Hydrogel tissue adhesive having reduced degradation time
First Claim
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1. A kit for forming a hydrogel comprising:
- a) at least one oxidized polysaccharide containing aldehyde groups, said oxidized polysaccharide 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 1500 Daltons;
b) at least one water-dispersible, multi-arm polyether amine wherein at least three of the arms are terminated by at least one primary amine group, said multi-arm polyether amine having a number-average molecular weight of about 450 to about 200,000 Daltons; and
c) at least one oligomer of the formula;
R1-(PS)-R2wherein;
(i) PS is a linear polymeric segment comprising ethylene oxide monomers or a combination of ethylene oxide and propylene oxide monomers, wherein said ethylene oxide monomers comprise at least 50 weight percent of said polymeric segment;
(ii) R1 is at least one nucleophilic group capable of reacting with aldehyde groups to form at least one reversible covalent bond;
(iii) R2 is at least one functional group which is not capable of reacting with an aldehyde, a primary amine, a secondary amine, or R1 to form a covalent bond, such that said oligomer does not induce gelation when mixed in an aqueous medium with either (a) alone or (b) alone;
(iv) said oligomer has a weight-average molecular weight of about 200 to about 10,000 Daltons; and
(v) said oligomer is water soluble; and
wherein said hydrogel has a decreased degradation time compared to a hydrogel formed under the same conditions in the absence of said oligomer.
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Abstract
A hydrogel tissue adhesive having decreased degradation time is described. The hydrogel tissue adhesive is formed by reacting an oxidized polysaccharide with a water-dispersible, multi-arm polyether amine in the presence of an oligomer additive, which promotes the degradation of the hydrogel. 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.
116 Citations
20 Claims
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1. A kit for forming a hydrogel comprising:
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a) at least one oxidized polysaccharide containing aldehyde groups, said oxidized polysaccharide 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 1500 Daltons; b) at least one water-dispersible, multi-arm polyether amine wherein at least three of the arms are terminated by at least one primary amine group, said multi-arm polyether amine having a number-average molecular weight of about 450 to about 200,000 Daltons; and c) at least one oligomer of the formula;
R1-(PS)-R2wherein; (i) PS is a linear polymeric segment comprising ethylene oxide monomers or a combination of ethylene oxide and propylene oxide monomers, wherein said ethylene oxide monomers comprise at least 50 weight percent of said polymeric segment; (ii) R1 is at least one nucleophilic group capable of reacting with aldehyde groups to form at least one reversible covalent bond; (iii) R2 is at least one functional group which is not capable of reacting with an aldehyde, a primary amine, a secondary amine, or R1 to form a covalent bond, such that said oligomer does not induce gelation when mixed in an aqueous medium with either (a) alone or (b) alone; (iv) said oligomer has a weight-average molecular weight of about 200 to about 10,000 Daltons; and (v) said oligomer is water soluble; and wherein said hydrogel has a decreased degradation time compared to a hydrogel formed under the same conditions in the absence of said oligomer. - View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12)
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13. A dried hydrogel formed by a process comprising the steps of:
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a) combining in a solvent (i) at least one oxidized polysaccharide containing aldehyde groups, said oxidized polysaccharide 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 1500 Daltons with (ii) at least one water-dispersible, multi-arm polyether amine, wherein at least three of the arms are terminated by at least one primary amine group, said multi-arm polyether amine having a number-average molecular weight of about 450 to about 200,000 Daltons, and (iii) at least one oligomer of the formula;
R1-(PS)-R2to form a hydrogel;
wherein;(A) PS is a linear polymeric segment comprising ethylene oxide monomers or a combination of ethylene oxide and propylene oxide monomers, wherein said ethylene oxide monomers comprise at least 50 weight percent of said polymeric segment; (B) R1 is at least one nucleophilic group capable of reacting with aldehyde groups to form at least one reversible covalent bond; (C) R2 is at least one functional group which is not capable of reacting with an aldehyde, a primary amine, a secondary amine, or R1 to form a covalent bond, such that said oligomer does not induce gelation when mixed in an aqueous medium with either (i) alone or (ii) alone; (D) said oligomer has a weight-average molecular weight of about 200 to about 10,000 Daltons; and (E) said oligomer is water soluble; and b) treating said hydrogel to remove at least a portion of said solvent to form the dried hydrogel; wherein said dried hydrogel has a decreased degradation time compared to a dried hydrogel formed under the same conditions in the absence of said oligomer.
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14. A hydrogel comprising the reaction product of:
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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, said oxidized polysaccharide having an equivalent weight per aldehyde group of about 65 to about 1500 Daltons; b) at least one water-dispersible, multi-arm polyether amine wherein at least three of the arms are terminated by at least one primary amine group, said multi-arm polyether amine having a number-average molecular weight of about 450 to about 200,000 Daltons; and c) at least one oligomer of the formula;
R1-(PS)-R2wherein; (i) PS is a linear polymeric segment comprising ethylene oxide monomers or a combination of ethylene oxide and propylene oxide monomers, wherein said ethylene oxide monomers comprise at least 50 weight percent of said polymeric segment; (ii) R1 is at least one nucleophilic group capable of reacting with aldehyde groups to form at least one reversible covalent bond; (iii) R2 is at least one functional group which is not capable of reacting with an aldehyde, a primary amine, a secondary amine, or R1 to form a covalent bond, such that said oligomer does not induce gelation when mixed in an aqueous medium with either (a) alone or (b) alone; (iv) said oligomer has a weight-average molecular weight of about 200 to about 10,000 Daltons; and (v) said oligomer is water soluble; and wherein said hydrogel has a decreased degradation time compared to a hydrogel formed under the same conditions in the absence of said oligomer.
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15. 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) at least one oxidized polysaccharide containing aldehyde groups, having a weight-average molecular weight of about 1,000 to about 1,000,000 Daltons, said oxidized polysaccharide having an equivalent weight per aldehyde group of about 65 to about 1500 Daltons; b) at least one water-dispersible, multi-arm polyether amine wherein at least three of the arms are terminated by at least one primary amine group, said multi-arm polyether amine having a number-average molecular weight of about 450 to about 200,000 Daltons; and c) at least one oligomer of the formula;
R1-(PS)-R2wherein; (i) PS is a linear polymeric segment comprising ethylene oxide monomers or a combination of ethylene oxide and propylene oxide monomers, wherein said ethylene oxide monomers comprise at least 50 weight percent of said polymeric segment; (ii) R1 is at least one nucleophilic group capable of reacting with aldehyde groups to form at least one reversible covalent bond; (iii) R2 is at least one functional group which is not capable of reacting with an aldehyde, a primary amine, a secondary amine, or R1 to form a covalent bond, such that said oligomer does not induce gelation when mixed in an aqueous medium with either (a) alone or (b) alone; (iv) said oligomer has a weight-average molecular weight of about 200 to about 10,000 Daltons; and (v) said oligomer is water soluble; wherein (a), (b), and (c) are applied to the site in any order, or (a), (b), and (c) are premixed and the resulting mixture is applied to the site before the mixture completely cures; and wherein said hydrogel coating has a decreased degradation time compared to a hydrogel coating formed under the same conditions in the absence of said oligomer. - View Dependent Claims (16, 17, 18, 19)
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20. A method for decreasing the degradation time of a hydrogel formed from at least one oxidized polysaccharide (component A) and at least one water-dispersible, multi-arm polyether amine (component B), said 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 an equivalent weight per aldehyde group of about 65 to about 1500 Daltons, and said at least one water-dispersible, multi-arm polyether amine wherein at least three of its arms terminated by at least one primary amine group, said multi-arm polyether amine having a number-average molecular weight of about 450 to about 200,000 Daltons;
- said method comprising the step of;
contacting component A and component B in the presence of an aqueous medium and at least one oligomer of the formula;
R1-(PS)-R2wherein; i) PS is a linear polymeric segment comprising ethylene oxide monomers or a combination of ethylene oxide and propylene oxide monomers, wherein said ethylene oxide monomers comprise at least 50 weight percent of said polymeric segment; (ii) R1 is at least one nucleophilic group capable of reacting with aldehyde groups to form at least one reversible covalent bond; (iii) R2 is at least one functional group which is not capable of reacting with an aldehyde, a primary amine, a secondary amine, or R1 to form a covalent bond, such that said oligomer does not induce gelation when mixed in an aqueous medium with either component A alone or component B alone; (iv) said oligomer has a weight-average molecular weight of about 200 to about 10,000 Daltons; and (v) said oligomer is water soluble; wherein, in said method the oligomer is used in an amount sufficient to decrease the degradation time of the resulting hydrogel under predetermined conditions by at least 10% compared to that of the hydrogel formed under said predetermined conditions, but in the absence of said oligomer.
- said method comprising the step of;
Specification