Hydrogel tissue adhesive having decreased gelation time and decreased degradation time
First Claim
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1. A kit for forming a hydrogel, said kit comprising:
- a) a first aqueous solution or dispersion comprising;
(i) at least one oxidized polysaccharide containing aldehyde groups, having a weight-average molecular weight of about 1,000 to about 1,000,000 Daltons and having an equivalent weight per aldehyde group of about 65 to about 1,500 Daltons, said first aqueous solution or dispersion containing from about 5% to about 40% by weight of the oxidized polysaccharide; and
(ii) at least one thiol additive, wherein the thiol additive is water-dispersible, contains only one reactive thiol (SH) group, does not contain any reactive carboxylic acid, primary amine or secondary amine groups, and has a molecular weight in the range of about 60 Daltons to about 40,000 Daltons, said first aqueous solution or dispersion containing about 0.1% to about 20% by weight of the thiol additive; and
b) a second aqueous solution or dispersion comprising(i) at least one water-dispersible, multi-arm amine wherein at least three of the arms are terminated by at least one primary amine group, said multi-arm amine having a number-average molecular weight of about 440 to about 200,000 Daltons, said second aqueous solution or dispersion containing from about 5% to about 70% by weight of the multi-arm amine;
or(ii) at least one a water-dispersible, multi-arm amine in the form of a neat liquid wherein at least three of the arms are terminated by at least one primary amine group, said multi-arm amine having a number-average molecular weight of about 440 to about 200,000 Daltons;
wherein the hydrogel has a decreased gelation time and a decreased degradation time compared to a hydrogel prepared with said oxidized polysaccharide and said water-dispersible, multi-arm amine in the absence of the thiol additive.
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Abstract
A hydrogel tissue adhesive having decreased gelation time and decreased degradation time is described. The hydrogel tissue adhesive is formed by reacting an oxidized polysaccharide containing aldehyde groups with a water-dispersible, multi-arm amine in the presence of a thiol additive. The thiol additive accelerates the process to form the hydrogel and accelerates the degradation of the hydrogel formed. The hydrogel may be useful as a tissue adhesive or sealant for medical applications, such as a hemostat sealant or to prevent undesired tissue-to-tissue adhesions resulting from trauma or surgery.
97 Citations
20 Claims
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1. A kit for forming a hydrogel, said kit comprising:
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a) a first aqueous solution or dispersion comprising; (i) at least one oxidized polysaccharide containing aldehyde groups, having a weight-average molecular weight of about 1,000 to about 1,000,000 Daltons and having an equivalent weight per aldehyde group of about 65 to about 1,500 Daltons, said first aqueous solution or dispersion containing from about 5% to about 40% by weight of the oxidized polysaccharide; and (ii) at least one thiol additive, wherein the thiol additive is water-dispersible, contains only one reactive thiol (SH) group, does not contain any reactive carboxylic acid, primary amine or secondary amine groups, and has a molecular weight in the range of about 60 Daltons to about 40,000 Daltons, said first aqueous solution or dispersion containing about 0.1% to about 20% by weight of the thiol additive; and b) a second aqueous solution or dispersion comprising (i) at least one water-dispersible, multi-arm amine wherein at least three of the arms are terminated by at least one primary amine group, said multi-arm amine having a number-average molecular weight of about 440 to about 200,000 Daltons, said second aqueous solution or dispersion containing from about 5% to about 70% by weight of the multi-arm amine;
or(ii) at least one a water-dispersible, multi-arm amine in the form of a neat liquid wherein at least three of the arms are terminated by at least one primary amine group, said multi-arm amine having a number-average molecular weight of about 440 to about 200,000 Daltons; wherein the hydrogel has a decreased gelation time and a decreased degradation time compared to a hydrogel prepared with said oxidized polysaccharide and said water-dispersible, multi-arm amine in the absence of the thiol additive. - View Dependent Claims (2, 3, 4, 5)
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6. A hydrogel comprising the reaction product of:
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a) a first aqueous solution or dispersion comprising; (i) at least one oxidized polysaccharide containing aldehyde groups, having a weight-average molecular weight of about 1,000 to about 1,000,000 Daltons and having an equivalent weight per aldehyde group of about 65 to about 1,500 Daltons, said first aqueous solution or dispersion containing from about 5% to about 40% by weight of the oxidized polysaccharide; and (ii) at least one thiol additive, wherein the thiol additive is water-dispersible, contains only one reactive thiol (SH) group, does not contain any reactive carboxylic acid, primary amine or secondary amine groups, and has a molecular weight in the range of about 60 Daltons to about 40,000 Daltons, said first aqueous solution or dispersion containing about 0.1% to about 20% by weight of the thiol additive; and b) a second aqueous solution or dispersion comprising (i) at least one water-dispersible, multi-arm amine wherein at least three of the arms are terminated by at least one primary amine group, said multi-arm amine having a number-average molecular weight of about 440 to about 200,000 Daltons, said second aqueous solution or dispersion containing from about 5% to about 70% by weight of the multi-arm polyether amine;
or(ii) at least one a water-dispersible, multi-arm amine in the form of a neat liquid wherein at least three of the arms are terminated by at least one primary amine group, said multi-arm amine having a number-average molecular weight of about 440 to about 200,000 Daltons; wherein the hydrogel has a decreased gelation time and a decreased degradation time compared to a hydrogel prepared with said oxidized polysaccharide and said water-dispersible, multi-arm amine in the absence of the thiol additive. - View Dependent Claims (7, 8, 9, 10)
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11. A method for applying a hydrogel coating to an anatomical site on tissue of a living organism comprising:
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applying to the site a) a first aqueous solution or dispersion comprising; (i) at least one oxidized polysaccharide containing aldehyde groups, having a weight-average molecular weight of about 1,000 to about 1,000,000 Daltons and having an equivalent weight per aldehyde group of about 65 to about 1,500 Daltons, said first aqueous solution or dispersion containing from about 5% to about 40% by weight of the oxidized polysaccharide; and (ii) at least one thiol additive, wherein the thiol additive is water-dispersible, contains only one reactive thiol (SH) group, does not contain any reactive carboxylic acid, primary amine or secondary amine groups, and has a molecular weight in the range of about 60 Daltons to about 40,000 Daltons, said first aqueous solution or dispersion containing about 0.1% to about 20% by weight of the thiol additive; and b) a second aqueous solution or dispersion comprising (i) at least one water-dispersible, multi-arm amine wherein at least three of the arms are terminated by at least one primary amine group, said multi-arm amine having a number-average molecular weight of about 440 to about 200,000 Daltons, said second aqueous solution or dispersion containing from about 5% to about 70% by weight of the multi-arm amine;
or(ii) at least one water-dispersible, multi-arm amine in the form of a neat liquid wherein at least three of the arms are terminated by at least one primary amine group, said multi-arm amine having a number-average molecular weight of about 440 to about 200,000 Daltons;
wherein (a) and (b)(i) or (b) (ii) are applied to the site in any order, or (a) and (b) (i) or (b) (ii) are premixed and the resulting mixture is applied to the site before the mixture completely cures; andwherein the hydrogel coating has a decreased gelation time and a decreased degradation time compared to a hydrogel coating prepared with said oxidized polysaccharide and said water-dispersible, multi-arm amine, in the absence of the thiol additive. - View Dependent Claims (12, 13, 14, 15)
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16. A method of reducing the gelation time of a hydrogel comprising an oxidized polysaccharide and a water-dispersible, multi-arm amine, the method comprising:
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a) combining the oxidized polysaccharide containing aldehyde groups, having a weight-average molecular weight of about 1,000 to about 1,000,000 Daltons and having an equivalent weight per aldehyde group of about 65 to about 1,500 Daltons, said hydrogel containing from about 5% to about 40% by weight of the oxidized polysaccharide;
with a thiol additive, wherein the thiol additive is water-dispersible, contains only one reactive thiol (SH) group, does not contain any reactive carboxylic acid, primary amine or secondary amine groups, and has a molecular weight in the range of about 60 Daltons to about 40,000 Daltons, said hydrogel containing about 0.1% to about 20% by weight of the thiol additive;
to form a combination;b) allowing the combination to stand for a predetermined amount of time; and c) mixing the combination of oxidized polysaccharide and thiol additive with the water-dispersible, multi-arm amine to form the hydrogel; d) wherein the hydrogel has a decreased gelation time compared to a hydrogel prepared with said oxidized polysaccharide and said water-dispersible, multi-arm amine in the absence of the thiol additive. - View Dependent Claims (17)
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18. A method of reducing the degradation time of a hydrogel comprising an oxidized polysaccharide and a water-dispersible, multi-arm amine, the method comprising:
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a) combining the oxidized polysaccharide containing aldehyde groups, having a weight-average molecular weight of about 1,000 to about 1,000,000 Daltons and having an equivalent weight per aldehyde group of about 65 to about 1,500 Daltons, said hydrogel containing from about 5% to about 40% by weight of the oxidized polysaccharide;
with a thiol additive, wherein the thiol additive is water-dispersible, contains only one reactive thiol (SH) group, does not contain any reactive carboxylic acid, primary amine or secondary amine groups, and has a molecular weight in the range of about 60 Daltons to about 40,000 Daltons, said hydrogel containing about 0.1% to about 20% by weight of the thiol additive;
to form a combination;b) allowing the combination to stand for a predetermined amount of time; and c) mixing the combination of oxidized polysaccharide and thiol additive with the water-dispersible, multi-arm amine to form the hydrogel; d) wherein the hydrogel has a decreased degradation time compared to a hydrogel prepared with said oxidized polysaccharide and said water-dispersible, multi-arm amine in the absence of the thiol additive. - View Dependent Claims (19)
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20. An aqueous solution or dispersion comprising:
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a) at least one oxidized polysaccharide containing aldehyde groups, having a weight-average molecular weight of about 1,000 to about 1,000,000 Daltons and having an equivalent weight per aldehyde group of about 65 to about 1,500 Daltons, and b) at least one thiol additive, wherein the thiol additive is water-dispersible, contains only one reactive thiol (SH) group, does not contain any reactive carboxylic acid, primary amine or secondary amine groups, and has a molecular weight in the range of about 60 Daltons to about 40,000 Daltons.
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Specification