Organic compounds -- part of the class 532-570 series – Organic compounds – Carbohydrates or derivatives
Reexamination Certificate
1999-02-18
2001-05-08
Lee, Howard C. (Department: 1623)
Organic compounds -- part of the class 532-570 series
Organic compounds
Carbohydrates or derivatives
C525S054100, C536S002000, C536S020000, C536S021000, C536S080000, C536S088000, C536S106000, C536S119000, C424S488000
Reexamination Certificate
active
06229009
ABSTRACT:
The invention relates to cross-linked copolymers based on non cross-linked polycarboxylic polymers, said copolymers containing at least one polycarboxylic polysaccharide. The invention also relates to a process for the preparation of these copolymers and their use in particular as a support in pharmaceutical compositions.
Certain compounds with a polymeric structure containing a polycarboxylic polysaccharide, optionally modified, have been described in the literature. For example, Patent Application WO89/02445 describes a gel based on hyaluronic acid; but, in its structure, this gel only comprises hyaluronic acid and no other polycarboxylic polymer. Moreover, no cross-linking agent is used in the preparation of this gel. The compound obtained in this way is mainly used in surgery. Patent Application WO91/16881 describes, among others, the combination of an active ingredient with a matrix constituted by a modified polymer, i.e. to which saccharides are grafted. This modified polymer can be a natural polymer such as chondroitin sulphate. However, this matrix contains only one type of polymer.
The copolymers according to the invention based on polycarboxylic polymers contain at least one polycarboxylic polysaccharide and at least one other polycarboxyclic polymer which is not a polysaccharide. The combination of a polysaccharide with another type of polycarboxylic polymer allows the modulation of the properties of the polysaccharides such as the hydrophilicity. In this way, copolymers can be obtained with appropriate degradation properties according to their uses. Moreover, the copolymers according to the invention are advantageously prepared in an aqueous medium. This is a real advantage as it is almost impossible to totally eliminate the solvents in a polymer structure: the existence of traces of residual aqueous solvents is generally more easily acceptable and accepted than traces of residual organic solvents such as dimethylsulphoxide or dimethylformamide.
A subject of the invention is cross-linked copolymers based on non cross-linked polycarboxylic polymers and a cross-linking agent comprising at least two amine functions, said copolymers comprising at least one polycarboxylic polysaccharide and at least one other non cross-linked polycarboxylic polymer which is not a polycarboxylic polysaccharide.
The non cross-linked polycarboxylic polysaccharides can be chosen, for example, from glycosaminoglycans, pectinic acid, alginic acid, carboxylic derivatives of dextran such as carboxymethyldextrans, or the carboxylic derivatives of cellulose such as carboxymethylcelluloses. Among the glycosaminoglycans, there can be mentioned hyaluronic acid, chondroitin sulphate, heparin, dermatan sulphate, heparan sulphate, keratan sulphate or a mixture of the latter. Among the polycarboxylic polymers which are not polysaccharides, there can be mentioned poly(glutamic acid), poly(aspartic acid), poly(maleic acid), poly(malic acid) or poly(fumaric acid), the polycarboxylic acrylic polymers such as poly(acrylic acid), poly(methacrylic acid) or the copolymers of the latter such as the Eudragits® L and S. The expression polycarboxylic polymers includes polymers as defined above but also the partly or totally substituted derivatives of these polymers such as, for example, their esters, their amides or their salts, copolymers containing the units present in these polycarboxylic polymers or in their derivatives as defined above, but also a mixture of these polymers and/or their derivatives and/or their copolymers as defined above.
A more particular subject of the invention is cross-linked copolymers as defined above, characterized in that the polysaccharide is chosen from pectinic or alginic acid, glycosaminoglycans, and preferably hyaluronic acid, chondroitin sulphate, heparin, dermatan sulphate, heparan sulphate, keratan sulphate or a mixture of the latter.
A more particular subject of the invention is cross-linked copolymers as defined above, characterized in that the non cross-linked polycarboxylic polymer which is not a polycarboxylic polysaccharide is chosen from polycarboxylic acrylic polymers, poly(glutamic acid), poly(aspartic acid), poly(maleic acid), poly(malic acid) or poly(fumaric acid). The non cross-linked polycarboxylic polymer which is not a polycarboxylic polysaccharide is preferably a polycarboxylic acrylic polymer and more particularly poly(acrylic acid) or poly(methacrylic acid).
The polycarboxylic polymers according to the invention are linked together by a cross-linking agent. This cross-linking agent comprises at least two amine functions which are capable of reacting with the free carboxylic functions of said non cross-linked carboxylic polymers. It can be chosen, for example, from proteins, polyamines, triamines, diamines, natural or synthetic amino acids, or the derivatives of compounds as defined above such as, for example, their salts, esters or amides. Among the amino acids there can be mentioned, for example, arginine, lysine, histidine and ornithine. Among the diamines there can be mentioned ethylenediamine, butanediamine, hexanediamine, heptanediamine, octanediamine or dodecanediamine. Among the polyamines there can be mentioned chitosan, poly(amino acids) such as polylysine or polyornithine, as well as the copolymers of these polyamines. The cross-linking agent can also be chosen from compounds such as spermine, spermidine, melamine, guanidine or diethylenetriamine. The cross-linking agent used is preferably an amino acid and advantageously lysine, ornithine or histidine.
A more particular subject of the invention is also cross-linked copolymers as defined above, characterized in that the polycarboxylic polysaccharide is a polycarboxylic polysaccharide which can be degraded by the microbial flora of the colon such as chondroitin sulphate, hyaluronic acid, pectinic acid or heparin.
A more particular subject of the invention is cross-linked copolymers as defined above, characterized in that the polycarboxylic polysaccharide is chondroitin sulphate and the other said polcarboxylic polymer is chosen from poly(acrylic acid) and poly(methacrylic acid), and the cross-linking agent is lysine or histidine.
A subject of the invention is also a process for the preparation of cross-linked copolymers as defined above, said process characterized in that said non cross-linked polycarboxylic polymers constituting the cross-linked copolymer are reacted in the presence of an activator and a cross-linking agent comprising at least two amine functions, in an appropriate reaction medium. The preparation of cross-linked copolymers as defined above is preferably carried out in an aqueous medium. The expression aqueous medium means a medium only containing water or water mixed with one or more solvents which are miscible with water such as, for example, acetone or lower alcohols such as ethanol. The aqueous medium preferably only comprises water. The implementation of the process according to the invention can be carried out in various manners. In fact, the process may consist in mixing non cross-linked polycarboxylic polymers and the cross-linking agent, then adding the activator. The cross-linking process according to the invention can also consist in mixing together non cross-linked polycarboxylic polymers and the activator, then adding the cross-linking agent. The process may also consist in cross-linking one of the non cross-linked polycarboxylic polymers constituting the copolymer, mixing said polymer with the cross-linking agent then the activator, or with the activator then the cross-linking agent, then adding at least one other non cross-linked polycarboxylic polymer to the reaction medium, in order to cross-link it with said polymer present in the reaction mixture. During the implementation of the process, the reagents introduced can previously be solubilized in the chosen reaction medium. The non cross-linked polycarboxylic polymers and the cross-linking agent are preferably mixed together in an aqueous medium until solubilization then the activator is added. The process is implem
Fessi Hatem
Labarre Denis
Lambert Nada
Bierman, Muserlian and Lucas
Lee Howard C.
Societe de Conseils de Recherches et d'Applications Scienti
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