Sustained-release microcapsules of a bone formation stimulant, TAK-778, for local injection into a fracture site.
The benzothiepin derivative (2R,4S)-(-)-N-(4-diethoxyphosphorylmethylphenyl)-1,2,4,5-tetrahydro-4-methyl-7,8-methylenedioxy-5-oxo-3-benzothiepin-2-carboxamide (TAK-778) is a potent bone formation stimulant. A sustained release formulation was prepared by encapsulating the drug into biodegradable microcapsules for local application to fracture repair in rats. The microcapsules consisted of TAK-778 (10% w/w) and a biodegradable polymer, copoly (d,l-lactic/glycolic acid), with a copolymer ratio of 85:15 (mol/mol) and an average molecular weight of 15 k. The TAK-778 amount at the injection site progressively diminished for 4 weeks after administration, and the serum level of TAK-778 was sustained over the same period. The local concentration of TAK-778 after administration of the microcapsules was simulated by a two-compartment open model. In the model, a first-order release rate constant and a transfer rate constant were obtained from the release profile of the microcapsules and the serum level of TAK-778 after administration of the TAK-778 solution, respectively. Localization at the injection site was examined by radiography using microcapsules in which iodoform was encapsulated as a contrast agent. The microcapsules formed a clot at the injection site, and their spread was narrowly restricted. The local concentration was calculated to be maintained within the range 10(-3)-10(-6) M over 4 weeks on the assumption that the dose and spread volume were 5 mg of TAK-778/site and 3 mL, respectively.
Hoshino
T
T
Pharmaceutical Research Division, Takeda Chemical Industries Ltd. 2-17-85 Juso-honmachi, Yodogawa-ku, Osaka 532-8686, Japan. Hoshino_Tetsuo@takeda.co.jp
Saito
K
K
Muranishi
H
H
Sohda
T
T
Ogawa
Y
Y
D000818:Animals; D001582:Benzothiepins / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D002214:Capsules; D003692:Delayed-Action Preparations / Q000008:administration & dosage / Q000493:pharmacokinetics; D004337:Drug Carriers / Q000008:administration & dosage / Q000493:pharmacokinetics; D005264:Femoral Fractures / Q000000981:diagnostic imaging / Q000188:drug therapy / Q000378:metabolism*; D006810:Humeral Fractures / Q000000981:diagnostic imaging / Q000188:drug therapy / Q000378:metabolism*; D007273:Injections, Intramuscular; D007275:Injections, Intravenous; D007279:Injections, Subcutaneous; D008297:Male; D008855:Microscopy, Electron, Scanning; D010012:Osteogenesis / Q000187:drug effects* / Q000502:physiology; D011859:Radiography; D051381:Rats; D017207:Rats, Sprague-Dawley
D001582:Benzothiepins; D002214:Capsules; D003692:Delayed-Action Preparations; D004337:Drug Carriers; C120450:TAK 778