CA1340120C - Hydroxyacids for topical treatment of wrinkles and skin changes associated with aging - Google Patents

Abstract

Composition and method for enhancing therapeutic effects of topically applied agents are disclosed. The cosmetic or therapeutic composition may include one or more of cosmetic or pharmaceutical agents present in a total amount of from 0.01 to 40 percent and one or more of hydroxycarboxylic acids or related compounds present in a total amount of from 0.01 to 99 percent by weight of the total composition. The cosmetic and pharmaceutical agents may include but not limited to age spots, wrinkles and keratoses removing agents: vitamins; aloes; sun screens; tanning, depigmenting and shampooing agents; antiyeasts; antifungal, antibacterial and antiviral agents; topical bronchial dilators and topical cardiovascular agents; hormonal agents; vasodilators;
retinoids and other dermatological agents. The hydroxycarboxylic acids and related compounds include organic alpha and beta hydroxycarboxylic acids, alpha and beta ketocarboxylic acids and salts thereof. Topical application of the cosmetic or therapeutic composition has been found to achieve a substantial increase in cosmetic or therapeutic effect of the active ingredient in humans and domesticated animals.

Description

Thls ls a dlvlslonal applicatlon of appllcatlon No.
549,964 flled October 22, 1987.
The lnvention of the parent appllcatlon relates generally to method and composltlon contalnlng hydroxyacld or related compound for enhanclng therapeutlc effects of cosmetlc or pharmaceutlcal agent. As wlll be subsequently descrlbed ln detall, we lnltlally dlscovered that alpha hydroxy or keto aclds and thelr derlvatlves were effectlve ln the toplcal treatment of dlsease condltlons such as dry skln, lchthyosls, eczema, palmar and plantar hyperkeratoses, dandruff, acne and warts.
We have now dlscovered that hydroxyaclds or related compounds whereln lncorporated lnto a therapeutlc composltlon can substantlally enhance toplcal effects of cosmetlc and pharmaceutlcal agents.
The lnventlon of thls appllcatlon relates to use of a therapeutlcally or prophylactlcally effectlve amount of a toplcally appllcable therapeutlc or prophylactlc composltlon comprlslng at least one hydroxycarboxyllc acld as a free acld or salt form and a pharmaceutlcally or cosmetlcally acceptable vehlcle ln treatment of flne or coarse wrlnkles, or skln changes assoclated wlth aglng selected from flne llnes, skln llnes, deepenlng of skln llnes, thlnnlng of skln, plgmented age spots and leslons, coarse skln, rough skln, blemlshes, blotches, xerosls, ltchlng skln, loss of skln elastlclty and recollablllty, and old-looklng skln.

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- 1~4~120 The lnventlon of further dlvlslonal appllcatlon 617,036 relates to a prophylactlc and therapeutlc composltlon effectlve agalnst acne and for olly skln and as skln cleanser comprlsing an effectlve amount of benzlllc acld ln a pharmaceutlcally acceptable vehlcle for toplcal appllcatlon to skln of human or anlmal body.
In our prlor U.S. Patent No. 3,879,537 entltled "Treatment of Ichthyoslform Dermatoses", we descrlbed and clalmed the use of certaln alpha hydroxy aclds, alpha keto aclds and related compounds for toplcal treatment of flsh-scale llke lchthyotlc condltlons ln humans. In our U.S.
Patent No. 3,920,835 entltled "Treatment of Dlsturbed Keratlnlzatlon", we descrlbed and clalmed the use of these certaln alpha hydroxy aclds, alpha keto aclds and thelr derlvatlves for toplcal treatment of dandruff, acne, and palmar and plantar hyperkeratosls.
In our prlor U.S. Patent No. 4,105,783 entltled "Treatment of Dry Skln", we descrlbed and clalmed the use of alpha hydroxy aclds, alpha keto aclds and thelr derivatlves for toplcal treatment of dry skln. In our recent U.S. Patent No. 4,246,261 entltled "Addltlves Enhanclng Toplcal Cortlcosterold Actlon", we descrlbed and clalmed that alpha hydroxy aclds, alpha keto aclds and thelr derlvatlves, ln small amounts could greatly enhance the therapeutlc efflcacy of cortlcosterolds ln toplcal treatment of psorlasls, eczema, seborrhelc dermatltls and other lnflammatory skln condltlons.

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In our more recent U.S. Patent No. 4,363,815 entitled nAlpha Hydroxy acids, Alpha Keto acids and Their Use in Treating Skin Conditions: we described and claimed that alpha hydroxy acids and alpha keto acids related to or originating from amino acids, whether or not found in proteins, were effective in topical treatment of skin disorders associated with disturbed keratinization or inflammation. These skin disorders include dry skin, ichthyosis, palmar and plantar hyperkeratosis, dandruff, Darier's disease, lichen simplex chronicus, keratoses, acne, psoriasis, eczema, pruritus and possibly warts and herpes.
In our most recent U.S. Patent No. 4,518,789 entitled ~Phenyl Alpha-Acyloxyacetamide Derivatives and Their Therapeutic Use~ we described and claimed that phenyl alpha acyloxyacetamide derivatives in topical or systemic administration were useful and effective for pruritus, atopic dermatitis, eczema, psoriasis, acne, dry skin, dandruff, malodors of integumental areas, various aches, pains and discomforts of skin, joints and other body parts in humans and domestic animals.
The intact skin of humans is a very effective barrier to many natural and synthetic substances. Cosmetic and pharmaceutical agents may be pharmacologically effective by systemic administration, but many of them are much less or totally ineffective on topical application to the skin. Topical effectiveness of a pharmaceutical agent depends on two ma;or factors a) Percutaneous absorption and penetration b) Bioavailability of the penetrated ph~rmaceutical agent to the target site in the skin. To be therapeutically effective as a topical agent a pharmaceutical drug must penetrate the stratum corneum into the epidermal layers, distributed and bioavailable 13~ 12~J

to the target sites for pharmacologic action. Many pharma-cologic agents can readily penetrate the skin but they are not bioavailable to the target sites in the skin, therefore therapeutic effect is minimal and ineffective.
It has now been discovered that hydroxyacids and related compounds including those described or not described in our previous patents and additional compounds can substantially enhance the therapeutic efficacy of cosmetic and pharmaceutical agents in topical treatment of cosmetic conditions, dermatologic disorders or other afflictions. The topical treatment means topical application to the skin of humans and animals other than through a mucous membrane (such as rectal or nasal application) and a pour-on composition (that is often applied to animals) is excluded. Cosmetic and pharmaceutical agents may include any chemical substances natural or synthetic, intended for topical application to the skin or its appendages in human and animals. Some examples of cosmetic and pharmaceutical agents include age spots and keratoses removing agents, analgesics, anesthetics, antiacne agents, antibacterials, antiyeast agents, antifungal agents, antiviral agents, antiburn agents, anti-dandruff agents, antidermatitis agents, antipruritic agents, antiperspirants, antiinflammatory agents, antihyperkeratolytlc agents, antidryskin agents, antipsoriatic agents, antiseborrheic, agents, astringents, softeners, emollient agents, coal tar, bath oils, sulfur, rinse conditioners, foot care agents, fungicides, hair growth promoters, hair removers, keratolytic agents, moisturizer agents, powder, shampoos, skin bleaches, skin protectants, soaps, cleansers, antiaging agents, sunscreen agents, wart removers, wet dressings, vitamins, tanning agents, topical antihistamin agents, hormones, vasodilators, retinoids, 1~0 12~

bronchial dilators, topical cardiovascular agents and other dermatologicals. Further excluded from the invention of the parent application is a combination of lactic acid as the hydroxyacid and nicardipine hydrochloride as the cosmetic or pharmaceutical agent.
In this invention among preferred active compounds useful in therapeutic compositions for preventing or treating undesirable skin conditions and disorders by topical application to the skin as described above are:
citramalic acid, diphenyl 2-hydroxyacetic acid (benzilic acid), 2-phenyl 3-hydroxypropanoic acid (tropic acid), aleuritic acid, ribonic acid, ribonoloactone, 2,3,4-trihydroxybutanoic acid, 2,3,4,5-tetrahydroxypentanoic acid, 2,3,4,5,6-pentahydroxyhexanoic acid, 2-hydroxylauric acid, 2,3,4,5,6,7-hexahydroxyheptanoic acid, 4-hydroxymandelic acid, 4-chloromandelic acid, 2-hydroxy-3-methyl-butanoic acid, 2-hydroxy-4-methylpentanoic acid, 3-hydroxy-4-methoxymandelic acid, 4-hydroxy-3-methoxymandelic acid, 3-(3-hydroxyphenyl) lactic acid, 3-(4-hydroxyphenyl) lactic acid, hexahydromandelic acid, 3-hydroxy-3-methylpentanoic acid, 1-hydroxy-1-cyclopropane carboxylic acid, 4-hydroxybutanoic acid, 2-hydroxyhexanoic acid, 5-hydroxylauric acid, 12-hydroxylauric acid, 10-hydroxydecanoic acid, 16-hydroxyhexadecanoic acid, 4-hydroxydecanoic acid, 5-hydroxydecanoic acid, and 4-hydroxy-2,2-diphenylbutanoic acid as a free acid or salt form.

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1~ The c..hs~ai..~ compounds of the instant invention are hydroxycarboxylic acids and related compounds. There are three group~ of ~uch hydroxyacids. The first is hydroxymonocarboxylic acids having the following chemical structure:
Rl (CR20H)m(CH2)n COOH

wherein Rl, R2 -H, alkyl, aralkyl or aryl group of saturated or un~aturated, ~traight or branched chain or cyclic form, having 1 to 25 carbon atom~.
m-l, 2, 3, 4, 5, 6, 7, 8 or 9 n-0 or a numerical number up to 23 When n=0 and m=l or more, the hydroxymonocarboxylic acid is also called aldonic acid. The name comes from a carbohydrate, aldose, which may be oxidized to aldonic acid by the oxidation of the aldehyde group in aldose to the carboyxlic group.
The hydroxymonocarboxylic acid may be present as a free acid, lactone, or salt form. The lactone form could be either inter or intramolecular lactone, however, most common one~ are intramolecular lactones with a ring structure formed by elimination of one or more water molecules between a hydroxy group and the carboxylic group. Since the hydroxymonocarboxylic acid~ are organic in nature, they may form a salt or a complex with an inorganic or organic base ~uch as ammonium hydroxide, sodium or potas~ium hydroxide, or triethanolamine.
The hydroxymonocarboxylic acld and its related compounds may also exist a~ stereoisomers such as D, L, and DL forms.

1 ~ ~ O 1 2 3 ._ The typical alkyl, aralkyl and aryl groups for R1 and R2 include methyl, ethyl, propyl, i~opropyl, benzyl and phenyl. The hydrogen atoms of the Rl and R2 and (CH2)n may be substituted by a nonfunctional element such as F, Cl, Br, I, S or a radical such a~ a lower alkyl or alkoxy, ~aturated or unsaturated, having 1 to 9 carbon atom~. Representative hydroxymonocarboxylic acids are li~ted below: -1. 2-Hydroxyacetic acid (Glycolic acid) Rl=H, R2-H, m=l, n=O
2. 2-Hydroxypropanoic acid (Lactic acid) Rl~CH3, R2=H, m=l, n=o 3. 2-Methyl 2-hydroxypropanoic acid (Methyllactic acid) 1 CH3~ R2=CH3, m=l, n=o 4. 2-Hydroxybutanoic acid Rl-C2H5~ R2=H, m=l, n=o 5. Phenyl 2-hydroxyacetic acid (Mandelic acid) 1 6H5, R2 H, m 1, n o 6. Phenyl 2-methyl 2-hydroxyacetic acid (Atrolactic acid) 1 C6Hs~ R2 CH3, m~l, n=o 7. 3-Phenyl 2-hydroxypropanoic acid (Phenyllactic acid) Rl C6H5, R2-H, m~l, n-l 8. 2,3-Dihydroxypropanoic acid (Glyceric acid) Rl-H, R2-H, m-2, n-O

9. 2, 3, 4-TrihydL~xy~Lanoic acid Rl H, R2-H, m-3, n~o 10. 2, 3, 4, S-Tetrahyd~oxy~entanoic acid Rl-H, R2-H,m-4, n~O

11. 2, 3, 4, S, 6-Pentahydroxyhenxanoic acid Rl-H, R2-H, m~S, n-O

i 3 ~ 2 3 -12. 2-Hydroxydodecanoic acid (alpha hydroxylauric acid) Rl CloH21~ R2=H, m=l, n=o 13. 2, 3, 4, S, 6, 7-Hexahydroxyheptanoic acid Rl-H, R2-H, m=6, n=o 14. Diphenyl 2-hydroxyacetic acid (benzilic acid) 1 C6H5' R2=C6H5~ m=l, n=o 15. 4-Hydroxymandelic acid Rl-C6H4(OH), R2=H, m=l, n=o 16. 4-Chloromandelic acid Rl~C6H4(Cl), R2=H, m-l, n=o 17. 3-Hydroxybutanoic acid Rl~CH3, R2~H, m-l, n~l 18. 4-Hyd-oxybutanoic acid Rl-H, R2-H, m=a, n~2 19. 2-Hyd~oxyh~xanoic acid 1 C4Hg, R2 H, m 1, n 0 20. 5-Hydroxydodecanoic acid Rl'C7Hls~ R2~H, m-l, n-3 21. la-Hydroxydodecanoic acid - --Rl-H, R2-H, m~l, n~l0 22. 10-Hyd~G~yd~-noic acid Rl-H, R2-H, ~--1, n-8 23. 16-Hydroxyhexadecanoic acid Rl H, R2-H, m-l, n-14 24. 2-Hydroxy-3-methylbutanoic acid Rl-C3H7, R2~H, m-l, n-o 25. 2-hyd~o~y-4-methylpentanoic acid Rl-C4Hg, R2-H, m~l, n-o 26. 3-Hydroxy-4-methoxymandelic acid ) 1 2 3 Rl-C6H3 (OH) (OCH3), R22H, m=l, n=o 27. 4-Hydroxy-3-methoxymandelic acid Rl=C6H3 (OH) (OCH3), R2=H, m=l, n=o 28. 2-Hydroxy-2-methylbutanoic acid Rl C2H5~ R2~CH3, m=l, n=o 29. 3-(2'Hydroxyphenyl) lactic acid Rl=C6H4(0H) CH2, R2=H, m=l, n=o 30. 3-(4-Hydroxyphenyl) lactic acid Rl=C6H4(0H) CH2, R2=H, m=l, n=O

31. Hexahydromandelic acid 1 C6Hll~ R2=H, m-l, n=o 32. 3-Hydroxy-3-methylpentanoic acid 1 C2Hs~ R2~CH3, m-l, n=l 33. 4-Hydroxydeeanoie aeid 1 C6H13~ R2SH, m-l, n=2 34. 5-Hydroxydeeanoie aeid Rl CsHll~ R2eH, m=l, n=3 35. Aleuritie aeid Rl-C6H12(0H), R2-H, m-2, n=7 The linear laetie aeid polymer is an intermoleeular lactone formed by elimination of one water moleeule between the hydroxy group of one moleeule of laetie aeid and the earboxylie group of a seeond moleeule of laetie aeid. The common linear lactic acid polymer may eontain 3 laetie aeid units.
Ribonie aeid i~ one of the stereoisomers of 2, 3, 4, 5-tetrahydroxypentanoic aeid, and the corresponding lactone is ribonolaetone. Glueonie aeid, galactonie acid, gulonic acid and mannonic aeid are typical 2, 3, 4, 5, 6-pentahydroxyhexanoic 134~ 12i~
-acids and thelr co~esponding lactone~ are gluconolactone, galactonolactone, gulonolactone and mannonolactone respectively.
The related compounds of hydroxymonocarboxylic acids are ketomonocarboxylic acids which are formed from the former by a oxidation reaction or in vivo by a dehydrogenase enzyme. For example, 2-ketopropanoic acid (pyruvic acid) and 2-hydroxypropanoic acld (lactic acid) are converted to each other in vivo by the enzyme, lactate dehydrogenase. Although pure pyruvic acid (liquid form) can be kept in a refrigerator for an extended period of time a ~_ ,osition containing pyruvic acid for topical use is not very stable at an elevated temperature.
Therefore, for practical purposes pyruvic acid esters are used instead.
The ~e~eaentatlve esters are methyl pyruvate, ethyl pyruvate, propyl pyruvate and isopropyl pyruvate. Other repre~entative ketomonocarboxylic acids and their esters are phenyl pyruvic acid and its ester~ such as methyl phenyl pyruvate, ethyl phenyl pyruvate and propyl phenyl pyruvate;
formyl formic acid ~2-ketoacetic acid) and its esters such as methyl, ethyl and propyl formyl formate: benzoyl formic acid and its esters such as methyl, ethyl and propyl benzoyl formate;
4-hydloxyb~l~zoyl~ormic acid and its esters: 4-hydroxyphenyl-pyruvic acid and its esters: 2-hydroxyphenylpyruvic acid and its esters.
Many hydroxy or ketomonocarboxylic acids are structurally related to amino acids either naturall-y occurring in proteins or not. For example alanine and pyruvlc acid are interconverted to each other in vlvo by an enzyme alanine dehydrogenase or alanine ketoglutarate transaminase. As mentioned earlier pyruvic acid 13~0120 and lactic acid are interconverted to each other in vivo by the enzyme lactate dehydrogenase. Therefore, alanine, pyruvic acid and lactic acid are chemically related in that the amino group of alanine may be converted to the keto group of pyruvic acid or the hydroxy group of lactic acid. The same relationships may apply to formyl for~ic acid and glycolic acid to glycine; hydroxpyruvic acid and glyceric acid to serine: phenyl pyruvic acid and phenyl lactic acid to phenylalanine; 2-keto- and 2-hydroxy-4 (methylthio) butanoic acids to methionine.
The second kind of hydroxyacid is hydroxydicarboxylic acid having the following chemical ~tructure:

( fH2 ) nCOOH
(CHOH)mCOOH

wherein m-l, 2, 3, 4, 5, 6, 7, 8 or 9 n~O or a numerical number up to 23 The hydroxydicarboxylic acid may al~o be present as a free acid, lactone or salt form. The lactone form could be either inter or intramolecular lactone. However, the common lactone is an intramolecular lactone with a ring ~tructure formed by eliminatlon of one or more water molecule between a hydroxy group and one of the carboxylic ytou~s. Since the hydroxydicarboxylic acid i8 organic in nature, it may form a salt or a complex with an inorganic or organic base such a~ ammonium hydroxide. sodium or pota~sium hydroxide, or triethanolamine.
The hydroxydicarboxylic acid and its related compounds may al~o exi~t a~ stereoi~omer~ ~uch as D, L, DL and meso forms.

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The hydrogen atom attached to the carbon atom may be .cub~tituted by a nonfunctional element such as F, Cl, Br, I, S or a radical such a~ a lower alkyl or alkoxy of saturated or unsaturated, having 1 to 9 carbon atoms.
When n=O and m=l or more, the hydroxydicarboxylic acid is also called aDdaric acid. The name comes from the carbohydrate, and the common ones are saccharic acid and galactaric acid.
~epresentative hydroxydicarboxylic acid~ are listed below:
1. 2-Hydroxypropanedioic acid (Tartronic acid) m-l, n=o 2. 2-Hyd~Gxy~utanedioic acid (Malic acid) m-l, n-l 3. Erythrarlc acid and Threaric acid (Tartaric acid) m-2, n~O
4. Arablraric acid, Ribaric acid, Xylaric acid and Lyxaric acid m-3, n-O
5. Glucaric acid (saccharic acid), Galactaric acid (Mucic acid), Mannaric acid, Gularic acid, Allaric acid, Altraric acid, Idaric acid and Talaric acid m-4, n~O
Commercially available saccharolactone (D-saccharic acid 1, 4-lactone) is an intramolecular lactone formed by elimination of one water molecule between the hydroxy group at position 4 and the carboxylic group at position 1.
The third type of hydroxyacid is a miscellaneous group of compoul.do which i~ not readily represented by the above generic structure of either the first type or the second type. Included in the third type of hydroxyacids are th~ following:

Hydroxycarboxylic acid of R (OH)m (COOH)n Wherein m,n = 1,2,3,4,5,6,7,8,or 9 R=H, alkyl, aralkyl or aryl group of saturated or unsaturated, straight or branched chain or cyclic form, having 1 to 25 carbon ~toms, citric acid, isocitric acid, citramalic acid, agaricic acid (n-hexadecylcitric acid), quinic acid, uronic acids including glucuronic acid, glucuronolactone, galacturonic-acid, galacturonolactone, hydroxypyruvic acid, hydroxypyruvic acid phosphate, ascorbic acid, dihydroascorbic acid, dihydroxytartaric acid, 2-hydroxy-2-methylbutanoic acid, 1-hydroxy-1-cyclopropane carboxylic acid, 2-hydroxyhexanedial, 5-hydroxylysine, 3-hydroxy-2-aminopentanoic acid, tropic acid, 4-hydroxy-2, 2-diphenylbutanoic acid, 3-hydroxy-3-methylglutaric acid, and 4-hydroxy-3-pentenoic acid.
The third type of hydroxyacid may also be present a~ a free acid, lactone or salt form. The lactone form could be either an inter or intramolecular lactone, however, mo~t common are intramolecular lactones with a ring structure. Commonly known glucuronolactone is a r-lactone i.e. 1,4-lactone of intramolecular typo.
The hydroxyacid of the third type may also exist as stereoisomers such as D, L, DL and meso forms. The hydrogen atom attached to the carbon atom may be substitùted by a nonfunctional element such a~ P, Cl, Br, I, S or a radical such as a lower alkyl or alkoxy of saturated or unsaturated, having 1 to 9 carbon atom~.

~3413 l~D

Any hydroxyacid and related compound of the above three kinds may be used a~ an additive in a combination composition to enhance the percutaneous penetration or the therapeutic efficacy of co~metic and pharmaceutical agents. The cosmetic and pharmaceutical agents may include but not limited to: age spots and keratoses ~emoving agents, vitamins, aloe~, retinoids, sun screens; tanning, depigmenting and shampooing agents;
antiperspirant~, antiyeasts, antifungal, antibacterial and antiviral agent~; topical bronchial dilators; topical cardiovascular agents; kerato~es, age spots and wrinkles removal agents, hair growth promoting agents and other dermatological agents.
Hydroxyacids and related compounds may also be used alone in the prophylactic and therapeutic treatment of cosmetic conditions or dermatologic disorders characterized by disturbed keratinization, aging, lipid metabolism or inflammation. The repre~entative hydroxyacids are listed below:
citramalic acid, tropic acid, benzilic acid, ribonic acid and ribonolactone, gulonic acid and gulonolactone, 2,3,4-trihydroxybutanoic acid, 2,3,4,5-tetrahydroxypentanoic acid, 2,3,4,5,6-pentahydroxyhexanoic acid, 2-hydroxylauric acid, 2,3,4,5,6,7-hexahydroxyheptanoic acid, aleuritic acid, 4-hydroxymandelic acid, 4-chloromandelic acid, 2-hydroxy-3-methylbutanoic acid, 2-hydroxy-4-methylpentanoic acid, 3-hydroxy-3-methylbutanoic acid, 2-hydroxy-4-methylpentanoic acid, 3-hydroxy-4-methoxymandelic acid, 4-hydroxy-3-methoxymandelic acld, 3-(2-hyd~xy~hcnyl) lactlc acid, 3-(4-hydroxyphenyl) lactic acid, hexahydromandelic acid, 3-hydroxy-3-methylpentanoic acid, l-hydroxy-l-cyclopropane carboxylic acid, 4-hydroxybutanoic acid, 13'~123 2-hydroxyhexanoic acid, 5-hydroxylauric acid, 12-hydroxylauric acid, 10-hydroxydecanoic acid, 16-hydroxyhexadecanoic acid, 4-hydroxydecanoic acid, 5-hydroxydecanoic acid, and 4-hydroxy-2, 2-diphenylbutanoic acid.
Preparation of the Therapeutic Compositions To prepare a therapeutic composition in solution form at least one of the aforementioned enhancing compounds of hydroxyacids and a cosmetic or pharmaceutical agent are dissolved in a solution which may consist of ethanol, water, propylene glycol, acetone or other pharmaceutically acceptable vehicles.
The concentration of hydroxyacids may range from 0.01 to 99 percent by weight of the total composition. The concentration of the cosmetic or pharmaceutical agent ranges from 0.01 to 40 percent by weight of the total composition.
In the preparation of a therapeutic compo~ition in cream or ointment form at lea~t one of hydroxyacids and one of cosmetic or pharmaceutic agents are initially dissolved in a solvent such as water, ethanol, acetone, propylene glycol or poly~orbate 80. the solution thus prepared is then mixed in a conventlonal manner with commonly available cream or ointment base such as hydrophilic ointment or petrolatum. The concentrations of hydroxyacid~, cosmetic and pharmaceutical agents may range from 0.01 to 99 percent by weight of the total composition.
Therapeutic compositions of the instant invention may also be formulated in gel, lotion, shampoo, spray, stick or powder.
typical gel compo~ition of the in~tant invention utilizes at least one of hydroxyacids and one of cosmetic or pharmaceutical aqents di~olved in a mixture of ethanol, water and propylene glycol in a volume ratio of 40:40:20, respectively. A gelling 1 34$~

agcnt ~uch a~ hydroxyethylc-llulo~-, hydroxypropylcellulo~-, hydroxypropylmethylc-llulo-- or am~onlat-d glycyrrhlzlnat- 1-then add-d to the mlxture with agltation Tho preferred concentratlon of the golling agent ~-y rang- fron 0 1 to 4 porcent by woight of the total conpo-ltion Th- followlng are illu~trativo ~xaapl-~ of formulation- and compo~ition~ accorting to th- lnventlon of the parent and divi~ional applicatlons Althouqh th- examplo~
utillzo only ~-l-cted co~pound~ and formulatlonc, lt should bo under~tood that th- followlng ~xa~plo- ar- illu~trativo and not limltativo Th-r-foro, any of tho afor-nention-d hydroxyacids, cosmetic and pharmaceutlcal ag-nts ~ay b- ~ub~titutod according to th- t-aching~ of thi~ invontlon in th- following examples Exanpl- 1 A prophylactic and th-rapeutlc co~po~ltlon in ~olution for- for ag- ~pot~ and for koratoc-~ ~ay b- propared as follo~-Mall¢ acid 1 gra~, gluconolacton- 19 gra-s and citric acid 0 5 gr-m ar- di~olv-d in a ~lxtur- of othanol 30 ml, wat-r 42 ml and glyc-rin 5 ~1 80diu~ bl~ulfit- 0 5 g and hydroquinon- 2 gran~ aro add-d with ~tirring untll a cl-ar ~olutlon 1~ obtained Tho hydroxyacid-, nallc acid, gluconolacton- and citric acid hav- be-n add-d a) a-antloxldant- to h-lp ~tablllz- th- hydroqulnono in the compo~ition b) to ~nhance th- p-n-tration and tho ~f~lcacy of hydroquinon- c) to nor~allz- th- di~turb-d koratlnlzation in ag- ~pota and k-rato~
~h- composition thu~ fornulat-d contain~ 2%
hydroqulnon-, 1% malic acid, 19% gluconolaaton-, 0 5~ citrlc acid, and ha- pH 3 3 . 13~0.121~

Exa~ple 2 A therapeutlc compo~ltlon ln ~olutlon for~ for age ~pot- and for ~-rato~eo ~ay be formulated ~~ follow~

l~a 13 ~ 2 ~3 Alpha hydroxyi~obutyric acid (Methyllactic acid) 20 grams and citric acid 2 grams are dissolved in a mixture of ethanol 49 ml, water 20 ml and propylene glycol 7 ml. Sodium bisulfite 0.5 g and hydroquinone 2 grams are added with stirring until a clear solution is obtained. The co ~osition thus formulated contains 2% hydroguindne, 2% citric acid, 20% methyllactic acid, and has pH 3.6.
Example 3 A prophylactic and therapeutic composition ~ontaining minoxidil and lactic acid for hair growth and for prevention of hair 1088 on the scalp may be formulated a~ follows.
Minoxidil 2 grams and lactic acid 3 ml are di~solved in a mixture of ethanol 80 ml and propylene glycol 15 ml with stirring until a clear solution iB obtained. The composition thus formulated contain~ 2% minoxidil, 3% lactic acid, and has pH 4.7.
The lactic acid ha~ been added to help minoxidil di~solved into solution, to enhance the penetration and the efficacy of minoxidil for hair growth.
Example 4 A prophylactic and therapeutic composition in solution form for hair growth on the scalp may be formulated as follows.
Minoxidil 2 grams and ethyl pyruvate 2 ml are dissolved in a mixture o~ ethanol 80 ml and propylene glycol 16 ml. The composition thus formulated contains 2~ minoxidil, Z% ethyl p~vato, and has pH 5Ø The ketoacid ester, ethyl pyruvate has been added to enhance the penetration-and the efficacy of minoxidll for hair growth on the scalp.

Examplo 5 A therapeutic cv ,Gsition containing anthralin and hydroxyacid for psoriasis may be formulated as follows.
Anthralin powder 0.5 gram and alpha hydroxyisobutyric acid 4 gram~ are dissolved in a mixture of ethanol 50 ml, acetone 30 ml and diisopro ~ 1 adipate 16 ml with stirring until a clear yellowish solution is obtained. The composition thus formulated contains 0.5% anthralin, 4~ alpha hydroxyi~obutyric acid, and has pH 4.2. The hydroxyacid ha~ been added to enhance the penetration and the efficacy of anthralin for psoriasis.
Example 6 A therapeutic composition containing thionicotinamide and hydroxyacid for psoriasis, keratoses and warts may be formulated as follows.
Thionlcotinamide 2 grams and lactic acid 20 ml are dissolved in a mixture of ethanol 40 ml, water 30 ml and propylene glycol 8 ml with stirring until a clear yellowish solution is obtained.
The composition thus formulated contains 2% thionicotinamide, 20%
lactic acid, and has pH 3.3. The lactic acid has been added to enhance the penetration and the efficacy of thionicotinamide, and also to normallze the disturbed keratinization in psoriasis, keratoses and warts.
Example 7 A therapeutic composition containing 6-amlnonicotinamide and hydroxyacid for psoriasis, kerato~es and warts may be formulated a~ follows.

1~4~ i~3 ~ 6-Aminonicotlnamide 1 gram and glycolic acid 19 grams are dissolved in a mixture of ethanol 40 ml, water 32 ml and propylene glycol 8 ml with stirring until a clear ~olution i5 obtained. The composition thus formulated contains 1~
6-aminonicotinamide, 19% glycolic acid, and has pH 3Ø The glycolic acidlha~ been added to enhance the penetration and the efficacy of 6-Aminonicotinamide, and also to normalize the disturbed keratinization in psoriasis, keratose~ and warts.
Examplo 8 A therapeutic c~ ~Fition containing clotrimazole and hydroxyacid for fungal infection may be formulated as follows.
Clotrimazole 1 gram and lactic acid 4 ml are dissolved in 4 ml of ethanol, and the solution thus obtained i~ mixed with 91 gram~ o~ hydrophilic ointment USP. The mixing i~ continued until a uniform con~istency i~ obtained. The composition thus formulated contains 1% clotrimazole, 4% lactic acid, and has p~
3.2. The lactic acid has been added to enhance the penetration and the efficacy of clotrimazole for athlete's foot, and also to ~peed up healing and normalize the disturbed keratinization.
Example 9 A prophylactic and therapeutic composition containing chlorhexidine and hyJLox~acid as general anti~eptics on ~kin, and for prophylactio and therapeutic treatment of acne may be formulated as follows. Chlorhexidine diacetato 1 gram and benzilic acid S grams aro dissolved in a mixturo of ethanol 70 ml, water 10 ml and propyleno glycol 14 ml with ~tlrring until a clear solution iJ obtained. The composition thu~ formulated contains 1% chlorhexidine, 5% benzilic acid, and has pH 4.4.

13~-~0 120 ~3enzilic acid has been added to enhance the antibacterial effect of chlorhexidine, to eliminate the oiliness of the skin, and to improve the acne lesions.
Example 10 A prophylactic and therapeutic composition containing benzilic acidlas the only active ingredient for oily skin, acne, skin cleansinq and skin malodor may be formulated as follows.
Benzilic acid 7 gram~ is dissolved in a mixture of ethanol 60 ml, water 20 ml and propylene glycol 13 ml with stirring until a cle~r solution is obtained. The CG Fo6ition thus prepared contains 7% benzilic acid, and has pH 3Ø
Example 11 A therapeutic composition containing tropic acid a~ the only active ingredient for severe dry skin may be formulated as follows.
Tropic acid 10 grams is dissolved in 20 ml of ethanol, and the solution thus obtained is mixed with 70 grams of hydrophilic ointment USP. The mixing is continued until a uniform consistency is obtained. The c- ,o~ition thus formulated contains 10% tropic acid as an active ingredient, and has pH 3.7.
Exampl- 12 A prophylactic and therapeutic composition containing ribonolactone as the only active ingredient for oily skin, acne and skin cleansing may be formulated as follows.
Ribonolactone 4 grams is dissolved in a mixture of ethanol 36 ml and water 60 ml with stirring until a clear solution i~
obtained. The composition thus prepared contains 4%
ribonolactone as an active in~redient, and has pH 3.8.

134~123 Example 13 A therapeutic composition containing hydrocortisone and tropic acid for inflammatory and/or pruritic skin disorders may be formulated as follows.
Hydrocortisone 0.5 gram and tropic acid 5 grams are dis~olved inl10 ml of ethanol and 4 ml of acetone, and the solution thus obtained is mixed with 80 grams of hydrophilic ointment USP. The mixing is continued until a uniform consistency is obtained. The composition thus formulated contains 0.5% hydrocortisone and 5~ tropic acid as active ingredients, and has pH 3.4. The tropic acid has been added to enhance the penetration and the efficacy of hydrocortisone and al~o to normalize the disturbed keratinization.
Example 14 A therapeutic composition containing triamcinolone acetonide and benzilic acid for eczema, psoriasis and other inflammatory and pruritic skin disorders may be formulated as follows.
Triamcinolone acetonide 0.1 gram and benzilic acid 5 grams are dissolved in 10 ml of ethanol, and the solution thus obtained i~ mixed with 85 gram~ of hydrophilic ointment USP. The mixing i~ continued until a-uniform consistency i8 obtained. The composition thus formulated contains 0.1% triamcinolone acetonide, 5% benzilic acid, and has pH 3.4. The benzilic acid has been added to enhance the penetration and the eff$cacy of triamcinolone acetonide, and also to normalize the disturbed keratinizatlon in eczema, psoriasis and other inflammatory skin di~order~.

- l~4al20 Example 15 A prophylactic and therapeutic co ,osition containing dipyridamole and lactic acid for hair growth and for prevention of hair 1088 on the scalp may be formulated as follows.
Dipyridamole 2 gram~ and lactic acid 4 ml are dissolved in a mixture of e~hanol 80 ml and propylene glycol 14 ml with stirring until a clear yellowish solution is obtained. The composition thus formulated contains 2~ dipyridamole, 4% lactic acid, and has pH 4.4. The lactic acid has been added to help dipyridamole dissolved into solution, to enhance the penetration and the efficacy of dipyridamole for hair growth and for preventing hair 108~.
Example 16 A therapeutic composition containing clobetasol propionate and agaricic acid for eczema, psoriasi~ and other inflammatory and pruritic skin disorders may be formulated as follows.
Agaricic acid fine powder 2 grams and 98 grams of clobetasol propionate cream are mixed until a uniform consistency is obtained. the composition thus formulated contains approximately 0.05% clobetasol propionate, 2% agaricic acid, and has pH 4.3.
The agarlcic acid has been added to enhance the penetration and the efficacy of clobetasol propionate, and also to normalize the dlsturbed keratinization in eczema, psoriasis and other inflammatory ~kin disorder~.
Example 17 A therapeutic composition containing betamethasone diproplonate and benzilic acid for eczema, psoriasis, contact dermatitis and other inflammatory and pruritic skin disorders may be formulated as follows.

Benzillc acld powder 5 grams and 95 grams of betamethasone diproplonate ointment are mixed untll a uniform consistency is obtained. the c~ po~ltion thus formulated contains approximately 0.05~ betamethasone dipropionate and S~ benzilic acid. The benzilic acid has been added to enhance the penetration and the efficacy of betamethasone dipropionate, and also to normalize the disturbed keratinization in eczema, p~oriasis and other inflammatory skln disorders.
Example 18 A p~ophylactic and therapeutic composition containing aloe, malic acid and gluconolactone for oily skin and acne may be formulated as follows.
Aloe powder 200 fold 0.2 gram and ammoniated glycyrrhizinate 2 gram~ are mixed with water 61 ml and propylene glycol 2 ml.
The mlxture ls heated to 50-C until the aloe powder and the ammoniated gly~yLrl.izinate are completely dissolved. Ethanol lo ml is added to the solution followed by the addition of partially neutralized malic acid stock solution 3 ml and gluconolactone stock solution 22 ml wlth ~tlrring. The warm solution is poured into container ~ar~ before cooling. The gel composition thus formulated contains 40~ aloe, 1% malic acid, 9% gluconolactone, and has pH 4Ø Malic acid and gluconolactone have been added to enhance the skin softne~s and ~moothness by alo-, and also to normalize any di~turbed keratinization of the skin.
Exampl- 19 A ~un screen composition containlng Octyl dimethyl PABA, dioxybe.,zone and lactic acid may be formulated as follows. Octyl dlmethyl PABA 5 gram~, diox~enzone 3 grams and lactic acid 2 ml are dlssolved ln a mixture of ethanol 65 ml, water 10 ml and 13~120 .
propylene glycol 15 ml with ~tirring until a clear solution is obtained. The cc osition thus formulated contain~ 5% octyl dimethyl PABA, 3% dioxybenzone, 2% lactic acid, and has pH 3.6.
The lactic acid has been added to substantiate the absorption of sunscreen agents, octyl dimethyl PABA and dioxybenzone, and to enhance the s~n ~creen effect.
Example 20 A prophylactic and therapeutic composition containing tetracycline and glycolic acid for oily ~kin and-acne may be formulated as follow~.
Tetracycline 3 gram~ and glycolic acid S grams are dissolved in a mlxture of ethanol 40 ml, water 40 ml and propylene glycol 12 ml with stirring until the tetracycline and glycolic acid are completely dissolved. The CG ,osition thu~ formulated contains 3% tetracycline, S~ glycolic acid, and has pH 3.4. The glycolic acid has been added to help tetracycline dissolved into the solution, to enhance the penetration and the efficacy of tetracycline, and to normalize the disturbed keratlnizatlon in acne.
Example 21 A therapeutic composition containing griseofulvin and methyl pyruvate for fungal infection of nail~ may be formulated at follows .
Griseofulvin 1 gram and methyl ~Luvate 2 ml are dissolved in a mixture of 2 py.~olidone 20 ml. PEG-400 47 ml and ethanol 30 ml with stirring until the griseofulvin is completely dissolved.

The composition thus formulated contain~ 1% griseofulvin, 2%

methyl p~L uvate, and has pH 4.4. The methyl ~yluvate has been ~13 1012~

added to help griseofulvin dis~olve into the solution, to enhance the penetration and the efficacy of griseofulvin, and to normalize the disturbed keratinization in nails.
Example 22 A therapeutic composition containing lidocaine and atrolactic aclid for pruritic skin may be formulated as follows.
Lidocaine 2 grams and atrolactic acid hemihydrate 3 grams are di~solved in a mixture of ethanol 40 ml, water 40 ml and propylene glycol 15 ml with stirring until the lidocaine and atrolactic acid are completely dissolved. The composition thus formulated contains 2% lidocaine, 3% atrolactic acid, and has pH
4.6. The atrolactic acid has been added to help lidocaine dissolved and stabilized in the solution and to enhance the efficacy of lidocaine for pruritic skin.
Example 23 A ~o~hylactic and therapeutic composition containing retinoic acid and ethyl pyruvate for oily skin and acne may be formulated as follow~.
Retinoic acid, all-trans 0.1 gram and ethyl pyruvate 2 ml are dissolvod in a mixture of ethanol 80 ml, water 10 ml and propylene glycol 8 ml with stirring until a yellowlsh solution is obtained. The compo~ition thus formulated contains 0.1% vitamin A acid, 2~ ethyl p~.uv&te, and has pH 3.6. The ethyl pyruvate has been added to enhance the penetration and the efficacy of retinoic acid, and to normalize the disturbed ke~atinization in acne.

.

1:~4~)120 "
Example 24 A prophylactic and therapeutic cu ~osition containing erythromycin and aleuritic acid for oily skin and acne may be formulated as follows.
Erythromycin 2 grams and aleuritic acid 2 grams are dissolved in la mixture of ethanol 50 ml, water 40 ml and propylene glycol 6 ml with stirring until a clear solution is obtained. The cv osition thus formulated contain~ 2%
erythromycin, 2% aleuritic acid, and ha~ pH 5.7.~- The aleuritic acid has been added to help erythromycin dissolve into the solution, to enhance the penetration and the efficacy of erythromycin, and to normalize the di~turbed keratinization in acne.
Example 25 A therapeutic composition containing P-hydroxymandelic acid for dry skin may be formulated a~ follow~.
P-Hydroxymandelic acid 10 grams is dis~olved in 20 ml of ethanol, and the pinkish solution thus obtained is mixed with 70 grams of hydrophilic ointment USP with stirring until a uniform con~istency i~ obtained. The composition thus formulated contains 10~ P-hydroxymandelic acid as an active ingredient, and has pH 3.2. P-Hydroxymandelic acid has been incorporated into the composition to alleviate any scaly or flaky skin, and to change the dry skin into normal smooth and soft skin.
~ xample 26 A therapeutic composition containing hydroquinone and lactic acid in solution form for age spots, keratoses, melasmas, lentigines and other pigmented skin spots may be formulated as ~ollows .

134~120 ..
Lactic acid 10 ml, hydroquinone 4 grams and sodium metabisulfite 0.6 gram are dissolved in a mixture of ethanol 70 ml, water 10 ml and propylene glycol 6 ml with stirring until a clear solution is obtained. The co~position thus formulated contains 4~ hydroquinone, 10% lactic acid, and has p~ 4Ø The lactic acid has been added to help stabilize and enhance the penetration and the efficacy of hydroquinone, and also to normalize the disturbed keratinization in the skin lesions. The composition thu~ formulated is packaged in felt pens for controlled delivery to skin lesions.
Example 27 A therapeutic composition containing hydroquinone and glycolic acid in solution form for age spots, keratoses, melasmas, lentigines and other pigmented skin spots may be formulated as follows.
Glycolic acid 8 grams, hydroquinone 5 grams and sodium metabisulfite 0.5 gram are dissolved in a mixture of ethanol 70 ml, water 10 ml and propylene glycol 7 ml with stirring until a clear solution is obtained. The c~ po~ition thus formulated contains 5% hydroquinone, 8% glycolic acid, and has pH 3.9. The glycolic acid ha~ been added to help stabilize and enhance the penetration and the efficacy of hydroquinone, and also to normalize the disturbed keratinization in the skin lesions. The composition thus prepared is packaged in felt pen~ for controlled delivery to skin leslons.
Example 28 --A therapeutlc composition containing hydroquinone and i~j, 4~)120 2-methyl 2-hydroxypropanoic acid in solution form for age spots, keratoses, melasmas, lentigines and other pigmented skin spots may be formulated as follows.
2-Methyl 2-hydroxypropanoic acid 12 grams, hydroquinone 4 grams and sodium bisulfite 0.3 gram are dissolved in a mixture of ethanol 60 ml, water 20 ml and propylene glycol 4 ml with stirring until a clear solution is obtained. The composition thus formulated contains 4% hydroquinone, 12% 2-methyl 2-hydroxypropanoic acid, and ha~ pN 4Ø The composition solution i~ packaged in felt pens for controlled delivery to skin le~ion~. The 2-methyl 2-hydroxypropanoic acid has been added to help stabilize and enhance the penetration and the efficacy of hydroquinone, and also to normalize the disturbed keratinization in the skin lesions.
Example 29 A composition containing hydroquinone alone in solution form for age spot~ and keratoses studies may be formulated as follows.
Hydroquinone 5 grams and sodium metal bisulfite o.s gram are dissolved in a mixture of ethanol 70 ml, water 15 ml and propylene glycol 10 ml with stirring until a clear solution is obtained. The compo~ition thus prepared contains 5~ hydroquinone and ha~ pH 6Ø The composition solution is packaged in felt pen~ for comparative studies; with or without hydroxyacids on age spot~ and kerato~e~.

TEST RESULTS
In order to determine whether addition of a hydroxyacid in the composition could enhance the therapeutic action of a cosmetic or pharmaceutical agent a total of more than 55 1 2 ~
-- , volunt--r- and patl-nt- havlng dlt~-r-nt ~kln dl~ord~r~
partlalpat-d ln th-~- ~tudl-- Each partlclpating ~ub~ot wa~
glv-n two pr-paratlon~t l - wlth or wlthout th- addltlon of a hydroxyaold ln th- th-rap~utia aompo~ltlon Toplcal app11aatlon~ w-r- oarrl-d out ~lth-r by bl1at-ral or tla1 admpari-on, In bllat-ral Oc ~rl~on the ~ub~-ct wa~
ln-truat-d to apply on- preparatlon on one ~ld- Or th- body and th- oth-r on- on th- oth-r ~ld- ot th- body rOr p~orla~
~a~-ma, ~-v-r- dry ~kln, athl-to'~ rOot, ~ta , wh-r- both slde-w-r- lnvolv-d, th- ~ub~-ct wa- ln~truat-d to apply two to three tla-- dally on- a-dlaatlon on on- ~ld~ Or the body tor a perlod ot up to ~-v-ral aonths of tlm- In th- pu1~- tr-atment for p-orla~l~ or oth-r lntlammatory d~ a- th- ~odl¢ation waa appli-d only on¢- every three dayo or twla~ a week Th-a-dlaatlon wa- ~ ntlnu-d wh~n-ver a total ~ lon Or the 1-~lon- ocaurr-d prlor to th- t-~t p-riod o~ up to ~ev~ral month-For th- ~aalp or raa- lnvolv-m-nt ~uah a- ln dandrurr, olly ~kln, aan- and ~-borrh-la dermatltl~ th- ~ub~-ct wa~ lnstructed to apply t~o to thr-- ti~- dally on- ~-dlaatlon on on- eid- Or th- ~calp or th- ~ac- and th- oth-r aedlaatlon on th- other ~lde o~ th- ~aalp or th- ~aae ~or a perlod ot up to 1~ w-ek~ o~ tlme For ag- ~pota, ~-rato--~ or wart- th- a-dlaatlon wa- aontlnu~
~or up to ~ aonth- o~ tl~-8-qu-ntla1 admlnl-tratlon- o~ ~-dlaatlon~ w-r- aarrl-d out wh-n-v-r th- bllat-ral aomparl-on wa- dlttlau1t. For ~xampl- ln prurltl~ aondltlon~ th~ ~ub~at w~- ln~tsuat-d to apply tour tlm~
dally or ~- ott-n aa n~ ry on- ~-dlaatlon on th- prurltlo lesion~ for two days, then switched to the other medication on the same lesions for another two days, thus to compare which medication was more effective in relieving the itching.
1. Dry skin.
Human subject~ having ordinary dry skin or with moderate degrees of d~y skin as evidenced by dry, flaking and cracking of the skin were in~tructed to apply topically the lotion, cream or ointment containing 3 to 7 percent of hydroxyacids of the instant invention on the affected skin areas. Topical application, two to three times daily, was continued for two to three weeks. In all the nine sub~ects tested, the feeling of the skin dryness disappeared within a week of topical application. The roug~ and cracked ~kin became less pronounced and the skin appeared normal and felt smooth after 10 days of topical treatment.
The ordinary dry skin conditions once restored to normal appearing skin remained improved for some time until causes of dry skin, such as low humidity, cold weather, excessive contact pressure, detergents, soaps, solvents, chemicals, etc., again caused recurrence of the dry skin condition. On continued use it wa~ al~o found that twice daily topical application of a composition containing one or more hydroxyacids of instant invention prevented the development of new dry skin lesions.
In ~evere dry skin the skin lesions are different from the above. The involved skin is hyperpla~tic, fissured and has thic~
adherent scales. The degree of thickening is such that lesions are palpably and vi~ually elevated. The thickened adherent ~cale~ cause the surface of involved 6kin to be markedly rough and uneven. The two attributes of thickness and texture can be 13~0120 quantified to allow ob~ective measurement of degree of improvement from topically applied therapeutic test materials as follows:

DEGREE OF IMPROV~ T

None Mild Moderate Substantial Complete (O)(1+) (2~) (3+) (4+) THICKNESS HighlyDetectable Readily Barely Normal elevated reduction apparent elevated thickness reduction E Visibly Palpably Uneven but Slightly Visibly and rough rough not rough uneven palpably smooth By mean~ of ~uch parameters deg~e3 of change in lesions can be numerically noted and comparisons made of one treated site to another.
In order to evaluate the hydroxyacids and their related com~ounds of the instant invention a total of ~ix patients with severe dry ~kin condition~ or ichthyosis were treated with the composition~ containing 7 to 15% of hydroxyaeids as described in the ~xample~.
Treated areas were of a size eonvenient for topical application~, i.e., eircles 5 cm in diameter demarcated with a pla~tie ring of that size inked on a stamp pad. The medieinal ereams or olntment~ were toplcally applled by the patlent in an amount ~uffieient to eover the treatment sltes. Appllcations were made three time daily and withou~ ocelusive dressings.
Applications were di~eontinued at any time when re601ution of the le~ion on the treatment area was clinically ~udged to be complete.

13'~12~

The test results on patients with severe dry skin are ~ummarized on the following table.

Topical Effectiveness of Hydroxyacids on Severe Dry Skin Compound~ Number of Therapeutic Patients Effectiveness 1. Tropic acid 4 4+
2. ~en2ilic acid 5 4+
3. Ribonolactone 3 4. 4-Hydroxymandelic acid 2 3+
5. 3-Chloro 4-hydroxymandelic acid 2 3+
6. 3,4-Dihyd~G~y ?ndelic acid 2 3+

2. P~oriasis The involved skin in psoriasis is hyperplastic (thickened), erythematous (red or inflamed), and has thick adherent scales.
the de~ce of thickening is such that lesions are elevated up to 1 mm above the surface of ad~acent normal skin; erythema is usually an intense red: the thickened adherent scale~ cause the ~urface of involved skin to be markedly rough and uneven. These three attributes of thickness, color and texture can be quantified to allow ob~ective mea~urement of degree of improvement from topically applied therapeutic test materials as follow~.

1 2 ~
._ DEGREE OF IMPROVEMENT

None Mild Moderate Substantial Complete ( O) ( 1+) ( 2+) ( 3+) ( 4+) Thlckness Hiqhly Detectable Readily Barely Normal elevated reduction apparent elevated thickness Texture Visibly Palpably Uneven but Slightly Visibly and rough rough not rough uneven palpably smooth Color Inten~e Red Dark PinX Light Normal skin red pink color By means of such parameters degree of improvements in psoriatic le~ion~ can be numerically recorded and comparisons made of one treated site to another. The treatment schedule was quite different from the previously described in that the present study was employing a ~Pulse Treatment. n Instead of several time~ daily application the therapeutic composition of antipsoriatic agent with or without a hydroxyacid in solution form was topically applied to the involved skin only once in every three days or twice a week. The test results on patients having psoriasi~ are summarized on the following table.

, - 13~tl20 Topical Effects on Psoriasis of Antipsoriatic Agents With or without Hydroxyacids Compositions Number of Therapeutic Patients Effectiveness Thionicotinamide 3% alone 6 2+
with 10% Lactic acid 6 4+
with 5% Glycolic acid 4 4+
with 5t 2-methyl 2-hydroxypropanoic acid 3 4+
6-Aminonlcotinamide 15 alone 5 3+
with lOS Lactic acid 5 4+
with 10% Glycolic acid 4 4+
Betamethasone dipropionate o.os% ointment alone 5 3+
with 5% Benzilic acid 4 4+
with 5% Tropic acid 3 4+
with 5% 2-Methyl 2-Hydroxypropanoic acid 3 4+
Clobetasol propionate 0.05~ cream alone 4 Z+
with 5% Benzilic acid 3 3+
with 5% Tropic acid 2 3+
with 5~ 2-Methyl 2-hydroxypropanoic acid 3 3+

In a topical treatment of eczema patients, betamethasone diproplonate or clobetasol propionate alone at 0.05% would achieve only a 3+ improvement on all the eczema patients tested.
As shown by the table with the additional of 5% gluconolactone or ribonolactone betamethasone dipropionate or clobetasol propionate could attain a 4+ maximal clearing on all the eczema patients to~ted.

i ~ 4C~ 12~
-Topical Effects on Eczema of Corticosteroids With and Without Hydroxyacid Lactone Composition Number of Therapeutic Patients Effectiveness Betamethasone dipropionate 0.05~ alone 3 3 with 5% Gluconolactone 3 4+
with 5% Ribonolactone 2 4+
Clobetasol propionate 0.05~ alone 4 3+
with 5% Gluconolactone 4 4 with 5t Ribonolactone 3 4+

3. Age Spots, Wrinkles, Kerato~es and Pigmented Skin lesions.
Therapeutic compositions packaged in felt pens as described in Examples were provided to 14 patients for treatment of age spots, wrinkles, keratoses and other pigmented skin spots. Each participating patient received two felt pens; i.e. with or without the addition of hydroxyacid to the composition containing hydroquinone. The patients were instructed to apply topically ono medication on one side of the body such as on the back of the left hand and th- other medication on the other side of the body such as on the back of the right hand. Specific instructions were given to the patients that the medications were applied twice daily and discretely only to the skin lesions of age spots, wrinkles, keratoses, melasmas, lentigines or other pigmented skin spot~.
Within one to three weeks, improvement o~ age spot~ and keratoses was clinically discernible. After one to three months substantial eradication of age seots, wrinkles and keratoses occurred in all the patients tested. Complete eradication of age spots usually occurred within two to four months of topical administration in most cases. Therapeutic compositions containing higher concentrations of hydroxyacids (10 to 20%) and hydroquinone (3 to 5%) were judged to be more efficient in eradicating age spots, wrinkles and keratoses within shorter periods of t~me. Without the addition of a hydroxyacid to the composition of hydroquinone, eradication of age spots, wrinkles or keratoses did not occur within four months of time.
It was also found that while compositions containing hydroxyacid~ without hydroquinone were effective for eradication of keratoses and wrinkles, the co ~,ositions were not efficient in eradicating pigmented age spots, melasmas or lentigines within 4 months of time. In any case, with the addition of a hydroxyacid to the composition containing hydroquinone, pigmented age spots, melasmas, lentigines and other pigmented skin spots had been substantially eradicated.
4. Acne.
Therapeutic compositions containing tetracycline, erythromycin or chlorhexidine with or without the addition of a hydroxyacid were provided to 9 patients having papulopustular or pustular lesions of acne. Each participating patient received two medications, with or without the addition of a hydroxyacid to the composition containing an antibiotic. The patients were instructed to apply topically one medication on one side of the body such as ths left side forehead, face, back or chest, and the other medication on the other side of the body such as right side forehead, face, back or chest. Twic- daily administration was continued for 4 to 12 weeks.

13~12~
The degree and rate of improvement on acne lesions were clinically evaluated, and comparison was made between the two sides; one side with and the other side without a hydroxyacid in the compositions containing an antibiotic. It was found that the degree and rate of improvement on acne lesions were substantially better on the side treated with a combination composition containing both the hydroxyacid and the antibiotic as compared to that of the antibiotic alone. The time for complete clearing of acne le~ions treated with a combination cc ~osition varied from 4 to 12 weeks of time, with an average time of 8 weeks, whereas complete clearing with that of the antibiotic alone ranged from 8 weeks to 9 months, with an average of 4 months.
5. Preventing Hair Lo6s And For Hair Growth.
Prophylactic and therapeutic compositions containing minoxidil or dipyridamole with or without a hydroxyacid or related compound were provided to 6 human subjects having a pLo~Le3sive 1088 of hair on the scalp. Each participating sub~ect received two medications; i.e. with or without the addition of a hydroxyacid to the composition containing minoxidil or dipyridamolo. The sub~ects were instructed to apply topically one medication on one side of the scalp and the other medication on the other side of the ~calp. Twice daily topical applications were continued for 2 to 6 months. Clinical evaluation ~hows that the comblnation compositions containing minoxidil or dipyridamole and a hydroxyacid or related compound were therapeutically more efficient in preventing the hair loss and enhancing hair growth on the scalp.

lX4û 120 -Therapeutic compositions containing clotrimazole or griseofulvin wlth or without the addition of a hydroxyacid were provided to 6 patients having recurrent fungal infections of the foot: i.e. athlete's foot with or without toe nail involvement.
Each participating patient received two medications with or without the alddition of a hydroxyacid to the composition containing clotrimazole or griseofulvin. The patients were instructed to apply topically one medication on one side of the body such as left foot, and the other medicatio~ on the other side of the body such as right foot. Three time daily applications were continued for one to two weeks. When nail infections were involved the topical application was continued for up to 4 months using the composition~ containing griseofulvin with or without the addition of a hydroxyacid.
Ths degree and rate of improvement on skin lesions were clinically evaluated, and comparison was made one side of the body against the other. It was found that the skin lesions improved much faster with the compositions containing both the antifungal agent and the hydroxyacid. The presence of hydroxyacid appeared to enhance the efficacy of the antifungal agent, and also to eliminate the discomforts such as itching, tingling, burning and heat due to the fungal infection.
Generally the iniected skin healed within a week from topical application o~ the compositions containing an antifungal agent and a hydroxyacid. When toe nails were involved in the fungal inrectlon the complete healing and ~e~Lo~h of nails usually took several month~ on continued topical application Or medications containing grlseofulvin and a hydroxyacid.

~ ~4'~120 ".~ .
The hydroxyacids and related compound~ which may be useful as dermatologic agents for various conditions and disorders including age spots, keratoses, skin wrinkles etc. or as additives to enhance therapeutic effects of other cosmetic or pharmaceutical agents include 2-Hydroxyacetic acid;
2-hydroxypropanoic acid; 2-methyl 2-hydroxypropanoic acid;
2-hydroxybutanoic acid; phenyl 2-hydroxyacetic acid; phenyl 2-methyl 2-hydroxyacetic acid; 3-phenyl 2-hydroxyacetic acid;
2,3-dihyroxypropanoic acid; 2,3,4-trihydroxybutanoic acid;
2,3,4,5,6-pentahydroxyhexanoic acid; 2-hydroxydodecanoic acid;
2,3,4,5-tetrahydroxypentanoic acid; 2,3,4,5,6,7-hexahydroxyheptanoic acid; diphenyl 2-hydroxyacetic acid;
4-hydroxymandelic acid; 4-chloromandelic acid; 3-hydroxybutanoic acid: 4-hydroxybutanoic acid; 2-hydroxyhexanoic acid:
5-hydroxydodecanoic acid: 12-hydroxydodecanoic acid;
10-hydroxydecanoic acid; 16-hydroxyhexadecanoic acid;
2-hydroxy-3-methylbutanoic acid; 2-hydroxy-4-methylpentanoic acid; 3-hydroxy-4-methoxymandelic acid; 4-hydroxy-3--methoxymandelic acid; 2-hydroxy-2-methylbutanoic acid;
3-(2-hydroxphenyl) lactic acid; 3-(4-hydroxyphenyl) lactic acid;
hexahydromandelic acid: 3-hydroxy-3-methylpentanoic acid:
4-hydroxydecanoic acid: 5-hydroxydecanoic acid: aleuritic acid.
2-Hydroxypropanedioic acid: 2-hydroxybutanedioic acid;
erythraric acid: threaric acid arabiraric acid: ribaric acid;
xylaric acid: lyxaric acid glucaric acid: galactaric acid;
mannaric acid: gularic acid allaric acid altraric acid; idaric acid: talaric acid: 2-hydroxy-2-methylbutanedioic acid.

1~0120 .
Citric acid, isocitric acid, agaricic acid, quinic acid, glucuronic acid, glucuronolactone, galacturonic acid, galacturonolactone, uronic acids, uronolactones, ascorbic acid, dihydroascorbic acid, dihydroxytartaric acid, tropic acid, ribonolactone, gluconolactone, galactonolactone, gulonolactone, mannonolactonle, citramalic acid.
Pyruvic acid, hydroxypyruvic acid, hydroxypyruvic acid phosphate, their esters: methyl pyruvate, ethyl pyruvate, propyl pyruvate, isopropyl pyruvate; phenyl pyruvic acid, its esters:
methyl phenyl pyruvate, ethyl phenyl pyruvate, propyl phenyl ~ytu~ate; formyl formic acid; its esters; methyl formyl formate, ethyl formyl formate, propyl formyl formate; benzoyl formic acid, its esters; methyl benzoyl formate, ethyl benzoyl formate and propyl benzoyl formate: 4-hydroxybenzoyl formic acid, its esters;
4-hydroxyphenyl pyruvic acid, its esters; 2-hydroxyphenyl pyruvic acid and its esters.
The invention may be embodied in other specific forms without departing from the spirit or essential characteristics thereof. The present embodiments are therefore to be considered in all Le_~e_~s as illustrative and not restrictive, the scope of the invention being indicated by the appended claim~ and all changes which come within the meaning and equivalency of the claims are therefore intended to be embraced therein.

Claims (38)

1. Use of a therapeutically or prophylactically effective amount of a topically applicable therapeutic or prophylactic composition comprising at least one hydroxycarboxylic acid as a free acid or salt form and a pharmaceutically or cosmetically acceptable vehicle in treatment of fine or coarse wrinkles, or skin changes associated with aging selected from fine lines, skin lines, deepening of skin lines, thinning of skin, pigmented age spots and lesions, coarse skin, rough skin, blemishes, blotches, xerosis, itching skin, loss of skin elasticity and recoilability, and old-looking skin.

2. Use of a therapeutically or prophylactically effective amount of a topically applicable therapeutic or prophylactic composition comprising at least one compound selected from the group consisting of 2-hydroxyacetic acid, 2-hydroxypropanoic acid, 2,3 dihydroxypropanoic acid, 2,3,4-trihydroxybutanoic acid, 2,3,4,5-tetrahydroxypentanoic acid, 2,3,4,5,6,7-hexahydroheptanoic acid, 2-hydroxy-2-methyl butanoic acid, 2-hydroxypropanedioic acid, citric acid, isocitric acid, glucuronic acid, glucuronolactone, galactonolactone, galacturonic acid, gluconolactone, pyruvic acid, methyl pyruvate, ethyl pyruvate, isopropyl pyruvate phenyl pyruvic acid, benzoyl formic acid, methyl-benzoyl formate, ethyl-benzoyl formate, citramalic acid, 2-methyl 2-hydroxypropanoic acid, 2-hydroxybutanoic acid, phenyl 2-hydroxyacetic acid, phenyl-2-methyl-2-hydroxyacetic acid, diphenyl 2-hydroxyacetic acid (benzilic acid), 3-phenyl 2-hydroxypropanoic acid, 2-hydroxy-dodecanoic acid, 2-phenyl 3-hydroxypropanoic acid (tropic 39a acid), aleuritic acid, ribonic acid, ribonolactone, 2-hydroxy-lauric acid, 5-hydroxydecanoic acid, 4-hydroxymandelic acid, 4-chloromandelic acid, 2-hydroxy-3-methylbutanoic acid, 2-hydroxy-4-methyl-pentanoic acid, 3-hydroxy-4-methoxy-mandelic acid, 4-hydroxy-3-methoxymandelic acid, 3-(2-hydroxy-phenyl) lactic acid, 3-(3-hydroxyphenyl)-lactic acid,

3-(4-hydroxyphenyl) lactic acid, hexahydromandelic acid, 3-hydroxy-3-methylpentanoic acid, 1-hydroxy-1-cyclopropane carboxylic acid, 4-hydroxybutanoic acid, 2-hydroxyhexanoic acid, 5-hydroxylauric acid, 12-hydroxylauric acid, 10-hydroxy-decanoic acid, 12-hydroxyhexadecanoic acid, 16-hydroxyhexa-decanoic acid, 4-hydroxydecanoic acid, 2-hydroxybutanedioic acid (malic acid) 5-hydroxydecanoic acid, tartaric acid, erythraric acid and threaric acid; arabiraric acid; ribaric acid; xylaric acid; lyxaric acid; glucaric acid; galactaric acid; mannaric acid; gularic acid; allaric acid; attraric acid; idaric acid; talaric acid;
agaricic acid, quinic acid, galacturonolactone, uronic acid, uronolactone, ascorbic acid, dihydroascorbic acid, dihydroxytartaric acid, ribonolactone, gulonolactone, mannonolactone, ribonic acid, gluconic acid;
hydroxypyruvic acid, hydroxypyruvic acid phosphate, propyl pyruvate, isopropyl pyruvate; methyl-phenyl pyruvate, ethyl-phenyl pyruvate, propyl-phenyl pyruvate; formyl formic acid, methyl-formyl formate, ethyl-formyl formate, propyl-formyl formate, propyl-benzoyl formate, 4-hydroxy-benzoyl formic acid, 4-hydroxy-phenyl pyruvic acid, 2-hydroxy-phenyl pyruvic acid, 4-hydroxy-2,2-diphenylbutanoic acid as a free acid or salt form and a pharmaceutically or cosmetically acceptable vehicle in treatment of skin changes associating with aging.

3. A use according to claim 2, wherein the compound is selected from lactic acid, glycolic acid, gluconolactone, citric acid, malic acid, tartaric acid and methyllactic acid.

4. A use according to claim 3, wherein the compound is lactic acid.

5. A use according to claim 3, wherein the compound is glycolic acid.

6. A use according to claim 3, wherein the compound is gluconolactone.

7. A use according to claim 3, wherein the compound is citric acid.

8. A use according to claim 3, wherein the compound is malic acid.

9. A use according to claim 3, wherein the compound is tartaric acid.

10. A use according to claim 3, wherein the compound is methyllactic acid.

11. Use of a therapeutically or prophylactically effective amount of a topically applicable therapeutic or prophylactic composition comprising at least one hydroxycarboxylic acid as a free acid or salt form and a pharmaceutically or cosmetically acceptable vehicle in treatment of wrinkles.

12. Use of a therapeutically or prophylactically effective amount of a topically applicable therapeutic or prophylactic composition comprising of at least one compound selected from the group consisting of 2-hydroxyacetic acid, 2-hydroxypropanoic acid, 2,3-dihydroxypropanoic acid, 2,3,4-trihydroxybutanoic acid, 2,3,4,5-tetrahydroxy-pentanoic acid, 2,3,4,5,6,7-hexahydroheptanoic acid, 2-hydroxy-2-methyl butanoic acid, 2-hydroxypropanedioic acid, citric acid, isocitric acid, glucuronic acid, glucuronolactone, galactonolactone, galacturonic acid, gluconolactone, pyruvic acid, methyl pyruvate, ethyl pyruvate, isopropyl pyruvate, phenyl-pyruvic acid, benzoyl-formic acid, methyl-benzoyl formate, ethyl-benzoyl formate, citramalic acid, 2-methyl-hydroxy-propanoic acid, 2-hydroxy-butanoic acid, phenyl-2-hydroxyacetic acid, phenyl-2-methyl-2-hydroxyacetic acid, diphenyl-2-hydroxyacetic acid (benzilic acld), 3-phenyl-2-hydroxypropanoic acid, 2-hydroxydodecanoic acid, 2-phenyl-3-hydroxypropanoic acid (tropic acid), alauritic acid, ribonic acid, ribonolactone, 2-hydroxylauric acid, 5-hydroxydecanoic acid, 4-hydroxymandelic acid, 4-chloromandelic acid, 2-hydroxy-3-methylbutanoic acid, 2-hydroxy-4-methyl-pentanoic acid, 3-hydroxy-4-methoxy-mandelic acid, 42a 4-hydroxy-3-methoxymandelic acid, 3-(2-hydroxyphenyl) lactic acid, 3-(3-hydroxyphenyl) lactic acid, 3-(4-hydroxyphenyl) lactic acid, hexahydromandelic acid, 3-hydroxy-3-methylpentanoic acid, 1-hydroxy-1-cyclopropane carboxylic acid, 4-hydroxy-butanoic acid, 2-hydroxyhexanoic acid, 5-hydroxylauric acid, 12-hydroxylauric acid, 10-hydroxydecanoic acid, 12-hydroxy-hexadecanoic acid, 16-hydroxyhexadecanoic acid, 4-hydroxy-decanoic acid, 2-hydroxybutanedioic acid (malic acid), 5-hydroxydecanoic acid, tartaric acid, erythraric acid and threaric acid; arabiraric acid; ribaric acid; xylaric acid;
lyxaric acid; glucaric acid; galactaric acid; mannaric acid;
gularic acid; allaric acid; altraric acid; idaric acid;
talaric acid;
agaricic acid, quinic acid, galacturonolactone, uronic acid, uronolactone, ascorbic acid, dihydroascorbic acid, dihydroxytartaric acid, ribonolactone, gulonolactone, mannonolactone, ribonic acid, gluconic acid;
hydroxypyruvic acid, hydroxypyruvic acid phosphate, propyl pyruvate, isopropyl pyruvate; methyl-phenyl pyruvate, ethyl-phenyl pyruvate, propyl-phenyl pyruvate; formyl formic acid, methyl-formyl formate, ethyl-formyl formate, propyl-formyl formate, propyl-benzoyl formate, 4-hydroxy-benzoyl formic acid, 4-hydroxy-phenyl pyruvic acid, 2-hydroxy-phenyl pyruvic acid, 4-hydroxy-2,2-diphenylbutanoic acid as a free acid or salt form and a pharmaceutically or cosmetically acceptable vehicle in treatment of wrinkles.

13. A use according to claim 12, wherein the compound is selected from lactic acid, glycolic acid, gluconolactone, citric acid, malic acid, tartaric acid and methyllactic acid.

14. A use according to claim 13, wherein the compound is lactic acid.

15. A use according to claim 13, wherein the compound is glycolic acid.

16. A use according to claim 13, wherein the compound is gluconolactone.

17. A use according to claim 13, wherein the compound is citric acid.

18. A use according to claim 13, wherein the compound is malic acid.

19. A use according to claim 13, wherein the compound is tartaric acid.

20. A use according to claim 13, wherein the compound is methyllactic acid.

21. A use according to claim 12, wherein the compound is in the form of a free acid.

22. A use according to claim 12, wherein the compound is in salt form with an organic base useful in topical preparations.

23. A use according to claim 12, wherein the compound is in salt form with a nonmetallic inorganic alkali useful in topical preparations.

24. A use according to claim 14, wherein said lactic acid is in the form of ammonium lactate.

25. A use according to claim 15, wherein said glycolic acid is in the form of ammonium glycolate.

26. A use according to claim 17, wherein said citric acid is in the form of ammonium citrate.

27. A use according to claim 12, together with instructions to apply said compound periodically for a period of time sufficient to achieve at least a visibly mild to moderate reduction of wrinkles.

28. A use according to claim 12, together with instructions to apply said compound periodically for a period of time sufficient to achieve at least a substantial reduction of wrinkles.

29. A use according to claim 12, together with instructions for use for at least two months.

30. A use according to claim 12, together with instructions for use for at least three months.

31. A use according to claim 12, together with instructions for use for at least four months.

32. A use according to claim 12, together with instructions for use on a daily basis.

33. A use according to claim 12, wherein the compound or topically effective salt thereof is present in a topically acceptable composition comprising a carrier.

34. A use according to claim 33, wherein said composition is a lotion, cream, gel, ointment or solution.

35. A use according to any one of claims 12 to 34, wherein said wrinkle is a facial wrinkle.

36. A use according to any one of claims 12 to 34, wherein said wrinkle is a fine wrinkle.

37. A use according to any one of claims 12 to 34, wherein said wrinkle is a coarse wrinkle.

38. Use of a therapeutically effective amount of at least one compound selected from the group consisting of:
citramalic acid, 2-methyl-2-hydroxypropanoic acid, 2-hydroxybutanoic acid, phenyl-2-hydroxyacetic acid, phenyl-2-methyl 2-hydroxyacetic acid, diphenyl-2-hydroxyoacetic acid (benzilic acid), 3-phenyl-2-hydroxyacetic acid, 2-hydroxy-dodecanoic acid, 2-phenyl-3-hydroxypropanoic acid (tropic acid), aleuritic acid, ribonic acid, ribonolactone, 2-hydroxy-lauric acid, 5-hydroxydecanoic acid, 4-hydroxymandelic acid, 4-chloromandelic acid, 2-hydroxy-3-methylbutanoic acid, 2-hydroxy-4-methyl-pentanoic acid, 3-hydroxy-4-methoxy-mandelic acid, 4-hydroxy-3-methoxyomandelic acid, 3-(2-hydroxyphenyl) lactic acid, hexahydromandelic acid, 3-hydroxy-3-methylpentanoic acid, 1-hydroxy-1-cyclopropane carboxylic acid, 4-hydroxybutanoic acid, 2-hydroxyhexanoic acid, 5-hydroxylauric acid, 12-hydroxylauric acld, 10-hydroxy-decanoic acid, 12-hydroxyhexadecanoic acid, 10-hydroxydecanoic acid, 12-hydroxyhexadecanoic acid, 16-hydroxyhexadecanoic acid, 4-hydroxydecanoic acid 2-hydroxybutanedioic acid 5-hydroxydecanoic acid, and erythraric acid; threaric acid, arabiraric acid; ribaric acid; xylaric acid; lyxaric acid;
glucaric acid; galactaric acid; mannaric acid; gularic acid;
allaric acid; altraric acid; idaric acid; talaric acid;
agaricic acid,, quinic acid, galacturonolactone, uronic acid, uronolactone, ascorbic acid, dihydroascorbic acid, dihydroxytartaric acid, ribonolactone, galacturonolactone, gulonolactone, mannonolactone, ribonic acid, gluconic acid;

hydroxypyruvic acid, hydroxypyruvic acid phosphate, propyl pyruvate, isopropyl pyruvate; methyl-phenyl pyruvate, ethyl-phenyl pyruvate, propyl-phenyl pyruvate; formyl formic acid, methyl-formyl formate, ethyl-formyl formate, propyl-formyl formate, propyl-benzoyl formate, 4-hydroxy-benzoyl formic acid, 4-hydroxy-phenyl pyruvic acid, 2-hydroxy-phenyl pyruvic acid, 4-hydroxy-2,2-diphenylbutanoic acid as a free acid or salt form and a pharmaceutically or cosmetically acceptable vehicle in treatment of fine or coarse wrinkles, or skin changes associated with aging selected from fine lines, skin lines, deepening of skin lines, thinning of skin, pigmented age spots and lesions, coarse skin, rough skin, blemishes, blotches, xerosis, itchlng skin, loss of skin elasticity and recoilability, and old-looking skin in a human or animal.