Intra-subject variability in lung dose in healthy volunteers using five conventional portable inhalers.

High intra-subject variability in lung dose achieved when using aerosol delivery systems may impact on the efficacy of treatment in clinical practice. While the dose delivered by metered dose inhalers (pMDIs) is highly reproducible when tested in vitro, the variability in dose delivered to the lungs is known to be high. It has been suggested that newer delivery systems such as dry powder inhalers (DPIs) or breath actuated pMDIs significantly reduce the intra-subject variability in lung dose, but this remains untested. The 30-min urinary salbutamol technique was used to assess intra-subject variability in lung dose for five portable inhaler devices. Thirteen healthy adult subjects inhaled salbutamol from five different devices. Each device was used at five separate study days, a total of 25 visits. The devices studied were the Evohaler pMDI, a pMDI with Volumatic (pMDI + HC), the Easibreath, the Accuhaler and the Turbohaler. Subjects inhaled 400 microg of salbutamol and produced a urine sample exactly 30 min later. Quantities of salbutamol contained in the urine were determined using an HPLC technique. The mean coefficient of variation (CV% and range) for lung dose were 31.8% (20.1-87.4) for the pMDI + HC, Easi-breathe 35.9% (10.4-66.2), Accuhaler 40.4% (15.6-75.2), Turbohaler 42.4% (20.7-74.2), and 52.0% (27.1-49.3) for the pMDI alone. There was no significant statistical significant difference between any of the devices. In seven of 13 subjects, the greatest lung dose was achieved with the Volumatic. The observed intra-subject in health volunteers is similar to the reported intra-subject variability of bioavailability for a number of oral medications. Though there was trend towards higher variability when using the pMDI, this was not statistically significant and was largely attributable to one subject in with a poor technique.

Relative lung and systemic bioavailability of sodium cromoglycate inhaled products using urinary drug excretion post inhalation.

The relative lung and systemic bioavailability of sodium cromoglycate following inhalation by different methods have been determined using a urinary excretion pharmacokinetic method. On three separate randomised study days, 7 days apart, subjects inhaled (i) 4x5 mg from an Intal metered dose inhaler (MDI), (ii) 4x5 mg from an MDI attached to a large volume spacer (MDI+SP) and (iii) 20 mg from an Intal Spinhaler (DPI). Urine samples were provided at 0, 0.5, 1, 2, 5 and 24 h post dose. The mean (S.D.) amount of sodium cromoglycate excreted in the urine during the first 30 min post inhalation was 38.1 (27.5), 222.3 (120.3) and 133.1 (92.2) microg following MDI, MDI+SP and DPI, respectively. The mean ratio (90% confidence interval) of these amounts excreted in the urine over the first 30 min for MDI+SP vs. MDI, DPI vs. MDI and MDI+SP vs. DPI was 801.0 (358.0, 1244; p<0.002)%, 457.0 (244.0, 670.0; p<0.02)% and 262.4 (110.2, 414.5)%, respectively. Similarly for the 24 h cumulative amount of sodium cromoglycate excreted over the 24 h post inhalation the ratios were 375.4 (232.9, 517.9; p<0.005)%, 287.5 (183.4, 391.6; p<0.02)% and 211.4 (88.3, 334.5)%, respectively. The results highlight better lung deposition of sodium cromoglycate from a metered dose inhaler attached to a large volume spacer.