Self Nanoemulsifying Drug Delivery System of Sorafenib Tosylate: Development and In Vivo Studies
Self Nanoemulsifying Drug Delivery System of Sorafenib Tosylate: Development and In Vivo Studies
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DOI：
10.2174/2211738508666201016151406
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发表时间：
2020-01-01
影响因子：
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通讯作者：
Bhikshapathi, Darna V. R. N.
中科院分区：
文献类型：
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作者：
Sandhya, Pamu;Poornima, Pamu;Bhikshapathi, Darna V. R. N.
背景资料：甲苯磺酸索拉非尼（SFN）属于BCS II类药物，溶解度低，易发生首过代谢，生物利用度降低38%。构建了准三元相图，根据相区选择纳米乳液的区域。共制备了15种SFN SNEDDS制剂，并使用热力学稳定性研究筛选了相分离和温度变化。这些SNEDDS进一步表征了%透射率、药物含量和体外溶出分析。结果：根据拟三元相图，确定了以Acrysol EL 135、Kolliphor和transcutol-P为油相、表面活性剂和助表面活性剂的处方。所有制剂都是稳定的，没有相分离，最大%透射率为98.92%。以最大药物含量为99.89%，1小时内药物释放度为98.94%，可稳定6个月，选择处方F15作为优化处方。根据体内生物利用度研究，优化SNEDDS的C-max（94.12 +/- 2.12ng/ml）高于纯SFN混悬液（15.32 +/- 1.46 ng/ml）和AUC优化的SNEDDS（0-无穷大）也增加了5倍（512.1 +/- 8.54 ng.h/m1）（98.75 +/- 6.45ng.h/ml），这表明制剂的生物利用度提高。SFN负载SNEDDS可以潜在地被开发作为用于通过最小化首过代谢和增加溶解度来改善口服生物利用度的递送系统。肾细胞癌占全球癌症诊断和死亡的2%，在过去的半个世纪里，它在发达国家的发病率增加了一倍多，如今它是美国第九大常见肿瘤索拉非尼是一种蛋白激酶抑制剂，适用于治疗晚期肾细胞癌。本研究旨在开发索拉非尼SNEDDS，以提高其溶解度和生物利用度。共制备了15种索拉非尼SNEDDS制剂，并使用热力学稳定性研究筛选了相分离和温度变化。与纯药物相比，索拉非尼SNEDDS可通过最小化首过代谢和增加溶解度，使口服生物利用度提高5倍。
Background: Sorafenib tosylate (SFN) belongs to the BCS class II drug with low solubility and undergoes first-pass metabolism, which leads to reduced bioavailability of 38%.Objective: The present study aimed at developing SFN SNEDDS to improve their solubility and bioavailability.Methods: Preliminary solubility studies were performed to identify oil, surfactant, and co-surfactant ratios. Pseudo tertiary phase diagram was constructed to select the areas of nanocmulsion based on the monophasic region. A total of 15 formulations of SFN SNEDDS were prepared and screened for phase separation and temperature variation using thermodynamic stability studies. These SNEDDS further characterized for % transmission, content of the drug, and in vitro dissolution analysis. The optimized formulation was analyzed for particle size, Z average, entrapment efficiency, and SEM analysis.Results: Based on the pseudo tertiary phase diagram, acrysol EL 135, kolliphor, and transcutol-P as oil, surfactant, and co-surfactant were selected, respectively. All the formulations were stable with no phase separation and maximum % transmittance of 98.92%. The formulation F15 was selected as an optimized one, based on maximum drug content of 99.89%, with 98.94% drug release within 1 hour and it will be stable for 6 months. From in vivo bioavailability studies, the C-max of optimized SNEDDS (94.12 +/- 2.12ng/ml) is higher than pure SFN suspension (15.32 +/- 1.46 ng/ml) and the AUC(0-infinity )of optimized SNEDDS is also increased by 5 times (512.1 +/- 8.54 ng.h/m1) than pure drug (98.75 +/- 6.45ng.h/ml), which indicates improved bioavailability of the formulation.Conclusion: SFN loaded SNEDDS could potentially be exploited as a delivery system for improving oral bioavailability by minimizing first-pass metabolism and increased solubility.Lay Summary: Renal cell carcinoma accounts for 2% of global cancer diagnoses and deaths, it has more than doubled in incidence in the developed world over the past half-century, and today is the ninth most common neoplasm in the United States. Sorafenib is a protein kinase inhibitor indicated as a treatment for advanced renal cell carcinoma. The present study aimed at developing Sorafenib SNEDDS to improve their solubility and bioavailability. A total of 15 formulations of Sorafenib SNEDDS were prepared and screened for phase separation and temperature variation using thermodynamic stability studies. Sorafenib loaded SNEDDS could potentially be exploited as a delivery system for increased oral bioavailability by 5 times when comparing with pure drug by minimizing first-pass metabolism and increased solubility.