The use of inhaled aerosol medications is becoming more and more popular as it has many advantages over oral and parenteral routes of delivery. The use of inhaled therapies allows for more targeted treatment to the respiratory tract and nasal cavity while reducing systemic adverse effects by reducing systemic drug levels. Orally Inhaled and Nasal Drug Products (OINDP) include inhalers, nebulisers and nasal sprays. Spacers can be used in conjunction with some inhalers to support compliance. Each device works in a different way to allow for the drug to be inhaled and have associated advantages and disadvantages. It is important to give patients appropriate training on using the device to ensure that a subclinical dose is not delivered. Cost, disease indication, patient preference and inhaler technique are all factors that decide suitability of devices amongst patients.
Keywords: pressurised metered dose inhalers, dry powder inhaler, nebuliser, spacer, nasal spray
Orally Inhaled and Nasal Drug Products (OINDP) are becoming increasingly popular as a route of administration locally as well as systemically. OINDPs include pressurised metered dose inhalers, dry powder inhalers, nebulisers and nasal sprays. This route of drug delivery offers a number of advantages compared to oral or parenteral routes as it allows for direct targeting to the lungs or nasal cavity and often has a rapid onset of action. Direct delivery of medication to the target organ results in a high ratio of local to systemic bioavailability.
The most common use of inhaled therapy is for the treatment of diseases of the respiratory tract such as asthma and COPD. Before the 1950's inhaled drugs were mainly delivered via hand-held, squeeze-bulb nebulizers. These devices were easily broken, and since the dose varied with hand pressure, they did not give consistent drug delivery. There are now a variety of different devices that can be used to deliver drugs to the lungs such as metered dose inhalers, dry powder inhalers and nebulisers. Compliance can be aided with the used of spacers. Variables such as efficacy and safety is also consideration when choosing a device, but patient acceptability is also important because it may affect treatment compliance.
Nasal sprays were traditionally used for the local treatment of antihistamines, decongestants and steroids in order to relieve cold or allergy symptoms and nasal congestion. More recently attention has been focused on other areas such as taking advantage of the quick drug absorption into the systemic system via the lymphoid tissues located at the back of the nasal cavity. Treatments currently in use via this route are in migraine and pain relief, osteoporosis and vaccines. Also the possibility of 'nose to brain' entry to the central nervous system from the olfactory region at the top of the nasal cavity can be used as a possible route of inhaled drug delivery for the treatment of Alzheimer's.
There are a number of different types of inhaled devices, which have a range in cost to the health service and have a differences in bioequivalence[4,5]. This can have an effect on product choice. The large variety of products available can lead to patient as well as prescriber confusion. It is important that healthcare professionals know about the differences in devices available and how to council the patient appropriately to aid compliance.
Metered Dose Inhalers (MDIs) are commonly used devices for delivery of drug inhaled medication (fig.1). MDIs consist of a pressurised canister containing the medication and a propellant along with a delivery device. The canister may be coated to prevent chemical degradation of drug and adhesion of drug particles . Pressing down on the canister opens a metering valve allowing the emission of the drug as an aerosol cloud, which is then inhaled into the lungs. Propellants are liquids when compressed, but are in the gaseous phase when exposed to atmospheric pressure. To ensure reliable dosing, the vapour pressure must be constant all the way through the product's life; the typical vapour pressure inside a pMDI is 300-500 kPa .
Figure 1. An example of a MDI 
In 1987 the Montreal protocol banned the use of chlorofluorocarbon (CFC) propellant in pressurised metered-dose inhalers (pMDIs) due to its effect on depletion of the ozone layer. This posed a problem to drug companies to find a new propellant that could be safely used in pMDIs which did not affect the ozone layer. CFCs have been replaced with hydrofluoroalkane (HFA) propellants. Extensive testing had to be carried out on inhalers that had HFA propellants to ensure no toxicity was caused and clinical trials had to be conducted to ensure safety and efficacy. HFA propellants also caused problems with the filling methods used for CFC propellants, which lead to the design of novel filling methods for pMDIs.
The aerodynamic diameters of HFA are much smaller than those of CFC, suggesting a greater distribution in peripheral airways. For good clinical efficacy, an aerosol with particle size of 1-5µm needs to be generated by an inhaler in order for lung deposition. Particles greater than 5µm will be deposited in the mouth, throat and pharynx and will have no clinical effect, particles smaller than this will either be deposited in the peripheral airways or may not even be deposited in the lungs and exhaled resulting in a reduced clinical effect[3,13].
Table 1 lists common advantages and disadvantages of pMDIs. One of the most common problems experienced when using a pMDI is the lack of patient co-ordination to press the inhaler and breathe in at the same time which can be overcome by using a different inhalation device.
Table 1. The advantages and disadvantages associated with pMDIs
Low lung deposition
Quick and immediately available
High oropharyngeal deposition
Protected from pathogens due to being pressurised
Drug delivery is highly dependent on patient's inhaler technique
Breath-actuated MDIs were designed to overcome the co-ordination issues surrounding the use of pMDIs. Examples of such devices are Autohaler® and Easibreathe®. They work by sensing when a patient inhales through an actuator and the device automatically releases the dose. Patients seem to find breath-actuated inhalers easier to use than conventional pMDIs and may prefer them over other devices. Some devices need priming before use, it is therefore important that the user is shown how to use the device correctly.
Spacers (Fig.2) are also used to overcome co-ordination issues as well as reducing the cold-Freon effect - where the cold blast of propellants causes patients either to stop inhaling or to inhale via the nose, and reducing oropharyngeal deposition. They are an add-on attachment used with pMDIs to increase the space, thus increasing the time, between the point of aerosol generation and the patient's mouth. They are often used by young children or patients who suffer from oral thrush as a result of the medication.
Figure 2. An Volumatic® spacer device attached to a pMDI
There are a variety of different devices available which have different chamber volumes, ranging from tube spacers with a volume of <50 mL to holding chambers with a volume of 750 mL. Spacers are grouped into 3 categories: (a) simple tube extensions to the actuator mouthpiece, (b) holding chambers, which have a one-way valve in the mouthpiece to stop the patient blowing in to the device, and (c) reverse-flow devices, in which the spray is actuated away from the patient, into the spacer. Static electricity can accumulate on spacers attracting drug particles which become charged when they are produced by the pMDI. Highly charged spacers deliver less drug than those with an antistatic lining. One way to overcome the static build up is to wash the spacer device with soapy water and allow to air dry. Table 2 shows other advantages and disadvantages for using a pMDI with a spacer device.
Table 2. The advantages and disadvantages associated with spacer devices
Reduces oropharyngeal deposition
Reduces need for patient coordination
Inhalation can be more complex for some patients
Less portable than MDI alone
Can reduce dose available if not used properly
Cleaning of the device
May modify aerosol properties
Metered Dose Liquid Inhalers (MDLIs) are a new generation of inhaler that deliver a pre-metered dose of a liquid without using a propellant (fig.3). The MDLI generates a 'mist' of fine particles which is inhaled. Aerosol generation can be done in four different ways: (a) forcing the liquid through a nozzle, (b) thermal generation, (c) vibration mesh and (d) electro-spraying. The advantages of these devices over MDIs or DPIs is that they generally deliver a higher fine particle fraction to the lung, thus increased lung deposition as well as giving greater dose uniformity as patient's coordination and inspiration do not play a role in the generation of the 'mist'.
Figure 3. An example of an Aqueous Droplet Inhaler
Dry Powder Inhalers (DPIs) have increased in popularity since the Montreal Protocol banned the use of CFCs. This meant that the pharmaceutical industry needed to develop a new way of delivering drugs to the lung. The DPI was developed which uses the patient's inspiration to generate turbulent flow within the device to allow for the release of the powder. DPIs can be divided into two sub-groups: pre-metered and device-metered (fig.4). Pre-metered is where the dose is pre-measured during manufacture as blisters or capsules. Device-metered is where the drug is contained in a reservoir within the device which pre-measures each dose on actuation.
Figure 4. Left: An accuhaler is an example of a pre-metered DPI. Right: A turbohaler is an example of a device-metered DPI 
Drug delivery from a DPI is dependent upon resistance of the inhaler and the inspiratory flow rate of the patient. If the patient cannot generate adequate inspiratory flow, the drug will not be released and be de-aggregated from the larger carrier lactose molecules. Turbulent force is created inside the inhaler as a result of the inhalation procedure, which results in a pressure drop within the device. Resistance between DPI devices varies (Fig.5). A device that has a high resistance (e.g. Twisthaler) will result in a slower inhalation rate than that of an inhaler with low resistance (e.g. Rotahaler) resulting in a reduced amount of drug leaving the inhaler. This is particularly a problem when a patient is suffering from an acute exacerbation of asthma / COPD as their ability to inhale at the required rate will be reduced, at a time when they need optimal performance from their inhaler meaning the emitted dose will be reduced. These differences in pressure mean that the devices are not interchangeable and once a patient disease is controlled they should not be swapped devices.
Figure 5. the relationship between pressure drop and flow rate for a range of commercially available DPI's
Table 3 shows the common advantages and disadvantages related to the use of DPIs. One of the main problems is the reproducibility of the dose, especially with device-metered DPIs. It is important that the patient primes the inhaler properly before use.
Table 3. The advantages and disadvantages associated with DPIs
Less patient co-ordination required
Requires moderate to high inspiratory flow
Some units are single dose
Propellant not needed
Reproducibility of dose
Dose counters in most newer designs
Can result in high oropharyngeal deposition
Short treatment time
Not all medications available
Small and portable
Nebulisers are the oldest form of aerosol generation devices. They turn liquids into aerosol droplets to produce a respirable cloud suitable for inhalation, this process is called atomisation. The drug is loaded into the nebuliser and once activated it operates on a continuous basis, allowing for lack of patient's coordination to no longer be a problem as with other inhalation devices. Some drugs for inhalation are only available as a solution so can only be delivered by nebulisers. However these devices are generally large and heavy meaning that they are not easily carried about.
Nebulisers are split into three categories: jet, ultrasonic and mesh nebulisers. Jet nebulisers (Fig.6) use compressed air to atomise the drug to produce a fine mist using the Bernoulli principle - where compressed air passes through a small gap creating an area of low pressure resulting in the solution being drawn up from the tank and turn into droplets in the air stream. Ultrasonic nebulisers use electricity to vibrate a piezoelectric crystal at a high frequency. These vibrations causes a series of waves in the reservoir of drug which generates droplets for form an aerosol. Mesh nebulisers are a recently new device which uses the same principle as ultrasonic nebulisers to create droplets, which are then forced through a vibrating mesh to form a cloud which can then be inhaled.
Figure 6. Basic components of the design of jet nebulisers
Nebulisers are ideal for patients who have problems with co-ordination and so cannot use pMDIs and cannot generate enough inspiratory flow to use a DPI. The breathing pattern of the patient still has an effect on the amount of aerosol deposited in the lower respiratory tract. To improve aerosol penetration and deposition in the lungs, the patient should be encouraged to use a slow and deep breathing pattern. Some nebulisers can be used with a face mask, it is important that the patient inhales through their mouth and not their nose as this reduces aerosol delivery to the lungs by almost 50%. Performance differences among nebulizers from the same manufacturer and different manufactures have been reported, but this can be kept to a minimum with good maintenance consisting of washing with soapy water, rinsing, and air drying after each use. Table 4 shows other advantages and disadvantages associated with using nebulisers.
Table 4. The advantages and disadvantages associated with nebulisers
Patient coordination not required
Lack of portability
High dose possible
Lengthy treatment time
Dose modification possible
Device cleaning required
No CFC release
Does not nebulise suspensions well
Device preparation required
Nasal sprays can be split into 3 main categories (Fig.7): (a) metered spray pumps, (b) propellant based nasal sprays, and (c) powder based devices. Metered spray pumps consist of a syringe like device that when compressed delivers the dose out from the device and into the nasal cavity. Multi-dose devices contain preservatives for the prevention of microbial contamination. Propellant based nasal sprays, are similar to pMDIs that use a pressurised canister containing the drug and a propellant. Powder based devices are similar to DPIs. They are activated by the user 'snorting' the powder from the inhaler.
Figure 7. Left: Metered Nasal Spray Pump. Right: Propellant Based Nasal Aerosol
There are currently two novel nasal drug delivery systems that are under development. (a) a nebuliser using ampoules to dispense the drug by 'controlled particle dispersion', and (b) a bi-directional nasal device (Fig.8) which uses the natural reaction of the body to close the soft palate whilst exhaling to avoid lung deposition[3, 29].
Figure 8. A Bi-Directional Nasal Device
Nasal sprays typically produce particles which have a particle size of 20-200µm, however many produce a fraction of fine particles less that 10µm in diameter (typically <5%) which can penetrate past the nasal tract and into the lungs. Particles greater than 10µm are deposited in the nasal pathway, particles bigger than 5 µm but less than 10 µm will be destined for the GI tract, and particle with a diameter less that 5 µm have the potential to be deposited in the lungs.
It is important to thoroughly test the inhalation devices to ensure safety, quality and efficacy. Many of the test suggested by the regulatory authorities are common to all pharmaceutical dosage forms such as testing for contaminants and leachable. OINDP specific tests include delivered dose uniformity and aerodynamic particle size distribution. Development studies should include physical characterisation such as solubility, size, shape and density of drug substance and excipients to ensure reproducibility. For many of the inhaled products a minimum fill volume is needed to ensure that it can provide the labelled number of doses, so that the patient receives a dose each time that they expect to. Studies should also be carried out to determine the consistency of the minimum delivered dose and the fine particle mass through the life of the container, which should be carried out at a range of inhalation volumes. One in vitro method of measuring the delivered dose would be using an Anderson Cascade Impactor (ACI). Using the ACI method the particle sizes can also be measured, which are quoted as the mass median aerodynamic diameter (MMAD) which shows if the particles are the correct size for lung or nasal deposition. The devices themselves should also undergo testing for shaking requirements, initial priming of the container, re-priming of the container, cleaning requirements and robustness.
Inhaled drug therapies are an ideal way to treat local and systemic diseases due to their quick onset of action and reduced systemic side effects. There many different devices available for a range of indications and each have their own advantages and disadvantages. There are many factors to consider when choosing the most appropriate device such as cost, availability and patient preference but ultimately the deciding factor should be the patient's ability to use the device as if it is not used how the manufacturer intended then little or no benefit will be seen. There is upmost importance on all healthcare professionals having knowledge of a range of ONIDPs in order to give appropriate advice and counselling on individual treatment regimes.