Method for detecting the presence of a liquid in a diaphragm sprayer

Abstract

A breath actuated inhalation device is provided, comprising an aerosol generator comprising a vibrator and a membrane, and a reservoir for a liquid to be aerosolized in fluid communication with the membrane. A method of operating the device is also provided. The vibrator is driven intermittently so that the aerosol generator has periods of aerosol generation during patient inhalation and little or no aerosol generation periods before and / or after inhalation. A scan is performed in which an electrical parameter of the vibrator is measured as the membrane is vibrated at a plurality of frequencies. A frequency spectrum obtained from the scan during inhalation is compared to a frequency spectrum obtained from a scan during a period before or after the inhalation to determine whether liquid is present in the reservoir.

Description

TECHNICAL FIELD

[0001] The present invention relates to a vibrating membrane nebuliser, and in particular to a method for detecting the presence of liquid in contact with the membrane. BACKGROUND

[0002] Aerosols for medical inhalation therapy typically comprise an active ingredient dissolved or suspended in a nebulisable liquid, usually water. To reach the deep lung, a uniform distribution of aerosol droplets with a droplet size of about 5 pm is required. Vibrating membrane nebulisers are one type of device that produces such aerosols. These devices have an aerosol generator comprising a vibrator, for example a piezoelectric element, which is excited at ultrasonic frequencies to cause vibration; a membrane (sometimes referred to as a mesh or orifice plate) having a large number of orifices, typically with diameters of 1-10 pm; and a reservoir providing the liquid medicament formulation to the membrane.

[0003] Continuing to operate a vibrating membrane nebuliser after the liquid reservoir has been emptied can result in the membrane breaking or rupturing. It is therefore important to be able to reliably detect whether liquid is present in the reservoir / whether liquid is in contact with the membrane (“empty detection”). When the liquid is used up, the nebuliser can indicate to the patient that the treatment is over and / or automatically shut off the vibrator.

[0004] One approach is to simply measure the amount of liquid in the reservoir with a suitable sensor. For example, US 2006 / 0255174 discloses a nebuliser in which the amount of liquid in the reservoir is sensed by a piezoelectric sensor, an optical sensor, an electrical conductivity sensor or a strain gauge. However, this requires a dedicated sensor, thereby increasing the cost and complexity of the device; furthermore, the sensor can need to be in contact with the liquid, which can be problematic.

[0005] An alternative approach takes advantage of the fact that the vibration characteristics (e.g. resonant frequency, power consumption etc.) of the aerosol generator are typically very different when the membrane is in contact with liquid compared to when it is dry. For example, US 2006 / 0102172 discloses a nebuliser which determines whether liquid is present by comparing the detected value of an electrical parameter (e.g. the current flowing to the piezoelectric element) at a particular frequency with a stored value. US 9272101 uses impedance measurements in a similar way. Instead of using a single frequency, the electromechanical behaviour of the aerosol generator can be represented as a frequency spectrum, for example a plot of power or current consumption as a function of vibration frequency. WO 2014 / 062175 and WO 2015 / 091356 disclose methods of comparing the measured frequency spectrum with a stored frequency spectrum using mean values and various mathematical techniques to improve the reliability of the empty detection. The comparison is typically made at regular intervals during the treatment, as the membrane is vibrating, until it is determined that the liquid has all been used up.

[0006] However, inherent variations in the hardware components of the nebulizer (e.g. the aerosol generator, the driver electronics) and / or changes in these components during the lifetime of the nebulizer, or due to changes in external conditions (e.g. ambient temperature), can affect the electromechanical performance. For example, if the characteristics of the aerosol generator and / or the driver electronics differ from the characteristics on which the standard stored values are based, the method relying on comparison to preset values can produce erroneous results. Thus, the vibrator can continue to vibrate after the liquid is exhausted, which can damage the membrane; or can stop vibrating while there is still liquid to be nebulized, so that the full dose is not delivered to the patient. Therefore, there is still a need for improved methods to reliably detect the presence of liquid in the reservoir and / or in contact with the membrane. SUMMARY

[0007] The present invention provides an improved method for determining when the liquid to be nebulized is exhausted. The inventors have realized that transient effects can be observed in the frequency spectrum immediately after the vibration starts or stops, and that these can be used to reliably detect the presence of liquid in contact with the membrane. Therefore, in a first aspect, the invention provides a breath-actuated inhalation device comprising: an aerosol generator comprising a vibrator and a membrane; a reservoir for liquid to be nebulized in fluid communication with the membrane; and a controller providing a driver signal to drive the vibrator so that the membrane vibrates and generates an aerosol; wherein the controller is configured to:

[0008] • intermittently drive the vibrator so that the aerosol generator repeatedly experiences an aerosol generation period during a patient inhalation and a period with little or no aerosol generation before and / or after the inhalation;

[0009] • perform a scan in which the membrane is vibrated at a plurality of frequencies and in which at least one electrical parameter of the vibrator is measured at the plurality of frequencies to provide a frequency spectrum; wherein the scan is performed during an inhalation and during a period before or after the inhalation;

[0010] • compare the frequency spectrum obtained during an inhalation with a frequency spectrum obtained during a period before or after the inhalation;

[0011] • determine, based on the comparison of the frequency spectra, whether there is liquid in the reservoir; and

[0012] • stop driving the vibrator if the controller determines that there is no liquid.

[0013] Previous methods of empty detection measure the value of an electrical parameter while the membrane is vibrating, and such methods rely on changes in the electromechanical characteristics of the aerosol generator as the volume of liquid decreases over time. In contrast, the present invention relies on effects that occur when the membrane is vibrating intermittently, as in a breath-actuated nebulizer. The present invention compares the frequency spectrum obtained during an aerosol generation period with that obtained during a period of little or no aerosol generation, to identify changes caused by the formation or dissipation of standing waves in the reservoir at the start or stop of vibration, respectively. The present invention is less dependent on the characteristics of the aerosol generator than previous methods, as it does not rely on a comparison with, for example, a stored frequency spectrum; instead, it detects a transient change that only occurs in the presence of liquid. The present invention is therefore more robust to changes in hardware, changes in hardware over the lifetime of the nebulizer, and changes in external conditions.

[0014] The controller can be configured to perform a first scan to obtain a first frequency spectrum before each inhalation or aerosol generation period; subsequently perform a second scan to obtain a second frequency spectrum during each inhalation or aerosol generation; and compare the first and second frequency spectra. The first scan can be performed immediately before the start of an aerosol generation period. The second scan can be performed at least 50 or 100 ms after the start of an aerosol generation period. This provides sufficient time for the formation of a standing wave, so that it can be detected in the second scan. The second scan can be performed less than 1000 ms or 500 ms after the start of an aerosol generation period. The time delay between the first and second scans determines the point at which the absence of liquid can be detected. A smaller delay results in earlier empty detection, so that the vibration of the membrane can be stopped more quickly.

[0015] The inhalation device is breath-actuated, i.e. the aerosol is not generated continuously, but only when the patient is inhaling. The device can comprise a passageway having an air inlet and an aerosol outlet, and a pressure sensor pneumatically connected to the passageway, and the controller can be configured to: receive a signal from the pressure sensor; sense inhalation by the patient at the aerosol outlet opening based on the signal from the pressure sensor; and initiate an aerosol generation period in response to inhalation. The controller can be configured to initiate a period of little or no aerosol generation a preset time after the initiation of the aerosol generation period. Alternatively, the controller can be configured to sense when the patient stops inhaling based on the signal from the pressure sensor, and initiate a period of little or no aerosol generation in response to the cessation of inhalation. The method of the present invention is particularly suitable for use in breath-actuated nebulizers, as the aerosol is inherently generated intermittently, so that the way the nebulizer operates does not need to be changed.

[0016] The aerosol generator can comprise a support member on which the vibrator and / or the membrane is mounted. The vibrator can be a ring-shaped piezoelectric element. The support element can be a transducer in the form of a hollow tubular body having a flange at or near a first end on which the piezoelectric element is attached and at or near a second end into which or on which the membrane is mounted. The device can comprise a fill chamber located above and in fluid communication with the support member, such that the fill chamber and the hollow tubular body together form the reservoir. Alternatively, the support member can comprise a substantially flat ring or disc, and the membrane and / or the vibrator can be mounted on the support member, for example on opposite sides.

[0017] The controller can be configured to determine a resonance frequency of the aerosol generator from the frequency spectrum, and to drive the vibrator at the resonance frequency or a frequency related to the resonance frequency during an aerosol generation period other than the scan, for example a fixed offset from the resonance frequency.

[0018] The plurality of frequencies can comprise from about 10 or 15 kHz below the resonance frequency to about 10 or 15 kHz above the resonance frequency, for example from about 75 kHz to about 100 kHz.

[0019] The controller can be configured to perform the comparison of the frequency spectra by calculating an overlap function. The controller can also be configured to determine that there is no liquid in the reservoir if the overlap function value is above a threshold value. The controller can also be configured to stop driving the vibrator if the overlap function is above the threshold value for a plurality of consecutive inhalations or aerosol generation periods, for example three or five inhalations or aerosol generation periods. The overlap function provides a reliable comparison method.

[0020] In a second aspect, the present application provides a method of operating an inhalation device of the first aspect of the present application, and / or a method of operating a breath-actuated inhalation device comprising an aerosol generator comprising a vibrator and a membrane and a reservoir for a liquid to be aerosolised in fluid communication with the membrane, the method comprising:

[0021] a) driving the vibrator intermittently to cause the aerosol generator to repeat during a patient inhalation having an aerosol generation period and little or no aerosol generation period before and / or after the inhalation;

[0022] b) performing a scan in which the membrane is vibrated at a plurality of frequencies, and in which at least one electrical parameter of the vibrator is measured at the plurality of frequencies to provide a frequency spectrum; wherein the scan is performed during the inhalation and during little or no aerosol period;

[0023] c) comparing the frequency spectrum obtained during the inhalation with a frequency spectrum obtained during a period before or after the inhalation;

[0024] d) determining whether there is liquid in the reservoir based on the comparison of the frequency spectra; and

[0025] e) if it is determined in step d) that no liquid is present, stopping driving the vibrator.

[0026] A first scan can be performed before each inhalation to obtain a first frequency spectrum, a second scan can subsequently be performed during each inhalation to obtain a second frequency spectrum, and the first and second frequency spectra can be compared.

[0027] When the inhalation device comprises a passageway having an air inlet opening and an aerosol outlet opening, and a pressure sensor pneumatically connected to the passageway, the aerosol generation period can be initiated in response to inhalation by the patient in dependence on a signal from the pressure sensor. The little or no aerosol generation period can be initiated a preset time after initiation of the aerosol generation period. Alternatively, the little or no aerosol generation period can be initiated in response to the patient stopping inhalation.

[0028] The frequency spectra can be compared by calculating an overlap function. If the overlap function is above a threshold value, it can be determined that no liquid is present in the reservoir. If the overlap function is above the threshold value for a plurality of consecutive inhalations or aerosol generation periods, for example three or five inhalations or aerosol generation periods, the driving of the vibrator can be stopped.

[0029] In a specific embodiment, the present application provides a breath-actuated inhalation device comprising: an aerosol generator comprising a vibrator and a membrane; a reservoir for liquid to be nebulized in fluid communication with the membrane; and a controller providing a driver signal to drive the vibrator so that the membrane vibrates and generates aerosol in a passageway; wherein the controller is configured to:

[0030] • intermittently drive the vibrator so that the aerosol generator repeats with an aerosol generation period during inhalation by a patient and a little or no aerosol generation period before and / or after inhalation;

[0031] • immediately before or at the start of each inhalation or aerosol generation period, a first scan is performed in which the membrane is vibrated at a plurality of frequencies and in which for each of the plurality of frequencies at least one electrical parameter of the vibrator is measured to provide a first frequency spectrum;

[0032] • subsequently during each inhalation or aerosol generation period, a second scan is performed in which the membrane is vibrated at a plurality of frequencies and in which for each of the plurality of frequencies at least one electrical parameter of the vibrator is measured to provide a second frequency spectrum;

[0033] • comparing the first and second frequency spectra;

[0034] • determining whether or not liquid is present in the reservoir based on the comparison of the first and second frequency spectra; and

[0035] • if the controller determines that no liquid is present, stopping driving the vibrator.

[0036] The present application also provides a method of operating a breath actuated inhalation device according to the specific embodiment, the method comprising:

[0037] a) intermittently driving the vibrator to cause the aerosol generator to repeatedly have an aerosol production period during a patient inhalation and little or no aerosol production period before and / or after the inhalation;

[0038] b) immediately prior to or at the start of each inhalation or aerosol production period, performing a first scan in which the membrane is vibrated at a plurality of frequencies and in which at least one electrical parameter of the vibrator is measured for each of the plurality of frequencies to provide a first frequency spectrum;

[0039] c) subsequently during each inhalation or aerosol production period, performing a second scan in which the membrane is vibrated at a plurality of frequencies and in which at least one electrical parameter of the vibrator is measured for each of the plurality of frequencies to provide a second frequency spectrum;

[0040] d) comparing the first and second frequency spectra;

[0041] e) determining whether there is liquid in the reservoir based on the comparison of the first and second frequency spectra; and

[0042] f) if it is determined in step e) that there is no liquid, stopping driving the vibrator. BRIEF DESCRIPTION OF DRAWINGS

[0043] The application will now be further described with reference to the drawings in which:

[0044] Figure 1 An enlarged view of the vibrating membrane nebulizer is shown.

[0045] Figure 2 is a cross-sectional view through the aerosol generator of the nebulizer. Figure 1 is a cross-sectional view through the aerosol generator of the nebulizer.

[0046] Figure 3 is a schematic diagram of the driver circuit of the aerosol generator.

[0047] Figure 4 shows a schematic diagram of the surface of the liquid in the reservoir before (a) and during (b) membrane vibration. Figure 4A Figure 4B

[0048] Figure 5 shows a frequency spectrum obtained with no liquid in the reservoir.

[0049] Figure 6 shows a frequency spectrum obtained with liquid in the reservoir.

[0050] Figure 7 ​​Overlaid function plots during a representative treatment are shown. DETAILED DESCRIPTION

[0051] The term "aerosol generation period" refers to a period of time in which the vibrator is primarily driven at a normal intended frequency, typically at or near the resonance frequency (e.g. within 2 kHz), to generate aerosol. The aerosol generation period can also include short periods of time in which one or more scans are performed. The aerosol generation period can correspond to the typical length of a patient inhalation, e.g. 1 to 10 seconds, 2 to 6 seconds or 3 to 5 seconds. The term "a period of little or no aerosol generation" refers to the interval between aerosol generation periods in which the vibrator is not substantially driven. The period of little or no aerosol generation can also include short periods of time in which one or more scans are performed. Because most scan frequencies are quite far from the resonance frequency (e.g. more than 2 kHz), little or no aerosol is generated during scanning. Thus, little or no aerosol is generated in the period of little or no aerosol generation. The period of little or no aerosol generation can correspond to the typical time between patient inhalations, e.g. 1 to 10 seconds, 2 to 6 seconds or 3 to 5 seconds. Thus, driving the vibrator intermittently (at the normal drive frequency) results in alternating periods of aerosol generation and no aerosol generation.

[0052] The term "scan" refers to the process of sequentially vibrating the vibrator at a number of different frequencies in a defined range with step increments, and measuring the value of an electrical parameter at some or all of the frequencies. The term "frequency spectrum" refers to the graph obtained by plotting the measured values of the electrical parameter as a function of frequency. The electrical parameter can be current, voltage, power, impedance and / or current / voltage phase shift. In particular, the electrical parameter can be the current consumption of the vibrator, or the current consumption of a power converter that provides power to the vibrator, or the voltage drop at the vibrator. These parameters can be measured in a direct or indirect manner by using one or more current and / or voltage sensors.

[0053] Figure 1 An enlarged view of the vibrating membrane nebulizer device described in EP2724741 and WO2013 / 098334 is shown. The device comprises three parts: a base unit, a mouthpiece component and an aerosol head. The base unit 100 has one or more air inlet openings (not visible in Figure 1 at its rear end, an air outlet opening 102, a recess 103 for receiving the mouthpiece component 200 and one or more key lock members 104. Channels (not visible in Figure 1The base unit 100 has one or more notches 106 positioned at or near the recess 103, and the mouthpiece 200 has one or more positioning members 204. The notches of the base unit are complementary to (i.e. shaped to receive) the positioning members of the mouthpiece. In this context, a notch is a recess whose "negative" shape is complementary to the "positive" shape of a positioning member, e.g. a ledge, a protrusion, etc. The notches and positioning members work together to correctly position the mouthpiece in the base unit. The notches and positioning members can be asymmetrical, so that the mouthpiece can only be inserted into the base unit in one way. This ensures that the device is assembled so that the position and orientation of the mouthpiece and base unit relative to each other is correct. The base unit contains a controller, e.g. a printed circuit board (PCB) that controls the operation of the nebulizer.

[0054] The base unit 100, mouthpiece 200 and aerosol head 300 are detachably connected to each other. The device is assembled by inserting the mouthpiece 200 into the recess 103 in the base unit 100, then placing the aerosol head 300 on the mouthpiece 200 and engaging the keying members 303 of the aerosol head 300 with the keying members 104 of the base unit 100 by gently pressing on the aerosol head and base unit. The aerosol generator 301 is positioned in the aerosol head 300 in such a way that, when the keying members are engaged, the aerosol generator 301 is inserted into the lateral opening 202 of the mouthpiece 200. This creates an airtight connection between the aerosol generator 301 and the lateral opening 202 in the mouthpiece, and between the air outlet opening 102 of the base unit 100 and the air inlet opening 201 of the mouthpiece 200. The base unit 100, mouthpiece 200 and aerosol head 300 can be separated by reversing these steps.

[0055] The base unit 100 has one or more notches 106 positioned at or near the recess 103, and the mouthpiece 200 has one or more positioning members 204. The notches of the base unit are complementary to (i.e. shaped to receive) the positioning members of the mouthpiece. In this context, a notch is a recess whose "negative" shape is complementary to the "positive" shape of a positioning member, e.g. a ledge, a protrusion, etc. The notches and positioning members work together to correctly position the mouthpiece in the base unit. The notches and positioning members can be asymmetrical, so that the mouthpiece can only be inserted into the base unit in one way. This ensures that the device is assembled so that the position and orientation of the mouthpiece and base unit relative to each other is correct. The base unit contains a controller, e.g. a printed circuit board (PCB) that controls the operation of the nebulizer.

[0056] Figure 2An aerosol generator is shown in WO 2008 / 058941. It comprises a vibrator, e.g. a piezoelectric element 308, a transducer body 306 and a membrane 309. The piezoelectric element is preferably a ring-shaped single or multi-layer ceramic that vibrates the transducer body in a longitudinal mode. The transducer body is e.g. made of stainless steel, titanium or aluminium and encloses a cavity 307 containing the liquid to be atomized. The interior of the filling chamber 302 is conical so that the liquid flows under the influence of gravity into the upstream end 306a of the transducer body and down into the cavity. The filling chamber 302 and the cavity 307 together form a reservoir for the liquid.

[0057] The membrane 309 is located at the downstream end 306b of the transducer body 306. The holes in the membrane can be formed by electroforming or laser drilling, the openings are typically in the range of about 1 μm to about 10 μm. In the absence of vibration of the membrane, pressure balance, the shape of the holes and the properties of the material used for the membrane are such that the liquid does not seep through the membrane. However, vibration of the membrane leads to the formation and discharge of aerosol droplets through the holes. The membrane can be made of plastic, silicon, ceramic or, more preferably, metal and can be fixed to or in the downstream end of the transducer body by various means, e.g. gluing, soldering, crimping or laser welding. Optionally, the membrane is at least partially dome-shaped in its central region, which leads to a diverging spray of the nascent aerosol droplets and thus reduces the risk of droplet coalescence.

[0058] Figure 3 The drive circuit 400, which is shown schematically, generates a driver signal that excites the piezoelectric element, causing the membrane to vibrate, typically at a frequency in the range of 50-200 kHz. The input direct current is provided by a battery 401. This is converted into an alternating drive voltage by a power converter 402 and a transformer 403. A closed loop controller 404 controls the power supplied to the aerosol generator 301 by pulse width modulation, by varying the duty cycle, i.e. the fraction of time for which power is supplied to the aerosol generator. The controller 404 inputs the drive frequency and the duty cycle to the power converter 402. The controller 404 also measures the current drawn by the aerosol generator 301 through a shunt resistor 405 in series with the input to the power converter 402. The effective power consumption and the absolute value of the impedance can be derived from the measured current. The aerosol generator is driven using near-resonance driving, in which the frequency of the driver signal has a fixed offset (e.g. 500 Hz or 1 kHz) from the resonance frequency of the aerosol generator, which is typically around 85 kHz.

[0059] Excitation of the piezoelectric element causes a small longitudinal displacement and / or deformation in a direction parallel to the axis of symmetry of the transducer body 306. The transducer body has a region with a relatively large wall thickness proximal to the piezoelectric element 308, which acts as a stress concentration zone 306c, and a region with a relatively small wall thickness downstream thereof 306d, which acts as a deformation amplification zone. This configuration amplifies the vibration or deformation of the transducer body 306 caused by the piezoelectric element 308. The piezoelectric element 308 is located at or near the level of the stress concentration zone 306c. The inner diameter of the transducer body at the deformation amplification zone can be the same as the inner diameter of the stress concentration zone, so that the difference in wall thickness corresponds to a different outer diameter. Alternatively, the outer diameter of the transducer body can be constant, while the inner diameter is different at the location of the two regions.

[0060] The nebulizer is breath-actuated, so it produces aerosol only when the patient is inhaling. This avoids wasting aerosol produced when the patient is exhaling, which would occur with a nebulizer operating in a continuous fashion. A pressure sensor (e.g. atmospheric pressure sensor) is located near and in pneumatic connection with the passage in the base unit between the air inlet opening and the air outlet opening 102. The pressure sensor measures the pressure in the passage and sends a signal representative of the pressure to the controller. When the patient begins to inhale on the mouthpiece, the pressure in the passage drops. If the pressure drops below a certain value, the controller determines that the patient has begun to inhale and causes the piezoelectric element to vibrate, causing the membrane to vibrate, thereby producing aerosol droplets.

[0061] When the nebulizer is operated, aerosol produced by the membrane 309 is released into the passage 205. Air enters through the air inlet in the base unit and passes through the passage in the base unit, the air outlet opening 102 and the air inlet opening 201 of the mouthpiece component, and into the passage 205, where it mixes with the aerosol. The air and aerosol then flow along the passage 205, out through the aerosol outlet opening 203 of the mouthpiece and into the patient's airway.

[0062] The controller stops aerosol production when a preset length of time (e.g. 3s) has elapsed from the start of aerosol production. The preset length of time can correspond to the length of a typical inhalation, and can be configured by the patient. Alternatively, the preset length of time can be shorter than a typical inhalation, so that at the last part of the inhalation, the patient receives air but no aerosol. This ensures that the aerosol reaches the middle and lower parts of the patient's airway, but is not delivered to the upper airway (e.g. throat) of the patient, where the aerosol is ineffective. However, the controller can instead detect when the patient has stopped inhaling by sensing an increase in pressure in the passage, and then stop aerosol production.

[0063] The resonance frequency of the aerosol generator changes during the treatment as the amount of liquid in the reservoir decreases. In order to maintain a fixed offset between the driver signal frequency and the resonance frequency, it is necessary to measure the resonance frequency at intervals throughout the operation of the aerosol generator, for example every 0.5 seconds. This is done by sweeping the frequency of the driver signal over a range of frequencies from below the resonance frequency to above the resonance frequency, for example from about 10 or 15 kHz below the resonance frequency to about 10 or 15 kHz above the resonance frequency, for example from 75 kHz to about 100 kHz in steps of 0.1 kHz. At each frequency, an electrical parameter related to the vibration of the aerosol generator is measured, for example the current consumption of the aerosol generator. The resulting plot of current as a function of frequency (spectrum) has a peak at the resonance frequency of the aerosol generator. The sweep takes about 70 ms to perform, for example. During the sweep, the aerosol generator is not operating at the optimum frequency, so the aerosol output rate falls. Therefore, almost all of the aerosol is produced in the time between sweeps (430 ms in this case).

[0064] The point at which the film dries out can be determined from the sweep, for example from the change in the shape of the spectrum as a function of time, or compared to a standard spectrum, as described for example in US2006 / 0102172, US9272101, WO2014 / 062175 and WO2015 / 091356. However, as described above, these methods can produce false results due to variations in the hardware, variations in the hardware during the life of the nebuliser, and variations in external conditions.

[0065] The present application is based on a different effect that is independent of these variations, and is therefore more reliable. When the nebuliser is turned off, the liquid in the chamber has a flat surface, with a meniscus at the edge. When the nebuliser is turned on and the aerosol generator is vibrating at or close to its resonance frequency, a standing wave is formed in the liquid within about 50 ms. When the vibration stops, the opposite effect is observed, although it takes longer (about 1 s) for the wave to dissipate and the liquid surface to become flat again.

[0066] Figure 4 shows Figure 1 a schematic view of the liquid surface in the reservoir of the nebuliser of Figure 4A shows the liquid before the vibration starts; the surface is flat, i.e. the liquid is evenly distributed over the transducer body. Figure 4B shows the surface during the vibration; this liquid forms a standing wave, with a wave crest in the centre.

[0067] Figure 5 and 6 shows the current consumption of the power converter at each frequency by vibrating the membrane at a series of different frequencies from 75 kHz to 100 kHz in steps of 0.1 kHz with a constant duty cycle, and measuring the current consumption of the power converter at each frequency. Figure 1The spectra obtained with the nebulizer in the absence of liquid are shown. The main peak at 89.5 kHz, where the maximum current consumption occurs, is the resonance frequency of the aerosol generator. There is also a smaller peak at about 83 kHz, which is the resonance frequency of the membrane. There is no liquid present, so no standing wave is formed; therefore, the electromechanical properties of the aerosol generator do not change between scans. Thus, although each spectrum is plotted as a separate line, they almost completely overlap, and it is not possible to distinguish between them.

[0068] Figure 5 The spectra obtained with the nebulizer in the absence of liquid are shown. The main peak at 89.5 kHz, where the maximum current consumption occurs, is the resonance frequency of the aerosol generator. There is also a smaller peak at about 83 kHz, which is the resonance frequency of the membrane. There is no liquid present, so no standing wave is formed; therefore, the electromechanical properties of the aerosol generator do not change between scans. Thus, although each spectrum is plotted as a separate line, they almost completely overlap, and it is not possible to distinguish between them.

[0069] Figure 6 The spectra obtained with the nebulizer in the presence of liquid are shown. There are differences in the overall shape of the spectra compared to Figure 5 Firstly, the main resonance peak is at a lower frequency (86.5 kHz) than in Figure 5 i.e. the resonance is slightly less pronounced when liquid is present. These changes in the main resonance peak over multiple inhalations form the basis of some known empty detection methods. Secondly, the smaller peak has disappeared.

[0070] Furthermore, there are also clear differences between the spectra in Figure 5 compared to Figure 6 due to the redistribution of the liquid as a standing wave is formed when the aerosol generator is switched on. The resonance peak moves to a slightly higher frequency and becomes slightly wider in each successive spectrum. The largest differences are between the first spectrum 10 and the second spectrum 20. The third spectrum 30 and subsequent spectra are similar to each other because the liquid has redistributed by the time these are measured.

[0071] Because these changes only occur when liquid is present, they can be used to distinguish between the wet state and the dry state of the membrane. This forms the basis of the present invention. Thus, rather than comparing the measured values or spectra to preset values or spectra, or comparing the spectra obtained in different inhalations to identify changes that occur during treatment, the present invention compares the spectra obtained without aerosol generation to the spectra obtained after aerosol generation has started. If no liquid is present, there is no standing wave, so the pre- and in-vibration spectra are identical. However, if liquid is present, the spectra are different: the first spectrum reflects the initially flat liquid surface, and the subsequent spectra reflect the standing wave.

[0072] Figure 6The first spectrum (at t=0 s, before aerosol generation) can be compared to one (or more) of the subsequent spectra, preferably to the second spectrum (at t=0.5 s). This effect is most pronounced between the first and second spectrum, because most of the redistribution of the liquid occurs very quickly, usually within about 50 ms, i.e. before the second spectrum is obtained. This difference is also present when comparing the first spectrum to any of the subsequent spectra. However, the spectra are also influenced by the liquid fill level in the reservoir. Between the times at which the first and second spectrum are recorded, the fill level changes little. In contrast, if the first spectrum is compared to, for example, the seventh spectrum (t=3 s), the difference between them will reflect both the decrease in liquid fill level and the formation of a standing wave. Therefore, while it is possible to use a subsequent spectrum for the comparison, this is not preferred, because these spectra reflect a combination of two effects.

[0073] The degree to which two spectra match each other can be expressed in terms of an "overlap function". The overlap function can be calculated as the inverse of the sum of the absolute values of the difference between the spectra at each frequency. Thus, when the spectra are different (e.g. the first and second spectrum in Figure 6 , the sum of the absolute differences is large, and its inverse is small; thus, the overlap function has a low value. On the other hand, when the spectra are very similar (as shown in Figure 5 ), the overlap function has a higher value.

[0074] A representative treatment session was performed using the nebulizer of Figure 1 to nebulize 4 ml of a 0.9% saline solution. The treatment session comprised 195 inhalations, i.e. about 20 litres of solution were nebulized per inhalation. When an inhalation by the patient was detected, aerosol generation was started and continued for 3 s per inhalation. Seven scans were performed during each inhalation (at t=0, 0.5 s, 1 s, 1.5 s, 2 s, 2.5 s and 3 s). Each scan took 70 ms. The resonance frequency was determined from the peak of each scan. Between scans, the membrane was vibrated at a frequency of 470 Hz, which was higher than the resonance frequency, for 430 ms, the frequency being determined from the previous scan.

[0075] Figure 7 A graph of the overlap function per inhalation in a representative treatment session is shown. For the first 180 inhalations, the overlap function is approximately constant at a low value (mostly below 1000). This indicates that the first and second spectrum are different in these inhalations, because a standing wave is formed in the liquid when the membrane starts to vibrate. Thereafter, the overlap function value rises sharply, indicating that the first and second spectrum become more similar in the 180-190 breaths, i.e. the standing wave effect is disappearing because there is only little liquid left.

[0076] A preset threshold can be used to determine the point at which the reservoir no longer contains liquid. For example, a threshold of 5000 will indicate that the reservoir is empty when the overlap function is below this value. Figure 7It is suitable if the overlap function value is larger than a threshold of a number of consecutive breaths (e.g. three or five breaths). The determination of when the liquid is exhausted can be made more robust by determining that the reservoir is empty alone. This prevents incorrect determinations caused by noise or false measurements in the overlap function.

[0077] Using the first and second spectrum means that the overlap function can be calculated slightly faster than using the subsequent spectra, because the time delay between the first and second spectrum (0.5 s) is smaller than the time delay between e.g. the first and seventh spectrum (3 s). This has the advantage that it is possible to determine earlier when the threshold (2.5 s in this example) has been crossed, so that the vibration of the membrane stops as soon as possible.

[0078] The present invention is particularly suitable for breath-actuated nebulizers, because the vibrator has to be operated intermittently, i.e. only when the patient inhales. By introducing a period in which the vibrator is switched off, it can also be used in nebulizers that are normally operated continuously. The duration of the off period should be at least about 0.5 s, preferably 1 s, in order to allow the liquid to return to the flat surface before the vibration is restarted.

[0079] Figure 7 The overlap function in the equation is obtained by comparing the spectra before and during an aerosol generation period, so the difference between them reflects the formation of the standing wave when the membrane starts to vibrate. In other words, the spectrum obtained during an aerosol generation period is compared with a spectrum obtained during a previous period in which little or no aerosol was generated. However, the overlap function can equally well be obtained by comparing the spectrum obtained during an aerosol generation period with a spectrum obtained during a subsequent period in which little or no aerosol was generated. The difference between the spectra during and after aerosol generation reflects the dissipation of the standing wave when the membrane stops vibrating. This requires that the spectrum is measured a sufficient time after the vibration has stopped. Typically, the time required for the standing wave to dissipate (500-1000 ms) is longer than the time required for it to form (about 50 ms). This is not a problem in breath-actuated inhalers, because the time between inhalations is typically more than 1 second. However, in non-breath-actuated nebulizers, the time during which the membrane does not vibrate needs to be longer to allow dissipation, which will result in a reduction of the total aerosol output rate.

[0080] The present invention is particularly suitable for Figure 1 nebulizers of the type shown in which periodic scans are made to determine the resonance frequency. The method of the present invention can use the spectra from these scans and extract additional information from them. Thus, implementing the present invention requires only some additional spectral analysis and does not require a change in the way the nebulizer is operated.

[0081] The principles of the invention are applicable to any vibrating membrane nebuliser in which a membrane is in contact with a liquid reservoir in which a standing wave can be formed. The invention can therefore be used with other types of nebuliser, for example those described in WO2012 / 046220, WO2015 / 193432, WO2015 / 091356, US2006 / 0102172 and US9027548. These nebulisers do not have a transducer in the form of a hollow tubular body. Instead, the membrane is mounted directly on a piezoelectric element, or there is a ring-shaped planar support member on which the membrane and / or piezoelectric element is mounted.

[0082] The method of the invention can be used instead of or in addition to other empty detection methods (for example those described in US2006 / 0102172, US9272101, WO2014 / 062175 and WO2015 / 091356, which measure changes in an electrical parameter as the volume of liquid decreases over time) to provide a combined decision process for determining whether the membrane is dry. Because the method of the invention relies on a completely different effect to these other methods, it provides completely independent information about whether a liquid is present. The combination of the method of the invention and a different method therefore provides particularly robust empty detection.

Claims

1. A respiratory-actuated inhalation device, comprising an aerosol generator having a vibrator and a membrane, a reservoir for a liquid to be atomized in fluid communication with the membrane, and a controller providing a drive signal to drive the vibrator to vibrate the membrane and generate an aerosol, wherein, The controller is configured to: • The vibrator is driven intermittently so that the aerosol generator repeatedly experiences aerosol generation cycles during patient inhalation and little or no aerosol generation cycles before and / or after inhalation; • Perform a scan in which the membrane vibrates at multiple frequencies, and in which at least one electrical parameter of the vibrator is measured at multiple frequencies to provide a spectrum; wherein the scan is performed during inhalation and during cycles before or after inhalation; • Compare the spectrum obtained during inhalation with the spectrum obtained during a cycle before or after that inhalation; • Based on spectral comparison, determine whether liquid is present in the reservoir; as well as • If the controller determines that there is no liquid, it stops driving the vibrator.

2. The inhalation device according to claim 1, wherein, The controller is configured to perform a first scan before each inhalation to obtain a first spectrum, and then perform a second scan during each inhalation to obtain a second spectrum, and compare the first and second spectra.

3. The inhalation device according to claim 1 or 2, comprising a channel having an air inlet opening and an aerosol outlet opening, and a pressure sensor pneumatically connected to the channel, wherein, The controller is configured to detect a patient's inhalation at the aerosol outlet opening based on a signal from the pressure sensor, and to initiate an aerosol generation cycle in response to such inhalation.

4. The inhalation device according to claim 3, wherein, The controller is configured to initiate a few or no aerosol generation cycles at a preset time after the aerosol generation cycle has been started.

5. The inhalation device according to any one of claims 1 to 2, wherein, The aerosol generator has a support member comprising a hollow tubular body having flanges at or near a first end to which the vibrator is attached and a second end to which the membrane is mounted, and wherein the device includes a filling chamber located above the support member, such that the filling chamber and the hollow tubular body together form the reservoir.

6. The inhalation device according to any one of claims 1 to 2, wherein, The controller is configured to determine the resonant frequency of the aerosol generator from the spectrum and drive the vibrator at the resonant frequency or a frequency associated with the resonant frequency during the aerosol generation cycle other than scanning.

7. The inhalation device according to claim 6, wherein, The plurality of frequencies range from 10 or 15 kHz below the resonant frequency to 10 or 15 kHz above the resonant frequency.

8. The inhalation device according to claim 6, wherein, The frequencies range from 75 kHz to 100 kHz.

9. The inhalation device according to any one of claims 1 to 2, wherein, The controller is configured to compare the spectrum by calculating an overlap function.

10. The inhalation device according to claim 9, wherein, The controller is configured to determine that there is no liquid in the reservoir if the overlap function is higher than a threshold.

11. The inhalation device according to claim 10, wherein, The controller is configured to stop driving the vibrator if the overlap function is higher than the threshold for multiple consecutive cycles generated by the aerosol.

12. The inhalation device according to claim 10, wherein, The controller is configured to stop driving the vibrator if the overlap function is higher than the threshold for three or five cycles of aerosol generation.

Images