Formulation optimization of Docetaxel loaded self-emulsifying drug delivery system to enhance bioavailability and anti-tumor activity.

Guru R Valicherla,Akhilesh Singh,Wahajuddin Wahajuddin,Anand P Gupta,Kandarp M Dave,Kalyan Mitra,Dipak Datta,Jiaur R Gayen,Anees A Syed,Mohammed Riyazuddin

doi:10.1038/srep26895

Abstract

Poor bioavailability of Docetaxel (DCT) arising due to its low aqueous solubility and permeability limits its clinical utility. The aim of the present study was to develop DCT loaded self-emulsified drug delivery systems (D-SEDDS) and evaluate its potential ability to improve the oral bioavailability and therapeutic efficacy of DCT. D-SEDDS were characterized for their in vitro antitumor activity, in situ single pass intestinal perfusion (SPIP), bioavailability, chylomicron flow blocking study and bio-distribution profile. The D-SEDDS were prepared using Capryol 90, Vitamin E TPGS, Gelucire 44/14 and Transcutol HP with a ratio of 32.7/29.4/8.3/29.6 using D-Optimal Mixture Design. The solubility of DCT was improved upto 50 mg/mL. The oral bioavailability of the D-SEDDS in rats (21.84 ± 3.12%) was increased by 3.19 fold than orally administered Taxotere (6.85 ± 1.82%). The enhanced bioavailability was probably due to increase in solubility and permeability. In SPIP, effective permeability of D-SEDDS was significantly higher than Taxotere. D-SEDDS showed 25 fold more in vitro cytotoxic activity compared to free DCT. Chylomicron flow blocking study and tissue distribution demonstrated the intestinal lymphatic transport of D-SEDDS and higher retention in tumor than Taxotere. The data suggests that D-SEDDS showed desired stability, enhanced oral bioavailability and in vitro antitumor efficacy.

Highlights

Docetaxel (DCT), a second generation taxoid, is twice as potent as Paclitaxel (PCT) in stabilization and inhibition of microtubule depolymerisation in vitro[1]
Maximum solubility of DCT was observed in Transcutol HP (173.13 ± 5.96 mg/mL) followed by Gelucire 44/14 (54.39 ± 1.87 mg/mL), Vit E TPGS (47.63 ± 1.56 mg/mL) and Capryol 90 (45.15 ± 6.03 mg/mL)
Visual appearance suggested that a surfactant concentration of greater than 60% solidified the formulations while a Capryol 90 concentration of greater than 40% decreased the solubility and increased the droplet size

Summary

Introduction

Docetaxel (DCT), a second generation taxoid, is twice as potent as Paclitaxel (PCT) in stabilization and inhibition of microtubule depolymerisation in vitro[1]. Taxotere and Duopafei are available for clinical use but still oral administration is restricted due to poor aqueous solubility, P-glycoprotein (P-gp) mediated drug efflux, pre-absorptive metabolism by gut membrane-bound cytochrome enzymes, hepatic first-pass metabolism, and decreased gastrointestinal membrane permeability that leads to low oral bioavailability[5,6,7]. SEDDS can enhance the bioavailability by avoiding the first pass metabolism, increasing drug stability in harsh GI environment, facilitating intestinal lymphatic transport of drugs, preventing pre-absorptive metabolism by gut membrane-bound cytochrome enzymes and inhibiting P-gp mediated drug efflux[8,9]. The applicability of DoE in pharmaceutical industries is increasing enormously because FDA recommends and approves quality by design based experiments[19] In this present study, DCT-loaded SEDDS (D-SEDDS) were formulated to improve the oral bioavailability as well as antitumor properties of DCT. Bio-distribution of DCT in tissues upon administration of optimized formulation was compared with commercially available Taxotere

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Discussion

Conclusion