Issue link: http://www.e-digitaleditions.com/i/880535
the first "combination" inhaler containing two drugs (Medihaler Duo TM ). e problem of "loss of prime" caused by formulation draining out of the metering chamber during storage was quickly recognized and addressed by adding a retaining cup that surrounded the valve, a feature that is still used today. e earliest pMDIs were formulated with drug dissolved in propel- lants, but these products tended to have low fine parti- cle doses owing to the presence in the spray of high concentrations of non-volatile excipients. e first sus- pension pMDI formulations were available from 1957, with oleic acid surfactant being used to mini- mize particle aggregation. e pMDI became the most important drug delivery device for treatment of asthma and related conditions, a position which it still holds 60 years later. Selective beta 2 -agonists including albuterol, and inhaled cortico- steroids including beclomethasone dipropionate, were metering valves that were patented by Philip Mesh- berg. 3 e first pMDI products (Medihaler Epi TM and Medihaler Iso TM , containing epinephrine and iso- proterenol, respectively, Riker Laboratories) were for- mulated with the drug in solution in a mixture of two chlorofluorocarbons (CFC-12 and CFC-114), together with ascorbic acid as an antioxidant and etha- nol as a co-solvent. By today's standards, the develop- ment and approval of the first pMDIs occurred with remarkable speed and the New Drug Application (NDA) dossier was only 13 mm thick. e introduc- tion of these products marked the beginning of the modern era of inhaled drug delivery. 2 Several other important developments involving both topical and systemic drug delivery followed from the same team at Riker Laboratories (Table 1), including pMDIs delivering drugs to treat angina (Medihaler Nitro TM ) and migraine (Medihaler Ergotamine TM ), and 1956 First pMDIs (Riker): isoproterenol (Medihaler Iso TM ) and epinephrine (Medihaler Epi TM ) 1956 Medihaler Nitro TM (Riker) marketed for treatment of angina; withdrawn in 1958 1957 First nasal pMDI (Medihaler Phen TM , Riker) marketed 1959 Medihaler Ergotamine TM (Riker) marketed for migraine therapy 1962 First pMDI containing two drugs, isoproterenol and phenylephrine (Medihaler Duo TM , Riker) 1968 First albuterol pMDI (Ventolin ® , A&H) marketed in Europe 1970 First breath-actuated pMDI (Autohaler ® , Riker) 1972 First beclomethasone dipropionate pMDI (Becotide ® , A&H) marketed in Europe 1976 First valved holding chamber (Nebuhaler ® , Astra) patented 1981 Albuterol pMDIs marketed in US (Ventolin, Glaxo; Proventil ® , Schering) 1982 Beclomethasone dipropionate pMDIs in US (Vanceril ® , Glaxo; Beclovent ® , Schering) 1987 Montreal Protocol requires phase out of CFC propellants 1995 First HFA-134a albuterol pMDI launched in UK (Airomir ® , 3M) 1996 First HFA-134a albuterol pMDI launched in US (Proventil, Schering) 2000 Launch of first HFA-134a beclomethasone dipropionate pMDI (Qvar ® , 3M) 2001 Ventolin HFA (GSK) launched in US 2003 FDA recommends that all new pMDIs incorporate dose counters 2004 First pMDI with integrated dose counter (Seretide TM Evohaler TM , GSK) 2006 First HFA-227ea pMDI containing budesonide and formoterol (Symbicort ® , AstraZeneca) 2006 Advair ® HFA (GSK) containing fluticasone propionate and salmeterol approved in US 2010 CFC pMDI phase out completed in Europe 2011 CFC pMDI phase out completed in US 2015 Launch of Sirdupla TM (Mylan) as generic version of Seretide Evohaler in Europe 2016 Amendment to Montreal Protocol proposes reduction in use of HFA-134a and HFA-227ea Table 1 Various key dates in the history of pMDIs. A&H: Allen and Hanbury, GSK: GlaxoSmithKline Inhalation OctOber 2017 13