US3729568A - Acne treatment - Google Patents

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US3729568A
US3729568A US00860296A US3729568DA US3729568A US 3729568 A US3729568 A US 3729568A US 00860296 A US00860296 A US 00860296A US 3729568D A US3729568D A US 3729568DA US 3729568 A US3729568 A US 3729568A
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vitamin
acid
acne
glycol
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A Kligman
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C57/00—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms
    • C07C57/26—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms containing rings other than six-membered aromatic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • 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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0014—Skin, i.e. galenical aspects of topical compositions
    • 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

Definitions

  • Acne is a dermatological disorder which is more prevalent in adolescence and is found mainly within the age group of about to 22. As it occurs primarily in the face and trunk are'as, affecting the appearance of the patient, it probably causes more mental pain and anguish to those afiiicted than many other diseases which, from a physical standpoint, may be much more severe.
  • the basic lesion of acne is the comedo or blackhead of a pilosebaceous follicle. The condition may be mild and transient with only a few blackheads which can readily be ejected by pressure and are of little concern, or may be severe, persistent, and very disfiguring with the more serious cases frequently leaving permanent scarring.
  • Vitamin A Its Effects on Acne, Northwest Med., 42; 219-225, August 1943
  • other investigators 3,729,568 Patented Apr. 24, 1973 have felt it to be ineffective
  • Easterson, J. A. D. et al. Vitamin A in Acne Vulgaris, Brit. Med. J., 2: 294-296, August 1963
  • Lynch, F. W. et al. Acne Vulgaris Treated With Vitamin A, Arch Derm., 55: 355, 357, March 1947, and Mitchell, G. H. et al., Results of Treatment of Acne Vulgaris by Intramuscular Injections of Vitamin A, Arch. Derm., 64: 428430, October 1951).
  • Vitamin A acid has been applied topically, Beer (Beer, Von P., Informen iiber diecode der Vitamin A-Sure, Dermatologica, 124: 192-l95, March 1962) and Stiittgen (Stiittgen, G., Zur Lokal opposition von Keratosen mit Vitamin A-Saure, Dermatologica, 124: 6580, February 1962) achieving good results in those hyperkeratotic disorders which are responsive to high oral doses of vitamin A. Among those treated by Beer and Stiittgen were patients with acne; however, these investigators reported no eifective results on this disorder. British Patent 906,000 discloses a cosmetic preparation containing vitamin A acid for regulation of the cornification processes of human skin.
  • Vitamin A acid is used in the present specification and claims refers to a composition in which the terminal methylene group of vitamin A has been replaced by a carboxyl group. It is also known as retinoic acid.
  • the vitamin A acid is preferably applied in a liquid solvent.
  • a composition found to be particularly effective is vitamin A acid dispersed in small amounts in a watermiscible (substantially oiland fat-free) liquid carrier made up of hydrophylic liquids having a high solvating action.
  • a particularly suitable solvent carrier in this regard consists essentially of a combination of (A) from about 25 to about by weight, of ethyl alcohol or isopropyl alcohol, preferably the former, and (B) the balance essentially a liquid glycol above ethylene glycol or a liquid glycol above ethylene glycol and a liquid ethylene glycol mono methyl or mono ethyl ether.
  • the balance is essentially a combination of a liquid glycol and a liquid ethylene glycol mono ether
  • the former will usually predominate; that is to say, the liquid glycol will be present in an amount, by weight, greater than the liquid ethylene glycol mono ether.
  • suitable glycols are liquid polyethylene glycols, such as polyethylene glycol 400, propylene glycol and liquid polypropylene glycols. Of these the polyethylene glycols and propylene glycol are preferred.
  • suitable liquid ethylene glycol ethers are the mono-, diand triethylene glycol monomethyl ethers and the mono-, diand triethylene glycol monoethyl ethers. Of these the monoand diethylene glycol monoethers are preferred.
  • Small amounts of other materials which do not materially alter the advantageous characteristics of the composition may be included. For example, a small amount of polyethylene glycol 4000 may be included to thicken the composition. Likewise, a small amount of an antioxidant, like butylated hydroxytoluene, may be included as a stabilizer to increase shelf life.
  • Typical such solvent carriers are as follows (percent being by weight):
  • the concentration of the vitamin A acid in the topically-applied composition is generally in the order of about 0.1%, by weight, of the applied composition.
  • the vitamin A acid concentration in the applied composition may range from 0.20% to 0.5%, by weight, with a concentration in the range of from about 0.05 to about 0.25% being preferred.
  • the vitamin A acid composition is applied daily until the desired relief is obtained, and this may require one or two (or possibly three) applications each day, depending upon the particular individual. Normally the treatment requires at least a month. Thus, acne in its mildest form (only a small number of comed'ones) may be substantially cleared in four to six weeks. However, more severe cases may require two to three months or longer.
  • the vitamin A acid appears to have an effect substantially diiferent from the irritants generally employed. Its effect is twofold: it causes an intercellular edema of the epithelium lining the comedo which thereby becomes porous allowing products within the comedo to leak into the tissue. This incites the inflammation which converts the comedones. Secondly, it increases the rate of reproduction of epithelial cells so that the horny cells stream out more rapidly carrying the impaction with them. This is illustrated, for example, in the drawings wherein the several tfigures show the progressive stages of expulsion of the comedo, inflammatory in one case, increased keratinization in other. Not infrequently, new pustules and papules suddenly appear during the initial period of therapy.
  • FIG. 1 shows an open comedo (blackhead) before treatment.
  • FIG. 2 Shows the inflammatory reaction, caused by the present treatment, destroying epith'elia lining with consequent unseating of the comedo which will soon be exfoliated.
  • FIG. 3 shows extrusion of the comedo as a result of speeding up of keratinization. Horny cells are being produced at an accelerated rate, and the comedo is being swept out by this stream of cells.
  • FIG. 4 shows normal sebaceous follicles of the face. These follicles are the sites in which cornedones form.
  • FIG. 5 shows the filling of the follicle with horny material, the intermediate stage of comedo formation.
  • the method of treating acne comprising applying vitamin A acid topically to the aflected area in a concentration eflective for the treatment of acne and repeating such applications daily, whereby said applications result in the peeling and diffuse redness of the skin treated, and continuing said treatment until the acne has subsided.
  • said carrier consists essentially of (A) from about 25 to 75%, by weight, of an alcohol selected from the group consisting of ethyl and isopropyl, alcohol and 5 (B) the balance being essentially a liquid selected from the group consisting of (a) a liquid glycol above ethylene glycol, and (b) a mixture of a liquid glycol above ethylene glycol and a liquid lower alkyl ether of an ethylene glycol selected from the group consisting of the monomethyl and monoethyl ethers.
  • said alcohol is ethyl alcohol
  • said liquid glycol is a liquid polyethylene 10 glycol
  • said liquid ethylene glycol mono ether is selected from the group consisting of monoethylene glycol monomethyl ether, monoethylene glycol monoethyl ether, diethyleneglycol monomethyl ether and diethyleneglycol monoethyl ether.

Abstract

THEDERMATOLOGIC DISORDER CALLED ACNE VULGARIS IS CONTROLLED BY TOPICAL APPLICATION OF VITAMIN A ACIDT THE AFFECTED AREA. THE APPLICATION IS MADE DAILY WITH A COMPOSITION OF LOWVITAMIN A ACID CONTENT IN THE ORDER OF ABOUT 0.1%, BY WEIGHT, UNTIL THE ACNE IS RELIEVED. PARTICULARLY SUITABLE COMPOSITIONS FOR TOPICAL APPLICATIONS ARE ALSO PROVIDED.

Description

April 24, 1973 A. M. KLIGMAN 3,729,568
ACNE TREATMENT Filed Sept. 23, 1969 5 Sheets-Sheet 1 INVE TOR JZBE/Ff M z/a ATTORNEYS April 24, 1973 A. M. KLIGMAN ACNE TREATMENT 3 Sheets-Sheet 2 Filed Sept. 23, 1969 FIG.
INVENTOR 4zamr/Mfl/aM/1/v ATTORN EYS April124, 1973 A. M. KLIGMAN 3,729,568
ACNE TREATMENT Filed Sept. 23, 1969 3 Sheets-Sheet 3 FIGA mv TOR "WM 414mm ATTORNEYS United States Patent 3,729,568 ACNE TREATMENT Albert M. Kligman, Philadelphia, Pa., assignor to Johnson & Johnson, New Brunswick, NJ.
Continuation-impart of application Ser. No. 678,493,
Oct. 25, 1967. This application Sept. 23, 1969, Ser.
Int. Cl. A611; 15/02 US. Cl. 424-318 Claims ABSTRACT OF THE DISCLOSURE The dermatologic disorder called acne vulgaris is controlled by topical application of vitamin A acid to the affected area. The application is made daily with a composition of low vitamin A acid content in the order of about 0.1%, by weight, until the acne is relieved. Particularly suitable compositions for topical applications are also provided.
This application is a continuation-in-part of application Ser. No. 678,493 filed Oct. 25, 1967 now abandoned.
BACKGROUND OF INVENTION Acne is a dermatological disorder which is more prevalent in adolescence and is found mainly within the age group of about to 22. As it occurs primarily in the face and trunk are'as, affecting the appearance of the patient, it probably causes more mental pain and anguish to those afiiicted than many other diseases which, from a physical standpoint, may be much more severe. The basic lesion of acne is the comedo or blackhead of a pilosebaceous follicle. The condition may be mild and transient with only a few blackheads which can readily be ejected by pressure and are of little concern, or may be severe, persistent, and very disfiguring with the more serious cases frequently leaving permanent scarring.
There have been many treatments proposed for acne, almost any treatment giving some relief. What appears to occur in the development of acne is that there is an initial filling up of the follicle with a rather tough, keratinous material. This impaction of horny material is the whitehead and blackhead. As a result of bacterial growth in these horny impactions, the follicle ruptures initiating the inflammatory phase of the disease which takes the form of pustules, papules, cysts and nodules.
One of the commonly used methods for acne treatment is the use of peeling agents which cause exfoliation with the removal of some of the keratinous plugs. In the more serious cases where pustular or cystic lesions exist, the same are evacuated by incision and the contents expressed. Various other therapies have been employed, such as vaccine therapy, to assist in the control of chronic infection and increase the patients resistance to Staphylococci; hormone therapy, which is applicable only for female patients who may be put on routine contraceptive regimen with estrogens; antibacterial therapy for the treatment of extensive pustular or cystic acne where the patient may be treated with tetracycline's, penicillin, erythromycin, or other of the antibacterial agents and, in some instances, general surgical skin planing may be used.
Although many different approaches have been used for the treatment of this almost universal afliiction, none of the heretofore topical treatments has been found to be particularly effective, although the systematic adminis tration of hormones and antibacterials has been shown to have some merit.
The administration of large oral doses of vitamin A has been suggested as being beneficial in acne, Straumford, J. V.: Vitamin A: Its Effects on Acne, Northwest Med., 42; 219-225, August 1943), although other investigators 3,729,568 Patented Apr. 24, 1973 have felt it to be ineffective (Anderson, J. A. D. et al., Vitamin A in Acne Vulgaris, Brit. Med. J., 2: 294-296, August 1963; Lynch, F. W. et al., Acne Vulgaris Treated With Vitamin A, Arch Derm., 55: 355, 357, March 1947, and Mitchell, G. H. et al., Results of Treatment of Acne Vulgaris by Intramuscular Injections of Vitamin A, Arch. Derm., 64: 428430, October 1951).
Vitamin A acid has been applied topically, Beer (Beer, Von P., Untersuchungen iiber die Wirkung der Vitamin A-Sure, Dermatologica, 124: 192-l95, March 1962) and Stiittgen (Stiittgen, G., Zur Lokalbehandlung von Keratosen mit Vitamin A-Saure, Dermatologica, 124: 6580, February 1962) achieving good results in those hyperkeratotic disorders which are responsive to high oral doses of vitamin A. Among those treated by Beer and Stiittgen were patients with acne; however, these investigators reported no eifective results on this disorder. British Patent 906,000 discloses a cosmetic preparation containing vitamin A acid for regulation of the cornification processes of human skin.
It has now been shown that acne vulgaris can be relieved and the skin cleared of comedones, and, in some cases, of the disfiguring pustules and cysts through the repeated daily application of vitamin A acid applied topically to the aifected areas. The application of the vitamin A acid results in an irritation, as shown by peeling and diffuse redness of the skin in the treated areas. The topical treatment with the vitamin A acid is continued until the acne is no longer apparent. If the irritation resulting from the treatment appears to be substantially subsiding while the acne is still present, the number of daily treatments may be increased and/or the concentration of vitamin A acid in the topical application may be increased. Normally, however, daily topical applications, one to two times each day, with the vitamin A acid at a fixed concentration in the applied composition, are entirely satisfactory.
I have discovered that acne vulgaris can be effectively cleared through the repeated topical application of vitamin A acid to the affected skin area when the vitamin A acid is applied over an extended period of time in such manner and such concentration as to cause noticeable irritation when applied. Vitamin A acid is used in the present specification and claims refers to a composition in which the terminal methylene group of vitamin A has been replaced by a carboxyl group. It is also known as retinoic acid.
The vitamin A acid is preferably applied in a liquid solvent. A composition found to be particularly effective is vitamin A acid dispersed in small amounts in a watermiscible (substantially oiland fat-free) liquid carrier made up of hydrophylic liquids having a high solvating action. A particularly suitable solvent carrier in this regard consists essentially of a combination of (A) from about 25 to about by weight, of ethyl alcohol or isopropyl alcohol, preferably the former, and (B) the balance essentially a liquid glycol above ethylene glycol or a liquid glycol above ethylene glycol and a liquid ethylene glycol mono methyl or mono ethyl ether. When the balance is essentially a combination of a liquid glycol and a liquid ethylene glycol mono ether, the former will usually predominate; that is to say, the liquid glycol will be present in an amount, by weight, greater than the liquid ethylene glycol mono ether.
Examples of suitable glycols are liquid polyethylene glycols, such as polyethylene glycol 400, propylene glycol and liquid polypropylene glycols. Of these the polyethylene glycols and propylene glycol are preferred. Examples of suitable liquid ethylene glycol ethers are the mono-, diand triethylene glycol monomethyl ethers and the mono-, diand triethylene glycol monoethyl ethers. Of these the monoand diethylene glycol monoethers are preferred. Small amounts of other materials which do not materially alter the advantageous characteristics of the composition may be included. For example, a small amount of polyethylene glycol 4000 may be included to thicken the composition. Likewise, a small amount of an antioxidant, like butylated hydroxytoluene, may be included as a stabilizer to increase shelf life.
Typical such solvent carriers are as follows (percent being by weight):
Percent Ethylene glycol monomethyl ether 25 Ethyl alcohol (95 25 Polyethylene glycol 400 50 Ethylene glycol monomethyl ether Ethyl alcohol (95%) 25 Polyethylene glycol 400 70 Ethylene glycol monoethyl ether 25 Ethyl alcohol (95%) 25 Polyethylene glycol 400 50 Diethylene glycol monoethyl ether 25 Ethyl alcohol (95%) 25 Polyethylene glycol 400 50 Ethy lalcohol (95%) 5O Propylene glycol 50 Ethyl alcohol (95%) 50 Polyethylene glycol 400 50 Isopropyl alcohol 50 Polyethylene glycol 400 50 Ethyl alcohol (95%) 50 Polypropylene glycol 400 50 As previously indicated, application of the vitamin A acid should be in such manner and in such concentration as to cause visible irritation. The concentration of the vitamin A acid in the topically-applied composition is generally in the order of about 0.1%, by weight, of the applied composition. Thus, the vitamin A acid concentration in the applied composition may range from 0.20% to 0.5%, by weight, with a concentration in the range of from about 0.05 to about 0.25% being preferred.
The vitamin A acid composition is applied daily until the desired relief is obtained, and this may require one or two (or possibly three) applications each day, depending upon the particular individual. Normally the treatment requires at least a month. Thus, acne in its mildest form (only a small number of comed'ones) may be substantially cleared in four to six weeks. However, more severe cases may require two to three months or longer.
On application there is an irritation to the skin, the patient feeling a tingling or irritating sensation which is caused by the vitamin A acid present. The irritation is readily observed by a flushing or diffuse reddening of the skin to which the vitamin A acid is applied followed by a peeling of the skin surface. It is important that the patient feel this irritation as this is indicative of the concentration needed to be eflective. Not only peeling, but, with inflammation, blackheads and whiteheads are converted into pustules followed by extrusion of the horny plug and healing of the lesions.
The vitamin A acid appears to have an effect substantially diiferent from the irritants generally employed. Its effect is twofold: it causes an intercellular edema of the epithelium lining the comedo which thereby becomes porous allowing products within the comedo to leak into the tissue. This incites the inflammation which converts the comedones. Secondly, it increases the rate of reproduction of epithelial cells so that the horny cells stream out more rapidly carrying the impaction with them. This is illustrated, for example, in the drawings wherein the several tfigures show the progressive stages of expulsion of the comedo, inflammatory in one case, increased keratinization in other. Not infrequently, new pustules and papules suddenly appear during the initial period of therapy. This has been found to be due to an inflammatory explosion of pre-existing comedones. Under the influence of the vitamin A acid, comedones, inert for Weeks or months, suddenly blow up. Since these inflammatory lesions are normally rather small, it is believed that the vitamin A acid excites inflammatory explosions at an earlier stage than could occur naturally. After this initial phase of exfoliation, the situation improves. If the treatment is to be ultimately effective on the particular individual there is usually an initial indication of the beginning of this effect at about the end of the third Week of treatment. Continued application of the vitamin A acid prevents the formation of new comedones and ameliorates the condition. When treatment is discontinued, however, comedones again develop since the present treatment does not reduce the amount of sebum or oil excreted by the skin.
Referring then to the figures, these are photornicrographs of exised specimens of skin. FIG. 1 shows an open comedo (blackhead) before treatment. FIG. 2 Shows the inflammatory reaction, caused by the present treatment, destroying epith'elia lining with consequent unseating of the comedo which will soon be exfoliated. FIG. 3 shows extrusion of the comedo as a result of speeding up of keratinization. Horny cells are being produced at an accelerated rate, and the comedo is being swept out by this stream of cells. FIG. 4 shows normal sebaceous follicles of the face. These follicles are the sites in which cornedones form. FIG. 5 shows the filling of the follicle with horny material, the intermediate stage of comedo formation.
The results of clinical tests on 103 patients using 0.1%, by weight, vitamin A acid in a clear vehicle consisting of equal parts of ethyl alcohol and propylene glycol are reported in Topical Vitamin A Acid in Acne Vulgaris, by Kligman, Fulton and Plewig in Arch. Derm., vol. 99, April 1969, pages 469476.
Having thus described my invention, I claim:
1. The method of treating acne comprising applying vitamin A acid topically to the aflected area in a concentration eflective for the treatment of acne and repeating such applications daily, whereby said applications result in the peeling and diffuse redness of the skin treated, and continuing said treatment until the acne has subsided.
2. The method of claim 1 comprising applying topically to the aifected area a composition comprising vitamin A acid and a carrier, and continuing said applications at spaced intervals of one to two times a day.
3. The method of claim 2 in which the concentration of vitamin A acid in the composition is in the order of about 0.1 percent, by weight, of the topically-applied composition.
4. The method of claim 2 in which the concentration of vitamin A acid in the composition is from 0.02 to 0.5 percent, by weight, of the topically applied composition.
5. The method of claim 2 in which the concentration of vitamin A acid in the composition is from 0.05 to 0.25 percent, by weight, of the topically applied composition.
6. The method of claim 2 wherein said carrier is a water-miscible organic liquid.
7. The method of claim 6 wherein said carrier consists essentially of (A) from about 25 to 75%, by weight, of an alcohol selected from the group consisting of ethyl and isopropyl, alcohol and 5 (B) the balance being essentially a liquid selected from the group consisting of (a) a liquid glycol above ethylene glycol, and (b) a mixture of a liquid glycol above ethylene glycol and a liquid lower alkyl ether of an ethylene glycol selected from the group consisting of the monomethyl and monoethyl ethers. 8. The method of claim 7 in which said alcohol is ethyl alcohol, said liquid glycol is a liquid polyethylene 10 glycol and said liquid ethylene glycol mono ether is selected from the group consisting of monoethylene glycol monomethyl ether, monoethylene glycol monoethyl ether, diethyleneglycol monomethyl ether and diethyleneglycol monoethyl ether.
9. The method of claim 8 in which said carrier consists essentially of. ethyl alcohol and liquid polyethylene glycol.
10. The method of claim 9 in which said ethyl alcohol and said polyethylene glycol are present in approximately equal parts by weight.
Refere ces Cited FOREIGN PATENTS 7/ 1962 Great Britain 424344 9/ 1962 Great Britain 424344 OTHER REFERENCES Beer: Dermatologica, vol. 124 (1962), pp. 192-195.
Stuttgen: Dermatologica, vol. 124 1962), pp. 78-79.
Flesch: American Perfume: and Cosmetics (July 1963), vol. 78, pp. 15-17.
Harry: Cosmetic Materials, 1st Edition (1950), pp. 113-1 15.
Mellan: Industrial Solvents, 2nd Edition (1950), pp. 448, 451, 463, 464, 544, 656-657.
ALBERT T. MEYERS, Primary Examiner N. A. DREZIN, Assistant Examiner U.S. C1. X.R.
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US3882244A (en) * 1971-12-13 1975-05-06 Univ California Method of treating acne with a c{hd 20 {b acid
US3906108A (en) * 1973-10-12 1975-09-16 Johnson & Johnson Stabilized tretinoin cream emulsion
US3932665A (en) * 1974-04-05 1976-01-13 Scott Eugene J Van Process for the treatment of acne vulgaris utilizing retinal
US3934028A (en) * 1974-04-22 1976-01-20 The Regents Of The University Of California Acne and psoriasis treatment with retinoic acid analogs
DE2601489A1 (en) * 1975-01-17 1976-07-22 Johnson & Johnson GEL PREPARATIONS CONTAINING TRETINOIN
US4021573A (en) * 1974-04-22 1977-05-03 The Regents Of The University Of California Psoriasis treatment with retinoic acid analogs
US4034114A (en) * 1976-09-15 1977-07-05 Yu Ruey J Treatment of skin keratoses with retinal
US4055659A (en) * 1975-11-03 1977-10-25 Johnson & Johnson Retinoic acid derivatives
US4108880A (en) * 1975-11-03 1978-08-22 Johnson & Johnson Esters of retinoic acid
US4126697A (en) * 1975-11-03 1978-11-21 Johnson & Johnson Retinoic acid derivatives in the treatment of acne
US4170229A (en) * 1978-01-16 1979-10-09 Dominion Pharmacal, Inc. Method for improved health care of hair and scalp using a vitamin A aqueous emulsion
US4190594A (en) * 1975-11-03 1980-02-26 Johnson & Johnson Retinoic acid derivatives
US4200647A (en) * 1977-12-21 1980-04-29 Hoffmann-La Roche Inc. Vitamin A compositions to treat rheumatic disease
US4214000A (en) * 1978-10-30 1980-07-22 Johnson & Johnson Zinc salt of all-trans-retinoic acid for the treatment of acne
US4239781A (en) * 1979-05-03 1980-12-16 Roy Edwards Method for treating skin ailments
US4247547A (en) * 1979-03-19 1981-01-27 Johnson & Johnson Tretinoin in a gel vehicle for acne treatment
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US4843096A (en) * 1985-06-26 1989-06-27 Stiefel Laboratories, Inc. Treatment of acne
US4877805A (en) * 1985-07-26 1989-10-31 Kligman Albert M Methods for treatment of sundamaged human skin with retinoids
US4889847A (en) * 1986-11-03 1989-12-26 Ortho Pharmaceutical Corporation Prevention of glucocorticoid-induced skin atrophy
WO1990014833A1 (en) * 1989-06-07 1990-12-13 Bazzano Gail S Slow release vehicles for minimizing skin irritancy of topical compositions
US4985235A (en) * 1988-08-02 1991-01-15 Kligman Albert M Treatment of periodontoclasia with retinoic acid
US5019569A (en) * 1986-11-03 1991-05-28 Ortho Pharmaceutical Corporation Reversal of glucocorticoid-induced skin atrophy
AU614643B2 (en) * 1988-08-02 1991-09-05 Albert M. Kligman Treatment of periodontoclasia with retinoic acid
US5051449A (en) * 1991-02-27 1991-09-24 Kligman Albert M Treatment of cellulite with retinoids
US5124313A (en) * 1989-06-02 1992-06-23 Schaeffer Hans A Methods of improved skin care and the treatment of dermatological conditions
US5183817A (en) * 1981-02-17 1993-02-02 Bazzano Gail S Combinations of retinoids and minoxidil-type compounds for hair growth
WO1993006086A1 (en) * 1991-09-24 1993-04-01 Pfizer Inc. Retinoids and their use in treating skin diseases and leukemia
US5273739A (en) * 1990-12-07 1993-12-28 Jim Baral Composition and treatment for darkening hair color
US5380764A (en) * 1989-06-08 1995-01-10 Herzog; Paul Composition of vitamin A, glucose and hydrogen peroxide for cosmetic or pharmaceutical use
US5459153A (en) * 1990-03-27 1995-10-17 Leung; Lit-Hung Composition and methods for treatment of acne vulgaris and for retardation of aging
EP0699439A2 (en) 1994-08-31 1996-03-06 Pfizer Inc. Treatment of diseases caused by sebaceous gland disorders with acyl CoA cholesterol acyl transferase inhibitors
US5514672A (en) * 1981-02-17 1996-05-07 Bazzano; Gail S. Use of retinoids and compositions containing same for hair growth
US5643584A (en) * 1992-04-16 1997-07-01 Ortho Pharmaceutical Corporation Aqueous gel retinoid dosage form
US5661141A (en) * 1995-03-27 1997-08-26 Petrow; Vladimir 19-oxygenated steroids as therapeutic agents
US5670547A (en) * 1989-04-17 1997-09-23 Dow Pharmaceutical Sciences Moisturizing vehicle for topical application of vitamin A acid
US5698593A (en) * 1988-04-26 1997-12-16 The United States Of America As Represented By The Department Of Health And Human Services Method for treating acne
WO1998050023A1 (en) * 1997-05-09 1998-11-12 Kligman Douglas E Use of high dose retinoids for the treatment of skin disorders
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US5273739A (en) * 1990-12-07 1993-12-28 Jim Baral Composition and treatment for darkening hair color
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US5998395A (en) * 1992-02-07 1999-12-07 Kligman; Albert M. Methods of treating inflammatory dermatosis
US5643584A (en) * 1992-04-16 1997-07-01 Ortho Pharmaceutical Corporation Aqueous gel retinoid dosage form
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US6344448B1 (en) 1992-09-11 2002-02-05 Stb Family Limited Partnership Composition for the treatment of hair loss
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US6169110B1 (en) 1995-11-21 2001-01-02 Vivant Pharmaceuticals Rejuvenating the skin using a combination of vitamin A and alphahydroxy acids
US6063817A (en) * 1997-02-21 2000-05-16 Bristol-Myers Squibb Company Use of substituted (5,6) dihydronaphthalenyl compounds having retinoid-like activity to prevent or reduce ischemic injury
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US6008254A (en) * 1997-05-09 1999-12-28 Kligman; Douglas E. Method of treating skin disorders with high-strength tretinoin
US6228887B1 (en) 1997-05-09 2001-05-08 Douglas E. Kligman Method of treating skin disorders with high-strength retinoids
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US7179475B1 (en) 1998-12-04 2007-02-20 Johnson & Johnson Consumer Companies, Inc. Anhydrous topical skin preparations
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US20050159485A1 (en) * 2002-01-04 2005-07-21 Jost-Price Edward R. Combinations for the treatment of immunoinflammatory disorders and proliferative skin diseases
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US20090264527A1 (en) * 2008-04-14 2009-10-22 Skinvisible Pharmaceuticals, Inc. Method for stabilizing retinoic acid, retinoic acid containing composition, and method of using a retinoic acid containing composition
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CA945069A (en) 1974-04-09
FR2070083A1 (en) 1971-09-10
GB1325732A (en) 1973-08-08
DE2046119A1 (en) 1971-04-22
DE2046119C2 (en) 1984-05-30
IT1059655B (en) 1982-06-21
FR2070083B1 (en) 1974-05-24
ZA706459B (en) 1972-04-26

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