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.

Use of conventional surfactant media as surrogates for FaSSIF in simulating in vivo dissolution of BCS class II drugs.

The usefulness of selected conventional surfactant media to enhance dissolution of BCS class II drugs similarly to fasted state simulated intestinal fluid (FaSSIF) and to predict the absorption of drugs in vivo was evaluated. Dissolution behavior of danazol (Danol), spironolactone (Spiridon) and N74 (phase I compound) was compared between FaSSIF, containing physiological levels of sodium taurocholate (STC) and lecithin, and dissolution media containing various concentrations of anionic surfactant, sodium lauryl sulfate (SLS) or non-ionic surfactant, polysorbate (Tween) 80. Although these media differed largely in their solubilization ability, micelle size, diffusivity and surface tension, similar dissolution enhancing levels were achieved between FaSSIF and drug-specific concentrations of conventional surfactants. The dissolution enhancement was shown, however, to be important only for danazol and N74, molecules that are characterized by high hydrophobicity. An in vivo pharmacokinetic dog study was carried out with N74. Comparison of observed plasma profiles with simulated profiles obtained using compartmental absorption and transit model (CAT) indicated that 0.1% SLS medium was the best to predict in vivo plasma profiles and pharmacokinetic parameters (C(max) and AUC). This study demonstrates the potential of substituting FaSSIF with more simple and cost-effective conventional surfactant media. Use of in vivo prognostic amounts of synthetic surfactants in dissolution testing could largely assist in industrial drug development as well as in quality control purposes.