Platelet-derived growth factor compositions and methods of use thereof

Abstract

A method for promoting growth of bone, periodontium, ligament, or cartilage in a mammal by applying to the bone, periodontium, ligament, or cartilage a composition comprising platelet-derived growth factor at a concentration in the range of about 0.1 mg/mL to about 1.0 mg/mL in a pharmaceutically acceptable liquid carrier and a pharmaceutically-acceptable solid carrier.

1 . A method for promoting growth of bone, periodontium, ligament, or cartilage of a mammal comprising administering to said mammal an implant material comprising platelet-derived growth factor (PDGF) at a concentration in the range of about 0.1 mg/mL to about 1.0 mg/mL in a pharmaceutically acceptable liquid carrier and a pharmaceutically acceptable solid carrier, wherein said implant material promotes the growth of said bone, periodontium, ligament, or cartilage. 
     
     
         2 . The method of  claim 1 , wherein said PDGF has a concentration of about 0.3 mg/mL. 
     
     
         3 . The method of  claim 2 , wherein said PDGF has a concentration of 0.3 mg/mL. 
     
     
         4 . The method of  claim 1 , wherein said pharmaceutically acceptable solid carrier comprises one or more of the following: a biocompatible binder, a bone substituting agent, or a gel. 
     
     
         5 . The method of  claim 4 , wherein said biocompatible binder is a natural or synthetic polymer. 
     
     
         6 . The method of  claim 5 , wherein said natural or synthetic polymer is selected from polysaccharides, nucleic acids, carbohydrates, proteins, polypeptides, collagen, poly(α-hydroxy acids), poly(lactones), poly(amino acids), poly(anhydrides), poly(orthoesters), poly(anhydride-co-imides), poly(orthocarbonates), poly(α-hydroxy alkanoates), poly(dioxanones), poly(phosphoesters), polylactic acid, poly(L-lactide) (PLLA), poly(D,L-lactide) (PDLLA), polyglycolic acid, polyglycolide (PGA), poly(lactide-co-glycolide (PLGA), poly(L-lactide-co-D, L-lactide), poly(D,L-lactide-co-trimethylene carbonate), polyhydroxybutyrate (PHB), poly(ε-caprolactone), poly(δ-valerolactone), poly(γ-butyrolactone), poly(caprolactone), polyacrylic acid, polycarboxylic acid, poly(allylamine hydrochloride), poly(diallyldimethylammonium chloride), poly(ethyleneimine), polypropylene fumarate, polyvinyl alcohol, polyvinylpyrrolidone, polyethylene, polymethylmethacrylate, carbon fibers, poly(ethylene glycol), poly(ethylene oxide), poly(vinyl alcohol), poly(vinylpyrrolidone), poly(ethyloxazoline), poly(ethylene oxide)-co-poly(propylene oxide) block copolymers, poly(ethylene terephthalate)polyamide, and copolymers and mixtures thereof. 
     
     
         7 . The method of  claim 5 , wherein said natural or synthetic polymer is selected from collagen, polyglycolic acid, polylactic acid, and polymethylmethacrylate. 
     
     
         8 . The method of  claim 4 , wherein said biocompatible binder is selected from alginic acid, arabic gum, guar gum, xantham gum, gelatin, chitin, chitosan, chitosan acetate, chitosan lactate, chondroitin sulfate, N,O-carboxymethyl chitosan, a dextran, fibrin glue, glycerol, hyaluronic acid, sodium hyaluronate, a cellulose, a glucosamine, a proteoglycan, a starch, lactic acid, a pluronic, sodium glycerophosphate, collagen, glycogen, a keratin, silk, and derivatives and mixtures thereof. 
     
     
         9 . The method of  claim 4 , wherein said biocompatible binder is sodium hyaluronate or derivatives thereof. 
     
     
         10 . The method of  claim 9 , wherein said biocompatible binder is hyaluronic acid. 
     
     
         11 . The method of  claim 4 , wherein said biocompatible binder is selected from methylcellulose, carboxymethylcellulose, hydroxypropyl methylcellulose, or hydroxyethyl cellulose. 
     
     
         12 . The method of  claim 10 , wherein said biocompatible binder is carboxymethylcellulose. 
     
     
         13 . The method of  claim 8 , wherein said dextran is α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, or sodium dextran sulfate. 
     
     
         14 . The method of  claim 8 , wherein said starch is hydroxyethyl starch or starch soluble. 
     
     
         15 . The method of  claim 4 , wherein said bone substituting agent is selected from a calcium phosphate, calcium sulfate, or demineralized bone. 
     
     
         16 . The method of  claim 15 , wherein said calcium phosphate is selected from tricalcium phosphate, hydroxyapatite, poorly crystalline hydroxyapatite, amorphous calcium phosphate, calcium metaphosphate, dicalcium phosphate dihydrate, heptacalcium phosphate, calcium pyrophosphate dihydrate, calcium pyrophosphate, and octacalcium phosphate. 
     
     
         17 . The method of  claim 15 , wherein said calcium phosphate is provided as a paste or putty that forms a hardened calcium phosphate upon in vivo administration. 
     
     
         18 . The method of  claim 15 , wherein said calcium phosphate is provided as a hardened calcium phosphate. 
     
     
         19 . The method of  claim 15 , wherein said calcium phosphate is bioresorable. 
     
     
         20 . The method of  claim 16 , wherein said tricalcium phosphate is β-tricalcium phosphate (β-TCP). 
     
     
         21 . The method of  claim 20 , wherein said β-TCP comprises a matrix of micron- or submicron-sized particles. 
     
     
         22 . The method of  claim 21 , wherein said β-TCP particles have a size of less than about 5000 μm. 
     
     
         23 . The method of  claim 21 , wherein said β-TCP particles have a size in the range of about 100 to about 5000 μm. 
     
     
         24 . The method of  claim 23 , wherein said β-TCP particles have a size in the range of about 100 to about 3000 μm. 
     
     
         25 . The method of  claim 24 , wherein said β-TCP particles have a size in the range of about 250 to about 2000 μm. 
     
     
         26 . The method of  claim 21 , wherein said β-TCP particles are porous. 
     
     
         27 . The method of  claim 26 , wherein said β-TCP particles are greater than 40% porous. 
     
     
         28 . The method of  claim 27 , wherein said β-TCP particles are greater than 65% porous. 
     
     
         29 . The method of  claim 28 , wherein said β-TCP particles are greater than 90% porous. 
     
     
         30 . The method of  claim 20 , wherein said β-TCP is provided in a shape suitable for implantation. 
     
     
         31 . The method of  claim 30 , wherein said shape is selected from a sphere, a cylinder, and a block. 
     
     
         32 . The method of  claim 15 , wherein said demineralized bone is cortical or cancellous bone. 
     
     
         33 . The method of  claim 1 , wherein said pharmaceutically acceptable liquid carrier is selected from water, a physiologically acceptable buffer, or a cell culture medium. 
     
     
         34 . The method of  claim 33 , wherein said physiologically acceptable buffer is sodium acetate buffer. 
     
     
         35 . The method of  claim 1 , wherein said composition further comprises a biologically active agent. 
     
     
         36 . The method of  claim 35 , wherein said biologically active agent is selected from an antibody, an antibiotic, a polynucleotide, a polypeptide, a protein, an anti-cancer agent, a growth factor, an anti-inflammatory agent, and a vaccine. 
     
     
         37 . The method of  claim 36 , wherein said protein is an osteogenic protein. 
     
     
         38 . The method of  claim 37 , wherein said osteogenic protein is selected from insulin-like growth factor I (IGF-I), insulin-like growth factor II (IGF-II), transforming growth factor-β1 (TGF-β1), transforming growth factor-β2 (TGF-β2), transforming growth factor-α (TGF-α), a bone morphogenetic protein (BMP), or osteogenin. 
     
     
         39 . The method of  claim 1 , wherein said implant material further comprises autologous bone marrow or autologous platelet extracts. 
     
     
         40 . The method of  claim 1 , wherein said PDGF is partially or substantially purified. 
     
     
         41 . The method of  claim 1 , wherein said PDGF is obtained from a natural source or a recombinant source. 
     
     
         42 . The method of  claim 41 , wherein said natural source comprises blood, platelets, serum, platelet concentrate, platelet-rich plasma (PRP), or bone marrow. 
     
     
         43 . The method of  claim 41 , wherein said natural source is platelet-rich plasma (PRP). 
     
     
         44 . The method of  claim 1 , wherein said implant material delivers said PDGF to said bone, periodontium, ligament, or cartilage for at least 1 day following administration. 
     
     
         45 . The method of  claim 1 , wherein said implant material delivers said PDGF to said bone, periodontium, ligament, or cartilage for less than about 28 days following administration. 
     
     
         46 . The method of  claim 1 , wherein said implant material delivers said PDGF to said bone, periodontium, ligament, or cartilage for less than about 21 days following administration. 
     
     
         47 . The method of  claim 1 , wherein said implant material delivers said PDGF to said bone, periodontium, ligament, or cartilage for less than about 14 days following administration. 
     
     
         48 . The method of  claim 1 , wherein said implant material delivers said PDGF to said bone, periodontium, ligament, or cartilage from about 1 day to about 14 days following administration. 
     
     
         49 . The method of  claim 1 , wherein said bone, periodontium, ligament, or cartilage is damaged. 
     
     
         50 . The method of  claim 1  further comprising the step of allowing said bone, periodontium, ligament, or cartilage to grow. 
     
     
         51 . The method of  claim 50  further comprising the steps of exposing said bone, periodontium, ligament, or cartilage by producing a surgical flap of skin prior to administering said implant material, and replacing said flap after administering said implant material. 
     
     
         52 . The method of  claim 51  further comprising, following the step of producing a surgical flap of skin to expose said bone, periodontium, or ligament, but prior to step (a), the step of planing said bone or periodontium to remove organic matter from said bone or periodontium. 
     
     
         53 . The method of  claim 1 , wherein said PDGF is released from the implant material upon administration at an average rate of less than or equal to 300 μg/day. 
     
     
         54 . The method of  claim 1 , wherein said PDGF is released from the implant material upon administration at an average rate of less than 100 μg/day. 
     
     
         55 . The method of  claim 1 , wherein said PDGF is released from the implant material upon administration at an average rate of less than 50 μg/day. 
     
     
         56 . The method of  claim 1 , wherein said PDGF is released from the implant material upon administration at an average rate of less than 10 μg/day. 
     
     
         57 . The method of  claim 1 , wherein said PDGF is released from the implant material upon administration at an average rate of less than 1 μg/day. 
     
     
         58 . The method of  claim 1 , wherein said pharmaceutically acceptable liquid carrier is sterile. 
     
     
         59 . The method of  claim 1 , wherein said PDGF is PDGF AA, PDGF BB, PDGF CC, or PDGF DD, or combinations or derivatives thereof. 
     
     
         60 . The method of  claim 59 , wherein said PDGF is PDGF-BB. 
     
     
         61 . The method of  claim 59 , wherein said PDGF is PDGF-AB. 
     
     
         62 . A method for promoting growth of bone, periodontium, ligament, or cartilage of a mammal comprising (a) administering to said mammal an implant material comprising platelet-derived growth factor (PDGF) at a concentration in the range of less than or equal to 0.3 mg/mL in a pharmaceutically acceptable liquid carrier and a pharmaceutically acceptable solid carrier, wherein said implant material promotes the growth of said bone, periodontium, ligament, or cartilage. 
     
     
         63 . A vial comprising platelet-derived growth factor (PDGF) at a/concentration in the range of about 0.1 mg/mL to about 1.0 mg/mL in a pharmaceutically acceptable liquid. 
     
     
         64 . The vial of  claim 63 , wherein said liquid is sterile sodium acetate buffer. 
     
     
         65 . The vial of  claim 63  comprising PDGF at a concentration of about 0.3 mg/mL. 
     
     
         66 . The vial of  claim 63 , wherein said PDGF is PDGF-BB. 
     
     
         67 . The vial of  claim 64 , wherein said PDGF is stable in said buffer for at least 36 months when stored at a temperature in the range of 2° C. to 80° C. 
     
     
         68 . The vial of  claim 64 , wherein said PDGF is stable for at least 24 months when stored at a temperature in the range of 2° C. to 80° C. 
     
     
         69 . The vial of  claim 64 , wherein said PDGF is stable for at least 18 months when stored at a temperature in the range of 2° C. to 80° C. 
     
     
         70 . The vial of  claim 64 , wherein said PDGF is stable for at least 12 months when stored at a temperature in the range of 2° C. to 80° C. 
     
     
         71 . An implant material comprising a porous calcium phosphate having adsorbed therein a liquid comprising platelet-derived growth factor (PDGF) at a concentration in the range of about 0.1 mg/mL to about 1.0 mg/mL. 
     
     
         72 . The implant material of  claim 71 , wherein the concentration of PDGF is about 0.3 mg/mL. 
     
     
         73 . The implant material of  claim 71 , wherein said calcium phosphate is selected from tricalcium phosphate, hydroxyapatite, poorly crystalline hydroxyapatite, amorphous calcium phosphate, calcium metaphosphate, dicalcium phosphate dihydrate, heptacalcium phosphate, calcium pyrophosphate dihydrate, calcium pyrophosphate, and octacalcium phosphate. 
     
     
         74 . The implant material of  claim 71 , wherein said PDGF is provided in a sterile liquid. 
     
     
         75 . The implant material of  claim 74 , wherein said liquid is sodium acetate buffer. 
     
     
         76 . A method of preparing an implant material comprising saturating a calcium phosphate material in a sterile liquid comprising platelet-derived growth factor (PDGF) at a concentration in the range of about 0.1 mg/mL to about 1.0 mg/mL. 
     
     
         77 . The method of  claim 76 , wherein the concentration of PDGF is about 0.3 mg/mL. 
     
     
         78 . The method of  claim 76 , wherein said calcium phosphate is selected from tricalcium phosphate, hydroxyapatite, poorly crystalline hydroxyapatite, amorphous calcium phosphate, calcium metaphosphate, dicalcium phosphate dihydrate, heptacalcium phosphate, calcium pyrophosphate dihydrate, calcium pyrophosphate, and octacalcium phosphate.