|
Abstract:
|
Poorly water soluble drugs have been manipulated to make them more soluble , increasing the bioavailability of these drugs . Several cryogenic processes allow for production of drug nanoparticles , without mechanical stress that could cause degradation . The Ultra Rapid Freezing (URF ) process is a technique which improves water solubility of drugs by reducing primary drug particle size by producing amorphous solid dispersions . Heat conduction is improved , using a cryogenic material with a high thermal conductivity relative to the solution being frozen to maintain the surface temperature and heat transfer rate while the solution is being frozen . With URF technology , the freezing rate is fixed , which drives the particle formation and determines its characteristics . Supersaturation of drug in aqueous solution can allow for better absorption of the drug via the oral and pulmonary routes . Drug formulations that supersaturate the dissolution media show the possibility for increased bioavailability from an amorphous drug form . If the concentration of drug in solution is significantly increased , higher chemical potential will lead to an increase in flux across an exposed membrane , leading to higher blood levels for an amorphous drug , compared to an identical crystalline formulation . During oral delivery , supersaturated drug concentrations would also saturate PGP efflux sites in the gut lumen , increasing the drug's bioavailability . Saturated PGP sites show zero order efflux kinetics , so increasing the drug concentration in supersaturated biological fluid will increase serum drug levels . High supersaturation levels maintained for prolonged periods would have a beneficial effect on a drug's absolute bioavailability . Pulmonary administration offers therapeutic advantages over more invasive routes of administration . Limited amount of metabolizing enzymes like CYP 3A4 in lung tissue along with avoidance of first pass metabolism are advantages to pulmonary delivery . The objective of the research presented in this dissertation is to show the versatility of nanoparticulate poorly water soluble drug formulations . Due to the reduced particle size and the URF manufacturing process , a wide range of applications can be used with these nanoparticles . Oral and pulmonary administration routes can be explored using nanoparticles , but in vitro cell culture testing can show clinical benefits from this type of processing technology . |