Compliance Monitoring Module for a Breath-Actuated Inhaler

Abstract

Compliance monitoring module for a breath actuated inhaler, comprising: a micro pressure sensor, the sensor port of which is pneumatically coupled to an air flow path (through which a user can inhale); a processor configured to: receive a signal indicating that a drug has been released from a drug delivery device of the inhaler, receive data from a sensing element of the sensor, and make a decision based on the signal from the drug delivery device and the data from the sensing element that the inhalation of the drug through the air flow path meets one or more predetermined requirements for successful drug delivery; and a transmitter configured to, in response to the decision, issue a dose report.

Description

[0001] This application claims the benefit of U.S. Application Serial No. 62 / 043,120, filed August 28, 2014, entitled Compliance Monitoring Module for a Breath-Actuated Inhaler, the content of which is incorporated herein by reference in its entirety. TECHNICAL FIELD

[0002] The present disclosure generally relates to monitoring patient compliance with the administration of medicaments via an inhaler. More specifically, the present disclosure relates to the use of a micro pressure sensor for compliance monitoring in a breath actuated inhaler. BACKGROUND OF THE DISCLOSURE

[0003] Inhalers or puffers are used to deliver drugs into the human body via the lungs. They can be used, for example, to treat asthma and chronic obstructive pulmonary disease (COPD). Types of inhalers include metered dose inhalers (MDIs), dry powder inhalers (DPIs), and nebulisers.

[0004] Modern breath-controlled nebulisers generally fall into one of two categories: breath enhanced or breath actuated. Breath enhanced nebulisers use the patient's air flow to control the flow of the drug-containing aerosol to the patient. Since the aerosol is continuously generated in these nebulisers, a portion is wasted to the environment. Breath actuated nebulisers use inhalation and / or exhalation detection to use the patient's breath to open and close an aerosol generator. This improves efficiency compared to breath enhanced nebulisers since little (if any) drug is lost to the environment. Detection in breath actuated devices is typically by thermal and / or pressure sensors.

[0005] Regardless of the device used, a common problem faced in respiratory drug delivery is how to monitor patient adherence and compliance.

[0006] Adherence refers to following the patient's prescription label, e.g., taking the prescribed number of doses per day. If the prescription calls for two doses per day and the patient is taking two doses a day, they are considered 100% adherent. If the patient is taking only one dose a day, they are considered 50% adherent. In the latter case, the patient is not receiving the treatment prescribed by their doctor.

[0007] Compliance, on the other hand, relates to how patients use their drug delivery devices. If used in the manner recommended for effective treatment, they are 100% compliant. But if not used properly, they are less than 100% compliant. The use of breath-actuated inhalers involves inhaling in a specific manner; for example, the inhalation may need to be long enough and forceful enough to entrain a full dose of the medicament. For some patients, such as children and the elderly, meeting the requirements for full compliance can be very difficult. But failure to reach 100% compliance reduces the effectiveness of the prescribed medicament.

[0008] When a doctor prescribes a drug, the efficacy of that treatment depends entirely on the patient using their device properly and the appropriate number of times each day. If they do not, the patient is likely to experience no improvement in their condition. Without any tools to verify patient adherence / compliance and faced with a patient whose condition shows no improvement, the doctor may have no choice but to prescribe a stronger dose or even a stronger drug. In some cases, this may put the patient at risk. This could be avoided if the doctor had some way of confirming that the patient actually received the prescribed drug.

[0009] One approach some pharmaceutical companies have followed has been to incorporate cumulative dose counters into their drug delivery products. For example. The dose counter can be triggered by pressing a drive button or opening a cap or lid. Some breath-actuated inhalers include adherence dose counters triggered by opening the aerosol valve, indicating that the patient has inhaled forcefully enough to release a dose of the medicament. While this provides objective evidence to the patient and caregiver that the device has been used, it still does not provide any type of compliance information. There is no way to determine whether the user has inhaled the entire dose, or whether their inhalation was only sufficient to drive the aerosol valve and then they stopped inhaling or reduced the intensity of their inhalation below the level at which the drug can be entrained into the air stream. As such, there is a need for products that provide not only adherence information but also compliance information.

[0010] A spirometer is an instrument used to measure the volume of air inhaled or exhaled by a patient's lungs. A spirometer measures ventilation, the movement of air into and out of the lungs. From the trace known as a spirogram, the output of the spirometer, it is possible to identify abnormal (obstructive or restrictive) ventilation patterns. Current spirometers use a variety of different measurement methods, including pressure sensors, ultrasound, and water gauges.

[0011] For monitoring airflow related to breathing, pressure sensors are the most convenient because pressure information can be used to determine flow, which can then be used to determine volume.

[0012] Pressure sensors for respiratory detection typically measure the differential pressure across the cross-section of an airway through which a patient breathes. This is generally done using two connections, via tubes or other suitable conduits, to connect the sensor to the airway. It is also possible to use a single connection to the airway, with another port open to the atmosphere. If the pressure within the airway is measured before and after airflow is applied, a single-port gauge-type sensor can also be used, and the difference in readings represents the desired pressure drop across the air path resistance. However, the uncertainty associated with the first (no airflow) reading is typically high.

[0013] Regardless of the type of pressure sensor used, pressure sensors are typically connected to a patient's airway using a flexible tube. A drawback of such a system is the possibility of sensor damage related to fluid contaminants in the form of spilled medications or patient secretions (mucus, sputum, etc.). To isolate the pressure sensor from such contaminants, manufacturers often position the pressure sensor a distance away from the measurement site using a flexible tube. However, liquid can still condense in the tube, creating an environment for bacterial growth in an area that is exposed to the patient but generally not accessible for cleaning.

[0014] Another problem with traditional pressure sensors is thermal drift; the phenomenon where pressure readings change over time with changes in local temperature. It is possible to use additional circuitry to compensate for such drift, but this increases cost, volume, and power requirements. Such circuitry can be located within the pressure sensor itself, but considering that the sensor is typically slightly removed from the gas being measured, the detected temperature may not represent that gas. A temperature monitoring circuit can be located on the patient, but this adds additional components, cost, and complexity.

[0015] Yet another problem with traditional pressure sensors is sensitivity to high radio frequency (RF) exposure. This can be a practical problem when operating in close proximity to a radio transmitter (such as a mobile phone). Other potential sources include wireless communication devices such as Wi-Fi routers and cordless phones, and various other forms of information technology (IT) equipment such as wireless network printers. Another problem with some traditional pressure sensors is hysteresis, the magnetic resistance of pressure sensor materials such as diaphragms that return to their original form, shape, or position after deformation. This is observed as a difference in output when crossing the same pressure from different directions (above or below the target pressure). When dealing with very low pressure changes, such an offset can be large enough to mask the signal being measured. Summary of the Invention

[0016] The present description relates to a new compliance monitoring tool that uses a pressure sensor to avoid some or all of the problems described above.

[0017] According to a first aspect, there is provided a compliance monitoring module for a breath actuated inhaler, the module comprising: a micro pressure sensor, the sensor port of the pressure sensor being configured to be pneumatically coupled to a flow channel through which a user can inhale; a processor configured to receive a signal indicating that a drug has been released from a dosing mechanism of the inhaler, receive data from a sensing element of the pressure sensor, and make a decision based on the signal from the dosing mechanism and the data from the sensing element that an inhalation of a drug through the flow channel meets one or more predetermined requirements for successful drug delivery, and a transmitter configured to issue a dose report in response to the decision.

[0018] The micro pressure sensor can be a microelectromechanical system (MEMS) pressure sensor or a nanoelectromechanical system (NEMS) pressure sensor.

[0019] One or more of the predetermined requirements for successful drug delivery may include one or more of the following: an airflow rate exceeding a predetermined threshold; an inhalation duration exceeding a predetermined threshold; an airflow rate at least exceeding a predetermined threshold for a predetermined threshold duration; an overall volume of inhalation exceeding a predetermined threshold; and a peak inspiratory flow (PIF) exceeding a predetermined threshold.

[0020] The module can be configured to be used with an inhaler that includes means for initiating a user-driven dosing mechanism and means for releasing a breath-actuated medicament.

[0021] The signal from the dosing mechanism can be sent in response to the initiation of the user-driven dosing mechanism.

[0022] The transmitter can be wireless.

[0023] The pressure sensor can be a MEMS barometric pressure sensor. The sensor can be a piezo-resistive or capacitive MEMS pressure sensor.

[0024] Any two or more of the pressure sensor, the processor, and the transmitter may be included in a single integrated circuit or a System on Chip (SoC).

[0025] The module may further include the airflow channel, with the pressure sensor positioned inside the airflow channel, and the pressure sensor may optionally be positioned in a recess in the inner wall of the airflow channel.

[0026] The module may further include the airflow channel, with the pressure sensor positioned outside the airflow channel, and the sensor port is pneumatically coupled to the airflow channel via an opening in the wall of the airflow channel.

[0027] The module may further include a seal arranged to pneumatically couple the sensor port to the opening, at least a portion of the seal may optionally be clamped between the pressure sensor and the wall, and at least a portion of the seal may optionally extend from the outer surface of the wall to the surface on which the pressure sensor is mounted so as to encapsulate the pressure sensor in a pneumatic chamber adjacent to the wall.

[0028] The wall and the seal may be made by a two-shot moulding process.

[0029] The module may further include a thermally conductive gasket clamped between the pressure sensor and the wall. The thermally conductive gasket may optionally act as a seal.

[0030] The module may further include an air-permeable and water-impermeable filter separating the sensor port from the airflow channel.

[0031] The pressure sensor may include a metal housing.

[0032] The module may be configured to be fixed to the main housing portion of the inhaler (the topmost in use) after sterilizing one or more of the main housing portions.

[0033] The processor may be included in the pressure sensor.

[0034] The module may further include a data buffer configured to store data received from the sensing element of the pressure sensor. The data buffer may optionally be included in the pressure sensor. The data buffer may be configured to store data equivalent to one inhalation / exhalation waveform. The data buffer may be a First-In-First-Out (FIFO) data buffer.

[0035] The module may further include an additional MEMS barometric pressure sensor configured to monitor ambient barometric pressure activity.

[0036] The transmitter may be included in a transceiver configured to communicate data from and / or to a pressure sensor. The transmitter may be wireless. The wireless transmitter may be Bluetooth TM subsystem, optionally Bluetooth TM Low Energy (BLE) integrated circuit or system-on-chip (SoC).

[0037] The pressure sensor and / or the transmitter may be mounted on a printed circuit board (PCB).

[0038] The module may further include a battery, optionally a button cell, arranged to supply power to the pressure sensor.

[0039] The pressure sensor may have a sensitivity of 20 pascals or less.

[0040] The pressure sensor may include a sensing element. The processor may be configured to interrogate the sensing element at a frequency greater than or equal to 100 Hz.

[0041] The module may further include a control means for switching on and / or waking up the pressure sensor from a low power state.

[0042] The control means may be activated by movement of a yoke attached to a mouthpiece cover such that opening of the mouthpiece cover causes the yoke to move in a manner that activates the control means.

[0043] The control means may be a mechanical switch, an optical sensor, an accelerometer or a Hall effect sensor.

[0044] The processor may be configured to respond to the control means which switches on and / or wakes up the pressure sensor by obtaining a tare reading from the sensing element and subsequently using the tare reading to correct data received from the sensing element.

[0045] The processor may be configured to determine a dynamic zero point from a moving average of measurements made by the pressure sensor and dynamically correct the pressure sensor according to the dynamic zero point.

[0046] The processor may be configured to filter out electrical noise inherent in the pressure sensor and / or environmental anomalies in data received from the sensing element of the pressure sensor.

[0047] The module may further include a temperature sensor optionally integrated with the pressure sensor. A processor optionally included in one of the pressure and temperature sensors may be configured to apply temperature compensation determined from data received from the temperature-sensing sensing element to data received from the sensing element of the pressure sensor.

[0048] The inhaler may further include a mouthpiece, and the sensor port is pneumatically coupled to an air flow passage in pneumatic communication with the mouthpiece.

[0049] According to a second aspect, there is provided a breath actuated inhaler including the module of the first aspect.

[0050] According to a third aspect, there is provided an inhaler accessory including the module of the first aspect, which is configured to be connected to an inhaler such that the sensor port is pneumatically coupled to an air flow passage in pneumatic communication with the mouthpiece of the inhaler.

[0051] According to a fourth aspect, there is provided a method of monitoring patient compliance with drug administration via a breath actuated inhaler, the method including receiving a signal from the drug delivery device of the inhaler indicating that a drug has been released; a micro pressure sensor, the sensor port of the sensor being pneumatically coupled to an air flow passage through which a user can inhale; detecting a pressure change at the sensor port; receiving data from the sensing element of the sensor; making a determination, based on the signal from the drug delivery device and the data from the sensing element, that an inhalation of breath containing the drug through the air flow passage meets one or more predetermined requirements for successful drug administration; and in response to the determination, sending a drug administration report.

[0052] The micro pressure sensor may be a microelectromechanical system (MEMS) pressure sensor or a nanoelectromechanical system (NEMS) pressure sensor. The MEMS pressure sensor may be a MEMS barometric pressure sensor. The sensor may be a piezoresistive or capacitive MEMS pressure sensor.

[0053] One or more of the predetermined requirements for successful drug administration may include one or more of the following: a flow rate exceeding a predetermined threshold; an inhalation duration exceeding a predetermined threshold; a flow rate exceeding a predetermined threshold for at least a predetermined threshold duration; an overall volume of inhalation exceeding a predetermined threshold; and a peak inspiratory flow (PIF) exceeding a predetermined threshold.

[0054] The method may further include: monitoring ambient barometric pressure activity using an additional MEMS barometric pressure sensor; and calibrating the sensor having a sensor port pneumatically coupled to the air flow passage adjacent to the additional sensor.

[0055] The method may further comprise turning on the sensor or waking up the sensor from a low power state; in the sensor in response to being turned on or woken up, obtaining a tare reading from the sensing element of the sensor; and subsequently using the tare reading to correct the data received from the sensing element.

[0056] The method may further comprise: determining a dynamic zero point from a moving average of the measured values through the sensor; and dynamically correcting the pressure sensor according to the dynamic zero point.

[0057] The method may further comprise applying temperature compensation to the data received from the sensing element of the pressure sensor by using the data received from the sensing element of the temperature sensor.

[0058] The method may further comprise storing the data received from the sensing element of the sensor in a data buffer. The data may correspond to an inhalation / exhalation waveform.

[0059] The transmission may be wireless. The wireless transmission may use the Bluetooth TM protocol, and optionally, the Bluetooth TM Low Energy (BLE) protocol.

[0060] The method may further comprise testing the processing program of the sensing element of the sensor at a frequency greater than or equal to 100 Hz.

[0061] The method may further comprise filtering out the inherent electrical noise and / or environmental anomalies in the data received from the sensing element of the sensor.

[0062] The method may further comprise determining the volume of air inhaled or exhaled by the user of the inhaler from the data sensed by the sensing element of the sensor.

[0063] According to a fifth aspect, there is provided a computer program product comprising instructions for execution by a computer processor to perform the method of the fourth aspect.

[0064] According to a sixth aspect, there is provided a compliance monitoring module substantially as described herein, with reference to the accompanying drawings.

[0065] According to a seventh aspect, there is provided an inhaler substantially as described herein, with reference to the accompanying drawings.

[0066] According to an eighth aspect, there is provided an inhaler accessory substantially as described herein, with reference to the accompanying drawings.

[0067] According to a ninth aspect, there is provided a method substantially as described herein, with reference to the accompanying drawings.

[0068] According to a tenth aspect, there is provided a computer program product substantially as described herein, with reference to the accompanying drawings. BRIEF DESCRIPTION OF THE DRAWINGS

[0069] Embodiments of the present invention will now be described with reference to the accompanying drawings, in which:

[0070] Figures 1 to 5 Illustrates an exemplary apparatus of a micro pressure sensor for respiratory detection with respect to an air flow path.

[0071] Figure 6 Is a schematic diagram of an exemplary sensor electronic component.

[0072] Figures 7 to 13 illustrate exemplary configurations of the compliance module in an inhaler.

[0073] Figure 14 Is a flowchart illustrating an exemplary compliance monitoring method.

[0074] Figure 15 Is a flowchart illustrating an exemplary user device interaction.

[0075] Figure 16A And 16B Is a graph showing test data. DETAILED DESCRIPTION

[0076] The elements shown in the figures are not drawn to scale and are merely for illustrative purposes. The same elements are denoted by the same reference numerals.

[0077] In addition to differential (two port) type pressure sensors and single port metering sensors, using separate measurements made before and after use, as discussed above, absolute or barometric pressure sensors are available. Barometric pressure sensors reference a vacuum. They are sometimes referred to as altimeters because altitude can be inferred from barometric pressure readings. This type of sensor is generally not considered for respiratory detection because of their extremely wide measurement range (20 to 110 kPa) and very low resolution. Considering how typical respiratory properties can produce pressure changes of only about 0.2 kPa, this would require operating the sensor over an extremely narrow portion of its operating range.

[0078] However, with miniaturization, including the introduction of MEMS and NEMS technologies, many improved sensors are now available. Typical MEMS barometric pressure sensors can operate from 20 kPa to 110 kPa and can detect air flow velocities of less than 30 lpm (liters per minute) when pneumatically coupled to an air flow path with a known air flow resistance.

[0079] Using a barometric pressure sensor can enable the barometric pressure to be used as a baseline throughout the measurement period, thereby resolving the uncertainty of other single port methods.

[0080] Also, knowing the local air pressure can provide some understanding of a patient's lung function. It is suspected that changes in atmospheric pressure, such as those associated with approaching storm fronts, may have an impact on a patient's breathing and may even be associated with asthma and COPD events.

[0081] The pressure sensors are already in a stress state and have an integral reference port sealed in a vacuum device. This means they have low hysteresis in the area of interest.

[0082] Due to the extremely small size and mass of their sensing elements, MEMS sensors are able to respond to extremely small pressure changes. Some are able to resolve pressure changes as low as 1 Pa.

[0083] MEMS pressure sensors can include all the necessary analog circuitry in the sensor package. Temperature compensation and / or digital interfaces can also be integrated with the pressure sensor.

[0084] For example, the Freescale MPL3115A2 MEMS barometer / altimeter chip (pressure sensor) is digital and uses an I 2 C interface to communicate pressure information to the host microcomputer.

[0085] MEMS pressure sensors can be packaged in metal. This provides RF shielding and good thermal conductivity for temperature compensation.

[0086] MEMS pressure sensors are also low-cost, exhibit low power consumption, and are very small. This makes them particularly suitable for use in portable and / or disposable devices, which can be powered, for example, by a battery (such as a button battery).

[0087] The small size of MEMS pressure sensors makes them easy to incorporate into existing inhaler designs. They can also be easily incorporated into or near the mouthpiece to more accurately measure the pressure changes caused by a patient's inhalation or exhalation.

[0088] Micro air pressure sensors can be directly connected to a patient's airway simply using a small hole leading to the air passage, which does not require any type of tubing. This minimizes the possibility of moisture condensation and potential bacterial growth associated with flexible tubing. An internal seal, such as a gel seal, can be included to protect the sensor element from contamination.

[0089] An embodiment of this type of device is shown in Figure 1Inside. The micro pressure sensor 110 is placed against the air flow path 120 (through which the patient breathes). The air flow is substantially axial as indicated by arrow 130. The sensor port 111 is sealed and aligned with the opening 121 in the air flow path wall 122 via a pneumatic (sealed) seal 140. (Note that the seal does not need to be perfectly airtight as long as there is a pneumatic connection between the sensor port and the air flow path). The sensor port 111 optionally includes a filter, such as a filter that allows air to pass through but not water.

[0090] The air flow path and the seal can be made by a two-shot molding process. The pressure sensor 110 can be mounted on a printed circuit board (PCB) 150 to provide connections to a power supply and other electronic components.

[0091] Rather than positioning the seal 140 around the passage between the opening 121 and the sensor port 111, the entire micro pressure sensor can be encapsulated in a chamber adjacent to the air flow path, as Figure 2 illustrated. The pneumatic seal 240 is located outside the footprint of the sensor and extends from the outside of the air flow path wall 222 to the surface 250 on which the sensor 210 is mounted (e.g., the component surface of the PCB). Figure 2 Shows a cross-section; the pneumatic seal 240 surrounds the perimeter of the sensor 210, whether it is circular, square, rectangular, or any other shape. The seal 240, the sensor base 250, and the air flow path wall 222 thus form a chamber that is pneumatically isolated from the external environment (except for the air flow path at the opening 221). The pressure at the sensor port 211 thus equilibrates with the pressure in the air flow path at the opening 221.

[0092] Since MEMS sensors with built-in temperature compensation are available, there may be no need for the use of an external thermal sensor. The compensation can be provided exactly at the measurement site, increasing the accuracy of the compensation. MEMS sensors with built-in temperature compensation can also act as a compact respiratory thermometer, providing further information to the patient and / or their caregiver. If the housing of the sensor is metallic, then not only the sensitive internal circuitry is isolated from RF fields (e.g., RF fields associated with mobile phones or nearby interference), but also the sensor will quickly equilibrate with the local temperature to provide optimal temperature compensation.

[0093] In Figure 1 and 2 's embodiments, the micro sensor is separated from the air flow path wall by an air gap. To improve the ability of the micro sensor to quickly detect changes in the temperature of the air flow path, a thermally conductive pad can be used, as Figure 3 shown. ( Figure 3 In other respects similar to Figure 2)。

[0094] In Figure 3 an exemplary device, a thermal interface material 360, such as a silicone type for transistor heatsinks, is provided between the housing (optionally metal) of the microsensor 310 and the air flow channel wall 322. The larger the adjacent area covered by the interface material, the faster the temperature equilibrium. The interface material 360 can thus substantially cover the entire surface of the sensor 310 facing the air flow channel wall 322.

[0095] Figure 4 An exemplary device is shown where the thermal interface material 460 is made of an air-impermeable material that deforms to the surface profile between the sensor 410 and the air flow channel 422 (which it compresses). It thus provides excellent thermal connection while acting as a pneumatic seal, eliminating the need for a separate sealing element.

[0096] An alternative to positioning a sensor adjacent to an air flow channel is to place the entire sensor within a low-pressure air passage of the device being monitored, as Figure 5 illustrated. For example, the sensor can be placed within a DPI housing or within the 'boot' of a pressurized MDI (pMDI). (The term 'boot' refers to the body of an inhaler that typically holds a canister of medication.) In this device, the sensor truly measures the pressure (and optionally temperature) of the air passage itself, providing improved accuracy. Thus, there is no need for any sealing element to create a pneumatic conduit between the air flow channel 520 and the sensor port 511, nor is there a need for any thermal interface material to assist with temperature equilibrium between them. It is also not necessary to provide a sensor with any inlet to an external pressure environment (for reference purposes) since the reference is already built into the sensor itself in the form of a vacuum reference.

[0097] In Figure 5 an embodiment, a micro pressure sensor 510 is mounted inside the air flow channel wall 522, optionally via a PCB 550. The air flow channel wall 522 can include a recess 523 in which the sensor 510 is positioned (as shown) to reduce disruption to the air flow indicated by 530. For example, the depth of such a recess 523 can be substantially equal to the thickness of the sensor 510 such that for both sides of the sensor 510, the surface of the sensor including the sensor port 511 is flush with the inner surface of the air flow channel wall 522. The recess 523 can be a large cutout of the wall 522 or a portion of the wall that extends radially outward relative to the remainder, as shown.

[0098] It should be noted that due to their small size, MEMS pressure sensors can be used to monitor patient airflow through, for example, nebulizers, DPIs or pMDIs, thus facilitating low-cost compliance monitoring, in addition to / instead of adherence monitoring, the confirmation of which drives the device. The compliance monitoring can be performed using an auxiliary device that is coupled to the dosing device through a small hole leading to the airway being monitored (or in the dosing device itself). The small size, high performance and low cost of MEMS sensors make them ideally suited for such applications where size and weight are major considerations for the user (who may have to carry their inhaler with them at all times).

[0099] If the output from the micro pressure sensor is digital, all low-level signal processing can be performed in the sensor, protecting it from external interference. This makes it possible to work with signals of around a few tens of Pascals without the difficulties that many traditional sensors with external circuitry would challenge.

[0100] Figure 6 The illustration shows some of the electronic components of an exemplary micro air pressure sensor. The sensing element 601 passes an analog signal to an analog-to-digital converter (ADC) 602. The digital output signal of the ADC 602 is then averaged over multiple cycles by a rolling average filter to reduce noise. Various averages can be selected under program control to balance noise against response time.

[0101] As an example, block 603 represents a means of selecting one of eight different oversample (i.e., filter) ratios for output at 604. The fastest response is associated with OSR = 1, but this is also the noisiest setting. Conversely, OSR = 128 introduces the least noise, but has the slowest response. The optimal setting can be selected according to the specific application. With the OSR set to 16, the output is clear enough for most breathing applications and the update time is fast enough.

[0102] For example, in order to record a patient's airflow properties, it may be desirable to create a waveform related to the real-time fluctuations of the pressure detected by the sensor. If one were to create such a waveform from single readings of the sensor each time, as new data becomes available, due to the latency associated with each tap, the resulting waveform would exhibit blocky artefacts rather than a smooth waveform. However, by manipulating the ADC 602 at an appropriate frequency (e.g., approximately 100 Hz) and reading the data at the same rate, the data representing each tap is further averaged, resulting in a smoother waveform.

[0103] The averaged output is then passed to a circular first-in, first-out (FIFO) buffer (not shown) for storage until the data can be processed by a processor integrated in the device via a connection, or transmitted for offloading processing. Such a FIFO buffer can, for example, store a number of samples approximately equal to or slightly larger than a typical respiratory waveform to ensure that the entire inhalation / exhalation properties can be captured. In cases where the waveform does not need to be real-time, using the buffer reduces the need for the serial port of the sensor. With the addition of a communication system, it is possible to monitor patient adherence and compliance and convey such information, including, for example, the patient's airflow properties, to a user device such as a smartphone or tablet. Optionally, the data from the user device can be communicated to a caregiver's device, such as a doctor's personal computer (PC). This can be done using a wired connection, for example, via a Universal Serial Bus (USB) port. Alternatively, using wireless technology, it is possible to communicate the results to the outside world without interfering with the product inside the enclosure in any significant way. Suitable wireless technologies can include, for example, WiFi technology (e.g., IEEE 802.11), Medical Body Area Network (MBAN) technology (e.g., IEEE 802.15), Near Field Communication (NFC) technology, mobile technology (e.g., 3G), and Bluetooth TM technology (e.g., Bluetooth TM Low Energy (BLE)). A wireless transceiver, for example in the form of a BLE chip, can be connected to or integrated with the micro sensor.

[0104] Such wireless connectivity can be used, for example, to report device actuations and / or sensed inhalations with date and time stamps in real time. This data can be processed externally and if the result of such processing is that a prescription should be refilled, an alert can be sent to the patient and / or caregiver and / or pharmacist. The alert can be provided via one or more user interfaces of the inhaler (such as an LED and / or buzzer) or via text message or email. As another example, a reminder can be sent to the patient and / or caregiver if a dosing report is not received within a predetermined period after a scheduled dosing time. An alert can also be generated if, for example, the usage frequency exceeds a safety threshold. The compliance module can communicate directly or indirectly with one or more of the following: a user device of the patient or caregiver (such as a mobile phone, such as a smartphone, tablet, laptop, or desktop computer), such as a server of a health service provider or an inhaler or drug manufacturer or distributor, or a cloud storage system. Such communication can be via a network, such as the Internet, and may involve a dedicated app, such as on the patient's smartphone.

[0105] Compliance monitoring tools (such as one or more sensors, such as a device actuation sensor such as a mechanical switch that detects adherence and compliance reporting tools, such as a micro pressure sensor that detects sufficient air flow for proper dose delivery) and compliance reporting tools (such as a wireless transmitter or a wired output port) can be included in a single module. This module can be sold as a separate inhaler accessory / upgrade for attachment to an existing or slightly modified inhaler design. Alternatively, the compliance monitoring module can be incorporated into the inhaler during the manufacturing process. It is not required that all components of the compliance monitoring module be included in a single physical unit, although this can be the case. In the case of an inhaler accessory version, the module can consist of one or more connectable units. In the case of the module being incorporated into the inhaler, the individual components can be located in any suitable position within or on the inhaler and do not require any further assembly or connection than is required for them to operate.

[0106] Sensors can be used, for example, in the types of breath actuated dry powder inhalers described in PCT patent application publication numbers WO 01 / 97889, WO 02 / 00281, WO 2005 / 034833, or WO 2011 / 054527. These inhalers are configured such that inhalation by the user through the mouthpiece causes an air flow through the device to entrain the dry powder medicament. Inhalation also causes another air flow to enter the inhaler from the outside. The inhaler includes a vortex chamber and chamber walls in which the two air flows collide, and the chamber walls are used to break up the agglomeration of the dry powder medicament for more effective delivery.

[0107] These inhalers include a dose counting device for determining that a large dose of powder entering the dosing chamber from a hopper has been metered after being activated by a user. The dose counting system includes a pawl that is movable along a predetermined path during the metering of the pharmaceutical dose to the mouthpiece by the dose counting system. The dose counter includes a bobbin, a rotatable spool, and a rolled ribbon received on the bobbin that is rotatable about the axis of the bobbin. The ribbon has markings thereon that extend continuously between a first end of the ribbon secured to the spool and a second end of the ribbon placed on the bobbin. The dose counter also includes teeth that extend radially outward from the spool into the path of a predetermined pawl so that the spool is rotated by the pawl and the ribbon travels on the spool during the metering of the dose to the mouthpiece.

[0108] However, these inhalers do not include any means for determining whether the dose has been successfully administered. Adding a micro pressure sensor anywhere in the air flow path through the inhaler or anywhere in fluid communication with the air flow path enables compliance monitoring because such a micro sensor can collect sufficient data to indicate whether the patient is inhaling in an appropriate manner (e.g., with sufficient effort and for sufficient duration) to receive the full dose of the pharmaceutical.

[0109] Combined with an indication from the dose metering system of the availability of a large dose of the pharmaceutical prior to inhalation for the air flow path through which the patient inhales, this information is sufficient to confirm that the dose has been successfully administered.

[0110] The signal can be obtained from the dose metering system in any convenient manner. For example, an electronic switch can be arranged so that it is actuated by the movement of the pawl or the rotation of the spool. This switch can be connected to the input circuitry of a processor so that the processor receives an electronic pulse when the dose is metered.

[0111] Figures 7 to 9 illustrate a detailed description of how the compliance module can be integrated in such an inhaler.

[0112] Figure 7 illustrates an embodiment in which a PCB 750 carries a MEMS pressure sensor and, optionally, a processor and a transmitter are incorporated into the housing of an inhaler 700 proximate to the mouthpiece 770. In Figure 7A which, the mouthpiece 770 is hidden by a lid 780. In Figure 7BIn [the device], the lid 780 is pulled down to expose the suction port 770. The lid 780 is connected to the yoke 790 such that when the lid 780 is shaken downward, the suction port 770 is exposed, and pulling the yoke 790 downward closes the tactile switch 795. When the switch 795 is closed, an electrical connection is formed between the PCB 750 and the battery 755 (such as a button battery) so that the PCB 750 is powered only when the suction port lid 780 is open. This helps conserve battery power when it is needed. Alternatively, the PCB 750 can be constantly connected to the battery 755, but closing the switch 795 (or activating some other switching means, e.g., an optical sensor, an accelerometer, or a Hall effect sensor) can wake up the PCB 750 from a power-saving sleep mode.

[0113] Figure 8 shows an alternative device. Similar to the embodiment shown in Figure 7, the suction port 870 is exposed by swinging the lid 880 downward (which causes the yoke 890 to be pulled down). However, in this embodiment, the PCB 850 (which still carries the MEMS pressure sensor, and optionally, a processor and a transmitter) is incorporated into the middle part of the inhaler 800 housing. The yoke 890 is formed in an "n" shape to be on the left, right, and above the PCB when the inhaler 800 is oriented for use (with the suction port remaining horizontal at the downward end). Figure 8B Shows an enlarged view of the PCB and the yoke when the lid is closed. Figure 8C Shows a similar view when the lid is open. In Figure 8C [the device], the horizontal portion of the yoke 890 is pulled down to close the tactile switch 895. Similar to the embodiment in Figure 7, when the switch 895 is closed, an electrical connection is formed between the PCB 850 and the battery 855 (such as a button battery) such that the PCB 850 is powered only when the suction port lid 880 is open. Alternatively, the PCB 850 can be constantly connected to the battery 850, but closing the switch 895 (or activating some other switching means, e.g., an optical sensor, an accelerometer, or a Hall effect sensor) can wake up the PCB 850 from a power-saving sleep mode.

[0114] A further alternative device is shown in a partially disassembled form in Figure 9Similar to the embodiments shown in FIGS. 7 and 8, the suction opening 970 is exposed by swinging the lid 980 downwardly, which causes the yoke 990 to be pulled down. However, in this embodiment, the PCB 950 (which still carries the MEMS pressure sensor, and optionally, the processor and transmitter) is incorporated into the top of the inhaler 900 housing. The collar 997 around the PCB 950 is fixed on top of the yoke (not shown) near the end of the manufacture of the inhaler 900. This can be done after the inhaler housing part has been sterilized. This is advantageous because the sterilization process would damage the sensitive electronics on the PCB 950. In this embodiment, the yoke 990 is configured to lift when the suction opening lid 980 is opened. This pushes up the horizontal top of the yoke 990 (which is similar to that shown in FIG. 8) to close the tactile switch 995. Similar to the embodiments of FIGS. 7 and 8, when the switch 995 is closed, an electrical connection is formed between the PCB 950 and the battery 955 (such as a button cell), such that the PCB 950 is only powered when the suction opening lid 980 is open. Alternatively, the PCB 950 can be connected to the battery 955 all the time, but closing the switch 995 (or activating some other switching means, e.g., an optical sensor, an accelerometer or a Hall effect sensor) can wake up the PCB 950 from a power saving sleep mode.

[0115] Indicator light emitting diodes (LEDs) visible through a (optionally colored) window or light guides 952 shown on the outside of the inhaler 900, preferably in a position visible to the user during administration, can also be powered by the battery 955 and can be controlled by a processor on the PCB. By indicating, for example, with different color and flash combinations that, for example, the suction opening lid is open (and thus the inhaler is activated for administration) and / or it is time to refill the prescription and / or (processed according to the pressure sensor readings) the administration is completed / has not been completed yet, the LEDs 952 can be used to provide information to the user and / or caregiver.

[0116] Another alternative device is shown in FIG. 10. In this case, the yoke 1090 connected to the hinged suction opening cap (not shown) carries a bellows 1091 made of a partially compliant material.

[0117] Figure 10A The position of the bellows when the cap is closed is shown. The feet of the spring arm 1092 are received in recesses 1093 in the upper wall of the bellows. The bottom of the recess 1093 thus pushes against the lower surface of the feet such that the spring arm is deflected upwardly. This causes the head of the spring arm 1092 to close the switch 1095, which keeps the PCB 1050 in the sleep mode.

[0118] Figure 10AShows the start of the device as the yoke 1090 and bellows 1091 are thus moved slightly upward when the cap is opened. The spring arm 1092 remains in contact with the switch 1095, and the compliant bellows material relieves any additional tension that would otherwise open the switch as the bottom of the recess 1093 bends to take up the tension.

[0119] Figure 10C Shows the device when the cap is fully open. The yoke 1090 and bellows 1091 move downward away from the spring arm 1092, which relaxes downward away from the switch 1095. The switch 1095 is thus opened, waking up the PCB 1050.

[0120] Optionally, a setscrew may be included to adjust the contact between the switch and the spring arm.

[0121] As another example, a sensor may be used in a respiratory-driven pressurized aerosol inhaler of the type described in PCT patent application publication numbers WO 01 / 93933 or WO 92 / 09323. These inhalers include means for releasing a measured dose of medicament, the release means including means for initiating the device by applying a preload that can drive the delivery means, means for applying an aerodynamic resistance that can prevent the delivery means from driving, and a release means that can release the aerodynamic resistance to allow the preload to drive the delivery means and dispense the medicament. The aerodynamic resistance can be established by means including, for example, a diaphragm, a piston cylinder, a bellows, or a spring. Inhalation through a valve or through a vane mechanism allows the preload to drive the aerosol valve to release the medicament. While adherence can be monitored for such inhalers by determining when the device is initiated and / or when the aerosol valve opens, they do not include any means for determining whether the user has inhaled the entire dose. Again, introducing a MEMS barometric pressure sensor at any location in the air flow channel through the inhaler or at any location in fluid communication with the air flow channel, in combination with means for determining when the device has been initiated and / or when the aerosol valve opens, enables adherence monitoring to be carried out.

[0122] Initiating the device can cause a preload to be applied to the delivery means and a load to be applied to an electronic switch. This switch can be connected to the input circuit of a processor such that when the device is initiated, the processor receives an electronic pulse. Alternatively or in addition, the electronic switch can be arranged to be driven by the movement of the aerosol valve or a valve or vane mechanism preceding the aerosol valve. This switch can be connected to the input circuit of a processor such that when the aerosol is released into the air flow channel (through which the patient inhales), the processor receives an electronic pulse. The switch can be, for example, mechanical, optical, proximity-based, or an accelerometer.

[0123] Figures 11 to 1 Figure 3 illustrates how the compliance module can be integrated in such an inhaler.

[0124] Figure 11 It shows the compliance module 1150 located at the bottom of the inhaler 1100.

[0125] Figure 12A , B, and C show the compliance module 1250 located at the top, middle part, and bottom of the back of the inhaler 1200, respectively.

[0126] Figure 11 The compliance modules of FIGS. 11 and 12 can be incorporated during the manufacturing process of the inhaler or can be optional accessories that can be later fixed onto the inhaler. That is, the modules can be connected (optionally reversibly) to the inhaler via a fixing tool and be in fluid communication with the interior of the inhaler and thus with the air flow passage via small holes in one or more of the inhaler housings.

[0127] Figure 13 illustrates how the compliance module 1350 can be incorporated into the top of the inhaler. Figure 13A It shows the default position of the retainer ring 1390. Pushing up the tactile switch 1395 turns it on. With the switch 1395 on, there is no electrical connection between the compliance module 1350 and the battery 1355 (such as a button battery). Figure 13B It shows the position of the retainer ring 1390 when the inhaler is activated for use. The retainer ring 1390 is lowered relative to the switch 1395 to turn it off so that the compliance module 1350 is powered.

[0128] Figure 13C illustrates Figure 13A the final stage of the manufacture of the inhaler shown in FIGS. 13A and 13B. The compliance module 1350 is lowered onto the inhaler housing and then the cap 1398 is fixed in place. As in the Figure 9 embodiment of FIGS. 13C and 13D, an LED indicator 1352 can be provided.

[0129] It should be noted that since the MEMS barometric pressure sensor response varies with the ambient air pressure over time, attention should be paid to the raw readings on which any subsequent analysis of the sensor output signal is based. An auto-zero reading (i.e., the tare weight) can be performed immediately before monitoring any inhalation signal. Although it is possible for this value to change over time in response to local ambient air pressure changes, it is not expected to cause any problems if the treatment is completed within a few minutes. Alternatively, a second barometer chip can be used to record the barometric activity, allowing the main chip to be dedicated to breath detection.

[0130] The point at which drug administration is completed (where the vital capacity reaches its peak) may correspond to the point at which the airflow reverses direction. Thus, when the data from the pressure sensor indicates that the airflow direction has reversed, the processor may make a decision that drug administration is complete.

[0131] Not all processing needs to be done by the module. Any or all of the processing can be handed over to an external data processing device. A wireless solution (such as including a BLE module) can be used to send the patient's airflow properties to an app, which can then calculate specific breathing parameters. The inhaler can thus hand over the processing required for such tasks to, for example, a smartphone processor. This would facilitate the smallest possible form factor for the inhaler. A further advantage of this approach is that the software running on the smartphone can be more easily replaced than the software running on the inhaler.

[0132] Figure 14 A flowchart illustrating an exemplary compliance monitoring method. In step 1410, the user activates their inhaler for use, for example by pressing a button or opening the mouthpiece lid. In 1420, the user begins to inhale through the mouthpiece of the inhaler. In 1430, the processor of the compliance module receives a dose release signal. This signal may have been transmitted by the drug delivery device in response to the activation of the inhaler in 1410 or in response to a pressure sensor or other device that senses that inhalation has begun. For example, inhalation may cause a valve to open, and the opening of the valve causes the release of the medicament into the airflow passage (through which the user is inhaling) and drives an electronic switch to trigger the dose release signal. In 1440, the MEMS pressure sensor detects a change in pressure in the airflow passage. In 1450, the processor receives the data from the sensor. In 1460, the processor determines from the sensor data that one or more predetermined requirements for successful drug administration have been met. For example, the sensor data may indicate that the airflow velocity in the inhalation direction in the airflow passage exceeds a predetermined threshold for at least a predetermined threshold duration. Alternatively, the sensor data can be processed such that the airflow velocity is integrated over the time period during which the sensor detects inhalation to determine the total inhalation volume, and this volume can be compared to a predetermined minimum volume for successful drug administration. In 1470, a drug administration report is transmitted in response to the processor's decision, for example via a wireless transmitter or via a wired output.

[0133] Figure 15It is a flowchart that describes exemplary control logic for indicating compliance data of a breath-actuated inhaler for a user and an external entity. The implemented inhaler is equipped with an indicator LED, a buzzer, and a wireless transmitter. It also has a cap connected to the dosing device such that opening of the cap activates the inhaler by making a large dose of medicament available to an air flow path (through which the user can then inhale). To make the next dose available, the cap must be closed and then opened again. A MEMS pressure sensor is arranged to sense an inhalation through the air flow path, and further sensors (such as switches) are arranged to detect opening and closing of the cap.

[0134] At 1510, the inhaler is in the sleep mode. Opening of the cap wakes up the inhaler at 1520 and turns on the LED at 1530. If a compliant inhalation (i.e., an inhalation that meets any criteria for confirming completion of dosing) is detected at 1540, the LED is turned off at 1550 and the buzzer emits a short confirmation beep. If the cap is then closed at 1560, compliance data indicating that the dose has been successfully taken and the device has been correctly closed is sent at 1590 to a device such as the user or a caregiver. The inhaler then returns to the sleep mode.

[0135] If the cap is not closed at 1560, the device enters a timeout loop at 1561. If a timeout occurs, a long error beep is emitted at 1562. Compliance data indicating that the dose has been taken but the device remains on and is thus not ready for subsequent dosing is then sent at 1590 before the inhaler re-enters the sleep mode. If the device is a rescue inhaler, such as used during an asthma attack, this type of compliance data can indicate that the drug has been successfully taken but has not restored the user. The automated system can thus call a caregiver to the user's location in situ (which can be known, for example, due to a GPS tracker in the inhaler or the user's device (such as a smartphone or tablet that communicates with the inhaler)).

[0136] If a compliant inhalation is not detected at 1540, it is decided at 1570 whether the cap has been closed. If not, a timeout loop is entered at 1571, which loops through 1540, 1570, 1571. If a timeout occurs at 1571, a long error beep is emitted through the buzzer at 1572. Compliance data is then sent at 1590 indicating that the dose has been loaded but not yet successfully taken. The inhaler then returns to the sleep mode. Again, if the inhaler is a rescue inhaler, the occurrence of this type of compliance data will trigger a call to a caregiver.

[0137] If the cap is closed at 1570, then the LED is turned off at 1580, and compliance data is sent at 1590 indicating that the dose has been incorrectly loaded. The inhaler then returns to the sleep mode.

[0138] The inhaler may further be able to determine when to attempt inhalation again after a compliant inhalation without a new dose being loaded first (i.e., without the cap being closed and opened). This may trigger an error beep.

[0139] Figure 16A and 16B Show the average pressure measured using a micro relative pressure sensor fixed to the upper part of the cartridge of 10 different inhalers versus a series of air flow velocities applied through the device. Repeated measurements are included for the start, middle, and end of the life of each inhaler (depending on the progression of the number of "shots" before the dose is used up). In Figure 16A error bars are shown for + / - 3 sigma variation. In Figure 16B error bars are shown for + / - 2 sigma variation, capturing the band within which 95% of the inhalers will fall. We thus know the air flow uncertainty of the pressure measurements by such sensors used in the inhaler.

[0140] For typical inhalation air flow velocities (30 - 60 l / min), the uncertainty can be calculated from Figure 16A to be ~16 l / min. (The uncertainty of the air flow velocity for each measurement can be estimated as the difference in the air flow axis between the top of the measured error bar and the point where the line joins the bottom of that measured error bar, and the next measured pressure. So, for the 30 l / min measurement, the difference is ~41 l / min minus 30 l / min = 11 l / min. For 45 l / min, the difference is 15 l / min, and for 60 l / min, it is 22 l / min). The converted value from Figure 16B is ~10 l / min. Thus sufficient accuracy is obtained to provide useful compliance data.

[0141] The above description relates to exemplary applications of the invention, but it should be understood that other implementations and variations are possible.

[0142] In addition, those skilled in the art can vary or change the specific geometries and arrangements of the particular features of the device. Other variations and modifications will also be apparent to those skilled in the art. Such variations and modifications may involve known and available equivalents or other features for substitution, which equivalents or other features may replace the features described herein or be used in addition to the features described herein. Features described in the context of separate embodiments may be provided in combination in a single embodiment. Conversely, features described in the context of a single embodiment may also be provided separately or in any suitable sub-combination.

Claims

1. An inhaler, comprising: An air flow path through which a user can inhale; A dose metering system configured to make a large dose of dry powder medicament available to the air flow path before the user inhales through the air flow path, and A compliance monitoring module, the compliance monitoring module including an electronic switch configured to generate a signal indicating that the large dose of dry powder medicament is available to the air flow path, a micro pressure sensor, a sensor port configured to be pneumatically coupled to the micro pressure sensor of the air flow path, and a processor, wherein the processor is configured to: Before inhalation, receive the signal from the electronic switch indicating that the large dose of dry powder medicament is available to the air flow path; Receive data from the sensing element of the micro pressure sensor during inhalation; And Based on the signal from the dose metering system and the data from the sensing element, determine that an inhalation of a breath through the air flow path containing the medicament meets one or more predetermined requirements for successful drug delivery, Wherein the requirements for successful drug delivery are selected from one or more of the following criteria: The air flow velocity exceeds a predetermined threshold; The inhalation duration exceeds a predetermined threshold; The air flow velocity exceeds a predetermined threshold for at least a predetermined threshold duration; or The total volume of inhalation exceeds a predetermined threshold.

2. The inhaler according to claim 1, wherein the inhaler further comprises a hopper and a dosing chamber, wherein the dose metering system is configured to meter the large dose of dry powder medicament entering the dosing chamber from the hopper.

3. The inhaler according to claim 1, wherein the inhaler further comprises a mouthpiece cap mechanically connected to the dose metering system such that opening of the mouthpiece cap activates the inhaler by making the large dose of dry powder medicament available to the air flow path.

4. The inhaler according to claim 1, wherein the compliance monitoring module is configured to be fixed to a main housing that is a part of the uppermost inhaler housing during use.

5. The inhaler according to claim 1, the inhaler further comprising: A first housing including the dry powder medicament; And A second housing mechanically coupled to the first housing, wherein the second housing includes the micro pressure sensor and the processor.

6. The inhaler according to claim 1, wherein the micro pressure sensor includes a barometric pressure sensor configured to measure a change in barometric pressure outside the air flow path generated by inhalation or exhalation into the mouthpiece of the inhaler.

7. The inhaler according to claim 1, wherein the micro pressure sensor is positioned outside the air flow path and the sensor port of the inhaler is pneumatically coupled to the air flow path via an opening in the wall of the air flow path.

8. The inhaler according to claim 7, wherein the inhaler further comprises a seal arranged to pneumatically couple the sensor port to the opening.

9. The inhaler according to claim 8, wherein at least a portion of the seal is sandwiched between the micro pressure sensor and the wall, and at least a portion of the seal selectively extends from the outer surface of the wall to the surface on which the micro pressure sensor is mounted so as to encapsulate the micro pressure sensor in a pneumatic chamber adjacent to the wall.

10. The inhaler according to claim 8, wherein the inhaler further comprises a thermal conductive gasket sandwiched between the micro pressure sensor and the wall, and the thermal conductive gasket is configured to act as the seal.

11. The inhaler according to claim 1, wherein the compliance monitoring module comprises a wireless transmitter configured to issue a dosing report in response to the determination.

12. The inhaler according to claim 1, wherein the compliance monitoring module is configured to be removed from or attached to the inhaler.

13. The inhaler according to claim 1, the inhaler further comprising a light emitting diode (LED), wherein the processor is configured to control the LED.

14. The inhaler according to claim 1, wherein the compliance monitoring module is incorporated into the top of the inhaler when facing the user.

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