In vitro and in vivo performance modelling and optimisation of different dry powder inhalers: A complementary study of neural networks, genetic algorithms and decision trees.

INTRODUCTION: Aerosol delivery from DPIs could be affected by different factors. This study aimed to evaluate and predict the effects of different factors on drug delivery from DPIs. METHODS: Modelling and optimisation for both in vitro and in vivo data of different DPIs (Diskus, Turbohaler and Aerolizer) were carried out using neural networks associated with genetic algorithms and the results are confirmed using a decision tree (DT) and random forest regressor (RFR). All variables (the type of DPI, inhalation flow, inhalation volume, number of inhalations and type of subject) were coded as numbers before using them in the modelling study. RESULTS: The analysis of the in vitro model showed that Turbohaler had the highest emitted dose compared with the Diskus and the Aerolizer. Increasing flow resulted in a gradual increase in the emitted dose. Little differences between the inhalation volumes 2 and 4 litres were shown at fast inhalation flow, and interestingly two inhalations showed somewhat higher emitted doses than one-inhalation mode with Turbohaler and Diskus at slow inhalation flow. Regarding the in vivo model, the percent of drug delivered to the lung was highly increased with Turbohaler and Diskus in healthy subjects where continuous contour lines were observed. The Turbohaler showed increased lung bioavailability with the two-inhalation modes, the Diskus showed a nearly constant level at both one and two inhalations at slow inhalation. The Turbohaler and Aerolizer showed little increasing effect moving from one to two inhalations at slow inhalation. CONCLUSIONS: Modelling of the input data showed a good differentiating and prediction power for both in vitro and in vivo models. The results of the modelling refer to the high efficacy of Diskus followed by Turbohaler for delivering aerosol. With two inhalations, the three DPIs showed an increase in the percent of drug excreted at slow inhalations.

Lung deposition and systemic bioavailability of dose delivered to smoker compared with non-smoker COPD subjects.

INTRODUCTION: Inhaled drugs are the most commonly used class of medications for COPD subjects. No studies have been performed to assess the influence of smoking on lung deposition of aerosolized medication, especially for the exacerbated COPD subject. The present study aimed to assess the influence of smoking on the lung deposition of the aerosol delivered to exacerbated COPD subjects. METHODS: Twenty-four exacerbated COPD subjects using automatic continuous positive airway pressure (Auto-CPAP), 12 smokers (six females) and 12 non-smokers (six females) were recruited in the study. The subjects participated in the study received four salbutamol study doses; 1200 µg (12 puffs 100 µg/puff) of salbutamol emitted from pMDI canister connected to AeroChamber MV spacer; 1200 µg of salbutamol emitted from pMDI canister connected to Combihaler spacer; 1 mL of salbutamol respirable solution (5000 µg/mL) nebulized by Aerogen Solo connected to its T-piece; and 1 mL of salbutamol respirable solution nebulized by Aerogen Solo connected to Combihaler spacer with 2 puffs salbutamol MDI (200 µg salbutamol) before nebulisation. The subjects were randomised to receive the four selected dose-adaptor combination in a sealed envelope design on days 1, 3, 5 and 7. A washout period of 24 hours was provided between each salbutamol dosing. Auto-CPAP was adjusted at non-invasive ventilation mode with the integrated heated humidifier, as a source of humidity. Urine samples were provided by subjects, 30 minutes and cumulatively 24 hours post inhalation, as an index of the relative and systemic bioavailability, respectively, and aliquots were retained for salbutamol analysis using solid-phase extraction and high-performance liquid chromatography (HPLC). On day 2 of the study, a collecting filter was placed between the aerosol generator and the subject's mask so that the subjects would not inhale the salbutamol delivered. The same study doses and/or adapters were delivered to each subject, with filters changed with each dose-adapter combination. Salbutamol entrained on the filter was desorbed to be analysed by the HPLC. RESULTS: Significantly higher lung deposition (30 minutes urinary salbutamol) was detected with the non-smoker compared with smokers (P < .05). Significantly higher systemic bioavailability (pooled 24-hour urinary salbutamol) for smokers compared with non-smokers was found with Aerogen Solo connected to its T-piece and CombiHaler spacer with pMDI (P < .05) only. Significantly higher amount desorbed from the ex-vivo filter were found from pMDI with both spacers in non-smokers (P < .05) compared with the smokers. CONCLUSION: The study demonstrated that smoking reduced the lung deposition of inhaled salbutamol delivered by nebulizer or pMDI. However, the smoking effect on cytochrome p450 was observed to increase systemic absorption of the ingested portion of the inhaled dose. The lower lung deposition and possible higher systemic absorption should be taken into consideration while prescribing inhaled medication to COPD smokers especially exacerbated patients that need ventilation. Further studies are needed.

Total emitted dose of salbutamol sulphate at different inhalation flows and inhalation volumes through different types of dry powder inhalers.

The aim of the present study was to compare the performance of two different dry powder inhalers (DPIs) at different inhalations volumes and inhalation flows. Ventolin Diskus contain blisters of 200µg salbutamol. To test the TED from Aerolizer, salbutamol in Diskus blister was emptied and placed in size 3 capsules suitable for use with Aerolizer. Total emitted dose (TED) delivered by Diskus and Aerolizer was determined using DPI sampling apparatus after one and two inhalations from the same dose. 10-60L/min inhalation flows at 2 and 4L inhalation volume were used in the determination. At inhalation flow ≤30L/min, two inhalations resulted in higher TED than one inhalation (p < 0.05) and Diskus resulted in higher TED than Aerolizer (p < 0.05). The highest TED was at inhalation flow 40L/min above which the effect of the second inhalation and formula device relation were negligible. Device formula relation is present at low inhalation flow but at flow >30L/min Diskus drug formula can be delivered by Aerolizer with no significant difference in TED produced. For the best TED patients are required to inhale as fast as possible (a minimum of 40L/min). At lower inhalation flow two inhalations results in better emitted dose than one inhalation for both DPIs. So, we recommend patients with poor inspiratory efforts to inhale twice and as hard and deep as possible from each dose as they may not receive much benefit from one inhalation even when using DPI with low resistance (Aerolizer) or medium resistance (Diskus). However, further in-vivo study are required to validate this recommendtation.

In-vitro/in-vivo comparison of inhaled salbutamol dose delivered by jet nebulizer, vibrating mesh nebulizer and metered dose inhaler with spacer during non-invasive ventilation.

BACKGROUND: Patients receiving noninvasive ventilation (NIV) may benefit from medical aerosol, but most guidance on dosing with different aerosol devices is limited to in-vitro studies. The study was designed to in-vitro, ex-vivo, and in-vivo compare aerosol delivery during bilevel NIV with three types of aerosol generators: metered dose inhaler with AeroChamber-MV spacer (AC), Aerogen Pro vibrating mesh nebulizer (PRO), and Sidestream jet nebulizer (SIDE). MATERIALS AND METHOD: A bilevel ventilator with dry single limb circuit and fixed expiratory port was set in spontaneous mode with initial inspiratory and expiratory pressures of 20 and 5 cmH20, 1:3 inspiratory-expiratory ratio, and 15 breaths.min-1. Aerosol generators were placed proximal to facial mask of NIV chronic obstructive pulmonary disease (COPD) patients. 1 mL salbutamol nebulizer solution (5 mg/mL) was nebulized using PRO and SIDE. 12MDI doses, containing 100µg salbutamol each, were delivered using AC. In-vitro aerosol fate and aerodynamic droplet characteristics, in-vivo amount of salbutamol excreted 30 mins and pooled up to 24 h post inhalation in urine from 12 COPD patients (as indices of pulmonary deposition and systemic absorption, respectively) and amount of salbutamol deposited on ex-vivo filters (expected inhalable amount) was determined. RESULTS: The in-vitro, in-vivo and ex-vivo testing showed that PRO had better aerosol delivery compared to SIDE (p < 0.01). However, with smaller nominal dose MDI with AC resulted in similar aerosol delivery to PRO suggesting better aerosol delivery stress on careful attention and proper delivery by health care provider. CONCLUSIONS: These similarities and differences between the three aerosol generators tested suggest that aerosol delivery methods should be carefully chosen or substituted in non-invasive ventilated patients.

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

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 (0.5hQ) and amount absorbed systemically (24hQ) were dependent directly on MMAD and TED. Female patients showed higher 24hQ values than males. Nebuliser type affected TED, 0.5hQ but not 24hQ 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.