TY - JOUR
T1 - Biopharmaceutical Evaluation of Novel Cyclosporine A Nano-matrix Particles for Inhalation
AU - Sato, Hideyuki
AU - Suzuki, Hiroki
AU - Yakushiji, Keisuke
AU - Wong, Jennifer
AU - Seto, Yoshiki
AU - Prud’homme, Robert K.
AU - Chan, Hak Kim
AU - Onoue, Satomi
N1 - Funding Information:
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.
Publisher Copyright:
© 2016, Springer Science+Business Media New York.
PY - 2016/9/1
Y1 - 2016/9/1
N2 - Purpose: This study was undertaken to evaluate the biopharmaceutical properties of cyclosporine A (CsA)-loaded nano-matrix particles for inhalation. Methods: 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. Results: 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. Conclusion: 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.
AB - Purpose: This study was undertaken to evaluate the biopharmaceutical properties of cyclosporine A (CsA)-loaded nano-matrix particles for inhalation. Methods: 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. Results: 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. Conclusion: 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.
KW - anti-inflammatory effect
KW - cyclosporine A
KW - inhalation
KW - nano-matrix particles
KW - pharmacokinetic control
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U2 - 10.1007/s11095-016-1949-6
DO - 10.1007/s11095-016-1949-6
M3 - Article
C2 - 27225495
AN - SCOPUS:84969931875
SN - 0724-8741
VL - 33
SP - 2107
EP - 2116
JO - Pharmaceutical Research
JF - Pharmaceutical Research
IS - 9
ER -