Characteristics, supply and use of the hydrofluorocarbons HFA 227 and HFA 134a for medical aerosols in the past, present and future. Manufacturers perspectives
HFA 227 (heptafluoropropane; Apaflurane) and HFA 134a (tetrafluoroethane; Norflurane), both of which were developed by the chemical industry as CFC substitutes in the eighties, now have been used by the pharmaceutical industry as propellants for medical aerosols, particularly for asthma sprays, for approx. 10 years. Thus, for example, Aventis Pharma Ltd. have in the meantime changed the formulation of their products, Intal(R) (disodium cromoglycate), and Tilade(R) (nedocromil) by using HFA 227.Now, innovative approaches of pharmaceutical research are leading to the administration of active substances for the treatment of possibly a large number of known diseases via the lungs or throat. Thus, already in the clinical trial phase are active substances for buccal or respiratory drug delivery for the treatment of diabetes (insulin), pain management (morphine), multiple sclerosis (interferon beta 1a), osteoporosis (parathyroid hormone), viral diseases and cancers, septic shock and of course, asthma (18). Almost as many companies are developing the technology platforms for administering these active substances to the lungs, nose or throat. For this purpose, among others, the very reasonable and patient-friendly p-MDI technology which has already proved itself over many years in the treatment of asthma, is exploited. The only two propellants affirmed to be suitable for use in metered dose inhalers, HFA 134a and HFA 227ca, are discussed with respect to their physicochemical properties and technical suitability. Comparing HFA 227ca with HFA 134a, smaller amounts of excipients such as ethanol appear to be used for HFA 227ca. Another benefit of HFA 227ea is the higher boiling point, which allows the use of both the cold and pressure filling method, thus minimizing the need for new production equipment. Furthermore, HFA 227ea is preferred for formulations liable to change due to absorption of water during the MDI shelf-life, especially in the case of hydroscopic drugs. HFA 227ca may also be used as a vapour pressure depressant to HFA 134a and for suspension-based p-MDIs in blends with HFA 134a to match the drugs density. In order to ensure that the propellants HFA 227 and HFA 134a used for the p-MDIs are compatible, Solvay Fluor & Derivate GmbH as a manufacturer of HFAs for medical aerosols (Solkane(R) 227 pharma and Solkane(R) 134a pharma) have set about investigating important new characteristics. These are, among others, the solubility of oxygen and silicone oil in the HFAs.This paper looks back over the manufacture and use of HFAs in p-MDIs as well as examining the present and future prospects. It summarises existing HFA properties relevant to p-MDI formulations adding new values important for the p-MDI technology recently determined for the first time by Solvay Fluor in HFA 227 and HFA 134a.Glaxo with salbutamol (VENTOLIN EVOHALER(TM)), salmeterol (SEVERENT(TM)), fluticasone propionate (FLIXOTIDE(TM)) and salmeterol combined with fluticasone (SERETIDE EVOHALER(TM)). In addition, Norton in Ireland and Chiesi in Italy each developed beclometasone MDIs with HFA 134a (BECLAZONE(TM) and BECLOJET(TM)), both of them already launched. Asta Medica developed reproterol combined with disodium cromoglycate (AARANE(TM)), while Aventis Pharma Ltd developed disodium cromoglycate (INTAL(TM)) and nedocromil (TILADE(TM)), both these companies using HFA 227.In the meantime, HFA 227 has long since become commercially available and is used in numerous formulations which will reach the market in the next few years.