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.

Evaluation of the clinical efficacy and safety of dexmedetomidine or medetomidine in cats and their reversal with atipamezole.

OBJECTIVE: To evaluate and compare the clinical effects of dexmedetomidine (DEX) and medetomidine (MED) in cats, and their reversal with atipamezole (ATI). Study design Prospective blinded randomized multi-centre clinical trial. Animals One hundred and twenty client-owned cats. METHODS: Cats were randomly allocated to receive a single intramuscular (IM) injection of either DEX (0.04 mg kg(-1), n = 62) or MED (0.08 mg kg(-1), n = 58) for minor procedures requiring sedation and analgesia. Afterwards, ATI (0.2 mg kg(-1)) was administered IM to half the cats, randomly assigned. Prior to, during and after the procedure the sedative, analgesic and cardiorespiratory effects and body temperature were assessed. RESULTS: Dexmedetomidine and MED produced clinically and statistically comparable effects. The intended procedure(s) could be performed in over 90% of cats. Sedation and analgesia were apparent within 5 minutes, peak effects were observed at approximately 30 minutes and spontaneous recovery occurred by 180 minutes of injection. Heart and respiratory rate and body temperature decreased significantly over time and had not returned to baseline values 180 minutes after administration. ATI administration completely reversed the sedative and analgesic effects, returned the heart rate to normal and prevented any further reductions in respiratory rate and body temperature in both DEX- and MED-treated cats. The reporting of adverse events was low and the most commonly observed event was vomiting (7%). No serious adverse events or concerns regarding safety were reported. CONCLUSIONS AND CLINICAL RELEVANCE: Dexmedetomidine (0.04 mg kg(-1)) produced comparable sedative and analgesic effects to MED (0.08 mg kg(-1)) in cats. DEX produced adequate sedation and analgesia for radiography, grooming, dental care and lancing of abscesses. ATI fully reversed the clinical effects of DEX.