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Local Lung Delivery for Small and Large Molecules Via Dry Powder Inhaler

Inhalation is a familiar route of delivery for many drugs designed to treat asthma and related conditions. Asthmatics routinely carry some form of metered dose inhaler around with them to relieve the symptoms of attacks, and many take preventative medicines such as steroids via inhalers, too. Nebulisers are also used to deliver asthma medications directly to the lungs, often for those who find using a metered dose inhaler difficult (such as children and the elderly).

The growing incidence of chronic obstructive pulmonary disorder (COPD) has led to a rise in drug treatments for respiratory conditions being delivered by inhalation, but other lung diseases also benefit from direct delivery to the lungs. Mannitol, for example, can be given in a dry powder inhaler (Chiesi’s Bronchitol) to help cystic fibrosis patients clear mucus from their lungs. And for pulmonary arterial hypertension iloprost (Ventavis, Janssen) can be delivered directly to the lungs with using a mesh nebuliser. This greatly aids its efficacy, as the drug only has a half-life of about half an hour; multiple doses are required every day, and newer nebuliser types have since helped reduce the treatment burden.

Delivering treatments for lung diseases by inhalation is an obvious choice, as there are significant advantages when diseased tissue or infection is within the lung itself. Pulmonary administration also circumvents first-pass metabolism in the liver. On account of the high surface area of the lung, the onset of action can be faster, as is clearly the case for beta-agonists such as salbutamol/ albuterol when treating acute exacerbations of asthma.

However, small molecule APIs such as these are not the only drugs used to treat lung disease. Monoclonal antibodies (mAbs) and other proteins, peptides and oligonucleotides have all been investigated as both systemic and local treatments for lung diseases. For example, at least five FDA-approved mAb treatments are available for asthma today, all of which are administered by injection.

In 2022, a mAb was approved in the EU for the prophylactic prevention of respiratory syncytial virus (RSV) in children. And during the Covid-19 pandemic, mAb treatments were approved in the EU and the US for severe cases of the disease. Some of these combined more than one agent in the same treatment.

As with small molecule APIs, there can be significant advantages in delivering biotherapeutics locally to the lung, including tissue-specific targeting, which can improve side-effect profiles. There are significant manufacturing challenges involved in formulating sensitive biotherapeutics such as dry powder for inclusion in an inhaler device, and most investigations into inhaled delivery of biologics rely on devices such as mesh nebulisers. Yet DPIs are much preferred by patients and caregivers because of their ease of use, portability, and shelf stability.