Souad Sfar

Liposome preparation using a hollow fiber membrane contactor—Application to spironolactone encapsulation

In this study, we present a novel liposome preparation technique suitable for the entrapment of pharmaceutical and cosmetic agents. This new method uses a membrane contactor in a hollow fiber configuration. In order to investigate the process, key parameters influence on the liposome characteristics was studied. It has been established that the vesicle size distribution decreased with the organic phase pressure decrease, the phospholipid concentration decreases and the aqueous to organic phase volume ratio increases. Liposomes were filled with a hydrophobic drug model, spironolactone that could be used for a paediatric medication. The mean size of drug-free and drug-loaded liposomes was, respectively, 113 ± 4 nm and 123 ± 3 nm. The zeta potential of drug-free and drug-loaded liposomes was, respectively, -43 ± 0.7 mV and -23 ± 0.6 mV. High entrapment efficiency values were successfully achieved (93 ± 1.12%). Transmission electron microscopy images revealed nanometric sized and spherical shaped oligo-lamellar vesicles. The release profile showed a rapid and complete release within about 5h. Additionally, special attention was paid on process reproducibility and long term lipid vesicles stability. Results confirmed the robustness of the hollow fiber module based technique. Moreover, the technique is simple, fast and has a potential for continuous production of nanosized liposome suspensions at large scale.

Citrulline: from metabolism to therapeutic use.

Citrulline possesses a highly specific metabolism that bypasses splanchnic extraction because it is not used by the intestine or taken up by the liver. The administration of citrulline may be used to deliver available nitrogen for protein homeostasis in peripheral tissues and as an arginine precursor synthesized de novo in the kidneys and endothelial and immune cells. Fresh research has shown that citrulline is efficiently transported across the intestinal luminal membrane by a set of transporters belonging to the B⁰,⁺, L, and b⁰,⁺ systems. Several pharmacokinetic studies have confirmed that citrulline is efficiently absorbed when administered orally. Oral citrulline could be used to deliver arginine to the systemic circulation or as a protein anabolic agent in specific clinical situations, because recent data have suggested that citrulline, although not a component of proteins, stimulates protein synthesis in skeletal muscle through the mammalian target of rapamycin signaling pathway. Hence, citrulline could play a pivotal role in maintaining protein homeostasis and is a promising pharmaconutrient in nutritional support strategies for malnourished patients, especially in aging and sarcopenia.

Drug carriers in osteoporosis: preparation, drug encapsulation and applications.

Carriers are largely used to enhance therapy efficiency via the encapsulation of active molecules. The encapsulation enhances the stability of drug molecules, improves the targeting properties and prolongs pharmacological activity via continuous local release of active molecules. The aim of this review is to report the carrier systems used in osteoporosis therapy. This state of the art research has mainly focused on describing all types of carriers used in this area, their elaboration and properties, the drug characteristics used in such specific application, and drug release and efficiency. In this field, various processes have been used in order to obtain well-defined capsules, spheres and more complex carriers. In this exhaustive review, each process is described, illustrated and discussed.

Resveratrol self-emulsifying system increases the uptake by endothelial cells and improves protection against oxidative stress-mediated death

The aim of the present study was to develop and characterize a resveratrol self-emulsifying drug delivery system (Res-SEDDS), and to compare the uptake of resveratrol by bovine aortic endothelial cells (BAECs), and the protection of these cells against hydrogen peroxide-mediated cell death, versus a control resveratrol ethanolic solution. Three Res-SEDDSs were prepared and evaluated. The in vitro self-emulsification properties of these formulations, the droplet size and the zeta potential of the nanoemulsions formed on adding them to water under mild agitation conditions were studied, together with their toxicity on BAECs. An optimal atoxic formulation (20% Miglyol® 812, 70% Montanox® 80, 10% ethanol 96% v/v) was selected and further studied. Pre-incubation of BAECs for 180 min with 25 μM resveratrol in the nanoemulsion obtained from the selected SEDDS significantly increased the membrane and intracellular concentrations of resveratrol (for example, 0.076±0.015 vs. ethanolic solution 0.041±0.016 nmol/mg of protein after 60 min incubation, p<0.05). Resveratrol intracellular localization was confirmed by fluorescence confocal microscopy. Resveratrol nanoemulsion significantly improved the endothelial cell protection from H2O2-induced injury (750, 1000 and 1500 μM H2O2) in comparison with incubation with the control resveratrol ethanolic solution (for example, 55±6% vs. 38±5% viability after 1500 μM H2O2 challenge, p<0.05). In conclusion, formulation of resveratrol as a SEDDS significantly improved its cellular uptake and potentiated its antioxidant properties on BAECs.

A novel approach for the development and optimization of self emulsifying drug delivery system using HLB and response surface methodology: application to fenofibrate encapsulation.

The aim of this work was to elaborate a novel approach for the development and optimization of self-emulsifying drug delivery system (SEDDS), using response surface methodology and hydrophilic lipophilic balance (HLB). Fenofibrate was selected as drug model. Rapid selection of excipients was operated with reference to their toxicity and capacity to solubilize the drug. A three level Box-Behnken design was used. The independent variables were (X1) surfactants/oil, (X2) cosurfactant/surfactant and (X3) percentage of cosolvent. The high and low levels of these factors were selected with reference to the experimental domain that covers an interval of HLB from 7.8 to 15. This interval of HLB is assumed to lead to oil in water emulsification and to contain the required HLB. The responses were (Y1) droplet size and (Y2) cumulative percentage drug released in 20 mn.Various response surface graphs were constructed to understand the effects of different factor level combinations. The optimized SEDDS with predicted drug release 83.6%, and droplet size 137 nm was prepared; the experimental values were in close agreement. The required HLB was 9.85. Optimized SEDDS showed significant increase in dissolution rate compared to conventional prepared gelatin capsules. In conclusion, this paper demonstrated the reliability, rapidity, and robustness of the approach.

Comparative Study of Two In Vitro Methods for Assessing Drug Absorption: Sartorius SM 16750 Apparatus Versus Everted Gut Sac

PURPOSE Oral drug administration remains the most common and most convenient way used in clinical therapy. The availability of a simple, rapid, economic and reproducible in vitro method to assess the rate, extent and mechanism of intestinal drug absorption is a very helpful tool. The purpose of this study was to compare the performance of Sartorius SM 16750 Absorption Simulator apparatus to Everted Gut Sac (EGS) technique in terms of predicting drug permeability. METHODS Permeation studies across these two in vitro models were performed with six drugs selected across the Biopharmaceutics Classification System (BCS) categories: tramadol (class I of BCS), doxycycline (class I of BCS), diclofenac (class II of BCS), clopidogrel (class II of BCS), metformin (class III of BCS) and chlorothiazide (class IV of BCS). RESULTS Apparent permeability coefficient (Papp) and diffusion profiles obtained with EGS and Sartorius SM 16750 apparatus were similar for diclofenac and metformin, whereas, we noticed significant differences (p ≤ 0.05), for tramadol, doxycycline, clopidogrel and chlorothiazide. CONCLUSION Compared to Everted Gut Sac model, Sartorius SM 16750 absorption simulator apparatus seems to have limited application for the assessment of intestinal drug absorption since it does not take into consideration the involvement of others processes than the passive transcellular pathway as mechanism of drug absorption.

Absorption enhancement studies of clopidogrel hydrogen sulphate in rat everted gut sacs

Objectives  Clopidogrel, a thienopyridine antiplatelet agent, is a poor aqueous soluble compound and a P‐glycoprotein (P‐gp) efflux pump substrate. These two factors are responsible for its incomplete intestinal absorption. In this study, we have attempted to enhance the absorption of clopidogrel by improving its solubility and by inhibiting intestinal P‐gp activity.

Impregnation of Ethylcellulose Microcapsules Containing Jojoba Oil onto Compressive Knits Developed for High Burns

The medical uses of textile fibers and fabric forms keep on growing. Today, the knits can be used in the medical field. The aim of this present work was to prepare compressive knits, impregnated by ethylcellulose (EC) microcapsules, for the burnt skin. Ethylcellulose microcapsules containing jojoba oil were prepared via the phase separation method. Jojoba oil was chosen because it plays an essential role in skin hydration and avoids the sebum accumulation. Ethylcellulose microcapsules obtained were grafted on two different compressive knit surfaces by impregnation, using the Acrylic Resin (AR) as binder. The prepared microcapsules were analyzed by Scanning Electron Microscopy (SEM). The stability of the microcapsules, the efficiency of the microencapsulation method and the jojoba oil content determination were also investigated. This method of application improved the fabric surface and permitted in maximum the preserving of initial characteristics of knit, such as touch, flexibility and lightness.

Self-emulsifying drug delivery system developed by the HLB-RSM approach: Characterization by transmission electron microscopy and pharmacokinetic study.

Recently, we developed a new approach to rationalize an optimized design for self-emulsifying drug delivery system (SEDDS) by introducing the HLB and the response surface as determinant factors in SEDDS development. The aim of this current paper is to assess the suitability of this HLB-RSM approach to enhance the oral bioavailability of BCS class II compounds using fenofibrate as drug model. Eight SEDDS formulations (I→VIII) were pre-selected regarding their self-emulsification capacity and their effect on increasing in vitro drug release. They were firstly evaluated for their thermodynamic stability and zeta potential. Unstable SEDDS were discarded meanwhile the structural morphology of the stable ones (I, VI and VIII) was characterized using transmission electron microscopy (TEM). A pharmacokinetic study was then undertaken on male BALB/cJRj mices. The in vivo results showed a significant increase of fenofibrate absorption for all the three stable SEDDS formulations compared to the commercialized form, (LIPANTHYL micronized(®) (p<0.05)). The highest enhancement was recorded for SEDDS I, where AUC and Cmax values respectively increased by 2 and 4.4 folds. This justifies the fact that HLB-RSM approach could be considered as a promising method for the development of efficient and highly stable SEDDS aiming to increase the poor bioavailability of BCS class II molecules.

Assessment of the cytotoxic effect and in vitro evaluation of the anti-enteroviral activities of plants rich in flavonoids

Nanoparticles derived from plants known for their high content of flavonoids provide a biologically inspired route to designing therapeutic agents and a means of reducing nanoparticle toxicity. Little is currently known on the antiviral activity of Salvia officinalis L. and Washingtonia filifera H.Wendl aqueous extracts and their corresponding nanoparticles. In the present study, antiviral activity of subset extracts obtained from aerial parts of Salvia officinalis L. and Washingtonia filifera H.Wendl and nanoparticles derived from these plants were investigated against coxsackievirus B3 (CVB3). Different concentrations of extracts (7.8, 15.6, 31.25, 62.5, 125, 250, 500, and 1000 µg/mL) were tested for their cytotoxic effect and the antiviral activity was carried out using three non cytotoxic concentrations against CVB3 in Vero cells. The cell viability was carried out using tetrazolium dye (MTT). The experiment was carried out by incubating the extracts with either virus or cells prior to infection. The silver nanoparticles derived from the tested plant extracts enhance antiviral activity at non cytotoxic concentrations. The biosynthesized nanoparticles may be further characterized to better evaluate their antiviral potential against other viral pathogens.