GR106642X: a new, non-ozone depleting propellant for inhalersBMJ 1995; 310 doi: https://doi.org/10.1136/bmj.310.6995.1639a (Published 24 June 1995) Cite this as: BMJ 1995;310:1639
- Simon C O Taggart, honorary research registrara,
- Adnan Custovic, honorary research registrara,
- David H Richards, clinical research managerb,
- Ashley Woodcock, consultant respiratory physiciana
- a North West Lung Centre, Wythenshawe Hospital, Manchester M23 9LT
- b Glaxo Research and Development, Stockley Park West, Uxbridge, Middlesex UB11 1BT
- Correspondence to: Dr Woodcock.
- Accepted 31 March 1995
Metered dose inhalers are the most popular choice of drug delivery system for treating asthma and chronic airflow limitation. Unfortunately, they contain chlorofluorocarbon propellants, which contribute to the depletion of stratospheric ozone.1 The Montreal Protocol of 1987 has therefore called for a gradual phasing out of manufacture of chlorofluorocarbons in all developed countries by 1996. Inhalers containing chlorofluorocarbons have been given a temporary exemption, but there remains considerable environmental pressure for their early withdrawal.
GR106642X (1, 1, 1, 2-tetrafluoroethane) is a new propellant which does not deplete ozone. It has been used alone, with no other excipients, to reformulate salbutamol. We investigated the safety and efficacy of the new non-ozone depleting formulation for salbutamol in a randomised, double blind, placebo controlled, crossover comparison with the traditional salbutamol inhaler containing chlorofluorocarbons 11 and 12 (Ventolin, Allen and Hanburys) in protecting adults with asthma from bronchoconstriction induced by histamine.
Subjects, methods, and results
The study was approved by the local research and ethics committee of the university hospitals of south Manchester. During three weeks, 24 non-smoking, asthmatic subjects with bronchial hyperresponsiveness to histamine at screening (with a dose arbitrarily defined as <3.9 μmol, which represents the cumulative dose required to cause a 20% drop in post-saline forced expiratory volume in one second with a dosimeter and Yan's protocol2) attended for testing on three occasions not less than 24 hours but not more than 7 days aprt. At each visit, provided that forced expiratory volume in one second was within an arbitrarily defined 15% of the result at the screening visit, the subjects took two puffs with a Volumatic spacer from one of three different inhalers—delivering placebo GR106642X; salbutamol 100 μg plus GR106642X (new inhaler); or salbutamol 100 μg plus propellants 11 and 12 (traditional inhaler). The subjects then rested for 30 minutes before their bronchial responsiveness to histamine was measured. Throughout the study each subject was monitored for any adverse events.
Log normalised values of bronchial responsiveness to histamine were compared between treatments with analysis of covariance appropriate to a three period crossover,3 in which the terms for treatment sequence, period, and forced expiratory volume in one second before challenge with histamine were included. Equivalence of effect between the treatments with salbutamol was defined as a ratio of less than 4 (equivalent to a difference of two doubling doses of histamine) as in inexperienced subjects successive results after challenge with histamine are likely to be within 1.87 doubling doses of one another.4
All 24 subjects (10 men, 14 women; mean age 37 years) completed the study without systemic side effects attributable to the new propellant. Twenty two subjects were maintained on regular inhaled steroid prophylaxis (median dose 400 μg/day) and two on sodium cromoglycate.
Equivalence of effect was shown between new and traditional inhalers (ratio (90% confidence interval) 1.06 (0.63 to 1.79, P=0.842)), but both these treatments were found to be significantly more protective of bronchoconstriction induced by histamine than the placebo (new inhaler v placebo 3.35 (1.92 to 5.83, P<0.001), traditional inhaler v placebo 3.14 (1.86 to 5.31, P<0.001)). The table shows the effects of the treatments.
We have shown in asthmatic adults with bronchial hyperresponsiveness an equivalence of effect between 200 μg salbutamol delivered with GR106642X (an almost universal dose for the relief of symptoms) and the same dose delivered with propellants 11 and 12 in the protection from bronchoconstriction induced by histamine. This finding does not necessarily imply equivalence of effect at all doses of salbutamol as 200 μg rests on the plateau of the dose-response curve.5 Nor does it imply equivalence of effect in all other methods of inducing bronchoconstriction, although a degree of association probably exists between them.
The results of our study suggest that the new, nonozone depleting formulation for salbutamol is a promising alternative to current metered dose inhalers containing chlorofluorocarbons. The introduction of the new formulation would ensure continuity of choice of treatment in subjects with asthma and chronic airflow limitation.
This study was supported by Glaxo Group Research. DHR is employed by Glaxo.