Aerosol

Effects of Realistic In Vitro Test Factors on the Aerosol Properties of Metered-Dose Inhalers

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Background

Metered dose inhalers (MDIs) are drug-device combination products that use energy stored in a liquefied gas propellant, under pressure, for generating aerosols suitable for pulmonary drug delivery1. These products are mainstays in the treatment of asthma, COPD, and other respiratory diseases and CDER is engaged in wide ranging efforts to advance their development.

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

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

The regulatory science challenge

The procedures and instrumentation for determining the APSD are quite complex with many factors that can vary in test design. One such complex factor is the MT model. These anatomical models are used to provide a more realistic assessment of MT deposition than a simple induction port, and they allow for estimation of a range of depositions representing population variance in lieu of a clinical study, but there are many models an investigator can choose from (Figure 1). The choice of the MT model and inhalation profiles, along with other experimental factors (coating type, insertion angles of the MDI, etc.) is usually made by each individual laboratory. The impact of the various choices on the APSD of MDI products has not been systematically assessed.

The most common technique for assessing size distribution of an MDI aerosol is the cascade impactor as it provides a quantitative link between mass of the drug deposited and its aerodynamic particle size2. In contrast to the cascade impactor-based measurements, LD provides 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 for establishing bioequivalence (BE) found in FDA product-specific guidances (PSGs) for nasal sprays, but not for MDI products, and whether the LD based droplet size distribution of aerosols exiting MT models are relevant for MDI product performance has not been established.

The study

This study undertook a systematic analysis of the effects of the five different factors with a goal of better understanding the effects of the experimental factors on APSD and droplet size distribution of the MDI’s in a realistic in vitro set-up. In the testing, inhalers were actuated to deliver the drug substance through a simple induction port or an MT model to a cascade impactor to separate aerosolized particles of different densities and dynamic shape. 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 a model solution MDI, Atrovent® HFA (ipratropium bromide, 0.021 MG/INH). In the study, a total of five factors and 10 different MT models were studied (Figure 1).

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

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

Systematically analyzing factors that influence aerosol particle size distribution

In this systematic analysis of the five in vitro factors on the particle size distribution of the two model suspension MDIs, the MT geometries appeared to have the strongest effects on APSD-derived parameters, while the effects of inhalation profiles depended on the product type. The choice of the MT model significantly affected the fine particle fraction (FPF) <5 µm (Figure 2), mass median aerodynamic diameter and in vitro lung dose (dose exiting the MT model) for all the three MDI products. Furthermore, the effects of the investigated factors on the APSD and droplet size distribution were often product-specific and unrelated to the formulation type (i.e., suspension or solution).

Figure 2: Fine Particle Fraction<5 μm (FPF<5 μm) of Flovent® 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. 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 in this study3 concluded that during the development of inhalers, applicants who utilize more realistic in vitro studies should consider how the experimental conditions, particularly the MT model type and inhalation profiles, affect the amount and particle size distribution of aerosols exiting 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 the product type. LD may serve as an additional supporting characterization method rather than an alternative to cascade impactor-based realistic in vitro methods for the estimation of the particle size distribution of MDIs, given the limited and product-specific correlations that were found between the APSD-derived parameters and LD measurements.

How does this research improve generic drug development and support their approval?

Development of generic versions of inhalation products is challenging because the generic product should generally have the same delivery of small aerosol particles through the mouth and throat and into the lungs as the brand product. CDER scientists are helping develop more realistic laboratory models of the mouth-throat (MT) region that allow the generic industry to efficiently test their products and speed access to generic products. The experiments in this study measure the effects of in vitro test variables on the particle size distribution of aerosols exiting an anatomical MT model and may improve the predictability of in vivo lung disposition which could accelerate the development of generic as well as branded drug inhalers.

(This Impact Story is based on the Aerosol Society DDL Conference Paper 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, select publications

  1. See FDA draft guidance Metered Dose Inhaler (MDI) and Dry PowderInhaler (DPI) Products – Quality Considerations for a complete definition of these products.
  2. Bonam, M., Christopher, D., Cipolla, D., Donovan, B., Goodwin, D., Holmes, S., … & Wyka, B. (2008). Minimizing variability of cascade impaction measurements in inhalers and nebulizers. AAPS Pharmscitech, 9(2), 404-413.
  3. Dhapare S, Newman B, Svensson M, Elfman P, Sandell D, Winner L, Bulitta J, Hochhaus G: Factors Influencing Plume Characteristics of Metered Dose Inhalers (MDIs) Following Passage through Bio- relevant Mouth-Throat Model. (Abstract). Presented at: Respiratory Drug Delivery 2021, Virtual Conference. May 4-7, 2021; 1; 301-306; (online).

Electronic Cigarettes Contain Higher Levels of Toxic Metal.

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Electronic Cigarettes Found To Contain Dangerous Metal Nanopartices

A concerning new study found that the aerosol from electronic cigarettes contains higher levels of measurable nanoparticle heavy metals than conventional tobacco smoke.

A new study published in the journal PLoS One has uncovered a concerning fact about electronic cigarettes (EC): toxic metal and silicate particles including nanoparticles are present in both the cigarette fluid and aerosol.1

Researchers at the Department of Cell Biology and Neuroscience, University of California Riverside, tested the hypothesis that electronic cigarettes (EC) contain metals from various components in EC.  They employed a variety of testing methods to ascertain the level of contamination, including light and electron microscopy, cytotoxicity testing, and x-ray microanalysis. Their results were reported as follows:

The filament, a nickel-chromium wire, was coupled to a thicker copper wire coated with silver. The silver coating was sometimes missing. Four tin solder joints attached the wires to each other and coupled the copper/silver wire to the air tube and mouthpiece. All cartomizers had evidence of use before packaging (burn spots on the fibers and electrophoretic movement of fluid in the fibers). Fibers in two cartomizers had green deposits that contained copper. Centrifugation of the fibers produced large pellets containing tin. Tin particles and tin whiskers were identified in cartridge fluid and outer fibers. Cartomizer fluid with tin particles was cytotoxic in assays using human pulmonary fibroblasts. The aerosol contained particles >1 µm comprised of tin, silver, iron, nickel, aluminum, and silicate and nanoparticles (<100 nm) of tin, chromium and nickel. The concentrations of nine of eleven elements in EC aerosol were higher than or equal to the corresponding concentrations in conventional cigarette smoke. Many of the elements identified in EC aerosol are known to cause respiratory distress and disease.

The study authors concluded that “The presence of metal and silicate particles in cartomizer [atomizer/cartridge connecting to the battery] aerosol demonstrates the need for improved quality control in EC design and manufacture and studies on how EC aerosol impacts the health of users and bystanders.”

Cartomizer Anatomy

Discussion

While e-cigarettes are rightly marketed as safer than conventional tobacco cigarettes, which contain thousands of known toxic compounds including highly carcinogenic radioactive isotopes, they have not been without controversy.  In May 2009, the US Food and Drug Administration Division of Pharmaceutical Analysis found diethylene glycol, a poisonous liquid used in explosives and antifreeze, in one of the cartridges they sampled. They also discovered the cancer-causing agent, tobacco-specific nitrosamines, in a number of commonly used brands.2

The findings of this latest PLoS One study refutes proponents of e-cigarettes who claim that the health risks of smoking are eliminated with their use. Heavy metals like tin, aluminum, cadmium, lead and selenite are increasingly being recognized as carrying significant endocrine disrupting potential and belong to a class of metals known as ‘metalloestrogens.’

One of the unintended, adverse consequences of nanotechnology in general is that by making a substance substantially smaller in size than would occur naturally, or though pre-nanotech production processes, the substance may exhibit significantly higher toxicity when in nanoparticle form. Contrary to older toxicological risk models, less is more: by reducing a particle’s size the technology has now made that substance capable of evading the body’s natural defenses more easily, i.e. passing through pores in the skin or mucous membranes, evading immune and detoxification mechanisms that evolved millions of years before the nanotech era.

For example, when nickel particles are reduced in size to the nanometer range (one billionth of a meter wide) they may actually become more toxic to the endocrine system as now they are capable of direct molecular interaction with estrogen receptors in the body, disrupting their normal structure and function.3 4 5 Moreover, breathing these particles into the lungs, along with other metals, ethylene glycol and nicotine produces a chemical concoction exhibiting synergistic toxicity, i.e. the toxicity of the whole is higher than the sum of their parts. These sorts of “chemical soups” are exceedingly difficult to study, as they embody a complexity that analytical and theoretical models within toxicology are not equipped to readily handle. Nonetheless, it is likely that when taken together the harms done by e-cigarettes are significant, and will likely manifest only after chronic use when identifying ‘singular causes’ of disease is nearly impossible. Regulators will have a hard time, therefore, identifying a “smoking” gun even after a broad range of health issues do emerge in exposed populations.

Ultimately, finding a less harmful alternative to tobacco smoking is justified, but let buyer (and user) beware, the products are not without possible harm as some marketers falsely advertise.

 

Pulmonary drug delivery: from generating aerosols to overcoming biological barriers—therapeutic possibilities and technological challenges.

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Summary

Research in pulmonary drug delivery has focused mainly on new particle or device technologies to improve the aerosol generation and pulmonary deposition of inhaled drugs. Although substantial progress has been made in this respect, no significant advances have been made that would lead pulmonary drug delivery beyond the treatment of some respiratory diseases. One main reason for this stagnation is the still very scarce knowledge about the fate of inhaled drug or carrier particles after deposition in the lungs. Improvement of the aerosol component alone is no longer sufficient for therapeutic success of inhalation drugs; a paradigm shift is needed, with an increased focus on the pulmonary barriers to drug delivery. In this Review, we discuss some pathophysiological disorders that could benefit from better control of the processes after aerosol deposition, and pharmaceutical approaches to achieve improved absorption across the alveolar epithelium, prolonged pulmonary clearance, and targeted delivery to specific cells or tissues.

PIIS2213260013700729.gr5.lrg

Conclusions

Since the introduction of the first metered dose inhalers to the market in 1956,88 pulmonary drug delivery has made substantial progress, even leading to the first introduction of an inhalation form of insulin (Exubera) to the market. However, since the withdrawal of Exubera from the market in 2007, the field of advanced pulmonary drug delivery, other than delivery of anti-asthma and bronchodilating drugs, has stagnated. Until now the main focus of research and development efforts has been on generation of better aerosols by engineering more sophisticated particles or devices. However, optimised aerosol deposition is a necessary, but not sufficient component of pulmonary drug delivery. To overcome the biopharmaceutical challenges associated with absorption across the alveolar epithelium, control of particle clearance and targeting of specific regions or cells within the lungs requires a thorough understanding of the processes occurring at the cellular and non-cellular elements of the air—blood—barrier after aerosol drug deposition.

To achieve these goals, advanced in-vitro models, preferentially based on human cells and tissues, will be important. Furthermore, nanotechnology might contribute to the development of aerosol drug carriers, and might be necessary for the success of pulmonary drug delivery in the future.

Source: Lancet

 

 

 

 

Pulmonary drug delivery: from generating aerosols to overcoming biological barriers—therapeutic possibilities and technological challenges.

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Research in pulmonary drug delivery has focused mainly on new particle or device technologies to improve the aerosol generation and pulmonary deposition of inhaled drugs. Although substantial progress has been made in this respect, no significant advances have been made that would lead pulmonary drug delivery beyond the treatment of some respiratory diseases. One main reason for this stagnation is the still very scarce knowledge about the fate of inhaled drug or carrier particles after deposition in the lungs. Improvement of the aerosol component alone is no longer sufficient for therapeutic success of inhalation drugs; a paradigm shift is needed, with an increased focus on the pulmonary barriers to drug delivery. In this Review, we discuss some pathophysiological disorders that could benefit from better control of the processes after aerosol deposition, and pharmaceutical approaches to achieve improved absorption across the alveolar epithelium, prolonged pulmonary clearance, and targeted delivery to specific cells or tissues.
Source: Lancet

Measuring Aerosol Production from Patients with Active TB.

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Twenty-eight of 101 patients with culture-confirmed pulmonary tuberculosis had culture-positive cough aerosols, suggesting infectiousness; likelihood of a culture-positive aerosol was directly correlated with degree of sputum-smear positivity.

Although tuberculosis (TB) is transmitted by aerosols of droplet nuclei <5 µm in diameter, determination of infectiousness has been based on microscopic examination of sputum for the presence of organisms (smear assessment) — a method that may be neither sensitive nor specific. The magnitude and particle-size distributions of the aerosols generated by patients with active TB are unknown.

In a study conducted in Uganda, researchers attempted to collect, quantify, and size the aerosols produced by voluntary coughing in patients with active pulmonary TB and to compare these findings with results from sputum smears and aerosol cultures. Patients with culture-confirmed TB were asked to cough in two 5-minute sessions into a custom-built chamber that analyzed and collected their cough aerosol. Plates within the chamber contained 7H11 agar for mycobacterial culture.

Among the 101 patients, 28 produced aerosols that grew Mycobacterium tuberculosis. The proportion of patients who generated culture-positive aerosols increased significantly as the sputum smear microscopy grade increased (P=0.03). All patients with a culture-positive aerosol were smear positive; none of those with a negative smear produced a culture-positive aerosol. More than 96% of the culturable particles collected were between 0.7 and 4.7 µm in diameter.

Comment: Although the authors conclude that cough aerosols might provide a better determination of infectiousness than smear assessment, the data indicate that smear results correlate well with aerosol culture results.

Source: Journal Watch Infectious Diseases