Rising incidence of respiratory illnesses is expanding the market for specialised inhalation devices. Richard Turner, business development director at Presspart, looks at inhaler development and recent improvements
An estimated 300 million people suffer from asthma and a further 210 million from chronic obstructive pulmonary disease.1 The primary treatment is through inhaled aerosol medications containing agents such as b-agonists, anti-cholinergic agents and corticosteroids. The technology has evolved in recent decades to address regulatory, cost and compliance issues, but challenges remain to ensure each dose delivered by the device provides the correct level of drug to the appropriate part of the respiratory system.
Inhaled aerosols are favoured due to their selective treatment of the lungs, achieving high drug concentrations in the airway while minimising systemic drug levels. Aerosol drug delivery is painless, and for some drugs (e.g. b-2-agonists) the onset of action is faster than oral drugs;2 some corticosteroids are active therapeutically only when they are inhaled3.
Nebulisers, pressurised metered dose inhalers (MDIs) and dry powder inhalers (DPIs) each have advantages and disadvantages, depending on factors such as the patient's age, severity of condition, situation (e.g. hospitalised versus out-patient), and ability to operate the device.
Nebulisers were the only available device for delivering inhaled aerosol drugs until the pressurised MDI was developed in 1955. Several types are in use today, particularly pneumatic jet nebulisers, which are powered by a gas source that aerosolises the drug solution and delivers it to the patient via a mouthpiece or face mask. These are widely used to treat patients unable to operate a portable inhaler due to lack of co-ordination, in cases such as infancy, disability, hospitalisation or severe illness.
Nebulisers" advantages include the flexibility to adjust the dose over time as required, and the ability to provide high doses to seriously ill patients. They can also deliver combination therapies (if compatible).
However, they have many disadvantages, in particular a lack of portability that results from their cumbersome design and the fact that they commonly need a source of pressurised gas to function. Treatment can require relatively long periods of administration (minutes or hours), and it is usually necessary to prepare the device prior to treatment and clean it afterwards.
Performance can also vary between nebulisers from the same and from different manufacturers.4,5 Unreliable dose delivery can result from evaporative loss within the nebuliser, which causes the solution to become increasingly concentrated. The solution cools during nebulisation, and temperature can also directly affect the nebuliser output and droplet size.
Other issues include the risk of drug degradation and contamination; the problem of the "dead zone" - a volume of 0.5-1.0ml where solution can become trapped; and relatively high costs. However, a newer class of ultrasonic nebulisers is available that is small and portable, with faster delivery than jet nebulisers. Breath-actuated devices have also been developed that reduce drug loss during exhalation.
The pressurised MDI was the first small, portable device for pulmonary drug delivery. Typically consisting of a metal canister, which contains the medication as a pressurised aerosol, with a crimped cap that contains the drug metering valve, the system is enclosed in an actuator through which the drug is inhaled.6
MDIs are popular due to their compact size and portability. They provide immediate, self-administered treatment with rapid relief from symptoms and have no requirement for drug preparation. There is no risk of contamination of the drugs, and dose to dose reproducibility is relatively high.
The main disadvantage is that patients must use proper inhaler technique to co-ordinate breathing with device actuation to ensure the correct dose is delivered to the lungs. Poor inhaler technique9,10 can reduce drug distribution and efficacy at the target tissues. Open-tube spacer devices, developed in the late 1970s,9 allow the aerosol to be contained in a chamber and released on demand, but they reduce the portability of the MDI as well as increase the costs. Breath-actuated MDIs have recently been designed that release the drug on demand, avoiding the need for co-ordinated breathing.10
Inaccurate delivery can also be caused by drug deposit on the device components, oral deposit, blockage or instability of the device and unwanted pharyngeal deposition of the drug. Furthermore, the MDI's size limits the unit dose content that can be provided and it can be difficult to determine how many doses remain, unless a dose counter is incorporated .
DPIs were developed in 1971, when the spin-haler was introduced;8 the drug is delivered in dry powder form from single- or multiple-dose capsules that need to be pre-loaded into the device. DPIs are breath-actuated, reducing the need for patients to co-ordinate their breathing and device actuation exactly. These devices also offer portability and rapid treatment time, but do not require propellants and newer designs incorporate dose counters.
However, they do require moderate to high inspiratory flow, which excludes many patients, while preloading can be a problem for others. They also result in high pharyngeal deposition and not all medications are available for DPIs.
In the 1990s, MDIs were redesigned to use HFA propellants when CFCs were phased out with the 1987 Montreal protocol.7 However, when drug formulations are in suspension the molecular properties of an active ingredient can cause it to interact with the canister, resulting in drug deposition on the canister wall or exposed surfaces of the valve components. Interactions with solutions can cause degradation, resulting in increased impurity levels. In both cases the interaction leads to a reduction in the drug content in the formulation, so that the patient receives less than the prescribed dose.
A range of coatings can be applied to both the canister and valve components to protect the contents from deposition and degradation. This improves the stability of the formulation as well as product performance, and helps to extend the product's shelf life. For solution formulations, internal coating or anodisation of the canister can be used to change its surface characteristics and ultimately act as a protective barrier. Low surface energy coatings can be used with suspension formulations to reduce deposition.
The range and compatibility of available coatings is far greater for canisters that are manufactured by deep-drawing; this is suitable for a variety of metal substrates, whereas canisters that are manufactured by impact extrusion may be created only from aluminium.
The pressurised aerosol mechanism of MDIs depends on the highly accurate design of the stem block and MDI components to avoid the risk of actuator failure or propellant leakage. The geometry of the stem block must be carefully developed to ensure its suitability and fit with the valve. The stem block geometry, spray hole diameter and spray hole length are designed to ensure reliable delivery of the desired spray particle characteristics, with reduced drug deposition around the mouthpiece. Actuators produced by injection moulding can be customised for optimal function with a wide variety of aerosol metering valves to within tightly controlled tolerances.
tighter tolerances
HFA-MDIs require great stringency and tight tolerances during canister manufacture to avoid leakage and ensure accurate filling weights. Deep-drawn canisters are safer for HFA-MDIs, because the process uses a cut edge design rather than a rolled neck, forming a more effective seal with the inhaler's valve gasket.
The neck of impact-extruded canisters is formed as a secondary process and can become unrolled at the higher temperatures and pressures used during later MDI manufacturing steps. The weakness under pressure of impact extruded cans is a major deficiency when manufacturing HFA-MDIs.
Developments in recent years have helped to improve the reliability and performance of MDIs, broadening the choice of treatments as well as providing safer and more dependable inhalers.