Treatment of Acne Or of Pseudofolliculitis Barbae Behandlung Von Akne Oder Von Folliculitis Barbae Traitement De L'acne De La Pseudofolliculite De La Barbe

Patentamt Europaisches || || 1 1| || || || 1 1|| 1 1| || || || � European Patent Office

Office europeen des brevets (1 1 ) EP 0 610 368 B1

(12) EUROPEAN PATENT SPECIFICATION

(45) Date of publication and mention (51 ) |nt. CI.6: A61 K 7/1 5, A61 K 7/48 of the grant of the patent: 23.12.1998 Bulletin 1998/52 (86) International application number: PCT/US92/09128 (21) Application number: 92922984.7 (87) International publication number: (22) Date of filing: 28.10.1992 w0 93/08790 (13.05.1993 Gazette 1993/12)

(54) TREATMENT OF ACNE OR OF PSEUDOFOLLICULITIS BARBAE BEHANDLUNG VON AKNE ODER VON FOLLICULITIS BARBAE TRAITEMENT DE L'ACNE DE LA PSEUDOFOLLICULITE DE LA BARBE

(84) Designated Contracting States: (74) Representative: AT BE CH DE DK ES FR GB GR IE IT LI NL SE Baillie, lain Cameron et al Ladas & Parry, (30) Priority: 30.10.1991 US 785032 Altheimer Eck 2 80331 Munchen (DE) (43) Date of publication of application: 17.08.1994 Bulletin 1994/33 (56) References cited: US-A- 4 207 31 5 US- A- 4 720 489 (73) Proprietor: THE GILLETTE COMPANY US.A. 4 651 Boston, Massachusetts 02199 (US) • Taber's Cyclopedic Medical Dictionary, 13th (72) Inventors: edition, 1977, A-26 • SHANDER, Douglas . inhibition of Polyamine Metabolism; Peter Gaithersburg, MD 20878 (US) McCann et al., 1 987, Academic Press, London, • HARRINGTON, F. Eugene page 197 New Market, MD 21774 (US) • WHITMORE, Mary Claire Lynchburg, VA 24503 (US)

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).

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Description no unwanted side effects. Among the preferred inhibitors of ornithine decarboxylase, in addition to DFMO, This invention relates to the use of the ornithine which can be used in the present invention, are alpha- decarboxylase (ODC) inhibitors for the treatment of ethynyl ornithine; 6-heptyne-2,5-diamine; and esters of acne and pseudofolliculitis barbae (PFB). s (E)-2-fluoromethyldehydroornithine. In choosing ODC Although the exact mechanisms leading to acne inhibitors for use in the practice of the present invention are not known, antiandrogens, retinoic acid, steroids it is important to avoid those having undesirable sec- and antibiotics, inter alia have generally been proposed ondary pharmacological effects such as 5-hexyne-1 ,4- for its treatment, as described in U.S. Patent Nos. diamine. The inhibitors of ornithine decarboxylase are 4,139,638; 4,161,540; 4,191,775; 4,344,943; and West w employed by dissolving or dispersing them in a conven- German OLS no. 2,840,144. tional non-toxic pharmacologically acceptable vehicle or PFB relates to the removal of hair by shaving or carrier which may be in the form of a lotion, cream, plucking. It has been treated by procedures such as the salve, ointment, or stick composition; while the precise use of electric clippers or depilatories for hair removal, concentration of inhibitor in vehicle or carrier is not criti- or by topical treatment with tretinoin (Retin-A), benzoyl is cal it is generally desired that the composition contain peroxide, chlorohydroxyquinoline, chloroalkylphenols, from 1 to 20% of inhibitor by weight so that it can be phospholipids in combination with wheat germ oil and applied to the affected areas of the skin of patients suf- vitamin E, alpha-hydroxy acids, salicylic acid in combi- fering from acne or PFB, particularly to the pimples or nation with glucocorticoids and sulfur as shown for inflamed areas of the skin, at the rate of 40 to 800 micro- example in U.S. patents 4,228,163, 4,463,016; 20 grams per square centimeter. The composition is prefer- 4,525,344; 4,775,530; and 4,944,939; and in Klingman ably applied only to the pustules, vacuoles or inflamed et al., Arch. Dermatol., vol. 107, 551-52 (1973). areas of the skin although application to adjacent areas Many of the treatments for PFB, and particularly for need not be avoided. acne, produce such serious side effects that the treat- The following examples will serve to illustrate fur- ment can be justified only in the most severe cases; 25 ther the nature of the invention without acting as a limi- other treatments are of limited effectiveness. tation upon its scope. According to the present invention there is provided the use of an inhibitor of the enzyme ornithine decar- EXAMPLE 1 boxylase for the manufacture of a medicament for the treatment of pseudofolliculitis barbae. 30 Ten women suffering from mild to moderately Also, according to the present invention there is severe grades of acne treated themselves twice daily provided the use of 2-(difluoromethyl)-2,5-diaminopen- over a 6 month period with an aqueous based vehicle tanoic acid for the manufacture of a medicament for the (68% water, 16% ethanol, 5% propylene glycol, 5% treatment of acne. dipropylene glycol, 4% benzoyl alcohol, and 2% propyl- US-A-4786651 discloses the use of manoalide for 35 ene carbonate) containing 10g of DFMO per 100 ml of the treatment of acne. the total composition. Dermatological observations US-A-4720489 discloses that the compound 2-(dif- were recorded by a dermatologist who noted skin condi- luoromethyl)-2, 5-diaminopentanoic acid has ornithine tions prior to treatment, at 12 and 24 weeks of treat- decarboxylase inhibiting activity. ment, and 1 2 weeks after withdrawal of treatment. The compound 2-(difluoromethyl) ornithine (DFMO, 40 Of the ten women on treatment nine showed signif- 2-difluoromethyl-2. 5-diaminopentanoic acid) and other icant improvement in their acne condition. Of the nine inhibitors of ornithine dicarboxylase have been pro- who responded, four demonstrated complete resolution posed for use in treating cancer and certain non-malig- of acne within 1 2 weeks, and a fifth subject, for whom no nant diseases such as erythroderma, psoriasis, and 1 2 week observation was available, exhibited complete some forms of dermatitis, etc. as described in Splinter 45 clearance by the 24th week. The four subjects in which et al., Eur. J. Cancer and Clin. Oncology. Vol. 22:I-E, 61 - acne was not completely cleared demonstrated pro- 67 (1985); McCullough et al. J. Investig. Dermatology. gressively marked improvements through the course of Vol. 85, 518-521 (1985); McCullough et al., J. Investig. treatment. After cessation of treatment at twenty-four Dermatology. Vol. 81, 388-392 (1983); Kousa et al., weeks, continued observations were made on the nine Acta Dermatovener (Stockholm) Vol. 62, 221-224 so of the original 10 subjects including the eight who (1982); and U.S. Patent 4,207,315. responded to treatment. This post treatment follow up It has now been found that topical administration of revealed that seven of eight exhibited a recurrence of a cytostatic nontoxic agent such as 2(difluoromethyl)- acne after withdrawal of treatment. The total clearance 2.5-diaminopentanoic acid (d-difluoromethylornithine, or marked improvement in acne in 9 of 10 subjects after DFMO) which inhibits the activity of the enzyme orni- ss treatment with elfluornithine and its recurrence after thine decarboxylase can be used to effectively amelio- treatment cessation demonstrates the efficacy of rate or control PFB, and that DFMO can be used to DFMO. ameliorate or control acne, in patients with minimal or

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EXAMPLE 2

Nine women suffering from pseudofolliculitis treated themselves and were evaluated as described in Example 1. Five exhibited complete clearance, four of s whom cleared within 12 weeks. Four additional women showed progressive improvements during 24 weeks of treatment. Of the nine women with pseudofoliculitis six were women from the group of 10 in Example 1 who suffered from acne as well. In the six women with both 10 acne and PFB, three demonstrated complete clearing of both conditions and the other three exhibited substantial clearing of both conditions.

Claims w

1. The use of an inhibitor of the enzyme ornithine decarboxylase for the manufacture of a medicament for the treatment of pseudofolliculitis barbae. 20 2. The use as claimed in claim 1 in which said inhibitor is 2-(difluoromethyl)-2,5-diaminopentanoic acid.

3. The use of 2-(dif luoromethyl)-2,5-diaminopentanoic acid for the manufacture of a medicament for the 25 treatment of acne.

Patentanspruche

1 . Verwendung eines Inhibitors des Enzyms Ornithin- 30 decarboxylase fur die Herstellung eines Medika- ments fur die Behandlung von Pseudofolliculitis barbae.

2. Verwendung nach Anspruch 1 , wobei der Inhibitor 35 2-(Difluormethyl)-2,5-diaminopentansaure ist.

3. Verwendung von 2-(Difluormethyl)-2,5-diaminopentansaure fur die Herstellung eines Medikaments fur die Behandlung von Akne. 40

Revendications

1. Utilisation d'un inhibiteur de I'enzyme ornithine decarboxylase pour la fabrication d'un medicament 45 pour le traitement de la pseudofolliculite de la barbe.

2. Utilisation selon la revendication 1, dans laquelle ledit inhibiteur est I'acide 2-(difluoromethyl)-2,5-dia- so minopentanoi'que.

3. Utilisation de I'acide 2-(difluoromethyl)-2,5-diami- nopentanoi'que pour la fabrication d'un medicament pour le traitement de I'acne. 55