INHALE'S DRY-POWDER PULMONARY DRUG DELIVERY SYSTEM: CHALLENGES TO CURRENT MODELING OF GAS-SOLID FLOWS.

摘要

In this paper, we present a summary of experimental and computational approaches that have been employed to enhance our understanding of the de-agglomeration, dispersion and conveyance processes in a specialized, advanced dry-powder inhaler developed by Inhale Therapeutic Systems. Inhale is the leader in the development of pulmonary delivery systems for proteins (such as insulin), peptides and other molecules, enabling the systemic and local lung delivery of large molecule drugs through inhalation into the deep lung. A key component of Inhale's system is its proprietary dry-powder inhaler device used to deliver the drug to the patient. Efficiency and reproducibility of delivery are of paramount importance. Both are measured in terms of the quantity and quality of the aerosol that can be delivered to the deep lung. The portable (6.5 × 2.2 × 1.8 in - 16.5 × 5.6 × 4.6 cm) device performs two key functions: 1) disperses a small amount of fine dry powder (between 1 and 10 mg, depending on the drug and dose) contained initially in a sealed blister into a fine aerosol captured in a holding chamber, 2) delivers this fine aerosol to the patient. In the Inhale device, powder dispersion and inspiration control are accomplished by the TransJector, a small (1.25 in × 1 in × 1 in - 3.2 × 2.6 × 2.6 cm) flow-amplifier component driven by a charge of about 10 mg of pressurized air. The sudden sonic discharge of this mass of air through small jets in the TransJector is responsible for the extraction, de-agglomeration and dispersion of the powder. This event occurs within 80 milliseconds. More than 90% (by mass) of the particles in the aerosol extracted from the chamber have aerodynamic particle diameters less than 5 microns, and a high fraction of the starting mass in the blister is delivered. The transient two-phase flow in the Inhale device poses unique challenges to modeling and experimental characterization. It is transonic and extremely brief. Particle number densities are extremely high inside the TransJector. The powder particles undergo flow transitions from contact-dominated to collision-dominated to a dilute flow. The particle size distribution changes by at least two orders of magnitude from the loosely cohesive powder agglomerates to the aerosol particles delivered to the patient. Lagrangian and Eulerian approaches are discussed to model aspects of this de-agglomeration, dispersion and conveyance process. A commercial code (Fluent), supplemented with additional models, is employed for the numerical simulations. Conclusions will be presented on the applicability of these methods to advanced dry-powder inhaler design and optimization. Directions for future study will be outlined.