Enhancement of Absorption of Insulin-Loaded Polyisobutylcyanoacrylate Nanospheres by Sodium Cholate After Oral and Subcutaneous Administration in Diabetic Rats

Abstract

Polyisobutylcyanoacrylate (PIBCA) nanospheres were employed as biodegradable polymeric carriers for oral (p.o.) and subcutaneous (s.c.) delivery of insulin. The polymerization technique used was able to hold 65%–95% of insulin added 30 min after initiation of polymerization. The percentage drug loading was monomer concentration dependent. Insulin adsorption to the nanospheres was measured by radioimmumoassay. Although Pluronic F68 (0.5%) did not significantly alter the in vitro insulin degradation half-life T_50%, sodium cholate (0.5%) increased the degradation T_50% of insulin by 56% (from 13.6 ± 1.6 to 22.1 ± 2 min). This study also investigated the in vivo performance of insulin-loaded PIBCA in aqueous suspension with or without sodium cholate (0.5%) and Pluronic F68 (0.5%) surfactants after oral and subcutaneous administration to alloxan-induced diabetic rats. Insulin absorption was evaluated by its hypoglycemic effect. Insulin associated with PIBCA nanospheres retains its biological activity up to 15 h and 24 h after oral and subcutaneous administrations, respectively. Administered orally, insulin-loaded (75 U/kg) nanospheres, in the presence of surfactants, significantly reduced the mean blood glucose level from 392 ± 32 to 80 ± 13 mg/dl within 2 h and maintained it at 100 mg/dl or less for more than 8 h. On the other hand, the subcutaneous administration of insulin-loaded (25 U/kg) nanospheres significantly decreased the blood glucose level from 406 ± 33 to 88.5 ± 12.8 mg/dl within 1 h, and the lowered glucose level was maintained at 100 mg/dl or less for more than 12 h; it returned to its initial value 24 h after administration. Insulin-loaded nanospheres with surfactants showed significant P < 05) pharmacological availability (PA%) of 37.6% ± 3.7% and 65.2% ± 2.7% after oral and subcutaneous dosages, respectively. The existence of surfactants with PIBCA nanospheres improved the oral PA% by 49.2%. These findings suggest that the developed PIBCA, in the presence of surfactants, would be useful not only in improving insulin gastrointestinal absorption, but also in sustaining its systemic action by lowering the blood glucose to an acceptable level.

Key Words:

• Absorption enhancer
• Insulin
• Nanospheres
• Polyisobutylcyanoacrylate
• Sodium cholate