| Dr Gerallt Williams |
In 1948, the first commercial dry powder inhalation device, the Aerohaler was launched by Abbot Laboratories. The technology seems archaic by today’s standards: a deep breath in would cause a ball to strike a cartridge containing penicillin powder and shake the powder out into the airstream. However, the same device was later used to treat asthma, which set a precedent for future treatment of the disease. Today, throughout Europe, dry powder inhalers (DPIs) are used by an estimated 40 per cent of patients to treat asthma and chronic obstructive pulmonary disease (COPD)1.
The Aerohaler was followed by the ‘Spinhaler’ of the 1960s. The inhaler was developed for asthma treatment by Fisons Pharmaceuticals (later taken over by Rhone-Poulenc Rorer, acquired by what is now known as Sanofi) and represented a breakthrough in powdered drug delivery to the lungs. By using a capsule containing the active drug, sodium cromoglycate, which was released on inhalation, the device was very easy to use and meant that patients did not have to coordinate the inhalation of the drug with the actuation of the device.
Since this time, changes in the drug delivery market and regulatory pressures have driven innovation of DPIs forward: to-date, there are dozens of different DPI devices are commercially available and the DPI market itself is worth approximately $18 billion2. This article takes a look at the market forces driving DPI innovation and focuses on a novel solution that has simplicity at the heart of its design, and which hopes to address the growing pressure to reduce healthcare costs, as well as the needs of new markets, arising from emerging economies in South America, India and China.
The anatomy of a DPI
The basic components of a DPIs remain the same for most types: a powder formulation, a dose mechanism containing (or measuring) a single drug dose, a powder de-agglomeration principle, which disperses the powder into the inhaled airstream and the mouthpiece of the inhaler. Secondary parts of the inhaler have been developed to fulfill functions such as safety, ease of handling, patient feedback and moisture protection of the drug formulation. However, over the past few decades, much research has focused on the design of the inhaler with respect to the most important technical aspects that ensure the right amount of drug reaches the lungs i.e. powder de-agglomeration and air flow that is generated by the patient through the inhaler (and the resultant drug particle dynamics in the respiratory tract).
The needs of DPI market
The most successful DPI solutions will be those that match the changing needs of the drug delivery market as well as those of different patient groups, countries and cultures, diseases etc, as detailed below:
Reusability and cost: Single-dose vs multi-dose –
As a DPI is used repeatedly by the same user, reusability is a key factor driving down the cost per dose. Single-dose inhalers, which rely on capsules to be loaded into the device, can cause difficulties for patients having to load up a capsule; there is a need, therefore, for more patient-friendly devices. Multi-dose DPIs have also been developed to overcome some of the inherent limitations of single dose inhalers. The AB Draco company (now a division of Astra Zeneca) pioneered the design of multi-dose DPIs with their Turbuhaler. In this device, the drug formulation is contained in a reservoir and can be dispensed into the dosing chamber by a twisting back and forth action at the lower end of the device. One of the criticisms of reservoir designed DPIs, however, is the delivery of the drug at variable flow rates. The issues of multiple dosing and consistent dose-to-dose delivery have been addressed with the development of individual aluminium blisters to contain the doses (as initially developed in the Diskhaler of the 1980s by Glaxo, now GlaxoSmithKline). Multiple pre-metred dose DPIs have seen strong market growth in recent years, aided in part by the introduction of combination drugs in this category of device.
Complexity and compliance
The way the patient uses the inhaler can play a major role in ensuring a consistent dose to the patient’s lungs: therefore, capsule loading and inhalation technique are critical elements that can affect the efficacy of a DPI. It is important that patients are correctly trained to use the inhaler by the healthcare provider. Easy to use devices and those that can be easily taught to patients are ultimately ones that ensure high patient compliance and an accurate and acceptable dosage regime: a device requiring only a few basic steps will therefore be easy for the patient to master.
Filling technology
The introduction of capsules has meant standardised filling technologies can be incorporated into the manufacturing process, thus meeting the needs of large scale industrial filling of such devices, with millions of doses being manufactured yearly. Modern and accurate large-scale filling processes are also available to meet the needs of pre-metered devices (blisterstrips). With the availability of the above filling technologies it is realistic to manufacture and fill DPIs on a large scale to meet worldwide volume needs at acceptable costs.
Regulatory pressures
The 1987 Montreal Protocol3, which called for the phase-out of chlorofluorocarbons (CFCs), diverted market interest away from CFC-propelled metered dose inhalers (MDIs) to DPIs; as a result, resources were channeled into creating new models of DPIs that could meet specific patient needs. In the past 25 years, there have been an increasing range of regulations affecting the design, testing and use of inhalation devices; namely for user safety4, optimising design for usability5 and for re-use of individual units. Specific guidance documents have been issued by various regulatory bodies on the subject of DPI performance and documents necessary for chemistry, manufacturing and controls for such products6,7. The US market and the corresponding FDA regulatory standards in the inhalation field are probably the most challenging, e.g. for issues such as moisture protection, dose content uniformity etc and this can lead to some products being absent from the US although present in Europe or the rest of the world.
Emerging economies
In Asia and Latin America, asthma has been treated predominantly with pMDIs which are considered to be a more cost-effective proposition than DPIs. However, healthcare reforms in these regions are making asthma diagnosis and medication more available to patients so it is anticipated that the DPI growth trend will spread to these areas. The availability of lost-cost, patient friendly DPI options would encourage their use in emerging economies.
Efficacy through simplicity: Twister sets the record straight
Twister is a new cost-effective way to improve drug delivery, as well as patient compliance. The design of the patient-friendly device fulfills many of the market needs described previously: the versatile and affordable, capsule-based dry powder inhaler works well with most inhaled powders on the market and is simple to use; a simple twist of the device opens the internal capsule containing the drug.
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Figure 1 – Simple steps for operating the Twister DPI device
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Only three simple steps are needed to operate the inhaler – Insert, Twist and Inhale (see Figure 1) – and the patient is guided by various audible and visual feedbacks confirming that the full dose has been properly delivered. The capsule is easy to insert and a healthcare provider can easily teach a patient how to use the device.
Patient safety has been optimised in the design of Twister: unlike other DPI designs, the capsule is not pierced, which reduces the risk of contamination and the patient inhaling particles of the container closure system, improving safety. The design avoids repeated dosage as inhalation is from a single capsule only that is inserted into the device at each inhalation.
The transparent dispersion chamber makes it easy for the patient to see that there is powder in the device and, after inhalation; the patient can see that they have taken the full dose providing a clear visual feedback and helping to improve compliance. The transparent chamber also allows the patient to see if cleaning is necessary.
Twister, developed by the Aptar Pharma product development team in France, has been developed for fast growing markets but also has its place in developed markets as a low-cost alternative to pressurised metered-dose inhalers (pMDIs). Aptar Pharma’s aim is to bring cost effective drug delivery devices to pharma companies, helping them market affordable healthcare treatment to patients worldwide. Cost for the patient is reduced, allowing a wider range of asthma sufferers to gain better access to medication: capsules can be bought in small batches (30 or 60 capsules) by the patient to spread out the cost. The inhaler can also be used for COPD treatment, and during the development process, Aptar Pharma’s dedicated inhalation drug formulation research team tested and collected data on various drug formulations, validating Twister as an off-the-shelf device, suitable for a variety of different drug compounds and formulations.
Twister is designed for ‘size 3’ capsules; a format suitable for high speed filling technology, and functions with HPMC and gelatin capsule material, with a wide filling range from 5-30mg. Air inlets can be tuned to adjust the device resistance and the rotating and rattling of the capsule during inhalation helps with the de-agglomeration process. (Figure 1)
Key performance characteristics
| Figure 2 – Dose delivery performance at varying flow rates |
Some of the performance characteristics essential to DPIs are related to dose delivery (See Figure 2), fine particle fraction (FPF) content (See Figure 3) and performance at varying airflows. These characteristics can vary from one powder formulation to another and some amount of fine tuning of either device or formulation or a combination of both, may be necessary to achieve optimal performance.
| Figure 3 – Fine particle fraction content at varying flow rates |
Promoting better healthcare worldwide
DPIs have shown great promise in their ability to deliver drugs reliably and effectively and novel designs can ensure that future cost, compliance and safety challenges are overcome. Twister provides an easy to use solution that aims to meet the needs of fast growing markets generated from emerging economies, where resources may be an issue. A key factor helping to tap into new markets are the presence of local manufacturing sites, for example, Aptar Pharma’s state-of-the-art manufacturing facilities in China (Suzhou), India (Mumbai) and South America (Varela). The site in China facilitates logistical and regulatory support and allows changes in the needs of the local market to be quickly met. With the development of Twister, Aptar Pharma aims to provide a novel solution to fulfill the demands of the DPI market, whilst maintaining its goal of promoting better global healthcare access worldwide.
References:
1. Atkins PJ. Dry Powder Inhalers: an overview. Resp. Care. 2005;50:1306 -1312.
2. Market figures reference (Datamonitor)
3. United Nations Environment Programme. Handbook for the Montreal Protocol on Substances that Deplete the Ozone Layer – 7th Edition http://ozone.unep.org/Publications/MP_Handbook/Section_1.1_The_Montreal_Protocol/ Published 2006 by the Secretariat of The Vienna Convention for the Protection of the Ozone Layer & The Montreal Protocol on Substances that Deplete the Ozone Layer. Accessed August 28, 2012.
4. U.S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER). Guidance for Industry Bioequivalence Recommendations for Specific Products. Maryland, USA: Office of Communication Division of Drug Information Center for Drug Evaluation and Research Food and Drug Administration; 2010.
5. U.S. Food and Drug Administration. Draft Guidance for Industry and Food and Drug Administration Staff. Applying Human Factors and Usability Engineering to Optimize Medical Device Design. Maryland, USA: U.S. Food and Drug Administration; 2011.
6. U.S. Food and Drug Administration. Guidance for Industry Metered Dose Inhaler (MDI) and Dry Powder Inhaler (DPI) Drug Products. Chemistry, Manufacturing, and Controls Documentation, draft guidance. Maryland, USA: U.S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research; 1998.
7. European Medicines Agency. Committee for Medicinal Products for Human use (CHMP) guideline on the pharmaceutical quality of inhalation and nasal products EMEA/CHMP/QWP/49313/2005 Corr. London: European Medicines Agency; 2006.