Pharmaceutical Manufacturing Handbook: Production and

690 AEROSOL DRUG DELIVERY
5.8.5
METERED DOSE INHALERS
5.8.5.1 Introduction
Since their development, MDIs have been widely used for pulmonary aerosol drug
delivery [103] . Despite their recognized limitations, they remain the device of choice
for many physicians around the globe. From a patient ’ s perspective, they are light,
portable, and robust and contain multiple doses of medication. They are also relatively
simple to operate (press and fi re); however, signifi cant numbers of patients
experience diffi culties correctly using the MDI due to coordination problems [104] .
To maximize lung drug deposition, actuation (pressing the MDI canister) by the
patient must be coordinated with a slow, deep inhalation. Studies have reported that
51% of patients fail to operate the MDI correctly [104] . This leads to low lung
deposition, high oropharyngeal deposition, and ultimately perhaps therapeutic
failure. From the pharmaceutical industry perspective, the components are relatively
inexpensive; however, the formulation and manufacturing have become increasingly
complex. There are numerous studies describing the multifaceted and interactive
effects of propellant [105 – 110] , excipient [111 – 115] , metering valve [110, 116] , and
actuator [116 – 119] on the aerosol particle size characteristics of the MDI [120, 121] .
To date, the success of the MDI has relied in part on the potency and relative safety
of the bronchodilators and corticosteroids commonly used for the treatment of
respiratory disorders rather than its delivery effi ciency. The relatively low and often
variable aerosol deposition effi ciency, only around 10 – 20% of the nominal dose
being delivered to the lungs, is the challenge that is beginning to be addressed as
the MDI looks to enter the next 50 years of aerosol drug delivery.
5.8.5.2
Metered Dose Inhaler and HFA Reformulation
The basic design and operation of the MDI has changed little over its lifetime.
Aerosols are generated from a formulation of drug (0.1 – 1% w/w) either suspended
or in solution in the liquefi ed propellant. The formulation is held under pressure in
a canister.
Figure 1 shows the basic components of the MDI, consisting of a canister sealed
with a metering valve which is inserted into a plastic actuator containing the mouthpiece.
Aerosol generation takes place when the canister is pressed against the actuation
sump by the patient. Actuation causes the outlet valve to open and the liquefi ed
propellant formulation is released through the actuator nozzle and subsequently
through the mouthpiece to the patient. Metered volumes between 20 and 100 μ L
are dispensed, and as the pressurized propellant is released, it forms small liquid
droplets traveling at high velocity. These droplets evaporate to leave drug particles
for inhalation [117] . Purewal and Grant (1998) have assembled a defi nitive reference
source for issues relating to the design, manufacturing, and performance of
MDIs [122] .
The currently marketed MDIs may look similar to the devices that were fi rst
developed by Riker in 1950. However, due to the replacement of the ozone -
depleting chlorofl uorocarbon (CFC) propellants with HFA propellants, virtually all
of the components of the MDI have been altered. In 1987, the Montreal Protocol
was drawn up, leading to the eventual phase - out of CFC propellants. MDIs contain-