Polymer-based tissue-adhesive form medical use

• US 8,790,632 B2
• Filed: 10/05/2005
• Issued: 07/29/2014
• 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: Arthur, Samuel David
• Primary Examiner(s): ROGERS, JAMES WILLIAM
• Application Number:
  US11/244,758
• Publication Number:
  US 20060079599A1
• Time in Patent Office: 3,219 Days
• Field of Search: 424/78.31
• US Class Current: 424/78.17
• 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

Abstract

Tissue adhesives formed by reacting poly(hydroxylic) compounds derivatized with acetoacetate groups and/or polyamino compounds derivatized with acetoacetamide groups with an amino-functional crosslinking compound 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; and anti-adhesive applications are described.

Claims

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

(a) optionally priming said anatomical site with an aqueous solution comprising an 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 90 to about 1500 Daltons, said aqueous solution containing from about 2% to about 40% by weight of the oxidized polysaccharide;

(b) applying to said anatomical site a first component comprising an aqueous solution comprising

(i) at least one poly(hydroxylic) compound derivatized with acetoacetate groups selected from the group consisting of

at least one poly(vinyl alcohol) derivatized with acetoacetate groups;

at least one poly(vinyl alcohol) copolymer derivatized with acetoacetate groups wherein said poly(vinyl alcohol) copolymer comprises between about 1 mole percent and about 25 mole percent of the comonomer relative to the vinyl alcohol units;

at least one linear or branched poly(ether) derivatized with acetoacetate groups;

at least one polysaccharide derivatized with acetoacetate groups;

at least one low molecular weight polyol derivatized with acetoacetate groups wherein said low molecular weight polyol has at least two hydroxy groups and has a molecular weight of less than about 300 Daltons;

at least one hydrolyzed polyvinyl acetate-methyl acrylate copolymer derivatized with acetoacetate groups;

at least one monosaccharide derivatized with acetoacetate groups;

at least one reduced monosaccharide derivatized with acetoacetate groups;

at least one polyether condensation product derivatized with acetoacetate groups wherein said polyether condensation product is produced by reacting at least one core molecule bearing more than one carboxylic acid group thereon with a sufficient amount of at least one polyether terminated with hydroxy groups to produce an esterified polyether with an average of at least two hydroxy end groups; and

mixtures thereof

and/or

(ii) a first polyamino compound derivatized with acetoacetamide groups selected from group consisting of amino-terminated linear or branched poly(ethylene oxide), amino-terminated linear or branched poly(propylene oxide), amino-terminated linear or branched copolymers of poly(ethylene oxide) and poly(propylene oxide), amino-terminated linear or branched poly(1,3-trimethylene oxide), amino-terminated linear or branched poly(1,4-tetramethylene oxide), amino-terminated star poly(ethylene oxide), amino-terminated comb poly(ethylene oxide), amino-terminated star poly(propylene oxide), amino-terminated comb poly(propylene oxide), and mixtures thereof;

each of (i) or (ii) having a weight-average molecular weight of less than about 200,000 Daltons and having an equivalent weight per acetoacetate group or acetoacetamide group, respectively, of about 100 to about 2000 Daltons; and

(c) applying to said anatomical site a second component comprising at least one of

(iii) an aqueous solution of at least one second polyamino compound, wherein said at least one second polyamino compound has an equivalent weight per amino group of about 100 to about 1,000 Daltons

(iv) at least one 3-aminopropyltrialkoxysilane, 3-aminopropyldialkoxyalkylsilane or 3-aminopropylmonoalkoxydialkylsilane, neat or in aqueous solution, and

(v) an aqueous solution of at least one second polyamino compound and at least one 3-aminopropyltrialkoxysilane, 3-aminopropyldialkoxyalkylsilane or 3-aminopropylmonoalkoxydialkylsilane; and

(d) mixing said components on the surface of said anatomical site;

or

(e) applying said second component to said anatomical site, followed by said first component, followed by mixing the solutions on the surface of said anatomical site;

or

(f) premixing said first and second components, and applying the resulting mixture to said anatomical site before said resulting mixture completely cures;

wherein the acetoacetate and/or acetoacetamide groups of step (b) react at ambient temperature with the amine groups of step (c) to form a hydrogel.

2. The method as recited in claim 1, wherein said poly(vinyl alcohol) has a weight-average molecular weight in the range of from about 10,000 Daltons to about 50,000 Daltons.

3. The method as recited in claim 1, wherein the degree of hydrolysis of said poly(vinyl alcohol) is from about 60% to about 100% OH groups, the balance being acetate groups.

4. The method as recited in claim 1, wherein said at least one second polyamino compound is selected from the group consisting of amino-terminated linear or branched poly(ethylene oxide), amino-terminated linear or branched poly(propylene oxide), amino-terminated linear or branched copolymers of poly(ethylene oxide) and poly(propylene oxide), amino-terminated linear or branched poly(1,3-trimethylene oxide), amino-terminated linear or branched poly(1,4-tetramethylene oxide), amino-terminated star poly(ethylene oxide), amino-terminated comb poly(ethylene oxide), amino-terminated star poly(propylene oxide), amino-terminated comb poly(propylene oxide), linear or branched poly(ethyleneimine), poly(allylamine), poly(lysine), poly(vinyl alcohol) derivatized with 4-aminobutyral acetal groups, poly(vinyl alcohol-co-vinylamine), linear or branched diaminoalkanes in the weight average molecular weight range of from about 80 Daltons to about 300 Daltons, 4,9-dioxa-1,12-dodecanediamine, N,N′

-bis(3-aminopropyl)piperazine, 5-amino-1,3,3-trimethylcyclohexanemethylamine, 1,3-bis(aminomethyl)cyclohexane, 1,4-diaminocyclohexane, xylylenediamine, adipic dihydrazide, (hydrazidocarboxymethyl)-terminated linear or branched poly(ethylene oxide), (hydrazidocarboxymethyl)-terminated linear or branched poly(propylene oxide), (hydrazidocarboxymethyl)-terminated linear or branched poly(ethylene oxide)-poly(propylene oxide) copolymer, (hydrazidocarboxymethyl)-terminated linear or branched poly(1,3-trimethylene oxide), (hydrazidocarboxymethyl)-terminated linear or branched poly(1,4-tetramethylene oxide), spermine, spermidine, dendrimeric amino-terminated copoly(ethylenediaminetetrapropionic acid-ethylenediamine) poly(amidoamines), and mixtures thereof.

5. The method as recited in claim 1, wherein the concentration of poly(hydroxylic) compound derivatized with acetoacetate groups in the aqueous solution of (b) is from about 15% to about 30% by weight.

6. The method as recited in claim 1, wherein the concentration of said second polyamino compound in the aqueous solution of (c) is about 15% to about 30% by weight.

7. The method as recited in claim 1, wherein the weight-average molecular weight of said oxidized polysaccharide is from about 3,000 to about 250,000 Daltons.

8. The method as recited in claim 1, wherein said oxidized polysaccharide is selected from the group consisting of dextran, chitin, starch, agar, cellulose, and hyaluronic acid.

9. The method as recited in claim 1, wherein said aqueous solutions and said at least one neat 3-aminopropyltrialkoxysilane, 3-aminopropyldialkoxyalkylsilane or 3-aminopropylmonoalkoxydialkylsilane are sterilized.

10. The method as recited in claim 1, wherein said aqueous solution of (b) further comprises 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 90 to about 1500 Daltons, said aqueous solution containing from about 2% to about 20% by weight of the oxidized polysaccharide.

11. The method as recited in claim 10, wherein said oxidized polysaccharide is selected from the group consisting of dextran, chitin, starch, agar, cellulose, and hyaluronic acid.

12. The method as recited in claim 1 wherein said anatomical site is on an intestine or blood vessel and the method is used in an anastomosis procedure.

13. The method as recited in claim 1 wherein at least one of said aqueous solutions further comprises a pharmaceutical drug or therapeutic agent and said method is used for drug delivery to the anatomical site.

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

(a) optionally priming at least one anatomical site with an aqueous solution comprising an 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 90 to about 1500 Daltons, said aqueous solution containing from about 2% to about 40% by weight of the oxidized polysaccharide;

(b) applying a first component to at least one anatomical site comprising an aqueous solution comprising

(i) at least one poly(hydroxylic) compound derivatized with acetoacetate groups selected from the group consisting of

at least one poly(vinyl alcohol) derivatized with acetoacetate groups;

at least one poly(vinyl alcohol) copolymer derivatized with acetoacetate groups wherein said poly(vinyl alcohol) copolymer comprises between about 1 mole percent and about 25 mole percent of the comonomer relative to the vinyl alcohol units;

at least one linear or branched poly(ether) derivatized with acetoacetate groups;

at least one polysaccharide derivatized with acetoacetate groups;

at least one low molecular weight polyol derivatized with acetoacetate groups wherein said polyol has at least two hydroxy groups and has a molecular weight of less than about 300 Daltons;

at least one hydrolyzed polyvinyl acetate-methyl acrylate copolymer derivatized with acetoacetate groups;

at least one monosaccharide derivatized with acetoacetate groups;

at least one reduced monosaccharide derivatized with acetoacetate groups;

at least one polyether condensation product derivatized with acetoacetate groups wherein said polyether condensation product is produced by reacting at least one core molecule bearing more than one carboxylic acid group thereon with a sufficient amount of at least one polyether terminated with hydroxy groups to produce an esterified polyether with an average of at least two hydroxy end groups; and

mixtures thereof and/or

(ii) a first polyamino compound derivatized with acetoacetamide groups, amino-terminated linear or branched poly(ethylene oxide), amino-terminated linear or branched poly(propylene oxide), amino-terminated linear or branched copolymers of poly(ethylene oxide) and poly(propylene oxide), amino-terminated linear or branched poly(1,3-trimethylene oxide), amino-terminated linear or branched poly(1,4-tetramethylene oxide), amino-terminated star poly(ethylene oxide), amino-terminated comb poly(ethylene oxide), amino-terminated star poly(propylene oxide), amino-terminated comb poly(propylene oxide), and mixtures thereof

each of (i) or (ii) having a weight-average molecular weight of less than about 200,000 Daltons and having an equivalent weight per acetoacetate group or acetoacetamide group, respectively, of about 100 to about 2000 Daltons;

(c) applying to said at least one anatomical site a second component comprising at least one of

(iii) an aqueous solution of at least one second polyamino compound, wherein said polyamino compound has an equivalent weight per amino group of about 100 to about 1,000 Daltons;

(iv) at least one 3-aminopropyltrialkoxysilane, 3-aminopropyldialkoxyalkylsilane or 3-aminopropylmonoalkoxydialkylsilane, neat or in aqueous solution; and

(v) an aqueous solution of at least one polyamino compound and at least one 3-aminopropyltrialkoxysilane, 3-aminopropyldialkoxyalkylsilane or 3-aminopropylmonoalkoxydialkylsilane;

(d) mixing said components on the surface of said at least one anatomical site;

or

(e) applying said second component to said at least one anatomical site, followed by said first component, followed by mixing the solutions on the surface of said at least one anatomical site;

or

(f) premixing said first and second components, and applying the resulting mixture to said at least one anatomical site before said resulting mixture completely cures;

wherein the acetoacetate and/or acetoacetamide groups of step (b) react at ambient temperature with the amine groups of step (c) to form a hydrogel, and

(g) contacting said at least two anatomical sites together.

15. The method as recited in claim 14, wherein polyvinyl alcohol) has a weight-average molecular weight in the range of from about 10,000 Daltons to about 50,000 Daltons.

16. The method as recited in claim 14, wherein the degree of hydrolysis of said poly(vinyl alcohol) is from about 60% to about 100% OH groups, the balance being acetate groups.

17. The method as recited in claim 14, wherein said second polyamino compound is selected from the group consisting of amino-terminated linear or branched poly(ethylene oxide), amino-terminated linear or branched poly(propylene oxide), amino-terminated linear or branched copolymers of poly(ethylene oxide) and poly(propylene oxide), amino-terminated linear or branched poly(1,3-trimethylene oxide), amino-terminated linear or branched poly(1,4-tetramethylene oxide), amino-terminated star poly(ethylene oxide), amino-terminated comb poly(ethylene oxide), amino-terminated star poly(propylene oxide), amino-terminated comb poly(propylene oxide), linear or branched poly(ethyleneimine), poly(allylamine), poly(lysine), poly(vinyl alcohol) derivatized with 4-aminobutyral acetal groups, poly(vinyl alcohol-co-vinylamine), linear or branched diaminoalkanes in the weight average molecular weight range of from about 80 Daltons to about 300 Daltons, 4,9-dioxa-1,12-dodecanediamine, N,N′

-bis(3-aminopropyl)piperazine, 5-amino-1,3,3-trimethylcyclohexanemethylamine, 1,3-bis(aminomethyl)cyclohexane, 1,4-diaminocyclohexane, xylylenediamine, adipic dihydrazide, (hydrazidocarboxymethyl)-terminated linear or branched poly(ethylene oxide), (hydrazidocarboxymethyl)-terminated linear or branched poly(propylene oxide), (hydrazidocarboxymethyl)-terminated linear or branched poly(ethylene oxide)-poly(propylene oxide) copolymer, (hydrazidocarboxymethyl)-terminated linear or branched poly(1,3-trimethylene oxide), (hydrazidocarboxymethyl)-terminated linear or branched poly(1,4-tetramethylene oxide), spermine, spermidine, dendrimeric amino-terminated copoly(ethylenediaminetetrapropionic acid-ethylenediamine) poly(amidoamines), and mixtures thereof.

18. The method as recited in claim 14, wherein the concentration of the poly(hydroxylic) compound derivatized with acetoacetate groups in the aqueous solution of (b) is from about 15% to about 30% by weight.

19. The method as recited in claim 14, wherein the concentration of said second polyamino compound in the aqueous solution of (c) is about 15% to about 30% by weight.

20. The method as recited in claim 14, wherein said aqueous solution of (b) further comprises 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 90 to about 1500 Daltons, said aqueous solution containing from about 2% to about 20% by weight of the oxidized polysaccharide.

21. The method as recited in claim 20, wherein said oxidized polysaccharide is selected from the group consisting of dextran, chitin, starch, agar, cellulose, and hyaluronic acid.