pH- and Amylase-Responsive Carboxymethyl Starch/Poly(2-isobutyl-acrylic acid) Hybrid Microgels as Effective Enteric Carriers for Oral Insulin Delivery.

Oral delivery of insulin has the potential to revolutionize diabetes care since it is regarded as a noninvasive therapeutic approach without the side effects caused by frequent subcutaneous injection. However, the insulin delivery efficiency through oral route was still limited, likely due to the chemical, enzymatic and absorption barriers. In this study, a novel type of pH- and amylase-responsive microgels as an insulin drug carrier for oral administration was developed to improve the drug delivery efficiency. The microgels were prepared via aqueous dispersion copolymerization of acrylate- grafted-carboxymethyl starch (CMS- g-AA) and 2-isobutyl-acrylic acid ( iBAA). The resulting hybrid microgels with the P iBAA contents of 13.6-45.3 wt% exhibited sharp pH-sensitivity, which was revealed by the changes in particle size of the microgels and the transmittance of the microgel aqueous solution. The accelerated decomposition of the CMS-containing microgels in response to amylase was demonstrated by chromogenic reaction and morphology change. Insulin was loaded into the microgels by swelling-diffusion method, and the insulin release from the insulin-loaded microgels in vitro was found to be triggered by pH change and addition of amylase, which was highly dependent on the microgel component. Cytotoxicity assay was performed to show the good biocompatibility of the microgels. In addition, the tests of cellular uptake by Caco-2 cells and transmembrane transport through the Caco-2 cell monolayers were carried out to confirm the intestinal absorption ability of the insulin-loaded microgels. Finally, the oral administration of insulin-loaded microgels to STZ-induced diabetic rats led to a continuous decline in the fasting blood glucose level within 2 to 4 h, and the hypoglycemic effect maintained over 6 h in vivo. The relative pharmacological availability of the insulin-loaded microgels was enhanced 23-38 times compared to free-form insulin solution through oral route. Therefore, the novel starch-based microgels may have potential as an efficient platform for oral insulin delivery.