Metered Dose Inhalers
(MDI)
Drugs for treating respiratory and nasal disorders are frequently
administered in aerosol formulations through the mouth or nose.
Aerosol drug formulation or inhalation drug formulation refer to
one or more physiologically active chemical compounds in
combination with excipients such as surfactants and propellants.

In aerosol drug formulation, drug is usually a finely divided powder
in a liquefied gas or a propellant. This suspension is stored in a
sealed container capable to withstand the pressure to maintain
the propellant as a liquid. The suspension is dispensed in fixed
amounts of the drug formulation upon each-activation of a
dose-metering valve. During the dosing, the suspension is forced
through the dose-metering valve by the high vapor pressure of the
propellant, and the propellant rapidly vaporizes forming a fast
moving cloud of the fine drug particles. A channeling device
directs this cloud into the body of the patient via patient's mouth or
nose from the outlet of the pressurized container.

Concurrently with the activation of the aerosol dose-metering
valve, the patient inhales the drug formulation particles into the
lungs or nasal cavity.

For an aerosol delivery system to work properly the particle size
should generally not exceed about five microns. With particle size
larger than 5 microns, it becomes difficult to maintain an
efficacious aerosol dose. Particles have a tendency to aggregate
or flocculate in a suspension, during storage. The suspension
should be uniform and free from aggregation of the drug particles.
Nontoxic surfactants are always added to coat the particle surface
to minimize the chance of aggregation of the fine particles.

The System
The micronized inhalation drug or combination of drugs are mixed
with one or more P 134a-soluble surfactants and, optionally, other
excipients and then placed in a suitable container capable of
withstanding the vapor pressure of P 134a and fitted with a
metering valve. The propellant is then forced as a liquid through
the valve into the container. The completed metered dose inhaler
is shaken vigorously to form the suspension. Or, an metered dose
inhaler can also be produced by adding drug, surfactant and
liquefied propellant 134a (chilled below it's boiling point) to the
container and then a metering valve fitted to the container. The
completed metered dose inhaler can then be brought to ambient
temperature and shaken vigorously to form the suspension.

Propellant
In early 1980s, chlorofluorocarbons (CFCs) such as
trichloromonofluoromethane (propellant 11, P 11),
dichlorotetrafluoroethane (propellant 114, P 114) and
dichlorodifluoromethane (propellant 12, P 12) were widely used in
inhalation drug formulations. They are nonflammable, have low
toxicity and reactivity, and compatible with many drug
formulations. However, these chlorofluorocarbons were found to
cause depletion of the ozone layer of the atmosphere.
Consequently, manufacturers use nonchlorinated propellant
chemicals such as 1,1,1,2-tetrafluoroethane (propellant 134a or P
134a) as an alternative. Though P 134a has physical properties
similar to P 12, it is much less stable than P 12.  

The amount of P 134a can be varied according to the amount of
drug formulation to be delivered with each activation of the
dose-metering valve. Typically for an inhalation drug the amount of
P 134a for each formulation of active drug depends on the volume
of the metering valve and the dose desired. In general, the ratio of
active drug or drugs to P 134a is in the range from about 1:100 to
about 1:4000 by weight. For albuterol in an aerosol inhalation
system outfitted with a Bespak BK300 valve, 18 g of P 134a are
utilized per 50 mg of albuterol to deliver an effective dose of
albuterol. And, the amount of drug, surfactant and propellant is
adjusted to deliver 90 .mu.g per valve actuation.

Surfactant
Surfactant is important for a stable dispersion. At the early stage,
propellant-insoluble perfluorinated (i.e. at lease one alkyl group
essentially all of the hydrogens are substituted with fluorine)
surfactants were used in CFC. The surfactants were insoluble in
the propellant. And, the drug was coated with the surfactant in an
organic solvent dried, then added to the propellant mixture. Later
on, P 134a-soluble surfactants were also found to effectively
improve or provide a "sufficient stability" of micronized inhalation
drug suspensions in P 134a. "Sufficient stability" means that the
aerosol drug formulation remains as a suspension after shaking
at least long enough to allow activation of MDI and administration
by the patient. The time between shaking and administration is
typically about 10 sec. and generally the period of stability is at
least about 30 sec.

Particular 134a-soluble surfactants are a mixture of potassium
perfluoroalkyl sulfonates and a mixture of ammonium
perfluoroalkyl carboxylates available under the trademarks FC-95
and FC-143, respectively, from 3M Corporation, Saint Paul, Minn.
Most suitable are the perfluoroalkanoic acids, perfluorooctanoic
acid and perfluorodecanoic acid.
The ratio of surfactant to drug is usually in the range of 1:25 to
about 1:1 by weight.

Active Ingredients
Active ingredients such as antiallergic, respiratory (e.g. antiasthmatic and
bronchodilating), antibiotic, antiinflammatory, antifungal, analgesic, antiviral, and
cardiovascular drugs are suitable for this delivery system, examples include albuterol
(salbutamol), salmeterol and amiloride, fluticasone esters, beclomethasone esters and (-
)-4-amino-3,5-dichloro-.alpha.-[[[6-(2-pyridinyl)ethoxy]hexyl]amino]methyl
]benzenemethanol.

Salmeterol, in British Patent Application No. 8,310,477, is a
second generation bronchodilator which is longer acting and
more potent than albuterol.  The genetic disease cystic fibrosis is
characterized by abnormalities that produce excessive pulmonary
secretion which can make breathing difficult. U.S. Pat. No.
4,501,729 discloses the use of the drug amiloride in an aerosol
formulation to reduce the excess secretion. United Kingdom
Patent Specification No. 2088877 discloses fluticasone esters.
Fluticasone esters are corticosteriods having topical
anti-inflammatory action. Corticosteroids may be used in the
management of patients whose asthma is inadequately treated by
bronchodilators.

Other Ingredients
In addition to surfactants, you may want to add other excipients to
an aerosol formulation to improve drug delivery, shelf life and
patient acceptance. Such optional excipients include coloring
agents, taste masking agents, buffers, antioxidants and chemical
stabilizers.  

PROCEDURE

Weigh micronized drug and surfactant into a 15 mL transparent
aerosol vial (No. S-24F6, produced by Wheaton Industries, NJ).
Crimp a metering valve (Bespak valve No. BK300 produced by
Bespak plc, England) onto each vial.
Add Propellant 134a (from E. I. DuPont de Nemours and
Company, Wilmington Del to the vial through the valve.
Shake vials vigorously for 30 min with a wrist-action shaker.

DISCUSSIONS

Immediately after shaking, the suspension in the transparent vial
is very milky or turbid. If left undisturbed, the drug particles
eventually flocculate and concentrate at the gas/liquid interface
(creaming) or at the bottom of the vial (sedimentation) leaving
behind a relatively clear Propellant 134a region.  By shaking a
formulation, a good formula should be able to quickly re-disperse
to a milky suspension.

If flocculation occurs in less than 15 seconds, your formulation is
not stable enough for a practical aerosol inhalation.

                         
Aerosol
               metered dose inhaler
         Testing of Metered Dose Inhaler

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