title: Preparation and in vitro/in vivo evaluation of nano-sized crystals for dissolution rate enhancement of ucb-35440-3, a highly dosed poorly water-soluble weak base.
abstract: Ucb-35440-3 is a new drug entity under investigation at UCB S.A. Due to its physicochemical characteristics, the drug, a poorly water-soluble weak base, shows poor solubility and dissolution characteristics. In rat, the low oral bioavailability (F < 10%) is largely due to poor absorption. In order to enhance the solubility and dissolution characteristics, formulation of ucb-35440-3 as nanocrystals has been achieved in this study. Nanoparticles were prepared using high pressure homogenization and were characterized in terms of size and morphology. In vitro dissolution characteristics were investigated and compared to the un-milled drug in order to verify the theoretical hypothesis on the benefit of increased surface area. In vivo pharmacokinetic evaluation of ucb-35440-3 nanoparticles was also carried out on rats. Crystalline state evaluation before and following particle size reduction was conducted through polarized light microscopy and PXRD to denote any possible transformation to an amorphous state during the homogenization process. Drug chemical stability was also assessed following homogenization. The dissolution rate increased significantly at pH 3.0, 5.0 and 6.5 for ucb-35440-3 nanoparticles. However, the pharmacokinetic profile obtained yielded lower systemic exposure than the un-milled compound (in fed state), this although being thought to be the consequence of the drug and formulation characteristics.
authors.affiliation: Laboratory of Pharmaceutics and Biopharmaceutics, Université Libre de Bruxelles, Campus Plaine, Boulevard du Triomphe, Brussels, Belgium.
authors.forename: J
authors.initials: J
authors.lastname: Hecq
authors.forename: M
authors.initials: M
authors.lastname: Deleers
authors.forename: D
authors.initials: D
authors.lastname: Fanara
authors.forename: H
authors.initials: H
authors.lastname: Vranckx
authors.forename: P
authors.initials: P
authors.lastname: Boulanger
authors.forename: S
authors.initials: S
authors.lastname: Le Lamer
authors.forename: K
authors.initials: K
authors.lastname: Amighi
mesh_terms: D000284:Administration, Oral; D000818:Animals; D018927:Anti-Asthmatic Agents / Q000008:administration & dosage / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics*; D001549:Benzamides / Q000008:administration & dosage / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics*; D001682:Biological Availability; D002626:Chemistry, Pharmaceutical; D003460:Crystallization; D004355:Drug Stability; D005079:Excipients / Q000737:chemistry; D006863:Hydrogen-Ion Concentration; D065347:Hypromellose Derivatives; D008297:Male; D008747:Methylcellulose / Q000031:analogs & derivatives / Q000737:chemistry; D053758:Nanoparticles; D010316:Particle Size; D010879:Piperazines / Q000008:administration & dosage / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics*; D011312:Pressure; D051381:Rats; D017208:Rats, Wistar; D012995:Solubility; D013678:Technology, Pharmaceutical; D013997:Time Factors
chemical_list: C515874:5-(4-((aminocarbonyl)(hydroxy)amino)but-1-ynyl)-2-(2-(4-((4-chlorophenyl)(phenyl)methyl)piperazin-1-yl)ethoxy)benzamide; D018927:Anti-Asthmatic Agents; D001549:Benzamides; D005079:Excipients; D010879:Piperazines; D065347:Hypromellose Derivatives; D008747:Methylcellulose