Pharmacokinetics of inhaled monodisperse beclomethasone as a function of particle size

Abstract

What is already known about this subject • For asthmatic adults, bronchodilators with a MMAD between 3 and 6 mm were shown to give the best improvement in lung function and the least systemic side-effects.• It is not known, however, what is the most efficacious particle size for inhaled steroids in asthmatic adults. Clinical efficacy and systemic side-effects of inhaled steroids should be measured to define the optimal particle size.What this study adds • Our study investigated the systemic absorption of inhaled steroids. We found that a particle size of 2.5 mm and 4.5 mm gave a higher pulmonary bioavailability compared with the 1.5 mm monodisperse aerosols in adults with mild asthma and therefore were more likely to elicit systemic adverse effects. AimsFor optimal efficacy, antiasthma drugs should be delivered to the desired region in the airways. To date, the optimal particle size for steroids in adults is not known. The aim of the study was to evaluate the pulmonary bioavailability for inhaled beclomethasone dipropionate (BDP) aerosols of different particle sizes. MethodsIn a randomized single-blind crossover trial, 10 mild asthmatic patients inhaled monodisperse BDP aerosols with mass median aerodynamic diameters (MMADs) of 1.5, 2.5 and 4.5 mm. Gastrointestinal absorption was blocked by activated charcoal. Plasma concentrations of 17-beclomethasone monopropionate (17-BMP) were measured by liquid chromatography plus mass spectrometry. ResultsAerosols with MMADs of 1.5 mm, 2.5 mm, and 4.5 mm gave mean maximum concentrations (Cmax) of 17-BMP of 475 pg ml -1 , 1300 pg ml -1 , and 1161 pg ml -1 , respectively. The area under the curve (AUC) values of 17-BMP for MMADs of 1.5 mm, 2.5 mm, and 4.5 mm were 825 pg ml -1 h, 2629 pg ml -1 h, and 2276 pg ml -1 h, respectively. The mean terminal half-time of 17-BMP for all three aerosol sizes was around 1.5 h. ConclusionsMonodisperse BDP aerosols with a MMAD of 1.5 mm gave two-three fold lower values for Cmax and AUC than those with MMADs of 2.5 and 4.5 mm.

In Vitro Drug Delivery Performance of a New Budesonide/Formoterol Pressurized Metered-Dose Inhaler

“…A lower MMAD of 1.1 m for the pMDI HFA beclomethasone has been reported. (10) Interestingly, clinical studies of ␤ 2 -agonist delivered from monodisperse aerosols demonstrated a greater improvement in lung function with particle sizes of 2.8 and 3 m compared with those of 1.5 m. (13,14) Currently, there are no similar data evaluating particle size and clinical outcome for inhaled corticosteroids, although one study has shown higher pulmonary bioavailability for beclomethasone with particle size of 2.5 m compared with 1.5 m. (15) Assessment of dose proportionality indicated that delivered dose of budesonide was proportional across the three product strengths studied (budesonide 40, 80, and 160 g). The budesonide FPD increased in a slightly less than proportional manner with increasing labeled dose (i.e., doubling the labeled dose produced a slightly less than double FPD).…”

The function and performance of aqueous aerosol devices for inhalation therapy

“…[176] Clinical trials using EHDA aerosol generation have shown the feasibility of delivering ethanolic solutions of beclomethasone dipropionate. [178] Interestingly, evaluation of monodisperse aerosols (GSD < 1.2) shows bioavailability of larger droplets (MMADs of 2.5 and 4.5 lm) to be greater when compared to small droplet aerosols (MMAD of 1.5 lm). Additionally, this technology can produce aerosols from dispersed dosage forms.…”

In Vitro Considerations to Support Bioequivalence of Locally Acting Drugs in Dry Powder Inhalers for Lung Diseases

“…The result of this study suggests that regional targeting of inhaled β 2 -agonist to the proximal airways is more effective than alveolar deposition with respect to bronchodilatation. It is also well known that deposition of aerosols in the deeper part of the lungs (i.e., the alveolar region) results in an increased proportion of the drug reaching the systemic circulation (10)(11)(12). This can be attributed to the absence of clearance by the mucociliary escalator, the pronounced increase in the total surface area as a result of progressive branching of airways, and the enhanced permeability of the thin alveolar membranes in comparison to that of the airway surface.…”