Biopharmaceutical Evaluation of Novel Cyclosporine A Nano-matrix Particles for Inhalation
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.
KEY WORDSanti-inflammatory effect cyclosporine A inhalation nano-matrix particles pharmacokinetic control
Bronchoalveolar lavage fluid
Chronic obstructive pulmonary disease
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
ACKNOWLEDGMENTS AND DISCLOSURES
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.
- 21.Wu X, Zhang W, Hayes Jr D, Mansour HM. Physicochemical characterization and aerosol dispersion performance of organic solution advanced spray-dried cyclosporine A multifunctional particles for dry powder inhalation aerosol delivery. Int J Nanomedicine. 2013;8:1269–83.PubMedPubMedCentralGoogle Scholar
- 50.Rohatagi S, Calic F, Harding N, Ozoux ML, Bouriot JP, Kirkesseli S, et al. Pharmacokinetics, pharmacodynamics, and safety of inhaled cyclosporin A (ADI628) after single and repeated administration in healthy male and female subjects and asthmatic patients. J Clin Pharmacol. 2000;40(11):1211–26.PubMedGoogle Scholar