Claims for Patent: 5,618,551

Summary for Patent: 5,618,551

Title:	Biocompatible bioresorbable and non-toxic adhesive composition for surgical use
Abstract:	The invention relates to a biocompatible, bioresorbable and non-toxic adhesive composition for surgical use, for the bonding, in particular, of biological tissues to one another or in an implanted biomaterial, characterized in that it comprises a reactive acidic solution of non-crosslinked and potentially crosslinkable collagen or gelatin modified by oxidative cleavage, at a concentration which is preferably between approximately 5 and 30 by weight. It also relates to reactive acidic solutions and powders based on non-crosslinked collagen or gelatin modified by oxidative cleavage which are used as intermediate products in the preparation of the above-mentioned composition, and to the process for their preparation. It also relates to adhesive kits which comprise, on the one hand, the above-mentioned reactive acidic solution and, on the other hand, a neutralizing solution and which are intended for extemporaneous mixing. Finally it relates to a method of application of the adhesive, composition according to the invention. The invention is particularly useful in the areas of adhesion, haemostasis, leaktightness with respect to liquids or gases, cicatrization, filling, avoiding adhesion in surgery, embolization, as a local system for release of medicamentary active principles, etc.
Inventor(s):	Tardy; Michel (Lyons, FR), Tiollier; J er ome (Lyons, FR), Tayot; Jean-Louis (La Tour De Salvagny, FR)
Assignee:	Imedex (Chaponost, FR)
Application Number:	08/376,185
Patent Claims:	1. Non-crosslinked and potentially crosslinkable pepsin-treated collagen or gelatin powder modified by oxidative cleavage in an aqueous solution, which is soluble at an acidic pH and stable on storage at a temperature of below 0.degree. C. and for a period of at least one month. 2. Powder according to claim 1, characterized in that it comprises collagen or gelatin oxidized using a solution of periodic acid or one of its salts at a concentration of between approximately 1 and 10.sup.-5 M. 3. Powder according to claim 1, characterized in that it is stored at a temperature of below 0.degree. C. 4. Powder according to claim 3, characterized in that it is stored at a temperature of between approximately -10.degree. C. and -80.degree. C. 5. Powder according to claim 1, characterized in that the collagen or gelatin is of human or animal origin. 6. Process for the preparation of a powder according to claim 1, characterized in that it consists in: preparing an acidic solution of pepsin-treated collagen; subjecting the said acidic aqueous solution at room temperature to controlled oxidation by a solution of periodic acid or one of its salts at a concentration of between approximately 1 and 10.sup.-5 M; precipitating the oxidized and non-crosslinked pepsin-treated collagen at an acidic pH; and isolating and concentrating, and then dehydrating, the said non-crosslinked pepsin-treated collagen modified by oxidative cleavage so as to obtain it in the form of a reactive acidic powder; freezing and storing the obtained reactive acidic powder at a temperature of below 0.degree. C. 7. Process according to claim 6, characterized in that the oxidized and non-crosslinked collagen is precipitated at an acidic pH by addition of a salt, in particular by addition of sodium chloride. 8. Process according to claim 6, characterized in that collagen of human or animal origin is used. 9. Concentrated reactive acidic solution of non-crosslinked and potentially crosslinkable pepsin-treated collagen or gelatin modified by oxidative cleavage, substantially free from iodine or iodine derivatives and which is stable for a period of time of at least one month on storage at a temperature of below 0.degree. C., to form an adhesive composition. 10. Reactive acidic solution according to claim 9, characterized in that it is prepared from a non-crosslinked and potentially crosslinkable pepsin-treated collagen or gelatin powder modified by oxidative cleavage by dissolution in water at an acidic pH. 11. Solution according to claim 9, characterized in that the concentration of collagen or gelatin is between approximately 5 and 30% by weight. 12. Solution according to claim 9, characterized in that it is stored at a temperature of below 0.degree. C. 13. Solution according to claim 9, characterized in that it is stored at a temperature of between approximately -10.degree. C. and -80.degree. C. 14. Process for the preparation of a stable reactive acidic solution according to claim 10, characterized in that it consists in: preparing a sterile powder of non-crosslinked and potentially crosslinkable pepsin-treated collagen or gelatin modified by preparing an acidic solution of pepsin-treated collagen, subjecting the said acidic aqueous solution at room temperature to controlled oxidation by a solution of periodic acid or one of its salts at a concentration of between approximately 1 and 10.sup.-5 M, precipitating the oxidized and non-crosslinked pepsin-treated collagen at an acidic pH, and isolating and concentrating, and then dehydrating, the said non-crosslinked pepsin-treated collagen modified by oxidative cleavage so as to obtain it in the form of a reactive acidic powder, dissolving the required quantity of this powder in water by heating at a temperature of between approximately 40.degree. C. and 80.degree. C., cooling and storing the obtained reactive acidic solution at a temperature of below 0.degree. C. 15. Process according to claim 14, characterized in that the non-crosslinked collagen or gelatin powder modified by oxidative cleavage is dissolved in sterile water in a proportion of approximately 5% (weight/weight). 16. Biocompatible, bioresorbable and non-toxic adhesive kit intended for surgical use for the bonding, in particular, of biological tissues to one another or to an implanted biomaterial, characterized in that it consists of: a reactive acidic solution of non-cross-linked and potentially crosslinkable pepsin-treated collagen or gelatin modified by oxidative cleavage, and substantially free from iodine or iodine derivatives stored at a temperature of below 0.degree. C.; a neutralizing solution; and mixing means for extemporaneous mixing of the said solutions. 17. Kit according to claim 16, characterized in that the reactive acidic solution is a concentrated reactive acidic solution of non-crosslinked and potentially crosslinkable collagen or gelatin modified by oxidative cleavage. 18. Kit according to claim 16, characterized in that the reactive acidic solution is stored at a temperature of below 0.degree. C. 19. Kit according to claim 18, characterized in that the reactive acidic solution is stored at a temperature of between approximately -10.degree. C. and -80.degree. C. 20. Kit according to claim 16, characterized in that the reactive acidic solution is obtained by preparing a sterile powder of non-crosslinked and potentially crosslinkable pepsin-treated collagen or gelatin modified by preparing an acidic solution of pepsin-treated collagen; subjecting the said acidic aqueous solution at room temperature to controlled oxidation by a solution of periodic acid or one of its salts at a concentration of between approximately 1 and 10.sup.-5 M; precipitating the oxidized and non-crosslinkable pepsin-treated collagen at an acidic pH; and isolating and concentrating, and then dehydrating, the said non-crosslinked pepsin-treated collagen modified by oxidative cleavage so as to obtain it in the form of a reactive acidic powder; and dissolving the required quantity of this powder in water by heating at a temperature of between approximately 40.degree. and 80.degree. C. cooling the obtained reactive acidic solution at a temperature of below 0.degree. C. 21. Kit according to claim 16, characterized in that the neutralizing solution is a buffer which makes it possible to obtain, after mixture with the reactive acidic solution, a pH of between approximately 6 and 10. 22. Kit according to claim 21, characterized in that the said buffer consists of sodium phosphate or sodium carbonate. 23. Kit according to claim 16, characterized in that it is present in the form of a double syringe equipped with mixing means, one of which syringes contains the reactive acidic solution of non-crosslinked and potentially crosslinkabled pepsin-treated collagen or gelatin modified by oxidative cleavage, while the other contains the neutralizing solution, said double syringe being frozen or refrigerated at a temperature of below 0.degree. C. 24. Method according to claim 19, wherein the reactive acidic solution is heated to approximately 37.degree. C. 25. Method according to claim 19, wherein the neutralizing solution is a sodium phosphate or sodium carbonate buffer. 26. Method of bonding biological tissues to one another and/or to a biomaterial, comprising: preparing a stable acidic solution of non-crosslinked and potentially crosslinkable pepsin-treated collagen or gelatin modified by oxidative cleavage, according to claim 16; storing said stable solution at a temperature of below 0.degree. C.; heating said stable stored solution to a temperature of between approximately 30.degree. C. and 60.degree. C. to obtain a level of fluidity which is suitable for appropriate distribution on the said tissues and/or biomaterial; extemporaneously mixing the acidic solution of collagen or gelatin with a neutralizing solution so as to obtain a pH of between 6 and 10; applying the neutralizing reactive mixture which has a suitable level of fluidity immediately, before crosslinking, to the biological tissues and/or biomaterial to be bonded; and leaving the mixture to polymerize by crosslinking at the temperature of the human body.

Details for Patent 5,618,551

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Merck Sharp & Dohme Corp.	ZOSTAVAX	zoster vaccine live	For Injection	125123	05/25/2006		2014-04-08