Self-nanoemulsifying drug delivery system of docosahexanoic acid: development, in vitro, in vivo characterization.

CONTEXT: Docosahexanoic acid (DHA) is an essential omega-3 fatty acid for normal brain development and its use has increased considerably in recent years. OBJECTIVE: The aim of this study is to develop and evaluate self-nanoemulsifying drug delivery systems (SNEDDS) of DHA for improved palatability, dispersibility and bioavailability. METHODS: The SNEDDS were prepared and evaluated for miscibility, employing different combinations of olive oil and soyabean oil as oil phase, Span 80, Span 20, soya phosphatidylcholine, Labrafil M 1944 CS as surfactants while Tween 80, PEG 400, Cremophor RH40 and propylene glycol as cosurfactants. Thermodynamically stable SNEDDS were characterized for dispersibility, self-emulsification time, droplet size, zeta potential along with sensory analysis. The optimized formulation was subjected to ex vivo and in vivo evaluation such as intestinal permeability, memory performance test, brain concentration and histopathology studies. RESULTS: The optimized SNEDDS formulation showed emulsification time of 27 ± 4.7 s with droplet size of 17.6 ± 3.5 nm and zeta potential of -37.6 ± 0.5 mV. Intestinal absorption study depicted 18.3%, 21.5%, 41.5%, 98.7% absorption of DHA with SNEDDS-based formulation in comparison to 8.2%, 15.1%, 28.8%, 46.1% absorption of DHA with oil-based marketed formulation after 0.5, 1, 2 and 4 h. DHA concentration in brain homogenate was found to be increased to 2.6-fold in comparison to DHA-marketed formulation. This could be ascribed to enhanced dispersibility and bioavailability of DHA from nanosized formulation. CONCLUSION: The developed formulation led to enhanced dispersibility and bioavailability of DHA due to the formation of nanodroplets.

Paclitaxel Loaded Nanoliposomes in Thermosensitive Hydrogel: A Dual Approach for Sustained and Localized Delivery.

In an attempt to improve the localized paclitaxel delivery, carrier based thermoresponsive chitosan hydrogel was exploited in the present study. Nanoliposomes as carrier for paclitaxel were prepared and optimized in strength of 6 mg/ml similar to marketed paclitaxel formulation. The chitosan solution (2% w/v) mixed with different concentrations of dibasic sodium phosphate (DSP) was evaluated as thermoresponsive systems in terms of gelling temperature and time. Finally, the drug loaded nanoliposomes were incorporated in optimized chitosan- DSP hydrogel base to form nanoliposomal in situ thermosensitive hydrogel formulations having dual mechanism of protection and release. The optimal formulation containing DSP was selected on the basis of minimal gelation temperature (37±0.8 ºC) and time (6.7±0.3 min). In vitro drug release experiment illustrated that developed formulation manifested sustained release action in which drug release was extended for more than 72 h compared to marketed formulation. In addition, optimized nanoliposomal hydrogel demonstrated enhanced biological half-life of 15.7±1.5h, depicting maintenance of constant plasma concentration in contrast to marketed formulation that showed the half-life (t1/2) of 3.6±0.4h. The in vivo anti tumor activity tested using EAC model also corroborated the above findings that developed formulation was having significant higher anti-tumor activity and reduced toxicity than the marketed formulation. Tumor volume was found to reduce upto 89.1±3.5% by treatment with in situ hydrogel formulation. The histopathological study of tumor also demonstrated the better safety and efficacy of developed formulation in comparison to marketed paclitaxel formulation. Our results suggest that carrier based chitosan hydrogel could be an efficacious vehicle for sustained and localized delivery of paclitaxel.

The Sojourn from Parenteral to Oral Taxanes using Nanocarrier Systems: A Patent Review.

Natural diterpenoid taxanes and their semisynthetic analogues have already made an indelible mark in the chemotherapeutic world for treating various kinds of malignancies. However, due to the absence of any functional groups which could be ionized by pH alteration or which may participate in salt formation, these taxanes, exhibit low solubility. Parenteral administration of taxanes with solubilising agents such as Cremophor EL and Polysorbate 80 results in undesirable side effects like hypersensitivity reactions, myelosuppression and peripheral neuropathy. Nanoengineered drug delivery systems like nanoemulsions, nanocrystals, dendrimers, micelles, selfnanoemulsifying systems, liposomes, solid-lipid nanoparticles and biodegradable polymeric nanoparticles, in this regard, tend to surmount these ostensible challenges, when administered orally. The bare taxanes encounter several inadequacies, namely poor aqueous solubility, structural instability in physiological fluids, p-glycoprotein recognition, hepatic first-pass effect, gastrointestinal permeability, and Cytochrome P450 enzymatic metabolism, etc. In addition, nanoscaled oral delivery improves drug encapsulation, thus facilitating diffusion through intestinal epithelium, modification of pharmacokinetic and tissue distribution profile of the drug, eventually resulting in flexibility of dosing schedules, prevention of discomfort of the injection and hospitalization, and improved patient convenience. The current review paper endeavors to provide a bird's eye view on the significant headway made on orally-administered nanosystems of taxanes and their analogues through patent applications published till date since its discovery.

Emerging Strategies and Challenges for Controlled Delivery of Taxanes: A Comprehensive Review.

Taxanes introduction in the mid 90 s leads to significant advancement as well as superlative improvement in the treatment of cancer. Since then, several strategies have been designed to enhance therapeutic potential of these agents by overcoming the limitations in drug delivery and pharmacokinetic constraints associated with conventional delivery. In this regard, controlled drug delivery systems for taxanes have contributed enormously by altering the pharmacokinetic profile, thus ultimately enhancing their therapeutic response. With their conferred stellar merits, controlled drug delivery systems have been able to surmount many of the challenges associated with conventional drug delivery systems. The altered absorption, resistance, low toxicity and cellular uptake profiles that lead to better safety from variegated carrier systems like nanocarriers, liposomes, solid lipid nanoparticles, nanoemulsions, nanocapsules, hydrogels and micelles for controlled delivery of taxanes call for an exhaustive review for future progressive work. Therefore, this review focuses on the altered pharmacokinetic, pharmacodynamic and toxicity patterns achieved from various controlled drug delivery approaches, with the latter half highlighting the clinical profile set ups and commercial aspects of controlled release drug delivery systems.

Nanovesicular carrier-based formulation for skin cancer targeting: evaluation of cytotoxicity, intracellular uptake, and preclinical anticancer activity.

CONTEXT: Skin cancer has turned into global epidemic leading to higher incidences among cancer stricken population. OBJECTIVE: The aim of the present investigation is to evaluate the anticancer potential and intracellular uptake of a novel nanovesicular formulation of 5-FU. MATERIALS AND METHODS: Detailed intracellular uptake study in conjunction with estimation of intracellular reactive oxygen species was done using skin melanoma cell lines (A375) along with cytotoxicity studies. To further obtain the mechanistic insights into inhibition of tumor cell proliferation, cell-cycle arrest studies were conducted. The preclinical anticancer activity was carried out employing in vivo DMBA-croton oil-induced skin cancer model in mice. RESULTS AND DISCUSSION: Significant reduction in the number of papillomas was observed in skin cancer-bearing mice on treatment with nanovesicular formulation (51.4 ± 3.2%) in comparison with marketed formulation (21.3 ± 2.1%) of 5-FU. Tumor volume was found to be reduced to 46.3 ± 3.5% with prepared formulation, whereas the marketed formulation-treated group showed the reduction of 18.6 ± 1.8% in comparison with the control (untreated) group. CONCLUSION: The results of present study demonstrated that nanovesicular formulation of 5-FU possessed the enhanced anticancer activity which could be attributed to better intracellular uptake, cellular retention, and sustained release of drug.

Anti-cancer, pharmacokinetic and biodistribution studies of cremophor el free alternative paclitaxel formulation.

PURPOSE: The aim of the present investigation is to determine the in vivo potential of previously developed and optimized Cremophor EL free paclitaxel (CF-PTX) formulation consisting of soya phosphatidylcholine and biosurfactant sodium deoxycholate. CF-PTX was found to have drug loading of 6 mg/ml similar to Cremophor EL based marketed paclitaxel formulation. In the present study, intracellular uptake, repeated dose 28 days sub-acute toxicity, anti-cancer activity, biodistribution and pharmacokinetic studies were conducted to determine in vivo performance of CF-PTX formulation in comparison to marketed paclitaxel formulation. METHODS: Intracellular uptake of CF-PTX was studied using A549 cells by fluorescence activated cell sorting assay (FACS) and fluorescence microscopy. In vivo anti-cancer activity of CF-PTX was evaluated using Ehrlich ascites carcinoma (EAC) model in mice followed by biodistribution and pharmacokinetic studies. RESULTS: FACS investigation showed that fluorescence marker acridine orange (AO) solution showed only 19.8±1.1% intracellular uptake where as significantly higher uptake was observed in the case of AO loaded CF-PTX formulation (85.4±2.3%). The percentage reduction in tumor volume for CF-PTX (72.5±2.3%) in EAC bearing mice was found to be significantly (p<0.05) higher than marketed formulation (58.6±2.8%) on 14th day of treatment. Pharmacokinetic and biodistribution studies showed sustained plasma concentration of paclitaxel depicted by higher mean residence time (MRT; 18.2±1.8 h) and elimination half life (12.8±0.6 h) with CF-PTX formulation as compared to marketed formulation which showed 4.4±0.2 h MRT and 3.6±0.4 h half life. The results of the present study demonstrated better in vivo performance of CF-PTX and this formulation appears to be a promising carrier for sustained and targeted delivery of paclitaxel.