EP4232815A1 - Urine analyser for monitoring therapeutic compliance - Google Patents

Abstract

The invention relates to a urine analysis device (1) for monitoring the compliance of a user with a treatment comprising the regular taking of a drug, the device comprising a collection channel (4) for collecting the urine of the user when the user urinates in a toilet, and an analysis module (3) for detecting the presence of an analyte in the urine collected by the collection channel, the analyte being an active ingredient of the drug or a metabolite of the active ingredient, the analysis module being configured to determine a concentration of analyte in the collected urine or a quantity related by a monotonic function to the concentration of analyte in the urine. The invention also relates to a system and a method for monitoring therapeutic compliance of a user.

Description

Urine analyzer to monitor therapeutic compliance

Technical area

The general field of the invention is that of devices making it possible to control and improve therapeutic compliance with a drug treatment.

[0002] The invention relates more specifically to a urinalysis device suitable for monitoring the compliance of a user with a treatment comprising the regular intake of a drug. It also relates to a method for monitoring the compliance of a user with his treatment implementing such a device.

Prior technique

[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 “the lack of therapeutic observance is said to be the cause of 200,000 premature deaths each year in Europe. People with any of the major chronic diseases, in particular, are at serious risk from not taking their medications correctly. In diabetics and people with heart disease, patients who neglect their treatment in this way experience almost twice the mortality of patients who stick to it rigorously.”

[0004] Therapeutic compliance therefore represents an important issue in order to better support a patient during his treatment, to improve the chances of success of his treatment, or even in the context of carrying out clinical studies.

[0005] Devices are known such as connected medicine boxes, whether or not associated with wearable devices (for example comprising an RFID tag or implementing NFC technology), which make it possible to detect whether a patient opens a medicine box. drugs or if he came near them. Such devices do not, however, make it possible to know with certainty whether a patient has taken his medication correctly.

[0006] When one wishes to detect the taking of a drug, one must go to a laboratory which will be able to carry out an analysis on a biological fluid and detect the presence of the drug or of a metabolite thereof.

[0007] In addition to the costs, the need for qualified personnel and the sometimes invasive nature of these checks, laboratory measurements do not make it possible to realistically estimate compliance with a treatment for several reasons:

- the measurements are unique and it is difficult to estimate whether a drug was 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 can be eliminated from the body before the measurement (false negatives);

- medicinal products with a long half-life can give rise to a positive result even though the treatment is no longer followed (false positives); and

- the variability between patients and during the same day implies taking the measurement at a precise moment.

[0008] Thus, the presence of the drug or of a metabolite thereof only makes it possible 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 of the patient. . However, it is impossible to deduce from this measurement whether the patient follows his treatment on a regular basis, and in particular over the long term.

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

Disclosure of Invention

[0010] This object is achieved by a urinalysis device for monitoring the compliance of a user with a treatment comprising the regular intake of a drug, the device comprising a collection channel for collecting urine from the user when the user performs urination 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 principle of the drug or a metabolite of the active principle, the analysis module being configured to determine a concentration of analyte in the collected urine or a quantity proportional to the concentration (C) of analyte in the urine.

[0011] The term "quantity linked by a monotonic function to the concentration of analyte in the urine" means, for example, an optical quantity (for example: fluorescence rate, absorbance rate, color, etc.) or a quantity conductometric (for example: conductance). The magnitude 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 analyte concentration is mentioned, this may also include any quantity measurable by the device which is linked by a monotonic function to the analyte concentration.

The urine analysis device according to the invention makes it possible to follow the taking of a drug in a simple and regular way, in particular daily. It can indeed be configured to carry out several successive analyzes corresponding to several distinct urinations of 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 for the results to be automatically transmitted, for example, to their doctor, an authorized organization or a relative. This device thus makes it possible to improve the care of the user during his treatment and compliance with his 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, this which makes the analysis more reliable and avoids any contamination of the urine by undesirable compounds.

[0014] In an exemplary embodiment, the medicament may be a medicament 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 chosen from the following classes: calcium channel blockers (for example from the family of dihydropyridines: 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), inhibitors converting enzyme (eg captopril, ramipril, enalapril), diuretics (eg hydrochlorothiazide, indapamide, amiloride) and beta-blockers (eg metoprolol, bisoprolol, atenolol, propranolol).

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

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

[0018] In an exemplary embodiment, the analysis module can be configured to, at each analysis, bring the collected urine into contact 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 binding selectively to the analyte. The detection compound can be detected directly (for example 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 (for example a fluorescent label or detectable by an electrochemical method) which can bind to the complex formed by the detection compound and the analyte.

In an exemplary embodiment, the detection compound is a molecularly imprinted polymer (“Molecularly Imprinted Polymer” in English, abbreviated “MIP”). [0021] When the detection compound is a MIP, it can change its optical or electrochemical property when it binds to the analyte. For example, MIP can fluoresce when it binds to the analyte. For example, the conductance of a solution comprising the MIP can change when the MIP binds to the analyte. As a variant, it is possible to use a fluorescent marker or one detectable by an electrochemical method which makes it possible to detect the complex formed by the MIP and the analyte. A detection compound in the form of 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 long time, for example when it comes to following a long-term treatment. Further, a MIP can be stored in solution or in solid form. Also, MIP can be used to make a quantitative measurement of analyte concentration 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 also possible to design a MIP capable of forming a complex with several different analytes, for example with the active principles of drugs of a particular class of drugs (that is to say 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 can be configured to additionally measure a correction quantity of the analyte concentration which is characteristic of the user's hydration, for example the correction quantity is chosen among: 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.

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 according to the days, which influences the volume urinated during urination and the concentration of analyte in the urine independently of the quantity of drug. ingested. This arrangement makes it possible to improve the result of the analysis and to be able to compare several successive analyzes by taking into account the hydration of the user.

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

An analysis module comprising test strips is advantageous in that its use is simple and inexpensive to implement. It is also 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 detection of the intake of different drugs. Test strips can be used to measure the analyte concentration correction quantity.

In an exemplary embodiment, the test strip may be a colorimetric test strip or a lateral or vertical flow immunoassay test strip. For example, the rate of fluorescence from a portion of the test strip can be directly related to the analyte concentration in urine.

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 with respect 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 the taking of medication.

[0030] In an exemplary embodiment, where the analysis module comprises a microfluidic chip, the urine and the solution of detection compound can be conveyed in the form of drops, the microfluidic chip is then adapted to merge the drops of urine and of solution of detection compound at the level of 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 (discretely).

[0031] Alternatively, the urine and the detection compound solution can 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 only uses small quantities of detection compound solution, which makes it possible to economize on it and to carry out a large number of analyses. In particular, the use of a microfluidic chip with a detection compound in the form of MIP is particularly advantageous for these reasons. It is also possible to use the same microfluidic chip to detect the presence of several different analytes. It should be noted that the detection compound can be stored in solid form and then put into solution before being injected into the chip, or be stored directly in solution.

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

[0034] In an exemplary embodiment, the urine analysis device may in fact comprise a box configured to be removably positioned in the toilet, the analysis module being contained in said box. With such an arrangement, the urinalysis device can be transported, for example supplied or delivered directly to a user at the request of his doctor or of an authorized body when he begins his treatment, and then possibly be returned. Such a device makes it possible to start monitoring the treatment immediately. The installation of the device in a toilet is also facilitated. For example, the device can be installed directly in a user's toilet without having to modify the design of the toilet. The removable nature of the case makes it possible to be able to example changing a consumable in the analysis module, modifying the analysis module to be able to detect another analyte, installing it in other toilets, or recharging the device when the latter is powered by a battery. The device is thus versatile and modular.

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

In an exemplary embodiment, the housing may have a front face intended to directly receive a jet of urine resulting from the urination of the user seated on the toilet, a rear face opposite the front face, and an orifice collection present on the front face or the rear face which is in fluid communication with the collection channel. The user's urine can run down the front side and possibly the back side to reach the collection hole. 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 his urine to be collected, allowing better monitoring of medication intake at home in a non-invasive way.

[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.

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 telephone and/or to a remote server. . Thus, the result of the analysis can be transmitted automatically, and a doctor or an organization concerned can be informed in real time.

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

[0040] The result may for example be that the user has missed one or more intake(s) of his medicine or that he has overdosed in relation to his prescription. The result can 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 observance of a user following a treatment comprising the regular intake of a drug, implementing 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 by the collection channel of the urinalysis device, and a2) analyzing the urine collected by the analysis module to obtain an analyte concentration in the collected urine; and b) obtaining a result as to the follow-up of the treatment from the analyte concentration obtained.

In an exemplary embodiment, the method may further comprise a step a3) for obtaining a corrected analyte concentration to take account of the user's hydration, 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 output 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 a predetermined threshold. By “compare” we mean verifying whether the analyte concentration is below or above the predetermined threshold. It is also possible to check whether the analyte concentration is lower than a first threshold (low) and/or higher than a second threshold (high). For example, if the concentration is lower than the first threshold, it can be deduced that the user has missed a dose, or, if the concentration is higher than the second threshold, it can be deduced that the user is overdosing. [0044] In an exemplary embodiment, the method may comprise a preliminary step of personalized calibration 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 is calculated from the concentrations obtained. The predetermined threshold can be obtained from the mean and the standard deviation of the sample of concentrations obtained during the calibration step. The calibration step can 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 control of compliance to the user in order to increase its reliability. This calibration step makes it possible to take into account the variations during the same day of the analyte concentration in the urine, but also over several days. It can also be used to better understand the user's response to the drug, especially to the prescribed dosage.

In an exemplary embodiment, the predetermined threshold can be a lower control limit (LCI) or an upper control limit (LCS) calculated on the sample of concentrations obtained during the calibration step. For example, if the analyte concentration is below the lower control limit, it can be inferred that the user has missed a dose of their medication. For example, if the analyte concentration is above the upper control limit, it can be inferred that the user has taken too much medication (“overdose”), or that there has been an interaction with another medication.

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

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 analyzes and on the half-life of the drug.

Brief description of the drawings

Other characteristics and advantages of the present invention will become apparent from the description given below, with reference to the appended drawings which illustrate them. thirty examples of realization devoid of any limiting character. In the figures:

Figure 1 is a diagram schematically showing the different parts of a device according to one embodiment of the invention.

Figure 2 is a schematic view of a device according to a first embodiment of the invention positioned inside a toilet bowl.

Figure 3A and Figure 3B are respectively front and rear views of the device according to the first embodiment.

Figure 4A and Figure 4B are perspective views of the inside of the device according to the first embodiment from the front.

[0054] Figure 5 shows a perspective view of a rotary support comprising test strips present inside the device according to the first embodiment.

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.

Figure 7 shows the different steps of a method for monitoring the therapeutic compliance of a user.

FIG. 8 is a graph showing concentrations obtained during the calibration step.

Figure 9 shows the different steps for obtaining an analysis result.

Figure 10 shows three graphs giving the concentrations measured during treatment monitoring as a function of time corresponding respectively to a normal situation, a missed intake situation and an overdose situation.

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] Figure 12 shows an example of a user's smartphone application allowing him to follow his treatment and an example of a doctor's application allowing him to follow his patient.

Detailed Description of Embodiments [0062] General description of the urine analysis device.

Figure 1 schematically illustrates the different parts of a urine analysis device 1 according to one embodiment of the invention.

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

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

[0066] Advantageously, the box 2 is configured to be removably positioned 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. According to an exemplary embodiment, the box is contained in a parallelepiped of dimensions 110mm×110m×50mm. According to an exemplary embodiment, the case has a general discoid shape with a diameter of between 80 and 100 millimeters and a thickness of between 40 and 50 millimeters.

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.

The device 1 can be supplied with a remote button 13, for example communicating wirelessly with the communication module 11 . The remote button 13 can be provided with user identification means, 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 can 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) can identify the user and to trigger an analysis. In the case of toilets used by several people, the means of identifying a particular user make it possible not to take into account a measurement carried out for another person. The monitoring of medication intake is therefore totally personalized.

The analysis module 3 can comprise a storage zone 3a in which is present a detection compound making it possible to detect the analyte when it binds to the latter, and a detection module 3b for detecting the presence of a complex formed between the detection compound and the analyte (and optionally a label).

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.

The detection module 3b can for example comprise 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).

The analysis module 3 can also be configured to measure an analyte concentration correction quantity which is characteristic of the user's hydration, for example the creatinine concentration in the urine collected, the urine specific gravity, urine conductivity or voiding urine output. The correction of the analyte concentration will be described in more detail later.

The analyte to be tested is characteristic of the taking of a drug by the user, that is to say it is present in the urine when the user has taken the drug and absent when he did not take it. For example, the analyte can be an active ingredient of the drug or a metabolite of the active ingredient.

The detection compound can 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 made from one or more given analytes.

The MIP can be functionalized with a fluorescent marker which is activated 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 marker detectable by an electrochemical method that activates when the MIP binds to the analyte (e.g. the conductance of a solution containing the MIP may vary when it binds to the analyte). It is then possible to directly detect the presence of a second compound consisting of the MIP/analyte complex. Other uses of a MIP are of course possible to detect the analyte.

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

A label detectable by an electrochemical measurement can be chosen for example from: graphene oxide nanoparticles, gold nanoparticles, diamond doped with boron.

The analysis module 3 can 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 can 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 system for monitoring therapeutic compliance can comprise a device 1 and a processing unit making it possible to compare an analyte concentration obtained by the analysis module with a predetermined threshold in order to deduce whether the user has followed his treatment according to a prescription. The processing unit can be present in the device 1 or remote, for example in a remote server or a mobile telephone.

[0081] First embodiment - test strips.

In Figure 2, there is shown a urine analysis device 100 according to a first embodiment of the invention 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 by means of a suction cup 24 and magnets fixed on 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 to say that it does not protrude from the edge 22 of the bowl 21, which makes it discreet and thus improves the monitoring of the user who is not bothered by the presence of the device 100.

As seen in Figure 3A and Figure 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 roller. 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 case. Thus, the user can urinate on the front face 111 of the device when he is seated on the toilet, and the urine can trickle and be channeled towards the collection orifice 113. An example of the path of urine when a user urinating on the device 100 is represented by dotted arrows in FIG. 3A. The urine can then be detected by the 115 urine detector located near from the collection orifice 113 and an analysis can be launched (for example if a user has been previously identified). A purge port 116 is also present in the recess 114 below the collection port 113 to drain excess urine after a test.

[0084] In a variant not shown, 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. . Positive or negative relief allows better collection by channeling urine, but is not essential to achieve collection in the described embodiments.

FIG. 4A and FIG. 4B show various elements inside the housing 110 of the device 100. In this embodiment, the analysis module comprises a removable rotating support 120 on which test strips 121 are attached. (FIG. 5), and a detection module comprising an optical sensor 130 capable of detecting a color change (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 orifice 113 to an injector 150 via a collection channel 141. The injector 150 is provided with an automated syringe 151 . The injector 150 allows a controlled amount of urine to be injected onto a test strip 121 when the device 100 is in an injection position, or to evacuate the urine through the purge channel 142 when it is in a purge position (as in Figure 4A and Figure 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 rotary support 120 here takes the form of a hollow cylinder or ring on which the test strips 121 are attached. In this example, the test strips 121 are fixed in housings 122 present on the outer surface 123 of the rotary support 120. The strips 121 are isolated from each other and from the outside environment to allow their conservation. The rotary support 120 here comprises an opening 124 through which the syringe 151 of the injector 150 can pass in the purge position. The rotary 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. , at an analysis position where the optical sensor 130 can detect a color change of the strip 121 to detect the presence of an analyte. The rotary support 120 can be removable with respect to the casing 110, that is to say be a consumable that can be replaced for example when all the test strips 121 have been used. In an example not illustrated, the strips 121 can be present on an internal face of the rotary support 120, and if an optical measurement is used, it can be carried out for example by transmission. The test strips 121 generally comprise a storage area 121a for the detection compound, in which the compound can for example be stored in solid form. The test strips 121 can be standard colorimetric strips or lateral or vertical flow immunoassay strips. A MIP can be used in a test strip 121 . [0089] A conventional colorimetric strip can comprise a buffer containing the detection compound which, when it is soaked in urine, can change color if the analyte is present in sufficient concentration.

[0090] In a lateral or vertical flow immunoassay strip, urine deposited on the strip can migrate by capillarity to an area or test line where the detection compound is attached and can 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 allow detection.

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

[0092] Second embodiment - microfluidic chip.

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 casing 110 such as that described above to benefit from a simple collection of urine without air bubbles by streaming urine on the casing up to the orifice of collection.

In this example, the principles of microfluidics with drops 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 appropriate material.

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 31 b. The second injection point 31b may be in direct or indirect fluid communication with the urine collection channel of the urinalysis device. The generator 31 generates the first drops 32 of urine in a first channel 34.

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 compound solution detection by a second injection point 35b in fluid communication with a reservoir of detection compound in solution (and optionally of a label). 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 placed in solution before being injected into the chip 30 .

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.

The first channel 34 and the second channel 37 then meet 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 can comprise any type of means for merging two drops in a carrier fluid which are known to those skilled in the art. It is in particular possible to use electrodes or particular geometries of channels allowing two consecutive drops to merge. After having traveled in 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 the bringing the detection compound and the analyte into contact in a third drop 39.

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

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

Of course, other microfluidic chip configurations are possible. In particular, one could test several analytes by adding other mixing and detection zones on the same chip. Several microfluidic chips can be used. It is possible to use both an optical sensor and an electrochemical sensor with the same microfluidic chip.

The microfluidic chip 30 can also be configured to measure the creatinine concentration in the urine or the specific gravity of the urine using corresponding reagents.

[0104] Method for monitoring the therapeutic observance of a user.

[0105] FIGS. 7 to 10 illustrate a method for monitoring the therapeutic observance of a user according to one embodiment of the invention.

A preliminary personalized calibration step E100 is carried out during which successively analyzes the urine collected from several distinct urinations of the user when the latter follows his treatment correctly, that is to say in accordance with his prescription. The analyzes 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 analyzes of the calibration step, and be positioned in the toilets of the user who only has to urinate on it. The duration of the calibration step can be determined by a prior clinical trial. The calibration step can be started after a predetermined period depending on the half-life of the drug, in order to carry out the calibration when the concentration of analyte in the urine is in steady state, that is to say oscillates around an average concentration. For example, the calibration phase can be started after a time since the start of treatment greater than four or five times the half-life of the drug in urine.

During this step E100, a plurality of analyte concentrations C are obtained. These C concentrations can be corrected in Ccorr to take into account the hydration of the user and improve the reliability of the process, for example:

- using the concentration Ccreat in creatinine in the urine: Ccorr=C/Ccreat

- using the specific gravity S _g of urine: Ccorr=C.(Sg-1 )/(S _g +1 ),

- using urine conductivity, or

- using the urine output U: Ccorr=a-b.log(U); a and b being analyte-dependent constants to be determined experimentally.

FIG. 8 shows an example of analyte concentrations measured by device 1 during a calibration step (here 15 measurements were obtained). In this example, a reference concentration Cret is calculated corresponding to the average of the concentrations C or Ccorr 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= Cret -3S. Of course, other statistical variables can be used depending on the drug considered and the sensitivity chosen. For example, LCS=Cref +2S and LCI=Cref -2S, or alternatively LCS=Cref +S and LCI=Cref -S can be used as a variant.

Then, once the calibration has been performed, the processing is monitored (step E200). To do this, the device 1 is positioned in the toilets of the user 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.

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 concentration Ccorr (E222) as described above. The use of the corrected concentration Ccorr makes it possible in particular to reduce false alerts that would be due to dehydration or excessive hydration of the user (alerts of overdose or missed intake). The corrected concentration Ccorr can then be normalized by the concentration Cref (E223) obtained during the calibration phase, in order to allow easier processing of the data.

Then, we compare (E224) the normalized corrected concentration Cn=Ccorr/Cref obtained 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 may be used depending on the selected sensitivity and drug.

The result of the analysis (E230) is obtained according to 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 monitoring of the treatment.

If Cn is less than Ti, it is checked that it is not less than a predetermined low error threshold SerrB, which would signal an error in the measurement. For example, SerrB may correspond to the theoretical concentration which 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 rate of decrease t1 =ACn/At can be calculated between the concentration obtained at this analysis and at the previous analysis to evaluate, according to the half-life of the drug in the urine, if the user should take his drug immediately or wait for the next dose. A notification can for example be sent to the user or to his doctor.

If Cn is greater than T2, it is checked that it is not greater than a high error threshold SerrH, which would signal an error in the measurement or a drug interaction requiring additional investigation. For example, SerrH may correspond to the theoretical concentration that would be obtained after two simultaneous doses of the drug. If this is not the case, we can deduce that there has been an overdose resulting from at least two doses of medication too close to the prescription. We can then calculate a growth rate t2=ACn/At between the concentration obtained at this analysis and at the previous analysis to evaluate, according to the half-life of the drug in the urine, the moment of the additional intake and the associated risk for the user. A notification can for example be sent to the user or to his doctor.

The error thresholds SerrB and SerrH can be determined during the calibration phase.

[0118] Figure 10 shows three examples of changes in the concentration Cn as a function of time, corresponding to three behaviors of a user with respect to his treatment: normal monitoring of his treatment (user observing), taking missed medication (non-observant user), and a double intake of medication (overdose user). Each graph represents Cn as a function of time over four days. The arrows pointing to the abscissa axis indicate the moment of taking the drug.

In the “normal” case, it can be seen that the Cn concentrations obtained are always between the low Ti and high T2 thresholds, signifying that the user is following his treatment in accordance with the prescribed schedule.

In the case of a “missed take” on day 2, we can see that Cn is lower than the low threshold T1 at the end of the day at the level of the analysis referenced a1, triggering a missed take alert. The rate of decrease of Cn compared to the previous analysis (schematized by the segment t1 ) makes it possible to deduce that the intake was missed the same morning, and a notification can be sent to the user.

To increase the reliability of the detection of a missed tap, it is possible to wait until two successive values of Cn are below the low threshold T1. This avoids sending a notification when the user has taken his medicine with a delay compared to the usual time of taking.

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 (schematized by the t2 segment) makes it possible to deduce that the two intakes took place the same morning, and to trigger an alert accordingly. The user can be invited (for example with a notification) to get closer to his doctor, and not to take any medicine before a next normal analysis or before a predetermined duration.

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 making it possible, for example, to detect a medication intake that is delayed in time compared to the time provided for in the prescription (both early and late).

[0124] As a variant, the personalized calibration phase can comprise the determination of the thresholds making it possible to deduce that a dose has been missed or an overdose from a pharmacokinetic curve of the drug in the urine and from data related to the user, i.e. without using the urinalysis device.

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

The result of the analysis, if it is obtained directly by the urine analysis device 1, can be transmitted by the communication module 11 of the device has 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 authorized organization 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] Figure 12 shows, on the left, an example of application 200 for a user's smartphone. The application 200 can make it possible to 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 does not has not taken his treatment (230). The application can integrate a set of automated recommendations (“coach”) to help the user better monitor their treatment.

[0129] Figure 12 shows, on the right, an example of application 300 which could be used by a doctor or an authorized organization to follow the treatment of a patient. The application 300 can aggregate useful information for monitoring the user's state of health, for example: the treatment prescribed (310); treatment monitoring (320) with a message when a dose has been missed; 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 bathroom scale; or the resting heart rate (350) as measured for example by a connected watch.

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

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

[0132] Other applications.

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

[0134] Unusual variations in the analyte concentration in the urine compared to a history can also make it possible to detect a disease of the kidneys.

Claims

1. Urinalysis device (1, 100) for monitoring a user's compliance with a treatment comprising the regular intake of a drug, the device comprising a collection channel (4, 141) for collecting the urine of the user when the user performs urination 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 drug 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 related by a monotonic function to the concentration ( C) in analyte in urine.

2. Device according to claim 1, in which the analysis module is configured to, at each analysis, bring the collected urine into contact 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. Device according to claim 1 or 2, in which the detection compound is a molecularly imprinted polymer (MIP).

4. Device according to claim 3, in which the molecularly imprinted polymer (MIP) can form a complex with several different analytes.

5. Device according to any one of claims 1 to 4, in which 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 electrochemical sensor.

7. Device according to any one of claims 1 to 6 in combination with claim 3 or 4, in which the molecularly imprinted polymer (MIP) is stored in solid form or stored in solution.

8. Device according to any one of claims 1 to 7, in combination with claims 3, 4 and / or 7, wherein the molecularly imprinted polymer (MIP) is functionalized with a label detectable by an electrochemical method configured to s activate when the Molecularly Imprinted Polymer (MIP) is bound to the analyte.

9. Device according to any one of claims 1 to 4, in which the analysis module comprises a plurality of test strips

10. Device according to any one of claims 1 to 4 and 9, comprising a box configured to be removably positioned in the toilet, the analysis module being contained in said box, the box including a collection port (113) for collecting urine dripping onto the case. . A device according to claim 9 or 10, further comprising a pump (140) for conveying urine from the collection port (113) to an injector (150) via a collection channel (141), the injector (150) being configured to inject a controlled amount of urine onto a test strip (121). . Device according to any one of Claims 9 to 11, in combination with Claim 9, in which the analysis module comprises a rotating support in the form of a hollow cylinder or of a ring, the strips being fixed in housings (122) present on a surface of the rotatable support (120), said support being removable from the urine device. . Device according to any one of Claims 9 to 12, in which the analysis module comprises an optical sensor. . Device according to any one of claims 9 to 13, in combination with claims 3 or 4, in which the molecularly imprinted polymer (MIP) is stored in solid form. . A device according to any of claims 9 to 14, wherein the MIP is incorporated into a test strip. . Device according to any one of claims 1 to 15, in which the molecularly imprinted polymer (MIP) is functionalized with a label, for example fluorescent, configured to activate when the molecularly imprinted polymer (MIP) is bound to the analyte. . Device according to any one of Claims 1 to 16, in which the analysis module is configured to additionally measure a correction quantity for the concentration of analyte which is characteristic of the hydration of the user, for example the quantity correction is chosen from: the creatinine concentration in the urine collected, the specific gravity of the urine collected, the urinary flow rate of urination, the conductivity of the urine collected. . Device according to any one of claims 1 to 17, further comprising a communication module (11) configured to transmit the concentration of analyte (C) or an analysis result to a remote device

(12), for example to a mobile telephone (13) and/or to a remote server (14). . System for monitoring therapeutic compliance of a user following a treatment comprising the regular intake of a drug, the system comprising a urinalysis device (1, 100) according to any one of Claims 1 to 18 , and a processing unit for comparing the concentration (C) of analyte in the urine collected with at least one predetermined threshold (Ti, T2) in order to obtain a result as regards the monitoring of the treatment.

20. Method for monitoring the therapeutic observance of a user following a treatment comprising the regular intake of a drug, implementing a urinalysis device (1, 100) according to any one of claims 1 to 18 or a system according to claim 19, 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) through the collection channel (4, 141) of the urinalysis device, and a2) analyzing (E220) the urine collected by the analysis module to obtain a concentration (C) in analyte in the urine collected (E221) or a quantity linked by a monotonic function to the concentration (C) in analyte in the urine; and b) obtaining a result (E230) as regards the monitoring of the treatment from the concentration (C) of analyte or the quantity obtained.

21. Method according to claim 20, further comprising a step a3) of obtaining a corrected analyte concentration (ccorr) 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 rate of urination, or by the conductivity of the collected urine.

22. Method according to claim 20 or 21, in which step b) comprises: comparing the concentration of analyte (C, Ccorr) in the urine collected with at least a predetermined threshold (Ti, T2).

23. Method according to any one of claims 20 to 22, comprising a preliminary personalized calibration step (E100) during which a plurality of analyte concentrations are obtained corresponding to different micturitions of the user when he follows his treatment in accordance with to a prescription, and the predetermined threshold (T1, T2) is calculated from the concentrations obtained.

24. Method according to claim 23, in which the predetermined threshold is a lower control limit (LCI) or an upper control limit (LCS) calculated on the sample of concentrations obtained during the calibration step.

25. Method according to any one of claims 20 to 24, comprising sending or displaying a notification when the result is that the user has not followed his treatment correctly.

26. Method according to claim 25, in which the content of the notification depends on a rate of variation (t1, t2) of the analyte concentration between at least two successive analyses.