The future of inhalers: how can we improve drug delivery in asthma and COPD?

KEYWORDS:

• Asthma
• COPD
• drug delivery
• inhalers
• adherence
• compliance

The choices of inhaler therapies have been driven by technologists; the voice of patients and clinicians is now being getting louder and that will lead to a change in inhaler technology.

There is a dichotomy in the way inhaler devices are designed, while technologists are concerned with consistent and safe dosing, drug deposition, and inhaler reliability based on intrinsic device airflow resistance and patients’ inspiratory flow, clinicians are focused on patient adherence and device handling training, while keeping in mind cost-effectiveness as an important factor in current health-care systems. More and more patients’ preferences are being considered as these have implications with patients’ compliance and adherence [1,2].

Asthma, the leading chronic disease in children, and chronic obstructive pulmonary disease (COPD) are predicted to become the third leading cause of death in the word by 2030 [3]. They are a major global concern for national health-care systems, significantly affecting the quality of life of patients. There is a general consensus that when it comes to technologies, formulations and inhaler devices have improved tremendously in the past few years [4,5], yet according to some clinicians, 41%–69% of patients with COPD inappropriately use inhalers with critical errors in at least 88% of patients [6]. About half of patients with asthma and COPD do not adhere to their prescribed treatment [7,8], leading to a poor control of asthma symptoms [9].

‘Successful asthma management is 10% medication and 90% education’ [10].

Over the past decade, the efficiency of inhalers, as measured by total lung deposition, has increased from less than 10% to nearly 50% of the total dose, yet less than half the dose becomes available to the site of absorption [11,12]. There is space for new technologies to improve these numbers, but there is still confusion in the scientific community as to how these improvements will be brought about.

Deposition patterns in the lungs are highly dependent on patient’s inhalation patterns. It is usually accepted that a high flow is required for dry powder inhalers (DPI) so as to disperse particulate aggregates. Since not all patients can achieve these flow rates due to age or disease, it has been accepted that flow-independent inhalers should be developed. Hoppentocht et al. [11] debunked these myths and claim that the design of new DPI inhalers is based on false premises: (i) DPIs do not perform best at 4 kPa or 60 L/min; (ii) fine particle fraction (FPF) independence from flow rate is irrelevant for efficiency; (iii) high resistance DPIs do not require a high flow rate nor considerable effort to be operated correctly; and (iv) increase FPFs does not mean higher clinical effect. It is difficult in this context to see where device/formulation technology improvements will come from.

In 2011, there were more than 230 different device–drug combinations available in Europe, with 48 different inhaler products currently available to prescribers in the UK. Hoppentocht et al. [11] list 32 different device technologies recently developed or in development, and this count does not register recent generic devices. These numbers speak of the inventiveness of technologists, but fail to translate in clinical improvements.

Chrystyn et al. mention that 92% of patients that use pressurized metered dose inhalers (pMDI) perform at least one critical handling error, while only 54% of patients using DPIs do [13]. Other studies find that DPIs elicit higher rates of misuse and lesser clinical efficacy than pMDIs [8]: in this study, it was found that patients using pMDI had significantly greater odds of achieving asthma control. This finding could be due to patients enrolled in a clinical trial being more educated about pMDIs handling than DPIs, raising the possibility that familiarity with a particular device does improve clinical outcome. A more balanced view is provided by a meta-analysis of efficacy outcome between a number of devices in a manuscript by Dolovich et al. [14]. They found that all devices provided similar outcomes in patients when using the correct technique for inhalation. Therein lies a key word: Education.

The major finding from a number of clinical studies is that patients are often neither compliant with nor adhere to their treatment, and this lack of compliance and adherence has a direct effect on clinical efficacy. A wrong inhaler technique is the most prevalent cause of poor asthma and COPD control. The errors usually made are in order or prevalence: (i) no exhalation before inhaling the medication; (ii) incorrect device positioning; (iii) incorrect loading of inhaler; (iv) lack of forceful inhalation; (v) shallow inhalation; and (vi) no breath hold. These errors have therefore no relation with inhaler design. Incorrect inhaler technique may further be influenced by other patients’ determinants: like age, gender, and education level of the patient [15]. Device training and repeated checks of patients’ device use and technique are necessary to improve adherence [16].

The misuse of inhalers is linked to poor disease control [17,18]. This is not due to a lack of efficiency of the therapies, but about not taking the medication. In this context, the solution to improving treatment is not about making devices with more or better features (breath actuation, electronic dose counting, cap/actuation mechanisms, improved FPF), but educating patients to use their therapies and how to use the devices correctly.

Bonini and Usmani [19] have presented a convincing argument stating there are too many different types of inhaler devices available to patients and that they all require a different level of dexterity, lung capacity, and hand-to-mouth coordination [20]. There is an obvious need for a simplification and rationalization of type of devices if we want to increase patient adherence [21]. One of the findings of Price et al. [22] is that patients prescribed the same device were significantly more likely to achieve asthma control and recorded significantly lower severe exacerbation rates than those prescribed mixed devices. This is endorsed by Rootmensen et al. [23] who found that patients using different devices for their therapy are more prone to performing incorrect inhalation maneuvers.

Innovation in inhalers technology will be incremental and will follow 4 axis: (i) molecules combination; (ii) new devices; (iii) generic products; and (iv) evidence-based digital health solutions.

There is an obvious lack of new molecules candidates to drive innovation in asthma and COPD. GlaxoSmithKline is the only company who has introduced new compounds, such as vilanterol and umeclidinium. Others, such as AstraZeneca, Boehringer Ingelheim, or Chiesi, have opted for combinations of existing molecules like olodaterol, tiotropium, glycopyrronium, and indacaterol. Some of these molecules have been advertised as enhancing patient’s adherence by allowing once daily treatment. There is no evidence that a once daily treatment improves adherence, in fact in view of the lack of compliance and adherence a once daily treatment is problematic: if a patient misses a daily dose, there is no way to catch up 12 hours later. There is also the suspicion that these combinations are more about product life-cycle management filling up product pipelines to avoid revenue collapse from patent expiry of existing therapies.

Innovations are not limited to creating new device concepts, but adding to existing ones, i.e. adding dose counters or extending patent coverage to pediatrics. Dose counters have been added to the TEVA QVAR® range admittedly to improve the patient’s experience, but more likely to create a further hurdle to generic approvals. All these inventions were driven by technologists, it will be interesting how they fare in the clinic over the next 5 years and how clinicians will rate them.

A number of generic inhalers will soon be approved. Some will be 505j or substitutable options: they will make use of popular inhaler designs such as Diskus® or Breezhaler®. As these generic device designs become available, there may be pressure to switch patients from reference inhaled medication to cheaper generic inhaled drugs, and this may contribute to increasing inhaler compliance by raising awareness on their handling [24,25]. This could drive adherence, and may transform the way DPIs are designed: why go into the expense of designing new devices when a standard platform would be sufficient?

Not all generic devices are based on popular technology, Mylan’s forthcoming generic version of Advair® Diskus® is based on a disc design, while TEVAs’ multi-dose generic device is a complex reservoir. Understandably, some generic manufacturers have created unique platforms to create 505b2 generics to avoid drastic price erosion. These devices have been designed with a view to match an originator and not with patient’s adherence in mind. Some will require unique training and consequently it will be of interest to monitor their efficacy in the clinic and their impact on adherence.

One of the solutions envisaged to increase patients’ adherence to their therapies is ‘evidence-based digital health solutions’: monitoring systems based on phone applications (Apps) and electronic sensors. A few companies are leading the way for asthma and COPD: Propeller (www.propellerhealth.com), Adherium (www.adherium.com), and Philips Respironics (www.philips.co.uk). E-health solutions are currently designed to help patients with their care management via electronic dose counting, calendar reminder, and in the measurement of physiological parameters. A lot of publicity has been made around these applications, but few results on their benefits have been published. Kim et al. [26] from Propeller shared some insights in the use of such technology. It is not clear if such Apps do improve clinical outcomes, although their results point at an improvement of adherence via a reduction in rescue inhaler use for patients in a clinical setting, whereas patients without additional clinical supervision did not show such an improvement. This study opens new ways to look at care management, and may improve inhalers use, but the values of Apps could be limited; if people do not adhere to their treatment already would a ‘smart’ inhaler linked to a phone really be useful in improving compliance? Wouldn’t the App only help people that already have a strong adherence? Who does the App really help? And who is going to pay for it?

‘The most expensive inhaler is the one that is not used correctly’ [27]. What is interesting in recent publications is not so much what is being said but what is not being said: the call for inhaler improvements is not about improving pharmaceutical efficiency or clinical efficacy; it is about improving an extraneous factor: patient adherence. Inhalers can be improved but if patients do not take their medication, these improvements will be wasted. The pharmaceutical advances that have led to the re-design of pMDIs and the invention of DPIs and softmist inhalers are of no avail without improving adherence.

The education of patients and medical professionals should drive innovation [28]. The pharmaceutical industry encourages innovation in the hope of future returns. It is of the interest to the pharmaceutical industry to market new molecules, formulations, and devices: these yield intellectual property that protect future revenues. Education on inhalers use might increase prescriptions and market share, but it is a model that has not been tried. The revenues of selling education are not as large as from selling a medication. It is the tax payers that stand to benefit the most from patients’ education by reducing cost of hospitalization and crisis management.

Mobile applications that help patients track their inhaler use might improve adherence, but probably only for those patients who enjoy connected technologies and feel confident to use them, and are already disciplined enough to manage their therapies. It is possible that being able to educate patients, whatever their circumstances, will drive clinical improvements more than new fanciful inhalers. Can mobile Apps answer that need? It is too early to say, more clinical data is needed so as not to dismiss them as tools for clinical trials only or distracting gizmos. At present an App can track if and when a dose is activated, it does not indicate if a dose has been taken correctly and does not educate nor monitor patient behavior, in particular breathing maneuvers.

Some clinicians have noted that mixing inhalers (i.e. DPI and pMDI) leads to reduce patients’ compliance [22]. The data from Price et al. [29] shows that patient taking pMDIs are less prone to making errors. From this, we might conclude that familiarity with devices might lead to increased compliance. The advent of generic inhalers, based on existing technologies, such as generic Advair Diskus® options, might drive compliance by using a popular device platform. The changes afoot over the next few years by the approval of new generic inhalers might change the game of inhaler therapies. Ibrahim et al. [5] and Hoppentocht et al. [11] argue in favor of tailoring devices to molecules, but this would lead to a proliferation of different molecules at the expenses of patients’ compliance, and therefore may not be wise. A reduction in the number of DPI platforms might improve education and patients’ use. When a pMDI inhaler is manufactured, ‘standard’ off-the-shelf technology is used, patients recognize a ‘puffer’ inhaler. DPIs use proprietary technology and require specific handling instructions. Simplifying the number of inhalers might help compliance. In this respect, the new device paradigm introduced by Merxin Ltd might change the device market dynamics. Furthermore, many active pharmaceutical ingredients (APIs) are now produced in India, and, gradually, China is claiming a market share of APIs and soon of inhaled finished dosage forms [30]. These markets are comfortable with generic devices and products. In these countries, manufacturers are not so interested in proprietary technology, as long as units are sold as soon as possible for a minimum investment. It will be interesting to see how these markets will change the type of inhaler devices available on other markets, and if it will rationalize the numbers and types of inhaler devices and in turn impact patient adherence and compliance.

Declaration of interest

Professor Traini is the recipient of an Australian Research Council Future Fellowship (project number FT12010063). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Additional information

Funding

No funding to declare.