title: Carbon dioxide-mediated generation of hybrid nanoparticles for improved bioavailability of protein kinase inhibitors.
abstract: OBJECTIVE
  A versatile methodology is demonstrated for improving dissolution kinetics, gastrointestinal (GI) absorption, and bioavailability of protein kinase inhibitors (PKIs).
  
  
  METHODS
  The approach is based on nanoparticle precipitation by sub- or supercritical CO2 together with a matrix-forming polymer, incorporating surfactants either during or after nanoparticle formation. Notably, striking synergistic effects between hybrid PKI/polymer nanoparticles and surfactant added after particle formation is investigated.
  
  
  RESULTS
  The hybrid nanoparticles, consisting of amorphous PKI embedded in a polymer matrix (also after 12 months), display dramatically increased release rate of nilotinib in both simulated gastric fluid and simulated intestinal fluid, particularly when surfactants are present on the hybrid nanoparticle surface. Similar results indicated flexibility of the approach regarding polymer identity, drug load, and choice of surfactant. The translation of the increased dissolution rate found in vitro into improved GI absorption and bioavalilability in vivo was demonstrated for male beagle dogs, where a 730% increase in the AUC0-24h was observed compared to the benchmark formulation. Finally, the generality of the formulation approach taken was demonstrated for a range of PKIs.
  
  
  CONCLUSIONS
  Hybrid nanoparticles combined with surfactant represent a promising approach for improving PKI dissolution rate, providing increased GI absorption and bioavailability following oral administration.
authors.affiliation: XSpray Microparticles AB, Fogdevreten 2B, 171 65, Solna, Sweden.
authors.forename: Gérald
authors.initials: G
authors.lastname: Jesson
authors.forename: Magnus
authors.initials: M
authors.lastname: Brisander
authors.forename: Per
authors.initials: P
authors.lastname: Andersson
authors.forename: Mustafa
authors.initials: M
authors.lastname: Demirbüker
authors.forename: Helene
authors.initials: H
authors.lastname: Derand
authors.forename: Hans
authors.initials: H
authors.lastname: Lennernäs
authors.forename: Martin
authors.initials: M
authors.lastname: Malmsten
mesh_terms: D000284:Administration, Oral; D000818:Animals; D002245:Carbon Dioxide / Q000737:chemistry*; D004285:Dogs; D004337:Drug Carriers / Q000737:chemistry*; D007408:Intestinal Absorption; D008297:Male; D053758:Nanoparticles / Q000737:chemistry* / Q000648:ultrastructure; D011108:Polymers / Q000737:chemistry; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D012995:Solubility; D013501:Surface-Active Agents / Q000737:chemistry
chemical_list: D004337:Drug Carriers; D011108:Polymers; D047428:Protein Kinase Inhibitors; D013501:Surface-Active Agents; D002245:Carbon Dioxide