Metered-dose inhaler function

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... 

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. 

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

Isoproterenol is administered almost exclusively by inhalation from metered-dose inhalers or from nebulizers. The response to inhaled isoproterenol and other inhaled adrenomimetics is instantaneous. The action of isoproterenol is short-lived, although an objective measurement of pulmonary function has shown an effective duration of up to 3 hours. When it is administered by inhalation, the cardiac effects of isoproterenol are relatively mild, although in some cases a substantial increase in heart rate occurs. 

Reproductive Toxicity. No data were located from studies of the reproductive toxicity of HFC-134a in humans. The animal data were sufficient to show that HFC-134a exposures similar to those metered-dose inhalers did not affect fertility and sexual function. Although there was an effect of exposure to... 

Co-solvents in metered dose inhalers were commonly used in CFG formulations to aid in drug solubilization. In HFA formulations, co-solvents continue this same function, but have additional benefits in the new systems, such as solubilization of other excipients. Vervaet and Byron discuss water solubility in the various propellants addressed here, where the addition of ethanol to the HFA system considerably increases the solubility of water (Vervaet and Byron, 1999). Likewise, ethanol was found to increase the solubility of several surfactants in HFA (Vervaet and Byron, 1999 Stein and Stefely, 2003). Suspension formulations using this technique (surfactant plus ethanol) must be made with caution however, as ethanol can also increase the solubility of the drug substance, potentially causing increased particle growth via Ostwald ripening. Nonetheless,... 

Although chronic theophylline administration has been used extensively in the past, this therapy is being employed with decreasing frequency in favor of aerosolized /32-receptor agonists. Albuterol is used most commonly, one to two puffs of the metered-dose inhaler three to four times daily. The role of aerosolized surfactant also has been assessed in patients with stable chronic bronchitis and has demonstrated encouraging results with respect to improvement in pulmonary function and sputum transport by cilia (i.e., clearance). The role of surfactant as a carrier vehicle for other aerosol medications also appears promising and most likely will continue to be evaluated. 

Information about the true density of a powder can be used to predict whether a compound will cream or sediment in a metered dose inhaler (MDI) formulation. The densities of the hydrofluoroalkane (HFA) propellants, 227 and 134a, which are replacing chlorofluoro-carbons (CFCs) in MDI formulations, are 1.415 and 1.217 g/cm , respectively. Therefore, suspensions of compounds that have a true density less than these figures will cream (rise to the surface), and those that are denser will sediment. Those that match the density of the propellant will stay in suspension for a longer period (Williams III et al. 1998). It should be noted, however, that the physical stability of a suspension is not merely a function of the true density of the material. 

In the United States, federal regulation of aerosol doses varies with devices. The metered-dose inhaler (MDI) utilizes a metering valve that is highly regulated and functionally precise. Nebulizers as drug delivery systems are essentially unregulated. 

The AERx, developed by Aradigm (Hayward, CA), is a metered dose liquid inhaler designed to deliver various pharmaceutical compounds to the peripheral lungs. The system, as shown in Fig. 10, consists of a unit dose disposable container equipped with a nozzle array, a piston assembly, and electronics associated with breath actuation and compliance monitoring functions. ... 

Several individual factors may also influence the variability of asthma. Poor inhaler technique for both metered-dose and dry powder inhalers is often observed in asthma patients and may be the cause for an increased risk of death. Further, personnel characteristics may also be the cause for the changes in lung functions. In healthy individuals, lung function exhibits a circadian rhythm. However, this will be changed in the individuals those who have nocturnal asthma. Moreover, obesity may also be a risk factor for asthma. Further, women may experience premenstrual and perimenstrual worsening of asthma symptoms. Asthma symptoms may be also triggered by exercise. 

The droplet size of topical aerosol sprays does not need to be carefully controlled, and the dose usually is not metered as in inhalers. The spray may be used to apply the drug to the skin (topical aerosol) or mouth (lingual aerosol) and the functionality of the sprayer should be addressed. The drug product has no contact with the cap and short-term contact with the nozzle. A topical aerosol may be sterile or may conform to acceptance criteria for microbial limits. However, the physical stability of aerosols can lead to changes in total drug delivered per dose and total number of doses that may be obtained from the container. 

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