Mohamed E.A. Abdelrahim

In-vitro characterisation of the nebulised dose during non-invasive ventilation

Objectives  Non‐invasive ventilation (NIV) with nebulised bronchodilators helps some patients to maintain effective ventilation. However, the position of the nebuliser in the ventilation circuit may affect lung delivery.

Disposable versus reusable jet nebulizers for cystic fibrosis treatment with tobramycin.

BACKGROUND Jet nebulizers are commonly used to administer aerosolized tobramycin to CF patients. The aim of this study was to assess the performance of disposable jet nebulizers as an alternative to reusable nebulizers such as the Pari LC Plus. METHOD From a survey conducted in 49 CF centers in France, 18 disposable jet nebulizer systems were selected. An in vitro study was performed with 20 jet nebulizer/air source combinations (18 disposable and 2 reusable) to determine their performance with tobramycin solution (300 mg/5 mL). A scintigraphic deposition study in baboons was performed to validate the in vitro data. RESULTS In vitro and in vivo results correlated. There was no overall relationship between the compressed air source and nebulizer performance, but the nebulizer interface was responsible for significantly different results. CONCLUSIONS None of the disposable nebulizers tested in this study can be recommended as an alternative to the Pari LC Plus nebulizer for tobramycin.

Emitted dose and lung deposition of inhaled terbutaline from Turbuhaler at different conditions

Turbuhaler has a very high resistance hence patient inhalation flow when using it would be low. The total emitted dose (TED) of 500microg terbutaline sulphate from a Bricanyl Turbuhaler was determined using a range of inhalation flows (10-60L min(-1)) with inhalation volume of 2 and 4L using a DPI sampling apparatus after one and two inhalations. The relative lung and systemic bioavailability of terbutaline from Bricanyl Turbuhaler when used by healthy subjects and COPD patients were determined after one and two inhalations at slow and fast inhalation flows using a novel urinary terbutaline pharmacokinetic method. The TED resulted from the one and two inhalations increased significantly (p<0.05) with the increase of the inhalation flow at both 2 and 4L inhalation volumes. The relative lung and systemic bioavailability after one inhalation at fast inhalation flow were significantly higher (p<0.01) than at slow inhalation flow in both healthy subjects and patients. Also the healthy subjects results were significantly higher (p<0.05) than the COPD patients after one inhalation. However after two inhalations there was no significant difference between slow and fast inhalation flow or healthy subjects and COPD patients. Hence it is essential to inhale twice and as deep and hard as possible from each dose of Turbuhaler for patients with low inspiratory flow and limited inhalation volume as they may not receive much benefit from one inhalation.

The relative lung and systemic bioavailability of terbutaline following nebulisation in non-invasively ventilated patients

Nebulising a bronchodilator during non-invasive ventilation (NIV) is effective but there is a lack of consensus on the system to use because comparator in vivo studies in these patients are difficult. Urinary pharmacokinetic methodology post inhalation could provide this information. Chronic obstructive pulmonary disease patients requiring NIV received randomised study doses of either 2mg terbutaline nebulised from an Aeroneb Pro (AERO) or 5mg from a Sidestream (SIDE) on days 1 and 3 of admission. Urine samples were provided at 30 min then pooled up to 24h post inhalation and amounts of urinary terbutaline (UTER0.5 and UTER24; indices of relative lung and systemic bioavailability, respectively) were determined. Twelve consenting patients receiving NIV mean (SD) age and weight of 74.8 (8.2) years and 61.0 (10.7)kg completed the study. The mean (SD) UTER0.5 following AERO and SIDE was 9.4 (3.7) and 10.4 (4.1) μg with a mean ratio (90% confidence interval) of 89.7 (87.8, 92.3)%. UTER24 was 192.3 (52.4) and 205.3 (58.0)mcg with a mean ratio (90% CI) of 93.7 (113.5, 77.3)%. This urinary pharmacokinetic method to identity relative lung and systemic bioavailability between two nebuliser systems was easy to perform and is a useful and simple in vivo method to compare different nebulisers in patients receiving non-invasive ventilation.

Aerodynamic characteristics of nebulized terbutaline sulphate using the Andersen Cascade Impactor compared to the Next Generation Impactor

Characterization of the aerosol emitted from nebulizers is determined using the Next Generation Impactor (NGI). The Andersen Cascade Impactor (ACI) was previously used but the limitation of high flow rate used decreased its uses. We have investigated the use of ACI with different operational conditions compared to the NGI methodology. NGI was operated at a flow rate of 15 L min−1 after cooling at 5°C for 90 min. ACI was operated using flow rates 15 and 28.3 L min−1 at room (ROOM) temperature and after cooling at 5°C for 60 min (COLD). ACI was also operated using a flow rate 15 L min−1 through the nebulizer T-piece with a flow rate 28.3 L min−1 through ACI (15 Mix) using the mixing valve at ROOM and COLD. Two nebulizer systems, the Sidestream (SIDE) and the Aeroneb Pro (AERO) were used to nebulize terbutaline sulphate respiratory solution. Overall there was a highly significant difference (P < 0.001) between different ACI operating conditions for FPF and MMAD of both nebulizer systems. The ACI at higher flow rate increased the evaporation effect whilst cooling minimized evaporation of both nebulizer systems. Hence cooling and using slow flow rate minimizes evaporation effects with ACI. The ACI 15COLD results were similar to that of NGI. That supports the use of ACI at inhalation flow rate 15 L min−1 without fear of domination of gravity on ACI stages.

In vitro/in vivo correlation and modeling of emitted dose and lung deposition of inhaled salbutamol from metered dose inhalers with different types of spacers in noninvasively ventilated patients

Abstract Substituting spacer by another in noninvasive ventilation (NIV) involves many variables, e.g. total emitted dose (TED), mass median aerodynamic diameter (MMAD), type of spacer, total lung deposition and total systemic absorption, which must be adjusted to ensure patient optimum therapy. Data mining based on artificial neural networks and genetic algorithms were used to model in vitro inhalation process, predict and optimize bioavailability from inhaled doses delivered by metered dose inhaler (MDI) using different spacers in NIV. Modeling of data indicated that in vitro performance of MDI-spacer systems was dependent mainly on fine particle dose (FPD), fine particle fraction (FPF), MMAD and to lesser extent on spacer type. Ex vivo model indicated that amount of salbutamol collected on facemask filter was directly affected by FPF. In vivo model (24hQ) depended directly on spacer type, FPF and TED. Female patients showed higher 0.5hQ and 24hQ values than males. AeroChamber VC spacer demonstrated higher TED and 24hQ in vivo values. Results indicated suitability of MDI-spacer systems in achieving appropriate in vitro inhalation performance. The possibility of modeling and predicting both ex vivo and in vivo capabilities of MDI-spacer systems from knowledge of in vitro attributes enabled detailed focus on important variables required to deliver safe and accurate doses of salbutamol to ventilated patients.

Dose emission and aerodynamic characterization of the terbutaline sulphate dose emitted from a Turbuhaler at low inhalation flow.

Previously, dose emission below 30 L min−1 through DPI has not been routinely determined. However, during routine use some patients do not achieve 30 L min−1 inhalation flows. Hence, the aim of the present study was to determine dose emission characteristics for low inhalation flows from terbutaline sulphate Turbuhaler. Total emitted dose (TED), fine particle dose (FPD) and mass median aerodynamic diameter (MMAD) of terbutaline sulphate Turbuhaler were determined using inhalation flows of 10–60 L min−1 and inhaled volume of 4 L. TED and FPD increase significantly with the increase of inhalation flows (p <0.05). Flows had more pronounced effect on FPD than TED, thus, faster inhalation increases respirable amount more than it increases emitted dose. MMAD increases with decrease of inhalation flow until flow of 20L min−1 then it decreases. In vitro flow dependent dose emission has been demonstrated previously for Turbuhaler for flow rates above 30 L min−1 but is more pronounced below this flow. Minimal FPD below 30 L min−1 suggests that during routine use at this flow rate most of emitted dose will impact in mouth. Flow dependent dose emission results suggest that Pharmacopoeias should consider the use variety of inhalation flows rather than one that is equivalent to pressure drop of 4 KPa.

Nanosized rods agglomerates as a new approach for formulation of a dry powder inhaler

Background: Nanosized dry powder inhalers provide higher stability for poorly water-soluble drugs as compared with liquid formulations. However, the respirable particles must have a diameter of 1–5 μm in order to deposit in the lungs. Controlled agglomeration of the nanoparticles increases their geometric particle size so they can deposit easily in the lungs. In the lungs, they fall apart to reform nanoparticles, thus enhancing the dissolution rate of the drugs. Theophylline is a bronchodilator with poor solubility in water. Methods: Nanosized theophylline colloids were formed using an amphiphilic surfactant and destabilized using dilute sodium chloride solutions to form the agglomerates. Results: The theophylline nanoparticles thus obtained had an average particle size of 290 nm and a zeta potential of −39.5 mV, whereas the agglomerates were 2.47 μm in size with a zeta potential of −28.9 mV. The release profile was found to follow first-order kinetics (r2 > 0.96). The aerodynamic characteristics of the agglomerated nanoparticles were determined using a cascade impactor. The behavior of the agglomerate was significantly better than unprocessed raw theophylline powder. In addition, the nanoparticles and agglomerates resulted in a significant improvement in the dissolution of theophylline. Conclusion: The results obtained lend support to the hypothesis that controlled agglomeration strategies provide an efficient approach for the delivery of poorly water-soluble drugs into the lungs.

Relative bioavailability of terbutaline to the lung following inhalation, using urinary excretion

AIMS The aim of the study was to determine the relative lung and systemic bioavailability of terbutaline. METHODS On separate days healthy volunteers received 500 µg terbutaline study doses either inhaled from a metered dose inhaler or swallowed as a solution with and without oral charcoal. Urine samples were provided at timed intervals post dosing. RESULTS Mean (SD) urinary terbutaline 0.5 h post inhalation, in 12 volunteers, with (IC) and without (I) oral charcoal and oral (O) dosing was 7.4 (2.2), 6.5 (2.1) and 0.2 (0.2) µg. I and IC were similar and both significantly greater than O (P<0.001). Urinary 24 h terbutaline post I was similar to IC + O. The method was linear and reproducible, similar to that of the urinary salbutamol method. CONCLUSIONS The urinary salbutamol pharmacokinetic method post inhalation applies to terbutaline. Terbutaline study doses can replace routine salbutamol during these studies when patients are studied.

Modelling of in-vitro and in-vivo performance of aerosol emitted from different vibrating mesh nebulisers in non-invasive ventilation circuit

&NA; Substituting nebulisers by another in non‐invasive ventilation circuit (NIV) involves many process variables which must be adjusted to ensure patient optimum therapy. However, there is a doubt when nebulisers use the same technology. Data mining technology based on artificial neural networks and genetic algorithms were used here to model in‐vitro inhalation process and predict bioavailability from inhaled doses delivered by three different vibrating mesh nebulisers (VMNs) in NIV. Modelling of data indicated that in‐vitro performance of VMNs was dependent mainly on fine particle fraction, mass median aerodynamic diameter (MMAD), total emitted dose (TED) and to lesser extent on nebuliser type. Ex‐vivo model indicated that amount of salbutamol collected on facemask filter was directly affected by TED. In‐vivo model showed that amount of salbutamol deposited into the lung (0.5 hQ) and amount absorbed systemically (24 hQ) were dependent directly on MMAD and TED. Female patients showed higher 24 hQ values than males. Nebuliser type affected TED, 0.5 hQ but not 24 hQ values. Results indicate suitability of VMNs in achieving appropriate in‐vitro inhalation performance model. The results also, indicate that the three VMNs are comparable and can be interchanged with no fear of any additional toxicity. Graphical abstract Figure. No caption available.