Deposition and Pharmacokinetics of Flunisolide Delivered from Pressurized Inhalers Containing Non-CFC and CFC Propellants

Abstract

Our objective was to assess the deposition and pharmacokinetics of a novel formulation of flunisolide (Aerobid, Forest Laboratories) in hydrofluoroalkane (HFA) 134a delivered by pressurized metered dose inhaler (pMDI). The design was a two-way crossover investigation in 12 healthy male subjects comparing HFA-134a flunisolide by pMDI versus pMDI plus 50 mL spacer device. Four of these subjects also took part in a two-way crossover investigation comparing chlorofluorocarbon (CFC) flunisolide pMDI versus pMDI plus Aerochamber holding chamber. The imaging technique of gamma scintigraphy was used to quantify total and regional lung deposition of flunisolide. Plasma levels of flunisolide and its major metabolite (6beta-OH flunisolide) were also determined. The spacer and Aerochamber reduced oropharyngeal deposition dramatically for both the HFA and CFC products (mean 59.8 to 14.9% (p < 0.01) of ex-valve (metered) dose for HFA product; 66.3 to 12.3% (p < 0.01) of ex-valve dose for CFC product) owing to deposition of part of the dose on the walls of the add-on devices themselves. Lung deposition averaged 22.6 and 40.4% (p < 0.01) of the ex-valve dose for the HFA formulation used with pMDI alone and with pMDI plus spacer. Mean lung deposition of the CFC formulation delivered via the Aerochamber (mean 23.4%) was higher than that for the CFC pMDI alone (mean 17.0%), but this difference was not statistically significant. Lung deposition expressed as percentage ex-device (delivered) dose averaged 68.3% for HFA pMDI plus spacer and 19.7% for CFC pMDI. Plasma levels of flunisolide were higher for the pMDI plus spacer than for pMDI alone, reflecting higher lung deposition via the spacer, but plasma levels of the 6beta-OH flunisolide metabolite were higher for the pMDI alone as a consequence of higher oropharyngeal deposition. When delivered via the spacer, pulmonary targeting of the flunisolide HFA formulation was improved compared with the CFC formulation, which should benefit patients by providing satisfactory asthma therapy from a much-reduced delivered dose of flunisolide.

What the pulmonary specialist should know about the new inhalation therapies

“…They allow patients to inhale a static cloud. VHCs overcome the issue of coordinating actuation with inhalation, and they increase pulmonary deposition in those subjects who do not have optimal coordination when actuating a pMDI [47][48][49][50]. Spacers and VHCs should not be used with BA-pMDIs.…”

Mechanisms of Pharmaceutical Aerosol Deposition in the Respiratory Tract

“…The calculated deposition patterns shown in Table I for lung and oropharyngeal deposition were outside the error bars of the in vivo data, indicating that they were not in good agreement. Additional in vivo data were also used for comparison, for deposition in the lung and oropharyngeal region (39)(40)(41)(42)(43). In general, the LUDEP method underestimated the oropharyngeal deposition and overestimated the lung deposition and drug expiration.…”

Effect of Oropharyngeal Length in Drug Lung Delivery via Suspension Pressurized Metered Dose Inhalers

“…Despite considering the effect of respiratory tract length on aerosol deposition and length of the inlet of a cascade impactor on the MMAD of aerosol particles emitted from a pMDI, a better understanding of the high intersubject variation in the lung dose via pMDIs in adults is required (11,12,25,26). Although lack of coordination between device actuation and inhalation has been accounted for the observed high variation of drug lung dose via pMDIs (26), observing such a high intersubject lung dose variation (up to 9 times) via a pMDI in clinical studies in which subjects were trained well and their inhalation techniques were observed closely (11,12,25,26) remains to be investigated.…”

“…Although lack of coordination between device actuation and inhalation has been accounted for the observed high variation of drug lung dose via pMDIs (26), observing such a high intersubject lung dose variation (up to 9 times) via a pMDI in clinical studies in which subjects were trained well and their inhalation techniques were observed closely (11,12,25,26) remains to be investigated. Our understanding of aerosol delivery via pMDIs can be significantly improved by employing physiologically faithful oropharyngeal models.…”

“…Based on this observation, we investigated the effect of oropharyngeal length on the lung dose of a suspension pMDI by employing oropharyngeal models. This information may help us to better understand aerosol deposition in the mouth and throat via pMDIs, and improve our understanding of the observed high intersubject lung dose variation via pMDIs (11,12,25,26). To further reveal the mechanism of aerosol deposition via pMDIs in the oropharyngeal models, aerosol deposition distributions in the models were determined.…”