Metered-dose inhaler containers

Some physicians recommend epinephrine metered-dose inhalers as an alternative to epinephrine autoinjectors. While a few inhalations might relieve mild or moderate respiratory symptoms, for relief of life-threatening airway obstruction or shock, adults need to inhale 20-30 puffs and children need to inhale 10-20 puffs, which is hard to do [35]. Epinephrine metered-dose inhalers contain chlorofluorocarbon propellants. For environmental reasons, they might not be manufactured in the future. 

The AEGL-1 concentration was based on a 1-hour (h) no-effect concentration of 8,000 parts per million (ppm) in healthy human subjects (Emmen et al. 2000). This concentration was without effects on pulmonary function, respiratory parameters, the eyes (irritation), or the cardiovascular system. Because this concentration is considerably below that causing any adverse effect in animal studies, an intraspecies uncertainty factor (UF) of 1 was applied. The intraspecies UF of 1 is supported by the absence of adverse effects in therapy tests with patients with severe chronic obstructive pulmonary disease and adult and pediatric asthmatics who were tested with metered-dose inhalers containing HFC-134a as the propellant. Because blood concentrations in this study approached equilibrium following 55 minutes (min) of exposure and effects are determined by blood concentrations, the value of 8,000 ppm was made equivalent across all time periods. The AEGL-1 of 8,000 ppm is supported by the absence of adverse effects in experimental animals that inhaled considerably higher concentrations. No adverse effects were observed in rats exposed at 81,000 ppm for 4 h (Silber and Kennedy 1979) or in rats exposed... 

Intraspecies 1—this no-effect concentration for eight healthy individuals was far below concentrations causing effects in animals. At this low exposure concentration there was no indication of differences in sensitivity among the subjects. This uncertainty factor is supported by the lack of effects in COPD and adult and pediatric asthmatic patients treated with metered-dose inhalers containing HFC-134a as a propellant. 

N. Butz, C. Porte, H. Courrier, M.P. Krafft, T.F. Vandamme, Reverse water-in-fluorocarbon emulsions for use in pressurized metered-dose inhalers containing hydrofluor-oalkane propellants, Int. J. Pharm. 238 (2002) 257-269. 

Tiwari D, Goldman D, Malick WA, Madan P. Formulation and evaluation of albuterol metered dose inhalers containing tetrafluoroethane (PI 34a), a non-CFC propellant. Pharma Dev Technol 1998 3 163-174. 

Smyth HDC, Mejia-Millan EA, Hickey AJ. The effect of ethanol on solvency vapor pressure, and emitted droplet size of solution metered dose inhalers containing HFA 134a. Respir Drug Delivery VIII 2002 2 735-738. 

Berry, J., Kline, L. C., Hart, J. L., and Sequeira, J. (2003), Influence of the storage orientation on the aerodynamic particle size of a suspension metered dose inhaler containing propellant HFA-227, Drug Dev. Ind. Pharm., 29, 631-639. 

Newman, S. Picairn, G.R. Steed, K. Harrison, A. Nagel, J. Deposition of fenoterol from pressurized metered dose inhalers containing hydrofluoroalkanes. J. Allergy Clin. Immunol. 1999, 104 (6), S253-S257. 

Dalby RN. Prediction and assessment of flammability hazards associated with metered-dose inhalers containing flammable propellants. Pharm Res 1992 9 636-642. 

Sommerville, M.L. and Hickey, A.J. (2003) Aerosol generation by metered-dose inhalers containing dimethyl ether/propane inverse microemulsions. AAPS Pharmscitech, 4, Article 58. 

To monitor the amount of drug in a metered-dose inhaler, you can periodically place the canister in a container of water. The figure shows the positioning of the canister with various amounts of medication remaining in the canister. (Adapted from the American Uung Assoaation. [1993]. Understanding lung medications How they work—how to use them, p. 4)... 

Do not puncture metered dose inhalers or store them near heat or open flame the contents of such inhalers are under pressure Never throw the container into a fire or incinerator. If an unusual smell or taste is noted with use of the inhaler, discontinue use and contact the primary care provider. 

The database for HFC-134a is extensive it contains studies with both human subjects and animal models. Potentially sensitive populations, including patients with COPD and adult and pediatric asthmatic patients, were tested with direct inhalation of HFC-134a from metered-dose inhalers. The response of these groups was no different than that of healthy adults. The animal studies covered acute, subchronic, and chronic exposure durations and addressed systemic toxicity as well as neurotoxicity, reproductive and developmental effects, cardiac sensitization, genotoxicity, and carcinogenicity. The metabolism of HFC-134a is well understood, and the relationship of exposure con... 

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). 

The metered dose inhalers consist of four basic functional elements, container, metering valve, actuator and mouthpiece. 

Inhalation aerosols have been used for the delivery of drugs to the respiratory system since the mid-1950s. The most common dosage form for inhalation is the metered-dose inhaler (MDI), by which the drug is delivered from a pressurized container using a liquefied gas propellant. Medication delivered via this dosage form has allowed for a quick therapeutic response to the symptoms of asthma, emphysema, and chronic obstructive pulmonary disease (COPD), and has resulted in an improvement in the quality of life for millions of asthma sufferers. 

Fewer than 12 different excipients in MDI products have been formulated into metered aerosols. The availability of established FDA-approved excipients limits the formulator to a select few such ingredients. Table 1 lists excipients and the approximate amounts of some of these excipients that are currently used in MDIs. Metered-dose inhalers formulated with CFCs contain propellant 12, propellant 12/11, propellant 12/114, or propellant 12/114/11. These propellant... 

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. 

Specific considerations for container/closure system components for specialized delivery systems such as metered dose inhalers, dry-powder inhalers, disposable pen injectors, transdermal patches, or other novel dosage forms... 

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... 

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