title: Intact nanoparticulate indomethacin in fast-dissolving carrier particles by combined wet milling and aerosol flow reactor methods.
abstract: OBJECTIVE
  Drug development is often hindered by a drug's low dissolution rate. We present a method to increase dissolution rate of a drug powder by producing crystalline nanoparticles that are dispersed in carrier microparticles.
  
  
  METHODS
  Indomethacin crystals of a few hundred nanometers are prepared by media milling using poloxamer 188 as a stabilizer. Nanoparticles are embedded into microparticles with a mannitol matrix and an L-leucine coating layer using an aerosol flow reactor method.
  
  
  RESULTS
  Microparticles stabilize the primary nanoparticles in an intact crystalline form and release them when re-dispersed in aqueous medium. Secondary microparticle structure dissolves rapidly, resulting in a fast release and dissolution of indomethacin. In this manner, it is possible to change the surface layer of the particles from the one needed for nanoparticle production to one more suitable for process formulation of pharmaceuticals for, e.g., tablet or pulmonary products.
  
  
  CONCLUSIONS
  Particle assemblies where nano-sized crystalline drug domains are embedded in solid microparticles are presented. The present work is a promising approach towards a "nanos-in-micros" concept as a tool for pharmaceutical nanoparticle processing.
authors.affiliation: Division of Pharmaceutical Technology, Faculty of Pharmacy, University of Helsinki, P.O. Box 56, 00014, Helsinki, Finland. timo.laaksonen@helsinki.fi
authors.forename: Timo
authors.initials: T
authors.lastname: Laaksonen
authors.forename: Peng
authors.initials: P
authors.lastname: Liu
authors.forename: Antti
authors.initials: A
authors.lastname: Rahikkala
authors.forename: Leena
authors.initials: L
authors.lastname: Peltonen
authors.forename: Esko I
authors.initials: EI
authors.lastname: Kauppinen
authors.forename: Jouni
authors.initials: J
authors.lastname: Hirvonen
authors.forename: Kristiina
authors.initials: K
authors.lastname: Järvinen
authors.forename: Janne
authors.initials: J
authors.lastname: Raula
mesh_terms: D000336:Aerosols / Q000737:chemistry; D002152:Calorimetry, Differential Scanning / Q000379:methods; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D004337:Drug Carriers / Q000737:chemistry*; D005079:Excipients / Q000737:chemistry; D007213:Indomethacin / Q000737:chemistry*; D007930:Leucine / Q000737:chemistry; D008353:Mannitol / Q000737:chemistry; D008855:Microscopy, Electron, Scanning / Q000379:methods; D053758:Nanoparticles / Q000737:chemistry*; D010316:Particle Size; D011208:Powders / Q000737:chemistry; D012995:Solubility; D013678:Technology, Pharmaceutical / Q000379:methods*; D014961:X-Ray Diffraction / Q000379:methods
chemical_list: D000336:Aerosols; D004337:Drug Carriers; D005079:Excipients; D011208:Powders; D008353:Mannitol; D007930:Leucine; D007213:Indomethacin