Flow detector

Abstract

Disclosed is a flow detector (1) for releasable coupling with a flow channel (20) in a channel coupling area and detecting a flow of liquid drug in the flow channel (20), the flow detector including: an upstream thermoelectric element (10a) and a downstream thermoelectric element (10b), wherein the upstream thermoelectric element (10a) and the downstream thermoelectric element (10b) are arranged spaced apart from each other and movable independent from each other; an upstream biasing element (15a) and a downstream biasing element (15b), wherein the upstream biasing element (15a) acts on the upstream thermoelectric element (10a), thereby biasing the upstream thermoelectric element (10a) towards the channel coupling area, and the downstream biasing element (15b) acts on the downstream thermoelectric element (10b), thereby biasing the downstream thermoelectric element (10b) towards the channel coupling area independently from the upstream biasing element (15a).

Claims

1. A flow detector for releasable coupling with a flow channel in a channel coupling area and detecting a flow of liquid drug in the flow channel, the flow detector including: an upstream thermoelectric element and a downstream thermoelectric element, wherein the upstream thermoelectric element and the downstream thermoelectric element are arranged spaced apart from each other and movable independent from each other; an upstream biasing element and a downstream biasing element, wherein the upstream biasing element acts on the upstream thermoelectric element, thereby biasing the upstream thermoelectric element towards the channel coupling area, and the downstream biasing element acts on the downstream thermoelectric element, thereby biasing the downstream thermoelectric element towards the channel coupling area independently from the upstream biasing element; and wherein the upstream thermoelectric element and the downstream thermoelectric element have an air gap therebetween to inhibit thermal conduction.

2. The flow detector according to claim 1, wherein the flow detector further includes a middle thermoelectric element, wherein the middle thermoelectric element is arranged between and spaced apart from the upstream thermoelectric element and the downstream thermoelectric element and is movable independent from the upstream thermoelectric element and the downstream thermoelectric element; and wherein the flow detector comprises a middle biasing element, wherein the middle biasing element acts on the middle thermoelectric element, thereby biasing the middle thermoelectric element towards the channel coupling area independent from the upstream biasing element and the downstream biasing element.

3. An ambulatory infusion device, including: a fluidic device coupler, the fluidic device coupler being designed for releasable mating coupling, in an operational configuration, with an infusion device coupler of a fluidic device with a flow channel; a pump drive unit, configured to administer liquid drug out of a drug container to a patient's body via the flow channel; a pump control unit, configured to control operation of the pump drive unit for continuous drug administration according to a time-variable basal infusion administration rate; the flow detector according to claim 1 in operative coupling with the pump control unit.

4. The ambulatory infusion device according to claim 3, wherein the pump control unit is configured to control the pump drive unit to administer drug pulses of pre-set pulse volume and to vary a time between consecutive pulses in dependence of a required basal administration rate, and wherein the flow detector is configured to be intermittently operated for administration of the drug pulses.

5. The flow detector according to claim 1, wherein the upstream thermoelectric element and the downstream thermoelectric element are configured to contact an exterior wall of the flow channel.

6. The flow detector according to claim 5, wherein the upstream thermoelectric element is configured to operate as a heating element to heat the liquid drug in the flow channel via conduction through the exterior wall of the flow channel.

7. A flow detector for releasable coupling with a flow channel in a channel coupling area and detecting a flow of liquid drug in the flow channel, the flow detector including: an upstream thermoelectric element and a downstream thermoelectric element, wherein the upstream thermoelectric element and the downstream thermoelectric element are arranged spaced apart from each other, and wherein the upstream thermoelectric element is arranged to couple to the flow channel in the channel coupling area at an upstream position and the downstream thermoelectric element is arranged to releasably couple to the flow channel in the channel coupling area at a downstream position, such that the downstream thermoelectric element operates as a downstream temperature sensor and senses a downstream temperature at the downstream position; wherein the upstream thermoelectric element is configured to operate as a heating element, thereby heating liquid inside the flow channel at the upstream position, and operate as an upstream temperature sensor and sense an upstream temperature at the upstream position; wherein the upstream thermoelectric element is arranged on an upstream flexible printed circuit board element; wherein the downstream thermoelectric element is mounted on a downstream flexible printed circuit board element; and wherein the upstream flexible printed circuit board element and the downstream flexible printed circuit board element form fingers that are able to flex independently from one another.

8. The flow detector according to claim 7, the flow detector further including a first reference thermoelectric element and a second reference thermoelectric element, the first reference thermoelectric element and the second reference thermoelectric element being arranged in a thermal isolated manner with respect to the flow channel.

9. The flow detector according to claim 7, wherein the upstream thermoelectric element is arranged on an upstream element carrier and the downstream thermoelectric element is arranged on a downstream element carrier, and a gap is present between the upstream element carrier and the downstream element carrier.

10. The flow detector according to claim 7, wherein the flow detector includes a positioning structure, the positioning structure being designed to position the flow channel with respect to the upstream thermoelectric element and the downstream thermoelectric element.

11. The flow detector according to claim 7, wherein the upstream thermoelectric element and the downstream thermoelectric element are thermistors, in particular negative temperature coefficient (NTC) thermistors.

12. The flow detector according to claim 11, wherein the upstream thermoelectric element and the downstream thermoelectric element are NTC thermistors of different electric resistance.

13. The flow detector according to claim 7, wherein the flow detector includes an evaluation unit, wherein the evaluation unit is designed to provide an output signal of variable frequency, wherein the frequency depends on a difference between the upstream temperature as sensed by the upstream thermoelectric element and the downstream temperature as sensed by the downstream thermoelectric element.

14. The flow detector according to claim 7, wherein a gap is present between the upstream flexible printed circuit board element and the downstream flexible printed circuit board element, and wherein the gap is an air gap between the upstream flexible printed circuit board element and the downstream flexible printed circuit board element to inhibit thermal conduction therebetween.

15. A method for releasably coupling a flow detector with a flow channel for detecting a flow of liquid drug in the flow channel, the method including: releasably coupling an upstream thermoelectric element and a downstream thermoelectric element with the flow channel, wherein the upstream thermoelectric element and the downstream thermoelectric element are arranged spaced apart from each other along an extension direction of the flow channel and movable independent from each other; biasing the upstream thermoelectric element towards the flow channel, and independently biasing the downstream thermoelectric element towards the flow channel, wherein the biasing the upstream thermoelectric element includes pressing the upstream thermoelectric element against an exterior wall of the flow channel; and heating the liquid drug in the flow channel by conducting heat from the upstream thermoelectric element through the exterior wall of the flow channel.

16. The method according to claim 15, the method further including providing a first reference thermoelectric element and a second reference thermoelectric element, the first reference thermoelectric element and the second reference thermoelectric element being arranged in a thermal isolated manner with respect to the flow channel, the method further including: determining a flow-dependent output signal by processing a signal provided by the upstream thermoelectric element and the downstream thermoelectric element; independently determining a reference output signal by processing a signal provided by the first reference thermoelectric element and the second reference thermoelectric element; evaluating a relation between the flow-dependent output signal and the reference output signal.

Description

BRIEF DESCRIPTION OF THE FIGURES

(1) FIG. 1 shows an embodiment of a flow detector in operative coupling with a flow channel in a schematic side view;

(2) FIG. 2 shows a further embodiment of a flow detector in operative coupling with a flow channel in a schematic side view;

(3) FIG. 3 shows the embodiment of FIG. 2 in a schematic three-dimensional view;

(4) FIG. 4 illustrates the operation of an embodiment of a flow detector;

(5) FIG. 5 illustrates the operation of a further embodiment of a flow detector;

(6) FIG. 6 shows an embodiment of the coupling of a flow detector with an evaluation unit;

(7) FIG. 7 shows the coupling of a flow detector with an evaluation unit according to a further embodiment;

(8) FIG. 8 shows the output of an evaluation unit for different drug pulse volumes;

(9) FIG. 9 shows an embodiment of an ambulatory infusion system in a schematic functional view;

(10) FIGS. 10a, 10b show a further embodiment of a flow detector in operative coupling with a dosing unit;

(11) FIG. 11 shows the outputs of flow curve and a reference curve for an embodiment of a flow detector;

(12) FIG. 12 shows an arrangement of a flow detector in a schematic functional view.

WAYS OF CARRYING OUT THE INVENTION

(13) In the following, reference is first made to FIG. 1, showing an exemplary embodiment of a flow detector 1 and a fluidic device 2 in a schematic structural view.

(14) For the sake of clarity, elements that are present in different figures and/or embodiments are not necessarily referenced separately in each and every figure.

(15) The flow detector 1 includes an upstream thermoelectric element 10a, a downstream thermoelectric element 10b, and an optional middle thermoelectric element 10c. In this example, the upstream thermoelectric element 10a and the downstream thermoelectric element 10b are NTC thermistors of identical characteristics, while the middle thermoelectric element 10c is a heating element (resistor). In an embodiment without the middle thermoelectric element 10c, the upstream thermoelectric element 10a and the downstream thermoelectric element 10b are NTC thermistors of favorably different characteristics, in particular different resistance.

(16) The thermoelectric elements 10a, 10b, 10c are surface mounted elements or surface mounted devices (SMDs), each of them being mounted on a corresponding separate element carrier 11a, 11b, 11c in form of flexible circuit board elements. The thermoelectric elements 10a, 10b, 10c are mounted on and connected to the corresponding printed circuit board elements 11a, 11b, 11c via soldering joints 12 (typically two soldering joints 12 for each of the thermoelectric elements 10a, 10b, 10c).

(17) On the opposite side of the printed circuit board elements 11a, 11b, 11c, corresponding insulator elements 13a, 13b, 13c are arranged. Each of the insulator elements 13a, 13b, 13c has a central blind bore in which an end section of a corresponding biasing element 15a, 15b, 15c is arranged. The biasing element 15a is the upstream biasing element, the biasing element 15b the downstream spring element and the biasing element 15c the middle biasing element of the flow detector 1. The opposite ends of the biasing elements 15a, 15b, 15c are supported by a support structure (not shown) that may be part of an ambulatory infusion device housing. The biasing elements 15a, 15b, 15c are exemplarily realized as coil springs. The biasing elements 15a, 15b, 15c each separately exert a biasing force onto the corresponding carrier element 11a, 11b 11c and the thermoelectric elements 10a, 10b, 10c in direction B.

(18) The upstream element carrier 11a and the middle element carrier 11c, as well as the middle element carrier 11c and the downstream element carrier 11b are pairwise separated by a gap 14 of identical width.

(19) The fluidic device 2 includes the flow channel 20 with a hollow lumen 22 of circular cross section that is circumferentially surrounded by a flow channel wall 21, in combination forming a tubular structure. Other types of flow channels may be used as well.

(20) At a side adjacent to the flow detector 1 respectively the thermoelectric elements 10a, 10b, 10c, the fluidic device 2 includes a plate-shaped abutment element 23 that supports the flow channel 20 and absorbs the contact forces respectively biasing forces. The flow channel exemplarily extends along a straight line with the flow direction being indicated by F.

(21) The upstream thermoelectric element 10a contacts the flow channel 20 at an upstream position (16b) where the elastic flow channel wall 21 is accordingly slightly deformed under the influence of the contact force respectively biasing force. The same holds true for the downstream thermoelectric element 10b that contacts the flow channel 20 at a downstream position 16b and the middle thermoelectric element 10c that contacts the flow channel 20 at the middle position 16c (not shown for the middle thermoelectric element 10c for clarity reasons). The area of the upstream contact position 16a, the downstream contact position 16b, and the middle contact position 16c, in combination, forms the channel coupling area.

(22) In the following, reference is additionally made to FIG. 2, showing a further exemplary embodiment of the flow detector 1 together with components of a fluidic device 2. In a number of aspects, the embodiment of FIG. 2 is identical to the before-discussed embodiment of FIG. 1. The following discussion is focused on the differences.

(23) In the embodiment of FIG. 1, the thermoelectric elements 10a, 10b, 10c are arranged on the side of the carrier elements (flexible printed circuit board elements 11a, 11b, 11c) that face the flow channel 20 and the channel coupling area. The thermoelectric elements 10a, 10b, 10c accordingly directly contact the flow channel 20 respectively the flow channel wall 21. In the embodiment of FIG. 2, in contrast, the thermoelectric elements 10a, 10b 10c are arranged on the corresponding carrier elements 11a, 11b, 11c on a side pointing away from the flow channel 20 and the channel coupling area, but pointing towards the biasing elements 15a, 15b, 15c instead.

(24) The thermoelectric elements 10a, 10b, 10c accordingly contact the flow channel 20 indirectly, via the carrier elements 11a, 11b, 11c, rather than directly. The result is a further improvement of the thermal coupling, as explained before in the general description. Additionally, it can be seen that the channel coupling area between the carrier elements 11a, 11b, 11c and the flow channel 20 is larger as compared to the thermoelectric elements 10a, 10b, 10c. The deformation of the flow channel wall 21 is accordingly favourably reduced or even avoided.

(25) In order to improve the desired thermal isolation between the thermoelectric elements and the (typically metallic) biasing elements, an optional insulator cap 17a, 17b, 17c is provided in this embodiment for each of the thermoelectric element and the corresponding insulator 13a, 13b, 13c and biasing element 15a, 15b, 15c, thus preventing a direct contact between the thermoelectric elements 10a, 10b, 10c and the insulators 13a, 13b, 13c on the one side and the biasing elements 15a, 15b, 15c on the other side. The insulator caps 17a, 17b, 17c are made from a material of low thermal conductivity, typically plastics, and put over the thermoelectric elements 10a, 10b, 10c. The insulator caps 17a, 17b, 17c may, e.g., be glued onto the carrier elements 11a, 11b, 11c after soldering of the thermoelectric elements 10a, 10b, 10c. The insulator caps 17a, 17b, 17c may in principle also be realized integral with the insulators 13a, 13b, 13c.

(26) In the following, reference is additionally made to FIG. 3, showing the arrangement form FIG. 2 in a perspective view. It can be seen that the carrier elements (flexible printed circuit board elements) 11a, 11b, 11c are finger-shaped and extend parallel from a common flexible printed circuit board 11d, traverse to the extension direction of the flow channel 20. It can further be seen that flow channel 20 is partly arranged in a groove 24 of the abutment element 23, the groove 24 positioning the flow channel 20 relative to the flow detector 1, thereby serving as positioning structure. A corresponding arrangement may also be used in the embodiment of FIG. 1.

(27) FIG. 1 to FIG. 3 show embodiments with three separate thermoelectric elements where a middle thermoelectric element 10c as heating element is distinct from the upstream and downstream thermoelectric elements 10a, 10b as temperature sensors. Embodiments where the upstream thermoelectric element 10a serves as both heating element and as upstream temperature sensor may be realized in the same way, omitting, however, the middle thermoelectric element 10c and associated components.

(28) In the following, reference is additionally made to FIGS. 4a, 4b, illustrating the operation of an embodiment of a flow detector with three thermoelectric elements. FIG. 4a shows the situation shortly before a drug pulse is administered. Both the upstream thermoelectric element 10a as upstream temperature sensor and the downstream thermoelectric element 10b as downstream temperature sensor are at a low base temperature that corresponds to a temperature that can be measured in a static state without liquid flow in the lumen 22. The middle thermoelectric element 10c as heating element heats the liquid in its proximity to an increased temperature. Without liquid flow, the heat would be transported equally into the upstream direction (against the flow direction F) and the downstream direction (with the flow direction F) via thermal conduction, resulting in substantially equal temperatures at the upstream thermoelectric element 10a and the downstream thermoelectric element 10b.

(29) FIG. 4b illustrates the situation shortly after switching off the heating via middle thermoelectric element 10c and administering a drug pulse. Now, the heat is transported with the drug in the lumen 22 in the flow direction F, resulting in the downstream thermoelectric element 10b as downstream temperature sensor being at a higher temperature than the upstream thermoelectric element 10a as upstream temperature sensor. The measured temperature difference between the downstream thermoelectric element 10b and the upstream thermoelectric element 10a is evaluated in order to determining whether or not a liquid flow has actually occurred. Optionally, the heating may be continued during the measurement.

(30) FIGS. 5a, 5b show situations corresponding to FIGS. 4a, 4b for an embodiment with only two thermoelectric elements, where the upstream thermoelectric element 10a serves as both heating element and upstream temperature sensor, and the downstream thermoelectric element 10b serves as downstream temperature sensor. In FIG. 5a, the upstream thermoelectric element 10a is operated as heating element that heats the liquid in its proximity to an increased temperature, while the downstream thermoelectric element 10b is at a lower temperature. As discussed further below in the context of FIG. 6 in more detail, the upstream thermoelectric element 10a heats the liquid continuously or substantially continuously, resulting in the upstream thermoelectric element 10a being at a higher temperature than the downstream thermoelectric element 10b. Since, however, heated liquid drug is, in FIG. 5b, transported towards the downstream thermoelectric element 10b and replaced by colder liquid from upstream of the flow detector, the temperature at the upstream thermoelectric element 10a will be somewhat decreased and the temperature at the downstream thermoelectric element 10b will be somewhat increased. The temperature difference between the upstream thermoelectric element 10a and the downstream thermoelectric element 10b is accordingly reduced because of the liquid drug flow.

(31) In the following, reference is additionally made to FIG. 6, illustrating an embodiment of an evaluation unit 3 in interaction with the thermoelectric elements 10a, 10b. In this embodiment, the upstream thermoelectric element 10a and the downstream thermoelectric element 10b are NTCs (also referred to as NTC1 and NTC2) of exemplary identical characteristics and are arranged in series with corresponding fixed resistors R1 and R2 such that fixed resistor R1 and NCT1 respectively fixed resistor R2 and NTC2 each form a branch of a Wheatstone bridge that is selectively connectable to a voltage supply Vcc via switches S1 S2 that are closed for operation and otherwise open. The differential voltage between the midpoints M1, M2 of the two branches is fed to a differential amplifier 30 that is typically realized based on an operational amplifier (op-amp). The output of the differential amplifier 30 is fed into an analogue-to-digital converter (ADC) 31, the output of which (referenced as “counts” is) is accordingly dependent on and favourably substantially proportional to the temperature difference between NTC1 and NTC2.

(32) The upstream thermoelectric element 10a (NTC1) may serve as both heating element and upstream temperature sensor with switch S1 being closed. After a heating period, switch S2 is additionally closed and the downstream thermoelectric element 10b (NTC2) is additionally powered for measuring the temperature difference. During the preceding heating time, switch S2 is opened in order to prevent NTC2 from heating the liquid at the downstream position. If no flow detection is carried out, both S1 and S2 are favourably open in order to save energy and avoid an unnecessary and generally unfavourable liquid heating.

(33) In particular in embodiments of the above-described type where the first thermoelectric element 10a and the second thermoelectric element 10b are of identical characteristics and the upstream thermoelectric element 10a additionally serves as heating element, the downstream thermoelectric element 10b is only powered for a short period of time (typically in the range of some milliseconds) for the temperature measurement and is in particular not powered during the preceding heating time, as it would otherwise heat the liquid in the same way as the upstream thermoelectric element.

(34) In a variant (not shown), a branch with a further switch and a further resistor in serial arrangement (like resistor R1 and switch S1) is provided in parallel to resistor R1 and switch S1, such that NTC1 may be powered alternatively via the further switch and the further resistor. The further resistor is favourably considerably smaller as compared to the resistor R1 and NTC1 is powered for the heating time via the further switch and further resistor, resulting in a favourable shortened heating time. The heating may be controlled by operating the further switch via pulse-width modulation. For the subsequent temperature difference measurement, the further switch is opened and switches S1, S2 are closed as explained before.

(35) In a further variant, both the upstream thermoelectric element 10a (NTC1) and the downstream thermoelectric element 10b (NTC2) serve as temperature sensors only and an additional middle thermoelectric element is provided as dedicated heating element.

(36) In the following, reference is additionally made to FIG. 7, illustrating a further embodiment of an evaluation unit 3 in interaction with the thermoelectric elements 10a, 10b. This type of embodiment is particularly favourable if the upstream thermoelectric element 10a serves as both upstream temperature sensor and as heating element, and the upstream thermoelectric element 10a and the downstream thermoelectric element 10b are NTCs of different characteristics, in particular different resistance. The resistance of the upstream thermoelectric element 10a is considerably lower than the resistance of the downstream thermoelectric element 10b in order to prevent the downstream thermoelectric element 10b from heating the liquid in the same way as the upstream thermoelectric element 10a. Favorably, the resistance ration may be about 1:10 or more.

(37) In the embodiment of FIG. 7, an e.g. op-amp-based comparator 32 forms, together with the thermoelectric elements NTC1, NTC2, a Schmitt-Trigger, the two thresholds of which are determined by the resistances of NTC1 respectively NTC2. Further, an oscillator of given frequency is present and coupled to the comparator 32. The oscillator is exemplarily realized as simple R-C oscillator with a frequency of, e.g. some Kilohertz (kHz) to some Megahertz (MHz). As a result, the output of the comparator 32 provides a square signal, the frequency of which depends on the temperature difference between NTC1 and NTCs and can be measured in a straight forward way.

(38) Modern microcontrollers typically include components such as comparators, reference voltage supplies, timers and highly accurate crystal oscillators. Based on such a microcontroller, an evaluation unit 3 according to FIG. 7 may be realized with a very small number of further components (the resistor R, the capacitor C, and the NTCs as thermoelectric elements), thus providing a very compact and cost-efficient solution.

(39) The evaluation unit 3, e.g. according to FIG. 6 or FIG. 7, may be realized partly or fully integral further functional units or circuitry, e.g. a pump control unit of an ambulatory infusion device.

(40) In the following, reference is additionally made to FIG. 8. FIG. 8 shows exemplary measurement results as obtained in a flow detection element with a thermal flow detector 1 in accordance with FIG. 5 and an evaluation unit based on a Wheaton bridge as shown in FIG. 6.

(41) The diagrams show the output of the ADC 31 (vertical axis) as a function of time (horizontal axis), with an increasing absolute value of the (exemplarily negative) ADC output corresponding to an increased temperature difference.

(42) In the flow detection element, the upstream thermoelectric element 10a started operating as heating element at t=1 sec (not visible), and a drug pulse was administered at t=4 sec. The experiment was carried out with drug pulse volumes V of 100, 200, 300, 500 nl (nano litres), with 0 nl (i.e. no drug pulse is administered) being shown additionally as reference.

(43) It can be seen that before the drug pulse is administered, all curves are substantially equal, indicating good reproducibility. The temperature difference between the upstream thermoelectric element 10a and the downstream thermoelectric element 10b increases over time in the shown period because of the heating, which decreases the resistance of the upstream thermoelectric element 10a due to its negative temperature coefficient. Also the potential of M1 (see FIG. 6) accordingly decreases.

(44) The administration of the drug pulse results in a temporary and relatively sudden decrease of the temperature difference, resulting from the cooling effect caused by heated liquid being replaced by cooler downstream liquid at upstream thermoelectric element 10a and from the heating effect caused by cooler liquid being replaced by heated liquid at downstream thermoelectric element 10b. It can be seen that the effect increases with the drug pulse volume V. Subsequent to the administration of the drug pulse, the temperature difference again approaches the reference curve. All curves for the different drug pulse volumes V clearly distinguished from both the reference curve and each other and in particular drug pulses 200 nl or more are clearly distinguished. The evaluation may be carried out by evaluating the slope of the temperature difference versus time curve.

(45) It is noted that in the flow detection experiment as illustrated in FIG. 8, heating was continuously carried out by powering the upstream thermoelectric element 10a (NTC1) over the duration of the experiment, while the downstream thermoelectric element 10b (NTC2) was powered by switching S2 only periodically for few milliseconds for temperature measurement, with a frequency of e.g. 10 Hz or less. In a practical application, heating would typically be stopped after the drug administration, e.g. at t=4.5 sec. This is also the time when the temperature difference may be evaluated.

(46) In the following, reference is additionally made to FIG. 9, illustrating major components and functional units of an ambulatory infusion system in a schematic functional view.

(47) In an operational state, the ambulatory infusion system includes an ambulatory infusion device 7, a drug container 5, and a fluidic device 2. The drug container 5 is exemplarily assumed to be a cylindrical cartridge that receives a sealing and displaceable piston, such that displacement of the piston along a longitudinal cartridge axis results in a corresponding displacement of liquid drug out of the container.

(48) The ambulatory infusion device 7 includes a pump drive unit 4 in operative mechanical coupling with the drug container 5. For the before-mentioned type of drug container, the pump drive unit 4 may a spindle drive in releasable engagement with the piston, as generally known in the art, thus forming a syringe driver arrangement.

(49) The ambulatory infusion device 7 further includes an electronic pump control unit 6 that is operatively coupled with the pump drive unit for controlling operation of the pump drive unit 4. The pump control unit 6 is favourably configured to control the pump drive unit 4 for the administration of drug boli of desired volume on demand and further for a basal drug administration according with an infusion rate according to a time-variable schedule. With respect to basal administration, individual drug pulses may be administered in fixed time intervals, e.g. every three minutes, with the drug pulse volume depending on the infusion rate. In particular for small infusion rates, basal delivery may also be carried out with a fixed pulse volume in a range of, e.g. 200 nano litres to 1 micro litre, and the time interval between consecutive pulses is adjusted in accordance with the desired rate. The evaluation unit 3 is exemplarily shown as part of the pump control unit 6 and may be realized integral with the general electronics circuitry of the ambulatory infusion pump 7. The evaluation unit 3 may, e.g. be designed according to FIG. 6 or FIG. 7.

(50) The fluidic device 2 comprises an infusion device coupler 25 and the ambulatory infusion device 7 comprises a fluidic device coupler 70 that are designed for releasable mating coupling and are realized, e.g. as snap-fit coupling, bayonet coupling, or the like. In a coupled and operational state, both a mechanical coupling is provided as well as a fluidic coupling between the drug container 5 and the flow channel 20. Further in a coupled state, the flow channel 20 couples with thermoelectric elements 10a, 10b, 10c as explained before. The thermoelectric elements 10a, 10b, 10c are, like the overall flow detector, part of the ambulatory infusion device 7. A fluidic outlet 26 of the flow channel 20 is, in application, in fluidic coupling with an infusion site of the patient. For this purpose, the fluidic outlet may releasable couple with an infusion tubing, or include an infusion tubing or directly an infusion cannula. All of such designs are generally known in the art.

(51) The flow detector 1 may be designed according to any embodiment in accordance with the present document, for example according to embodiments as shown in FIG. 1, FIG. 2, and FIG. 3. In FIG. 9, only the thermoelectric elements 10a, 10b, 10c are shown in interaction with the flow channel 20 for clarity reasons. It is noted that the flow detector 1 may, as discussed before, also comprise the upstream thermoelectric element 10a and the downstream thermoplastic element 10b, omitting the middle thermoelectric element 10c.

(52) The drug container shown is shown separately from the ambulatory infusion pump 7 and the fluidic device 2 in FIG. 9 for illustrative purposes. In practice, it may, e.g., be received inside a container receptacle a housing of the ambulatory infusion pump 7. It may also be integral with the fluidic device 2. Further alternative fluidic designs may be used instead of an ordinary syringe-driver design. In particular, the fluidic device 2 may include respectively be realized as downstream dosing unit as mentioned before and disclosed, e.g. in EP1970677A1. Also, the drug container 5 is not necessarily realized as cylindrical cartridge but may also be, e.g., a flexible or semi-rigid pouch, as generally known in the art. Independent form the system design and the specific fluidic architecture, the ambulatory infusion pump 7, the drug container 5 and the fluidic design 2 favorably form a common compact unit during application.

(53) In a typical application, the upstream thermoelectric element 10a is operated as heating element for a pre-administration heating time in a range of a number of seconds prior the administration of a drug pulse and the heating favorably continues during the administration of the drug pulse. Favorably, heating is further continued for an after-administration heating time subsequent to the drug pulse administration. The after-administration heating time may, e.g. be in a range of 0.5 sec.

(54) Further, the heating time, in particular the pre-administration heating time, may be selected in dependence of the drug pulse volume and may in particular increase with decreasing drug pulse volume. The following list gives exemplary values for the total heating time (including pre-administration heating time and after-administration heating time):

(55) 7 sec for a drug pulse volume from 100 nl up to 299 nl

(56) 6 sec for a drug pulse volume from 300 nl up to 399 nl

(57) 5 sec for a drug pulse volume from 400 nl up to 499 nl

(58) 4 sec for a drug pulse volume from 500 nl up to 599 nl

(59) 3 sec for a drug pulse volume of 600 nl or more.

(60) The ambulatory infusion device 7 may be arranged to be carried, e.g. in a trousers' pocket, with a belt clip, or the like, and/or may be designed for direct attachment to the skin as so-called patch pump. A number of suited overall designs and architectures is known in the art.

(61) In the following, reference is additionally made to FIGS. 10a, 10b, showing a further exemplary embodiment of a flow detector 1 in accordance with the present disclosure. In this example, the flow detector 1 is shown in the context of a downstream dosing unit as mentioned before and disclosed, e.g. in EP1970677A1, EP EP2881128A1. This however, is not essential and the flow detector 1 of this type of embodiment may also be used in the context of other ambulatory infusion systems, as discussed, e.g. in the context of FIG. 9. The views of FIGS. 10a, 10b are identical, except that a number of elements is omitted as explained further below.

(62) In FIGS. 10a, 10b, ref. 99 refers to the dosing cylinder of the downstream dosing unit. A fluidic platform 21a is provided with the dosing cylinder 99 in an integral way. The fluidic platform 21 comprises the flow channel 20 in form of a groove that is fluidic coupled with the outlet port respectively draining port of a valve (not shown) of the dosing unit and a fluidic outlet (not shown) as generally explained in the context of FIG. 9. The flow channel 20 is covered by a foil 21b (removed in FIG. 10b) of good thermal conductivity. In combination, the fluidic platform 21a and the foil 22b delimit the flow channel 20.

(63) Regarding the arrangement and operation of the upstream thermoelectric element 10a and the downstream thermoelectric element 10b, the design of FIGS. 10a, 10b substantially corresponds to the design shown in FIGS. 2, 3 to which reference is additionally made in this regard.

(64) The separate element carriers 11a, 11b extend from a flexible printed circuit board 11 on which also a first reference thermoelectric element 10a′ and a second reference thermoelectric element 10b′ are arranged. In contrast to the upstream thermoelectric element 10a and the downstream thermoelectric element 10b, the first reference thermoelectric element 10a′ and the second reference thermoelectric element 10b′ are thermally decoupled from the flow channel by way of a plastic insulating element 93 that is arranged between the first and second reference thermoelectric elements 10a′, 10b′ on the one side and the flow channel 20 respectively the foil 21b. Further, an insulating cover 92 is provided that covers the portion of the flexible circuit board 11 where the first and second reference thermoelectric element 10a′, 10b′ are located. The first and second reference thermoelectric element 10a′, 10b′ are accordingly arranged between the insulating element 93 and the insulating cover 92.

(65) The positioning of the first and second reference thermoelectric element 10a′, 10b′ with respect each other favourable corresponds to the positioning of the upstream thermoelectric element 10a and the downstream thermoelectric element 10b with respect to each other. In particular, the distance between the first reference thermoelectric element 10a′ and the second reference thermoelectric element 10b′ corresponds to the distance between the upstream thermoelectric element 10a and the downstream thermoelectric element 10b. The insulating cover 92 is designed such that the mutual thermal coupling between the first r4ference thermoelectric element 10a′ and the second reference thermoelectric element 10b′ corresponds to the mutual thermal coupling between the upstream thermoelectric element 10a and the downstream thermoelectric element 10b if no flow is present in the flow channel.

(66) It is noted that the design of FIGS. 10a, 10b does not use a middle thermoelectric element as dedicated heating element. If such middle thermoelectric element (arranged between the upstream thermoelectric element 10a and the downstream thermoelectric element 10b) is present, a third reference thermoelectric element as dedicated reference heating element is favourable also provided and arranged between the first and second reference thermoelectric element, respectively.

(67) In the following, reference is additionally made to FIG. 11. FIG. 11 shows exemplary measurement results, similar to FIG. 8, as obtained in an arrangement with additional first and second reference thermoelectric elements 10a′, 10b′, as explained before with reference to FIGS. 10a, 10b. In FIG. 11, the solid curve (labelled “Canal NTC”, also referred to as “flow curve”) shows the measurement results based on the upstream thermoelectric element 10a and the downstream thermoelectric element 10b. The dashed curve (labelled “Control NTC”, also referred to as “reference curve”) shows the measurement results based on the first and second reference thermoelectric elements 10a′, 10b′. The start of the liquid flow within the flow channel 20 is indicated by “S”, while the end of the liquid flow is indicated by “E”.

(68) Considering the flow curve alone, it can be seen that the start and in particular the end of the liquid flow is hard to determine. It can further be seen that both curves substantially coincide before the start of the liquid flow, indicating a good correspondence. With the beginning of the liquid flow, both curves start diverging, with the reference curve not being influenced by the liquid flow, in contrast to the flow curve. Further, with the liquid flow ending, the flow curves again approaches the reference curve until both curves finally coincide again. By evaluating both curves in combination and in particular the deviation between the flow curve and the reference curve, the start and end of the liquid flow can accordingly be determined with substantially improved precision and reliability. It can be seen that at the change in flow is comparatively fast at “S”, while it is slow and creeping at “E”. As short flow events (e.g. the administration of volumes of less than 1 μl during administering low basal rates) always change the flow rapidly, it is sufficient to evaluate short flow events just with the thermoelectric elements 10a and 10b as explained before. Any obstructions of flow will lead to slow or no change in flow and will be detected reliably as “no flow” since a rapid flow change is expected. Larger boli are flow events of longer duration which can eventually be obstructed in a slow manner. Therefore, these long flow events are evaluated preferably with both pairs of thermoelectric elements 10a, 10b and 10a′, 10b′. While the slow decrease in flow cannot be reliably detected using the upstream thermoelectric element 10a and the downstream thermoelectric element 10b alone, the creeping decrease of flow will reliably be detected by comparison with of the flow-independent signals that are generated by the reference thermoelectric elements 10a′, 10b′.

(69) In the following, reference is additionally made to FIG. 12. Fig. shows an arrangement with a flow detector 1 with reference thermoelectric elements in a schematic functional view. Reference is, in this context, additionally made to FIG. 9. It can be seen that two separate evaluation units 3 are present, which may be designed according to any of the before-discussed embodiments, based, e.g. on circuitry as shown in FIG. 6 or FIG. 7. One of the two evaluation units 3 is coupled with the upstream thermoelectric element 10a and the downstream thermoelectric element 10b. The other evaluation unit 3 is coupled with the first reference thermoelectric element 10a′ and the second reference thermoelectric element 10b′. Both evaluation units are independent from each other. The outputs of the two evaluation units generally corresponds to the flow curve as shown in FIG. 11. The outputs of the two evaluation units 3 are fed into an compensation unit that is exemplarily realized as difference computation unit 33 that determines the difference of the output signals provided by the two evaluation units 3. The output of the difference computation unit 33 corresponds to the difference between the flow curve and the reverence curve as explained before, indicating the actual liquid flow within the flow channel 20. The two evaluation units 3 and the difference computation unit 33 form, in combination, an evaluation and compensation unit as explained before. Optionally, it may be designed to operate in a first mode of operation or a second mode of operation as explained before.