Injectable calcium phosphate solid rods and pastes for delivery of osteogenic proteins
View Patent ↗Osteogenic proteins are delivered via an injectable solid rod or hardenable paste. The formulation comprises a calcium phosphate material, an osteogenic protein, and optional additives and active ingredients such as a bone resorption inhibitor. Methods of making injectable pharmaceutical compositions and methods of using the osteogenic compositions to treat bone defects are also disclosed.
1. A composition for injectable delivery of osteogenic proteins, comprising:
at least one osteogenic protein in an amount ranging from 0.01% to 2% by weight of the composition, and
at least one calcium phosphate material chosen from amorphous apatitic calcium phosphate and poorly crystalline apatitic calcium phosphate,
wherein said composition is in the form of a hardenable paste that hardens into a solid form at 37° C.
2. The composition of claim 1 , wherein the at least one osteogenic protein is chosen from members of the bone morphogenetic protein (BMP) family.
3. The composition of claim 1 , wherein the at least one osteogenic protein is chosen from BMP-2, BMP-4, BMP-5, BMP-6, BMP-7, BMP-8, BMP-9, BMP-10, BMP-12, BMP-13, and MP52.
4. The composition of claim 1 , wherein the at least one osteogenic protein comprises BMP-2.
5. The composition of claim 1 , wherein the at least one osteogenic protein is heterodimeric.
6. The composition of claim 5 , wherein the at least one heterodimeric osteogenic protein comprises BMP-2 and BMP-6.
7. The composition of claim 1 , wherein the at least one osteogenic protein is present in an amount ranging from 0.03% to 1% by weight of the composition.
8. The composition of claim 1 , further comprising at least one bone resorption inhibitor.
9. The composition of claim 8 , wherein the at least one bone resorption inhibitor comprises a bisphosphonate.
10. The composition of claim 9 , wherein the at least one bisphosphonate is chosen from alendronate, cimadronate, clodronate, EB 1053, etidronates, ibandronate, neridronate, olpadronate, pamidronate, risedronate, tiludronate, YH 529, zoledronate, and pharmaceutically acceptable salts, esters, and acids.
11. The composition of claim 1 , wherein the at least one calcium phosphate material comprises poorly crystalline apatitic calcium phosphate.
12. The composition of claim 11 , wherein the poorly crystalline apatitic calcium phosphate has a calcium-to-phosphate ratio of less than 1.5.
13. The composition of claim 12 , wherein the poorly crystalline apatitic calcium phosphate has a calcium-to-phosphate ratio of 1.4.
14. The composition of claim 1 , wherein the at least one calcium phosphate material chosen from amorphous apatitic calcium phosphate and poorly crystalline apatitic calcium phosphate is present in an amount ranging from 30% to 70% by weight of the composition.
15. The composition of claim 14 , wherein the at least one calcium phosphate material chosen from amorphous apatitic calcium phosphate and poorly crystalline apatitic calcium phosphate is present in an amount ranging from 45% to 55% by weight of the composition.
16. A method of treating a mammal having a bone defect, comprising administering to the site of the bone defect an effective amount of the composition for injectable delivery of osteogenic proteins of claim 1 .
17. A method of treating a mammal having a bone defect, comprising the steps of:
(a) administering to the site of the bone defect an effective amount of the composition for injectable delivery of osteogenic proteins of claim 1 ; and
(b) administering to the site of the bone defect an effective amount of a bone resorption inhibitor.
18. The method of claim 17 , wherein step (a) is performed prior to step (b).
19. The method of claim 17 , wherein step (b) is performed prior to step (a).
20. The method of claim 17 , wherein step (a) and step (b) are performed simultaneously.
21. A method for preparing a composition for injectable delivery of osteogenic proteins comprising mixing a dry form of at least one calcium phosphate material chosen from amorphous apatitic calcium phosphate and poorly crystalline apatitic calcium phosphate with an aqueous buffer containing at least one osteogenic protein to form a paste, wherein said paste hardens into a solid form at 37° C. and wherein the at least one osteogenic protein is present in the paste in an amount ranging from 0.01% to 2% by weight of the paste.
22. The method of claim 21 , wherein the at least one osteogenic protein is chosen from members of the bone morphogenetic protein family.
23. The method of claim 21 , wherein the at least one osteogenic protein is chosen from BMP-2, BMP-4, BMP-5, BMP-6, BMP-7, BMP8, BMP-9, BMP-10, BMP-12, BMP-13, and MP52.
24. The method of claim 21 , wherein the at least one osteogenic protein comprises BMP-2.
25. The method of claim 21 , wherein the at least one osteogenic protein is heterodimeric.
26. The method of claim 25 , wherein the at least one heterodimeric osteogenic protein comprises BMP-2 and BMP-6.
27. The method of claim 21 , wherein the at least one osteogenic protein is present in the paste in an amount ranging from 0.03% to 1% by weight of the paste.
28. The method of claim 21 , wherein the composition comprises at least one bone resorption inhibitor and wherein a dry form of the at least one bone resorption inhibitor is mixed in the paste.
29. The method of claim 28 , wherein the at least one bone resorption inhibitor is a bisphosphonate.
30. The method of claim 29 , wherein the bisphosphonate is chosen from alendronate, cimadronate, clodronate, EB 1053 etidronates, ibandronate, neridronate, olpadronate, pamidronate, risedronate, tiludronate, YH 529, zoledronate, and pharmaceutically acceptable salts, esters, and acids.
31. The method of claim 21 , wherein the at least one calcium phosphate material comprises a poorly crystalline apatitic calcium phosphate.
32. The method of claim 31 , wherein the at least one poorly crystalline apatitic calcium phosphate has a calcium-to-phosphate ratio of less than 1.5.
33. The method of claim 32 , wherein the at least one poorly crystalline apatitic calcium phosphate has a calcium-to-phosphate ratio of 1.4.
34. The method of claim 21 , wherein an amount of the at least one calcium phosphate material chosen from amorphous apatitic calcium phosphate and poorly crystalline apatitic calcium phosphate ranging from 30% to 70% by weight of the composition is mixed with the aqueous buffer.
35. The method of claim 34 , wherein an amount of the at least one calcium phosphate material ranging from 45% to 55% by weight of the composition is mixed with the aqueous buffer.
36. The method of claim 21 , wherein the aqueous buffer is chosen from phosphate-buffered saline, saline, and glycine-based buffers.
37. The method of claim 21 , wherein the ratio of the aqueous buffer to the at least one calcium phosphate material ranges from 0.5:1 to 2:1.