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WO2019204568A1 - Appareil et procédés pour caractériser la géométrie d'un panache - Google Patents

Appareil et procédés pour caractériser la géométrie d'un panache Download PDF

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Publication number
WO2019204568A1
WO2019204568A1 PCT/US2019/028059 US2019028059W WO2019204568A1 WO 2019204568 A1 WO2019204568 A1 WO 2019204568A1 US 2019028059 W US2019028059 W US 2019028059W WO 2019204568 A1 WO2019204568 A1 WO 2019204568A1
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WIPO (PCT)
Prior art keywords
plume
conduit
angle
deposition
lateral conduit
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/US2019/028059
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English (en)
Inventor
Hugh D.C. Smyth
Daniel MORAGA-ESPINOZA
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University of Texas System
University of Texas at Austin
Original Assignee
University of Texas System
University of Texas at Austin
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Publication of WO2019204568A1 publication Critical patent/WO2019204568A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N15/00—Investigating characteristics of particles; Investigating permeability, pore-volume or surface-area of porous materials
    • G01N15/02—Investigating particle size or size distribution
    • G01N15/0205—Investigating particle size or size distribution by optical means
    • G01N15/0211—Investigating a scatter or diffraction pattern
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M11/00—Sprayers or atomisers specially adapted for therapeutic purposes
    • A61M11/04—Sprayers or atomisers specially adapted for therapeutic purposes operated by the vapour pressure of the liquid to be sprayed or atomised
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M15/00—Inhalators
    • A61M15/009—Inhalators using medicine packages with incorporated spraying means, e.g. aerosol cans
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M15/00—Inhalators
    • A61M15/08—Inhaling devices inserted into the nose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M2202/00—Special media to be introduced, removed or treated
    • A61M2202/04—Liquids
    • A61M2202/0468—Liquids non-physiological
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M2205/00—General characteristics of the apparatus
    • A61M2205/33—Controlling, regulating or measuring
    • A61M2205/3306—Optical measuring means
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M2209/00—Ancillary equipment
    • A61M2209/02—Equipment for testing the apparatus
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M2210/00—Anatomical parts of the body
    • A61M2210/06—Head
    • A61M2210/0618—Nose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M2210/00—Anatomical parts of the body
    • A61M2210/06—Head
    • A61M2210/0625—Mouth
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N15/00—Investigating characteristics of particles; Investigating permeability, pore-volume or surface-area of porous materials
    • G01N2015/0023—Investigating dispersion of liquids
    • G01N2015/0026—Investigating dispersion of liquids in gas, e.g. fog

Definitions

  • HSLI high-speed laser imaging
  • Plume geometry by laser sheet has been used for many years as quality control for pressurized metered dose inhalers (pMDIs), but its indirect measurement makes it unsuitable for comparison of bioequivalence since it lacks drug mass quantification (1-3).
  • High-speed laser Imaging is an analytical method used to characterize a spray based on two dimensional images obtained upon aerosolization (15).
  • HSLI uses a laser sheet to illuminate the droplets of the aerosol and generate a cross-sectional image of the plume. Then, a high speed digital camera captures an image of a fully developed plume, measuring its width and the angle of the conical region (2). Because of its fast data collection and non- invasive sampling approach, the technique has proven to be useful when evaluating modifications on nozzle designs, materials, and formulations (16-18). However, planar laser imaging is not without disadvantages.
  • Exemplary embodiments of the present disclosure address the issues described above.
  • an apparatus referred to herein as a Plume Induction Port Evaluator (PIPE) was developed by the inventors to characterize the plume geometry based on deposition patterns.
  • PIPE Plume Induction Port Evaluator
  • the apparatus and methods disclosed herein are adaptable to current pMDI characterization methodologies, uses similar calculations methods, and can be used under airflow.
  • MMPA Mass Median Plume Angle
  • MMAD Mass Median Aerodynamic Diameter
  • the techniques disclosed herein investigated the effect of formulation and airflow on the geometry of the plume using solution based pMDIs. It is anticipated that the new Plume Induction Port Evaluator (PIPE) can allow for better understanding of pMDI plume geometry during inhalation while expanding the scope of use for cascade impactors.
  • PIPE Plume Induction Port Evaluator
  • Coupled is defined as connected, although not necessarily directly, and not necessarily mechanically.
  • a step of a method or an element of a device that“comprises,” “has,”“includes” or“contains” one or more features, possesses those one or more features, but is not limited to possessing only those one or more features.
  • a device or structure that is configured in a certain way is configured in at least that way, but may also be configured in ways that are not listed.
  • FIGS. 1A and 1B (collectively referred to as FIG. 1) illustrate a partially exploded perspective view of an apparatus according to an exemplary embodiment of the present disclosure.
  • FIG. 2 illustrates a partial section view of the embodiment of FIG. 1.
  • FIG. 3 illustrates a flowchart presenting an overview of steps used in a method of operation of the embodiment of FIG. 1
  • FIG. 4 illustrates a linear log-probit plot of the cumulative distribution of the deposition patterns generated by using the embodiment of FIG. 1.
  • FIG. 5 illustrates drug mass distribution in the Next Generation Impactor (NGI) of a solution pMDI formulation (0.01% Rhodamine B) at different flow rates using the embodiment of FIG. 1.
  • NTI Next Generation Impactor
  • FIG. 6 illustrates a heat map of the drug deposited from a solution based pMDI formulation into the embodiment of FIG. 1.
  • FIG. 7 illustrates deposition patterns and its cumulative distributions using the embodiment of FIG. 1.
  • FIG. 8 illustrates descriptive plume geometry parameters calculated from deposition patterns using the embodiment of FIG. 1.
  • FIG. 9 illustrates cross-sectional images of three marketed pMDI products obtained by High Speed Laser Imaging.
  • FIG. 10 illustrates the effect of cosolvent in the geometry of the plume emitted from a solution based pMDI using the embodiment of FIG. 1.
  • FIG. 11 illustrates plume angle data collected from three albuterol sulfate suspension pMDI products using the embodiment of FIG. 1.
  • FIG. 12 illustrates a cross-sectional image of the aerosol generated by the pressurized metered dose inhaler recorded using a high-speed camera and plume characteristics as measured using image analysis.
  • FIG. 13 illustrates effective median angles between nozzle and sections in PIPE apparatus used to calculate the Mass Median Plume Angle (MMPA) of the pMDI using the embodiment of FIG. 1.
  • MMPA Mass Median Plume Angle
  • FIG. 14 illustrates an experimental setup for analysis of plume structure at different distances from the mouthpiece using the embodiment of FIG. 1.
  • FIG. 15 illustrates the influence of ethanol in the plume angle was evaluated by high- speed laser imaging.
  • FIG. 16 illustrates descriptive plume geometry parameters calculated from deposition patterns in the segmented induction port using the embodiment of FIG. 1.
  • FIG. 17 illustrates the effect of flow and formulation on plume induction port deposition using the embodiment of FIG. 1.
  • FIG. 18 illustrates a comparison of spray angles obtained by laser imaging and mass median plume angles using the embodiment of FIG. 1.
  • FIG. 19 illustrates the effect of distance traveled by the plume on particle size using the embodiment of FIG. 1.
  • FIG. 20 illustrates a configuration of the embodiment of FIG. 1 with carbon conductive tap located on each section of the lateral conduit.
  • FIG. 21 illustrates an experimental layout for laser-based characterization techniques.
  • FIG. 22 describes the calculation of the effective angles (EA) and median angles at each section of the embodiment of FIG. 1.
  • FIG. 23 illustrates deposition patterns of suspension based pMDI products (Ventolin®HFA, ProAir®HFA on drug distribution along the embodiment of FIG. 1.
  • FIG. 24 illustrates a comparison of residual particles distributed along the sections of the embodiment of FIG. 1.
  • FIG. 25 illustrates the effect of airflow on deposition patterns for Mass Median Plume Angle calculations using the embodiment of FIG. 1.
  • FIG. 26 illustrates a comparison of plume angles measurements obtained in presence and absence of airflow using the embodiment of FIG. 1.
  • FIG. 27 illustrates the effect of the distance traveled by the plume on the particle size as evaluated by laser diffraction.
  • FIG. 28 illustrates an experimental layout for high-speed laser imaging.
  • FIG. 29 illustrates an experimental layout for use of the embodiment of FIG. 1 with nasal sprays.
  • FIG. 30 illustrates an example of log normal distributed deposition patterns and calculation of the Mass Median Plume Angle using the embodiment of FIG. 1.
  • FIG. 31 illustrates a representation of the human nasal airway replica casts sectioned for regional deposition analysis.
  • FIG. 32 illustrates the effect of airflow and formulation on plume angle using the embodiment of FIG. 1.
  • FIG. 33 illustrates the effect of formulation on the variability of plume geometry angle measurements evaluated by the embodiment of FIG. 1 (0 L/min) and high-speed laser imaging.
  • FIG. 34 illustrates deposition patterns of the formulation 0.1% HPMC in the nasal replica casts.
  • FIG. 35 illustrates the effect of inhalation maneuvers selected from patient instructions for use.
  • FIG. 36 illustrates a cross correlation between MMPAs obtained using the embodiment of FIG. 1 and turbinate deposition in nasal casts in the absence and presence of airflow using.
  • FIG. 37 provides a summary table of the analysis of the instruction of use of 35 nasal spray products approved by the FDA/
  • FIG. 38 shows an Experimental setup for plume angle analysis by High-speed laser imaging using an automatic actuator b) Experimental setup for measuring droplet size by laser diffraction at high temperature (37°C).
  • FIG. 39 shows illustrative calculation tables describing the calculating Mass Median Plume Angles based on Induction Port deposition (MMPAIP) and Emitted Dose (MMPAED
  • FIG. 40 shows the effect of relevant ambient temperatures on the formulation vapor pressure of solution formulations inside of the pMDI canister.
  • FIG. 41 shows an example of composite images obtained by High-Speed Laser Imagine for all formulations (Ethanol concentration 2.49%, 9.99% and 19.99%) at different temperatures (5°C, 25°C, and 37°C).
  • FIG. 45 shows the effect of formulation and temperature on: a) drug mass deposition at the actuator b) total drug mass deposition at the Plume Induction Port Evaluator c) Fraction of the emitted dose deposited in the cascade impactor with an aerodynamic particle size ⁇ 5pm.
  • MMPAIP Induction Port deposition
  • MMPAED Mass Median Plume Angles calculated based on the Emitted Dose
  • FIG. 47 shows a correlation between mass-based plume geometry parameters and delivery efficiency for pressurized metered dose inhalers.
  • FIGS . 1 -2 an apparatus 100 is shown for characterizing orally inhaled product plume geometry.
  • FIG. 1 illustrates a partially exploded perspective view of apparatus 100
  • FIG. 2 illustrates a partial section view of apparatus 100 during operation.
  • not all components are labeled with reference numbers in each figure.
  • apparatus 100 may be referred to herein as a Plume Induction Port Evaluator (PIPE).
  • apparatus 100 comprises a lateral conduit 110 in fluid communication with an exit conduit 120.
  • lateral conduit 110 is coupled to exit conduit 120 via elbow coupling 160.
  • lateral conduit 110 comprises a plurality of sections 111-118 and a primary axis 119 through its center. It is understood that other embodiments may comprise a different number of sections in lateral conduit 110, and the eight sections 111-118 shown are merely exemplary for the illustrated embodiment.
  • sections 111-118 are configured such that they can be separated both perpendicular and parallel to primary axis 119.
  • sections 111 and 112 which are distal from exit conduit 120 can be separated from sections 113 and 114 in a manner that is perpendicular to primary axis 119.
  • section 111 can be separated from section 112 in a manner that is parallel to primary axis 119.
  • reference to primary axis 119 for configuration purposes is made with respect to the sections positioned in arrangement shown in FIGS. 1 and 2. Because of the interlocking nature of the sections, it may be necessary to first separate sections in a manner that is perpendicular to primary axis 119 and subsequently separate the sections in a manner that is parallel to primary axis 119.
  • a user can obtain an apparatus comprising a conduit comprising a plurality of sections that can be separated perpendicular and parallel to the primary axis of the conduit (e.g. an apparatus equivalent to apparatus 100 shown in FIGS. 1-2).
  • the user can couple a device configured to dispense orally inhaled products to the conduit.
  • the user can dispense a particle spray (e.g. atomized liquid, powder, etc.) from the device into the lateral conduit.
  • the user can separate the sections of the lateral conduit.
  • the user can determine the amount of the particle spray deposited on each section of the lateral conduit. Specific techniques for determining the amount of particle spray deposited on each section of the lateral conduit are discussed below, including discussion of the working examples provided herein.
  • sections 111-118 may comprise an adhesive inner surface to assist in determining the amount of the particle spray deposited on each section of the lateral conduit.
  • an adhesive tape may be applied to the inner surface of the upper and lower sections.
  • a double-sided adhesive carbon conductive tape 101 can be applied to section 111.
  • a double-sided adhesive carbon conductive tape 102 can be applied to section 112.
  • the remaining sections 113-118 may also comprise a double-sided adhesive carbon conductive tape (not labeled in FIG. 1 for purposes of clarity).
  • apparatus 100 may be coupled to a delivery device 130 (e.g . an inhaler) via an adapter 135.
  • Apparatus 100 may also be coupled to a flow device 140 (e.g. an impactor configured for inhaler testing).
  • the flow rate may be varied (e.g. from 0 to 90 L/min) to provide different testing conditions.
  • the external dimensions of the exit conduit 120 can allow to apparatus 100 to connect with standard testing equipment such as the Next Generation Impactor (NGI), allowing it to be interchangeable with original induction ports.
  • NTI Next Generation Impactor
  • lateral conduit 110 comprises four sections, each with a top or upper section and a bottom or lower section.
  • section 1 of lateral conduit 110 comprises upper section 111 and lower section 112
  • section 2 comprises upper section 113 and lower section 114
  • section 3 comprises upper section 115 and lower section 116
  • section 4 comprises upper section 117 and lower section 118.
  • the embodiment shown is merely exemplary and other embodiments may comprise a different number of sections in the conduit.
  • particle spray 137 comprises a plurality of particles 138 that are deposited throughout apparatus 100.
  • the ability to separate sections 111-118 in lateral conduit 110 can allow a user to quantify the amount of product dispensed from drug delivery device 130 that is deposited on the different sections 111-118. Accordingly, the effect of different parameters (e.g. flow rate, product composition, etc.) can be determined on the deposition rates in the different sections.
  • Apparatus 100 can be operated to calculate a Mass Median Plume Angle (MMPA) as explained further below.
  • MMPA Mass Median Plume Angle
  • geometric mean of the angles (Og) and its geometric standard deviation (og) are the main statistical parameters that can be used to describe the characteristics of the aerosol.
  • Og geometric standard deviation
  • a least- squares linear regression is required, however, the inherent non-linear relationship between the cumulative distribution of the deposition patterns and the effective angles must be considered.
  • the Probit method is a mathematical approach used in cascade impactors to calculate Mass Median Aerodynamic Diameter (MMAD), which describes the aerodynamic diameter of a particle collected on the stage with fifty percent efficiency (11, 12).
  • MMAD Mass Median Aerodynamic Diameter
  • the method allows the calculation of the geometric mean and standard deviation of log normal distributed data by plotting the cumulative distribution of the drug deposited in the impactor stages in probability scale versus the logarithm of the diameter cut-off (11).
  • a linear transformation of the effective median angles can be done by simply calculating its natural logarithm since the distribution is assumed to be lognormal.
  • the linear transformation is achieved by using a probability scale. Considering the standardized normal probability density function that defines the cumulative fraction F(z), a z linear value of the cumulative percent can be stablish as the independent variable for following linear equation (12).
  • MMPA Mass Median Plume Angle
  • Mass Median Plume Angle is a new parameter that describes the effective angle of the plume where fifty percent of the drug deposits in the induction port.
  • Calculation of MMPA and o g is possible using a linear probit scale by transforming the cumulative percent for the drug deposited in the induction port to its linear z value and plotted relative to the logarithm of the median angles in the segmented induction port (Q0.5) as shown in Table 1 and FIG. 4, which shows a linear log-probit plot of the cumulative distribution of the deposition patterns generated by using the PIPE.
  • the plot represents a linear regression for calculating Mass Median Plume Angle (MMPA).
  • Table 1 below shows the mass summaries for analyses of cumulative percentage (Cum %) of mass less than the stated effective angle.
  • Patient inhalation is an important variable that affects the performance of OIPs, to a greater or lesser extent, depending on the aerosolization mechanism and the integrity of lung function.
  • PIPE uses the capabilities of cascade impactors to simulate different flow rates so its effect on plume geometry can be evaluated.
  • Preliminary data has shown that MMPA is a suitable parameter to evaluate the effect of flow rate on solution and suspension based pMDI formulations.
  • Rhodamine B (Sigma- Aldrich) was used as a model HFA- soluble drug (0.01% w/w), dissolved in ethanol (Pharmco-Aape) as a cosolvent and 1, 1,1,2- tetrafluoroethane (HFA l34a; Dupont) as the liquid propellant.
  • Manufacturing procedure follows the method developed by Smyth and coworkers (24) in which the solubilization of the fluorescent dye in the co-solvent is used to prepare a Rhodamine B stock solution.
  • NTI Next Generation Impactor
  • pMDI 0.01% Rhodamine B
  • Induction port data is expressed as the sum of all the individual parts of PIPE.
  • FIG. 6 illustrates a heat map of the drug deposited from a solution based pMDI formulation into the Plume Induction Port Evaluator (PIPE) at different flow rates. Shifts on drug deposited toward the end of the segmented cylinder are illustrated as flow rate increases.
  • PIPE Plume Induction Port Evaluator
  • effective angles for this study were calculated as the median angle formed between the limits of the segments at each section respect to the pMDI nozzle (as shown in FIG. 2). Deposition patterns and its cumulative distributions in PIPE are summarized in FIG. 7.
  • FIG. l6a illustrates a linear log-probit plot of the deposition patterns for the solution based pMDI formulation at different flow rate.
  • Deposition patterns were obtained by chemical assay of the fluorescent dye (rhodamine B) into the PIPE apparatus.
  • FIG. 9 illustrates cross-sectional images of three marketed pMDI products obtained by High Speed Laser Imaging (HSLI) (Ventolin HFA ®, ProAir HFA ® , and Proventil HFA ® ).
  • HSLI High Speed Laser Imaging
  • FIG. 10 shows the effect of cosolvent in the geometry of the plume emitted from a solution based pMDI. Plume angles are evaluated using laser (HSLI) and chemical assay based (MMPA) methods. Inner dimensions of the Plume Induction Port Evaluator (PIPE) were overlap to the cross-sectional images of the plume.
  • HSLI laser
  • MMPA chemical assay based
  • FIG. 11 summarized results obtained by PIPE and HSLI.
  • FIG. 11 illustrates plume angle data collected from three albuterol sulfate suspension pMDI products. Geometry of the plume was evaluated using High Speed Laser Imaging and PIPE in absence of flow. Inner dimensions of the PIPE were overlapped to the cross-sectional images of the plume. In this opportunity, experimental data show good agreement between methods with respect to the rank order, of which albuterol sulfate based formulation has the largest angle.
  • Embodiments of the present invention directly address the need, solving the limitations of the current gold standard by providing a tool that is easy to transfer to the industry, and does not require high cost instrumentation.
  • DPIs Dry Powder Inhalers
  • the FDA in its guidance for evaluating OIPs does not require the analysis of plume geometry for DPIs because of the limitation of the available methods. Since embodiments of the present invention are not limited by the aerosolization mechanism of the tested inhaler, it is possible to characterized DPI plume geometry while cascade impaction experiments are performed. This will have a significant effect in the understanding of the performance of DPIs since it is well known that performance of such devices is highly variable depending on the inhalation effort of the patient, but the reasons are still not fully understood.
  • embodiments of the present invention can be utilized as an attachment for cascade impactors that allows mapping deposition patterns inside of an induction port while performing aerodynamic characterization.
  • Plume deposition patterns can be used to characterize the plume geometry of an OIP by a chemical assay methodology, which results can be verified by mass balance.
  • embodiments of the present invention can be used to solve the problem of quantifying the plume structure of inhaled pharmaceutical products. This problem is a long standing issue in the industry and the regulatory agencies (i.e. the FDA) require this testing to be done. This is typically conducted using indirect methods, e.g. high speed laser imaging (HSLI). While plume geometry by HSLI requires the aerosol to be emitted by using some sort of aerosolization energy (mechanic or propellant), the technology disclosed herein uses the air flow provide by the cascade impactor, so its application is independent of the aerosolization mechanism.
  • HSLI high speed laser imaging
  • Methods using the embodiments disclosed herein can be applied to any OIPs under air flow conditions and are not limited by actuation mechanisms.
  • the disclosed methods can quantify plume angle by mass (dose) and are therefore relevant to pharmacological activity of the drug (unlike imaging with lasers).
  • the disclosed methods can also be more accurate than laser methods (e.g. coefficient of variation ⁇ 4% compare to the ⁇ 16% obtained by commercially available laser system (SprayView (Provertis) and EnVision system (Oxford Laser)).
  • the disclosed methods are sensitive to small changes in the plume geometry, and thus provides better sensitivity for characterizing the plume. It is anticipated that embodiments of the present disclosure may be used in conjunction with other devices including for example, dry powder inhalers, nasal sprays, and nebulizers.
  • Rhodamine B Sigma- Aldrich
  • Rhodamine B Sigma- Aldrich
  • ethanol Pharmco-Aape
  • HFA l34a l,l,l,2-tetrafluoroethane
  • Specific amounts of the components used are shown in Table 2. Manufacturing procedure follows the method developed by Smyth and coworkers (22), which considers the solubilization of the fluorescent probe in the co-solvent to prepare a rhodamine B stock solution.
  • the Plume Induction Port Evaluator was designed in Autodesk Inventor 2017 and prototyped using a 3D printer (Viper si2TM) based on stereolithography technology.
  • the material employed in the prototype was ProtoThermTM 12120, a liquid photoreactive polymer with high tolerance to temperature and resistant to water.
  • PIPE was designed using the inner geometry of the current USP induction port (USP IP) (23) to prevent variations on recirculation regions and deposition patterns.
  • the segmented induction port design is composed of three main pieces: A cylinder that can be disassembled in eight segments, a ninety-degree connector (elbow) and a non-segmented secondary cylinder (throat) (as shown in FIG. 1 and FIG. 2, which illustrates a representation of effective angles used to calculate Mass Median Plume Angles (MMPA)).
  • a cylinder that can be disassembled in eight segments
  • elbow ninety-degree connector
  • throat non-segmented secondary cylinder
  • FIG. 1 and FIG. 2 which illustrates a representation of effective angles used to calculate Mass Median Plume Angles (MMPA)
  • the angle of a full developed plume of each formulation was measured by image analysis using the software Image!
  • Cross-sectional images of the plume were captured at 400 frames per second using a high-speed monochromatic camera (Flea3®,Pointgrey), a laser source (532nm, 200mW Laser module, Direct Voltage) and a laser line generating lens (45° Fan angle, Thorlabs Inc.).
  • the camera was set up perpendicular to the laser sheet plane, so the illuminated droplets of the aerosol could be captured as shown in FIG. 12.
  • a cross- sectional image of the aerosol generated by the pressurized metered dose inhaler is recorded using a high-speed camera and plume characteristics are measured using image analysis.
  • Plume angles were calculated from a composite image of the plume, analyzing the slope of the edges of the aerosol at the first five centimeters of the conical region, close to the mouthpiece.
  • the pMDI was actuated manually after shaking for five seconds. Plume angles are reported as the average of ten measurements at room conditions (25°C, 45% RH).
  • Deposition patterns of solution pMDI formulations were collected using the Plume Induction Port Evaluator (PIPE) connected to a Next Generation Impactor (NGI). Influence of formulation in deposition patterns, in absence and presence of airflow was investigated (0 and 30 L/min flow rate respectively). The inhaler was shaken for five seconds and primed by discharging two wasted shots before runs. Five doses were actuated manually into PIPE within intervals of twenty seconds, preventing variations in the emitted dose and allowing complete deposition. After delivering all doses, PIPE was disassembled and each segment was thoroughly rinsed with 10 mL of the solvent (ethanol/water 1 : 1).
  • Actuator and valve stem were pooled together, and mouthpiece adapter was rinsed separately using 25 mL of the solvent. Each NGI stage was rinsed with 10 mL of solvent.
  • the fluorescent dye Rhodamine B was collected and assayed by fluorescence spectroscopy using a wavelength of 550 nm excitation and 610 nm emission. Each experimental condition was tested in triplicates using the same actuator.
  • Mass Median Plume Angle is a new chemical assay based method that can characterize the geometry of a plume using the deposition profile of pMDIs into the induction port.
  • PIPE is a segmented induction port designed so it can have similar features to cascade impactors such as good drug recovery (mass balance), good accuracy, and good precision ( ⁇ 5%) (24).
  • MMPA was calculated using the median angle formed at each section with respect to the pMDI nozzle, which are represented in FIG. 2. Particles deposited on the mouthpiece adapter are considered to have a deposition angle higher than the maximum angle allowed by the mouthpiece opening (>53° for the used actuator).
  • Calculation of MMPA follows the same approach used for calculating Mass Median Aerodynamic Diameter (MMAD) (25). Briefly, the log normal distribution of the deposited drug in PIPE and the calculated effective angles can be plot in a log-probabilistic plot so the angle where fifty percent of the drug is deposited can be calculated (FIG. 13). As shown in FIG. 13, effective median angles between nozzle and sections in PIPE apparatus are used to calculate the Mass Median Plume Angle (MMPA) of the pMDI. Calculation method is analogous to USP calculation for Mass Median Aerodynamic Diameter (MMAD)(23).
  • FIG. l5a shows an example of a cross-sectional image of the plumes with different ethanol concentrations obtained after image processing. Specifically, FIG. l5a shows a cross-sectional image of the plume emitted by three evaluated Rhodamine B (0.01%) solution pMDI formulations. Inner geometry of the Plume Induction Port Evaluator (PIPE) was overlapped to correlate plume orientation with deposition maps. The results demonstrate that the macroscopic characteristics of the plume were successfully modified by changing the concentration of the semi volatile co-solvent (ethanol) and therefore the final vapor pressure of the formulation (Table 2).
  • PIPE Plume Induction Port Evaluator
  • FIGS. 6b and 6c Deposition patterns of solution pMDIs with different concentrations of ethanol are presented in FIGS. 6b and 6c as a‘heat map’.
  • the deposition map has been colored to represent the distribution of the drug into the induction port.
  • White represents the segment with the lowest amount of deposited drug and darker red (or gray in grayscale representations) shows the segment with the highest. All tested formulations show different drug distributions along the induction port as ethanol increases.
  • the highest deposition or‘hot spot’ was found at four centimeters from the mouth piece (“Bottom 2”).
  • FIG. 16 also illustrates the deposition patterns in the mouthpiece adapter and used sections in PIPE to calculate MMPA (Sections 1-4, and Elbow) at no flow (0 L/min) and flow conditions (30 L/min).
  • MMPA Sections 1-4, and Elbow
  • FIG. 16 illustrates the deposition patterns in the mouthpiece adapter and used sections in PIPE to calculate MMPA (Sections 1-4, and Elbow) at no flow (0 L/min)
  • Mass median plume angles were found to be significantly lower (narrower plume and smaller angle) for the three tested formulations under airflow conditions emphasizing the need to test and understand plume shape during more realistic use conditions. This finding was also supported by the observed decrease in the overall drug deposition on the pMDI actuator and mouthpiece adapter. It is expected that narrower spray angles generated during inhalation flow will generate less deposition on the actuator device when exiting the device mouthpiece (FIG. 7).
  • the total drug mass deposited in the induction port was not significantly affected by airflow for formulations A and C (FIG. 7). Still, formulations with smaller droplets (Formulation A and B) showed a decrease in drug deposition. On the contrary, deposition patterns inside of PIPE did change as airflow was introduced. Reduced deposition in the early sections of PIPE and increased deposition on distal regions (elbow and throat) was observed in presence of airflow (FIG. 17).
  • Plume angles based on drug mass quantifies the plume geometry as a function of dose, not droplet illumination.
  • Laser light sheet for determination of spray angle is an indirect method of quantification based on Mie scattering (Fansler and Parrish, 2015). After the laser sheet passes through the spray, photons are scattered from the droplets (first-order scattering or single scattering) in several directions and captured by the camera, revealing the final cone shape (Kalt et al, 2007).
  • image data has been reported to be biased or distorted in several cases for sprays. For example, so-called “corrupted images” have been reported even in the case of moderately dense sprays (Linne, 2013; Rahm et al, 2016).
  • the scattering of light is governed by the ratio of the particle size (d) to the wavelength of the incident light (l), also known as size parameter (a) (Eq. 2) (Hinds, 1999) r nd
  • Plumes of larger angle emitted from pMDIs will likely have increased deposition on the mouthpiece of the actuator.
  • the actuator mouthpiece may generally constrict the emitted plume because of the position of the nozzle relative to the outer edge of the actuator. Therefore, an analysis of the deposition on the mouthpiece may reveal differences in plume angle.
  • Mass- based plume angles were smaller (narrower) (FIG. 18) and presented lower drug deposition in the actuator (FIG. 16) as ethanol concentration increases.
  • the increase in droplet size did not result in an increase in the total drug mass deposited on the actuator (FIG. 16). This supports the plume angle observations made using the PIPE rather than those obtained from the laser light sheet.
  • Plumes emitted from pMDIs have been reported to be either upward or downward oriented respected to the origin point depending on the device and formulation (Chen et al, 2016).
  • Plume geometry of solution pMDI formulations was evaluated by high-speed laser imaging and a novel mass-based plume angle analysis using a segmented induction port called“Plume Induction Port Evaluator.”
  • the PIPE apparatus was connected to a cascade impactor to study the effect of the compendial flow rate on the geometry of the plume.
  • deposition patterns of the aerosol were log-normal distributed under all test conditions and plume angles could be easily calculated using a combination of the inner geometry of the segmented induction port and the distribution of the deposited drug.
  • MMPA Mass Median Plume Angle
  • MMPA parameter demonstrated being highly reproducible and sensitive to changes in flow and formulation, even when they have similar deposition fraction in the induction port.
  • the laser-based angles and MMPAs determined in the absence of flow were inversely correlated. This was attributed to multiple scattering in the highly dense region of analysis, and a significant increase in droplet size when increasing ethanol concentrations.
  • Our findings emphasize that the induction port deposition mechanism of solution pMDIs are not yet fully understood, and the study of induction port deposition patterns may be important for pMDI development.
  • the PIPE apparatus provides an alternative to address laser-based systems limitations, allowing aerosol characterization under flow by cascade impaction while evaluating the geometry of the plume.
  • the Plume Induction Port Evaluator is a modified induction port for cascade impactors that allows to calculate the angle of a plume based on drug mass quantitation rather than indirectly via droplet illumination.
  • the objective of this study was to investigate the use of the PIPE instrument to evaluate the effect of airflow on the mass-based plume angle of suspension based pMDIs that are commercially available (Ventolin®HFA, ProAir®HFA, and Proventil®HFA).
  • Aerodynamic characterization was also performed. Deposition patterns within PIPE were log normally distributed allowing the calculation of the Mass Median Plume Angle for all the three suspension products. Mass based plume angles were significantly smaller (narrower angle) when inhalation airflow was used (Reduction of MMPA was 8%, 16%, and 13% for Ventolin®HFA, ProAir®HFA: and Proventil®HFA respectively). Drug mass based plume angles for suspension pMDI formulations were successfully characterized. They were also shown to be affected by inhalation flow, and therefore should be evaluated under flow conditions.
  • Characterization of the plume geometry for pressurized metered dose inhalers has been carried out mainly by high speed imaging and high-speed laser imaging (HSLI) because of their fast data acquisition, non-intrusive sampling approach, and the possibility for automation (1, 2).
  • HSLI high-speed laser imaging
  • these methods lack on simulating the patient inhalation, allowing the plume to expand indefinitely on the air which is not the case in the oral cavity.
  • data obtained by these techniques lose relevance when attempting to predict mouth-throat deposition.
  • Droplet formation for suspension-based pMDIs is more complex than for solution formulations, as the drug content in the droplets will vary depending on the number of suspended drug particles, with some droplets containing no drug at all (6, 7). Therefore, the use of indirect laser-based characterization techniques, such as laser diffraction or high-speed laser imaging (HSLI) are inherently limited because their detection method does not distinguish between drug loaded droplets and those without the active component.
  • characterization techniques capable of evaluating these products under physiologically relevant conditions such as inhalation airflow and based on reliable drug quantification are necessary.
  • the Plume Induction Port Evaluator (PIPE) apparatus is a modified induction port for cascade impactors that allows the calculation of median plume angle, also called Mass Median Plume Angle (MMPA).
  • MMPA Mass Median Plume Angle
  • the method for calculating MMPA was developed based on and is analogous to the well-established method for calculating the Mass Median Aerodynamic Diameter (MMAD) in cascade impaction studies (9).
  • the PIPE apparatus has been shown to be capable of precisely characterizing the plume angle of solution based pMDIs under flow. Plume angles were significantly narrowed in presence of airflow compared to no flow conditions (8). The method was highly reproducible (CV ⁇ 3%), did not rely on proprietary software, and could be used while performing aerodynamic characterization.
  • Ventolin®HFA GaxoSmithKline, Research Triangle Park, NC, USA
  • ProAir®HFA Teva Specialty Pharmaceuticals LLC, Horsham, PA, USA
  • Proventil®HFA 3M Pharmaceuticals, St. Paul, MN
  • Standard of Albuterol sulfate was bought from Sigma-Aldrich (St. Louis, USA).
  • High-performance liquid chromatography (HPLC) grade acetonitrile was purchased from Fisher Scientific (Pittsburgh, PA).
  • O- Phosphoric acid, 85% (certified ACS) was purchased from Fischer Chemical.
  • the Plume Induction Port Evaluator was designed in Autodesk Inventor 2017 and 3D printed using stereolithography technology as described previously by Moraga-Espinoza et al. (8).
  • Each albuterol sulfate pMDI formulation was manually actuated two times into the PIPE apparatus and NGI, within intervals of 20 seconds while the pump was operated at flow rates of 0 and 30 L/min for a period of 8 seconds.
  • NGI stages were coated using a solution of 1% (v/v) glycerol/ethanol to prevent particle re-entrainment.
  • Drug deposited on PIPE segments and NGI stages was collected adding 10 mL of a solution 0.1% phosphoric acid in Water (v/v). Each of these components was shaken gently for 20 seconds.
  • Drug deposited on the actuator and mouthpiece adapter was collected using 25 mL of the same 0.1% phosphoric acid solution (v/v).
  • MMPA values reported for each product and airflow conditions are the average of three independent runs.
  • Albuterol based was assay by high-performance liquid chromatography with a Thermo Scientific Dionex Ultimate 3000 HPLC system (Thermo Scientific, Sunnyvale, CA, USA).
  • the autosampler (Ultimate 3000) was programed to inject 10 pL of samples into a HPLC column TSK gel® ODS80Ts Cl 8 - L x I.D:25 cm x 4.6mm, 5pm particle size (TOSOH, Japan) kept at room temperature.
  • the aqueous mobile phase (MP) consisted of 0.1% phosphoric acid (v/v) while the organic MP consisted of acetonitrile.
  • the isocratic method used a mixture of 93% of the aqueous MP and 7 % of the organic MP, at a flow rate of lmL/min.
  • the wavelength detector was operated at 225 nm.
  • the retention time of albuterol was 5.2 minutes.
  • Chromeleon Version 6.80 software (Thermo Scientific, Sunnyvale, CA, USA) was used to process all chromatography data.
  • FIG. 20 illustrates the design of the Plume Induction Port Evaluator (PIPE).
  • Carbon conductive tape was located on the surface of each segment in the PIPE apparatus to collect residual particles.
  • Conductive tape was located on“elbow” and “throat” segments following potential impact regions predicted by Longest et al. (10).
  • SEM tape was located in the center of the eight initial segments of PIPE (top and bottom segments 1 to 4).
  • FIG. 21 illustrates an experimental layout for laser-based characterization techniques.
  • FIG. 21 a shows high-speed laser imaging using an automatic actuator
  • FIG. 2lb shows the effect of distance on particle size distribution by laser diffraction using a long travel linear translation stage.
  • the laser sheet was aligned at the centerline of the mouthpiece of the inhaler (FIG. 2la).
  • the automatic actuator Mighty Runt (InnovaSystems, Inc., Moorestown, USA) was used to actuate the pMDI device (FIG. 21 a) using similar actuation parameters reported by Liu et al. (11) (actuation force of 6.4 kg, force rise time of 0.1 seconds, a hold time of 0.5 seconds and a force fall time of 0.1 secs).
  • Inhalers were manually shaken before each actuation.
  • Emitted plumes were captured at 400 frames per second.
  • Composite image of the plume was generated using the frames from the initial development of the aerosol until the last frame where the plume was in contact with the actuator. Calculation of the plume angle was done using the software ImageJ (12). Plume angles are reported as the average of ten independent measurements.
  • FIG. 22 describes the calculation of the effective angles (EA) and median angles at each section of PIPE.
  • EA effective angles
  • Median angles used for the calculation of Mass Median Plume Angle of Ventolin@HFA, ProAir®HFA, and Proventil® HFA are shown as an example considering the Nozzle Distance (ND) and Mouthpiece Opening (M 0 ) on Table 3.
  • the equation for the effective angles considers the two physical characteristics of the actuator described above.
  • the median angles used for this study are shown as an example.
  • Table 4 summarizes the results of the aerodynamic performance for the three suspension pMDI formulations evaluated by cascade impaction under flow (30 L/min). Results for Mass Median Aerodynamic Diameter (MMAD), Fine Particle Fraction (FPF) and Geometric Standard Deviation (GSD) were comparable to those reported in the literature which demonstrated the interchangeability of the USP induction port and the PIPE apparatus (13-15). The vapor pressure of the formulation inside the canisters was measured at the stem of the metered valve using a pressure gauge (ATL-TK, Aero-Tech equipment co., Maryland, US). Table 4. Aerodynamic and physical properties of the albuterol sulfate pMDI products
  • FIG. 23 illustrates deposition patterns of suspension based pMDI products (Ventolin®HFA, ProAir®HFA on drug distribution along the Plume Induction Port Evaluator (PIPE). Results are based on the discharge of two actuations within the PIPE apparatus connected to a Next Generation Impactor operated in absence and presence or airflow (0 and 30 L/min respectively). Presented data is the average of three independent cascade impaction studies (Labeled dose is equivalent to 90 pg of albuterol base).
  • FIG. 23 presents a color-coded map of the drug mass deposition patterns of the three albuterol sulfate pMDI products along the mouthpiece adapter and the segmented induction port.
  • Ventolin®HFA and Proventil®HFA had a reduction on the total mass deposited in the induction port of 14 and 17% respectively while ProAir®HFA showed the largest reduction on total mass deposited with about 50% less albuterol in the presence of flow. All the products showed higher deposition on the bottom segments compare to the top segments regardless of whether or not airflow was used.
  • Residual particles deposited on the surface of the segmented induction port were collected using double-sided adhesive carbon conductive tape and imaged using SEM.
  • FIG. 24 illustrates a comparison of residual particles distributed along the Plume Induction Port Evaluator segments.
  • Spherical agglomerates of albuterol sulfate microcrystals are present at all suspension pMDI products (Ventolin®HFA, ProAir®HFA, and Proventil®HFA). Images correspond to two actuations discharged on the PIPE apparatus when connected to a Next Generation Impactor operated under flow (30 L/min) (Top: Top segment, Bot: bottom segment, ELB:“Elbow” section,“Throat”:“Throat” section). Large and small field of view images were obtained using a magnification of lOOOx and 20000x respectively.
  • FIG. 24 summarized the images using two magnifications: a larger field of view ( ⁇ 80 mm 2 ) to illustrate the overall deposition and a higher magnification and smaller field of view (0.2mm 2 ) to analyze the morphology and geometrical size of the individual particles/agglomerates.
  • a larger field of view ⁇ 80 mm 2
  • a higher magnification and smaller field of view 0.2mm 2
  • the agglomerates ranged between 3 to 10 pm in size as determined by SEM.
  • FIG. 25 illustrates the effect of airflow on deposition patterns for Mass Median Plume Angle calculations.
  • Suspension based pMDI products a) Ventolin®HFA, b) ProAir®HFA, and c) Proventil®HFA were evaluated in absence (0 L/min) and presence of airflow (30 L/min).
  • Deposition patterns of drug deposited on the region of interest of PIPE for MMPA calculations are shown in FIG. 25 following the method described by Moraga-Espinoza et al. (8) (mouthpiece adapter and all the PIPE sections except“throat” segment).
  • Data in FIG. 25 is presented as a function of PIPE sections (sections are defined as the combination of top and Bottom segments) to facilitate initial deposition comparisons.
  • Albuterol sulfate emitted from Ventolin®HFA was more evenly distributed along the sections of PIPE compared to the other two products for both flow conditions.
  • Section 2 was the region of PIPE with the highest deposition for all tested formulations and the less affected by airflow.
  • Inner geometry of the Plume Induction Port Evaluator was overlapped to composite images obtained by HSLI to estimate the orientation of the plume generated by Ventolin®HFA (FIG. 26b), ProAir®HFA (FIG. 26c), and Proventil®HFA (FIG. 26d).
  • Horizontal brackets show significant differences between pairs (* p ⁇ 0.05, ** p ⁇ 0.01.)
  • FIG. 26a presents a comparison between MMPAs obtained using PIPE apparatus with and without airflow, and plume angles obtained by HSLI.
  • Plume angles determined by HSLI correspond to the equivalent of no flow conditions. Within the angles determined from HSLI experiments, only Ventolin®HFA and Proventil®HFA were found to be statistically different in terms of plume angle (p ⁇ 0.05).
  • the inner geometry of PIPE is overlaid on the composite images obtained by HSLI to illustrate the overall orientation of the plumes (FIGS. l7b, l7c, and l7d). Plumes generated by all the products expanded beyond the induction port geometry, with a downward orientation with respect the horizontal axis.
  • Mass-based plume angles of all the suspension pMDI products tested under flow showed a significant reduction on MMPA (narrower angle) compared to no flow conditions.
  • plumes generated by Ventolin®HFA presented a reduction of ⁇ 8% on MMPA compared to a ProAir®HFA and Proventil®HFA, which MMPA reduced 15 and 13% respectively when 30 l/min flow was used.
  • the effect of the distance traveled by the plume on the particle size was evaluated by laser diffraction and summarized in FIG. 27.
  • Laser diffraction was used to evaluate the volume median diameter of the droplets emitted from three marketed suspension pMDI products (Ventolin®HFA, ProAir®HFA, and Proventil®HFA). Selected distances represent the center point of each section in the Plume Induction Port Evaluator. Results are presented as the average of five independent actuations. The actuator was moved away from the laser beam at distances that represent the center point of each section in PIPE.
  • Ventolin®HFA showed the largest droplets at the beginning of the aerosolization process (6.6 pm), but also the largest reduction in size as a function of distance ( ⁇ 2 pm after 3 cm).
  • Proventil®HFA has the second largest droplets of the three products (4.7 - 5.3 pm), but the initial droplet size did not change significantly over the tested distances. Similarly ProAir®HFA, had droplets slightly smaller (4 - 4.5 pm) than Proventil®HFA , but remained practically the same size over distance changes.
  • MMPA Mass Median Plume Angle
  • Mass-based plume angles for suspension formulations are significantly affected by compendial airflow conditions
  • the PIPE apparatus was designed to be connected to aNGI and therefore can evaluate the effect of airflow on the plume angle while also characterizing aerodynamic properties of the aerosol using typical cascade impaction practices. Overall, a significant decrease in the MMPA (narrower angle) was observed when applying airflow (30 L/min) compared to no flow conditions (0 L/min) for all tested formulations. Ventolin®HFA was observed to have the narrowest angle and the least reduction in MMPA when airflow was used compared to ProAir®HFA and Proventil®HFA. We propose that this observation is likely related to the combination of formulation and nozzle design of this product. Ventolin®HFA was the only evaluated formulation without ethanol in its composition, which is also reflected in its higher formulation vapor pressure (Table 4).
  • ProAir®HFA showed the largest reduction in MMPA and drug deposition in the induction port when using airflow (30 L/min). Considering that ProAir®HFA and Proventil®HFA have similar droplet size and velocities, impaction forces, and MMPAs under flow, comparable total mass deposition on PIPE would be expected. However, the largest mouthpiece opening and further nozzle distance of Proventil®HFA generated a plume that fully develops earlier and expands closer to the surface of the induction port (FIGS. l7c and l7d). Therefore, Proventil®HFA showed higher drug deposition at section 1 (FIG. 25c) compare to ProAir®HFA (FIG. 25b) which results in higher induction port deposition and lower efficiency (FPF for ProAir®HFA: 65.32% , Proventil®HFA: 37.91%).
  • Proventil®HFA and Ventolin®HFA had comparable drug deposition in the PIPE apparatus in absence and presence of airflow (FIG. 23).
  • the inventors proposed this similarity was because even though Ventolin®HFA generates narrower plumes, the droplet velocity and formulation pressure are considerably higher increasing deposition by inertial impaction.
  • much slower droplets emitted byProventil®HFA should be less likely to impact on the induction port, however the wider plume angle and closer distance to the surface of the induction port compare to Ventolin, could also increase the early deposition.
  • Actuator geometry can influence the calculation of mass-based plume angles
  • the geometry of the actuator has been reported previously to have a significant effect on the characteristics of the sprays emitted from pMDIs, in particular by changing the nozzle and expansion chamber design (1, 22, 23).
  • the calculations for MMPA can also to take into account where the point the plume originates from inside of the actuator, and therefore, it is affected by this initial point (nozzle position) and is restricted by the mouthpiece opening.
  • the method for calculating MMPA can be achieved by determining the isosceles triangle formed between the nozzle and the edges of the PIPE sections. Therefore, the first (and greatest) angle that can be calculated depends on a combination of the distance between the nozzle and the mouthpiece (N ⁇ j ), and the mouthpiece opening (M 0 ) (FIG. 22).
  • Proventil®HFA had a maximum achievable angle (34.6°; FIG. 22) compared to Ventolin®HFA and ProAir®HFA (31.28° and 33.4° respectively).
  • Actuator geometries between ProAir®HFA and Ventolin®HFA were more comparable, with exactly the same Nd but with a slightly smaller (i.e. Less restrictive) mouthpiece opening for ProAir®HFA.
  • just one millimeter of difference in the opening of the mouthpiece is enough to increase in two degrees the initial median angle between actuators (Ventolin®HFA and ProAir®HFA max angles 31.28° and 33.4° respectively).
  • Distribution of the drug along the PIPE apparatus was driven by the formulations properties rather than particle size, with all formulations presenting downward oriented plumes
  • Delvadia et al. studied the effect of the insertion angle of administration for Proventil®HFA, showing that oral deposition was maximized when the inhaler oriented downward (-20°) and decreases when oriented upward (+10°) (24). They attributed their results to the velocity, aerosol size and formulation. Our results showed that the three marketed products present downward oriented plumes confirmed by visual assessment of the residual particles distributed within PIPE (SEM), the deposition map after drug mass quantification (with or without airflow), and composited images obtained by HSLI. Therefore, it is possible that this factor also contributed to the results observed by Delvadia et al.
  • Ventolin®HFA presented the most even drug distribution from Section 1 to 4 (FIG. 24) (i.e. section one corresponding to Topl and bottoml segments) and the highest mass of drug on the“elbow” segment (FIG. 23). These was attributed to the higher pressure of the formulation faster droplet velocity that do not deaccelerate even after within six centimeters from the orifice (corresponding to section 3), and with plume impaction forces almost three fold higher than ProAir®HFA and Proventil®HFA (11).
  • PIPE offers an alternative to laser-based and high-speed imaging methods to evaluate the plume angle of suspension pMDIs, using reliable drug quantitation while allowing for simulating inhalation flow during measurement.
  • the method proved to be sensitive in differentiating marketed albuterol sulfate pMDI products, with lower variability than the laser assisted imaging approach.
  • MMPA values were comparable for ProAir®HFA and Proventil®HFA when airflow was applied which was influenced by large differences on actuator geometry. Highly reproducible results (CV ⁇ 6% under flow) for MMPA makes PIPE a robust analytical tool, capable of comparing products with similar formulations, different actuators, and different macroscopic aerosol characteristics.
  • Mass median plume angles (MMPAs) of four nasal spray formulations with increasing viscosities were determined using the PIPE apparatus in the absence and presence of airflow. MMPAs were then correlated to drug deposition within 3D printed nasal casts using airflow. We evaluated different inhalation instructions obtained from the package insert of nasal products. MMPA significantly reduced (narrower angles) when using flow for the three formulations with the lowest viscosities. An increase in the turbinate deposition was observed in the nasal casts when just one of the nostrils was closed during inhalation, except by the highest viscosity formulation. The turbinate deposition numerically correlated with changes in the plume angles observed using PIPE.
  • Nasal drug delivery is a favorable route for the treatment of local and systemic diseases as well as central nervous system diseases.
  • the respiratory region encompassing the turbinates of the nasal cavity, is highly vascularized making it a target for systemic drug delivery. This region also serves as a target site for treatment of local diseases such as nasal allergies (Illum, 2003).
  • Nasal drug delivery can be administered by drops, sprays, aerosols and powders (Kublik and Vidgren, 1998).
  • nasal sprays are the most common device among FDA approved nasal commercial products. Due to differences in efficacy based on the regional deposition of nasal products, control and quantification of spray performance is an important aspect for characterizing new nasal products as well as assessing bioequivalence between products.
  • a camera is used to capture the actuation of the nasal spray device, and the spray angle is calculated from the images.
  • the angle is calculated either manually or from image analysis technique from an image with a fully developed plume (Cheng et al, 2001; Foo et al., 2007b).
  • the advantage of using a laser sheet to illuminate the aerosol with high-speed imaging is the ability to focus on the single plane of the plume at the centerline (Berrocal et al, 2008; Chen et al, 2016; Smyth et al, 2006).
  • FIG. 37 provides a summary table of the analysis of the instruction of use of 35 nasal spray products approved by the FDA.
  • Plume geometry analysis using high-speed imaging is limited due to its inability to assess plume characteristics under their actual use conditions, e.g. in the presence of physiologically relevant flow. Furthermore, the high-speed laser imaging technique is subjective with regards to determining the edge of the plume for analysis (ITFG/IPACR, 2002). Recently, a new apparatus to assess the plume geometry angle for pMDI products with and without flow conditions has been described (Moraga-Espinoza et al). While, Foo et al. and Guo et al.
  • Cromolyn Sodium (> 98% purity) was bought from Letco Medical (Decatur, USA). Commercially available cromolyn sodium nasal solution, USP (Bausch and Lomb, Tampa, USA) was obtained from 38 th Street Pharmacy (Austin, USA). Hypromellose E4M was donated by The Dow Chemical Company (Midland, MI). Disodium edetate dihydrate and benzalkonium chloride 50% solution were bought from Sigma- Aldrich (St. Louis, USA).
  • Cromolyn sodium nasal spray solutions were prepared in the same manner as reported previously by Wamken et al. (2018a). Cromolyn sodium nasal solution, USP without hypromellose was purchased and transferred into 95.5 pL VP7 spray devices (Aptar Pharma, Le Vadreuil, France). Formulations with 0.1%, 0.2% and 0.4% hypromellose E4M (HPMC) were prepared by dissolving benzalkonium chloride, disodium edetate and cromolyn sodium at 40 mg/mL in either 0.1%, 0.2% or 0.4% hypromellose E4M solutions. The resulting formulations were placed for testing in VP7 spray devices.
  • Plume geometry angle analysis using a laser plane and high-speed imaging was performed in the same manner as previously reported by Wamken et al (2018b). Briefly, the laser sheet was aligned at the centerline of the spray device. The devices were actuated using a Mighty Runt automatic actuator (InnovaSystems, Inc., Moorestown, USA) using the actuation parameters reported by Doughty et al: actuation force of 5.8 kg, force rise time of 0.3 seconds, hold time of 0.1 seconds and force fall time of 0.2 secs. In each case, images of the emitted plumes from the devices were captured at 350 frames/second. Analysis of the plumes was performed using Fiji (https://imagej.net/Fiji) (Schindelin et al., 2012). Plume angles are reported as the average of five independent angle measurements.
  • FIG. 28 illustrates an experimental layout for high-speed laser imaging.
  • a cross-sectional image of the aerosol generated by the nasal spray is recorded using a high-speed camera, and plume characteristics are assessed by image analysis using the software Image! Plume geometry of nasal sprays by mass-based plume angle analysis
  • the Plume Induction Port Evaluator (PIPE) apparatus is a segmented induction port designed in Autodesk Inventor 2017 and manufactured from aluminum (University of Texas at Austin). Its inner geometry reflects the original design of the United States Pharmacopoeia induction port (USP38-NF-33., 2015) and has demonstrated the ability to evaluate the plume geometry of pMDIs during inhalation simulations when connected to a cascade impactor.
  • FIG. 29 illustrates an experimental layout for use of Plume Induction Port Evaluator (PIPE) with nasal sprays. Illustration represents in colors the effective angles used to calculate Mass Median Plume Angles (MMPA).
  • MMPA Mass Median Plume Angles
  • the filter allowed for the passage of air when the pump is in use to evaluate the effect of flow rates on the mass-based plume angle of the nasal spray.
  • Complete collection of the emitted dose was achieved by disassembling PIPE and rinsing the nasal spray adapter, each of the four sections in PIPE, and the filter with 5 mL of deionized water. Collected samples were analyzed by UV absorption at 326 nm wavelength.
  • PIPE was operated in the absence and presence of airflow to evaluate the effect of physiologically relevant flow rates on the geometry of the plume (0, 10 and 45 L/min). Nasal sprays were actuated using the same settings and automatic actuator as those describe in the plume geometry of nasal sprays by high-speed laser imaging section. Mass Median Plume angles are reported as the average of five independent doses actuated into PIPE for all tested conditions.
  • Mass Median Plume Angle (MMPA) calculated using the PIPE apparatus is an alternative method to high-speed laser imaging.
  • the method characterizes the emitted plume by direct quantification of the drug, using a single descriptor to report where fifty percent of the drug is deposited along the segmented induction port.
  • FIG. 30 illustrates an example of log normal distributed deposition patterns in PIPE and calculation of the Mass Median Plume Angle. Effective Median angles between nozzle and sections in PIPE apparatus are used to calculate the Mass Median Plume Angle (MMPA) of the plume.
  • Spreadsheet format was modified from Probit method described by O’Shauhnessy and Raabe for calculation of Mass Median Aerodynamic Diameter (MMAD) (O'Shaughnessy and Raabe, 2003).
  • FIG. 30 represents an example of how deposition patterns obtained from PIPE apparatus are used to calculate the MMPA of nasal sprays. Briefly, median angles were calculated using the effective angles formed at each section with respect to the nasal spray nozzle, which are represented in FIG. 29, and listed in FIG. 30a.
  • Particles deposited on the nasal spray adapter were considered to have a deposition angle higher than 180°, and therefore, are not part of the calculation for MMPA as described in FIG. 30a.
  • the calculation method follows the spreadsheet arrangement developed by O’Shauhnessy to calculate Mass Median Aerodynamic Diameter (MMAD) by the Probit method (O'Shaughnessy and Raabe, 2003). Briefly, the cumulative percent of the drug deposited on each section in PIPE is transformed into its linear equivalent Z value, so the scale of the probability axis is transformed into a linear scale. Then, the linear Z values are plotted relative to the logarithm of the median angles in PIPE, where the intercept of the curve represents the MMPA (FIG. 30c).
  • FIG. 31 illustrates a representation of the human nasal airway replica casts sectioned for regional deposition analysis.
  • Deposition paterns obtained under flow conditions (45 L/min) were tested with both nostril open and with only one nostril open.
  • Actuation of the nasal sprays in the nasal casts was performed using the same actuation conditions as those for the plume geometry angle analysis.
  • the nasal sprays were inserted into the nasal casts at an angle of 30 degrees from horizontal plane and an insertion depth of 5 mm.
  • the nasal casts were maintained upright without any forward or backward tilting.
  • Airflow rates tested in the casts were no flow, 45 L/min with both nostrils open and 45 L/min with only one nostril open.
  • the airflow rate was monitored using an in-line digital flow meter (TSI 4000 Series, TSI incorporated, MN, US).
  • the vacuum was initiated 2.3 sec before the actuation of the nasal sprays and maintained for 0.5 sec after actuation.
  • the PIPE apparatus was operated at 0, 10 and 45 L/min. A significant decrease in plume angle (i.e. narrower angle) was observed when comparing MMPA values obtained in the absence of airflow (0 L/min) and the highest flow rate (45 L/min). These differences were found for formulations with a HPMC concentration between 0.0% and 0.2%. A non-significant difference was found when comparing similar conditions (0 and 45L/min) for the highest HPMC concentration, 0.4%.
  • FIG. 33 illustrates the effect of formulation on the variability of plume geometry angle measurements evaluated by PIPE (0 L/min) and high-speed laser imaging. Coefficient of variations were calculated from five independent actuations. The coefficient of variation of the plume angle measurements obtained by PIPE in the absence of flow and high-speed laser imaging were calculated and compared in FIG. 33. This was considered as a fair assessment of the variability of the methods since high-speed laser imaging cannot evaluate the plume geometry angle under flow, but was capable of differentiating between
  • FIG. 34 illustrates deposition patterns of the formulation 0.1% HPMC in the nasal replica casts (7 year old female, 12 year old female and 48 year old male).
  • Three different instructions for use related to inhalation maneuvers were identified after analysis of 35 different FDA approved nasal spray products.
  • the formulation with 0.1% HPMC was selected to evaluate these variables on nasal regional deposition using a fixed administration angle (30°). This formulation was selected due to the largest difference in MMPA values found in absence and presence of airflow (0 and 45 L/min).
  • Turbinate deposition of nasal sprays increase when using flow with one nostril closed
  • FIG. 35 illustrates the effect of inhalation maneuvers selected from patient instructions for use (no flow/ two nostril open vs flow and one nostril open) and nasal spray formulation on overall deposition at the anterior and turbinate regions.
  • Results are the average of 5 independent actuations on each nasal replica casts using a fixed administration angle of 30° (7 year old female, 12 year old female and 48 year old male).
  • Regional drug distribution data of the three nasal casts was averaged to evaluate the overall effect of the selected inhalation maneuvers obtained from the product’s
  • Patient Instructions for Use no flow/two nostrils open, and flow/one nostril open
  • formulation on turbinate deposition Comparisons between anterior and turbinate deposition (lower + middle + upper sections) for each formulation are displayed in FIG. 35.
  • Mass-based plume angles correlate with turbinate deposition with and without flow conditions
  • FIG. 36 illustrates a correlation between plume angle ( ) and turbinate deposition (%).
  • Mass median plume angles (MMPA) were obtained in presence and absence of airflow (0 and 45L/min) using the PIPE apparatus.
  • Turbinate deposition is reported as the average of the three nasal casts using an administration angle of 30 °, similar to reported data by Foo et al. (Foo et al, 2007a). Dashed line represents the nonlinear quadratic regression of both data sets (PIPE vs Nasal cast, R 2 : 0.9366; Foo et al. 2007, R 2 : 0.9034).
  • the plume geometries angle of nasal sprays were successfully measured by a mass-based technique using the Plume Induction Port Evaluator.
  • the amounts of drug deposited on each section of the apparatus were found to be log normally distributed, allowing for the mass median plume angle to be calculated in the same manner as previously reported for analyzing the pMDIs.
  • the method used for determining the MMPA from PIPE is based on the long-standing calculation currently used for determining the mass median aerodynamic diameter from cascade impaction studies detailed in the United States Pharmacopoeia (USP30-NF25, 2007).
  • the 0.1% HPMC nasal spray formulation was used in this study as it is the highest concentration of HPMC listed in the FDA inactive ingredients database providing evidence for it being well representative of some marketed products (FDAdatabase, 2018). Additionally, 0.1% HPMC formulation was shown to have the greatest absolute differences in plume angle with flow in the studies using PIPE (FIG. 32). An increase in the deposition to the lower and middle portion of the turbinate region was observed as inhalation airflow increases for each of the nasal casts as depicted in FIG. 34. Closing a single nostril decreases the cross-sectional area for airflow to pass through the casts.
  • a decrease in the cross-sectional area results in increases in the velocity of the inspiratory air in the cast, increasing its ability to affect the droplets developed from the nasal spray.
  • Nasal spray formulations with high viscosity generate narrower plume geometry angles with lower chances of early impaction in the anterior area and higher rates of success targeting the turbinate region (Dayal et al., 2004; Foo et al, 2007a; Newman et al, 1988).
  • the use of viscosity for tuning the delivery efficacy of the nasal sprays presents limitations since this decreases the atomization efficiency of the nozzle, transforming the spray into a jet that has been reported to generate discomfort in patients (Berger et al., 2007). Therefore, despite the high turbinate deposition achieved (-84%) by the formulation with the highest HPMC concentration (0.4%), its use for targeting the turbinated region would be limited as it could be considered as a non-pharmaceutically acceptable formulation by current standards.
  • PIPE apparatus was adapted to be used in nasal spray products and is capable of detecting variations in the plume angle generated from the formulations at all tested conditions. Deposition patterns along PIPE were log-normal distributed, allowing the calculation of the Mass Median Plume Angle. Changes in the deposition within the nasal casts correlated with the narrowing of the plume angle determined by PIPE with increasing viscosity and airflow. Therefore, we proposed that changes detected in turbinate deposition are likely due to changes in plume geometry during inhalation. The ability of PIPE to analyze the plume angle of nasal spray products under the conditions recommended for use by the patient may contribute to assessing the bioequivalence of nasal spray products as well as correlating their in vitro performance to in vivo results.
  • Plume geometry was modulated using a combination of formulation and temperature to achieve a range of plume angles to be assessed using laser- based imaging and mass-based plume characterization approaches.
  • Mass-based plume angles were determined under flow conditions using the deposition patterns within the Plume Induction Port Evaluator (PIPE).
  • PIPE Plume Induction Port Evaluator
  • a parameter was derived in this study that correlated the geometry of the plume to the in vitro aerosol performance of the inhalers. This parameter, the Mass Median Plume Angle of emitted dose (MMPAED), allows calculation of plume angle based on the entire mass emitted from the inhaler.
  • MMPAED Mass Median Plume Angle of emitted dose
  • Pressurized metered dose inhalers are well-known and ubiquitous handheld devices used in the treatment of lung diseases such as asthma and chronic obstructive pulmonary disease (COPD).
  • plume geometry is a central test to evaluate the physical integrity of the device (3).
  • Plume angle analysis has been carried out by high-speed imaging approaches such as time sequence sound triggered flash photography, and, laser light sheet technology (4).
  • the literature related to the plume geometry of pMDIs remains scarce, with most of these publications focused on the effect of the formulation, nozzle design, and actuator materials (5-9). Indeed, all these reports, with the exception of Mitchell et al. (8), have not accounted for the effects of inhalation airflow on plume geometry. Instead, plume geometry has been quantified as the aerosol plume to expand in open space and in the still air. Mitchell et al. (8) applied airflow through the actuator using positive pressure and the plume was emitted into open air.
  • Formulations used in this study were prepared following the same method used by Moraga-Espinoza et al. (10). In summary, three ethanol concentrations (2.49%, 9.99%, 19.99%) were used to manufacture solution pMDIs with different Mass Median Plume Angles (MMPAIP) by changing the composition and vapor pressure of the formulation.
  • Rhodamine B Sigma- Aldrich
  • Rhodamine B was used as a soluble drug model (0.01% w/w)
  • ethanol Pharmco-Aape
  • HFA l34a tetrafluoroethane
  • Canisters were crimped with 28pL metered valves and filled gravimetrically with the liquid propellant (HFAl34a) using a burette pressure filler (Aero-Tech, Maryland, NY). Actuators had an orifice diameter of 0.3 mm. Valois of America kindly donated canisters and actuators, and Aptargroup donated the metered valves.
  • Influence of formulation and relevant ambient temperatures on the plume geometry of the solution pMDIs was evaluated by laser and mass-based approaches, using a high-speed laser imaging system and the Plume Induction Port Evaluator.
  • Plume angle of the solution pMDIs was obtained by high-speed laser imaging using the method described by Moraga-Espinoza-et al (10). Briefly, a laser source and a cylindrical lens were used to generate a laser sheet and illuminate the aerosol emited by the pMDI device. Cross-sectional images of the plume were obtained by using a high-speed monochromatic camera (Flea3®, FLIR Systems, Wilsonville, OR, USA) operated at 400 frames per second perpendicular to the trajectory of the plume (FIG. 38a). A composite image of the plume was generated using frames (images) that encompass the beginning of the aerosol formation and the last frame (image) where the plume was in contact with the actuator as suggested by FDA guidance’s (4).
  • the pMDIs were actuated using an automatic actuator (Mighty Runt, InnovaSystem, Inc, Moorestown, USA), operated under the following actuation parameters: actuation force of 6.4 kg, force rise time of 0.1 seconds, a hold time of 0.5 seconds and a force fall time of 0.1 seconds(l5). Plume angles were reported as the average of ten actuations for each of the tested temperatures and formulation.
  • FIG. 38 shows an experimental setup for plume angle analysis by High-speed laser imaging using an automatic actuator b) Experimental setup for measuring droplet size by laser diffraction at high temperature (37°C).
  • the PIPE apparatus is a segmented induction port that allows the characterization of the plume angle of aerosols emitted by pMDIs and nasal sprays by drug mass quantification during inhalation simulations (10, 15, 16).
  • Mass Median Plume Angle (MMPA) is a characterization parameter that uses the deposition patterns within the PIPE apparatus to calculate the median angle of the plume (10).
  • MMPAIP Induction Port deposition
  • MMPAED Emitted Dose
  • NGI Next Generation Impactor
  • FIG. 39 provides illustrative calculation tables describing the calculating Mass Median Plume Angles based on Induction Port deposition (MMPAIP) and Emitted Dose (MMPAED). Calculations were developed derived and adapted from O'Shaughnessy et al. that description of the Probit method for log-normal distributions (17).
  • MMPA Median angles used for calculating MMPA were calculated using the method developed by Moraga-Espinoza et al. to account for the geometry of the actuator (15). Thus, for actuators with a mouthpiece opening, and a nozzle distance of 18 mm respectively, the calculated median angles at each section of PIPE are >53.13, 43.92, 27.33, 17.29, 12.69, 5.37, corresponding to the mouthpiece, section 1 to 4, and elbow respectively. MMPA data was reported as the average of three independent runs for each condition.
  • the PIPE apparatus was connected to a NGI to be used during cascade impaction studies.
  • the pump used to generate the airflow conditions was operated following USP specifications (30L/min) (18).
  • the inhaler was shaken for five seconds and primed by discharging two wasted shots. Then, five doses were actuated manually into PIPE within intervals of twenty seconds.
  • the aerosolized drug deposited within the PIPE apparatus was collected by rinsing each of the segments thoroughly with 10 mL of an ethanol/water (1 : 1) solution. Additionally, drug deposited within the pMDI actuator and the mouthpiece adapter was collected using 25 mL of solvent.
  • the drug model (Rhodamine B) was assessed by fluorescence spectroscopy using a wavelength of 550 nm excitation and 610 nm emission.
  • Particle size analysis of the emitted droplets from the solution pMDI formulations was performed by laser diffraction (Geometrical particle size) and cascade impaction (Aerodynamic particle size). The three formulations were evaluated at three different temperature conditions (5°C, 25°C, 37°C).
  • the aerosolized drug deposited on the cascade impactor was collected by rinsing the NGI stages with 10 mL of an ethanol/water (1: 1) solution. Rhodamine B was assessed using the same method described above for the PIPE apparatus (fluorescence spectroscopy, 550 nm excitation and 610 nm emission). NGI stages were coated with a 1% silicone oil/hexane solution to prevent particle re-entrainment. MMPAs, Fine Particle Fraction (FPF: Percentage of the emitted dose with an aerodynamic particle size ⁇ 5 pm), and Mass Median Aerodynamic Diameter (MMAD) were calculated from the same cascade impaction experiment. Data was reported as the average of three independent runs for each condition. Statistical Analysis
  • the vapor pressure of the formulation was measured using a pressure gauge connected to the stem of the canister. Each formulation was tested after being exposed to the target temperature conditions for two hours. In general, the formulation vapor pressure presented a significant decrease as ethanol increases (FIG. 40). This trend was consistent at low (5°C) and high temperatures (37°C) as well. Concerning temperature effect, a significant decrease in vapor pressure was observed for all formulation when exposed to low temperatures compared to room temperature (25°C). On the other hand, high temperatures showed a slight but not statistically significant increase in vapor pressure for the lowest and highest ethanol concentration formulations (2.49% and 19.99% respectively).
  • FIG. 41 Composite images obtained from high speed laser imaging, after image processing, are displayed in FIG. 41 for all tested conditions.
  • the cross-sectional images illustrate the changes induced in the macroscopic characteristics of the plume due to the different formulation compositions and temperature variables used.
  • the inner geometry of the PIPE apparatus was overlaid to the plume images to emphasize the plume orientation (upward or downward oriented). Analysis of the ninety collected videos showed that all the plumes presented downward orientation respect to the horizontal axis of PIPE.
  • FIG. 41 illustrates an example of composite images obtained by High-Speed Laser Imagine for all formulations (Ethanol concentration 2.49%, 9.99% and 19.99%) at different temperatures (5°C, 25°C, and 37°C).
  • the inner geometry of the Plume Induction Port Evaluator was overlaid to the cross-sectional images to determine the plume orientation respect to the vertical axis.
  • FIG. 42 shows the influence of formulation and temperature on the deposition patterns within the PIPE apparatus in the presence of flow (30 L/min). Color coding was used to show the“hot spots” where higher concentrations of the drug model (Rhodamine B) was deposited (white was used for identifying the segments with the lower mass of drug while red indicates higher deposition).
  • the deposition map shows that for all formulations, more than 40% of the total drug deposited in the induction port was found along the bottom segments (From sections 1 to 4) compared to a 23 to 29% on the top segments. Additionally, the majority of the drug deposited in PIPE (52-70%), regardless of the formulation or temperature, was found to be deposited in the first 4 cm (From mouthpiece adapter to section 2).
  • Section 2 (sections 2 defined as the combination of top 2 and Bottom 2 segments) presented the highest concentration of drug deposited. Overall, the mass of drug deposited on the mouthpiece adapter and section 1 did not change as a function of temperature.
  • FIG. 43 shows a summary of the plume angle measurements for all the formulations as a function of temperature.
  • Laser- based results showed a positive correlation between ethanol concentration and plume angle (i.e., larger/wider plume angle as ethanol concentration increase).
  • Mass-based plume angle analysis focusing only on the mass deposited within the induction port (MMPAIP) (FIG. 43b) showed an opposite trend compared to both the laser- based system and the MMPAED (FIG. 43).
  • Increase in ethanol concentration resulted in a decrease in plume angle (narrower angle) for formulations using 2.49% and 19.99% ethanol concentration.
  • temperature and MMPAIP were positively correlated, resulting in larger (wider) plume angles as temperature increases for formulations 2.49% and 19.99%. Similar results were observed for the formulation using 9.99% ethanol.
  • the increase in angle was not significant when increasing from 25°C to 37°C.
  • Particle size distribution (PSD) of the aerosol emitted by solution-based pMDIs was investigated by laser diffraction (geometric particle size) and by drug mass quantification through cascade impaction (aerodynamic particle size).
  • FIG. 44 presents the data generated by both techniques as a function of formulation and temperature. More than one order of magnitude of difference was observed between particle sizes measured by laser and cascade impaction. These results are related to the differences on particle size calculation (geometric vs. aerodynamic particle size) and droplet evaporation stages during sampling (i.e., LD samples close to the nozzle were evaporation is still on process, while cascade impaction collects residual particles after complete evaporation of the liquid propellant).
  • Fine Particle Fraction was calculated as the fraction of the emitted dose with a particle size ⁇ 5 pm size.
  • FPF was inversely correlated to the ethanol concentration (i.e., higher ethanol concentrations results in lower FPF) at all tested temperatures (FIG. 45c). FPF was significantly higher for all formulations with increased temperatures (5°C compared to 37°C conditions).
  • FIG. 46 shows the effect of the formulation vapor pressure on the plume angles measured by laser and mass-based techniques (MMPAIP and MMPAED).
  • the final pressure inside of the canister was modified by changing the proportions of the pressurized liquid propellant (HFAl34a) and the semi-volatile co-solvent (Ethanol). Additionally, canisters were exposed to different relevant ambient temperatures that could be present during the product lifespan, and therefore, may change the formulation vapor pressure.
  • Plume angles obtained by HSLI in the absence of flow (0 L/min) showed a negative correlation with respect to the formulation pressure (i.e., higher pressure, narrower angle) (FIG. 46a).
  • MMPAIP Induction Port deposition
  • MMPAED Mass Median Plume Angles calculated based on the Emitted Dose
  • Mass-based plume geometry is a characterization method for pMDIs capable of measuring the angle and orientation of a plume by drug mass quantification under airflow conditions(lO).
  • pMDIs mass-based plume geometry
  • MM PA ED is correlated to in vitro delivery efficiency of MDIs.
  • the MMPAED calculation accounts for the overall plume angle of the emitted aerosol within the airflow applied during cascade impaction analysis.
  • the MMPAED calculation includes (in contrast to MMPAIP) the mass of drug that avoids deposition in the horizontal pathway within the induction port of PIPE (i.e. sections 1-4 and Elbow) (FIG. 39b).
  • This modification to the previously reported MMPAIP parameter resulted in a strong correlation to the in vitro aerosol delivery efficiency of pMDIs (FIG. 47a).
  • MMPAIP demonstrated a poor correlation with respect to delivery efficiency (FPF) (FIG. 47b), which suggest that changes in the MMPAIP cannot be completely linked to the efficiency of the inhaler since it accounts for only the drug deposited with in the induction port.
  • MMPAED is sensitive to changes in the plume angle for both the smaller and larger droplet size populations and is a better predictor of plume angle for pMDI overall performance compared to the MMPAIP parameter.
  • MMPAED since the MMPAED also includes the fine particle fraction in the plume angle calculation and calculates the angle of the droplets with the potential to overcome the oropharyngeal deposition. Additionally, due to the normalization of the data by the emitted dose, MMPAED provides a parameter that can be compared across different products (i.e., solution vs. suspension pMDI formulations).
  • MMPAIP size of the plume angle is reduced
  • Planar orifice atomizers such as the nozzle in pMDI actuators, generate wider spray cone angles as the injection pressure increases (27).
  • MMPAIP was, as expected, positively correlated with formulation vapor pressure (i.e., higher pressure, wider angle), however, the laser system showed an opposite trend. Plumes with wider angles are likely to get more deposition in the surface of the actuator, which was the case for the formulation with lowest ethanol concentration (2.49%) (FIG. 45a). However, size-dependence deposition is also a factor to consider. At 5°C , this formulation (2.49% ethanol) presented the largest droplets and lowest vapor pressure compare to 25°C and 37°C.
  • Plume geometry of pMDIs is a long-standing characterization technique, usually measured by high-speed laser imaging. Its use has been focused to evaluate the integrity of the metered valve or nozzle in the device, but correlations to aerodynamic performance have not been studied. To our knowledge, this is the first attempt to correlate the angle of the plume to the aerodynamic performance of pMDIs.
  • a new parameter for predicting delivery efficiency has been developed focusing on different stages of the aerosolization process.
  • MMPAIP has the potential to predict the oropharyngeal deposition since its calculation focuses on the edges of the plume which are likely to interact with the oral cavity.
  • MMPAED is a second parameter that described the angle of the droplets entrapped in the airflow toward the cascade impactor, and has shown a strong correlation with the delivery efficiency.
  • Our results proved to be particularly relevant for comparing formulations, showing a good correlation with either solution and suspension formulations.
  • our results have shown the potential of using PIPE for connecting the gap between the early stage of aerosol formation and the final aerodynamic performance under relevant inhalation flow rates. It is important to mention that temperatures used in this study were selected to reflect the variations in the geometry of the plume at environmentally relevant temperatures. Additionally, the authors are aware that these results may not reflect the reality of other orally inhaled drug products. Hence, more studies on the use of mass-based plume geometry as the complement of cascade impaction data should be done to determine the capabilities and limitations of the PIPE apparatus.
  • MDI metered dose inhaler
  • DPI dry powder inhaler
  • hydrofluoroalkane-l34a beclomethasone in asthmatic patients Annals of Allergy, Asthma & Immunology. 20l2;l08(3): 195-200.
  • MDI metered dose inhaler
  • DPI dry powder inhaler
  • OINDPnews Mexichem discusses potential for using HFA l52a as pMDI propellant: OINDP news; 2016 [Available from: http://www.oindpnews.com/20l6/l2/mexichem- discusses-potential-for-using-hfa-l52a-as-pmdi-propellant/.
  • Fiji an open-source platform for biological-image analysis. Nature methods. 20l2;9(7):676.
  • Intranasal corticosteroids the development of a drug delivery device for fluticasone furoate as a potential step toward improved compliance. Expert opinion on drug delivery 4, 689-701.
  • MDI metered dose inhaler
  • DPI dry powder inhaler
  • USP38-NF-33 USP/NF General Chapter ⁇ 60l> Physical Tests and determinations- Inhalation and Nasal drug products: Aerosols, Sprays, and Powders -Performance Quality Tests. National Formulary, USP38-NF-33 Rockville, MD: USP. 2015.

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Abstract

L'invention concerne un appareil et des procédés pour caractériser la géométrie d'un panache de produit inhalé par voie orale. L'appareil peut comprendre un conduit latéral comprenant une pluralité de sections qui peuvent être séparées perpendiculairement et parallèles à l'axe principal du conduit latéral.
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WO2022081847A1 (fr) * 2020-10-15 2022-04-21 Proveris Scientific Corporation Systèmes et procédés d'essai d'inhalateur
EP3930807B1 (fr) * 2019-02-27 2023-11-08 NuvoAir AB Procédé et dispositif d'estimation d'une quantité d'un matériau poudreux passant par un coude dans un canal d'écoulement
US12502491B2 (en) 2023-04-13 2025-12-23 Proveris Scientific Corporation Systems and methods for inhaler testing

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Publication number Priority date Publication date Assignee Title
EP3930807B1 (fr) * 2019-02-27 2023-11-08 NuvoAir AB Procédé et dispositif d'estimation d'une quantité d'un matériau poudreux passant par un coude dans un canal d'écoulement
WO2022081847A1 (fr) * 2020-10-15 2022-04-21 Proveris Scientific Corporation Systèmes et procédés d'essai d'inhalateur
CN113449668A (zh) * 2021-07-08 2021-09-28 杭州迅蚁网络科技有限公司 一种飞行装置的靶标角度识别方法、装置
CN113449668B (zh) * 2021-07-08 2023-05-23 杭州迅蚁网络科技有限公司 一种飞行装置的靶标角度识别方法、装置
US12502491B2 (en) 2023-04-13 2025-12-23 Proveris Scientific Corporation Systems and methods for inhaler testing

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