Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Radical -xh acid – or anhydride – acid halide or salt thereof...
Patent
1996-07-05
1998-05-12
Henley, III, Raymond
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Radical -xh acid, or anhydride, acid halide or salt thereof...
562561, 562562, 562598, A61K 3120, C07C22900, C07C 5702
Patent
active
057505721
DESCRIPTION:
BRIEF SUMMARY
This is a 371 of PCT/EP94/03943 filed Nov. 28, 1994.
The present invention relates to the salts of a polyunsaturated fatty acid of the omega-3 series, i.e. 4,7,10,13,16,19-cis-docosahexaenoic acid (in the following names DHA) with basic amino acids. It should be understood that the invention comprises both the amino acids in the natural laevo form and in the dextro form and also the racemic forms. Preferred amino acids are arginine and lysine.
DHA is obtained from natural sources containing it (fish oils) through chemical-physical methods leading to an acid of high purity (higher than 90%), or alternatively to enriched mixtures, in which it is together with other polyunsaturated fatty acids of the omega-3 series. The mixtures are also used in therapy or as food supplementers, therefore the invention comprises salts of DHA, which is either pure or present as a component of enriched mixtures.
DHA, together with 5,8,11,14,17-cis-eicosapentaenoic acid (in the following names EPA), is the more interesting component of the group of the polyunsaturated omega-3 fatty acids, present in fish oils. Said acids were recently object of a marked interest, since they have shown important therapeutical properties against various diseases of the cardiocirculatory system (thrombosis, aterosclerosis, platelet hyper-aggregation, and the like; see New Engl. J. Med., 318, 549, 1988), diseases of inflammatory origin (see J. Biol. Chem., 359, 7615, 1984), and some tumour forms (see Acta Med. Scand., 220, 69, 1976). The therapeutical efficacy of DHA and of polyunsaturated omega-3 acids, moreover, is also directed to a wide range of other pathological conditions, such as hyperlipemia and hypercholesterolemia, psoriasis, immune and nervous (central and peripheral) disorders, disorders of memory and learning, etc. In the studies carried out up to now, DHA showed a pharmacological profile and biological characteristics similar, but not superimposable, to those of EPA, both in terms of activity range and of potency of action (for example a higher anti-platelet aggregation activity). The administration of DHA increases its in vivo level in tissue phospholipids.
Particularly interesting is that, in principle, DHA is present in phospholipids in a much higher amount than EPA. Since DHA is known to be partly converted into EPA in vivo, it can also be considered as a potential form for the storage of EPA.
In man, DHA is present in a particularly high amount in phospholipids of the brain, retina and testes (from 20 to 40% of fatty acid content); the meaning and the function of this presence is up to now an object of research (v. New Engl. J. Med., 318, 549, 1988). From what is stated above, the importance of DHA both for its own physiological and pharmacological actions and as an EPA source or precursor in vivo is clear.
DHA, with EPA, is widely present in oils of sea origin (fish oils), in which it is present mainly as a triglycerid, together with other acids both unsaturated and saturated, from which it can be obtained both as an enriched mixture and in a very pure form.
From the pharmaceutical technology point of view, DHA and the glycerids or esters thereof are in the form of thick oily liquids, completely insoluble in water, and can accordingly be formulated in practice only in soft gelatin capsules. Therefore, the liquid formulations connected with the presence of water are excluded, from which the oily phase would separate also in the presence of any organic solvents (which on the other hand would be unsuitable for toxicity reasons) used to improve solubility.
Apparently, the easiest method to make DHA water soluble, i.e. salification with alkali metals, proved to be impracticable since the resulting salts give strongly basic aqueous solutions which therefore are poorly tolerated.
An EPA sale with lysine, used to prevent cyclosporin nephrotoxicity, is known from literature (Transplant. Proc., 24, 6, 2583, 1992).
Now it has surprisingly been found that unpredictable, high advantages can be obtained, not only in view of capability to prep
REFERENCES:
patent: 3952035 (1976-04-01), Galantay et al.
patent: 5502077 (1996-03-01), Breivik et al.
Henley III Raymond
Prospa B.V.
Schneider Walter H.
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