title: Optimum formulation for sustained-release insulin.
abstract: Our aim was to prepare an optimum formulation for a sustained-release preparation of insulin using biodegradable polymer composed of co-poly(D,L-lactic/glycolic) acids (PLGA)(L/G ratio: 50/50). Various kinds of PLGA microcapsules containing 3% insulin were administered subcutaneously (250 U/kg) as a single dose to rats with streptozotocin-induced diabetes, and plasma insulin levels were monitored. The following results were obtained. (1) Glycerin and water were suitable additives to prepare a reproducible injectable formulation. (2) Addition of zinc compounds was essential to diminish rapid insulin release and six-fold molar excess of ZnO to insulin was desirable. (3) The size of insulin particles showed the following order: human insulin > lyophilized human insulin > Zn-free human insulin. Zn-free insulin was similar to lyophilized insulin with respect to control of rapid release, so a smaller particle size was essential. (4) The size of the microcapsules also affected the release of insulin. With larger microcapsules (approximately 30 microm), there was gradual release and a significant second phase of insulin release, while smaller microcapsules did not allow sustained release. Some variation in microcapsule size contributed to more constant and sustained release. (5) Based on the insulin release profile in vivo, a suitable molecular weight for PLGA was around 6000. The biological activity of insulin extracted from the formulation was similar to that of normal insulin. These experiments allowed us to prepare a desirable sustained-release insulin formulation.
authors.affiliation: Institute of Medical Science, St. Marianna University School of Medicine, 2-16-1 Sugao, Miyamae-ku, Kawasaki, Japan. m2take@marianna-u.ac.jp
authors.forename: Mitsuko
authors.initials: M
authors.lastname: Takenaga
authors.forename: Yoko
authors.initials: Y
authors.lastname: Yamaguchi
authors.forename: Aki
authors.initials: A
authors.lastname: Kitagawa
authors.forename: Yasuaki
authors.initials: Y
authors.lastname: Ogawa
authors.forename: Shinichi
authors.initials: S
authors.lastname: Kawai
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Mizushima
authors.forename: Rie
authors.initials: R
authors.lastname: Igarashi
mesh_terms: D000818:Animals; D002214:Capsules; D003692:Delayed-Action Preparations; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy; D005990:Glycerol / Q000737:chemistry; D007279:Injections, Subcutaneous; D007328:Insulin / Q000008:administration & dosage* / Q000737:chemistry* / Q000627:therapeutic use; D019344:Lactic Acid / Q000737:chemistry*; D008297:Male; D051379:Mice; D008855:Microscopy, Electron, Scanning; D008970:Molecular Weight; D041681:NIH 3T3 Cells; D010316:Particle Size; D011100:Polyglycolic Acid / Q000737:chemistry*; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011108:Polymers / Q000737:chemistry*; D051381:Rats; D017208:Rats, Wistar; D013311:Streptozocin; D014867:Water / Q000737:chemistry; D015034:Zinc Oxide / Q000737:chemistry
chemical_list: D002214:Capsules; D003692:Delayed-Action Preparations; D007328:Insulin; D011108:Polymers; D014867:Water; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid; D013311:Streptozocin; D005990:Glycerol; D015034:Zinc Oxide