Particle engineering for high dose dry powder inhalation of itraconazole

Abstract

Itraconazole (ITZ) is considered as first-line therapy against respiratory infections such as allergic bronchopulmonary aspergillosis. Local treatment of these infections is regarded beneficial as it might reduce systemic side effects. Significantly higher doses compared to those applied in asthma or COPD therapy are demanded. Therefore, particle engineering with the aim of developing a carrier-free, high dose powder formulation with excellent dispersibility is required. The combination of media milling and spray drying enables the generation of tailored spherical particles with low density in a desired particle size range and with a defined surface structure and an API in a crystalline state. Nanocrystals of ITZ were stabilized by electrosteric stabilization using hydroxypropyl cellulose (HPC-SL), sodium dodecyl sulfate (SDS) and polysorbate 80 (PS80). A concentration of 0.9% (w/w) HPC-SL, 0.14% (w/w) SDS and 0.14% (w/w) PS80 was necessary for a sufficient nanoparticle stabilization. Choosing lower stabilizer concentrations resulted in a pronounced increase in particle size due to agglomeration, which was confirmed by SEM imaging and a decrease of magnitude in zeta potential in combination with an amorphization of the particles. Process evaluation of spray drying revealed an outlet temperature of 60 °C, a nozzle gas flow rate of 23 SL/min and a feed rate of 5 g/min as optimized parameters. Nanoization and spray drying led to spherical, hollow, low-density nano-in-microparticles (ITZ nanoparticles with mannitol (MAN) as matrix former) with poor powder flow characteristics, regardless of the drug load. Both ITZ and MAN were found in crystalline state after spray drying, although less stable forms of MAN were present as the suspended ITZ particles might favor the formation of the metastable a- and d-polymorphic forms of MAN. The performance of a DPI formulation strongly depends on the interplay between the device, the formulation, and the primary packaging material. Automatic filling with the BI drum filler was possible for the nano-in-microparticles but not for samples JM (jet-milled) and JM SD (jet-milled and spray dried) because of their strong cohesiveness. This finding was supported by the cascade impaction experiments. Samples JM and JM SD showed a significantly lower FPF (fine particle fraction) and FPD (fine particle dose) compared to the nano-in-microparticles. Hence, consecutive nanoization and spray drying seems to be a superior particle engineering technique and enabled the generation of high dose formulations for ITZ up to 4 mg FPD. The reason for the improved dispersibility of the engineered particles was most likely the optimized morphology (low density with a slightly rough surface), as indicated by SEM images. The great impact of the device has also been demonstrated. The HandiHaler^® generated a significantly higher FPD compared to the GyroHaler^®. This was most likely related to the capsule motion in the HandiHaler^®, which enhanced the powder aerosolization. Thus, the HandiHaler^® is preferred over the GyroHaler^® for delivering the nano-in-microparticles of ITZ. The ITZ:MAN ratio most likely did not affect the aerosolization of the composite ITZ particles. Presumably, other factors (such as particle morphology, surface roughness and the dispersion force of the device) exceeded the potential effect of the drug load. However, the MAN content in the nano-in-microparticles highly affected the reconstitution of the nanoparticles in water. The higher the MAN content was, the faster was the reconstitution. An ITZ:MAN ratio of 75:25 (resulting in a drug loading of 65% (w/w) ITZ) was the preferred formulation as this enabled a balance between a high FPD and nearly complete reconstitution of the nanoparticles.