Drug – bio-affecting and body treating compositions – Extract – body fluid – or cellular material of undetermined... – Digestive system
Patent
1997-02-18
1999-07-13
Witz, Jean C.
Drug, bio-affecting and body treating compositions
Extract, body fluid, or cellular material of undetermined...
Digestive system
514 56, 536 21, A61K 35407, A01N 4304, C08B 3710
Patent
active
059223588
DESCRIPTION:
BRIEF SUMMARY
The present invention relates to heparin-based compositions as well as to a process for their preparation and to their therapeutic applications.
The invention relates more particularly to heparin-based compositions neutralized with protamine, having antithrombotic activity but largely devoid of haemorrhagic and anticoagulant activities.
Heparins have been known and used for many decades for the preparation of medicaments with antithrombotic and/or anticoagulant activity intended in particular for the preventive and curative treatment of venous and arterial thromboses or alternatively for preventing the activation of coagulation in extracorporeal circulations.
It has for many years been known how to prepare low molecular weight heparins, which always have antithrombotic activity but whose anticoagulant activities are reduced.
Nevertheless, as regards either non-fractionated heparins or low molecular weight heparin, the risk of haemorrhage remains the main complication of heparin-based treatments. As a result, there is a considerable limit on the use of heparins, which are contraindicated in particular in patients with a predisposition towards haemorrhaging, patients suffering from duodenal or gastric ulcers or alternatively patients who have recently undergone a surgical intervention, in whom antithrombotic treatment with heparin may lead to haemorrhaging.
Consequently, the advantageous properties of heparins, namely their antithrombotic or anticoagulant activity, cannot be correctly exploited on account of their considerable side effects associated with this permanent risk of haemorrhaging.
When haemorrhages occur during treatments with heparin, the treatment makes use of protamine sulphate which brings about the in vivo neutralization of the heparin.
Although protamine has been used in this way for many years, the mechanism by which heparin is neutralized by protamine is not well known. A relatively recent study has shown simply that low molecular weight heparins were neutralized to a lesser degree than non-fractionated heparins ("In Vitro Protamine Neutralization Profiles of Heparine Differing in Source and Molecular Weight", SEMINARS IN THROMBOSIS AND IN HEMOSTASIS, vol. 15 No. 4, 1989).
The problem which the present invention aims to solve is thus one of reducing the considerable risk of haemorrhaging outlined above, which limits the therapeutic use of heparins.
The aim of the invention is, more precisely, to eliminate the risk of haemorrhaging associated with heparins as much as possible while at the same time retaining their main properties, in particular the antithrombotic activity.
Thus, the aim of the present invention is to provide heparin compositions which have very advantageous pharmacological properties, in particular antithrombotic properties, which are essentially equivalent to those of the heparins used hitherto, without therewith exhibiting the major drawback which lies in the considerable risk of haemorrhaging.
Another aim of the present invention is also to provide a process for the preparation of such compositions which is simple to carry out and inexpensive, moreover allowing their therapeutic applications to be developed.
The invention is also directed towards the therapeutic applications of these compositions.
These aims are achieved using heparin compositions according to the invention which have antithrombotic activity and are substantially free of haemorrhagic activity. These compositions are characterized by the fact that they consist essentially of heparin fractions as obtained by the in vitro neutralization of heparin with protamine.
The expression heparin fraction neutralized with protamine is understood to refer to any fraction derived from a native or already fractionated heparin, or from a synthetic heparin, whose haemorrhagic power has been neutralized by the action of protamine or any analogue or equivalent thereof having a similar capacity to reduce the haemorrhagic power.
The compositions according to the invention advantageously consist of heparin fractions as obtaine
REFERENCES:
patent: 4175182 (1979-11-01), Schmer
patent: 4438108 (1984-03-01), Sanders et al.
patent: 4687765 (1987-08-01), Vairel et al.
patent: 4800016 (1989-01-01), Yang
Chargraff et al. "Studies on the chemistry of blood coagulation. VI. Studies on the action of heparin and other anticoagulatns. The influence of protamine on the anticoagulant effect in vivo" J. Biol. Chem. (1937) 122: 153-167.
Shanberge et al. "Heparin-protamine complexes in the production of heparin rebound and other complication of extracorporeal bypass procedures," Amer. J. Clin. Pathol. (1987) 87: 210-217.
Mannarino et al. "Efficacy of low-molecular weight heparin in the management of intermittent claudication", Angiology (1991) 42(1): 1-7.
Walsh et al. "Heparin and heparan sulphate are inhibitors of human leucocyte elastase", Clinical Sci. (1991) 81(3): 341-346.
Barkagan et al. "Determination of heparin in serum", Lab. Delo (1971) 6: 331-5; abstract only.
Doutremepuich et al. "Protamine neutralization of a very low molecular weight heparin fragment CY 222 in vitro and in vivo study", Thrombosis Res. (1986) Suppl. VI, p. 88; absytract only.
Sugiuama et al. "Study on neutralization of low molecular weight heparin (LHG) by protamine sulfate and its neutralization characterisitics", (1992) Thrombosis Res. 68: 119-129.
Lafuma et al. "Prevention of leucocyte elastase-induced emphysema in mice by heparin fragments", Eur. Respir. J. (1991) 4: 1004-1009.
Patent Abstracts of Japan vol. 4, No. 77, Jun. 4, 1980 & JP-A-55 043123 (Amano Pharmaceut. Co.Ltr.) Mar. 26, 1980.
Doutremepuich Christian Raymond
Saudubray Francois Eugene Pierre Marie
Debiopharm S.A.
Hanley Susan
Witz Jean C.
LandOfFree
Antithrombotic and non-hemorrhagic heparin-based compositions, p does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Antithrombotic and non-hemorrhagic heparin-based compositions, p, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Antithrombotic and non-hemorrhagic heparin-based compositions, p will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2273740