Balance responses to lateral perturbations in human treadmill walking

During walking on a treadmill 10 human subjects (mean age 20 years) were perturbed by 100 ms pushes or pulls to the left or the right, of various magnitudes and in various phases of the gait cycle. Balance was maintained by (1) a stepping strategy (synergy), in which the foot at the next step is positioned a fixed distance outward of the 'extrapolated centre of mass', and (2) a lateral ankle strategy, which comprises a medial or lateral movement of the centre of pressure under the foot sole. The extrapolated centre of mass is defined as the centre of mass position plus the centre of mass velocity multiplied by a parameter related to the subject's leg length. The ankle strategy is the fastest, with a mechanical delay of about 200 ms (20% of a stride), but it can displace the centre of pressure no more than 2 cm. The stepping strategy needs at least 300 ms (30% of a stride) before foot placement, but has a range of 20 cm. When reaction time is sufficient, the magnitude of the total response is in good agreement with our hypothesis: mean centre of pressure (foot) position is a constant distance outward of the extrapolated centre of mass. If the reaction time falls short, a further correction is applied in the next step. In the healthy subjects studied here, no further corrections were necessary, so balance was recovered within two steps (one stride)

Comparative in vitro performance evaluation of the Novopulmon® 200 Novolizer® and Budesonid-ratiopharm® Jethaler:Two novel budesonide dry powder inhalers

A special single dose collector and a multi stage liquid impinger were used to assess the consistency of delivered dose and fine particle fraction respectively, of the Novopulmon 200 Novolizer (Viatris, Frankfurt, Germany) and Budesonid-ratiopharm Jethaler (Ratiopharm, Ulm, Germany). The obtained average delivered dose from the Jethaler at 4 kPa is 199 microg (99.5% of the label claim) versus 219 microg (109.6%) for the Novolizer (mean of 90 doses from the same device). The corresponding relative standard deviation (RSD) for the Jethaler is on average 14.05% (maximal and minimal dose are 289 and 148 microg respectively), versus an RSD of 5.56% for the Novolizer (max. is 240; min. is 187 microg). It can be shown that the rather extreme spread in the delivered dose from the Jethaler is caused by a variation in metered mass, and to less extent by a poor content uniformity of the drug-lactose compact. The fine particle fractions (FPFs, as percent of label claim, for particles <5.1 microm) of both devices show an increase with increasing pressure drop across the inhalers, although at 4 kPa already 62% (Jethaler), respectively 72% (Novolizer) of the 'maximal' value (at 8 kPa) is achieved. FPF from the Novolizer is highest at all pressure drops and varies between 23.2% (at 2 kPa) and 54.3% (at 8 kPa). The difference in FPF between both devices increases with decreasing upper class for the FPF: the ratio of FPF from Novolizer to that from Jethaler (at 4 kPa) is 1.42 for particles < 5.1 microm versus 2.14 for particles < 1.8 microm, suggesting that the aerosol produced by the Novolizer has much greater potential for deep lung deposition

Air classifier technology (ACT) in dry powder inhalation. Part 1: Introduction of a novel force distribution concept (FDC) explaining the performance of a basic air classifier on adhesive mixtures

Air classifier technology (ACT) is introduced as part of formulation integrated dry powder inhaler development (FIDPI) to optimise the de-agglomeration of inhalation powders. Carrier retention and de-agglomeration results obtained with a basic classifier concept are discussed. The theoretical cut-off diameter for lactose of the classifier used, is between 35 and 15μm for flow rates ranging from 20 to 70l/min. Carrier retention of narrow size fractions is higher than 80% for flow rates between 30 and 60l/min, inhalation times up to 6s and classifier payloads between 0 and 30mg. The de-agglomeration efficiency for adhesive mixtures, derived from carrier residue (CR) measurement, increases both with increasing flow rate and inhalation time. At 30l/min, 60% fine particle detachment can be obtained within 3s circulation time, whereas at 60l/min only 0.5s is necessary to release more than 70%. More detailed information of the change of detachment rate within the first 0.5s of inhalation is obtained from laser diffraction analysis (LDA) of the aerosol cloud. The experimental results can be explained with a novel force distribution concept (FDC) which is introduced to better understand the complex effects of mixing and inhalation parameters on the size distributions of adhesion and removal forces and their relevance to the de-agglomeration in the classifier. © 2003 Elsevier B.V. All rights reserved

Inhalation of tobramycin in cystic fibrosis. Part 1: The choice of a nebulizer

Forteen commercially available jet and ultrasonic nebulizers were investigated with the aim to select the most suitable type of apparatus for the inhalation of a 10% tobramycin solution. Two different techniques for measurement of particle size distribution were evaluated: laser diffraction and cascade impactor analysis. The final selection of the nebulizers is based on particle size distribution, output and stable performance during nebulization. All 14 nebulizers (eight jet and six ultrasonic) were filled with a solution of 10% m/v tobramycin (as sulphate) in water. The volume in the tested devices ranged from 4.5 to 10 ml (=450-1000 mg tobramycin) in accordance with the prescribed usage by the suppliers. The nebulizers were connected with a special designed adapter to a laser diffraction analyser in order to measure particle size distribution of the aerosol. Inhalation was simulated with a static flow of 40 l/min. The particle size distribution (expressed as X-10, X-50, and X-90) was determined after 10 s, 1.5, 3, 4.5, 6, 9 and 12 min of nebulization. Furthermore, the tobramycin solutions were assayed for tobramycin content before and after nebulization. For all nebulizers, the mean particle size distribution, depicted as X-50, was within the range of 1-5 mm. There were no relevant differences between the nebulizers in concentration or particle size distribution during nebulization. The output of the nebulizers is a result of both nebulization and evaporation. The output, expressed as volume of tobramycin solution, ranged from 0.06 to 0.50 ml/min. The output of tobramycin ranged from 1.2 to 39.5 mg/min. For clinical practice 300-600 mg have to be nebulized within 20-30 min. Lt was concluded that only three jet nebulizers [Porta-Neb Sidestream (PNS), Porta-Neb Ventstream (PNV) and Pariboy Pari LC + (PLC)] have a reasonable output and an acceptable particle size distribution for the administration of a 10% tobramycin solution in the therapeutic dosage range. (C) 1999 Elsevier Science B.V. All rights reserved

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 mug up to 400 jig were given. The FEV1 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 mug. 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 mum) of at least 10 mug. (C) 2002 Elsevier Science B.V. All rights reserved