Title:  Compositions containing polyanionic polysaccharides and hydrophobic bioabsorbable polymers

United States Patent:  6,294,202

Assignee:  Genzyme Corporation (Cambridge, MA)

Filed:  October 6, 1994

Biocompatible compositions comprising polyanionic polysaccharides such as Hyaluronic Acid combined with hydrophobic bioabsorbable polymers as well as methods for making and using the compositions are described.

DETAILED DESCRIPTION OF THE INVENTION

Polyanionic polysaccharides and their salts may be obtained from a variety of standard commercial sources. Water-insoluble polyanionic polysaccharide gels, films, and foams can be prepared by any method for use in this invention. The gels may be generated via the formation of covalent intra- and inter-chain crosslinks as previously described (e.g., see Sparer et al., supra; DeBelder et al., supra; Balazs et al. supra; Malson et al., supra; and Prestwich et al. EP Publication No. 0416250A2, 1991). Alternatively, water-insoluble gels which do not contain covalent cross-links between the polyanionic polysaccharide molecules may be formed using the methods described in Hamilton et al., U.S. Pat. No. 4,937,270; Burns et al., U.S. Pat. No. 5,017,229, U.S. Ser. No. 07/703,254 and 07/833,973 (all of the above hereby incorporated by reference).

A polyanionic polysaccharide is said to be "activated", as that term is used herein, when it is treated in an aqueous mixture in a manner that renders the carboxyl groups on the polyanionic polysaccharide vulnerable to nucleophilic attack; and an "activating agent" is a substance that, in an aqueous mixture including a polyanionic polysaccharide, causes the polyanionic polysaccharide to become so activated.

Polyanionic polysaccharide gels, films, and foams are prepared generally by mixing at least one polyanionic polysaccharide (e.g., HA, CMC, CMA) with an activating agent to form a water-insoluble material. Preferred activating agents include the carbodiimides, EDC and ETC. The reaction may be carried out at a pH between 3.5 and 8, with optimal reaction conditions occurring between pH 4.7 and 5.1. The polysaccharide molecular weight used in the reaction may range from 9.0x10⁴ to 3.0x10⁶ daltons, but preferably is between 2.5x10⁵ to 1.0x10⁶ daltons.

Foams and films of compositions containing soluble polyanionic polysaccharides and their derivatives can be generated by lyophilizing or freeze drying the solution.

Compositions containing water-insoluble polyanionic polysaccharide composition can also be treated to generate the desired film, foam, powder, or fibers. For example, to obtain films, the reaction mixture is typically poured into a vessel, e.g., a tray, having the desired size and shape and allowed to air dry.

Alternatively a film can be formed by compressing a water-insoluble gel under conditions that permit escape of water, as, for example, by compressing the water-insoluble gel between two surfaces, at least one of which is porous, as described, for example, in EPO 0 193 510.

Another alternative method of producing sheets of the material is to subject it to freeze drying. The pore size of the final product can be controlled by adjusting the initial freezing temperature and drying conditions. Curved surfaces and other shapes can be produced in a similar manner by initially casting the water-insoluble gel onto a negative image surface and then processing as described. The dried sheet can be processed further, if desired, by pressing to a defined thickness, e.g., in a Carver laboratory press. This is particularly useful for applications requiring placement of a thin film between anatomical structures where space is limited, and for imparting additional mechanical strength.

The formation of foams, fibers and other shapes or articles can also be accomplished using techniques well-known in the plastics and textile industries.

For instance, foams of the water-insoluble polysaccharide derivatives can be generated by freeze drying procedures that are well known in the art, e.g., Yannas et al., (U.S. Pat. No. 4,280,954) and Dagalakis et al., (1980, J. Biomed. Mater. Res., vol. 14, p. 511-528), describe methods of freeze drying collagen-mucopolysaccharide composites and controlling pore structure. Typical conditions are temperatures below -20^oC. and a vacuum below 250 mTorr.

Fibers of the water-insoluble polysaccharide derivatives can be made by wet spinning procedures that are well known in the art. For example, Rupprecht (1979, Acta Chem. Scand., vol. 33, p. 779-780) describes the wet spinning of aqueous hyaluronic acid solutions into an ethanol coagulation bath to form fibers. Alternatively, fibers of the hydrophobic bioabsorbable polymers can be made by more conventional melt spinning techniques that are well known in the art. For example, Wasserman et al. (U.S. Pat. Nos. 3,792,010 and 3,839,297) describe the manufacture of monofilament and braided polyester sutures of lactide-glycolide copolymers. The fibers can be made into fabrics by knitting and weaving techniques well known in the art.

The film and foam derivatives of polyanionic polysaccharide compositions can be strengthened by dehydrothermal treatment (DHT: 95-105^oC. at 200-760 mm Hg for 6-24 hrs) and combined with hydrophobic bioabsorbable polymers. For example, bioabsorbable polymers such as polyglycolide (PGA), polylactide (PLA), and copolymers of PGA/PLA are dissolved in volatile solvents such as methylene chloride, acetone, ethylacetate, tetrahydrofuran, n-methyl-pyrrolidone at concentrations of 0.5-50.0% w/w with a preferred range of 1%-3% (w/w). Various ratios of PGA and PLA can be used including 100% PGA, 85% PGA:15% PLA, 50% PGA:50% PLA, and 100% PLA; 1:1 PGA:PLA is preferred.

Additionally, other hydrophobic bioabsorbable polymers such as polydioxanones, polyorthoesters, polyestercarbonates, polylactones (especially polycaprolactone) and polyhdroxybutyrate/valerate can be used alone or as copolymers, especially copolymers of PLA and polycaprolactone. These solutions are then sprayed onto the polyanionic polysaccharide based device using spraying devices such as a small chromatography sprayer with compressed air or argon gas at 2-20 psi to achieve a 5-100% weight gain. Coated foams can be pressed into thin membranes at 1.0-5.0 metric tons employing a Carver laboratory press with 1-50 mm spacers or left unpressed as thick foams.

In one alternative method, the polysaccharide-based 15 materials and hydrophobic bioabsorbable polymers are laminated together by heat-pressing a form of the polymer (film, foam, mesh, etc.) onto a polyanionic polysaccharide foam or film. The preferred conditions of lamination depend on the thermal properties of the various hydrophobic polymers but generally fall within the following ranges: 40-230^oC. at 0-8 metric tons of compression for 0-5 minutes. In addition, the hydrophobic polymer can be rendered more hydrophilic following lamination by plasma treatment.

In a second alternative method, bioabsorbable polymer fibers are incorporated into the polysaccharide-based materials by cutting or chopping the fibers to specific sizes and dispersing them into polysaccharide-based solutions before casting or lyophilizing into films or foams. The bioabsorbable-polymer fibers can also be laid onto a substrate as a mesh or matte and then polysaccharide-based solutions can be cast on top.

In a third method, the polysaccharide-based films and foams are coated with hydrophobic polymers by means other than the spray-coating method described above. For example, bioabsorbable polymers such as PGA, PLA, and copolymers of PGA/PLA, PLA/polycaprolactone, and PGA/polycaprolactone can be dissolved in organic solvents at concentrations of 0.5-50%, preferably 1.0-3.0%. The polymer solution can then be spread with a drawdown knife or cast on the surface of a polysaccharide-based film or foam and then dried. Alternatively, the water-insoluble polysaccharide-based devices can be dipped or soaked in the polymer solution and then allowed to air dry to achieve incorporation.

In still another method, composite fibers can be made which contain a water-insoluble polysaccharide derivative core and a hydrophobic bioabsorbable polymer coating. Aqueous solutions containing polysaccharide derivatives are extruded through a spinneret or syringe needle into a coagulation bath containing a bioabsorbable polymer solution, such as PGA/PLA, PLA/polycaprolactone, or PGA/polycaprolactone dissolved in organic solvent. The water-insoluble polysaccharide-based material precipitates in the coagulation bath and is simultaneously coated with bioabsorbable polymer. Alternatively, the water-insoluble polysaccharide-based fiber can be coated with bioabsorbable hydrophobic polymer after the coagulation stage of the wet-spinning process by drawing the polysaccharide derivative fiber through a solution of bioabsorbable hydrophobic polymer.

Claim 1 of 52 Claims

We claim:

1. A water-insoluble biocompatible composition comprising a non-covalently crosslinked water-insoluble polyanionic polysaccharide derivative combined with a hydrophobic bioabsorbable polymer, wherein said composition is produced by:

a) reacting hyaluronic acid with an activating agent to form a non-covalently crosslinked water-insoluble hyaluronic acid derivative bearing an i) amide or amine group or ii) N-acyl urea group; and

b) non-covalently combining said non-covalently crosslinked water-insoluble hyaluronic acid derivative with a polyglycolide to form said water-insoluble biocompatible composition.

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