Bioavailability enhancement, Caco-2 cells uptake and intestinal transport of orally administered lopinavir-loaded PLGA nanoparticles.

Nanoparticles (NPs) can be absorbed via M cells of Peyer's patches after oral delivery leading to passive lymphatic targeting followed by systemic drug delivery. Hence, the study was aimed to formulate PLGA NPs of lopinavir. The NPs were prepared by nanoprecipitation, optimized by 33 factorial design and characterized by TEM, DSC, FTIR studies and safety was assessed by MTT assay. In vivo pharmacokinetic studies were performed in rats. The NPs were discrete spherical structures having particle size of 142.1 ± 2.13 nm and entrapment of 93.03 ± 1.27%. There was absence of drug-polymer interaction. Confocal images revealed the penetration and absorption of coumarin-loaded NPs in Caco-2 cells and intestine after oral delivery. There was 3.04 folds permeability and 13.9 folds bioavailability enhancement from NPs. The NPs can be promising delivery system for antiretroviral drug by delivering the drug to lymph (major HIV reservoir site) via direct absorption through intestine before reaching systemic circulation.

Enhanced bioavailability and intestinal uptake of Gemcitabine HCl loaded PLGA nanoparticles after oral delivery.

The aim of study was to formulate PLGA nanoparticles (NPs) of Gemcitabine HCl for enhanced oral bioavailability via absorption through M cells of Peyer's patches. Commercially, the drug is available as i.v. infusion due to its short half life (8-17 min), rapid metabolism and limited tumor uptake. The NPs were prepared by multiple solvent emulsification method. Optimized formulation had particle size of 166.4±2.42 nm, and entrapment of 56.48±3.63%. TEM image revealed discrete spherical structures of NPs. DSC and FTIR studies confirmed absence of interaction between drug and polymer. In vitro and ex vivo studies demonstrated sustained release from the NPs. The enhanced absorption and uptake of NPs in Caco-2 cells and in vivo absorption in intestinal tissue after oral delivery in rats was confirmed by confocal microscopy. Transport studies in Caco-2 cells confirmed 6.37-fold permeability for NPs. In vitro antiproliferative studies confirmed marked cytotoxicity of NPs on K562 leukemia cell lines. In vivo pharmacokinetic studies in rats showed 21.47-folds bioavailability enhancement from NPs. Hence, orally delivered Gemcitabine HCl loaded NPs have the potential for improving its bioavailability and avoiding side effects associated with iv infusions as well as enhancing patient compliance through "Chemotherapy at Home".

Application of multiple regression analysis in optimization of anastrozole-loaded PLGA nanoparticles.

The present investigation deals with development of anastrozole-loaded PLGA nanoparticles (NPs) as an alternate to conventional cancer therapy. The NPs were prepared by nanoprecipitation method and optimized using multiple regression analysis. Independent variables included drug:polymer ratio (X1), polymer concentration in organic phase (X2) and surfactant concentration in aqueous phase (X3) while dependent variables were percentage drug entrapment (PDE) and particle size (PS). Results of desirability criteria, check point analysis and normalized error were considered for selecting the formulation with highest PDE and lowest PS. Prepared NPs were characterized for zeta potential, transmission electron microscopy (TEM), differential scanning calorimetry (DSC) and in vitro drug release studies. DSC and TEM studies indicated absence of any drug-polymer interaction and spherical nature of NPs, respectively. In vitro drug release showed biphasic pattern exhibiting Fickian diffusion-based release mechanism. This delivery system of anastrozole is expected to reduce the side effects associated with the conventional cancer therapy by reducing dosing frequency.

Development of solid lipid nanoparticles based controlled release system for topical delivery of terbinafine hydrochloride.

The study describes the development and evaluation of solid lipid nanoparticles (SLNs) of terbinafine hydrochloride (TH) for sustained release and skin targeting. TH-loaded SLNs were prepared by solvent-injection technique and optimized using 3(3) full-factorial design. Effect of drug:lipid ratio, surfactant concentration and volume of organic solvent were studied on % entrapment efficiency (%EE) and particle size (PS). The optimum formulation based on desirability (0.945) exhibited %EE of 73.74% and PS of 300 nm. Optimized SLNs were incorporated into Carbopol gel and evaluated for drug content, pH, in vitro release, ex vivo retention, in vivo pharmacodynamic and stability studies. Drug release from SLNs dispersion followed Korsmeyer-Peppas model, indicating Fickian drug release, while that from the gel followed Higuchi model. The ex vivo studies through rat abdominal skin indicated skin retention ability of SLNs as compared to commercial product. In vivo pharmacodynamic studies showed that the SLNs based gel reduced fungal burden of Candida albicans in rats as compared to commercial product in shorter duration of time. The SLNs dispersion and gel exhibited physicochemical stability under refrigeration upto 3 months. It was concluded that SLNs incorporated Carbopol gel had skin targeting ability and may serve as a promising carrier in treatment of fungal skin infections.

Design and development of multiple emulsion for enhancement of oral bioavailability of acyclovir.

The objective of this investigation was to design and develop water-in-oil-in-water type multiple emulsions (w/o/w emulsions) entrapping acyclovir for improving its oral bioavailability. Multiple emulsions (MEs) were prepared and optimized using Span-80 and Span-83 as lipophilic surfactant and Brij-35 as hydrophilic surfactant. The physio-chemical properties of the w/o/w emulsions - particle size, viscosity, phase separation (centrifugation test) and entrapment efficiency were measured and evaluated along with macroscopic and microscopic observations to confirm multiple nature, homogeneity and globule size. Stability study, in vitro and ex vivo release studies were performed followed by in vivo studies in rats. Stable w/o/w emulsions with a particle size of 33.098 ± 2.985 µm and 85.25 ± 4.865% entrapment efficiency were obtained. Stability studies showed that the concentration of lipophilic surfactant was very important for stability of MEs. Drug release from the prepared formulations showed initial rapid release followed by a much slower release. In vivo studies in rats indicated prolonged release and better oral bioavailability as compared to drug solution. The overall results of this study show the potential of the w/o/w emulsions as promising drug delivery systems for acyclovir.

Encapsulation of exemestane in polycaprolactone nanoparticles: optimization, characterization, and release kinetics.

This study was aimed at developing a polymeric drug delivery system for a steroidal aromatase inhibitor, exemestane (exe) intended for sustained targeted delivery of drug through intravenous route. Carboxylated polycaprolactone (cPCL) was synthesized by ring opening polymerization of caprolactone. Exe-loaded cPCL nanoparticles (NPs) were prepared by interfacial deposition of preformed polymer and characterized. A 3-factor, 3-level Box-Behnken design was used to derive a second-order polynomial equation and construct contour and response plots for maximized response of percentage drug entrapment (PDE) with constraints on particle size (PS). The independent variables selected were ratio of exe/cPCL, amount of cPCL, and volume of organic phase. Polymerization of caprolactone to cPCL was confirmed by Fourier transform infrared (FTIR) and gel permeation chromatography. The prepared NPs were evaluated for differential scanning calorimetry (DSC), transmission electron microscopy (TEM), and in vitro release studies. Optimum formulation based on desirability (1.0) exhibited PDE of 83.96 % and PS of 180.5 nm. Check point analysis confirmed the role of the derived polynomial equation and contour plots in predicting the responses. Zeta potential of optimized formulation was -33.8 ± 2.1 mV. DSC studies confirmed the absence of any interaction between drug and polymer. TEM image showed non-aggregated and spherical shaped NPs. Drug release from NPs showed sustained release and followed Korsmeyer-Peppas model, indicating Fickian drug release. Thus, preparation of exe-loaded cPCL NPs with high PDE and desired PS suitable for providing passive targeting could be statistically optimized using Box-Behnken design.

Opsonization, biodistribution, cellular uptake and apoptosis study of PEGylated PBCA nanoparticle as potential drug delivery carrier.

PURPOSE: For nanocarrier-based targeted delivery systems, preventing phagocytosis for prolong circulation half life is a crucial task. PEGylated poly(n-butylcyano acrylate) (PBCA) NP has proven a promising approach for drug delivery, but an easy and reliable method of PEGylation of PBCA has faced a major bottleneck. METHODS: PEGylated PBCA NPs containing docetaxel (DTX) by modified anionic polymerization reaction in aqueous acidic media containing amine functional PEG were made as an single step PEGylation method. In vitro colloidal stability studies using salt aggregation method and antiopsonization property of prepared NPs using mouse macrophage cell line RAW264 were performed. In vitro performance of anticancer activity of prepared formulations was checked on MCF7 cell line. NPs were radiolabeled with 99mTc and intravenously administered to study blood clearance and biodistribution in mice model. RESULTS: These formulations very effectively prevented phagocytosis and found excellent carrier for drug delivery purpose. In vivo studies display long circulation half life of PBCA-PEG20 NP in comparison to other formulations tested. CONCLUSIONS: The PEGylated PBCA formulation can work as a novel tool for drug delivery which can prevent RES uptake and prolong circulation half life.

Bone metastasis targeting: a novel approach to reach bone using Zoledronate anchored PLGA nanoparticle as carrier system loaded with Docetaxel.

In spite of good research in drug delivery, bone targeting remains largely unexplored. Even some of the bone diseases are seldom cured just because of poor distribution of drug at the bone site. Zoledronate (ZOL) having strong affinity towards bone and its utility in bone metastasis management makes it perfect ligand for bone targeting. Recent studies revealed that ZOL in combination with docetaxel showed significant synergism in the management of bone metastasis. From the results, it is clear that ZOL-conjugated PLGA nanoparticles (NPs) showed more cellular uptake than pegylated PLGA NPs with change in cellular uptake route. In vitro studies on MCF-7 and BO2 cell line revealed that ZOL anchored PLGA-PEG NPs showed enhanced cell cytotoxicity, increase in cell cycle arrest and more apoptotic activity. PLGA-PEG-ZOL NPs found to block mevalonate pathway and increase accumulation of apoptotic metabolites such as ApppI. In vivo animal studies using technetium-99m radiolabeling showed prolong blood circulation half-life, reduced liver uptake and significantly higher retention of ZOL tagged NPs at the bone site with enhanced tumor retention. Here, we can conclude that the targeting ability of ZOL enhanced by strong affinity to bone, enhanced endocytosis of ZOL anchored PLGA-PEG NPs.