Tarek A. Ahmed

Preparation, characterization, and potential application of chitosan, chitosan derivatives, and chitosan metal nanoparticles in pharmaceutical drug delivery

Naturally occurring polymers, particularly of the polysaccharide type, have been used pharmaceutically for the delivery of a wide variety of therapeutic agents. Chitosan, the second abundant naturally occurring polysaccharide next to cellulose, is a biocompatible and biodegradable mucoadhesive polymer that has been extensively used in the preparation of micro-as well as nanoparticles. The prepared particles have been exploited as a potential carrier for different therapeutic agents such as peptides, proteins, vaccines, DNA, and drugs for parenteral and nonparenteral administration. Therapeutic agent-loaded chitosan micro- or nanoparticles were found to be more stable, permeable, and bioactive. In this review, we are highlighting the different methods of preparation and characterization of chitosan micro- and nanoparticles, while reviewing the pharmaceutical applications of these particles in drug delivery. Moreover, the roles of chitosan derivatives and chitosan metal nanoparticles in drug delivery have been illustrated.

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.

Exploring recent developments to improve antioxidant, anti-inflammatory and antimicrobial efficacy of curcumin: A review of new trends and future perspectives

Curcumin derivatives have been well-documented due to their natural antioxidant, antimicrobial and anti-inflammatory activities. Curcuminoids have also gained widespread recognition due to their wide range of other activities which include anti-infective, anti-mutagenic, anticancer, anti-coagulant, antiarthrititc, and wound healing potential. Despite of having a wide range of activities, the inherent physicochemical characteristics (poor water solubility, low bioavailability, chemical instability, photodegradation, rapid metabolism and short half-life) of curcumin derivatives limit their pharmaceutical significance. Aiming to overcome these pharmaceutical issues and improving therapeutic efficacy of curcuminoids, newer strategies have been attempted in recent years. These advanced techniques include polymeric nanoparticles, nanocomposite hydrogels, nanovesicles, nanofibers, nanohybrid scaffolds, nanoconjugates, nanostructured lipid carriers (NLCs), nanoemulsion, polymeric micelles and polymeric blend films. Incorporation of curcumin in these delivery systems has shown improved solubility, transmembrane permeability, long-term stability, improved bioavailability, longer plasma half-life, target-specific delivery, and upgraded therapeutic efficacy. In this review, a range of in vitro and in vivo studies have been critically discussed to explore the pharmaceutical significance and therapeutic viability of the advanced delivery systems to improve antioxidant, anti-inflammatory and antimicrobial efficacies of curcumin and its derivatives.

Development of biodegradable in situ implant and microparticle injectable formulations for sustained delivery of haloperidol

The objective of this study is to formulate injectable, biodegradable sustained release in situ implant (ISI), and in situ microparticle (ISM) formulations of haloperidol. Factors affecting the in vitro drug release, pharmacokinetics, and stability of the formulations were investigated. The concentration of the polymer, poly(lactide-co-glycolide) acid (PLGA), and the type of solvents showed a pronounced effect on the in vitro drug release from the ISI and ISM formulations. The ISM formulation [20% PLGA in N-methyl-2-pyrrolidone (NMP)-peanut oil, 1:4] showed reduced maximum plasma concentration (60 versus 44 ng/mL) and longer release (30 days, plasma concentration of 8 ng/mL versus 20 days, plasma concentration of 6 ng/mL) compared with the ISI formulation (20% PLGA in NMP) after intramuscular injection in rats. The delivery of haloperidol can be extended further by changing the concentration, molecular weight, and lactide-to-glycolide ratio of the PLGA. These formulations can be easily administered by both intramuscular and subcutaneous injections. The shelf lives of both systems were found to be 2 years when stored at 4°C. Haloperidol can be formulated as an injectable ISI or ISM systems suitable for 1 month or longer release.

Preparation of transfersomes encapsulating sildenafil aimed for transdermal drug delivery: Plackett–Burman design and characterization

Abstract The aim of this work was to study the effect of different processing and formulation parameters on the preparation of sildenafil (SD) transfersomes utilizing the Plackett–Burman design. The drug to phospholipid molar ratio (X1), phospholipid to surfactant ratio (X2), hydrophilic–lipophilic balance of the surfactant (X3), hydration medium pH (X4), hydration time (X5) and the temperature of hydration (X6) were investigated to study their effect on the vesicle size (Y1) and entrapment efficiency (EE) of the drug (Y2). The preparation conditions were optimized to minimize the vesicle size and maximize the EE. The prepared transfersomes were also subjected to zeta potential measurements, morphological and physicochemical characterization. The combinations of factors that achieve the optimum desirability were identified. An optimized formulation was prepared and characterized once more for its vesicle size, EE, in vitro permeation and deformability index. The results revealed that both X3 and X6 had a pronounced effect on Y1, while X1 and X4 showed a significant effect on Y2. Morphological and physicochemical study confirmed the transfersomes spherical shape and compatibility of the formulation ingredients. The formulation with optimum desirability showed EE and vesicle size of 97.21% and 610 nm, respectively. In vitro permeation of the drug-loaded transfersome showed more than 5-fold higher permeation rate compared with drug suspension. Deformability index verified elasticity of the preparation. The significant variables could be optimized again to produce smaller vesicle size that could increase SD permeation from transdermal delivery systems loaded drug optimized transfersomes.

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.

In vitro release, rheological, and stability studies of mefenamic acid coprecipitates in topical formulations

A suitable topical formulation of mefenamic acid was developed in order to eliminate the gastrointestinal disorders associated with its oral administration. Drug coprecipitates prepared with different polymers at various drug-to-polymer ratios improved drug solubility and dissolution compared to pure drug and physical mixtures. PVP polymers (ratio 1:4) produced the best results. Aqueous ionic cream, ointments of absorption and water soluble bases and gels of methylcellulose, carboxymethylcellulose sodium, HPMC, Carbopol® 934 and 940, and Pluronic® F127 bases containing 1–10% drug as coprecipitates of PVP polymers (1:4) were prepared. The highest drug release was achieved at 1% drug concentration from water soluble base and methylcellulose among cream/ointment and gel bases, respectively. Gels, in general yielded better release than creams/ointments. All tested medicated creams/ointments exhibited plastic flow while all gels conformed to pseudoplasticity. Most of them showed thixotropy, a desired property of topical preparations. Stability studies revealed that HPMC and methylcellulose had the smallest changes in drug content, viscosity, and pH among the formulations. Considering drug release, rheological properties, and stability, methylcellulose gel containing 1% drug as coprecipitates of PVP K90 was the best among the studied formulations, was promising for improving bioavailability of mefenamic acid and can be used in future studies.

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.

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.