Nebulizers used in acute care wards must be relied upon to rapidly deliver aerosols to patients who may be suffering an asthma attack. Both the respirable delivered dose and the respirable output rate are of significance for the rapid delivery of therapeutic doses to the target sites of action in the lungs. We tested 4 nebulizers used in acute care wards, in vitro, to determine their aerosol delivery performance into simulated adult breathing. Six of each nebulizer brand (Table 1; SSD -Philips SideStream Disposable, HMM -Hudson Micro Mist, AMF -AirLife Misty Fast, SND-Salter Nebutech Disposable 8960) were tested once for particle size and output. Each nebulizer was tested with salbutamol sulphate (Salamol 5 mg/ 2.5 mL) for particle size (Malvern Spraytec) and separately for delivered dose. Delivered dose was determined using a filter connected to a breathing simulator set to generate a sine wave (Vt=500 mL, f=15 bpm, I:E=1:1). Nebulizers were run until sputter plus 60 s. Salbutamol was quantitated by high performance liquid chromatography. There was a wide range in performance, nebuilzers with the shortest nebulization time delivered the lowest respirable delivered doses and lowest respirable output rates. Speed of treatment in acute cae should be assessed using respirable output rate not nebulization time alone.

Delivery of a therapeutic dose of bronchodilator aerosol into the lungs is crucial for patient care in acute care departments. Most nebulizer test data is collected using simulated breathing with a 1:1 inhalation exhalation (I:E) ratio. We examined the effect of I:E ratio on the respirable delivered dose (RDD) from 4 nebulizers used in acute care wards, in vitro. The fine particle fraction of aerosol output of six of each nebulizer brand (Figure 1) were tested with salbutamol sulphate (Salamol 5 mg/ 2.5 mL) using a Malvern Spraytec laser diffractor. Delivered dose was then determined for each nebulizer using simulated breathing (Vt = 500 mL, f = 15 bpm and I:E ratios of 1:1, 1:2 and 1:3) by inserting a filter between the nebulizer and the breathing simulator. Nebulizers were run at 8 L/min until sputter plus 60 s and drug on filters was quantitated by HPLC. Respirable delivered dose (RDD) = delivered dose x fine particle fraction. Patient breathing pattern I:E ratio’s can vary during their treatment in acute care wards. Only one nebulizer brand delivered a mean RDD of over 400 mg of albuterol across breathing patterns with I:E ratio’s 1:1 to 1:3. Both nebulizer brand and breathing pattern I:E ratio affect the RDD of bronchodilator, which could have significance in patient treatment.

Valved holding Chambers (VHCs) are used with pressurized metered dose inhalers (pMDIs) to counter issues patients have in coordinating pMDI actuation and inhalation. The fine particle dose (FPD <4.7μg) of aerosol from the pMDI & VHC should be similar to the FPD from the pMDI. We reviewed in vitro test results of FPD from the VHC (OptiChamber Diamond; OCD) when used with 7 drugs commonly used for the treatment of asthma and COPD. The 7 pMDI drugs (Table 1) included 2 inhaled corticosteroids (Flovent and QVAR), 1 anticholinergic (Atrovent) and 4 bronchodilator formulations of salbutamol sulphate (SALB; Ventolin Evohaler sold in the UK, Ventolin HFA, Proventil and ProAir HFA sold in the USA). Two pMDI’s were used for each drug except Flovent, QVAR and Atrovent (1 pMDI), all were tested in duplicate. Six new, unwashed VHCs were used for all drugs except QVAR (6 washed VHCs). The FPD of aerosol emitted from either pMDI alone or pMDI with OCD VHC was assessed using a next generation impactor operated at 30 L/min, 10 pMDI actuations were used for each run. FPD from the pMDI with VHC was equivalent or greater than pMDI alone. Although the 4 bronchodilator drug formulations delivered the same drug (SALB) the FPD differed by up to a factor of 2.

Mesh nebulizers have been designed to deliver a dose of drug quietly and rapidly, with a high delivered dose to maximise drug delivery efficiency and short treatment times to reduce the treatment burden to the patient. The dose outputs and treatment times of 5 mesh nebulizers were measured to determine typical doses and treatment times. Three of each nebulizer (MicroAir U22, Aeroneb Go, production equivalent InnoSpire Go, Voyager Pro, and IH50) were tested in triplicate with 2.5 mL of 2 mg/mL salbutamol sulphate. Nebulizers were attached to a breathing simulator producing a CEN breathing pattern (500 mL tidal volume, 1:1 inhalation:exhalation ratio, 15 breaths per minute), loaded with the contents of a drug nebule, and run until nebulization was complete. Drug output was collected on filters attached to the nebulizer mouthpiece, and assessed by high performance liquid chromatography. Treatment time was recorded using a timer. Dose delivered to the filter (as a percentage of the drug nebule label claim) and treatment time were plotted (Figure 1). Figure 1. Mean dose and time of the nebulizers (n=9), error bars show 1 standard deviation about the mean. Differences of 22.4% were found between the highest and lowest mean dose delivered to filter, and 4.5 minutes between the fastest and slowest mean treatment times. Dose delivered to filter and treatment times varied across the mesh nebulizers tested.

A rapid and simple reversed-phase high performance liquid chromatography (HPLC) method for the quantitation of colistimethate sodium in pharmaceutical formulations has been developed. The chromatographic separation was performed using a Phenomenex Kinetex XB-C18 column with gradient elution using a mobile phase containing acetonitrile and 32mM sodium sulphate. Quantitation is based on the sum of the areas of two prominent peaks in the chromatogram, which produces a total peak area that is stable for 120 sample injections. The HPLC method was validated over the range 0.05-7mg/mL, and was shown to be suitable for the analysis of aerosolised pharmaceuticals in terms of aerosol output onto filter and for the analysis of samples from a cascade impactor, which is used for the determination of aerosol particle size.

BACKGROUND:Valved holding chambers (VHCs) are used in children to deliver pressurized metered dose inhalers (pMDI). In vitro data suggest that uncoordinated use decreases the amount of drug available for inhalation. We hypothesize that in an ex vivo study, the coordinated maneuver will deliver more drug than the uncoordinated one. PATIENTS AND METHODS:Thirty-two clinically stable asthmatic children, ages 5-8 years, completed the study. An aerosol filter was interposed between a small-volume nonelectrostatic VHC and a mouthpiece to capture the drug emitted by one puff of Flovent® 220 mcg during tidal breathing. Inhalation and actuation parameters were measured by an electronic monitor, and the number of breaths required to empty the VHC was calculated. Subjects completed three coordinated and three uncoordinated (actuation at the beginning of inhalation and exhalation, respectively) runs in random order. Drug content from the filter and VHC was measured by high-performance liquid chromatography and expressed as percentage of emitted dose. RESULTS:[mean (99% confidence interval)] Filter dose was higher during coordinated technique 46% (43%-50%) than during uncoordinated technique 41% (37%-44%) (p < 0.001). Peak inspiratory flow and tidal volume were 23.2 L/min (21.3-25.1 L/min) and 281 mL (251-311 mL), respectively. Subjects required three breaths to empty the VHC in 96% of the tests. CONCLUSIONS:Actuating the pMDI into a small-volume nonelectrostatic VHC during exhalation reduced by 11% the amount of fluticasone captured at the exit of the VHC. Asthmatic children (5-8 years old) need three or less breaths to empty the small-volume VHC (NCT01714063).

Mesh nebulizers are designed to generate aerosol in 1 of 2 ways, passively with a horn vibrating ultrasonically against a static mesh or actively with a mesh mounted in an ultrasonically vibrating piezo ring, and have 4 distinct advantages over jet or ultrasonic devices: they benefit from a single-pass aerosol production mechanism, there is no variability in drug delivered across the treatment due to concentration by evaporation, no increase in drug temperature during operation, and the potential for shear forces acting on the formulation during aerosol production is low. We conducted in vitro studies using 4 mesh nebulizers of both active and passive designs to test their suitability for delivering formulations with a wide range of characteristics, including polypeptides and proteins up to 150 kDa, bi- and multi-laminar liposomal formulations, non-ionic surfactant vesicles, non-water-soluble suspensions, and formulations with physicochemical parameters ranging from 1-2 mPa.s viscosity and 44-71 mN/m surface tension. Aerosols were characterized in terms of predicting the amount of active pharmaceutical component delivered into simulated tidal breathing, particle size distribution, and post-nebulization formulation integrity. Among the formulations examined, the mesh nebulizers tested did not affect physical or biologic integrity in terms of retention of enzymatic or antibiotic activities and liposomal structure, and there were no quantifiable changes to component identity after nebulization, as determined by HPLC. The use of mesh nebulizers offers the potential for successful delivery of new and increasingly complex biologics. Results from the testing of 30 formulations will be presented.

Introduction: Nebulizers are a common device choice for use when developing a new drug product, but the range of nebulizer devices available can make it difficult to select the right device. Increasingly, companies are only able to promote a drug with the device that was used during the development program; therefore, choosing the best device at an early stage is important in order to achieve commercial success. Selecting a device that is inappropriate for the intended drug can result in poor drug delivery from the nebulizer to the patient, which would have obvious implications for the development program. As device performance varies, it is important to ensure that the most appropriate device is chosen for the intended drug to ensure optimal drug delivery to the patient population.Areas covered: In this review, the types of nebulizer devices available are highlighted, and the factors that should be taken into consideration when selecting the most appropriate device for a new drug are discussed. The review is broadly divided into drug, device, patient and trial characteristics.Expert opinion: Efficient nebulizer devices that combine electronic monitoring capabilities as a form of telehealth are likely to provide superior drug delivery to patients and accurate clinical trial data. Their use in adaptive clinical trials may help to vastly reduce the time and costs associated with achieving drug approval.

The in vitro characterization of device-related parameters such as the rate of aerosol output, total aerosol output, particle size, and fine particle fraction, is essential when assessing the potential performance of a nebulizer or making comparisons with other nebulizers as they are indicative of potential clinical performance. This article reviews a number of in vitro studies designed to characterize the I-neb Adaptive Aerosol Delivery (AAD) System in terms of drug delivery (particle size, residual, reproducibility, precise dose delivery, dose equivalence), in terms of drug-related performance (osmolality, surface tension, viscosity), and in terms of nebulizer orientation during operation. The results of the in vitro tests of drug delivery indicate that the I-neb AAD System is suitable for delivery of aqueous solutions by nebulization. The evaluation of equivalent doses between the I-neb AAD System (metered dose) and a conventional jet nebulizer (delivered dose), demonstrates that the amount of drug required to deliver the same dose is up to five times less with the I-neb AAD System due to the low residual and controlled drug delivery. The lack of change in osmolality during nebulization might be of importance as it presents an opportunity for delivery of drugs to patients with hyperreactive airways, or where a specific tonicity of the formulation is required. The physicochemical characteristics (surface tension, viscosity) of a number of drugs delivered with the I-neb AAD System highlights some of the demands created by existing and new drug formulations. Finally, the study of the impact of nebulizer orientation shows how important it is to also consider how the nebulizer will actually be physically used by the patient rather than solely under standard conditions used within the laboratory.