A simple method for assaying colistimethate sodium in pharmaceutical aerosol samples using high performance liquid chromatography.

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.

Drug Delivery in Asthmatic Children Following Coordinated and Uncoordinated Inhalation Maneuvers: A Randomized Crossover Trial.

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).

Variability in Delivered Dose from Pressurized Metered-Dose Inhaler Formulations Due to a Delay Between Shake and Fire.

BACKGROUND: Pressurized metered-dose inhalers (pMDIs) should be shaken before use to prevent creaming or sedimentation of the drugs in solution; however, data published on this topic are limited, and it is rarely specified how soon after shaking the device should be actuated. Delays between shaking and firing the pMDI have previously been shown to cause significant inhomogeneity in delivered dose. We studied the effect of various shake-fire delays on the drug delivered from five commercially available pMDIs commonly prescribed for asthma and chronic obstructive pulmonary disease to assess the potential variability in delivered dose. METHODS: The pMDI formulations tested were the Flovent HFA, Ventolin Evohaler, Airomir Inhaler, and Symbicort (suspension pMDIs), and the QVAR 100 Inhaler (solution pMDI). Each pMDI was shaken for 5 seconds before attachment to a dosage unit sampling apparatus collection tube and filter, and it was actuated once with shake-fire delays of 0, 5, 10, 20, 30, 40, 50, and 60 seconds. Analysis of the eluates from the collection tubes and filters was performed by using high-performance liquid chromatography. Three of each pMDI were tested twice with each time delay. RESULTS: All of the suspension pMDIs produced variable amounts of drug over the shake-fire delays tested. A comparison of the delivered doses after the 0- and 60-second delays showed that the drug delivered increased for the Flovent HFA (320%), Ventolin Evohaler (346%), and Airomir Inhaler (230%) pMDIs; decreased for the Symbicort budesonide (75%) and formoterol fumarate (76%) pMDI; and remained consistent for the QVAR 100 Inhaler pMDI. CONCLUSIONS: The amount of drug delivered can vary widely over different shake-fire delays with suspension pMDIs. Therefore, guidance should be given to users/caregivers on the timing of firing after shaking their device, particularly with pediatrics, who may take time to become receptive to accepting their medication after pMDI shaking and before dose administration.

Factors to consider when selecting a nebulizer for a new inhaled drug product development program.

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.

In vitro characterization of the OptiChamber Diamond valved holding chamber.

BACKGROUND: Use of a valved holding chamber (VHC) in conjunction with a pressurized metered dose inhaler (pMDI) can reduce issues relating to poor actuation-inhalation coordination and potentially improve the lung deposition of aerosol, compared with use of a pMDI alone. However, the performance of a VHC is influenced by different device-related factors, including the size and shape of the VHC and the material it is manufactured from (conventional versus antistatic). This study aimed to provide an in vitro characterization of an antistatic VHC, the OptiChamber Diamond VHC, comparing the aerodynamic particle size distribution of aerosol delivered via this VHC with results from a second antistatic VHC and a conventional VHC. METHODS: The pMDI drug formulations (albuterol, suspension; beclomethasone dipropionate, solution) were connected to a Next Generation Impactor, either directly (pMDI alone tests) or via a VHC (VHC tests). The pMDIs were actuated (×10 per product pair) and tested at extraction flow rates of 15 L/min and 30 L/min, without any time delay between actuation and inhalation. Dose delivery using the two pMDI drug formulations was compared, and is presented with reference to key aerodynamic particle size parameters. RESULTS: Compared with tests on pMDIs alone, use of a VHC increased the dose of aerosol within the respirable range, particularly at a 15 L/min flow rate. Between-VHC comparisons indicated that the two antistatic VHCs were equivalent. Delivery of albuterol appeared to be influenced by the VHC used, but beclomethasone dipropionate seemed unaffected. CONCLUSIONS: The two antistatic VHCs were equivalent for both pMDI brands. Aerosol delivered from the antistatic VHCs at 15 L/min had a higher proportion of fine particles compared with the conventional VHC.

In vitro comparison of the effect of inhalation delay and flow rate on the emitted dose from three valved holding chambers.

BACKGROUND: Valved holding chambers (VHCs) are accessory devices for pressurized metered dose inhalers (pMDIs). Use of a VHC may help overcome coordination issues associated with drug delivery via the pMDI alone. Previous work has established that aspects of VHC use, including the time between actuation and inhalation (inhalation delay) and inhalation flow rate, can influence the amount of drug available to inhalation. This study compared the impact of inhalation delay and flow rate on the in vitro delivery of aerosol from different VHC brands. METHODS: A custom-built inhalation delay test rig, which enabled automation of controlled inhalation delays (0, 5, or 10 sec), was developed. Extraction air flow was set to 5, 15, or 30 L/min. Delivery of albuterol (ProAir HFA 90 µg) to a filter (emitted dose) was assessed using three commercially available VHC brands (one conventional, two antistatic). Emitted dose under 27 different combinations of inhalation delay, flow rate, and VHC brand was determined in order to assess the effects of inhalation delay and flow rate. Pairwise comparisons of the different VHC brands with different inhalation delay/flow rate combinations were conducted to assess in vitro equivalence. RESULTS: Emitted dose increased with flow rate and decreased with longer inhalation delays. Dependence on flow rate was similar for the two antistatic VHCs and more pronounced for the conventional VHC. The two antistatic VHCs showed equivalent results for the emitted dose of albuterol, across a range of flow rates and using different inhalation delays; the relation between the two antistatic VHCs fell within the ± 15% acceptance interval criteria for in vitro equivalence. CONCLUSIONS: The different inhalation delays and flow rates had similar effects on the delivery of drug via the three VHCs. The two antistatic VHCs were shown to be equivalent in vitro in terms of emitted dose of albuterol.

In vitro characterization of the I-neb Adaptive Aerosol Delivery (AAD) system.

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.