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Preparation and Optimization of Rivaroxaban by Self-Nanoemulsifying Drug Delivery System (SNEDDS) for Enhanced Oral Bioavailability and No Food Effect

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Abstract

In this paper, a novel self-nanoemulsifying drug delivery system (SNEDDS) was used to improve the oral bioavailability in fasted state and diminish the food effect for rivaroxaban. Oil, surfactant, and co-surfactant were selected by saturated solubility study. IPM, Tween80, and 1,2-propanediol were finally selected as oil, surfactant, and co-surfactant, respectively. The pseudo-ternary-phase diagram was utilized to optimize the preliminary composition of SNEDDS formulation. The optimized rivaroxaban-SNEDDS formulation was selected by central composite design (CCD) of response surface methodology. Optimized SNEDDS formulation was evaluated for drug content, self-emulsifying time, droplet size, zeta potential, polydispersity index, Fourier transform-infrared (FTIR) spectroscopy, and transmission electron microscope (TEM). The drug dissolution profile compared to the commercial formulation Xarelto® (20 mg rivaroxaban) was determined in four different media (pH 1.2HCl, pH 4.5NaAc-HAc, pH 6.8PBS, and water). The result indicated that the SNEDDS formulation had successfully increased the drug solubility in four different media. A HPLC-MS method that indicated a high sensitivity, strong attribute, and high accuracy characteristic was built to measure the drug concentration in plasma. The fast/fed in vivo pharmacokinetics studies of SNEDDS formulation and Xarelto® were carried out in adult beagle dog, rivaroxaban with no food effect was achieved in SNEDDS formulation compared with Xarelto® in fed state. The result suggested that SNEDDS formulation in this study is useful to increase the oral bioavailability and diminish the food effect in fasted state.

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Authors and Affiliations

  1. School of Pharmacy, Nanjing Tech University, 5th Mofan Road, Nanjing, 210009, China

    Xu Xue, Mengyuan Cao, Lili Ren, Yiwen Qian & Guoguang Chen

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  1. Xu Xue
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  2. Mengyuan Cao
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  3. Lili Ren
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Correspondence to Lili Ren or Guoguang Chen.

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Xue, X., Cao, M., Ren, L. et al. Preparation and Optimization of Rivaroxaban by Self-Nanoemulsifying Drug Delivery System (SNEDDS) for Enhanced Oral Bioavailability and No Food Effect. AAPS PharmSciTech 19, 1847–1859 (2018). https://doi.org/10.1208/s12249-018-0991-6

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