Injectable calcium phosphate solid rods and pastes for delivery of osteogenic proteins

• US 20050089579A1
• Filed: 09/10/2004
• Published: 04/28/2005
• Est. Priority Date: 09/12/2003
• Status: Active Grant

• Current Assignee: Wyeth (Pfizer Inc.), Etex Corporation (Zimmer Biomet Holdings, Inc.)
• Original Assignee: Wyeth (Pfizer Inc.), Etex Corporation (Zimmer Biomet Holdings, Inc.)
• Inventors: Kim, Hyun, Li, Rebecca, Seeherman, Howard
• Granted Patent: US 7,771,755 B2
• Time in Patent Office: Days
• US Class Current: 424/602
• CPC Class Codes: A61K 38/1875 Bone morphogenic factor; Osteogenins; Osteogenic factor; Bone-inducing factor
• CPC Class Codes: A61L 2400/06 Flowable or injectable implant compositions
• CPC Class Codes: A61L 27/12 Phosphorus-containing materials, e.g. apatite
• CPC Class Codes: A61L 27/227 Other specific proteins or polypeptides not covered by A61L27/222, A61L27/225 or A61L27/24
• CPC Class Codes: A61L 27/425 of phosphorus containing material, e.g. apatite
• CPC Class Codes: A61L 27/46 with phosphorus-containing inorganic fillers
• CPC Class Codes: A61L 27/50 Materials characterised by their function or physical properties , e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
• CPC Class Codes: A61P 19/00 Drugs for skeletal disorders
• CPC Class Codes: A61P 19/08 for bone diseases, e.g. rachitism, Paget's disease
• CPC Class Codes: A61P 19/10 for osteoporosis

Abstract

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.

Claims

1. A composition for injectable delivery of osteogenic proteins comprising:

an osteogenic protein; and

a calcium phosphate material,

wherein said composition is in the form of a solid rod.

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. The composition of claim 1, wherein the osteogenic protein is present in an amount ranging from about 1% to about 90% by weight of the composition.

6. The composition of claim 5, wherein the osteogenic protein is present in an amount ranging from about 15% to about 40% by weight of the composition.

7. The composition of claim 1, further comprising a bone resorption inhibitor.

8. The composition of claim 7, wherein the bone resorption inhibitor is a bisphosphonate.

9. The composition of claim 8, wherein the bisphosphonate is selected from the group consisting of alendronate, cimadronate, clodronate, EB 1053, etidronates, ibandronate, neridronate, olpadronate, pamidronate, risedronate, tiludronate, YH 529, zoledronate, and pharmaceutically acceptable salts, esters, acids, and mixtures thereof.

10. The composition of claim 1, wherein the calcium phosphate material comprises a material selected from the group consisting of amorphous apatitic calcium phosphate, poorly crystalline apatitic calcium phosphate, hydroxyapatite, tricalcium phosphate, fluorapatite and combinations thereof.

11. The composition of claim 10, wherein the 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:

1.5.

13. The composition of claim 12, wherein the poorly crystalline apatitic calcium phosphate has a calcium-to-phosphate ratio of about 1:

1.4.

14. The composition of claim 1, wherein the calcium phosphate material is present in an amount ranging from about 10% to about 99% by weight of the composition.

15. The composition of claim 14, wherein the calcium phosphate material is present in an amount ranging from about 40% to about 60% by weight of the composition.

16. The composition of claim 1 further comprising an additive selected from the group consisting of pharmaceutically acceptable salts, polysaccharides, peptides, proteins, amino acids, synthetic polymers, natural polymers, surfactants, and combinations thereof.

17. The composition of claim 16, wherein the additive is selected from the group consisting of carboxymethylcellulose, hydroxypropylmethylcellulose, methylcellulose, polylactide, polyethylene glycol, polyvinylpyrrolidone, polyoxyethylene oxide, carboxyvinyl polymer, polyvinyl alcohol, dextran sulfate and combinations thereof.

18. The composition of claim 16, wherein the additive is present in an amount ranging from about 1% to about 90% by weight of the composition.

19. The composition of claim 18, wherein the additive is present in an amount ranging from about 20% to about 40% by weight of the composition.

20. The composition of claim 1 further comprising a bone resorption inhibitor and an additive selected from the group consisting of pharmaceutically acceptable salts, polysaccharides, peptides, proteins, amino acids, synthetic polymers, natural polymers, surfactants, and combinations thereof.

21. The composition of claim 1, wherein said rod is cylindrical and a diameter of said cylindrical rod is between about 0.1 mm and 3.0 mm.

22. The composition of claim 1, wherein the length of said rod is between about 1.0 mm and 5.0 cm.

91. 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.

92. The method of claim 91, wherein the bone defect is osteoporotic bone.

93. 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.

94. The method of claim 93, wherein step (a) is performed prior to step (b).

95. The method of claim 93, wherein step (b) is performed prior to step (a).

96. The method of claim 93, wherein step (a) and step (b) are performed simultaneously.

23. A composition for injectable delivery of osteogenic proteins comprising:

an osteogenic protein; and

a calcium phosphate material,

wherein said composition is in the form of a hardenable paste.

24. The composition of claim 23, wherein the osteogenic protein is selected from the group consisting of members of the bone morphogenetic protein family.

25. The composition of claim 24, 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.

26. The composition of claim 25, wherein the osteogenic protein is BMP-2.

27. The composition of claim 23, wherein the osteogenic protein is present in an amount ranging from about 0.01% to about 2% by weight of the composition.

28. The composition of claim 27, wherein the osteogenic protein is present in an amount ranging from about 0.03% to about 1% by weight of the composition.

29. The composition of claim 23, further comprising a bone resorption inhibitor.

30. The composition of claim 29, wherein the bone resorption inhibitor is a bisphosphonate.

31. The composition of claim 30, wherein the bisphosphonate is selected from the group consisting of alendronate, cimadronate, clodronate, EB 1053, etidronates, ibandronate, neridronate, olpadronate, pamidronate, risedronate, tiludronate, YH 529, zoledronate, and pharmaceutically acceptable salts, esters, acids, and mixtures thereof.

32. The composition of claim 23, wherein the calcium phosphate material comprises a material selected from the group consisting of amorphous apatitic calcium phosphate, poorly crystalline apatitic calcium phosphate, hydroxyapatite, tricalcium phosphate, fluorapatite and combinations thereof.

33. The composition of claim 32, wherein the calcium phosphate material comprises poorly crystalline apatitic calcium phosphate.

34. The composition of claim 33, wherein the poorly crystalline apatitic calcium phosphate has a calcium-to-phosphate ratio of less than 1:

1.5.

35. The composition of claim 34, wherein the poorly crystalline apatitic calcium phosphate has a calcium-to-phosphate ratio of about 1:

1.4.

36. The composition of claim 23, wherein the calcium phosphate material is present in an amount ranging from about 30% to about 70% by weight of the composition.

37. The composition of claim 36, wherein the calcium phosphate material is present in an amount ranging from about 45% to about 55% by weight of the composition.

38. The composition of claim 23 further comprising an additive selected from the group consisting of pharmaceutically acceptable salts, polysaccharides, peptides, proteins, amino acids, synthetic polymers, natural polymers, surfactants, and combinations thereof.

39. The composition of claim 38, wherein the additive is selected from the group consisting of carboxymethylcellulose, hydroxypropylmethylcellulose, methylcellulose, polylactide, polyethylene glycol, polyvinylpyrrolidone, polyoxyethylene oxide, carboxyvinyl polymer, polyvinyl alcohol, dextran sulfate and combinations thereof.

40. The composition of claim 38, wherein the additive is present in an amount ranging from about 1% to about 90% by weight of the composition.

41. The composition of claim 40, wherein the additive is present in an amount ranging from about 10% to about 20% by weight of the composition.

42. The composition of claim 23 further comprising a bone resorption inhibitor and an additive selected from the group consisting of pharmaceutically acceptable salts, polysaccharides, peptides, proteins, amino acids, synthetic polymers, natural polymers, surfactants, and combinations thereof.

97. 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 23.

98. 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 23;

and

(b) administering to the site of the bone defect an effective amount of a bone resorption inhibitor.

99. The method of claim 98, wherein step (a) is performed prior to step (b).

100. The method of claim 98, wherein step (b) is performed prior to step (a).

101. The method of claim 98, wherein step (a) and step (b) are performed simultaneously.

43. A method for preparing a composition for injectable delivery of osteogenic proteins, said composition comprising an osteogenic protein and a calcium phosphate material, comprising the steps of:

(a) mixing a dry form of the osteogenic protein with a dry form of the calcium phosphate material 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.

44. The method of claim 43, wherein the osteogenic protein is selected from the group consisting of members of the bone morphogenetic protein family.

45. The method of claim 44, 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.

46. The method of claim 45, wherein the osteogenic protein is BMP-2.

47. The method of claim 43, wherein an amount of osteogenic protein ranging from about 1% to about 90% by weight of the composition is mixed with the calcium phosphate carrier.

48. The method of claim 47, wherein an amount of osteogenic protein ranging from about 15% to about 40% by weight of the composition is mixed with the calcium phosphate carrier.

49. The method of claim 43, 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.

50. The method of claim 49, wherein the bone resorption inhibitor is a bisphosphonate.

51. The method of claim 50, wherein the bisphosphonate is selected from the group consisting of alendronate, cimadronate, clodronate, EB 1053, etidronates, ibandronate, neridronate, olpadronate, pamidronate, risedronate, tiludronate, YH 529, zoledronate, and pharmaceutically acceptable salts, esters, acids, and mixtures thereof.

52. The method of claim 43, wherein the calcium phosphate material comprises a material selected from the group consisting of amorphous apatitic calcium phosphate, poorly crystalline apatitic calcium phosphate, hydroxyapatite, tricalcium phosphate, fluorapatite and combinations thereof.

53. The method of claim 52, wherein the calcium phosphate material comprises a poorly crystalline apatitic calcium phosphate.

54. The method of claim 53, wherein the poorly crystalline apatitic calcium phosphate has a calcium-to-phosphate ratio of less than 1:

1.5.

55. The method of claim 54, wherein the poorly crystalline apatitic calcium phosphate has a calcium-to-phosphate ratio of about 1:

1.4.

56. The method of claim 43, wherein an amount of calcium phosphate material ranging from about 10% to about 99% by weight of the composition is mixed with the osteogenic protein.

57. The method of claim 56, wherein an amount of calcium phosphate material ranging from about 40% to about 60% by weight of the composition is mixed with the osteogenic protein.

58. The method of claim 43, wherein the composition further comprises an additive selected from the group consisting of pharmaceutically acceptable salts, polysaccharides, peptides, proteins, amino acids, synthetic polymers, natural polymers, surfactants, and combinations thereof and wherein a dry form of the additive is mixed in the dry mixture.

59. The method of claim 58, wherein the additive is selected from the group consisting of carboxymethylcellulose, hydroxypropylmethylcellulose, methylcellulose, polylactide, polyethylene glycol, polyvinylpyrrolidone, polyoxyethylene oxide, carboxyvinyl polymer, polyvinyl alcohol, dextran sulfate and combinations thereof.

60. The method of claim 58, wherein an amount of additive ranging from about 1% to about 90% by weight of the composition is mixed in the dry mixture.

61. The method of claim 60, wherein an amount of additive ranging from about 20% to about 40% by weight of the composition is mixed in the dry mixture.

62. The method of claim 43, wherein the composition further comprises a bone resorption inhibitor and an additive selected from the group consisting of pharmaceutically acceptable salts, polysaccharides, peptides, proteins, amino acids, synthetic polymers, natural polymers, surfactants, and combinations thereof.

63. The method of claim 43, wherein the aqueous buffer is selected from the group consisting of phosphate-buffered saline, saline, glycine-based buffers and combinations thereof.

64. The method of claim 43, wherein the ratio of aqueous buffer to dry mixture ranges from about 0.5:

1 to about 2;

1.

65. The method of claim 43, wherein the molding is accomplished using a method selected from the group consisting of molding, extruding, pressing, boring and combinations thereof.

66. The method of claim 43 further comprising a step of cutting the rod-shaped composition before or after step (d).

67. The method of claim 43, wherein said rod-shaped composition is cylindrical and a diameter of said cylindrical rod-shaped composition is between about 0.1 mm and 3.0 mm.

68. The method of claim 43, wherein the length of said rod-shaped composition is between about 1.0 mm and 5.0 cm.

69. A method for preparing a composition for injectable delivery of osteogenic proteins, said composition comprising an osteogenic protein and a calcium phosphate material, comprising the step of:

mixing a dry form of the calcium phosphate material with an aqueous buffer containing an osteogenic protein to form a paste.

70. The method of claim 69, wherein the osteogenic protein is selected from the group consisting of members of the bone morphogenetic protein family.

71. The method of claim 70, 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.

72. The method of claim 71, wherein the osteogenic protein is BMP-2.

73. The method of claim 69, wherein the osteogenic protein is present in the paste in an amount ranging from about 0.01% to about 2% by weight of the paste.

74. The method of claim 73, wherein the osteogenic protein is present in the paste in an amount ranging from about 0.03% to about 1% by weight of the paste.

75. The method of claim 69, wherein the composition further comprises a bone resorption inhibitor and wherein a dry form of the bone resorption inhibitor is mixed in the paste.

76. The method of claim 75, wherein the bone resorption inhibitor is a bisphosphonate.

77. The method of claim 76, wherein the bisphosphonate is selected from the group consisting of alendronate, cimadronate, clodronate, EB 1053, etidronates, ibandronate, neridronate, olpadronate, pamidronate, risedronate, tiludronate, YH 529, zoledronate, and pharmaceutically acceptable salts, esters, acids, and mixtures thereof.

78. The method of claim 69, wherein the calcium phosphate material comprises a material selected from the group consisting of amorphous apatitic calcium phosphate, poorly crystalline apatitic calcium phosphate, hydroxyapatite, tricalcium phosphate, fluorapatite and combinations thereof.

79. The method of claim 78, wherein the calcium phosphate material comprises a poorly crystalline apatitic calcium phosphate.

80. The method of claim 79, wherein the poorly crystalline apatitic calcium phosphate has a calcium-to-phosphate ratio of less than 1:

1.5.

81. The method of claim 80, wherein the poorly crystalline apatitic calcium phosphate has a calcium-to-phosphate ratio of about 1:

1.4.

82. The method of claim 69, wherein an amount of calcium phosphate material ranging from about 30% to about 70% by weight of the composition is mixed with the aqueous buffer.

83. The method of claim 82, wherein an amount of calcium phosphate material ranging from about 45% to about 55% by weight of the composition is mixed with the aqueous buffer.

84. The method of claim 69, wherein the composition further comprises an additive selected from the group consisting of pharmaceutically acceptable salts, polysaccharides, peptides, proteins, amino acids, synthetic polymers, natural polymers, surfactants, and combinations thereof and wherein a dry form of the additive is mixed in the paste.

85. The method of claim 84, wherein the additive is selected from the group consisting of carboxymethylcellulose, hydroxypropylmethylcellulose, methylcellulose, polylactide, polyethylene glycol, polyvinylpyrrolidone, polyoxyethylene oxide, carboxyvinyl polymer, polyvinyl alcohol, dextran sulfate and combinations thereof.

86. The method of claim 84, wherein an amount of additive ranging from about 1% to about 90% by weight of the composition is mixed in the paste.

87. The method of claim 86, wherein an amount of additive ranging from about 10% to about 20% by weight of the composition is mixed in the paste.

88. The method of claim 69, wherein the composition further comprises a bone resorption inhibitor and an additive selected from the group consisting of pharmaceutically acceptable salts, polysaccharides, peptides, proteins, amino acids, synthetic polymers, natural polymers, surfactants, and combinations thereof.

89. The method of claim 69, wherein the aqueous buffer is selected from the group consisting of phosphate-buffered saline, saline, glycine-based buffers and combinations thereof.

90. The method of claim 69, wherein the ratio of aqueous buffer to calcium phosphate material ranges from about 0.5:

1 to about 2;

1.