Design Of Self-nanoemulsifying System For Poorly Water-soluble Drugs And Study Of Oral Absorption

With the discovery of new drug targets as well as the wide application of highthroughput screening and combinatorial chemistry synthesis technology,more and more compounds with highly potent receptor activity were emerging,but low solubility limits their application.Self-nanoemulsifying systems(SNEs)have excellent ability to improve the solubility of poorly water-soluble drugs(PWSD).Compared to traditional nanoparticles,SNEs are degraded in gastrointestinal tract(GIT)when their surface is recognized by lipase/co-lipase enzyme complex,resulting in rapid release and precipitation of encapsulated drugs.The precipitates are then captured and removed by intestinal mucus,reducing the delivery efficacy of SNEs.Thus,to overcome enzyme and mucus barriers,the amphiphilic polymer Pluronic? F127 was incorporated into long and short-chain triglycerides(LCT,SCT)based SNEs to increase the steric hindrance,and diminish the recognition and therefore minimized their degradation by enzymes and clearance by mucus.We prepared four formulations: SCT-SNE,SCT-F127-SNE,LCT-SNE and LCT-F127-SNE.The SNEs were characterized in terms of particle size,zeta potential and stability.The average particle size of SNEs was 100 nm.The structure was observed under transmission electron microscopy(TEM),showing sphere-like morphology obtained for both SNEs.In vitro studies showed that SNEs were stable in phosphate buffer saline(PBS)and simulated gastric fluid(SGF).However,SCT-SNE and SCT-F127-SNE had approximately 35.7% 48.2% reduction in fluorescence in simulated intestinal fluid(SIF),and the particle size and PDI increased dramatically.The in vitro digestion rate of SNEs were found to be in following order SCT-SNE > SCT-F127-SNE > LCT-SNE > LCT-F127-SNE.Ex vivo multiple particles tracking studies showed that SNEs modified with 5% F127 exhibited increased diffusivity in the mucus.The mucus penetration of DiI loaded SNEs were studied with confocal microscopy using z-stack scanning technique in mucus secreting HT29 MTX E12(E12)cells.Three dimensional(3D)images reconstructed from a series of z-stack images revealed that LCT-F127-SNE could increase the concentration of DiI in the mucus,Moreover,the LCT-F127-SNE was found to be most effective in enhancing cellular uptake,resulting in 3.5-fold,2.1-fold and 1.7-fold higher than that of SCT-SNE,LCT-SNE and SCT-F127-SNE,respectively.Ex vivo absorption studies also showed that LCT-F127-SNE could enhance Di I concentration in ileum villi by improving their mucus penetration property.Cyclosporine A(CsA)was used as the model drug.The in vivo results revealed that orally administered LCT-F127-SNE could significantly increase the bioavailability of CsA,which was approximately 2.43-fold,1.33-fold and 1.80-fold higher than that of SCT-SNE,SCT-F127-SNE and LCT-SNE,respectively.We address in this work that F127-modified SNEs have potentials to improve oral drug absorption by significantly reducing gastrointestinal enzymatic degradation and simultaneously enhancing mucus penetration.