Nebulisers and components thereof

Abstract

In various embodiments, the present invention provides mouthpiece modules for use in breath actuated nebulisers, breath actuated nebulisers, and kits of parts for a breath actuated nebuliser. The mouthpiece modules and / or breath actuated nebulisers include a breath sensor arranged to detect inhalation and / or exhalation of a user via the airflow path. The breath sensor is configured to output a signal indicative of the inhalation and / or exhalation of the user. Also provided are uses of a piezoelectric sensor for sensing inhalation and / or exhalation of a user along an airflow path through at least part of a breath actuated nebuliser.

Description

[0001] 008852709

[0002] 1

[0003] Nebulisers and components thereof

[0004] This application claims priority from GB 2416461 .8 filed 8 November 2024, the contents and elements of which are herein incorporated by reference for all purposes.

[0005] Field of the Invention

[0006] The present invention relates to components for nebulisers and particularly, although not exclusively, to breath actuated nebulisers that contain sensors for detecting inhalation / exhalation of a user, and to component parts of such nebulisers (e.g. mouthpiece modules) that may contain such sensors.

[0007] Background

[0008] Breath actuated nebulisers (BAN) can offer a significant advancement in respiratory therapy by providing more efficient and effective drug delivery. Precise dosing, reduced drug wastage, lower fugitive aerosol generation and enhanced user experience are key features, driving the development of the next generation of smart nebulisers.

[0009] Known arrangements for BAN typically employ a breath sensor which is embedded within the main body of the device: as one example, see discussion of known systems including the ‘l-neb Adaptive Aerosol Delivery (AAD) System’ in Denyer et al “The Adaptive Aerosol Delivery (AAD) Technology: Past, Present, and Future”, JOURNAL OF AEROSOL MEDICINE AND PULMONARY DRUG DELIVERY (2010). This device uses a combination of a pressure sensor and a flexible valve to monitor the patient’s inspiratory flow pattern. The flexible valve provides a known pressure-to-flow characteristic through the device, and a pressure sensor located on the main body of the device, separate to the mouthpiece, measures the pressure, which allows a determination of flow measurement through the device.

[0010] The present inventors have realised that there is a desire for alternative arrangements for breath actuated nebulisers as compared with those known in the art.

[0011] The present invention has been devised in light of the above considerations.

[0012] Summary of the Invention

[0013] Specifically, the present inventors have realised that known arrangements suffer from a number of problems. As noted above, known arrangements typically employ a breath sensor which is embedded within the main body of the unit: this is because often the sensors are relatively high-cost components in order to provide suitable accuracy to measurement of the inhalation / exhalation of a user. However, in the event of sensor failure or malfunction, it is then necessary to completely replace the device, or to perform costly maintenance. 008852709

[0014] 2

[0015] The present inventors have realised that it would be advantageous to develop a more modular approach to BAN design, in particular by incorporating a simple, cost-effective, sensitive, and robust sensor within a detachable mouthpiece for a BAN.

[0016] Accordingly, in a first aspect, the present invention provides a mouthpiece module configured for removable attachment to a main body of a breath actuated nebuliser, the mouthpiece module comprising: an airflow path defined within the mouthpiece module for transmission of airflow between the main body of the breath actuated nebuliser and a user during inhalation and / or exhalation of the user, and a breath sensor arranged to detect inhalation and / or exhalation of a user via the airflow path, and configured to output a signal indicative of the inhalation and / or exhalation.

[0017] By providing an arrangement in which the breath sensor is provided as part of a detachable mouthpiece module, some or all of the above-noted issues can be addressed: By localizing the breath sensing system to a replaceable and upgradable component, maintenance becomes more cost-effective, the lifespan of the main nebuliser unit is extended, and a more sustainable solution is provided. This offers significant advantages as compared with conventional arrangements where the breath sensor is embedded in e.g. a main body of the device, wherein when this sensor fails, the entire nebuliser becomes unusable and must be replaced, incurring significant costs. The flexibility of a modular design as described above allows for easier customisation for patients and makes it an appealing option for manufacturers.

[0018] In a second aspect, the present invention provides a breath actuated nebuliser comprising: a mouthpiece module according to the first aspect; and a main body comprising a nebulising unit and a reservoir configured to store a substance to be nebulised, wherein the nebulising unit is configured to operate based on the signal indicative of the inhalation and / or exhalation output by the breath sensor of the mouthpiece module.

[0019] In a third aspect, the present invention provides a kit of parts for a breath actuated nebuliser, comprising: a mouthpiece module comprising an airflow path defined within the mouthpiece module for transmission of airflow between the main body of the breath actuated nebuliser and a user during inhalation and / or exhalation of the user, and a breath sensor arranged to detect inhalation and / or exhalation of a user via the airflow path, and configured to output a signal indicative of the inhalation and / or exhalation; and a main body comprising a nebulising unit and a reservoir configured to store a substance to be nebulised, wherein the nebulising unit is configured to operate based on the signal indicative of the inhalation and / or exhalation output by the breath sensor of the mouthpiece module; wherein the mouthpiece module is configured to be removably attachable to the main body.

[0020] The breath sensor may be configured to deflect or be displaced as a result of inhalation and / or exhalation of a user via the airflow path, the deflection or displacement causing the breath sensor to output a signal indicative of the inhalation and / or exhalation. For example, the sensor may comprise a deflectable member that is attached in a cantilever fashion (attached at one end of the sensor) to the mouthpiece module, and which is configured to bend along its length, said bending resulting in outputting of a signal (e.g. an electrical signal, such as a voltage). Deflection / displacement based sensors are relatively low- 008852709

[0021] 3 cost and resilient options for breath sensors. Examples of suitable deflection / displacement based sensors include but are not limited to: strain gauges, force-sensing resistors and / or piezoelectric sensors. Each of these types of sensors converts stress or strain induced by an external force into a measurable electrical signal. Further details about preferred sensor types are discussed below.

[0022] In some arrangements, the breath sensor may be configured to deflect or be displaced only as a result of inhalation of a user via the airflow path (in other words, the sensor may additionally be arranged such that substantially no sensor response is induced as a result of exhalation of a user via the airflow path). In other arrangements, the breath sensor may be configured to deflect or be displaced as a result of both inhalation and exhalation of a user via the airflow path. It is also contemplated that in some arrangements, first and second sensors may be provided, wherein the first sensor is arranged to detect inhalation of the user, and the second sensor is arranged to detect exhalation of the user.

[0023] The mouthpiece may be configured such that the breath sensor only deflects in response to airflows having a magnitude greater than a threshold flow rate. In some arrangements, the mouthpiece may be configured such that the breath sensor only deflects in response to flow rates of 2 L / min or more, 5 L / min or more, or 10 L / min or more. It is contemplated that providing arrangements in which a minimum flow rate is required to provide for sensor deflection, more efficient nebulisation may be possible, as nebulisation will not be trigged at flow rates which are too low to allow for successful delivery of the nebulised substance to the user during use of the device.

[0024] Whilst it is contemplated that a wide variety of sensor types may be suitable for use in BAN systems, preferably the breath sensor comprises a piezoelectric sensor configured to deflect as a result of inhalation and / or exhalation of a user via the airflow path, to thereby generate the signal. The present inventors have found particular advantages associated with use of piezoelectric sensors in view of their fast response time compared to other types of sensors. Additionally, it has been found that the use of piezoelectric sensors can provide a low-cost option that is readily commercially available in a suitable form-factor for use in BAN systems.

[0025] The piezoelectric sensor may comprise a piezoelectric film. The piezoelectric film may have a thickness of 0.5 mm or less, 0.1 mm or less, or 0.05 mm or less. It will be appreciated that the exact film thickness may be selected in view of the piezoelectric material of the film, and the desired sensor response properties of the piezoelectric sensor. In some arrangements, the piezoelectric film may be around 28 pm thick.

[0026] The piezoelectric sensor may comprise any suitable piezoelectric material. Conveniently, the piezoelectric material may comprise or consist of polyvinylidene fluoride (PVDF).

[0027] The piezoelectric sensor may comprise electrodes in electrical contact with the piezoelectric material of the sensor (e.g. with the piezoelectric film). Suitably, one or more electrodes may be disposed on opposing sides of the piezoelectric film. Conveniently, silver ink electrodes may be screen printed on opposing sides of the piezoelectric film, although it is also contemplated that a wide range of alternative contact structures may be possible. 008852709

[0028] 4

[0029] The piezoelectric sensor may have a laminated structure. In other words, the piezoelectric sensor may comprise a plurality of layers having different properties. In preferred arrangements, the piezoelectric sensor comprises a piezoelectric film that is laminated (directly or indirectly) onto a polymeric substrate. In some arrangements, the piezoelectric sensor may further comprise a second polymeric layer laminated (directly or indirectly) on an opposing side of the piezoelectric film from the polymeric substrate. In other words, in such arrangements, the piezoelectric film may be laminated between polymeric layers, i.e. be encapsulated by the polymeric layers. It is contemplated that non-polymeric layers could be used in some arrangements. Preferably, the piezoelectric film is laminated between protective layers (which may be polymeric as noted above). Use of a piezoelectric sensor having a laminated structure where a piezoelectric film is laminated onto or between protective (e.g. polymeric) layers has been found to offer a particularly robust solution for breath sensing in a BAN context: this is of particular importance when the sensor is located in an easily-accessible location within the BAN system, such as within a mouthpiece module of the system. The use of this kind of laminated structure also provides advantages in terms of ease of cleaning of the sensor, compared to other possible forms of sensor, thereby offering a more hygienic option for patients.

[0030] One example of a suitable commercially available piezoelectric sensor is a laminated piezoelectric filmbased sensor such as the LDT0-028K sensor available from TE Connectivity pic: this is a flexible component comprising a 28 pm thick piezoelectric PVDF polymer film with screen-printed silver ink electrodes, laminated to a 0.125 mm polyester substrate, and fitted with two crimped contacts. As the piezoelectric film is displaced from the mechanical neutral axis, bending creates very high strain within the piezopolymer and high voltages are generated.

[0031] The airflow path defined within the mouthpiece module for transmission of airflow between the main body of the breath actuated nebuliser and a user during inhalation and / or exhalation of the user may be defined by an airflow passage extending along the mouthpiece module. The airflow passage may have at least one hole formed in a sidewall thereof, the breath sensor being arranged adjacent the at least one hole such that it can detect inhalation and / or exhalation of a user via the airflow path as a result of changes in pressure across the hole. Changes in pressure within the airflow path may occur as a result of the inhalation and exhalation of a user: inhalation may cause generation of a negative inspiratory pressure along the airflow path. Exhalation may cause generation of a positive expiratory pressure along the airflow path. Preferably the breath sensor is configured to deflect or be displaced as a result of changes in pressure across the hole caused by inhalation and / or exhalation of a user via the airflow path.

[0032] The term ‘sidewall’ is used herein to refer generally to a wall portion that forms at least part of at least one side (upper side, lower side, lateral side etc) of the mouthpiece module. The sidewall may be an external sidewall (e.g. having at least one surface that provides part of an exterior surface of the mouthpiece module). The specific shape of the sidewall is not particularly limited.

[0033] The mouthpiece module may comprise at least one first opening for fluid communication with the mouth of a user when in use. It may have at least one second opening for fluid communication with a nebuliser main body when attached to said main body, for use. The opening which is arranged to be in fluid 008852709

[0034] 5 connection with the nebuliser main body may act as an inlet for receipt of a nebulised substance from a nebulising unit of the nebuliser main body (discussed in more detail below), for delivery of the nebulised substance along the airflow pathway to the user via the opening which is arranged for fluid communication with the mouth of a user when in use, and which accordingly acts as an outlet of the airflow pathway.

[0035] In some arrangements, the breath sensor may be located externally of the airflow passage which defines the airflow path. For example, the breath sensor may be provided on, or attached to, an external surface of the mouthpiece module. In such arrangements, the breath sensor may be arranged to be in fluid connection with the airflow path via one or more one holes formed in a sidewall of the airflow passage, as discussed above. Providing arrangements in which the breath sensor is provided externally to the airflow passage, such as on an external surface of the mouthpiece module can provide advantages such as allowing for improved ease of access for replacement or repair of the sensor.

[0036] It is contemplated that the hole formed in the sidewall of the airflow passage may take a variety of forms. In some preferred arrangements, the hole formed in the sidewall of the airflow passage may have a substantially square or rectangular shape. Suitably, the hole may have a length (in a direction parallel to the airflow path), in a range of from 0.5 mm to 15 mm, e.g. from 1 mm to 10 mm, or from 5 mm to 9 mm.

[0037] In some arrangements, the hole may have a length of around 5 mm. Suitably, the hole may have a width (in a direction perpendicular to the airflow path), in a range of from 0.5 mm to 15 mm, e.g. from 1 mm to 10 mm, or from 5 mm to 9 mm. In some arrangements, the hole may have a width of around 9 mm.

[0038] It has been found that holes of such dimensions may provide a suitable sensor response for a breath sensor arranged to be in fluid communication with the airflow path via the hole. In particular, holes of such dimensions can provide suitable pressure drop across the hole during a user inhalation via the airflow path. The use of holes having a length in a direction parallel to the airflow path in a range of 5 to 9 mm may be particularly preferred, as the use of a larger hole may provide a quicker sensor response time and longer percentage hold time, as a result of more air passing through the hole to induce deflection / displacement of the sensor.

[0039] Whilst the use of square or rectangular holes may be preferred, it is also contemplated that alternative shapes may also be employed for the hole in some arrangements: for example, the hole may have a substantially quadrilateral or trilateral shape, or may have a substantially circular or oval cross-sectional shape.

[0040] As noted above, breath actuated nebuliser according to the invention include a main body comprising a nebulising unit and a reservoir configured to store a substance to be nebulised, and the nebulising unit is configured to operate based on the signal indicative of the inhalation and / or exhalation output by the breath sensor of the mouthpiece module.

[0041] The nebulising unit may be configured to operate when the signal indicative of the inhalation and / or exhalation output by the breath sensor of the mouthpiece exceeds a predetermined threshold. In one suitable example, the nebulising unit may be configured to operate when the signal indicative of the 008852709

[0042] 6 inhalation and / or exhalation output by the breath sensor of the mouthpiece exceeds a predetermined threshold which is set as x1 .5, x1 .75 or x2 of the baseline voltage value output by the breath sensor when the sensor is at rest. Preferably, the predetermined threshold is set as x1.5, x1.75 orx2 of the baseline voltage value output by the breath sensor when the sensor is at rest: this value has been found to be high enough to prevent any false detections due to noise or unexpected signal changes and low enough that the lag between the start of inhalation and nebulisation is minimised. The predetermined threshold may be corrected based on a detected flowrate through the mouthpiece. Alternatively, the predetermined threshold may be a set value which is irrespective of the flowrate through the mouthpiece.

[0043] The mouthpiece module may be configured for electrical connection to the main body of the nebuliser device by means of circuitry for conveying the signal indicative of the inhalation and / or exhalation output by the breath sensor of the mouthpiece module. The mouthpiece module may be reversibly electrically connected to the main body, i.e. can be electrically (and physically) disconnected from the main body. For example, the mouthpiece module may comprise one or more electrical contacts which are configured to interface with corresponding electrical contacts on the nebuliser main body in order to provide an electrical connection between the mouthpiece module and the nebuliser main body.

[0044] The breath actuated nebuliser may comprise a microcontroller configured to control one or more functions of the breath actuated nebuliser. For example, the microcontroller may be configured to process the signal indicative of the inhalation and / or exhalation output by the breath sensor of the mouthpiece module. The microcontroller may be configured to control operation of the nebulising unit (e.g. based on the processed signal indicative of the inhalation and / or exhalation output by the breath sensor of the mouthpiece module). The microcontroller may be configured to process signals from other components of the nebuliser.

[0045] The breath actuated nebuliser may comprise a signal conditioning circuit for conditioning of the signal indicative of the inhalation and / or exhalation output by the breath sensor of the mouthpiece module. The signal conditioning circuit may comprise a charge mode amplifier. The signal conditioning circuit may perform one or more (e.g. all) of the following functions: (i) produces a voltage output proportional to the integrated value of the input current, said current being a result of the charge generated by the sensor when it is mechanically deformed / deflected; (ii) eliminates the effect of stray or parasitic capacitance arising from the cables which could affect the output; (iii) amplifies the sensor output to the desired range for the microcontroller to detect; and (iv) filters out any unwanted frequencies that could affect the signal read by the microcontroller.

[0046] It is considered that the present invention may find application in a wide range of different types of breath actuated nebuliser. In this regard, the precise mode of function of the nebulising unit is not limited: the nebulising unit may comprise a mesh-based nebulising unit, a jet nebulising unit, or an ultrasonic nebulising unit.

[0047] The breath actuated nebuliser may comprise a fluid flow path for conveying a substance to be nebulised from the reservoir to the nebulising unit for nebulisation. 008852709

[0048] 7

[0049] The reservoir may comprise e.g. a tank or other suitable storage space. The reservoir may be refillable.

[0050] The breath actuated nebuliser may comprise a power source (e.g. a battery) for powering one or more operations of the breath actuated nebuliser.

[0051] In use, the amount of nebulised substance that is delivered to a user as a percentage of a total amount of nebulised substance may be greater than 10%, greater than 20%, greater than 30%, greater than 40%, or greater than 50%. The total amount of the nebulised substance may conveniently be referred to as the ‘total nebulised dose’. The amount of nebulised substance that is delivered to a user may conveniently be referred to as the ‘delivered dose’. The delivered dose is preferably greater than 60%, more preferably greater than 70%. Providing arrangements in which the delivered dose is suitably high can allow for decreased wastage of the nebulised substance, and allow for improved control of dosing of the user (in view of greater certainly about the amount of dose respired by the use vs lost to the environment, or retained in the nebuliser).

[0052] Other portions of the ‘total nebulised dose’ other than the delivered dose may also be quantified. For example, the ‘dose loss’ may be quantified as the amount of nebulised substance that is lost to the environment as a percentage of a total amount of the nebulised substance. The ‘residual dose’ may be quantified as the amount of substance that is retained in the nebuliser (e.g. as a result of impaction on nebuliser sidewalls during delivery of the nebulised substance) as a percentage of a total amount of the substance loaded into the nebuliser. The delivered dose, residual dose and dose loss may sum to 100%. In some arrangements, the residual dose is less than 30%, preferably less than 25%. In some arrangements, the dose loss is less than 10%, preferably less than 5%.

[0053] A respirable dose may also be defined as the product of fine particle fraction and delivered dose - that is, the percentage of the delivered dose which comprises aerosols of less than 5 micrometres in diameter (the accepted range for respirable aerosols being 0.4 to 5 pm, as aerosols smaller than this tend to be exhaled, and aerosols larger than this tend to impact the mouth / throat rather than being inhaled). In some arrangements, the respirable dose may be greater than 40%, preferably greater than 50%. The fine particle fraction produced by the nebuliser may be dependent both on the mechanism of aerosolization and the mouthpiece / airflow / nebuliser design. In some arrangements, the mouthpiece module may be configured to filter out aerosol particles outside the respirable range of 0.4 to 5 pm by e.g. causing impaction of aerosol droplets within the mouthpiece of aerosol droplets outside of the respirable range.

[0054] Whilst the above discussion relates primarily to arrangements in which the breath sensor is located in a mouthpiece module of a modular BAN, the present inventors also consider that some of the specific structures of breath sensor discussed above (e.g. piezoelectric sensors) may find more general applicability in BAN devices. In particular, it is contemplated that such sensors may offer particular convenient and effective sensors for breath sensing in a BAN, regardless of the precise location of the breath sensor. 008852709

[0055] 8

[0056] Accordingly, in a fourth aspect, the present invention provides a breath actuated nebuliser having a main body comprising a nebulising unit and a reservoir configured to store a substance to be nebulised, and a mouthpiece connected to the main body, the breath actuated nebuliser further comprising: an airflow path for transmission of airflow through at least part of the breath actuated nebuliser to or from a user during inhalation and / or exhalation of the user; and a breath sensor arranged to detect inhalation and / or exhalation of a user via the airflow path, and configured to output a signal indicative of the inhalation and / or exhalation of the user, wherein the nebulising unit is configured to operate based on the signal indicative of the inhalation and / or exhalation output by the breath sensor; wherein the breath sensor comprises a piezoelectric sensor arranged to deflect as a result of the inhalation and / or exhalation of the user via the airflow path, and thereby output the signal indicative of the inhalation and / or exhalation.

[0057] In arrangements according to this aspect, the location of the breath sensor is not limited to being in a mouthpiece module of the BAN, but rather may be located at any point along an airflow path through the BAN), although in preferred arrangements it may still be provided on the mouthpiece of the BAN. In arrangements according to this aspect, the mouthpiece may be fixedly connected to the main body and is not necessarily removable from the main body.

[0058] In a fifth aspect, the present invention provides the use of a piezoelectric sensor for sensing inhalation and / or exhalation of a user along an airflow path in a breath actuated nebuliser.

[0059] Optional or preferred features of the piezoelectric sensor are discussed above in relation to the other aspects.

[0060] The invention includes the combination of the aspects and preferred features described except where such a combination is clearly impermissible or expressly avoided.

[0061] Summary of the Figures

[0062] Embodiments and experiments illustrating the principles of the invention will now be discussed with reference to the accompanying figures in which:

[0063] Figure 1 is a perspective view of a mouthpiece module according to the present invention;

[0064] Figure 2 is a cross-sectional view of the mouthpiece module of Figure 1 illustrating inhalation by a user through the mouthpiece.

[0065] Figure 3 is a cross-sectional view of the mouthpiece module of Figure 1 illustrating exhalation by a user through the mouthpiece.

[0066] Figure 4 is an image of a breath sensor as proposed to be used in the mouthpiece module of Figure 1 , in a resting state. 008852709

[0067] 9

[0068] Figure 5 is an image of a breath sensor as proposed to be used in the mouthpiece module of Figure 1 , taken during inhalation by a user through the mouthpiece.

[0069] Figure 6 is a schematic cross-sectional view of a laminated piezoelectric sensor suitable for use in the present invention.

[0070] Figure 7 shows various possible geometries for the mouthpiece module.

[0071] Figure 8 shows a yet further arrangement of a mouthpiece module.

[0072] Figure 9 is a graph showing real-time monitoring of different parameters associated with the mouthpiece module during use.

[0073] Figure 10 is a graph showing how different breathing pattens affect sensor sensitivity.

[0074] Figure 11 is a graph showing inhalation percentage hold time against inhalation time for various adult breathing patterns.

[0075] Figure 12 is a graph showing inhalation percentage hold time for various child breathing patterns.

[0076] Figure 13 is a graph showing various performance characteristics of a prototype BAN according to the present invention in comparison with other nebulizer arrangements.

[0077] Detailed Description of the Invention

[0078] Aspects and embodiments of the present invention will now be discussed with reference to the accompanying figures. Further aspects and embodiments will be apparent to those skilled in the art. All documents mentioned in this text are incorporated herein by reference.

[0079] Figs. 1-3 show various views of a mouthpiece module 100 configured for attachment to the main body of a breath actuated nebuliser (BAN).

[0080] The mouthpiece module comprises a breath sensor 101 provided on an external surface of the mouthpiece module, the features of which will be discussed in greater detail below.

[0081] The main body of the mouthpiece module includes sidewalls 103 which define an airflow passage 102 extending through the mouthpiece module. In other words, the airflow passage 102 is surrounded by the sidewall 103. Conveniently, sidewall 103 in this embodiment defines a substantially tubular body through which the airflow passage extends. The airflow passage provides an airflow path defined within the mouthpiece module for transmission of airflow between the main body of the breath actuated nebuliser and a user during inhalation and / or exhalation of the user, between first opening 104 and second opening 105 (best seen in Fig. 2 and 3). The first opening 104 is for fluid communication with the mouth of a user when in use. The second opening 105 is for fluid communication with a nebuliser main body when the mouthpiece is attached to said main body.

[0082] The mouthpiece module 100 comprises a rectangular hole 106 formed in through sidewall 103 adjacent the breath sensor 101 . Providing of this hole allows the breath sensor 101 to be in fluid connection with 008852709

[0083] 10 the airflow path within airflow passage 102. In this embodiment, the hole has a length (in a direction parallel to the airflow path), of around 7 mm, and a width (in a direction perpendicular to the airflow path) of around 9 mm. Alternative geometries for this hole are discussed below in relation to Fig. 7 and 8.

[0084] The mouthpiece module further comprises two lateral openings 107, formed on respective lateral side of the mouthpiece module.

[0085] The mouthpiece module comprises an attachment portion 120, for attachment to the main body of a breath actuated nebuliser (BAN), e.g. via a snap-fit connection. The tubular body defined by sidewall 103 extends outwardly in a generally perpendicular fashion from the attachment portion 102.

[0086] Operation of the mouthpiece during use of the BAN will now be explained. The airflow path through the mouthpiece module is best shown in Fig. 2 and 3, which show sections of the mouthpiece module of Fig.

[0087] 1 during inhalation and exhalation. Fig. 2 illustrates inhalation by a user through the mouthpiece, with arrows showing an air flow moving in response to a negative pressure caused by inhalation of a user through the mouthpiece. During inhalation, air travels from the second opening 105 along the airflow path 102 and out of the first opening 104. Air may additionally flow in via lateral openings 107, with airflow from the nebuliser opening 105 and the lateral openings 107 becoming entrained into a single airflow which then exits via first opening 104 into the user’s mouth. The negative pressure cause by the inhalation causes a pressure drop across hole 106, shown by the dashed arrow. The breath sensor 101 is flexible, and as a result, deflects towards hole 106 as a result of the pressure drop across the hole cause by the inhalation of the user. As the breath sensor is a piezoelectric sensor, deflection of the sensor causes generation of a voltage across the sensor, which the sensor outputs via electrodes e.g. to a microcontroller provided in a main body of the BAN, not shown. This signal is a signal indicative of the inhalation. It will be appreciated that the magnitude of the signal output corresponds to the magnitude of the deflection of the sensor (which itself may correspond at least partly to the magnitude of the inhalation by a user). The nebulising unit is configured to operate based on the signal indicative of the inhalation and / or exhalation output by the breath sensor of the mouthpiece module, e.g. to trigger nebulisation based on this signal, as discussed in more detail below in relation to Fig. 9.

[0088] Fig. 3 illustrates exhalation by a user through the mouthpiece, with arrows showing an air flow moving in response to a positive pressure caused by exhalation of a user through the mouthpiece. During exhalation, air travels from the first opening 104 along the airflow path 102 and out of the lateral openings 107. In some arrangement a valve may be provided such that air cannot flow back into the BAN main body via second opening 105. This positive pressure within the airflow passage 102 may also cause a secondary airflow to travel out of the airflow passage through the hole 106, as shown by the dashed arrow. The breath sensor 101 shown in this figure is configured not to deflect in response to this positive pressure at the hole I secondary airflow, however it will be appreciated that in some other embodiments, the breath sensor may be configured to deflect away from the hole in response to the secondary airflow, causing the breath sensor to output a signal indicative of the exhalation.

[0089] Fig. 4 and Fig. 5 are images of a breath sensor mounted on a 3D-printed mouthpiece module having a geometry as shown in Fig. 1 . The breath sensor is provided on an external surface of the mouthpiece 008852709

[0090] 11 module and is fixedly attached to the mouthpiece module at one end of the sensor, in a cantilever fashion, such that the sensor can bend along its length during inhalation / exhalation by a user. Fig. 4 shows the breath sensor in a resting state. Fig. 5 shows the breath sensor during inhalation. It can be seen that during inhalation, the breath sensor is deflected towards the sidewall 103 relative to its position in the resting state.

[0091] The structure of the breath sensor of Fig. 4 and Fig. 5 is shown schematically in Fig. 6. In this embodiment, the breath sensor is a laminated piezoelectric sensor comprising a plurality of layers, and more specifically is a LDT0-028K sensor from TE Connectivity. The sensor comprises a 28 pm thick piezoelectric PVDF polymer film layer 109 with screen-printed silver ink electrodes 111 a,b provided on either side of the piezoelectric film layer. A 0.125 mm polyester substrate 113 is provided on a first side of the sensor, and provides a protective layer on that side. A protective coating 115 (which is conveniently polymeric e.g. polyester) is provided on a second side of the sensor. The thickness of this protective coating is conveniently selected to be in a range between 0.05 mm and 0.125 mm.

[0092] Fig. 7 shows a range of possible alternative geometries for part of the mouthpiece module, and in particular, a range of possible hole geometries. In these images, the breath sensor is not shown, but would in practice be attached to the mouthpiece module using two screws which engage with the two holes shown at the upper end of each model. The breath sensor would then extend to cover the holes 106a-d to allow cantilever deflection of the breath sensor in a manner described above in relation to Fig. 1-5.

[0093] Four different hole geometries are illustrated here: hole 106a is a rectangular hole having a length (in a direction parallel to the airflow path), of around 5 mm, and a width (in a direction perpendicular to the airflow path) of around 9 mm; hole 106b is a rectangular hole having a length (in a direction parallel to the airflow path), of around 1 mm, and a width (in a direction perpendicular to the airflow path) of around 9 mm; hole 106c is a square hole having a length (in a direction parallel to the airflow path), of around 9 mm, and a width (in a direction perpendicular to the airflow path) of around 9 mm; hole 106d is an oval hole having a major axis (in a direction parallel to the airflow path) of around 6mm, and a minor axis (in a direction perpendicular to the airflow path) of around 3mm.

[0094] Figure 8 shows a yet further arrangement of a mouthpiece module. This mouthpiece module has a generally similar structure to those shown in Fig. 7, but a cover portion 130 is provided which extends to cover the region of the mouthpiece module comprising the hole. Providing a cover portion as shown here can help protect the breath sensor and / or prevent debris from entering the hole.

[0095] In order to assess performance of the device and of different hole geometries, a Copley BRS200i breathing simulator (BRS) was used to characterise the breath sensor and its integration in the mouthpiece module, as well as perform dose delivery testing. The breath sensor was characterised based on its sensitivity, response time, and the length of time a detectable output signal was achieved during inhalation. To study these parameters, the breathing profiles used on the BRS were varied and different geometries of the hole in the mouthpiece module were tested. 008852709

[0096] 12

[0097] Fig. 9 is a graph showing real-time monitoring of different parameters associated with the mouthpiece module and the BRS during use, in particular, showing real-time monitoring of the BRS breathing pattern signal, piezo sensor response and dosing (nebulisation). As can be seen from this graph, the nebulising unit was configured to operate when the signal indicative of the inhalation and / or exhalation output by the breath sensor of the mouthpiece exceeds a predetermined threshold corresponding to x1 .75 of the baseline voltage value output by the breath sensor when the sensor is at rest - on this graph this is seen as dosing occurring for the entire time period in which the raw digital value of the signal output by the piezo sensor exceeded ~1700.

[0098] During characterisation, the sensor was observed to exhibit a varying output dependant on the breathing profile used. The flow rate at which the sensor deflected to trigger nebulisation was lower when the tidal air volume was larger given the same inhalation time (Fig. 10, which is a graph of flow rate against time). This is likely due to a higher air flow acceleration for the larger volumes given the same breath cycle duration which results in longer pressure drop in the mouthpiece module.

[0099] Similarly, the response time for the sensor decreased as the tidal volume (the amount of air that moves in and out of the lungs during a respiratory cycle) increased, as shown in Table 1 , below.

[0100] Table 1 - Characterisation results for breathing pattern and vent geometry

[0101] Profile Tidal volume (mL) Slot geometry Inhalation time (s) Percentage hold (%) Response time (ms)

[0102] Adult 900 5mm slot 2 65 170

[0103] Adult 750 5mm slot 2 51 230

[0104] Adult 500 5mm slot 2 46 560

[0105] Adult 900 1 mm slot 2 75 300

[0106] Adult 900 9mm slot 2 84 20

[0107] The ‘slot geometry’ referred to in Table 1 refers to the length of the slot in a direction parallel to the airflow path. Each of the geometries testing had the same slot width (in a direction perpendicular to the airflow path).

[0108] The ‘response time’ as indicated in table 1 is the calculated lag between the time a user begins to inhale and the time the BAN begins nebulising - in other words the time taken for the signal indicative of the inhalation to exceeds the predetermined threshold for triggering nebulisation, after the start of an inhalation. It was found that for the same tidal volume, the use of a larger slot resulted in quicker response times (see comparison of 1 mm and 9mm slot for 900mL tidal volume).

[0109] The ‘percentage hold’ as indicated in table 1 is calculated as the ratio between the time the output signal is above a defined nebulisation threshold, to the entire inhalation time from the BRS. It was found that for the same tidal volume, the use of a larger slot resulted in greater percentage hold times (see comparison of 1 mm and 9mm slot for 900mL tidal volume).

[0110] Figs.11 and 12 show how the percentage hold differs with the inhalation time and different breathing profiles. Fig. 11 shows the calculated percentage hold time for adult breathing patterns having 1s, 2s and 3s inhalation times. Fig. 12 shows the calculated percentage hold time for child, infant, and neonate breathing patterns. The child, infant, and neonate profiles had inhalation times of 0.8s, 0.5s, and 0.38s respectively. It was found that the percentage hold decreased with lower inhalation volumes and 008852709

[0111] 13 increased with shorter inhalation times for the adult profiles. A similar pattern was seen in the child breathing patterns - percentage hold was generally observed to decrease with decreasing tidal volume.

[0112] In order to test effectiveness of BAN’S according to the present invention, analysis was done to determine performance characteristics of a prototype BAN according to the present invention in comparison with other nebulizer arrangements. The results are shown in Fig. 13. This graph quantifies delivered dose, residual dose, dose loss, and respirable dose for the ‘Prototype - BAN’ (a BAN according to the present invention e.g. having a mouthpiece module as shown in Fig. 1) when used to nebulise three different substances (saline, ventolin, cromolyn sodium), and compares these results against two other nebuliser arrangements - a prototype non-breath actuated nebuliser (‘Prototype - Non-BAN’) having the same mouthpiece geometry as the ‘Prototype - BAN’ but no breath sensor, and the InnoSpireGo non-breath- actuated nebuliser. In Figure 13, results are expressed as the mean ± standard deviation.

[0113] Dose delivery tests was conducted with an adult breathing pattern (900 ml tidal volume) while nebulising 0.9% saline (containing 1 .1 mg Allura Red AC), 5 mg / ml Ventolin, and 10 mg / ml cromolyn sodium into collection filters. Drugs were extracted from the filters and nebuliser, and dose recovery (%) was calculated relative to the total dose loaded into the device. Residual dose (RD) was calculated as the dose recovered from the nebuliser, while delivered dose (DD) was calculated as the dose recovered from the collection filter. Respirable dose (RPD) was determined by multiplying the DD with the fine particle fraction (FPF). NGI (Next Generation Impactor) experiments were performed to determine the FPF (0.4 pm - 4.7 pm). Dose loss (DL) is defined as the dose lost to the environment and was calculated by subtracting the recovered / residual dose from the total loaded dose.

[0114] It was found that for the Prototype - Non-BAN device, the delivered dose (DD) and respirable dose (RPD) were both 35%, while the dose loss (DL) and residual dose (RD) were 30% and 34%, respectively.

[0115] The InnoSpireGo non-BAN nebulizer was found to have a DD of 33%, RD of 42%, DL of 25%, and RPD of 14%.

[0116] With the introduction of the mouthpiece module with the breath sensor, the Prototype - BAN device (according to the invention) showed a DD of 79%, RD of 22%, DL of 0.5%, and RPD of 77%, for saline nebulisation. Further testing of the Prototype - BAN device with Ventolin and cromolyn sodium formulations produced comparable dose delivery results as seen for nebulisation of saline. BANs according to the invention were found to increase the DD by more than 40% compared to non-BAN arrangements having identical mouthpiece geometry but no breath sensor, while reducing the DL to below 3% across tested formulations.

[0117] It can be concluded that BAN arrangements as disclosed herein offer an encouraging advancement to BAN technologies, creating a pathway for sustainable practices with lower dose volumes and reduced wastage. Furthermore, the use of a laminated piezoelectric sensor in a BAN has been found to be particularly advantageous in view of the fast response time of the sensor, its simple integration, and versatility when used with different breathing patterns. 008852709

[0118] 14

[0119] The features disclosed in the foregoing description, or in the following claims, or in the accompanying drawings, expressed in their specific forms or in terms of a means for performing the disclosed function, or a method or process for obtaining the disclosed results, as appropriate, may, separately, or in any combination of such features, be utilised for realising the invention in diverse forms thereof.

[0120] While the invention has been described in conjunction with the exemplary embodiments described above, many equivalent modifications and variations will be apparent to those skilled in the art when given this disclosure. Accordingly, the exemplary embodiments of the invention set forth above are considered to be illustrative and not limiting. Various changes to the described embodiments may be made without departing from the spirit and scope of the invention.

[0121] For the avoidance of any doubt, any theoretical explanations provided herein are provided for the purposes of improving the understanding of a reader. The inventors do not wish to be bound by any of these theoretical explanations.

[0122] Any section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described.

[0123] Throughout this specification, including the claims which follow, unless the context requires otherwise, the word “comprise” and “include”, and variations such as “comprises”, “comprising”, and “including” will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps.

[0124] It must 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. Ranges may be expressed herein as from “about” one particular value, and / or to “about” another particular value. When such a range is expressed, another embodiment includes from the one particular value and / or to the other particular value. Similarly, when values are expressed as approximations, by the use of the antecedent “about,” it will be understood that the particular value forms another embodiment. The term “about” in relation to a numerical value is optional and means for example + / - 10%.

[0125] References

[0126] A number of publications are cited herein in order to more fully describe and disclose the invention and the state of the art to which the invention pertains. Full citations for these references are provided below. The entirety of each of these references is incorporated herein.

[0127] Denyer et al “The Adaptive Aerosol Delivery (AAD) Technology: Past, Present, and Future”, JOURNAL OF AEROSOL MEDICINE AND PULMONARY DRUG DELIVERY (2010).

[0128] Macdonald EK et al, “Tuneable Nebulizer Platform for Targeted Inhalation Drug Delivery”, Respiratory Drug Delivery, 2023; 2023:291-294.

Claims

00885270915Claims:1 . A mouthpiece module configured for removable attachment to a main body of a breath actuated nebuliser, the mouthpiece module comprising: an airflow path defined within the mouthpiece module for transmission of airflow between the main body of the breath actuated nebuliser and a user during inhalation and / or exhalation of the user, and a breath sensor arranged to detect inhalation and / or exhalation of a user via the airflow path, and configured to output a signal indicative of the inhalation and / or exhalation.2 The mouthpiece module according to claim 1 , wherein the breath sensor is configured to deflect or be displaced as a result of inhalation and / or exhalation of a user via the airflow path, the deflection or displacement causing the breath sensor to output a signal indicative of the inhalation and / or exhalation.

3. The mouthpiece module according to claim 2 wherein the breath sensor is a piezoelectric sensor configured to deflect as a result of inhalation and / or exhalation of a user via the airflow path, to thereby generate the signal.

4. The mouthpiece module according to claim 3 wherein the piezoelectric sensor is a piezoelectric film-based sensor comprising a piezoelectric film layer and one or more electrodes.

5. The mouthpiece module according to claim 4 wherein the piezoelectric film layer and one or more electrodes are laminated between protective layers, optionally wherein the protective layers are polymeric layers.

6. The mouthpiece module according to any preceding claim, wherein the breath sensor is arranged to detect inhalation of a user via the airflow path and output a signal indicative of the inhalation, and is further arranged such that substantially no sensor response is induced as a result of exhalation of a user via the airflow path.

7. The mouthpiece module according to any one of the preceding claims wherein the airflow path is defined by an airflow passage extending along the mouthpiece module, wherein the airflow passage has at least one hole formed in a sidewall thereof, the breath sensor being arranged adjacent the at least one hole such that it can detect inhalation and / or exhalation of a user via the airflow path as a result of changes in pressure across the hole, optionally wherein the breath sensor is attached in a cantilever fashion to the mouthpiece module such that deflection of the breath sensor occurs via a cantilever bending mechanism.

8. The mouthpiece module according to claim 7 wherein the breath sensor is located externally of the airflow passage.008852709169. The mouthpiece module according to claim 7 or claim 8 wherein the hole formed in the sidewall of the airflow passage has a substantially rectangular shape.

10. The mouthpiece module according to claim 7 wherein the length of the hole, in a direction parallel to the airflow path, is in a range of from 0.5 mm to 15 mm.

11. A breath actuated nebuliser comprising: a mouthpiece module according to any one of claims 1 to 10; and a main body comprising a nebulising unit and a reservoir configured to store a substance to be nebulised, wherein the nebulising unit is configured to operate based on the signal indicative of the inhalation and / or exhalation output by the breath sensor of the mouthpiece module.

12. The breath actuated nebuliser according to claim 11 , wherein nebulising unit is configured to operate when the signal indicative of the inhalation and / or exhalation output by the breath sensor of the mouthpiece exceeds a predetermined threshold.

13. The nebuliser according to claim 11 or claim 12 wherein the mouthpiece module is electrically connected to the main body by means of circuitry for conveying the signal indicative of the inhalation and / or exhalation output by the breath sensor of the mouthpiece module.

14. The nebuliser according to any one of claims 11 to 13, wherein the breath actuated nebuliser comprises a microcontroller operable to process the signal indicative of the inhalation and / or exhalation output by the breath sensor of the mouthpiece module, and configured to control operation of the nebulising unit.

15. The nebuliser according to any one of claims 11 to 14 wherein the breath actuated nebuliser comprises a signal conditioning circuit for conditioning of the signal indicative of the inhalation and / or exhalation output by the breath sensor of the mouthpiece module.

16. The nebuliser according to any one of claims 11 to 15, wherein the nebulising unit comprises a mesh-based nebulising unit, a jet nebulising unit, or an ultrasonic nebulising unit.

17. The nebuliser according to any one of claims 11 to 16 wherein, in use, the amount of nebulised substance that is delivered to a user as a percentage of a total amount of the nebulised substance is greater than 50%.

18. A kit of parts for a breath actuated nebuliser, comprising: a mouthpiece module comprising an airflow path defined within the mouthpiece module for transmission of airflow from the main body of the breath actuated nebuliser to a user during inhalation and / or exhalation of the user, and a breath sensor arranged to detect inhalation and / or exhalation of a user via the airflow path, and configured to output a signal indicative of the inhalation and / or exhalation;00885270917 and a main body comprising a nebulising unit and a reservoir configured to store a substance to be nebulised, wherein the nebulising unit is configured to operate based on the signal indicative of the inhalation and / or exhalation output by the breath sensor of the mouthpiece module; wherein the mouthpiece module is configured to be removably attachable to the main body.

19. A breath actuated nebuliser having a main body comprising a nebulising unit and a reservoir configured to store a substance to be nebulised, and a mouthpiece connected to the main body, the breath actuated nebuliser further comprising: an airflow path for transmission of airflow through at least part of the breath actuated nebuliser to or from a user during inhalation and / or exhalation of the user; and a breath sensor arranged to detect inhalation and / or exhalation of a user via the airflow path, and configured to output a signal indicative of the inhalation and / or exhalation of the user, wherein the nebulising unit is configured to operate based on the signal indicative of the inhalation and / or exhalation output by the breath sensor; wherein the breath sensor comprises a piezoelectric sensor arranged to deflect as a result of the inhalation and / or exhalation of the user via the airflow path, and thereby output the signal indicative of the inhalation and / or exhalation.

20. Use of a piezoelectric sensor for sensing inhalation and / or exhalation of a user along an airflow path through at least part of a breath actuated nebuliser.21 . Use according to claim 20, wherein the piezoelectric sensor is a piezoelectric film-based sensor comprising a piezoelectric film layer and one or more electrodes.

22. Use according to claim 21 wherein the piezoelectric film layer and one or more electrodes are laminated between protective layers, optionally wherein the protective layers are polymeric layers.

Images