Injectable solid hyaluronic acid carriers for delivery of osteogenic proteins

• US 20050287135A1
• Filed: 05/12/2003
• Published: 12/29/2005
• Est. Priority Date: 05/17/2002
• Status: Abandoned Application

• Current Assignee: Fidia Advanced Biopolymers S.R.L. (Anika Therapeutics Incorporated), Wyeth (Pfizer Inc.)
• Original Assignee: Wyeth (Pfizer Inc.)
• Inventors: Li, Rebecca H., Kim, Hyun D.
• Application Number:
  US10/525,441
• Publication Number:
  US 20050287135A1
• Time in Patent Office: Days
• US Class Current: 424/94.63
• 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 31/663 Compounds having two or more phosphorus acid groups or esters thereof, e.g. clodronic acid, pamidronic acid
• CPC Class Codes: A61K 31/728 Hyaluronic acid
• CPC Class Codes: A61K 38/1875 Bone morphogenic factor; Osteogenins; Osteogenic factor; Bone-inducing factor
• CPC Class Codes: A61K 47/36 Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
• 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 27/20 Polysaccharides
• 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 27/26 Mixtures of macromolecular compounds
• 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
• CPC Class Codes: A61P 3/14 for calcium homeostasis vitamin D A61P3/02; parathyroid hormones A61P5/18; calcitonin A61P5/22; osteoporosis A61P19/10; bone metastasis A61P35/04
• CPC Class Codes: A61P 5/00 Drugs for disorders of the endocrine system
• CPC Class Codes: C07K 14/51 Bone morphogenetic factor; Osteogenins; Osteogenic factor; Bone-inducing factor
• CPC Class Codes: C08L 5/08 Chitin; Chondroitin sulfate; Hyaluronic acid; Derivatives thereof
• CPC Class Codes: C08L 89/00 Compositions of proteins; Compositions of derivatives thereof foodstuff preparations A23J3/00

Abstract

An injectable or implantable rod-shaped formulation is disclosed for delivery of osteogenic proteins. The formulation comprises hyaluronic acid derivatives and osteogenic proteins, and optional excipients and active ingredients such as a bone resorption inhibitor. Methods of making injectable rod-shaped pharmaceutical compositions and methods of using the osteogenic compositions to treat osteoporotic and/or osteopenic bone are also disclosed.

Claims

1-71. -71. (canceled)

72. A composition for injectable delivery of osteogenic proteins comprising an osteogenic protein and a hyaluronic acid ester, wherein the composition is in the form of a cylindrical rod suitable for injecting or implanting in solid state into a body.

73. The composition of claim 72, wherein the osteogenic protein is selected from the group consisting of members of the bone morphogenic protein (BMP) family.

74. The composition of claim 72, 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, BMP-13, or MP52.

75. The composition of claim 72, wherein the osteogenic protein is BMP-2

76. The composition of claim 72, wherein the osteogenic protein is BMP-6.

77. The composition of claim 72, wherein the osteogenic protein is BMP-12.

78. The composition of claim 72, wherein the osteogenic protein is BMP-13.

79. The composition of claim 72, wherein the osteogenic protein is MP52.

80. The composition of claim 72, further comprising an excipient selected from the group consisting of pharmaceutically acceptable salts, polysaccharides, peptides, proteins, amino acids, synthetic polymers, natural polymers, and surfactants.

81. The composition of claim 72, further comprising a bone resorption inhibitor.

82. The composition of claim 81, wherein the bone resorption inhibitor is a bisphosphonate.

83. The composition of claim 82, wherein the bisphosphonate is selected from the group consisting of alendronate, cimadronate, clodronate, EB-1053, etidronates, ibandronate, neridronate, olpadronate, pamidronate, risedronate, tiludronate, YH 529, zolendronate, and pharmaceutically acceptable salts, esters, acids, and mixtures thereof.

84. The composition of claim 81, further comprising an excipient selected from the group consisting of pharmaceutically acceptable salts, polysaccharides, peptides, proteins, amino acids, synthetic polymers, natural polymers, and surfactants.

85. The composition of claim 72, wherein the hyaluronic acid ester comprising from about 50 percent to about 100 percent hyaluronic acid esterification.

86. The composition of claim 72, wherein the hyaluronic acid ester is at least 50% esterified.

87. The composition of claim 72, wherein the hyaluronic acid ester is at least 60% esterified.

88. The composition of claim 72, wherein the hyaluronic acid is at least 65% esterified.

89. The composition of claim 72, wherein the hyaluronic acid is at least 75% esterified.

90. The composition of claim 72, wherein the hyaluronic acid is at least 80% esterified.

91. The composition of claim 72, wherein the hyaluronic acid is 100% esterified.

92. The composition of claim 72, wherein the hyaluronic acid is Hyaff11p65.

93. The composition of claim 72, wherein the hyaluronic acid is Hyaff11p65 and the osteogenic protein is BMP-12.

94. The composition of claim 72, wherein the hyaluronic acid is Hyaff11p65 and the osteogenic protein is BMP-13.

95. The composition of claim 72, wherein the hyaluronic acid is Hyaff11p65 and the osteogenic protein is MP52.

96. The composition of claim 72, wherein the hyaluronic acid ester is a cross-linked hyaluronic acid.

97. The composition of claim 72, wherein the diameter of said cylindrical rod is between about 0.5 to 1.5 mm.

98. The composition of claim 72, wherein the length of said cylindrical rod is between about 2 cm and about 5 cm.

119. A method for preparing a composition of claim 72 comprising the steps of:

(a) mixing an osteogenic protein with a hyaluronic acid ester to form an osteogenic mixture comprising the hyaluronic acid ester in an amount of between about 1 to about 50 (w/v) percent;

(b) molding the osteogenic mixture to form a rod-shaped product; and

(c) drying the rod-shaped product from step (b).

120. A method of treating a mammal having a bone defect comprising administering to the site of bone defect an effective amount of a composition of claim 72.

99. A composition for treating osteoporotic bone prepared by a process comprising the steps of:

(a) mixing an osteogenic protein and an hyaluronic acid ester to form an osteogenic mixture; and

(b) forming and drying the osteogenic mixture into a cylindrical rod suitable for injecting or implanting in solid state into a body.

100. The composition of claim 99, wherein the step of mixing comprises mixing the osteogenic protein and hyaluronic acid ester with an excipient selected from the group consisting of pharmaceutically acceptable salts, polysaccharides, peptides, proteins, amino acids, synthetic polymers, natural polymers, and surfactants.

101. The composition of claim 99, wherein the step of mixing further comprises mixing the osteogenic protein and hyaluronic acid ester with a bone resorption inhibitor.

102. The composition of claim 101, wherein the bone resorption inhibitor is a bisphosphonate.

103. The composition of claim 101, wherein the bisphosphonate is selected from the group consisting of alendronate, cimadronate, clodronate, EB-1053, etidronate, ibandronate, neridronate, olpadronate, pamidronate, risedronate, tiludronate, YH 529, zolendronate, and pharmaceutically acceptable salts, esters, acids, and mixtures thereof.

104. The composition of claim 101, wherein the step of mixing further comprises mixing the osteogenic protein, hyaluronic acid ester, and bisphosphonate with an excipient selected from the group consisting of pharmaceutically acceptable salts, polysaccharides, peptides, proteins, amino acids, synthetic polymers, natural polymers, and surfactants.

105. The composition of claim 99, wherein the hyaluronic acid ester is prepared by hydration or solubilization of insoluble or partially soluble particles, films, fibers, non-woven pads, or sponges of hyaluronic acid benzyl esters in water, an organic solvent or an aqueous buffer.

106. The composition of claim 99, wherein the osteogenic protein is selected form the group consisting of members of the bone morphogenic protein (BMP) family.

107. The composition of claim 99, 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, BMP-13, and MP52.

108. The composition of claim 99, wherein the osteogenic protein is BMP-2

109. The composition of claim 99, wherein the osteogenic protein is BMP-6.

110. The composition of claim 99, wherein the osteogenic protein is BMP-12.

111. The composition of claim 99, wherein the osteogenic protein is BMP-13.

112. The composition of claim 99, wherein the osteogenic protein is MP52.

113. The composition of claim 99, wherein the step of mixing comprises mixing the osteogenic protein and hyaluronic acid ester with a solvent;

and wherein the step of forming and drying the osteogenic mixture into a cylindrical rod comprise extruding the osteogenic mixture in a nonsolvent.

114. The composition of claim 99, where in the step of forming and drying the osteogenic mixture comprises extruding the osteogenic mixture in a nonsolvent.

115. The composition of claim 114, wherein the nonsolvent is ethanol or water.

116. The composition of claim 99, where in the step of forming and drying the osteogenic mixture comprises extruding the osteogenic mixture into air and drying.

117. The composition of claim 99, wherein the diameter of said cylindrical rod is between about 0.5 to 1.5 mm.

118. The composition of claim 99, wherein the length of said cylindrical rod is about 2 cm to about 5 cm.