Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Cyclopentanohydrophenanthrene ring system doai
Patent
1993-08-24
1997-03-25
Shah, Mukund J.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Cyclopentanohydrophenanthrene ring system doai
540 63, C07J 7100, A61K 3158
Patent
active
056145144
DESCRIPTION:
BRIEF SUMMARY
FIELD OF INVENTION
The present invention relates to novel anti-inflammatory and anti-allergic active compounds and to processes for their preparation. The invention also relates to pharmaceutical compositions containing the compounds and to methods of the pharmacological use of the composition.
The object of the invention is to provide an anti-inflammatory, immunosuppressive and anti-allergic glucocorticosteroid or a pharmaceutical composition thereof with high activity at the application place, e.g. in the respiratory tract, on the skin, in the intestinal tract, in the joints or in the eye, directing the drug to delimited target area, thereby inducing low glucocorticoid systemic effects.
A further object of the invention is to provide a pharmaceutical composition containing liposomes including a pharmacologically active steroid fatty acid ester of the invention in order to improve drug delivery and to minimize side effects of the therapy.
BACKGROUND ART
Glucocorticosteroids (GCS) are the most valuable drugs for relief of asthma and rhinitis. It is widely accepted that GCS exert their therapeutic efficacy by anti-inflammatory and anti-anaphylactic actions within airway and lung tissue. The long term oral use of GCS is greatly hampered by severe side effects outside the lung region. Accordingly, only a minor part of patients with asthma or rhinitis currently undergo oral GCS therapy. A better safety can be reached by delivering GCS by inhalation. However, also the potent inhaled GCS in current wide clinical use--beclomethasone 17.alpha.,21-dipropionate and budesonide--have a rather narrow safety margin and for both unwanted GCS actions within the general circulation have been reported with the highest of the recommended doses for inhalation.
Liposomes are membrane-like vesicles consisting of series of concentric lipid bilayers alternating with hydrophilic compartments. Liposomes have been used as carriers for different kinds of pharmaceutically active compounds in order to improve drug delivery and to minimize side effects of the therapy.
Glucocorticosteroids are incorporated into liposomes only at a low concentration and are poorly retained in the vesicles. Esterification of GCS in 21-position with fatty acids increases the degree of incorporation and the retention of the steroid in the vesicles. It has been shown that the fatty acid chain acts as a hydrophobic "anchor" which holds the steroid nucleus in the hydrated polar head groups of the phospholipid and thereby improves the interaction between the glucocorticosteroid and the liposome.
Liposome-encapsulated glucocorticosteroids for therapeutic use have been described (M. De Silva et al., Lancet 8130 (1979), 1320) and U.S. Pat. No. 4,693,999 describes liposomal formulations of glucocorticosteroids for inhalation.
DISCLOSURE OF THE INVENTION
One object of the present invention is to provide new GCS compounds. The new compounds are characterized by anti-inflammatory, immunosuppressiv and anti-anaphylactic potency at the application site and particularly they have a markedly improved relationship between that potency and the activity to provoke GCS actions outside the treated region. The preferred mode of administration of the new compounds is by inhalation when the application site is within the airways.
Another object of the invention is to provide an anti-inflammatory and anti-allergic pharmaceutical composition containing steroid ester liposomes for local administration primarily to the respiratory tract. Such a composition provides for an improvement of the therapeutic properties of the steroid ester by a prolongation of the local retention in the airways and a direction of the drug to specific target cells.
The compounds of the invention are characterized by the formula ##STR2## or a stereoisomeric component thereof, in which formula the 1,2-position is saturated or is a double bond,
R.sub.1 is hydrogen or a straight or branched hydrocarbon chain having 1-4 carbon atoms,
R.sub.2 is hydrogen or a straight or branched hydrocarbon chain having 1-
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Axelsson Bengt
Brattsand Ralph
Kallstrom Leif
Thalen Arne
Aktiebolaget Astra
Bottino Anthony
Shah Mukund J.
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