glycol monobutyl ether, diethylene
• the oil phase of the emulsions, oleogels or hydro- or lipodispersions in accordance with the present invention is advantageously selected from the group of the esters of saturated and/or unsaturated, branched and/or unbranched alkanecarboxylic acids with a chain length of 3 to 30 C atoms and saturated and/or unsaturated branched and/or unbranched alcohols with a chain length of 3 to 30 C atoms, from the group of the esters of aromatic carboxylic acids and saturated and/or unsaturated, branched and/or unbranched alcohols with a chain length of 3 to 30 C atoms.
• ester oils may be selected advantageously from the group consisting of isopropyl myristate, isopropyl palmitate, isopropyl stearate, isopropyl oleate, n-butyl stearate, n-hexyl laurate, n-decyl oleate, isooctyl stearate, isononyl stearate, isononyl isononanoate, 2-ethylhexyl palmitate, 2-ethylhexyl laurate, 2-hexyldecyl stearate, 2-octyldodecyl palmitate, oleyl oleate, oleyl erucate, erucyl oleate, erucyl erucate, and synthetic, semisynthetic and natural mixtures of such esters, for example jojoba oil.
• the oil phase may advantageously be selected from the group of the branched and unbranched hydrocarbons and hydrocarbon waxes, the silicone oils, the dialkyl ethers, the group of the saturated or unsaturated branched or unbranched alcohols and of the fatty acid triglycerides, viz. the triglycerol esters of saturated and/or unsaturated, branched and/or unbranched alkanecarboxylic acids with a chain length of 8 to 24, in particular 12-18, C atoms.
• the fatty acid triglycerides may advantageously be selected from the group of the synthetic, semisynthetic and natural oils, for example olive oil, sunflower oil, soya oil, peanut oil, rapeseed oil, almond oil, palm oil, coconut oil, palm kernel oil, and the like. Any mixtures of such oil and wax components may also advantageously be employed in accordance with the present invention. If appropriate, it may also be advantageous to employ waxes, for example cetyl palmitate, as the only lipid component of the oil phase.
• the synthetic, semisynthetic and natural oils for example olive oil, sunflower oil, soya oil, peanut oil, rapeseed oil, almond oil, palm oil, coconut oil, palm kernel oil, and the like. Any mixtures of such oil and wax components may also advantageously be employed in accordance with the present invention. If appropriate, it may also be advantageous to employ waxes, for example cetyl palmitate, as the only lipid component of the oil phase.
• the oil phase is advantageously selected from the group consisting of 2-ethylhexyl isostearate, octyldodecanol, isotridecyl isononanoate, isoeicosan, 2-ethylhexyl cocoate, C 12-15 -alkyl benzoate, caprylic/capric acid triglyceride, dicaprylyl ether.
• Especially advantageous mixtures are those of C 12-15 -alkyl benzoate and 2-ethylhexyl isostearate, those of C 12-15 -alkyl benzoate and isotridecyl isononanoate and those of C 12-15 -alkyl benzoate, 2-ethylhexyl isostearate and isotridecyl isononanoate.
• liquid paraffin, squalane and squalene may advantageously be used according to the present invention.
• the oil phase may furthermore advantageously comprise cyclic or linear silicone oils, or consist entirely of such oils, but it is preferred to use an additional content of another oil phase components, apart from the silicone oil(s).
• Cyclomethicone (octamethylcyclotetrasiloxane) is advantageously employed as silicone oil to be used according to the invention.
• other silicone oils may also be used advantageously in accordance with the present invention, for example hexamethylcyclotrisiloxane, polydimethylsiloxane, poly(methylphenylsiloxane).
• Especially advantageous mixtures are furthermore those of cyclomethicone and isotridecyl isononanoate and of cyclomethicone and 2-ethylhexyl isostearate.
• the aqueous phase of the preparations according to the invention advantageously comprises alcohols, diols or polyols of low C number, and their ethers, preferably ethanol, isopropanol, propylene glycol, glycerol, ethylene glycol, ethylene glycol monoethyl ether or ethylene glycol monobutyl ether, propylene glycol monomethyl ether, propylene glycol monoethyl ether or propylene glycol monobutyl ether, diethylene glycol monomethyl ether or diethylene glycol monoethyl ether and analogous products, furthermore alcohols of low C number, for example ethanol, isopropanol, 1,2-propanediol, glycerol, and, in particular, one or more thickeners which may advantageously be selected from the group consisting of silicon dioxide, aluminum silicates, polysaccharides and their derivatives, for example hyaluronic acid, xanthan gum, hydroxypropylmethyl
• Gels used according to the invention usually comprise alcohols of low C number, for example ethanol, isopropanol, 1,2-propanediol, glycerol and water, or an abovementioned oil in the presence of a thickener, which is preferably silicon dioxide or an aluminum silicate in the case of oily-alcoholic gels and preferably a polyacrylate in the case of aqueous-alcoholic or alcoholic gels.
• a thickener which is preferably silicon dioxide or an aluminum silicate in the case of oily-alcoholic gels and preferably a polyacrylate in the case of aqueous-alcoholic or alcoholic gels.
• Solid sticks comprise, for example, natural or synthetic waxes, fatty alcohols or fatty acid esters.
• Customary basic materials which are suitable for use as cosmetic sticks in accordance with the present invention are liquid oils (for example liquid paraffin, castor oil, isopropyl myristate), semi-solid constituents (for example petrolatum, lanolin), solid constituents (for example beeswax, ceresine and micro-crystalline waxes, or ozocerite) and waxes of high melting point (for example carnauba wax, candelilla wax).
• liquid oils for example liquid paraffin, castor oil, isopropyl myristate
• semi-solid constituents for example petrolatum, lanolin
• solid constituents for example beeswax, ceresine and micro-crystalline waxes, or ozocerite
• waxes of high melting point for example carnauba wax, candelilla wax.
• Suitable propellants for cosmetic and/or dermatological preparations in accordance with the present invention which can be sprayed from aerosol containers are the customary known volatile, liquefied propellants, for example hydrocarbons (propane, butane, isobutane), which may be employed singly or as a mixture with each other. Pressurized air may also be used advantageously.
• hydrocarbons propane, butane, isobutane
• Pressurized air may also be used advantageously.
• FCHCs fluorohydrocarbons and fluorochlorohydrocarbons
• compositions for topical administration in accordance with the present invention can also be in the form of gels comprising not only an effective amount of active ingredient according to the invention and conventionally used solvents therefor, but also organic thickeners.
• thickeners include gum arabic, xanthan gum, sodium alginate, cellulose derivatives, preferably methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, or inorganic thickeners, for example aluminum silicates such as, for example, bentonites, or a mixture of polyethylene glycol and polyethylene glycol stearate or polyethylene glycol distearate.
• an acceptable cosmetic/dermatological formulation containing the above-noted active ingredients can include the following inert ingredients:
• Glyceryl Stearate and PEG-100 Stearate (ARLACEL® 165);
• BHT Butylated hydroxytoluene
• an acceptable cosmetic/dermatological formulation containing the above-noted active ingredients can include the following inert ingredients:
• composition can be prepared by a process, for example, as follows:
• the combinations of the invention are useful in the treatment of several conditions described herein evidenced by damaged skin, and the method typically involves topical administration of the formulations of the invention to a mammal, preferably a human.
• the retinoid/salicylic acid combination of the invention exhibit useful activities for treating a number of skin conditions.
• the present invention provides for improved treatment of such conditions by recognizing the ability of these active ingredients to provide a synergistic result.
• Exemplary skin conditions include acne vulgaris, cystic acne, hyper-pigmentation, hypo-pigmentation, dermal and epidermal hypoplasia and keratoses, wrinkles of the skin as an incident of aging and actinic damage, enlarged pores, surface roughness, ichthyoses (e.g., ichthyosis hystrix, epidermolytic hyperkeratosis, and lamellar ichthyosis), follicular disorders (e.g., pseudofolliculites, senile comedones, nevus comidonicas, and trichostatis spinulosa), benign epithelial tumors (e.g., flat warts, trichoepithelioma, and molluscum contagiosum), perforated dematoses (e.g., elastosis perforans seripiginosa and Kyrles disease), and disorders of keratinization (e.g., Dariers disease,
• the retinoids and salicylic acid of the invention typically provide a localized treatment effect through topical application. Accordingly, in certain embodiments, the present invention is directed to methods of treatment comprising co-administering a retinoid and salicylic acid.
• the composition of the invention and thus the method of treatment, can include multiple retinoids and/or multiple salicylic acid ingredients (e.g., multiple salicylic acid derivatives).
• reference to the combination of a retinoid with salicylic acid is not intended to be limited to merely two active ingredients, but rather encompasses usage of multiple active ingredients within either class of compounds.
• both the retinoid and the salicylic acid are provided in the form of a dermatological or cosmetic composition for topical administration.
• a composition for topical administration is intended to encompass any formulation that can be applied directly to the skin of a patient, particularly to the area of skin suffering from damage that is to be treated.
• the retinoid component and the salicylic acid component can be combined in a single dosage form, such as a single dermatological or cosmetic composition for topical administration.
• the two active ingredients can be in separate formulations and simply co-administered to the patient.
• co-administration refers to administration of both active ingredients simultaneously (either together in same formulation or in separate formulations administered at the same time) or administration of the two active ingredients in close temporal proximity to one another.
• the term temporal proximity is intended to mean that administration of the two active ingredients is sufficiently close in time such that the treatment effects provided by the retinoid at least partially overlap with the treatment effects provided by the salicylic acid.
• treatment effective temporal proximity comprises administering the combination such that the intervening time between administration of the retinoid and administration of the salicylic acid is no more than 24 hours.
• the combination is administered such that the intervening time between administration of the retinoid and administration of the salicylic acid is no more than 20 hours, no more than 18 hours, no more than 16 hours, no more than 14 hours, no more than 12 hours, no more than 10 hours, no more than 8 hours, no more than 6 hours, no more than 4 hours, no more than 2 hours, no more than 1 hour, no more than 45 minutes, no more than 30 minutes, no more than 15 minutes, no more than 10 minutes, or no more than five minutes.
• the above time frames defining temporal proximity can be termed “co-administering” the retinoid and the salicylic acid.
• co-administration can also encompass different numbers of administrations of the components over a given time period.
• the salicylic acid could be administered once per day while the retinoid formulation could be administered multiple times per day.
• the opposite could also be true.
• different permutations of administrations of the formulations comprising the combination are encompassed by the invention in line with the dosages described herein.
• the invention preferably comprises one or more dermatological or cosmetic compositions for topical administration, the compositions comprising a retinoid and salicylic acid.
• the composition is in the form of a lotion, cream, gel, or ointment.
• Such compositions are applied to areas of damaged skin in need of treatment with a frequency suitable to cause treatment or lessening of the damage being treated.
• the topical composition is applied daily. Specifically, the composition may be applied once daily, twice daily, three times daily, four times daily, or more often as necessary to treat the damaged skin.
• a therapeutically effective amount of the combination of active ingredients of the invention may be obtained via administration of a therapeutically effective dose of the components of the combination (i.e., the retinoid compound and the salicylic acid compound).
• a therapeutically effective amount is an amount effective to treat acne.
• the therapeutically effective amount for treating acne is defined as the amount that produces a visible reduction in skin lesions in one week or less following the initiation of treatment.
• the therapeutically effective amount is that which produces a visible reduction in skin lesions in three days following the initiation of treatment.
• a therapeutically effective amount is an amount effective to treat wound, such as a burn, puncture, cut, or abrasion.
• a therapeutically effective amount is an amount effective to treat skin damage related to age.
• the active agents included in the combinations are present in an amount sufficient to deliver to a patient a therapeutic amount of an active ingredient in vivo in the absence of serious toxic effects.
• concentration of active agent in the drug composition will depend on absorption, inactivation, and excretion rates of the drug as well as other factors known to those of skill in the art. It is to be noted that dosage values will also vary with the severity of the condition to be alleviated. It is to be further understood that for any particular subject, specific dosage regimens should be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the combinations, and that the dosage ranges set forth herein are exemplary only and are not intended to limit the scope or practice of the combinations.
• an effective dose of a compound or composition for treatment of any of the conditions or diseases described herein can be readily determined by the use of conventional techniques and by observing results obtained under analogous circumstances.
• the effective amount of the compositions would be expected to vary according to the weight, sex, age, and medical history of the subject. Of course, other factors could also influence the effective amount of the composition to be delivered, including, but not limited to, the specific disease involved, the degree of involvement or the severity of the disease, the response of the individual patient, the particular compound administered, the mode of administration, the bioavailability characteristics of the preparation administered, the dose regimen selected, and the use of concomitant medication.
• the compound is preferentially administered for a sufficient time period to alleviate the undesired symptoms and the clinical signs associated with the condition being treated. Methods to determine efficacy and dosage are known to those skilled in the art. See, for example, Isselbacher et al. (1996) Harrison's Principles of Internal Medicine 13 ed., 1814-1882, herein incorporated by reference.
• a composition for topical administration according to the invention can comprise a retinoid compound in an amount of at least about 0.001% by weight.
• the combinations of the invention comprise a retinoid compound in an amount of about 0.001% to about 20% by weight, about 0.01% to about 10% by weight, about 0.01% to about 5% by weight, about 0.01% to about 2.5% by weight, about 0.01% to about 2% by weight, about 0.01% to about 1.5% by weight, about 0.01% to about 1% by weight, about 0.01% to about 0.75% by weight, or about 0.01% to about 0.5% by weight (e.g., about 0.1% by weight, about 0.2% by weight, about 0.3% by weight, about 0.4% by weight, and about 0.5% by weight).
• a composition for topical administration according to the invention can comprise a salicylic acid compound in an amount of at least about 0.001% by weight.
• the combinations of the invention comprise a retinoid compound in an amount of about 0.001% to about 20% by weight, about 0.01% to about 10% by weight, about 0.01% to about 5% by weight, about 0.03% to about 2.5% by weight, about 0.05% to about 2% by weight, about 0.05% to about 1.5% by weight, about 0.05% to about 1% by weight, or about 0.05% to about 0.75% by weight (e.g., about 0.5% by weight, about 0.6% by weight, about 0.7% by weight, about 0.8% by weight, and about 0.9% by weight).
• the antimicrobial peptide component is present in the composition in an amount of at least about 0.001% by weight. In particular embodiments, the antimicrobial peptide component is present in an amount of about 0.001% to about 20% by weight, about 0.001% to about 10% by weight, about 0.001% to about 5% by weight, about 0.001% to about 2.5% by weight, about 0.001% to about 2% by weight, about 0.001% to about 1.5% by weight, about 0.001% to about 1% by weight, or about 0.001% to about 0.75% by weight. Exemplary amounts include about 0.005% by weight, about 0.01% by weight, about 0.05% by weight, about 0.075% by weight, and about 0.1% by weight.
• the present invention also includes an article of manufacture providing a combination as described herein.
• the article of manufacture can include vials or other containers that contain the combination in forms suitable for use according to the present invention.
• the article of manufacture can comprise a kit including one or more containers with a combination according to the invention.
• the combinations can be delivered in a variety of forms.
• the combination can be provided as a single dosage form comprising both the retinoic component and the salicylic acid component.
• the combination can be provided as multiple dosage forms, each comprising one or more active ingredients, the dosages being intended for administration in combination, in succession, or in other close proximity of time.
• both the retinoid and the salicylic acid can be provided in a form for local, topical application, such as a cream, lotion, or gel, that is provided in a bulk form (i.e., a container including a content of the formulation sufficient for multiple applications) or in a unit dosage form (i.e., a single-use container including a content of the formulation sufficient for a single application, or a single day's applications, to an affected site).
• the article of manufacture further includes instructions in the form of a label on the container, in the form of an insert included in a box in which the container or containers are packaged, or in the form of a computer readable media, describing a method of treatment.
• the instructions can also be printed on the box in which the vial or vials are packaged.
• the instructions contain information such as sufficient dosage and administration information so as to allow the patient or a worker in the field to administer the combination. It is anticipated that a worker in the field encompasses any doctor, nurse, technician, spouse, or other caregiver that might administer the combination.
• the combination can also be self-administered by the patient.
• the first treatment comprised about 0.025% by weight of MDI 403 in a solvent composition comprising about 25% polyethylene glycol 400, about 75% ethanol, and a small amount of BHT.
• the second treatment comprised the same formulation as the first treatment with the exception that MDI 403 was replaced with all-trans retinoic acid.
• Each subject was instructed to apply the topical treatment once per day at night and to discontinue treatment for one to two days if skin irritation occurs.
• Each subject was evaluated at the beginning of the study, after one week of treatment, and after two weeks of treatment. The evaluation including counting of the following facial lesions: open comedones, closed comedones, pustules, and papules. Cook's method was used to grade the acne at each evaluation (See Cook, et al. (1979) Arch. Derm. 115:571-575).
• Tables 1-4 below summarize the percentage reduction at each evaluation point as compared to the baseline evaluation prior to treatment for comedones, pustules, papules, and total acne lesions, respectively. Note that three subjects receiving Treatment No. 2 dropped out of the study within the first seven days due to skin irritation. Accordingly, the data for all-trans retinoic acid is based on a very small sample size and must be evaluated accordingly.
• Lotion 1 contained only salicylic acid (0.5% by weight) as an active ingredient.
• the inactive ingredients were as follows: water, cyclopentasiloxane, dimethyl isosorbide, cetearyl ethylhexanoate, butylene glycol, polysilicone-11, polymethylsilesquioxane, potassium cetyl phosphate, C12-16 alcohols, trimethylol hexyllactone crosspolymer, carnauba wax, fragrance, ceteth-20, glyceryl behenate, hydrogenated lecithin, hydroxyanasatil retinoate, palmitic acid, isohexadecane, ammonium polyacryloyldimethyl taurate, polysorbate 80, sodium cocamidopropyl PG-dimonium chloride phosphate, triethanolamine, caprylyl glycol, phenoxyethanol, hexylene glycol, and BHT.
• Lotion 2 contained benzoyl peroxide (2.5% by weight) as the sole active ingredient.
• the inactive ingredients were as follows: water, cyclomethicone, ethoxydiglycol, propylene glycol, glyceryl stearate, PEG-100 stearate, cetearyl alcohol, dimethicone, panthenol, allantoin, carbomer, ceteareth-20, xanthan gum, triethanolamine, diazolidinyl urea, methylparaben, propylparaben, and fragrance.
• Lotion 3 was an exemplary formulation of the invention, containing both salicylic acid (0.5% by weight) and the retinoid MDI 403 (0.3% by weight) as active ingredients.
• the inactive ingredients were as follows: water, cyclopentasiloxane, dimethyl isosorbide, cetearyl ethylhexanoate, butylene glycol, polysilicone-11, polymethylsilesquioxane, potassium cetyl phosphate, C12-16 alcohols, trimethylol hexyllactone crosspolymer, carnauba wax, fragrance, ceteth-20, glyceryl behenate, hydrogenated lecithin, palmitic acid, isohexadecane, ammonium polyacryloyldimethyl taurate, polysorbate 80, sodium cocamidopropyl PG-dimonium chloride phosphate, triethanolamine, caprylyl glycol, phenoxyethanol, hexylene glycol, and BHT.
• test material Lotion 3 demonstrated a higher percentage decrease in the total number of lesions observed on days 3 (16%), 7 (25%) and 28 (59%), clearly indicating that Lotion 3 is more effective at improving the acne condition when compared with Lotions 1 and 2.
• Lotion 3 demonstrated an almost equal degree of activity against non-inflammatory (Table 5, comedones, 65%) and inflammatory (Table 7, pustules, 67%) acne lesions. While test product Lotion 1 did show activity against non-inflammatory (comedones) and inflammatory (pustules) lesions, an increase in the number of inflamed acne lesions (papules) was observed after 3 days ( ⁇ 16%).
• Lotion 2 performed better in reducing the number of inflammatory (papules and pustules) acne lesions; however, it was the least effective among the three products against non-inflammatory (comedones) lesions and caused an adverse reaction in one test panelist who was discontinued from the study.
• Chromameter data indicated that, over a period of 28 days, all three test products improved skin condition by reducing, to some degree, facial skin erythema (a* value) associated with acne and increased skin lightness (L* value).
• a* value facial skin erythema
• L* value skin lightness
• Example A confirms that the anti-acne activity of a composition comprising MDI 403 alone is also lower than the exemplary combination of MDI 403 and salicylic acid utilized in Example B at every evaluation point, as evidenced by the percentage reduction of comedones, pustules, papules, and overall acne lesions.
• Example A the composition comprising only MDI 403 did not provide significant acne reduction as quickly as the exemplary combination product tested in Example B.
• Treatment No. 1 in Example A produced a lower percentage reduction of papules, pustules, and total lesions after seven days of treatment than Lotion 3 of Example B produced after only three days of treatment.
• neither MDI 403 nor salicylic acid when used singly as an active ingredient in an anti-acne treatment, appears to exhibit an onset of significant anti-acne activity comparable to the inventive formulation used in this study, which demonstrates a synergistic effect attributable to the combination of a retinoid component and a salicylic acid component.
• the combination of the two active ingredients provided a greater overall anti-acne effect than a treatment comprising benzoyl peroxide, a commercially successful anti-acne ingredient.

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