title: Usefulness of a nanoparticle formulation to investigate some hemodynamic parameters of a poorly soluble compound.
abstract: Drug solubility is an important issue when progressing investigational compounds into clinical candidates. The present paper describes the development and characterization of a nanosuspension that was formulated to overcome problems with poor water solubility and possible adverse events caused by cosolvent mixtures, using ticagrelor as a model compound. A homogeneous nanosuspension of ticagrelor was formed using a wet milling approach, which yielded particle sizes around 230 nm. The nanosuspensions were chemically stable for at least 10 months at both room temperature and when refrigerated, and physically (i.e., particle size) stable for at least 10 months under refrigeration, and approximately 3 years at room temperature and when frozen. One rat model and two dog models were used to assess the pharmacokinetics and hemodynamic-related effects following intravenous administration of nanoparticles. There were no biologically consistent or dose-dependent effects of the nanoparticles on the hemodynamic parameters tested, that is, heart rate, mean aortic pressure, cardiac output, left femoral artery blood flow, or cardiac inotropy (measured as max dP/dt). In conclusion, a stable ticagrelor nanosuspension formulation was developed, suitable for intravenous administration. At the doses evaluated, this formulation was without hemodynamic effects in three sensitive preclinical models.
authors.affiliation: Pharmaceutical Development, AstraZeneca R&D Mölndal, S-431 83 Mölndal, Sweden. carl-gustav.sigfridsson@astrazeneca.com
authors.forename: Kalle
authors.initials: K
authors.lastname: Sigfridsson
authors.forename: Jan-Arne
authors.initials: JA
authors.lastname: Björkman
authors.forename: Pia
authors.initials: P
authors.lastname: Skantze
authors.forename: Helen
authors.initials: H
authors.lastname: Zachrisson
mesh_terms: D000241:Adenosine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D002626:Chemistry, Pharmaceutical; D003460:Crystallization; D004285:Dogs; D004353:Drug Evaluation, Preclinical; D004355:Drug Stability; D006439:Hemodynamics / Q000187:drug effects*; D007262:Infusions, Intravenous; D008297:Male; D053758:Nanoparticles / Q000008:administration & dosage / Q000737:chemistry*; D010316:Particle Size; D051381:Rats; D017207:Rats, Sprague-Dawley; D012995:Solubility; D000077486:Ticagrelor; D014961:X-Ray Diffraction
chemical_list: D000077486:Ticagrelor; D000241:Adenosine