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Evaluation of preclinical formulations for a poorly water-soluble compound
- Source :
- International Journal of Pharmaceutics. 511:630-637
- Publication Year :
- 2016
- Publisher :
- Elsevier BV, 2016.
-
Abstract
- One central aim of the present work was to find a robust oral formulation approach for Compound A, both to achieve reliable pharmacodynamic read outs but also for long time safety assessment studies. The compound has low aqueous solubility (0.4μM at 37°C), is highly lipophilic and has high Caco-2 permeability, i.e. a typical BCS II compound. A nanocrystal formulation, some oil approaches and a fat diet approach were evaluated in vivo in rats. The two latter strategies resulted in significantly higher in vivo exposures after oral administration compared to the nanocrystal approach. For simplicity, and due to the project development program, a food pellet formulation was selected. In addition, tentative data from a subcutaneous study in mice using nanocrystals of the compound are presented, showing extended profiles on the cost of Cmax. Exposure data in monkeys after administration of nanocrystals both intravenously and per oral are presented. When switched from nanocrystals to an oil formulation, the observed oral exposure behavior was similar as observed in rats.
- Subjects :
- Male
Drug Compounding
Drug Evaluation, Preclinical
Cmax
Pharmaceutical Science
02 engineering and technology
Pharmacology
030226 pharmacology & pharmacy
Rats, Sprague-Dawley
Mice
03 medical and health sciences
0302 clinical medicine
In vivo
Oral administration
Animals
Humans
Rats, Wistar
Solubility
Chemistry
Drug Administration Routes
Water
021001 nanoscience & nanotechnology
Rats
Macaca fascicularis
Water soluble
Pharmaceutical Preparations
Nanocrystal
Pharmacodynamics
Female
Caco-2 Cells
0210 nano-technology
Exposure data
Subjects
Details
- ISSN :
- 03785173
- Volume :
- 511
- Database :
- OpenAIRE
- Journal :
- International Journal of Pharmaceutics
- Accession number :
- edsair.doi.dedup.....6e74b5b04d5393198129a51bc34d9f0c