期刊
MOLECULAR PHARMACEUTICS
卷 7, 期 4, 页码 1169-1182出版社
AMER CHEMICAL SOC
DOI: 10.1021/mp100033k
关键词
Cyclosporin A; monomethoxy poly(ethylene glycol)-b-poly(D,L-lactic acid); polymeric micelles; oral administration; Caco-2 cells; transport mechanism; P-glycoprotein
资金
- National Development of Significant New Drugs [2009zx09310-001]
- National Basic Research Program of China [2009CB930300]
To improve the oral bioavailability of poorly water-soluble cyclosporin A (CyA), polymeric micelles based on monomethoxy poly(ethylene glycol)-b-poly(D,L-lactic acid) (mPEG-PLA) were prepared. In vitro release test showed that the cumulative release percentage, about 85%, of CyA from polymeric micelles within 24 h was comparable to that from Sandimmun Neoral, the currently available oral formulation of CyA. A relative oral bioavailability of 137% in rats compared with Sandimmun Neoral was demonstrated for CyA-loaded polymeric micelles. The other aim of the current work was to study the transport mechanism of mPEG-PLA micelles across the intestinal barrier. It was found that polymeric micelles could significantly increase the permeability of CyA across Caco-2 monolayers without significantly affecting transepithelial electrical resistance values, and the apparent permeation coefficient (P-app) of CyA was significantly higher in the AP-BL direction compared to that in the BL-AP direction, suggesting that polymeric micelles might undergo an active AP to BL transport that probably involved endocytosis which was confirmed by confocal microscope observation. The permeation of CyA through Caco-2 monolayers showed that the P-app was significantly increased when CyA was formulated with the copolymer below its critical association concentration (CAC) and no significant difference was found above its CAC, implying that mPEG-PLA monomers affected the intestinal P-gp efflux pumps. Therefore, the mPEG-PLA micelles seemed to be a good candidate for oral delivery of poorly soluble drugs.
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