Novel uses of pharmaceutical polymers as enabled by KinetiSol® dispersing

Poor water-solubility is a common characteristic of drug candidates in pharmaceutical development pipelines today. Various processes have been developed to increase the solubility, dissolution rate and bioavailability of these active ingredients belonging to BCSII and IV classifications. Over the last decade, nano-crystal delivery forms and amorphous solid dispersions have become well established in commercially available products and industry literature. Chapter 1 is a comparative analysis of these two methodologies primarily for orally delivered medicaments. The thermodynamic and kinetic theories relative to these technologies are presented along with a survey of commercial relevant scientific literature. Marketed products from both technologies are presented, but there appears to be more amorphous dispersion products on the U.S. market today and current development trends are showing an industry preference for amorphous solid dispersions. Many pharmaceutical polymers have been investigated as the primary component in amorphous solid dispersions for their ability to increase the apparent water solubility of poorly water-soluble drugs. Polyvinyl alcohol (PVAL) has not been investigated as a concentration enhancing polymer owing to its high melting point/high viscosity and poor organic solubility. Due to the unique attributes of the KinetiSol® Dispersing (KSD) technology, PVAL has been enabled for this application and Chapter 2 contains an initial investigation into various grades for improvement of the solubility and bioavailability of the poorly water-soluble model drug, itraconazole (ITZ). Polymer grades were chosen with variation in molecular weight and degree of hydroxylation to determine the effects on performance. Differential scanning calorimetry, powder x-ray diffraction, polarized light microscopy, size exclusion chromatography and dissolution testing were used to characterize the amorphous dispersions. An in vivo pharmacokinetic study in rats was also conducted to compare the selected formulation to current market formulations of ITZ. Chapter 3 continues the investigation into the use of PVAL as a concentration enhancing polymer for amorphous solid dispersion. The previous chapter revealed that the 88% hydrolyzed grade was optimal for ITZ compositions with regard to solid-state properties, non-sink dissolution performance and bioavailability enhancement. This chapter explores the influence of molecular weight for the 88% hydrolyzed grade in the range of 4 to 8 mPa·s with the top performing grade from both chapters emerging as PVAL 4-88. Amorphous dispersions at 10, 20, 30, 40 and 50% ITZ drug loads in PVAL 4-88 were compared by dissolution performance. Analytical tools of diffusion-ordered spectroscopy and Fourier transform infrared spectroscopy were employed to understand the interaction between drug and polymer. Finally, results from a 30 month stability test of a 30% drug loaded ITZ:PVAL 4-88 composition shows that stable amorphous dispersions can be achieved. The KinetiSol® Dispersing (KSD) technology has been shown to create solid dispersion systems from challenging drugs and highly viscous polymers. The focus has been primarily using this technology for solubility enhancement, but it can be advantageous for other obstacles facing the pharmaceutical development industry. Chapter 4 contains an investigation into the use of the technology for producing abuse deterrent formulations for the drug, theophylline, which is used as a model for oxycodone. Various high molecular weight polymers are combined with plasticizers to produce mechanical and chemical properties sufficient to resist alcohol dose dumping, size reduction for immediate release and syringeability for injection. Thus, the KinetiSol® Dispersing (KSD) technology can be used as a formulation platform for creating abuse deterrent delivery forms in addition to solid amorphous dispersions for solubility enhancement.