Medical inhalers, particularly metered-dose inhalers (MDIs), have traditionally employed chlorofluorocarbons (CFCs) as propellants. While effective in delivering medication, CFCs are potent greenhouse gases that play a role in the depletion of the ozone layer. Recognizing this, the international community took steps under the Montreal Protocol to phase out the use of CFCs. This has led to the adoption of hydrofluoroalkanes (HFAs) in inhalers. HFAs have a significantly lower global warming potential than CFCs and do not have the same ozone-depleting properties.
The Clinical Need
While it is essential to shift to environmentally-friendly propellants, the onus is on us to ensure that these new propellants are as clinically effective as their predecessors. Patients should not have to compromise on their health while we address environmental concerns.
The regulatory authorities have published extensive guidelines on the requirements for changing propellants in existing marketed products.
In 2023, the EMEA published its document “Questions and answers on data requirements when replacing hydrofluorocarbons as propellants in oral pressurised metered dose inhalers.” (Questions and answers on data requirements when 5 replacing hydrofluorocarbons as propellants in oral 6 pressurised metered dose inhalers (EMA/CHMP/83033/2023). This document was prepared to
provide the pharmaceutical industry with advice regarding data requirements for such replacements. In the guidance documentation it outlined the need for safety and local tolerance.
For local tolerance, the requirements for data on ciliary function and airway sensitivity are outlined and gamma scintigraphy is highlighted as an acceptable option for evaluation of this.
Gamma Scintigraphy is an established method to study the in vivo performance of respiratory products. By radiolabelling the formulation with a gamma-emitting isotope, we can visualise and assess its performance clinically and in real-time.
Mucociliary clearance (MCC) is the physiological mechanism of the lungs which clears airways of mucus, biological debris and inhaled particles. MCC can be affected by lung pathology but also pharmacological agents. Gamma Scintigraphy can be used to measure MCC and thus assess the effect a pharmacological agent or a medical device / propellant has on the process. MCC as a pulmonary function biomarker has been recognised by regulators.
The test involves the inhalation of a pre-specified amount of radiolabelled particles via a nebuliser; usually human albumin colloid radiolabelled with technetium-99m which has minimal to negligible absorption. Scintigraphic imaging measures the clearance from the lungs of the inhaled radioaerosol by calculating the percent particle retention (PPR) at various time points after the administration of the radiotracer.
MCC can be assessed using this method before (baseline reading) and after administration of the study product to evaluate the presence or absence of a significant change in the overall rate of clearance as well as any change in the central to peripheral deposition of radiotracer (C/P ratio).
The uses of gamma scintigraphy in the development and assessment of respiratory products and devices is much broader than just mucociliary clearance and this technique allows us to evaluate metrics such as:
- Deposition patterns: Where does the drug end up within the lungs? Is it reaching the target areas? (Figure 1.)
- Retention: How long does the drug stay in the lungs? Is it cleared quickly, or does it remain for an effective period?
Figure 1. Images from a lung deposition study in which dry powder inhalation of a product was compared to nebulisation. This study provided quantitative data to clearly demonstrate superiority of the dry powder formulation and informed the next stages of product development.
BDD are dedicated to, and are expert in, clinical trials in the respiratory space, we recognize the balance that needs to be struck between environmental responsibility and patient health. By offering comprehensive clinical trials and using state-of-the-art technologies like gamma scintigraphy, we aim to ensure that the next generation of inhalers is not just greener, but also safe and effective.
The journey towards environmentally conscious healthcare is not a simple one. But with rigorous testing and innovation, we can breathe easier – both for our planet and our health.
BDD have been leaders in gamma scintigraphic imaging for more than twenty years and provide a single centre CRO and investigative site to allow rapid and cost effective performance of your clinical evaluation studies.
Read Case study “An open label, randomized two-way crossover scintigraphic study to investigate lung deposition of radiolabelled alginate oligosaccharide delivered as a dry powder and as a nebulized solution in cystic fibrosis patients” here https://www.bddpharma.com/resources/lungdepositionstudyincf/
Read Article “Inhaled dry powder alginate oligosaccharide in cystic fibrosis: a randomised, double-blind, placebocontrolled, crossover phase 2b study” here https://www.bddpharma.com/wp-content/uploads/2023/07/Alignate-Oligosacchaide-in-CF-Paper-1.pdf
Read more – https://www.bddpharma.com/
Contact us – firstname.lastname@example.org