Aldol-crosslinked polymeric hydrogel adhesives

• US 20070048337A1
• Filed: 08/24/2006
• Published: 03/01/2007
• Est. Priority Date: 08/24/2005
• Status: Active Grant

• Current Assignee: Actamax Surgical Materials, LLC (DSM-Firmenich AG)
• Original Assignee: Actamax Surgical Materials, LLC (DSM-Firmenich AG)
• Inventors: Arthur, Samuel
• Granted Patent: US 8,679,536 B2
• Time in Patent Office: Days
• US Class Current: 424/400
• CPC Class Codes: A61K 9/06 Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels composition of ointments, creams or gels A61K47/00

Abstract

Adhesives formed by reacting an oxidized polysaccharide with a poly(hydroxylic) compound derivatized with acetoacetate groups in the presence of a base catalyst are disclosed. The use of the adhesives for medical and veterinary applications such as topical wound closure; and surgical procedures, such as intestinal anastomosis, vascular anastomosis, tissue repair, and ophthalmic procedures; and drug delivery are described. The adhesive may also be used for industrial and consumer applications.

Claims

1. A kit comprising:

(a) a first aqueous solution comprising from about 5% to about 40% by weight of a polysaccharide that has been oxidized to provide an oxidized polysaccharide that contains aldehyde groups, said polysaccharide having a molecular weight of about 1,000 to about 1,000,000 Daltons, and said oxidized polysaccharide having an equivalent weight per aldehyde group of about 90 to about 1500 Daltons, such that the oxidized polysaccharide has on average more than two aldehyde groups per chain; and

(b) a second aqueous solution comprising from about 5% to about 40% by weight of a poly(hydroxylic) compound that has been derivatized to provide a derivatized poly(hydroxylic) compound that contains acetoacetate groups, said poly(hydroxylic) compound having a molecular weight of less than or equal to about 100,000 Daltons, and said derivatized poly(hydroxylic) compound having an equivalent weight per acetoacetate group of about 100 to about 2000 Daltons, such that the derivatized poly(hydroxylic) compound has on average more than two acetoacetate groups per molecule;

provided that;

(i) at least one of the first aqueous solution or the second aqueous solution further comprises a base catalyst;

or

(ii) the kit further comprises a base catalyst as a neat liquid or as part of a third aqueous solution;

or

(iii) a combination of (i) and (ii); and

(iv) if the oxidized polysaccharide is oxidized starch, then the derivatized poly(hydroxylic) compound is not poly(vinyl alcohol) derivatized with acetoacetate groups.

2. The kit according to claim 1 wherein the molecular weight of the polysaccharide is from about 3,000 to about 250,000 Daltons.

3. The kit according to claim 1 wherein the polysaccharide is selected from the group consisting of dextran, chitin, agar, starch, cellulose, and hyaluronic acid.

4. The kit according to claim 1 wherein the poly(hydroxylic) is selected from the group consisting of poly(vinyl alcohol), partially-esterified poly(vinyl alcohol), poly(vinyl alcohol) copolymers, linear or branched polyethers, polysaccharides, monosaccharides, reduced monosaccharides, low molecular weight polyols, hydrolyzed polyvinyl acetate-methacrylate copolymers, polyether condensation products, and mixtures thereof.

5. The kit according to claim 1 wherein the first aqueous solution, the second aqueous solution, and the neat liquid or the third aqueous solution, if present, are sterilized.

6. The kit according to claim 1 wherein the polysaccharide is dextran and the poly(hydroxylic) compound is poly(vinyl alcohol).

7. The kit according to claim 6 wherein said poly(vinyl alcohol) has a weight-average molecular weight in the range of from about 10,000 Daltons to about 50,000 Daltons.

8. The kit according to claim 6 wherein said poly(vinyl alcohol) has a weight-average molecular weight in the range of from about 30,000 Daltons to about 50,000 Daltons.

9. The kit according to claim 1 wherein the base catalyst is selected from the group consisting of sodium carbonate, sodium bicarbonate, trisodium phosphate, dibasic sodium phosphate, tetrasodium ethylenediaminetetraacetic acid, calcium carbonate, potassium carbonate, potassium bicarbonate, tripotassium phosphate, dibasic potassium phosphate, tetrapotassium ethylenediaminetetraacetic acid, triethanolamine and imidazole.

10. The kit according to claim 1 wherein the base catalyst is present in at least one of the first aqueous solution, the second aqueous solution, or the third aqueous solution at a concentration of about 0.01% to about 1% by weight relative to the total weight of the solution.

11. The kit according to claim 1 wherein at least one of the first aqueous solution, the second aqueous solution, or the third aqueous solution further comprises at least one additive selected from the group consisting of viscosity modifiers, antimicrobials, colorants, healing promoters, surfactants, anti-inflammatory agents, thrombogenic agents, and radio-opaque compounds.

12. The kit according to claim 11 wherein the antimicrobial is selected from the group consisting of methylparaben, ethylparaben, propylparaben, butylparaben, cresol, chlorocresol, hydroquinone, sodium benzoate, potassium benzoate, triclosan and chlorhexidine.

13. The kit according to claim 11 wherein the colorant is selected from the group consisting of FD&

C Violet No. 2, D&

C Green No. 6, D&

C Green No. 5, and D&

C Violet No. 2.

14. The kit according to claim 1 wherein at least one of the first aqueous solution, the second aqueous solution, or the third aqueous solution further comprises a pharmaceutical drug or therapeutic agent.

15. The kit according to claim 1 wherein the concentration of the oxidized polysaccharide in the first aqueous solution is from about 15% to about 30% by weight.

16. The kit according to claim 1 wherein the concentration of the derivatized poly(hydroxylic) compound in the second aqueous solution is from about 15% to about 30% by weight.

17. The kit according to claim 1 wherein at least one of the second aqueous solution or the third aqueous solution further comprises a termonomer that has been derivatized with acetoacetate groups.

18. The kit according to claim 16 wherein the termonomer is selected from the group consisting of linear polyethers, branched polyethers, water-dispersible hydroxyl-ended linear polyesters, water-dispersible hydroxyl-ended branched polyesters, star polyethers, and partially-esterified poly(vinyl alcohol).

19. The kit according to claim 1 further comprising a fourth aqueous solution comprising a water-dispersible termonomer that has been derivatized with acetoacetate groups.

20. The kit according to claim 19 wherein the termonomer is selected from the group consisting of linear polyethers, branched polyethers, water-hydroxyl-ended linear polyesters, water-dispersible hydroxyl-ended branched polyesters, star polyethers, and partially-esterified poly(vinyl alcohol).

21. The kit according to claim 19 wherein the fourth aqueous solution is sterilized.

22. A composition comprising the reaction product of:

(a) a first aqueous solution comprising from about 5% to about 40% by weight of a polysaccharide that has been oxidized to provide an oxidized polysaccharide that contains aldehyde groups, said polysaccharide having a molecular weight of about 1,000 to about 1,000,000 Daltons, and said oxidized polysaccharide having an equivalent weight per aldehyde group of about 90 to about 1500 Daltons, such that the oxidized polysaccharide has on average more than two aldehyde groups per chain; and

(b) a second aqueous solution comprising from about 5% to about 40% by weight of a poly(hydroxylic) compound that has been derivatized to provide a derivatized poly(hydroxylic) compound that contains acetoacetate groups, said poly(hydroxylic) compound having a molecular weight of less than or equal to about 100,000 Daltons, and said derivatized poly(hydroxylic) compound having an equivalent weight per acetoacetate group of about 100 to about 2000 Daltons, such that the derivatized poly(hydroxylic) compound has on average more than two acetoacetate groups per molecule;

provided that;

(i) at least one of the first aqueous solution or the second aqueous solution further comprises a base catalyst;

or

(ii) the kit further comprises a base catalyst as a neat liquid or as part of a third aqueous solution;

or

(iii) a combination of (i) and (ii); and

(iv) if the oxidized polysaccharide is oxidized starch, then the derivatized poly(hydroxylic) compound is not poly(vinyl alcohol) derivatized with acetoacetate groups.

23. The composition according to claim 22 wherein the molecular weight of the polysaccharide is from about 3,000 to about 250,000 Daltons.

24. The composition according to claim 22 wherein the polysaccharide is selected from the group consisting of dextran, chitin, agar, cellulose, and hyaluronic acid.

25. The composition according to claim 22 wherein the poly(hydroxylic) compound is selected from the group consisting of poly(vinyl alcohol), partially-esterified poly(vinyl alcohol), poly(vinyl alcohol) copolymers, linear or branched polyethers, polysaccharides, monosaccharides, reduced monosaccharides, low molecular weight polyols, hydrolyzed polyvinyl acetate-methacrylate copolymers, polyether condensation products, and mixtures thereof.

26. The composition according to claim 22 wherein the polysaccharide is dextran and the poly(hydroxylic) compound is poly(vinyl alcohol).

27. The composition according to claim 26 wherein said poly(vinyl alcohol) has a weight-average molecular weight in the range of from about 10,000 Daltons to about 50,000 Daltons.

28. The composition according to claim 26 wherein said poly(vinyl alcohol) has a weight-average molecular weight in the range of from about 30,000 Daltons to about 50,000 Daltons.

29. The composition according to claim 22 wherein the base catalyst is selected from the group consisting of sodium carbonate, sodium bicarbonate, trisodium phosphate, dibasic sodium phosphate, tetrasodium ethylenediaminetetraacetic acid, calcium carbonate, potassium carbonate, potassium bicarbonate, tripotassium phosphate, dibasic potassium phosphate, tetrapotassium ethylenediaminetetraacetic acid, triethanolamine and imidazole.

30. The composition according to claim 22 wherein the base catalyst is present in at least one of the first aqueous solution, the second aqueous solution, or the third aqueous solution at a concentration of about 0.01% to about 1% by weight relative to the total weight of the solution.

31. The composition according to claim 22 wherein at least one of the first aqueous solution, the second aqueous solution, or the third aqueous solution further comprises at least one additive selected from the group consisting of viscosity modifiers, antimicrobials, colorants, healing promoters, surfactants, anti-inflammatory agents, thrombogenic agents, and radio-opaque compounds.

32. The composition according to claim 31 wherein the antimicrobial is selected from the group consisting of methylparaben, ethylparaben, propylparaben, butylparaben, cresol, chlorocresol, hydroquinone, sodium benzoate, potassium benzoate, triclosan and chlorhexidine.

33. The composition according to claim 31 wherein the colorant is selected from the consisting of FD&

C Violet No. 2, D&

C Green No. 6, D&

C Green No. 5, and D&

C Violet No. 2.

34. The composition according to claim 22 wherein at least one of the first aqueous solution, the second aqueous solution, or the third aqueous solution further comprises a pharmaceutical drug or therapeutic agent.

35. The composition according to claim 22 wherein the concentration of the oxidized polysaccharide in the first aqueous solution is from about 15% to about 30% by weight.

36. The composition according to claim 22 wherein the concentration of the derivatized poly(hydroxylic) in the second aqueous solution is from about 15% to about 30% by weight.

37. The composition according to claim 22 wherein at least one of the second aqueous solution or the third aqueous solution further comprises a termonomer that has been derivatized with acetoacetate groups.

38. The composition according to claim 37 wherein the termonomer is selected from the group consisting of linear polyethers, branched polyethers, water-dispersible hydroxyl-ended linear polyesters, water-hydroxyl-ended branched polyesters, star polyethers, and partially-esterified poly(vinyl alcohol).

39. The composition according to claim 22 further comprising a fourth aqueous solution comprising a water-dispersible termonomer that has been derivatized with acetoacetate groups.

40. The composition according to claim 39 wherein the termonomer is selected from the group consisting of linear polyethers, branched polyethers, water-dispersible hydroxyl-ended linear polyesters, water-dispersible hydroxyl-ended branched polyesters, star polyethers, and partially-esterified poly(vinyl alcohol).

41. The composition according to claim 22 wherein the ratio of aldehyde groups of the oxidized polysaccharide of the first aqueous solution to the acetoacetate groups of the derivatized poly(hydroxylic) compound of the second aqueous solution is greater than or equal to 1.