Insulin micropiles comprising biodegradable polymers for production of a long-term hypoglycemic effect.
As a percutaneous sustained-release preparation, insulin micropiles (MPs) were prepared with biodegradable polymers poly(lactic acid) (PLA), poly(ϵ-caprolactone) (PCL) and poly(lactic-co-glycolic acid) (PLGA) as the base. The obtained PLA, PCL, and PLGA MPs of which the insulin:polymer ratio was 1:2 were administered to rat skin at 40 IU/kg and hypoglycemic effects measured for 6 days. The order of the hypoglycemic effect was PLA>PCL>PLGA. PLA MP showed the strongest hypoglycemic effect (2 days). The hypoglycemic effect of insulin PLA MP was dependent on the formulation; the order was insulin:PLA (2:1)>insulin:PLA (1:1)>insulin:PLA (1:2). As the ratio of insulin to the polymer base increased, the hypoglycemic effect increased. The area above the plasma glucose levels vs. time curves for 6 days from insulin:PLA (2:1) MPs, 10, 20, 30, and 40 IU/ kg, were 249 ± 108, 2003 ± 379, 3960 ± 794, and 6311 ± 726%·h. A dose-dependent hypoglycemic effect was obtained at 10-40 IU/kg and pharmacological availabilities were 11.1%, 44.5%, 58.6%, and 70%, respectively. Insulin:PLA (2:1) MP showed high plasma insulin level, 86.9-134.7 IU/mL, for 3 days. There was no damage to rat skin. These results suggest the usefulness of insulin:PLA (2:1) MP as a sustained-release percutaneous delivery system for insulin.
Fukushima
Keizo
K
Department of Pharmacokinetics, Kyoto Pharmaceutical University, Yamashina-ku, Kyoto, Japan.
Ito
Yukako
Y
Ishihata
Masahiro
M
Sugioka
Nobuyuki
N
Takada
Kanji
K
D020341:Absorbable Implants; D000818:Animals; D003692:Delayed-Action Preparations / Q000737:chemistry*; D020405:Dermis / Q000378:metabolism; D007004:Hypoglycemic Agents / Q000097:blood / Q000737:chemistry* / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology; D007328:Insulin / Q000097:blood / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D019344:Lactic Acid / Q000737:chemistry; D008086:Lissamine Green Dyes; D008297:Male; D011091:Polyesters / Q000737:chemistry; D011100:Polyglycolic Acid / Q000737:chemistry; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011108:Polymers / Q000737:chemistry*; D051381:Rats; D017208:Rats, Wistar; D013535:Suspensions
D003692:Delayed-Action Preparations; D007004:Hypoglycemic Agents; D007328:Insulin; D008086:Lissamine Green Dyes; D011091:Polyesters; D011108:Polymers; D013535:Suspensions; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; C016240:polycaprolactone; D011100:Polyglycolic Acid; D019344:Lactic Acid; C033616:poly(lactide); C024537:green 5