Abstract

Docetaxel (DTX) is a highly lipophilic, BCS class IV drug with poor aqueous solubility (12.7 µg/mL). Presently, only injectable formulation is available in the market which uses a large amount of surfactant (Tween 80) and dehydrated alcohol as a solubilizer. High concentrations of Tween 80 in injectable formulations are associated with severe consequences i.e. nephrotoxicity, fluid retention, and hypersensitivity reactions. The present study aims to eliminate Tween 80, thus novel biocompatible surfactant Vitamin E TPGS based nanovesicle formulation of DTX (20 mg/mL) was developed and evaluated for different quality control parameters. Optimized nanovesicular formulation (NV-TPGS-3) showed nanometric size (102.9 ± 2.9 nm), spherical vesicular shape, high drug encapsulation efficiency (95.2 ± 0.5%), sustained-release profile and high dilution integrity with normal saline. In vitro cytotoxicity assay, showed threefold elevation in the IC₅₀ value of the optimized formulation in comparison to the commercial formulation. Further, no mortality and toxicity were observed during 28 days repeated dose sub-acute toxicity studies in Swiss albino mice up to the dose of 138 mg/kg, whereas, commercial formulation showed toxicity at 40 mg/kg. In addition, in vivo anticancer activity on Ehrlich Ascites Carcinoma induced mice showed a significant tumour growth inhibition of 76.3 ± 5.3% with the NV-TPGS-3 treatment when compared to Ehrlich Ascites Carcinoma control. Results demonstrated that the developed Vitamin E TPGS based nanovesicular formulation of DTX could be a better alternative to increase its clinical uses with improved therapeutic efficacy, reduced toxicity and dosing frequency, and sustained drug release behaviour.

摘要

多西紫杉醇 (DTX) 是一种高度亲脂性的 BCS IV 类药物，水溶性较差 (12.7 µg/mL)。目前市场上只有注射剂，它使用大量的表面活性剂（吐温80）和无水乙醇作为增溶剂。注射制剂中高浓度的吐温 80 会导致严重的后果，即肾毒性、体液潴留和超敏反应。本研究旨在消除吐温 80，因此开发了基于 DTX（20 毫克/毫升）的新型生物相容性表面活性剂维生素 E TPGS 纳米囊泡制剂，并评估了不同质量控制参数。优化的纳米囊泡制剂 (NV-TPGS-3) 具有纳米尺寸 (102.9 ± 2.9 nm)、球形囊泡形状、高药物包封率 (95.2 ± 0.5%)、体外细胞毒性试验表明，与商业制剂相比，优化制剂的 IC ₅₀值提高了三倍。此外，在瑞士白化小鼠中进行的 28 天重复剂量亚急性毒性研究中，在剂量高达 138 mg/kg 时未观察到死亡和毒性，而商业制剂在 40 mg/kg 时显示出毒性。此外，体内与 Ehrlich 腹水癌对照相比，NV-TPGS-3 治疗对 Ehrlich 腹水癌诱导的小鼠的抗癌活性显示出 76.3 ± 5.3% 的显着肿瘤生长抑制。结果表明，开发的基于维生素 E TPGS 的 DTX 纳米囊泡制剂可能是增加其临床用途的更好替代品，具有提高的治疗效果、降低的毒性和给药频率以及持续的药物释放行为。