Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Phosphorus containing other than solely as part of an...
Patent
1992-03-02
1994-01-25
Lee, Mary C.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Phosphorus containing other than solely as part of an...
558177, A61K 3166
Patent
active
052815862
DESCRIPTION:
BRIEF SUMMARY
The present invention relates to pharmaceutical compositions for the treatment of peripheral neuropathies of dysmetabolic or toxic origin, and of cerebropathies of organic and functional origin, containing as the active ingredient L-.alpha.-glycerophosphoryl-D-myo-inositol (hereinafter called GFI) of formula 1 or the alkali or alkaline-earth metal salts thereof. ##STR1##
The present invention also relates to the alkali and alkaline-earth metal salts of GFI, particularly the calcium salt of GFI.
From a chemical point of view, GFI is structurally similar to phosphatidylinositol (hereinafter called FI); FI being the double-acylated product with fatty acids, mainly unsaturated acids, at the hydroxy groups of the glycerine residue of glycerophosphorylinositol.
FI is a molecule of natural origin, almost unsoluble in water, which is generally extracted from bovine brain and/or soy-bean, in admixture with phosphatidylethanolamine ("cephalinic fraction") and subsequently purified.
FI turns out to be rather unstable, since the unsaturated fatty acid chains bound to the hydroxy groups of the glycerin residue easily undergo peroxydation reactions, yielding a number of decomposition products.
On the contrary, GFI is the deacylated analogue and therefore it is water-soluble as such or salified, it is stable and the alkali and alkaline-earth metal salts thereof, specifically the sodium, potassium, calcium and magnesium salts, are crystalline and particularly suited for use in pharmaceutical formulations.
The advantages involved in the use of said salts, particularly the calcium salt, compared with the free acid GFI, consist in a lower hygroscopicity, a higher stability, a better adaptability to the use thereof in pharmaceutical compositions, since the salts themselves, being poorly hygroscopic, can be preserved for a long time without appreciable decompositions.
GFI, or the salts thereof with alkali and/or alkaline-earth metals, particularly the calcium salt, are obtained by controlled saponification of the acylated phospholipid mixture contained in soy-bean, subsequent separation with purification of the obtained free acid GFI and optionally salification with alkali and/or alkaline-earth metals.
A known method for the preparation of GFI is described in EP-A-0.217.765.
From a biochemical point of view, FI catabolism is known to play a very important role in the biochemical events connected with physiological activity, as far as phosphorus turnover is concerned (Ansell G. B. and Dohmen H.; J. Neurochem. 2, 1, 1957; Sheltaway A. and Dawson R. M. C.; Biochem. J., 111, 157, 1969).
When calcium is available as a support for the activity of phosphatidylinositol phosphodiesterase (phospholipase C), this enzyme is probably the main responsible for FI degradation (Friedel R. O., Brown J. D. and Durrell J.; Biochim. biophys. Acta., 144, 684, 1967; Keough K. M. W. and Thompson W.; Biochim. biophys. Acta., 270, 324, 1972; Thompson W.; Can. J. Biochem., 45, 853, 1967; Dawson R. M. C. et al.; Biochem. J., 122, 605, 1971; Irvine R. F.; Biochem. J., 176, 475, 1978), the main metabolits of which are diacylglycerole and inositolphosphate; the whole metabolic cycle (Hawthorne J. N. and Pickard M. R.; J. Neurochem., 32, 5, 1979) can be represented as follows: ##STR2##
Even though a poor acylation of FI can occur under particular physiological conditions (low Ca.sup.++ concentration), which acylation being catalysed by the enzyme phospholipase A.sub.1 and giving raise to lysophosphatidylinositol (Hong S. L. and Deykin D.; J. Biol. Chem., 256, 5215, 1981), the specificity of phosphatidylinositol phosphodiesterase, the ubiquitous distribution in animal cells and the extremely high activity thereof, evidenced also in vitro (Friedel R. O. Brown J. D. and Durrell J.; Biochim. biophys. Acta., 144, 684, 1967; Keough K. M. W. and Thompson W.; Biochim. biophys. Acta., 270, 324, 1972; Thompson W.; Can. J. Biochem., 45, 853, 1967; Dawson R. M. C. et al.; Biochem. J., 122, 605, 1971; Irvine R. F.; Biochem. J., 176, 475, 1978), make this enzyme the main
REFERENCES:
Brown, D. M. et al. J. Chem. Soc. 1959, 3547-3552.
Clinton, E. et al. Chem. Abstr. 1963 58(4), 3644b.
Palazzi Camillo M. F. G.
Procida Carla
Scolastico Carlo
Ambrose Michael
Apotekna S.A.
Lee Mary C.
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