The Pressurized Metered-Dose Inhaler

The most important development in antiasthma drug delivery was the advent of the metered-dose inhaler in 1956, which resulted in a huge increase in the use of antiasthma therapy. Sales of pressurized metered-dose inhalers now run at approximately 500 million per year. However, the introduction of this device was not without problems. This section of the chapter covers the early use of propellants in atomization, the origin of the metered-dose inhaler, and the epidemic of asthma deaths. 

Marcel Dekker, Inc. 270 Madison Avenue. New York, New York 10016 

The pressurized metered-dose inhaler (pMDI) for the delivery of antiasthma drugs originated in the U.S. cosmetic industry. George Maison, the president of Riker Laboratories, and Irvin Porash, who worked in Riker s pharmaceutical development laboratory, are credited with the development of the first pMDI (32). Experiments were conducted to formulate pressurized aerosols of isoproterenol and epinephrine, which had been dissolved in alcohol, using the freon propellants 12 and 114. 

At this very early stage, the possibility of using the lung to deliver systemic medication was considered possible. Other drug formulations intended for use in an MDI were also patented. These included both nicotine and insulin. Although insulin was shown in animal experiments to cause hypoglycemia, the effect was very variable and this initiative was not then pursued. It is of interest 

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Dunbar, C. A. (1998), Atomization mechanisms of the pressurized metered dose inhaler, Part. Sci. Technol., 15, 253-271. 

The pressurized metered dose inhalers in the use of environmentally friendly propellants means the choice of hydrofluoroalkanes, wherein the dosage form can be a suspension of the solution form. The problems of formulating suspensions, as discussed earlier, apply here as well, but particularly with respect to interactions with the formulation components specific to pressurized inhaler systems. 

The pressurized metered dose inhaler (pMDI) is a pocket sized, hand-held drug delivery system designed to deliver consistent small doses of medicines directly to the patient s lungs. The essential constituents are the medicine, the propellant, and a storage canister, a metering valve, and an actuator. This chapter is concerned with the propellants. It addresses... 

Donnell, D., L.I.Harrison, S.Ward, N.M.Klinger, B.P.Ekholm, K.M.Cooper, I. Porietis, and J.McEwen. 1995. Acute safety of the CFC-free propellant HFA134a from a pressurized metered dose inhaler. Eur. J. Clin. Pharmacol. 48 473— 477. ... 

Newman, S.P., Clark, A.R., Talaee, N., and Clarke, S.W., Pressurized aerosol deposition in the human lung with and without an open spacer device. Thorax, 44 706-710 (1989). Newman, S.P., Clark, A.R., Talaee, N., and Clarke, S.W., Lung deposition of 5 mg Intal from a pressurized metered dose inhaler assessed by radiotracer technique, Int. J. Pharm., 74 203-208 (1991). 

As described in Section 3.3 in more detah, particles in the aerosol cloud should preferably have an aerodynamic diameter between 0.5 and 7.5 pm. Currently three different types of devices are used to generate aerosol clouds for inhalation nebulizers (jet or ultrasonic), (pressurized) metered dose inhalers (pMDIs) and dry powder inhalers (DPIs). The basic function of these three completely different devices is to generate a drug-containing aerosol cloud that contains the highest possible fraction of particles in the desired size range. 

Pressurized metered dose inhalers are still the most frequently used systems and they have proven their value in therapy. However, their application in early phases of biopharmaceuti-cal research and further development of dosage forms seems less convenient, since they require special components including propellants, special containers, metering valves, and controlled filling conditions (pressure-filling or cold-filling). 

Williams RO III, Brown J, Liu J. Influence of micronization method on the performance of a suspension triamcinolone acetonide pressurized metered-dose inhaler formulation. Pharm Dev Technol 1999 4(2) 167-179. 

Hallworth, G. W. The formation and evaluation of pressurized metered-dose inhalers. In I. Gandeston, I. Jones, eds. Drug Delivery to the Respiratory Tract. Chichester, UK Ellis Horwood, pp. 87-118 (1987). 

The Easyhaler (by Orion Pharma, Finland) and the Clickhaler (by Innovata pic, United Kingdom) are available at present in some European markets. Unlike the DPIs described earlier, these two reservoir-type inhalers meter the dose when the patient presses the top of the device similar to actuation of a pressurized metered-dose inhaler. Both devices contain a dose indicator, which is standard for reservoir multidose DPIs. Recently, Innovata presented the Twinhaler for asthma combination therapy, a new development based on the Clickhaler. This device does not require the combined drugs to be formulated in one powder blend but delivers two powder formulations from two reservoirs into one airflow path. 

Three different types of inhalers are used to deliver drugs to the deep lung. Nebulizers, the oldest type of inhaler, work by producing a mist of aqueous, drug-containing droplets. The drug can be either dissolved or suspended in the water phase. In a pressurized metered dose inhaler (pMDI), the drug is... 

Sander, N., Fusco-Walkert, S. J., Harder, J. M., and Chipps, B. E. (2006), Dose counting and the use of pressurized metered-dose inhalers Running on empty, Ann. Allergy Asthma Immunol., 97, 34-38. 

Hochrainer, D., Holz, H., Kreher, C., Scaffidi, L., Spallek, M., and Wachtel, H. (2005), Comparison of the aerosol velocity and spray duration of respimat soft mist inhaler and pressurized metered dose inhalers, /. Aerosol Med., 18,273-282. 

Most inhalation devices deliver approximately 10% of the administered dose to the lower respiratory tract. A number of devices have been developed to increase lung delivery, and delivery of up to 21% has been reported with a pressurized metered-dose inhaler. Despite these advances, drug delivery via the lung is still inefficient. 

In the mid-1950s the first pressurized metered dose inhaler (MDI) was developed for the administration of bronchodilator drugs locally to the lung. It was a major advance for the treatment of asthma since it made aerosol medications readily available in an inexpensive small multidose device. 

The modern pressurized metered dose inhaler (pMDI) was developed between 1955 and 1956. However, the pMDI had its roots in research carried out many years before.During the 1930s and 1940s, the discovery of liquefied propellants (chlorinated-fluorocarbons or freon propellants) such as CFC12, CFC114, CFCll, and CFC22 was a major step in the realization of a portable inhaler. However, the first pMDI was not invented until 1956, when the metering valve used in the device was developed and patented. ... 

Ganderton D, Lewis D, Davies R, Meakin B, BrambiUa G, Church T. Modulite a means of designing the aerosols generated by pressurized metered dose inhalers. Respir Med 2002 96(Suppl D) S3-8. 

The efficacy and safety of salbutamol inhaled using a dry powder inhaler has been compared with salbutamol inhaled using a pressurized metered-dose inhaler (pMDI) in a randomized, open, crossover study in 12 patients with moderate to severe asthma. A total of 1600 micrograms of salbutamol was given on two separate days in a cumulative dose fashion in increments of 100,100,200, 400, and 800 micrograms at 3-minute intervals. FEVi rose progressively with each increment. The dose-response curves showed that powdered salbutamol was 3.0 times as potent (Cl = 1.8,5.8) as salbutamol from... 

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