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 composition
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.
대표청구항▼
What is claimed is: 1. A composition for injectable delivery of osteogenic proteins comprising an osteogenic protein and a poorly crystalline apatitic calcium phosphate, wherein the composition is in the form of a solid rod suitable for intraosseous injection in solid state, and wherein the osteoge
What is claimed is: 1. A composition for injectable delivery of osteogenic proteins comprising an osteogenic protein and a poorly crystalline apatitic calcium phosphate, wherein the composition is in the form of a solid rod suitable for intraosseous injection in solid state, and wherein the osteogenic protein is present in an amount ranging from about 15% to about 40% by weight of the composition. 2. The composition of claim 1, wherein the osteogenic protein is selected from the group consisting of members of the bone morphogenetic protein family. 3. The composition of claim 2, wherein the osteogenic protein is selected from the group consisting of BMP 2, BMP 4, BMP 5, BMP 6, BMP 7, BMP 10, BMP 12 and BMP 13. 4. The composition of claim 3, wherein the osteogenic protein is BMP 2. 5. A method for preparing a composition of claim 1 comprising the steps of: (a) mixing a dry form of the osteogenic protein with a dry form of the poorly crystalline apatitic calcium phosphate to produce a dry mixture; (b) reconstituting the dry mixture by adding an aqueous buffer to form a paste; (c) molding the paste to form a rod shaped composition; and (d) drying the rod shaped composition of step (c) to form a rod-shaped composition for injectable delivery of osteogenic proteins, wherein the osteogenic protein is present in an amount ranging from about 15% to about 40% by weight of the composition. 6. The method of claim 5, wherein the osteogenic protein is selected from the group consisting of members of the bone morphogenetic protein family. 7. The method of claim 6, wherein the osteogenic protein is selected from the group consisting of BMP 2, BMP 4, BMP 5, BMP 6, BMP 7, BMP 10, BMP 12 and BMP 13. 8. The method of claim 7, wherein the osteogenic protein is BMP 2. 9. The method of claim 5, wherein the aqueous buffer is selected from the group consisting of phosphate-buffered saline, saline, glycine-based buffers and combinations thereof. 10. The method of claim 5, wherein the ratio of aqueous buffer to dry mixture ranges from about 0.5:1 to about 2:1. 11. The method of claim 5, wherein the molding is accomplished using a method selected from the group consisting of molding, extruding, pressing, boring and combinations thereof. 12. The method of claim 5, further comprising a step of cutting the rod-shaped composition before or after step (d). 13. The method of claim 5, wherein the length of said rod-shaped composition is between about 1.0 mm and 5.0 cm. 14. A method of treating a mammal having a bone defect comprising administering to the site of the bone defect an amount of the composition for injectable delivery of osteogenic proteins of claim 1, wherein the amount is effective to treat the bone defect. 15. The method of claim 14, wherein the bone defect is osteoporotic bone. 16. A method of treating a mammal having a bone defect comprising the steps of: (a) administering to the site of the bone defect an amount of the composition for injectable delivery of osteogenic proteins of claim 6, wherein the amount is effective to treat the bone defect; and (b) administering to the site of the bone defect an effective amount of a bone resorption inhibitor. 17. The method of claim 16, wherein step (a) is performed prior to step (b). 18. The method of claim 16, wherein step (b) is performed prior to step (a). 19. The method of claim 16, wherein step (a) and step (b) are performed simultaneously. 20. A composition for injectable delivery of osteogenic proteins comprising an osteogenic protein and a poorly crystalline apatitic calcium phosphate, wherein the composition is in the form of a solid rod suitable for intraosseous injection in solid state, further comprising a bone resorption inhibitor. 21. The composition of claim 20, wherein the bone resorption inhibitor is a bisphosphonate. 22. The composition of claim 21, wherein the bisphosphonate is selected from the group consisting of alendronate, cimadronate, clodronate, EB 1053, etidronates, ibandronate, neridronate, olpadronate, pamidronate, risedronate, tiludronate, YH 529, and zoledronate. 23. A method for preparing a composition of claim 20 comprising the steps of: (a) mixing a dry form of the osteogenic protein with a dry form of the poorly crystalline apatitic calcium phosphate to produce a dry mixture; (b) reconstituting the dry mixture by adding an aqueous buffer to form a paste; (c) molding the paste to form a rod shaped composition; and (d) drying the rod shaped composition of step (c) to form a rod-shaped composition for injectable delivery of osteogenic proteins, wherein the composition further comprises a bone resorption inhibitor and wherein a dry form of the bone resorption inhibitor is mixed in the dry mixture. 24. The method of claim 23, wherein the bone resorption inhibitor is a bisphosphonate. 25. The method of claim 24, wherein the bisphosphonate is selected from the group consisting of alendronate, cimadronate, clodronate, EB 1053, etidronates, ibandronate, neridronate, olpadronate, pamidronate, risedronate, tiludronate, YH 529, and zoledronate. 26. A method of treating a mammal having a bone defect comprising administering to the site of the bone defect an amount of the composition for injectable delivery of osteogenic proteins of claim 20, wherein the amount is effective to treat the bone defect. 27. A composition for injectable delivery of osteogenic proteins comprising an osteogenic protein and a poorly crystalline apatitic calcium phosphate, wherein the composition is in the form of a solid rod suitable for intraosseous injection in solid state, further comprising an additive selected from the group consisting of carboxymethylcellulose, hydroxypropylmethylcellulose, methylcellulose, polylactide, polyethylene glycol, polyvinylpyrrolidone, polyoxyethylene oxide, carboxyvinyl polymer, polyvinyl alcohol, dextran sulfate and combinations thereof. 28. The composition of claim 27, wherein the additive is present in an amount ranging from about 1% to about 90% by weight of the composition. 29. The composition of claim 28, wherein the additive is present in an amount ranging from about 20% to about 40% by weight of the composition.
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