Claims for Patent: 6,949,251

Summary for Patent: 6,949,251

Title:	Porous .beta.-tricalcium phosphate granules for regeneration of bone tissue
Abstract:	A porous .beta.-tricalcium phosphate material for bone implantation is provided. The multiple pores in the porous TCP body are separate discrete voids and are not interconnected. The pore size diameter is in the range of 20-500 .mu.m, preferably 50-125 .mu.m. The porous .beta.-TCP material provides a carrier matrix for bioactive agents and can form a moldable putty composition upon the addition of a binder. Preferably, the bioactive agent is encapsulated in a biodegradable agent. The invention provides a kit and an implant device comprising the porous .beta.-TCP, and a bioactive agent and a binder. The invention also provides an implantable prosthetic device comprising a prosthetic implant having a surface region, a porous .beta.-TCP material disposed on the surface region and optionally comprising at least a bioactive agent or a binder. Methods of producing the porous .beta.-TCP material and inducing bone formation are also provided.
Inventor(s):	Dalal; Paresh S. (Shrewsbury, MA), Dimaano; Godofredo R. (Edison, NJ), Toth; Carol Ann (Sharon, MA), Kulkarni; Shailesh C. (Natick, MA)
Assignee:	Stryker Corporation (Kalamazoo, MI)
Application Number:	09/960,789
Patent Claims:	1. A composition comprising porous .beta.-tricalcium phosphate (.beta.-TCP) granules that have a particle size of 0.1-2 mm and that comprise a multiplicity of pores having a pore diameter size of 20-500 .mu.m and being single separate voids partitioned by walls and being not interconnected. 2. A composition comprising porous .beta.-TCP granules that have a particle size of 0.1-2 mm and that comprise a multiplicity of pores having a pore diameter size of 410-460 .mu.m and being single separate voids partitioned by walls and being not interconnected. 3. A composition comprising porous .beta.-TCP granules that have a particle size of 0.1-2 mm and that comprise a multiplicity of pores having a pore diameter size of 40-190 .mu.m and being single separate voids partitioned by walls and being not interconnected. 4. A composition comprising porous .beta.-TCP granules that have a particle size of 0.1-2 mm and that comprise a multiplicity of pores having a pore diameter size of 20-95 .mu.m and being single separate voids partitioned by walls and being not interconnected. 5. A composition comprising porous .beta.-TCP granules that have a particle size of 0.1-2 mm and that comprise a multiplicity of pores having a pore diameter size of 50-125 .mu.m and being single separate voids partitioned by walls and being not interconnected. 6. The composition of any one of claims 1 to 5, wherein said .beta.-TCP granules have a particle size of 0.5-1.7 mm. 7. The composition of any one of claims 1 to 5, wherein said .beta.-TCP granules have a particle size of 1-1.7 mm. 8. The composition of any one of claims 1 to 5, wherein said .beta.-TCP granules have a particle size of 0.5-1.0 mm. 9. The composition of any one of claims 1 to 5, wherein the total porosity of said .beta.-TCP granules is in the range of5-80%. 10. The composition of any one of claims 1 to 5, wherein the total porosity of said .beta.-TCP granules is in the range of 40-80%. 11. The composition of any one of claims 1 to 5, wherein the total porosity of said .beta.-TCP granules is in the range of 65-75%. 12. The composition of any one of claims 1 to 5, wherein the total porosity of said .beta.-TCP granules is 70%. 13. The composition of any one of claims 1 to 5, further comprising a bioactive agent. 14. The composition of claim 13, wherein the bioactive agent is a bone morphogenic protein. 15. The composition of claim 14, wherein the bone morphogenic protein is selected from the group consisting of OP-1, OP-2, OP-3, COP-1, COP-3, COP-4, COP-5, COP-7, COP-16, BMP-2, BMP-3, B-3b, BMP-4, BMP-5, BMP-6, BMP-9, BMP-10, BMP-11, BMP-12, BMP-13, BMP-14, BMP-15, BMP-16, BMP-17, BMP-18, GDF-1, GDF-2, GDF-3, GDF-5, GDF-6, GDF-7, GDF-8, GDF-9, GDF-10, GDF-11, GDF-12, MP121, dorsalin-1, DPP, Vg-1, Vgr-1, 60A protein, NODAL, UNIVIN, SCREW, ADMP, NEURAL, TGF-.beta. and conservative amino acid sequence variants thereof having osteogenic activity. 16. The composition of claim 13, wherein the bioactive agent is an osteogenic protein comprising an amino acid sequence having at least 70% homology with the C-terminal 102-106 amino acids of human OP-1. 17. The composition of claim 14 further comprising a morphogenic protein stimulatory factor. 18. The composition of claim 17, wherein the morphogenic protein stimulatory factor is selected from the group consisting of insulin-like growth factor I (IGF-I), estradiol, fibroblast growth factor (FGF), growth hormone (GH), growth and differentiation factor (GDF), hydrocortisone (HC), insulin, progesterone, parathyroid hormone (PTH), vitamin D, retinoic acid and IL-6. 19. The composition of claim 13, wherein the bioactive agent is a nucleic acid molecule comprising a sequence encoding a bone morphogenic protein. 20. The composition of claim 13, wherein the bioactive agent is encapsulated in a biodegradable agent. 21. The composition of claim 20, wherein the biodegradable agent is selected from the group consisting of ethylenevinylacetate, natural and synthetic collagen, poly(glaxanone), poly(phosphazenes), polyglactin, polyglactic acid, polyaldonic acid, polyacrylic acids, polyalkanoates, polyorthoesters, poly(L-lactide) (PLLA), poly(D,L-lactide) (PDLLA), polyglycolide (PGA), poly(lactide-co-glycolide) (PLGA), poly(.zeta.-caprolactone), poly(trimethylene carbonate), poly(p-doxanone), poly(.zeta.-caprolactone-co-glycolide), poly(glycolide-co-trimethylene carbonate) poly(D,L-lactide-co-trimethylene carbonate), polyarylates, polyhydroxybutyrate (PHB), polyanhydrides, poly(anhydride-co-imide) and co-polymers thereof, polymers of amino acids, propylene-co-fumarates, a polymer of one or more .alpha.-hydroxy carboxylic acid monomers, bioactive glass compositions, admixtures thereof and any derivatives and modifications thereof. 22. The composition of claim 21, wherein the PLGA has a molecular weight of 5 kD to 500 kD. 23. The composition of claim 21, wherein the PLGA has a molecular weight of 10 kD to 30 kD. 24. The composition of claim 13, wherein the bioactive agent is an allograft or autograft. 25. The composition of claim 5, wherein the porous .beta.-TCP granules have a particle size of 0.5-1 mm. 26. The composition of claim 25, wherein the composition further comprises carboxy methylcellulose sodium as a binder, and is moldable putty. 27. A kit comprising the composition of claim 25, and carboxy methylcellulose sodium. 28. A kit comprising: a) the composition of any one of claims 1 to 5; and b) a bioactive agent. 29. The kit of claim 28, wherein the bioactive agent is a bone morphogenic protein. 30. The kit of claim 29, wherein the bone morphogenic protein is selected from the group consisting of OP-1, OP-2, OP-3, COP-1, COP-3, COP-4, COP-5, COP-7, COP-16, BMP-2, BMP-3, BMP-3b, BMP-4, BMP-5, BMP-6, BMP-9, BMP-10, BMP-11, BMP-12, BMP-13, BMP-14, BMP-15, BMP-16, MP-17, BMP-18, GDF-1, GDF-2, GDF-3, GDF-5, GDF-6, GDF-7, GDF-8, GDF-9, G-10, GDF-11, GDF-12, MP121, dorsalin-1, DPP, Vg-1, Vgr-1, 60A protein, NODAL, UNIVIN, SCREW, ADMP, NEURAL, TGF-.beta. and conservative amino acid sequence variants thereof having osteogenic activity. 31. The kit of claim 28, wherein the bioactive agent is an osteogenic protein comprising an amino acid sequence having at least 70% homology with the C-terminal 102-106 amino acids of human OP-1. 32. The kit of claim 29 further comprising a morphogenic protein stimulatory factor. 33. The kit of claim 32, wherein the morphogenic protein stimulatory factor is selected from the group consisting of insulin-like growth factor I (IGF-I), estradiol, fibroblast growth factor (FGF), growth hormone (GH), growth and differentiation factor (GDF), hydrocortisone (HC), insulin, progesterone, parathyroid hormone (PTH), vitamin D, retinoic acid and IL-6. 34. A kit comprising: a) the composition of any one of claims 1 to 5; and b) a binder. 35. The kit of claim 34, wherein the binder is selected from the group consisting of sodium alginate, hyaluronic acid, sodium hyaluronate, gelatin, collagen, peptides, mucin, chrondroitin sulfate, chitosan, poloxamer, glycosaminoglycan, polysaccharide, polyethylene glycol, methylcellulose, carboxy methylcellulose, carboxy methylcellulose sodium, carboxy methylcellulose calcium, hydroxypropyl methylcellulose, hydroxybutyl methylcellulose, hydroxyethyl methylcellulose, hydroxyethylcellulose, methylhydroxyethyl cellulose, hydroxyethyl cellulose, polylactic acid, polyglycolic acid, co-polymers of polylactic acid and polyglycolic acid, polyhydroxybutyric acid, polymalic acid, polyglutamic acid, polylactone, mannitol, white petrolatum, mannitol/dextran combinations, mannitol/white petrolatum combinations, sesame oil, fibrin glue and admixtures thereof. 36. The kit of claim 35, wherein the fibrin glue is formed from human fibrinogen and thrombin. 37. A moldable putty composition comprising the composition of any one of claims 1 to 5 and a binder. 38. The moldable putty composition of claim 37, wherein the binder is selected from the group consisting of sodium alginate, hyaluronic acid, sodium hyaluronate, gelatin, collagen, peptides, mucin, chrondroitin sulfate, chitosan, poloxamer, glycosaminoglycan, polysaccharide, polyethylene glycol, methylcellulose, carboxy methylcellulose, carboxy methylcellulose sodium, carboxy methylcellulose calcium, hydroxypropyl methylcellulose, hydroxybutyl methylcellulose, hydroxyethyl methylcellulose, hydroxyethylcellulose, methylhydroxyethyl cellulose, hydroxyethyl cellulose, polylactic acid, polyglycolic acid, co-polymers of polylactic acid and polyglycolic acid, polyhydroxybutyric acid, polymalic acid, polyglutamic acid, polylactone, mannitol, white petrolatum, mannitol/dextran combinations, mannitol/white petrolatum combinations, sesame oil, fibrin glue and admixtures thereof. 39. The moldable putty composition of claim 38, wherein the fibrin glue is formed from human fibrinogen and thrombin. 40. The moldable putty composition of claim 37 further comprising a bioactive agent. 41. An implantable prosthetic device comprising: a) a prosthetic implant having a surface region implantable adjacent to a target tissue; and b) the composition of any one of claims 1 to 5 disposed on the surface region. 42. The prosthetic device of claim 41, wherein the composition further comprises a bioactive agent. 43. The prosthetic device of claim 42, wherein the bioactive agent is a bone morphogenic protein. 44. The prosthetic device of claim 43, wherein the bone morphogenic protein is selected from the group consisting of OP-1, OP-2, OP-3, COP-1, COP-3, COP-4, COP-5, COP-7, COP-16, BMP-2, BMP-3, BMP-3b, MP-4, BMP-5, BMP-6, BMP-9, BMP-10, BMP-11, BMP-12, BMP-13, BMP-14, B-15, BMP-16, BMP-17, BMP-18, GDF-1, GDF-2, GDF-3, GDF-5, GDF-6, GDF-7, GDF-8, GDF-9, GDF-10, GDF-11, GDF-12, MP121, dorsalin-1, DPP, Vg-1, Vgr-1, 6 A protein, NODAL, UNIVIN, SCREW, ADMP, NEURAL, TGF-.beta. and conservative amino acid sequence variants thereof having osteogenic activity. 45. The prosthetic device of claim 42, wherein the bioactive agent is an osteogenic protein comprising an amino acid sequence having at least 70% homology with the C-terminal 102-106 amino acids of human OP-1. 46. The prosthetic device of claim 43 further comprising a morphogenic protein stimulatory factor. 47. The prosthetic device of claim 46, wherein the morphogenic protein stimulatory factor is selected from the group consisting of insulin-like growth factor I (IGF-I), estradiol, fibroblast growth factor (FGF), growth hormone (GH), growth and differentiation factor (GDF), hydrocortisone (HC), insulin, progesterone, parathyroid hormone (PTH), vitamin D, retinoic acid an IL-6. 48. The prosthetic device of claim 42, wherein the bioactive agent is a nucleic acid molecule comprising a sequence encoding a bone morphogenic protein. 49. The prosthetic device of claim 42, wherein the bioactive agent is encapsulated in a biodegradable agent. 50. The prosthetic device of claim 49, wherein the biodegradable agent is selected from the group consisting of ethylenevinylacetate, natural and synthetic collagen, poly(glaxanone), poly(phosphazenes), polyglactin, polyglactic acid, polyaldonic acid, polyacrylic acids, polyalkanoates, polyorthoesters, poly(L-lactide) (PLLA), poly(D,L-lactide) (PDLLA), polyglycolide (PGA), poly(lactide-co-glycolide) (PLGA), poly(.zeta.-caprolactone), poly(trimethylene carbonate), poly(p-dioxanone), poly(.zeta.-caprolactone-co-glycolide), poly(glycolide-co-trimethylene carbonate), poly(D,L-lactide-co-trimethylene carbonate), polyarylates, polyhydroxybutyrate (PHB), polyanhydrides, poly(anhydride-co-imide) and co-polymers thereof; polymers of amino acids, propylene-co-fumarates, a polymer of one or more .alpha.-hydroxy carboxylic acid monomers, bioactive glass compositions, admixtures thereof and any derivatives and modifications thereof. 51. The prosthetic device of claim 50, wherein the PLGA has a molecular weight of 5 kD to 500 kD. 52. The prosthetic device of claim 50, wherein the PLGA has a molecular weight of 10 kD to 30 kD. 53. The prosthetic device of claim 41, wherein the device is selected from the group consisting of a hip device, a fusion cage and a maxillofacial device. 54. The prosthetic device of claim 41, wherein the composition further comprises a binder. 55. The prosthetic device of claim 54, wherein the binder is selected from the group consisting of sodium alginate, hyaluronic acid sodium hyaluronate, gelatin, collagen, peptides, mucin, chrondroitin sulfate, chitosan, poloxamer, glycosaminoglycan, polysaccharide, polyethylene glycol, methylcellulose, carboxy methylcellulose, carboxy methylcellulose sodium, carboxy methylcellulose calcium, hydroxypropyl methylcellulose, hydroxybutyl methylcellulose, hydroxyethyl methylcellulose, hydroxyethylcellulose, methylhydroxyethyl cellulose, hydroxyethyl cellulose, polylactic acid, polyglycolic acid, co-polymers of polylactic acid and polyglycolic acid, polyhydroxybutyric acid, polymalic acid, polyglutamic acid, polylactone, mannitol, white petrolatum, mannitol/dextran combinations, mannitol/white petrolatum combinations, sesame oil, fibrin glue and admixtures thereof. 56. The prosthetic device of claim 55, wherein the fibrin glue is formed from human fibrinogen and thrombin.

Details for Patent 6,949,251

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Nps Pharmaceuticals, Inc.	NATPARA	parathyroid hormone	For Injection	125511	01/23/2015		2021-03-02