Breathe It In

Historically, inhaled drugs have targeted the main respiratory diseases, namely asthma and chronic obstructive pulmonary disease. Inhaled drug delivery, however, has a number of inherent advantages that can also benefit other therapeutic areas. Compared with oral drugs, for example, inhaled medicines avoid first-pass metabolism and degradation in the GI tract. Inhaled drugs also often require lower dose levels and usually provide faster onset of action (1). And when it comes to comparison with parenterals, inhaled drugs are less intrusive and provide improved stability, especially for proteins and peptides (2).

Despite the benefits, however, the development of inhaled products poses unique challenges; for instance, creating an effective drug formulation requires considerable expertise in particle science. The size of the particle is pivotal for inhalation studies to ensure effective lung deposition. Traditionally, the fine drug particles required have been produced by mechanical micronization, using air jet mills. These particles are then often combined with a lactose carrier to improve drug stability and dose control, depending on the drug type or compound class. More recently, formulation options have expanded thanks to advances in particle engineering techniques and technologies, as well as nanotechnology, which allow for greater control over the size, shape and chemistry of particles.

When planning efficacy and toxicology studies using inhalation technologies (regardless of formulation), dose delivery methodology and the reproducibility of effective dosing are crucial. The main methodologies for drug delivery in non-clinical studies are intratracheal and inhalation dosing. Intratracheal dosing involves anesthesia and intubation, with the drug delivered via bolus through the intubation tube, and is principally used for early screening studies. This method is simple, uses minimal amounts of drug, and the delivered dose is easily quantified. However, it is prone to artefactual toxicological and pharmacological results, and the particle size used in testing often differs from that which will be used non-clinically.

Inhalation dosing, on the other hand, delivers compounds to conscious animals by the clinical route of administration (the lung), removing the risk of intratracheal artefacts. The challenging aspect of this method is the necessity for specialist inhalation technology capabilities and experience. Having the ability to reproducibly control the aerosol during both intra- and inter-exposures is pivotal in ensuring that study integrity is maintained; failure to achieve reproducible control may compromise study endpoints, allowing poorer data interpretation and reducing the scientific impact of the study. At worst, the study may need to be repeated if the aerosol is not controlled effectively.

There is also the inhaler device to consider – another significant development challenge. A proprietary inhaler provides a unique opportunity for extended patent protection; in the US, for example, GlaxoSmithKline’s Advair (Seretide) came off patent in 2010, but the Diskus delivery device remained in patent through 2016. An inhaler device must be matched to the patient, easy to use, forgiving of poor technique, and able to provide feedback to the user about dose emission and technique. And though this may sound straightforward, it is challenging to achieve in practice – and without a good inhaler device, a drug is unlikely to
be successful.

In my view, although the challenges involved in inhaled drug development are perhaps greater than for other routes of administration, inhaled drugs do offer benefits to those companies that have the scientific expertise to develop them. The industry is competitive, and companies need to move beyond the traditional methods of drug discovery and development. Switching established products to another delivery format can extend a product’s value proposition – and potentially lead to a more effective medicine. Drugs can easily be de-risked early in development by incorporating additional endpoints into initial in vivo studies and by taking advantage of new particle engineering methods. There are still tremendous opportunities to develop new and improved therapies that will have a positive impact on the lives of patients – and there are many drug delivery options, including the inhaled route, and technologies that have yet to be fully explored.