Recently, deleterious effects to ozone layer have come to the fore in the wake of concerns about wide chlorofluorocarbon (CFC) use in pharmaceutical aerosols. An aerosol product for pulmonary delivery is an important drug delivery route and offers local targeting for the treatment of various respiratory disorders. The aerosol, used as metered dose inhaler (MDI), has become the dosage for choice for delivery of medicaments to the lungs.
The term pharmaceutical aerosol is commonly used when referring to aerosol medication or aerosol dosage form. Technologically pharmaceutical aerosols are pressurised dosage forms that upon actuation emit a very fine dispersion of liquid or solid particles in gas. The metered dose inhaler aerosol is also known as pressurised metered dose inhaler (pMDI). In such an aerosol dosage form, an active pharmaceutical ingredient (API) is dissolved or suspended in a propellant, a material that is liquid under high pressure in a closed pack (canister) but that forms a gas when pressure is reduced. The administration of medicaments by aerosol differs from usual dosage forms in their dependence upon the container and valve together with a propellant. Propellants are responsible for pushing the medication out of the inhaler system.
Pressurised metered dose inhalers
Metering valves are employed which permit release of only one dose of the medicine(s) upon single depression of the actuator. The pMDI was developed in the 1950's for the treatment of respiratory disorders. It is estimated that sale of pMDI today is more than 600 million units a year and is increasing. Corticosteroids for the management of persistent asthma are delivered via pMDI. Besides, a variety of agents are administered orally by means of MDI.
Propellants
Chlorofluorocarbon (CFC) have traditionally been used as propellants in these pMDI since they are inexpensive, stable, safe and effective, but their use is tightly regulated due to their adverse effect on the ozone layer and for responsibility for greenhouse effect. The first evidence that CFC containing aerosols deplete ozone layer was reported in the 1970s. Therefore, the non-essential use of CFCs has been banned/phased out in most aerosols by a promulgation of the environmental protection agency (EPA). Certain essential pMDIs are exempted, from this regulation, which were commercially available before 2000.
CFCs, the propellants in pMDIs, contribute to ozone layer depletion in the stratosphere high above the earth. A thinner ozone layer allows harmful ultraviolet (UV) radiation to reach the Earth's surface. The importance of ozone layer depletion by CFCs was recognized in 1995, when Mario J Molina, Sherwood F Rowland and Paul Crutzen were awarded Nobel Prize in chemistry by Swedish Academy. Overexposure to UV radiation can lead to serous health effects, such as skin damage, cataracts, and immune suppression, as well ecological hazards.
An international agreement, the Montreal Protocol on substances that deplete ozone layer was adopted in the year 1987 and amended four times; last amendment was ratified in Beijing 1999. The aim of the agreement is to protect the ozone layer by phasing out substances that deplete ozone layer, including CFCs. Today, more than 191 countries have signed the Montreal Protocol and continue to phase out the production of chemicals that deplete the ozone layer.
Ozone-safe propellants
Hydrofluoroalkanes (HFAs) are ozone-safe/friendly propellants and are proper replacements for CFCs propellants. Two safe and effective HFAs available are: HFA 134a (1,1,1,2-Tetrafluoroethane; CF3CH2F) and HFA 227ea (1,1,1,2,3,3,3-Heptafluoropropane; CF3CHFCF3). In 1996, US FDA approved the use of HFA 134a in pMDI. The shift to CFCs-free pMDIs is part of the commitment to implementing the Montreal Protocol.
Albuterol inhalers
The US FDA has removed the essential status for albuterol pMDI. After December 31, 2008, CFC-albuterol pMDIs cannot be sold, distributed or offered for sale in the US pursuant to clean air act. HFA-propelled albuterol inhalers will replace CFC-propelled inhalers in the US on and after 1 January 2009. FDA advises patients to switch to HFA albuterol inhalers. Albuterol inhalers are for emergencies, for quick relief of bronchospasm or wheezing caused by asthma and COPD. Other old nonprescription inhalers containing CFCs will be at pharmacies until December 31, 2011. Three HFA inhalers containing albuterol have already been approved by the FDA: Proair HFA Inhalation Aerosol, Proventil HFA Inhalation Aerosol, and Ventolin HFA Inhalation Aerosol. In addition Xopenex HFA Inhalation Aerosol that contains levalbuterol is also available. It is relevant to state that more than 52 million albuterol pMDI are prescribed in the US each year, making them among the top 10 prescribed medications in the country.
HFA-albuterol pMDI is five times costlier than CFC pMDI because HFA-albuterol pMDI is not currently available in generic form. HFA propelled inhalers must be used differently, the actuator of the inhaler must be cleaned under warm running water once a week. Each HFA inhaler has different priming instruction.
Many more countries are planning to switch to HFA propelled pMDI in the near future, given the imminent CFC phase out deadline vis-à-vis international obligation. CFC phase out will encourage the development of new treatments for respiratory disorders and new technology of inhalation drug delivery systems.
Safety and efficacy
The use of HFA in pressurised metered dose inhaler is a therapeutic option with enormous value to both health and environment. HFA, according to research reports, is a safe propellant, has better pulmonary deposition as compared to CFC inhalers and efficient. However, post marketing surveillance studies are necessary to assess further safety on prolong use in all patient demographics.
(The author is Reader in Pharmacy,
Annamalai University, Annamalainagar 608 002, Tamil Nadu)