(602c) Bulk Properties Assessment and Drum Capsule Filling Evaluation of High Dose Inhaled Formulations

Inhaled therapeutics are routinely used for the treatment of pulmonary diseases such as asthma, COPD, and cystic fibrosis. In recent years, the need to deliver a high therapeutic dose into the lungs is becoming increasingly more commonplace. In the case of recently approved anti-infectives (e.g. colobreathe, tobramycin DPI, and aerovanc) and Parkinson’s therapy (inbrija), for example, the total lung doses are thousands of times greater than those of conventional asthma medications (e.g. ICS, LABA, and LAMA).

Inhaled drug products, typically a blend comprising the active pharmaceutical ingredient (API) and excipients, are often packaged in blisters or standard-sized capsules and subsequently dispersed and delivered to the lungs by a specially designed inhaler. To promote patient compliance, administering the required lung dose in as few inhalations as possible is desirable. Minimizing inhalations, combined with the fill volume constraint of standard capsules, often leads to the need for maximizing the drug loading in each dose.

This work presents the challenges associated with the process of filling a model high drug loading formulation into capsules. These challenges arise from the drug product’s cohesive nature, which is a consequence of the size of the API payload: in order to reach the lung regions relevant to drug absorption, a common approach is to micronize the API to a specific size range. While certain excipients can be blended with the API to improve filling capability, the fact remains that the amount that can be added is limited due to the reasons explained above.

We studied the effects of drug loading, excipient particle size, the amount of force normalizing agents (e.g. magnesium stearate) in the formulation, the order of excipient addition during blending, blending method (high- vs low-shear), and surface modifying agents (e.g. leucine and tri-leucine) on the flowability and compressibility of the API/excipient blends. High- and low-shear mixing were achieved using a Turbula blender and a ProCepT, respectively. Filling experiments were performed on select blends using a Harro Hofliger Drumlab, a lab-scaled drum-filling machine. The following drum-filling parameters were studied: bore size, vacuum pressure, and drum/stirrer offset. Blend properties were subsequently correlated to the filling performance quantified by the consistency of dosage units.

We found that the blend properties are influenced primarily by the drug loading, excipient particle size, and the order of excipient addition during the blending process. The effects of force normalizing agent are complex—there appears to be an optimum amount of force normalizing agent that maximizes flowability and minimizes compressibility; however, increasing or decreasing the amount past this level will reverse these effects. Unit dosage consistency, on the other hand, was most sensitive to the drum filling vacuum pressure, with higher vacuum pressure generally resulting in more consistent dosage units. Operating the drum filler at its maximum pressure, however, will limit the versatility of the equipment because under such a constraint the fill weight will be a function of only the drum bore size and the blend compressibility. Perhaps as expected, poor dosage unit consistency resulted when filling poorly flowing and highly compressible materials (in this study, these properties were exhibited by the blends with the highest drug loading). This observation was the result of a powder ‘bridge’ that formed on the rotating stirrer inside the drum filler hopper, which in turn prevented the product from reaching the drum bore. Lastly, we also used DEM simulations to explore how to potentially redesign the drum filling equipment to optimize the filling process for cohesive and compressible materials.