Today, we have decades of development of inhaled products behind us. This development has led to the availability of very efficient products that have remarkably improved the quality of life for patients with lung diseases, and particularly the asthmatic patients. In the early days, they had to put up with a life-threatening disease – now they are practically able to live a normal life. The development of these products is a combination of effective molecules and efficient delivery devices.
The development of these inhalation products can be split into the development of the actual device and that of the formulation incorporating the drug. Two types of devices are available at the moment, the pressurised metered dose inhaler (pMDI) and the dry powder inhaler (DPI). The pMDI development started in 1956 and was based on chlorofluorocarbons (CFCs) to create the liquid formulation and the high pressure, around 6 bars. It turned out to be very efficient but as the CFCs prompted the depletion of the ozone layer, these CFCs had to be phased out. This led to the development of hydrofluoroalkanes (HFAs) and the transition started in the 1990s. The increased global warming awareness highlighted that the HFAs had a high global warming potential (GWP), hence the urgency to find and register products that have a driving gas with low or no GWP. At the moment, the transition from HFAs to those with low GWP is well underway. Further to the environmental issues mentioned above with pMDIs, there has also been concerns about inhaler handling and the coordination between the inhalation manoeuvre and the releasing of the dose. This coordination issue is a general problem for pMDIs. Solutions exists, such as breath-activated mechanisms, but these are costly and are therefore not always included in the product development.
Dry powder development started alongside the need for high doses, higher than what can be delivered via a pMDI. For example, Fisons developed the Spinhaler, capable of delivering 20 mg of active pharmaceutical ingredient (API). Also, low dose APIs were considered, which led to the development of capsule inhalers. Examples of such inhalers are the Rotahaler from GlaxoSmithKline (GSK) and HandiHaler from Boehringer Ingelheim. Likewise, the early developed Diskhaler from GSK is rather similar but has four or eight cavity blisters with each dose of the formulation individually packaged. These inhalers were technically simple, and the formulations were based on the use of large sugar particles, such as lactose or glucose. Two key benefits were identified with the capsule inhalers: 1. No need for hand-breath coordination as these DPIs were breath activated and 2. The API was kept dry in the capsules, resulting in a very beneficial stability.
DPIs were further refined with a focus on having many doses in each non-reusable inhaler. This led to the development of the Diskus (Accuhaler) from GSK and the Turbuhaler from AstraZeneca. The Diskus inhaler has up to 60 pre-filled doses separated on a blister strip, while the Turbuhaler has the powder in a reservoir from which the patient can measure a dose at use. The formulations also differ between these two inhalers. The Diskus has the traditional carrier-based lactose, in total 12.5 mg of powder, while the Turbuhaler has micronised particles only. Initially, the formulation in Turbuhaler was pure drug, e.g. budesonide. However, the low doses, e.g. 200 μg which is not much powder, made it difficult to meter a consistent dose. Later development increased the powder dose by mixing the API with micronised lactose resulting in a total amount of about 1 mg. Both these inhalers should be regarded as very modern, holding many doses, being portable, looking smart and having dose counters/indicators. These two inhalers were very successful, particularly the Diskus as it was registered and marketed in the USA. In 2011, the Advair Diskus was the best- selling pharmaceutical product globally with a total sale of $8.7 billion. Some additional development has taken place mainly with the new GSK device Ellipta. Ellipta is just a refinement of the Diskus that includes three different APIs.
Room for More Inhaled Products
Despite the accomplishments of very successful devices, not much has happened in recent years. One can probably say that asthma and COPD are at the moment well treated diseases even though COPD is the third highest global cause of death, responsible for more than 5% of total deaths according to the WHO. Some generics inhalation products have reached the market and have mainly resulted in a lower cost for patients/payers.
