Preparation Of 3DOM Nano-matrix As A Novel Vehicle For Improving Oral Bioavailability Of Indomethacin

Oral delivery is commonly recognized as the most convenient and preferred route for drug administration since it avoids the pain and discomfort associated with injections and is more attractive from a marketing and patient compliance perspective. However, the large majority of the newly discovered chemical entities and many existing drug substances suffer from poor aqueous solubility. Considering the unique structural advantages of 3DOM materials,3DOM silica possess several features that render it excellent candidate as matrix for drug nanoparticles.The goal of the present study was to exploit the potential of 3DOM silica as drug matrix so as to improve the dissolution and then the oral bioavailability of poorly soluble drugs. Indomethacin(IMC), a non-steroidal anti-inflammatory drug, was used as a BCS-2 model drug due to its dissolution-limited absorption.Non-crosslinked, monodisperse polystyrene (PS) and poly-(methyl methacrylate) (PMMA)latex spheres used as templates for the fabrication of 3DOM silica with different pore size were synthesized using an emulsifier-free emulsion polymerization technique. 3DOM silica samples with different pore sizes were prepared using PMMA and PS latex spheres as templates,respectively. Before use, the latex spheres were close-packed into highly ordered colloidal crystal templates by centrifugation, then allowed to air-dry. The SEM, TEM, N2 sorption and XRD tools were used to characterize the template and 3DOM silica, revealing the formation of well-defined three-dimensionally ordered macroporous structures.The solvent deposition method was adopted for drug loading process. The procedure was as following: Prior to drug loading, the solid silica monolith was first crushed gently with a mortar and pestle, and then passed through an 80-mesh sieve to obtain fine powders with good flowability. In detail, IMC was dissolved in acetone to obtain a yellow transparent solution, then an aliquot of this solution was mixed with certain amount of 3DOM silica to obtain samples with certain drug-silica ratios of 1:3. After gentle stirring for 24 h,the solvent was allowed to evaporate. The residue was placed in a vacuum desiccator with blue silica gel until no organic solvent was detected by thermal analysis.IMC was successfully loaded into the nano-pores of 3DOM silica and MCM1 silia by solvent deposition method at ratio of 1-3. Investigations using SEM, XRD,DSC and IR demonstrated the successful entrapment of IMC and the existing interactions between drug guest molecule and silica host. A significant loss of crystallinity and partial crystalline-amorphous transformation were observed for IMC after incorporation into 3DOM silica. It was showed that IMC nanoparticle formulations exhibited a marked promotion of in vitro dissolution rate. Several factors seemed to play roles for the dissolution enhancement effect, including the lack of crystalline form and presence of amorphous form, particle size reduction to the nanosize range and the hydrophilic surface as well as the interconnected pore networks of 3DOM silica.The capsules containing IMC-loaded silica system was prepared and evaluated by the color,weight and accelerated testing experiment. The method for determining the plasma concentration of IMC in Beagle dogs was constructed and verified. Overall, the relative bioavailability of IMC after oral administration of 3DOM silica and MCM-41 was 169.87%% and 153.90%,respectively.The cytotoxicity of 3DOM silica and MCM41 was evaluated by MTT, CCK8 and converted phase contrast microscopy. The result showed that at the tested concentrations (50mg/L-500mg/L),all the silica materials were non-toxic and the morphology of cells after incubation with each silica carrier didn't change obviously. Coumarin-6 was taken as the labeling agent and loaded into 3DOM silica and MCM41. The fluorescent-labeled 3DOM silica and MCM41 were then incubated with Caco-2 cells for 4hours. It was revealed that 3DOM silica could disperse the coumarin and hence released or leaked easily into the culture media. However, MCM41 can hold coumarin tightly and penetrate into cells because of its small particle size, spherical morphology as well as its high affinity with coumarin.