High dose dry powder inhalation of itraconazole nanocrystals: Impact of drug load and inhalation device

Abstract

The aerosol performance of dry powders for inhalation depends on the interplay between formulation, device, primary packaging, and patient inhalation profile. This study evaluated a particle engineered formulation for high dose delivery of itraconazole (ITZ), manufactured via wet media milling and consecutive spray drying with mannitol (MAN) as a matrix former.

Key objectives included preserving ITZ nanocrystals and assessing the effects of drug load and inhaler type (HandiHaler® vs. GyroHaler®) on aerosol performance using cascade impaction after automated filling with a drum filler.

Drum filling was suitable for media-milled and spray-dried particles (nano-in-microparticles) but not for jet-milled (JM) or jet-milled and spray-dried (JM SD) samples due to their cohesiveness. Samples JM and JM SD showed significantly lower fine particle fractions (FPF ≤ 26 %) compared to engineered formulations (FPF up to 49 % with the HandiHaler®). The ITZ:MAN ratio did not affect the FPFs of the nano-in-microparticles therefore the fine particle dose (FPD) was primarily determined by the drug loading. The GyroHaler® consistently yielded lower FPFs. The highest FPD of up to 4 mg and highest FPF were achieved with a formulation without MAN using the HandiHaler®, likely due to optimized particle morphology (e.g., low density, smooth surface). Drug loading had no relevant impact on aerosolization as other factors such as particle morphology, surface roughness and the dispersion force of the device were supposed to have the major effect. Nevertheless, higher MAN content improved nanoparticle redispersion: the higher the MAN content, the faster the reconstitution. An ITZ:MAN ratio of 75:25 (resulting in a drug loading of 65 % (w/w) ITZ) was identified as superior formulation with an optimal balance between a high FPD and nearly complete reconstitution of the nanoparticles.

In conclusion, media milling in combination with consecutive spray drying is a suitable formulation technology for high dose dry powder aerosol therapy. Poorly water-soluble compounds with challenging aerosolization parameters could be transformed into particles with much improved aerosol properties superior to those using a conventional jet-milling process. MAN as matrix former increased the redispersibility of the nanoparticles incorporated. The choice of an inhalation device was found crucial for an optimal aerosol performance irrespectively of the dry powder formulation.