| The main goal of this paper was to prepare insulin-loaded nanoparticles and to investigate the physico-chemical characteristics of them, drug efficacy in vivo, pharmacokinetics as well as pharmacological bioavailability relative to sc. On the basis of these knowledges, some measures were taken to increase the bioavailability of insulin formulations and the results were carried out to be promising.This paper included some works as following in order to increase the gastrointestinal absorption of insulin. Biodegradable and biocompatible copolymer poly(lactide-co-glycolide) acid (PLGA) used as a vehicle, insulin-loaded PLGA nanoparticles (INS-PLGA-NPs) were prepared by a multiple emulsion/solvent evaporation procedure. Orthogonal design experiments were performed to optimize the conditions for the process. The surface morphology and particle size distributions of the NPs were examined by transmission electron microscopy and laser diffraction, respectively. The entrapment efficiency was determined by HPLC after separating the NPs from the suspension under ultra centrifugation at 40 000rpm, 10 for 30min and the stability of the NPs suspension was investigated. The results showed that the NPs prepared in our experiment regular and well-distributed with a mean diameter of 149.5nm, a polydispersity index of 0.15 and an encapsulation efficiency up to (43.5 0.6)%, in addition, the nature and concentration of the emulsifier were two of the most important factors influencing on the characteristics of the NPs. Results of the stability experiments indicated that there weren't any changes on the NPs suspension after they were stored at 4癈 for 6 months.The loading pattern of different sizes of NPs was assayed by radioimmunoassay (RIA). The release behavior and biodegradable characteristics of the NPs were studied in vitro to explore the mechanism of release property. Results showed that much of the insulin loaded was absorbed on the surface of the NPs and the particle size may be one of the mostimportant factors affecting the pattern of loading. The release behavior in vitro showed an initial burst effect followed by a slower rate stage. The slower release was resulted from insulin diffusion from the matrix and the degradation of the polymers, among which the latter had a significant influence on it. However, the slow degradation of the polymers led to sustained release of insulin from the NPs.The results of the drug efficacy in vivo showed that the NPs had hypoglycemic effect not only on normal rats, but also on alloxan-inducing diabetic rats and adrenaline-inducing hyperglycemic mice. Furthermore, the hypoglycemic effect had a relationship with the dosage of insulin in the PLGA-NPs. After oral administration, the plasma glucose level decreased significantly after 4h, 10h later the glucose level decreased to the lowest. When oral administration at a dosage of 10U/kg, the glucose level decreased nearly (52.3d: 10.5)% and the hypoglycemic state lasted for 6 h, the relative pharmacological bioavailability was calculated to be (10.3 0.6) %. The result of 125I-radioimmunoassay showed that the serum insulin level of normal rats increased apparently after 8h (*P<0.05). On the base of above experiments, chitosan, a natural bioadhesive polymer, was used as a surface modification material, chitosan-coated INS-PLGA-NPs were prepared. These NPs had a higher capacity of decreasing the glucose level than non-coated PLGA-NPs and the pharmacological bioavailability increased up to ( 15.4 0.8) %. It proved that the surface modification of bioadhesive polymers could enhance gastrointestinal absorption of insulin to a greater extent than non-coated NPs.Besides, in order to investigate the relationship between particle size and drug efficacy in vivo, different sizes of bioadhesive polymer particles containing insulin were prepared and their various properties were studied. The results showed that particle size of (345 60) nm in diameter led to a greater hypoglycemic effect on alloxan-inducing diabetic rats than (123 40)...
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