Propellants in metered dose inhalers

Pulmonary delivery of drugs is the administration route of choice in respiratory diseases such as chronic obstructive pulmonary disease and asthma. Different devices are available, including metered-dose inhalers, dry powder inhalers, and nebulizers, and nearly 80% of asthmatic patients worldwide use metered dose inhalers (1). Chlorofluorocarbons have been used as an aerosol propellant in metered-dose inhalers however, they deplete the ozone layer and are being replaced by more environment-friendly propellants, even though the contribution of aerosols of this type to the total global burden of chlorofluorocarbons is less than 0.5%. The first chloro-fluorocarbon-free metered-dose inhaler for asthma treatment was approved by the FDA in 1996 (2) and the European Union has set 2005 as a target date for the withdrawal of all chlorofluorocarbon-based inhalers (1). In the USA, prescriptions for chlorofluorocarbon-free medications rose from 16.4 million in 1996 to 33.8 million in 2000 (2). Most of the chlorofluorocarbon-free medications were steroids for nasal use (27.2 million). However, chlorofluorocarbon-containing medications stiU represented two-thirds of all prescriptions and increased from 63.0 to 67.6 million dispensed (2). 

Dichlorodifluoromethane is used as an aerosol propellant in metered-dose inhaler (MDI) formulations, either as the sole propellant or in combination with dichlorotetrafluoroethane, trichloromonofluoromethane, or mixtures of these chlorofluorocarbons. Dichlorodifluoromethane may also be used as a propellant in an aerosolized sterile talc used for intrapleural administration and is also used alone in some MDIs containing a steroid. 

Trichloromonofluoromethane is used in combination with dichlorodifluoromethane as the propellant in metered-dose inhaler aerosols. It is also used in combination with dichlorotetrafluoroethane and dichlorodifluoromethane. 

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. 

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. 

HFCs, including HFC-134a, have been developed as an alternative to CFCs, which are known to contribute to the breakdown of ozone to oxygen in the stratosphere. HFCs do not contribute to the destruction of stratospheric ozone, but some HFCs have global warming potential. They primarily serve as replacements for CFCs in refrigeration equipment and mobile air conditioning they also have pharmaceutical applications (e.g., as propellants for metered-dose inhalers used to treat asthma). 

Dhillon, S., and Keating, G. M. (2006), Beclometasone dipropionate/formoterol In an HFA-propelled pressurised metered-dose inhaler, Drugs, 66,1475-1483. 

Smyth, H. D., Beck, V. P, Williams, D., and Hickey, A. J. (2004),The influence of formulation and spacer device on the in vitro performance of solution chlorofluorocarbon-free propellant-driven metered dose inhalers, AAPS PharmSciTech, 5, E7. 

Pharmaceutical inhalation aerosols are widely used for treatment of diseases such as asthma and chronic bronchitis. There are three basic types of aerosol products the propellant-driven metered-dose inhalers, the dry powder inhalers, and the nebulizers. Because of the ozone-depleting and greenhouse effects of the chlorofluorocarbon (CFG) propellants, interest in the dry powder aerosols has risen in recent years. 

Hickey, A.J. Evans, R.M. Aerosol generation from propellant-driven metered dose inhalers. In Inhalation Aerosols Hickey, A.J., Ed. Marcel Dekker, Inc. New York, 1996 417 39. 

Although hydrocarbon aerosol propellants are relatively inexpensive, nontoxic, and environmentally friendly (since they are not damaging to the ozone layer and are not greenhouse gases), their use is limited by their flammability. While hydrocarbon propellants are primarily used in topical aerosol formulations, it is possible that butane may also be useful in metered-dose inhalers as a replacement for chloro-fluorocarbons. 

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. 

For aerosols in which the particle velocity is determined by the inspiratory flow rate and the particle size is not sensitive to it, it is expected that the increase in flow rate increases the upper and central airway deposition. For example, Ryan et al. [90] found that fast vital capacity inhalation resulted in a greater proportion of nebulizer aerosol depositing in the central airways than when the aerosol was inhaled slowly. However, the dependence on the inspiratory flow rate becomes more subtle when the particles have intrinsic velocity (such as droplets generated by propellant-driven metered-dose inhalers that need to be entrained into the inhaled air) or the particle size is inspiratory flow dependent (as in the case of passive dry powder inhalers). 

Changes to manufacturing processes of propellant-based metered-dose inhalers (pMDIs) due to the transition to hydrofluoroalkane- (HFA-) based formu lations from chlorofluorocarbon- (CFC-) based systems are under way. These changes are proceeding concurrently with reformulation efforts of the pMDI systems themselves. In some cases, this may result in changes to the formulation [1],... 

Following the debate surrounding sampling by inertial impaction in the early 1990s, the apparatus required for propellant-driven metered-dose inhalers and dry powder inhalers has been specified by the USP [33] and EP [147]. In addition, the FDA has issued guidelines on the methods to be employed for both pulmonary and nasal delivery products [148]. 

The most significant developments in metered-dose inhaler technology to occur since the early 1990s have been the introduction of hydrofluoroalkane (HFA) systems as alternatives to chlorofluorocarbon (CFC) systems [174]. This has largely been caused by the link between the use of CFC systems and ozone depletion in the upper atmosphere [152,175]. Albuterol and beclomethasone have been reformulated in HFA products, but as yet the CFC products are still subject to an annually renewable medical exemption. The Food and Drug Administration has recently published its position on alternative propellant formulations, which should initiate the phase-out of CFCs [176]. In the meantime, a number of generic CFC products of albuterol have been manufactured. The opportunity for reformulation of products as they come of patent is likely to increase research and development in this area in the near future. New formulation opportunities will also arise from these developments, including solutions [177], micellar [178,179], and microemulsion [180]. 

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,... 

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... 

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. 

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. 

---