Patent Application
20230390507
The present invention relates to a vibrating membrane nebulizer, and in particular to a method for detecting the presence of liquid in contact with the membrane.
Aerosols for medical inhalation therapy generally comprise an active ingredient dissolved or suspended in an aerosolisable liquid (often water). A homogeneous distribution of aerosol droplets with a droplet size of around 5 μm is required in order to reach deep into the lungs.
Vibrating membrane nebulizers are one type of device for producing such aerosols. These devices comprise a vibrator, such as piezoelectric element, which is excited at ultrasonic frequencies in order to induce vibration of a membrane (sometimes called a mesh or aperture plate). The membrane has a large number of holes which typically have a diameter of 1 μm to 10 μm. A reservoir supplies the liquid drug formulation to the membrane. Vibration of the membrane leads to the formation and emission of aerosol droplets of the liquid through the holes.
Continuing to operate a vibrating membrane nebulizer after the liquid reservoir has been emptied can cause the membrane to crack or break. Therefore, it is important to be able to reliably detect the presence of liquid in the reservoir/or in contact with the membrane. When the nebulizer detects that the liquid has been used up, it can turn off the vibrator automatically and/or indicate the end of the therapy session to the patient.
One approach is simply to measure the presence or amount of liquid in the reservoir. For example, US2006/0255174 discloses a nebulizer in which the amount of liquid in the reservoir is sensed by a piezoelectric sensor, an optical sensor, a conductivity sensor or a strain gauge. However, this requires contact between the sensor and the liquid, which can present problems.
An alternative approach exploits the fact that the vibration characteristics of the membrane (e.g. resonant frequency, power consumption etc.) typically are quite different when the membrane is in contact with liquid compared to when it is dry. For example, US2006/0102172 discloses a nebulizer which determines whether liquid is present or not by comparing the detected value of an electrical parameter (such as the current to the piezoelectric element) with a stored value. WO2015/091356 discloses an aerosol delivery device with a membrane, a vibrator and a fluid reservoir. The device operates the vibrator at a plurality of different vibration frequencies, and a sensor measures an electrical parameter of the vibrator at each frequency. The device detects the presence of fluid in contact with the membrane and/or in the fluid reservoir on the basis of the dependence of the values of the electrical parameter on the frequency. However, variations between different membranes and/or changes in the membrane over its lifetime can result in these methods failing to detect that the membrane is dry. If the nebulizer does not correctly determine whether liquid is present in the reservoir, it could continue to vibrate the membrane after the liquid has been used up, or it could turn the vibrator off while liquid still remains.
Thus there remains a need for improved methods for reliably detecting whether the liquid is present in the reservoir and/or in contact with the membrane.
The present inventors have identified an improved method for determining when the liquid to be aerosolized has been used up. In particular, they recognized that light scattering can be used to reliably detect the absence of liquid in contact with the membrane, by detecting the absence of aerosol within the nebulizer. Accordingly, in a first aspect, the present invention provides an inhalation device comprising:
The aerosol generator may comprise a support member on which the vibrator and/or the membrane are mounted. The vibrator may be an annular piezoelectric element. The support member may be a transducer in the form of a hollow tubular portion having a flange at or close to a first end onto which the piezoelectric element is attached, and a second end into or onto which the membrane is mounted. Alternatively, the support member may comprise an essentially planar annulus or disk; in particular the membrane and/or the piezoelectric element may be mounted on opposite sides of the support member.
The optical sensor may operate in the infrared region of the electromagnetic spectrum. The optical sensor may comprise an emitter and a detector that are located on opposite sides of the channel so that the detector detects light from the emitter that is transmitted through the aerosol across the channel.
The controller may be configured (i) to modulate the amplitude of the driver signal at a frequency of from 1 to 100 Hz, (ii) to demodulate the output signal at the same frequency; and (iii) to determine whether aerosol is present in the channel on the basis of the demodulated output signal. The modulation frequency may be from 2 to 70 Hz or 3 to 55 Hz, or 5 to 40 Hz, for example about 10, 20 or 30 Hz. The controller may be configured to modulate the amplitude of the vibration of the membrane with a sinusoidal, saw-tooth or square wave.
The controller may be configured (i) to periodically perform a scan to determine a resonant frequency of the aerosol generator and/or the membrane, during which the membrane generates aerosol at a reduced rate; (ii) to demodulate the output signal at a scanning frequency, such as 2 Hz, that corresponds to the period between scans, such as 0.5 s; and (iii) to determine whether aerosol is present in the channel on the basis of the demodulated output signal.
The controller may be configured to determine the phase difference between the driver signal and the output signal, and thereby to determine the velocity of the aerosol as it passes the optical sensor.
The inhalation device may further comprise a variable flow restrictor which restricts the flow rate of the air and aerosol to a maximum flow rate of about 20 Litres/minute or 18 L/min, such as about 15 L/min. The inhalation device may further comprise a pressure sensor for measuring pressure in the channel, and a signalling device capable of emitting light of varying intensity, and the controller may be configured (i) to receive a signal representing the measured pressure and (ii) to cause the signalling device to emit light of lower intensity the further the measured pressure deviates from a target pressure.
The channel may have an internal volume between the membrane and the optical sensor of less than cm3 for example from 0.5 to 3 cm3 or from 1 to 2 cm3, such as about 1.5 cm3. The channel may be, be part of or comprise, a component that is removable from the rest of the device.
In a second aspect, the present invention provides a method of operating an inhalation device according to the first aspect of the invention, the method comprising:
The method may further comprise: in step a), modulating the amplitude of the driver signal at a frequency of from 1 to 100 Hz; in step b), demodulating the output signal at the same frequency; and in step c), determining whether aerosol is present in the channel on the basis of the demodulated output signal. The modulation frequency may be from 2 to 60 Hz or 3 to 50 Hz, or 5 to 40 Hz, for example about 10, 20 or 30 Hz. The controller may be configured to modulate the amplitude of the vibration of the membrane with a sinusoidal, saw-tooth or square wave.
The method may further comprise: in step a), periodically performing a scan to determine a resonant frequency of the aerosol generator and/or the membrane; in step b) demodulating the output signal at the scanning frequency; and in step c), determining whether aerosol is present in the channel on the basis of the demodulated output signal.
The method may further comprise, if aerosol is present in the channel, determining the phase difference between the driver signal and the output signal, and thereby determining the velocity of the aerosol as it passes the optical sensor.
Nebulizers that detect the presence of aerosol by measuring the amount of light (or other electromagnetic radiation) that is scattered by the droplets are known. For example, US2006/102178 discloses a nebulizer with a mouthpiece having translucent walls, a light transmitter and two light receivers, one for transmitted light and the other for scattered light. With appropriate calibration, the density of the aerosol in the mouthpiece can be determined from the output signals from the receivers. The transmitter may operate intermittently. By subtracting the signal obtained when the transmitter is off from the signal when the transmitter is on, the effect of ambient light can be reduced. US2006/102178 discloses that this method can be used with jet nebulizers or vibrating membrane nebulizers. It does not mention the problem of determining when the membrane becomes dry.
WO2013/042002 discloses a nebulizer that uses a light source and an optical sensor to determine the density of the aerosol by measuring the amount of scattered light. The nebulizer also determines the velocity of the aerosol, by measuring the time delay between the aerosol generator being switched on and the aerosol being detected by the optical sensor. Since the distance from the aerosol generator to the optical sensor is known, the velocity can be calculated. The aerosol generator can be switched on and off in a series of short pulses in order to modulate the average power, and hence the output rate. The nebulizer can be a jet nebulizer, a pressurized metered dose inhaler (pMDI) or a vibrating membrane nebulizer. WO2013/042002 does not mention the problem of determining when the membrane becomes dry.
WO2017/192778 discloses a nebulizer with optical aerosol sensors which measure and detect the presence of droplets within the inhalation channel in order to validate that a dose has been delivered. An LED source emits light which is scattered or absorbed by the droplets, and detected by a photodetector. Multiple light sources and multiple detectors may be used to determine a shape, including a cross-section and length, of the aerosol plume for estimating the ejected mass. However, the nebulizer does not use the detected light signal to determine when the membrane becomes dry. Instead, it monitors changes in the resonance frequency of the membrane.
It has not previously been recognized that this type of optical sensor can be used to reliably detect the absence of liquid in contact with the membrane, by detecting the absence of aerosol within the inhalation channel. In the context of the present invention, the term “optical sensor” means a sensor which detects light, such as visible or infrared light. Similarly, “optical signal” etc. includes both visible and infrared light.
The base unit 100, the mouthpiece 200 and the aerosol head 300 are detachably connectible with one another. The device is assembled by inserting the mouthpiece 200 into the groove 103 in the base unit 100, then placing the aerosol head 300 over the mouthpiece 200 and engaging the key lock member(s) 303 of the aerosol head 300 with the complementary member(s) 104 of the base unit 100 by gentle pressure on both the aerosol head and the base unit. The aerosol generator 301 is positioned in the aerosol head 300 in such a way that when engaging the key lock member(s), the aerosol generator 301 is inserted into the lateral opening 202 of the mouthpiece 200. This creates airtight connections between the aerosol generator 301 and the lateral opening 202 in the mouthpiece as well as 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, the mouthpiece 200 and the aerosol head 300 can be separated by reversing these steps.
The base unit 100 may have one or more indentation(s) 106 whose position may be at or near the groove 103, and the mouthpiece 200 may have one or more positioning member(s) 204. The indentation(s) of the base unit are complementary to (i.e. shaped to receive) the positioning member (s) 204 of the mouthpiece 200. In this context, an indentation is a depression (e.g. a recess, pit, cavity, void, notch or the like) whose “negative” shape is complementary to the “positive” shape of a positioning member (which may be a flange, projection, nose, bulge or the like). Together, such indentations and positioning members act to position the mouthpiece correctly in the base unit. The indentation(s) 106 and the positioning member(s) 204 may be asymmetrical, so as to ensure that the mouthpiece 200 can only be inserted into the indentation 106 of the base unit 100 in one particular manner. This ensures that the device is assembled in such a way that the position and orientation of the mouthpiece 200 and base unit 100 relative to each other are correct. The base unit contains a controller, such as a printed circuit board (PCB) which controls the operation of the nebulizer.
The membrane 309 is positioned at the downstream end 306b of the transducer body 306. The holes in the membrane may be formed by electroforming or by laser drilling, with openings normally being in the range from about 1 μm to about 10 μm. Without vibration of the membrane, the balance of pressures, the shape of the holes and the nature of the material used for the membrane are such that the liquid does not seep out through the membrane. However, vibration of the membrane leads to the formation and emission of aerosol droplets through the holes. The membrane may be made of plastic, silicon, ceramic or more preferably metal, and may be affixed onto or into the downstream end 306b of the aerosol generator 301 by various means, such as gluing, brazing, crimping or laser welding. Optionally, the membrane at least partially forms a dome in its central region, which causes the jet of nascent aerosol droplets to diverge and hence reduces the risk of droplet coalescence.
The piezoelectric element 308 is preferably an annular single or multi-layer ceramic, which vibrates the transducer body 306 in a longitudinal mode. A driver circuit generates the driver signal that excites the piezoelectric element and hence causes the membrane 309 to vibrate, typically at a frequency in the range of 50-200 kHz. The frequency of the driver signal may be chosen to be a fixed offset from the resonant frequency of the aerosol generator, for example 500 Hz below it. Excitation of the piezoelectric element causes micronic longitudinal displacements and/or deformations in a direction parallel to the symmetry axis of the transducer body 306. The transducer body 306 has a region close to the piezoelectric element 308 with a relatively large wall thickness, which serves as a stress concentration zone 306c, and a region downstream thereof 306d with a relatively low wall thickness which serves as a deformation amplification zone. In this configuration, the vibrations or deformations of the transducer body 306 caused by the piezoelectric element 308 are amplified. Preferably, the piezoelectric element 308 is located at the level of, or adjacent to, the stress concentration zone 306c. The internal diameter of the transducer body 306 at the deformation amplification zone 306d may be the same as at the stress concentration zone 306c, so that the differences in wall thickness correspond to different external diameters. Alternatively, the external diameter of the transducer body 306 may be constant, while the inner diameters differ at the position of the two zones.
When the nebulizer is operated, aerosol is generated by the membrane 309 and released into the channel 205 where it is mixed with incoming air from the air inlet opening 201 (via the air inlets and air outlet opening 102 of the base unit). The air and aerosol then flow along the channel 205 and out through the an aerosol outlet opening 203 of the mouthpiece and into the patient's airway. Thus the channel 205 is an inhalation channel which provides the pathway for the air and aerosol to the patient.
Alternatively, it would be possible to use an emitter and detector that operate in a different part of the electromagnetic spectrum, such as visible light. However, using infrared has a number of advantages. Firstly, it is strongly absorbed by aerosols and secondly it cannot distract the patient since it is not visible. This is particularly important if, as described in WO2013/098334, the nebulizer guides the patient by illuminating the mouthpiece with light that increases in intensity as the inhalation approaches the optimal rate.
In reality, the detector would pick up ambient background IR radiation, e.g. from sunlight or room lights, which adds noise to the signal. There are also other external sources of noise, such as deposition of aerosol droplets on the inside of the channel near the emitter and/or the detector, or slight changes in the orientation of the mouthpiece relative to the base unit as it is held by the patient. The noise could cause the detector signal to reach the threshold level while aerosol is still present in the channel, and hence result in the aerosol generator being switched off too early. Moreover, there may be small variances between different nebulizers, for example, in the orientation of the emitter and detector as they are soldered onto their PCBs; or there may be slight changes in the optical properties of the channel (in particular the windows) over time, for example as a result of it being repeatedly subjected to heating in order to sterilize the nebulizer between treatments. Since the threshold value for determining whether aerosol is present in the channel is pre-set, it cannot account for these effects. This could also result in an incorrect determination of when the reservoir becomes empty.
The present inventors have identified a method for eliminating, or at least substantially reducing these effects, so that the signal to noise ratio is increased and the sensitivity and reliability of the empty detection method is improved. This is achieved by modulating the amplitude of the driver signal 40, as shown schematically in
The modulation of the driver signal generates a corresponding modulation in the aerosol output rate from the membrane. This in turn creates a modulation in the aerosol density in the channel, and hence in the output signal from the detector. The modulation adds information to the driver signal, which is carried through to the output signal from the detector. This added information is immune to external influences, such as ambient IR radiation, droplet deposition on the inside of the channel, production variances and changes in the optical properties of the mixing channel over the lifetime of the nebulizer.
Modulation of the amplitude of the driver signal need not cause the aerosol output rate to decrease since the root mean square amplitude of the driver signal can be the same as that without modulation. In other words, lower aerosol output when the amplitude is reduced during modulation is balanced by higher aerosol output when the amplitude is increased during modulation.
The output signal from the detector can be demodulated, for example by digital signal processing, or by an analogue filter (e.g. using electronic components on the detector PCB).
As mentioned above, no external effects are included in the simulated data in
In some vibrating mesh nebulizers, the resonant frequency of the aerosol generator may change during the course of treatment, for example, as the amount of liquid within the reservoir decreases. The frequency of the driver signal may depend on, or be chosen according to, the resonant frequency of the aerosol generator. Consequently, it may be necessary to measure the resonant frequency at intervals throughout operation of the aerosol generator, for example every 0.5 seconds. Typically, in order to determine the resonant frequency, a scan is performed by vibrating the membrane at a series of different frequencies which span the range in which resonance occurs. However, because most of these frequencies are not the optimum driving frequency, the aerosol output rate is inevitably reduced during the period of the scan, which may typically take around 50 ms.
The inherent modulation from the scan could be used instead of the amplitude modulation described above, or in addition to this amplitude modulation as shown in
The modulation of the driver signal can also be used to measure the velocity of the aerosol and the volumetric flow rate. The time that the aerosol takes to travel from the membrane to the optical sensor can be determined by measuring the phase difference between the driver signal and the output signal from the detector. This phase difference can be obtained by cross-correlating the driver and detector signals. The aerosol velocity is then obtained from the calculated time and the known distance between the membrane and the optical sensor. The flow rate can be calculated from the aerosol velocity and the known geometry of the channel.
Using the phase difference to determine the aerosol velocity has the advantage that aerosol generation is not interrupted, so the output rate is not reduced. This contrasts with the method of WO2013/042002 in which the aerosol generator is repeatedly switched on and off to create a series of short bursts in the driver signal, in order to measure the time delay between the start of each burst and the time at which the optical signal decreases as the aerosol droplets arrive at the optical sensor.
The invention can be used in many vibrating membrane nebulizers, for example of the types described in U.S. Pat. No. 9,027,548, WO2012/046220 and WO2015/193432. In these type of nebulizer, the membrane is mounted directly on the piezoelectric element, or has an annular, planar support member on which the membrane and the piezoelectric element are mounted (in contrast to the tubular transducer body described above). However, the invention is especially advantageous in nebulizers of the type described in EP2724741 and WO2013/098334 for a number of reasons.
Firstly, this type of nebulizer is designed to operate with a constant, low flow rate in one direction only. In order to achieve this, it may have a variable flow restrictor that causes less restriction of the flow at a low under-pressure than at a high a under-pressure. Thus, if the patient tries to inhale too hard or fast (i.e. with too much under-pressure), the flow is restricted so that the flow rate does not increase. The nebulizer may be configured to allow the patient to inhale air and/or aerosol through the mouthpiece at an inspiratory flow rate of not more than about 20 L/min, such as from about 10 to 20 L/min, or from about 12 to 18 L/min, such as about 15 L/min. Alternatively, or in addition, the nebulizer may provide the patient with visible, audible or tactile feedback or guidance such as to enable the patient to inhale at the desired inspiratory flow rate. In particular, the nebulizer may provide inhalation effort feedback to the patient by illuminating the mouthpiece with light that increases in intensity as the inhalation approaches the optimal rate. Together, these guide the patient to inhale at a constant, low flow rate. The nebulizer may be breath-actuated, and may have a valve (e.g. just upstream of the air outlet opening of the base unit) which opens and closes at the start and end of each inhalation respectively (for example after a pre-set inhalation time), so that the patient is not able to exhale into the mouthpiece. This ensures that the flow is in one direction only, i.e. towards the aerosol exit aperture.
Secondly, the channel has a small internal volume and is shaped to produce laminar aerosol flow. The internal volume of the channel between the membrane and the optical sensor may be less than 5 cm3 for example from 0.5 to 3 cm3 or from 1 to 2 cm3, such as about 1.5 cm3. In contrast, some vibrating mesh nebulizers have an inhalation channel with a large internal volume, or a chamber in which aerosol is collected. For example, nebulizers which generate aerosol continuously (as opposed to being breath-actuated) may need a large volume in which to store the aerosol that is generated while the patient exhales so that it is not wasted. An inhalation channel which has a large volume between the membrane and the optical sensor would effectively act as a low pass filter for the modulation in the aerosol density. The modulation frequency (˜10 Hz) is too high to pass through a large chamber, and would be averaged to a “continuous” aerosol density. Consequently, the modulation would not be observed in the output signal from the detector. The constant, slow, laminar flow of aerosol past the optical sensor through the small volume channel prevents accumulation of the aerosol. If the aerosol did accumulate in the channel, the modulation of the aerosol density would not be detectable. Moreover laminar flow reduces deposition of the aerosol within the channel, and so reduces a source of noise in the optical signal.
Finally, the channel is part of the mouthpiece component that is detachable from the rest of the nebulizer, and so can easily be made from a material that is transparent to IR and/or visible radiation.
The combination of a slow, one-directional flow rate and a small channel that is separate component is ideal for the method of determining whether there is liquid present on the membrane by measuring a modulated optical signal arising from the aerosol in the channel.
| Number | Date | Country | Kind |
|---|---|---|---|
| 20202253.9 | Oct 2020 | EP | regional |
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/EP21/78627 | 10/15/2021 | WO |
