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.
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.
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.