Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Patent
1995-06-06
1998-01-06
Fonda, Kathleen K.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
536 53, 536 54, 536 55, 536 551, 536 552, 536 553, 536124, 514 62, A61K 31725, C08B 3700
Patent
active
057054932
DESCRIPTION:
BRIEF SUMMARY
This is the U.S. national stage entry under 35 U.S.C. 371 of PCT/EP93/03646, filed Dec 21, 1993.
TECHNICAL FIELD
The present invention relates to some oligosaccharides having biological activity and a procedure For the preparation of same from glycossminoglycans (GAGS).
As known, the biological activity of GAGS makes them pharmaceutically useful for the treatment of arterial and venous thrombotic states, atherosclerosis, lipoidoproteinosis, ischaemic states in general, hypofibrinolysis and more generally of disorders related to coagulation and haemostasis.
GAGS therapeutic use is, therefore, very interesting: consequently, extensive research has been carried out to define their structure. However, a complete structure determination has not been made so far since the extracts contain different substances of very similar structures, whose presence depends on the methods of extraction used and on the animal tissues wherefrom extractions were made. These actual difficulties, typical of the field under examination, have so far hindered a complete synthesis of the test products as well as a fairly approximate Forecast of what would happen should different GAGS be subjected to the same chemical treatment.
PRIOR ART
Since GAGS are increasingly being used in the medical practice, improved procedures of extraction and purification of extracts from various animal organs have been developed on an industrial scale. Since GAGS extracts have a high molecular weight, attempts have been made to breakdown the molecular structure of GAGS to obtain lower-molecular-weight fractions, such as for example dermatan sulphate or heparan sulphate.
The applicant has been studying this matter several years and owns several patents disclosing and claiming the results obtained (cf. U.S. Pat. No. 4,783,447, No. 4,870,166, No. 4,987,222, and No. 5,116,963).
Various treatments of GAGS are disclosed in said patents, from the treatment based on enzymes to that based on oxidizing agents, including the preparation of oligosaccharide fractions of dermatan sulphate using gamma radiation from cobalt 60.
The problem of the bioavailability of commercial GAGS has not been optimally settled yet: it follows that the Applicant as well as other companies are still working to find new oligosaccharides derived from the oligosaccharides already known, which would show the same biological activity as the starting products and, at the same time, provide a higher bioavailability.
Procedures to decrease the molecular weight of heparin (the best known glycosaminoglycan, used in anticoagulant-antithrombotic therapy) by esterification followed by depolymerization and subsequent hydrolysis of the esters in an aqueous medium are illustrated in European patent applications EP-A-40144 and EP-A-44228, and in French patent application 2548672. The aqueous medium and the high temperatures utilized bring about products showing remarkable activity losses in respect of starting heparin.
Said procedures, though allowing the production of a series of oligosaccharides of lower molecular weight in respect of starting heparin, have the great disadvantage of causing an excessive reduction in their biological activity, a useful characteristic for their therapeutic use.
In addition, such procedures, as applied by the Applicant, could not depolymerize dermatan sulphate and chondroitin sulphate, in contrast by heparin.
TECHNICAL PROBLEM
The present invention provides a solution of the technical problem, consisting in the development of a new procedure for the treatment of known GAGS or of mixtures thereof, either natural or previously supersulphated, allowing the obtainment of new oligosaccharides that, in respect of the starting products, show a noticeably lower molecular weight, a higher bioavailability and, at the same time, the same or an improved biological activity.
DETAILED DESCRIPTION OF THE INVENTION
The main characteristic of the oligosaccharides under this invention is a biological activity that is equal to or higher than that of the starting GAGS (or GAGS mixt
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Chemical Abstracts, vol. 82, p. 646. 156647, (Apr. 1974), Doi et al., "Ester Derivatives of Chordroitin Sulfate or Polysulfate or their Salts".
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Fonda Kathleen K.
Mediolanum Farmaceutici S.p.A.
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