Urine analyzer to monitor treatment adherence

Abstract

Urine Analyzer for Monitoring Therapeutic Adherence. The invention relates to a urine analysis device (1) for monitoring a user's adherence to a treatment regimen including the regular intake of a medication. The device comprises a collection channel (4) for collecting the user's urine when the user urinates in a toilet, and an analysis module (3) configured to detect the presence of an analyte in the urine collected by the collection channel. The analyte is an active ingredient of the medication or a metabolite of the active ingredient. The analysis module is configured to determine the concentration of the analyte in the collected urine or a quantity monotonically related to the analyte concentration in the urine. It also relates to a system and method for monitoring a user's therapeutic adherence. Figure for the abstract: Fig. 1

Description

Title of the invention: Urine analyzer for monitoring therapeutic compliance Technical field

[0001] The general field of the invention is that of devices for monitoring and improving therapeutic compliance with drug treatment.

[0002] The invention relates more specifically to a urine analysis device suitable for monitoring a user's compliance with a treatment comprising the regular taking of a medication. It also relates to a method for monitoring a user's compliance with their treatment using such a device. Prior art

[0003] In a 2018 study (OECD Health Working Paper No. 105, “Investing in medication adherence improves health outcomes and health system efficiency - Adherence to medicines for diabetes, hypertension, and hyperlipidaemia”), the OECD estimates that “non-adherence to medication is the cause of 200,000 premature deaths each year in Europe. People with major chronic diseases, in particular, are at serious risk from not taking their medication correctly. Among diabetics and people with heart disease, patients who neglect their medication experience almost twice the mortality rate of patients who adhere strictly to it.”

[0004] Therapeutic compliance therefore represents an important issue in enabling better support for a patient during their treatment, in improving the chances of success of their treatment, or even in the context of carrying out clinical studies.

[0005] Devices such as connected medication boxes, associated or not with wearable devices (for example comprising an RFID tag or implementing NFC technology), are known which make it possible to detect whether a patient opens a medication box or has approached it. However, such devices do not make it possible to know for sure whether a patient has taken their medication.

[0006] When you want to detect the taking of a medication, you have to go to a laboratory which will be able to carry out an analysis on a biological fluid and detect the presence of the medication or a metabolite of it.

[0007] In addition to the costs, the need for qualified personnel and the sometimes invasive nature of these controls, laboratory measurements do not allow for a realistic estimation of compliance with a treatment for several reasons: - the measurements are unique and it is difficult to estimate whether a medication has been ingested before the measurement; - it is easy to mislead the measurement if the patient takes his treatment only before going to the laboratory (false positive); - drugs with a reduced half-life may be eliminated from the body before measurement (false negatives); - drugs with a high half-life may give a positive result when the treatment is no longer followed (false positives); and - variability between patients and during the same day means that the measurement must be taken at a specific time.

[0008] Thus, the presence of the drug or a metabolite thereof only allows us to deduce that the drug was ingested within a given time interval preceding the measurement, which depends on the half-life of the drug and the patient. However, it is impossible to deduce from this measurement whether the patient is following his treatment regularly, and in particular over the long term.

[0009] It would be desirable to be able to monitor a user's compliance with their treatment over the long term, in a simple, practical, reliable, inexpensive and non-invasive manner. Presentation of the invention

[0010] This aim is achieved by a urine analysis device for monitoring a user's compliance with a treatment comprising the regular intake of a medication, the device comprising a collection channel for collecting the user's urine when the user urinates in a toilet, and an analysis module configured to detect the presence of an analyte in the urine collected by the collection channel, the analyte being an active ingredient of the medication or a metabolite of the active ingredient, the analysis module being configured to determine an analyte concentration in the collected urine or a quantity proportional to the analyte concentration (C) in the urine.

[0011] By “quantity related by a monotonic function to the concentration of analyte in the urine” is meant for example an optical quantity (for example: fluorescence rate, absorbance rate, color, etc.) or a conductimetric quantity (for example: conductance). The quantity may for example be proportional to the concentration at least over a range of concentrations. In the remainder of the text and the claims, when the concentration of analyte is mentioned, this may also include any quantity measurable by the device which is related by a monotonic function to the concentration of analyte.

[0012] The urine analysis device according to the invention makes it possible to monitor the taking of a medication in a simple and regular manner, in particular daily. It can in fact be configured to carry out several successive analyses corresponding to several distinct urinations by the user. The device is also non-invasive, since it can analyze urine without user intervention or complex sampling. The user only has to urinate in the toilet for the urine to be collected and analyzed by the device, and the results are automatically transmitted, for example, to their doctor, an authorized organization or a loved one. This device thus makes it possible to improve the user's care during their treatment and compliance with their treatment.

[0013] The urine collected by the collection channel comes directly from the user's urination, that is to say that the urine is not mixed with another liquid before being collected, which makes the analysis more reliable and avoids any contamination of the urine by undesirable compounds.

[0014] In an exemplary embodiment, the drug may be a drug for treating a cardiac pathology chosen from the following classes: diuretics (furosemide, amiloride, torsemide), statins (atorvastatin, pravastatin, lovastatin), anticoagulants (for example: warfarin, enoxaparin, heparin, aspirin, clopidogrel, dabigatran, apixaban, rivaroxaban).

[0015] In an exemplary embodiment, the medicament may be a medicament for treating hypertension selected from the following classes: calcium channel blockers (for example from the dihydropyridine family: lacidipine, efonidipine, clevidipine, cilnidipine, amlodipine, felodipine, nifedipine; or non-dihydropyridines: diltiazem, verapamil), angiotensin II antagonists (for example from the tetrazole family: candesartan, valsartan, losartan; or non-tetrazoles: eprosartan, telmisartan), angiotensin converting enzyme inhibitors (for example: captopril, ramipril, enalapril), diuretics (for example: hydrochlorothiazide, indapamide, amiloride) and beta-blockers (for example: metoprolol, bisoprolol, atenolol, propranolol).

[0016] In one exemplary embodiment, the drug may be a drug for treating epilepsy selected from the following classes: carbamazepine, phenytoin, or valproic acid.

[0017] In an exemplary embodiment, the drug may be an immunosuppressive drug (maintenance drugs) selected from the following classes: calcineurin inhibitors (e.g.: tacrolimus, cyclosporine), antiproliferative agents (e.g.: mycophenolic acid, mycophenolate mofetil, mycophenolate sodium, azathioprine), mTOR inhibitors (e.g.: sirolimus) steroids (e.g.: prednisone).

[0018] In an exemplary embodiment, the analysis module may be configured to, at each analysis, contact the collected urine with a detection compound capable of binding to the analyte and to detect the presence of the complex between the analyte and the detection compound.

[0019] The detection compound is capable of selectively binding to the analyte. The detection compound can be detected directly (e.g., by a change in color, fluorescence, or conductance of the solution when the detection compound binds to the analyte), or indirectly by using a label (e.g., a fluorescent or electrochemically detectable label) that can bind to the complex formed by the detection compound and the analyte.

[0020] In an exemplary embodiment, the detection compound is a molecularly imprinted polymer (“MIP” in English).

[0021] When the detection compound is a MIP, it may change its optical or electrochemical property when it binds to the analyte. For example, the MIP may become fluorescent when it binds to the analyte. For example, the conductance of a solution comprising the MIP may change when the MIP binds to the analyte. Alternatively, a fluorescent or electrochemically detectable label may be used that allows the complex formed by the MIP and the analyte to be detected.

[0022] A detection compound in the form of an MIP is advantageous in that it is more stable at room temperature than an aptamer, an antibody or a protein (other known detection compounds). This is particularly useful when this compound must be stored in a device positioned in the toilet for a significant period of time, for example when following a long-term treatment. In addition, an MIP can be stored in solution or in solid form. Also, the MIP can be used to carry out a quantitative measurement of the concentration of analyte in urine because its properties change when it binds with the analyte. Finally, the MIP is less expensive and easier to obtain than an aptamer or an antibody.

[0023] It is further possible to design a MIP capable of forming a complex with several different analytes, for example with the active ingredients of drugs of a particular drug class (i.e. a set of molecules having similar or identical portions). Thus, the use of a MIP makes the device according to the invention even more versatile.

[0024] In an exemplary embodiment, the analysis module may be configured to further measure a correction quantity of the analyte concentration which is characteristic of the hydration of the user, for example the correction quantity is chosen from: the creatinine concentration in the collected urine, the specific gravity of the collected urine, the urinary flow rate of urination, the conductivity of the collected urine.

[0025] The analyte concentration measured during an analysis can thus be corrected using the correction quantity. The hydration of a user can indeed vary during the same day and from day to day, which influences the volume urinated during urination and the analyte concentration in the urine independently of the amount of medication ingested. This arrangement makes it possible to improve the analysis result and to be able to compare several successive analyses while taking into account the user's hydration.

[0026] In one exemplary embodiment, the analysis module may comprise a plurality of test strips and / or a microfluidic chip.

[0027] An analysis module comprising test strips is advantageous in that its use is simple and inexpensive to implement. It is further possible to test several analytes with the same strip to detect the intake of several different drugs, or to use several strips each allowing the intake of different drugs to be detected. Test strips can be used to measure the correction quantity of the analyte concentration.

[0028] In an exemplary embodiment, the test strip may be a colorimetric test strip or a lateral or vertical flow immunoassay test strip. The fluorescence level of a portion of the test strip may, for example, be directly related to the analyte concentration in the urine.

[0029] In an exemplary embodiment, the analysis module may comprise a plurality of test strips and a rotating support on which the strips are fixed, said support being removable relative to the urine analysis device. Such a device makes it possible to have several test strips on the same support, which can be changed like a consumable and allows regular monitoring of medication intake.

[0030] In an exemplary embodiment, where the analysis module comprises a microfluidic chip, the urine and the detection compound solution can be conveyed in the form of drops, the microfluidic chip is then adapted to merge drops of urine and detection compound solution at the mixing zone. In this case, the presence of the complex between the analyte and the detection compound can be detected in the drops resulting from the fusion (in a discrete manner).

[0031] Alternatively, the urine and the detection compound solution may be supplied as continuous streams which are mixed at the mixing zone to obtain a single stream. In this case, the presence of the complex between the analyte and the detection compound can be detected in the single stream (continuously).

[0032] A microfluidic chip uses only small amounts of detection compound solution, which makes it economical and allows a large number of analyses to be carried out. In particular, the use of a microfluidic chip with a detection compound in the form of MIP is particularly advantageous for these reasons. In addition, the same microfluidic chip can be used to detect the presence of several different analytes. It should be noted that the detection compound can be stored in solid form. then be put into solution before being injected into the chip, or be stored directly in solution.

[0033] In an exemplary embodiment, the microfluidic chip may be removable from a housing of the device (and therefore be a consumable of the device) or fixed therein. The housing may comprise means for recharging the device with detection compound.

[0034] In an exemplary embodiment, the urine analysis device may in fact comprise a housing configured to be positioned in the toilet in a removable manner, the analysis module being contained in said housing. With such an arrangement, the urine analysis device may be transported, for example supplied or delivered directly to a user at the request of his doctor or an authorized organization when he begins his treatment, and subsequently returned if necessary. Such a device makes it possible to start monitoring the treatment immediately. Installation of the device in a toilet is also facilitated. For example, the device may be installed directly in a user's toilet without having to modify the design of the toilet.The removable nature of the housing allows, for example, the possibility of changing a consumable in the analysis module, modifying the analysis module to detect another analyte, installing it in other toilets, or recharging the device when it is powered by a battery. The device is therefore versatile and modular.

[0035] In an exemplary embodiment, the housing may be configured to be installed entirely within a toilet bowl. In an exemplary embodiment, the device may further comprise a pumping system for conveying urine from the collection channel to the analysis module.

[0036] In an exemplary embodiment, the housing may have a front face intended to directly receive a jet of urine from the urination of the user sitting on the toilet, a rear face opposite the front face, and a collection orifice present on the front face or the rear face which is in fluid communication with the collection channel. The user's urine can trickle down the front face and possibly the rear face to reach the collection orifice. Such a device is very simple and discreet to use, and makes it possible to collect enough urine without air bubbles to carry out the analysis. In addition, the user does not have to think about the analysis device for their urine to be collected, allowing better monitoring of medication intake at home in a non-invasive manner.

[0037] In an exemplary embodiment, the analysis module may comprise an optical sensor and / or an electrochemical sensor. The type of sensor depends in particular on the detection compound that is used.

[0038] In an exemplary embodiment, the device may further comprise a communication module configured to transmit the analyte concentration or an analysis result to a remote device, for example to a mobile phone and / or to a remote server. Thus, the analysis result can be transmitted automatically, and a doctor or a relevant organization can be informed in real time.

[0039] The invention also relates to a system for monitoring the therapeutic compliance of a user following a treatment comprising the regular taking of a medication, the system comprising a urine analysis device such as that described above, and a processing unit for comparing the analyte concentration in the collected urine with at least one predetermined threshold in order to obtain a result regarding the monitoring of the treatment. The device may comprise the processing unit, or the processing unit may be remote. The at least one predetermined threshold may be obtained from a personalized calibration or learning step.

[0040] The result may, for example, be that the user has missed one or more doses of their medication or that they are overdosing compared to their prescription. The result may also be a measurement error if the measured analyte concentration is below a low error threshold or above a high error threshold.

[0041] The invention also relates to a method for monitoring the therapeutic compliance of a user following a treatment comprising the regular taking of a medication, using a urine analysis device such as that described above, the method comprising: a) carrying out at least one analysis corresponding to at least one urination of the user by following the following steps: a1) collecting urine from a user performing urination in the toilet via the collection channel of the urine analysis device, and a2) analyzing the urine collected by the analysis module to obtain an analyte concentration in the collected urine; and b) obtain a result regarding the monitoring of the treatment from the analyte concentration obtained.

[0042] In an exemplary embodiment, the method may further comprise a step a3) of obtaining a corrected analyte concentration to take into account the hydration of the user, for example the analyte concentration is corrected by a creatinine concentration in the collected urine, by a specific gravity of the collected urine, by a urinary flow rate of urination, by the conductivity of the collected urine.

[0043] In an exemplary embodiment, step b) may comprise: comparing the analyte concentration (or the corrected analyte concentration) in the collected urine to at least one predetermined threshold. By “compare” is meant checking whether the analyte concentration is lower or higher than the predetermined threshold. It may be further check whether the analyte concentration is below a first threshold (low) and / or above a second threshold (high). For example, if the concentration is below the first threshold, it can be deduced that the user has missed a dose, or, if the concentration is above the second threshold, it can be deduced that the user is overdosing.

[0044] In an exemplary embodiment, the method may comprise a prior personalized calibration step during which a plurality of analyte concentrations corresponding to different urinations of the user are obtained when he follows his treatment in accordance with a prescription, and the predetermined threshold is calculated from the concentrations obtained. The predetermined threshold may be obtained from the mean and the standard deviation of the sample of concentrations obtained during the calibration step. The calibration step may preferably be carried out using a device according to the invention.

[0045] This preliminary step of personalized calibration or learning makes it possible to personalize the monitoring of compliance to the user in order to increase its reliability. This calibration step makes it possible to take into account variations during the same day in the concentration of analyte in the urine, but also over several days. It can also be used to better understand the user's response to the medication, in particular to the prescribed dosage.

[0046] In an exemplary embodiment, the predetermined threshold may be a lower control limit (LCL) or an upper control limit (UCL) calculated on the sample of concentrations obtained during the calibration step. For example, if the analyte concentration is lower than the lower control limit, it may be inferred that the user missed a dose of their medication. For example, if the analyte concentration is higher than the upper control limit, it may be inferred that the user took too much medication (“overdose”), or that there was an interaction with another medication.

[0047] In an exemplary embodiment, the method may comprise sending or displaying a notification when the result is that the user has not followed his treatment correctly (i.e. he has not been compliant with his treatment).

[0048] In an exemplary embodiment, the content of the notification may depend on a rate of variation of the analyte concentration between at least two successive analyses and the half-life of the drug. Brief description of the drawings

[0049] Other characteristics and advantages of the present invention will emerge from the description given below, with reference to the appended drawings which illustrate exemplary embodiments thereof which are not in any limiting nature. In the figures:

[0050] [Fig.l] is a diagram schematically showing the different parts of a device according to one embodiment of the invention.

[0051] [Fig.2] is a schematic view of a device according to a first embodiment of the invention positioned inside a toilet bowl.

[0052] [Fig.3A] and [Fig.3B] are views respectively of the front and rear of the device according to the first embodiment.

[0053] [Fig.4A] and [Fig.4B] are perspective views of the interior of the device according to the first embodiment from the front.

[0054] [Fig.5] shows a perspective view of a rotating holder comprising test strips present inside the device according to the first embodiment.

[0055] [Fig.6] schematically shows an example of a microfluidic chip that can be used in a device according to a second embodiment of the invention.

[0056] [Fig.7] shows the different stages of a method for monitoring a user's therapeutic compliance.

[0057] [Fig.8] is a graph showing concentrations obtained during the calibration step.

[0058] [Fig.9] shows the different steps for obtaining an analysis result.

[0059] [Fig. 10] shows three graphs giving the concentrations measured during treatment monitoring as a function of time corresponding respectively to a normal situation, a missed dose situation and an overdose situation.

[0060] [Fig. 11] schematically illustrates the use of a device according to one embodiment of the invention with a mobile telephone and / or a server.

[0061] [Fig. 12] shows an example of a user's smartphone application allowing them to monitor their treatment and an example of a doctor's application allowing them to monitor their patient. Detailed description of the embodiments

[0062] General description of the urine analysis device.

[0063] [Fig.l] schematically illustrates the different parts of a urine analysis device 1 according to one embodiment of the invention.

[0064] The device 1 may generally comprise: a housing 2 in which an analysis module 3 is present, a collection channel 4 for conveying urine from a collection orifice 5 to the analysis module 3, a pumping system 6 for transporting the urine into the collection channel 4, a purge channel 7 for evacuating the urine after an analysis through a purge orifice 8, a urine detector 9 (for example a thermistor) for automatically launching an analysis when urine is detected near the collection orifice 5, a control unit 10 for controlling the various elements of the device 1, and a communication module 11 for communicate with a device 12 such as a smartphone or a remote server. The device 1 may be powered by a battery (not shown).

[0065] The collection orifice 5 may be present on one face of the housing 2 to collect urine, or be connected to a channel or an arm extending from one face of the housing 2 allowing urine to be collected directly when the user urinates in the toilet.

[0066] Advantageously, the housing 2 is configured to be positioned removably in a toilet, for example by means of a suction cup fixed to a wall of the toilet or a hook fixed to the rim of the toilet. The housing 2 can be placed entirely inside the toilet bowl, which makes it discreet and increases its acceptability by a user.

[0067] The communication module 11 is wireless, and can use for example one or more of these technologies: Bluetooth, Low-Energy Bluetooth (BLE), Wi-Fi, GSM, 3G, 4G / LTE(M), and / or 5G. The communication module 11 can connect to the Internet directly, via a local network with a wireless router or a hub connected to the mobile telephone network.

[0068] The device 1 may be provided with a remote button 13, communicating for example wirelessly with the communication module 11. The remote button 13 may be provided with means for identifying the user, such as a biometric sensor (for example a fingerprint reader), and display means (for example a screen and / or colored diodes) to indicate that a user has been recognized. The analysis may then be triggered automatically without user intervention if urine is detected by the urine detector 9 and a user has been identified. Alternatively, the user's smartphone or a connected bracelet (such as a connected watch) may make it possible to identify the user and trigger an analysis.

[0069] The analysis module 3 may comprise a storage area 3a in which a detection compound is present for detecting the analyte when it binds to it, and a detection module 3b for detecting the presence of a complex formed between the detection compound and the analyte (and possibly a marker).

[0070] The analysis module 3 is adapted to bring urine collected by the collection channel 4 into contact with the detection compound in order to allow the detection of the complex formed between the detection compound and the analyte by the detection module 3b.

[0071] The detection module 3b may comprise, for example, an optical sensor (such as a photodiode or a CCD sensor) and / or an electrochemical sensor (such as a biosensor, a potentiostat, a galvanostat, an amperometric sensor, or a polarographic sensor).

[0072] The analysis module 3 may further be configured to measure an analyte concentration correction quantity that is characteristic of the user's hydration, for example the creatinine concentration in the collected urine, the specific gravity of the urine, the conductivity of the urine or the urinary flow rate of urination. The analyte concentration correction will be described in more detail later.

[0073] The analyte to be tested is characteristic of the user's taking of a drug, i.e. it is present in the urine when the user has taken the drug and absent when he has not. For example, the analyte may be an active ingredient of the drug or a metabolite of the active ingredient.

[0074] The detection compound may advantageously be a molecularly imprinted polymer (abbreviated MIP for “Molecularly Imprinted Polymer” in English) capable of binding specifically to (or capturing) the analyte to be detected.

[0075] A MIP for detecting a particular analyte can be obtained from crosslinkable functionalized monomers which are copolymerized in the presence of the analyte, the analyte then forms an imprinted molecule. A MIP can thus be manufactured from one or more given analytes.

[0076] The MIP can be functionalized with a fluorescent label that activates when the MIP is bound to the analyte (or in other words, whose fluorescence increases or decreases when the MIP is bound to the analyte), or with a label detectable by an electrochemical method that activates when the MIP is bound to the analyte (for example, the conductance of a solution containing the MIP can vary when it binds to the analyte). The presence of a second compound consisting of the MIP / analyte complex can then be directly detected. Other uses of a MIP are of course conceivable for detecting the analyte.

[0077] A fluorescent marker can be chosen for example from: nanoparticles (for example a quantum dot), a suppressor (“quencher probe”) such as QSY®9, 4-Amino-1,8-naphthalimide, a dye from the boron-dipyrromethene family (“BODIPY”).

[0078] A marker detectable by electrochemical measurement can be chosen for example from: graphene oxide nanoparticles, gold nanoparticles, boron-doped diamond.

[0079] The analysis module 3 may comprise test strips 121, as in the device illustrated in FIGS. 2 to 5, or a microfluidic chip 30 such as that illustrated in [Fig. 6]. The choice between these two solutions may depend on the analyte to be tested, the detection compound that is used and / or the detection method (optical and / or electrochemical for example).

[0080] A therapeutic compliance monitoring system may comprise a device 1 and a processing unit for comparing an analyte concentration obtained by the analysis module with a predetermined threshold in order to deduce whether the user has followed his treatment in accordance with a prescription. The processing unit may be present in the device 1 or remote, for example in a remote server or a mobile telephone.

[0081] First embodiment - test strips.

[0082] In [Fig. 2], a urine analysis device 100 according to a first embodiment of the invention is shown positioned in a toilet 20. The toilet 20 generally comprises a bowl 21, delimited by a rim 22, and having an internal wall 23. The device 100 here comprises a single housing 110 removably fixed to the internal wall 23 of the bowl 21 using a suction cup 24 and magnets fixed to the suction cup and in the housing 110. The housing 110 is fixed to the part of the internal wall 23 facing the cistern 25 of the toilet flush 20. The housing 110 is advantageously present entirely in the bowl 21 of the toilet, that is to say that it does not protrude from the rim 22 of the bowl 21, which makes it discreet and thus improves user monitoring. which is not bothered by the presence of the device 100.

[0083] As can be seen in [Fig.3A] and [Fig.3B], the housing 110 of the device 100 here has a front face 111 and a rear face 112, and generally takes the form of a circular pebble. In this example, a collection orifice 113 is present in a recess 114 (negative relief) located on a lower end (relative to a normal position of use) of the rear face 112 of the housing. Thus, the user can urinate on the front face 111 of the device when sitting on the toilet, and the urine can trickle and be channeled towards the collection orifice 113. An example of the path of the urine when a user urinates on the device 100 is shown diagrammatically by dotted arrows in [Fig.3A]. The urine can then be detected by the urine detector 115 located near the collection port 113 and an analysis can be launched (for example if a user has been previously identified).A drain port 116 is also provided in the recess 114 below the collection port 113 for draining excess urine after analysis.

[0084] In a variant not illustrated, the collection orifice 113 may be present on the front face 111 and a positive or negative relief makes it possible to channel urine received on the front face 111 to the collection orifice. The positive or negative relief allows for better collection by channeling the urine, but is not essential for achieving collection in the described embodiments.

[0085] [Fig.4A] and [Fig.4B] show various elements inside the housing 110 of the device 100. In this embodiment, the analysis module comprises a support removable rotating device 120 on which test strips 121 are fixed ([Fig.5]), and a detection module comprising an optical sensor 130 capable of detecting a change in color (for example by absorbance or fluorescence, by illuminating the strip 121 with appropriate lighting) on ​​a test strip 121. A pump 140, for example a piezoelectric pump, makes it possible to convey the urine from the collection port 113 to an injector 150 via a collection channel 141. The injector 150 is provided with an automated syringe 151. The injector 150 makes it possible to inject a controlled quantity of urine onto a test strip 121 when the device 100 is in an injection position, or to evacuate the urine via the purge channel 142 when it is in a purge position (as in [Fig.4A] and [Fig.4B]). [Fig.4B]). The different channels of the device can be hydrophobic to avoid contamination between the different analyses.

[0086] As can be seen in [Fig. 5], the rotating support 120 here takes the form of a hollow cylinder or ring on which the test strips 121 are fixed. In this example, the test strips 121 are fixed in housings 122 present on the external surface 123 of the rotating support 120. The strips 121 are isolated from each other and from the external environment to allow their conservation. The rotating support 120 here comprises an opening 124 which can be crossed by the syringe 151 of the injector 150 in the purge position. The rotating support 120 coupled to a stepper motor present in the housing 110 (not visible in the figures) makes it possible to selectively bring a test strip 121 from the injection position where urine can be deposited thereon, to an analysis position where the optical sensor 130 can detect a change in color of the strip 121 to detect the presence of an analyte.The rotating support 120 may be removable from the housing 110, i.e. be a consumable item that can be replaced, for example, when all the test strips 121 have been used.

[0087] In an example not illustrated, the strips 121 may be present on an internal face of the rotating support 120, and if an optical measurement is used, it may be carried out for example by transmission.

[0088] The test strips 121 generally comprise a storage area 121a for the detection compound, in which the compound may, for example, be stored in solid form. The test strips 121 may be conventional colorimetric strips or lateral or vertical flow immunoassay strips. A MIP may be used in a test strip 121.

[0089] A conventional colorimetric strip may include a pad containing the detection compound which, when soaked with urine, may change color if the analyte is present in sufficient concentration.

[0090] In a lateral or vertical flow immunoassay strip, urine deposited on the strip may migrate by capillary action to a test area or line where the detection compound is attached and may bind to the analyte to form a detectable complex. Optionally, depending on the configuration used, a label may also be present on the strip to enable detection.

[0091] The test strips 121 may be used to measure a correction quantity for the analyte concentration in urine, such as creatinine concentration or urine specific gravity.

[0092] Second embodiment - microfluidic chip.

[0093] [Fig. 6] schematically shows an example of a microfluidic chip 30 that can be used in an analysis module 3 of a urine analysis device 1 according to a second embodiment of the invention. The microfluidic chip 30 can be used in a housing 110 such as that described above to benefit from simple urine collection without air bubbles by trickling the urine over the housing to the collection orifice.

[0094] In this example, the principles of droplet microfluidics are used. In [Fig. 6], the arrows symbolize the direction of flow of the fluids in the chip 30 and the circles represent the entry or exit points of the fluids in the chip. The chip 30 can be made, for example, of ceramic such as glass, of polymer such as polydimethylsiloxane (PDMS), or any other suitable material.

[0095] In this example, the chip 30 comprises a generator 31 of first drops 32 of urine which is supplied on the one hand with carrier fluid (for example a mineral oil) by a first injection point 31a and with urine by a second injection point 31b. The second injection point 31b may be in direct or indirect fluid communication with the urine collection channel of the urine analysis device. The generator 31 generates the first drops 32 of urine in a first channel 34.

[0096] The chip 30 further comprises a generator 35 of second drops 36 of detection compound in solution which is supplied on the one hand with carrier fluid 33 by a first injection point 35a and on the other hand with solution of detection compound by a second injection point 35b in fluid communication with a reservoir of detection compound in solution (and possibly a marker). The generator 35 generates the second drops 36 of detection compound in solution in a second channel 37. It will be noted that the detection compound can be stored in solution, or in solid form then put into solution before being injected into the chip 30.

[0097] The drop generators 31 and 35 can be of any type known to those skilled in the art, and for example implement the “flow focusing” technique.

[0098] The first channel 34 and the second channel 37 then join in a mixing zone 38 in which the first drops 32 can merge with the second drops 36 to form third drops 39. The third drops 39 are found at the outlet of the mixing zone 38 in a third channel 40. The mixing zone 38 may comprise any type of means for merging two drops in a carrier fluid which are known to those skilled in the art. In particular, electrodes or particular channel geometries may be used allowing two consecutive drops to merge.

[0099] After having traveled through the third channel 40, the third drops 39 can pass through a detection zone 41 where a sensor (for example optical or electrochemical - not shown) can detect the presence of the second compound formed by bringing the detection compound and the analyte into contact in a third drop 39.

[0100] Finally, all of the fluids leaving the detection zone 41 can be evacuated from the chip 30 via an outlet point 43 connected to the purge channel 7 of the urine analysis device 1.

[0101] It is possible to use a microfluidic chip in which not drops are used, but continuous flows of urine and detection compound solution which are mixed to obtain a single flow which is continuously analyzed by one or more sensors.

[0102] Of course, other microfluidic chip configurations are possible. In particular, multiple analytes could be tested by adding additional mixing and detection zones on the same chip. Multiple microfluidic chips can be used. Both an optical sensor and an electrochemical sensor can be used with the same microfluidic chip.

[0103] The microfluidic chip 30 may further be configured to measure the creatinine concentration in urine or the specific gravity of urine using corresponding reagents.

[0104] Method for monitoring a user's therapeutic compliance.

[0105] Figures 7 to 10 illustrate a method for monitoring a user's therapeutic compliance according to one embodiment of the invention.

[0106] A preliminary personalized calibration step E100 is carried out during which the urine collected from several separate urinations of the user is successively analyzed when the user follows his treatment correctly, that is to say in accordance with his prescription. The analyses can be carried out at random times of the day, for a predetermined duration. To do this, the device 1 can be used to obtain the analyses of the calibration step, and be positioned in the toilet of the user who only has to urinate on it. The duration of the calibration step can be determined by a preliminary clinical test.

[0107] The calibration step may be started after a predetermined duration depending on the half-life of the drug, in order to carry out the calibration when the analyte concentration in the urine is in a steady state, i.e. oscillates around an average concentration. For example, the calibration phase may be started after a duration since the start of treatment greater than four or five times the half-life of the drug in the urine.

[0108] During this step E100, a plurality of analyte concentrations C are obtained. These concentrations C can be corrected in Ccoir to take into account the hydration of the user and improve the reliability of the process, for example: - using the creatinine concentration CCTeat in urine: CcorT=C / Ccréat - using the specific gravity Sg of urine: CCOIT=C.(Sg-l) / (Sg+l), - using the conductivity of urine, or - using the urine flow rate U: Ccoir=ab.log(U); a and b being constants depending on the analyte to be determined experimentally.

[0109] [Fig.8] shows an example of analyte concentrations measured by the device 1 during a calibration step (here 15 measurements were obtained). In this example, a reference concentration Cref is calculated corresponding to the average of the concentrations C or CCOIT obtained during the calibration step, and a standard deviation S, making it possible to calculate, for example, an upper control limit LCS=Cref +3S and a lower control limit LCI= Cref -3S. Of course, other statistical variables can be used depending on the drug considered and the chosen sensitivity. For example, LCS=Cref +2S and LCI=Cref -2S, or LCS=Cref +S and LCI=Cref -S, can be used as a variant.

[0110] Then, once the calibration is carried out, the treatment is monitored (step E200). To do this, the device 1 is positioned in the user's toilet, who only has to urinate on it. The urine is collected (step E210) automatically during urination, and analyzed (step E220) automatically by the device 1, and possibly a remote processing unit to which the device 1 will have sent the result of its concentration measurements.

[0111] [Fig.9] details an example of processing carried out during an analysis (E220). A concentration of analyte C is obtained at each analysis (E221), and can be corrected to obtain a CCOIT concentration (E222) as described previously. The use of the corrected CCOIT concentration makes it possible in particular to reduce false alerts which would be due to dehydration or excessive hydration of the user (overdose or missed dose alerts). The corrected concentration Ccoir can then be normalized by the concentration Cref(E223) obtained during the calibration phase, in order to allow easier processing of the data.

[0112] Then, we compare (E224) the normalized corrected concentration Cn=CcorT / CrefObtained with a first low threshold (Ti=LCI / Cref in this example) and / or a second high threshold (T2=LCS / Cref in this example). Other thresholds can be used depending on the chosen sensitivity and the drug.

[0113] The result of the analysis (E230) is obtained as a function of the comparison of the concentration Cn with the predetermined threshold(s) chosen:

[0114] - If Cn is between Ti and T2, the analyte concentration in the urine is considered to correspond to correct treatment monitoring.

[0115] - If Cn is less than we check that it is not less than an error threshold predetermined low SerrB, which would signal an error in the measurement. For example, Sen-B may correspond to the theoretical concentration that would be obtained after two successive missed doses. If this is not the case, it can be deduced that there has been a missed medication intake. A decay rate tl=ACn / At can be calculated between the concentration obtained in this analysis and in the previous analysis to assess, based on the half-life of the drug in urine, whether the user should take their medication immediately or wait until the next dose. A notification can, for example, be sent to the user or their doctor.

[0116] - If Cn is greater than T2, we check that it is not greater than an error threshold high SeirH, which would signal an error in the measurement or a drug interaction requiring further investigation. For example, SeirH may correspond to the theoretical concentration that would be obtained after two simultaneous doses of the drug. If this is not the case, it can be deduced that there has been an overdose resulting from at least two doses of the drug too close to the prescription. A growth rate t2=ACn / At can then be calculated between the concentration obtained in this analysis and in the previous analysis to assess, based on the half-life of the drug in the urine, the time of the additional dose and the associated risk for the user. A notification can, for example, be sent to the user or their doctor.

[0117] The error thresholds Sen-B and SeiTH can be determined during the calibration phase.

[0118] [Fig. 10] shows three examples of the evolution of the Cn concentration as a function of time, corresponding to three behaviors of a user with regard to his treatment: normal follow-up of his treatment (compliant user), a missed medication intake (non-compliant user), and a double medication intake (overdose user). Each graph represents Cn as a function of time over four days. The arrows pointing to the x-axis indicate the time of medication intake.

[0119] In the “normal” case, we can see that the Cn concentrations obtained are always between the low thresholds Ti and high thresholds T2, meaning that the user follows his treatment in accordance with the prescribed schedule.

[0120] In the case of a “missed intake” on day 2, we can see that Cn is lower than the low threshold Ti at the end of the day at the level of the analysis referenced al, triggering a missed intake alert. The rate of decrease of Cn compared to the previous analysis (shown by the segment tl) makes it possible to deduce that the intake was missed that same morning, and a notification can be sent to the user.

[0121] To increase the reliability of detecting a missed dose, we can wait until two successive Cn values ​​are lower than the low threshold Tb. This makes it possible to avoid sending a notification when the user has taken their medication later than usual.

[0122] In the case of a “double dose” on day 3, we can see that Cn exceeds the high threshold T2 in the second part of the day, triggering an overdose alert. The growth rate of Cn compared to the previous analysis (shown by the segment t2) makes it possible to deduce that the two doses took place on the same morning, and to trigger an alert accordingly. The user can be invited (for example with a notification) to contact their doctor, and not to take medication before a next normal analysis or before a predetermined duration.

[0123] Other thresholds for detecting a missed dose or an overdose can be used and determined from a personalized calibration step. It is also possible to define intermediate thresholds allowing, for example, the detection of medication intake delayed in time compared to the time provided for in the prescription (both early and late).

[0124] Alternatively, the personalized calibration phase may include determining thresholds for deducing that a dose has been missed or an overdose from a pharmacokinetic curve of the drug in urine and user-related data, i.e. without using the urine analysis device.

[0125] As a further variant, during the personalized calibration phase, the thresholds can be determined both from a plurality of analyses of the user's urine when he takes his treatment in accordance with his prescription, from a pharmacokinetic curve of the drug in the urine and from data linked to the user.

[0126] The result of the analysis, if obtained directly by the urine analysis device 1, can be transmitted by the communication module 11 of the device to a remote device 12, for example a smartphone 13 and / or a remote server 14 ([Fig. 11]). The transmission of the result of the analysis can allow the smartphone 13 and / or the server 14 to generate a notification 15 to the user, to a doctor 16 or to an organization enabled 17. If the result of the analysis is determined by a remote processing unit, for example in the smartphone 13 or the remote server 14, the latter can generate and send the notification.

[0127] Example of a mobile application for monitoring therapeutic compliance.

[0128] [Fig. 12] shows, on the left, an example of an application 200 for a user's smartphone. The application 200 can display to the user his prescription (210), the different doses of the prescribed medication (220) as determined by an analysis device according to the invention, and signal when the user has not taken his treatment (230). The application can integrate a set of automated recommendations (“coach”) to help the user better follow his treatment.

[0129] [Fig. 12] shows, on the right, an example of an application 300 that could be used by a doctor or an authorized organization to monitor a patient's treatment. The application 300 can aggregate useful information for monitoring the user's health status, for example: the prescribed treatment (310); the monitoring of the treatment (320) with a message when a dose has been missed; the blood pressure (330) as measured by the doctor or at home by a connected blood pressure monitor; the weight (340) as measured by the doctor or at home by a connected scale; or the resting heart rate (350) as measured for example by a connected watch.

[0130] More generally, the device can be connected to a telemedicine platform allowing a patient to be monitored remotely by a doctor or an authorized organization.

[0131] The user can thus have better visibility of his treatment, and be better monitored by his doctor or an authorized organization. Thus, with the urine analysis device according to the invention and such tools, the patient's compliance with his treatment can be improved.

[0132] Other applications.

[0133] A device 1 according to the invention can further be used to characterize more precisely the response of a user to a drug (in particular its elimination), or to study the possible interactions between his treatment and other drugs. The user's treatment, in particular the drug, the quantity of active ingredient and the dosage, can for example be personalized according to the data collected by the device.

[0134] Unusual variations in urine analyte concentration compared to history may also help detect kidney disease.

Claims

Claims

1. Urine analysis device (1, 100) for monitoring a user's compliance with a treatment comprising the regular intake of a medication, the device comprising a collection channel (4, 141) for collecting the user's urine when the user urinates in a toilet (20), and an analysis module (3, 130) configured to detect the presence of an analyte in the urine collected by the collection channel, the analyte being an active ingredient of the medication or a metabolite of the active ingredient, the analysis module being configured to determine a concentration (C) of analyte in the collected urine or a quantity linked by a monotonic function to the concentration (C) of analyte in the urine, characterized in that the analysis module comprises: *a plurality of test strips, and *a rotatable support in the form of a hollow cylinder or a ring, the strips being fixed in housings (122) present on a surface of the rotating support (120),said support being removable relative to the urine device.,

2. Device according to claim 1, in which the analysis module is configured to, at each analysis, contact the collected urine with a detection compound capable of binding to the analyte and to detect the presence of the complex between the analyte and the detection compound.

3. The device of claim 2, wherein the detection compound is a molecularly imprinted polymer.

4. Device according to any one of claims 1 to 3, wherein the analysis module is configured to further measure a correction quantity of the analyte concentration which is characteristic of the hydration of the user, for example the correction quantity is chosen from: the creatinine concentration in the collected urine, the specific gravity of the collected urine, the urinary flow rate of urination, the conductivity of the collected urine.

5. Device according to any one of claims 1 to 4, wherein the analysis module comprises a microfluidic chip (30).

6. Device according to any one of claims 1 to 5, wherein the analysis module comprises an optical sensor and / or an electrochemical sensor.

7. Device according to any one of claims 1 to 6, further comprising a communication module (11) configured to transmit the analyte concentration (C) or an analysis result to a remote device (12), for example to a mobile phone (13) and / or to a remote server (14).

8. Device according to any one of claims 1 to 7, comprising a housing configured to be positioned in the toilet in a removable manner, the analysis module being contained in said housing, the housing comprising a collection orifice (113), connected to the collection channel, for collecting the urine flowing over the housing.

9. Device according to claim 8, in which the housing has a front face intended to directly receive a jet of urine from urination and a rear face opposite the front face, the collection orifice being present on the rear face.

10. System for monitoring the therapeutic compliance of a user following a treatment comprising the regular taking of a medication, the system comprising a urine analysis device (1, 100) according to any one of claims 1 to 9, and a processing unit for comparing the concentration (C) of analyte in the collected urine with at least one predetermined threshold (Tb T2) in order to obtain a result regarding the monitoring of the treatment.

11. Method for monitoring the therapeutic compliance of a user following a treatment comprising the regular intake of a medication, implementing a urine analysis device (1, 100) according to any one of claims 1 to 9 or a system according to claim 10, the method comprising: a) carrying out at least one analysis corresponding to at least one urination of the user by following the following steps: a1) collecting (E210) urine from a user performing urination in the toilet (20) via the collection channel (4, 141) of the urine analysis device, and a2) analyzing (E220) the urine collected by the analysis module to obtain a concentration (C) of analyte in the collected urine (E221) or a quantity linked by a monotonic function to the concentration (C) of analyte in the urine; and b) obtain a result (E230) regarding the monitoring of the treatment from the concentration (C) of analyte or the quantity obtained.

12. The method of claim 11, further comprising a step a3) of obtaining a corrected analyte concentration (CcoiT) to take into account the hydration of the user (E222), for example the analyte concentration (C) is corrected by a creatinine concentration in the collected urine, by a specific gravity of the collected urine, by a urinary flow rate of the micturition, or by the conductivity of the collected urine.

13. The method of claim 11 or 12, wherein step b) comprises: comparing the analyte concentration (C, CCOIT) in the collected urine to at least one predetermined threshold (Tb T2).

14. Method according to any one of claims 11 to 13, comprising a prior personalized calibration step (E100) during which a plurality of analyte concentrations are obtained corresponding to different urinations of the user when he follows his treatment in accordance with a prescription, and the predetermined threshold (Ti, T2) is calculated from the concentrations obtained.

15. The method of claim 14, wherein the predetermined threshold is a lower control limit (LCL) or an upper control limit (UCL) calculated on the sample of concentrations obtained during the calibration step.

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