# US 5,702,688 A · Amphoteric compositions and polymeric forms of alpha hydroxyacids, and their therapeutic use

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- Number: US 5,702,688 A
- Document ID: US5702688A
- Status: Granted
- Kind: A
- Application number: 08/135,841
- Filed: 1993-10-07
- Granted: 1997-12-30
- Earliest claimed: 1986-12-23
- Assignees: Tristrata Technology, Inc.
- Inventors: Ruey J. Yu; Eugene J. Van Scott
- Web page: https://patentgrep.com/patent/US5702688A

## CPC

- A61K 8/26: Aluminium; Compounds thereof
- A61K 8/27: Zinc; Compounds thereof
- A61K 8/347: {Phenols}
- A61K 8/362: Polycarboxylic acids
- A61K 8/365: Hydroxycarboxylic acids; Ketocarboxylic acids
- A61K 8/37: Esters of carboxylic acids
- A61K 8/375: {the alcohol moiety containing more than one hydroxy group}
- A61K 8/42: Amides
- A61K 8/43: Guanidines
- A61K 8/494: {with more than one nitrogen as the only hetero atom}
- A61K 8/4953: {containing pyrimidine ring derivatives, e.g. minoxidil}
- A61K 8/4973: {with oxygen as the only hetero atom}
- A61K 8/553: {Phospholipids, e.g. lecithin}
- A61K 8/585: {Organosilicon compounds}
- A61K 8/60: Sugars; Derivatives thereof
- A61K 8/63: Steroids; Derivatives thereof
- A61K 8/671: {Vitamin A; Derivatives thereof, e.g. ester of vitamin A acid, ester of retinol, retinol, retinal}
- A61K 8/675: {Vitamin B3 or vitamin B3 active, e.g. nicotinamide, nicotinic acid, nicotinyl aldehyde (tocopheryl nicotinate A61K8/678)}
- A61K 8/678: {Tocopherol, i.e. vitamin E}
- A61K 8/8152: {Homopolymers or copolymers of esters, e.g. (meth)acrylic acid esters; Compositions of derivatives of such polymers}
- A61K 8/85: Polyesters
- A61K 9/0014: {Skin, i.e. galenical aspects of topical compositions (non-active ingredients are additionally classified in A61K47/00; A61K9/0009, A61K9/0021, A61K9/7015, A61K9/7023 take precedence; cosmetic preparations A61K8/00, A61Q; preparations for wound dressings or bandages A61L26/00)}
- A61K 31/19: Carboxylic acids, e.g. valproic acid (salicylic acid A61K31/60)
- A61K 31/191: having two or more hydroxy groups, e.g. gluconic acid
- A61K 31/192: having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid {(cannabinoids A61K31/658)}
- A61K 31/194: having two or more carboxyl groups, e.g. succinic, maleic or phthalic acid
- A61K 31/195: having an amino group
- A61K 31/20: having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids
- A61K 31/202: having three or more double bonds, e.g. linolenic (eicosanoids, e.g. leukotrienes A61K31/557)
- A61K 31/365: Lactones
- A61K 31/366: having six-membered rings, e.g. delta-lactones
- A61K 31/40: having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K 31/405: Indole-alkanecarboxylic acids; Derivatives thereof, e.g. tryptophan, indomethacin
- A61K 31/415: 1,2-Diazoles
- A61K 31/445: Non condensed piperidines, e.g. piperocaine
- A61K 31/66: Phosphorus compounds
- A61K 31/70: Carbohydrates; Sugars; Derivatives thereof (sorbitol A61K31/047)
- A61K 31/7048: having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin {, digitoxin or digoxin}
- A61K 31/715: Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61K 47/12: Carboxylic acids; Salts or anhydrides thereof
- A61K 47/183: {Amino acids, e.g. glycine, EDTA or aspartame}
- A61K 47/20: containing sulfur, e.g. dimethyl sulfoxide [DMSO], docusate, sodium lauryl sulfate or aminosulfonic acids
- A61K 47/24: containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids
- A61K 47/26: Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
- A61Q 5/006: {Antidandruff preparations}
- A61Q 5/02: Preparations for cleaning the hair
- A61Q 7/00: Preparations for affecting hair growth
- A61Q 15/00: Anti-perspirants or body deodorants (deodorisation of air A61L9/00)
- A61Q 17/00: 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
- A61Q 17/04: Topical preparations for affording protection against sunlight or other radiation; Topical sun tanning preparations
- A61Q 19/00: Preparations for care of the skin
- A61Q 19/007: {Preparations for dry skin}
- A61Q 19/008: {Preparations for oily skin}
- A61Q 19/02: for chemically bleaching or whitening the skin
- A61Q 19/08: Anti-ageing preparations
- A61Q 19/10: Washing or bathing preparations
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61Q: SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS

## Abstract

Preventive as well as therapeutic treatment to alleviate cosmetic conditions and symptoms of dermatologic disorders with amphoteric compositions containing alpha hydroxyacids, alpha ketoacids, related compounds or polymeric forms of hydroxyacids is disclosed. The cosmetic conditions and the dermatologic disorders in which the amphoteric compositions and the polymeric compounds may be useful include dry skin, dandruff, ache, keratoses, psoriasis, eczema, pruritus, age spots, lentigines, melasmas, wrinkles, warts, blemished skin, hyperpigmented skin, kyperkeratotic skin, inflammatory dermatoses, skin changes associated with aging, and skin requiring cleansers.

## Claims

### Claim 1

A composition comprising:
A. a first compound selected from the group consisting of a cosmetic agent and a pharmaceutical agent for topical treatment of dermatological disorders;
B. an amphoteric or pseudoamphoteric agent
wherein said amphoteric or pseudoamphoteric agent comprises at least one member selected from the group consisting of amino acid, dipeptide, creatine, aminoaldonic acid, aminouronic acid, lauryl aminopropylglycine, aminoaldaric acid, neuraminic acid, desulfated heparin, deacetylated hyaluronic acid, hyalobiuronic acid, chondrosine, deacetylated chondroitin, creatinine, cocoamphoglycine, cocoamphopropionate, cocoamphopropylsulfonate, phosphandyl ethanolamine, glycine, alanine, valine, leucine, isoleucine, serine, threonine, cysteine, cystine, methionine, asparagine, glutamine, arginine, lysine, 5-hydroxylysine, histidine, phenylalanine, ryrosine, tryptophan, 3-hydroxproline, 4-hydroxypropoline, proline, homocysteine, homocystine, homoserine, ornithine, citrulline, phosphatidylserine, and sphingomyelin, said amphoteric or pseudoamphoteric agent being present in a concentration effective to form an amphoteric or pseudoamphoteric system with an alpha hydroaxacid, alpha ketoacid or related compound;
C. an alpha hydroxyacid, an alpha ketoacid or a related compound present in a therapeutically effective amount in a pharmaceutically acceptable vehicle for topical treatment of disorders wherein,
said related compound is selected from the group consisting of ascorbic acid, quinic acid, isocitric acid, tropic acid, trethocanic acid, 3-chlorolactic acid, cerebronic acid, citramalic acid, agaricic acid, 2-hydroxynervonic acid, aleuritic acid and pantoic acid,
wherein said alpha hydroxyacid is at least one member selected from the group consisting of alkyl alpha hydroxyacid, aralkyl alpha hydroxyacid, aryl alpha hydroxyacid, polyhydroxy alpha hydroxyacid and polycarboxylic alpha hydroxyacid having the following structure: ##STR1## wherein Ra is H, F, Cl, Br, alkyl, aralkyl or aryl group of saturated or unsaturated, isomeric or nonisomeric, straight or branched chain, having 1 to 25 carbon atoms, or cyclic form having 5 or 6 ring members, and in addition Ra may carry OH, CHO, COOH and alkoxy group having 1 to 9 carbon atoms, said alpha hydroxyacid existing as a free acid or lactone form, or in salt form with an organic base or an inorganic alkali, and as stereoisomers as D, L, and DL forms when Ra and Rb are not identical,
said alpha ketoacid being at least one member selected from a group of compounds represented by the following chemical structure: ##STR2## wherein Ra and Rb are H, alkyl, aralkyl or aryl group of saturated or unsaturated, isomeric or nonisomeric, straight or branched chain, having 1 to 25 carbon atoms, or cyclic form having 5 or 6 ring members, and in addition Ra may carry F, Cl, Br, I, OH, CHO, COOH and alkoxy group having 1 to 9 carbon atoms, said alpha ketoacid existing as a free acid or ester form, or in salt form with an organic base or an inorganic alkali; and
wherein said composition has a pH less than or equal to 4.2.

### Claim 2 (depends on 1)

The composition of claim 1 wherein said cosmetic or pharmaceutical agent is selected from the group consisting of agents that improve or eradicate age spots, keratoses and wrinkles; analgesics; anesthetics; antiacne agents; antibacterials; antiyeast agents; antifungal agents; antiviral agents; antidandruff agents; antidermatitis agents; antipruritic agents; antimotionsickness agents; antiinflammatory agents; antihyperkeratolytic agents; antidry skin agents; antiperspirants; antipsoriatic agents; antiseborrheic agents; hair conditioners and treatments; antiaging and antiwrinkle agents; antiasthmatic agents and bronchodilators; sunscreen agents; antihistamine agents; skin lightening agents; depigmenting agents; vitamins; corticosteriods; tanning agents; hormones; retinoids; and topical cardiovascular agents or dermatologicals.

### Claim 3 (depends on 1)

The composition of claim 1 wherein said cosmetic or pharmaceutical agent is selected from the group consisting of clotrimazole, ketoconazole, miconazole, griseofulvin, hydroxyzine, diphenhydramine, pramoxine, lidocaine, procaine, mepivacaine, hydroquinone, menobenzone, erythromycin, tetracycline, clindamycin, melocycline, minocycline, naproxen, ibuprofen, theophylline, cromolyn, albuterol, retinoic acid, 13-cis retinoic acid, hydrocortisone, hydrocortisone 21-acetate, hydrocortisone 17-valerate, hydrocortisone 17-butyrate, betamethasone dipropionate, triamcinolone acetonide, fluocinonide, clobetasol propionate, benzoyl peroxide, crotamiton, propranolol, promethazine, vitamin A palmitate and vitamin E acetate.

### Claim 4 (depends on 1)

The composition of claim 1 wherein said amphoteric or pseudoamphoteric agent is selected from the group consisting of glycine, alanine, valine, leucine, isoleucine, serine, threonine, cysteine, cystine, methionine, asparagine, glutamine, arginine, lysine, 5-hydroxylysine, histidine, phenylalanine, tyrosine, tryptophan, 3-hydroxyproline, 4-hydroxyproline, proline, homocysteine, homocystine, homoserine, ornithine, citrulline, creatine, aminoaldonic acids, aminouronic acids, aminoaldaric acids, lauryl aminopropylglycine, neuraminic acid, desulfated heparin, deacylated hyaluronic acid, halobiuronic acid, chondrosine, deacylated chondroitin, creatinine, 2-aminobutanoic acid, 4-aminobutanoic acid, 2-amino-2-methylpropanoic acid, 2-methyl-3-aminopropanoic acid, theanine, phenylglycine, canavanine, canaline, 4-hydroxyarginine, 4-hydroxyornithine, 2,4-diaminobutanoic acid, 2,3-diaminopropanoic acid, 2,6-diaminopimelic acid, 2-amino-3-phenylbutanoic acid, taurine, methionine sulfoxide, methionine sulfone, 3,5-diiodotyrosine, thyroxine, monoiodotyrosine, pipecolic acid, 4-aminopipecolic acid, 4-methylproline, glycylglycine, carnosine, anserine, ophidine, homocamosine, .beta.-alanylarginine, glutathione, ophthalmic acid, norophthalmic acid, cocoamphoglycine, cocoamphopropionate, cocoamphopropylsulfonate, phosphatidyl ethanolamine, phosphatidyl serine, and shingomyeline.

### Claim 5 (depends on 1)

The composition of claim 1 wherein said alkyl alpha hydroxyacid is selected from the group consisting of 2-hydroxyethanoic acid (glycolic acid), 2-hydroxypropanoic acid (lactic acid), 2-methyl 2-hydroxypropanoic acid (methyllactic acid), 2-hydroxybutanoic acid, 2-hydroxypentanoic acid, 2-hydroxyhexanoic acid, 2-hydroxyheptanoic acid, 2-hydroxyoctanoic acid, 2-hydroxynonanoic acid, 2-hydroxydecanoic acid, 2-hydroxyundecanoic acid, 2-hydroxydodecanoic acid (alpha hydroxylauric acid), 2-hydroxytetradecanoic acid (alpha hydroxymyristic acid), 2-hydroxyhexadecanoic acid (alpha hydroxypalmitic acid), 2-hydroxyoctadecanoic acid (alpha hydroxystearic acid), and 2-hydroxyeicosanoic acid (alpha hydroxyarachidonic acid).

### Claim 6 (depends on 1)

The composition of claim 1 wherein said aralkyl and aryl alpha hydroxyacid is selected from the group consisting of 2-phenyl 2-hydroxyethanoic acid (mandelic acid), 2,2-diphenyl 2-hydroxyethanoic acid (benzilic acid), 3-benzyl 2-hydroxypropanoic acid (phenyllactic acid), 2-phenyl 2-methyl 2-hydroxyethanoic acid (atrolactic acid), 2-(4'-hydroxyphenyl) 2-hydroxyethanoic acid, 2-(4'-chlorophenyl) 2-hydroxyethanoic acid, 2-(3'-hydroxy-4'-methoxyphenyl) 2-hydroxyethanoic acid, 2-(4'-hydroxy-3'-methoxyphenyl) 2-hydroxypropanoic acid, 3-(4'-hydroxyphenyl) 2-hydroxypropanoic acid, and 2-(3',4'-dihydroxyphenyl) 2-hydroxyethanoic acid.

### Claim 7 (depends on 1)

The composition of claim 1 wherein said polyhydroxy alpha hydroxyacid or polycarboxylic alpha hydroxyacid is selected from the group consisting of 2,3-dihydroxypropanoic acid (glyceric acid), 2,3,4-trihydroxybutanoic acid and isomers erythronic acid and threonic acid 2,3,4,5-tetrahydroxypentanoic acid and isomers ribonic acid, arabinoic acid, xylonic acid and lyxonic acid), 2,3,4,5,6-pentahydroxyhexanoic acid and isomers allohio acid, altronic acid gulonic acid, idonic acid, galactonic acid and talonic acid, 2,3,4,5,6,7-hexahydroxyheptanoic acid and isomers glucoheptonic acid and galactoheptonic acid, 2-hydroxypropane-1,3-dioic acid (tartronic acid), 2-hydroxybutane-1,4-dioic acid (malic acid), 2,3-dihydroxybutane-1,4-dioic acid (tartaric acid), 2-hydroxy-2-carboxypentane-1,5-dioic acid (citric acid), 2,3,4,5-tetrahydroxyhexane-1,6-dioicacid and isomers saccharic acid and mucic acid, or lactone forms gluconolactone, galactonolactone, glucuronolactone, galacturonolactone, gulonolactone, ribonolactone, sasaccharic acid lactone, pantoyllactone, glucoheptonolactone, mannonolactone and galactoheptonolactone.

### Claim 8 (depends on 1)

The composition of claim 1 wherein said alpha ketoacid is a member selected from the group consisting of 2-ketoethanoic acid (glyoxylic acid), 2-ketopropanoic acid (pyruvic acid), 2-phenyl-2-ketoethanoic acid (benzoylformic acid), 3-phenyl-2-ketopropanoate (phenylpyruvic acid), 2-ketobutonic acid, 2-ketopentonic acid, 2-ketohexonic acid, 2-ketoheptonic acid, 2-ketooctonic acid and 2-ketododecanoic acid.

### Claim 9 (depends on 1)

The composition of claim 1 wherein said dermatological disorders are selected from one or more of the group consisting of dry skin, zerosis, ichthyosis, dandruff, brownish spots, keratoses, melasma, lentigines, age spots, liver spots, pigmented spots, wrinkles, blemishes, skin lines, oily skin, acne, warts, eczema, pruritic skin, psoriasis, inflammatory dermatoses, disturbed keratinization, sun damage, skin changes associated with aging, nail requiring cleansers, skin requiring cleansers, conditioning or treatment, hair requiring conditioning, and hair requiring shampooing.

### Claim 10 (depends on 2, 3, 4, 5, 7, 8, 9)

The composition of any one of claims 2, 3, 4, 5, 7, 8, 9, or 1, wherein said composition has a pH less than or equal to 4.0.

### Claim 11 (depends on 1, 2, 3, 4, 5, 7, 8, 9)

A method of treatment to alleviate a dermatological disorder comprising administering to a patient in need a therapeutically effective amount of a composition according to any of claims 2, 3, 4, 5, 7, 8, 9 and 1.

### Claim 12 (depends on 11)

The method of claim 11, wherein said composition has a pH less than or equal to 4.0.