Enhancement of fracture repair in rats with streptozotocin-induced diabetes by a single injection of biodegradable microcapsules containing a bone formation stimulant, TAK-778.
The feasibility of using microcapsules containing a bone formation stimulant, (2R,4S)-(-)-N-(4-diethoxyphosphorylmethylphenyl)-1,2,4, 5-tetrahydro-4-methyl-7, 8-methylenedioxy-5-oxo-3-benzothiepin-2-carboxamide (TAK-778) to enhance fracture repair was assessed in rats with streptozotocin-induced diabetes. The release profile of the microcapsules was designed to mimic a dosing regimen of multiple injections of TAK-778 solution. The solution was injected locally every third day from day 0 (the day of operation) to day 27 according to several dosing regimens, and fracture repair was assessed at day 28. The production of callus was most prominent when TAK-778 solution was injected so that 50-75% of the total dose (5 mg TAK-778/site) was administered during the first half of the treatment period. Thus, injectable microcapsules of 30 micrometer in mean diameter were prepared in order to release TAK-778 over 4 weeks using a biodegradable polymer, poly(d,l-lactic/glycolic) acid, with a copolymer ratio of 85:15 (mol/mol) and an average molecular weight of 14,000. A single local injection of the microcapsules markedly enhanced fracture repair, which resulted in recovery of destructive bending strength of the bone at day 28. Histologically, the injection of TAK-778 microcapsules stimulated both fibrous and cartilaginous proliferation and periosteal ossification in the callus at day 7; bony bridge formation was observed at day 28. At day 56, the callus was remodeled and cortical bony union was evidenced in the microcapsule-treated fractures compared with the controls, which showed only fibrous union.
Hoshino
T
T
DDS Research Laboratories, Pharmaceutical Research Division, Takeda Chemical Industries, Ltd., 2-17-85 Juso-honmachi, Yodogawa-ku, Osaka 532-8686, Japan. Hoshino_Tetsuo@takeda.co.jp
Muranishi
H
H
Saito
K
K
Notoya
K
K
Makino
H
H
Nagai
H
H
Sohda
T
T
Ogawa
Y
Y
D000818:Animals; D001582:Benzothiepins / Q000008:administration & dosage*; D001672:Biocompatible Materials; D001673:Biodegradation, Environmental; D002214:Capsules; D003921:Diabetes Mellitus, Experimental / Q000150:complications*; D005360:Fibula / Q000187:drug effects / Q000293:injuries / Q000473:pathology; D017102:Fracture Healing / Q000187:drug effects*; D050723:Fractures, Bone / Q000150:complications* / Q000188:drug therapy* / Q000473:pathology; D019344:Lactic Acid; D008297:Male; D008422:Materials Testing; D011100:Polyglycolic Acid; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011108:Polymers; D051381:Rats; D017207:Rats, Sprague-Dawley
D001582:Benzothiepins; D001672:Biocompatible Materials; D002214:Capsules; D011108:Polymers; C120450:TAK 778; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid