A device for aerosol tracking and characterisation

Abstract

The present invention relates to a device for aerosol characterisation. In particular, the present invention relates to a device and a method for providing dynamic measurement of an aerosol travelling in a mouth-throat model, a mouth-throat model comprising the device and an aerosol characterisation system comprising the device.

Description

A DEVICE FOR AEROSOL TRACKING AND CHARACTERISATIONRelated application

[0001] The present application claims priority to Australian Provisional Patent Application No. AU2023903966, filed 7 December 2023, which is incorporated by reference in its entirety.Field of the Invention

[0002] The present invention relates to a device for aerosol tracking and characterisation. In particular, the present invention relates to a device and a method for providing dynamic measurement of an aerosol travelling in a mouth-throat model, a mouth-throat model comprising the device and an aerosol characterisation system comprising the device. However, it will be appreciated that the invention is not limited to these particular fields of use.Background of the Invention

[0003] The following discussion of the prior art is provided to place the invention in an appropriate technical context and enable the advantages of it to be more fully understood. It should be appreciated, however, that any discussion of the prior art throughout the specification should not be considered as an express or implied admission that such prior art is widely known or forms part of the common general knowledge in the field.

[0004] The respiratory inhalation products market, in 2020, was valued at approximately 70 billion USD. In the United States, one of the largest inhaler markets, a key goal of the Food and Drug Administration (FDA) is to drive down the cost of inhalation products, however in competition with this desire are the stringent regulations that the FDA must impose on the introduction of new non-branded or “generic” inhalation products into the market. These regulations require lengthy bio-equivalence studies, including in-vitro and in-vivo tests as part of the product development stage. This testing can reach in the tens of millions of dollars over the duration of the product’s development.

[0005] The introduction of new, modern in-vitro technologies that can provide a quick screening or assessment of inhalation products under development would enable faster introduction of new products. Clinical trials currently are the largest source of product development cost, and can account for as much as 50% of the total development cost. Prior to going to human trials, and to be successful in these costly tests, the developer must be confident that the new products can achieve a certain aerodynamic particle size, consistently, i.e. an appropriate fraction of the dose of an inspired aerosol must always be located in particles less than 5 microns in aerodynamic diameter (these smallest particles are the ones that reach the therapeutic targets).

[0006] Impactors are well known tools that are used for the characterisation of particulate flows of aerosols. Among these, the next-generation impactor (NGI) is a well-known and widely recommended tool for measuring aerodynamic particle size distribution (APSD). The APSD is a critical metric that is measured as part of the development of a new oral inhalation drug product. Measurement of this quantity is achieved by combining NGI measurements with a method to delineate the mass fraction of powder or aerosol within each stage of an NGI. This could be done by weighing, or more commonly using a method such as high performance liquid chromatography (HPLC).

[0007] In the pharmaceutical aerosol context, an NGI is typically used with a “mouth-throat model” which is a physical replica or simplified representation of the upper airway of a human. This mouth-throat model is used in order to “simulate” the loss of aerosol to the human upper airway which occurs in practice. There are different variants of mouth throat models, with the simplest and standardized one being the United States Pharmacopeia (USP) throat. Other more physiologically accurate variants include the Alberta throat or Virginia Commonwealth University throat amongst others. At the inlet of the mouth-throat model is where an adapter and inhaler device would be attached. Particles flow through the inhaler device, then through the adapter, through the mouth throat model, and finally to the impactor for analysis.

[0008] With such a setup, there is currently no way to evaluate the quality and consistency of the aerosol emitted directly from the inhaler, in real-time, unless the inhaler is removed from the mouth-throat model and subjected to separate testing. This decoupling of tests adds to development time and also prevents any real-time monitoring or tracking of aerosol variability leading into the NGI. For drug developers, consistency in aerosols emitted from inhalers is an important piece of information to obtain early in the development of a new product as it can provide information on the dispersion capability of the powder formulation and device as well as consistency of the drug formulation properties under representative inspiratory conditions.

[0009] Further, NGIs are designed to accommodate steady flows as the particle cut-off diameters are determined through a calculation of parameters which assume that the flow-rate is constant through the NGI. If a steady flow is delivered through an inhaler device being tested in the laboratory then the outlet of the mouth-throat model is attached to an NGI directly. However, if a test is run with an inhaler under a more “realistic” transient breathing condition, then the outlet of the mouth throat model would attach to a mixing chamber or similar, and the outlet of this mixing chamber would be attached to an NGI.

[0010] US Patent No. 7,616,310 and US Patent No. 7,414,720 disclose a process for determining the size distribution of the particles contained in an aerosol using laser diffraction techniques and an apparatus for carrying out such a process. US Patent No. 8,508,732discloses a device and a method for use with a laser diffraction apparatus. In particular, the device is used as an adaptor for dry powder inhalers and provides a more consistent method for more accurately measuring particle size distribution and density of a plume of a powder composition emitted from a dry powder inhaler.

[0011] It is an object of the present invention to overcome or ameliorate at least one of the disadvantages of the prior art, or to provide a useful alternative.

[0012] Unless the context clearly requires otherwise, throughout the description and the claims, the words “comprise”, “comprising”, and the like are to be construed in an inclusive sense as opposed to an exclusive or exhaustive sense; that is to say, in the sense of “including, but not limited to”.

[0013] Although the invention will be described with reference to specific examples it will be appreciated by those skilled in the art that the invention may be embodied in many other forms.Summary of the Invention

[0014] According to a first aspect of the present invention there is provided a device comprising at least one pair of a light source and a sensor disposed on a circumference of the device, wherein the device is removably attachable to a mouth-throat model to thereby provide dynamic measurement of an aerosol travelling through the mouth-throat model in real time by directing a light beam from the light source through the aerosol to the sensor to obtain a dynamic light intensity from the sensor.

[0015] The inventors of the present invention have surprisingly found that the device of the present invention can advantageously provide optical access to aerosols during an impactor test, for example an NGI test, by integrating directly to the mouth-throat model or NGI. The device provides real-time characteristics of an aerosol, which provides valuable additional insights into aerosol behaviours during normal in-vitro testing operations. The device may interface directly with standardized mouth-throat models and impactor equipment in order to provide insights on aerosol behaviour such as aerosol run-to-run variability during an NGI test, average aerosol speed or acceleration and other qualitative metrics of aerosol behaviour, such as aerosol evacuation time from a device, and additional insights on how the aerosol evacuated (e.g. continuously or in a non-continuous manner).

[0016] Advantageously, the light source and the sensor are disposed on the circumference of the device to allow axial positioning of the light beams to be close to each other for accurate velocity measurement. It also allows for a compact device that is easily attachable and is easier to operate by an untrained user and is able to provide aerosol consistency data in real time during normal NGI operations.

[0017] The skilled person would appreciate that the dynamic light intensity provides a measurement of dynamic light attenuation, for example line integrated light attenuation measurements. The temporal evolution of line integrated attenuation measurements or signals, such as average signal attenuation, signal frequency over the acquisition time, and / or signal peak-to-trough data from multiple angular locations, may be used with plume velocity as a measure of batch-to-batch variability of an aerosol.

[0018] The skilled person would also appreciate that any system that transports aerosol, or systems that exist to define the physical or chemical properties of the aerosol can be used in conjunction with the device and technology disclosed herein.

[0019] In some embodiments, measurements of light attenuation are used to obtain aerosol morphology, mean aerosol velocity, aerosol acceleration or deceleration in real-time.

[0020] In some embodiments, the device is removably attachable to a mouth-throat model through an adapter.

[0021] In some embodiments, the device is airtight.

[0022] In some embodiments, the device, when attached to a mouth-throat model, maintains an existing inner geometry of the mouth-throat model.

[0023] In some embodiments, the device comprises an inner sleeve and an outer sleeve, wherein the outer sleeve is removably attached to the inner sleeve.

[0024] In some embodiments, the at least one pair of a light source and a sensor is disposed on the outer sleeve.

[0025] In some embodiments, the inner sleeve is removably attachable to a mouth-throat model.

[0026] In some embodiments, the inner and / or the outer sleeves are optically accessible.

[0027] In some embodiments, the inner and / or the outer sleeves are washable.

[0028] Advantageously, the inner sleeve is removable and washable. This enables the use of the device with an assembly that can be subsequently subjected to high performance liquid chromatograph (HPLC).

[0029] In some embodiments, the inner and / or the outer sleeves are made of quartz, acrylic and / or another optically accessible material such as glass, printed resin or silicone.

[0030] In some embodiments, the device comprises multiple pairs of light sources and sensors configured to provide at least two parallel light beams. In certain embodiments, thedevice comprises 2, 3, 4, 5, 6, 7, 8, 9, or 10 pairs of light sources and sensors. In some embodiments, the multiple pairs of light sources and sensors are configured to provide 2, 3, 4, 5, 6, 7, 8, 9 or 10 parallel light beams.

[0031] In some embodiments, the multiple pairs of light sources and sensors are configured to provide at least one light beam at an angle of between about 1 ° and about 179° to the parallel light beams. In certain embodiments, the angle is between about 60° and about 120°. In a particular embodiment, the angle is about 90°. For example, the angle may be between about 1° and about 10°, between about 10° and about 20°, between about 20° and about 30°, between about 30° and about 40°, between about 40° and about 50°, between about 50° and about 60°, between about 60° and about 70°, between about 70° and about 80°, between about 80° and about 90°, between about 90° and about 100°, between about 100° and about 110°, between about 110° and about 120°, between about 120° and about 130°, between about 130° and about 140°, between about 140° and about 150°, between about 150° and about 160°, between about 160° and about 170°, or between about 170° and about 179°. Examples of the angle include 1°, 10°, 20°, 30°, 40°, 50°, 60°, 70°, 80°, 90°, 100°, 110°, 120°, 130°, 140°, 150°, 160°, 170°, or 179°. The skilled person would appreciate that this angle may be changed depending on the application or condition of the flow. If the aerosol is substantially asymmetric then this would appear as a varying signal structure from different angles. If the aerosol is perfectly symmetric then on average, the same information may be obtained from each angle.

[0032] In some embodiments, the multiple pairs of light sources and sensors are configured to provide at least three light beams, wherein at least two light beams are parallel, and the remaining light beam(s) is either parallel to the parallel light beams or at an angle of between about 1° and about 179° to the parallel light beams.

[0033] In some embodiments, the multiple pairs of light sources and sensors are configured to provide 1 , 2, 3, 4, 5, 6, 7, 8, 9, or 10 light beams at an angle of between about 1 ° and about 179° to the parallel light beams.

[0034] In some embodiments, the multiple pairs of light sources and sensors are configured to provide at least two light beams that do not intersect each other.

[0035] In some embodiments, no light beam intersects another.

[0036] In some embodiments, the multiple pairs of light sources and sensors are configured such that at least two light beams have a minimum distance of about 1mm between each other in a travelling direction of the aerosol. In certain embodiments, the minimum distance is about 1mm, 2mm, 3mm, 4mm, 5mm, 6mm, 7mm, 8mm, 9mm or 10mm. The skilled person would appreciate that the minimum distance is about the same as the diameter of the light beam.

[0037] In some embodiments, the at least two light beams comprise parallel light beams.

[0038] In some embodiment, all the light beams have a minimum distance of about 1mm between each other in a travelling direction of the aerosol.

[0039] In a specific embodiment, the device comprises two pairs of light sources and sensors configured to provide two parallel light beams.

[0040] In another specific embodiment, the device comprises three pairs of light sources and sensors configured to provide two parallel light beams and one light beam at an angle to the parallel light beams. In yet another specific embodiment, the device comprises at least three pairs of light sources and sensors configured to provide two parallel light beams and one light beam at an angle to the parallel light beams.

[0041] Advantageously, the at least two pairs of light sources and sensors allows crosscorrelation of signal data between multiple beams along the aerosol path for extraction of inlet aerosol velocity as well as a measure of spray or aerosol characteristic. In some embodiments, the at least three pairs of light sources and sensors allows cross correlation between two different pairs of light beams enabling a measurement of aerosol acceleration.

[0042] In some embodiments, the light source is selected from the group consisting of a laser source, a violet light source, a blue light source, a cyan light source, a green light source, a yellow light source, an orange light source, a red light source, or any combination thereof. Preferably, the light source is a laser source.

[0043] In some embodiments, the light source has a power rating of between about 1 mW to about 10mW. For example, about 1mW, 2mW, 3mW, 4m W, 5mW, 6m W, 7mW, 8mW, 9mW or 10mW.

[0044] In some embodiments, the light source is configured to provide a light beam in the visible range and / or has a wavelength of between about 380 to about 750mm. For example, the wavelength may be between about 380 and about 450 mm, between 450 and about 500mm, between about 500 and about 550 mm, between about 550 and about 600 mm, between about 600 and about 650 mm, between about 650 and 700mm, or between about 700mm and about 750mm.

[0045] In some embodiments, the sensor is a photodiode or photodiode array.

[0046] In some embodiments, the device comprises a removable adapter removably attachable to an inhaler mouthpiece.

[0047] In some embodiments, the device is removably attachable to an inlet and / or an outlet of the mouth-throat model.

[0048] In some embodiments, the dynamic measurement of the aerosol comprises morphology, velocity, acceleration and / or deceleration.

[0049] In some embodiments, the device is removably attachable to a next-generation impactor (NGI) and / or a mixing chamber.

[0050] The skilled person would understand that the device may be directly attached an inlet of a mixing chamber or similar to enable a real-time monitoring of the dynamic behaviour of an aerosol as a result of being exposed to a transient inspiratory profile, before the flow turns steady.

[0051] According to a second aspect of the present invention there is provided a method of obtaining dynamic measurement of an aerosol travelling through a mouth-throat model in real time, the method comprising the steps of: i) attaching a device to the mouth-throat model, the device comprising at least one pair of a light source and a sensor disposed on a circumference of the device; ii) directing a light beam from the light source through the aerosol to the sensor; iii) obtaining a dynamic light intensity from the sensor; to thereby provide dynamic measurement of the aerosol.

[0052] In some embodiments, the device is a device according to the first aspect of the present invention.

[0053] According to a third aspect of the present invention there is provided a mouth-throat model comprising a device according to the first aspect of the present invention attached to an inlet and / or an outlet of the model.

[0054] According to a fourth aspect of the present invention there is provided an aerosol characterisation system comprising: an inhaler for providing an aerosol; a first device according to the first aspect of the present invention attached to a mouthpiece of the inhaler; wherein the first device is attached to an inlet of a mouth-throat model.

[0055] In some embodiments, the system further comprises a second device according to the first aspect of the present invention attached to an outlet of the mouth-throat model.

[0056] In some embodiments, the system further comprises an NGI or a mixing chamber attached to the second device.

[0057] Other aspects of the present invention will become apparent to those ordinarily skilled in the art upon review of the following description of specific embodiments of the invention.Definitions

[0058] In describing and claiming the present invention, the following terminology will be used in accordance with the definitions set out below. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments of the invention only and is not intended to be limiting. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one having ordinary skill in the art to which the invention pertains.

[0059] Unless the context clearly requires otherwise, throughout the description and the claims, the words “comprise”, “comprising”, and the like are to be construed in an inclusive sense as opposed to an exclusive or exhaustive sense; that is to say, in the sense of “including, but not limited to”.

[0060] As used herein, the phrase “consisting of’ excludes any element, step, or ingredient not specified in the claim. When the phrase “consists of” (or variations thereof) appears in a clause of the body of a claim, rather than immediately following the preamble, it limits only the element set forth in that clause; other elements are not excluded from the claim as a whole. As used herein, the phrase “consisting essentially of” limits the scope of a claim to the specified elements or method steps, plus those that do not materially affect the basis and novel characteristic(s) of the claimed subject matter.

[0061] With respect to the terms “comprising”, “consisting of”, and “consisting essentially of”, where one of these three terms is used herein, the presently disclosed and claimed subject matter may include the use of either of the other two terms. Thus, in some embodiments not otherwise explicitly recited, any instance of “comprising” may be replaced by “consisting of’ or, alternatively, by “consisting essentially of”.

[0062] Other than in the operating examples, or where otherwise indicated, all numbers expressing quantities of ingredients or reaction conditions used herein are to be understood as modified in all instances by the term “about”. The examples are not intended to limit the scope of the invention. In what follows, or where otherwise indicated, “%” will mean “weight %”, “ratio” will mean “weight ratio” and “parts” will mean “weight parts”.

[0063] The term ‘substantially’ as used herein shall mean comprising more than 50% by weight, where relevant, unless otherwise indicated.

[0064] The recitation of a numerical range using endpoints includes all numbers subsumed within that range (e.g., 1 to 5 includes 1 , 1.5, 2, 2.75, 3, 3.80, 4, 5, etc.).

[0065] Further, unless expressly stated to the contrary, “or” refers to an inclusive or and not to an exclusive or. For example, a condition A or B is satisfied by any one of the following: A is true (or present) and B is false (or not present), A is false (or not present) and B is true (or present), and both A and B are true (or present).

[0066] The terms “preferred” and “preferably” refer to embodiments of the invention that may afford certain benefits, under certain circumstances. However, other embodiments may also be preferred, under the same or other circumstances. Furthermore, the recitation of one or more preferred embodiments does not imply that other embodiments are not useful and is not intended to exclude other embodiments from the scope of the invention.

[0067] It must also be noted that, as used in the specification and the appended claims, the singular forms “a”, “an” and “the” include plural referents unless the context clearly dictates otherwise.

[0068] As used herein, with reference to numbers in a range of numerals, the terms “about,” “approximately” and “substantially” are understood to refer to the range of -10% to +10% of the referenced number, preferably -5% to +5% of the referenced number, more preferably -1 % to +1 % of the referenced number, most preferably -0.1 % to +0.1 % of the referenced number. Moreover, with reference to numerical ranges, these terms should be construed as providing support for a claim directed to any number or subset of numbers in that range. For example, a disclosure of from 1 to 10 should be construed as supporting a range of from 1 to 8, from 3 to 7, from 1 to 9, from 3.6 to 4.6, from 3.5 to 9.9, from 8 to 10, and so forth.

[0069] The prior art referred to herein is fully incorporated herein by reference.

[0070] The term “mouth-throat model” refers to a physical representation of the human upper airway as commonly used in the testing of pharmaceutical aerosols. This includes the widely adopted United States Pharmacopeia standard induction port as well as more physiologically realistic mouth-throat models which include additional anatomical features.

[0071] The term “impactor” refers to aerosol instruments designed to allow collection of size- fractionated aerosol samples onto removable substrates. This permits gravimetric and chemical analysis to be conducted on differing particle size fractions.

[0072] The term “Next Generation Impactor” refers to an impactor having a number of stages, for example seven stages. Similarly there is also the Andersen Cascade Impactor or Multistage Liquid Impinger which all serve the purpose of enabling particle size assessment. Impactors may be intended to operate over a broad range of flow-rates, however typically between 20 and 100 L / min. The skilled person would understand that the impactor may have a different number of stages and / or operate in a different flow rate range. The skilled person would also appreciate that the device may be used with any suitable impactor.

[0073] The term “aerosol” refers to a suspension of particles dispersed in air or gas.

[0074] The term “dynamic measurement” refers to measurement over a period of time or a number of time points. The measurement may be constant (that is, the measured value is the same for the whole period of time or all time points) or variable.

[0075] The term “pair” refers to a pair of one light source and one corresponding sensor. Accordingly, two pairs of light sources and sensors refer to two light sources and their two respective corresponding sensors, three pairs of light sources and sensors refer to three light sources and their three respective corresponding sensors, and n pairs of light sources and sensors refer to n light sources and their n respective corresponding sensors.

[0076] Although exemplary embodiments of the disclosed technology are explained in detail herein, it is to be understood that other embodiments are contemplated. Accordingly, it is not intended that the disclosed technology be limited in its scope to the details of construction and arrangement of components set forth in the following description or illustrated in the drawings. The disclosed technology is capable of other embodiments and of being practiced or carried out in various ways.Brief Description of the Drawings

[0077] Preferred embodiments of the invention will now be described, by way of example only, with reference to the accompanying drawings in which:

[0078] Figure 1 shows a front view of an embodiment of the device comprising one pair of a light source and a sensor.

[0079] Figure 2 shows an embodiment of the device comprising three pairs of light sources and sensors: a) front view; b) top view; c) side view

[0080] Figure 3 shows an embodiment of the invention where the device is attached to an inlet and an outlet of a mouth-throat model.

[0081] Figure 4 shows another embodiment of the invention where the device is attached to an inlet and an outlet of a mouth-throat model.

[0082] Figure 5 shows an embodiment of the invention attached to a mouth-throat model: a) oblique view; b) side view.

[0083] Figure 6 shows a data flow diagram for measuring aerosol dynamics when two devices are attached to an inlet and an outlet of the mouth-throat model.

[0084] Figure 7 shows examples of normalised signals measured from an embodiment of the invention as a function of time: a) two line integrated signals separated in time; b) a line- integrated signal with substantial fluctuation.

[0085] Figure 8 shows an example computation estimating the velocity obtained from a two sensor line integrated experiment, as it compares to conventional particle image velocimetry (PIV).

[0086] Figure 9 shows filtered signal data collected from an embodiment of the invention from an aerosol exiting a commercial dry powder inhaler (Wixela Inhub®) at 60LPM.

[0087] Figure 10 shows filtered signal data collected from an embodiment of the invention from an aerosol exiting a commercial dry powder inhaler (Osmohaler™) at 60LPM using an inhouse lactose and active ingredient blend.

[0088] Figure 11 shows filtered (and inverted) signal data collected from an embodiment of the invention from an aerosol exiting a commercial metered dose inhaler (Ventolin).

[0089] Figure 12 shows three-dimensional render of an embodiment of the invention showing casing of a device with an inner sleeve and external push buttons.Detailed Description of the Invention

[0090] The skilled addressee will understand that the invention comprises the embodiments and features disclosed herein as well as all combinations and / or permutations of the disclosed embodiments and features.Example 1 - A device comprising one pair of a light source and a sensor

[0091] Figure 1 shows a front view of a device 100 comprising a pair of a light source 101 and a sensor 106 disposed around a circumference of the device. The light source 101 and the sensor 106 are configured to provide a light beam 105 through an aerosol travelling in a direction 104 through the device. In this example, the light source 101 may be a laser source, the sensor 106 may be a photodiode, and the light beam 105 may be a laser beam.

[0092] The device comprises an inner sleeve 102 and an outer sleeve 103. The outer sleeve is removably attached to the inner sleeve, and the inner sleeve is removably attachable to a mouth-throat model.Example 2 - A device comprising three pairs of light sources and sensors

[0093] Figure 2(a) shows a front view of a device 200 comprising three pairs of light sources and sensors disposed around a circumference of the device. The light sources 201 , 204 may be laser sources, and the sensors 207, 208 may be photodiodes. The light source 201 and sensor 207 provide a light beam 206, and the light source 204 and the sensor 208 provide a light beam 205. The light beam 206 is at an angle of 90° with the light beam 205. The device also comprises a third pair of a light source and a sensor (not shown) providing a light beam (not shown) parallel to the light beam 205. The device comprises an inner sleeve 202 and an outer sleeve 203. The outer sleeve is removably attached to the inner sleeve, and the inner sleeve is removably attachable to a mouth-throat model.

[0094] Figure 2(b) shows a top view of a device comprising three pairs of light sources and sensors disposed around a circumference of the device. The light sources 213, 209 and 212 may be laser sources, and the sensor 211 may be a photodiode. The light source 213 and the sensor 211 are configured to provide a light beam 210. The light beam is at an angle of 90° with two parallel beams (not shown) provided by light sources 209 and 212 and two sensors (not shown).

[0095] Figure 2(c) shows a side view of a device comprising three pairs of light sources and sensors disposed around a circumference of the device. The light sources 218, 219 and 220 may be laser sources, and the sensors 215 and 216 may be photodiodes. The light source 218, 219 and the sensors 215, 216 are configured to provide parallel light beams 214 and 217 with a distance of at least about 1 mm. The parallel light beams are at an angle of 90° with another light beam (not shown) provided by the light source 220 and a sensor (not shown).

[0096] The skilled person would appreciate that Figures 2(a)-(c) illustrate three different views of a device comprising three pairs of light sources and sensors disposed around a circumference of the device. The device may or may not be the same device. In the case that Figure 2(b) and Figure 2(c) show the same device, the skilled person would understand that light sources 209 and 212 in Figure 2(b) correspond to light sources 218 and 219 in Figure 2(b).Example 3 - Devices attached to a mouth-throat model

[0097] Figure 3 shows two devices of the invention 302 and 305, for example the device shown in Figure 2, attached to an inlet and an outlet of a mouth-throat model 304. An aerosol 303 travelling in a direction 301 may be from an inhaler device (not shown). The device 305 may be attached to an impactor or a mixing chamber (not shown) that performs further analysis of the aerosol travelling in a direction of 306.

[0098] Figure 4 shows another embodiment of the invention with two devices 403 and 408 attached to an inlet and an outlet of a mouth-throat model. An aerosol (not shown) travelling in a direction 401 may be from an inhaler device or an aerosol delivery device 412. The device 408 may be attached to an impactor or a mixing chamber (not shown) that performs further analysis of the aerosol travelling in a direction of 409. The device 403 comprises three pairs of light sources and sensors configured to provide two parallel light beams 404 and 405, and a light beam 410 at angle of 90° to these two parallel light beams. The device 408 comprises three pairs of light sources and sensors configured to provide two parallel light beams 406 and 407, and a light beam 411 at angle of 90° to these two parallel light beams.

[0099] Figure 5(a) shows yet another embodiment of the invention with a device attached to an inlet of a mouth-throat model 505. The device comprises fours pairs of light sources (501 , 503, 506, 508) and sensors (502, 504, 507, not shown) disposed on a circumference of the device. Figure 5(b) shows a side view of the embodiment as shown in Figure 5(a), wherein a minimum distance of about 1 mm between the light beams is maintained.Example 4 - Aerosol characterisation and Aerosol quality indicationPost processing details:

[0100] A light beam, for example laser light, is emitted from a light source, and it forms a beam which is detected on the opposite side. We imagine a measurement volume located in between the light source and opposing photodiode. We define here a normalized light intensity as T=l / l0 where I is the measured light intensity (proportional to the measured voltage) after the measurement volume and I0 is the original light intensity (proportional to measured voltage), before the measurement volume or the original light intensity in the absence of aerosol. A value of T=1 would indicate that the light is not obscured at all by the aerosol which is located in the measurement volume. A value of T=0 would indicate that all light has been obscured by the aerosol that is in the measurement volume. The value of I0 can be measured over time as IO(t) prior to the initiation of any aerosol, or it can be measured, in real-time, during the aerosol flow through an additional reference photodiode as described e.g. in Mahmoudi et al. 2019 (Experimental Thermal and Fluid Science, vol. 103, pp.201-213, 2019). Thenormalized light intensity can also be background subtracted such that a measurement of transmittance of light can be obtained as Tb=(l-lb) / (IO-lb) where lb is a background intensity. Measurement of an equivalent T is made by comparing the signal voltage measured with and without aerosol. There are various standard post processing steps that can be taken to analyse these signals and these are provided here but are not intended to be exhaustive or restrictive.

[0101] Computation of the average value of T over the signal acquisition time, i.e. <T> provides a measurement of how obscured the flow is of aerosol. The randomness associated with the value of T(t) can also be obtained by computing the probability density function (PDF) of T and determining to what extent the signal is or is not normally distributed. From this PDF the variance of the signal can be computed or the standard deviation o(T) such that o(T) / <T> can be used as a measure of how much the signal fluctuates over the acquisition time.

[0102] Computation of the average value of T over the signal acquisition time, i.e. <T> provides a measurement of how obscured the flow is of aerosol. The randomness associated with the value of T(t) can also be obtained by computing the probability density function (PDF) of T and determining to what extent the signal is or is not normally distribution. From this PDF the variance of the signal can be computed or the standard deviation o(T) such that o(T) / <T> can be used as a measure of how much the signal fluctuates over the acquisition time.

[0103] Computation of the gradient of T with time i.e. dT / dt provides a measure of how rapidly the aerosol is obscuring the laser beam path. For example, if the obscuration is gradual, then T will not change rapidly with t and this would indicate a more regular flow of the aerosol through the beam path. Large changes in dT / dt and / or situations where value of T approaching unity are suddenly followed by values of T approaching zero, would indicate erratic aerosolization behaviour caused either by a very intermittent dense cloud of aerosol or intermittent large agglomerate populations (Mahmoudi et al. 2019).

[0104] Computation of simple statistical quantities such as the above can be performed on a single beam to glean line integrated information on the aerosol behaviour, as well as to determine overall consistency in aerosol behaviour entering or exiting a mouth-throat model from one inhaler actuation to the next or from one powder formulation to the next. Computations such as the above can also be computed for each beam within the device, which is located at a different angle. This will enable a comparison of average behaviour of the aerosol as measured from different lines through the aerosol.

[0105] Measurement of cross correlation between two parallel beams can be made through standard functions. For instance the correlation function between a signal at two different instances in time can be defined through the equation below where Xt is the value ofthe signal at time t, and Xt+k is the value of the signal at a displacement in time defined by t+k (the next time step). Here, n is the total number of samples, o the standard deviation of the signal and p the mean of the signal. A correlation function can be applied between two signals (separated spatially by two beams) in order to compute the time lag with maximum correlation. The function R(k) can be normalized by the cross co-variance (or variance in the case of an Autocorrelation) of the signal in order to compute a cross correlation coefficient. An example computation estimating the velocity obtained from a two sensor line integrated experiment, as it compares to conventional particle image velocimetry (PIV) is shown in Fig. 8.In the case of 3 beams, the above calculation step can be performed between beam 1 to 2 and beam 2 to 3 as well as between beam 1 to 3. Computation between 1 to 2 and 2 to 3 will allow estimate of velocity at two different spatial locations, enabling a subsequent estimate of how the aerosol velocity is changing from one location to the next (i.e. to determine if the aerosol is accelerating or not).

[0106] Spectral information from the signals can be obtained either using standard fast Fourier transforms in the situation where the signal is well sampled and not highly discontinuous, or using wavelet transformations. Both of these functions are readily available in various software packages and can be applied to the signals in question to define underlying patterns in the signal data. These patterns can be used to determine if there is for instance an underlying instability in the flow entering the mouth-throat model, and if the same instabilities are (or are not present) from one inhaler actuation to the next.

[0107] The device provides simple statistical quantities of aerosol (when there is at least one beam), aerosol velocity measurement (when there are at least two beams, for example parallel beams) and / or acceleration (in the case of at least three beams). These beams also provide data on the transient behaviour of the aerosol flow prior to it going through a mixing chamber. For example, the total time it takes for the aerosol to vacate the inhaler device can be measured at the same time as the aerosol is delivered into a mouth-throat model and mixing chamber. Provision of such a measurement enables tracking and / or monitoring of the aerosol during in-vitro testing. Use of standard cross correlation algorithms applied to the line- integrated laser attenuation signal data may be used for the purpose of computing velocity, and other standard signal processing methods can be used to determine the start and end time of the signal.

[0108] Each of the lasers terminates at a light detection unit on the opposing end of each laser (one photodiode for each laser) and measures an average, line integrated light attenuation. Each of these light detection units will output a signal of integrated light intensity vs. time. The light intensity registered on the photodiode will decrease as the aerosol crosses the beam path in a way that is understood in the literature using hardware as described in Figure 6. The data acquisition and post processing components of the invention as described in Figure 6 follow prior art in that signal detection, analogue to digital conversion, and subsequent software based post processing of the signals follow standard available signal processing tools.

[0109] Post processing algorithms including spectral and temporal analysis to analyse fluctuation information and signal quality, as well as standard cross-correlation algorithms to compute velocity are used to analyse these signals either in real-time or off-line. The software displays metrics of overall aerosol behaviour and quality, aerosol speed & aerosol acceleration behaviour to the user. Analysis of such signals (as per Figure 7 and 8) follow descriptions in prior art as it appears in Mahmoudi et al 2019, Dyakowsi and Williams 1993 or Kourmatzis, A. 2007 “Dry Powder Inhaler Flow: A Quantitative Study”, Imperial College London. The prior art identifies ways to use the signal data to compute velocity using cross co-variance or cross correlation algorithms, as well as use of standard signal processing routines such as fast Fourier transform, mean, standard deviation and other probabilistic “moments” of the data. This data is also used here to infer how continuous or non-continuous a given aerosol is (e.g. see Mahmoudi et al. 2019), which partly relates to the properties of the aerosol and the surrounding flow.

[0110] As it is typical that an aerosol test is repeated at least 3 times in the pharmaceutical context, integration of the device allows for a real-time monitoring of aerosol consistency though a measure of light attenuation over time which is an indicator of how agglomerated or dispersed the aerosol is. The user will be able to obtain signal data from the device in real-time to determine measures of variability in the aerosol between repeated tests, providing further information to complement the NGI data.

[0111] Variability is measured by looking at metrics of the signal over time such as (but not limited to) the average signal drop, the average number of troughs in the signal, as well as spectral analysis which can provide spectral signatures of the signal from each delivery of aerosol.

[0112] Figure 7 shows light intensity signals (normalised) as a function time in highly intermittent flow from a device with a single laser / detector (for example the device shown inFigure 1) and two pairs of laser / detector measuring mannitol powder. The device may repeat this process across multiple lasers placed close to each other.Example 5 - Characterisation of aerosols from different inhalers

[0113] Figure 9 shows a typical example of a non-erratic signal with a regular aerosol evacuation process. Time delay between two signals is also visible enabling velocity measurement.

[0114] Figure 10 shows a typical example of a more erratic signal with a more turbulent aerosol evacuation process. Time delay between two signals is also visible enabling velocity measurement.

[0115] Figure 10 is a good example of a signal that can be subjected to spectral analysis for further insight. Comparing the start of the signal (before time=1 .4 seconds) to the main aerosol evacuation portion of the signal (1.5 sec<t<2.4 sec) one can see that the aerosol evacuation portion is much more erratic than the baseline (baseline being the start of the signal). This is indicative of bulk turbulence or instability in the aerosol that can be subjected to post processing for further analysis. The total duration of the erratic signal represents the emptying time of the aerosol from the device. This emptying time can also very easily be extracted from Figure 9 (see arrow). Figure 9 shows a less erratic signal during evacuation indicating quite a different aerosol ejection behaviour.

[0116] Figure 11 shows experiment of three independent runs with consistent signal shape and repeatable measurement indicating the device can also measure these liquid and vapour based aerosols. It should be noted that the time axis is different as the time of experiment start was not kept fixed between runs.

[0117] The Table below shows velocity measurement results from 11 different powder blends using Osmohaler™ device at 60 litres per minute (LPM). The device was used to measure the velocity of multiple dry powders ejected from an Osmohaler™ device at a flowrate of 60LPM. The purpose was to determine if a broad range of blends could be detected by the device, in addition to the commercial aerosols it was able to detect (as shown in Figures. 9 and 11 which were both commercial aerosol formulations). Eleven experiments were run independently. Measurements are rounded to the nearest integer. Each experiment used a different blend of lactose, salbutamol sulphate, and salmeterol xinofoate powder. Runs where signals could not be used to measure velocity were rejected. Rejection of spurious velocity data from cross correlation velocimetry (or e.g. particle image velocimetry) is a widely accepted and unavoidable practice to ensure accurate results. Rejection rate (total number of rejected runs / total runs) is only 18% from these experiments. Typical rejection rates from othercommercial measurement instruments (e.g. such as from laser Doppler anemometry) can regularly exceed this number and would be widely known by an expert in the field. The velocities here are measured by standard statistical cross correlation between the “Laser 1” and “Laser 2” signals.

[0118] Other embodiments of the present invention as described herein are defined in the following paragraphs:1. A device comprising at least one pair of a light source and a sensor disposed on a circumference of the device, wherein the device is removably attachable to a mouththroat model to thereby provide dynamic measurement of an aerosol travelling through the mouth-throat model in real time by directing a light beam from the light source through the aerosol to the sensor to obtain a dynamic light intensity from the sensor.2. The device according to paragraph 1 , comprising an inner sleeve and an outer sleeve, wherein the outer sleeve is removably attached to the inner sleeve.3. The device according to any one or more of the preceding paragraphs, wherein the at least one pair of a light source and a sensor is disposed on the outer sleeve.4. The device according to any one or more of the preceding paragraphs, wherein the inner sleeve is removably attachable to a mouth-throat model.5. The device according to any one or more of the preceding paragraphs, wherein the inner and / or the outer sleeve are optically accessible.The device according to any one or more of the preceding paragraphs, comprising multiple pairs of light sources and sensors configured to provide at least two parallel light beams. The device according to any one or more of the preceding paragraphs, wherein the multiple pairs of light sources and sensors are configured to provide at least one light beam at an angle of between about 1° and about 179° to the parallel light beams. The device according to any one or more of the preceding paragraphs, wherein the angle is between about 60° and about 120°. The device according to any one or more of the preceding paragraphs, wherein the angle is about 90°. The device according to any one or more of the preceding paragraphs, wherein the multiple pairs of light sources and sensors are configured to provide at least two light beams that do not intersect each other. The device according to any one or more of the preceding paragraphs, wherein no light beam intersects another. The device according to any one or more of the preceding paragraphs, wherein the multiple pairs of light sources and sensors are configured such that at least two light beams have a minimum distance of about 1 mm between each other in a travelling direction of the aerosol. The device according to any one or more of the preceding paragraphs, wherein all the light beams have a minimum distance of about 1mm between each other in a travelling direction of the aerosol. The device according to any one or more of the preceding paragraphs, wherein the light source is selected from the group consisting of a laser source, a violet light source, a blue light source, a cyan light source, a green light source, a yellow light source, an orange light source, a red light source, or any combination thereof.The device according to any one or more of the preceding paragraphs, wherein the sensor is a photodiode or photodiode array. The device according to any one or more of the preceding paragraphs, further comprising a removable adapter removably attachable to an inhaler mouthpiece. The device according to any one or more of the preceding paragraphs, wherein the device is removably attachable to an inlet and / or an outlet of the mouth-throat model. The device according to any one or more of the preceding paragraphs, wherein the dynamic measurement of the aerosol comprises morphology, velocity, acceleration and / or deceleration. The device according to any one or more of the preceding paragraphs, wherein the device is removably attachable to a next-generation impactor (NGI) and / or a mixing chamber. A method of obtaining dynamic measurement of an aerosol travelling through a mouththroat model in real time, the method comprising the steps of: i) attaching a device to the mouth-throat model, the device comprising at least one pair of a light source and a sensor disposed on a circumference of the device; ii) directing a light beam from the light source through the aerosol to the sensor; iii) obtaining a dynamic light intensity from the sensor; to thereby provide dynamic measurement of the aerosol. The method according to paragraph 20, wherein the device comprises an inner sleeve and an outer sleeve, wherein the outer sleeve is removably attached to the inner sleeve. The method according to any one or more of the preceding paragraphs, wherein the at least one pair of a light source and a sensor is disposed on the outer sleeve. The method according to any one or more of the preceding paragraphs, wherein the inner sleeve is attached to the mouth-throat model.The method according to any one or more of the preceding paragraphs, wherein the inner and / or the outer sleeve are optically accessible. The method according to any one or more of the preceding paragraphs, wherein the device comprises multiple pairs of light sources and sensors configured to provide at least two parallel light beams. The method according to any one or more of the preceding paragraphs, wherein the multiple pairs of light sources and sensors are configured to provide at least one light beam at an angle between about 1 ° and about 179° to the parallel light beams. The method according to any one or more of the preceding paragraphs, wherein the angle is between about 60° and about 120°. The method according to any one or more of the preceding paragraphs, wherein the angle is about 90°. The method according to any one or more of the preceding paragraphs, wherein the multiple pairs of light sources and sensors are configured to provide at least two light beams that do not intersect each other. The method according to any one or more of the preceding paragraphs, wherein no light beam intersects another. The method according to any one or more of the preceding paragraphs, wherein the multiple pairs of light sources and sensors are configured such that at least two light beams have a minimum distance of about 1 mm between each other in a travelling direction of the aerosol. The method according to any one or more of the preceding paragraphs, wherein all the light beams have a minimum distance of about 1mm between each other in a travelling direction of the aerosol. The method according to any one or more of the preceding paragraphs, wherein the light source is selected from the group consisting of a laser source, a violet light source,a blue light source, a cyan light source, a green light source, a yellow light source, an orange light source, a red light source, or any combination thereof. The method according to any one or more of the preceding paragraphs, wherein the sensor is a photodiode or photodiode array. The method according to any one or more of the preceding paragraphs, wherein the step i) comprises attaching the device to an inlet and / or an outlet of the mouth-throat model. The method according to any one or more of the preceding paragraphs, wherein the dynamic measurement of the aerosol comprises morphology, velocity, acceleration and / or deceleration. A method of obtaining dynamic measurement of an aerosol travelling through a mouththroat model in real time comprising the step of using a device according to any one or more of the preceding paragraphs. A mouth-throat model comprising a device according to any one or more of the preceding paragraphs attached to an inlet and / or an outlet of the model. An aerosol characterisation system comprising: an inhaler for providing an aerosol; a first device according to any one or more of the preceding paragraphs attached to a mouthpiece of the inhaler; wherein the first device is attached to an inlet of a mouth-throat model. The system according to paragraph 39, further comprising a second device according to any one or more of the preceding paragraphs attached to an outlet of the mouththroat model. The system according to paragraph 40, further comprising an NGI or a mixing chamber attached to the second device.

Claims

THE CLAIMS DEFINING THE INVENTION ARE AS FOLLOWS:-1. A device comprising at least one pair of a light source and a sensor disposed on a circumference of the device, wherein the device is removably attachable to a mouththroat model to thereby provide dynamic measurement of an aerosol travelling through the mouth-throat model in real time by directing a light beam from the light source through the aerosol to the sensor to obtain a dynamic light intensity from the sensor.

2. The device according to claim 1 , comprising an inner sleeve and an outer sleeve, wherein the outer sleeve is removably attached to the inner sleeve, preferably the at least one pair of a light source and a sensor is disposed on the outer sleeve.

3. The device according to claim 2, wherein the inner sleeve is removably attachable to a mouth-throat model.

4. The device according to any one of claims 1 to 3, comprising multiple pairs of light sources and sensors configured to provide at least two parallel light beams.

5. The device according to claim 4, wherein the multiple pairs of light sources and sensors are configured to provide at least one light beam at an angle of between about 1° and about 179°, or between about 60° and about 120°, or about 90° to the parallel light beams.

6. The device according to claim 4 or claim 5, wherein the multiple pairs of light sources and sensors are configured to provide at least two light beams that do not intersect each other, preferably no light beam intersects another.

7. The device according to any one of claims 4 to 6, wherein the multiple pairs of light sources and sensors are configured such that at least two light beams have a minimum distance of about 1mm between each other in a travelling direction of the aerosol, preferably all the light beams have a minimum distance of about 1mm between each other in a travelling direction of the aerosol.

8. The device according to any one of claims 1 to 7, wherein the dynamic measurement of the aerosol comprises morphology, velocity, acceleration and / or deceleration.

9. A method of obtaining dynamic measurement of an aerosol travelling through a mouth-throat model in real time, the method comprising the steps of: i) attaching a device to the mouth-throat model, the device comprising at least one pair of a light source and a sensor disposed on a circumference of the device; ii) directing a light beam from the light source through the aerosol to the sensor; iii) obtaining a dynamic light intensity from the sensor; to thereby provide dynamic measurement of the aerosol.

10. The method according to claim 9, wherein the device comprises an inner sleeve and an outer sleeve, wherein the outer sleeve is removably attached to the inner sleeve, preferably the at least one pair of a light source and a sensor is disposed on the outer sleeve.11 . The method according to claim 10, wherein the inner sleeve is attached to the mouththroat model.

12. The method according to any one of claims 9 to 11 , wherein the device comprises multiple pairs of light sources and sensors configured to provide at least two parallel light beams.

13. The method according to claim 12, wherein the multiple pairs of light sources and sensors are configured to provide at least one light beam at an angle between about 1° and about 179°, or between about 60° and about 120°, or about 90° to the parallel light beams.

14. The method according to claim 12 or claim 13, wherein the multiple pairs of light sources and sensors are configured to provide at least two light beams that do not intersect each other, preferably no light beam intersects another.

15. The method according to any one of claims 12 to 14, wherein the multiple pairs of light sources and sensors are configured such that at least two light beams have a minimum distance of about 1mm between each other in a travelling direction of the aerosol, preferably all the light beams have a minimum distance of about 1mm between each other in a travelling direction of the aerosol.

16. The method according to any one of claims 9 to 15, wherein the dynamic measurement of the aerosol comprises morphology, velocity, acceleration and / or deceleration.

17. A mouth-throat model comprising a device according to any one of claims 1 to 8 attached to an inlet and / or an outlet of the model.

18. An aerosol characterisation system comprising: an inhaler for providing an aerosol; a first device according to any one of claims 1 to 8 attached to a mouthpiece of the inhaler; wherein the first device is attached to an inlet of a mouth-throat model.

19. The system according to claim 18, further comprising a second device according to any one of claims 1 to 8 attached to an outlet of the mouth-throat model.

20. The system according to claim 19, further comprising an NGI or a mixing chamber attached to the second device.

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