HYDROGEL TISSUE ADHESIVE HAVING REDUCED DEGRADATION TIME

• US 20120035129A1
• Filed: 04/09/2010
• Published: 02/09/2012
• Est. Priority Date: 04/09/2009
• Status: Active Grant

• Current Assignee: Actamax Surgical Materials, LLC (DSM-Firmenich AG)
• Original Assignee: Actamax Surgical Materials, LLC (DSM-Firmenich AG)
• Inventors: Wagman, Mark E.
• Granted Patent: US 8,951,989 B2
• Time in Patent Office: Days
• US Class Current: 514/57
• CPC Class Codes: A61L 24/0031 Hydrogels or hydrocolloids
• CPC Class Codes: A61L 24/0042 Materials resorbable by the body
• CPC Class Codes: A61L 24/043 Mixtures of macromolecular materials
• CPC Class Codes: A61L 31/041 Mixtures of macromolecular compounds
• CPC Class Codes: A61L 31/145 Hydrogels or hydrocolloids
• CPC Class Codes: A61L 31/148 Materials at least partially resorbable by the body
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 7/04 Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
• CPC Class Codes: C08L 1/04 Oxycellulose; Hydrocellulose , e.g. microcrystalline cellulose
• CPC Class Codes: C08L 3/10 Oxidised starch
• CPC Class Codes: C08L 5/02 Dextran; Derivatives thereof
• CPC Class Codes: C08L 5/08 Chitin; Chondroitin sulfate; Hyaluronic acid; Derivatives thereof
• CPC Class Codes: C08L 5/12 Agar or agar-agar , i.e. mixture of agarose and agaropectin; Derivatives thereof
• CPC Class Codes: C08L 71/02 Polyalkylene oxides

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.

Claims

1. A kit 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)-R2

wherein;

(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 about 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.

2. The kit according to claim 1 wherein the oxidized polysaccharide is a component of a first aqueous solution or dispersion, the water-dispersible, multi-arm polyether amine is a component of a second aqueous solution or dispersion, and the oligomer is a component of at least one of:

(i) the first aqueous solution or dispersion;

(ii) the second aqueous solution or dispersion;

or (iii) a third aqueous solution or dispersion.

3. The kit according to claim 2 wherein the first aqueous solution or dispersion comprises the oxidized polysaccharide at a concentration of about 5% to about 40% by weight relative to the total weight of the solution or dispersion.

4. The kit according to claim 2 wherein the second aqueous solution or dispersion comprises the water-dispersible, multi-arm polyether amine at a concentration of about 5% to about 70% by weight relative to the total weight of the solution or dispersion.

5. The kit according to claim 2 wherein at least one of the first aqueous solution or dispersion, the second aqueous solution or dispersion, or the third aqueous solution or dispersion comprises the oligomer at a concentration of about 0.25% to about 30% by weight relative to the total weight of the solution or dispersion.

6. The kit according to claim 1 wherein the oxidized polysaccharide is selected from the group consisting of oxidized derivatives of:

dextran, carboxymethyldextran, starch, agar, cellulose, hydroxyethylcellulose, carboxymethylcellulose, pullulan, inulin, levan, and hyaluronic acid.

7. The kit according to claim 6 wherein the oxidized polysaccharide is oxidized dextran.

8. The kit according to claim 1 wherein the water-dispersible, multi-arm polyether amine is selected from the group consisting of amino-terminated star polyethylene oxides, amino-terminated dendritic polyethylene oxides, amino-terminated comb polyethylene oxides, amino-terminated star polypropylene oxides, amino-terminated dendritic polypropylene oxides, amino-terminated comb polypropylene oxides, amino-terminated star polyethylene oxide-polypropylene oxide copolymers, amino-terminated dendritic polyethylene oxide-polypropylene oxide copolymers, amino-terminated comb polyethylene oxide-polypropylene oxide copolymers, and polyoxyalkylene triamines.

9. The kit according to claim 1 wherein PS is a linear polymeric segment terminating with a methylene group at both ends of said segment, wherein said segment is derived from a polymer selected from the group consisting of:

polyethylene oxide, block or random copolymers of polyethylene oxide and polypropylene oxide, and triblock copolymers of polyethylene oxide and polypropylene oxide.

10. The kit according to claim 1 wherein R1 is selected from the group consisting of primary amine, secondary amine, and carboxyhydrazide.

11. The kit according to claim 1 wherein R2 is selected from the group consisting of hydroxy, methoxy, ethoxy, propoxy, butoxy, and phenoxy.

12. The kit according to claim 1 wherein the oligomer is methoxy polyethylene glycol amine wherein PS is a linear polymeric segment derived from polyethylene oxide, R1 is a primary amine, and R2 is methoxy.

13. A dried hydrogel formed by a process comprising the steps of:

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 east 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)-R2

to 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 about 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.

14. A composition comprising the reaction product of:

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)-R2

wherein;

(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 about 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.

15. A method for applying a coating to an anatomical site on tissue of a living organism comprising applying to the site the composition of claim 14,

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.

16. The method according to claim 15 wherein the oxidized polysaccharide is a component of a first aqueous solution or dispersion, the water-dispersible, multi-arm polyether amine is a component of a second aqueous solution or dispersion, and the oligomer is a component of at least one of:

(i) the first aqueous solution or dispersion;

(ii) the second aqueous solution or dispersion;

or (iii) a third aqueous solution or dispersion.

17. The method according to claim 15 wherein the oxidized polysaccharide is selected from the group consisting of oxidized derivatives of:

dextran, carboxymethyldextran, starch, agar, cellulose, hydroxyethylcellulose, carboxymethylcellulose, pullulan, inulin, levan, and hyaluronic acid.

18. The method according to claim 15 wherein the water-dispersible, multi-arm polyether amine is selected from the group consisting of amino-terminated star polyethylene oxides, amino-terminated dendritic polyethylene oxides, amino-terminated comb polyethylene oxides, amino-terminated star polypropylene oxides, amino-terminated dendritic polypropylene oxides, amino-terminated comb polypropylene oxides, amino-terminated star polyethylene oxide-polypropylene oxide copolymers, amino-terminated dendritic polyethylene oxide-polypropylene oxide copolymers, amino-terminated comb polyethylene oxide-polypropylene oxide copolymers, and polyoxyalkylene triamines.

19. The method according to claim 15 wherein PS is a linear polymeric segment terminating with a methylene group at both ends of said segment, wherein said segment is derived from a polymer selected from the group consisting of:

polyethylene oxide, block or random copolymers of polyethylene oxide and polypropylene oxide, and triblock copolymers of polyethylene oxide and polypropylene oxide.

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)-R2

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 about 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 component A alone or component B 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;

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 about 10% compared to that of the hydrogel formed under said predetermined conditions, but in the absence of said oligomer.