Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – 9,10-seco- cyclopentanohydrophenanthrene ring system doai
Patent
1992-06-11
1994-03-08
Waddell, Frederick E.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
9,10-seco- cyclopentanohydrophenanthrene ring system doai
514171, 514859, 552653, A61K 31595
Patent
active
052927270
DESCRIPTION:
BRIEF SUMMARY
This invention relates to the use of certain Vitamin D analogues in the preparation of a pharmaceutical preparation for the treatment of acne.
Among the factors contributing to the aetiology of acne, an increased sebum production appears to be of major importance, as the severity of the acne parallels sebum excretion rates.
In accordance with this, the reduction of sebum production induced by treatment with oestrogens or isotretinoin leads to an improvement in acne. However, the hormonal effects of the former precludes its widespread use, and isotretinoin is teratogenic and is only used for very severe acne due to this and other side effects (Drug and Therapeutics Bulletin, Vol. 22, No. 24, Dec. 3, 1984).
Recently it has been found that topical application of 1.alpha., 25-dihydroxyvitamin D.sub.3 (1.alpha., 25-(OH).sub.2 D.sub.3 reduces the size of sebaceous glands in the ear of male Syrian hamsters (V. L. Malloy et al, The tricontinental Meeting for Investigative Dermatology, Washington, USA, 1989).
However, this observation may be of limited utility in the human medicine because transdermal absorption after topical application of 1.alpha., 25-(OH).sub.2 D.sub.3 or systemic treatment with this compound, may, due to its potent calcemic activity, give rise to undesired effects leading to hypercalcemia.
However, by choosing a vitamin D analogue which has only moderate activity on calcium metabolism compared to 1,25-(OH).sub.2 D.sub.3, but having retained the ability to activate receptors for 1,25-(OH).sub.2 D.sub.3 not associated with calcium absorption or bone calcium mobilization it is possible to treat acne successfully without having the risk of inducing hypercalcemia.
Examples of such vitamin D analogues for use in the present pharmaceutical preparations are PCT/DK86/00081, international filing date 14th Jul., 1986, International Publication No. WO 87/00834, in particular the compound designated MC 903 (example 5 in said patent application) (confer also Calverley, M., Tetrahedron 43, 4609-4619 (1987); Binderup, L. and Bramm, E., Biochemical Pharmacology 37, 889-895 (1988)), PCT/DK89/00079, international filing date 7th Apr., 1989, in particular Compound 35 (Example 2), Compound 37 (Example 4), Compound 38 (Example 5), Compound 54 (Example 9), Compound 55 (Example 10), and Compound 59 (Example 12) their 22,23-didehydro-analogues) (Ostrem, V. K. et al, Proc. Natl. Acad. Sci. USA 84, 2610-2614 (1987)), 22-oxa-1.alpha.,25-dihydroxyvitamin D.sub.3 (Abe, J. et al, FEBS Letters 226, 58-62 (1987)), and and 24,24-difluoro-24-homo-1.alpha.,25dihydroxyvitamin D.sub.3 (Ikekawa, N. et al, Chem. Pharm. Bull. 35, 4362-65 (1987)),
The mentioned compounds shall form part of pharmaceutical preparations, in particular for topical use, which are useful in the treatment of human disorders as described above, such as a liniment, a lotion or a cream which in addition to the vitamin D analogues in question may contain further active ingredients. The concentration of the active ingredients will depend upon the choice of vitamin D analogues but will generally be between 1 and 100 .mu.g/g.
The formulations will be applied once or twice daily for prolonged periods of time.
The formulations prepared according to the present invention comprise an active compound in association with a pharmaceutically acceptable carrier therefore and optionally other therapeutic ingredient(s). The carrier(s) must be "acceptable" in the sense of being compatible with the other ingredients of the preparations and not deleterious to the recipient thereof.
The preparations may conveniently be prepared by any of the methods well known in the art of pharmacy. All methods include the step of bringing the active compound into association with the carrier which constitutes one or more accessory ingredients. In general, the preparations are prepared by uniformly and intimately bringing the active compound into association with a liquid carrier or a finely divided solid carrier or both, and then, if necessary, shaping the product into the desired preparation.
P
REFERENCES:
patent: 5104864 (1982-04-01), DeLuca
patent: 5145846 (1992-09-01), Baggiolini et al.
Abstract of WO 87/00834 (1987).
Calverley, M., Tetrahedron, 43:4609-4619 (1987).
Binderup, L. and Bramm, E., Biochemical Pharmacology, 37:889-895 (1988).
Ostrem, V. K. et al. Proc. Natl. Acad. Sci. USA, 84:2610-2614 (1987).
Abe, J. et al. FEBS Letters, 226:58-62 (1987).
Ikekawa, N. et al. Chem. Pharm. Bull., 35:4362-4365 (1987).
Murdoch et al., "Calcipotriol", Drugs, 43(3):415-429 (1992).
Kragballe, Arch. Dermatol. Res., 284(Supp):S:30-36 (1992).
Chatelus et al., Pharmacol. Skin Basel Karger, 3:144-148 (1989).
Bouclier et al., Skin Pharmacol., 4:65-73 (1991).
Binderup et al., Biochemical Pharmacology, 42(8):1569-1575 (1991).
Chemical Abstracts, vol. 112, No. 10, Mar. 5, 1990, p. 446.
Chemical Abstracts, vol. 109, Jul. 4-25, 1988, pp. 391.
Schwetz, Rundschau Med. (PRAXIS), vol. 69, No. 7., 1980, A. Lassus: "Die Nachbehandlung Der Akne", pp. 225-227.
Criares T. J.
Leo Pharmaceutical Products Ltd.
Waddell Frederick E.
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