The delivery of therapeutics by inhalation is a medical process dating back thousands of years. The first written evidence of this can be found ca. 1550 BC in Egypt, where vapours of the black henbane plant were used to treat patients with breathing difficulties.1 We now know this vapour likely contained anticholinergic chemicals similar to those now used in modern inhalers to reduce inflammation and bronchoconstriction in the airways.
Despite major advances over the past three millennia in the treatment of pulmonary disease patients with inhaled medications, there is still no single therapy that controls the underlying lung disease, only temporary, symptom management-based approaches. This presents a significant opportunity for the development of novel medications that can be used to treat – and ultimately, cure – diseases that are responsible for the deaths of approximately 8 million people per year.2
Delivering drugs through the pulmonary route has several benefits. It is non-invasive, with relatively little metabolic activity compared to other therapeutic routes. Our lungs also provide a large, thin surface area with direct access to the whole systemic bloodstream. This means that as well as being the optimal route for drugs directly targeting the lungs, it is also a rapid and simple way to transport drugs to other target organs.
However, the lung presents many hurdles that must be overcome for the successful delivery of a compound to the target cell or bloodstream. Understanding these challenges is key for the design of inhaled medications, not only to ensure drugs are delivered to the site of action, but also that they remain efficacious relative to their role. Current models for measuring the ADME (absorption, distribution, metabolism, excretion) properties of compounds through the lung are limited due to lack of predictivity, high cost and time. However, new human-relevant techniques are emerging which are changing the face of preclinical testing. Organ-on-a-chip (OOC) technology, also known as microphysiological systems (MPS), is a key innovation which can be used to reduce our reliance on traditionally used animal testing, by providing a physiologically relevant and clinically translatable model that is both time and cost-effective. Engaging with these new technologies will allow a more analytical and rapid understanding of the multi-faceted journey of inhaled medications.
The first, and potentially most inhibitory challenge in a drug’s ability to deliver results is the physical act of inhalation from the device into the patient’s lungs. At this stage, a high proportion of the drug can already be lost due to poor technique, including lack of shaking the inhaler, or poor inhalation, which can lead to the drug being swallowed rather than inhaled into the lungs. Recent innovations in inhaler technology, including spacers and even smart inhalers connected to smartphones, have enabled more effective medication delivery to tackle this initial inefficiency.3
The next challenge is understanding where, in the lungs, a particle will be deposited. Ultimately, this depends on its size and chemical properties. Smaller particles will be deposited into the distal lung (smaller bronchioles and alveoli) whereas larger, heavier particles will deposit in the proximal lung (trachea and bronchi). Therefore, if the drug is designed to target bronchial function – such as a bronchodilator – then a larger particle (>5 μm diameter) will be advantageous, whereas if the drug is designated to act elsewhere in the body – such as insulin – the particle size should be smaller (1–5 µm) to allow it to reach the alveoli and then bloodstream. Any particle less than 1 µm would likely not be dense enough to settle and would instead be suspended in the air and exhaled.