Category: Formulation and Quality
Purpose: Orally inhaled drug products (OIDPs), including metered dose inhalers (MDIs), have been utilized to treat a variety of lung disorders.  Product performance for MDIs can be influenced by several factors including, but not limited to, the physiochemical properties of the drug, the amount and type of excipients, and device properties.  Currently, the impact of formulation factors on MDI performance and its interaction with actuator design is not fully understood. Therefore, the purpose of this work is to investigate how formulation factors along with actuator parameters influence in vitro product performance for mometasone furoate (MF) MDIs.
Methods: Three suspension-based MF MDIs were manufactured with changes in active pharmaceutical ingredient (API) particle size distribution (PSD D50), oleic acid (OA, surfactant), and ethanol content (EtOH, cosolvent) in relation to the levels found in the commercial MDI product Dulera® 200 mcg/inhalation (MF suspension only, the formulation of interest) (Table 1). The manufactured MF MDIs were characterized (e.g., API, excipient, and moisture content) and evaluated by an assortment of in vitro tests to determine their product performance (aerodynamic particle size distribution [APSD] by Next Generation Impactor [NGI], ex-anatomical throat dose by medium oropharyngeal consortium [OPC] throat model, spray pattern, and plume geometry). Four actuator variants differing in orifice diameter (OD), jet length (JL), and sump depth (SD) were encompassed in the analysis to evaluate formulation-actuator interactions (Table 1). Statistical analysis on the data (ANOVA and Pearson’s Correlation Coefficient) was conducted to determine the effects of formulation factors, actuator design, and formulation-actuator effects.
Results: Statistically significant effects on some key in vitro performance parameters were seen in these three MF MDI formulations and four different actuator variants. In APSD testing, Batch #2 demonstrated a significantly higher extra-fine particle mass (FPM< 2µm) (Figure 1) ranging from 1.7-2 times more when comparing Batch #2 to Batch #1 or #3 for each actuator variant. Actuator variants with smaller OD (Variants C or D) demonstrated higher FPM< 5µm and ex-anatomical throat dose when comparing to actuator variants with a lower OD (Variants A or B) for all the three formulation batches tested (Figure 1). No significant interactions were seen between different MF MDI formulations and actuator variants in APSD testing. All MF MDI formulations had significant effect on spray pattern area and plume geometry angle (p< 0.05). Batch #2 had the largest spray pattern area and plume geometry angle of the three batches. Of the actuator parameters, the JL was demonstrated to be most influential on spray pattern and plume geometry characteristics; an increase in JL from 0.4 to 0.6 mm led to decreases in spray pattern area (10-15%), plume geometry angle (5-10%), and plume geometry width (2-11%) for each formulation batch tested. Of all spray pattern and plume geometry parameters, spray pattern area was seen to correlate best with the APSD parameters delivered dose (DD) and mass median aerodynamic diameter (MMAD), as calculated by Pearson’s correlation coefficient ( >0.6). Batch #2 and smaller actuator JL demonstrated the highest spray pattern area (Figure 2).
Conclusion: The amount and type of excipients, the API PSD, and actuator design have shown to influence in vitro product performance for suspension-based MF MDIs. Results from this work allow for improvement in quality by design (QbD) approaches to streamline MDI drug product development (both brand-name products and their generic counterparts) and provide insights on how to control MDI drug product parameters to achieve a desired performance profile.
Denise Conti– Visiting Associate, Office of Research and Standards, Office of Generic Drugs, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, Maryland
Oluwamurewa Oguntimein– Silver Spring, Maryland
Poonam Sheth– Morrisville, North Carolina
Madeline Hallinger– Morrisville, North Carolina
Mårten Svensson– Lund, Skane Lan, Sweden
Dennis Sandell– Blentarp, Skane Lan, Sweden
Juergen Bulitta– Gainesville, Florida
Guenther Hochhaus– Professor, University of Florida, Gainesville, Florida