Biodegradable, anionic polymers derived from the amino acid l-tyrosine

Abstract

Polymers with a hydrolytically labile polymer backbones with non-toxic biocompatible diphenolic repeating units having the structure:wherein R9 is an alkyl, aryl or alkylaryl group with up to 18 carbon atoms having a pendent carboxylic acid group or the benzyl ester thereof; andnon-toxic biocompatible diphenolic repeating units having the structure:wherein R12 is an alkyl, aryl or alkylaryl group with up to 18 carbon atoms having a pendent carboxylic acid ester group selected from straight and branched alkyl and alkylaryl esters containing up to 18 carbon atoms and ester derivatives of biologically and pharmaceutically active compounds covalently bonded to the polymer, provided that said ester group is not a benzyl group or a group that is removed by hydrogenolysis. Implantable medical devices and treatment methods using the polymers are also disclosed.

Description

CROSS-REFERENCE TO RELATED APPLICATION[0001]This application is a Continuation of U.S. patent application Ser. No. 09 / 350,423 filed Jul. 8, 1999, which, in turn, is a Continuation of U.S. patent application Ser. No. 09 / 056,050 filed Apr. 7, 1998, now U.S. Pat. No. 6,120,491, which claims the benefit of U.S. Provisional Patent Application Ser. No. 60 / 064,656 filed on Nov. 7, 1997. The disclosures of all three applications are incorporated herein by reference.GOVERNMENT LICENSE RIGHTS[0002]The U.S. government has a paid-up license in this invention and the right in limited circumstances to require the patent owner to license others on reasonable terms as required by the terms of Grant Nos. GM-39455 and GM-49849 awarded by the National Institutes of Health.BACKGROUND OF THE INVENTION[0003]The present invention relates to biodegradable anionic polycarbonates and polyarylates having pendent carboxylic acid groups, and to block copolymers thereof with poly (alkylene oxides). The present i...

AI Technical Summary

Benefits of technology

[0011]These needs are met by the present invention. It has now been found that the incorporation of pendent carboxylic acid groups within the polymer bulk has a dramatic and previously unrecognized accelerating effect on the rate of polymer backbone degradation and resorption both in vitro and in vivo. Thus, the present invention makes it possible to modulate the rates of degradation and resorption to such a surprising extent that rod-like devices can be formulated that resorb completely from about 5 hours all the way to 3 years post implantation-simply by modifying the percentage of pendent carboxylic acid pendent chains available along the polymer backbone.

[0012]The present invention makes it possible to create pendent carboxylic acid groups on the polymer surface without concomitant backbone cleavage. This is in important difference relative to conventionally used medical polymers such as poly (lactic acid), poly (glycolic acid), polycaprolactone and others where the polymer backbone has to be cleaved (with the associated reduction in molecular weight and physical strength) in order to create chemically reactive attachment sites at the polymer surface. Thus, the present invention significantly improves the versatility and utility of the above mentioned polymer systems, specifically polycarbonates, polyarylates, and the respective poly (alkylene oxide) copolymers thereof.

[0013]Thus, a new method has now been discovered for preparing new polymeric materials in which the ester of pendent carboxylic acid groups is selectively removed from the polymer backbone. The resulting polymers contain pendent carboxylic acid groups on some or all of their monomeric repeating subunits. The pendent carboxylic acid groups impart increased hydrophilicity to the polymers and result in unexpected useful new properties. Polycarbonates, polyarylates, and poly (alkylene oxide) block copolymers thereof, with pendent carboxylic acid groups have been prepared.

Problems solved by technology

The polycarbonates, polyarylates and poly (alkylene oxide) block copolymers thereof cannot be prepared by conventional solution processes from monomers having free carboxylic acid groups.

The resulting polymers with protected carboxylic acid groups are limited in application because of their slow rate of degradation and significant hydrophobicity.

Thus, the selective removal of any carboxylic acid protecting groups is a challenge.

For polyarylates and poly (alkylene oxide) block copolymers thereof, the ester protecting groups cannot be removed by conventional hydrolysis techniques without complete degradation of the polymer backbone.

For polycarbonates and poly (alkylene oxide) block copolymers thereof, the ester protecting groups cannot be removed by conventional hydrolysis techniques without massive degradation of the polymer backbone.

Since cleavage of the pendent ester groups becomes slower (relative to backbone cleavage) as the bulkiness of the pendent group increases, conventional hydrolysis of methyl and ethyl ester pendent chains is accompanied by a dramatic loss of molecular weight, while attempts to remove bulkier ester pendent chains by either basic or acidic hydrolysis of polycarbonates results in total destruction of the polymer and the recovery of oligomeric species only.

Thus, conventional hydrolysis of polycarbonates and poly (alkylene oxide) block copolymers thereof is of marginal value if applied to methyl or ethyl ester pendent chains and is entirely unsuitable for the removal of bulkier pendent chains.

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