Editorials CFC transition : the Emperor ’ s new clothes . Each class of drug deserves a delivery system that meets its own requirements

It is likely that two related but very diVerent events during this coming year will form milestones in the history of aerosol therapy. One is likely to represent a genuine advance, ushering a new era in which aerosol delivery systems will be used to deliver potent systemically acting drugs via the lungs. The other will be the culmination of an enormously expensive exercise aimed at perpetuating inappropriate technology. It seems probable that, during the later part of 2000, the FDA will grant a licence to deliver insulin as an aerosol. The most exciting aspect of this is that, for the first time in half a century, an aerosol delivery system has been developed specifically to fulfil a specific task. The biggest market in North America for inhaled insulin is likely to be in the treatment of type II diabetes and, although the potential for significant adverse events related to swings in blood sugar is probably less than in those with traditional insulin dependent diabetes, it is still necessary to deliver the insulin in reproducible quantities to the lungs. If successful, this product is likely to be the first of a new generation of products designed to deliver systemically acting drugs via the respiratory tract. This concept is not new; early pioneers working with jet nebulisers in the 1930s and pressurised metered dose inhalers (pMDIs) in the 1950s considered delivering insulin as an aerosol but soon abandoned the idea because they realised that delivery of drug to the lung was so unpredictable that it was not possible to utilise aerosolised insulin safely with those devices. In contrast, this year is also likely to see the widespread introduction of chlorofluorocarbon (CFC) free pMDIs delivering inhaled steroids. This “seamless” transition in which hydrofluorocarbon (HFC) replacement devices have been detuned to perform as badly as their predecessors has been greeted with some enthusiasm by a number of influential clinicians yet, on reflection, this must represent one of the most costly mistakes in the history of pharmaceutical development. The process has been hugely expensive in financial terms, costing more than a billion dollars—the equivalent of bringing five or six new therapeutic compounds to market. The real cost, however, will be borne by the patients who are now likely to have these devices inflicted upon them during the coming years. To understand why the advent of CFC replacement pMDIs delivering inhaled corticosteroids as ineYciently and as unreliably as their CFC forebears should not be a cause for celebration we should briefly review the development of inhaled therapy for the treatment of asthma. The concept of a portable delivery system for bronchodilating agents surfaced almost 200 years ago with the advent of asthma cigarettes. These took an existing technology and used it to deliver anticholinergic agents. Unpredictable drug delivery and frequent side eVects led to their replacement with other delivery systems and agents. Jet nebulisers appeared in the 1930s when a baZe was added to an atomiser to produce droplets small enough to be inhaled, and some two decades later the pMDI was developed as a portable multidose alternative to the rubber bulb hand held nebulisers. The pMDI was developed specifically to provide a portable multidose delivery system for â agonists that would enable patients to obtain rapid relief wherever they were. The great advantage of the inhaled route for these agents was speed of onset, with maximal bronchodilation being achieved in minutes rather than in hours as is the case with â agonists delivered orally. It was also noted that systemic side eVects were substantially less than those observed when the same bronchodilation was achieved using the oral route. Thus, delivering â agonists directly to their site of action in the lung also conferred benefits in terms of their therapeutic index. However, the improved safety profile is only relative and, as with any form of drug therapy, adverse events do occur with inhaled medication if excessive doses are used, as illustrated by the epidemic of asthma deaths in the 1960s associated with high dose, non-selective â agonists. It was clear from the earliest days of the pMDI that this delivery system was not capable of delivering drugs in reproducible quantities to the lungs. However, the wide therapeutic index, even with non-selective â agonists, permitted supramaximal doses to be used that could compensate for poor technique. The rapid onset of action provided immediate feedback so that failure to deliver adequate quantities of drug to the lungs due to poor technique could be compensated for by the administration of additional doses. When a topically active steroid with significant first pass metabolism was developed in the late 1960s, it was unclear whether the concept of delivering inhaled steroids to treat asthmatic subjects would prove to be useful. It certainly was not evident that it would become the cornerstone of good management used by millions of asthmatics every day. Indeed, a number of previous attempts to use inhaled steroids such as hydrocortisone and dexamethasone had failed, largely because of the associated side eVects. At the time the pMDI was available and an understandable pragmatic decision was made to use this delivery system because it was available. The first trials proved disappointing and it was only the enthusiastic and committed eVorts of an allergist from Derby, Dr Harry Morrow-Brown, that permitted the potential of this form of treatment to be identified. Unfortunately, once the potential benefits of this approach had been identified a decision was taken, probably by default, to continue to use pMDI for inhaled steroids. Thorax 2000;55:811–814 811