Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Cyclopentanohydrophenanthrene ring system doai
Patent
1995-05-17
1998-02-24
Henley, III, Raymond
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Cyclopentanohydrophenanthrene ring system doai
A61K 3158
Patent
active
057212287
DESCRIPTION:
BRIEF SUMMARY
This is a 371 of PCT/EP93/03228 filed Nov. 18, 1993.
FIELD OF THE INVENTION
The present invention relates to topical rectal therapeutic compositions containing, the as active ingredient, flunisolide and/or ester derivatives of same in combination with suitable excipients and/or diluents, for the treatment of inflammatory intestinal disorders.
STATE OF THE ART
Among all inflammatory intestinal diseases, ulcerative colitis is certainly the best known. It essentially affects the large intestine, in particular and most severely the rectum, but sometimes, either marginally or entirely, the colon too.
Other types of inflammatory intestinal diseases may affect the rectum and result in a mild ulcerative colitis or in a slightly different, but pathologically similar syndrome, such as proctitis and sigmoiditis.
Another inflammatory intestinal disease is the so-called Crohn's disease, which affects the large intestine only marginally.
A known treatment of the above pathologies consists in the systemic and topical administration of corticosteroids, such as hydrocortisone, betamethasone, and prednisolone.
However, the systemic administration of the aforesaid drugs produces serious side effects, mainly related to the interference with the hypothalamus-hypophysis-adrenal gland axis.
Also the topical administration of said corticosteroids causes interference with the hypothalamus-hypophysis-adrenal gland axis, since said drugs are inevitably absorbed by the systemic route. The side effects more frequently arising from the topical treatment of ulcerative colitis with the aforesaid traditional corticosteroids are: transient or prolonged depression of adrenal gland functionality, weight increase, acne, and facies lunaris. It is to be noted that a characteristic of ulcerative colitis is an inflammed intestinal mucosa, which facilitates the systemic absorption of the drugs which are usually administered over an extended period of time. Therefore, the need of developing a corticosteroid exerting a high therapeutic activity in the treatment of inflammatory intestinal diseases and involving a reduced systemic absorption was deeply felt.
Takai et al. (J. Pharmacobiodyn. vol. 5, no. 3, 1982, pages 200-207, database Medline abstract) teach that flunisolide is highly active in topical use, while systemically it is relatively weak; these characteristics could be attributable to its rapid metabolic inactivation in the liver. Nevertheless it gives no indication of the absorption levels of fluticasone and its noxious effects, and there is no suggestion that it would be of use in treating inflammatory intestinal disorders.
Flunisolide is a corticosteroid having formula ##STR1## and is used for the treatment of asthma chiefly as nasal and bronchial topical preparations, of glaucoma as ophthalmic topical preparations, of allergic or inflammatory conditions of the skin as creams and ointments.
This molecule is characterized by not high absorption levels and by a metabolic process (hepatic first pass) which rapidly transforms same into the metabolite 6-.beta.-hydroxyderivative, whose glucocorticoid activity is approx. 350 times lower than that of flunisolide.
In other words, the amount of flunisolide inevitably absorbed by the systemic way after topical application can never reach plasma levels interfering with the hypothalamus-hypophysis-adrenal gland axis.
THE PRESENT INVENTION
It has surprisingly been found that flunisolide and its esters administered by the topical rectal way are very active in the treatment of the aforesaid intestinal disorders and--unlike the steroids known so far--do not cause the adverse effects related to the interference with the hypothalamus-hypophysis-adrenal gland axis.
In fact, clinical trials carried out by the Applicant evidenced that an improvement of the basal symptomatology was obtained as early as after a 15-day topical rectal treatment at doses of 2 mg/die and that a 3-mg/die administration for 30 days did not cause any appreciable clinical modification to cortisol plasmatic concentrations, an in
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Physicians Desk Reference, 46th ed. pp. 2244-2245, 1992.
Craig et al., "Modern Pharmacology", pp. 15-16, 1982.
Takai, et al., "The Predominance of Flunisolide In The Topical Use Of Anti-Inflammatory Steroids", J. Pharmacobiodyn, vol. 5, No. 3, 1982,pp. 200-207 (Abstract)*.
Bernareggi Virgilio
Fano Maurizio
Gagnoni Alessandro
Henley III Raymond
Valeas S.p.A. Industria Chimica E Farmaceutica
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