Mesoporous Materials For Oral Delivery of Poorly Soluble Drugs

Abstract

Oral delivery is considered the most preferred route for the administration of medicines due to patient convenience and practicality. However, many drugs are administered at higher doses than necessary to compensate for their low solubility and subsequent poor bioavailability. To overcome these challenges, mesoporous materials are increasingly utilised for the delivery of poorly soluble drugs and could overcome some of the bottlenecks faced with conventional solid dispersion processing. The work in this thesis aimed to develop a first-in-class polymeric mesoporous carrier for oral delivery of poorly soluble drugs. The work commenced by investigating the use of the currently available carrier, namely mesoporous silica, on release behaviour and thermal properties of loaded model drugs. This was followed by the design of a novel polymeric mesoporous carrier and investigating it thoroughly via in vitro characterisation, an in vivo animal study and computational modelling of the interaction between drug molecules and a model nano-scale mesopore. Drug loading into polymeric mesoporous carriers was also studied to supplement the process understanding for this new type of mesoporous materials. The novel mesoporous carrier was made from a cellulosic material, cellulose acetate butyrate, via spray drying without using any templating agents. Drug loading was carried out for either mesoporous silica or the new polymeric mesoporous carrier at different conditions of drug loads, loading methods, solvents and temperatures. Various techniques/tests including scanning electron microscopy (SEM) and transmission electron microscopy (TEM), differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), high performance liquid chromatography (HPLC), porosimetry, assay and dissolution were used to investigate the mesoporous carriers loaded with model drugs. Molecular dynamics simulation was also employed to explore the interaction between drug molecules and mesopore internal surfaces. Utilising mesoporous silica repeatedly brought a significant dissolution enhancement for two model drugs, felodipine and furosemide. However, incomplete drug release was observed at low drug load, possibly due to reversible adsorption to mesoporous carrier particles. The first-in-class polymeric mesoporous carrier was successfully prepared via spray drying, which has an average pore size of 20.8 nm, pore volume of 0.32 cm3/g and surface area of 56.7 cm2/g. The more soluble amorphous form of felodipine was preserved inside the polymeric mesopores, which translated into a significant enhancement of in vitro dissolution and in vivo relative bioavailability of 91.3%. In silico computational modelling showed that a ‘surface anchoring’ effect between drug molecules and pore surface might be responsible for the lack of crystal-like ordered structure of the drug within mesopores, which additionally facilitates the formation of amorphous form. The spray drying method can produce complete amorphisation with high loading efficiency which outperforms other loading techniques. Solvent polarity, temperature and concentration of drug solution are decisive factors for the outcome of loading process.  Polymeric materials would be an effective substitute for existing inorganic ones as mesoporous carrier systems for oral drug delivery. This work paves the way for further studies exploring the application of the polymeric mesoporous carriers for other drugs and potentially advancing these promising carriers to human studies.