US2006246150A1PendingUtilityA1

Composition and Process for Bone Growth and Repair

53
Individually held — no corporate assignee on recordPriority: Dec 22, 2000Filed: May 15, 2006Published: Nov 2, 2006
Est. expiryDec 22, 2020(expired)· nominal 20-yr term from priority
Inventors:Kevin Thorne
A61P 19/00A61K 38/1875A61L 27/12A61L 27/227A61P 19/08A61L 27/24A61L 27/22A61L 2430/02A61L 27/3608A61L 27/46A61L 27/3616
53
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Claims

Abstract

A composition for the induction of bone growth is disclosed. The composition includes a substrate, bone growth protein, and sources of calcium and phosphate. The composition is acidic which promotes high activity of the bone growth protein. The calcium and phosphate sources can be provided as an acidic calcium phosphate salt. Also disclosed are methods of the making the composition and methods of using it.

Claims

exact text as granted — not AI-modified
1 . A bone growth composition, comprising: 
 a bone growth protein having a first bioactivity; and    an acidic substrate;    wherein the bone growth protein has a second bioactivity greater than the first bioactivity when combined with the acidic substrate.    
   
   
       2 . The bone growth composition of  claim 1 , wherein the bone growth protein is selected from transforming growth factor β (TGFβ)1, TGFβ2, TGFβ3, bone morphogenic protein (BMP)-2, BMP-3, BMP-4, BMP-5, BMP-6, BMP-7, BMP-8, BMP-9, cartilage-derived morphogenic protein (CDMP)-1, CDMP-2, or CDMP-3.  
   
   
       3 . The bone growth composition of  claim 1 , wherein the acidic substrate comprises collagen, fibrin, alginate, or a mixture of two or more thereof.  
   
   
       4 . The bone growth composition of  claim 1 , wherein the acidic substrate comprises a calcium source and a phosphate source.  
   
   
       5 . The bone growth composition of  claim 4 , wherein the calcium source and the phosphate source are calcium hydrogen phosphate dihydrate, monocalcium phosphate, calcium pyrophosphate, or a mixture of two or more thereof.  
   
   
       6 . The bone growth composition of  claim 1 , further comprising a fluid selected from the group consisting of marrow, serum, whole blood, saline, and water.  
   
   
       7 . A bone growth composition, comprising 
 a bone growth protein; and    an acidic substrate comprising an acidic calcium phosphate compound;    wherein the bone growth composition comprises between about 0.5 μmol and about 6 μmol of the acidic calcium phosphate compound per 1 μg of total bone growth protein.    
   
   
       8 . The bone growth composition of  claim 7 , wherein the bone growth composition comprises between about 1 μmol and about 5 μmol of the acidic calcium phosphate compound per 1 μg of total bone growth protein.  
   
   
       9 . The bone growth composition of  claim 8 , wherein the bone growth composition comprises between about 2 μmol and about 4 μmol of the acidic calcium phosphate compound per 1 μg of total bone growth protein.  
   
   
       10 . The bone growth composition of  claim 7 , wherein the bone growth protein is selected from transforming growth factor β (TGFβ)1, TGFβ2, TGFβ3, bone morphogenic protein (BMP)-2, BMP-3, BMP-4, BMP-5, BMP-6, BMP-7, BMP-8, BMP-9, cartilage-derived morphogenic protein (CDMP)-1, CDMP-2, or CDMP-3.  
   
   
       11 . The bone growth composition of  claim 7 , wherein the acidic substrate comprises collagen, fibrin, alginate, or a mixture of two or more thereof.  
   
   
       12 . The bone growth composition of  claim 7 , wherein the acidic calcium phosphate compound is calcium hydrogen phosphate dihydrate, monocalcium phosphate, calcium pyrophosphate, or a mixture of two or more thereof.  
   
   
       13 . A method of promoting bone growth at a bone defect in a vertebrate, comprising: 
 delivering a bone growth protein having a first bioactivity to the bone defect; and    delivering an acidic substrate to the bone defect, wherein the bone growth protein has a second bioactivity greater than the first bioactivity when combined with the acidic substrate.    
   
   
       14 . The method of  claim 13 , wherein the bone growth protein is selected from transforming growth factor β (TGFβ)1, TGFβ2, TGFβ3, bone morphogenic protein (BMP)-2, BMP-3, BMP-4, BMP-5, BMP-6, BMP-7, BMP-8, BMP-9, cartilage-derived morphogenic protein (CDMP)-1, CDMP-2, or CDMP-3.  
   
   
       15 . The method of  claim 13 , wherein the acidic substrate comprises collagen, fibrin, alginate, or a mixture of two or more thereof.  
   
   
       16 . The method of  claim 13 , wherein the acidic substrate comprises a calcium source and a phosphate source.  
   
   
       17 . The method of  claim 16 , wherein the calcium source and the phosphate source are calcium hydrogen phosphate dihydrate, monocalcium phosphate, calcium pyrophosphate, or a mixture of two or more thereof.  
   
   
       18 . The method of  claim 13 , wherein the bone growth protein and the acidic substrate are delivered simultaneously to the bone defect.  
   
   
       19 . A method of forming a bone growth composition, comprising: 
 combining a bone growth protein having a first bioactivity with an acidic substrate, wherein the bone growth protein has a second bioactivity greater than the first bioactivity when combined with the acidic substrate.    
   
   
       20 . The method of  claim 19 , wherein the bone growth protein is selected from transforming growth factor β (TGFβ)1, TGFβ2, TGFβ3, bone morphogenic protein (BMP)-2, BMP-3, BMP-4, BMP-5, BMP-6, BMP-7, BMP-8, BMP-9, cartilage-derived morphogenic protein (CDMP)-1, CDMP-2, or CDMP-3.  
   
   
       21 . The method of  claim 19 , wherein the acidic substrate comprises collagen, fibrin, alginate, or a mixture of two or more thereof.  
   
   
       22 . The method of  claim 19 , wherein the acidic substrate comprises a calcium source and a phosphate source.  
   
   
       23 . The method of  claim 22 , wherein the calcium source and the phosphate source are calcium hydrogen phosphate dihydrate, monocalcium phosphate, calcium pyrophosphate, or a mixture of two or more thereof.  
   
   
       24 . The method of  claim 19 , wherein the bone growth protein and the acidic substrate are combined prior to delivery of the composition to a patient.  
   
   
       25 . A kit for promoting bone growth at a bone defect in a mammal, comprising: 
 a bone growth protein having a first bioactivity and an acidic substrate, wherein the bone growth protein has a second bioactivity greater than the first bioactivity when combined with the acidic substrate.    
   
   
       26 . The kit of  claim 25 , wherein the bone growth protein is selected from transforming growth factor β (TGFβ)1, TGFβ2, TGFβ3, bone morphogenic protein (BMP)-2, BMP-3, BMP-4, BMP-5, BMP-6, BMP-7, BMP-8, BMP-9, cartilage-derived morphogenic protein (CDMP)-1, CDMP-2, or CDMP-3.  
   
   
       27 . The kit of  claim 25 , wherein the acidic substrate comprises collagen, fibrin, alginate, or a mixture of two or more thereof.  
   
   
       28 . The kit of  claim 25 , wherein the acidic substrate comprises a calcium source and a phosphate source.  
   
   
       29 . The kit of  claim 28 , wherein the calcium source and the phosphate source are calcium hydrogen phosphate dihydrate, monocalcium phosphate, calcium pyrophosphate, or a mixture of two or more thereof.  
   
   
       30 . The kit of  claim 25 , wherein the bone growth protein and the acidic substrate are included in a common package.  
   
   
       31 . The bone growth composition of  claim 1 , produced by the process comprising: 
 combining the bone growth protein with an acidic substrate, wherein the bone growth protein has a second bioactivity greater than the first bioactivity when combined with the acidic substrate.    
   
   
       32 . The bone growth composition of  claim 31 , wherein the bone growth protein is selected from transforming growth factor β (TGFβ)1, TGFβ2, TGFβ3, bone morphogenic protein (BMP)-2, BMP-3, BMP-4, BMP-5, BMP-6, BMP-7, BMP-8, BMP-9, cartilage-derived morphogenic protein (CDMP)-1, CDMP-2, or CDMP-3.  
   
   
       33 . The bone growth composition of  claim 31 , wherein the acidic substrate comprises collagen, fibrin, alginate, or a mixture of two or more thereof.  
   
   
       34 . The bone growth composition of  claim 31 , wherein the acidic substrate comprises a calcium source and a phosphate source.  
   
   
       35 . The bone growth composition of  claim 31 , wherein the bone growth protein and the acidic substrate are combined ex vivo.  
   
   
       36 . The bone growth composition of  claim 34 , wherein the calcium source and the phosphate source are calcium hydrogen phosphate dihydrate, monocalcium phosphate, calcium pyrophosphate, or a mixture of two or more thereof.  
   
   
       37 . A composition, comprising: 
 about 3 parts by weight to about 10 parts by weight of a collagen:acidic calcium phosphate mineral material having an average particle size of about 125 microns to about 5000 microns, wherein the material comprises about 25 wt % to about 75 wt % of the acidic calcium phosphate mineral, the material has a porosity of about 85% to about 98%, and the collagen and the acidic calcium phosphate mineral are dehydrothermally crosslinked;    about 1 part by weight to about 20 parts by weight of collagen other than that crosslinked with the acidic calcium phosphate mineral material in the collagen:acidic calcium phosphate mineral material; and    about 2 parts by weight to about 15 parts by weight of a highly acidic calcium phosphate mineral other than that crosslinked with collagen in the collagen:acidic calcium phosphate mineral material.    
   
   
       38 . The composition of  claim 37 , wherein the acidic calcium phosphate mineral has a Ca:PO 4  ratio from about 0.5 to about 1, and the highly acidic calcium phosphate mineral has a Ca:PO 4  ratio from about 0.25 to about 0.5.  
   
   
       39 . The composition of  claim 38 , wherein the acidic calcium phosphate mineral comprises one or more of calcium hydrogen phosphate dihydrate (CaHPO 4 .2H 2 O), monocalcium phosphate (Ca(H 2 PO 4 ) 2 ), calcium pyrophosphate (2CaO.P 2 O 5 ), tricalcium phosphate (3CaO.P 2 O 5 ), hydroxyapatite (3.33CaO.P 2 O 5 (OH) 2 ), tetracalcium phosphate (4CaO.P 2 O 5 ), or calcium carbonate (CaCO 3 ).  
   
   
       40 . The composition of  claim 37 , wherein the highly acidic calcium phosphate mineral comprises monocalcium phosphate.  
   
   
       41 . The composition of  claim 37 , wherein the average particle size is about 125 microns to about 300 microns.  
   
   
       42 . The composition of  claim 37 , wherein the material comprises about 60 wt % to about 75 wt % of the acidic calcium phosphate mineral.  
   
   
       43 . The composition of  claim 37 , wherein the material has a porosity of about 94% to about 98%.  
   
   
       44 . The composition of  claim 37 , comprising about 85 parts by volume to about 95 parts by volume of the collagen:acidic calcium phosphate mineral material and about 5 parts by volume to about 15 parts by volume collagen.  
   
   
       45 . The composition of  claim 37 , further comprising about 2 parts by weight to about 150 parts by weight of a fluid.  
   
   
       46 . The composition of  claim 45 , wherein the fluid is bone marrow aspirate, whole blood, serum, saline, water, or two or more thereof.  
   
   
       47 . The composition of  claim 37 , further comprising one or more bone growth proteins.  
   
   
       48 . The composition of  claim 47 , wherein the one or more bone growth proteins are selected from TGFβ1, TGFβ2, TGFβ3, bone morphogenic protein (BMP)-2, BMP-3, BMP-4, BMP-5, BMP-6, BMP-7, BMP-8, BMP-9, cartilage-derived morphogenic protein (CDMP)-1, CDMP-2, or CDMP-3.  
   
   
       49 . A bone growth composition, comprising: 
 at least one bone growth protein; and    an acidic substrate comprising a substrate and at least one calcium phosphate salt;    wherein the at least one calcium phosphate salt is more than 95 wt % insoluble when 200 mg of the calcium phosphate are introduced at room temperature to 1 cc of an aqueous solution at pH 7 prior to addition of the calcium phosphate and the calcium phosphate does not excessively bind to the at least one bone growth protein.    
   
   
       50 . A bone growth composition, comprising: 
 at least one bone growth protein; and    an acidic substrate comprising a substrate and at least one calcium phosphate salt, wherein each calcium phosphate salt has a pKa from about 4 to about 6.5.

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