Key learning points

  • Drug inhalation is an important route of administration for patients with respiratory diseases, due to its high pulmonary efficacy and minimal side effects 
  • HFA-152a propellant use in pressurised metered-dose inhalers has the potential to reduce the environmental impact of inhalers by up to 92%
  • Nanotechnology development of small particle sizes can offer long-lasting drug release and overcome airway defences to target diseased cells or tissues
  • Smart inhaler technology includes monitoring capabilities, inhalation assistance and dosage reminders that may improve patient adherence and disease outcome

Introduction 

The inhaled route is essential for the administration of drugs used to treat patients suffering from respiratory diseases such as asthma or chronic obstructive pulmonary disease (COPD), mainly because drug inhalation is typically associated with high pulmonary efficacy and minimal systemic side effects.1 Over the years, inhalers have undergone improvements in terms of technical design and at present a huge number of inhaler devices are available for delivering drugs. However, there is still no perfect inhaler, each has their own advantages and disadvantages.1 Consequently, there are continuous efforts through several technical innovations to improve inhaler devices and drug delivery.

Pressurised metered-dose inhalers

New pressurised metered-dose inhaler (pMDI) formulations allow the quality of the aerosol cloud and the quantity of drug particles that reach the lungs to be tailored. This means that finer drug particles are able to penetrate deeper into the bronchi and, consequently, deliver therapy to both small and large airways.

An intriguing innovation in pMDI technology will be the replacement of HFA-134a (tetrafluoroethane) and HFA-227ea (heptafluoropropane) propellants with HFA-152a (1,1-difluoroethane).2 Using HFA-152a instead of HFA-134a can reduce the environmental impact of inhalers by up to 92%.2,3 The suspension settlement and re-suspension behaviour of salbutamol sulphate without any additional vehicle agents has shown to be significantly improved using HFA-152a.2,3 

Co-suspension delivery technology is another new pMDI formulation approach.4 This uses porous particles and drug crystals within a HFA propellant to deliver precise and uniform dosing of multiple drugs to the airways via pMDIs.4 Interestingly, this emerging technology reduces the potential for drug–drug interactions often observed when respiratory drugs are combined in a suspension-based formulation and thus allows for an increased deposition of drugs in the lung.4,5

Nanotechnology 

Continuous developments in nanotechnology have produced particles which are able to be used as drug delivery vehicles with submicron diameters in the size range of 1-100 nm. These have the potential to provide long-lasting drug release, overcoming airway defences, targeting diseased cells or tissues and also combining treatment drugs.6 Nanotechnologies will allow new therapies based on inhaled medicines to be introduced.

Nanotherapeutics are considered potentially most useful in the management of COPD.7 Nanometer-sized drug particles can be assembled in micron-sized agglomerate dry powders with the desired physical and chemical characteristics for aerosol delivery and dissolution. Nano-sizing may enhance regional deposition, and aerosol deposition patterns of these particles show they are capable of reaching the lower airways, with the potential to treat inflammation in this region.7

Dry powder inhalers 

With regard to dry powder inhalers (DPIs), a number of low-resistance devices have been developed. There is also interest in improving third-generation DPIs, also known as ‘active’ or power-assisted DPIs. Several active devices are still undergoing development, although, at this time, none are proposed as drug delivery devices to be used in COPD.8

Liposomes, solid lipid nanoparticles, polymeric nanoparticles, nanoaggregates, nanocomposites, polymeric microparticles and microspheres are examples of novel drug delivery systems that have been developed or currently in development.9 These systems offer advantages in physical and chemical stability, flow properties, tissue distribution and bioavailability.9 

Various carrier-free DPI powder formulations, such as soft aggregates of micronised particles (spheroids), coated particles of lipids or amino acids using spray drying methods have been developed or are under development to control powder dispersion and particle interaction during inhalation.10 

Carrier based liposomal DPI pulmonary drug delivery that uses liposomal-encapsulated drug in dry form is another new technology. Increased drug retention time, reduced extrapulmonary side effects and consequent improvements in therapeutic efficacy may be associated with liposome-mediated pulmonary drug delivery.11 Liposomes could be used to deliver secretory leukocyte peptidase inhibitor and also N-acetylcysteine via DPIs.12,13 However, some liposomal formulations are unstable in long-term storage and nebulisation.12 Delivering inhaled therapy via porous articles is a likely area of development in particle engineering that looks promising for the future.10

Soft mist inhalers

Continued innovation in inhaler technology has led to a new class of inhaler device called soft mist inhalers (SMIs) that generate aerosols by solution atomisation.14 SMIs have been developed to overcome the limitations of pMDI and DPIs.14 They actively deliver an aerosol with a high fine-particle fraction at a slow velocity, which improves overall drug deposition in the lungs with less unwanted oropharyngeal deposition.14 

The hand-held Respimat® is a propellant-free SMI.15 The Respimat® inhaler has recently been updated so that it can be reused with multiple cartridges.15 This new, reusable Respimat® inhaler improves ease of use without affecting drug delivery efficiency, size of aerosol particle or method of required inhalation.15 It is likely that more SMI-based delivery systems will be developed in the future, including digital versions. 

Nebulisers

Recent developments in nebulisers called ‘intelligent’ nebulisers are able to modify and match outputs to correspond with a patient’s breathing patterns, enhancing the accuracy of drug delivery.16 Current research is focused on how to provide more accurate and consistent pulmonary dosing by incorporating the benefits of vibrating mesh nebulisation with ‘smart’ devices for individualised controlled inhalation.17 

Smart inhalers

Some smart inhalers work as add-on devices for pMDIs, DPIs and SMIs and have been developed to increase patient adherence by helping them take their medications properly and punctually.18 Smart inhalers can provide compliance monitoring and inhalation assistance for patients, supported by microprocessors.18 Some devices can also collect data when an inhaler is used, connect to mobile phones or tablets to issue reminders to patients to take their next dose or give instant feedback on technique and timing.17,18

There is strong hope that the enhancement of inhalers with a wider range of monitoring capabilities holds the promise to further support and optimise patient outcomes in lung disease.18

Conclusions

Despite all the advances described above, I strongly believe that there will be further intense progress in the field of inhalation technology. In particular, technological innovations will be able to create increasingly ‘intelligent’ delivery systems that can target specific areas of the lungs more precisely, allowing better management of disease with a lower risk of adverse events. In addition, the use of smart inhalers able to provide feedback on the use of the inhaler to patients and healthcare professionals will certainly result in an increased adherence to treatment and ultimately lead to improved disease management.

Professor Mario Cazzola, Chair of Respiratory Medicine, University of Rome “Tor Vergata”, Rome, Italy

This project was initiated and funded by Teva Respiratory. Teva have had no influence over content. Topics and content have been selected and written by independent experts.

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