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 microm (GSD< or =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 microg/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 > or = 1:4 successfully enhanced absorption, achieving 88.0% bioavailability by virtue of HPC increasing the dissolution and retarding the mucociliary clearance.