Inhalable dry-emulsion formulation of cyclosporine A with improved anti-inflammatory effects in experimental asthma/COPD-model rats.

Abstract

The main purpose of the present study was to develop a novel respirable powder (RP) formulation of cyclosporine A (CsA) using a spray-dried O/W-emulsion (DE) system. DE formulation of CsA (DE/CsA) was prepared by spray-drying a mixture of erythritol and liquid O/W emulsion containing CsA, polyvinylpyrrolidone, and glyceryl monooleate as emulsifying agent. The DE/CsA powders were mixed with lactose carriers to obtain an RP formulation of DE/CsA (DE/CsA-RP), and its physicochemical, pharmacological, and pharmacokinetic properties were evaluated. Spray-dried DE/CsA exhibited significant improvement in dissolution behavior with ca. 4500-fold increase of dissolution rate, and then, nanoemulsified particles were reconstituted with a mean diameter of 317 nm. Laser diffraction analysis on the DE/CsA-RP suggested high dispersion of DE/CsA on the surface of the lactose carrier. Anti-inflammatory properties of the inhaled DE/CsA-RP were characterized in antigen-sensitized asthma/COPD-model rats, in which the DE/CsA-RP was more potent than the RP formulation of physical mixture containing CsA and erythritol in inhibiting inflammatory responses, possibly due to the improved dissolution behavior. Pharmacokinetic studies demonstrated that systemic exposure of CsA after intratracheal administration of the DE/CsA-RP at a pharmacologically effective dose (100 μg-CsA/rat) was 50-fold less than that of the oral CsA dosage form at a toxic dose (10 mg/kg). From these findings, use of inhalable DE formulation of CsA might be a promising approach for the treatment of airway inflammatory diseases with improved pharmacodynamics and lower systemic exposure.

• Authors: Satomi Onoue, Hideyuki Sato, Kumiko Ogawa, Yoshiki Kojo, Yosuke Aoki, Yohei Kawabata, Koichi Wada, Takahiro Mizumoto, Shizuo Yamada
• Journal: European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V (Eur J Pharm Biopharm) Vol. 80 Issue 1 Pg. 54-60 (Jan 2012) ISSN: 1873-3441 [Electronic] Netherlands
• PMID: 22008148 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2011 Elsevier B.V. All rights reserved.

Chemical References

• Anti-Inflammatory Agents
• Drug Carriers
• Emulsifying Agents
• Emulsions
• Glycerides
• Powders
• Cyclosporine
• monoolein
• Povidone
• Lactose

Topics

• Administration, Inhalation
• Animals
• Anti-Inflammatory Agents (administration & dosage, chemistry, pharmacokinetics)
• Asthma (drug therapy)
• Chemistry, Pharmaceutical (methods)
• Cyclosporine (administration & dosage, chemistry, pharmacokinetics)
• Drug Carriers (administration & dosage, chemistry)
• Emulsifying Agents (administration & dosage, chemistry)
• Emulsions (administration & dosage, chemistry, pharmacokinetics)
• Glycerides (administration & dosage, chemistry)
• Lactose (administration & dosage, chemistry)
• Male
• Particle Size
• Povidone (administration & dosage, chemistry)
• Powders (administration & dosage, chemistry, pharmacokinetics)
• Pulmonary Disease, Chronic Obstructive (drug therapy)
• Rats
• Rats, Sprague-Dawley
• Solubility