Metered dose inhalers propellants

Smith, D.L., S.L.Aikman, L.J.Coulby, J.Sutcliffe, and BJ.O Conner. 1994. The attenuation of methacholine-induced bronchoconstriction by salmeterol comparison between an alternative metered dose inhaler propellant GR106642X and chlorofluorocarbons 11 and 12. Eur. Resp. J. 7 (Suppl. 18) 318s. 

Taggart, S.C.O., A.Custovic, D.H.Richards, and A.Woodcock 1994. An alternative metered dose inhaler propellant GR106642X comparison to chlorofluorocarbon 11 and 12 in the attenuation of histamine-induced bronchoconstriction by salbutamol. Eur. Resp. J. (Suppl. 18) 400s. 

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. 

CFC, chlorofluorocarbon propellant HFA, hydrofluoroalkane propellant MDI, metered-dose inhaler. 

Fig. 4 (A) Propellant-driven metered dose inhaler. (B) Metering valve.

AJ Hickey, RM Evans. Aerosol generation from propellent-driven metered dose inhalers. In AJ Hickey, ed. Inhalation Aerosols. New York Marcel Dekker, Inc., 1996, pp. 417-439. 

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... 

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. ... 

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. 

Metered-dose inhalation aerosols Delivered dose per actuation, number of metered doses, color, particle-size distribution, loss of propellant, pressure, valve corrosion, spray pattern, and absence of pathogenic microorganisms... 

To measure lung deposition by imaging, the aerosol must be first labelled or tagged with a suitable radionuclide. Radiolabelling techniques have been developed for current inhalation products including nebulizers, propellant-driven metered dose inhalers, and dry powder inhalers. 

Propellant-Driven Metered Dose Inhalers (MDIs)... 

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). 

DPIs do not utilize Freon propellants, but use either with or without lactose as vehiculum. These devices have a clinical efficacy similar to standard metered-dose inhalers, but may be easier to use in selected patients, since a minimal inspiratory flow rate is necessary to inhale from a DPI. Therefore, the DPI may be difficult for patients with an insufficient inspiratory flow rate, which occurs in children, the elderly, people with severe COPD shared with diaphragm dysfunction, and during an exacerbation. The inspiratory flow rate is associated with the internal resistance of the device used. For instance the turbuhalor has a significant internal resistance and its delivered dose is dependent from the inspiratory flow rate. 

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. 

Smyth HDC. The influence of formulation variables on the performance of alternative propellant-driven metered dose inhalers. Adv Drug Delivery Rev 2003 55(7) 807-828. 

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. 

DeStefano G, Kelash-Cannavo LJ, inventors Boehringer Ingelheim Pharmaceuticals, Inc., U.S., assignee. Formulation for a Metered Dose Inhaler Using Hydrofluoroalkanes as Propellants. US Patent 2004184994, 2004. 

Tzou TZ. Density, excess molar volume, and vapor pressure of propellant mixtures in metered-dose inhalers deviation from ideal mixtures. Respir Drug Delivery YI, Int Symp 1998 439-443. 

Williams RO III, Repka M, Liu J. Influence of propellant composition on drug delivery from a pressurized metered-dose inhaler. Drug Dev Ind Phann 1998 24(8) 763-770. 

Pressurized metered-dose inhaler (pMDI) propellants... 

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... 

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