A novel sustained-release formulation of insulin with dramatic reduction in initial rapid release.
To ensure a strictly controlled release of insulin, a preparation method for insulin-loaded microcapsules was designed. Microcapsules were prepared with an injectable, biodegradable polymer composed of co-poly(D,L-lactic/glycolic) acids (PLGA) (mean molecular weight 6600, LA/GA ratio 50:50). Morphological examination using scanning electron microphotography demonstrated spherical particles with a main diameter of 15-30 microm. When 3% insulin-loaded PLGA microcapsules were administered subcutaneously as a single dose (250 U/kg) to streptozotocin-induced hyperglycemic rats, plasma insulin levels increased and were sustained at levels showing hypoglycemic effects. When glycerin, ethanol, or distilled water was used throughout the preparation procedure, the resultant microcapsules dramatically reduced the initial burst. The formulation in which glycerin was added to an oil phase containing PLGA, insulin, and ZnO increased plasma insulin levels to 86.7, 108.4, and 84.9 microU/ml at 1, 2, and 6 h, respectively. The levels remained at 36.2-140.7 microU/ml from day 1 to day 9. The AUC(0-24 h)/AUC(0-336 h) ratio was calculated to be 9.7%. The formulation prepared without additives gave such a rapid insulin release that animals receiving it became transiently hypoglycemic.
Takenaga
Mitsuko
M
Institute of Medical Science, St. Marianna University School of Medicine, 2-16-1 Sugao, Miyamae-ku, 216-8512, Kawasaki, Japan. m2take@marianna-u.ac.jp
Yamaguchi
Yoko
Y
Kitagawa
Aki
A
Ogawa
Yasuaki
Y
Mizushima
Yutaka
Y
Igarashi
Rie
R
D000818:Animals; D001672:Biocompatible Materials / Q000493:pharmacokinetics / Q000627:therapeutic use; D002214:Capsules; D002626:Chemistry, Pharmaceutical; D003692:Delayed-Action Preparations / Q000493:pharmacokinetics / Q000627:therapeutic use; D003921:Diabetes Mellitus, Experimental / Q000097:blood / Q000139:chemically induced / Q000188:drug therapy*; D004353:Drug Evaluation, Preclinical / Q000379:methods; D006801:Humans; D007004:Hypoglycemic Agents / Q000493:pharmacokinetics / Q000627:therapeutic use; D007328:Insulin / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D019344:Lactic Acid / Q000493:pharmacokinetics / Q000627:therapeutic use; D008297:Male; D008855:Microscopy, Electron, Scanning; D010316:Particle Size; D011100:Polyglycolic Acid / Q000493:pharmacokinetics / Q000627:therapeutic use; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011108:Polymers / Q000493:pharmacokinetics / Q000627:therapeutic use; D051381:Rats; D017208:Rats, Wistar
D001672:Biocompatible Materials; D002214:Capsules; D003692:Delayed-Action Preparations; D007004:Hypoglycemic Agents; D007328:Insulin; D011108:Polymers; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid