Fabrication of micro/nanoparticles of drugs for pharmaceutical applications

Abstract

Many drugs are of very poor water solubility, so they tend to be eliminated from the gastrointestinal tract before they could be absorbed into the blood circulation. This results in low bioavailability and poor dose proportionality, and therefore leads to an overall inefficient treatment for the patients. Modifications to the drug substance itself and the creation of specific formulations have been used to enhance the dissolution rate as well as bioavailability of poorly water soluble drugs. Physical modifications to increase the surface area, solubility and wettability of the drug particles typically focus on particle size reduction and generation of amorphous states. In this study, the particle size of several poorly water soluble drugs (artemisinin, quercetin, curcumin, glibenclamide, hesperetin, silymarin) was successfully reduced by employing three fabrication methods namely, spray drying, antisolvent precipitation with a syringe pump (APSP), and evaporative precipitation of nanosuspension (EPN). The hydrophilic carriers like polyvinylpyrrolidone (PVP) and polyethylene glycol (PEG) were also used in the fabrication processes in order to understand their effect on formation of drug particles. A percent dissolution surface-response model was regressed and statistically assessed to understand the direct relationships between the process parameters on one hand and percent dissolution on the other. Firstly, the microparticles of poorly water soluble drug, artemisinin, were produced by the modified spray drying and the particle size was further reduced by using the improved APSP method. Later micro/nanoparticles of quercetin, curcumin, glibenclamide and hesperetin were also prepared by the APSP method. Finally, the nanoparticles of all the drugs used in this study were successfully prepared by the newly developed EPN method. The dissolution rate of the drug nanoparticles prepared by the EPN method exhibited many folds increase in the dissolution rate of the drugs. The APSP and EPN method developed in this study have been found to be effective in decreasing the particle size of drugs and hence, increasing their dissolution rate. These methods also have advantages such as being less energy intensive and less time consuming, using low-cost set up and low temperature and pressure conditions, which protect sensitive drugs. Moreover, no impurities are introduced and no toxic surfactants or stabilisers are used. In the next stage, drug dispersions in a carrier matrix were prepared with the aim to reduce the particle size down to the molecular level. The binary dispersions of the drugs, curcumin and hesperetin, in the polymer (PVP or PEG) matrix were prepared which showed the better dissolution than the plain drug nanoparticles. The dispersions were further improved by adding surfactants (F38, F127, T20, T80), and the ternary dispersions thus formed presented higher dissolution rates and were physically more stable than the binary dispersions. The Korsemeyer–Peppas and Weibull models were used to study the drug release kinetics from the drug dispersions and diffusion was found to be the key release mechanism. Drug dispersions have been widely used for dissolution enhancement of poorly water soluble drugs but the ternary dispersions are yet to be fully explored and provide a potential improvement over the existing formulations in terms of dissolution and physical stability of drug. The enhanced dissolution of the drug nanoparticles and dispersions can potentially translate into an increased bioavailability in-vivo. This will lead to considerable dose reduction for patients. To conclude, these drug nanoparticles and dispersions produced by systematic methods in this study would have high potential for delivery in much smaller doses compared with commercial preparation containing the normal form of the drug.Doctor of Philosophy (MAE