Novel formulations and thermal processes for bioavailability enhancement of soluble and poorly soluble drugs

Formulation intervention, through the application of processing technologies, is a requirement for enabling therapy for the vast majority of drugs. Without these enabling technologies, poorly soluble drugs may not achieve therapeutic concentrations in the blood or tissue of interest. Conversely, freely soluble and/or rapidly cleared drugs may require frequent dosing resulting in highly cyclic tissue concentrations. During the last several years, thermal processing techniques, such as melt mixing, spray congealing, sintering, and hot-melt extrusion (HME), have evolved rapidly. Several new technologies, specifically dry powder coating, injection molding, and KinetiSol® dispersing (KSD), have been adapted to the pharmaceutical arena. Co-rotating twin screw extrusion is routinely applied for the purposes of dissolving poorly soluble drugs into glassy polymers to prepare amorphous solid dispersions, which create supersaturated drug concentrations in the gastro-intestinal tract. A potentially more advantageous alternate geometry, counter-rotating twin screw extrusion was evaluated for preparation of model amorphous solid dispersion and was observed to be more efficient in forming a solid solution and reduced the thermal stress on the drug. HME and KSD processes were utilized to prepare two phase systems consisting of a lipid, glyceryl behenate, and a polymeric amorphous solid dispersion intended to provide both controlled release of drug and supersaturated drug concentrations in the release medium. Such systems are challenging due to the potential for crystallization of the drug within the dosage form during release, which was observed to be influenced by lipophilicity and porosity of the formulation, as well as the surface area to volume ratio of the system. High molecular weight cellulose based glassy dispersions were prepared using a weakly basic model drug by KSD, which when formulated into tablets were optimized to provide either immediate or approximately 2 hours of controlled release under the pH conditions simulating the environment of the stomach. Without formulation intervention in the external phase of the tablet, these compositions gel, muting drug release and missing the drug absorption window. Compositions optimized by an in vitro dissolution test were compared to a lower molecular weight HME prepared commercial product in a beagle dog model and observed to have statistically similar bioavailability, and in one case improved variability. A modified twin screw extrusion machine was utilized to develop a continuous granulation process capable of producing granules that do not require subsequent grinding or sizing. This novel process, which employs previously un-reported temperature profiles, produces lipid based granules that when compressed into tablets produce a controlled release of tramadol hydrochloride, which were not susceptible to alcohol induced dose dumping.