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(12) Patent Application Publication (10) Pub. No.: US 2007/0259814 A1 Lynch (43) Pub

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(12) Patent Application Publication (10) Pub. No.: US 2007/0259814 A1 Lynch (43) Pub US 20070259814A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2007/0259814 A1 Lynch (43) Pub. Date: Nov. 8, 2007 (54) PLATELET DERIVED GROWTH FACTOR tion No. 10/965,319, filed on Oct. 14, 2004, now AND METHODS OF USE THEREOF abandoned. (76) Inventor: Samuel E. Lynch, Franklin, TN (US) Publication Classification Correspondence Address: (51) Int. Cl. JOHN S. PRATT, ESQ A6II 38/18 (2006.01) KILPATRICK STOCKTON, LLP A6IP 9/00 (2006.01) 11OO PEACHTREE STREET (52) U.S. Cl. ................................................................ S14/12 ATLANTA, GA 30309 (US) (57) ABSTRACT (21)21) Appl. NoNo.: 11 ft/84989 A method for promoting growth of bone, periodontium, (22) Filed: Jul. 16, 2007 ligament, or cartilage in a mammal by applying to the bone, periodontium, ligament, or cartilage a composition compris Related U.S. Application Data ing platelet-derived growth factor at a concentration in the range of about 0.1 mg/mL to about 1.0 mg/mL in a phar (60) Division of application No. 11/159.533, filed on Jun. maceutically acceptable liquid carrier and a pharmaceuti 23, 2005, which is a continuation-in-part of applica cally-acceptable solid carrier. Patent Application Publication Nov. 8, 2007 Sheet 1 of 2 US 2007/0259814 A1 ce e C Y ... < Patent Application Publication Nov. 8, 2007 Sheet 2 of 2 US 2007/0259814 A1 US 2007/0259814 A1 Nov. 8, 2007 PLATELET DERVED GROWTH FACTOR AND tered in an amount in the range of about 0.1 to about 1.0 METHODS OF USE THEREOF mg/ml. In several embodiments, the PDGF is administered in an amount of between about 0.2 to about 0.75 mg/ml, CROSS REFERENCE TO RELATED about 0.25 to about 0.6 mg/ml, and about 0.25 to about 0.5 APPLICATIONS mg/ml. In an embodiment, the PDGF is administered in an 0001. This application is a continuation-in-part of, and amount of about 0.1 mg/ml, 0.3 mg/ml, or 1.0 mg/ml. claims priority from, U.S. patent application Ser. No. preferably 0.3 mg/mL. In another embodiment, the PDGF is 10/965,319, filed Oct. 14, 2004, which is incorporated either partially or substantially purified. In yet a further herein by reference in its entirety. embodiment, the PDGF is isolated or purified from other contaminants. In a further embodiment, the PDGF is FIELD OF THE INVENTION released from the implant material upon administration at an average rate of 0.3 mg/day. In another embodiment, the 0002 This invention relates to the healing of bone and PDGF is released from the implant material upon adminis connective tissues. tration at an average rate of 300 lug/day. In still further embodiments, the PDGF is released from the implant mate BACKGROUND OF THE INVENTION rial at an average rate of less than 100 g/day, less than 50 0003 Growth factors are proteins that bind to receptors ug/day, less than 10 ug/day, or less than 1 g/day. Preferably, on a cell Surface, with the primary result of activating the PDGF is delivered over a few days, e.g., 1, 2, 5, 10, 15, cellular proliferation and/or differentiation. Many growth 20, or 25 days, or up to 28 days or more. factors are quite versatile, stimulating cellular division in 0007. A second aspect of the invention features a method numerous different cell types; while others are specific to a for promoting bone, periodontium, ligament, or cartilage particular cell-type. Examples of growth factors include growth in a mammal, e.g., a human, by administering an platelet-derived growth factor (PDGF), insulin-like growth implant material containing an amount of platelet-derived factors IGF-I and II), transforming growth factor beta (TGF growth factor (PDGF) of less than about 1.0 mg/ml and a B), epidermal growth factor (EGF), and fibroblast growth pharmaceutically acceptable carrier Such that the implant factor (FGF). PDGF is a cationic, heat stable protein found material promotes the growth of the bone, periodontium, in a variety of cell types, including the granules of circu ligament, or cartilage, and allowing the bone, periodontium, lating platelets, vascular Smooth muscle cells, endothelial ligament, or cartilage to grow. Preferably, the PDGF is equal cells, macrophage, and keratinocytes, and is known to to or less than about 0.3 mg/ml. In an embodiment, the stimulate in vitro protein synthesis and collagen production PDGF is administered in a range of about 0.1 to 1.0 mg/ml. by fibroblasts. It is also known to act as an in vitro mitogen In other embodiments, the amount of PDGF is about 0.1 and chemotactic agent for fibroblasts, Smooth muscle cells, mg/ml, 0.3 mg/ml, or 1.0 mg/ml, preferably 0.3 mg/mL. In osteoblasts, and glial cells. another embodiment, the PDGF is either partially or sub 0004 Recombinant human PDGF-BB (rhPDGF-BB) has stantially purified. In yet a further embodiment, the PDGF is been shown to stimulate wound healing and bone regenera isolated or purified from other contaminants. Prior to admin tion in both animals and humans. It is approved in both the istering the implant material to the mammal, the method can United States and Europe for human use in topical applica additionally include the step of producing a Surgical flap of tions to accelerate healing of chronic diabetic foot Sores. skin to expose the bone, periodontium, ligament, or carti Recombinant hPDGF-BB has also been shown to be effec lage, and following the administration step, replacing the tive either singly or in combination with other growth flap. In yet another embodiment, after producing the Surgical factors for improving periodontal regeneration, i.e., flap, but prior to administering the implant material to the regrowth of bone, cementum, and ligament around teeth bone, periodontium, ligament, or cartilage, the method can (see, e.g., U.S. Pat. No. 5,124.316, incorporated herein by additionally include the step of planing the bone or peri odontium to remove organic matter from the bone or peri reference). odontium. In yet another embodiment, the method promotes SUMMARY OF THE INVENTION the growth of damaged or diseased bone, periodontium, ligament, or cartilage. In yet another embodiment, the 0005 We have now demonstrated that a low dose of method promotes the growth of bone in locations where new rhPDGF (-0.1 to 1.0 mg/mL) promotes repair of bone, bone formation is required as a result of Surgical interven periodontium, ligament, and cartilage. A low amount of tions. Such as, e.g., tooth extraction, ridge augmentation, rhPDGF can be adsorbed to B-TCP, which can be implanted esthetic grafting, and sinus lift. at the site of repair, such that the rhPDGF is released in vivo. 0008. A third aspect of the invention features an implant Addition of rhPDGF to B-TCP has been shown to enhance material for promoting the growth of bone, periodontium, osteoblast cell attachment and proliferation compared to ligament, or cartilage in a mammal, e.g., a human. The untreated B-TCP. implant material includes a pharmaceutically acceptable 0006. In a first aspect, the invention features a method for carrier (e.g., a biocompatible binder, a bone Substituting promoting bone, periodontium, ligament, or cartilage agent, a liquid, or a gel) and platelet-derived growth factor growth in a mammal, e.g., a human, by administering an (PDGF), which is present at a concentration of less than implant material containing platelet-derived growth factor about 1.0 mg/mL. Preferably, the PDGF is present in the (PDGF) at a concentration of less than about 1.0 mg/ml, implant material at a concentration equal to or less than Such that the implant material promotes growth of the bone, about 0.3 mg/ml. In an embodiment, the PDGF is adminis periodontium, ligament, or cartilage. In an embodiment, the tered in a range of about 0.1 to 1.0 mg/ml. In other PDGF is administered in an amount of less than or equal to embodiments, the amount of PDGF is about 0.1 mg/ml, 0.3 0.3 mg/ml. In another embodiment, the PDGF is adminis mg/ml, or 1.0 mg/ml, preferably 0.3 mg/mL. In an embodi US 2007/0259814 A1 Nov. 8, 2007 ment, the pharmaceutically acceptable carrier of the implant concentration of PDGF is about 0.3 mg/mL, the calcium material includes a scaffold or matrix consisting of a bio phosphate is selected from tricalcium phosphate, hydroxya compatible binder (e.g., carboxymethylcellulose) or a bone patite, poorly crystalline hydroxyapatite, amorphous cal substituting agent (B-TCP) that is capable of absorbing a cium phosphate, calcium metaphosphate, dicalcium phos Solution that includes PDGF (e.g., a solution containing phate dihydrate, heptacalcium phosphate, calcium PDGF at a concentration in the range of about 0.1 mg/mL to pyrophosphate dihydrate, calcium pyrophosphate, and octa about 1.0 mg/mL). In another embodiment, the pharmaceu calcium phosphate, and the PDGF is provided in a sterile tically acceptable carrier is capable of absorbing an amount liquid, for example, Sodium acetate buffer. of the PDGF solution that is equal to at least about 25% of 0012. A seventh aspect of the invention features a method its own weight. In other embodiments, the pharmaceutically of preparing an implant material by Saturating a calcium acceptable carrier is capable of absorbing an amount of the phosphate material in a sterile liquid that includes platelet PDGF solution that is equal to at least about 50%, 75%, derived growth factor (PDGF) at a concentration in the 100%, 200%, 250%, or 300% or its own weight.
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