Pressurized metered-dose inhalers for delivery of medications have been available since the mid 1950s. In these systems, the drug is usually a polar solid which has been dissolved or suspended in a non-polar liquefied propellant. If the preparation is a suspension, as is most commonly the case, the powder is normally micronised by fluid energy milling and the suspension is stabilized by the addition of a surfactant. Lecithin, oleic acid, and the Span and Tween series surfactants have been widely used for this type of formulation. Oleic acid is particularly favoured and is added in some excess over the amount required for suspension stabilization, since it also functions as a lubricant for the metering valve.
Metered dose inhalers (MDIs) are the most commonly used drug delivery system for inhalation (Figure 10.6). The propellants have a high vapour pressure of around 400 kPa at room temperature, but since the device is sealed, only a small fraction of the propellant exists as a gas. The canister consists of a metering valve crimped on to an aluminum can. Individual doses are measured volumetrically by a metering chamber within the valve. Each
MDI canister can hold between 100 and 200 doses of between 20 pg and 5 mg of drug, which is released within the first 0.1 s after actuation.
The valve stem is fitted into an actuator incorporating a mouthpiece. The aerosol, consisting of propellant droplets containing drug, is delivered from the actuator mouthpiece at very high velocity, probably about 30 ms-1. There is partial (15-20%) evaporation of propellant prior to exit from the atomizing nozzle ("flashing"), and further break up of droplets beyond this point caused by the violent evaporation of the propellant. This results in a wide droplet size distribution from 1 to 5 pm. Only 10% of the particulates delivered in a single dose released by a metered-dose inhaler actually reach the lungs, since the bulk of it impacts in the oropharynx and the mouthpiece. Reduction of the plume velocity, for example in the Gentlehaler® device2 causes a significant reduction in oropharyngeal deposition.
A flurry of activity in aerosol formulation and technique of administration occurred following the adoption of the Montreal Protocol in 1987. This banned the manufacture of certain chlorofluorocarbon (CFC) propellants3 by developed countries for environmental reasons. The temporary exception was for those used in the treatment of asthma and chronic obstructive lung disease. In many inhalers CFC propellants have now been replaced with hydrofluoroalkanes (HFAs). These compounds do not deplete the atmospheric ozone layer, but unfortunately are still considered "greenhouse gases," and may contribute to global warming4.
With drugs which can be dissolved in the propellant, delivery to lungs can be increased to 40% of the ejected dose5 since the particle size of the drug remaining after propellant vaporization can be very small. Altering the vapour pressure of these systems can also improve deposition. Lung depositions of 51 and 65% were reported with low and high vapour pressures respectively6. The changeover of propellant from CFCs to HFAs has had a notable effect on the delivery of some drugs, notably beclomethasone dipropionate. This has a 51% delivery to the lungs in HFA, in which it is soluble, compared to 4% in CFC, in which it is a suspension7. Unfortunately both HFAs and CFCs are relatively poor solvents and so it not often possible to take advantage of this type of formulation, even with the addition of cosolvents such as ethanol.
In order to be effective, metered dose aerosols must be triggered as the patient is inhaling. Some patients have difficulty with this feat of coordination, and breath actuated inhalers such as the Autohaler® have been designed to overcome this by triggering the valve as the patient breathes in8. The Mist-Assist® inspiratory flow control device (IFCD, Ballard Medical, Draper, UT) is a compact device (similar in size to a spacer) through which both an MDI or medication from a nebulizer can be administered. By use of a floating ball within the inspiratory chamber, it provides visual and auditory (clicking sound) feedback to optimize timing of medication delivery and rate of inspiratory flow. Most important, the inspiratory flow rate (and therefore inspiratory resistance) can be adjusted on the device. This inspiratory flow control enhances laminar flow of particles and gas and increases the lung deposition.
The environmental concerns surrounding the use of chlorofluorocarbons have led to a resurgence of interest in dry powder inhaler devices. Early dry powder inhalers such as the Rotahaler® used individual capsules of micronized drug which were difficult to handle. Modern devices use blister packs (e.g. Diskus®) or reservoirs (e.g. Turbuhaler®) (Figure 10.7). The dry powder inhalers rely on inspiration to withdraw drug from the inhaler to the lung and hence the effect of inhalation flow rate through various devices has been extensively studied. The major problem to be overcome with these devices is to ensure that the finely micronized drug is thoroughly dispersed in the airstream. It has been recommended that patients inhale as rapidly as possible from these devices in order to provide the maximum force to disperse the powder9. The quantity of drug and deposition pattern varies enormously depending on the device10, for example the Turbuhaler® produces significantly greater lung delivery of salbutamol than the Diskus®. Vidgren and coworkers11 demonstrated by gamma scintigraphy that a typical dry powder formulation of sodium cromoglycate suffers losses of 44% in the mouth and 40% in the actuator nozzle itself.
Figure 10.7 A simplified view of the Turbuhaler, a typical dry powder device
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