Methods for sealing an orifice in tissue using an aldol-crosslinked polymeric hydrogel adhesive
View Patent ↗Methods for sealing an orifice in tissue in the body of a living animal using an adhesive formed by reacting an oxidized polysaccharide with a poly(hydroxylic) compound derivatized with acetoacetate groups in the presence of a base catalyst are disclosed. Methods for using the adhesive 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.
1. A method for sealing an orifice in tissue in the body of a living animal comprising:
applying to the orifice
(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, followed by
(b) a second aqueous solution comprising from about 5% to about 40% by weight of poly(vinyl alcohol) that has been derivatized to provide a derivatized poly(vinyl alcohol) that contains acetoacetate groups, said poly(vinyl alcohol) having a molecular weight of less than or equal to about 100,000 Daltons, and said derivatized poly(vinyl alcohol) having an equivalent weight per acetoacetate group of about 100 to about 2000 Daltons, such that the derivatized poly(vinyl alcohol) has on average more than two acetoacetate groups, or applying the second aqueous solution followed by the first aqueous solution and mixing the first and second aqueous solutions on the orifice, or premixing the first and second aqueous solutions and applying the resulting mixture to the orifice before the resulting mixture completely cures, thereby forming on said orifice a resorbable adhesive hydrogel, and allowing the hydrogel to remain on said orifice until said hydrogel is resorbed;
provided that:
(i) at least one of the first aqueous solution or the second aqueous solution further comprises a base catalyst; or
(ii) a base catalyst is applied to the orifice as a neat liquid or as part of a third aqueous solution, and said neat liquid or third aqueous solution is mixed with both the first aqueous and second aqueous solutions on the orifice or said neat liquid or third aqueous solution is premixed with both the first and second aqueous solutions, and the resulting mixture is subsequently applied to the orifice before the resulting mixture completely cures; or
(iii) a combination of (i) and (ii);
wherein the polysaccharide is selected from the group consisting of dextran, chitin, starch, agar, cellulose and hyaluronic acid.
2. A method for bonding at least two anatomical sites together comprising:
applying to at least one of the at least two anatomical sites
(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, followed by
(b) a second aqueous solution comprising from about 5% to about 40% by weight of poly(vinyl alcohol) that has been derivatized to provide a derivatized poly(vinyl alcohol) that contains acetoacetate groups, said poly(vinyl alcohol) having a molecular weight of less than or equal to about 100,000 Daltons, and said derivatized poly(vinyl alcohol) having an equivalent weight per acetoacetate group of about 100 to about 2000 Daltons, such that the derivatized poly(vinyl alcohol) has on average more than two acetoacetate groups, or
applying the second aqueous solution followed by the first aqueous solution and mixing the first and second aqueous solutions on the at least one site, or premixing the first and second aqueous solutions and applying the resulting mixture to the at least one anatomical site before the resulting mixture completely cures,
and contacting the at least two anatomical sites together;
provided that:
(i) at least one of the first aqueous solution or the second aqueous solution further comprises a base catalyst; or
(ii) a base catalyst is applied to the at least one site as a neat liquid or as part of a third aqueous solution, and said neat liquid or third aqueous solution is mixed with both the first aqueous and second aqueous solutions on said at least one site or said neat liquid or third aqueous solution is premixed with both the first and second aqueous solutions, and the resulting mixture is subsequently applied to the at least one site before the resulting mixture completely cures; or
(iii) a combination of (i) and (ii);
wherein the polysaccharide is selected from the group consisting of dextran, chitin, starch, agar, cellulose and hyaluronic acid.
3. The method according to claim 1 or claim 2 wherein the molecular weight of the polysaccharide is from about 3,000 to about 250,000 Daltons.
4. The method according to claim 1 or claim 2 wherein the first aqueous solution, the second aqueous solution, and the neat liquid or third aqueous solution, if present, are sterilized.
5. The method according to claim 1 or claim 2 wherein the polysaccharide is dextran.
6. The method according to claim 5 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.
7. The method according to claim 5 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.
8. The method according to claim 1 or claim 2 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.
9. The method according to claim 1 or claim 2 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.
10. The method according to claim 1 or claim 2 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.
11. The method according to claim 10 wherein the antimicrobial is selected from the group consisting of methylparaben, ethylparaben, propylparaben, butylparaben, cresol, chlorocresol, hydroquinone, sodium benzoate, potassium benzoate, triclosan and chlorhexidine.
12. The method according to claim 10 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.
13. The method according to claim 1 or claim 2 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.
14. The method according to claim 1 or claim 2 wherein the concentration of the oxidized polysaccharide in the first aqueous solution is from about 15% to about 30% by weight.
15. The method according to claim 1 or claim 2 wherein the concentration of the derivatized poly(vinyl alcohol) in the second aqueous solution is from about 15% to about 30% by weight.
16. The method according to claim 1 or claim 2 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.
17. The method 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).
18. The method according to claim 1 further comprising applying to the orifice a fourth aqueous solution comprising a water-dispersible termonomer that has been derivatized with acetoacetate groups, wherein the first and second aqueous solutions and the neat liquid or third aqueous solution if present, and the fourth aqueous solution are applied in any order and are mixed on the orifice, or are premixed and applied to the orifice before the resulting mixture completely cures.
19. The method according to claim 18 wherein the termonomer is selected from the group consisting of linear polyethers, branched polyethers, water-dispersible linear polyesters, water-dispersible branched polyesters, star polyethers, and partially-esterified poly(vinyl alcohol).
20. The method according to claim 2 further comprising applying to the at least one anatomical site a fourth aqueous solution comprising a termonomer that has been derivatized with acetoacetate groups, wherein the first and second aqueous solutions and the neat liquid or third aqueous solution if present, and the fourth aqueous solution are applied in any order and are mixed on the at least one site, or are premixed and applied to the at least one site before the resulting mixture completely cures.
21. The method according to claim 20 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).
22. The method according to claim 18 or claim 20 wherein the fourth aqueous solution is sterilized.
23. The method according to claim 1 or claim 2 wherein the ratio of aldehyde groups of the oxidized polysaccharide of the first aqueous solution to the acetoacetate groups of the derivatized poly(vinyl alcohol) of the second aqueous solution is greater than or equal to 1.
24. The method according to claim 1 wherein the orifice is a wound on the skin and the method is used for treatment of topical wounds.
25. The method according to claim 1 wherein the orifice is an incision, suture, or staple in the intestine or a blood vessel and the method is used in an anastomosis procedure.
26. The method according to claim 1 wherein the orifice is a surgical incision in the cornea and the method is used to seal the incision.
27. The method of 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 and the method is used for drug delivery to an anatomical site.