Morishita Mariko, Goto Takahiro, Peppas Nicholas A, Joseph Jeffery I, Torjman Marc C, Munsick Carey, Nakamura Koji, Yamagata Tetsuo, Takayama Kozo, Lowman Anthony M
Department of Pharmaceutics, Hoshi University, Ebara 2-4-41, Shinagawa, Tokyo 142-8501, Japan.
J Control Release. 2004 May 31;97(1):115-24. doi: 10.1016/j.jconrel.2004.03.008.
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.
由聚（甲基丙烯酸）和聚（乙二醇）组成的载胰岛素聚合物（ILP）微粒具有pH依赖性络合和粘膜粘附特性，被认为是胰岛素口服给药的潜在载体。然而，需要进一步优化聚合物递送系统以改善临床应用。因此，在原位肠袢系统中研究了ILP（L-ILP：180-230微米，S-ILP：43-89微米，SS-ILP：<43微米）粒径对胰岛素吸收的影响，假设较小粒径的ILP由于粘膜粘附能力增加可诱导更大的降血糖作用。为了验证该假设，评估了不同粒径ILP对粘膜组织的粘附能力。此外，还研究了ILP对胰岛素吸收的肠道部位特异性。还通过乳酸脱氢酶泄漏和膜电阻变化检查了细胞内和细胞间的完整性和/或损伤，以确保ILP作为口服载体的安全性。如假设的那样，与较大粒径的微粒相比，较小粒径的微粒（SS-ILP）显示出快速爆发型胰岛素释放和更高的胰岛素吸收，从而产生更大的降血糖作用且未检测到粘膜损伤。事实上，SS-ILP对空肠和回肠的粘膜粘附能力高于L-ILP。此外，SS-ILP对胰岛素粘膜吸收的增强作用具有部位特异性，在回肠段显示出最大效果。这些结果表明，粒径和递送部位是影响ILP口服给药后胰岛素生物利用度的非常重要的因素。
