Enhancing biopharmaceutical performance of an anticancer drug by long chain PUFA based self-nanoemulsifying lipidic nanomicellar system.

The aim of this study was to develop polyunsaturated fatty acid (PUFA) long chain glyceride (LCG) enriched self-nanoemulsifying lipidic nanomicelles systems (SNELS) for augmenting lymphatic uptake and enhancing oral bioavailability of docetaxel and compare its biopharmaceutical performance with a medium-chain fatty acid glyceride (MCG) SNELS. Equilibrium solubility and pseudo ternary phase studies facilitated the selection of suitable LCG and MCG. The critical material attributes (CMAs) and critical process parameters (CPPs) were earmarked using Placket-Burman Design (PBD) and Fractional Factorial Design (FFD) for LCG- and MCG-SNELS respectively, and nano micelles were subsequently optimized using I- and D-optimal designs. Desirability function unearthed the optimized SNELS with Temul 85% and Perm45min >75%. The SNELS demonstrated efficient biocompatibility and energy dependent cellular uptake, reduced P-gp efflux and increased permeability using bi-directional Caco-2 model. Optimal PUFA enriched LCG-SNELS exhibited distinctly superior permeability and absorption parameters during ex vivo permeation, in situ single pass intestinal perfusion, lymphatic uptake and in vivo pharmacokinetic studies over MCG-SNELS. [Abstract copyright: Copyright © 2017. Published by Elsevier B.V.

Clathrin-mediated endocytic uptake of PUFA enriched self-nanoemulsifying lipidic systems (SNELS) of an anticancer drug against triple negative cancer and DMBA induced preclinical tumor model

The current studies envisage unravelling the underlying cellular internalisation mechanism of the systematically developed docetaxel (DTH) polyunsaturated fatty acid (PUFA) enriched self-nanoemulsifying lipidic micellar systems (SNELS). The concentration-, time- and cytotoxicity-related effects of DTH-SNELS on triple negative breast cancer (TNBC) MDA-MB-231 and non-TNBC MCF-7 cell lines were assessed through Presto-blue assay. Subsequently, rhodamine-123 (Rh-123) loaded SNELS were employed for evaluating their internalisation through flow cytometry and fluorescence microscopy, establishing it to be “clathrin-mediated” endocytic pathway. Apoptosis assay (65% cell death) and cell cycle distribution (47% inhibition at G2/M phase) further corroborated the cytotoxicity of DTH-SNELS towards cancerous cells. Biodistribution, histopathology and haematology studies indicated insignificant toxicity of the optimized formulation on vital organs. Preclinical anticancer efficacy studies using 7,12-dimethylbenzantracene (DMBA)-induced model construed significant reduction in breast tumor-volume. Overall, extensive in vitro and in vivo studies indicated the intracellular localization and cytotoxicity, suggesting DTH-SNELS as promising delivery systems for breast tumor therapeutics including TNBC

Enhancing Biopharmaceutical Attributes of Phospholipid Complex-loaded Nanostructured Lipidic Carriers of Mangiferin: Systematic Development, Characterization and Evaluation

Mangiferin (Mgf), largely expressed out from the leaves and stem bark of Mango, is a potent antioxidant. However, its in vivo activity gets tremendously reduced owing to poor aqueous solubility and inconsistent gastrointestinal absorption, high hepatic first-pass metabolism and high P-gp efflux. The current research work, therefore, was undertaken to overcome the biopharmaceutical hiccups by developing the Mgf-phospholipid complex (PLCs) loaded in nanostructured lipidic carriers (NLCs). The PLCs and NLCs were prepared using refluxing, solvent evaporation and hot emulsification technique, respectively with various molar ratios of Mgf and Phospholipon 90 G, i.e., 1:1; 1:2; and 1:3. The complex was evaluated for various physicochemical parameters like drug content (96.57%), aqueous solubility (25-fold improved) and oil-water partition coefficient (10-fold enhanced). Diverse studies on the prepared complex using FTIR, DSC, PXRD and SEM studies ratified the formation of PLCs at 1:1 ratio. The PLCs were further incorporated onto NLCs, which were systematically optimized employing a face centered cubic design (FCCD), while evaluating for particle size, zeta potential, encapsulation efficiency and in vitro drug release as the CQAs. Caco-2 cell line indicated insignificant cytotoxicity, and P-gp efflux, bi-directional permeability model and in situ perfusion studies specified enhanced intestinal permeation parameters. In vivo pharmacokinetic studies revealed notable increase in the values of Cmax (4.7-fold) and AUC (2.1-fold), respectively, from PLCs-loaded NLCs vis-à-vis Mgf solution. In a nutshell, the promising results observed from the present research work signified boosted biopharmaceutical potential of the optimized PLCs-loaded NLCs for potentially augmenting the therapeutic efficacy of Mgf

In vitro physicochemical characterization of nanocarriers: a road to optimization

Today's drug delivery scientists and pharmaceutical technologists own unprecedented variety of characterization techniques at their disposal not only to assign precise numerical values to the particle parameters but also to probe their developmental phases as well as their internal environment. Therefore, mechanistic understanding of structure-function relationships of nanotherapeutic systems seems to be a dynamic avowal considering the optimization of final nanoformulation system intended for biodistribution and targeting. This chapter aims to decipher the key in vitro physicochemical parameters in dry state, liquid state, as well as in both dry and liquid states, with the perspective of nanoparticle technology, and the diverse physical and experimental means in which these parameters can be demarcated. Further, an attempt has been made to introduce some best suited specialized techniques that enable to expand the accessible range of information to gain deeper insights into specific nanoplatform properties

In vitro physicochemical characterization of nanocarriers: a road to optimization

Today's drug delivery scientists and pharmaceutical technologists own unprecedented variety of characterization techniques at their disposal not only to assign precise numerical values to the particle parameters but also to probe their developmental phases as well as their internal environment. Therefore, mechanistic understanding of structure-function relationships of nanotherapeutic systems seems to be a dynamic avowal considering the optimization of final nanoformulation system intended for biodistribution and targeting. This chapter aims to decipher the key in vitro physicochemical parameters in dry state, liquid state, as well as in both dry and liquid states, with the perspective of nanoparticle technology, and the diverse physical and experimental means in which these parameters can be demarcated. Further, an attempt has been made to introduce some best suited specialized techniques that enable to expand the accessible range of information to gain deeper insights into specific nanoplatform properties

Engineered Site Specific Vesicular Systems for Colonic Delivery: Trends and Implications

Steering drug loaded, site-specific, coated lipid vesicles to the target receptor sites has the potential of plummeting adverse effects and improving the pharmacological response in diverse pathologies of large bowel, especially colon. Colonic delivery via oral route has its own challenges, often governed by several glitches such as drug degradation or absorption in the upper GIT, instability of proteins/peptides due to high molecular weight and peptidase activity in the stomach. Consequently, colon specific coated liposomal systems (CSLS) offer a potential alternate for not only site specificity, but protection from proteolytic activity, and prolonged residence time for greater systemic bioavailability. On the other hand, liposomal delivery via oral route is also cumbersome owing to several barriers such as instability in GIT, difficulty in crossing membranes and issues related to production at pilot scale. New advancements in the field of CSLS have successfully improved the stability and permeability of liposomes for oral delivery via modulating the compositions of lipid bilayers, adding polymers or ligands. Despite these ostensible propitiousnesses, no commercial oral CSLS has advanced from bench to bedside for targeted delivery to the colon as yet. Nevertheless, CSLS have quite fascinated the manufacturers owing to its potential industrial viability, simplistic and low-cost design. Hence, this review aims to decipher the convolutions involved in the engineering process of industrially viable CSLS for colonic delivery