Structural Design of Micro-and Nano-gel Particles for Appropriate Controlled Release of Peptide Drugs

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The aim of the present research project is to develop nano-and micro-particulate systems with appropriate controlled release functions for peptide drug delivery. The proposed systems are directed to long-term delayed release for peroral colon-specific peptide delivery, externally temperature-activated periodically pulsatile release for chronopharmacological peptide delivery, and pH-dependent prolonged release using thermo-and pH-sensitive nanogels for oral peptide delivery. The results obtained are summarized as follows :1. The microcapsules composed of a lactose core, an insulin-layer and a coat of newly synthesized acrylic terpolymer made it possible to achieve a pH-independent delayed-release characterized by a lag-time and subsequent rapid insulin release. The microencapsulated insulin was found to be stable even after the storage at 4℃ for 24 months. In vivo oral administration studies of the microcapsules with a lag-time of 6h revealed a significant hypoglycemic effect, indicatin … More g insulin absorption through the colon. The pharmacological availability reached 5.1%.2. The microcapsules having an ability to thermosensitively control the drug-release could be achieved by fabricating an ethylcellulose matrix coat containing nano-sized p(NIPAAm) hydrogels onto a drug-layered core. Introduction of poly(□-caprolactone) macromer into p(NIPAAm) nanogels or use of hydroxypropylcellulose as an alternative thermosensitively component was useful to achieve distinct thermosensitive periodical pulsatile release.3. The nanogels composed of thermosensitive p(NIPAAm) core and pH sensitive (MAA-g-EG) shells (CSNPs) for oral peptide delivery were characterized in terms of drug loading capacity and muco-adhesive properties. Newly established drug-loading method was useful to significantly increase drug content (20 wt%). Atomic force microscopy (AFM) using colloidal probe of CSNPs for analyzing particle-mucin layer interaction could also be established : pH-dependent changes of interaction force were observed between CSNPs and mucin layer.4. As a solvent-free preparation process, dry-powder coating technique could be established. This technology is expected to process moisture-sensitive peptide-drug stably in an aseptic condition. Less