Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Patent
1996-04-12
1999-09-28
Fonda, Kathleen K.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
514 54, 536 21, 5361231, 536124, A61K 31715, C08B 3710
Patent
active
059588993
DESCRIPTION:
BRIEF SUMMARY
PRIOR ART
The glycosaminoglycans which are substances obtained by extraction from animal tissues having various origin, for instance intestinal mucosa, lung, etc. belong particularly to the class of the polysaccharides containing iduronic acid. Heparin, heparan sulfate, condroitin sulfates and hyaluronic acid belong to the family of glycosaminoglycans.
The various glycosaminoglycans have different chemical structures and they are formed by polysaccharide chains constituted by the repetition of an uronic acid and a hexosamine. In particular in heparin and heparan sulfate the uronic acid is constituted by glycuronic or iduronic acid and the hexosamine by glycosamine.
The glycosamine may be preferentially N-acetylated (heparan sulfate) or preferentially N-sulfated (heparin) and 6-0 sulfated. Moreover a sulfate group may be found also in the position 3 of the glycosamine.
The uronic acid may be 2-0 sulfated.
The heparin has great importance in the clinical practice as anticoagulant and antithrombotic.
Besides this therapeutic use an useful utilization for the heparin and the heparan sulfate in several other pathologies, for instance with antilipemic, antiproliferative, antiviral, antitumoral and antiangiogenic function is expected.
The utilization of the heparin and the heparan sulfate in these new therapeutic applications involves the necessity to obtain these products, or similar products, by processes different from the extractive one, in particular by more flexible processes allowing the preparation of different structures.
Moreover the extractive process from animal tissues does not guarantee to obtain a virus free product.
A process for the preparation of anticoagulant glycosaminoglycans by biosynthesis is described in the Patent Application No. WO 92/17507.
In this process the polysaccharide K5 from E. coli which is submitted to the following sequence of reactions: acid into residuals of L-iduronic acid; and compound.
In this process the critical stage is constituted by the epimerization which is limited to a 20% maximum. The epimerization is carried out at room temperature with two days duration in presence of the D-glycuronyl-L-iduronyl-C5-epimerase enzyme in a classical reaction medium to pH 7.4 constituted by HEPES, potassium chloride, EDTA and TRITON X-100. An epimerization limited to one third of the uronic acid had been formerly described (M. Hook et al., The J. of Biol. Chem. 249, 12 3908-3915, Jun. 25, 1974). And this epimerization degree seemed till now insuperable. Moreover it must be considered that in this document the epimerization in cellular environment is described in the murine mastocytoma in conditions in which every factor concerning the biosynthetic process is present.
However an epimerization degree as obtained from the known art does not allow to obtain a product with the requested characteristics for the various therapeutic treatments.
In fact the iduronic acid gives a superior flexibility to the product with respect to the glycuronic acid (Casu B., Petitou M., Provasoli M., and Sinay P. (1988) Conformational flexibility: a new concept for explaining binding and biological properties of iduronic acid containing glycosaminoglycans. Trends Biochem. Sci. 13, 221-225). It follows that the products containing high percentages of iduronic acid are more active with respect to those containing glycuronic acid as it is pointed out by the greater anticoagulant and antithrombotic activity of the heparin towards heparan sulfate and by other activities such as that one on the basic fibroblast growth factor (bFGF) wherein the iduronic acid is recognized to be essential part of the active site (Maccarana M., Casu B., and Lindahl U. (1993). Minimal sequence in Heparin/Heparan Sulfate Required for Binding of Basic Fibroblast Growth Factor. J. Biol. Chem. 268, 23898-23905). Therefore there is the problem to find a process allowing to obtain a product having a high degree of epimerization with yield and times acceptable according to the industrial point of view.
SUMMARY
We have found that polys
REFERENCES:
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Maccarana et al. Minimal Sequence in Heparin/Heparan Sulfate Required for Binding of Basic Fibroblast Growth Factor, J. Biol. Chem., vol. 268, No. 32, pp. 23898-23905, Nov. (1993).
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Cipolletti Giovanni
Oreste Pasqua
Zoppetti Giorgio
Fonda Kathleen K.
Inalco S.p.A.
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