Formulation et évaluation des systèmes lipidiques de type III et IV avec un nouveau tensioactif de la famille des Gélucire

Les substances actives faiblement solubles dans l eau classées BCS II (Biopharmaceutics Classification System) sont de plus en plus nombreuses dans l industrie pharmaceutique. Les systèmes lipidiques apportent une solution à leur faible biodisponibilité en les présentant à l état dissous dans le tractus intestinal. Selon les dernières recommandations du consortium LFCS (Lipid Formulation Classification System), ce travail met en place des formulations lipidiques dans le but de maintenir en solution différentes substances actives modèles : l ibuprofène, le piroxicam et la cinnarizine. Les formulations sont sélectionnées selon le pouvoir solvant des excipients et par l établissement de diagrammes binaires et ternaires puis sont évaluées par un test de digestion in vitro. Cette étude permet ainsi de développer un nouvel agent tensioactif, le Gélucire® 48/16, en le comparant à des SMEDDS (Self MicroEmulsifying Drug Delivery Systems) formés de Labrasol® ALF, et aux excipients concurrents. Les résultats montrent que le Gélucire® 48/16 a une efficacité égale ou supérieure aux autres excipients. De plus ce travail s intéresse au rapport de sursaturation maximale (Maximum Supersaturation Ratio, SRM) qui apparait comme un paramètre prédictif de la capacité solvante des formulations. Il pourra être utilisé pour optimiser la sélection des formulations dans les prochaines études.Poorly water soluble drugs classified BCS II (Biopharmaceutics Classification System) are more and more numerous in the pharmaceutical industry. Lipid-based formulations provide a solution to their weak bioavailibilty, presenting them in a dissolved state in the gastro-intestinal tract. According to the latest recommandations of the LFCS consortium (Lipid Formulation Classification System), this work establishes lipid-based formulations in order to maintain in solution differents model active pharmaceutical ingredients : ibuprofen, piroxicam and cinnarizine. Formulations are selected according to the solvant power of excipients and by the establishment of binary and ternary diagrams, and then evaluated by an in vitro digestion test. Thereby, this study allows to develop a new surfactant, the Gélucire® 48/16, comparing it to SMEDDS (Self MicroEmulsifying Drug Delivery Systems) formed of Labrasol® ALF, and to competitors. Results show that the Gélucire® 48/16 has an equal or superior efficacy to the other excipients. In addition this work focuses on the maximum supersaturation ratio (SRM) which appears as a predictive parameter to the formulations solvent power. It will be possible to use it to optimize the selection of formulations in future studies.ANGERS-BU Médecine-Pharmacie (490072105) / SudocSudocFranceF

Lauroyl polyoxylglycerides, functionalized coconut oil, enhancing the bioavailability of poorly soluble active substances

Gelucire® 44/14, a lauroyl polyoxylglycerides obtained by polyglycolysis of hydrogenated coconut oil with PEG-32, is used to increase the oral bioavailability of poorly-water soluble drugs. It is a solid dispersion composed of a PEG ester fraction under a lamellar phase of 120 Å with a helical conformation and an acylglycerol fraction under a hexagonal packing. This excipient spontaneously evolves to its most stable phase of 120 Å after storage at 25 °C for 21 hours leading to physically stable formulations. Gelucire® 44/14 is a hydrophilic system that hydrates and swells in contact with water and forms cubic mesophases before complete erosion/emulsification. It is also lipolyzed by various enzymes such as gastric lipase or carboxyl ester hydrolase. After an in vitro gastrointestinal lipolysis simulation, the main components remaining are mono and diesters of PEG-32. These amphiphilic metabolites can explain the beneficial role of Gelucire® 44/14 on the solubility of poorly-water soluble drugs such as cinnarizine even after partial lipolysis of the lipid-based system. Finally that excipient can also increase the bioavailability of active substances by interacting with enterocyte-based proteins like P-glycoprotein or cytochromes P450

Dispersion et lipolyse de formulations lipidiques d'Ibuprofène dans les fluides gastro-intestinaux simulés

LYON1-BU Santé (693882101) / SudocSudocFranceF

Contrôle de la libération d'une substance active à partir d'un mélange de glycérides et de polymères hydrophiles

AIX-MARSEILLE2-BU Pharmacie (130552105) / SudocSudocFranceF

Valorisation de la fonctionnalité des poudres microenrobées par des lipides

DIJON-BU Médecine Pharmacie (212312103) / SudocPARIS-BIUP (751062107) / SudocSudocFranceF

Gastrointestinal lipolysis of lipid-based excipients intended for the oral drug delivery of poorly water-soluble drugs

Labrasol® and Gelucire® 44/14 are lipid-based excipients used for the oral drug delivery of poorly water-soluble drugs. These macrogolglycerides are composed of acylglycerols and PEG esters, potential substrates of digestive lipases. We developed an in vitro method to simulate the gastrointestinal lipolysis of these excipients and to evaluate the impact of lipolysis in vivo. At the end of the gastric phase, the composition of both excipients was significantly modified underlining the importance of gastric lipolysis in vivo. We also studied the influence of excipients’ lipolysis on the solubilization of a poorly water-soluble drug, cinnarizine, in aqueous phase. Gastrointestinal lipolysis of Labrasol® was a prerequisite to maintain cinnarizine in aqueous solution, whereas the lipolysis of Gelucire® 44/14 did not affect the cinnarizine solubilization

Hydrodynamic size characterization of a self-emulsifying lipid pharmaceutical excipient by Taylor dispersion analysis with fluorescent detection

International audienceIn this work, the sizing of microemulsion droplets of a lipid-based pharmaceutical excipient (Labrasol® ALF) is performed by Taylor dispersion analysis (TDA) using fluorescent detection. An hydrophobic fluorescent marker is used to tag the microemulsion droplet and to increase the sensitivity of detection (compared to UV detection). Combined with the frontal TDA mode, fluorescent detection was mandatory for an accurate sizing of microemulsions containing large coacervates. Microemulsion sizing of Labrasol was performed at various concentrations from 1 to 70g.L-1 and at two different temperature (25°C and 37°C). Results obtained by TDA are compared to those derived from DLS measurements. The combination of both techniques allows estimating the size and proportion of coacervates in the microemulsion, as well as the polydispersity in size of the sample