Abstract
The aim was to study the potential of various hydroxypropyl methylcellulose (HPMC) grades (K100LV, E50LV, E5LV, E4M, K4M and K100M) in enhancing oral bioavailability of insulin. Enteric coated insulin-loaded-HPMC granules were compared with peroral solution of zinc insulin in glycerine IP (0.788 mg/0.2 ml). Since lowering of blood glucose levels (BGLs) was used as pharmacological response, the area above curve 24 0 AAC was measured as a pharmacokinetic parameter instead of area under curve (AUC) for calculating bioavailability or pharmacological efficacy. In vitro studies showed that insulin release from granules was barred in acidic medium while almost complete release took place in basic medium upto 8h. In vivo studies in normal rats showed a maximum blood glucose reduction by K100LV based insulin-loaded granules, which corresponded to a relative pharmacological efficacy of ~1.4% and absolute pharmacological efficacy of ~0.5%. In contrast, neither control granules nor control (peroral) solution showed a comparable effect. The multiple comparison post-hoc test, least square difference (LSD; at p = 0.05), showed a significant difference of K100LV-, E50LV-, E5LV-, E4M- based insulin-loaded granules from placebo and of K100LV-, E50LV- based insulin-loaded granules from peroral solution. The potential of insulin-loaded HPMC granules followed a general order of K100LV > E50LV > E5LV > E4M > K4M > K100M in lowering of % BGLs. Therefore, low viscosity grades of HPMC are efficient in enhancing oral insulin absorption as compared to high viscosity grades.
Highlights
The mucoadhesive polymers, if not targeted to colon may increase co-adherence of some drugs’ fate to normal physiology through small intestine, which is most usual site for drugs absorption
Insulin is secreted in small intestine, which enters into portal circulation and acts upon liver for controlling glucose metabolism
If insulin is made to get absorbed from small intestine instead of targeting to colon, it may follow normal route of absorption and can act as per its normal physiology
Summary
The mucoadhesive polymers, if not targeted to colon may increase co-adherence of some drugs’ fate to normal physiology through small intestine, which is most usual site for drugs absorption. The oral administration of granules to normal rats was followed by determination of BGLs as pharmacological response This is indirect approach of measuring pharmacological response instead of insulin concentration in blood. We have opted this methodology because; i) insulin concentration transitions in blood are not directly related with its pharmacological response; ii) pharmacological response of insulin is more important parameter in proving its therapeutic usefulness Due to these reasons, blood glucose lowering was measured and related with insulin absorption. The bioavailability measured in this manner may be referred more appropriately as pharmacological efficacy [8]
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