Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Phosphorus containing other than solely as part of an...
Reexamination Certificate
2001-06-11
2002-08-06
Krass, Frederick (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Phosphorus containing other than solely as part of an...
C514S100000, C514S114000, C514S119000, C514S450000, C514S452000, C514S453000, C514S456000, C424S450000, C424S456000, C424S464000, C549S220000, C549S352000
Reexamination Certificate
active
06429202
ABSTRACT:
TECHNICAL FIELD
The present invention relates to phospholipid complexes of proanthocyanidin A2 or of extracts enriched in proanthocyanidin A2 and the use thereof for the preparation of medicaments for the prophylaxis and the therapy of atherosclerosis, and myocardial and cerebral infarction.
BACKGROUND OF THE INVENTION
Proanthocyanidin A2 or 8,14-methano-2H, 14H-1-benzopyrano[7,8-d] [1,3]benzodioxocin-3,5,11,13,15-pentol-2,8-bis-(3,4-dihydroxyphenyl)3,4-dihydroxyphenyl)3,4-dihydro[2R-2&agr;,3&agr;,8&bgr;,14&bgr;,15R] of formula (I)
was isolated from seed of
Aesculus hippocastanum
(Tetrahedron Lett., 429, 1966). The therapeutical use of proanthocyanidin A2 as cicatrising, cytoprotective, antiulcer, venotonic, vasoprotective and antiperoxidative agent is disclosed in EP-A-210785 (Feb. 4, 1987).
SUMMARY OF THE INVENTION
It has now surprisingly been found that the phospholipid complexes of proanthocyanidin A2 exert a marked antiatherosclerotic activity both in animals and in humans when administered systemically, preferably through the oral route.
The complexes of the invention can consist of natural or synthetic phospholipids, such as lecithins, phosphatidylcholine, phosphatidylserine, phosphatidylethanolamine. The ratio of proanthocyanidin A2 to phospholipids ranges from 2:1 to 1:2, and preferably is about 1:1.5 w/w. A particularly preferred complex is that with soy phosphatidylcholine.
The complexes of the invention are prepared by reacting a solution of the phospholipid with a solution of proanchocyanidin A2 in suitable solvents, such as acetone, ethyl acetate, ethanol, then concentrating the reaction mixture under reduced pressure, to obtain a thick residue which can be ground.
The complexes of the invention dose-dependently prevent or reduce the formation of, atherosclerotic plaques. The activity was evidenced in rabbits fed with a hypercholesterolemic diet so as to induce atherosclerotic lesions similar to the human ones at the vasal level, particularly at the aortal arch, ventral aorta, carotids and cerebral vessels. In said model, the above mentioned phospholipid complexes change the macro- and microscopical vascular condition reducing, compared with untreated animals, both the number and the severity of the atheromatous plagues, with surprising vascular-tissutal benefit. In another atherosclerosis model, with the purpose of cerebral protection, wherein the vasal lumen of rabbit internal carotid had been surgically reduced while administering a hypercholesterolemic diet rich in saturated fats, a decrease in carotid obstruction, a reduction of vasal walls thickness and increased survival of the animals were observed. Atherosclerotic patients showed, after six month-treatment, a reduction of carotid obstruction due to atheromatous plaques and an improved carotid flow, evaluated by Doppler ultrasonography.
The phospholipid complexes of proanthocyanidin A2 can be used in suitable administration forms for the oral route such as tablets, soft- or hard-gelatin capsules, at dosages ranging from 50 to 500 mg two-three times a day, depending on the severity of the disease. The preparation of the pharmaceutical formulations can be carried out according to conventional techniques and excipients.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
REFERENCES:
patent: 4698360 (1987-10-01), Masquelier
patent: 4863956 (1989-09-01), Gabetta et al.
patent: 4963527 (1990-10-01), Bombardelli et al.
patent: 5648377 (1997-07-01), Bombardelli et al.
patent: 1 210 785 (1987-02-01), None
patent: 0 713 706 (1996-05-01), None
patent: WO 99/29331 (1999-07-01), None
Bombardelli Ezio
Morazzoni Paolo
Indena S.p.A.
Krass Frederick
Pennie & Edmonds LLP
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