Microspheres. Insulin-loaded chitosan microspheres were administered orally to male Wistar rats and intestinal absorption was evaluated by measuring the plasma insulin levels and hypoglycemic effects (23). A marked absorption of insulin and a corresponding decrease in plasma glucose levels was observed following the oral administration of capsules that contained 20 IU of insulin and sodium glycocholate, as compared with the capsules containing only lactose or only 20 IU of insulin. The hypoglycemic effect started from 8 h after the administration of chitosan capsules when the capsules entered the colon. These findings suggested that chitosan capsules maybe useful carriers for the colon-specific delivery of peptides including insulin.

Ubaidulla et al. synthesized chitosan phthalate polymer and prepared microspheres containing insulin with the emulsion phase-separation technique (24). The in vitro release behavior of the microspheres was investigated under pH 2.0 and pH 7.4. The degree of phthalate substitution in the synthesized polymer was 20%. The prepared microspheres were spherical with an average diameter 46.34 μm. The insulin-loading capacity in the microspheres was 62%. Chitosan phthalate microspheres protected the insulin from gastric enzymes degradation, thereby enhancing the oral stability of insulin. The encapsulated insulin was quickly released in a phosphate buffer saline (pH 7.4), whereas only a small amount of insulin was released under acidic condition (0.1N HCl at pH 2.0). This result could be attributed to the fact that under acidic conditions, carboxylic groups present in the system existed in nonionized form and were poorly hydrophilic. However, in alkaline conditions, they existed in ionized form and are considerably hydrophilic. Results suggested that chitosan phthalate microspheres may be used as a potential carrier for oral insulin delivery.

Qi et al. prepared and characterized insulin enteric micro-spheres (EMS) of HPMC using a multiple emulsion solvent evaporation method (25). The preparation and characteristics of insulin EMS were studied and the gastrointestinal absorption enhancement of insulin by coadministering EMS with sodium N-(8-(2-hydroxybenzoyl] amino) caprylate (SNAC) was determined. The hypoglycemic effects of these microspheres were studied by orally administrating the insulin EMS and SNAC to rats. The particle size of EMS (o(1)/o(2)) and EMS (w/o/w) was about 500 and 30 μm, respectively, and drug loading was 7 and 3%, respectively. After being incubated with 18 μg/mL pepsin solution (pH 1) at 37 °C, only 20% of insulin in EMS (o(1)/o(2)) was digested within 4 h, and 60% of the insulin in EMS (w/o/w) was digested within 1 h. In hydrochloric acid solution (pH 1.2), EMS (o(1)/o(2)) had less drug dissolution than EMS (w/o/w). In phosphate buffer solution (pH 6.8), the entire drug release time of EMS (o(1)/o(2)) and EMS (w/o/w) was 75 and 10 min, respectively. After orally administered with SNAC, EMS (o(1)/o(2)) decreased the blood glucose level of rats remarkably and maintained the hypoglycemic effect for 4 h. EMS (w/o/w) had just a weakly hypoglycemic effect. Results showed that the characteristic-optimized EMS (i.e., EMS (o(1)/o(2)) incorporating SNAC) could enhance insulin absorption significantly in the gastrointestinal tract by taking advantage of both protection from enzyme degradation and improvement of drug permeability.

Biodegradable microparticles also have been prepared with alginate using a piezoelectric ejection process (27). Lectin (wheat germ agglutinin, WGA) was conjugated to alginate microparticles to take advantage of the protective effects of alginate microparticles and the mucoadhesive properties of WGA for improved oral delivery of insulin. Their specific interaction with model mucin was determined by pig mucin immobilized surface plasmon resonance (SPR) biosensor and in vitro adsorption studies. In vitro experiments in the mucin solution showed that the conjugated WGA enhanced the interaction about three times. The hypoglycemic effects of alginate and WGA-conjugated alginate microparticles were examined after oral administration in streptozotocin-induced diabetic rats. In vivo studies with diabetic rats showed that the blood glucose level was lowest when alginate-WGA microparticles were orally administered. The absorption of insulin from alginate-WGA microparticles was sufficient to drop the glucose level of blood.