Fabrication of polymeric nanoparticles of poly(ethylene‐co‐vinyl acetate) coated with chitosan for pulmonary delivery of carvedilol

Carvedilol is a drug with low oral bioavailability due to its high first‐pass metabolism. The purpose of the present study was to prepare a mucoadhesive dry powder inhaler of this drug loaded in poly(ethylene‐co‐vinyl acetate)(PEVA) nanoparticles for pulmonary delivery. PEVA nanoparticles were prepared by an O/W solvent evaporation method and coated with different concentrations of chitosan as a mucoadhesive polymer. Encapsulation efficiency, particle size, zeta potential, release efficiency, and mucoadhesive properties of the different formulations were evaluated on mucin substrate. The optimized formulation of nanoparticles was spray dried using lactose and mannitol as carrier powders. The flowability of the obtained powders was checked by Carr's Index and Hausner ratio and the in vitro deposition of the aerosolized drug was investigated using a Next Generation Impactor. Increasing in the particle size and zeta potential of nanoparticles confirmed the settling of the chitosan coating layer on the surface of nanoparticles. The in vitro drug release from coated nanoparticles decreased with increasing of chitosan concentration. Mucoadhesive property of chitosan‐coated PEVA nanoparticles was higher than noncoated ones. Spray‐dried powders had different aerosilization behavior. Mannitol‐based formulation was found to have low density, better flow ability, smaller aerodynamic diameter (d_aer) and higher fine powder fraction. The results of the present study allow concluding that mannitol spray dried, mucoadhesive nanoparticles of PEVA are suitable inhaler powder for pulmonary delivery of carvedilol. © 2013 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2014 , 131, 39694.     

Efavirenz oral delivery via lipid nanocapsules: formulation,optimisation, and ex‐vivo gut permeation study

Present investigation aimed to prepare, optimise, and characterise lipid nanocapsules (LNCs) for improving the solubility and bioavailability of efavirenz (EFV). EFV‐loaded LNCs were prepared by the phase‐inversion temperature method and the influence of various formulation variables was assessed using Box–Behnken design. The prepared formulations were characterised for particle size, polydispersity index (PdI), zeta potential, encapsulation efficiency (EE), and release efficiency (RE). The biocompatibility of optimised formulation on Caco‐2 cells was determined using 3‐[4,5‐dimethylthiazol‐2‐yl]‐2,5‐diphenyltetrazolium bromide assay. Then, it was subjected to ex‐vivo permeation using rat intestine. EFV‐loaded LNCs were found to be spherical shape in the range of 20–100 nm with EE of 82–97%. The best results obtained from LNCs prepared by 17.5% labrafac and 10% solutol HS15 when the volume ratio of the diluting aqueous phase to the initial emulsion was 3.5. The mean particle size, zeta potential, PdI, EE, drug loading%, and RE during 144 h of optimised formulation were confirmed to 60.71 nm, −35.93 mV, 0.09, 92.60, 7.39 and 55.96%, respectively. Optimised LNCs increased the ex vivo intestinal permeation of EFV when compared with drug suspension. Thus, LNCs could be promising for improved oral delivery of EFV.Inspec keywords: biomedical materials, solubility, drugs, encapsulation, emulsions, nanoparticles, particle size, nanofabrication, suspensions, toxicology, nanomedicine, cellular biophysics, lipid bilayers, electrokinetic effects, drug delivery systems, molecular biophysicsOther keywords: ex‐vivo permeation, diluting aqueous phase, mean particle size, zeta potential, drug loading, optimised formulation, ex vivo intestinal permeation, improved oral delivery, efavirenz oral delivery, optimisation, ex‐vivo gut permeation study, solubility, bioavailability, phase‐inversion temperature method, formulation variables, Box–Behnken design, polydispersity index, encapsulation efficiency, Caco‐2 cells, lipid nanocapsules, 3‐[4,5‐dimethylthiazol‐2‐yl]‐2,5‐diphenyltetrazolium bromide assay, EFV‐loaded LNC, drug suspension, size 20.0 nm to 100.0 nm, time 144.0 hour, size 60.71 nm, voltage ‐35.93 mV     

Synthesis of biotin‐targeted chitosan/poly (methyl vinyl ether‐alt ‐maleic acid) copolymeric micelles for delivery of doxorubicin

Biotinylated chitosan/poly(methyl vinyl ether‐alt ‐maleic acid) (PMVEMA) copolymer was synthesised by an amide reaction in two steps. Structural characterisation was performed using ¹ HNMR and Fourier transform infra‐red (FTIR) spectra. Critical micelle concentration (CMC) of the copolymer was determined by pyrene as a fluorescent probe. Doxorubicin (DOX) was loaded in the micelles by the direct dissolution method. The effects of different variables including type of copolymer, copolymer concentration, stirring rate and stirring time were studied on the physicochemical properties of the micelles including: particle size, zeta potential, release efficiency and loading efficiency of nanoparticles using an irregular factorial design. The in vitro cytotoxicity of DOX‐loaded biotin‐targeted micelles was studied in HepG2 cells which over express biotin receptors by 3, 5‐[dimethylthiazol‐2‐yl]‐2, 5‐diphenyl tetrazolium bromide assay. The successful synthesis of the biotinylated copolymer of chitosan/PMVEMA was confirmed by FTIR and ¹ HNMR. The optimised micelles showed the CMC of 33 μg/ml, particle size of 247 ± 2 nm, zeta potential of +9.46 mV, polydispersity index of 0.22, drug‐loading efficiency of 71% and release efficiency of 84.5 ± 1.6%. The synthesised copolymer was not cytotoxic. The cytotoxicity of DOX‐loaded in targeted micelles on HepG2 cell line was about 2.2‐fold compared with free drug.Inspec keywords: biomedical materials, cellular biophysics, dissolving, drug delivery systems, drugs, electrokinetic effects, fluorescence, Fourier transform infrared spectra, particle size, polymer blends, spectrochemical analysis, toxicologyOther keywords: ¹ HNMR spectra, biotin‐targeted chitosan‐poly (methyl vinyl ether‐alt‐maleic acid) copolymeric micelles, doxorubicin delivery, amide reaction, structural characterisation, Fourier transform infrared spectra, pyrene, fluorescent probe, direct dissolution method, physicochemical properties, particle size, zeta potential, nanoparticles, irregular factorial design, in vitro cytotoxicity, DOX‐loaded biotin‐targeted micelles, 3, 5‐[dimethylthiazol‐2‐yl]‐2, 5‐diphenyl tetrazolium bromide assay, polydispersity index, drug‐loading efficiency, HepG2 cell line, voltage 9.46 mV     

In‐vitro and in‐vivo evaluation of chitosan‐based thermosensitive gel containing lorazepam NLCs for the treatment of status epilepticus

The objective of this study was to develop an in‐situ gel containing lorazepam (LZM) loaded nanostructured lipid carriers (NLCs) for direct nose‐to‐brain delivery in order to increase drug therapeutic efficacy in the treatment of epilepsy. Accordingly, LZM loaded NLCs were formulated using emulsification solvent diffusion and evaporation method; then the effects of the formulation variables on different physicochemical characteristics of NLCs were investigated. Thermosensitive in‐situ gels containing LZM‐NLCs were prepared using a combination of chitosan and β‐glycerol phosphate (β‐GP). The anticonvulsant efficacy of LZM‐NLCs‐Gel was then examined using the pentylenetetrazole (PTZ) model. The optimised NLCs were spherical, showing the particle size of 71.70 ± 5.16 nm and the zeta potential of −20.06 ± 2.70 mV. The pH and gelation time for the chitosan solution with 15% (w/v) β‐GP were determined to be 7.12 ± 0.03 and 5.33 ± 0.58 min, respectively. The in‐vivo findings showed that compared with the control group and the group that received LZM‐Gel, the occurrence of PTZ‐induced seizures in the rats was significantly reduced by LZM‐NLCs‐Gel after intranasal administration. These results, therefore, suggested that the LZM‐NLCs‐Gel system could have potential applications for brain targeting through nasal route and might increase LZM therapeutic efficacy in the treatment of epilepsy.Inspec keywords: biomedical materials, nanomedicine, cellular biophysics, electrokinetic effects, drug delivery systems, nanoparticles, brain, pH, drugs, particle size, nanofabrication, medical disorders, polymer gelsOther keywords: evaporation method, β‐glycerol phosphate, β‐GP, optimised NLCs, received LZM‐Gel, LZM therapeutic efficacy, chitosan‐based thermosensitive gel, lorazepam NLCs, nose‐to‐brain delivery, drug therapeutic efficacy, emulsification solvent diffusion, in‐vivo evaluation, in‐vitro evaluation, LZM‐NLC‐gel system, status epilepticus treatment, lorazepam loaded nanostructured lipid carriers, epilepsy treatment, physicochemical characteristics, thermosensitive in‐situ gel, anticonvulsant efficacy, pentylenetetrazole model, particle size, zeta potential, pH, gelation time, chitosan solution, PTZ‐induced seizures, intranasal administration