経皮経粘膜吸収とDDS

pH応答性高分子のインスリン経口製剤への応用

抄録

The potential of graft copolymer networks with poly (methacrylic acid-g-ethylene glycol ; P(MAA-g-EG) for oral dosage forms to enhance insulin absorption is reviewed. The polymer exhibited unique pH-responsive characteristics in which interpolymer complexes were formed and dissociated, respectively, in acidic and neutral/basic environments ; the latter forming hydrogels. Correspondingly, the polymer was capable of highly incorporating (94%) and rapidly releasing (<20 min) insulin in vitro. The swelling ratio, mesh size of the gel structure, and insulin incorporation of P (MAA-g-EG) were maximized when the polymer contained equimolar MAA and PEG (molecular weight=1000). This insulin loaded polymer was orally administered to both diabetic and non-diabetic rats. The polymer successfully enhanced insulin absorption in both animal groups, achieving 4.2% bioavailability(relative to subcutaneous administration) with significant hypoglycemic effects. Enhanced insulin absorption was demonstrated with direct intestinal administration (in situ closed loop) with a maximum effect seen in the ileum. This implies that the polymer has a direct absorption enhancing effect local to the intestine in addition to the protective effect (inhibition of insulin release) as the insulin loaded polymer passes through the low pH environment of the stomach. Indeed, it was shown in vitro that enzymatic degradation of insulin in intestinal fluid (pH=7.4) was inhibited in the presence of P (MAA-g-EG). The polymer was also shown to possess mucoadhesive properties, when the hydrogels were formed. Furthermore, the polymer demonstrated high calcium binding and water absorption, which may affect the proteolytic activity of calcium-dependent enzymes and/or reduce transepithelial resistances. Consequently, it was suggested that P (MAA-g-EG) was advantageous by virtue of pH-responsive interpolymer complexation (protection from enzymatic digestion and rapid release on absorption site), mucaadhesion, and protease inhibition and/or tight junction opening due to calcium-binding. Thus, the polymer has the potential to be used as a carrier for oral dosage forms of insulin to enhance its absorption following administration.