Pharmaceutical Research

, Volume 33, Issue 9, pp 2107–2116 | Cite as

Biopharmaceutical Evaluation of Novel Cyclosporine A Nano-matrix Particles for Inhalation

  • Hideyuki Sato
  • Hiroki Suzuki
  • Keisuke Yakushiji
  • Jennifer Wong
  • Yoshiki Seto
  • Robert K. Prud’homme
  • Hak-Kim Chan
  • Satomi Onoue
Research Paper



This study was undertaken to evaluate the biopharmaceutical properties of cyclosporine A (CsA)-loaded nano-matrix particles for inhalation.


Nano-matrix particles of CsA with mannitol (nCsAm) were prepared by a flash nano-precipitation technique employing a multi-inlet vortex mixer and evaluated in terms of physicochemical properties, anti-inflammatory effect in the rat model of airway inflammation, pharmacokinetic behavior, and distributions of CsA to side-effect-related organs after intratracheal administration.


In nCsAm, spherical nano-particles of CsA were covered with mannitol and the mean particle size was 1.3 μm. The in vitro Next Generation Impactor analysis demonstrated fine inhalation performance with a fine particle fraction value of 65.8%. Intratracheal nCsAm (100 μg-CsA/rat) significantly attenuated the recruitment of inflammatory cells into the airway in the rat model of airway inflammation, followed by suppression of the inflammatory biomarkers. After intratracheal nCsAm at a pharmacologically effective dose (100 μg-CsA/rat), there was a 42–47-fold decrease in the distribution of CsA to side-effect-related organs such as the kidney and liver compared with oral CsA at a toxic dose (10 mg-CsA/kg), potentially leading to avoidance of systemic side-effects of CsA.


Upon these findings, nCsAm prepared with the flash nano-precipitation technique could be a novel dosage form of CsA for inhalation therapy of airway inflammation with a better safety margin.


anti-inflammatory effect cyclosporine A inhalation nano-matrix particles pharmacokinetic control 



Bronchoalveolar lavage fluid


Chronic obstructive pulmonary disease


Cyclosporine A


Dynamic light scattering


Differential scanning calorimetry


Fine particle fraction


High performance liquid chromatography




Multi inlet vortex mixer




Nano-matrix CsA particles with mannitol


Next generation impactor




Powder X-ray diffraction


Scanning electron microscopy



This work was supported in part by a Grant-in-Aid for Scientific Research (C) (No. 24590200; S. Onoue) from the Ministry of Education, Culture, Sports, Science and Technology, and a grant from the Takeda Science Foundation. This research was supported under Australian Research Council’s Discovery Projects funding scheme (project number 120102778; H-K Chan). This work was also funded in part by the National Institutes of Health (Award No. 1RO1CA155061-1) which supported RKP.


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Copyright information

© Springer Science+Business Media New York 2016

Authors and Affiliations

  • Hideyuki Sato
    • 1
  • Hiroki Suzuki
    • 1
  • Keisuke Yakushiji
    • 1
  • Jennifer Wong
    • 2
  • Yoshiki Seto
    • 1
  • Robert K. Prud’homme
    • 3
  • Hak-Kim Chan
    • 2
  • Satomi Onoue
    • 1
  1. 1.Department of Pharmacokinetics and Pharmacodynamics, School of Pharmaceutical SciencesUniversity of ShizuokaSuruga-kuJapan
  2. 2.Advanced Drug Delivery Group, Faculty of PharmacyThe University of SydneySydneyAustralia
  3. 3.Department of Chemical & Biological EngineeringPrinceton UniversityPrincetonUSA

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