Characterization and in vitro evaluation of the formoterol/cyclodextrin complex for pulmonary administration by nebulization

Abstract

The aim of this work is to investigate the effect of cyclodextrin complexation on the pulmonary deposition of formoterol, a drug with a very poor aqueous solubility, after jet nebulization. Two types of cyclodextrins, a hydroxypropyl beta cyclodextrin (Kleptose HP) and a polydispersed methyl beta cyclodextrin (Crysmeb) were used. The interactions of formoterol with the cyclodextrins were studied by NMR. The aqueous cyclodextrin solutions containing formoterol were defined by their physicochemical properties in relation to nebulization capacity: density, surface tension and viscosity. Nebulization efficiency was evaluated by measuring droplet size, nebulization rate, quantity nebulized and nebulization time. The NMR ROESY spectra suggest that formoterol or a part of it is included inside the cyclodextrins. Densities and viscosities of the solutions tested are close to those of water; the lower surface tensions compared to water (53.7 and 56.7 vs 70 mN/m) favour the formation of small droplets. The aqueous solutions of cyclodextrins and formoterol studied can generate aerosols with a particle size that is compatible with pulmonary deposition. Respirable fraction values between 57.5% and 88 % were obtained when nebulizing the solutions with four nebulizers that differ geometrically. Nebulization rates varied from 0.19 to 0.47 g/min. Large quantities of drug nebulized over acceptable delivery times were observed. beta-cyclodextrin derivatives can be used to formulate nebulizable solutions of formoterol. It is indispensable to define the appropriate nebulizers and operating conditions associated with the solutions to obtain adapted and reproducible activity.