Lung diseases such as asthma, idiopathic pulmonary fibrosis and chronic obstructive pulmonary disease (COPD) are a growing global healthcare challenge, with figures suggesting they are responsible for around one in ten deaths in the EU. For those developing treatments for these chronic respiratory conditions, pulmonary drug delivery is seen by many as a more promising way of getting locally-acting drugs to where they’re needed. But while this non-invasive route of administration can be more targeted and result in fewer systemic side effects, it also comes with a number of specific challenges for medicinal and formulation chemists.
Challenge 1: Drug Design
Conventional orally administered drugs are designed for maximum absorption and bioavailability within the body.
When treating respiratory diseases with extracellular targets, topically-acting APIs should remain and act within the lungs. The systemic uptake of drug molecules may reduce efficacy and could cause undesirable side effects. The trouble is, our lungs have evolved to be very good at rapidly getting molecules into the circulatory system. This challenge is also compounded by the fact that a significant proportion of inhaled medicines will be swallowed without entering the lungs.
In order to develop APIs that are less easily transported out of the lungs and reduce the potential for systemic exposure, medicinal chemists must turn Lipinski’s Rules on their head. Developing drugs that are highly plasma protein-bound or rapidly metabolized and excreted may result in patients experiencing fewer side effects. Likewise, larger compounds are less able to cross the epithelial barrier, limiting their potential to be absorbed into the bloodstream.
Challenge 2: Physical form
Administering drugs in aerosol form using metered dose or dry powder inhalers can be a very effective way of delivering drugs locally to, or systemically through, the lungs. However, the size of these particles affects both the deposited dose and their distribution throughout the lungs, both of which should be carefully optimized.
Larger aerosol particles are more likely to deposit heavily on central airways, whereas finer aerosols tend to distribute in narrower airways with a lower amount deposited overall. As a result, the therapeutic effects are highly dependent on the distribution of the aerosol particles within the lung and the location of the target receptors. Moreover, in the humid environment of the respiratory system, larger particles can stick together, reducing efficacy and potentially causing irritancy.
To tailor the size of nanoparticles to the right application, a wide range of micronization technologies are available. These can be supported by post-micronization strategies designed to stabilize the surface of the material and reduce the potential for efficacy-reducing recrystallization that can occur during storage.
Challenge 3: Patient compliance
Studies suggest that, when developing local treatments for respiratory diseases, targeting multiple cellular pathways simultaneously can be a more effective strategy. In the treatment of asthma, for example, bronchodilators and anti-inflammatories are often more effective when used in combination. However, with ease of convenience an important factor influencing compliance, patients taking two inhalers containing separate medicines may be less inclined to follow their treatment regimens.
A promising solution to this challenge could be the use of single drug molecules capable of binding to multiple targets. Bifunctional muscarinic antagonist-beta agonists (MABAs), such as GSK’s batefenterol, have the potential to offer equal or greater efficacy than single mechanism bronchodilators whilst improving patient compliance. And when combined with an additional molecule, such as an anti-inflammatory corticosteroid, these strategies could even unlock the potential for triple combination therapies.
Pulmonary drug delivery is increasingly seen as a promising administration strategy that could bring effective and non-invasive treatments to patients more quickly and affordably. Whilst there are a number of additional points to be considered when developing these therapies, with the right skills and experience, these challenges can be overcome.