RESUMEN
PURPOSE: The aim of the study was to evaluate organogel nanoparticles as a lipophilic vehicle to increase the oral bioavailability of poorly soluble compounds. Efavirenz (EFV), a Biopharmaceutical Classification System (BCS) Class II, was used as drug model. METHODS: Organogel nanoparticles loaded with EFV were formulated with sunflower oil, 12-hydroxystearic acid (HSA) and polyvinyl alcohol (PVA). Various parameters have been investigated in the current study such as (i) the release profile of organogel assessed by USP 4 cell flow dialysis, (ii) the impact of organogel on intestinal absorption, using Caco-2 cells as in vitro model and jejunum segments as ex vivo assay and (iii) the bioavailability of organogel following oral pharmacokinetic study. RESULTS: 250-300 nm spherical particles with a final concentration of 4.75 mg/mL drug loading were obtained, corresponding to a thousand fold increase in EFV solubility, combined to a very high encapsulation efficiency (>99.8%). Due to rapid diffusion, drug was immediately released from the nanoparticles. The biopharmaceutical evaluation on ex vivo jejunum segments demonstrated an increased absorption of EFV from organogel nanoparticles compare to a native EFV suspension. In vitro assays combining Caco-2 cell cultures with TEM and confocal microscopy demonstrated passive diffusion, while paracellular integrity and endocytosis activity remain expelled. Oral pharmacokinetics of EFV organogel nanoparticles improve oral bioavailability (Fr: 249%) and quick absorption compared to EFV suspension. CONCLUSION: Organogel nanoparticles increase the bioavailability of BCS Class II drugs. The main phenomena is simply oil transfer from the gelled particles through the cell membrane.
Asunto(s)
Benzoxazinas/química , Portadores de Fármacos/química , Geles/química , Nanocápsulas/química , Alcohol Polivinílico/química , Ácidos Esteáricos/química , Aceite de Girasol/química , Alquinos , Animales , Benzoxazinas/administración & dosificación , Benzoxazinas/farmacocinética , Disponibilidad Biológica , Células CACO-2 , Permeabilidad de la Membrana Celular , Supervivencia Celular/efectos de los fármacos , Ciclopropanos , Difusión , Composición de Medicamentos/métodos , Liberación de Fármacos , Excipientes/química , Humanos , Absorción Intestinal , Masculino , Solubilidad , Suspensiones/química , Distribución TisularRESUMEN
The purpose of the study was to evaluate organogel nanoparticles as a drug delivery system by investigating their stability, according to the formulation strategy, and their release profile. The gelled nanoparticles were prepared by hot emulsification (above the gelation temperature) of an organogel in water, and cooling at room temperature. In the first step, we used DLS and DSC to select the most suitable formulations by optimizing the proportion of ingredients (HSA, PVA, castor oil) to obtain particles of the smallest size and greatest stability. Then, two lipophilic drug models, indomethacin and ketoconazole were entrapped in the nanoparticles made of castor oil gelled by 12-hydroxystearic acid. Thermal studies (DSC) confirmed that there was no significant alteration of gelling due to the entrapped drugs, even at 3% w/w. Very stable dispersions were obtained (>3 months), with gelled oil nanoparticles presenting a mean diameter between 250 and 300 nm. High encapsulation efficiency (>98%) was measured for indomethacin and ketoconazole. The release profile determined by in vitro dialysis showed an immediate release of the drug from the organogel nanoparticles, due to rapid diffusion. The study demonstrates the interest of these gelled oil nanoparticles for the encapsulation and the delivery of lipophilic active compounds.