Ordered mesoporous silica to enhance the bioavailability of poorly water-soluble drugs: Proof of concept in man.

Formulating poorly water soluble drugs using ordered mesoporous silica materials is an emerging approach to tackle solubility-related bioavailability problems. The current study was conducted to assess the bioavailability-enhancing potential of ordered mesoporous silica in man. In this open-label, randomized, two-way cross-over study, 12 overnight fasted healthy volunteers received a single dose of fenofibrate formulated with ordered mesoporous silica or a marketed product based on micronized fenofibrate. Plasma concentrations of fenofibric acid, the pharmacologically active metabolite of fenofibrate, were monitored up to 96h post-dose. The rate (Cmax/dose increased by 77%; tmax reduced by 0.75h) and extent of absorption (AUC0-24h/dose increased by 54%) of fenofibrate were significantly enhanced following administration of the ordered mesoporous silica based formulation. The results of this study serve as a proof of concept in man for this novel formulation approach.

In Vivo Performance of Fenofibrate Formulated With Ordered Mesoporous Silica Versus 2-Marketed Formulations: A Comparative Bioavailability Study in Beagle Dogs.

The present study aims to evaluate the in vitro and in vivo performance of ordered mesoporous silica (OMS) as a carrier for the poorly water-soluble compound fenofibrate. Fenofibrate was loaded into OMS via incipient wetness impregnation to obtain a 29% drug load and formulated into capsules. Two capsule dosage forms (containing 33.5 and 16.75 mg fenofibrate, respectively) were compared with the commercially available forms-Lipanthyl(®) (fenofibrate microcrystals) and Tricor(®) (fenofibrate nanocrystals). In vitro dissolution tests showed that the amount of fenofibrate released from Lipanthyl(®) and Tricor(®) was approximately 30%, whereas approximately 66% and 60% of the drug was released from OMS capsules containing 33.5 and 16.75 mg of fenofibrate, respectively. Storage of OMS capsules loaded with 33.5 mg of fenofibrate at 25°C/60% relative humidity (RH) or 40°C/75% RH did not alter the release kinetics, nor the physical state of the compound, pointing the stability of the present formulation. The in vivo study in dogs confirmed satisfying level of safety and tolerability of fenofibrate-OMS formulation (eq. 33.5 mg) with the potential to improve the absorption of fenofibrate. Though some variability in the data, this formulation is promising to be further investigated in a clinical trial setting.

Use of ordered mesoporous silica to enhance the oral bioavailability of ezetimibe in dogs.

The aim of this study was to investigate the bioavailability enhancement of the biopharmaceutics classification system class II compound ezetimibe loaded in ordered mesoporous silica (OMS) in dogs. The OMS was characterized as highly ordered mesoporous material with a narrow pore size distribution. Ezetimibe was loaded in OMS via incipient wetness impregnation to obtain a 20% (w/w) drug load, characterized by nitrogen adsorption and differential scanning calorimetry, and formulated in one capsule and two tablet formulations. Physicochemical characterization of loaded OMS indicated that ezetimibe molecules were molecularly deposited on the hydrophilic surface of the OMS. Two in vitro dissolution experiments were performed at 37°C in simulated gastric fluid with 0.1% sodium lauryl sulfate or Tween 80 to determine the drug release. All concepts were compared in vitro and in vivo with the commercially available tablet Ezetrol®. A dog study was designed to determine the oral bioavailability of ezetimibe capsules and tablets. The tablet preparations showed similar results to that of Ezetrol®. The capsule formulation demonstrated a faster absorption into the blood circulation, including a superior metabolization of ezetimibe into the active glucuronide conjugate. In vivo evaluation in dogs confirmed the improvement of ezetimibe absorption with the use of OMS as drug delivery technology.

Clinical study of solid dispersions of itraconazole prepared by hot-stage extrusion.

The aim of this study was to investigate the performance of three new solid dispersion formulations of itraconazole in human volunteers in comparison with Sporanox, the marketed form. Solid dispersions made up of itraconazole (40%, w/w) and HPMC 2910, Eudragit E100 or a mixture of Eudragit E100-PVPVA64 were manufactured by hot-stage extrusion and filled in gelatin capsules. The formulations were tested in eight human volunteers in a double blind, single dose, and cross-over study. Concentrations of the drug and its metabolite hydroxyitraconazole in the plasma were determined using HPLC. The in vivo performance was evaluated by comparing the mean area under the plasma concentration-time curves (AUC), the mean maximum plasma concentration (C(max)), and the mean time to reach C(max) (T(max)). The mean bioavailability of itraconazole was comparable after administration of the HPMC solid dispersion, compared to Sporanox, while it was lower after administration of the Eudragit E100 or Eudragit E100-PVPVA64 dispersions. Due to high variability, a significant decrease in AUC and C(max) was only observed for the Eudragit E100-PVPVA formulation. Although the solid dispersions showed different in vitro dissolution behaviour, T(max) values were comparable. The same observations with respect to AUC, C(max) and T(max) could be made for hydroxyitraconazole. The present results indicate that hot-stage extrusion can be considered as a valuable alternative for manufacturing solid dispersions of itraconazole.