| Atorvastatin calcium, the new 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, can competitively reduce the biosynthesis of cholesterol, significantly lower serum cholesterol and triglyceride levels, and with liver selectivity, which is currently better lipid-lowering drugs on clinical application. However, oral bioavailability of atorvastatin calcium is very low due to poor water solubility, gastrointestinal mucosal clearance and hepatic first pass metabolism. In recent years, solid lipid nanoparticles (SLNs) are alternative colloidal carrier system for controlled drug delivery. SLNs have attracted lots of interests due to high drug loading, good tolerability, physical stability, possibility of large-scale production, which could effectively promote oral absorption of poorly soluble drug.In this study, the HPLC analystical methods of atorvastatin calcium contained in sample were established, the results indicated that the analytical methods were acuity and reliable. SLNs were prepared by the emulsion/solvent evaporation method and quality was evaluated by size, Zeta potential and encapsulation efficiency. The prescription was optimized by single factor and central composite design and response surface method, and the best prescription was as follows:the dosage of atorvastatin calcium is 10.9 mg, glyceryl tripalmitin is 236.6 mg, palmitic acid is 63.4 mg, poloxamerl88 is 252.4 mg and sodium deoxycholate is 47.5 mg. The average particle size and Zeta potential were (158.3±4.23) nm and (-33.5±1.35) mV for ATC SLNs, (168.5±6.11) nm and (-36.0±2.06) mV for ATC CSK-SLNs, respectively. The encapsulation efficiencies of them were more than 75%. TEM demonstrated that all the ATC SLNs and ATC CSK-SLNs particles had spherical morphology and uniform size. The characterization of SLNs by FT-1R and DSC showed that atorvastatin calcium has been successfully dissolved in the solid lipid matrix and no crystal existed in SLNs. In vitro release assay the accumulated release percentages of atorvastatin calcium were about 80.9% at 72 h. Compared with atorvastatin calcium, ATC SLNs and ATC CSK-SLNs could be released in a sustained manner, and the drug behavior of CSK peptide modification SLNs was similar with that SLNs.Caco-2/HT29 co-cultured cell monolayer was used to evaluate the uptake in vitro. Compared with unmodified SLNs. CSK-SLNs exhibited more efficient cellular uptake as evidenced by confocal laser microscopy. Following the absorption mechanisms were studied using a modified in situ perfusion method in rats, which showed the absorption of ATC SLNs and ATC CSK-SLNs in duodenum, jejunum and ileum was increased. The Ka (0.076±0.23 min-1) and Papp (0.011±0.63 cm·min-1) of ATC CSK-SLNs raised to 2.97-fold and 2.99-fold in comparison with atorvastatin calcium solution, implying the CSK peptide modification for enhancement of the permeation of drugs across the epithelium.In conclusion, ATC SLNs and ATC CSK-SLNs were successfully prepared and characterized, the preparation process is simple and reproducible, both of them have a spherical morphology, uniform size, negative Zeta potential, and high drug entrapment efficiency with a sustained release profile in vitro. The results demonstrated that CSK peptide modified SLNs could significantly promote the oral absorption of atorvastatin calcium, the drug delivery system could be potential carriers for oral delivery of hydrophobic drugs across intestinal barriers. |
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