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Cross-linked collagen and uses thereof

Cross-linked collagen and uses thereof description/claims

This application is based, and claims priority under 35 U.S.C. § 120 to U.S. Provisional Patent Application No. 60/939,664 filed on May 23, 2007 and which is incorporated herein by reference.

The present invention relates in general to body treating compositions and methods. More specifically, the invention provides a cross-linked collagen implant of improved volume stability (“persistence”) for augmenting soft tissue in mammals.

Collagen has been used as a pharmaceutical carrier, as a surgical prosthesis (sutures and wound dressings), and as an implant material. In many instances, the collagen is cross-linked with chemical agents, radiation, or other means to improve its mechanical properties, decrease its immunogenicity, and/or increase its resistance to resorption. For example, U.S. Pat. No. 4,424,208 describes a collagen composition including cross-linked collagen and reconstituted collagen fibers having enhanced persistence. While these materials are remarkably effective, they shrink in volume after implantation due primarily to absorption of their fluid component by the body, although the shrinkage (syneresis) is less than non-cross-linked collagen. Since a constant volume or persistence is desirable, an additional injection or injections of supplemental implant material is required. It would thus be advantageous to provide collagen compositions having enhanced persistence after being introduced in vivo to a soft tissue treatment site.

The present invention relates to collagen cross-linked in a micro to non-fibrillar form and at a high concentration for augmenting soft tissue in mammals. The cross-linked collagen of the present invention has improved volume stability or persistence compared with collagen cross-linked at a neutral pH.

In one aspect, the invention features a method for preparing cross-linked collagen. The method involves the steps of obtaining micro to non-fibrillar collagen, treating the micro to non-fibrillar collagen with a cross-linking agent, and isolating cross-linked collagen. The micro to non-fibrillar collagen may be obtained by incubating fibrillar collagen in a suspension or solution of pH 2-5 or pH 9-12. In a preferred embodiment, the pH of the suspension or solution is between 4.2 and 5.0. The concentration of the micro to non-fibrillar collagen at the time of cross-linking is in the range of 3-150 mg/mL, and preferably, 38-52 mg/mL. Typically, the treating step includes treating the micro to non-fibrillar collagen with the cross-linking agent at pH 2-5 or pH 9-12, followed by treating the micro to non-fibrillar collagen with the cross-linking agent at pH 6-8 to encourage completion of the cross-linking. The method of the invention optionally may further include a step of admixing a local anesthetic agent (e.g., lidocaine) with the cross-linked collagen. Cross-linked collagen so prepared is within the invention.

Also provided in the present invention is cross-linked collagen comprising micro to non-fibrillar collagen and a cross-linking agent. The micro to non-fibrillar collagen is cross-linked by the cross-linking agent. Such cross-linked collagen may be prepared according to the method described above.

The cross-linked collagen may derive from type I, II, III, IV, or V collagen, or a combination thereof. It may also derive from telo-containing collagen, atelo-collagen, or derivatized collagen, or a combination thereof.

Preferably, the cross-linking agent is capable of forming covalent bonds between amino acid residues in the micro to non-fibrillar collagen. Examples of suitable cross-linking agents include, but are not limited to, carbodiimides, polyaldehydes, polysulfones, activated PEGs, epoxides, imidazoles, and diisocyanates. In one embodiment, the cross-linking agent is glutaraldehyde.

In some embodiments of the cross-linked type I collagen, the number of free hydroxy lysine and lysine residues per 1000 amino acid residues is in the range of 22-32, and more typically, in the range of 24-29.

The cross-linked collagen of this invention is in a gel but not fibrous state. It locks water in the gel and does not disperse like a fibrous collagen suspension. The cross-linked collagen in a gel state maintains its shape in vivo better than cross-linked collagen in a fibrous state. The fibers of the cross-linked collagen are smaller than those of fibrous collagen cross-linked at a neutral pH.

The invention further provides a composition containing the cross-linked collagen of the invention and a local anesthetic agent such as lidocaine. The local anesthetic agent is admixed with the cross-linked collagen. In addition, the invention provides a packaged product containing a syringe fitted with a needle, wherein the syringe is loaded with the cross-linked collagen of the invention.

In another aspect, the invention features a method for filling voids and defects and increasing tissue volume in a mammal. The method involves administering to a mammal the cross-linked collagen of the invention. Preferably, the cross-linked collagen is administered by intradermal or subcutaneous injection.

As used herein, “micro to non-fibrillar collagen” refers to collagen with a diameter of 5-70 nm; “fibrillar collagen” refers to collagen with a diameter of >70 nm; “fibrous collagen” refers to fibrillar collagen and larger fibers. “Telo-containing collagen” refers to collagen with intact telo peptide; “atelo-collagen” refers to collagen wherein the telo portions are removed partially or totally; “derivatized collagen” refers to chemically modified collagen. Examples of derivatized collagen include, but are not limited to, deamidated, methylated, succinylated, and phosphorylated collagen. Cross-linked collagen in a “gel state” contains micro to non-fibrillar collagen with a fiber diameter range of 5-70 nm; cross-linked collagen in a “fibrous state” contains fibrillar collagen with a fiber diameter of greater than 70 nm.

As used herein, “free hydroxyl-lysine and lysine” in collagen refers to unmodified hydroxyl-lysine and lysine; “neutral pH” refers to pH 6-8.

The present invention provides a cross-linked collagen filler for augmenting and filling soft tissue defects and voids with a material that plumps and bulks the soft tissue. The cross-linking collagen of the invention is particularly useful for deep dermal correction and sculpting. The superior shape retention makes it ideal for areas that are hard to correct and where a biocompatible bolus can provide mechanical strength to the body.

The above-mentioned and other features of this invention and the manner of obtaining and using them will become more apparent, and will be best understood, by reference to the following description, taken in conjunction with the accompanying drawings. The drawings depict only typical embodiments of the invention and do not therefore limit its scope.

• Provisional Patent
• Utility Patent

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