Drug delivery to a patient’s lung for disease treatment involves more than “simply” the performance of the drug delivery device; the mechanics of lung deposition in a patient’s lungs on each individual inhalation has a huge impact on the dose delivered. As airborne drug passes from the inhaler to the patient, it leaves a carefully designed and closely process-controlled environment and enters the hugely complex and highly variable space of the patient airways. As device designers and engineers, careful consideration of the patient is key to developing robust and effective products.
Challenges in inhaled drug delivery
Lung deposition is not an exact science, with a co-efficient of variability of 40% being typical (1), (2). It is also highly inefficient, as a consequence of the mouth and throat doing a very good job of protecting the lung from airborne matter. Delivery efficiencies are typically around 20-40% of the label dose, with the small number of high efficiency products achieving no more than around 60% (1). Low lung delivery efficiency may not be overly problematic depending on the side effect profile of the drug. However a high dose to the throat is associated with dysphonia and oral candidiasis for some steroids, so it may be beneficial to avoid this for those medicines. Variability in dosing is a problem for patients and physicians alike as discussed below.
Nonetheless, the dose benefits of delivering drugs intended to treat local lung diseases via the inhaled route, compared with doses required for oral solid dose delivery, outweigh these disadvantages (3). Likewise, the rapid uptake of drug into the systemic blood plasma can make the lung an attractive choice for some drugs intended for systemic delivery. Understanding lung delivery is an important challenge and ongoing mission for many.
So, what factors affect lung delivery? How can we understand them and even try to manipulate them?
Easy to control – particle size
Everyone involved in the development of inhaled products will be laughing (if a little ironically) at the notion that controlling particle size is easy, however, in terms of lung delivery, particle size is the most controllable of the various factors.
For delivery to the lung, particles need to be small enough to avoid impaction in the mouth and throat but large enough to impact and sediment once in the lung: typically the target is to maximise the particles in the range 5-1µm (2) (4). Nanoparticles smaller than 100nm are also effective at lung delivery (5) but are more difficult to deliver and handle in manufacturing processes. Particle size also influences the quantity of drug delivered to different lung regions such as the bronchi, bronchioles and alveolated airways, which has the potential to affect efficacy, safety and systemic uptake (2) (4). Nonetheless particles of all inhalable sizes deposit in all airways to some extent (6).
The development and manufacture of inhaled products relies heavily on the measurement and control of particle size. A virtual sub-industry of analytical chemists, instrument manufacturers and data quality systems exists to perform these measurements. However, this only controls one aspect of lung delivery and once particles enter the patient there are a multiplicity of factors to subvert this control.
Challenging to control – inhalation parameters
Inhalation air flow rate, inhaled volume and breath hold duration all affect deposition in the lung. If patients inhale with higher airflow rates then this results in increased impaction in the throat, and reduced lung dose (4) (7). The distribution of drug deposition in the lung is likewise affected with impaction in the bronchi increasing, resulting in reduced availability of particles to sediment in the alveoli (4) (8). However, a rapid air flow rate is often required to aerosolise the dose of a dry powder inhaler to the requisite fine particle sizes of around 5-1µm. There exists therefore a trade-off in the effects of inhalation flowrate for these devices. The volume inhaled by a patient determines its penetration into the lung and increases the proportion of alveolated airways being dosed (6). Similarly, asking patients to hold their breath post-inhalation for a few seconds increases the time available for particles to sediment and diffuse and therefore increases the deposited lung dose. Breath hold is particularly important for smaller particles, which have reduced sedimentation efficiency (9).
Inhalation parameters are manipulable, if not directly controllable. Instructions in patient information leaflets are the simplest and most widespread means of achieving this. However even a well-posed, well-understood set of instructions cannot mitigate the inherent high variability in how each person breathes from day to day (10). Furthermore, many patients do not follow the inhalation instructions correctly (11).
Numerous innovations have been developed to help reduce the variability associated with inhalation manoeuvre. Feedback to the patient can be provided via training aids such as flow meters (12) or an add-on device that produces a tone at the correct flowrate (13). Smart inhalers are in development that include passive technologies such as flowrate sensors and Bluetooth connection to a mobile phone and some of the most advanced inhalers can dynamically change flow rate resistance during inhalation (14) (15).
Nearly impossible to control – patient airways
The size and shape of the patient airways affect how particles are deposited in the lung. In particular, throat size and shape has been shown to profoundly affect throat impaction and the delivered lung dose (16), with smaller throats trapping more particles leading to reduced lung dose. The size of a patient’s lung airways also has some effect on the deposition efficiency, though this is less well characterised (17).
There is very little that can be done to change the size and shape of a patient’s airways, beyond the effect that mouthpiece shape may have on the geometry of the oral cavity, for example tongue position, at the time of drug delivery. Posture and the inhalation manoeuvre may also affect throat shape (18), which changes during the inhalation. However, these do not overcome the basic underlying fact that different people have different sized throats, so this is an unavoidable human variability. Smaller particles display reduced impaction in the throat so the variable effect of throat size on lung deposition may be reduced this way.
Challenging to control – other patient interaction factors
Other factors that may affect the successful dose delivery include how the patient interacts with the device, for example whether they make a good seal on the mouthpiece with their lips (ensuring air flows through the device and not around it). pMDIs require
co-ordination of the dose actuation with inhalation onset, which around half of patients fail to do correctly (11). Dose preparation is another challenge. pMDIs require shaking while many DPIs absolutely must not be shaken once opened. For some devices a lever needs to be pushed to a certain point, and others require loading of a capsule. Each of these steps have been shown to be performed incorrectly for around a third to a half of patients (11).
Impossible to control – patient disease state
The disease state of an individual patient can affect inhalation parameters and airway size and shape. These differences have been shown to lead to increased lung deposition compared to healthy cohorts, which, though potentially beneficial, may also incur harm and needs to be understood (19). These numerous disease-related factors interact in complex ways.
Patients with lung diseases do not always achieve the same inhalation flowrates as healthy individuals. This is a more significant problem for COPD (Chronic Obstructive Pulmonary Disease) subjects compared to asthmatic cohorts who may on occasion achieve flowrates comparable to healthy individuals (10). COPD patients suffer from hyperinflated lungs and consequently their inhaled volume is significantly reduced as the lung is already partially inflated compared to a healthy individual (10), which results in reduced penetration of the drug particles to the alveolated airways (6).
COPD affected lungs are subject to airway remodelling. In the bronchi and bronchioles some airways are increased in size by hyperinflation while others feature local narrowing and obstructions which reduce the dose passing that point. It may be that these obstructions prevent drug from reaching the part of the lung most in need of treatment, making them reliant on whatever dose passes back into the lung airways from systemic circulation. In the alveolar region, emphesymous voids appear, creating large, irregular spaces that greatly decrease deposition by sedimentation and Brownian diffusion which are heavily dependent on the small size of alveolated airways for efficiency.
Additionally, feeling unwell may make patients distracted, tired and less likely to comply closely with complex inhalation or lip-seal instructions.
Poorly understood let alone controlled – electrostatics
The electrostatic charge of the inhaled aerosol dose is likely to affect the emitted particle size and also has a direct effect on how those particles deposit in the lung.
Electrostatic charge is understood to be a key contributor to inter-particle adhesion forces (20) and has the potential to affect de-aggregation and re-aggregation events and hence the particle size emitted from the device and entering the patient. Once in the lung, both mirror charges and field charge effects have the potential to cause particles to be attracted to the airways and for this to significantly affect deposition (21). Measurement of electrostatic charge is very challenging to do repeatably and reliably and, compared to other factors,is in its infancy.
Nonetheless some recent developments show promise and may help grow our understanding of this much ignored factor in lung delivery. The BOLAR instrument measures the bi-polar charge for different particle sizes emitted from an inhaler and has greatly furthered understanding of charge effects. BOLAR data shows the aerosol plume to contain large quantities of both positive and negative charge that greatly exceed the net charge (22). Electrostatic charge effects have been incorporated both in lung deposition modelling (21) and DEM powder flow modelling tools (23) that have the potential to model de-aggregation events, which BOLAR data may be fed into.
Patients need easy-to-use devices that are consistent
So, what do patients need most from their inhaled drug product?
Patients try out different doses and different drugs, together with their physician, to understand what medicine best controls their disease symptoms. In order to get meaningful and accurate feedback on drug performance, patients need consistent drug delivery each time they use the product. Physicians likewise need consistency between patients so they can learn from experience.
It should be noted that common dosing scenarios where dose delivery variability has little impact on patient outcomes do exist. Once the overall drug dose has reached a certain level then the available pharmacological receptors become saturated and additional increases in drug dose have no additional efficacy. In this instance, the patient treatment is robust to lung delivery variability. However, if a patient is evaluating which dose works best for them, for example by switching to a higher dose product, then they are likely to be at a low enough dose that changes to that dose result in efficacy changes i.e. the drug receptors are not saturated. Unintended and uncontrolled changes in lung delivery efficiency due to its inherent variability therefore may likewise affect efficacy.
Equally important is device ease of use. There is overwhelming data showing that a large proportion of patients make errors when using their device (11), moreover incorrect inhaler usage has been shown to be linked to poor health (24). High tech solutions are not necessarily the best. While a phone app or sensor-enabled inhaler that measures flowrate is one way of obtaining dosing consistency, a product with reduced sensitivity to flowrate may achieve the same outcome with less complexity for the patient and regardless of their engagement with their therapy.
There exist few easy solutions to achieve the utopian goal of consistent lung delivery. A well-designed device that is simple to use, generates a consistent aerosol that has low sensitivity to flowrate is a good start. A breath-actuated mechanism can improve outcomes for pMDIs by taking co-ordination out of the patient’s hands. Additionally, there will undoubtedly be many patients who benefit from the high-tech solutions. The task of getting drug into the lung is one that will most likely continue to challenge scientists and engineers for decades to come!
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