Formulation and processing technologies for enhanced oral bioavailability of poorly water soluble compounds

Developments in high throughput screening and combinatorial chemistry have contributed to the unprecedented success of the pharmaceutical industry over the last twenty years, leading to a multitude of blockbuster compounds that revolutionized treatment for a variety of clinical indications. This success, particularly in drug discovery, has been tempered by an increased number of moieties exhibiting delivery limitations due to molecular structure. One of the most pressing areas of pharmaceutical research today is addressing the reduced aqueous solubility of developmental chemical entities in pharmaceutical pipelines, which has been estimated to affect up to 90% of such compounds. Current technologies have focused on maximizing dissolution rates or equilibrium solubilities of such compounds using platforms such as microemulsions, polymorph engineering, particle size reduction, and complexation. While these technologies have been shown to improve oral bioavailability for a number of compositions, further improvement can be achieved by developing new production and formulation technologies for amorphous systems. Within the frame work of this dissertation, two unique technologies for bioavailability enhancement were investigated; formulation with concentration enhancing polymers to provide extended durations of supersaturation and the development of a novel fusion based solid dispersion production process based on thermo-kinetic mixing, termed KinetiSol® Dispersing, for the production of amorphous solid dispersions. Studies of solid dispersions containing concentration enhancing polymers prepared by ultra rapid freezing showed the ability of these formulations to provide improved oral bioavailability of itraconazole when compared to the currently marketed product, which is a conventional hydrophilic solid dispersion. KinetiSol® Dispersing was also extensively studied within this work and shown to be a viable platform for the production of hydrophilic solid dispersions, plasticizer free solid dispersions and solid dispersions containing heat sensitive active ingredients. In a culminating study, KinetiSol® Dispersing was utilized for the production of amorphous solid dispersions containing concentration enhancing polymers for improved oral bioavailability of itraconazole. Ultimately, this body of work demonstrated that concentration enhancing polymers could provide improved oral bioavailability for poorly water soluble compounds, while KinetiSol® Dispersing could be used for the production of such compositions, thereby presenting novel technologies for addressing future development of poorly water soluble active ingredients.