Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Phosphorus containing other than solely as part of an...
Patent
1994-08-22
1997-03-25
Kumar, Shailendra
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Phosphorus containing other than solely as part of an...
514 23, 514104, 514109, 514554, 514555, 514556, 514642, 514643, A61K 3166
Patent
active
056145101
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 of PCT/SE93/00144, filed Feb. 23, 1993.
The present invention relates to an inositol phosphate containing pharmaceutical composition with improved bioavailability of inositol phosphate and the use of at least one nitrogen-containing compound for the preparation of an inositol phosphate containing medicament with improved bioavailability of inositol phosphate.
Hydrophilic and ionized drugs must often encounter rather poor penetration of the epithelial barriers to the capillaries of the portal circulation as most of these types of substances are transported by passive diffusion. Inositol phosphates belong to this group.
Normally it is the unionized fraction of the drug that partitions across the lipid membranes and this fraction is most often small over the pH-range encountered in the gastrointestinal tract.
It is known from the literature, for example Jonkman J. H. G. and Hunt C. A. (1983) Pharmaceutische Weekblad Scientific Edition 5, 41-48, that a combination of a quarternary ammonium compound and sulfonic acids are absorbed to a small extent after oral administration. The absorption is described as poor and in many cases contradictory.
In the literature nothing has been described about the use of counter ions such as nitrogen-containing compounds together with inositol phosphates for improvement of the bioavailability.
At oral administration the properties of inositol phosphates per se result in limitations in respect of the uptake of the compounds from the intestine. In order to optimize the effect of these substances in the body it is desirable that as large a portion as possible of the added amount can be utilized effectively. Thereby the added amount can be reduced which is advantageous for the patient for example when the drug D-myo-inositol-1,2,6-trisphosphate (IP.sub.3) is used.
According to the present invention it has now quite surprisingly been possible to meet the above desire and bring about an inositol phosphate containing pharmaceutical composition which comprises a nitrogen-containing compound for improvement of the bioavailability of the inositol phosphate in mammals including man at non-parenteral administration.
The expression bioavailability stands for a measurement of how large a portion of an administrated drug that occurs in the blood stream when the way of administration of the drug is non-parenteral. The term thus shows the amount of the drug that has been able to penetrate membrane barriers after for example oral administration, topical administration or intraperitoneal administration.
The nitrogen-containing compound can be for example a quarternary ammonium ion, a tertiary amine, a diamine, a polyamine, an amino acid or a derivative thereof.
The quarternary ammonium ions used according to the invention is defined as follows: R.sub.3 and R.sub.4 independently are ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, eicosyl and docosyl; and cyclohexyl; octadienyl, octenyl, decenyl, dodecenyl, tetradecenyl, hexadecenyl, octadecenyl, octadecadienyl, nonadecenyl, octadecatrienyl and arachidonyl; cyclopentadienyl, cyclohexenyl and cyclohexadienyl; alkenyl are as previously defined.
The above groups (ii) to (vii) are unsubstituted or substituted with hydroxy; oxo; alkoxy; aryloxy; carboxy; esterified carboxy; amino; substituted amino; formyl; acyl; acyloxy; or acylamine.
Preferred nitrogen-containing compounds in this group according to the invention are N-tetramethylammonium, N-tetraethylammonium, N-tetrapropylammonium, N-tetrabutylammonium, N-tetrapentylammonium, N-tetrahexylammonium, N-tetraheptylammonium and N-tetraoctylammonium. Other preferred nitrogen-containing compound are N-decyltrimethylammonium, N-undecyltrimethylammonium, N-dodecyltrimethylammonium, N-tridecyltrimethylammonium, N-tetradecyltrimethylammonoum, N-pentadecyltrimethylammonium, N-hexadecyltrimethylammonium, N-benzyltrimethylammonium. R.sub.3 are as defined above and preferably methyl, eth
REFERENCES:
patent: 4851560 (1989-07-01), Siren
patent: 5225349 (1993-07-01), Irth et al.
Jonkman et al. (1983) "Ion Pair Absorption of Ionized Drugs--Fact or Fiction?" Pharma. Weekblad Sci. Ed., 5: 41-48.
Chemical Abstracts, vol. 102, No. 1, 6465b, Jan. 7, 1985, p. 589 (Reg. No. 93712-95-9).
Kumar Shailendra
Perstorp AB
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