Ravi R. Patel

Lipopolysaccharide based oral nanocarriers for the improvement of bioavailability and anticancer efficacy of curcumin

Soluthin MD(®), a unique phosphatidylcholine-maltodextrin based hydrophilic lipopolysaccharide, which exhibits superior biocompatibility and bioavailability enhancer properties for poorly water soluble drug(s). Curcumin (CUR) is a potential natural anticancer drug with low bioavailability due to poor aqueous solubility. The study aims at formulation and optimization of CUR loaded lipopolysaccharide nanocarriers (C-LPNCs) to enhance oral bioavailability and anticancer efficacy in colon-26 tumor-bearing mice in vitro and in vivo. The Optimized C-LPNCs demonstrated favorable mean particle size (108 ± 3.4 nm) and percent entrapment efficiency (65.29 ± 1.0%). Pharmacokinetic parameters revealed ∼130-fold increase in oral bioavailability and cytotoxicity studies demonstrated ∼23-fold reduction in 50% cell growth inhibition when treated with optimized C-LPNCs as compared to pure CUR. In vivo anticancer study performed with optimized C-LPNCs showed significant increase in efficacy compared with pure CUR. Thus, lipopolysaccharide nanocarriers show potential delivery strategy to improve oral bioavailability and anticancer efficacy of CUR in the treatment of colorectal cancer.

Development and optimization of curcumin-loaded mannosylated chitosan nanoparticles using response surface methodology in the treatment of visceral leishmaniasis.

Objective: The study aims at formulation and optimization of macrophage-targeted curcumin-loaded mannosylated chitosan nanoparticles (Cur-MCNPs) of curcumin (CUR) to improve its therapeutic potential in the treatment of visceral leishmaniasis (VL). Methods: Response surface methodology (RSM) using central composite design was employed to study the effect of formulation factors on physicochemical-dependent characteristics. Chitosan was coupled with d-mannose, by reductive amination, to prepare a mannosylated chitosan, a conjugate polymer and a subsequent formulation of Cur-MCNPs. Optimized formulation prepared using RSM was evaluated for in vitro release kinetics at physiological pH 7.4 and endosomal macrophage pH 4.5; in vivo pharmacokinetic profile and targeting potential were evaluated by fluorescence microscopy. Results: Optimized Cur-MCNPs exhibited spherical and smooth surface with a mean particle size of 215 nm, polydispersity index of 0.381, zeta potential of + 24.37 mV and % entrapment efficiency of 82.12%. The pharmacokinetic study of optimized Cur-MCNPs showed significant improvement in the value of mean resident time (39.38 h) compared to free CUR solution (0.30 h) (p < 0.05). In vivo uptake study indicated that endocytosis took place effectively within the macrophages of reticuloendothelial system. Conclusions: Thus, Cur-MCNPs could be considered as a promising delivery strategy towards active targeting of CUR to macrophages for the effective treatment of VL.

Rationally developed core–shell polymeric-lipid hybrid nanoparticles as a delivery vehicle for cromolyn sodium: implications of lipid envelop on in vitro and in vivo behaviour of nanoparticles upon oral administration

In the present study, cromolyn sodium (CS), a highly water soluble molecule was encapsulated into rationally designed, core–shell polymeric-lipid hybrid nanoparticles (PLHNs) for enhancing its oral bioavailability, by improving its intestinal permeability through lymphatic uptake. The CS encapsulated PLGA–lecithin based core–shell PLHNs (CS–PLHNs) were engineered by a double emulsification solvent evaporation method and optimized using a response surface methodology based “Quality by Design” approach. The Box–Behnken experimental design was imperatively enforced to enhance encapsulation of CS inside PLHNs without compromising particle size. Optimized CS–PLHNs exhibited a particle size of 227 ± 3.8 nm and EE of 57.8 ± 1.32% with unimodal size distribution. The physico-chemical characterizations of CS–PLHNs suggested the encapsulation of CS in an amorphous form inside PLHNs without any interactions. The morphological studies pointed towards the existence of smooth, spherical core–shell architecture of CS–PLHNs, which extended release up to 48 h by a controlled diffusion process. The optimized CS–PLHNs exhibited remarkable stability at different environmental conditions as well as in biological milieu. An ex vivo intestinal permeation study showed that the permeation of CS was significantly improved by encapsulating it inside PLHNs compared to that of pure CS, which was additionally confirmed by the in vivo intestinal uptake study using confocal microscopy. A pharmacokinetic study in rats further exhibited 11.9 fold enhancement in the oral bioavailability of CS after its incorporation into PLHNs. In a nutshell, PLHNs can serve as a superior therapeutic carrier system by imparting lipophilicity to potentially obtain the high oral bioavailability of CS, which can further be extended towards numerous hydrophilic drug molecules.

Curcumin-polymeric nanoparticles against colon-26 tumor-bearing mice: cytotoxicity, pharmacokinetic and anticancer efficacy studies

Abstract Context: Curcumin (CUR), can inhibit proliferation and induce apoptosis of tumor cells, its extreme insolubility and limited bioavailability restricted its clinical application. Objective: An innovative polymeric nanoparticle of CUR has been developed to enhance the bioavailability and anti-cancer efficacy of CUR, in vitro and in vivo. Materials and methods: Cationic copolymer Eudragit E 100 was selected as carrier, which can enhance properties of poor bioavailable chemotherapeutic drugs (CUR). The CUR-loaded Eudragit E 100 nanoparticles (CENPs) were prepared by emulsification-diffusion-evaporation method. The in vitro cytotoxicity study of CENPs was carried out using sulphorhodamine B assay. Pharmacokinetic and anti-cancer efficacy of CENPs was investigated in Wister rats as well as colon-26 tumor-bearing mice after oral administration. Results: CENPs showed acceptable particle size and percent entrapment efficiency. In vitro cytotoxicity studies in terms of 50% cell growth inhibition values demonstrated ∼19-fold reduction when treated with CENPs as compared to pure CUR. ∼91-fold increase in Cmax and ∼95-fold increase in AUC0–12h were observed indicating a significant enhancement in the oral bioavailability of CUR when orally administered as CENPs compared to pure CUR. The in vivo anti-cancer study performed with CENPs showed a significant increase in efficacy compared with pure CUR, as observed by tumor volume, body weight and survival rate. Conclusions: The results clearly indicate that the developed polymeric nanoparticles offer a great potential to improve bioavailability and anticancer efficacy of hydrophobic chemotherapeutic drug.

Atorvastatin calcium encapsulated eudragit nanoparticles with enhanced oral bioavailability, safety and efficacy profile

Abstract Atorvastatin calcium (ATR), a second generation statin drug, was encapsulated in eudragit RSPO-based polymeric nanoparticles. The effect of independent variables (polymer content, stabilizer concentration, volume of chloroform and homogenization speed) on response variables (mean diameter particle size and entrapment efficiency) were investigated by employing central composite experimental design. All the independent variables were found to be significant for determining the response variables. Solid-state characterization study indicated the absence of physicochemical interaction between drug and polymer in formulation. Morphological study exhibited homogenous spherical shape of formulated nanoparticles. In vitro release study in phosphate buffer (pH 7.4) demonstrated sustained release profile over 24 h. Pharmacokinetic study in Charles Foster rats showed significant enhancement in oral bioavailability as compared to pure drug suspension. Efficacy study (lipid profile and blood glucose level) significantly justified the effectiveness of formulation having 50% less dose of ATR as compared to pure drug suspension. The effectiveness of formulation was further justified with an improved plasma safety profile of treated rats. Hence, ATR encapsulated eudragit RSPO nanoparticles can serve as potential drug delivery approach to enhance drug bioavailability, efficacy and safety profiles to alter existing marketed drug products.

Tinidazole functionalized homogeneous electrospun chitosan/poly (ε-caprolactone) hybrid nanofiber membrane: Development, optimization and its clinical implications

We have prepared tinidazole (TNZ) functionalized biodegradable chitosan (CH)/poly (ε-caprolactone) (PCL) mucoadhesive hybrid nanofiber membrane (TNZ-PCHNF) to alleviate existing shortcomings in treatment of periodontitis. Box-Behnken design was employed for evaluating influence of formulation and processing variables on quality of final formulation. Optimized nanofiber membrane was subjected to solid-state and surface characterization studies using FTIR, DSC, XRD, SEM and AFM, which revealed that TNZ was entrapped in an amorphous form inside smooth and uniform cylindrical nanofibers without any physicochemical interaction with excipients. The optimized TNZ-PCHNF membrane had a diameter of 143.55±8.5nm and entrapment efficiency of 83.25±1.8%. In vitro drug release and antibacterial study demonstrated capability of the developed nanofiber membranes for efficiently delivering TNZ in a sustained manner up to 18days, and its ability to inhibit bacterial growth, respectively. Further, reduction of contact angle (from 123.4±2.5 to 27.4±2.3) revealed that blending of CH with PCL increases hydrophilicity of the nanofiber membrane. MTT assay and CLSM study suggested that nanofiber membrane was devoid of cytotoxicity on mouse fibroblasts. Moreover, preliminary clinical trials on patients proved therapeutic efficacy of the nanofiber membrane by eliciting a significant (p<0.05) decrease in clinical markers of periodontitis.

Atorvastatin calcium loaded PCL nanoparticles: development, optimization, in vitro and in vivo assessments

The aim of the present study was to prepare atorvastatin calcium (ATR) loaded poly(e-caprolactone) nanoparticles (ALPNs) to enhance the oral bioavailability, efficacy and safety profile of drug. ALPNs were prepared by a nanoprecipitation technique while formulation and process parameters were optimized using a central composite factorial design. The optimized ALPNs were investigated through in vitro (solid state characterization, morphological, drug release study and stability study) analysis and in vivo (pharmacokinetic, efficacy and safety study) behaviour in rats. The optimized ALPNs having 197 ± 5 nm particle size, 0.213 ± 0.012 polydispersity index and 75.6 ± 3.2% entrapment efficiency, did not exhibit any physicochemical interaction of the drug with the carrier. The X-ray diffraction, differential scanning calorimetry and electron diffraction pattern has substantiated the amorphous character of ATR encapsulated in nanoparticles. The smooth and homogeneous spherical shape of the nanoparticles was evidenced in morphological analyses. The in vitro drug release profile of ALPNs showed a 96 h sustained release and the pharmacokinetic profile in rats exhibited significant enhancement in bioavailability, Cmax and mean resident time of the drug. ALPNs exhibited similar efficacy (plasma lipid profile and glucose level) and markedly improved biochemical safety profiles (creatinine, blood urea nitrogen, creatinine kinase, lactate dehydrogenase and aspartate amino transferase) of rat plasma at a 50% reduced dose compared to orally administered ATR.

Mannose-conjugated curcumin-chitosan nanoparticles: Efficacy and toxicity assessments against Leishmania donovani

Aim was to fabricate and optimize CUR-loaded mannose-functionalized chitosan nanoparticles (Cur-MCN) which overcome the limitations of drugs to reach the intracellular locations and to establish its therapeutic potential in visceral leishmaniasis by targeting of CUR to macrophages. Cur-MCN were developed by mannose-conjugated chitosan and have been tested for their efficacy and toxicit. In vivo antileishmanial activity in hamsters has shown significantly greater suppression of parasite replication in the spleen with Cur-MCN than unconjugated chitosan nanoparticles. The in vitro cytotoxicity study against the J774A.1 cell line demonstrated its comparative non-toxicity towards the macrophage cells. The potential of Cur-MCN was also confirmed by minimal observed cytotoxicity in our in vivo studies.

Exemestane encapsulated vitamin E-TPGS–polymeric nanoparticles: preparation, optimization, characterization, and in vitro cytotoxicity assessment

Abstract The objective of the present study was to formulate and optimize exemestane (EXM) encapsulated vitamin E-TPGS–poly-ɛ-caprolactone based polymeric nanoparticles (TPGS–PCLNPs) for enhancing its anticancer efficacy. The 23 factorial design was employed to investigate the combined influence of formulation and process variables on properties of TPGS–PCLNPs, prepared by nanoprecipitation method. The physicochemical characterization revealed the encapsulation of EXM in amorphous form without any interaction inside spherical shaped TPGS–PCLNPs. In vitro cytotoxicity study on MCF-7 breast cancer cells exhibited enhanced cytotoxicity of EXM by encapsulating in TPGS–PCLNPs. The TPGS–PCLNPs can serve as potential delivery vehicle for EXM to improve its therapeutic efficacy.

Development, optimization and evaluation of tinidazole functionalized electrospun poly(ε-caprolactone) nanofiber membranes for the treatment of periodontitis

The aim of this study was to alleviate shortcomings in the treatment of periodontitis by electrospinning of a novel biodegradable poly(e-caprolactone) (PCL) based nanofiber membrane functionalized with tinidazole (TNZ). Box–Behnken design was employed for evaluating influence of formulation and processing variables on entrapment efficiency (EE) and diameter of nanofiber. The optimum batch selected by desirability approach was subjected to physicochemical characterization such as FTIR, DSC and PXRD which revealed entrapment of drug in a molecular dispersion devoid of any chemical interaction with the excipients. Electron microscopy showed smooth structure in nanometre range, without any visible sign of fiber break-up or disruption within the nanofiber membrane. Optimized TNZ-PCL nanofiber membrane exhibited a diameter of 147.6 ± 7.6 nm and EE 84.36 ± 1.5%. In vitro release study and antibacterial study demonstrated sustained drug release for up to 20 days, depending upon the drug to polymer ratio and solvent composition. Further, reduction of contact angle (from 123.6 ± 2.8 to 57.2 ± 1.9) revealed that incorporation of TNZ enhanced the hydrophilicity of the nanofiber membrane which would facilitate its adhesion to the site of action and instigate proliferation of cells. MTT assay and CLSM study suggested that nanofiber membrane showed no cytotoxicity on mouse fibroblasts (L-929 cell lines). Moreover, in vivo study by ligature-induced periodontitis in rats confirmed that TNZ loaded nanofiber membrane can significantly (p < 0.05) improve continuity of epithelium and transseptal fiber of interdental papilla in comparison to tinidazole gel.