Insulin-loaded polymer (ILP) microparticles composed of poly(methacrylic acid) and poly(ethylene glycol), which have pH-dependent complexation and mucoadhesive properties have been thought to be potential carriers for insulin via an oral route. Nevertheless, further optimization of the polymer delivery system is required to improve clinical application. Therefore, the effect of particle size of the ILP (L-ILP: 180-230 microm, S-ILP: 43-89 microm, SS-ILP: <43 microm) on insulin absorption was studied in the in situ loop system, hypothesizing smaller particle sizes of ILP could induce bigger hypoglycemic effects due to increase mucoadhesive capacity. To verify the hypothesis, the adhesive capacities of differently sized ILPs to the mucosal tissues were evaluated. Additionally, the intestinal site-specificity of ILP for insulin absorption was investigated. Intra- and inter-cellular integrity and/or damage were also examined by lactate dehydrogenase leakage and membrane electrical resistance change to ensure the safety of ILP as a carrier for oral route. As hypothesized, the smaller sized microparticles (SS-ILP) showed a rapid burst-type insulin release and higher insulin absorption compared with the microparticles having larger sizes, resulting in greater hypoglycemic effects without detectable mucosal damage. In fact, SS-ILP demonstrated higher mucoadhesive capacity to the jejunum and the ileum than those of L-ILP. Moreover, SS-ILP's enhancement effect of insulin mucosal absorption showed a site-specificity, demonstrating maximum effect at the ileal segment. These results imply that the particle size and delivery site are very important factors for ILP with respect to increasing the bioavailability of insulin following oral administration.
Coyright 2004 Elsevier B.V.