Co-processing of API combinations for inhalation therapy

In order to use active pharmaceutical ingredient (API) particles in dry powder inhalers (DPIs) intended to target the deep lung, they must have an aerodynamic diameter of 1m - 5m. Particles of this size are cohesive and possess poor flow properties, which makes handling and dosing that is usually done volumetrically in DPIs challenging. To overcome this problem, carrier-based formulations, where the API is attached to the surface of larger carrier particles (50m 200m) of adequate flowability were developed. Drug detachment during inhalation is essential to ensure that the drug particles reach its target, the deeper lung. Most of the inhalation products on the market are used for the therapy of chronically obstructive pulmonary disease and asthma; additionally a lot of research in pulmonary drug delivery for tuberculosis is done. In both cases, a multidrug therapy with different APIs and various products is necessary. Therefore, this study addresses the co-processing of two API particles used in the therapy of these diseases in order to reduce dose variability and enhance patient compliance by reducing the amount of medications to take. Ideally co-processing leads to free flowing particles that can be administered in form of API agglomerates avoiding carrier-based formulations. Consequently, unit operations, such as mixing of API and carrier, can be circumvented. Alternatively, prevention of de-mixing/ particle segregation, and thereby, reduction in dose variability of carrier-based combination formulations, could be achieved using novel co-engineered API combinations. The aim of this proposal is to develop a co-processing platform including API as well as excipient screening, candidate batch production, downstream processing up to the final dosage form. Central focus will be exploring the guiding principles of co-formulation, governing the co-processed particles solid-state and bulk powder properties. In particular, the applicant will focus on: 1. Screening of different API combinations involving thermal techniques like hot stage microscopy and vacuum compression molding coupled with differential scanning calorimetry and molecular dynamic simulation. 2. Preparation of candidate batches of the selected model systems with an appropriate technique including spray drying, spray congealing or hot melt extrusion. 3. Detailed characterization of the formed intermediate particles in terms of powder properties/ micromeritics, solid-state and chemical analysis. 4. Preparation of the final dosage form including the selection of formulation approach and device for the most promising batches. 5. Evaluation of the final dosage form with respect to aerosolization performance, chemical and physical stability and in vitro biopharmaceutics. By combining experimental screening, computational modeling, detailed material characterization and the use of known techniques for the production of novel co-processed particles, this project will help to develop an innovative co-processing platform for DPIs.