Equivalence testing of salbutamol dry powder inhalers: in vitro impaction results versus in vivo efficacy.
The aim of the study was to evaluate several impactors for in vitro equivalence testing of salbutamol with respect to efficacy and to define in vitro equivalence limits validated with in vivo efficacy data. The four impactors described in Supplement 2000 of the European Pharmacopoeia were used: Glass Impinger (GI), Metal Impinger (MI), Multistage Liquid Impinger (MSLI) and Andersen Cascade Impactor (ACI). Three salbutamol dry powder formulations with different fine particle doses (FPDs) were prepared and the aerodynamic particle size distribution was measured. For each impactor also the recovery was determined. The same three preparations were administered to 12 asthmatic patients in a randomized, placebo-controlled, four-way crossover study. Cumulative doses from 50 microg up to 400 microg were given. The FEV(1) was measured at baseline and 15 min after each dose. The in vitro results showed large differences between the FPDs of the three preparations with all impactors, whereas only small differences were observed between the four impactors. Since the recoveries of the MI and GI were low, in vitro equivalence testing should only be performed with the MSLI or ACI. The in vivo measurements did not show significant differences in efficacy between the three active preparations, even at the most discriminatory dose of 50 microg. It is concluded that in case there are no relevant differences between delivered dose, inhalation device and excipients, for salbutamol dry powder inhalers equivalence can be assumed when the 90% confidence interval for the FPD ratio of the test product and reference product is within 0.50-1.20 and each of the two products has a FPD (particles <6 microm) of at least 10 microg.
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National Institute for Public Health and the Environment, Laboratory for Quality Control of Medicines, Postbak 40, P O Box 1, 3720 BA, Bilthoven, The Netherlands. marjolein.weda@rivm.nl
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D000328:Adult; D000420:Albuterol / Q000008:administration & dosage / Q000737:chemistry* / Q000493:pharmacokinetics*; D016001:Confidence Intervals; D018592:Cross-Over Studies; D006801:Humans; D008875:Middle Aged; D009330:Nebulizers and Vaporizers; D011208:Powders; D013810:Therapeutic Equivalency
D011208:Powders; D000420:Albuterol