Interaction of Opioids with TLR4-Mechanisms and Ramifications.

The innate immune receptor toll-like receptor 4 (TLR4) is known as a sensor for the gram-negative bacterial cell wall component lipopolysaccharide (LPS). TLR4 activation leads to a strong pro-inflammatory response in macrophages; however, it is also recognised to play a key role in cancer. Recent studies of the opioid receptor (OR)-independent actions of opioids have identified that TLR4 can respond to opioids. Opioids are reported to weakly activate TLR4, but to significantly inhibit LPS-induced TLR4 activation. The action of opioids at TLR4 is suggested to be non-stereoselective, this is because OR-inactive (+)-isomers of opioids have been shown to activate or to inhibit TLR4 signalling, although there is some controversy in the literature. While some opioids can bind to the lipopolysaccharide (LPS)-binding cleft of the Myeloid Differentiation factor 2 (MD-2) co-receptor, pharmacological characterisation of the inhibition of opioids on LPS activation of TLR4 indicates a noncompetitive mechanism. In addition to a direct interaction at the receptor, opioids affect NF-κB activation downstream of both TLR4 and opioid receptors and modulate TLR4 expression, leading to a range of in vivo outcomes. Here, we review the literature reporting the activity of opioids at TLR4, its proposed mechanism(s), and the complex functional consequences of this interaction.

Carboxylate cross-linked cyclodextrin: A nanoporous scaffold for enhancement of rosuvastatin oral bioavailability.

Cyclodextrins play an important role in supramolecular chemistry acting as building blocks than can be cross-linked by various linker molecules forming nano-porous structures called nanosponges (NS). NS have the ability to enhance the stability, solubility and bioavailability of various actives. This work aimed at elaborating rosuvastatin (ROS) loaded NS to improve its oral bioavailability. Carboxylate-linked NS were synthesized by reacting ß-CD with pyromellitic dianhydride (PDA) at different molar ratios under specific conditions. ROS-loaded NS were prepared by lyophilisation technique and characterized for particle size, zeta potential, entrapment efficiency and drug release. Occurrence of cross-linking and ROS incorporation within the NS were assessed by DSC, FT-IR and SEM micrographs. NS prepared at a molar ratio of 1:6 of ß-CD: PDA demonstrated the highest entrapment efficiency (88.76%), an optimum particle size of 275nm, a narrow size distribution (PDI of 0.392), and zeta potential of -61.9 indicating good colloidal stability. In vivo oral pharmacokinetics study in male Sprague Dawley rats showed that ROS-NS provided an outstanding enhancement in oral bioavailability compared to drug suspension and marketed tablets besides their physicochemical stability for 3month. Accordingly, ROS-NS represent a superior alternative to the conventional marketed formulation for effective ROS delivery.

Hexagonal Liquid Crystalline Nanodispersions Proven Superiority for Enhanced Oral Delivery of Rosuvastatin: In Vitro Characterization and In Vivo Pharmacokinetic Study.

This study aimed to explore the potential of tailoring the liquid crystalline structure for augmenting the oral absorption and biopharmaceutical performance of rosuvastatin. Rosuvastatin (ROS)-loaded liquid crystalline nanodispersions (LCNDs) were prepared via emulsification technique. The effect of incorporating oleic acid (OA) in various proportions in the lipid domain of the LCNDs was studied. The formulations were characterized for particle size, zeta potential, in vitro release, ex vivo intestinal permeation, in vivo oral bioavailability, and stability. All the prepared LCNDs possessed uniform nanometric size and negative zeta potential. Employing OA in the lipid domain enhanced ROS entrapment efficiency, and resulted in structural transition from cubic to hexagonal phase as proved by transmission electron microscopy. Increasing OA proportion up to a certain ratio prolonged the in vitro drug release rate, after which further increase in OA had no significant effect. The OA bearing hexagonal LCNDs provided a significant enhancement in the intestinal permeation compared to glyceryl monooleate cubical nanodispersion and demonstrated an outstanding in vivo performance by maintaining higher ROS plasma levels up to 8 h and enhancing oral bioavailability compared to commercial tablet. They proved to be promising carriers for improved oral delivery of ROS with substantial bioavailability enhancing effects, and superiority compared to cubosomes and OA emulsion.