Treatment of Aged Skin with Oral 13-Cis-Retinoic Acid

Europaisches Patentamt European Patent Office © Publication number: 0 357 646 B1 Office europeen des brevets

@ Date of filing: 05.04.88

The file contains technical information submitted after the application was filed and not included in this specification

® Priority: 06.04.87 US 35544 © Proprietor: DALTEX MEDICAL SCIENCES, INC. 50 Kulick Road @ Date of publication of application: Second Floor 14.03.90 Bulletin 90/11 Fairfield, NJ 07006 (US)

© Publication of the grant of the patent: @ Inventor: PLEWIG, Gerd 22.03.95 Bulletin 95/12 Cecilienallee 38 D-4000 Dusseldorf 30 (DE) © Designated Contracting States: Inventor: KLIGMAN, Albert, M. AT BE CH DE FR GB IT LI LU NL SE 637 Pine Street Philadelphia, PA 19106 (US) © References cited: GB-A- 1 335 867 Representative: Koepsell, Helmut, Dipl. Ing. Retinoids, ED.; C.E. ORFANOS et al., pub- Mittelstrasse 7 lished 29 July 1981, pp. 219-223, 232-235, see D-50672 Koln (DE) entire document 00 CO CO m Note: Within nine months from the publication of the mention of the grant of the European patent, any person may give notice to the European Patent Office of opposition to the European patent granted. Notice of opposition shall be filed in a written reasoned statement. It shall not be deemed to have been filed until the opposition fee has been paid (Art. 99(1) European patent convention). Rank Xerox (UK) Business Services (3. 10/3.09/3.3.3) EP 0 357 646 B1

DRUGS, vol. 28, 1984, pages 6-37, ADIS Press Ltd.; A. WARD et al.: "Isotretinoin. A review of Its pharmacological properties and therapeutic efficacy In acne and other skin disorders"

HAUTARTZT, vol. 35, 1984, pages 623-629, C. Sprlnger-Verlag, DE; R. CORLIN et al.: "13-cis-retin-saure. Nledrlg doslerte orale Anwendung bel Acne papulopustulosa"

DERMATOLOGICA, vol. 171, 1985, pages 213-219, S. KARGER AG, Basel, CH; J. GAR- IQUE et al.: "Action de I'acide 13-cls-re- tlnolque et du retlnolde aromatlque sur divers para metres cutanes, chez le rat rendu hyperseborrhelque"

MAYO CLINICAL PROC., vol. 57, 1982, pages 51-57, CH. DICKEN et al.: "Systemic retinoids In dermatology"

Z. HAUTKR., vol. 57, no. 15, 1982, pages 1137-1143, Grosse Verlag, Berlin, DE; E. HOT- ING et al.: "Systemische Retlonoldtheraple - Wlrkprlnzlplen und kllnlsche Erfahrungen bel erythematosquamosen und anderen Der- matosen"

INT. J. DERMATOL, vol. 25, no. 10, December 1986, pages 660-663; E. HOTING et al.: "Treat- ment of Rosacea with Isotretinoin"

J. AM. ACAD. DERMATOL, vol. 6, no. 4, 1982, pt 2, suppl., pages 766-785; G. PLEWIG et al.: "Action of Isotretinoin In acne rosacea and gramnegatlve folliculitis"

ACTA VITAMINOL. ENZYMOL, vol. 6, no. 4, 1984, pages 325-337; M. GANDOLA: "La terapla dell'acne grave e della Rosacea con acldo 13-cls-retlnolco (Isotretinoin) per via orale"

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Description skin of adults, usually starting about middle age, which acts to reverse and retard the effects of Field of the Invention photoaging through its actions on the damaged connective tissue and abnormal epidermis. Further, The present invention relates to the treatment 5 pending U.S. Patent Application Serial No. 886,595 of various associated disorders of the skin which of Albert M. Kligman for "Methods for Treatment of are typical of many elderly persons. More particu- Sundamaged Human Skin with Retinoids" dis- larly, the invention is directed to the treatment of closes the topical use of various retinoic acid de- such disorders with low oral doses of 13-cis-re- rivatives, including 13-cis-retinoic acid, for treating tinoic acid. io photoaged skin. 13-cis-retinoic acid, more commonly referred to Background of the Invention simply as cis-retinoic acid or isotretinoin or by the trademarks "ACCUTANE" (in U.S.) or "ROAC- Many older persons (i.e., generally over 50 CUTAN" (in Europe), is an FDA-approved oral years of age and referred to herein as "the el- 75 medication for the treatment of severe, refractory derly") have "problem" skin deriving from multiple acne vulgaris, in particular acne conglobata. Cis- influences. These increase steadily with age, and retinoic acid is also used, but not FDA-approved, all are worsened by years of earlier excessive for the treatment of certain chronic, uncurable in- exposure to sunlight. The sun is a significant contri- flammatory and scaling disorders, viz, psoriasis, butor to chronic skin problems which are very 20 ichthyosis, Darier's disease, lupus erythematosus, prevalent in the aging population. These skin prob- granulomatous rosacea, etc. Orally administered lems are most vividly expressed in the most ex- isotretinoin also has anti-tumor activity in very high posed areas of the skin, and especially on the face, doses and can bring about at least partial regres- an area rich in blood vessels, follicles, and seba- sion of actinic keratoses, keratoacanthomas, and ceous glands. The face is also a highly permeable 25 basal cell carcinomas. region with a poor barrier layer, allowing ready In such prior art treatments the recommended penetration of potentially toxic chemicals originat- oral doses for acne are generally in the range of 40 ing in soaps, cosmetics, fragrances, toiletries, etc. to 80 mg daily (0.5-2.0 mg/kg body weight per The face is under continuous chemical assault, as day), and higher doses, sometimes as much as well as radiation insults. The end result is abnormal 30 200 mg per day, are often given for other chronic, skin, a consequence of multiple factors acting in disabling disorders. At these high dosages adverse combination. One can recognize the following clini- side reactions occur in all patients and are recog- cal disorders: nized as the general signs of hypervitaminosis A, 1) Rosacea-like syndromes with persistent red- namely dry skin, conjunctivitis, cheilitis, nasal ness, papules, and solid edema-like swellings; 35 bleeding, fragile skin, hair loss, pruritus, muscle 2) Hyperplasia of the sebaceous glands; pains, hyperostosis of bone, calcification of liga- 3) A seborrheic-like dermatitis, peculiar to the ments, gastrointestinal upsets, pseudotumor cerebri elderly; and others. 4) Pityrosporon-induced folliculitis; In a certain proportion of patients taking oral 5) Infestation by Demodex mites, with mite-as- 40 isotretinoin, blood tests show potentially serious sociated folliculitis, erythema, and scaling; abnormalities, viz, increased cholesterol, reduction 6) Enlarged, roughened nose (rhinophyma ; of high density lipoproteins (which protect against 7) Overgrowth of P. acnes, an anaerobic bac- coronary heart disease), increased levels of teria living in the follicles; triglycerides, elevation of hepatic enzymes, xan- 8) Flat, keratotic and pigmented seborrheic 45 thoma formation and others. Moreover, cis-retinoic keratoses; acid has been found to be extremely teratogenic. 9) Rough, scaly lesions of the actinic keratoses Lower doses of cis-retinoic acid in the range of type; 0.05 or 0.1 mg/kg body weight per day, have been 10) Scaly, flaky, dandruff-like conditions of the reported to be beneficial in acne conglobata scalp; and 50 (nodulo-cystic acne). Corlin, R. et al., "13-cis-re- 11) Trichostasis spinulosa-follicular impactions tinoic acid. Low Dosage Oral Use in Acne on nose, cheeks, temples and nape of the neck. Papulopustulosa. Results of a Multicenter Study," Changes take place against a background of Hautarzt 35:623-629 (1984); Ward, A. et al., photoaged skin showing yellowing, wrinkling, dry- "Isotretinoin. A Review of its Pharmaceutical Prop- ness, dilated vessels and comedones. 55 erties and Therapeutic Efficacy in Acne and Other U.S. Patent 4,603,146 of Albert M. Kligman Skin Disorders," Drugs 28:6-37. (1984). The latter discloses the use of vitamin A acid (retinoic acid or publication notes that the pharmacological profile of tretinoin) as a topical medication for sun-damaged isotretinoin suggests that it acts primarily by reduc-

3 3 EP 0 357 646 B1 4 ing sebaceous gland size and sebum production, yeast-like fungi Pityrosporon species and espe- and as a result alters the composition of the sur- cially anaerobic P. acnes, producing papules face lipids. The follicular microflora are also re- and pustules. Unlike acne, these do not originate duced, owing to diminished sebum production. The from ruptured comedones. This reaction is a reference also reports encouraging preliminary re- 5 folliculitis due to sebum leakage; sults in small numbers of patients with rosacea, 5) Flushing and redness, associated with dilated gram-negative folliculitis, Darier's disease, ich- vessels, resembling rosacea, accompanied by thyosis and pityriasis rubra pilaris. The response in sensitive skin which stings and burns; keratinizing disorders resembles that of the related 6) Scaling and redness along the sides of the drug etretinate, another retinoic acid derivative. io nose and cheeks, also the eyebrows, mimicking Plewig, G. et al., "Effects of Two Retinoids in and related to seborrheic dermatitis of younger Animal Experiments and After Clinical Application persons; in Acne Patients: 13-Cis-Retinoic Acid Ro4-3780 7) Flat, brown pigmented keratotic lesions of the and Aromatic Retinoid Ro1 0-9359," Retinoids, seborrheic keratosis variety; Pages 219-235 (Springer-Verlag 1981) discloses is 8) Rough, scaly lesions of the actinic keratosis clinical studies of sixty patients with severe ("un- type; treatable") acne using oral doses of 13-cis-retinoid 9) Scaly, flaky, dandruff-like conditions of the acid ranging from 0.05 to 2.0 mg/kg body weight. scalp; The authors reported a dramatic but dose-depen- 10) Fine wrinkles caused by dryness or loss of dent response in all patients, where with lower 20 moisture from the aged skin; and doses the improvement showed delayed onset. An 11) Accelerated hair loss due to seborrheic der- anti-inflammatory response was said to be dem- matitis and perhaps other subclinical inflamma- onstrated. tory components of patterned baldness in males and females (androgenic familial alopecia). Brief Summary of the Invention 25 The unusually low doses, preferably given in capsule form, are in the range of about 1 to 5 mg According to the present invention, a number daily or every other day, and even lower doses are of skin disorders most often found in elderly per- possible for maintenance therapy. Though 1 or 2 sons (over 50 years of age) may be improved, mg daily may be below the teratogenic level, the moderated, and partially reversed by the oral ad- 30 treatment of females should be limited to post- ministration of unusually low doses of 13-cis-re- menopausal and non-childbearing women (that is, tinoic acid. These doses are therapeutically effec- women of childbearing potential must not be given tive, but lack cutaneous or systemic toxicity, and this drug). Males over 50 years of age are eligible are probably non-teratogenic as well. The disorders for treatment. that respond to the very low doses are often non- 35 descript, representing mixtures of conditions that Detailed Description of Preferred Embodiments are not clearly classified in modern dermatological textbooks and are aggravated by photoaging. This In the practice of the present invention, a new oral medication is a true treatment modality, therapeutically effective but low dose of 13-cis- not just of photodamaged skin, but of a group of 40 retinoic acid is administered orally which substan- associated conditions in the elderly. tially avoids all the adverse side effects of hyper- Specific indications against which the present vitaminosis A induced by higher, conventional invention is therapeutically effective include: therapeutic doses of cis-retinoic acid in severe 1) Sebaceous gland enlargement, giving the skin acne and chronic dermatoses. The effective doses a knobby, pebbly texture, sometimes taking the 45 according to the present invention are one-tenth to form of circumscribed growths, resembling lo- one-twentieth or less the doses of prior art treat- calized tumors, viz. circumscribed sebaceous ments. Although conventional doses of isotretinoin hyperplasia of the forehead; are prescribed in milligrams per kilogram of body 2) Demodex infestation of follicles, with ensuing weight, the doses of the present invention are so folliculitis, perifollicular erythema, and scaling; 50 low that it is irrelevant to take body weight into 3) Horny impactions of follicles leading to con- account. spicuous pores and retention of fine hairs and It has been surprisingly found that doses of horn (follicular hyperkeratosis), retention of about 5 mg or less daily, and as low as 1 or 2 mg comedo-like follicular plugs (trichostasis daily or every other day are effective while provid- spinulosa), particularly on the nose, cheeks, 55 ing the least danger of toxicity and teratogenicity. temples and nape of the neck; Isotretinoin is available commercially, being 4) Leakage of sebum out of follicles whose walls sold by Roche Laboratories under the trademark have been weakened by a dense growth of "ACCUTANE." Normally an oily suspension, it may

4 5 EP 0 357 646 B1 6 suitably be administered in capsule form containing (a) Rosacea-like dermatitis the required daily or less frequent dose. The oral dosage form may additionally comprise pharma- Rosacea, or a condition similar to it, increases ceutically acceptable diluents, flavoring agents, with age and is quite common in women and men lubricants, and other suitable excipients which are 5 past 50. Clinical signs and symptoms include: red- standard in the art. For example, suitable diluents ness, scaliness, papulo-pustules, "sensitive" skin for inclusion in filled capsules include, but are not (stinging and burning from fragrances, soaps, as- limited to lactose, mannitol, calcium carbonate and tringents, etc.), enlarged vessels (telangiectasia), magnesium carbonate. Other forms of oral admin- sometimes with enlargement of the nose istration will be evident to those of ordinary skill in io (rhinophyma). Minor forms are usually missed by the art. physicians. Patients are often flusher-blushers with Although no signs of toxicity or teratogenicity unstable vascular systems. Flushing may be in- have been found with the low doses of the present duced by heat, cold, wind, emotions, wine, al- invention, the low dose treatment regimen of the coholic spirits of various kinds, hot drinks, spices, present invention should be limited to older women is etc. Photophobia with blepharitis and conjunctivitis beyond childbearing potential, non-ovulating, main- can frequently be found when looked for. Many ly post-menopausal, ovariectomized or after tubal patients go from doctor to doctor with "problem ligation, to avoid any possible teratogenicity. The skin," which by history and inspection can be prop- treatment may be used without restriction to older erly classified as rosacea, a variable syndrome. men. Thus, in order to maintain the therapeutic 20 Topical retinoic acid aggravates rosacea be- effects of the present invention, the treatment must cause of its irritant effect and cannot be used for be continued for long periods, such as six months this indication. Low-dose cis-retinoic acid to two years, and preferably indefinitely, i.e., a moderates all of these manifestations, viz, the eye program of maintenance therapy should be used problems, the pimples, the redness and blushing, since significant residual effects are not generally 25 the unusual sensitivity to chemicals and sunlight. obtained at such low dosages. Maintenance doses This is a very strong indication for a problem that after achieving a therapeutic benefit may be 1 to is not properly diagnosed or recognized, even by 2.5 mg or even less two or three times a week. specialists. Dilated vessels, cosmetically trouble- The oral administration of isotretinoin according some, become less conspicuous. to the present invention may be combined with 30 other therapies, such as low strength topical re- (b) Enlarged sebaceous glands tinoic acid for even greater effects in treating and lessening the complications of photoaged skin. Hyperplasia of sebaceous glands occurs in var- While retinoic acid irritates many patients when ious forms including: (1) circumscribed sebaceous applied topically, oral administration of isotretinoin 35 hyperplasia of the forehead and (2) whitish-yellow- is very well tolerated. Topical tretinoin makes ish, small nodules, often in linear array, on the neck rosacea and seborrheic dermatitis worse. A further and face, especially in photodamaged skin, (so- advantage of oral isotretinoin is that topical retinoic called stippled skin-erythrosis interfollicularis colli). acid has no appreciable effect on enlarged seba- Sebaceous hyperplasia coarsens facial skin and ceous glands. Many of the indications for low-dose 40 makes the surface pebbly. One of the most dra- oral cis-retinoic acid are different than topical matic effects of cis-retinoic acid orally, unobtaina- tretinoin. ble topically by any other retinoid, is shrinkage of More than one hundred (100) women and men the sebaceous gland. The enlarged glands in older have been treated according to the invention with persons do not secrete more sebum; oiliness is not oral cis-retinoic acid at doses of 2.5 to 5 mg daily 45 the problem. It is their size that is aesthetically for periods ranging from six (6) months to two (2) unpleasing and unattractive. Low-dose cis-retinoic years. Even lower doses were successfully used in acid according to the present invention reduces the other patients. The results obtained were at a size of enlarged glands, accompanied by a great slower rate, but after four (4) to six (6) months, the improvement in skin appearance, texture and results were about equivalent to similar patients 50 smoothness. Sebaceous glands of the face and treated with 40 mg cis-retinoic acid daily. The neck involute and regress in about two months. following results were obtained with these low Also, sebaceous benign growths (circumscribed doses for the disorders indicated, which are primar- hyperplasia) of the forehead disappear. ily inflammatory disorders of the elderly: 55 (c) Elimination of Demodex

Demodex folliculorum is a mite which strongly colonizes the facial follicles of older persons. The

5 7 EP 0 357 646 B1 8 clinical signs are often subtle and go unrecognized collagen and enlargement of the sebaceous glands, by most physicians, including dermatologists. Usu- usually an end-stage of chronic rosacea. The latter ally, there is little more than scaling and follicular can reach huge size with a knobby appearance of thickening, some perifollicular erythema, and small the nose. Cis-retinoic acid, given orally, greatly papules, associated with sensitive skin. Histology 5 reduces the volume of nasal tissue in this con- always shows perifollicular inflammation and seba- dition. We have also recognized a variant not asso- ceous follicles crowded with mites. Invariably, ap- ciated with rosacea which we have called actinic plication of soaps, perfumes, astringents, alcohols, rhinophyma. The nose becomes chronically red- mild acids (e.g., lactic acid) includes intense sting- dened, with large, depressed pores, variably ening, owing to the sub-clinical inflammatory reaction. io larged, uneven surface, accompanied by oiliness. It Demodex infestation is very common, rarely di- is quite common in males with photodamaged skin. agnosed, but an important source of discomfort, Low-dosage oral cis-retinoic acid reduces the nasal contributing to a coarser appearance. It may be enlargement with a marked improvement of the associated with small papulo-pustules. In short, surface topography. Classic rhinophyma also re- when Demodex are numerous, typically so in sun- 15 sponds to a substantial degree. damaged skin, there is subclinical disease. Demodex takes its nourishment from sebum. It (f) Hyperkeratosis and abnormal epithelial growths disappears after cis-retinoic acid treatment because of deprivation of lipoid nutrients. Topical retinoic The stratum corneum becomes focally thick- acid, because it does not cause atrophy of seba- 20 ened in aged skin, accentuating dryness and scali- ceous glands, has no effect on Demodex infesta- ness. The surface becomes rough, brittle and sca- tion. ly. Oral cis-retinoic acid according to the invention thins down the horny layer and eliminates keratotic (d) Elimination of resident bacteria and yeasts scale. The surface, therefore, becomes very much 25 smoother. Incipient seborrheic keratoses (benign Propionibacteria are lipid dependent organisms tumors) become less evident. which disappear when sebum secretion is reduced. They make a number of enzymes and products (g) Epidermal atrophy which are potentially harmful to skin, viz, lipases, proteases and comedogenic substances which pro- 30 The viable epidermis becomes thin in the el- duce horny impactions within the follicles (pseudo- derly; the cells are smaller and somewhat dis- comedones). All this contributes to poor skin tex- orderly. Low dosage cis-retinoic acid induces thick- ture and tolerance to irritants. ening of the epidermis with larger, more normal- Pityrosporon species are follicular yeasts which looking epidermal cells. A more normal, thicker induce folliculitis and a weakening of the follicular 35 epidermis contributes to a better textured skin with wall. They are also comedogenic, and add to fol- more fullness. These particular effects are like licular hyperkeratosis. They too are lipophilic or- those of topical retinoic acid, but slower and of ganisms which disappear when the supply of se- lesser magnitude. There occurs acanthosis (epider- bum is reduced. mal thickening), return to normal patterns, correc- Oral cis-retinoic acid therapy results in follicular 40 tion of dysplasia, atypia, etc. This results in debridement with extrusion of retained horn. This smoother, nicer skin. Inhibition of tumor promotion elimination of horny material and vellus hairs also is probable but has not been proved. We have improves appearance since the follicular orifices observed that "flares" of subclinical actinic become smaller and are not distended with re- keratoses (pre-neoplastic growths) can be resolved. tained products. A result of eliminating follicular 45 contents, along with sebaceous gland shrinkage, is (h) Follicular papules and pustules that the population of P. acnes, P. ovales and Demodex strikingly diminishes. Sensitivity to exter- These are not acne but acneiform lesions. nal stimuli goes down and the skin returns to a These are scattered pimples which might be a more normal state. Before treatment, swabbing the 50 result of Demodex, bacteria (see above) or from cheek with 10% lactic acid produces great stinging cosmetics, soaps, etc. We are not referring to solar in many individuals. After treatment, stinging is comedones either, though these too are reduced. absent or slight. These are inflammatory follicular lesions of varied origin. With oral cis-retinoic acid treatment accord- (e) Actinic rhinophyma 55 ing to the invention, they disappear in 2-3 months to the great satisfaction of the users. Classical rhinophyma is an uneven enlargement of the nose due to increased deposition of

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(i) Seborrheic-like dermatitis 11) Reduction of microbial population of bacteria and fungi, along with Demodex folliculorum. This dermatitis is very common in older per- Aside from the positive benefits described sons, especially males. This is an inflammatory above for oral cis-retinoic acid therapy, laboratory condition which clears with low-dose oral cis-re- 5 studies with the present invention show none of the tinoic acid. Scaliness and redness regress. abnormalities commonly associated with the higher As is known in the art, oral cis-retinoic acid doses (40 to 80 mg) used for treating acne. Spe- therapy results in profound suppression of sebum cifically, the following values have remained normal production as a result of atrophy of the sebaceous in all subjects: triglycerides, cholesterol, liver en- glands, an effect not attainable by topical retinoic io zymes, SGOT and SGPT. These are elevated in acid. Measurements of sebum production after 6 one-third of patients receiving 80 mg daily. This months of treatment show 45 to 65% reduction in greatly improves safety and eliminates problems in all patients. Shrinkage of the sebaceous glands is patients with a familial or personal history of heart reversible after stopping use of the drug. Moreover, disease, obesity, hypercholesteremia, etc. oral cis-retinoic acid has an anti-inflammatory ef- is Adverse muco-cutaneous reactions are very fect, moderating chronic dermatitis. common with 40 to 80 mg doses. These include dry eyes, mouth and nose, cheilitis, itchy, and red (j) Facial lines and wrinkles friable skin. All of these are absent so that close monitoring by clinical and laboratory tests is un- The dermatalogic literature does not recognize 20 necessary. that finer alterations in facial texture, complexion, Laboratory follow-up of these patients reveals scaliness, etc. are amenable to cis-retinoic acid no changes in blood or urinary chemistries. SMA orally, at any dose. In fact, prior art treatments of 12's have remained within normal limits. No ad- various skin disorders with high doses of oral cis- verse effects have been encountered, despite care- retinoic acid have resulted in a worsening of the 25 ful surveillance for signs of hypervitaminosis A. No appearance and aesthetic quality of the skin, owing toxicity of any kind has been encountered, and it is to excessive scaling and dryness. believed that the doses of the invention are below a With the oral 13-cis-retinoic acid treatment ac- teratogenic dose as well. cording to the invention, effacement of fine wrinkles Quantitative bacteriology shows a sharp reduc- has unexpectedly been observed. While applicants 30 tion in anaerobic bacteria, principally P. acnes, do not wish to be bound by any particular theory, it along with virtual disappearances of yeast-like fungi is believed that this treatment may result in a (P. species) The latter fungi contribute to sebor- laying down or depositing of glycocollagen or rheic-like dermatitis in older persons. Cyanocrylate glycoproteins in the epidermis, and/or possibly a surface biopsies have shown elimination of the mite rehydration of the horny layer. This appears to be a 35 Demodex folliculorum. different mechanism from the effacement of lines The present invention may be embodied in and wrinkles with topical retinoic acid treatments. other specific forms without departing from the In summary, the low-dose oral cis-retinoic acid spirit or essential attributes thereof, and, accord- therapy according to the present invention results ingly, reference should be made to the appended in the following improvements in the skin: 40 claims, rather than the specification, as indicating 1) Improved texture of the skin; the scope of invention. 2) Reduced mottling-more uniform pigmentation; 3) Elimination of retained skin products in fol- Claims licles, viz. hairs and horny material; 4) Control of follicular pustules and papules; 45 1. The use of 13-cis-retinoic acid for the produc- 5) Shrinkage of sebaceous glands with disap- tion of a medicament in an oral dosage form pearance of "stippled neck," knobby skin and comprising 1 to 5 mg 13-cis-retinoic acid for sebaceous gland hyperplasia; the administration to women over child-bearing 6) Reduction of facial skin oiliness in persons age and males over 50 years once per day or with excessive oiliness (seborrhea) to a pleasant 50 once every second day for retarding and re- normal skin appearance; versing various age-related and associated dis- 7) Reduction of nasal deformity in actinic orders of the skin of elderly humans, said rhinophyma; disorders being a mixture of conditions se- 8) Inhibition of actinic keratoses; lected from sebaceous gland hyperplasia, dis- 9) Improved skin turgor and elasticity; ss tended sebaceous follicles, actinic rhinophyma, 10) Elimination of signs of seborrheic-like der- hyperkeratosis, elderly seborrheic-like dermati- matitis, a common skin condition; and tis, demodex infestation of follicles, rosacea- like redness and swelling, epidermal atrophy,

7 11 EP 0 357 646 B1 12

fine lines and wrinkles due to photoaging, ac- 4. Verwendung von 13-cis-Retinsaure gemaB An- celerated hair loss due to dermatitis or in- spruch 1, wobei die therapeutisch wirksame flammation associated with androgenic al- Menge auf eine Erhaltungsdosis von 1 bis 5 opecia, and Pityrosporon-induced folliculites. mg zwei- oder dreimal pro Woche nach Erlan- 5 gung eines therapeutischen Erfolges reduziert 2. The use of 13-cis-retinoic acid according to ist. claim 1 wherein the therapeutically effective amount is less than 2.5 mg daily. 5. Verwendung von 13-cis-Retinsaure gemaB An- spruch 1, wobei die orale Verabreichung in 3. The use of 13-cis-retinoic acid according to io Kapselform erfolgt. claim 1 wherein the therapeutically effective amount is 1 to 2 mg daily or every other day. Revendicatlons

4. The use of 13-cis-retinoic acid according to 1. Emploi de I'acide 13-cis-retino'fque pour la fa- claim 1 wherein the therapeutically effective 15 brication d'un medicament destine a etre ad- amount is reduced to a maintenance dose of 1 ministre par doses orales contenant de 1 a 5 to 5 mg two or three times a week after mg d'acide 13-cis-retino'fque, a des sujets fe- achieving therapeutic benefit. minins ayant depasse I'age de la maternite et a des sujets masculins de plus de cinquante 5. The use of 13-cis-retinoic acid according to 20 ans, a raison d'une fois par jour ou d'une fois claim 1 wherein the oral administration is in tous les deux jours, afin de retarder et faire capsule form. regresser divers desordres de la peau dus a I'age et qui se manifestent chez les sujets Patentanspruche ages, ces desordres correspondant a un me- 25 lange selectif des conditions ci-apres: hyper- 1. Verwendung von 13-cis-Retinsaure fur die Her- plasie des glandes sebacees, distension des stellung eines Medikamentes in oraler Dosie- follicules sebaces, rhinophyma actinique, hy- rungsform enthaltend 1 bis 5 mg 13-cis-Retin- perkeratose, dermatite quasi seborrhei'que due saure zur Verabreichung an Frauen jenseits a I'age, infestation des follicules par des de- des Gebaralters und Manner uber 50 Jahren 30 modex, rougeur rosacee et inflammation asso- einmal taglich oder einmal jeden zweiten Tag ciee, atrophie de I'epiderme, lignes fines et zur Verzogerung und Ruckbildung verschiede- rides dues au vieillissement sous I'effet de la ner altersbedingter und mit dem Alter verbun- lumiere, perte acceleree des cheveux due a dener Storungen der Haut bei alteren Men- une dermatite ou une inflammation associee a schen, wobei diese Storungen aus einer Kom- 35 une alopecie androgenique, et folliculites indui- bination von Zustanden von Talgdrusenhyper- tes par des pityrospores. plasie, erweiterten Talgdrusenfollikeln, aktini- schem Rhinophym, Hyperkeratose, seborr- 2. Emploi de I'acide 13-cis-retino'fque selon la hoisch-ahnlicher Dermatitis der alteren Men- revendication 1 , caracterise en ce que la dose schen, Demodexbefall von Follikeln, Rosazea- 40 therapeutiquement efficace est inferieure a 2,5 ahnlicher Rotung und Schwellung, Epidermal- mg par jour. Atrophie, feine Linien und Faltchen infolge von Altern durch Lichteinwirkung, beschleunigtem 3. Emploi de I'acide 13-cis-retino'fque selon la Haarausfall infolge von Dermatitis oder Entun- revendication 1 , caracterise en ce que la dose dung verbunden mit androgenetischer Alopezie 45 therapeutiquement efficace est comprise entre und durch Pityrosporon-Hefen hervorgerufener 1 et 2 mg par jour ou tous les deux jours. Follikulitis ausgewahlt sind. 4. Emploi de I'acide 13-cis-retino'fque selon la 2. Verwendung von 13-cis-Retinsaure gemaB An- revendication 1, caracterise en ce qu'on reduit spruch 1, wobei die therepeutisch wirksame 50 la dose therapeutiquement efficace a une dose Menge weniger als 2,5 mg taglich betragt. d'entretien de 1 a 5 mg, a raison de deux ou trois fois par semaine apres avoir obtenu le 3. Verwendung von 13-cis-Retinsaure gemaB An- bienfait therapeutique. spruch 1, wobei die therepeutisch wirksame Menge 1 bis 2 mg taglich oder jeden zweiten 55 5. Emploi de I'acide 13-cis-retino'fque selon la Tag betragt. revendication 1, caracterise en ce que I'administration orale s'effectue sous forme de capsules.