Preliminary Study On The Absorption And Pharmacodynamics Of Hydroxypropyl - β - Cyclodextrin / Insulin On Caco - 2 Cell Model

Diabetes is one of the major diseases that threat human health, and the most effe-ctive drug to treat type I diabetes is insulin(INS). The injection of insulin for whole li-fe brings major suffering and inconvenience for patients. Since insulin is a peptide, f-or its oral administration, insulin has to be associated to a drug carrier that prevents p-roteolytic degradation of the peptide in the gastrointestinal tract and facilitates its tran-sportion from the gut lumen to the blood compartment. Our laboratory has previously proofed that insulin/HP-β-cyclodextrin complexes is more stable than insulin-only co-ntrols in the acidic, base, high temperature, denaturation reagent, and enzyme treatme-nt conditions. The transcellular permeation of insulin in vitro Caco-2 model and initi-atory pharmacodynamics validation of insulin/HP-β-cyclodextrin complexes have be-en investigated in this study.The inclusion complexes were prepared by solution method, characterized by the DTA method and nuclear magnetic resonance method (1H-NMR). The neutral solubil-ity of insulin was measured by HPLC. The inclusion has excellent pharmacology per-formance with the solubility of insulin in the neutral solution up to 1.67g/100mL.Caco-2 cell line was used to examine the transcellular permeation of insulin in vi-tro model. The experiment showed that the permeative determination of the inclusion complexes and insulin of 15IU/ml increase linearly with time in 150 minutes, and the apparent permeability of inclusion complexes increased about ten times than the insu-lin(up to 4.7×10-6cm·s-1).The hypoglycemic effect of inclusion complexes after oral (20U-kg-1) was comp-ared with the hypoglycemic effect of insulin after subcutaneous injectio(1U·kg-1) in rats. In the group with injection, the blood glucose level reduced to about 20.53% of t-he control value within 30minutes then started rising and approached to 90.32% of the control value within 4 hours. In the group with oral delivery of inclusion complex, the blood glucose level reduced to about 84.22% of the control value within 2 hours then started rising and approached to 88.87% of the control value within 12hours.The hypoglycemic effect of inclusion complexes redissolved in normal saline aft-er oral (20U-kg-1) and the hypoglycemic effect of enteric capsule of inclusion comple-xes after oral (20U-kg-1) were compared with the hypoglycemic effect of insulin after subcutaneous injection(lU-kg-1) in rabbits. In the group with injection, the blood gluc-ose level reduced to about 40.53% of the control value within 1 hour then started risi- ng and approached to 89.33% of the control value within 6 hours. In the group with i-nclusion complexes solution, the blood glucose level reduced to about 83.26% of the control value within 2 hours then started rising and approached to 89.12% of the cont-rol value within 12 hours. In the group with enteric capsule of inclusion complexes, t-he blood glucose level reduced to about 78.22% of the control value within 4 hours t-hen started rising and remained below 85% of the control value within 12 hours. The group with enteric capsule of inclusion complexes had stronger and longer hypoglyce-mic effect than the group with inclusion complexes solution.