Nanoparticle-based oral formulation can surprise you with inferior in vivo absorption in humans.

Particle size reduction leads to an increase in the drug dissolution rate, which in turn can lead to a substantial increase in the bioavailability of a poorly soluble compound. To improve bioavailability, a practically insoluble investigational drug, ODM-106, was nanomilled and capsule formulations with three different drug amounts were prepared for the first-in-man study. Fast in vitro dissolution was achieved from all the capsules containing different amounts of drug nanoparticles but in the clinical study, surprisingly, low bioavailability was observed from the highest capsule strength (100 mg) in comparison to a lower strength (10 mg). In order to study further the discrepant in vitro-in vivo correlation (IVIVC), a discriminative dissolution method was developed. It was noticed that the degree of supersaturation increased significantly as the stabilizers' concentration within the dried nanoformulations was increased. Hypromellose provided a physical barrier between nanoparticles to prevent aggregation during drying. SLS on the other hand improved wettability and provided supersaturation. The drug load, nanoparticle/polymer/surfactant/filler ratios and selected drying step were discovered to be critical to the nanoformulations' performance. Aggregation of nanoparticles, in the absence of optimal stabilizer concentration, compromised dissolution due to decreased surface area. In conclusion, the early development of a discriminative dissolution method and cautious selection of the nanoparticle/polymer ratio before manufacturing clinical batches is recommended.

Fast-dissolving sublingual solid dispersion and cyclodextrin complex increase the absorption of perphenazine in rabbits.

OBJECTIVES: The sublingual administration route as well as solid dispersion formation with macrogol 8000 and complexation with ß-cyclodextrin (ß-CyD) were investigated as ways for improving the absorption of perphenazine, a poorly water-soluble drug subjected to substantial first-pass metabolism. METHODS: The absorption of perphenazine was studied in rabbits after sublingual administration of perphenazine/macrogol solid dispersion, solid perphenazine/ß-CyD complex and plain micronized perphenazine, as well as after peroral administration of an aqueous perphenazine solution. Solid formulations were prepared by freeze-drying (perphenazine/macrogol solid dispersion) or spray-drying (perphenazine/ß-CyD complex). KEY FINDINGS: The value for area under the curve from 0 to 360 min (AUC(0-360 min) ) of perphenazine after peroral administration was only 8% of the AUC(0-360 min) value obtained after intravenous administration, while the corresponding values for the sublingually administered formulations were 53% (perphenazine/macrogol solid dispersion), 41% (perphenazine/ß-CyD complex) and 64% (micronized perphenazine). There are three possible mechanisms to explain these results: avoidance of the first-pass metabolism; good sublingual absorption of perphenazine; and rapid dissolution rate of perphenazine from the studied formulations. CONCLUSIONS: With sublingual administration, the drug has to dissolve rapidly in a small volume of saliva. Based on the present absorption studies in rabbits, the solid dispersion preparation and cyclodextrin complexation were postulated to be useful ways to attain successful sublingual administration of perphenazine. Good sublingual absorption was also achieved by micronization of perphenazine. As far as we are aware, this paper is one of the first to evaluate the sublingual administration of a solid dispersion in vivo.