Compositions and systems for forming crosslinked biomaterials and methods of preparation and use

• US 20060210602A1
• Filed: 01/31/2006
• Published: 09/21/2006
• Est. Priority Date: 12/18/1995
• Status: Active Grant

• Current Assignee: Angiodevice International GmbH (Angiotech Pharmaceuticals (US), Inc.)
• Original Assignee: Angiodevice International GmbH (Angiotech Pharmaceuticals (US), Inc.)
• Inventors: Trollsas, Olof Mikael, Sehl, Louis C., Toman, David, Wallace, Donald G., Schroeder, Jacqueline A., Chu, George H., DeLustro, Frank A.
• Granted Patent: US 7,883,693 B2
• Time in Patent Office: Days
• US Class Current: 424/423
• CPC Class Codes: A61F 2/0063 Implantable repair or support meshes, e.g. hernia meshes
• CPC Class Codes: A61L 17/145 Coating
• 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 24/102 Collagen
• CPC Class Codes: A61L 27/24 Collagen
• CPC Class Codes: A61L 27/26 Mixtures of macromolecular compounds
• CPC Class Codes: A61L 27/34 Macromolecular materials
• CPC Class Codes: A61L 27/54 Biologically active materials, e.g. therapeutic substances A61L27/227 takes precedence
• CPC Class Codes: A61L 31/041 Mixtures of macromolecular compounds
• CPC Class Codes: A61L 31/044 Collagen
• CPC Class Codes: A61L 31/10 Macromolecular materials
• CPC Class Codes: A61L 31/16 Biologically active materials, e.g. therapeutic substances A61L31/047 takes precedence
• CPC Class Codes: C08B 37/0075 Heparin; Heparan sulfate; Derivatives thereof, e.g. heparosan; Purification or extraction methods thereof
• CPC Class Codes: C08F 283/00 Macromolecular compounds obtained by polymerising monomers on to polymers provided for in subclass C08G
• CPC Class Codes: C08F 283/04 on to polycarbonamides, polyesteramides or polyimides C08F283/004 takes precedence
• CPC Class Codes: C08F 283/06 on to polyethers, polyoxymethylenes or polyacetals C08F283/004 takes precedence
• CPC Class Codes: C08G 2650/50 containing nitrogen, e.g. polyetheramines or Jeffamines(r)
• CPC Class Codes: C08G 65/329 with organic compounds
• CPC Class Codes: C08G 65/33306 : acyclic
• CPC Class Codes: C08G 65/33337 : cyclic
• CPC Class Codes: C08G 75/045 : from mercapto compounds and unsaturated compounds
• CPC Class Codes: C08G 75/26 : Polythioesters
• CPC Class Codes: C08H 1/00 : Macromolecular products derived from proteins food proteins A23; glue, gelatine C09H
• CPC Class Codes: C08H 1/06 : derived from horn, hoofs, hair, skin or leather
• 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 5/00 : Compositions of polysaccharides or of their derivatives not provided for in groups C08L1/00 or C08L3/00
• CPC Class Codes: C08L 5/16 : Cyclodextrin; Derivatives thereof
• CPC Class Codes: C08L 51/003 : grafted on to macromolecular compounds obtained by reactions only involving unsaturated carbon-to-carbon bonds C08L51/04, C08L51/06 take precedence
• CPC Class Codes: C08L 53/00 : Compositions of block copolymers containing at least one sequence of a polymer obtained by reactions only involving carbon-to-carbon unsaturated bonds; Compositions of derivatives of such polymers
• CPC Class Codes: C08L 67/06 : Unsaturated polyesters
• CPC Class Codes: C08L 71/00 : Compositions of polyethers obtained by reactions forming an ether link in the main chain of polyacetals C08L59/00; of epoxy resins C08L63/00; of polythioether-ethers C08L81/02; of polyether-sulfones C08L81/06; Compositions of derivatives of such polymers
• CPC Class Codes: C08L 71/02 : Polyalkylene oxides
• CPC Class Codes: C08L 81/02 : Polythioethers; Polythioether-ethers
• CPC Class Codes: C08L 89/06 : derived from leather or skin , e.g. gelatin
• CPC Class Codes: C08L 91/06 : Waxes
• CPC Class Codes: C09D 167/02 : Polyesters derived from dicarboxylic acids and dihydroxy compounds C09D167/06 takes precedence
• CPC Class Codes: C09J 151/003 : grafted on to macromolecular compounds obtained by reactions only involving unsaturated carbon-to-carbon bonds C09J151/04, C09J151/06 take precedence
• CPC Class Codes: C09J 153/00 : Adhesives based on block copolymers containing at least one sequence of a polymer obtained by reactions only involving carbon-to-carbon unsaturated bonds; Adhesives based on derivatives of such polymers
• CPC Class Codes: C09J 189/06 : derived from leather or skin

Abstract

Crosslinkable compositions are provided that readily crosslink in situ to provide biocompatible, nonimmunogenic crosslinked materials that may be used as adhesive compositions. The compositions comprise collagen and a plurality of crosslinkable components having reactive functional groups thereon, with the functional groups selected so as to enable inter-reaction between the components, i.e., crosslinking. Methods for preparing and using the compositions are also provided. Exemplary uses include tissue augmentation, biologically active agent delivery, bioadhesion, prevention of adhesions following surgery or injury, and coating of surgically acceptable patches and solid implants, the latter including sutures.

Claims

1. A composition for coating a solid implant comprised of:

(a) a hydrophilic polymer;

(b) a crosslinkable component A having m nucleophilic groups, wherein m≧

2;

(c) a crosslinkable component B having n electrophilic groups capable of reaction with the m nucleophilic groups to form covalent bonds, wherein n≧

2 and m+n≧

4; and

wherein each of components A and B is biocompatible and crosslinking of the adhesive composition upon contact with moisture results in a biocompatible, crosslinked matrix.

2. The composition of claim 1, wherein at least one of components A and B is a hydrophilic polymer.

3. The composition of claim 1, wherein m+n>

4.

4. The composition of claim 1, wherein each of components A and B is nonimmunogenic.

5. The composition claim 1, wherein the solid implant is selected from the group consisting of sutures, surgically acceptable patches, artificial blood vessels, artificial heart valves, vascular grafts, vascular stents, vascular stent/graft combinations, bone implants, cartilage implants, artificial joints, bone prostheses, retaining pins, cranial plates, ophthalmic shields, corneal lenticules, breast implants, and drug delivery devices.

6. The composition claim 5, wherein the solid implant is a suture.

7. The composition of claim 6, wherein the suture is for dermal or internal use.

8. The composition of claim 6, wherein the solid implant is a surgically acceptable patch.

9. The composition of claim 8, wherein the surgically acceptable patch is selected from implantable surgical membranes and implantable surgical meshes.

10. The composition of claim 1, wherein the hydrophilic polymer is selected from synthetic polymers and naturally occurring polymers.

11. The composition of claim 10, wherein the naturally occurring hydrophilic polymer is selected from proteins, carboxylated polysaccharides, aminated polysaccharides, glycosaminoglycans, and activated polysaccharides.

12. The composition of claim 11, wherein the naturally occurring hydrophilic polymer is selected from nonfibrillar collagen, chemically modified collagen, fibrillar collagen, denatured collagen and combinations thereof.

13. The composition of claim 12, wherein the nonfibrillar collagen is selected from type IV collagen, type VI collagen, and type VII collagen.

14. The composition of claim 12, wherein the chemically modified collagen is methylated collagen.

15. The composition of claim 1, wherein the composition further comprises a third crosslinkable component C that is biocompatible and nonimmunogenic and has at least one functional group selected from

(a) nucleophilic groups capable of reacting with the electrophilic groups of component B and,

(b) electrophilic groups capable of reacting with the nucleophilic groups of component A, wherein the total number of functional groups on component C is represented by p, such that m+n+p>

5.

16. The composition of claim 1, wherein component A has the structural formula (I) and component B has the structural formula (II)

R¹(-[Q¹]_q-X)_m 

 

(I)
R²(-[Q²]_r-Y)_n 

 

(II)

wherein;

R¹ and R² are independently selected from the group consisting of C₂ to C₁₄ hydrocarbyl, heteroatom-containing C₂ to C₁₄ hydrocarbyl, hydrophilic polymers, and hydrophobic polymers;

X represents one of the m nucleophilic groups of component A;

Y represents one of the n electrophilic groups of component B;

Q¹ and Q² are linking groups;

m and n are the number of nucleophilic groups and electrophilic groups, respectively; and

q and r are independently zero or 1.

17. The composition of claim 15, wherein component C has the structural formula (III)

R³(-[Q³]_s-Fn)_p 

 

(III)

wherein;

R³ is selected from the group consisting of C₂ to C₁₄ hydrocarbyl, heteroatom-containing C₂ to C₁₄ hydrocarbyl, hydrophilic polymers, and hydrophobic polymers;

Fn represents a functional group on component C;

p≧

1; and

s is zero or 1.

18. The composition of claim 16, wherein at least one of R¹ and R² is a synthetic hydrophilic polymer.

19. The composition of claim 18, wherein:

(a) R¹ is a first synthetic hydrophilic polymer; and

(b) R² is selected from the group consisting of (i) a second synthetic hydrophilic polymer that may or may not be the same as R¹ and (ii) C₂ to C₁₄ hydrocarbyl groups containing zero to 2 heteroatoms selected from N, O and S.

20. The composition of claim 19, wherein the synthetic hydrophilic polymer is a linear, branched, dendrimeric, hyperbranched, or star polymer.

21. The composition of claim 18, wherein the synthetic hydrophilic polymer is selected from polyalkylene oxides;

polyols;

polyacrylic acid and analogs and copolymers thereof;

polymaleic acid;

polyacrylamides;

poly(olefinic alcohol)s;

poly(N-vinyl lactams);

polyoxazolines;

polyvinylamines; and

copolymers thereof.

23. The composition of claim 1, wherein the nucleophilic groups of component A are selected from —

NH₂, —

NHR⁴, —

N(R⁴)₂, —

SH, —

OH, —

COOH, —

C₆H₄—

OH, —

PH₂, —

PHR⁵, —

P(R⁵)₂, —

NH—

NH₂, —

CO—

NH—

NH₂, and —

C₅H₄N, wherein R⁴ and R⁵ are C₁-C₁₂ hydrocarbyl.

24. The composition of claim 1, wherein the electrophilic groups of component B are amino-reactive groups or sulfhydryl-reactive groups.

25. The composition of claim 24, wherein the amino-reactive groups are selected from carboxylic acid esters, carboxylic acids, acid chloride groups, anhydrides, ketones, aldehydes, halides, isocyanates, isothiocyanates, epoxides, activated hydroxyl groups, and olefins.

26. The composition of claim 1, wherein the composition further comprises a biologically active agent.

27. The composition claim 26, wherein the solid implant is selected from the group consisting of sutures, surgically acceptable patches, artificial blood vessels, artificial heart valves, vascular grafts, vascular stents, vascular stent/graft combinations, bone implants, cartilage implants, artificial joints, bone prostheses, retaining pins, cranial plates, ophthalmic shields, corneal lenticules, breast implants, and drug delivery devices.

28. The composition claim 27, wherein the solid implant is a suture.

29. The composition of claim 28, wherein the suture is for dermal or internal use.

30. The composition of claim 27, wherein the solid implant is a surgically acceptable patch.

31. The composition of claim 30, wherein the surgically acceptable patch is selected from implantable surgical membranes and implantable surgical meshes.

22. The composition of 21, wherein the synthetic hydrophilic polymer is selected from polyethylene glycol, poly(ethylene oxide)-poly(propylene oxide), mono-poly(oxyalkylene)-substituted propylene glycol, di-(polyoxyalkylene)-substituted propylene glycol, mono-poly(oxyalkylene)-substituted trimethylene glycol, di-(polyoxyalkylene)-substituted trimethylene glycol, mono-poly(oxyalkylene)-substituted glycerol, di-(polyoxyalkylene)-substituted glycerol, and tri-(polyoxyalkylene)-substituted glycerol;

poly(acrylic acid);

poly(methacrylic acid), poly(hydroxyethylmethacrylate), poly(hydroxyethylacrylate), poly(methylalkylsulfoxide acrylates), poly(methylalkylsulfoxide methacrylates), and copolymers thereof;

polymaleic acid;

polyacrylamide, poly(methacrylamide), poly(dimethylacrylamide), poly(N-isopropylacrylamide), and copolymers thereof;

poly(vinyl alcohol);

poly(vinyl pyrrolidone), poly(N-vinyl caprolactam), and copolymers thereof;

poly(methyloxazoline) and poly(ethyloxazoline);

polyvinylamines; and

copolymers thereof.