Browsing by Subject "Kinetisol dispersing"
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Item Novel formulations and thermal processes for bioavailability enhancement of soluble and poorly soluble drugs(2013-12) Keen, Justin Martin; McGinity, James W.; Williams, Robert O., 1956-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.Item Pharmaceutical technologies for improving drug loading in the formulation of solid dispersions(2011-12) O'Donnell, Kevin Patrick; Williams, Robert O., 1956-It is estimated that 90% of new chemical entities in development pipelines exhibit poor aqueous solubility. For compounds not limited by biological membrane permeability, this poor aqueous solubility is the limiting factor in bioavailability. Therefore, the formulation of such drugs has primarily been centered on improving dissolution properties. Traditional approaches for overcoming poor aqueous solubility include salt formation of the active ingredient, complexation, the use of surface active agents, formulation into oil based systems, particle size reduction, or a combination of these methods. More recently amorphous solid dispersions have been explored. Currently, the drug loading within solid dispersions is limited resulting in large quantities of the formulation being required for a therapeutically relevant dose. In the frame of the work herein, Thin Film Freezing was utilized to generate high drug loaded amorphous solid dispersions of the poorly water soluble drug phenytoin utilizing a hydrophilic polymer or an amphiphilic graft copolymer for system stabilization. Additionally a new solvent removal technique, atmospheric freeze drying, was investigated for removal of the solvents used during Thin Film Freezing. The Thin Film Freezing materials were subsequently incorporated into a polymeric carrier for solid dispersion formulation by a novel fusion production technique termed Kinetisol® dispersing. Studies of the solid dispersions produced by Thin Film Freezing revealed an amorphous system had been obtained for both stabilizing polymers. The formulation containing a hydrophilic carrier was capable of achieving supersaturation. Conversely, the amphiphilic graft copolymer demonstrated a phenytoin-polymer interaction resulting in poor dissolution. Atmospheric freeze drying of the Thin Film Freezing product demonstrated that the alternative drying technique generated powders with significantly improved handling properties as a result of reduced electrostatic interactions due to the increased pore size, reduced surface area, larger particle size, and higher, though acceptable, residual solvent levels. The use of Thin Film Freezing powders during Kinetisol Dispersing resulted in a single phase amorphous system while solid dispersions produced from physical mixtures of bulk materials were amorphous two-phase systems. This indicates that the use of amorphous drug compositions during solid dispersion production may increase drug loading in the final system while remaining single phase in nature.