No abstract

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 (C/dose increased by 77%; t reduced by 0.75h) and extent of absorption (AUC/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.

The interconversion of the ethanolate, hydrate and amorphous form of TMC114 ((3-[(4-amino-benzenesulfonyl)-isobutyl-amino]-1-benzyl-2-hydroxypropyl)-carbamic acid hexahydrofuro-[2,3-b]furan-3-yl ester) in open conditions was characterized. TMC114 hydrate and ethanolate form isostructural channel solvates. The crystal structure of TMC114 was obtained from single crystal X-ray diffraction, confirming that it is a channel solvate. Ethanol and water can exchange with one another. TMC114 ethanolate converts into TMC114 hydrate at moderate or high relative humidity (RH) at 25 degrees C, and it converts back into the ethanolate in ethanol atmosphere. The hydration level of the hydrate is determined by the environmental humidity. TMC114 hydrate collapses to the amorphous product when water is removed by drying at low RH or increasing temperature. TMC114 ethanolate becomes amorphous at elevated temperature in a dry environment below the desolvation temperature. Amorphous TMC114 obtained by dehydrating the hydrate during storage at room temperature/<5% RH, by increasing the temperature, or via desolvating the ethanolate by heating, converts into the hydrate at moderate or high RH at ambient conditions, and into TMC114 ethanolate in an ethanol atmosphere. Under ambient conditions, TMC114 ethanolate may convert into the hydrate, whereas the opposite will not occur under these conditions. The amorphous form, prepared by melting-quenching shows a limited water uptake. Whereas TMC114 ethanolate is stable in the commercialized drug product, special conditions can trigger its conversion.

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.

It is unclear whether the common belief that experience benefits new product development performance is driven by decision-makers allocating more attention to success experience or more attention to failure experience. This paper differentiates between the two aforementioned types of experience in order to explore their separate effects on new product development performance. We find that only late-stage failure experience improves performance, that success experience is more beneficial than late-stage failure experience and that, while others' related failure experience increases the likelihood of failure, others' related success experience decreases it. We conducted our research in the context of drug development in the biotech industry and obtained our data from Pharma Projects.