Nor- and homo- bile acids derivatives as absorption enhancers fo

Details Nor- and homo- bile acids derivatives as absorption enhancers fo Nor- and homo- bile acids derivatives as absorption enhancers fo

1994-12-28

1997-08-12

Kishore, Gollamudi S.

Drug, bio-affecting and body treating compositions

Preparations characterized by special physical form

424435, 424451, 424464, 424436, 424489, 514169, 514171, 514182, 514553, 514569, A61K 902, A61K 908, A61K 920, A61K 3119

Patent

active

056562772

DESCRIPTION:

BRIEF SUMMARY
The present invention relates to the use of nor- and homo-bile acids derivatives (hereinafter named NORAB and HOMOAB, respectively) as absorption enhancers for medicaments.
Particularly, the invention relates to the use of nor- and homo-bile acids derivatives having respectively the following formulae: ##STR1## wherein:


______________________________________ R.sub.1 R.sub.2 R.sub.3 R.sub.4 ______________________________________ a) .alpha.-OH .alpha.-OH H H b) .alpha.-OH .beta.-OH H H c) .alpha.-OH H .alpha.-OH H d) .alpha.-OH H .beta.-OH H e) .alpha.-OH H H .beta.-OH ______________________________________ ##STR2## wherein:


______________________________________ R.sub.1 R.sub.2 R.sub.3 R.sub.4 ______________________________________ f) .alpha.-OH .alpha.-OH H H g) .alpha.-OH .beta.-OH H H h) .alpha.-OH H .alpha.-OH H i) .alpha.-OH H .beta.-OH H l) .alpha.-OH H H .beta.-OH ______________________________________
It is also an object of the invention the use of the corresponding NORAB and HOMOAB conjugated respectively in C.sub.23 and C.sub.25 with taurine, glycine and alanine.
The present trend for pharmacological therapy, particularly in the case of slight disorders or of treatments involving multiple administrations repeated in time, and therapies for conscious patients, is the self-administration by the patient itself. From this point of view, the preferred administration routes are the enteral, i.e. buccal, rectal and intranasal ones.
The medicament administered through these routes, once released from the pharmaceutic form containing it (tablet, suppository, aerosol, and the like), must cross the different mucosae coating the gastrointestinal tract and the nasal cavity, in order to enter the circulatory stream and be distributed in the various body districts thus reaching the action site.
Due to the complex nature of the mucosae and the different chemical structure of the medicaments, the crossing of the mucosae involves different difficulties, depending on the kind of medicament and the type of mucosa.
One of the main problems involved in the design of medicaments consists in the need to give the pharmacologically active compound those hydrophilic characteristics which are generally required to have the active principle dissolved in the biological liquids (serum, interstitial liquid) and sometimes also lipophilic characteristics to cross the mucosa, which generally consists of a more or less complex cell barrier.
This approach finds a number of difficulties from the viewpoint of the medicament design, both in the synthesis and in the pharmacokinetic expectation.
A different approach to this problem consists in combining the active principle with a compound enhancing the absorption of the medicament through the mucosa.
Due to the single chemico-physical peculiarities of the different medicaments, up to now it was necessary to look for absorption enhancers suitable for both the considered medicament and the involved mucosa.
Bile acids (BA) are natural detergents capable of forming, with other poorly water-soluble medicaments, mixed micells with phospholipids and cholesterol at a relatively low concentration (1-4 mM).
Moreover, thanks to the structure thereof, they are also relatively lipophilic (log p=2.div.4) and therefore they can passively cross the biologic membranes. The bile acids crossing and partitioning in the lipidic domain exert their activity in this microenvironment modifying the cholesterol content and therefore increasing the permeability to other substances.
A bile acid designed to be an enhancer, moreover, must be: P.gtoreq.1; .ltoreq.7.+-.2 mM; 7-dehydroxylated and oxidized to potentially toxic or inactive compounds.
Now it has been found that bile acids derivatives in which the side chain has one carbon atom more (NOR) or one less (HOMO) proved remarkable properties as absorption enhancers for medicaments by the enteral route and other not-parenteral routes (intranasal, buccal, sublingual).
Particularly, the best resul

REFERENCES:
Nakada, J. Pharmacobio-Dyn, 11 (6), 395-401 1988.
Murakami, Chem. Pharm. Bull, 32 (5), pp. 1948-1955 1984.

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