PRIMING EVENT IDENTIFICATION IN DELIVERY DEVICES

Abstract

A method of monitoring a use cycle or delivery process by a variable-dose delivery device involves, by an electronic unit associated with the delivery device, determining, during the use cycle, first and second event details of a first and second dispense event. Thereafter, determining cycle properties including at least one of a number of dispense events in the use-cycle and a holding time status indicative of a regular holding time having been observed at the end of the use cycle. Evaluating an injection criteria, including a multi-event-criteria based on an event detail of the first event, or a cycle criteria based on a cycle property of the use cycle, to derive an injection score of the second event, indicating a probability that a second dispensed dose has been injected and was not a priming or air shot. Determining and forwarding a cycle dispense dose based on the injection score.

Claims

1. A method of monitoring a use cycle including a first dispense event and a second dispense event performed by a variable-dose delivery device, comprising, using an electronic unit associated with the delivery device to perform the steps of: determining, during the use cycle, first event details and second event details of the first and second dispense event, respectively; determining, at an end of the use cycle, cycle properties of the use cycle; evaluating, after the use cycle, an injection criteria to derive an injection score of the second dispense event indicative of a probability that the second dispense dose has been injected into a target tissue, wherein the injection criteria is a multi-event criteria based on an event detail of the first dispense event or a cycle criteria based on a cycle property of the use cycle; and determining a cycle injection dose based on the injection score.

2. The method of claim 1, wherein the first event details and the second event details include a first device orientation and a second device orientation, and a first dispensed dose amount and a second dispensed dose amount, respectively, and wherein evaluating the multi-event criteria comprises increasing the injection score of the second dispense event if: the second device orientation is different from the first device orientation, and/or the second dispensed dose amount is larger than the first dispensed dose amount.

3. The method of claim 1, wherein evaluating the cycle criteria comprises increasing the injection score of the second dispense event if: the second dispense event is a last dispense event in the use cycle, and/or a holding time following the second event is acknowledged.

4. The method of claim 2, wherein the first event details and second event details include a first dispense event time and a second dispense event time, the method comprising determining further event details including a further dispense event time of a further dispense event preceding the first dispense event, and wherein evaluating the multi-event criteria comprises increasing the injection score of the second dispense event if a time interval between the further dispense event time and the first dispense event time is smaller than a time interval between the first dispense event time and the second dispense event time.

5. The method of claim 2, wherein evaluating the injection criteria comprises increasing the injection score of the second dispense event if: the second device orientation of the delivery device is not upright, the second dispensed dose amount does match a dose according to a therapy plan, the second dispensed dose amount is above a threshold, and/or the second dispense event is not preceded by a knocking or tapping movement of the delivery device.

6. The method of claim 2, further comprising, at the end of the use cycle, using the electronic unit or a mobile device of a user to: signal the determined cycle injection dose to the user, and log a user-confirmed injection dose or an adjusted cycle injection dose.

7. The method of claim 2, wherein the electronic unit comprises an accelerometer configured as a delivery device orientation sensor for determining the first device orientation and the second device orientation, the method further comprising: sensing by the accelerometer, mechanical feedbacks of the delivery device; and determining, by the electronic unit, a dispensed dose amount based on the sensed mechanical feedbacks.

8. A delivery system including a variable-dose delivery device and an electronic unit for monitoring a use cycle including a first dispense event, a second dispense event, and a third dispense event performed by the delivery device, the electronic unit configured to: determine a first dispensed dose amount dispensed, a second dispensed dose amount dispensed, and a third dispensed dose amount dispensed; determine a first device orientation, a second device orientation, and a third device orientation assumed by the delivery device during the first dispense event, the second dispense event, and the third dispense event, respectively; and evaluate a relative priming criteria involving the third dispense amount and/or the third device orientation to acknowledge the second dispense event as a priming event.

9. The delivery system of claim 8, wherein the electronic unit is configured to evaluate the relative priming criteria by increasing a priming score of the second dispense event if: the second device orientation is different from the third device orientation, and/or the second dispensed dose amount is smaller than the third dispensed dose amount.

10. The delivery system of claim 8, wherein the electronic unit is configured to evaluate the relative priming criteria by increasing a priming score of the second dispense event if: the second device orientation is the same as the first device orientation, and/or the second dispensed dose amount is not larger than the first dispensed dose amount.

11. The delivery system of claim 8, wherein the electronic unit is configured to determine a first dispense event time, a second dispense event time, and a third dispense event time, and to evaluate the relative priming criteria by increasing a priming score of the second dispense event if a time interval between the first dispense event time and the second dispense event time is smaller than a time interval between the second dispense event time and the third dispense event time.

12. The delivery system of claim 8, wherein the electronic unit is configured to evaluate absolute priming criteria involving the second dispensed dose amount and/or the second device orientation, and/or further use cycle information available at an end of the second dispense event, and to evaluate the relative priming criteria by increasing a priming score of the second dispense event if: the second device orientation of the delivery device is upright, the second dispensed dose amount does not match a dose according to a therapy plan, the second dispensed dose amount is below a threshold, and/or the second dispense event is preceded by a knocking or tapping movement of the delivery device.

13. The delivery system of claim 9, wherein the electronic unit is configured to assess the priming score of the second dispense event, and to signal a priming status of the delivery device to a user.

14. The delivery system of claim 9, wherein the electronic unit comprises an accelerometer configured as a delivery device orientation sensor for determining the first device orientation, the second device orientation, and the third device orientation.

15. The delivery system of claim 8, wherein the electronic unit is a part of an electronic module and is releasably attachable to the electronic module at a main housing part of the delivery device, wherein the delivery system comprises guiding elements that define two rotational orientations of the electronic module with respect to a longitudinal axis of the main housing part of the delivery device when attached, and wherein the electronic module comprises an RFID tag reader antenna with comparable inductive coupling to an RFID tag antenna of the delivery device in either rotational orientation of the electronic module.

16. A method of monitoring a use cycle including a first dispense event and a second dispense event performed by a variable-dose delivery device, comprising using an electronic unit associated with the delivery device, to perform the steps of: determining, during the use cycle, first event details and second event details of the first dispense event and the second dispense event, respectively; determining, at an end of the use cycle, cycle properties of the use cycle; evaluating, after the use cycle, an injection criteria to derive an injection score of the second dispense event, the injection score indicative of a probability that a second dispensed dose has been injected into target tissue, wherein the injection criteria includes a cycle criteria based on a cycle property of the use cycle; and determining a cycle injection dose based on the injection score.

17. The method of claim 16, wherein evaluating the cycle criteria comprises increasing the injection score of the second dispense event if: the second dispense event is a last dispense event in the use cycle, and/or a holding time following the second dispense event is acknowledged.

18. The method of claim 16, wherein the injection criteria includes a multi-event criteria, wherein the first event details and the second event details include a first device orientation and a second device orientation and a first dispensed dose amount and a second dispensed dose amount, respectively, and wherein evaluating the multi-event criteria comprises increasing the injection score of the second dispense event if: the second device orientation is different from the first device orientation, and/or the second dispensed dose amount is larger than the first dispensed dose amount.

19. The method of claim 16, wherein the injection criteria includes a multi-event criteria, wherein the first event details and the second event details include a first dispense event time and a second dispense event time, the method further comprising determining further event details including a further dispense event time of a further dispense event preceding the first dispense event, and wherein evaluating the multi-event criteria comprises increasing the injection score of the second dispense event if: a time interval between the further dispense event time and the first dispense event time is smaller than a time interval between the first dispense event time and the second dispense event time.

20. The method of claim 16, wherein evaluating the injection criteria comprises increasing the injection score of the second dispense event if: the second device orientation of the delivery device is not upright, a second dispensed dose amount does match a dose according to a therapy plan, the second dispensed dose amount is above a threshold, and/or the second dispense event is not preceded by a knocking or tapping movement of the delivery device.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0047] The subject-matter of the invention will be explained in more detail in the following text with reference to preferred exemplary embodiments as illustrated in the attached drawings, of which

[0048] FIG. 1 depicts a medical injection monitoring and patient support system;

[0049] FIG. 2 summarizes the steps of the post-cycle dispense event identification; and

[0050] FIG. 3 shows a cross section of an injection device with a concentric electronic module.

[0051] For consistency, the same reference numerals are used to denote similar elements illustrated throughout the drawings.

DETAILED DESCRIPTION

[0052] In the present context, the terms “substance”, “drug”, “medicament” and “medication” are to be understood to include any flowable medical formulation suitable for controlled administration through a means such as, for example, a cannula or a hollow needle, and comprises a liquid, a solution, a gel or a fine suspension containing one or more medical active ingredients. A medicament can be a composition comprising a single active ingredient or a pre-mixed or coformulated composition with more than one active ingredient present in a single container. Medication includes drugs such as peptides (e.g., insulin, insulin-containing drugs, GLP-1 containing drugs or derived or analogous preparations), proteins and hormones, active ingredients derived from, or harvested by, biological sources, active ingredients based on hormones or genes, nutritional formulations, enzymes and other substances in both solid (suspended) or liquid form but also polysaccharides, vaccines, DNA, RNA, oligonucleotides, antibodies or parts of antibodies but also appropriate basic, auxiliary and carrier substances.

[0053] FIG. 1 depicts a medical injection or drug delivery monitoring and patient support system, comprising a variable dose injection device 1, an electronic module 2 detachably mounted, or releasably attached, to the injection device, and a mobile device 3. The injection device includes an elongate device housing 10 essentially symmetric around a main device axis, as well as a dose dialing facility as amply described for instance in EP 2812055 and in turn including a dosing sleeve 11, a rotary dosing knob 12, and a discharge button 13. The dosing knob enables the user to adjust a dose and is arranged on a proximal end of the dosing sleeve. The dosing sleeve features markings in the form of numbers on its outer surface. When the dosing sleeve is screwed out of the housing during the dosing operation, the adjusted dose is displayed in a window of the housing. The discharge button is snapped on the dosing sleeve in such a way that the discharge button can slightly move axially relative to the dosing sleeve.

[0054] The electronic module 2 comprises an essentially tubular module housing surrounding the injection device housing in the attached state, a feedback sensor 21, a processing unit 22 and a transmitter unit 23 for wireless transmission of data about the injection progress via Bluetooth Low Energy (BLE) or equivalent short or near range wireless communication technology to the mobile device. The electronic module additionally includes a data storage unit 24 or memory connected to the processing unit and a lock/release mechanism to secure the attachment of the electronic module to the injection device. Connection and system status indicator 25 provides visual feedback about a connection status indicative of an established communication link to the mobile device, and about a device, module, or process status including for instance an availability of battery power, a readiness of communication means, an attached/detached status of the electronic module and the injection device, or a progress of an ongoing injection process. The electronic module is further adapted to produce a time-stamp indicating at what date and time a monitored dose has been injected, and to store at least the dose expelled and the time-stamp in the data storage unit for later upload.

[0055] The mobile device 3 is a smartphone or tablet device running a dedicated application program; or a laptop computer configured accordingly. The mobile device is adapted to interact with a respective patient 31 as well as a remote server, cloud based computing facility, or expert system 32. The mobile device may comprise a bolus calculator for calculating insulin delivery doses, or be knowledgeable of therapy plan of a growth hormone therapy. Instantaneous bolus dose values or currently scheduled therapy dose values may be provided to the electronic module. Dialed doses may then be monitored in real time and compared to the dose values due, and a discrepancy signaled to the user via indicator 25.

[0056] FIG. 2 is a flow chart summarizing the essential steps of the method 200 including post-cycle dispense event identification and cycle injection dose determination. Method 200 involves step 201 “Detect start of use cycle”; step 202 “Determine event details of dispense events and cycle properties of the use cycle”; step 203 “Detect end of use cycle”; step 204 “Evaluate injection criteria”; step 205 “Derive injection scores for dispense events”; and step 206 “Determine cycle injection dose of the use cycle based on the injection scores of the dispense events”. Exemplary injection criteria to be evaluated in step 204 are listed in the following table, along with a rationale and/or conclusion for the present, or latest, dispense event being investigated.

TABLE-US-00001 # Criteria Conclusion for the latest dispense event 1 Relative device orientation A change in device orientation with respect to the preceding dispense event is indicative of a change from a preceding priming event to a present injection event 2 Relative dose size As successive priming doses are hardly increasing, an observed increase in dispense event dose points to a change from a preceding priming event to a present injection event 3 Time between events An increased inter-event time delay may be occasioned by the user preparing to inject, and is thus indicative of a change from preceding priming events to an injection event 4 Number of dose-units Priming is recommended with 2 or 3 dose-units. A higher number is indicative of an injection event 5 Last dispense event of the use cycle The last dispense event before re-capping the device is most probably an injection event 6 Priming cone A dispense event with a device orientation within a priming cone is probably a priming event 7 New device The first dispense event with a new device or reservoir is most probably a priming event 8 Dispensed dose according plan A dispensed dose according the therapy plan (and other than 2 or 3 units) is indicative of an injection event 9 Holding time An unchanged position of the device for a minimum holding time after the end of the product dispense is indicative of an injection event 10 Needle removal Removal or extraction of the needle device from the injection site and/or removal of the needle from the device (as detected in the response pattern of an accelerometer, gyroscope or other device movement sensor / Inertia Measurement Unit) after the dispense event is indicative of an injection event 11 Number of events If there are more than two events in the use cycle, the last event is probably an injection event

[0057] The criteria are assigned a weight or relative score that is involved when aggregating the results of the individual criteria evaluated into a final injection score. Each weight is indicative of a relevance or importance of a criteria, and may be determined by training on a large set of use cycles. Independent weights may be assigned for a criteria being fulfilled and for the criteria not being complied. The following table lists a selection of criteria with exemplary weights. The scores for the second dispense event of a sample use cycle with a priming event and a subsequent injection event of 4 or 5 dose units, both in upright direction, and followed by a holding time and needle removal, are reported in the last column. Despite the major weight attributed to the upright orientation of the device during the second event, the plurality of further criteria applied succeed in reversing the corresponding bias, such that the negative total score of the second event is correctly interpreted as an injection event.

TABLE-US-00002 Criteria Question: Weight Yes Weight No Sample Score 6 Device held upright during the event? 90 -70 90 4 1-2 dose units in the event? 50 0 0 3 dose units in the event? 30 0 0 4-5 dose units in the event? -20 0 -20 6-10 dose units in the event? -50 0 0 11-60 dose units in the event? -95 0 0 9 Holding time detected after event? -20 40 -20 10 Cannula removal detected after the event? -20 10 -20 5 Last event in the use cycle? -70 60 -70 1 Device orientation w.r.t. previous event? -30 20 20 3 Inter-event time delay has increased? -20 0 0 11 More than 2 events in the use cycle? -20 0 0 Sum -20

[0058] FIG. 3 discloses a cross-sectional view of an injection device 1 with an RFID tag or transponder and an electronic module 2 with an RFID tag reader surrounding the injection device 1. The RFID tag comprises a tag antenna 14 and the RFID tag reader comprises a reader antenna 26, both with an antenna area essentially parallel to the longitudinal axis of the injection device. The antenna areas are preferably made of a conductive track on a flexible circuit board which forms a coil defining the active antenna area with an extension or diameter between 2 and 3 cm. The antennas 14, 26 are generally arranged as close as possible to each other to allow for optimal inductive coupling. The RFID reader of the reusable electronic module may read an ID of the disposable injection device, alphanumeric drug information, and/or further information including an encryption key for securing communication between the electronic module and a user device. In the embodiment depicted the two antennas 14, 26 are planar or two-dimensional coils rotated by 90° with respect to each other, such that the antennas are perpendicular to each other and such that there is no immediate overlap of the two antenna areas. The four-fold rotational symmetry due to the square-shaped cross section is further reduced by guiding elements on the surface of the injection device that only allow two different orientations of the electronic module with respect to the injection device, i.e. the injection device may be rotated by 180° around the longitudinal axis and still fit into the electronic module. In this rotated position, the tag antenna is placed in position 14′ as indicated in broken lines, and has a similar inductive coupling to the reader antenna 26 as in the first orientation.

[0059] Turning the dosing knob of the injection device in a dose-increasing dialing direction or in a dose-reducing corrective direction causes a ratchet toothing to slide over a counterface toothing and to repeatedly perform a slight axial back and forth motion that gives rise to a clicking sound. The number of clicks is proportional to the dosage volume, wherein preferably each click or vibration burst corresponds to a single dosage unit, such as an International Unit IU. During dose-discharge, a tooth of a flexible arm rotates relative to a grating, which in turn generates an acoustic click sound and a tactile discharge feedback signal to the user. The dialing, corrective, and discharge clicks are captured by the feedback sensors and converted into a feedback signal on behalf of the processing unit.

[0060] The module housing is designed to be positioned on the injection device housing in such a way as to neither interfere with the dial-and-dose components nor obscure any display window or visual indicator of the device. To this purpose, the module housing has a recess or opening that matches with the window. Hence the patient may continue using a non-modified injection device in a known manner, despite the presence of the electronic module, with all device interface elements remaining fully accessible throughout the handling sequence. Specifically, in this case the electronic module excludes the presence of a mechanical sensor to mechanically detect a rotation angle or linear shift of the dosing knob. Likewise, the electronic module excludes the presence of an optical sensor to read a dialed dose from a dialing sleeve.

[0061] The electronic module comprises an accelerometer and/or a gyroscope as a feedback sensor for dose detection. The signal processing unit is adapted to detect device handling activities by the user from a non-click sensor signal measured independent of a dose setting or dose expel process of the delivery device, and not related to a feedback event generated by feedback means internal to the delivery device. Device handling activities relate to movements of the delivery device and/or the electronic module as a whole, and include, for instance, attachment/removal of the module to/from the delivery device by way of a snap or clip operation; seizure of delivery device and attached module after having rested immobile for some time, device cap attachment/removal to/from the delivery device, cannula attachment or removal. Detection of the aforementioned user activities may advantageously be used, individually or in combination, as a basis for a plausibility check confirming or questioning an expected handling sequence. Upon detection of these activities, the electronic module may end a sleep or low-power mode and enter an injection monitoring mode, and/or identify the start of a use cycle. Likewise, a dedicated wake-up activity such as double tapping or knocking the device to end a sleep mode may be detected by the same feedback sensor that primarily serves for dose determination. In these cases, no button or switch may be needed on the electronic module to activate the electronic module. Alternatively, a touch sensor may be used to wake up the electronic unit and identify the start of the use cycle.

[0062] The abovementioned device handling activities are identified from signal samples, or excerpts, having a predefined extension in time and frequency domain, and generated by the acceleration or gyroscope sensor. From these signal samples, plural features or characteristics such as a sum of correlation values of a test signal with single-axis gyroscope signals, or a sum of absolute derivatives of single-axis gyroscope signals, are derived. These features are evaluated and classified by a classifier to assign each signal sample to a device feedback class identifying, or corresponding to, a device handling activity. Various types of classifiers exist and may be employed to that purpose, such as a Support Vector Machine (SVM) with a linear kernel, a Feed Forward Artificial Neural Network (ANN), or a Gradient Boosted Decision Tree Neural Network.

[0063] Detection of device cap removal as an exemplary device handling activity identified as described may be used to trigger power-up of a user interface, to activate a further sensor, and/or to increase a sampling rate or sensitivity of the acceleration sensor in view of an imminent dose dispense detection. The identified device cap removal may also be used for user guidance, including issuance of a warning in case the drug dispense is not being started within a maximum pre-injection delay interval. Instead of or subsequent to the warning, the device may be blocked, in particular once the needle has been exposed to ambient for a time sufficient to contaminate the needle. Therapy monitoring by means of electronic modules embedded in an auto-injector or in a multiple variable dose injection pen, or integrated in an auxiliary device for attachment to either of the former, may thus be further improved.

[0064] The electronic components being integrated in the injection device or being part of an electronic module may comprise a visual, audible and/or tactile status indicator indicating to a user a status of the system. The status indicator may explicitly exclude any advanced human-machine interfacing capability, and be limited to a few, specifically less than ten, messages conveyable to the user. In particular, the electronic unit may not be wired to, and the electronic module may be devoid of, a display, screen, or projector for visually transmitting readable instructions, and likewise exclude an artificial speech assistant for reading out loud the instructions. Such advanced HMI functionality including elaborate graphic display and speech output capabilities are preferably being provided by a mobile device communicatively connected to the electronic unit. The status information may be redundant or complementary to primary signals from the injection device that a user may still capture in parallel. In particular, the status information may include a positive confirmation of a dose having been set or corrected, or an indication about a lapse of a minimum holding, delay, or dwell time following completion of a substance expel or piston forwarding activity to inform the user that it is now safe to remove the injection device.

[0065] While the invention has been described in detail in the drawings and foregoing description, such description is to be considered illustrative or exemplary and not restrictive. Variations to the disclosed embodiments can be understood and effected by those skilled in the art and practicing the claimed invention, from a study of the drawings, the disclosure, and the appended claims. In the claims, the word “comprising” does not exclude other elements or steps, and the indefinite article “a” or “an” does not exclude a plurality. The mere fact that certain elements or steps are recited in distinct claims shall not preclude the existence of further meaningful combinations of these elements or steps.

TABLE-US-00003 LIST OF REFERENCE NUMERALS 1 injection device 10 device housing 11 dosing sleeve 12 dosing knob 13 discharge button 14 tag antenna 2 electronic module 20 module housing 21 feedback sensor 22 processing unit 23 transmitter unit 24 data storage unit 25 status indicator 26 reader antenna 3 mobile device 31 patient 32 data server