Influence of Formulation Factors on the Aerosol Performance of Suspension and Solution Metered Dose Inhalers: A Systematic Approach

Abstract

Metered dose inhalers (MDIs) are complex drug-device combination products widely used to treat pulmonary disorders. The efficacy, driven by aerosol performance of the products, depends on a multitude of factors including, but not limited to, the physicochemical properties of drug and nature and amount of excipient(s). Under the quality by design (QbD) paradigm, systematic investigations are necessary to understand how changes in critical quality attributes (CQAs) of formulation, device, and manufacturing process influence key product performance parameters, such as delivered dose (DD) and fine particle dose (FPD). The purpose of this work is to provide a better understanding of the effects of different levels of excipients and drug particle size distribution on the aerosol performance of MDI products, while using two fundamentally different MDI products as relevant model systems, Proventil® HFA (albuterol sulfate suspension) and Qvar® (beclomethasone dipropionate solution). These MDI products, as model systems, provided mid-points around which a design of experiments (DOE), consisting of 22 suspension and 9 solution MDI formulations, were defined and manufactured. The DOE included formulations factors with varying ethanol (2 to 20% w/w and 7 to 9% w/w for the suspension and solution, respectively) and oleic acid concentrations (0.005 to 0.25% w/w and 0 to 2% w/w for the suspension and solution, respectively) and drug volumetric median particle size distribution (PSD D, 1.4 to 2.5 μm for the suspension). The MDI formulations were analyzed using compendial methods to elucidate the effect of these formulation variables (ethanol, oleic acid, and PSD D) on DD and FPD. The outcomes of this study allowed defining design spaces for the formulation factors, such that DD and FPD would remain within specific pre-defined requirements. The systematic approach utilized in this work can contribute as a QbD tool to evaluate the extent to which the formulation factors govern the aerosol performance of MDI drug products, helping to design MDI formulations with desired product performance parameters.

Study of pressurised metered dose inhalers for the purpose of standardization of quality attributes characterizing uniformity of dosing

“…During pharmaceutical development [2,23] it should be demonstrated that an average fine particle dose exceeds the established lower limit at least on the value of the highest deviation of individual fine particle doses from the average dose . The testing for uniformity of fine particle dose could be a tool for long-term study of the suspension stability in the containers because the aggregation of particles results the decrease of the fine particle dose [8,16,19]. The constant level of the uniformity of fine particle dose within the shelf life is a guarantee of the effectiveness of each dose of the pMDIs during their storage [8,12].…”

“…Therefore, it was necessary to validate the analytical procedures for quantitative determination of SS and BD in the appropriate ranges [6,15]. For different preparations, it was also necessary to compare the particle size distribution of SS, which for suspension pMDIs might also significantly affect the fine particle dose [11,16]. At this step of the study, apparatus A (glass impinger) was chosen to determine the fine particle dose for one inhaler actuation.…”

The Study of Spray-Freeze-Drying Technique for Development of Novel Combination pMDIs, Part I: Study on the Preparation Method

“…Unlike dry powder inhalers, the dispersion and suspension of drug microparticles in HFA must be considered in pMDI studies. 25,26 F9 inhalable microparticle was obtained by the SFD process, with MF and FF used as model drugs, and DSPC used as an excipient. Our data showed that the FPF of the pMDI made of F9 was significantly increased to 48% (►Table 5), which was higher than that of Dulera, and the FPF (MF) and FPF (FF) were similar, with a difference of less than 2%.…”

Dose-Ranging and Cumulative Dose Studies of Albuterol Sulfate MDI in Co-Suspension Delivery™ Technology (AS MDI; PT007) in Patients with Asthma: the ASPEN and ANTORA Trials

“…This could also explain the sharp peak in albuterol plasma concentrations following the final cumulative dose from Proventil, while AS MDI had a more prolonged absorption period. Proventil is currently the only formulation of albuterol to contain these additional compounds/absorption enhancers [ 13 ].…”