Khalid M. El-Say

Development of alginate-reinforced chitosan nanoparticles utilizing W/O nanoemulsification/internal crosslinking technique for transdermal delivery of rabeprazole.

AIMS First; to develop rabeprazole (RP)-alginate core coated chitosan nanoparticles (NP) utilizing water in oil (W/O) nanoemulsion technique. Second; formulation of transdermal patches loaded RP-NP that avoid drug peroral acid sensitivity and first pass effect. MAIN METHODS The influence of six factors on RP-NP formulation was investigated using Plackett-Burman (PB) design. The studied factors were considered for their effect on particle size (Y1) and loading efficiency (Y2). Formulation optimum desirability was identified; a proposed formulation was prepared and characterized. In vitro permeation of the prepared NP compared with RP was studied. Transdermal patches loaded drug or RP-NP were prepared and characterized. Patches ex vivo permeation through rat skin was studied, and kinetic analysis and permeation mechanism were investigated. KEY FINDING Chitosan, oil phase and surfactant to oil ratios had significant effects on Y1, while Y2 was significantly affected by the same variables affecting Y1 and span80-tween80 ratio. Scanning electron microscope imaging illustrated sphericity of the NP. The optimized RP-NP exhibited sustained release pattern. The prepared patches showed a minimal patch to patch variable. Patches loaded RP-NP exhibited substantial skin permeability and controlled drug release, and were in favor of Fickian diffusion. SIGNIFICANCE Transdermal patches loaded RP-NP is effective drug delivery and alternative to drug peroral route.

Polymeric nanoparticles: Promising platform for drug delivery

Nano medicine had viewed countless breakthroughs in drug delivery implementations. The main objective of nanotechnology application in delivering and carrying many promising therapeutics is to assure drugs carriage to their action sites, to maximize the pharmacological desired influence of remedies and to overcome their limitations and drawbacks that would hinder the required effectiveness. One of these applications was the particulates type of nano-range in size and tremendous impact in achievement. About this specific diversity of particulates, the different elaboration methodologies, mandatory and elementary components for design, and examples of splendid success stories for these particulates were emphasized in this humble review. Challenges such as oral delivery probability for peptide moieties and enhancement the harshly passage process of drugs across the blood brain barriers were accepted and defeated by the almost insurmountable latterly mentioned particulates. Behold, the polymeric nanoparticles.

Design and Optimization of Self-Nanoemulsifying Delivery System to Enhance Quercetin Hepatoprotective Activity in Paracetamol-Induced Hepatotoxicity

The present study aimed to develop optimized quercetin (QT)-loaded self-nanoemulsifying drug delivery system (SNEDDS) that offers protective effect against liver damage. Solubility study of QT in different oils, surfactants, and cosurfactants was performed. Ternary phase mixtures of the selected components were constructed to select a suitable range for each component. Experimental mixture design was utilized to optimize SNEDDSs that possess smaller globule size with enhanced emulsification and dissolution rates. QT SNEDDS was compared with QT suspension control and silymarin. In vivo evaluation and histopatholgical study of the selected QT SNEDDSs were achieved after administration of paracetamol over dosage to albino rats. Two optimized formulations were selected; one based on Sefsol and the other based on linoleic acid as an oily phase, Tween(®) 80 and polyethylene glycol 400 as surfactant and cosurfactant, respectively. Both Sefsol and linoleic-acid-optimized SNEDDS formulation showed no symptoms associated with toxicity and offered protective effect against paracetamol-induced hepatotoxicity by scavenging free radicals, attenuating lipid peroxidation, and enhancing the activity of antioxidants. The histopatholgical observations revealed that the inflammatory infiltrations induced by paracetamol were significantly ameliorated.

Transdermal glimepiride delivery system based on optimized ethosomal nano-vesicles: Preparation, characterization, in vitro, ex vivo and clinical evaluation.

This work aimed to develop an optimized ethosomal formulation of glimepiride then loading into transdermal films to offer lower drug side effect, extended release behavior and avoid first pass effect. Four formulation factors were optimized for their effects on vesicle size (Y1), entrapment efficiency (Y2) and vesicle flexibility (Y3). Optimum desirability was identified and, an optimized formulation was prepared, characterized and loaded into transdermal films. Ex-vivo permeation study for the prepared films was conducted and, the permeation parameters and drug permeation mechanism were identified. Penetration through rat skin was studied using confocal laser microscope. In-vivo study was performed following transdermal application on human volunteers. The percent of alcohol was significantly affecting all the studied responses while the other factors and their interaction effects were varied on their effects on each response. The optimized ethosomal formulation showed observed values for Y1, Y2 and Y3 of 61 nm, 97.12% and 54.03, respectively. Ex-vivo permeation of films loaded with optimized ethosomal formulation was superior to that of the corresponding pure drug transdermal films and this finding was also confirmed after confocal laser microscope study. Permeation of glimepiride from the prepared films was in favor of Higushi-diffusion model and exhibited non-Fickian or anomalous release mechanism. In-vivo study revealed extended drug release behavior and lower maximum drug plasma level from transdermal films loaded with drug ethosomal formulation. So, the ethosomal formulation could be considered a suitable drug delivery system especially when loaded into transdermal vehicle with possible reduction in side effects and controlling the drug release.

Optimization of self-nanoemulsifying systems for the enhancement of in vivo hypoglycemic efficacy of glimepiride transdermal patches.

Objectives: To optimize and use of glimepiride (GMD)-loaded self-nanoemulsifying delivery systems (SNEDs) for the preparation of transdermal patches. Methods: Mixture design was utilized to optimize GMD-loaded SNEDs in acidic and aqueous pH media. Optimized GMD-loaded SNEDs were used in the preparation of chitosan (acidic) and hydroxypropyl methyl cellulose (HPMC) (aqueous) films. The prepared optimized formulations were investigated for ex vivo skin permeation, for in vivo hypoglycemic activity and for their pharmacokinetic parameters using animal model. Results: The optimized formulations showed flux value of (2.88 and 4.428 μg/cm2/h) through rat skin for chitosan and HPMC films, respectively. The pattern of GMD release from both formulations was in favor of Higuchi and approaching zero order models. The n values for Korsmeyer–Peppas equation were characteristic of anomalous (non-Fickian) release mechanism. Moreover, HPMC patches have shown significant reductions (p < 0.05) in blood glucose levels; (213.33 ± 15.19) mg/100 ml from the base-line measurement after 12 h of application. Conclusions: Optimized GMD SNEDs patches were found to improve GMD skin permeability and the essential pharmacokinetic parameters. Further extensive pre/clinical studies are necessary prior to use transdermal GMD as a valuable alternative to peroral dosage forms with improved bioavailability, longer duration of action and more patient convenience.

Enhanced permeation parameters of optimized nanostructured simvastatin transdermal films: ex vivo and in vivo evaluation.

Abstract Objective: Detailed optimization process was carried out to enhance permeation parameters, and hence bioavailability, of simvastatin (SMV) transdermal films. Methods: SMV solubility was investigated in various oils, surfactants and co-surfactants/co-solvents. Mixtures of the selected components were prepared to identify zone of nanoemulsion formation that was utilized in Extreme Vertices mixture design to develop SMV self-nanoemulsifying drug delivery systems (SNEDDS) with minimum globule size. Optimized SMV-SNEDDS were included in the preparation of transdermal films. A fractional factorial design was implemented to evaluate effects of the factors on the amount of SMV permeated. The optimized film was investigated for ex vivo skin permeation and in vivo pharmacokinetic parameters. Results: The optimum SNEDDS formula was 0.09, 0.8 and 0.11 for Sefsol 218, tween 80 and PEG 200, respectively. Fractional factorial design depicted the optimized SMV transdermal film with 2% HPMC and 2% DMSO as permeation enhancer that showed 1.82-fold improvements in skin flux. The pharmacokinetic data showed higher Cmax and almost doubled AUC compared with raw SMV-loaded films. Conclusion: The two-step optimization implemented to optimize and control the experimental conditions for the preparation of SMV-SNEDDS-transdermal film with improved ex vivo skin permeation and enhanced in vivo parameters.

Utilization of nanotechnology to enhance percutaneous absorption of acyclovir in the treatment of herpes simplex viral infections.

This study aimed to formulate an optimized acyclovir (ACV) nanoemulsion hydrogel in order to provide a solution for the slow, variable, and incomplete oral drug absorption in patient suffering from herpes simplex viral infection. Solubility of ACV in different oils, surfactants, and cosurfactants was explored utilizing a cubic model mixture design to obtain a nanoemulsion with minimum globule size. Preparation of an optimized ACV nanoemulsion hydrogel using a three-factor, three-level Box–Behnken statistical design was conducted. The molecular weight of chitosan (X1), percentage of chitosan (X2), and percentage of Eugenol as a skin permeation enhancer (X3) were selected to study their effects on hydrogel spreadability (Y1) and percent ACV permeated through rat skin after 2.5 hours (Y2). A pharmacokinetic study of the optimized ACV nanoemulsion hydrogel was conducted in rats. Mixtures of clove oil and castor oil (3:1 ratio), Tween 80 and Span 80 (3:1 ratio), and propylene glycol and Myo-6V (3:1 ratio) were selected as the oil, surfactant, and cosurfactant phases, respectively. Statistical analysis indicated that the molecular weight of chitosan has a significant antagonistic effect on spreadability, but has no significant effect on the percent ACV permeated. The percentage of chitosan also has a significant antagonistic effect on the spreadability and percent ACV permeated. On the other hand, the percentage of Eugenol has a significant synergistic effect on percent ACV permeated, with no effect on spreadability. The ex vivo study demonstrated that the optimized ACV nanoemulsion hydrogel showed a twofold and 1.5-fold higher permeation percentage than the control gel and marketed cream, respectively. The relative bioavailability of the optimized ACV nanoemulsion hydrogel improved to 535.2% and 244.6% with respect to the raw ACV hydrogel and marketed cream, respectively, confirming improvement of the relative bioavailability of ACV in the formulated nanoemulsion hydrogel.

Diacerein niosomal gel for topical delivery: development, in vitro and in vivo assessment

Abstract The purpose of this study was to load diacerein (DCR) in niosomes by applying response surface methodology and incorporate these niosomes in gel base for topical delivery. Box–Behnken design was used to investigate the effect of charge-inducing agent (X1), surfactant HLB (X2) and sonication time (X3) on the vesicle size (Y1), entrapment efficiency (Y2) and cumulative drug released (Y3). DCR niosomal formulations were prepared by thin film hydration method. The optimized formula was incorporated in different gel bases. DCR niosomal gels were evaluated for homogeneity, rheological behavior; in vitro release and pharmacodynamic activity by carrageenan-induced hind paw edema method in the rat compared with DCR commercial gel. The results revealed that the mean vesicle sizes of the prepared niosomes ranged from 7.33 to 23.72 µm and the entrapment efficiency ranged from 9.52% to 58.43% with controlled release pattern over 8 h. DCR niosomal gels exhibited pseudoplastic flow with thixotropic behavior. The pharmacodynamic activity of DCR niosomal gel in 3% HPMC showed significant, 37.66%, maximum inhibition of edema size in comparison with 20.83% for the commercial gel (p < 0.05). These results recommended the incorporation of DCR niosomes in 3% HPMC for topical application as a potent anti-inflammatory drug for the treatment of osteoarthritis.

Statistical optimization of controlled release microspheres containing cetirizine hydrochloride as a model for water soluble drugs

Abstract The purpose was to improve the encapsulation efficiency of cetirizine hydrochloride (CTZ) microspheres as a model for water soluble drugs and control its release by applying response surface methodology. A 33 Box–Behnken design was used to determine the effect of drug/polymer ratio (X1), surfactant concentration (X2) and stirring speed (X3), on the mean particle size (Y1), percentage encapsulation efficiency (Y2) and cumulative percent drug released for 12 h (Y3). Emulsion solvent evaporation (ESE) technique was applied utilizing Eudragit RS100 as coating polymer and span 80 as surfactant. All formulations were evaluated for micromeritic properties and morphologically characterized by scanning electron microscopy (SEM). The relative bioavailability of the optimized microspheres was compared with CTZ marketed product after oral administration on healthy human volunteers using a double blind, randomized, cross-over design. The results revealed that the mean particle sizes of the microspheres ranged from 62 to 348 µm and the efficiency of entrapment ranged from 36.3% to 70.1%. The optimized CTZ microspheres exhibited a slow and controlled release over 12 h. The pharmacokinetic data of optimized CTZ microspheres showed prolonged tmax, decreased Cmax and AUC0–∞ value of 3309 ± 211 ng h/ml indicating improved relative bioavailability by 169.4% compared with marketed tablets.

Depot injectable atorvastatin biodegradable in situ gel: development, optimization, in vitro, and in vivo evaluation

This study aimed to develop an optimized depot injectable atorvastatin (ATR) biodegradable in situ gel (ISG) system with minimum initial burst using a central composite design. The factors selected were poly (d, l-lactide-co-glycolide) (PLGA) concentration (X1), molecular weight of polyethylene glycol (PEG) (X2), and PEG concentration (X3). The independent variables were the initial burst of ATR after 2 (Y1) and 24 hours (Y2). The optimized formulation was investigated using scanning electron microscopy, Fourier transform infrared spectroscopy, and in vitro drug release in phosphate-buffered saline of pH 7.4 for 72 hours. The in vivo pharmacokinetic study of the optimized ATR-ISG and the corresponding PEG-free ATR-ISG were conducted by intramuscular injection of a single dose (2 mg/kg) of ATR in male New Zealand White rabbits. A double-blind, randomized, parallel design was used in comparison with those of the marketed ATR tablet. Statistical analysis revealed that PLGA concentration and the molecular weight of PEG have pronounced effects on both Y1 and Y2. The optimized formulation was composed of 36.10% PLGA, PEG 6000, and 15.69% PEG, and exhibited characteristic in vitro release pattern with minimal initial burst. Incorporation of PEG in the formulation causes a slight decrease in the glass transition temperature value of PLGA, leading to a slight change in Fourier transform infrared spectroscopy spectrum due to possible interaction. Moreover, scanning electron microscopy photomicrograph showed smooth surface with disappearance of the cracks which characterize the surface of PEG-free formulation. The pharmacokinetic data for the optimized depot injectable ATR-ISG showed a significant (P<0.05) decrease in maximum plasma concentration from 547.62 to 346.84 ng/mL, and increasing time to reach the maximum plasma concentration from 12 to 72 hours in comparison with the marketed tablet. The optimized ATR-ISG formulation has shown minimal initial drug burst which confirms the suitability of the ISG system in the prolongation of drug release in patients with chronic long-term therapy.