Trends and future challenges in inhaled drug delivery 2nd December 2021
By Sandy Munro, Vice President – Pharmaceutical Development, Vectura
Inhaled drug delivery offers many advantages for the treatment of many diseases, and its use is far wider than just for respiratory conditions. The appropriate combination of formulation and device is vital for developmental success, and there are numerous factors that must be taken into account, including the drug molecule, target patient population and disease type. This article explores some of these factors, and looks at trends affecting future development in this area.
Inhalation is the obvious route of administration for many drugs designed to treat lung disease, as it delivers the active pharmaceutical ingredient (API) directly to its site of action, overcoming a number of inherent issues associated with oral and other routes of drug administration. Asthma drugs, whether ‘relievers’ such as salbutamol (albuterol),or ‘preventers’ such as the corticosteroids, are commonly delivered in this way, and the growing incidence ofchronic obstructive pulmonary disease(COPD) has led to a rise in novel drugs, as well as a number of asthma drugs being formulated for delivery using one form of inhaler or another, particularly as multi-drug combination products.
Over the past 20 years, the potential of inhaled delivery to treat a much broader range of respiratory and non-respiratory diseases has begun to gain traction. Inhaled biologics are being developed to treat a range of diseases; not just severe asthma and COPD, and there are a larger range of more niche diseases where inhalation therapy may prove to be beneficial. As biologic medicines such as antibody fragments, RNA-based therapeutics or oligonucleotides are generally water soluble, a mesh nebulizer is usually a highly appropriate mechanism via which to efficiently deliver these types of entities to the lungs. This is particularly advantageous in the early stages of development, where speed is of the essence, and drug material may be in short supply.
As COVID-19 primarily affects the lungs of those that become seriously ill, the pandemic has also provided new opportunities for inhaled therapies. As well as novel drugs, including antibodies, being developed or being retargeted from other indications, many older medicines have been tested and repurposed to potentially treat COVID patients. The huge unmet medical need has led to extremely rapid development of these options.
The first mass-produced inhaled medicines delivery device, the pressurized metered dose inhaler (pMDI), dates back to the 1950s, but is still in widespread use today, particularly for generic asthma products. Practice is required for the patient to use the device effectively, as the timing of inspiration has to match with the pressing down of the canister within the plastic actuator to release the dose, although a spacer can be employed to make this coordination less critical.
A passive dry powder inhaler (DPI), does not require this coordination, as a powdered form of the drug is aerosolized from the device as the patient inhales quickly and deeply through it, but the flow rate of that inhaled breath is important. A really fast inhalation can result in much of the drug depositing on the back of the patient’s throat instead of penetrating deep down into the patient’s lungs; whereas a slow inhalation can result in poor aerosolization of the powder, meaning poor evacuation from the device and similarly poor lung delivery. All inhalation delivery systems have their strengths and weaknesses, and all are only as good as the patient’s fundamental ability to use the system effectively. This really emphasizes the importance of careful device selection to match the intended patient group (cognisant of the stage of development) and careful patient training in using the device is critical
Simple capsule-based DPIs remain a popular choice for drug developers. There are multiple, non-proprietary options available off the shelf, providing a flexible and cost-effective inhaled delivery option that can deliver a broad range of doses and is already well understood. The devices are simple, and allow rapid progress to be made in the early stages of the development of an inhaled drug. While transferring into a more sophisticated proprietary device may be preferable later on for reasons of patient convenience, it is still very common for a product in development to use a capsule DPI right the way through to commercial launch.
It is possible to use the same filling technology for a capsule or a unit dose or multi-dose blister DPI device. As the filling method can have a big effect on the ultimate performance of the product, it is advisable in the early phases to employ a method that can be scaled-up effectively. This should speed up the later stages of development.
Inhaled drug doses can be very flexible when administered via a nebulizer, and a modern ‘smart’ nebulizer can give extremely high levels of delivery deep into the lung, with very little drug being wasted. As well as being an effective platform for patients once a medicine has been commercialized, smart nebulizer devices can make early clinical success more likely because of the efficiency of delivery. If the drug has good water solubility, formulation can be straightforward, however the cost is generally greater than for a DPI or a pMDI, so it can sometimes make sense to begin development via nebulization, and then switch to a different platform for commercialization once it has been proven that the medicine works.
There is also huge and growing interest in medicines where the route of administration is via an intranasal delivery device. Intranasal products are familiar as treatments for seasonal allergies such as hayfever, but more recently interest in this route has increased for the delivery of drugs for a variety of central nervous system indications because of the potential for drugs to cross the blood-brain barrier quickly, and also for the delivery of vaccines. Naturally, COVID-19 has also resulted in an explosion of interest in intranasal delivery, as the disease initially takes hold in the nasal passage and then progresses to the lungs.
One of the greatest areas of interest within the inhalation market, and for other routes of administration where a device is employed, is connected technology, with internet connectivity designed to improve patient compliance. This could be particularly beneficial for those with chronic conditions such as COPD or asthma, where remembering to take medicines regularly is an important factor in effective disease management. Such devices also offer great benefits in a clinical trial setting, as their use will allow study organizers to monitor precisely when a trial subject takes their medicine, and also whether the dose has been successfully administered. This additional data has the potential to be immensely powerful in the process of validating patient outcomes, and allows for improved clinical trial results. For example, patients can be excluded from the data set if it can be shown that they have not taken their medicine, or better still, it can be shown that they have not taken their medicine properly.
DPI, pMDI or nebulizer?
For a product where an inhaler device is appropriate, there are a number of factors that influence choice. Perhaps the biggest advantages of using a pMDI is that it is relatively inexpensive, and the ease with which large numbers can be manufactured. It is likely to be the appropriate choice for a potent small molecule that has already been on the market for some time delivered via pMDI, or products that are combinations of such drugs, including new combinations of established drugs. These are most often indicated for COPD or asthma.
A downside will always be the fact that pMDIs are not the easiest device to use successfully; a patient can struggle to time the inhalation and the press on the device to release the dose accurately. The dose that can be delivered in a single actuation is also limited (usually < 1mg). If the desire is to deliver a low-cost, potent small molecule that has a broad therapeutic window to very high numbers of patients, then a pMDI can be a good option.
The cost of the medicine a device contains may also be a concern for pMDIs because of the fact that, as reservoir devices, they have to be typically overfilled by up to 40% to ensure doses are delivered reliably throughout their use life. This overfill will be wasted when the device is discarded after the stated numbers of doses have been delivered; and, clearly, this is a lot more problematic if the drug is very expensive. Equally, a multi-dose reservoir device makes little sense for a drug that is taken only once a month, such as a biologic.
DPIs are, of course, also used for asthma and COPD treatments, and using many of the same drugs as delivered in pMDIs. However, DPIs typically have much broader application because larger doses can be administered in a single inhalation, and the absence of a potentially wasteful reservoir (for unit dose and multi-unit dose devices), means that much less expensive drug is potentially wasted. With a trend towards higher doses being prescribed, and inhaled medicines that do not require daily dosing, DPIs are likely to be an increasingly attractive choice, especially where the application is for a bigger disease where there are larger numbers of patients, or where the ease and convenience of a room-temperature-stable formulation are important
Of course, selecting the optimal delivery platform is rarely simple, with no one-size-fits-all option that will work for all drugs and applications. Careful planning is required for every project, including taking into account all of the technical considerations, as well as any commercial constraints that might be in place, not forgetting the paramount importance of the patient and what is best for them. What is deemed appropriate at the start of a drug’s development process because it offers rapid progress may not ultimately be the best option once it gets closer to commercialization. This flexible approach to development is particularly attractive for small biotech organizations, where the milestone payments they rely on may be tied into moving through the various stages of the pipeline. Pursuing a flexible development approach with openness to changing the device may allow costs to be minimized and progress to be made in a timely fashion, with the probability of success being maximized.
Propellant alternatives and pMDI development
For pMDIs, due to environmental concerns there is now a move towards the adoption of alternative propellants. The propellants that are typically used, HFA 134 and HFA 227, both have global warming potential (GWP) values more than a thousand times that of carbon dioxide. Another hydrofluoroalkane, HFA 152, could potentially be used instead as its GWP is about a tenth as large, and numerous studies have already been carried out to establish its clinical safety. However, it is flammable, which means that modifications to the normal manufacturing processes will be required for safety purposes.
Another alternative propellant, the hydrofluoroolefin HFO1234ze, has been developed by Honeywell, and is sold under the brand name Solstice for applications such as refrigeration and blowing spray polyurethane foam insulation. It has an extremely low GWP and is not flammable; however its clinical safety is not yet well established.
It is unlikely, however, that any alternative propellants will be simple drop-in replacements, as it is probable that changing the propellant will affect both the dose delivered and the particle size distribution of the aerosol emitted from the device. Both of these factors have the potential to impact lung delivery, so a simple swap of propellants is highly unlikely to result in equivalent products. Careful studies are required to determine what changes to the delivery device might be necessary to match the performance of existing products when reformulating an inhaler with lower GWP propellants.
Other variations in the performance of a formulation may arise from differences in the polarity of the new propellants compared to the older ones, as well as a difference in the relative vapour pressures. The solubility of both APIs and excipients may also be different, and these may have an effect on chemical stability. Even physical profiles for attributes such as aggregation, flocculation, creaming, sedimentation, and even electrostatic behaviour, may change, as might the rate at which they occur in the light of altering the density of the propellant in the new formulation, and these changes also have the potential to impact both the delivered dose and emitted particle size distribution. It is clear that there is much work to be done in this area to balance the environmental needs with drug product performance. The lesson learned from the first propellant transition (which saw the change from chlorofluorocarbons to hydrofluoroalkanes) was that almost every aspect of the system needed to be changed in order to come up with equivalent products, including new valves, new container systems, new excipients, modified actuator designs, and new manufacturing equipment. No aspect of existing products and devices was untouched.
Ultimately, there is no single delivery platform that is appropriate in every situation. A careful review of all the relevant factors should be carried out for each individual project to determine which device, and which formulation, will be the best option. These factors are important both in the early stages of clinical development, but also later on, as development programmes move into late-stage trials and eventually on to commercial launch. As well as all the technical requirements, all reviews into device choice should include the commercial constraints the product will be bound by. The success of an inhaled formulation depends heavily on the device, and taking the time to select the right option is vital to ensure all stakeholders – and especially the patient – achieve the optimal outcome from the development of a product.