Novel Vitamin E TPGS based docetaxel nanovesicle formulation for its safe and effective parenteral delivery: Toxicological, pharmacokinetic and pharmacodynamic evaluation

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.

Keywords:

• Vitamin E TPGS
• nanovesicle
• Tween 80
• acute and sub-acute toxicity studies
• pharmacokinetics
• pharmacodynamics

Acknowledgements

The authors are grateful to Government Medical College, Amritsar, Punjab, India for providing a facility for histopathology and IIIM, Jammu for cell line analysis and anticancer activity. The authors are also grateful to University Grant Commission (UGC), New Delhi to provide grants in aid to Guru Nanak Dev University, Amritsar under Rashtriya Uchchatar Shiksha Abhiyan (RUSA 2.0) Component 4.0 scheme.

Disclosure statement

The authors declare no conflict of interest in this work.

Additional information

Funding

The authors are thankful to the Department of Science of Technology (DST), New Delhi, India for providing financial support [Sanction no. EMR/2017/003648].