Systematic Evaluation of the Effect of Formulation Variables on In Vitro Performance of Mometasone Furoate Suspension-Metered Dose Inhalers

Abstract

The therapeutic benefits of metered dose inhalers (MDIs) in pulmonary disorders are mainly driven by aerosol performance, which depends on formulation variables (drug and excipients), device design, and patient interactions. The present study provides a comprehensive investigation to better understand the effect of formulation variables on mometasone furoate (MF) suspension-based MDI product performance. The effects of MF particle size (volume median diameter; X₅₀) and excipient concentration (ethanol and oleic acid, cosolvent, and surfactant, respectively) on selected critical quality attributes (delivered dose (DD), fine particle dose of particles lesser than 5 µm (FPD < 5), ex-throat dose and median dissolution time (MDT)) were studied. Eight MF-MDI formulations (one per batch) were manufactured based on a reduced factorial design of experiment (DOE) approach, which included relevant formulation levels with varying X₅₀ (1.1 and 2 μm), concentration of ethanol (0.45, 0.9, 1.8, and 3.6%w/w), and oleic acid (0.001 and 0.025%w/w). The in vitro evaluation of these MF-MDI formulations indicated the importance of drug particle's X₅₀, oleic acid, and ethanol canister concentration as critical formulation variables governing the performance of MF suspension-based MDI products. The effect of these formulation variables on DD, FPD < 5, ex-throat dose, and MDT was subsequently utilized to develop empirical relationships linking formulation factors with effects on in vitro performance measures. The developed strategy could be useful for predicting MF-MDI product performance during MDI product development and manufacturing. The systematic DOE approach utilized in this study may provide insights into the understanding of the formulation variables governing the MF-MDI product performance.

Keywords: cascade impactor; critical quality attributes; delivered dose; empirical correlations; fine particle dose; mean dissolution time; metered dose inhalers; mouth-throat models.

Fig. 1

Effect of formulation variables and 1-month storage at 40 °C/75%RH on moisture content (MC) (a, b) and delivered dose (DD) (c, d) of MF-MDI formulations. Symbols indicate mean values (n = 12) of each batch, and lines represent the linear regression

Fig. 2

Drug deposition on Next Generation Impactor (NGI) stages of MF-MDI batches at initial timepoint (a) and after 1-month storage at accelerated conditions (b). Effect of ethanol concentration (c and d) and moisture content (e) on NGI delivered dose. Symbols indicate mean values (n = 4) of each batch and lines represent the linear regression (c–e). IP = induction port, in which the mean value was divided by 2 to allow visualization of batch differences on NGI stages with low deposition

Fig. 3

Effect of formulation variables on fine particle dose lesser than 5 μm (FPD < 5) (a and b) and on mass median aerodynamic diameter (MMAD) (c and d). Symbols indicate mean values (n = 4) of each MF-MDI batch and lines represent the linear regression

Fig. 4

(a) Ex-throat dose (n = 2) for MF-MDI batches using (1) small, (2) medium, and (3) large Oropharyngeal Consortium (OPC) mouth-throats (MT) models at different flow rates (L/min). (b–d) Effect of formulation variables (MF particle size X₅₀, ethanol, and oleic acid concentrations) on ex-throat dose for (b) small, (c) medium, and (d) large OPC MT models at different flow rates (L/min); Symbols indicate mean values (n = 2) of each batch and lines represent the linear regression

Fig. 5

In vitro dissolution of MF-MDI formulations. (a) Cumulative in vitro dissolution profiles. (b) Monomolecular growth model: predicted vs. observed dissolution profiles. (c) and (d) Effect of formulation variables on median dissolution time (MDT); symbols indicate mean values (n = 6) of each MF-MDI batch

Fig. 6

(a) Predicting mean delivered dose (DD) as function of ethanol (EtOH) concentration (% w/w). (b) Residuals from predicting fine particle dose lesser than 5 μm (FPD < 5) by MF particle size (X50), ethanol, and oleic acid concentrations and 1-month storage at accelerated conditions. (c–e) Residuals from predicting ex-throat dose by MF particle size (X50), ethanol, and oleic acid concentrations and flow rate for (c) small, (d) medium, and (e) large OPC MT models. (f) Predicted median dissolution time (MDT) of MF-MDI batches using different models