title: Preparation of a clofazimine nanosuspension for intravenous use and evaluation of its therapeutic efficacy in murine Mycobacterium avium infection.
abstract: Clofazimine nanosuspensions were produced by high pressure homogenization and the formulation was optimized for lyophilization. Characterization of the product by photon correlation spectroscopy, laser diffraction and Coulter counter analysis showed that the clofazimine nanosuspensions were suitable for iv injection with a particle size permitting passive targeting to the reticuloendothelial system. Following iv administration to mice of either the nanocrystalline or a control liposomal formulation at a dose of 20 mg clofazimine/kg bodyweight, drug concentrations in livers, spleens and lungs reached comparably high concentrations, well in excess of the MIC for most Mycobacterium avium strains. When C57BL/6 mice were experimentally infected with M. avium strain TMC 724, nanocrystalline clofazimine was as effective as liposomal clofazimine in reducing bacterial loads in the liver, spleen and lungs of infected mice. Nanocrystalline suspensions of poorly soluble drugs such as riminophenazines are easy to prepare and to lyophilize for extended storage and represent a promising new drug formulation for intravenous therapy of mycobacterial infections.
authors.affiliation: Department of Pharmaceutics, Biopharmaceutics and Biotechnology, Free University of Berlin, Kelchstrasse 31, D-12169 Berlin, Germany.
authors.forename: K
authors.initials: K
authors.lastname: Peters
authors.forename: S
authors.initials: S
authors.lastname: Leitzke
authors.forename: J E
authors.initials: JE
authors.lastname: Diederichs
authors.forename: K
authors.initials: K
authors.lastname: Borner
authors.forename: H
authors.initials: H
authors.lastname: Hahn
authors.forename: R H
authors.initials: RH
authors.lastname: Müller
authors.forename: S
authors.initials: S
authors.lastname: Ehlers
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use*; D002991:Clofazimine / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use*; D004195:Disease Models, Animal; D004337:Drug Carriers; D005260:Female; D005612:Freeze Drying; D007262:Infusions, Intravenous; D008081:Liposomes; D051379:Mice; D008810:Mice, Inbred C57BL; D009162:Mycobacterium avium / Q000187:drug effects; D015270:Mycobacterium avium-intracellulare Infection / Q000188:drug therapy* / Q000378:metabolism; D013535:Suspensions
chemical_list: D000900:Anti-Bacterial Agents; D004337:Drug Carriers; D008081:Liposomes; D013535:Suspensions; D002991:Clofazimine