Porous calcium phosphate bone material

• US 8,147,860 B2
• Filed: 12/06/2005
• Issued: 04/03/2012
• Est. Priority Date: 12/06/2005
• Status: Active Grant

• Current Assignee: Etex Corporation (Zimmer Biomet Holdings, Inc.)
• Original Assignee: Etex Corporation (Zimmer Biomet Holdings, Inc.)
• Inventors: Rosenberg, Aron D., Bondre, Shrikar, Strunk, Michael, Gillès de Pélichy, Laurent D.
• Primary Examiner(s): Wax, Robert A
• Assistant Examiner(s): Sasan, Aradhana
• Application Number:
  US11/294,819
• Publication Number:
  US 20070128245A1
• Time in Patent Office: 2,310 Days
• Field of Search: 424/423, 424/466, 424/184.1, 424/649, 424/602, 514/12
• US Class Current: 424/423
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 38/1875 Bone morphogenic factor; Osteogenins; Osteogenic factor; Bone-inducing factor
• CPC Class Codes: A61K 9/0024 Solid, semi-solid or solidifying implants, which are implanted or injected in body tissue compositions for intravenous administration, normal injectable solutions or dispersions for, e.g. subcutaneous administration A61K9/0019; brain implants A61K9/0085; (coated) prostheses, catheters or stents A61L
• CPC Class Codes: A61L 2300/252 Polypeptides, proteins, e.g. glycoproteins, lipoproteins, cytokines
• CPC Class Codes: A61L 2300/256 Antibodies, e.g. immunoglobulins, vaccines
• CPC Class Codes: A61L 2300/406 Antibiotics
• CPC Class Codes: A61L 2300/414 Growth factors
• CPC Class Codes: A61L 2300/416 Anti-neoplastic or anti-proliferative or anti-restenosis or anti-angiogenic agents, e.g. paclitaxel, sirolimus
• CPC Class Codes: A61L 2300/434 of enzymes
• CPC Class Codes: A61L 2300/60 characterised by a special physical form
• CPC Class Codes: A61L 2430/02 for reconstruction of bones; weight-bearing implants
• CPC Class Codes: A61L 27/12 Phosphorus-containing materials, e.g. apatite
• CPC Class Codes: A61L 27/54 Biologically active materials, e.g. therapeutic substances A61L27/227 takes precedence
• CPC Class Codes: A61L 27/56 Porous materials, e.g. foams or sponges
• CPC Class Codes: A61P 19/00 Drugs for skeletal disorders

Abstract

Porous calcium phosphate implant compositions that approximate the chemical composition of natural bone mineral are provided. In addition to calcium phosphate, the compositions include an effervescent agent to promote the formation of interconnected pores and a cohesiveness agent to maintain the shape and hardness of the hardened composition. When introduced at an implant site, the calcium phosphate compositions are remodeled into bone. Methods for using the calcium phosphate compositions, e.g., to repair or replace bone, are also provided.

Claims

1. A self-setting, porous calcium phosphate composition comprising a calcium phosphate, an effervescent agent comprising carbonate and bicarbonate that are present in said composition at a molar ratio in the range of 1:

1 to 1;

9 and that react upon hydration of said composition to produce carbon dioxide as a gaseous component, and a biocompatible cohesiveness agent admixed with a physiologically acceptable fluid, wherein release of said gaseous component from said composition produces at least 5% porosity in said composition, and wherein, after hardening, said calcium phosphate composition has a compressive strength of 1 MPa or greater.

2. The composition of claim 1, wherein said calcium phosphate is selected from amorphous calcium phosphate, poorly crystalline calcium phosphate, hydroxyapatite, carbonated apatite (calcium-deficient hydroxyapatite), monocalcium phosphate, calcium metaphosphate, heptacalcium phosphate, dicalcium phosphate dihydrate, tetracalcium phosphate, octacalcium phosphate, calcium pyrophosphate, and tricalcium phosphate, or mixtures thereof.

3. The composition of claim 1, wherein said calcium phosphate is prepared using an amorphous calcium phosphate and a second calcium phosphate source.

4. The composition of claim 3, wherein said second calcium phosphate source is selected from poorly crystalline calcium phosphate, hydroxyapatite, carbonated apatite (calcium-deficient hydroxyapatite), monocalcium phosphate, calcium metaphosphate, heptacalcium phosphate, dicalcium phosphate dihydrate, tetracalcium phosphate, octacalcium phosphate, calcium pyrophosphate, and tricalcium phosphate.

5. The composition of claim 1, wherein said calcium phosphate has an average crystalline domain size of less than 100 nm.

6. The composition of claim 1, wherein pores of said composition have a pore size of between 1 and 1000 μ

m in diameter.

7. The composition of claim 6, wherein said pore size is between 10 and 100 μ

m in diameter.

8. The composition of claim 1, wherein release of said gaseous component produces at least 10% porosity.

9. The composition of claim 8, wherein release of said gaseous component produces at least 20% porosity.

10. The composition of claim 9, wherein release of said gaseous component produces at least 40% porosity.

11. The composition of claim 10, wherein release of said gaseous component produces at least 50% porosity.

12. The composition of claim 1, wherein release of said gaseous component produces a porosity in the range of 5% to 60%.

13. The composition of claim 1, wherein said carbonate and bicarbonate are present in said composition at a 1:

1 molar ratio.

14. The composition of claim 1, wherein said carbonate and bicarbonate are present in said composition at a 1:

9 molar ratio.

15. The composition of claim 1, wherein said effervescent agent is a solid material which liberates gas upon dissolution.

16. The composition of claim 15, wherein said solid material is combination of two or more components.

17. The composition of claim 1, wherein said effervescent agent produces a continuous matrix of interconnected porosity throughout said composition.

18. The composition of claim 1, wherein said effervescent agent is present in an amount in the range of about 1 to about 40 wt %.

19. The composition of claim 1, wherein said biocompatible cohesiveness agent comprises a polymer selected from polysaccharides, nucleic acids, carbohydrates, proteins, polypeptides, poly(α

-hydroxy acids), poly(lactones), poly(amino acids), poly(anhydrides), poly(orthoesters), poly(anhydride-co-imides), poly(orthocarbonates), poly(α

-hydroxy alkanoates), poly(dioxanones), poly(phosphoesters), poly(L-lactide) (PLLA), poly(D,L-lactide) (PDLLA), polyglycolide (PGA), poly(lactide-co-glycolide (PLGA), poly(L-lactide-co-D, L-lactide), poly(D,L-lactide-co-trimethylene carbonate), polyhydroxybutyrate (PHB), poly(ε

-caprolactone), poly(δ

-valerolactone), poly(γ

-butyrolactone), poly(caprolactone), polyacrylic acid, polycarboxylic acid, poly(allylamine hydrochloride), poly(diallyldimethylammonium chloride), poly(ethyleneimine), polypropylene fumarate, polyvinyl alcohol, polyvinylpyrrolidone, polyethylene, polymethylmethacrylate, carbon fibers, poly(ethylene glycol), poly(ethylene oxide), poly(vinyl alcohol), poly(vinylpyrrolidone), poly(ethyloxazoline), poly(ethylene oxide)-co-poly(propylene oxide) block copolymers, poly(ethylene terephthalate)polyamide, and copolymers thereof.

20. The composition of claim 1, wherein said biocompatible cohesiveness agent is selected from alginic acid, arabic gum, guar gum, xantham gum, gelatin, chitin, chitosan, chitosan acetate, chitosan lactate, chondroitin sulfate, N,O-carboxymethyl chitosan, a dextran, fibrin glue, glycerol, hyaluronic acid, sodium hyaluronate, a cellulose, a glucosamine, a proteoglycan, a starch, lactic acid, a pluronic, sodium glycerophosphate, collagen, glycogen, a keratin, silk, and mixtures thereof.

21. The composition of claim 20, wherein said cellulose is methylcellulose, carboxy methylcellulose, hydroxypropyl methylcellulose, or hydroxyethyl cellulose.

22. The composition of claim 20, wherein said dextran is α

-cyclodextrin, β

-cyclodextrin, γ

-cyclodextrin, or sodium dextran sulfate.

23. The composition of claim 20, wherein said starch is hydroxyethyl starch or starch soluble.

24. The composition of claim 1, wherein said biocompatible cohesiveness agent is present in an amount in the range of about 1 to about 20 wt %.

25. The composition of claim 24, wherein said biocompatible cohesiveness agent is present in an amount of less than about 20 wt %.

26. The composition of claim 25, wherein said biocompatible cohesiveness agent is present in an amount of less than about 10 wt %.

27. The composition of claim 26, wherein said biocompatible cohesiveness agent is present in an amount of less than about 5 wt %.

28. The composition of claim 27, wherein said biocompatible cohesiveness agent is present in an amount of less than about 1 wt %.

29. The composition of claim 1, wherein said composition further comprises a biologically active agent.

30. The composition of claim 29, wherein said biologically active agent is selected from an antibody, an antibiotic, a polynucleotide, a polypeptide, a protein, an anti-cancer agent, a growth factor, and a vaccine.

31. The composition of claim 30, wherein said protein is an osteogenic protein.

32. The composition of claim 31, wherein said osteogenic protein is selected from BMP-2, BMP-3, BMP-3b, BMP-4, BMP-5, BMP-6, BMP-7, BMP-8, BMP-9, BMP-10, BMP-11, BMP-12, BMP-13, BMP-14, BMP-15, BMP-16, BMP-17, and BMP-18.

33. The composition of claim 30, wherein said anti-cancer agent is selected from alkylating agents, platinum agents, antimetabolites, topoisomerase inhibitors, antitumor antibiotics, antimitotic agents, aromatase inhibitors, thymidylate synthase inhibitors, DNA antagonists, farnesyltransferase inhibitors, pump inhibitors, histone acetyltransferase inhibitors, metalloproteinase inhibitors, ribonucleoside reductase inhibitors, TNF alpha agonists, TNF alpha antagonists, endothelin A receptor antagonists, retinoic acid receptor agonists, immuno-modulators, hormonal agents, antihormonal agents, photodynamic agents, and tyrosine kinase inhibitors.

34. The composition of claim 29, wherein said biologically active agent is demineralized bone matrix (DBM).

35. The composition of claim 1, wherein said calcium phosphate has a calcium/phosphate (Ca/P) molar ratio of 1 to 1.67.

36. The composition of claim 35, wherein said calcium phosphate has a Ca/P molar ratio in the range of 1.3 to 1.65.

37. The composition of claim 36, wherein said calcium phosphate has a Ca/P molar ratio in the range of 1.4 to 1.6.

38. The composition of claim 37, wherein said calcium phosphate has a Ca/P molar ratio of 1.5.

39. The composition of claim 1, wherein said composition forms a self-hardening calcium phosphate paste when admixed with said physiologically acceptable liquid, wherein said paste hardens to form a poorly crystalline apatitic (PCA) calcium phosphate having an overall Ca/P molar ratio of less than 1.67.

40. The composition of claim 1, wherein said physiologically-acceptable fluid is selected from water, saline and a phosphate buffer.

41. The composition of claim 1, wherein, following hardening, said composition comprises a compressive strength of at least 2 MPa.

42. The composition of claim 1, wherein said composition comprises a compressive strength of between 1 MPa and 150 MPa.

43. The composition of claim 42, wherein said composition comprises a compressive strength of 10 MPa.

44. The composition of claim 1, wherein said composition hardens in less than 30 minutes at 37°

C.

45. The composition of claim 1, wherein said composition is suitable for use as a bone implant material.

46. A method of bone repair comprising administering to a subject in need thereof the self-setting, porous calcium phosphate composition of claim 1.