Dosage of 2,6-Bis (1.1-Dimethylethyl)-4-Methylphenol (BHT) in the Plant Extract Mesembryanthemum crystallinum

A naturally occurring BHT was identified in the leaves of the halophyte plant Mesembryanthemum crystallinum. This phenol was extracted in this study by two methods at the different plant growth stages. One of the methods was better for BHT extraction; the concentration of this phenol is plant growth stage dependent. In this study, the floraison stage has the highest BHT concentration. The antioxidant activity of the plant extract was not related to BHT concentration. The higher antioxidant activity is obtained at seedlings stage

Cytotoxic effect of nanoparticles synthesized from Salvia officinalis L. and Ricinus communis aqueous extracts against vero cell line and evaluation of their antioxidant activities

The development of safe carriers for the use of plant extracts in industrial and health fields constitute a matter of serious concern. The development of plant derived nanoparticles may help to overcome such barriers. However, the major concern is still the safety of these carriers. The present study describes the synthesis of nanoparticles derived from Salvia officinalis L. and Ricinus communis and the evaluation of their cytotoxic and antioxidant effects. It is shown in this study that the aqueous extracts of S. officinalis L. and R. communis have the potentials to reduce silver nitrate ions to silver nanoparticles. The biosynthesized nanoparticles were analyzed by spectrophotometer and granulometric tests. The biological activities of these extracts and nanoparticles were carried out. S. officinalis L. leaf extract had the strongest antioxidant activity, followed by R. communis leaf and fruit extracts. Altogether, the synthesized nanoparticles were safe and may serve as antioxidant products in many fields.Key words: Plant material, biosynthesis of nanoparticle, cytotoxicity, cell culture, free radicals

Citrulline: from metabolism to therapeutic use.: citrulline: metabolism and therapeutic

International audienceCitrulline 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

Contribution à une étude biopharmaceutique de la citrulline

L administration entérale de la citrulline (Cit) peut être avantageuse dans certaines situations d insuffisance intestinale. La Cit représente une source d arginine disponible pour la synthèse protéique dans les tissus. L objectif de notre travail est de supplémenter les patients en citrulline afin d améliorer leur statut nutritionnel. Cependant, la biodisponibilité tissulaire et l action de la Cit sont conditionnées par son absorption intestinale. Nous avons montré, en utilisant les cellules Caco-2 comme modèle d étude du transport intestinal, que la Cit est captée par les cellules entérocytaires grâce à deux types de transporteurs, un Na+-dépendant (Système B0,+) et deux Na+- indépendants (Systèmes L et b0,+). Ce nombre important de systèmes de transport pourrait compenser le faible taux de Cit dans l alimentation afin d améliorer sa disponibilité dans l organisme. Notre deuxième objectif a été de contourner l intestin et d atteindre directement le côlon pour administrer la Cit. Nous avons élaboré des formes galéniques par microencaspsulation en utilisant deux techniques différentes : le spray drying et la formulation de microsphères de pectinate de calcium par cross-linking . La technique de spray drying a abouti à la formulation de microsphères ayant de bonnes propriétés physiques en termes de morphologie et de taille, en revanche la libération de la Cit a été rapide en milieu gastrique. La formulation de microsphères de pectinate de calcium a permis d améliorer le contrôle de la libération de la Cit dans le milieu gastrique en réduisant le pourcentage de dissolution des microsphères à pH acide et de prolonger la durée de libération de la Cit au niveau coliqueCitrulline (Cit) is a major precursor of arginine by de novo synthesis in the kidneys. Thus, oral Cit supplementation may be beneficial in situations of intestinal failure. However, Cit bioavailability depends on its intestinal absorption. Since the mechanism of Cit transport across the intestine has not been established yet, this study was first designed to characterize Cit uptake by enterocytes. We have demonstrated, using Caco-2 cells as a model of intestinal transport, that citrulline uptake is mediated by the Na+-dependent carrier system B0,+ and two Na+- independent carriers : systems L and b0,+. The second aim of this work was to bypass the intestine and reach the colon directly to administer Cit; since intestinal absorption is reduced in patients with intestinal failure. For this purpose, we have developed microspheres by using two different techniques of microencapsulation: the spray drying technique and the formulation of calcium pectinate microspheres intented for colonic drug delivery. The spray drying technique led to the formulation of microspheres with suitable physical properties in terms of size and morphology; however the release of Cit has been rapid in the stomach. The formulation of calcium pectinate microspheres improved the control of Cit release by reducing its release at acidic pHPARIS-BIUP (751062107) / SudocSudocFranceF

Nutrition parentérale du prématuré (étude de la compatibilité et stabilité phosphocalcique dans les mélanges binaires et ternaires)

Le phénomène de precipitation phosphocalcique est l un des risques majeurs de déstabilisation des mélanges pédiatriques de nutrition parentérale qui nécessitent de hautes concentrations calciques. Méthode : La solubilité phosphocalcique en mélanges binaires ou ternaires ainsi que l influence des additifs sur la stabilité des émulsions lipidiques (Clinoleic® et Ivelip®) utilisées seuls ou en mélange ont été évaluées sur six mélanges de composition variables. Résultats : L observation visuelle des mélanges binaires ainsi que l analyse granulométrique par diffraction laser n ont révélé aucun précipité même pour des concentrations élevées des formes organiques de Ca et P. Cependant, un précipité immédiat en présence de P inorganique (K2HPO4) a été observé. Une réaction phosphocalcique organique a été mise en évidence au microscope optique et après dosage du Ca par spectrophotométrie d absorption atomique. L investigation des mélanges ternaires a révélé: - une baisse de pH sous l effet du Primène® (pH ~ 5,5), et un début de crémage avec l eau ppi en présence d électrolytes. La mesure du potentiel zêta a permis d estimer l intégrité du film inter facial. Il est possible que la solution d acides aminés et le glucose offrent une protection contre les effets délétères provoqués par les cations divalents. Conclusion : Les résultats obtenus montrent l importance de l utilisation du phosphate organique dans les mélanges pour nutrition parentérale pédiatriques, la nécessité de standardiser le mode de préparation, de conservation et d administration de ces solutions, avec obligation d utiliser des filtres pendant la perfusionBackground: Calcium-phosphate precipitation represents one of the major risks of destabilization of paediatric parenteral nutrition admixtures requiring high Ca concentrations. Method: The calcium-phosphate solubility in binary and in all-in-one admixtures and the effect of additives on two intravenous lipid emulsions (Clinoleic® and Ivelip®) used either alone or in admixture have been evaluated on six formulas with different compositions. Results: Precipitations have not been visually detected nor quantified by particle size analysis using laser diffraction on binary admixtures even for samples containing high organic Ca-P. However, precipitation of Ca-P was immediately observed with inorganic P (K2HPO4). Interaction between organic Ca-P has been revealed by optical microscopy and by Ca determination using atomic absorption spectrophotometer. Investigations of lipid-nutrient admixtures showed a significant decrease of the pH with Primene® (pH~5.5) and a visual instability when mixing with sterile water alone. Zeta potential determination allowed estimating the integrity of the interfacial film. It is possible that amino acids and glucose offer a protection to the lipid emulsion from its physicochemical degradation due to divalent cations. Conclusion: Our data indicated that the use of organic P in paediatric parenteral nutrition admixtures greatly improves solubility but the risk of Ca-P precipitation exist and appropriate measures should be developed for standardization of the preparation, conservation and administration of these solutions, with the necessity of using filters during infusion.PARIS-BIUP (751062107) / SudocSudocFranceF

Impact of crystal polymorphism of rifaximin on dissolution behavior

Introduction: Rifaximin is an intestinal antiseptic which has five (pseudo) polymorphs α, β, γ, δ and ε. These last (pseudo)polymorphs have different physicochemical properties. The objective of the study is to assess the impact of rifaximin polymorphism on its dissolution rate which could affect its bioavailability. Material and methods: The analytical validation of dissolution assay method by UV–Visible spectrophotometry was carried out according to ICH Q2. The physicochemical characterization (solubility test, FTIR, DSC, XRD) was carried out on four active pharmaceutical ingredient (MP1, MP2, MP3, MP4). MP1 and MP2 were used by the manufacturer of generic brand 1 (G1) and MP3 and MP4 were used by the manufacturer of generic brand 2 (G2). The comparative in-vitro dissolution study was carried out on the leader brand (P), G1 and G2. Results: The four MPs were analyzed by XRD. The results of analysis showed that MP1 and MP4 were a mixture of α form and amorphous form. MP2 had an amorphous form and MP3 had a crystalline form β. The spectra of FTIR showed that the four MP had characteristics bands of rifaximin in the domain 4000-400 cm−1. The differences between the spectra of the four MPs were observed among the amorphous form (MP2), around the region 1800 to 1820 cm−1 which is attributed to the vibration of the CO group. An additional difference observed among the amorphous form (MP2) is around the region 1400 cm−1 which is attributed to the banding OH. The thermograms of MP1, MP2 and MP4 showed endothermic peaks which are probably attributed to the departure of water which indicate that MP1, MP2 and MP4 are pseudopolymoph (hydrate). For the four MPs, probably the melting points are interrupted by the phenomenon of phase transformations (Crystallization) which are reflected by exothermic peaks around 200°C–250 °C.Our results showed that the crystalline polymorphism of rifaximin influences its solubility. According to the results of the solubility test, the β crystal form of rifaximin (MP3) had the lowest solubility (3.47 μg/ml). MP2 had the highest solubility (8.35 μg/ml) and MP1 and MP4 had intermediate solubilities (5.47 μg/ml and 6.74 μg/ml). Comparative in vitro dissolution results showed that the dissolution profile of P was not similar to that of G1 and G2 (% dissolution (P)30min = 60%; % dissolution (G1) 30 min = 100% and % dissolution (G2) 30 min = 115%; f1(P versus G1) = 44; f1(P versus G2) = 61) in M1, while G1 and G2 had comparatively similar dissolution profiles (% dissolution (G1) 30 min = 100%; % dissolution (G1) 30 min = 110%; f1 (G1 versus G2) = 14) in M1. Conclusion: This study highlighted the impact of rifaximin polymorphism on its physico-chemical properties (crystal structure, thermal behavior, solubility) and on its dissolution behavior which could affect the rifaximin bioavailability

Use of mouse model in pharmacokinetic studies of poorly water soluble drugs: Application to fenofibrate

International audienceFenofibrate has recently been used as drug model in several studies with the objective of optimizing the development of some drug delivery systems to overcome the problem of poor aqueous solubility of the newly discovered API. The adequacy of the drug delivery systems to improve the oral bioavailability of encapsulated drug is generally evaluated by a pharmacokinetic study. The use of mouse as animal model for pharmacokinetic studies has become more important in the last decade because of many similarities with the human model in terms of the mechanisms of absorption, metabolism and elimination. Nevertheless, the mouse is often hampered by the very small volumes of blood that could be obtained during sampling. The aim of this work was to overcome the problem of lower volumes of plasma withdrawn by developing an appropriate protocol for sample preparation and a suitable HPLC method for drug quantification in mouse plasma. Linear calibration curve was obtained over the concentration range from 0,16 μg/mL to 32 μg/mL (r 2 = 0,9999) with LLOQ of 0,16 μg/mL The RSD in both intra-run and inter-run precision study was less than 11% and the extraction recoveries were above 91.9%. The reproducible method was successfully applied to the pharmacokinetic study of fénofibrate in mouse

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

International audienceRecently, 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 (R) (p < 0.05)). The highest enhancement was recorded for SEDDS I, where AUC and C-max 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. (C) 2015 Elsevier B.V. All rights reserved

Development and Optimization of Dipyridamole- and Roflumilast-Loaded Nanoemulsion and Nanoemulgel for Enhanced Skin Permeation: Formulation, Characterization, and In Vitro Assessment

This study explores developing and optimizing a nanoemulsion (NE) system loaded with dipyridamole and roflumilast, aiming to improve skin penetration and retention. The NE formulation was further transformed into a nanoemulgel to enhance its application as a topical treatment for psoriasis. Solubility studies were conducted to select the oil, surfactant, and co-surfactant. Phase diagrams were constructed using the aqueous phase titration method. All the formulations were in nanoscale, and Formula (F2) (which contains oleic acid oil as the oil phase, a mixture of Surfactant Tween 80 and co-surfactant (ethanol) at a ratio of 1:2 in addition to distilled water as an aqueous phase in a ratio of 1:5:4, respectively) was the selected formula depending on the particle size, PDI, and zeta potential. Formula (F2) has the best ratio because it gives the smallest nanoemulsion globule size (particle size average of 167.1 nm), the best homogenicity (lowest PDI of 0.195), and the highest stability (higher zeta potential of −32.22). The selected formula was converted into a nanoemulgel by the addition of 0.5% (w/w) xanthan gum (average particle size of 172.7 nm) and the best homogenicity (lowest PDI of 0.121%) and highest stability (higher zeta potential of −28.31). In conclusion, the selected formula has accepted physical and chemical properties, which enhanced skin penetration