Aerosolization Performance, Antitussive Effect and Local Toxicity of Naringenin-Hydroxypropyl-β-Cyclodextrin Inhalation Solution for Pulmonary Delivery.

Abstract

The aim of present study was to evaluate the feasibility of a naringenin-hydroxypropyl-β-cyclodextrin (naringenin-HPβCD) inhalation solution for pulmonary delivery. Naringenin, a flavanone derived from citrus fruits, has been proven to exhibit excellent peripheral antitussive effect. To address the limitation of its poor oral bioavailability and low local concentration in the lung, a naringenin-HPβCD inhalation solution was prepared for pulmonary delivery. The aerosolization performance of formulation was evaluated by next generation impactor (NGI). Both dose-dependent and time-dependent antitussive effects of naringenin-HPβCD inhalation solution on acute cough induced by citric acid in guinea pigs were investigated. In vitro toxicity of naringenin-HPβCD inhalation solution in pulmonary Calu-3 cells was evaluated by MTS assay, and in vivo local toxicity investigation was achieved by assessing bronchoalveolar lavage (BALF) and lung histology after a 7-day inhalation treatment in guinea pigs. Fine particle fraction (FPF) of the formulation was determined as 53.09%. After inhalation treatment of 15min, naringenin-HPβCD inhalation solution within the studied range of 0.2-3.6mg/kg could dose-dependently reduce the cough frequency with the antitussive rate of 29.42-39.42%. Naringenin-HPβCD inhalation solution in concentration range of 100-400μM did not decrease cell viability of Calu-3 cells, and the maximum effective dose (3.6mg/kg) was non-toxic during the short-term inhalation treatment for guinea pigs. In conclusion, naringenin-HPβCD inhalation solution was capable for nebulization and could provide rapid response with reduced dose for the treatment of cough.