title: Aerosol Performance and Stability of Liposomes Containing Ciprofloxacin Nanocrystals.
abstract: BACKGROUND
  Previously we showed that the release properties of a liposomal ciprofloxacin (CFI) formulation could be attenuated by incorporation of drug nanocrystals within the vesicles. Rather than forming these drug nanocrystals during drug loading, they were created post manufacture simply by freezing and thawing the formulation. The addition of surfactant to CFI, either polysorbate 20 or Brij 30, provided an additional means to modify the release profile or incorporate an immediate-release or 'burst' component as well. The goal of this study was to develop a CFI formulation that retained its nanocrystalline morphology and attenuated release profile after delivery as an inhaled aerosol.
  
  
  METHODS
  Preparations of 12.5 mg/mL CFI containing 90 mg/mL sucrose and 0.1% polysorbate 20 were formulated between pH 4.6 to 5.9, stored frozen, and thawed prior to use. These thawed formulations, before and after mesh nebulization, and after subsequent refrigerated storage for up to 6 weeks, were characterized in terms of liposome structure by cryogenic transmission electron microscopy (cryo-TEM) imaging, vesicle size by dynamic light scattering, pH, drug encapsulation by centrifugation-filtration, and in vitro release (IVR) performance.
  
  
  RESULTS
  Within the narrower pH range of 4.9 to 5.3, these 12.5 mg/mL liposomal ciprofloxacin formulations containing 90 mg/mL sucrose and 0.1% polysorbate 20 retained their physicochemical stability for an additional 3 months refrigerated storage post freeze-thaw, were robust to mesh nebulization maintaining their vesicular form containing nanocrystalline drug and an associated slower release profile, and formed respirable aerosols with a mass median aerodynamic diameter (MMAD) of ∼3.9 μm and a geometric standard deviation (GSD) of ∼1.5.
  
  
  CONCLUSIONS
  This study demonstrates that an attenuated release liposomal ciprofloxacin formulation can be created through incorporation of drug nanocrystals in response to freeze-thaw, and the formulation retains its physicochemical properties after aerosolization by mesh nebulizer.
authors.affiliation: 1 Department of Pharmacuetical Sciences, Aradigm Inc. , Hayward, California.|2 Faculty of Pharmacy, University of Sydney , Sydney, New South Wales, Australia .
authors.forename: David
authors.initials: D
authors.lastname: Cipolla
authors.affiliation: 1 Department of Pharmacuetical Sciences, Aradigm Inc. , Hayward, California.
authors.forename: Huiying
authors.initials: H
authors.lastname: Wu
authors.affiliation: 1 Department of Pharmacuetical Sciences, Aradigm Inc. , Hayward, California.
authors.forename: Igor
authors.initials: I
authors.lastname: Gonda
authors.affiliation: 2 Faculty of Pharmacy, University of Sydney , Sydney, New South Wales, Australia .
authors.forename: Hak-Kim
authors.initials: HK
authors.lastname: Chan
mesh_terms: D000280:Administration, Inhalation; D000336:Aerosols; D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000737:chemistry*; D002626:Chemistry, Pharmaceutical; D002939:Ciprofloxacin / Q000008:administration & dosage / Q000737:chemistry*; D003692:Delayed-Action Preparations; D004355:Drug Stability; D005615:Freezing; D006863:Hydrogen-Ion Concentration; D007700:Kinetics; D008055:Lipids / Q000737:chemistry*; D008081:Liposomes; D053758:Nanoparticles; D036103:Nanotechnology / Q000379:methods; D009330:Nebulizers and Vaporizers; D010316:Particle Size; D011136:Polysorbates / Q000737:chemistry; D012995:Solubility; D013395:Sucrose / Q000737:chemistry; D013501:Surface-Active Agents / Q000737:chemistry
chemical_list: D000336:Aerosols; D000900:Anti-Bacterial Agents; D003692:Delayed-Action Preparations; D008055:Lipids; D008081:Liposomes; D011136:Polysorbates; D013501:Surface-Active Agents; D013395:Sucrose; D002939:Ciprofloxacin
keywords: aerosol; ciprofloxacin; liposomes; nanocrystals; nebulization