HYDROGEL TISSUE ADHESIVE FORMED FROM AMINATED POLYSACCHARIDE AND ALDEHYDE-FUNCTIONALIZED MULTI-ARM POLYETHER

• US 20110224724A1
• Filed: 08/31/2009
• Published: 09/15/2011
• Est. Priority Date: 11/19/2008
• Status: Active Grant

• Current Assignee: Actamax Surgical Materials, LLC (DSM-Firmenich AG)
• Original Assignee: Actamax Surgical Materials, LLC (DSM-Firmenich AG)
• Inventors: Shuey, Steven Willis, Lu, Helen S.M.
• Granted Patent: US 9,044,529 B2
• Time in Patent Office: Days
• US Class Current: 606/214
• CPC Class Codes: A61K 47/34 Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers A61K47/10 takes precedence
• CPC Class Codes: A61K 47/36 Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
• CPC Class Codes: A61L 24/0031 Hydrogels or hydrocolloids
• CPC Class Codes: A61L 24/043 Mixtures of macromolecular materials
• CPC Class Codes: A61L 24/046 obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds A61L24/043 takes precedence
• CPC Class Codes: A61L 24/08 Polysaccharides A61L24/043 takes precedence
• CPC Class Codes: A61L 26/0019 obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds
• CPC Class Codes: A61L 26/0023 Polysaccharides
• CPC Class Codes: C08L 71/02 Polyalkylene oxides

Abstract

A hydrogel tissue adhesive formed by reacting an aminated polysaccharide with a water-dispersible, aldehyde-functionalized multi-arm polyether is described. The hydrogel tissue adhesive may be useful as a general tissue adhesive and sealant for medical and veterinary applications such as wound closure, supplementing or replacing sutures or staples in internal surgical procedures such as intestinal anastomosis and vascular anastomosis, tissue repair, ophthalmic procedures, drug delivery, and to prevent post-surgical adhesions. Additionally, due to the presence of the aminated polysaccharide, the hydrogel tissue adhesive may also promote wound healing and blood coagulation, and provide antimicrobial properties.

Claims

1. A kit comprising:

a) at least one aminated polysaccharide containing primary amine groups, said at least one aminated polysaccharide having a weight-average molecular weight of about 1,000 to about 1,000,000 Daltons and an equivalent weight per primary amine group of about 100 to about 3400 Daltons, wherein the at least one aminated polysaccharide is not chitosan; and

b) at least one water-dispersible, aldehyde-functionalized multi-arm polyether having at least three arms wherein at least three of the arms are terminated with an aldehyde group, wherein said water-dispersible, aldehyde-functionalized multi-arm polyether has a number-average molecular weight of about 450 to about 200,000 Daltons.

2. The kit according to claim 1, wherein the aminated polysaccharide is a component of a first aqueous solution or dispersion and the water-dispersible, aldehyde-functionalized multi-arm polyether is a component of a second aqueous solution or dispersion.

3. The kit according to claim 1, wherein the aminated polysaccharide and the water-dispersible, aldehyde-functionalized multi-arm polyether are finely divided powders.

4. The kit according to claim 1, wherein the aminated polysaccharide is selected from the group consisting of aminated derivatives of:

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

5. The kit according to claim 4, wherein the aminated polysaccharide is aminated dextran or aminated carboxymethyldextran.

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

7. The kit according to claim 6, wherein the water-dispersible, aldehyde-functionalized multi-arm polyether is a four-arm PEG tetra(thiomethylaldehyde), an eight-arm PEG octa(thiomethylaldehyde), or an eight-arm PEG octa-aldehyde.

8. The kit according to claim 1, wherein the aminated polysaccharide is aminated dextran and the water-dispersible, aldehyde-functionalized multi-arm polyether is a four-arm PEG tetra(thiomethylaldehyde), an eight-arm PEG octa(thiomethylaldehyde), or an eight-arm PEG octa-aldehyde.

9. The kit according to claim 1, wherein the aminated polysaccharide is aminated carboxymethyldextran and the water-dispersible, aldehyde-functionalized multi-arm polyether is an eight-arm PEG octa-aldehyde.

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

a) combining (i) a first solution or dispersion comprising at least one aminated polysaccharide containing primary amine groups in a first solvent, said aminated polysaccharide having a weight-average molecular weight of about 1,000 to about 1,000,000 Daltons and an equivalent weight per primary amine group of about 100 to about 3400 Daltons, wherein the at least one aminated polysaccharide is not chitosan;

with (ii) a second solution or dispersion comprising at least one water-dispersible, aldehyde-functionalized multi-arm polyether having at least three arms in a second solvent, wherein at least three of the arms of said multi-arm polyether are terminated by an aldehyde group, said water-dispersible, aldehyde-functionalized multi-arm polyether having a number-average molecular weight of about 450 to about 200,000 Daltons, to form a hydrogel, wherein the first solvent is either the same as or different from the second solvent; and

b) treating the hydrogel to remove at least a portion of said first solvent and said second solvent to form the dried hydrogel.

11. The dried hydrogel according to claim 10, wherein said dried hydrogel is in the form of a film.

12. The dried hydrogel according to claim 10, wherein the process further comprises comminuting the dried hydrogel to form finely divided particles.

13. A method for coating an anatomical site on tissue of a living organism comprising:

a) applying to the anatomical site at least one aminated polysaccharide containing primary amine groups, said at least one aminated polysaccharide having a weight-average molecular weight of about 1,000 to about 1,000,000 Daltons and an equivalent weight per primary amine group of about 100 to about 3400 Daltons, wherein the at least one aminated polysaccharide is not chitosan;

followed by

b) applying to the anatomical site at least one water-dispersible, aldehyde-functionalized multi-arm polyether having at least three arms wherein at least three of the arms are terminated with an aldehyde group, wherein said water-dispersible, aldehyde-functionalized multi-arm polyether has a number-average molecular weight of about 450 to about 200,000 Daltons;

or

c) applying to the anatomical site the polyether of step b) followed by applying to the anatomical site the aminated polysaccharide of step a) and mixing the polyether and the aminated polysaccharide on the anatomical site;

or

d) premixing the aminated polysaccharide of step a) and the polyether of step to form a mixture and applying the mixture to the anatomical site.

14. The method according to claim 13, wherein the aminated polysaccharide is a component of a first aqueous solution or dispersion and the water-dispersible, aldehyde-functionalized multi-arm polyether is a component of a second aqueous solution or dispersion.

15. The method according to claim 14, wherein the aminated polysaccharide and the water-dispersible, aldehyde-functionalized multi-arm polyether are finely divided powders.

16. A composition comprising the reaction product of:

a) at least one aminated polysaccharide containing primary amine groups, said at least one aminated polysaccharide having a weight-average molecular weight of about 1,000 to about 1,000,000 Daltons and an equivalent weight per primary amine group of about 100 to about 3400 Daltons, wherein the at least one aminated polysaccharide is not chitosan; and

b) at least one water-dispersible, aldehyde-functionalized multi-arm polyether having at least three arms wherein at least three of the arms are terminated with an aldehyde group, wherein said water-dispersible, aldehyde-functionalized multi-arm polyether has a number-average molecular weight of about 450 to about 200,000 Daltons.

17. The composition according to claim 16, wherein the aminated polysaccharide is selected from the group consisting of aminated derivatives of:

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

18. The composition according to claim 17, wherein the aminated polysaccharide is aminated dextran or aminated carboxymethyldextran.

19. The composition according to claim 16, wherein the water-dispersible, aldehyde-functionalized multi-arm polyether is selected from the group consisting of aldehyde-terminated star polyethylene oxides, aldehyde-terminated dendritic polyethylene oxides, aldehyde-terminated comb polyethylene oxides, aldehyde-terminated star polypropylene oxides, aldehyde-terminated dendritic polypropylene oxides, aldehyde-terminated comb polypropylene oxides, aldehyde-terminated star polyethylene oxide-polypropylene oxide copolymers, aldehyde-terminated dendritic polyethylene oxide-polypropylene oxide copolymers, and aldehyde-terminated comb polyethylene oxide-polypropylene oxide copolymers.

20. The composition according to claim 19, wherein the water-dispersible, aldehyde-functionalized multi-arm polyether is a four-arm PEG tetra(thiomethylaldehyde), an eight-arm PEG octa(thiomethylaldehyde), or an eight-arm PEG octa-aldehyde.