Tanya Church

Plume temperature emitted from metered dose inhalers

The temperature of the drug cloud emitted from a pressurised metered dose inhaler (pMDI) may result in patient discomfort and inconsistent or non-existent dose delivery to the lungs. The effects of variations in formulation (drug, propellant, co-solvent content) and device hardware (metering volume, actuator orifice diameter, add-on devices) upon the temperature of pMDI plumes, expressed as replicate mean minimum values (MMPT), collected into a pharmacopoeial dose unit sampling apparatus (DUSA), have been investigated. Ten commercially available and two development products, including chlorofluorocarbon (CFC) suspensions and hydrofluoroalkane (HFA) solutions or suspensions, were examined together with a number of drug products in late stage development and a variety of HFA 134a placebo pMDIs. Plume temperatures were observed to be lowest in the proximity of the products actuator mouthpiece where rapid flashing and evaporation of the formulations propellant and volatile excipients cause cooling. The ability to control plume temperature by judicious choice of formulation co-solvent content, metering volume and the actuator orifice diameter is identified. An ethanol based HFA 134a formulation delivered through a fine orifice is inherently warmer than one with 100% HFA 134a vehicle delivered through a coarse actuator orifice. Of the 10 commercial products evaluated, MMPTs ranged from -54 to +4°C and followed the formulation class rank order, HFA suspensions<CFC suspensions<HFA solutions. For all systems examined it was possible to raise pMDI plume temperature to that of the ambient surroundings by use of an add-on or integrated spacer device.

Towards the bioequivalence of pressurised metered dose inhalers 1: Design and characterisation of aerodynamically equivalent beclomethasone dipropionate inhalers with and without glycerol as a non-volatile excipient

A series of semi-empirical equations were utilised to design two solution based pressurised metered dose inhaler (pMDI) formulations, with equivalent aerosol performance but different physicochemical properties. Both inhaler formulations contained the drug, beclomethasone dipropionate (BDP), a volatile mixture of ethanol co-solvent and propellant (hydrofluoroalkane-HFA). However, one formulation was designed such that the emitted aerosol particles contained BDP and glycerol, a common inhalation particle modifying excipient, in a 1:1 mass ratio. By modifying the formulation parameters, including actuator orifice, HFA and metering volumes, it was possible to produce two formulations (glycerol-free and glycerol-containing) which had identical mass median aerodynamic diameters (2.4μm±0.1 and 2.5μm±0.2), fine particle dose (⩽5μm; 66μg±6 and 68μg±2) and fine particle fractions (28%±2% and 30%±1%), respectively. These observations demonstrate that it is possible to engineer formulations that generate aerosol particles with very different compositions to have similar emitted dose and in vitro deposition profiles, thus making them equivalent in terms of aerosol performance. Analysis of the physicochemical properties of each formulation identified significant differences in terms of morphology, thermal properties and drug dissolution of emitted particles. The particles produced from both formulations were amorphous; however, the formulation containing glycerol generated particles with a porous structure, while the glycerol-free formulation generated particles with a primarily spherical morphology. Furthermore, the glycerol-containing particles had a significantly lower dissolution rate (7.8%±2.1%, over 180min) compared to the glycerol-free particles (58.0%±2.9%, over 60min) when measured using a Franz diffusion cell. It is hypothesised that the presence of glycerol in the emitted aerosol particles altered solubility and drug transport, which may have implications for BDP pharmacokinetics after deposition in the respiratory tract.

A correlation equation for the mass median aerodynamic diameter of the aerosol emitted by solution metered dose inhalers

A correlation equation for the mass median aerodynamic diameter (MMAD) of the aerosol emitted by solution metered dose inhalers (MDIs) is presented. A content equivalent diameter is defined and used to describe aerosols generated by evaporating metered dose inhaler sprays. A large set of cascade impaction data is analyzed, and the MMAD and geometric standard deviation is calculated for each datum. Using dimensional analysis, the mass median content equivalent diameter is correlated with formulation variables. Based on this correlation in combination with mass balance considerations and the definition of the aerodynamic diameter, an equation for prediction of the MMAD of an inhaler given the pressure of the propellant in the metering chamber of the MDI valve and the surface tension of the propellant is derived. The accuracy of the correlation equation is verified by comparison with literature results. The equation is applicable to both HFA (hydrofluoroalkane) propellants 134a and 227ea, with varying levels of co-solvent ethanol.

High-Speed Laser Image Analysis of Plume Angles for Pressurised Metered Dose Inhalers: The Effect of Nozzle Geometry

The aim of this study is to investigate aerosol plume geometries of pressurised metered dose inhalers (pMDIs) using a high-speed laser image system with different actuator nozzle materials and designs. Actuators made from aluminium, PET and PTFE were manufactured with four different nozzle designs: cone, flat, curved cone and curved flat. Plume angles and spans generated using the designed actuator nozzles with four solution-based pMDI formulations were imaged using Oxford Lasers EnVision system and analysed using EnVision Patternate software. Reduced plume angles for all actuator materials and nozzle designs were observed with pMDI formulations containing drug with high co-solvent concentration (ethanol) due to the reduced vapour pressure. Significantly higher plume angles were observed with the PTFE flat nozzle across all formulations, which could be a result of the nozzle geometry and material’s hydrophobicity. The plume geometry of pMDI aerosols can be influenced by the vapour pressure of the formulation, nozzle geometries and actuator material physiochemical properties.

The Influence of Actuator Materials and Nozzle Designs on Electrostatic Charge of Pressurised Metered Dose Inhaler (pMDI) Formulations

ABSTRACTPurposeTo investigate the influence of different actuator materials and nozzle designs on the electrostatic charge properties of a series of solution metered dose inhaler (pMDI) aerosols.MethodsActuators were manufactured with flat and cone nozzle designs using five different materials from the triboelectric series (Nylon, Polyethylene terephthalate, Polyethylene–High density, Polypropylene copolymer and Polytetrafluoroethylene). The electrostatic charge profiles of pMDI containing beclomethasone dipropionate (BDP) as model drug in HFA-134a propellant, with different concentrations of ethanol were studied. Electrostatic measurements were taken using a modified electrical low-pressure impactor (ELPI) and the deposited drug mass assayed chemically using HPLC.ResultsThe charge profiles of HFA 134a alone have shown strong electronegativity with all actuator materials and nozzle designs, at an average of –1531.34 pC ± 377.34. The presence of co-solvent ethanol significantly reduced the negative charge magnitude. BDP reduced the suppressing effect of ethanol on the negative charging of the propellant. For all tested formulations, the flat nozzle design showed no significant differences in net charge between different actuator materials, whereas the charge profiles of cone designs followed the triboelectric series.ConclusionThe electrostatic charging profiles from a solution pMDI containing BDP and ethanol can be significantly influenced by the actuator material, nozzle design and formulation components. Ethanol concentration appears to have the most significant impact. Furthermore, BDP interactions with ethanol and HFA have an influence on the electrostatic charge of aerosols. By choosing different combinations of actuator materials and orifice design, the fine particle fractions of formulations can be altered.

Experimental and computational study of the effect of breath-actuated mechanism built in the NEXThaler® dry powder inhaler

The breath-actuated mechanism (BAM) is a mechanical unit included in NEXThaler® with the role of delaying the emission of the drug until the inhalation flow rate of the patient is sufficiently high to detach the drug particles from their carriers. The main objective of this work was to analyse the effect of the presence of BAM on the size distribution of the emitted drug and its airway deposition efficiency and distribution. Study of the hygroscopic growth of the emitted drug particles and its effect on the deposition was another goal of this study. Size distributions of Foster® NEXThaler® drug particles emitted by dry powder inhalers with and without BAM have been measured by a Next Generation Impactor. Three characteristic inhalation profiles of asthmatic patients (low, moderate and high flow rates) were used for both experimental and modelling purposes. Particle hygroscopic growth was determined by a new method, where experimental measurements are combined with simulations. Upper airway and lung deposition fractions were computed assuming 5s and 10s breath-hold times. By the inclusion of BAM the fine particle fraction of the steroid component increased from 24 to 30% to 47-51%, while that of bronchodilator from 25-34% to 52-55%. The predicted upper airway steroid and bronchodilator doses decreased from about 60% to 35-40% due to BAM. At the same time, predicted lung doses increased from about 20%-35% (steroid) and from 22% to 38% (bronchodilator) for the moderate flow profile and from about 25% to 40% (steroid) and from 29% to 47% (bronchodilator) for the high inhalation flow profile. Although BDP and FF upper airway doses decreased by a factor of about two when BAM was present, lung doses of both components were about the same in the BAM and no-BAM configurations at the weakest flow profile. However, lung dose increased by 2-3% even for this profile when hygroscopic growth was taken into account. In conclusion, the NEXThaler® BAM mechanism is a unique feature enabling high emitted fine particle fraction and enhanced drug delivery to the lungs.

Transient flashing propellant flow models to predict internal flow characteristics, spray velocity, and aerosol droplet size of a pMDI

ABSTRACT Despite the popularity of the pMDI as an asthma remedy, the mechanism leading to spray generation is elusive, mainly due to small length scales and short time scale, causing experimental difficulties to obtain flow information. This mechanism involves transient development of two-phase flashing propellant flow inside pMDI actuator as well as transfer of heat, mass, and momentum between the liquid and vapor phase. Variations in the rate of such interphase phenomena dictate the two-phase mass flow rate emission, which itself determines spray velocity and droplet size. In this work, we compare the performance of existing two-phase flow models to predict the flow conditions and the rate of propellant flow through a pMDI actuator: the homogenous equilibrium model (HEM), the slip equilibrium model (SEM), and the homogenous frozen model (HFM). The velocity prediction of the HFM was found to be in good agreement with phase Doppler anemometry (PDA) data indicating the metastable nature of the emitted propellant spray. This work also considers Clarks correlation for the aerosol droplet size based on the results of the flow model. The results of the correlation were compared with PDA droplet size measurements. Clarks correlation was found to be effective in predictions of the temporal droplet size variations. However, the value of an empirical constant had to be tuned to fix the droplet size for a given combination of formulation, device, and to a lesser extent also the distance from the spray orifice where predictions are compared with PDA data. This highlights the need to develop first principle atomization models without the need for case-by-case adjustment.

Humidity affects the morphology of particles emitted from beclomethasone dipropionate pressurized metered dose inhalers

The effects of propellant type, cosolvent content, and air humidity on the morphology and solid phase of the particles produced from solution pressurized metered dose inhalers containing the corticosteroid beclomethasone dipropionate were investigated. The active ingredient was dissolved in the HFA propellants 134a and 227ea with varying levels of the cosolvent ethanol and filled into pressurized metered dose inhalers. Inhalers were actuated into an evaporation chamber under controlled temperature and humidity conditions and sampled using a single nozzle, single stage inertial impactor. Particle morphology was assessed qualitatively using field emission scanning electron microscopy and focused ion beam-helium ion microscopy. Drug solid phase was assessed using Raman microscopy. The relative humidity of the air during inhaler actuation was found to have a strong effect on the particle morphology, with solid spheroidal particles produced in dry air and highly porous particles produced at higher humidity levels. Air humidification was found to have no effect on the solid phase of the drug particles, which was predominantly amorphous for all tested formulations. A critical level of air relative humidity was required to generate porous particles for each tested formulation. This critical relative humidity was found to depend on the amount of ethanol used in the inhaler, but not on the type of propellant utilized. The results indicate that under the right circumstances water vapor saturation followed by nucleated water condensation or ice deposition occurs during particle formation from evaporating propellant-cosolvent-BDP droplets. This finding reveals the importance of condensed water or ice as a templating agent for porosity when particle formation occurs at saturated conditions, with possible implications on the pharmacokinetics of solution pMDIs and potential applications in particle engineering for drug delivery.

Deposition of micrometer-sized aerosol particles in neonatal nasal airway replicas

ABSTRACT The nasal aerosol filtration properties of infants 0–3 months old have been quantified through in vitro measurements. Computed tomography (CT) scan data was obtained of seven individuals with ages of 5–79 days. Nasal airway replicas based on these images were manufactured using rapid prototyping. Deposition in the replicas was measured using an electrical low pressure impactor (ELPI) to measure the concentration of aerosol particles in the inertial regime. Comparing the difference in concentration when sampling through the model versus sampling through a blank line gave the deposition fraction. Deposition was measured for particles with aerodynamic diameters between 0.53 and 5.54 μm. Nonlinear least squares curve fitting was performed to collapse intersubject variability and represent the data with a single curve. To achieve satisfactory intersubject variability collapse, a non-dimensional pressure drop, the Euler number (Eu), was required in addition to the Reynolds number (Re) and the particle Stokes number (Stk) where the dimensionless parameters are evaluated with a length scale, D, defined as the airway volume divided by the airway surface area. The equation describing the deposition fraction, η, is η = 1- (14590 / (14590 + Stk1.2201Re1.7742Eu1.5772))0.3687. An analysis of the expected intersubject variability in in vivo deposition was also performed, yielding a method for predicting variance in neonatal nasal airway deposition. Copyright

Pulmonary aerosol delivery and the importance of growth dynamics

Aerosols are dynamic systems, responding to variations in the surrounding environmental conditions by changing in size, composition and phase. Although, widely used in inhalation therapies, details of the processes occurring on aerosol generation and during inhalation have received little attention. Instead, research has focused on improvements to the formulation of the drug prior to aerosolization and the resulting clinical efficacy of the treatment. Here, we highlight the processes that occur during aerosol generation and inhalation, affecting aerosol disposition when deposited and, potentially, impacting total and regional doses. In particular, we examine the response of aerosol particles to the humid environment of the respiratory tract, considering both the capacity of particles to grow by absorbing moisture and the timescale for condensation to occur.