Enhanced pulmonary absorption following aerosol administration of mucoadhesive powder microspheres

Mucoadhesive, hydroxypropylcellulose (HPC) microspheres were prepared for powder inhalation and their feasibility for enhancing pulmonary drug absorption was investigated. Respirable-sized microspheres, incorporating crystalline or amorphous fluorescein (used as a model drug), were prepared by spray-drying aqueous or ethanol HPC systems, respectively. These were prepared from a variety of HPC grades (SL, L, M and H types) in different fluorescein–HPC ratios (1:1–1:10). The microspheres were administered to tracheally-intubated guinea pigs as powder aerosols and their fluorescein pharmacokinetics studied, and compared to those for pure crystalline fluorescein (‘control’). All microspheres were prepared and aerosolized within a MMAD range of 1.3–2.6 μm (GSD≤2.1). Fluorescein’s dissolution was increased in the amorphous form by 6.5-fold when compared to the crystalline material (83.9–87.2 vs. 13.5 μg/ml, respectively). Poor dissolution for the ‘control’ crystalline fluorescein appeared to be rate-determined, which showed bi-phasic absorption profiles ( T max=60 min), simultaneously competing with mucociliary clearance out of the lower airways. While the crystalline/HPC microspheres prolonged absorption, the amorphous fluorescein/HPC microspheres showed rapid absorption with T max=0 min (immediately after the administration had terminated). This was explained by enhanced fluorescein dissolution and was consistently observed irrespective of the fluorescein–HPC ratio or HPC grade. However, the microspheres with the least viscous HPC-SL and the lowest fluorescein–HPC ratio (1:1) failed to enhance bioavailability, presumably because the mucociliary clearance was undisturbed. In contrast, the microspheres with the highly viscous HPC-H with ratios ≥1:4 successfully enhanced absorption, achieving 88.0% bioavailability by virtue of HPC increasing the dissolution and retarding the mucociliary clearance.