Hideyuki Sato1, Hiroki Suzuki1, Keisuke Yakushiji1, Jennifer Wong2, Yoshiki Seto1, Robert K Prud'homme3, Hak-Kim Chan4, Satomi Onoue5. 1. Department of Pharmacokinetics and Pharmacodynamics, School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka, 422-8526, Japan. 2. Advanced Drug Delivery Group, Faculty of Pharmacy, The University of Sydney, Building A15, Sydney, NSW, 2006, Australia. 3. Department of Chemical & Biological Engineering, Princeton University, A301 EQUAD, Princeton, New Jersey, 08544, USA. 4. Advanced Drug Delivery Group, Faculty of Pharmacy, The University of Sydney, Building A15, Sydney, NSW, 2006, Australia. kim.chan@sydney.edu.au. 5. Department of Pharmacokinetics and Pharmacodynamics, School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka, 422-8526, Japan. onoue@u-shizuoka-ken.ac.jp.
Abstract
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.
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.
Entities:
Keywords:
anti-inflammatory effect; cyclosporine A; inhalation; nano-matrix particles; pharmacokinetic control
Authors: M Bohdanecká; O Schück; M Chadimová; J Sedivý; A Glagolicová; J Skibová; J Kunes; Z Dobesová; M Stuchlík; J Veselá; L Kazdová Journal: Physiol Res Date: 1999 Impact factor: 1.881
Authors: Aldo T Iacono; Bruce A Johnson; Wayne F Grgurich; J Georges Youssef; Timothy E Corcoran; Deidre A Seiler; James H Dauber; Gerald C Smaldone; Adriana Zeevi; Samuel A Yousem; John J Fung; Gilbert J Burckart; Kenneth R McCurry; Bartley P Griffith Journal: N Engl J Med Date: 2006-01-12 Impact factor: 91.245