Oxidized cationic polysaccharide-based polymer tissue adhesive for medical use

• US 8,426,492 B2
• Filed: 11/14/2008
• Issued: 04/23/2013
• Est. Priority Date: 11/14/2007
• Status: Active Grant

• Current Assignee: Actamax Surgical Materials, LLC (DSM-Firmenich AG)
• Original Assignee: Actamax Surgical Materials, LLC (DSM-Firmenich AG)
• Inventors: Lu, Helen S. M.
• Primary Examiner(s): PEPITONE, MICHAEL F
• Application Number:
  US12/742,457
• Publication Number:
  US 20100272804A1
• Time in Patent Office: 1,621 Days
• Field of Search: 523/118, 424/488, 424/486, 514/54, 525/509
• US Class Current: 523/118
• CPC Class Codes: A61L 24/0031 Hydrogels or hydrocolloids
• CPC Class Codes: A61L 24/043 Mixtures of macromolecular materials
• CPC Class Codes: A61L 27/26 Mixtures of macromolecular compounds
• CPC Class Codes: A61L 27/52 Hydrogels or hydrocolloids
• CPC Class Codes: A61L 31/041 Mixtures of macromolecular compounds
• CPC Class Codes: A61L 31/145 Hydrogels or hydrocolloids
• CPC Class Codes: A61P 17/02 for treating wounds, ulcers, burns, scars, keloids, or the like
• CPC Class Codes: C08L 1/02 Cellulose; Modified cellulose
• CPC Class Codes: C08L 5/00 Compositions of polysaccharides or of their derivatives not provided for in groups C08L1/00 or C08L3/00
• CPC Class Codes: C08L 71/02 Polyalkylene oxides

Abstract

A tissue adhesive formed by reacting an oxidized cationic polysaccharide containing aldehyde groups and amine groups with a multi-arm amine is described. The oxidized cationic polysaccharide-based polymer tissue adhesive may be useful for medical applications including wound closure, supplementing or replacing sutures or staples in internal surgical procedures such as intestinal anastomosis and vascular anastomosis, ophthalmic procedures, drug delivery, anti-adhesive applications and as a bulking agent to treat urinary incontinence. Additionally, due to the presence of the positively charged amine groups on the oxidized polysaccharide, the polymer tissue adhesive disclosed herein may promote wound healing and blood coagulation, and may possess antimicrobial properties.

Claims

1. A kit comprising:

a) at least one oxidized polysaccharide containing aldehyde groups and amine groups, wherein said amine groups are not primary amine 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 90 to about 1500 Daltons and an amine substitution level of about 5% to about 50%; and

b) at least one water-dispersible, multi-arm amine wherein at least three of the arms are terminated by a primary amine group, wherein the multi-arm amine has a number-average molecular weight of about 450 to about 200,000 Daltons.

2. The kit according to claim 1, wherein the oxidized polysaccharide is a first aqueous solution or dispersion and the multi-arm amine is a second aqueous solution or dispersion.

3. The kit according to claim 1, wherein the oxidized polysaccharide and the multi-arm amine are finely divided powders.

4. The kit according to claim 1, wherein the oxidized polysaccharide containing aldehyde groups and amine groups is derived from a polysaccharide selected from the group consisting of dextran, carboxymethyldextran, starch, agar, cellulose, hydroxyethylcellulose, carboxymethylcellulose, pullulan, inulun, levan, agarose, and hyaluronic acid.

5. The kit according to claim 1, wherein the oxidized polysaccharide containing aldehyde groups and amine groups is oxidized diethylaminoethyl dextran or oxidized aminated dextran.

6. The kit according to claim 1, wherein the multi-arm amine is selected from the group consisting of water dispersible multi-arm polyether amines, amino-terminated dendritic polyamidoamines, and branched end amines.

7. The kit according to claim 6, wherein the water dispersible multi-arm polyether amines are 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.

8. The kit according to claim 1, wherein the oxidized polysaccharide containing aldehyde groups and amine groups is oxidized diethylaminoethyl dextran or oxidized aminated dextran and the multi-arm amine is a multi-arm polyethylene glycol amine.

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

a) reacting in a solvent (i) at least one oxidized polysaccharide containing aldehyde groups and amine groups, wherein said amine groups are not primary amine 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 aldehydes group of about 90 to about 1500 Daltons and an amine substitution level of about 5% to about 50%;

with (ii) at least one water-dispersible, multi-arm amine wherein at least three of the arms are terminated by a primary amine group, wherein the multi-arm amine has a number-average molecular weight of about 450 to about 200,000 Daltons to form a hydrogel; and

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

10. The dried hydrogel according to claim 9, wherein said dried hydrogel is a film.

11. The dried hydrogel according to claim 9, wherein the process further comprises the step of comminuting the dried hydrogel to form finely divided particles.

14. A product for coating an anatomical site, the product comprising the dried hydrogel of claim 9.

23. A method for applying a coating to an anatomical site on tissue of a living organism comprising applying to the site the dried hydrogel of claim 9.

24. The method according to claim 23 wherein said dried hydrogel is in the form of a film.

25. The method according to claim 23 wherein said dried hydrogel is in the form of finely divided particles.

12. A composition for coating an anatomical site, the composition comprising the reaction product of:

a) at least one oxidized polysaccharide containing aldehyde groups and amine groups, wherein said amine groups are not primary amine 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 90 to about 1500 Daltons and an amine substitution level of about 5% to about 50%; and

b) at least one water-dispersible, multi-arm amine wherein at least three of the arms are terminated by a primary amine group, wherein the multi-arm amine has a number-average molecular weight of about 450 to about 200,000 Daltons.

13. A composition for bonding at least two anatomical sites together, the composition comprising the reaction product of:

a) at least one oxidized polysaccharide containing aldehyde groups and amine groups, wherein said amine groups are not primary amine 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 90 to about 1500 Daltons and an amine substitution level of about 5% to about 50%; and

b) at least one water-dispersible, multi-arm amine wherein at least three of the arms are terminated by a primary amine group, wherein the multi-arm amine has a number-average molecular weight of about 450 to about 200,000 Daltons.

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

a) at least one oxidized polysaccharide containing aldehyde groups and amine groups, wherein said amine groups are not primary amine 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 90 to about 1500 Daltons and an amine substitution level of about 5% to about 50%;

followed by

b) at least one water-dispersible, multi-arm amine wherein at least three of the arms are terminated by a primary amine group, wherein the multi-arm amine has a number-average molecular weight of about 450 to about 200,000 Daltons;

or applying (b) followed by (a); and

mixing (a) and (b) on the site;

or

premixing (a) and (b) and applying the resulting mixture to the site;

or

applying (a) and (b) simultaneously to the site.

16. The method according to claim 15 wherein the oxidized polysaccharide is in the form of a first aqueous solution or dispersion and the multi-arm amine is in the form of a second aqueous solution or dispersion.

17. The method according to claim 15 wherein the oxidized polysaccharide and the multi-arm amine are in the form of finely divided powders.

18. The method according to claim 15 wherein the oxidized polysaccharide is diethylaminoethyl dextran or aminated dextran and the multi-arm amine is a multi-arm polyethylene glycol amine.

19. A method for bonding at least two anatomical sites together comprising applying to at least one of the at least two anatomical sites:

a) at least one oxidized polysaccharide containing aldehyde groups and amine groups, wherein said amine groups are not primary amine 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 90 to about 1500 Daltons and an amine substitution level of about 5% to about 50%;

followed by

b) at least one water-dispersible, multi-arm amine wherein at least three of the arms are terminated by a primary amine group, wherein the multi-arm amine has a number-average molecular weight of about 450 to about 200,000 Daltons;

or applying (b) followed by (a); and

mixing (a) and (b) on the at least one site;

or

premixing (a) and (b) and applying the resulting mixture to the at least one site;

or

applying (a) and (b) simultaneously to the at least one site; and

contacting the at least two anatomical sites together.

20. The method according to claim 19 wherein the oxidized polysaccharide is in the form of a first aqueous solution or dispersion and the multi-arm amine is in the form of a second aqueous solution or dispersion.

21. The method according to claim 19 wherein the oxidized polysaccharide and the multi-arm amine are in the form of finely divided powders.

22. The method according to claim 19 wherein the oxidized polysaccharide is diethylaminoethyl dextran or aminated dextran and the multi-arm amine is a multi-arm polyethylene glycol amine.