Vince Russell is director of Respiratory Discovery at Aptuit, www.aptuit.com/drug-design-and-discovery/therapeutic-areas/respiratory.Â 

Vince Russell

Respiratory diseases such as asthma, chronic obstructive pulmonary disease (COPD), and idiopathic pulmonary fibrosis are among the most serious and widespread healthcare challenges facing the developed world, accounting for more than 400,000 deaths in the European Union, equivalent to 8% of the total mortality figure (1). Such figures highlight the growing need for innovative and effective treatments. Pulmonary drug delivery is receiving increased attention as a non-invasive means for local treatment of a wide range of major lung diseases; this route of administration, however, poses additional challenges for medicinal and formulation chemists.

	The lungs have the ability to deliver compounds into the circulatory system quickly; oxygen is transported into the bloodstream and carbon dioxide is offloaded in each breath.

	But when treating respiratory diseases with extracellular targets, it’s vital that topically acting drugs remain and act within the lungs. Absorption into the body could cause significant side effects, such as those affecting the digestive, cardiovascular, and central nervous systems, depending on the mechanism of the drug administered, as well as off-target effects. This challenge is at odds with the goal of conventional orally administered drug design, where medicinal chemists aim to modify the chemical properties of an API to improve absorption and bioavailability within the body.

	When predicting the suitability of molecules as orally administered drugs, medicinal chemists often consider a set of four approximations to predict absorption in the gut, known as Lipinski’s Rule of Five. Lipinski’s rules state that an orally active drug should have no more than one violation of the following criteria:

		An octanol-water partition coefficient (log P) not greater than five

		No more than 10 hydrogen bond acceptors.

	But for extracellular luminal targets, to develop APIs that are less easily transported out of the lungs, it’s necessary to use molecules that defy these rules. Larger compounds, for instance, are less able to cross the epithelial barrier, meaning they will be less easily absorbed into the bloodstream. Likewise, less lipophilic APIs will find it harder to penetrate the airway lining, remaining at the site of action for longer.

	To minimize systemic exposure, it’s again important to go against conventional orally active drug design thinking. Developing drugs that won’t be easily absorbed in the gut, which may be highly plasma protein-bound and/or rapidly metabolized and excreted, will be more successful at limiting the potential for treatment side effects.

	The delivery of therapeutic agents as aerosols using metered dose (MDIs) or dry powder inhalers (DPIs) can be very effective for administering drugs locally to, or systemically through, the lungs. A key challenge, however, is to generate drug particles of a suitable size range.

	Aerosol particle size affects both the dose deposited and the distribution of aerosol particles in the lungs and must be carefully optimized. Large-sized particle aerosols predominantly deposit on central airways with more drug deposited per unit surface area, whereas finer aerosols tend to be distributed in more peripheral airways with less drug deposited per unit surface area (2). Both of these factors can affect therapeutic efficacy, with the effects of distribution of a particular treatment strongly dependent on the location of the target receptors within the lung.

	Control of particle size is also an important safety consideration. In the humid environment of the respiratory system, drug particles may readily stick together, potentially causing irritancy issues in addition to a reduction in efficacy.

	Various micronization technologies based on air jet-milling are available for the preparation of suitably sized nanoparticles used for pulmonary drug delivery. These processes, however, do not always result in optimal particle properties, and they often create disordered surfaces that can cause recrystallization of the material during shelf storage, which subsequently affects product performance. Post-micronization treatment, designed to stabilize the material surface and reduce this physical instability, is therefore an important step that must often be considered.

	It’s often not possible to predict which particular form of the drug is going to cause problems until preclinical toxicology studies are undertaken. Robust, readily available predictive assays capable of quickly determining which form of a molecule is going to cause problems are essential. Developing animal models where drugs are administered intra-nasally or intra-tracheally requires careful planning and technical expertise. As it is inherently necessary for animals to breathe in while the drug is administered, multiple factors must be considered, including dosage timing, volume, and depth of anesthesia.

	It’s worth noting that even before planning formal preclinical toxicology studies, it’s important to have a good understanding of how a drug might act in vivo. Significant amounts of time and resources can be saved through the use of simple and qualitative comparisons of candidate drugs early in the drug development process. These simple studies can offer an early indication of signs of lung irritation or inflammation, and this knowledge can guide development decisions and minimize the potential for unexpected and costly failure at later stages.

	When developing local treatments for respiratory diseases, it can be beneficial to target multiple biological pathways. In the treatment of COPD, for instance, long-acting beta-2-agonists and muscarinic acetylcholine antagonist bronchodilators are more effective when used in combination to relax the muscles that tighten around the airways (3, 4). Many asthma treatments employ both bronchodilators and anti-inflammatories, such as corticosteroids, which offer improved benefits when taken in combination.

	However, the requirement for multiple drugs to be administered can have a negative impact on patient adherence to treatment regimen. With ease of convenience an important factor influencing compliance (5), a patient who must take two inhalers containing separate medicines may therefore be less likely to follow treatment. This issue may contribute to the relatively high rates of nonadherence to asthma medication regimens, with nonadherence figures as high as 70% reported (6).

	One way to overcome this challenge could be to develop a single drug molecule that targets multiple mechanisms. Bifunctional muscarinic antagonist-beta agonists (MABAs) are a novel approach to dual bronchodilator therapy, which may offer greater efficacy than single mechanism bronchodilators with equal or better compliance. Such approaches could also open up the possibility of triple combination therapy when used in combination with a second molecule, such as a corticosteroid.

	When opting for pulmonary drug delivery for treatment of lung diseases, it is also important to consider the impact of the condition or effect of age on the patient’s ability to inhale the compound. If the lung function is compromised, the ability to get enough compound to the right place is potentially an issue. Some older patients may lack respiratory muscle strength to use DPIs correctly. In these cases, inhalation using a nebulizer may need to be considered.

	Pulmonary drug delivery is becoming an increasingly used non-invasive route of administration to treat widespread and debilitating lung diseases. However, when developing treatments that rely on this delivery mechanism, it is important to consider the key challenges associated with this approach. By partnering with experienced industry experts, these challenges can be overcome, helping to bring safe, effective treatments to patients more rapidly and affordably.

		Eurostat, “Respiratory diseases statistics; data extracted in October 2016,” http://ec.europa.eu/eurostat/statistics-explained/index.php/Respiratory_diseases_statistics, accessed April 25, 2017.	

		G.J. Rodrigo, V. Plaza, J.A. Castro-Rodriguez, 

Pharmaceutical Technology APIs, Excipients, & Manufacturing 2017


	Supplement to Vol. 41, No. 9
	September 2017
	Pages: s16–s18

	When referring to this article, please cite it as V. Russell, "Four Challenges for Pulmonary Drug Delivery," in 

Pharmaceutical Technology APIs, Excipients, & Manufacturing 2017. 

	Vince Russell is director of Respiratory Discovery at Aptuit. 

Articles

Pulmonary drug delivery is becoming increasingly used. When developing pulmonary drugs, pharmaceutical chemists must consider drug absorption, control of particle size, suitable toxicology models, and patient compliance. The author reviews the issues specific to developing drugs designed for pulmonary delivery and considers how-with the right knowledge and expertise-these challenges can be overcome.