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Cross-linked polysaccharide compositionRelated Patent Categories: Drug, Bio-affecting And Body Treating Compositions, Preparations Characterized By Special Physical Form, Matrices, Synthetic PolymerCross-linked polysaccharide composition description/claimsThe Patent Description & Claims data below is from USPTO Patent Application 20070026070, Cross-linked polysaccharide composition. Brief Patent Description - Full Patent Description - Patent Application Claims
TECHNICAL FIELD [0001] The present invention relates to cross-linked polysaccharide compositions, processes for preparing the compositions, and uses of the compositions in cosmetic, medical and pharmaceutical applications. BACKGROUND ART [0002] Hyaluronic acid (HA) is a member of a class of polymers known as glycosaminoglycans. HA is a long chain linear polysaccharide and is usually present as a sodium salt having the molecular formula (C.sub.14H.sub.20NNa.sub.11).sub.n where n may vary according to the source of the HA and the method of isolating the HA. Molecular weights of HA of up to 14.times.10.sup.6 have been reported. [0003] HA and its salts may be isolated from many sources including the human umbilical cord, rooster combs and nearly all connective matrices of vertebrate organisms. HA is also a capsular component of bacteria such as streptococci and may therefore be obtained by fermentation methods such as reported in U.S. Pat. No. 5,411,874 (Fermentech Ltd). [0004] HA is non-immunogenic and therefore has great potential in medicine. Because of its visco-elastic properties, HA having a high molecular weight (over 1 million) has been found to be particularly useful in a variety of clinical fields, including wound treatment, ophthalmic surgery, orthopedic surgery and drug delivery. HA is also potentially useful in a variety of non-medical fields, including cosmetic applications. [0005] However, one drawback to administering HA to humans is that HA is degraded by enzymes such as hyaluronidase and free radicals found in the human body. Furthermore, HA is soluble in water at room temperature, which may also make it less suited to certain applications. [0006] Various attempts have been made to prepare more stable forms of HA, in particular, by cross-linking the HA molecules. For example, hydroxyl groups have been cross-linked via an ether linkage and carboxyl groups via an ester linkage. HA has been cross-linked at pH levels less than 9 at which ester bonds form via carboxyl groups, and at pH levels greater than 9 at which ether bonds form via hydroxyl groups. The present inventors have found that ether bonds may be beneficial because these bonds are more resistant to physiological degradation. [0007] A number of documents report a variety of methods of cross-linking HA gels. For example, U.S. Pat. No. 4,582,865 (Biomatrix Inc) reports cross-linked gels of HA formed by cross-linking HA (either by itself or mixed with other hydrophilic polymers) using divinyl sulfone as the cross-linking agent. [0008] U.S. Pat. No. 5,827,937 (Agerup) reports polysaccharide gel compositions prepared by forming an aqueous solution of the polysaccharide, initiating cross-linking in the presence of a polyfunctional cross-linking agent, sterically hindering the cross-linking reaction from being terminated before gelation occurs (e.g. by diluting the solution) and then reintroducing sterically unhindered conditions (e.g. by evaporating the solution) so as to continue the cross-linking such that a viscoelastic gel is formed. The cross-linking in this method may be performed under alkaline or acidic conditions. [0009] WO 00/46253 (Fermentech Ltd) reports cross-linking HA with other polymers by two different types of cross-linking bonds. The formation of different types of bonds is achieved by cross-linking via different functional groups. For example, one type of bond may be formed by cross-linking via hydroxyl groups, and a different functional bond may be formed by cross-linking via carboxyl groups. [0010] WO 87/07898 reports reacting a polysaccharide with a polyfunctional epoxide, removing excess epoxide and employing a drying operation to cross-link the polysaccharide into a film, powdered material or similar dry product. [0011] U.S. Pat. No. 4,963,666 (Pharmacia) reports a process in which a polysaccharide is monosubstituted with a cross-linking agent at low concentration under alkaline conditions to form ether linkages. The mixture is washed to pH 5.5 inducing some ester linkages and then, in one example, concentrated by slow evaporation to complete cross-linking with ester linkages. In another example, the pH is increased by the addition of ammonia, and then slowly evaporated to complete the cross-linking with primarily ether linkages and some ester linkages. [0012] Although attempts have been made to improve the properties of cross-linked HA, it would be beneficial to provide cross-linked HA gels having improved degradation characteristics when administered to a patient. DISCLOSURE OF INVENTION [0013] In one embodiment, the present invention provides a process for producing a cross-linked polysaccharide gel. First, a polysaccharide mixed with an alkaline medium is contacted with a bifunctional or polyfunctional epoxide to form an essentially epoxy cross-linked polysaccharide in which the epoxide is linked to the polysaccharide substantially by ether bonds. The epoxy cross-linked polysaccharide is then dried without removing the epoxide from the alkaline medium. The resulting dried cross-linked polysaccharide matrix may then be washed in a suitable water miscible solvent, and treated with an acidic medium to form a cross-linked polysaccharide gel. [0014] A variety of polysaccharide starting materials may be used in embodiments of the present invention. Suitable polysaccharides include HA, pectin, xanthan or alginic acid, as well as anionic derivatives of carboxymethyl cellulose, carboxymethyl dextran or carboxymethyl starch. HA may be a particularly suitable starting material. Suitable epoxides for use as the cross-linking agent include 1,4-butanediol ether, 1,2-ethanediol diglycidyl ether and/or epoxy-substituted pentaerythritol. It will be appreciated, however, that other epoxides may also be suitable for the present invention. [0015] In another embodiment, the present invention provides a cross-linked polysaccharide gel prepared by the process reported herein. The gel may have improved degradation characteristics when administered to a patient. [0016] In yet another embodiment, the present invention provides a biocompatible gel including HA cross-linked substantially by ether bonds with 1,4-butanediolglycidyl ether that is sufficiently cross-linked to resist to degradation. [0017] As used herein, the phrase "sufficiently cross-linked to resist degradation" means that the gel is relatively stable to hyaluronidase attack under physiological conditions over prolonged periods or can tolerate extrusion or being expelled from a small gauge needle. In one embodiment, the present inventors have been able to produce biocompatible gels which release less than 75 percent uronic acid when 0.4 ml of the gel having a concentration of 15 mg/ml is combined with 0.5 mg hyaluronidase and 3 ml phosphate buffered saline, and stored at a temperature of at least 37.degree. C. for two days. Uronic acid release may be measured by the UV absorbance techniques reported in the Examples. In certain embodiments, the gels may release no more that 70 percent uronic acid, more particularly no more that 65 percent uronic acid under the foregoing conditions. [0018] In a first aspect, the present invention provides a process for producing a cross-linked polysaccharide gel comprising: [0019] (a) contacting a polysaccharide mixed in an alkaline medium with a bifunctional or polyfunctional epoxide to provide an essentially epoxy cross-linked polysaccharide wherein the epoxide is substantially linked to the polysaccharide by ether bonds; [0020] (b) drying the epoxy cross-linked polysaccharide without substantially removing epoxide from the alkaline medium to form a cross-linked polysaccharide matrix; [0021] (c) optionally washing the cross-linked polysaccharide matrix with a water miscible solvent; and [0022] (d) neutralising the cross-linked polysaccharide matrix with an acidic medium to form a cross-linked polysaccharide gel. [0023] In a second aspect, the present invention provides a cross-linked polysaccharide gel substantially resistant to hyaluronidase degradation prepared by the process according to the first aspect of the present invention. [0024] In a third aspect, the present invention provides a biocompatible gel comprising hyaluronic acid cross-linked substantially by ether bonds with 1,4-butanediol diglycidyl ether such that the gel is sufficiently cross-linked to substantially resist degradation. [0025] In a fourth aspect, the present invention provides a pharmaceutical composition comprising a cross-linked polysaccharide gel according to the second aspect of the present invention; a biologically active substance; and a pharmaceutically acceptable carrier. Continue reading about Cross-linked polysaccharide composition... 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