Controlled drug delivery systems based on mesoporous silica and erythrocyte membranes)

The main aim of this study is the development of two controlled drug delivery systems based on ordered mesoporous silica and erythrocyte membranes (in further text ghosts) for two widely used drugs: fenofibrate and sodium diclofenac. In the first part of the study, in vitro and in vivo performance of ordered mesoporous silica (OMS) as a carrier for the poorly water soluble compound fenofibrate was evaluated. 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 mg and 16.75 mg fenofibrate) were compared to 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 ca. 66 and 60% of the drug was released from OMS capsules containing 33.5 and 16.75 mg of fenofibrate, respectively. 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 was promising to be further investigated in a clinical trial setting. Subsequent clinical trial 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 96 hours post-dose. The rate (Cmax/dose increased by 77%; tmax reduced by 0.75 h) and extent of absorption (AUC0-24h/dose increased by 54%) of fenofibrate were significantly enhanced following administration of the ordered mesoporous silica based formulation. In the second part of the study controlled drug delivery system based on erythrocyte ghosts for amphiphilic compound sodium diclofenac was developed considering the differences between erythrocytes derived from two readily available materials porcine slaughterhouse and outdated transfusion human blood. Starting erythrocytes, empty erythrocyte ghosts and diclofenac loaded ghosts were compared in terms of the encapsulation efficiency, drug releasing profiles, size distribution, surface charge, conductivity, surface roughness and morphology. The encapsulation of sodium diclofenac was performed by an osmosis based process gradual hemolysis. During this process sodium diclofenac exerted mild and delayed antihemolytic effect and increased potassium efflux in porcine but not in outdated human erythrocytes. FTIR spectra revealed lack of any membrane lipid disorder and chemical reaction with sodium diclofenac in encapsulated ghosts. Localization in the suspension and spatial distribution (i. e. mapping) of residual hemoglobin in erythrocyte ghosts has been resolved by two photon excitation fluorescence microscopy. Outdated human erythrocyte ghosts with detected nanoscale damages and reduced ability to shrink had encapsulation efficiency of only 8%. On the other hand, porcine erythrocyte ghosts had encapsulation efficiency of 37% and relatively slow drug release rate. More preserved structure and functional properties of porcine erythrocytes related to their superior encapsulation and release performances, define them as more appropriate for the usage in sodium diclofenac encapsulation process.