الفهرس 
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Abstract
The current study aimed to develop an optimized nanostructured lipid carrier (NLC) formula of Apixaban (APX), using Box-Behnken design of experiments, in order to enhance its oral bioavailability and anticoagulant activity. Additionally, surface modification of drug-loaded NLCs was carried out using PEGylation as well as chitosanization to study the influence of surface modification on in-vivo pharmacokinetic and pharmacodynamic profiles of APX. As solid lipid, liquid lipid, hydrophilic, and lipophilic stabilizers, stearic acid, oleic acid, Tween 80, and lecithin were used, respectively. Utilizing Box–Behnken design, the effects of three factors on NLC particle size (Y1), zeta potential (Y2), and entrapment efficiency percent (Y3) were examined and optimized. The optimized formula was prepared, characterized, morphologically studied, and pharmacokinetically and pharmacodynamically assessed. The observed responses of the optimized APX formula were 315.2 nm, -43.4 mV, and 89.84% for Y1, Y2, and Y3, respectively. Electron microscopy revealed the homogenous spherical shape of the NLC particles. The in-vivo pharmacokinetic study conducted in male Wistar rats displayed an increase in AUC and Cmax by 8 and 2.67 folds, respectively, compared to oral APX suspension. Moreover, the half-life was increased by 1.94 folds, and clearance was diminished by about 8 folds. Interestingly, the pharmacodynamic results displayed the superior effect of the optimized formula over the drug suspension with prolongation in the cuticle bleeding time. Moreover, both prothrombin time and activated partial thromboplastin time are significantly increased. We have investigated how chitosanization and PEGylation of NLCs affected their ability to function as a delivery system for APX. In-vitro and in-vivo studies were carried out to examine APX-loaded NLCs, chitosan-modified NLCs, and PEGylated NLCs. The three nanoarchitectures displayed an in-vitro Higuchi-diffusion release pattern and proved their vesicular outline via electron microscopy. PEGylation and chitosanization of NLCs retained good stability over 3 months versus the non-PEGylated and non-chitosanized NLCs. The absorption profile of APX (AUC0-inf) in rats pretreated with APX-loaded PEGylated NLCs (108.59 μg.ml−1.h−1) was significantly higher than AUC0-inf of APX in rats pretreated with APX-loaded chitosan-modified NLCs (93.397 μg.ml−1.h−1), and both were also significantly higher than AUC0-inf of APX-loaded NLCs (55.435 μg.ml−1.h−1).