Metered-dose inhalers (MDIs) are combination drug-device products that use energy stored in liquefied propellant gas, under pressure, to generate aerosols suitable for pulmonary drug delivery.1. These products are mainstays in the treatment of asthma, COPD and other respiratory diseases and CDER is engaged in extensive efforts to advance their development.

The size of droplets and particles emitted from metered-dose inhalers (MDIs) that pass through the mouth-throat (MT) region play a key role in determining how inhaled particles are deposited in the airways. Understanding the effects of in vitro test variables on the particle size distribution of aerosols exiting an anatomical model of TM may therefore help improve the predictability of in vivo lung layout and the development of generic and branded drug inhalers.

In a recent study, the Office of Generic Drugs at CDER investigated how the aerodynamic particle size distribution (APSD) and droplet size distribution of commercial solution and suspension MDIs are affected by environmental conditions. in vitro test. Five factors were considered, including MT models of different geometry and size, inhalation profiles representing strong, medium, and weak inhalation, two commonly used MT model coatings, MDI insertion angles, and two firing points MDI after the start of the inhalation profiles. Two analytical methods, cascade impactor and laser diffraction (LD), were used to measure the APSD and droplet size distribution, respectively.

The regulatory science challenge

The procedures and instrumentation for determining APSD are quite complex with many factors that can vary in test design. One of these complex factors is the MT model. These anatomical models are used to provide a more realistic assessment of TM deposition than a simple induction orifice, and they allow estimation of a range of deposition representing population variance instead of a clinical study, but it There are many models from which a researcher can choose. (Figure 1). The choice of MT pattern and inhalation profiles, as well as other experimental factors (coating type, MDI insertion angles, etc.) is usually made by each laboratory. The impact of different choices on the APSD of metered-dose inhaler products has not been systematically evaluated.

The most common technique for assessing the particle size distribution of an MDI aerosol is the cascade impactor as it provides a quantitative link between the mass of the deposited drug and its aerodynamic particle size.2. Unlike cascade impactor-based measurements, LD provides an assessment of the droplet size distribution of the entire aerosol plume over the duration of the spray. Measurement of droplet size distribution using LD is included as part of the recommended in vitro studies to establish bioequivalence (BE) found in the FDA Product Specific Guidelines (PSG) for vaporizers nasal but not for MDI products, and whether droplet size based on the LD distribution of aerosols exiting MT models are relevant to the performance of MDI products has not been established.

The study

This study undertook a systematic analysis of the effects of five different factors with the aim of better understanding the effects of the experimental factors on the APSD and droplet size distribution of MDIs in a realistic in vitro setup. In testing, inhalers were actuated to deliver the drug substance through a simple induction port or MT model to a cascade impactor to separate aerosolized particles of varying densities and dynamic shapes. MDI products used included two suspension MDIs, Flovent® HFA (fluticasone propionate, 0.22 MG/INH) and Symbicort® (budesonide; formoterol fumarate, 0.16 MG/INH; 0.0045 MG/INH), and an MDI model solution, Atrovent® HFA (ipratropium bromide, 0.021 MG/INH). In the study, a total of five factors and 10 different MT models were investigated (Figure 1).

Figure 1: Mouth-throat (MT) models used in the study. AIT: Idealized Alberta Gorge; OPC: Oropharyngeal Consortium; USP: United States Pharmacopeia; VCU: Virginia Commonwealth University.

Systematically analyze the factors that influence the particle size distribution of aerosols

In this systematic analysis of the in vitro five factors on the particle size distribution of the two suspension MDI models, the MT geometries appeared to have the strongest effects on the APSD-derived parameters, while the effects of the d inhalation depended on the type of product. The choice of MT model significantly affected the fine particle fraction (FPF)

Figure 2 : Fraction de particules fines < 5 μm (FPF < 5 μm) de Flovent® HFA, Symbicort® (fumarate de formotérol dihydraté (FF) et budésonide (bud)) et Atrovent® HFA pour les différents modèles MT.  Point de données individuel : moyenne (N=3) pour une condition de test donnée.  La ligne horizontale représente la médiane.  FF : fumarate de formotérol dihydraté, Bud : budésonide, Me : métal, Pl : plastique, S : petit, M : moyen et L : grand.

Figure 2: Fraction of fine particles® HFA, Symbicort® (Formoterol fumarate dihydrate (FF) and budesonide (Bud)) and Atrovent® HFA for the different MT models. Individual data point: mean (N=3) for a given test condition. The horizontal line represents the median. FF: formoterol fumarate dihydrate, Bud: budesonide, Me: metal, Pl: plastic, S: small, M: medium and L: large.

Results and conclusions

Based on the results, the researchers of this study3 concluded that when developing inhalers, candidates who use more realistic in vitro studies should consider how the experimental conditions, in particular the type of MT model and the inhalation profiles, affect the quantity and the particle size distribution of aerosols emerging from an anatomical MT model when designing their studies. MT geometries appear to have the strongest effects on APSD-derived parameters, while the effects of inhalation profile depended on product type. LD can serve as an additional supportive characterization method rather than an alternative to realistic in vitro cascade impactor-based methods for the estimation of the particle size distribution of MDIs, given the limited and product-specific correlations that have been found. between parameters derived from APSD and LD measurements.

How does this research improve the development of generic drugs and support their approval?

Developing generic versions of products for inhalation is a challenge because the generic product is generally expected to have the same release of small aerosol particles through the mouth and throat and into the lungs as the brand name product. CDER scientists are helping to develop more realistic laboratory models of the mouth-throat (MT) region that allow the generics industry to effectively test their products and accelerate access to generics. The experiments in this study measure the effects of in vitro test variables on the particle size distribution of aerosols exiting an anatomical model of TM and may improve the predictability of lung disposition in vivo, which could accelerate the development of inhalers of generic and brand name drugs.

(This impact story is based on the Aerosol Society conference paper DDL by Sneha Dhapare, Abhinav Ram Mohan and Bryan Newman – Office of Research and Standards, Office of Generic Drugs, Center for Drug Evaluation and Research, Food and Drug Administration3)

References, selection of publications

  1. See the draft FDA guidelines Metered Dose Inhaler (MDI) and Dry Powder Inhaler (DPI) Products – Quality Considerations for a complete definition of these products.
  2. Bonam, M., Christopher, D., Cipolla, D., Donovan, B., Goodwin, D., Holmes, S., … and Wyka, B. (2008). Minimize the variability of cascade impaction measurements in inhalers and nebulizers. APSA Pharmacy9(2), 404-413.
  3. Dhapare S, Newman B, Svensson M, Elfman P, Sandell D, Winner L, Bulitta J, Hochhaus G: Factors influencing metered-dose inhaler (MDI) plume characteristics after passing through a bio-relevant mouth-throat model. (Abstract). Presented at: Respiratory Drug Delivery 2021, virtual conference. May 4-7, 2021; 1; 301-306; (in line).