Gaetano Brambilla

Modulation of aerosol clouds produced by pressurised inhalation aerosols

The inclusion of non-volatile components such as glycerol or polyethylene glycol in hydrofluoralkane (HFA) solution formulations for pressurised metered dose inhalers (pMDIs), greatly increases the particle size of the aerosol. Cloud characteristics can be further modulated by permuting this factor with the choice of propellant and the dimensions of the actuator, to give a chosen fine particle dose and particle diameter. This principle has been used to design solutions which closely match the performance of chlorofluorocarbon based suspension formulations containing beclomethasone dipropionate, budesonide and ipratropium bromide as assessed for pharmaceutical equivalence using the Andersen Cascade impactor.

Modulite: a means of designing the aerosols generated by pressurized metered dose inhalers.

Although popular, the pressurized metered dose inhaler generates coarse, fast moving clouds so that the fraction reaching the lung is small. These shortcomings can be redressed by Modulite which permutes the following variables: the non-volatile components of a solution formula, the actuator orifice geometry, the volume of the metered solution and the vapour pressure of the propellants. This permits the design of aerosols with chosen particle size and plume speed. This facilitates co-ordination of dose generation with inspiration, reduces oropharyngeal deposition and provides a mechanism for targeting drug delivery to different parts of the lung. These principles are exemplified by designing an HFA-propelled beclometasone dipropionate product which closely matches existing products which use chlorofluorocarbons.

Effect of Flow Rate on In Vitro Aerodynamic Performance of NEXThaler® in Comparison with Diskus® and Turbohaler® Dry Powder Inhalers

Abstract Background: European and United States Pharmacopoeia compendial procedures for assessing the in vitro emitted dose and aerodynamic size distribution of a dry powder inhaler require that 4.0 L of air at a pressure drop of 4 kPa be drawn through the inhaler. However, the product performance should be investigated using conditions more representative of what is achievable by the patient population. This work compares the delivered dose and the drug deposition profile at different flow rates (30, 40, 60, and 90 L/min) of Foster NEXThaler® (beclomethasone dipropionate/formoterol fumarate), Seretide® Diskus® (fluticasone propionate/salmeterol xinafoate), and Symbicort® Turbohaler® (budesonide/formoterol fumarate). Methods: The delivered dose uniformity was tested using a dose unit sampling apparatus (DUSA) at inhalation volumes either 2.0 or 4.0 L and flow rates 30, 40, 60, or 90 L/min. The aerodynamic assessment was carried out using a Next Generation Impactor by discharging each inhaler at 30, 40, 60, or 90 L/min for a time sufficient to obtain an air volume of 4 L. Results: Foster® NEXThaler® and Seretide® Diskus® showed a consistent dose delivery for both the drugs included in the formulation, independently of the applied flow rate. Contrary, Symbicort® Turbohaler® showed a high decrease of the emitted dose for both budesonide and formoterol fumarate when the device was operated at airflow rate lower that 60 L/min. The aerosolizing performance of NEXThaler® and Diskus® was unaffected by the flow rate applied. Turbohaler® proved to be the inhaler most sensitive to changes in flow rate in terms of fine particle fraction (FPF) for both components. Among the combinations tested, Foster NEXThaler® was the only one capable to deliver around 50% of extra-fine particles relative to delivered dose. Conclusions: NEXThaler® and Diskus® were substantially unaffected by flow rate through the inhaler in terms of both delivered dose and fine particle mass.

Differences in physical chemistry and dissolution rate of solid particle aerosols from solution pressurised inhalers.

Solution composition alters the dynamics of beclomethasone diproprionate (BDP) particle formation from droplets emitted by pressurised metered dose inhalers (pMDIs). The hypothesis that differences in inhaler solutions result in different solid particle physical chemistry was tested using a suite of complementary calorimetric techniques. The atomisation of BDP-ethanol solutions from commercial HFA-pMDI produced aerodynamically-equivalent solid particle aerosols. However, differences in particle physico-chemistry (morphology and solvate/clathrate formation) were detected by differential scanning calorimetry (DSC), thermogravimetric analysis (TGA) and supported by hot stage microscopy (HSM). Increasing the ethanol content of the formulation from 8 to 12% (w/w), which retards the evaporation of propellant and slows the increase in droplet surface viscosity, enhanced the likelihood of particles drying with a smooth surface. The dissolution rate of BDP from the 12% (w/w) ethanol formulation-derived particles (63% dissolved over 120 min) was reduced compared to the 8% (w/w) ethanol formulation-derived particles (86% dissolved over 120 min). The addition of 0.01% (w/w) formoterol fumarate or 1.3% (w/w) glycerol to the inhaler solution modified the particles and reduced the BDP dissolution rate further to 34% and 16% dissolved in 120 min, respectively. These data provide evidence that therapeutic aerosols from apparently similar inhaler products, including those with similar aerodynamic performance, may behave non-equivalently after deposition in the lungs.

Modulite®: A Simple Solution to a Difficult Problem

The development of HFA-based pMDIs has proved difficult due to differences in the physico-chemical properties of CFC and HFA propellants. However, the development of solution formulations instead of suspensions has provided a way to formulate products whose cloud characteristics can be modulated in a controlled manner by permuting different formulation and device hardware variables. The new approach has proved successful in formulating several different drugs including steroids and has now been applied to developing a formoterol Modulite® solution formulation characterized by good chemical stability, delivery performance, and clinical results.

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.

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.

Transient aerodynamic atomization model to predict aerosol droplet size of pressurized metered dose inhalers (pMDI)

ABSTRACT Pressurized metered dose inhalers (pMDI) produce large numbers of droplets with smaller sizes than 5 μm to treat asthma and other pulmonary diseases. The mechanism responsible for droplet generation from bulk propellant liquid is poorly understood, mainly because the small length scales and short time scales make it difficult to characterize transient spray formation events. This article describes the development and findings of a numerical atomization model to predict droplet size of pharmaceutical propellants from first principles. In this model, the velocity difference between propellant vapor and liquid phase inside spray orifice leads to formation of wave-like instabilities on the liquid surface. Two variants of the aerodynamic atomization model are presented based on assumed liquid precursor geometry: (1) cylindrical jet-shaped liquid ligaments surrounded by vapor annulus; (2) annular liquid film with vapor flow in the core. The growth of instabilities on the liquid precursor surfaces and the size of the subsequently formed droplets are predicted by numerical solutions of dispersion equations. The droplet size predictions were compared with phase doppler anemometry (PDA) data and the predictions were in good agreement with the number mean diameter D10, which is representative of the respirable droplets. The temporal behavior of droplet size production was captured consistently well during the period of the first 95% of the propellant mass emission. The outcome of our modeling activities also suggests that, in addition to saturated vapor pressure of the propellant, its viscosity and surface tension are also key properties that govern pMDI droplet size.

Optical diagnostics studies of air flow and powder fluidisation in Nexthaler®. Part II: Use of fluorescent imaging to characterise transient release of fines from a dry powder inhaler

Graphical abstract Scattered and fluorescent intensity image pairs in mouthpiece exit region of Nexthaler® over a period of 15 ms representing the main fines emission (test conditions: Qmax = 60 l.min−1, Trise = 1.2 s). Figure. No Caption available. Abstract The fine particle fraction is a key indicator of therapeutic effectiveness of inhaled pharmaceutical aerosols. This paper presents a fluorescence imaging technique to visualise and characterise the emission of active pharmaceutical ingredient (API) fines in model formulations containing coarse lactose carrier and 1.5–2 &mgr;m diameter fluorescent microspheres (model API fines). A two‐camera arrangement was used to acquire simultaneous images of spatial and temporal distribution of model API fines and fluidised powder formulation near the mouthpiece exit of a DPI. Digital image analysis showed that the model API fines were released along with the bulk of the powder dose. More rapidly accelerating airflows were found to cause earlier release of API fines. The fluorescence imaging technique analyses a substantial fraction of the aerosol plume and was found to provide effective time‐resolved characterisation of the de‐aggregation and release of API fines with consistent results across a wide range of model API concentrations. Future studies should demonstrate the usefulness of the fluorescence imaging technique across different formulations and DPI devices.

A model of transient internal flow and atomization of propellant/ethanol mixtures in pressurized metered dose inhalers (pMDI)

ABSTRACT This article reports the extension to binary propellant/excipient mixtures of the multiphase model of transient internal flow and atomization in pressurized metered dose inhalers (pMDIs) of Gavtash and colleagues for propellant-only flows. The work considers different accounts of the effect of less volatile ethanol on the saturated vapor pressure (SVP), viscosity and surface tension of HFA-based pMDI formulations. Representation of the SVP of HFA/ethanol mixtures by Raoults law is compared with the empirical model developed by Gavtash and colleagues as well as different theoretical mixing rules for surface tension and viscosity. For initial ethanol contents ranging from 0 to 20% by mass, the temperature, pressure and spray velocity were predicted to be almost independent of ethanol concentration when using the empirical SVP model of Gavtash and colleagues. The predicted aerosol droplet size increases with increasing concentration of ethanol. These model predictions compare favorably with phase Doppler anemometry (PDA) measurements of pMDI sprays. Exploration of model predictions with different mixing rules suggest that variations of the dynamic viscosity could result in 0.7 µm droplet size change, and different surface tension models yield around 1.5 µm droplet size change. The findings of this work challenge the view that the increase of droplet size is caused by the low volatility of excipients such as ethanol. Instead, attention is focused on composition-dependent viscosity and surface tension as potential controlling parameters with significant effect on the droplet size of HFA/ethanol sprays. Copyright