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Synthesis of Novel Chitosan Derivatives for Micellar Solubilization of Cyclosporine A

Centre for Drug Discovery China Pharmaceutical University, Nanjing 210009, PR China

Song Ding

Centre for Drug Discovery China Pharmaceutical University, Nanjing 210009, PR China

Guowei Qu

Centre for Drug Discovery China Pharmaceutical University, Nanjing 210009, PR China

Can Zhang

Centre for Drug Discovery China Pharmaceutical University, Nanjing 210009, PR China, zhangcan{at}cpu.edu.cn

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 ofATMCs 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 (C₁₀—C ₁₈), and characterized by ¹H-NMR, ¹³C-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 (C₁₄) 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.

Key Words: drug delivery • chitosan • trimethyl chitosan • saturated fatty acid • absorption enhancer • micelle • Cyclosporine A • solubilization of insoluble drugs.

Journal of Bioactive and Compatible Polymers, Vol. 23, No. 6, 563-578 (2008)
DOI: 10.1177/0883911508097371


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