Processes and compositions to expand drug processing

Background

Dr. Robert O. Williams III and his team have developed a method to expand the ability of the hot-melt extrusion process to increase drug loading in amorphous solid dispersions (ASD). Dr. Williams is the Division Head and Professor of Molecular Pharmaceutics and Drug Delivery and the Johnson & Johnson Centennial Chair in Pharmacy at UT Austin with primary interests in the formulation, development, optimization, and delivery of small organic compounds, peptides, and proteins using a range of technologies, including depot drug, oral, and pulmonary/nasal/ophthalmic drug delivery systems. He has published various research articles in trade journals related to his area of expertise and is Editor-in-Chief of AAPS PharmSciTech. The focus of his work has broad applicability in drug formulation and delivery systems through the use of novel engineering technologies.

Invention

Up to 90% of new active pharmaceutical ingredient (API) candidates exhibit poor water solubility (PWS), limiting their bioavailability for therapeutic use. Low bioavailability can result in the need for higher/more frequent dosing and can result in less-than-desirable patient outcomes. ASDs are a widely employed formulation technique to improve the water solubility of PWS in API candidates, which improves the bioavailability of these molecules/drugs by increasing the rate and extent of dissolution in the drug development process. A variety of different processing techniques, including hot-melt extrusion (HME), are used to prepare API into ASDs. But HME, as used today, has many drawbacks, including limitations in reaching maximum drug loads for ASDs and difficulty of use with drugs with high melting points or that degrade when exposed to thermal or mechanical energy.

To address concerns with low drug loading in ASDs, use with high melting point drugs (e.g., >200ºC), thermal/shear sensitivity, and drugs with low-pH-dependent solubility, a technique that uses pH modification of drug-polymer systems during the HME process to create ASDs composed of either a basic or acidic API has been developed. The method adds <10% w/w of a strong base/acid to the premix, which is then extruded, increasing the loading of drugs exhibiting pH-dependent solubility to at least 30% and >50% in an ASD. Experiments indicated that a small amount (w/w) of ~5% NaOH improves the drug loading of an ASD comprised of telmisartan, a weak acid, and Soluplus from a maximum of ~5% to 30%-50 % to create a high drug-loaded ASD. The use of the base KOH realized similar results. This increase in drug loading of an ASD results in the ability to provide greater flexibility in dosage formulation, thereby improving drug performance and/or patient acceptability.