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A cyclosporin A/maltosyl--cyclodextrin complex for inhalation therapy of asthma

¹ Discovery Biology Unit in Research Division and ³ Pharmaceutical R&D Group in Preclinical Development Dept, Novartis Pharma K.K. Research Institute, Tsukuba, and ² Dept of Neuropsychopharmacology and Hospital Pharmacy, Nagoya University Graduate School of Medicine, Nagoya, Japan

CORRESPONDENCE: H. Fukaya, Discovery Biology Unit in Research Division, Novartis Pharma K.K. Research Institute, Tsukuba 300-2611, Japan. Fax: 81 298652385. E-mail: hiroaki.fukaya@pharma.novartis.com

Keywords: asthma, cyclosporin A, eosinophil, inhalation therapy, maltosyl--cyclodextrin, mice airway

Received: March 4, 2002
Accepted April 14, 2003

The inhalation of cyclosporin (Cs)A to the lung is limited by its hydrophobic properties. In order to improve the poor solubility of CsA, cyclodextrin (CD) was evaluated for its suitability for dry powder inhaler formation, and the benefit of an inhaled CsA/CD complex in vivo was demonstrated.

The solubilising effect of CDs on CsA was measured by high-performance liquid chromatography. Ciliostatic activity and haemolysis were determined to assess some safety profiles of CDs. The efficacy of an inhaled CsA/CD complex was evaluated by eosinophil infiltration into the bronchoalveolar lavage fluid in actively sensitised mice.

CDs markedly improved the poor solubility of CsA. The ciliostatic and haemolytic activities of maltosyl--CD were the weakest of all the tested CDs. CsA inhaled alone showed inhibitory effects on allergen-induced eosinophilia. Inhalation of the complex of CsA with maltosyl--CD, where the dose of CsA was approximately nine-times less than that of CsA inhaled alone, also inhibited eosinophil accumulation significantly, with a longer duration of action in comparison with the response to CsA alone.

Thus the effective dose of cyclosporin A could be reduced by formation of a complex with maltosyl--cyclodextrin, and a wider therapeutic safety margin by inhalation of cyclosporin A as a complex with maltosyl--cyclodextrin could be expected.