Organic compounds -- part of the class 532-570 series – Organic compounds – Carboxylic acid esters
Reexamination Certificate
2002-06-27
2004-03-30
Richter, Johann (Department: 1621)
Organic compounds -- part of the class 532-570 series
Organic compounds
Carboxylic acid esters
C560S312000
Reexamination Certificate
active
06713646
ABSTRACT:
BACKGROUND OF THE INVENTION
Biocompatible polymeric materials have been used extensively in medical implant devices. For some applications, the polymers should not only be biocompatible but also degradable, into non-toxic products (bone fixtures, sutures, drug containing implants etc.). This degradability removes the need to later remove the device from the implant site.
The first degradable polymers were based on hydrophobic polymers like PLGA, poly(orthoesters), polyanhydrides and polyiminocarbonates, which degrade hydrolytically into water-soluble monomers and oligomers. The degradation times can be adjusted by the chemical composition of these polymers. The problem with these polymers is the need to keep them completely dry during storage. The majority of degradable polymers are essentially hard, brittle materials, developed for drug delivery uses.
Other degradable polymers are based on naturally-occurring polymers, e.g., polysaccharides or polypeptides. The degradation process is based on enzymatic hydrolysis of the polysaccharides or polypeptides. While these products can be formed as hydrogels, and therefore may be stored in an aqueous environment, the degradation time is not controllable due to variable enzyme expression in humans. Additionally, only the unmodified part of the protein or polysaccharide is degradable, while modified sites are nondegradable. Furthermore, naturally derived products have to undergo vigorous testing to ensure that they are free of endotoxins and contaminating proteins. For human or animal derived proteins, viral contamination is a constant worry.
Another approach is to synthesize a hydrogel, which contains an unstable crosslinker. This approach has been investigated by a number of groups. The first approach was to polymerize the hydrogel in situ using photopolymerization of monomers that contain a hydrolytically unstable lactic acid component. The degradation time can be adjusted through the numbers of lactic acid units incorporated into the monomer. However, these monomers must be stored under anhydrous conditions.
Another approach has been to synthesize crosslinkers containing hydrolytically labile carbonate (Bruining et al, Biomaterials 21 (2000) 595-604), ester (Argade et al, Polymer Bulletin 31 (1993) 401-407), and phosphazene linkers (Grosse-Sommer et al, Journal of Controlled Release 40 (1996) 261-267). These hydrogels are not stable under any of the conditions described and start to degrade immediately following synthesis and placement into an aqueous environment. Yet another approach utilizes a reduction/oxidation cleavable crosslinker, such as a disulfide bridge. However, the reduction product from the disulfide bridge is two thiols, which are easily reoxidized to the disulfide bridge, restoring the crosslink.
Still another approach would use a crosslinker that is stable under either basic or acidic conditions, and starts to degrade at blood pH of pH 7.4. Ruckenstein et al (Ruckenstein et al, Macromolecules, 32 (1999) 3979-3983; U.S. Pat. No. 6,323,360) described one such crosslinker as the addition product between ethylene glycol divinyl ether and methacrylic acid. The resulting crosslinker, containing hemiacetal functional groups, is base stable and degrades under acidic conditions. However, the publication does not provide a means to control the degradation time nor are the described degradation conditions in organic solvents useful for biological applications.
Another degradable crosslinker has been described by Ulbrich (Ulbrich et al, Journal of Controlled Release, 24 (1993) 181-190; Ulbrich et al, Journal of Controlled Release, 34 (1995) 155-165; U.S. Pat. No. 5,130,479; U.S. Pat. No. 5,124,421). The crosslinker is N,O-dimethacryloylhydroxylamine. The degradation of this crosslinker is based on the base-catalyzed Lossen rearrangement of substituted hydroxamic acids. The crosslinker appears to be stable under acidic conditions, while degradation occurs at neutral to basic pH values. The only way described in the articles and patents by Ulbrich et al to control degradation is through the crosslink density. Increasing the crosslink density from 1.2% to 2.4% increases the degradation time from 21 hours to 45 hours at pH 7.4 (U.S. Pat. No. 5,124,421). Akala (Akala, Pharm Pharniacol Lett 8 (1998) 129-132) discovered that the introduction of acrylic acid groups into a linear polymer accelerated the degradation of the pendant N, O-diacylhydroxyamine moieties, an effect not reported by Ulbrich et al.
SUMMARY OF THE INVENTION
One aspect of the present invention relates to base-labile crosslinkers. A second aspect of the present invention relates to degradable crosslinked polymers and hydrogels comprising a base-labile crosslinker. The present invention also relates to a method of influencing the degradation rate of a crosslinked polymer or hydrogel, comprising the step of incorporating uncharged acrylamides into the crosslinked polymer or hydrogel.
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Argade et al.; “Preparation and Characterization of Novel Biodegradable tri-and tetraacrylate Intermediates”, Polymer Bulletin 31: 401-407, (1993).
Bruining et al.; “Biodegradable Three-Dimensional Networks of Poly(dimethylamino ethyl methacrylate), Synthesis, Characterization and in Vitro Studies of Structural Degradation and Cytotoxicity”, Biomaterials 21: 595-604 (2000).
Bruining et al., “New Biodegradable Networks of Poly(N-vinylpyrrolidinone) Designed for controlled Nonburst Degradation in the Vittreous Body”, J Biomed. Mater. Res. 47:189-197, (1999).
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Ulbrich et al.; “Synthesis Of Novel Hydrolytically degradable Hydrogels for Controlled Drug Release”, Journal of Controlled Release 34: 155-165, (1995).
Schwarz Alexander
Zhang Hongmin
Biosphere Medical
Foley & Hoag LLP
Gordon Dana M.
Richter Johann
Zucker Paul A.
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