Ahmed S. Geneidi

Microemulsion formulations for the transdermal delivery of testosterone

The objective was to develop a microemulsion formulation for the transdermal delivery of testosterone. Microemulsion formulations were prepared using oleic acid as the oil phase, Tween20 as a surfactant, Transcutol as cosurfactant, and water. The microemulsions were characterized visually, with the polarizing microscope, and by dynamic light scattering. In addition, the pH, conductivity (sigma) and viscosity (eta) of the formulations were measured. Moreover, differential scanning calorimetry and diffusion-ordered nuclear magnetic resonance spectroscopy were used to study the formulations investigated. Conductivity measurements revealed, as a function of the weight fraction of the aqueous phase, the point at which the microemulsion made the transition from water-in-oil to bicontinuous. Alterations in the microstructure of the microemulsions, following incorporation of testosterone, have been evaluated using the same physical parameters (pH, sigma and eta) and via Fourier-transform infrared spectroscopy (FT-IR), (1)H NMR and (13)C NMR. These methods were also used to determine the location of the drug in the colloidal formulation. Finally, testosterone delivery from selected formulations was assessed across porcine skin in vitro in Franz diffusion cells. The physical parameter determinations, combined with the spectroscopic studies, demonstrated that the drug was principally located in the oily domains of the microemulsions. Testosterone was delivered successfully across the skin from the microemulsions examined, with the highest flux achieved (4.6+/-0.6microgcm(-2)h(-1)) from a formulation containing 3% (w/v) of the active drug and the composition (w/w) of 16% oleic acid, 32% Tween20, 32% Transcutol and 20% water. The microemulsions considered offer potentially useful vehicles for the transdermal delivery of testosterone.

Uptake of Microemulsion Components into the Stratum Corneum and Their Molecular Effects on Skin Barrier Function

This research determined the uptake of individual components of topically applied microemulsions into the stratum corneum (SC) and assessed their molecular effects on skin barrier function. The microemulsions comprised oleic acid, Tween20, Transcutol and water. The effects of selected formulations, and of the individual components, on the conformational order of the SC intercellular lipids, and on SC hydration, were assessed by infrared spectroscopy. Measurements were made as a function of SC depth by progressively tape-stripping the membrane in the normal way. SC uptake of microemulsion components was quantified via extraction and analysis of the collected tape strips. SC hydration increased in proportion to the water content of the microemulsion. Each of the microemulsion components penetrated into the SC, but to different extents. Oleic acid decreased the conformational order of the SC lipids, and induced some phase separation, as revealed by the frequency shifts and peak areas of the absorbances associated with -CH(2) symmetric and asymmetric stretching vibrations. Tween20 extracted some of the SC intercellular lipids. In summary, SC structure was perturbed by all components of the microemulsions, and the degree of the effects detected was proportional to the level of the respective component present in the skin.

Exploring the use of nanocarrier systems to deliver the magical molecule; Curcumin and its derivatives.

Curcumin and its derivatives; curcuminoids have been proven as potential remedies in different diseases. However, their delivery carries several challenges owing to their poor aqueous solubility, photodegradation, chemical instability, poor bioavailability and rapid metabolism. This review explores and criticizes the numerous attempts that were adopted through the years to entrap/encapsulate this valuable drug in nanocarriers aiming to reach its most appropriate and successful delivery system.

Visualization, dermatopharmacokinetic analysis and monitoring the conformational effects of a microemulsion formulation in the skin stratum corneum

The use of nano-systems such as the microemulsions is considered as an increasingly implemented strategy in order to enhance the percutaneous transport into and across the skin barrier. The determination of the major pathway of penetration and the mechanisms by which these formulations work remains crucial. In this study, laser confocal scanning microscopy was used to visualize the penetration and the distribution of a fluorescently-labelled microemulsion (using 0.1% w/v Nile red) consisting of (%, w/w) 15.4% oleic acid, 30.8% Tween 20, 30.8% Transcutol® and 23% water. The surface images revealed that the microemulsion accumulated preferentially in the intercellular domains of the stratum corneum. Additionally, by analysis of the images taken across the whole stratum corneum (SC), the penetration was found to occur along its whole depth. The latter result was confirmed using tape stripping and the subsequent sensitive analysis using liquid chromatography mass spectroscopy. Dermatopharmacokinetic parameters were obtained for the microemulsion different components. These values proved the breakage of the microemulsion during its penetration across the stratum corneum. Moreover, the mechanisms of penetration enhancement and the micro molecular effects on the skin stratum corneum were investigated using attenuated Fourier transform infra-red spectroscopy. The results revealed the penetration of all the microemulsion components in the stratum corneum and demonstrated the microemulsion interaction with the skin barrier perturbing its architecture structure.

Bioavailability enhancement of verapamil HCl via intranasal chitosan microspheres

Chitosan microspheres are potential drug carriers for maximizing nasal residence time, circumventing rapid mucociliary clearance and enhancing nasal absorption. The aim of the present study was to develop and characterize chitosan mucoadhesive microspheres of verapamil hydrochloride (VRP) for intranasal delivery as an alternative to oral VRP which suffers low bioavailability (20%) due to extensive first pass effect. The microspheres were produced using a spray-drying and precipitation techniques and characterized for morphology (scanning electron microscopy), particle size (laser diffraction method), drug entrapment efficiency, thermal behavior (differential scanning calorimetry) and crystallinity (X-ray diffractometric studies) as well as in vitro drug release. Bioavailability of nasal VRP microspheres was studied in rabbits and the results were compared to those obtained after nasal, oral and intravenous administration of VRP solution. Results demonstrated that the microspheres were spherical with size 21-53 μm suitable for nasal deposition. The spray-drying technique was superior over precipitation technique in providing higher VRP entrapment efficiency and smaller burst release followed by a more sustained one over 6h. The bioavailability study demonstrated that the nasal microspheres exhibited a significantly higher bioavailability (58.6%) than nasal solution of VRP (47.8%) and oral VRP solution (13%). In conclusion, the chitosan-based nasal VRP microspheres are promising for enhancing VRP bioavailability by increasing the nasal residence time and avoiding the first-pass metabolism of the drug substance.

Comparative effects of different cosurfactants on sterile prednisolone acetate ocular submicron emulsions stability and release.

Pluronic F68 is a nonionic, thermogelling block copolymer showing a high dehydration resistance during autoclaving due to its high cloud point (>100 degrees C). Tween 80 (with cloud point of 72.5 degrees C), is a polyoxyethylene-based cosurfactant, susceptible to temperature because of a decrease in its solubility by temperature increase. This study was done to explore whether or not, when compared with Tween 80, Pluronic F68 could be used blindly as a suitable cosurfactant for the preparation of terminally sterilized ocular submicron emulsions containing a lipid soluble drug, prednisolone acetate (PA). Various oils of variable viscosities were also tried. The results proved that no prediction can be made based on previously known physico-chemical properties alone and that emulsion stability depends on the contribution of the various emulsion components including: oil, surfactant and cosurfactant, in addition to the drug properties.

Chitosan-tripolyphosphate nanoparticles: Optimization of formulation parameters for improving process yield at a novel pH using artificial neural networks

At a novel pH value of the polymeric solution (6.2), variable chitosan (Cs) and sodium tripolyphosphate (TPP) concentrations and mass ratios were optimized to improve the process yield without undesirable particle flocculation. Prepared formulations were characterized in terms of particle size (PS), zeta potential (ZP) and percentage yield (% yield). Artificial neural networks (ANN) were built up and used to identify the parameters that control nanoparticle (NP) size and yield, in addition to being tested for their ability to predict these two experimental outputs. Using these networks, it was found that TPP concentration has the greatest effect on PS and% yield. The most optimum formulation was characterized by a notable process yield reaching 91.5%, a mean hydrodynamic PS 227 nm, ZP+24.13 mv and spherical compact morphology. Successful Cs-TPP interaction in NP formation was confirmed by both Fourier transform-infrared spectroscopy (FT-IR) and differential scanning calorimetry (DSC). This study demonstrated the ability of ANN to predict not only PS of the formed particles but also NP% yield. This may have a great impact on Cs-TPP NPs preparation and can be used to customize the required target formulations.

Composite chitosan-transfersomal vesicles for improved transnasal permeation and bioavailability of verapamil.

The creation of composite systems has become an emerging field in drug delivery. Chitosan has demonstrated several pharmaceutical advantages, especially in intranasal delivery. In this manuscript, a comparative study was conducted between regular vesicles (transfersomes and penetration enhancer vesicles) and composite vesicles (chitosan containing transfersomes and penetration enhancer vesicles) loaded with a model antihypertensive drug; verapamil hydrochloride VRP. Composite vesicles displayed larger particle size than regular vesicles owing to the coating potential of chitosan on the vesicular bilayer as displayed by transmission electron microscopy, with an increased viscosity of composite vesicles and a shift in the zeta potential values from negative to positive. The entrapment efficiency of VRP in the vesicles ranged from 24 to 64%, with best physical stability displayed with transfersomal vesicles prepared using sodium deoxycholate. Chitosan slowed the in vitro release of VRP from the selected formulation but managed to achieve high penetrability across sheep nasal mucosa as displayed by confocal laser microscopy. The chitosan composite transfersomal formulation exhibited absolute bioavailability of 81.83% compared to the oral solution which displayed only 13.04%. Findings of this manuscript highly recommend chitosan as a promising functional additive in vesicular formulations to improve the intranasal delivery of drugs with low oral bioavailability.

Nanoethosomes for transdermal delivery of tropisetron HCl: multi-factorial predictive modeling, characterization, and ex vivo skin permeation

Abstract Objective: The aim of the present work is to exclusively optimize and model the effect of phospholipid type either egg phosphatidylcholine (EPC) or soybean phosphatidylcholine (SPC), together with other formulation variables, on the development of nano-ethosomal systems for transdermal delivery of a water-soluble antiemetic drug. Tropisetron HCl (TRO) is available as hard gelatin capsules and IV injections. The transdermal delivery of TRO is considered as a novel alternative route supposing to improve BAV as well as patient convenience. Methods: TRO-loaded ethanolic vesicular systems were prepared by hot technique. The effect of formulation variables were optimized through a response surface methodology using 3 × 22-level full factorial design. The concentrations of both PC (A) and ethanol (B) and PC type (C) were the factors, while entrapment efficiency (Y1), vesicle size (Y2), polydispersity index (Y3), and zeta potential (Y4) were the responses. The drug permeation across rat skin from selected formulae was studied. Particle morphology, drug–excipient interactions, and vesicle stability were also investigated. Results: The results proved the critical role of all formulation variables on ethosomal characteristics. The suggested models for all responses showed good predictability. Only the concentration of phospholipid, irrespective to PC type, had a significant effect on the transdermal flux (p < 0.01). The ethosomal vesicles were unilamellar with a nearly spherical shape. EPC-based ethosomes proved good stability. Conclusion: The study suggests the applicability of statistical modeling as a promising tool for prediction of ethosomal characteristics. The ethanolic vesicles were considered as novel potential nanocarriers for accentuated transdermal TRO delivery.

Methotrexate loading in chitosan nanoparticles at a novel pH: Response surface modeling, optimization and characterization.

The aim of this study was to assess the feasibility of employing a novel but critical formulation pH (6.2) to encapsulate an anionic model drug (methotrexate, MTX) into chitosan(Cs)-tripolyphosphate nanoparticles(NPs). A response surface methodology using a three-level full factorial design was applied studying the effects of two independent variables namely; Cs concentration and MTX concentration. The responses investigated were the entrapment efficiency (EE%), mean hydrodynamic particle size (PS), polydispersity index (PDI) and zeta potential (ZP). In order to simultaneously optimize the series of models obtained, the desirability function approach was applied with a goal to produce high percent of MTX encapsulated into highly charged Cs-TPP NPs of homogenous optimum PS. MTX-loaded CsNPs were successfully prepared at the novel pH applied. The suggested significant models were found quadratic for EE, PS and ZP responses, while 2-factor interaction model for PDI. The optimization overlay graph showed that the maximum global desirability, D=0.856, was reached when the conditions were set at high Cs and MTX concentration. Thus, the use of such optimized conditions, at this novel pH, achieved a maximum drug EE% (73.38%) into NPs characterized by optimum PS (232.6nm), small PDI value (0.195) and highly surface charged (+18.4mV).