Crosslinkable biomaterial compositions containing hydrophobic and hydrophilic crosslinking agents
View Patent ↗The present invention discloses novel crosslinked biomaterial compsotions which are prepared using hydrophobic polymers as a crosslinking agent. Preferred hydrophobic polymers are those that contain two or more reactive succinimidyl groups, including disuccinimidyl suberate, bix(sulfosuccinimidyl) suberate, and dithiobis(succinimidylpropionate). Crosslinked biomaterial compositions prepared using mixtures of hydrophobic and hydrophilic crosslinking agents are also disclosed. The compositions of the present invention can be used to prepare formed implants for use in a variety of medical applications.
1. An injectable, crosslinkable composition that crosslinks in situ following administration to a patient to form a heterogeneous, crosslinked biomaterial composition, comprising:
a biomaterial comprised of a biocompatible polymer containing nucleophilic groups;
a hydrophobic crosslinking agent containing up to about 14 carbon atoms and comprised of a polyacid esterified with a reactive moiety selected from the group consisting of succinimidyl and sulfosuccinimidyl groups; and
a hydrophilic crosslinking agent, wherein both the hydrophobic crosslinking agent and the hydrophilic crosslinking agent crosslink the biomaterial in situ following administration of the composition to a patient, but are not reactive with respect to each other.
2. The composition of claim 1 , further including water, such that the composition is comprised of an aqueous suspension.
3. The composition of claim 1 , wherein the nucleophilic groups are primary amino groups.
4. The composition of claim 1 , wherein the biomaterial is selected from the group consisting of collagen, glycosaminoglycans, and mixtures thereof.
5. The composition of claim 4 , wherein the biomaterial is comprised of collagen.
6. The composition of claim 5 , wherein the collagen is fibrillar collagen.
7. The composition of claim 5 , wherein the collagen is nonfibrillar collagen.
8. The composition of claim 7 , wherein the non-fibrillar collagen is comprised of chemically derivatized collagen selected from the group consisting of succinylated collagen and methylated collagen.
9. The composition of claim 8 , wherein the collagen is succinylated collagen.
10. The composition of claim 8 , wherein the collagen is methylated collagen.
11. The composition of claim 5 , wherein the collagen is selected from the group consisting of Type I collagen, Type II collagen, Type III collagen, Type IV collagen, and mixtures thereof.
12. The composition of claim 11 , wherein the collagen is Type I collagen.
13. The composition of claim 5 , wherein the collagen is telopeptide collagen.
14. The composition of claim 5 , wherein the collagen is atelopeptide collagen.
15. The composition of claim 5 , wherein the collagen is denatured collagen.
16. The composition of claim 4 , wherein the biomaterial is a glycosaminoglycan.
17. The composition of claim 16 , wherein the glycosaminoglycan is selected from the group consisting of hyaluronic acid, chondroitin sulfate A, chondroitin sulfate C, dermatan sulfate, keratan sulfate, keratosulfate, chitin, chitosan, heparin, and derivatives thereof.
18. The composition of claim 1 , wherein the hydrophobic crosslinking agent is disuccinimidyl suberate.
19. The composition of claim 1 , wherein the hydrophobic crosslinking agent is comprised of a polyacid containing two, three or four carboxylic acid groups each esterified with a succinimidyl group.
20. The composition of claim 19 , wherein the polyacid is selected from the group consisting of trimethylolpropane tricarboxylic acid, di(trimethylol propane) tetracarboxylic acid, heptanedioic acid, suberic acid and hexadecanedioic acid.
21. The composition of claim 1 , wherein the hydrophobic crosslinking agent is comprised of a polyacid containing two, three or four carboxylic acid groups each esterified with a sulfosuccinimidyl group.
22. The composition of claim 21 , wherein the polyacid is selected from the group consisting of trimethylolpropane tricarboxylic acid, di(trimethylol propane) tetracarboxylic acid, heptanedioic acid, suberic acid and hexadecanedioic acid.
23. The composition of claim 1 , wherein the hydrophobic crosslinking agent is selected from the group consisting of disuccinimidyl suberate, dithiobis(succinimidyl-propionate, bis(sulfosuccinimidyl) suberate, bis(2-succinimidooxycarbonyloxy)ethyl sulfone, and 3,3′-dithiobis(sulfosuccinimidylpropionate).
24. The composition of claim 1 , wherein the hydrophilic crosslinking agent is comprised of an activated hydrophilic polymer.
25. The composition of claim 24 , wherein the activated hydrophilic polymer is selected from the group consisting of polyethylene glycol succinimidyl glutarate, polyethylene glycol succinimidyl, polyethylene glycol succinimidyl succinamide, and polyethylene glycol succinimidyl carbonate.
26. The composition of claim 24 , wherein the activated hydrophilic polymer is polyethylene glycol succinimidyl glutarate.
27. The composition of claim 24 , wherein the activated hydrophilic polymer is polyethylene glycol succinimidyl.
28. A kit for administering an in situ crosslinkable composition to a patient via injection, comprising:
a first syringe containing a biomaterial comprised of a biocompatible polymer containing nucleophilic groups;
a second syringe containing a mixture of a hydrophilic crosslinking agent and a hydrophobic crosslinking agent containing up to about 14 carbon atoms and comprised of a polyacid esterified with reactive moieties selected from the group consisting of succinimidyl groups and sulfosuccinimidyl groups, wherein both the hydrophobic crosslinking agent and the hydrophilic crosslinking agent crosslink the biomaterial in situ following administration of a combination of the biomaterial and the crosslinking agents to a patient, but are not reactive with respect to each other.
29. The kit of claim 28 , wherein the first syringe further contains water, such that the biomaterial is in an aqueous suspension.
30. The kit of claim 28 , wherein the nucleophilic groups are primary amino groups.
31. The kit of claim 28 , wherein the biomaterial is selected from the group consisting of collagen, glycosaminoglycans, and mixtures thereof.
32. The kit of claim 31 , wherein the biomaterial is comprised of collagen.
33. The kit of claim 32 , wherein the collagen is fibrillar collagen.
34. The kit of claim 32 , wherein the collagen is nonfibrillar collagen.
35. The kit of claim 34 , wherein the nonfibrillar collagen is comprised of chemically derivatized collagen selected from the group consisting of succinylated collagen and methylated collagen.
36. The kit of claim 35 , wherein the collagen is succinylated collagen.
37. The kit of claim 35 , wherein the collagen is methylated collagen.
38. The kit of claim 32 , wherein the collagen is selected from the group consisting of Type I collagen, Type II collagen, Type III collagen, Type IV collagen, and mixtures thereof.
39. The kit of claim 38 , wherein the collagen is Type I collagen.
40. The kit of claim 32 , wherein the collagen is telopeptide collagen.
41. The kit of claim 32 , wherein the collagen is atelopeptide collagen.
42. The kit of claim 32 , wherein the collagen is denatured collagen.
43. The kit of claim 31 , wherein the biomaterial is a glycosaminoglycan.
44. The kit of claim 43 , wherein the glycosaminoglycan is selected from the group consisting of hyaluronic acid, chondroitin sulfate A, chondroitin sulfate C, dermatan sulfate, keratan sulfate, keratosulfate, chitin, chitosan, heparin, and derivatives thereof.
45. The kit of claim 28 , wherein the hydrophobic crosslinking agent is comprised of a polyacid containing two, three or four carboxylic acid groups each esterified with a succinimidyl group.
46. The kit of claim 28 , wherein the hydrophobic crosslinking agent is comprised of a polyacid containing two, three or four carboxylic acid groups each esterified with a sulfosuccinimidyl group.
47. The kit of claim 45 , wherein the polyacid is selected from the group consisting of trimethylolpropane tricarboxylic acid, di(trimethylol propane) tetracarboxylic acid, heptanedioic acid, suberic acid and hexadecanedioic acid.
48. The kit of claim 46 , wherein the polyacid is selected from the group consisting of trimethylolpropane tricarboxylic acid, di(trimethylolpropane) tetracarboxylic acid, heptanedioic acid, suberic acid and hexadecanedioic acid.
49. The kit of claim 28 , wherein the hydrophobic crosslinking agent is selected from the group consisting of disuccinimidyl suberate, dithiobis(succinimidylpropionate, bis(sulfosuccinimidyl) suberate, bis(2-succinimidooxycarbonyloxy)ethyl sulfone, and 3,3-dithiobis(sulfosuccinimidylpropionate).
50. The kit of claim 49 , wherein the hydrophobic crosslinking agent is disuccinimidyl suberate.
51. The kit of claim 28 , wherein the hydrophilic crosslinking agent is comprised of an activated hydrophilic polymer.
52. The kit of claim 51 , wherein the activated hydrophilic polymer is selected from the group consisting of polyethylene glycol succinimidyl glutarate, polyethylene glycol succinimidyl, polyethylene glycol succinimidyl succinamide, and polyethylene glycol succinimidyl carbonate.
53. The kit of claim 52 , wherein the activated hydrophilic polymer is polyethylene glycol succinimidyl glutarate.
54. The kit of claim 52 , wherein the activated hydrophilic polymer is polyethylene glycol succinimidyl.