Polysaccharide-based polymer tissue adhesive for medical use

• US 8,771,738 B2
• Filed: 03/08/2013
• Issued: 07/08/2014
• Est. Priority Date: 10/07/2004
• Status: Active Grant

• Current Assignee: Actamax Surgical Materials, LLC (DSM-Firmenich AG)
• Original Assignee: Actamax Surgical Materials, LLC (DSM-Firmenich AG)
• Inventors: Kodokian, George K., Arthur, Samuel David
• Primary Examiner(s): DICKINSON, PAUL W
• Application Number:
  US13/789,865
• Publication Number:
  US 20130189221A1
• Time in Patent Office: 487 Days
• Field of Search: None
• US Class Current: 424/486
• CPC Class Codes: A61K 31/09 having two or more such linkages
• CPC Class Codes: A61K 31/715 Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
• CPC Class Codes: A61K 31/765 Polymers containing oxygen
• CPC Class Codes: A61K 31/785 Polymers containing nitrogen
• CPC Class Codes: A61K 45/00 Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• 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: C08B 37/00 Preparation of polysaccharides not provided for in groups C08B1/00 - C08B35/00; Derivatives thereof cellulose D21; microbiological processes C12P
• CPC Class Codes: C08B 37/0021 Dextran, i.e. (alpha-1,4)-D-glucan; Derivatives thereof, e.g. Sephadex, i.e. crosslinked dextran
• CPC Class Codes: C08B 9/00 Cellulose xanthate; Viscose formation of films C08J5/18; formation of fibres D01F; rendering cellulose suitable for esterification C08B1/02
• CPC Class Codes: C08G 2650/50 containing nitrogen, e.g. polyetheramines or Jeffamines(r)
• CPC Class Codes: C08G 65/33306 acyclic
• CPC Class Codes: C08L 2203/02 for biomedical use
• CPC Class Codes: C08L 2666/26 Natural polymers, natural resins or derivatives thereof according to C08L1/00 - C08L5/00, C08L89/00, C08L93/00, C08L97/00 or C08L99/00
• CPC Class Codes: C08L 71/02 Polyalkylene oxides
• CPC Class Codes: C09J 105/02 Dextran; Derivatives thereof
• CPC Class Codes: C09J 171/02 Polyalkylene oxides

Abstract

Method of forming tissue adhesives by reacting an oxidized polysaccharide with a water-dispersible multi-arm polyether amine, wherein at least three of the arms are terminated by primary amine groups, are disclosed. The use of the tissue adhesives for medical and veterinary applications such as topical wound closure; and surgical procedures, such as intestinal anastomosis, vascular anastomosis, tissue repair, and ophthalmic procedures; drug delivery; anti-adhesive applications; and as a bulking agent to treat urinary incontinence are described.

Claims

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

applying to the site

a) a first aqueous solution comprising an oxidized dextran containing aldehyde groups, having a molecular weight of about 1,000 to about 1,000,000 Daltons, said oxidized dextran having an equivalent weight per aldehyde group of about 90 to about 1500 Daltons, said solution containing from about 5% to about 40% by weight of the oxidized dextran, followed by

b) a second aqueous solution comprising

a first polyethylene glycol comprising eight arms terminated by a primary amine group, wherein the first polyethylene glycol has a molecular weight of about 450 to about 200,000 Daltons, said solution containing from about 5% to about 70% by weight of the first polyethylene glycol,

a second polyethylene glycol comprising four arms terminated by a primary amine group, wherein the second polyethylene glycol has a molecular weight of about 450 to about 200,000 Daltons, said solution containing from about 5% to about 70% by weight of the second polyethylene glycol,

or the aqueous solution of (b) followed by the aqueous solution of (a), or premixing the aqueous solutions of (a) and (b) and applying the resulting mixture to the site before the resulting mixture completely cures.

2. The method of claim 1, wherein

the oxidized dextran has a molecular weight of about 3,000 to about 250,000 Daltons;

the first aqueous solution contains from about 5% to about 30% by weight of oxidized dextran;

the first and second polyethylene glycol has a molecular weight of about 2,000 to about 40,000 Daltons;

the second aqueous solution contains from about 5% to about 50% by weight of the first polyethylene glycol and from about 5% and about 20% by weight of the second polyethylene glycol; and

the solutions (a) and (b) are premixed and applied to the anatomical site before the resulting mixture completely cures.

3. The method of claim 1, wherein

the oxidized dextran has a molecular weight of about 3,000 to about 40,000 Daltons;

the first aqueous solution contains from about 10% to about 20% by weight of oxidized dextran;

the first and second polyethylene glycol has a molecular weight of about 2,000 to about 40,000 Daltons;

the second aqueous solution contains from about 20% to about 50% by weight of the first polyethylene glycol and from about 5% and about 10% by weight of the second polyethylene glycol; and

the solutions (a) and (b) are premixed and applied to the anatomical site before the resulting mixture completely cures.

4. The method of claim 1, wherein

the oxidized dextran has a molecular weight of about 10,000 Daltons;

the first aqueous solution contains from about 10% to about 15% by weight of oxidized dextran;

the first polyethylene glycol has a molecular weight of about 2,000 to about 40,000Daltons;

the second polyethylene glycol has a molecular weight of about 2,000 Daltons;

the second aqueous solution contains from about 25% to about 50% by weight of the first polyethylene glycol and about 5% by weight of the second polyethylene glycol; and

the solutions (a) and (b) are premixed and applied to the anatomical site before the resulting mixture completely cures.

5. The method of claim 1, wherein the first and second aqueous solutions are sterilized.

6. The method of claim 1, wherein the anatomical site is a wound on the skin and the method is used for treatment of topical wounds.

7. The method of claim 1, wherein the anatomical site is on an intestine or blood vessel and the method is used in an anastomosis procedure.

8. The method of claim 1, wherein the anatomical site is on the eye and the method is used to seal a corneal incision.

9. The method of claim 1, wherein the first or second aqueous solution further comprises a pharmaceutical drug or therapeutic agent and the method is used for drug delivery to the anatomical site.

10. A method for bonding at least two anatomical sites together comprising:

applying to at least one site

a) a first aqueous solution comprising an oxidized dextran containing aldehyde groups, having a molecular weight of about 1,000 to about 1,000,000 Daltons, said oxidized dextran having an equivalent weight per aldehyde group of about 90 to about 1500 Daltons, said solution containing from about 5% to about 40% by weight of the oxidized dextran , followed by

b) a second aqueous solution comprising

a first polyethylene glycol comprising eight arms terminated by a primary amine group, wherein the first polyethylene glycol has a molecular weight of about 450to about 200,000 Daltons, said solution containing from about 5% to about 70% by weight of the first polyethylene glycol,

a second polyethylene glycol comprising four arms terminated by a primary amine group, wherein the second polyethylene glycol has a molecular weight of about 450 to about 200,000 Daltons, said solution containing from about 5% to about 70% by weight of the second polyethylene glycol,

or premixing the solutions of (a) and (b) and applying the resulting mixture to at least one site before the resulting mixture completely cures; and

contacting the at least two anatomical sites together.

11. The method of claim 10, wherein

the oxidized dextran has a molecular weight of about 3,000 to about 250,000 Daltons;

the first aqueous solution contains from about 5% to about 30% by weight of oxidized dextran;

the first and second polyethylene glycol has a molecular weight of about 2,000 to about 40,000 Daltons;

the second aqueous solution contains from about 5% to about 50% by weight of the first polyethylene glycol and from about 5% and about 20% by weight of the second polyethylene glycol; and

the solutions (a) and (b) are premixed and applied to the anatomical site before the resulting mixture completely cures.

12. The method of claim 10, wherein

the oxidized dextran has a molecular weight of about 3,000 to about 40,000 Daltons;

the first aqueous solution contains from about 10% to about 20% by weight of oxidized dextran;

the first and second polyethylene glycol has a molecular weight of about 2,000 to about 40,000 Daltons;

the second aqueous solution contains from about 20% to about 50% by weight of the first polyethylene glycol and from about 5% and about 10% by weight of the second polyethylene glycol; and

the solutions (a) and (b) are premixed and applied to the anatomical site before the resulting mixture completely cures.

13. The method of claim 10, wherein

the oxidized dextran has a molecular weight of about 10,000 Daltons;

the first aqueous solution contains from about 10% to about 15% by weight of oxidized dextran;

the first polyethylene glycol has a molecular weight of about 2,000 to about 40,000Daltons;

the second polyethylene glycol has a molecular weight of about 2,000 Daltons;

the second aqueous solution contains from about 25% to about 50% by weight of the first polyethylene glycol and about 5% by weight of the second polyethylene glycol; and

the solutions (a) and (b) are premixed and applied to the anatomical site before the resulting mixture completely cures.

14. The method of claim 10, wherein the first and second aqueous solutions are sterilized.

15. The method of claim 10, wherein the anatomical site is a wound on the skin and the method is used for treatment of topical wounds.

16. The method of claim 10, wherein the anatomical site is on an intestine or blood vessel and the method is used in an anastomosis procedure.

17. The method of claim 10, wherein the anatomical site is on the eye and the method is used to seal a corneal incision.

18. The method of claim 10, wherein the first or second aqueous solution further comprises a pharmaceutical drug or therapeutic agent and the method is used for drug delivery to the anatomical site.

19. A kit comprising:

a) a first aqueous solution comprising an oxidized dextran containing aldehyde groups, having a molecular weight of about 1,000 to about 1,000,000 Daltons, said oxidized dextran having an equivalent weight per aldehyde group of about 90 to about 1500 Daltons, said solution containing from about 5% to about 40% by weight of the oxidized dextran; and

b) a second aqueous solution comprising;

a first polyethylene glycol comprising eight arms terminated by a primary amine group, wherein the first polyethylene glycol has a molecular weight of about 450to about 200,000 Daltons, said solution containing from about 5% to about 70% by weight of the first polyethylene glycol, and

a second polyethylene glycol comprising four arms terminated by a primary amine group, wherein the second polyethylene glycol has a molecular weight of about 450 to about 200,000 Daltons, said solution containing from about 5% to about 70% by weight of the second polyethylene glycol.

20. The kit of claim 19, wherein

the oxidized dextran has a molecular weight of about 3,000 to about 250,000 Daltons;

the first aqueous solution contains from about 5% to about 30% by weight of oxidized dextran;

the first and second polyethylene glycol has a molecular weight of about 2,000 to about 40,000 Daltons; and

the second aqueous solution contains from about 5% to about 50% by weight of the first polyethylene glycol and from about 5% and about 20% by weight of the second polyethylene glycol.

21. The kit of claim 19, wherein

the oxidized dextran has a molecular weight of about 3,000 to about 40,000 Daltons;

the first aqueous solution contains from about 10% to about 20% by weight of oxidized dextran;

the first and second polyethylene glycol has a molecular weight of about 2,000 to about 40,000 Daltons; and

the second aqueous solution contains from about 20% to about 50% by weight of the first polyethylene glycol and from about 5% and about 10% by weight of the second polyethylene glycol.

22. The kit of claim 19, wherein

the oxidized dextran has a molecular weight of about 10,000 Daltons;

the first aqueous solution contains from about 10% to about 15% by weight of oxidized dextran;

the first polyethylene glycol has a molecular weight of about 2,000 to about 40,000Daltons;

the second polyethylene glycol has a molecular weight of about 2,000 Daltons; and

the second aqueous solution contains from about 25% to about 50% by weight of the first polyethylene glycol and about 5% by weight of the second polyethylene glycol.

23. The kit of claim 19, wherein the first and second aqueous solutions are sterilized.

24. The kit of claim 19, wherein the first or second aqueous solution further comprises a pharmaceutical drug or therapeutic agent and the method is used for drug delivery to the anatomical site.