Implants having a high drug load of an oxysterol and methods of use

Abstract

Provided is an implant configured to fit at or near a bone defect to promote bone growth, the implant comprising: a biodegradable polymer in an amount of about 0.1 wt % to about 20 wt % of the implant and an oxysterol in an amount of about 20 wt % to about 90 wt % of the implant. The implant has a high oxysterol load. Methods of making and use are further provided.

1 . An implant configured to fit at or near a bone defect to promote bone growth, the implant comprising: a biodegradable polymer in an amount of about 0.1 wt % to about 20 wt % of the implant and an oxysterol in an amount of about 20 wt % to about 90 wt % of the implant wherein the oxysterol has a particle size range of about 5 microns to about 100 microns. 
     
     
         2 . An implant according to  claim 1 , wherein the implant is moldable and comprises autocrat, allograft and/or xenograft bone particles. 
     
     
         3 . An implant according to  claim 1 , wherein the implant is configured to form a coherent mass and be moldable after being wetted with a fluid. 
     
     
         4 . An implant according to  claim 1 , further comprising mineral particles in an amount of about 0.1 wt % to about 75 wt % of the implant. 
     
     
         5 . An implant according to  claim 4 , wherein the biodegradable polymer is in an amount of about 8.0 wt % to about 20 wt % of the implant, the oxysterol is in an amount of about 35 wt % to about 80 wt % of the implant, and the mineral particles are in an amount of about 7.0 wt % to about 50 wt % of the implant. 
     
     
         6 . An implant according to  claim 1 , wherein (i) the biodegradable polymer is crosslinked and the oxysterol is loaded into the implant in an amount of about 1 mg/cc to about 1.0 g/cc; or (ii) the biodegradable polymer is uncrosslinked and the oxysterol is loaded into the implant in an amount of about 1 mg/cc to about 1.0 g/cc. 
     
     
         7 . An implant according to  claim 1 , wherein the biodegradable polymer comprises porcine-derived collagen, human-derived collagen, bovine-derived collagen, piscine-derived collagen, ovine-derived collagen, recombinant collagen, gelatin, or combinations thereof. 
     
     
         8 . An implant according to  claim 4 , wherein (i) the mineral particles comprise bone powder, demineralized bone powder, porous calcium phosphate ceramics, hydroxyapatite, tricalcium phosphate, bioactive glass or a combination thereof; (ii) the mineral particles include a particle size between about 125 μm and about 750 μm; (iii) the mineral particles comprise tricalcium phosphate and hydroxyapatite in a ratio of about 70:75 to about 90:10; or (iv) the mineral particles comprise tricalcium phosphate and hydroxyapatite in a ratio of about 85:15. 
     
     
         9 . An implant according to  claim 1 , wherein the oxysterol comprises (3S,5S,6S,8R,9S,10R, 13S, 14S,17S) 17-((S)-2-hydroxyoctan-2-yl)-10, 13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-3,6-diol (Oxy133), Oxy153 or hydrates, solvates, amorphous forms, or pharmaceutically acceptable salts thereof. 
     
     
         10 . An implant according to  claim 3 , wherein the fluid comprises water, sodium chloride, dextrose, Lactated Ringer's solution, blood, bone marrow or a combination thereof. 
     
     
         11 . An implantable matrix configured to fit at or near a bone defect site to promote bone growth, the matrix comprising: a crosslinked biodegradable polymer in an amount of about 0.1 wt % to about 15 wt % of the matrix and an oxysterol in an amount of about 20 wt % to about 90 wt % of the matrix, the oxysterol having a concentration of about 100 mg/cc to about 1.0 g/cc, wherein the oxysterol has a particle size range of about 5 microns to about 100 microns. 
     
     
         12 . A matrix according to  claim 11 , wherein the matrix is moldable to the shape of a sponge, plug, pin, peg, or cylinder and comprises autograft, allograft and/or xenograft bone particles. 
     
     
         13 . A matrix according to  claim 11 , wherein the matrix is configured to form a coherent mass and be moldable after being wetted with a fluid. 
     
     
         14 . A matrix according to  claim 11 , further comprising mineral particles in an amount of about 0.1 wt % to about 75 wt % of the matrix. 
     
     
         15 . A matrix according to  claim 14 , wherein the crosslinked biodegradable polymer is in an amount of about 8.0 wt % to about 13 wt % of the matrix, the oxysterol is in an amount of about 35 wt % to about 80 wt % of the implant, and the mineral particles are in an amount of about 7.0 wt % to about 50 wt % of the implant. 
     
     
         16 . A matrix according to  claim 11 , wherein the crosslinked biodegradable polymer comprises porcine-derived collagen, human-derived collagen, bovine-derived collagen, piscine-derived collagen, ovine-derived collagen, recombinant collagen, gelatin, or combinations thereof. 
     
     
         17 . A matrix according to  claim 14 , wherein (i) the mineral particles comprise bone powder, demineralized bone powder, porous calcium phosphate ceramics, hydroxyapatite, tricalcium phosphate, bioactive glass or a combination thereof; (ii) the mineral particles include a particle size between about 125 μm and about 750 μm; (iii) the mineral particles comprise tricalcium phosphate and hydroxyapatite in a ratio of about 70:75 to about 90:10; or (iv) the mineral particles comprise tricalcium phosphate and hydroxyapatite in a ratio of about 85:15. 
     
     
         18 . A matrix according to  claim 11 , wherein the oxysterol comprises (3S,5S,6S,8R,9S,10R, 13S, 14S,17S) 17-((S)-2-hydroxyoctan-2-yl)-10, 13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-3,6-diol (Oxy133), Oxy153 or hydrates, solvates, amorphous forms, or pharmaceutically acceptable salts thereof. 
     
     
         19 . A matrix according to  claim 13 , wherein the fluid comprises water, sodium chloride, dextrose, Lactated Ringer's solution, blood, bone marrow aspirate or a combination thereof. 
     
     
         20 . A method for making an implant, the method comprising adding an oxysterol in an amount of about 20 wt % to about 90 wt % based on a total weight of the implant to a biodegradable polymer, the biodegradable polymer being in an amount of about 0.1 wt % to about 20 wt % based on the total weight of the implant to form the implant, wherein the oxysterol has a particle size range of about 5 microns to about 100 microns.