Pressurized metered dose inhaler propellants

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

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. ... 

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... 

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). 

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. 

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. 

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. 

Metered-Dose Inhalation Aerosols Quantity of delivered dose, total number of acceptable doses delivered, color, solvate formation with propellant, particle size distribution, weight loss of canister (i.e., loss of propellant), pressure, valve corrosion, and storage in both upright and inverted positions. 

Metered dose inhaler has been the most popular aerosol delivery device for the treatment of respiratory diseases, which is attributable to its portability and simple operation. Although seemingly easy to use, the MDI is a sophisticated device in design. The drug(s) are suspended or dissolved in a liquefied propellant system, which may also contain excipients such as cosolvents or surfactants. The formulation is kept pressurized in a small canister, sealed with a metering valve. Upon actuation through an actuator, the valve opens and the metered dose is dispensed as an aerosol spray from the expansion and vaporization of the propellant under ambient pressure. The inhalers may be used alone or with spacer devices, the electrostatic issues of which are considered in a later section. The present discussion focuses on the inherent charging of particles produced from MDIs. 

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. ... 

Metered dose inhalers (MDIs) are pharmaceutical delivery systems designed for oral or nasal use, which deliver discrete doses of aerosolized medicament to the respiratory tract. The MDI contains the active substance, dissolved or suspended in a liquefied propellant system held in a pressurized container that is sealed with a metering valve. Actuation of the valve discharges a metered dose of medicament as an aerosol spray through an actuator during oral or nasal inhalation. 

Clarke, J.G. Wicks, S.R. Earr, S.J. Surfactant mediated 42. effects in pressurized metered dose inhalers formulated as suspensions. I. Drug/surfactant interactions in a model propellant systems. Int. J. Pharm. 1993, 93, 221-231. 

Tetrafluoroethane is a hydrofluorocarbon (HFC) or hydro-fluoroalkane (HFA) aerosol propellant (contains hydrogen, fluorine, and carbon) as contrasted to a CFC (chlorine, fluorine, and carbon). The lack of chlorine in the molecule and the presence of hydrogen reduces the ozone depletion activity to practically zero. Hence tetrafluoroethane can be considered as an alternative to CFCs in the formulation of metered-dose inhalers (MDIs). It has replaced CFC-12 as a refrigerant since it has essentially the same vapor pressure. Its very low Kauri-butanol value and solubility parameter indicate that it is not a good solvent for the commonly used surfactants for MDIs. Sorbitan trioleate, sorbitan sesquioleate, oleic acid, and soya lecithin show limited solubility in tetrafluoroethane and the amount of surfactant that actually dissolves may not be sufficient to keep a drug readily dispersed. 

Raoult s law is important because it allows the calculation of vapour pressure from a knowledge of the composition of the solution. The requirement of the Montreal Protocol in 1989 for the replacement of chlorofluorocarbon (CFG) propellants in pressurised metered-dose inhalers with hydrofluoroalkanes (HFAs), because of the ozone-depleting... 

In particular, the propellant-driven metered-dose inhalers release the aerosol cloud at the very high velocity caused by the pressure of the propellant. The open-mouth technique of inhalation [79] helps to slow down the droplets (and to evaporate the volatile excipients). An even more effective solution is to use spacer devices [4,79-87], in which the aerosol cloud can slowed down, the volatile constituents can evaporate, and any large particles will sediment out. Moreover, the patient can then inhale the remaining aerosol under optimal conditions for pulmonary delivery [4,8,56,79], that is, with a slow inspiratory flow rate. 

Williams III RO, Repka M, and LiuJ. Influence of Propellant Composition on Drug Delivery from a Pressurized Metered-dose Inhaler. Drug Deuel Ind Pharm 1998 24(8) 763-770. 

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 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. 

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. 

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... 

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