Metered-dose inhaler factors

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. 

Data adequacy The key study was well designed and conducted and documented a lack of effects on heart and lung parameters as well as clinical chemistry. Pharmacokinetic data were also collected. The compound was without adverse effects when tested as a component of metered-dose inhalers on patients with COPD. 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 values are supported by a study with rats in which no effects were observed during a 4-h exposure to 81,000 ppm. Adjustment of the 81,000 ppm concentration by an interspecies and intraspecies uncertainty factors of 3 each, for a total of 10, results in essentially the same value (8,100 ppm) as that from the human study. ... 

Since the introduction of metered-dose inhalers, nasal solutions have increasingly been formulated as nasal sprays. Initially, aerosol-based systems containing chloro-fluorocarbons were employed however, the Montreal Protocol put an end to this. Thereafter, mechanical pumps or actuators were employed to deliver nasal formulations as sprays. These devices, using actuators, can precisely deliver as little as 25 pL and as much as 200 pL of a formulation. However, various factors must be considered in formulating the spray these include viscosity, particle size, and surface tension, all of which may affect the accuracy of the dose administered. 

Everard, M.L. Devadason, S.G. Summers, Q.A. Le Souef, P.N. Factors affecting total and respirable dose delivered by a salbumatol metered dose inhaler. Thorax 1995, 746-749. 

The patient factors enter into play in several ways. The effectiveness of all aerosol delivery systems depends to some extent on the ability of the patients to use them properly. This has been shown for different types of inhalation systems, such as metered-dose inhalers [28,29] and the breath-driven powder generators [15,30]. The second determinant is the state of the patient s airways. These effects are discussed in greater detail in the following section. 

Prevention of acute bronchospasm - The usual dose is inhalation of 2 metered dose sprays shortly (ie, 10 to 15 minutes but not more than 60 minutes) before exposure to the precipitating factor. 

As with aerosols, the effective dose to patient is difficult to quantify and validate, as this depends on a range of factors. Although when questioned patients generally prefer the apparent convenience of metered dose aerosols, the dose is very much dependent on the use of correct techniques and procedures. Since powder inhalation systems more readily couple synchronisation with use , the more complex operating procedures may be more than compensated by a more effective dose guarantee. 

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 manufacturing factors that may be affected by the choice of a particular polymorphic form include granulation, milling and compression, stability (particularly for semisolid forms), amount of dose delivered in metered inhalers, crystallization from different solvents at different speeds and temperature, precipitation, concentration or evaporation, crystallization from the melt, grinding and compression, lyophilization, and spray drying. In the manufacturing processing, crystallization is a major problem and it can be avoided by a careful study of polymorphic transition, particularly in supercritical fluids. 

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