Non-invasive blood glucose meter using reverse iontophoresis

Abstract

The present invention relates to a supracutaneous self-adhesive patch sensor (S1, S2) which, when coupled to an electronic circuit (C1, C2), is capable of continuously monitoring blood glucose levels in the human body via the interstitial fluid without any invasion of the patient's body, since it uses reverse iontophoresis, wherein continuous monitoring is possible for a predetermined time period without the need to change the adhesive patch, using the same electronic circuit (C1, C2).

Description

DRILL-FREE BLOODSIGHT METER BY REVERSE IONOPHORESIS Introduction

[0001] This patent application refers to a PERFORATION-FREE BLOOD GLUCOSE METER USING REVERSE IONTOPHORESIS. It is a self-adhesive, over-cutaneous sensor coupled to an electronic circuit, which allows the identification of blood glucose levels present in the patient's body in a constant and non-invasive manner, and for this purpose it is necessary to remove glucose molecules from the body, present in the blood, using the reverse iontophoresis process. Field of application

[0002] The field of application of the invention is the medical segment, more specifically for the monitoring and treatment of diabetes, therefore, serving to provide information that identifies trends in blood glucose fluctuations; understand the factors that can cause hypoglycemia or hyperglycemia; evaluate the impact of diet, physical activity and medications on diabetes; identify the need for changes in treatment; confirm whether certain symptoms are related to some type of glycemic imbalance. Conviction

[0003] Diabetes Mellitus is a disease characterized by elevated blood glucose levels (hyperglycemia). It can occur due to defects in the secretion or action of the hormone insulin, which is produced in the pancreas by the so-called Langerhans beta cells.

[0004] There are several conditions that can lead to diabetes, but the vast majority of cases are divided into two groups: Type 1 Diabetes and Type 2 Diabetes.

[0005] Insulin promotes the entry of glucose into the body's cells in a diabetic person so that it can be used for various cellular activities. A lack of insulin or a defect in its action therefore results in the accumulation of glucose in the blood.

[0006] A blood glucose monitoring system measures glucose levels on a special occasion, or whenever necessary. This can help keep blood glucose levels controlled by indicating adjustments in insulin doses, physical activity, diet, or diabetes medication. Some people, however, have difficulty managing their blood glucose levels and have persistently high or low blood glucose levels. This can include frequent hypoglycemia, sometimes without warning.

[0007] A continuous glucose monitoring (CGM) system, invasive or non-invasive, can help in these cases.

[0008] Iontophoresis is a non-invasive technique based on the application of a low-intensity electrical current to the skin to facilitate the release of a variety of drugs, charged or not, through biological membranes and into the bloodstream. Reverse iontophoresis works in a similar way, but in the opposite direction, facilitating the release of chemicals present in biological membranes through the so-called interstitial fluid. Like iontophoresis, it promotes the release of drugs through the layers until they penetrate into the bloodstream. Reverse iontophoresis can promote the removal of substances from this same bloodstream.

[0009] In this context, new technologies that make it possible to monitor diabetes non-invasively are welcome in the segment in question. State of the art

[0010] The current state of the art anticipates some patent documents that deal with invasive and non-invasive devices for monitoring glucose levels, such as US4517978 entitled “BLOOD SAMPLING INSTRUMENT” - instrument for taking a few drops of blood from a finger or similar, in which the sampling device consists mainly of a tubular element that conceals all working parts and that has a flange so that it can be easily held by a patient and pressed against a finger while releasing a trigger mechanism to actuate a plunger within the instrument.

[0011] It is an invasive instrument and despite using a spring in the recoil mechanism, which makes the lancet's penetration faster, it is still not enough to prevent the user from feeling pain due to the density of nerves in this region.

[0012] document US2011213225 AA entitled “MEDICAL DEVICES AND METHODS” - an analyte sensor having a portion configured to be in fluid contact with body fluid under a skin surface and configured to generate signals corresponding to the level of analyte monitored in the body fluid; a power supply; a data storage unit for storing analyte sensor calibration information, the analyte sensor calibration information including a factory calibration value for calibrating data for the generated signals corresponding to the monitored analyte level in the body fluid, wherein the factory calibration value is not modified throughout the useful life of the analyte sensor; and sensor electronics operatively coupled to the analyte sensor and the power supply.

[0013] The solution in the document above measures blood glucose using a sensor applied to the upper arm. The reading is taken with a device (US 10923218 B2) that scans the sensor and measures glucose without the need for a drop of blood, as the sensor uses interstitial fluid. The sensor consists of a fistula, a small needle that allows communication between the viscera and the skin to obtain the interstitial fluid sample. Although multiple punctures are not necessary, it still causes some discomfort and is therefore intrusive. One problem observed with this sensor is monitoring failure caused by fistula clogging, which necessitates premature replacement of the sensor. In addition to the questionable results, it is recommended that some fingerstick measurements be taken in parallel with its use.The device itself (US 10923218 B2) has a blood glucose meter integrated into the reader, which works with blood ketone and glucose test strips.

[0014] US 7972862, titled "NONINVASIVE GLUCOSE MONITOR" - detecting glucose in individuals, includes the steps of providing a detection solution containing a plurality of metal ions, and introducing a sample of a subject's body fluid into the detection solution. An optically based measurable derived from directing incident light into the solution is generated. The glucose concentration in the body fluid is then determined using the measurable, allowing the blood glucose level to be derived.

[0015] The first known attempt to measure blood glucose levels using a less invasive method was the Gluco Watch®, which consisted of two parts: the device itself, which was attached to the person's forearm, and the autosensor, an adhesive device attached to the watch, to check blood glucose levels. It was used It used a low electrical current to measure glucose levels through the skin and interstitial fluid. It allowed programming a built-in alarm to warn when glucose levels were dangerously low or high. Its initial use required at least two hours, at least for calibration, which was done by comparing it with conventional meters that measure glucose from the fingertip. Compared to these meters, the GlucoWatch® had a delay of about 15 minutes in analyzing results. In clinical studies, GlucoWatch® measurements were generally consistent with traditional fingerstick tests, but with results differing by 30% or more, especially at low glucose levels. Some people experienced skin irritation while using the GlucoWatch®. In addition to skin irritation, calibration could take more than one attempt.Like any watch, the device's anchoring allows the electrodes to move over the skin, which causes discomfort to its users due to the electrical current, in addition to causing contamination of fluids since, in the case of physical exertion, excessive sweat, being a natural diluent, alters the glucose concentration. Objectives of the invention

[0016] The objective of the present invention is to propose a painless reverse iontophoresis puncture-free blood glucose meter with acceptable glucose level accuracy without interference from other body fluids;

[0017] The objective of the present invention is to propose a reverse iontophoresis puncture-free blood glucose meter capable of humanizing treatment by making the monitoring process painless, easy and with continuous monitoring, providing correct monitoring of the disease with low cost and effectiveness;

[0018] The objective of the present invention is to propose a blood glucose meter without perforation by reverse iontophoresis that, in addition to being painless, does not cause wounds over time, avoiding infections;

[0019] The objective of the present invention is to propose a blood glucose meter without drilling by reverse iontophoresis that provides the patient with constant monitoring of blood glucose levels and with the automatic transmission of measurements to an interface, which allows not only their visualization but also the issuance of an alert in case of variation outside the ideal range known and established as clinical average;

[0020] The objective of the present invention is to propose a blood glucose meter without perforation by reverse iontophoresis that, being fixed to the skin, does not generate electrical discomfort and also “isolates” any excessive amounts of sweat that run over the membrane and not directly onto the skin in the area of ​​interest where glucose monitoring is being carried out;

[0021] The objective of the present invention is to propose a reverse iontophoresis, puncture-free blood glucose meter with an excellent cost-benefit ratio. Summary of the invention

[0022] GUCEMSA METER WITHOUT DRILLING BY REVERSE ONTHOPHORESIS, is based on the use of a wearable self-adhesive adhesive sensor that, through a membrane, with silver-based ink, Prussian blue and a catalytic enzyme, enables, through contact with the skin, the realization of the reverse iontophoresis process to obtain a sample of the interstitial fluid and, through an electrical and / or electrochemical transducer, allows the detection of glucose in this interstitial fluid and the consequent obtaining of an electrical signal through an electronic interface, in order to promote a relationship between the electrical current recorded with the concentration of glucose in the interstitial fluid, and, therefore, in the glycemic level of the individual, with the consequent processing of this data by the electronic interface in a digital way so that it is available to the user / patient or their doctor.

[0023] The reverse iontophoresis method allows the capture of a sample that contains glucose molecules extracted from the bloodstream and therefore provides results that are more faithful to the measurement process carried out in the laboratory. Description of figures

[0024] The following figures are presented to better explain the patent application in an illustrative and non-limiting manner: Figure 1: Schematic view of the self-adhesive adhesive sensor of the reverse iontophoresis drilling-free blood glucose meter. Figure 2: Architecture of the self-adhesive adhesive sensor of the reverse iontophoresis drill-free blood glucose meter. Figure 3: Electrical circuit of the self-adhesive adhesive sensor of the reverse iontophoresis drilling-free blood glucose meter. Figure 4: Analog signal conditioning electrical circuit of the self-adhesive adhesive sensor of the blood glucose meter without drilling by reverse iontophoresis. Figure 5: Electrical circuit for delivery of iontophoresis current of the self-adhesive adhesive sensor of the reverse iontophoresis puncture-free blood glucose meter. Detailed description of the invention

[0025] The PERFORATION-FREE BLOOD GLUCOSE METER USING REVERSE IONTOPHORESIS, the subject of this invention patent application, concerns a self-adhesive over-cutaneous adhesive sensor (S1, S2) that, coupled to an electronic circuit (C1, C2), has the capacity to continuously monitor blood glucose levels in the human body through the interstitial fluid without any type of intrusion into the patient's body, since it uses reverse iontophoresis, making continuous monitoring possible for a certain period of time without the need to change the adhesive, however with the same electronic circuit (C1, C2).

[0026] More particularly, the claimed invention relates to a continuous, non-invasive, reverse iontophoresis blood glucose meter (1), formed from an analysis area (2), where a transduction process occurs, in which the analyte is degraded in an enzymatic reaction by means of a wearable, self-adhesive adhesive sensor (S1, S2) with a membrane, with silver-based ink, Prussian blue and a catalytic enzyme, and another part, an electronic circuit (C1, C2), which operates in two steps: polarization of the electrode to generate reverse iontophoresis and capture of the signal from the reaction absorption zone, in a form of enabling the invention, glucose oxidase. Reverse iontophoresis involves the application of a gentle current through two electrodes worn on the skin to extract interstitial fluids. Due to the negative charge of the skin, the flow of positive sodium ions induces an electro-osmotic flow towards the cathode, resulting in the movement of neutral glucose.The working electrode (W1, W2) is then capable of electrochemically detecting interstitial glucose levels extracted through enzymatic oxidation of glucose in the skin by the interfaced sensing electrodes. The working electrodes (W1, W2) include an electrochemical transducer layer (Prussian Blue (PB)) and catalyst (glucose oxidase) to selectively catalyze glucose. Glucose oxidation occurs in the presence of glucose oxidase (GOx), oxygen (O2), and water (H2O) to form gluconic acid and hydrogen peroxide (H2O2). The hydrogen peroxide is electrochemically oxidized, producing an amperometric signal that is proportional. to the glucose concentration in the sample. The non-invasive glucose adhesive sensor (S1, S2) includes anodic and cathodic components. Each component is a three-electrode system: the working electrode (W1, W2), reference electrode (R1, R2), and iontophoresis electrodes (RI1, RI2), which are integrated into the adhesive sensor (S1, S2), which is a flexible wearable. The iontophoresis electrode (RI1, RI2) applies a gentle current of 0.2 mA / cm 2on the skin for 10 minutes to drive the flow of ions from the interstitial fluid toward the working electrode (W1, W2) and the reference electrode (R1, R2). The amperometric response of glucose should be recorded at an applied potential of the order of 0.0 V vs. on the Ag / AgCl sensors for 5 minutes, followed by a 5-minute rest. The next detection session changes the anodic and cathodic properties of the electrodes. This iontophoretic detection process is repeated every 40 minutes. The expected current range is 0.5 to 15 pA. As shown in Figure 1, both sensors (S1, S2) are illustrated with the working electrodes (W1, W2), reference electrodes (R1, R2), and reverse iontophoresis electrodes (RH, RI2).As already mentioned, the self-adhesive sensor (S1, S2) must be connected to an external electronic circuit (C1, C2) used to power the device's electrochemical sensor. This circuit is responsible for receiving and analyzing the sensor signal, translating the glucose concentration data. The information is transmitted wirelessly from the electronic circuit (C1, C2) to a device such as a smartphone, tablet, or other device whose information is processed and transmitted wirelessly using radiofrequency and / or Bluetooth® communication, making it comprehensible to the patient, who receives it numerically, as is the case with current glucometers. The detection circuit has two paths for conducting the transduced signal, each including an analog end to amplify the signal and a low-pass filter to minimize high-frequency and electromagnetic noise / interference.The circuit consists of a printed circuit board, which can be flexible, providing the structure for this electronic device. It is equipped with a microcontroller programmed to set the operating mode by controlling a bank of switches to turn on and off the respective circuits and electrical pathways. The microcontroller's digital-to-analog (DAC) port is used to drive the iontophoresis circuit, while its analog-to-digital (ADC) port is used to convert the processed analog signal to digital. Figure 2 illustrates the overall system design and the relationship between the central microcontroller and the iontophoresis process. The overall system is based around an 8-bit microcontroller with analog circuitry that tracks the readings from the adhesive sensor (S1, S2) and delivers the current for the reverse iontophoresis process. The microcontroller's integrated 8-bit ADC (Analog-to-Digital Converter) is used to read data from the adhesive sensor (S1, S2) and monitor the reverse iontophoresis current. A Bluetooth® transceiver is connected to the microcontroller to interface the system with a cell phone. Using the cell phone, the system transmits readings in real time. Figure 3 illustrates, as an example, an Atmel ATmega328P microcontroller with pin configurations included. Pins 19 and 22 are highlighted, which are the microcontroller's ADC ports, as well as all signal filters.The self-adhesive adhesive sensor (S1, S2) is connected to the electronics through two amperometric glucose sensor circuits, illustrated in Figure 4, as well as two reverse iontophoresis circuits that deliver the required current to the sensor, illustrated in Figure 5. The output of the current shunt monitor must be connected to one of the microcontroller's ADC ports to provide real-time monitoring of the current delivery, allowing the microcontroller to turn off the current output. The values ​​obtained at the system output, Figure 3, are analyzed, processed, and digitized so that the obtained value is palatable to the patient's understanding and is presented to them in a known numerical format.

[0027] To manufacture the self-adhesive adhesive sensor, which can be manufactured by printing or silkscreening, a silver ink, Ag / AgCl in a 45:55 ratio, and a graphite-prussian blue mediator ink are used, applied to different types of thin films such as Kapton polyimide (PI), TT paper from Silhouette America (Lindton, UT) or manometric membrane (Nanoskin).

Claims

CLAIMS 1) GUCEMIÂ METER WITHOUT DRILLING BY REVERSE IONTOPHORESIS, uses reverse iontophoresis characterized by being formed by an analysis area (2), transduction process, the analyte is degraded in an enzymatic reaction by means of a wearable self-adhesive adhesive sensor (S1, S2) with a membrane, with silver-based ink, Prussian blue and a catalytic enzyme, and another part, an electronic circuit (C1, C2), power supply and data analyzer, which operates in two stages; polarization of the electrode that generates reverse iontophoresis (RI1, RI2) and signal capture from the reactional absorption zone, in a form of enabling the invention, glucose oxidase. 2) DRILL-FREE GLUCOSE EDITOR BY REVERSE IONTOPHORESIS, according to claim 1 characterized by the non-invasive self-adhesive glucose sensor (S1, S2) including anodic and cathodic components. 3) DRILL-FREE GUAM METER BY REVERSE IONTOPHORESIS, according to claim 2, characterized in that each component is a three-electrode system; working electrode (W1, W2); reference electrode (R1, R2) and iontophoresis electrodes (RI1, RI2) integrated into the self-adhesive adhesive sensor (S1, S2), a flexible wearable. 4) DRILL-FREE GUCEMIA EDITOR BY REVERSE IONTOPHORESIS, according to claim 1, characterized in that the detection circuit has two paths for conducting the transduced signal, each of which includes an analog end to amplify the signal, as well as a low-pass filter to minimize high-frequency and electromagnetic noise / interference. 5) DRILL-FREE BLOOD GLUCOSE METER BY REVERSE IONTOPHORESIS, according to claim 4, characterized in that the programmed microcontroller sets the operating mode by controlling a bank of switches to turn on / off the respective circuits and electrical paths; the digital-to-analog port (DAC) of the microcontroller is used to drive the iontophoresis circuit while its analog-to-digital port (ADC) is used to convert the processed analog signal to digital. 6) DRILL-FREE BLOOD GLUCOSE METER BY REVERSE IONTOPHORESIS, according to claim 5, characterized by an 8-bit microcontroller with analog circuitry that monitors the sensor reading and delivers the current for the reverse iontophoresis process; the integrated 8-bit ADC of the microcontroller is used to read data from the sensor and monitor the reverse iontophoresis current. 7) DRILL-FREE GLUCOSE METER BY REVERSE IONTOPHORESIS, according to claim 4, characterized in that the self-adhesive adhesive sensor (S1, S2) is connected to the electronics by means of two amperometric glucose sensor circuits, as well as two circuits for reverse iontophoresis that deliver the current to the sensor.

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