Paliperidone-Loaded Nanolipomer System for Sustained Delivery and Enhanced Intestinal Permeation: Superiority to Polymeric and Solid Lipid Nanoparticles.

Paliperidone (PPD) is the most recent second-generation atypical antipsychotic approved for the treatment of schizophrenia. An immediate release dose causes extrapyramidal side effects. In this work, a novel nanolipomer carrier system for PPD with enhanced intestinal permeability and sustained release properties has been developed and optimized. PPD was successfully encapsulated into a lipomer consisting of a specific combination of biocompatible materials including poly-ε-caprolactone as a polymeric core, Lipoid S75, and Gelucire® 50/13 as a lipid shell and polyvinyl alcohol as a stabilizing agent. The lipomer system was characterized by dynamic light scattering, TEM, DSC, and FTIR. An optimized lipomer formulation possessed a particle size of 168 nm, PDI of 0.2, zeta potential of -23 mV and an encapsulation efficiency of 87.27% ± 0.098. Stability in simulated gastrointestinal fluids investigated in terms of particle size, zeta potential, and encapsulation efficiency measurements ensured the integrity of the nanoparticles upon oral administration. PPD-loaded nanolipomers demonstrated a superior sustained release behavior up to 24 h and better ex vivo intestinal permeation for PPD compared to the corresponding polymeric and solid lipid nanoparticles and drug suspension. The in vitro hemocompatibility test on red blood cells revealed no hemolytic effect of PPD-loaded lipomers which reflects its safety. The elaborated nanohybrid carrier system represents a promising candidate for enhancing the absorption of PPD providing a 2.6-fold increase in the intestinal permeation flux compared to the drug suspension while maintaining a sustained release behavior. It is a convenient alternative to the commercially available dosage form of PPD.

An insight on human skin penetration of diflunisal: lipogel versus hydrogel microemulsion.

Diflunisal is a NSAID used in acute and long term management of pain and inflammation associated with osteoarthritis, rheumatoid arthritis and symptoms of primary dysmenorrhea. However, its oral use is associated with side effects such as peptic ulceration, dyspepsia, gastrointestinal disturbances and bleeding. The aim of this work was to develop lecithin organogels (LO) transdermal delivery system for diflunisal and to study its human skin penetration ability in comparison with an optimized microemulsion-based hydrogel. Ternary phase diagrams were constructed using butyl lactate as an organic solvent and two commercial grades of lecithin. The formation of gel phase was lecithin concentration dependent with Phosholipion 85 G being capable of forming organogels at lower lecithin concentration than Lipoid S75. The gels prepared using butyl lactate were able to tolerate higher amounts of water than could be incorporated in the lipogels prepared with other organic solvents. All the investigated gels possessed acceptable physical properties and were able to deliver diflunisal through human skin. The lipogels delivered higher total drug amount through the skin than the hydrogel. The composition of lecithin seemed to have some effect on the skin permeability enhancement ability of the lipogel. Lecithin containing higher amount of phosphatidyl ethanolamine could provide better transdermal delivery. The elaborated lecithin organogels are potential carriers that create a good opportunity for transdermal delivery of diflunisal overcoming the side effects associating its oral route.

A modern approach for controlled transdermal delivery of diflunisal: optimization and in vivo evaluation.

The purpose of the present work was to elaborate an optimized transdermal therapeutic system for diflunisal. Selection of suitable ingredients was done via solubility and phase behavior studies. Composition of microemulsion (ME) systems consisting of butyl lactate, Brij(®) 97, Transcutol(®) and water was optimized using augmented simplex lattice mixture design. The independent variables selected were the percentages of butyl lactate, surfactant mixture and water. The dependent variables were refractive index, pH, conductivity, viscosity, drug solubility in the ME formulation and the ex vivo skin permeation flux. Mathematical equations and response surface plots were used to relate the dependent and independent variables. The statistical validity of the polynomials was established. Optimized formulation factors were selected by desirability approach. The optimized ME formulation was converted into gel using Carbomer(®) 934. The microemulsion based gel (MBG) showed better spreadability and 5.07-fold increase in the transdermal flux than Carbomer(®) 934 gel. The in vivo antihyperalgesia assay performed on mice showed significant reduction of the licking time in the treated group compared to the control group. This demonstrated the reliability of the simplex lattice statistical design for predicting optimum ME formulation. The developed MBG proved its in vivo efficiency for transdermal delivery of diflunisal.

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.

Rationally designed nanocarriers for intranasaltherapy of allergic rhinitis: influence of carrier type on in vivo nasal deposition.

The aim of this study is to develop a locally acting nasal delivery system of triamcinolone acetonide (TA) for the maintenance therapy of allergic rhinitis. The effect of encapsulating TA in different nanocarriers on its mucosal permeation and retention as well as in vivo nasal deposition has been studied. A comparative study was established between polymeric oil core nanocapsules (NCs), lipid nanocarriers such as nanoemulsion (NE), and nanostructured lipid carriers (NLCs). The elaborated nanocarriers were compared with TA suspension and the commercially available suspension "Nasacort(®)". The study revealed that NC provided the highest mucosal retention, as 46.14%±0.048% of the TA initial dose was retained after 24 hours, while showing the least permeation through the nasal mucosa. On the other hand, for TA suspension and Nasacort(®), the mucosal retention did not exceed 23.5%±0.047% of the initial dose after 24 hours. For NE and NLC, values of mucosal retention were 19.4%±0.041% and 10.97%±0.13%, respectively. NC also showed lower mucosal irritation and superior stability compared with NE. The in vivo nasal deposition study demonstrated that NC maintained drug in its site of action (nasal cavity mucosa) for the longest period of time. The elaborated polymeric oil core NCs are efficient carriers for the administration of nasally acting TA as it produced the least permeation results, thus decreasing systemic absorption of TA. Although NCs have been administered via various routes, this is the first study to implement the polymeric oil core NC as an efficient carrier for localized nasal drug delivery.