Composite containing collagen and elastin as a dermal expander and tissue filler

Abstract

An injectable composition having dermal filling and tissue expanding activity comprises: (1) a quantity of elastin sufficient to bring about dermal filling and tissue expansion when injected into a subject in need of dermal filling and tissue expansion; and (2) a pharmaceutically acceptable carrier. The composition can further comprise collagen; in other alternatives, the composition can further comprise hyaluronic acid; and one or more of the elastin, the collagen, and the hyaluronic acid, if present can be cross-linked, either intramolecularly or intermolecularly. The elastin, however, is the primary filler, even if collagen or hyaluronic acid are included in the composition. Proanthocyanidin can act as a cross-linker and as a protector of elastin against UV degradation. Proanthocyanidin combined with a collagen or gelatin-hyaluronic acid matrix can inhibit matrix degradation and contraction with fibroblasts. Additionally, the present invention encompasses a method for augmenting the volume area of dermal tissue at sites where wrinkles and other tissue imperfections have caused visible changes associated with loss or rearrangement of the subcutaneous collagen network comprising the step of: providing an effective amount of a composition, which can be injected locally, and which consists of a mixture of macromolecules which are native constituents of the skin, the mixture comprising collagen, elastin and hyaluronic acid, which are held together by covalent, ionic or hydrogen bonds, and which include natural materials which have been demonstrated to increase the natural synthesis of these molecules by cells which reside in the dermis.

We claim: 
     
         1 . An injectable composition having dermal filling and tissue expanding activity comprising:
 (a) a quantity of elastin sufficient to bring about dermal filling and tissue expansion when injected into a subject in need of dermal filling and tissue expansion;   (b) a pharmaceutically acceptable carrier, wherein the carrier comprises an excipient selected from the group consisting of glucose, maltose, gelatin, and carboxymethylcellulose;   (c) collagen;   
       wherein the composition provides space-filling activity owing to the quantity of elastin; 
       wherein the quantity of elastin is from 20 mg/mL to 300 mg/mL; and 
       wherein the elastin is full-length elastin. 
     
     
         2 . The composition of  claim 1  wherein the collagen is in soluble form, fibrillar form, a form of an insoluble slurry, or hydrogel form. 
     
     
         3 . The composition of  claim 1  wherein the collagen is cross-linked intramolecularly. 
     
     
         4 . The composition of  claim 1  wherein the composition further comprises a glycosaminoglycan, wherein the glycosaminoglycan is selected from the group consisting of hyaluronic acid, chondroitin sulfate, pentosan polysulfate, dermatan sulfates, heparin, heparan sulfates, and keratan sulfates. 
     
     
         5 . The composition of  claim 1  wherein the collagen is crosslinked to the elastin or is crosslinked to a glycosaminoglycan, wherein the glycosaminoglycan is selected from the group consisting of hyaluronic acid, chondroitin sulfate, pentosan polysulfate, dermatan sulfates, heparin, heparan sulfates, and keratan sulfates. 
     
     
         6 . The composition of  claim 1  wherein the elastin is selected from the group consisting of non-human mammalian elastin and human elastin. 
     
     
         7 . The composition of  claim 1  wherein the pharmaceutically acceptable carrier comprises gelatin. 
     
     
         8 . The composition of  claim 1  wherein the composition further comprises a rapid-acting local anesthetic selected from the group consisting of lidocaine, benzocaine, tetracaine, bupivacaine, etidocaine, flecainide, mepivacaine, pramoxine, prilocaine, chloroprocaine, proparacaine, ropivacaine, dyclonine, dibucaine, propoxycaine, chloroxylenol, cinchocaine, dexivacaine, diamocaine, hexylcaine, levobupivacaine, pyrrocaine, risocaine, and rodocaine. 
     
     
         9 . The composition of  claim 8  wherein the rapid-acting local anesthetic is lidocaine. 
     
     
         10 . The composition of  claim 1  wherein the elastin is crosslinked with a cross-linking agent selected from the group consisting of a compound that is a member of the class of proanthocyanidins, a bifunctional epoxide, a carbodiimide, and glutaraldehyde. 
     
     
         11 . The composition of  claim 10  wherein the cross-linking agent is a compound that is a member of the class of proanthocyanidins. 
     
     
         12 . The composition of  claim 11  wherein the compound that is a member of the class of proanthocyanidins is selected from the group consisting of proanthocyanidin, procyanidin (2H-1-benzopyran-3,4,5,7-tetrol, 2-(3,4-dihydroxyphenyl)-2-((2-(3,4-dihydroxyphenyl)-3,4-dihydro-5,7-dihydroxy-2H-1-benzopyran-3-yl)oxy)-3,4-dihydro), procyanidin B, procyanidin B2, rhatannin, procyanidol oligomer, procyanidin C, procyanidin B3, procyanidin B1, selligueain A (8,14-methano-2H,14H-1-benzopyrano(7,8-d)(1,3)benzodioxocin-3,5,11,13,15-pentol, 4-(3,4-dihydro-3,5,7-trihydroxy-2-(4-hydroxyphenyl)-2H-1-benzopyran-8-yl)-3,4-dihydro-2,8-bis(4-hydroxyphenyl)-,(2R-(2α, 3α, 4β(2R*, 3S*), 8β, 14β,15R*)), geranin A, geranin D, procyanidin B5, procyanidin B5-3′-O-gallate, vitisinol, amurensisin, terminalin, geranin B, 6,8-dihydroxyafzelin, afzelin-3″-O-gallate, geranin C, afzelin, flavangenol, carallidin, mahuannin A, proanthocyanidin A1, proanthocyanidin A2, and procyanidin D. 
     
     
         13 . The composition of  claim 12  wherein the compound that is a member of the class of proanthocyanidins is proanthocyanidin. 
     
     
         14 . The composition of  claim 10  wherein the cross-linking agent is a bifunctional epoxide and wherein the bifunctional epoxide is 1,4-butanediol glycidyl ether. 
     
     
         15 . The composition of  claim 10  wherein the cross-linking agent is a carbodiimide selected from the group consisting of 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDC), dicyclohexylcarbodiimide (DCC), 1-ethyl-3-(4-azonia-4,4-dimethylpentyl) carbodiimide iodide (EAC); 1-cyclohexyl-3-(2-morpholinyl-(4)-ethyl-carbodiimide metho-p-toluenesulfonate (CMC), and N-benzyl-N′-3-dimethylaminopropylcarbodiimide hydrochloride (BDC). 
     
     
         16 . The composition of  claim 10  wherein the cross-linking agent is selected from the group consisting of glutaraldehyde and periodate. 
     
     
         17 . The composition of  claim 1  wherein the elastin is crosslinked with a glycosaminoglycan selected from the group consisting of hyaluronic acid, chondroitin sulfate, pentosan polysulfate, dermatan sulfates, heparin, heparan sulfates, and keratan sulfates. 
     
     
         18 . The composition of  claim 1  wherein the elastin is cryofractured into a fine particle. 
     
     
         19 . The composition of  claim 1  wherein the collagen is native or denatured collagen obtained from skin, tendon, ligament, pericardium, dural membrane, small intestine mucosa, or bone. 
     
     
         20 . The composition of  claim 1  wherein the collagen is human Type I collagen. 
     
     
         21 . An injectable composition having dermal filling and tissue expanding activity comprising:
 (a) an insoluble collagen suspension in a quantity sufficient to bring about dermal filling and tissue expansion when injected into a subject in need of dermal filling and tissue expansion; and   (b) a pharmaceutically acceptable carrier.   
     
     
         22 . The composition of  claim 21  wherein the concentration of collagen is from about 20 mg/mL to about 100 mg/mL. 
     
     
         23 . The composition of  claim 21  wherein the collagen is cross-linked with a cross-linking agent selected from the group consisting of a compound that is a member of the class of proanthocyanidins, a bifunctional epoxide, a carbodiimide, and glutaraldehyde. 
     
     
         24 . The composition of  claim 23  wherein the cross-linking agent is a compound that is a member of the class of proanthocyanidins. 
     
     
         25 . The composition of  claim 24  wherein the compound that is a member of the class of proanthocyanidins is selected from the group consisting of proanthocyanidin, procyanidin (2H-1-benzopyran-3,4,5,7-tetrol, 2-(3,4-dihydroxyphenyl)-2-(2-(3,4-dihydroxyphenyl)-3,4-dihydro-5,7-dihydroxy-2H-1-benzopyran-3-yl)oxy)-3,4-dihydro), procyanidin B, procyanidin B2, rhatannin, procyanidol oligomer, procyanidin C, procyanidin B3, procyanidin B1, selligueain A (8,14-methano-2H,14H-1-benzopyrano(7,8-d)(1,3)benzodioxocin-3,5,11,13,15-pentol, 4-(3,4-dihydro-3,5,7-trihydroxy-2-(4-hydroxyphenyl)-2H-1-benzopyran-8-yl)-3,4-dihydro-2,8-bis(4-hydroxyphenyl)-,(2R-(2α,3α,4β(2R*,3S*), 8β,14β,15R*)), geranin A, geranin D, procyanidin B5, procyanidin B5-3′-O-gallate, vitisinol, amurensisin, terminalin, geranin B, 6,8-dihydroxyafzelin, afzelin-3″-O-gallate, geranin C, afzelin, flavangenol, carallidin, mahuannin A, proanthocyanidin A1, proanthocyanidin A2, and procyanidin D. 
     
     
         26 . The composition of  claim 25  wherein the compound that is a member of the class of proanthocyanidins is proanthocyanidin. 
     
     
         27 . The composition of  claim 23  wherein the cross-linking agent is a bifunctional epoxide and wherein the bifunctional epoxide is 1,4-butanediol glycidyl ether. 
     
     
         28 . The composition of  claim 23  wherein the cross-linking agent is a carbodiimide selected from the group consisting of 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDC), dicyclohexylcarbodiimide (DCC), 1-ethyl-3-(4-azonia-4,4-dimethylpentyl) carbodiimide iodide (EAC); 1-cyclohexyl-3-(2-morpholinyl-(4)-ethyl-carbodiimide metho-p-toluenesulfonate (CMC), and N-benzyl-N′-3-dimethylaminopropylcarbodiimide hydrochloride (BDC). 
     
     
         29 . The composition of  claim 23  wherein the cross-linking agent is selected from the group consisting of glutaraldehyde and periodate. 
     
     
         30 . The composition of  claim 21  wherein the pharmaceutically acceptable carrier comprises an excipient selected from the group consisting of glucose, maltose, gelatin, and carboxymethylcellulose.