Synthesis of Novel Chitosan Derivatives for Micellar Solubilization of Cyclosporine A

摘要

In this study, the solubilization of poor water-soluble drugs using N-acyl, O-acyl-N-trimethyl chitosan chloride (ATMC) micelles as a carrier system was investigated. Three series of ATMCs were synthesized by N-trimethyl chitosan chloride (TMC) with substitutions of 21.3, 44.8, and 45.2% as start material grafting five different long-chain saturated fatty acids (C_(10)-C_(18)), and characterized by ~1H-NMR, ~(13)C-NMR, and FT-IR spectra, respectively. The degree of long-chain acyl group of ATMC was ～8.1%. These ATMC micelles self-assemble and were used to encapsulate the poorly soluble drug, Cyclosporine A. These assemblies were prepared by a dialysis, wherein the drug loading capacity of the ATMC micelles ranged from 9.6% to 17.1% and encapsulation capacity ranged from 35.8% to 69.8%, with the mean micellar particle size of 288 nm. The critical micellar concentrations of the 70,000 Mw ATMC2 were 0.028-0.038 mg/mL. Nanoscale near-spherical ATMC micelles were observed by transmission electron microscopy. Additionally, the chitosan derivatives with a high methylation degree, medium-sized long-chain acyl groups (C_(14)) and large molecular weight had the most effective capacity for loading Cyclosporine A. These ATMC micelles are being investigated as carriers to improve oral administration absorption of poorly permeable drugs.