Delivery of aerosolized bronchodilator agents through metered-dose inhalers (MDI) has enjoyed wide popularity because these devices are portable and convenient, require minimum time for administration, and have the potential for effecting rapid relief of bronchospasm. More recently, it has been shown that MDI-delivered corticosteroids may reduce oral corticosteroid requirements in asthmatic patients who are chronically steroid dependent. Depression of the MDI canister by the fingers to actuate a valve mechanism for release of a puff of aerosolized drug appears to be a simple procedure. However, this must be coordinated with a slow, deep inhalation, a hand-breath maneuver which as many as 70 percent of adults find impossible to perform correctly. Patients often are unable to depress the canister as they inhale and even may actuate the MDI during exhalation, thereby receiving none of the drug. Further, the recommended techniques for administration include various combinations of inspiratory flow rate, breath-holding times, and actuation of MDI at different lung volumes, creating confusion both to patients and physicians.
Newman and Clarke, well-known investigators in this field, have recommended that: “aerosol should be inhaled during a slow, deep inhalation (at about 30 L/min”) and the breath should then be held for 10 seconds ideally or, failing that, for as long as possible. The lung volume at which the aerosol is released and the volume of air exhaled are both relatively unimportant. These authors add that it is vital that patients receive adequate instructions which should be followed by regular checks. However, they do not provide directions as to how a “slow deep inhalation” at a flow rate of 30 L/min can be accomplished by the patient in his/her own environment.
A number of auxiliary devices have been introduced to facilitate the utilization of MDI systems. The purpose of this article is to describe the (1) technical features of metered dose inhalers alone; (2) aerosol deposition characteristics from the MDI; (3) technical features of auxiliary MDI aerosol delivery systems, (4) deposition characteristics from combined auxiliary MDI aerosol delivery systems; and (5) effectiveness of auxiliary MDI aerosol delivery systems.
Technical Features of metered dose inhalers (MDI)
The size distribution of MDI aerosols is influenced by (1) the formulation, (2) canister pressure, (3) physicochemical properties of propellants and other chemicals including viscosity, density, surface tension, vapor pressure, heat of vaporization, etc, and (4) design of the valve and the actuator orifice. The formulation is usually accomplished by either suspending micron-ized powder as an active agent in a liquefied propellant or preparing a solution of the active agent with a solvent such as alcohol and adding this to the propellant. When the formulation is released from the pressurized canister, it undergoes volume expansion in the exit passage and forms a mixture of gas and liquid before being discharged through the orifice of the device. High-speed gas flow breaks up the liquid stream at the orifice of the device. Droplets of smaller size occur with propellants of higher vapor pressure and vice versa. For example, the mass median aerosol diameter (MMAD) of dry isoproterenol particles as measured at a distance from the orifice, decreases from 3.7 to 4.0 it to 1.9 to 2.5 jjl when propellant pressure is increased from 310 to 550 kPa (1 kPa = l kilonewton/ m2=0.145 lb/in2). However, excessive increase of pressure may not cause further reduction of particle size, because the higher atomization force produces a larger number of small particles, which in turn promotes rapid particle coagulation. The latter is proportional to the square of particle number concentration. The average droplet size is a direct function of increased viscosity and surface tension of the formulation, because higher pressure is needed to accelerate and break up the viscous liquid jet. This is a minor factor in practice because propellants and solvents commonly used for MDI formulations have low viscosities and surface tensions. Small quantities of surfactant are often added to the formulation to promote dispersion of droplets and prevent aggregation of solid particles.
Once the initial droplets are formed, the effective particle size at the time of measurement is dependent on the rate of vaporization of the droplets. Although the droplets composition is primarily propellant, which vaporizes rapidly by flashing at the exit of the orifice, the amount of propellant which flashes to vapor is limited because of rapid reduction of droplet temperature. Commonly used propellants are trichlorofluoro-methane (P-ll), dichlorodifluoromethane (P-12), and dichlorotetrafluoroethane (P-114) which have boiling points of 23.8, —29.8, and 3.8°C, respectively. The propellants in most MDI devices consist of a mixture of two or more agents with varying ratios to maintain a desired pressure and volatility. For example, Medi-haler ISO utilizes a mixture of P-ll, P-12, and P-114 with a 1:2:1 ratio, whereas Mistometer employs a mixture of P-12 and P-114 with a 1:4 ratio. Droplets of 30-|im diameter of P-ll propellant vaporize completely in about 3 msec in calm vapor free air at 25°C, but in air saturated with propellant vapor, it takes about 20 sec for this phenomenon to achieve completion. In actual use of the MDI, the rate of vaporization will fall between these two extremes because air around the droplets is partially saturated with propellant vapor. Because of rapid dispersion of aerosol by flow turbulence in the jet stream, the vaporization time probably approaches the lower value. The droplets associated with P-12 propellant vaporize ten times faster than P-ll droplets, because the former is more volatile. Vaporization rate decreases as droplet size increases. For example, droplets of 50-|xm diameter take 24 times longer to completely vaporize than 10-(xm diameter droplets. To obtain small aerosol particles, it is essential to produce an initial droplet of a small size.
At the instant of release from the jet orifice of the MDI canister, the droplet size ranges from 20 to 50 |xm MMAD. The virtually instantaneous vaporization of propellants causes the initial mass of the droplet to fall 30 percent, which in turn reduces droplet diameter by 12 percent. The droplets then undergo slower vaporization to reach their final particle size, which ranges from 2.4 to 5.5 ц,т in dry air (Table 1) as measured with a cascade impactor technique.
Enlargement of the diameter of the MDI canister orifice creates larger droplets. Reduction of the orifices diameter diminishes jet discharge efficiency; too small an orifice diameter promotes obstruction of the orifice as a result of clogging with aerosol particles.
The particle size and the jet pattern of MDI aerosol are also influenced by factors such as metered volume, orifice diameter, design of actuator housing, etc. If the metered volume of MDI is reduced thereby producing a short, broken jet, forward jet velocity may be reduced more efficiently because back pressure quickly develops after stopping the jet. The extent of the jet expansion is small because of the diminished quantity of propellant. Further, there is less aerosol loss by impaction, but if the metered volume is too small, dosage accuracy and reproducibility may be adversely affected.
Table 1—Aerodynamic Size Distribution of Several Commercial Metered-dose Inhaler Aerosols
|Trade Name Proventil||Generic Name Albuterol||DryMMAD*±SD2.4±.3||AirGSD±SD1.7±.2||90% RMMAD±SD2.6±.l||H AirGSD±SD 2.3 ±.1|
|Beclovent||Bedomethasone||3.9±.2||2.1 ±.6||4.0±.l||2.1 ±.1|
|Medihaler-Iso||Isoproterenol||3.9±.2||2.1 ±. 1||4.1 ±.2||2.0±.l|
|Mistometer||Isoproterenol||4.2 ±.1||2.5±.2||3.9±.2||2.2 ±.1|
|Medihaler-Epi||Epinephrine||4.7±.6||2.1 ±. 1||5.2±.6||2.2 ±.1|
|Alupent||Metaproterenol||4.8±.7||2.1 ±. 1||5.3±.4||2.1 ±. 1|