STATE ESTIMATION FOR DRUG DELIVERY SYSTEMS

Abstract

A flexible and reliable delivery state estimator or evaluator is provided for a drug delivery device. The proposed delivery status estimation architecture includes a position sensor that provides a continuous position sensor signal indicative of a current position of a component of the delivery device movable continuously from a first to a second component position, as well as a position discriminator that redefines the continuous position sensor signal to generate an approximate binary input signal on behalf of a state estimator. The discriminator absorbs any difficulty that may arise from a limited reproducibility or enhanced variability of the original continuous sensor signal, specifically including a user-originated signal spread in a movement of a needle protection sleeve of the delivery device.

Claims

1. A method of evaluating a delivery status of a drug delivery device with a container holding a liquid drug, comprising: providing, by a position sensor, a continuous position sensor signal indicative of an instantaneous position of a component of the delivery device movable from a first to a second component position; generating, by a position discriminator, a binary position signal associated with the first and the second component position; and deriving, by a status evaluator, the delivery status from the binary position signal.

2. The method of claim 1, further comprising: (a) defining, by the position discriminator, for a continuous component position signal with a first value and a second value below the first value, a top slow tracker signal with predetermined relaxation properties; or (b) defining, by the position discriminator, for a continuous component position signal with a first value and a second value above the first value, a bottom slow tracker signal with predetermined relaxation properties; and using (a) or (b): determining a difference between an instantaneous value of the continuous component position signal and either one of the top slow tracker signal or the bottom slow tracker signal, and comparing the difference to a threshold to derive the binary position signal.

3. The method of claim 2, wherein a relaxation property of at least one slow tracker signal is determined by a linear drift parameter defining a linear variation of the slow tracker signal as long as an instantaneous value of the continuous component position signal does not exceed a top slow tracker signal value or fall below a bottom slow tracker signal value.

4. The method of claim 2, further comprising: defining, by the position discriminator, for the continuous component position signal with the second value below the first value, a fast bottom tracker signal smaller than and approximating the continuous component position signal; and determining the difference between the top slow tracker signal and the fast bottom tracker signal of the continuous component position signal; or defining, by the position discriminator, for the continuous component position signal with the second value above the first value, a fast top tracker signal larger than and approximating the continuous component position signal; and determining the difference between the fast top tracker signal and the bottom slow tracker signal of the continuous component position signal.

5. The method of claim 2, further comprising: comparing the difference to a second threshold to derive a discrete position signal being associated with the first component position, the second component position, and a third component position.

6. The method of claim 1, wherein the step of deriving the delivery status is based on a table assigning each delivery status to a combination of binary augmented sensor signals, further comprising: deriving the delivery status based on a preceding delivery status.

7. A computer program which, when being executed by a processing unit of a monitoring unit of a drug delivery device with a container holding a liquid drug, causes the processing unit to execute a method of evaluating a delivery status of the drug delivery device, comprising: providing, by a position sensor, a continuous position sensor signal indicative of an instantaneous position of a component of the delivery device movable from a first to a second component position; generating, by a position discriminator, a binary position signal associated with the first and the second component position; and deriving, by a status evaluator, the delivery status from the binary position signal.

8. A monitoring unit for a drug delivery device with a container holding a liquid drug, comprising: a position discriminator for generating, from a continuous position sensor signal provided by a position sensor and indicative of an instantaneous position of a component of the delivery device movable from a first component position to a second component position, a binary position signal associated with the first component position and the second component position; and a status evaluator for deriving a delivery status from the binary position signal.

9. The monitoring unit of claim 8, wherein the monitoring unit comprises: a position discriminator for generating, from a further continuous position sensor signal provided by a further position sensor and indicative of an instantaneous position of a further component of the delivery device movable from a first further component position to a second further component position, a further binary position signal associated with the first further component position and the second further component position; and a status evaluator configured to derive the delivery status from both of the binary position signal and the further binary position signal.

10. The monitoring unit of claim 8, further comprising a position sensor adapted to provide a continuous position sensor signal indicative of an instantaneous position of a manually movable component of the delivery device from a first to a second component position.

11. The monitoring unit of claim 10, wherein the manually movable component is a cover sleeve spring base of an auto-injector.

12. The monitoring unit of claim 10, wherein the position sensor is adapted to provide a continuous position sensor signal indicative of a distance of the delivery device from a target injection site.

13. An electronic module for removable attachment to a drug delivery device with a container holding a liquid drug, the module comprising a monitoring unit, comprising: a position discriminator for generating, from a continuous position sensor signal provided by a position sensor and indicative of an instantaneous position of a component of the drug delivery device movable from a first component position to a second component position, a binary position signal associated with the first component position and the second component position; and a status evaluator for deriving a delivery status from the binary position signal.

14. The electronic module of claim 13, further comprising a tag reader for reading information from a machine-readable tag mounted to a device housing of the drug delivery device, wherein the information comprises parameter values for the generation of the binary position signal by the position discriminator.

15. The electronic module of claim 13, wherein the monitoring unit further comprises: a position discriminator for generating, from a further continuous position sensor signal provided by a further position sensor and indicative of an instantaneous position of a further component of the delivery device movable from a first further component position to a second further component position, a further binary position signal associated with the first further component position and the second further component position; and a status evaluator configured to derive the delivery status from both of the binary position signal and the further binary position signal.

16. The electronic module of claim 13, wherein the monitoring unit comprises a position sensor adapted to provide a continuous position sensor signal indicative of an instantaneous position of a manually movable component of the delivery device from a first to a second component position.

17. The electronic module of claim 16, wherein the manually movable component is a cover sleeve spring base of an auto-injector.

18. The electronic module of claim 16, wherein the position sensor is adapted to provide a continuous position sensor signal indicative of a distance of the delivery device from a target injection site.

19. The computer program of claim 7 wherein the method of evaluating a delivery status of the drug delivery device further comprises: (a) defining, by the position discriminator, for a continuous component position signal with a first value and a second value below the first value, a top slow tracker signal with predetermined relaxation properties; or (b) defining, by the position discriminator, for a continuous component position signal with a first value and a second value above the first value, a bottom slow tracker signal with predetermined relaxation properties; and after (a) or (b): determining a difference between an instantaneous value of the continuous component position signal and either one of the top slow tracker signal or the bottom slow tracker signal; and comparing the difference to a threshold to derive the binary position signal.

20. The computer program of claim 19 wherein the method of evaluating a delivery status of the drug delivery device further comprises: wherein a relaxation property of the slow tracker signal is determined by a linear drift parameter defining a linear variation of the slow tracker signal as long as an instantaneous value of the continuous component position signal does not exceed a top slow tracker signal value or fall below a bottom slow tracker signal value.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0036] The subject matter of the invention will be explained in more detail in the following text with reference to preferred exemplars, embodiments which are illustrated in the attached drawings, in which:

[0037] FIG. 1 depicts a variant of a medical monitoring system with an auto-injector;

[0038] FIG. 2 depicts a flow chart with selected blocks of the monitoring unit;

[0039] FIGS. 3A-3C depict a relative arrangement of sensor induction coils and spring bases in an initial state and two additional positional states of spring bases of a device cover sleeve;

[0040] FIG. 4 shows two continuous position signals recorded during an injection event;

[0041] FIG. 5 shows corresponding binary position signals;

[0042] FIG. 6 shows the evaluated consolidated state evolution;

[0043] FIG. 7 shows two continuous position signals with slow device removal; and

[0044] FIG. 8 shows a continuous signal together with the bottom slow tracker BST signal.

[0045] The reference symbols used in the drawings, and their primary meanings, are listed in summary form in the list of designations below. In principle, identical parts are provided with the same reference symbols in the figures.

Detailed Description of Preferred Embodiments

[0046] FIG. 1 depicts an embodiment of a medical monitoring system comprising an auto-injector as an exemplary disposable delivery device 1, an electronic module 2 releasably attached to a device housing of the injection device, and a mobile device 31 such as a smartphone or tablet device running a dedicated application program; or a laptop computer configured accordingly. The mobile device 31 is communicatively connected via a data communication network, e.g. the Internet, to a remote server, cloud based computing facility, or expert system 32. The electronic module 2 includes a monitoring unit with a position sensor 21, a position discriminator 22, and a status evaluator 23. The electronic module further comprises a status indicator 24 such as a LED, buzzer, vibration alarm, or any other type of human-machine interface (HMI) element for providing visual, acoustic, or tactile feedback about a derived injection status. A memory or data storage unit 25 (with associated unit) is adapted to store status or delivery information. The electronic module also comprises a communication unit 26 for wireless transmission of an injection status or drug status to the mobile device 31 via Bluetooth Low Energy (BTLE) or equivalent short or near range wireless communication technology. The electronic module 2 has a rear, or proximal, part where some or all electronic components as described are located.

[0047] FIG. 2 depicts a flow chart of the pertinent blocks/logic components of the monitoring unit, of which the position sensor 21 provides a continuous position sensor signal CS to the position discriminator 22 that in turn generates a binary position signal BS based on the continuous position signal. The binary position signal is evaluated, together with optional further binary position signals (dotted lines), by the status evaluator 23, based on an evaluation table 23a coding the delivery states as a combination of binary position signal values, to identify a delivery state DS.

[0048] At least the position sensor 21 of a monitoring unit with block-wise state estimation may be part of, or embedded in, a delivery device that is designed or adaptable to accommodate sensing elements. In this embodiment, contact-based sensing means relying on position dependent electrical resistance or mechanical force may be employed, such as a piezo-based force or pressure transducer provided adjacent to the base of a linear compression spring. Alternatively, the monitoring unit may be part of an electronic module 2 adapted to be removably attached to a device housing of an delivery/injection device 1 as depicted in FIG. 1. In this case, contact-free, non-invasive sensing means are preferably employed, based on electrical, optical, acoustical signals indicative of an injection process executed by means of the injection device 1 and well-discernable outside of, but reasonably close to, the device. Specifically, the injection status sensing means may include an electrical sensor such as a contact-free inductive or capacitive sensor to detect initial, intermediate, and final values of, and/or corresponding changes or differences in, a static or alternating electromagnetic field or flux depending on a position or displacement of a magnetic or inductively responding device component. The inductive position sensor includes an inductive sensor comprising a sensor induction coil and a sensor control unit for detecting, in an attached state of the electronic module 2 and the injection device, an inductance of the sensor induction coil which is dependent on a position of a component of the injection device that is at least partly made of a magnetic or of an electrically conductive material. The electronic module may also operate with non-invasive sensing means that depend on a sound mechanical contact with the delivery device, such as inertia, vibration, force or pressure measurements.

[0049] The exemplary disposable injection device 1 in FIG. 1 is an auto-injector for automatically injecting a liquid medicament as described for instance in EP 2781230. The auto injector has an elongate casing including a syringe holder part for accommodating an active agent container or pre-filled syringe with an injection needle at a distal end. A driving or injection spring is provided for powering a piston rod and shifting a piston comprised in the container in order to deliver the active agent. The auto-injector also includes a cover sleeve or needle protective sleeve that surrounds the needle in a first position, and that may be axially moved in a proximal direction towards a second position. When the distal end of the auto-injector is pressed onto the skin of a patient, the cover sleeve is displaced in a proximal direction, and a cover sleeve spring is loaded or tensioned. Towards the end of this initial cover sleeve retraction, a click element is displaced in a distal direction by means of the relaxing injection spring, which in turn causes an additional tensioning of the cover sleeve spring. Alternatively, the click element is displaced in a proximal direction by means of the relaxing cover sleeve spring. At the end of an ejection, an end-click element is released to move in a proximal direction under the effect of the injection spring or of the cover sleeve spring until it abuts and generates an end-click.

[0050] A conductive spring section including two winding turns that at least partially contact or overlap is preferred for being evaluated as a moving component in the context of the present invention. Such spring sections may be formed anywhere along a compressive spring, but are naturally found at a base, foot, or end of the spring. The base of the cover sleeve spring may comprise base winding loops with a diameter adapted to the diameter of the cover sleeve, and hence radially close to a circumferential device housing and at minimum radial distance to the sensor induction coil. Other conductive spring bases, such as those of a compressive injection spring or of a release button restoring spring, likewise appear suitable for an inductive position sensor. The spring base may include a first helical winding with an electrical contact between a first turn of the winding and a second, adjacent winding turn at a point of overlap, permitting the flow of circular currents. Such an electrical contact may be established preferably by laser, spot, or resistive welding or soldering techniques applied to the first and the second turn of the winding at a point of contact or overlap. Other techniques may also be suitable for preparing the contacting surfaces in order to enable a galvanic contact of low resistance and/or in order to mechanically stabilize the spring base and prevent the end turn from radial misalignment. In addition to the circular current, eddy currents circulating independently of a conductor topology in the bulk of the conductor may also contribute to the inductive response or feedback of the spring section.

[0051] FIG. 3A depicts schematically a relative arrangement of the sensor induction coils 21a, 21b and the cover sleeve spring bases 13a, 13b in an initial state of the cover sleeve spring 13. FIG. 3B depicts a compressed cover sleeve spring 13 with the first cover sleeve spring base 13a having moved in proximal direction (p) by virtue of the retracted cover sleeve, and with the second cover sleeve spring base 13b having moved in distal direction (d). FIG. 3C depicts the cover sleeve spring 13 with the first cover sleeve spring base 13a having moved proximally and with the second cover sleeve spring base now also having moved proximally, to position 13b, prior to drug ejection. Once the piston has reached its distal end position, the end-click element is released and accelerated in distal direction by one of the injection spring or the cover sleeve spring undergoing an ultimate expansion. In the latter case, the second cover sleeve spring base will move further proximally to position 13b. Incidentally, the FIG. 3C arrangement additionally depicts (in broken lines and schematically) a retracted cover sleeve 12 and the exposed needle or cannula 11 of a syringe or container held by the delivery device. The cover sleeve 12 is coupled to the cover sleeve spring to move conjointly between a first, initial and/or eventually final position in which the cover sleeve 12 essentially surrounds a needle of the injection device and a second, operational position in which the cover sleeve exposes the needle. On the other hand, the click sound generating elements that are arranged proximally of, and move jointly with, the proximal base 13b of the cover sleeve spring are not depicted.

[0052] In the proposed delivery status determination architecture including a state estimator block distinct from a position discriminator, only the latter needs to be modified when passing from the arrangement of FIG. 3B to the arrangement of FIG. 3C. Specifically, the second cover sleeve spring base 13b undergoing an initial movement in distal or proximal direction prior to drug ejection at most requires an additional change in sign when converting the continuous sensor signal into the binary signal, such that the state recognition block can be reused integrally.

[0053] Arranging the first, or front, sensor induction coil 21a at the distal side of the expanded, or first, position of the first cover sleeve spring base 13a has the advantage that the signal detected is rather independent of the actual cover sleeve displacement or stroke. Arranging the first sensor induction coil at an alternative position 21a (indicated in broken lines in FIG. 3A) proximally of the compressed, or second, position 13a of the first cover sleeve spring base (FIG. 3B) is likewise possible. With the above exemplary auto-injector and monitoring unit, an injection process is characterized by a sequence of four events that are observable with the two inductive sensor means of FIGS. 3A-C as the displacements of the first and the second spring base of the cover sleeve spring 13.

[0054] FIG. 4 depicts two exemplary continuous signals recorded during an injection performed with an auto-injector as described, in arbitrary units and over a time scale of a few seconds. The first signal (channel CH0, broken line) originates from a distal or front inductive sensor and represents the movement of the cover sleeve or, equivalently, of the distal base of the cover sleeve spring as the first device component. The second signal (channel CH1, continuous line) results from a proximal or rear inductive sensor and is indicative of a start and end of the ejection of medication and results from a proximal base of the cover sleeve spring. Both sensor signals may be pre-processed, including filtering by an average filter in order to remove noise without adding large delays, and converting into digital signals at an adaptable sampling rate between 1 and 1000 Hz, and preferably between 10 and 100 Hz.

[0055] FIG. 5 depicts the binary output of the position discriminator when provided with the continuous position signals of FIG. 4. The pre-processed signal of CH0 is tracked or characterized by a slow bottom tracker signal and a fast top tracker signal. The pre-processed signal of CH1 is tracked by a slow top tracker and a fast bottom tracker. The slow trackers represent a baseline of the signal and the fast trackers approximate the instantaneous or current signal such that the latter is always in a band between the baseline and the fast tracker signal. The difference between top and bottom tracker is calculated for both channels as a measure of how much the current signal deviates from the baseline. Comparison of the calculated difference to a pre-determined, channel-specific and properly calibrated threshold allows to define the binary position signal. For instance, if and as long as for the first signal the difference exceeds the threshold, the binary signal CH0 is set to one or on, otherwise to zero or off. For the second signal, if and as long as the difference is below the applicable threshold, the binary signal CHF is set to one or on. The assignment of the binary states may be inverted independently for any one or both of the two signals.

[0056] FIG. 6 depicts the evaluated consolidated state evolution as determined by the state evaluator or state machine based on the binary position signals of FIG. 5. The following states are being defined and complemented by suitable inter-state events.

[0057] (a): INITIAL: initial state

[0058] (b): TRANSITION: transitional state between INITIAL and EJECT MEDICATION.

[0059] (c): EJECT MEDICATION: eject medication into body

[0060] (d): HOLDING: holding the auto-injector at injection site

[0061] (e): AIR SHOT: eject medication into air

[0062] (f): FINAL: final state

[0063] Each of the aforementioned states is assigned a horizontal broken line in FIG. 5 in the order given. In a regular injection event, the states (a), (b), (c), (d) and (f) are successively entered by the delivery system as indicated by the continuous stair-case line. The air shot state is defined by the binary position value zero in both the first signal CH0 and the second signal CH1, implying an incomplete ejection and an expanded cover sleeve (due to premature needle retraction). This abort state occurs when the user removes the auto-injector from the injection site prior to completion of the fluid ejection, and replaces the holding state. It is evident that the initial and the final state are assigned to a same combination of binary component positions (CH0 off, CH1 on) and distinguished by their history. The same applies to the transition and the holding state (CH0 on, CH1 on); again they are distinguished by their preceding state (transition only occurs following initial). Depending on the delivery device design, the transition state may be considerably shorter than depicted, and hence rather qualify as an inter-state event.

[0064] FIG. 7 depicts two exemplary continuous signals recorded during a different injection performed with the auto-injector. In this case, the needle has been removed from the injection site very slowly, causing a slow change in the first signal CH0 from the intermediate value back to the initial value. Similar ill-defined transitions in the first continuous position signal may occur because of a slow insertion of the needle. On the other hand, if the tissue into which the needle is inserted provides an increased resistance against fluid dispersion, the second signal may present a slower decrease. The proposed method has been proven to be capable of defining sharp and reasonable signal steps even for the soft, more gradual transitions and corresponding signal ramps as described.

[0065] FIG. 8 depicts an exemplary continuous signal recorded during another injection (broken or dash-dot line), together with the bottom slow tracker BST signal and the top fast tracker TFT signal (both shown as dotted lines). The BST signal is gently relaxing towards the second value of the continuous signal (top plateau) such that there is a slight discrepancy between the BST signal and the continuous signal upon the latter returning to the first value (indicated by the bottom arrow x). At the same instant, the TFT signal is rapidly relaxing to the first value of the continuous signal, such as to appear to be closely following the latter (indicated by the right-hand side arrow y).

[0066] The time constant of the slow trackers is chosen to be fast enough to follow long term changes of the sensor and slow enough to provide a baseline. The time constant of the fast tracker signals is chosen to be fast enough to follow component-position motivated changes of the signal and slow enough to not follow potential short noise impulses, and may be smaller than the time constant of the slow tracker by a factor of at least 500 and preferably at least 5000. The thresholds are dependent on an absolute change in signal from the first to the second value, which in turn is dependent on geometric device design parameters, including distance traveled by the moving component, and tolerances of start position of the moving component, sensitivity of the sensors, and on the velocity of the trackers.

[0067] 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 teachings herein, 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 does not indicate that a combination of these elements or steps cannot be used to advantage, specifically, in addition to the actual claim dependency, any further meaningful claim combination shall be considered disclosed.

LIST OF DESIGNATIONS

[0068] 1 Delivery device [0069] 10 Device housing [0070] 11 Syringe needle [0071] 12 Cover sleeve [0072] 13 Cover sleeve spring [0073] 13a, b Cover sleeve spring base [0074] 2 Electronic module [0075] 21 Position sensor [0076] 21a, b Induction coil [0077] 22 Position discriminator [0078] 23 Status evaluator [0079] 23a Evaluation table [0080] 24 Status indicators [0081] 25 Memory unit [0082] 26 Communication unit [0083] 31 Mobile device [0084] 32 Remote server