Self-nanoemulsifying drug delivery system (SNEDDS) of docetaxel and carvacrol synergizes the anticancer activity and enables safer toxicity profile: optimization, and in-vitro, ex-vivo and in-vivo pharmacokinetic evaluation.

Abstract

Docetaxel (DTX) is a first-line chemotherapeutic molecule with a broad-spectrum anticancer activity. On the other hand, carvacrol (CV) has anti-inflammatory, antioxidant, cytotoxic, and hepatoprotective properties that could reduce undue toxicity caused by DTX chemotherapy. Thus, in order to overcome the challenges posed by DTX's poor aqueous solubility, low permeability, hepatic first pass, and systemic toxicities, we have developed a novel solid self-nanoemulsifying drug delivery system (S-SNEDDS) co-loaded with DTX and CV. In the present investigation, liquid-SNEDDS (L-SNEDDS) were fabricated using Nigella sativa oil, Cremophor RH 40, and Ethanol which was converted into solid by lyophilization using Aerosil 200. The reconstituted CV-DTX-S-SNEDDS showed an average globule size of < 200nm with promising flow properties (angle of repose θ: 33.22 ± 0.06). Additionally, 2.3-fold higher dissolution of DTX was observed from CV-DTX-S-SNEDDS after 6h as compared to free DTX. Similar trend was followed in dialysis release experiments with 1.5-fold higher release within 24h. Ex vivo permeation studies demonstrated significantly increased permeation of 1077.02 ± 12.72μg/cm2 of CV-DTX-S-SNEDDS after 12h. In vitro cell cytotoxicity studies revealed 5.2-fold reduction in IC50 as compared to free DTX in MDA-MB-231 cells. Formulation was able to induce higher apoptosis in cells treated with CV-DTX-S-SNEDDS as compared to free DTX and CV. It was evident from toxicity studies that CV-DTX-S-SNEDDS was well tolerated at higher dose where CV was able to manage the toxic effects of free DTX. In vivo pharmacokinetic study showed 3.4-fold increased Cmax and improved oral bioavailability as compared to free DTX. Thus, CV-DTX-S-SNEDDS could be an encouraging option for facilitating DTX oral therapy.