Controlled release of rhBMP-2 from collagen minipellet and the relationship between release profile and ectopic bone formation.
The purpose of this study was to examine the effects of various additives on the profiles of rhBMP-2 release from minipellet, which is a sustained release formulation for protein drugs using collagen as a carrier, and to examine the influence of varying release profiles on ectopic bone formation. When the amount of rhBMP-2 remaining in the preparation after subcutaneous implantation to mice was examined, it was found that the addition of sucrose, glucose, PEG4000, alanine (Ala) or acacia in a concentration of 20% (w/w) to the minipellet with 5% (w/w) of rhBMP-2 did not accelerate the drug release in a noticeable manner, while the addition of sodium chondroitin sulfate, glutamic acid (Glu) or citric acid accelerated the release of rhBMP-2 markedly. When two types of minipellets (a fast release type added with 20% Glu and 20% Ala and a slow release type without additives) containing varying amounts of rhBMP-2 were implanted subcutaneously to mice, the soft X-ray observation, histological examination and measurement of calcium formation 3 weeks after implantation revealed extensive ectopic bone formation in mice implanted with the fast release type preparation. Ectopic bone formation was dose-dependent. The result of this study exhibited that the effects of controlled release formulation of rhBMP-2 on bone formation vary depending on their release profiles, and suggested that combination of initial burst and sustained release was effective for bone formation. It was also shown that minipellet is useful as a controlled release formulation which can release rhBMP-2 to areas around the implanted site with various release profiles.
Maeda
Hiroo
H
Formulation Research Laboratories, Sumitomo Pharmaceuticals Co. Ltd., 3-45 Kurakakiuchi 1-Chome, Ibaraki-shi, Osaka 567-0878, Japan. maedah@sumitomopharm.co.jp
Sano
Akihiko
A
Fujioka
Keiji
K
D000818:Animals; D055396:Bone Morphogenetic Protein 2; D019485:Bone Morphogenetic Proteins / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D001842:Bone and Bones / Q000737:chemistry / Q000000981:diagnostic imaging / Q000187:drug effects; D002118:Calcium / Q000032:analysis; D003094:Collagen / Q000737:chemistry*; D004337:Drug Carriers; D004343:Drug Implants; D005079:Excipients / Q000737:chemistry; D066298:In Vitro Techniques; D007279:Injections, Subcutaneous; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D010012:Osteogenesis / Q000187:drug effects*; D011859:Radiography; D013997:Time Factors; D016212:Transforming Growth Factor beta
C525719:Bmp2 protein, mouse; D055396:Bone Morphogenetic Protein 2; D019485:Bone Morphogenetic Proteins; D004337:Drug Carriers; D004343:Drug Implants; D005079:Excipients; D016212:Transforming Growth Factor beta; D003094:Collagen; D002118:Calcium