WO2024259501A1 - Dispositif de mesure de glycémie sans perforation par iontophorèse inverse - Google Patents

Dispositif de mesure de glycémie sans perforation par iontophorèse inverse Download PDF

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Publication number
WO2024259501A1
WO2024259501A1 PCT/BR2023/050202 BR2023050202W WO2024259501A1 WO 2024259501 A1 WO2024259501 A1 WO 2024259501A1 BR 2023050202 W BR2023050202 W BR 2023050202W WO 2024259501 A1 WO2024259501 A1 WO 2024259501A1
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WIPO (PCT)
Prior art keywords
reverse iontophoresis
sensor
iontophoresis
adhesive
glucose
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PCT/BR2023/050202
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English (en)
Portuguese (pt)
Inventor
Marcelo Martins GRASTI
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Individual
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Individual
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Priority to PCT/BR2023/050202 priority Critical patent/WO2024259501A1/fr
Publication of WO2024259501A1 publication Critical patent/WO2024259501A1/fr
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/05—Detecting, measuring or recording for diagnosis by means of electric currents or magnetic fields; Measuring using microwaves or radio waves
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N1/00—Electrotherapy; Circuits therefor
    • A61N1/18—Applying electric currents by contact electrodes
    • A61N1/20—Applying electric currents by contact electrodes continuous direct currents
    • A61N1/30—Apparatus for iontophoresis, i.e. transfer of media in ionic state by an electromotoric force into the body, or cataphoresis

Definitions

  • This patent application for the invention refers to a PERFORATION-FREE BLOOD GLUCOSE METER USING REVERSE IONTOPHORESIS, which is a self-adhesive, over-cutaneous adhesive 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.
  • 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 the tendencies of oscillation of glycemia; to know the factors that can cause hypoglycemia or hyperglycemia; to evaluate the impact of diet, physical activities and medications on diabetes; to identify the need for changes in treatment; to confirm whether certain symptoms are related to some type of glycemic imbalance.
  • Diabetes Mellitus is a disease characterized by high 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.
  • Type 1 Diabetes 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.
  • 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 an accumulation of glucose in the blood.
  • a blood glucose monitoring system measures glucose levels on a special occasion or whenever needed. This can help keep blood glucose levels under control by indicating adjustments to insulin doses, exercise, diet, or diabetes medications. Some people, however, have difficulty managing their blood glucose levels and have persistently very high or very low blood glucose levels. This can include frequent hypos, sometimes without warning.
  • a continuous glucose monitoring (CGM) system can help in these cases.
  • Iontophoresis is a non-invasive technique based on the application of a low-intensity electric current to the skin to facilitate the release of a variety of drugs, whether charged or not, through biological membranes into the bloodstream.
  • the reverse iontophoresis process acts in a similar manner, but in the opposite direction, i.e., it facilitates the release of chemical substances present in biological membranes through the so-called interstitial fluid.
  • interstitial fluid Like iontophoresis, it can promote the release of drugs through the layers until they penetrate into the bloodstream.
  • Reverse iontophoresis is capable of promoting the removal of substances from this same bloodstream.
  • the solution in the document above measures blood glucose levels using a sensor applied to the upper arm.
  • the reading is taken using a device (US 10923218 B2) that scans the sensor and measures glucose levels without needing 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 a sample of interstitial fluid. Although there is no need for multiple punctures, it still causes some discomfort and is therefore intrusive.
  • One problem found with this sensor is the failure in monitoring caused by the clogging of the fistula, which makes it necessary to replace the sensor prematurely, in addition to the questionable result, for which the recommendation is to perform some measurements with fingertip tests 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.
  • US 7972862 entitled “NONINVASIVE GLUCOSE MONITOR' - detecting glucose in individuals includes the steps of providing a detection solution including a plurality of metal ions, introducing a sample of body fluid from an individual into the detection solution. An optically based measurable derived from directing incident light into the solution is generated. The concentration of glucose in the body fluid using the measurable is then determined, which allows the blood glucose level to be derived.
  • GlucoWatch® measurements were generally consistent with traditional finger prick tests, but with results that differed by 30% or more, especially at low glucose levels.
  • some people experienced skin irritation when using the GlucoWatch®.
  • skin irritation it could take more than one attempt to calibrate.
  • 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.
  • the aim 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;
  • the objective of the present invention is to propose a blood glucose meter without drilling by reverse iontophoresis capable of humanizing the treatment by making the monitoring process painless, easy and with continuous monitoring, providing the correct monitoring of the disease with low cost and efficiency;
  • the objective of the present invention is to propose a puncture-free blood glucose meter using reverse iontophoresis that, in addition to being painless, does not cause wounds over time, preventing infections;
  • 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 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, because it is 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;
  • the objective of the present invention is to propose a reverse iontophoresis puncture-free blood glucose meter with an excellent cost-benefit ratio.
  • DRILL-FREE GUCEMSA METER 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 recorded electrical current and the concentration of glucose in the interstitial fluid, and, therefore, in the individual's glycemic level, with the consequent processing of this data by the electronic interface in a digital manner so that it is available to the user/patient or their doctor.
  • the reverse iontophoresis method allows the capture of a sample that contains glucose molecules extracted from the bloodstream and therefore with results that are more faithful to the measurement process carried out in the laboratory.
  • Figure 1 Schematic view of the self-adhesive adhesive sensor of the reverse iontophoresis puncture-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.
  • THE PERFORATION-FREE GLUCOSE METER USING REVERSE IONTOPHORESIS concerns a self-adhesive over-the-skin adhesive sensor (S1, S2) that, coupled to an electronic circuit (C1, 02), has the capacity to continuously monitor blood glucose levels in the human body through interstitial fluid without any type of intrusion into the patient's body, since it uses reverse iontophoresis, allowing continuous monitoring for a certain period of time without the need to change the adhesive, however with the same electronic circuit (C1, C2).
  • 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 stages: 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.
  • S1, S2 wearable self-adhesive adhesive sensor
  • C1, C2 an electronic circuit
  • 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 movement of neutral glucose.
  • the working electrode (W1, W2) is then capable of electrochemically detecting levels of interstitial glucose 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.
  • the noninvasive self-adhesive glucose sensor includes anodic and cathodic components. Each component is a three-electrode system which are the working electrode (W1, W2), reference electrode (R1, R2) and iontophoresis electrodes (RI1, RI2) that are integrated into the self-adhesive sensor (S1, S2), which is a flexible wearable.
  • the iontophoresis electrode (RI1, RI2) applies a gentle current of 0.2 mA/ cm2 to the skin for 10 minutes to drive the flow of ions from the interstitial fluid towards 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. 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.
  • both sensors are illustrated with the working electrodes (W1, W2), reference electrodes (R1, R2) and reverse iontophoresis electrodes (RH, RI2).
  • the self-adhesive sensor S1, S2 must be connected to an external electronic circuit (C1, C2) used to power the device's electrochemical sensor, which is responsible for receiving and analyzing the sensor signal, translating the data into glucose concentration.
  • the information is transmitted wirelessly from the electronic circuit (C1, C2) to a device such as a smartphone, tablet or device whose information is processed and transmitted wirelessly, using radio frequency and/or Bluetooth® communication, becoming understandable 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 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.
  • the circuit consists of a printed circuit board that can be flexible, providing structure for this electronic device that is equipped with a microcontroller programmed to set the operating mode by controlling a bank of switches to turn on/off the respective circuits and electrical paths.
  • the digital-to-analog (DAC) port of the microcontroller is used to drive the iontophoresis circuit while its analog-to-digital (ADC) port is used to convert the processed analog signal to digital as
  • ADC analog-to-digital
  • Figure 2 shows the overall system design and the relationship between the central microcontroller and the iontophoresis process.
  • the overall system was based around an 8-bit microcontroller with analog circuitry that tracks the reading 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
  • a Bluetooth® transceiver is connected to the microcontroller to interface the system with a cell phone. Using the cell phone, the system transmits the readings in real time.
  • Figure 3 illustrates, as an example, an Atmel ATmega328P 8-bit microcontroller with pin configurations included. Emphasized are pins 19 and 22 which are the ADC ports of this microcontroller as well as all the signal filters.
  • the self-adhesive sensor (S1, S2) is connected to the electronics via 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 shunt current monitor must be connected to one of the ADC ports of the microcontroller 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 value obtained is palatable to the patient's understanding and is presented to him in a known numerical format.
  • the self-adhesive adhesive sensor which can be manufactured by means of printing or silkscreen process, a silver ink, Ag/AgCI 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), Silhouette America TT paper (Lindton, UT) or manometric membrane (Nanoskin).
  • PI Kapton polyimide
  • Silhouette America TT paper Lidton, UT
  • Nanoskin manometric membrane

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Biomedical Technology (AREA)
  • Animal Behavior & Ethology (AREA)
  • Radiology & Medical Imaging (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Engineering & Computer Science (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Health & Medical Sciences (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Molecular Biology (AREA)
  • Surgery (AREA)
  • Medical Informatics (AREA)
  • Physics & Mathematics (AREA)
  • Pathology (AREA)
  • Biophysics (AREA)
  • Measurement Of The Respiration, Hearing Ability, Form, And Blood Characteristics Of Living Organisms (AREA)

Abstract

L'invention concerne un capteur (S1, S2) adhésif autocollant appliqué sur la peau qui, couplé à un circuit électronique (C1, C2), est apte à réaliser la surveillance continue des niveaux de glycémie dans le corps humain par le liquide interstitiel sans aucun type d'intrusion dans le corps du patient, une iontophorèse inverse étant utilisée, la surveillance continue étant possible pendant une durée déterminée sans qu'il soit nécessaire de changer l'adhésif et avec le même circuit électronique (C1, C2).
PCT/BR2023/050202 2023-06-20 2023-06-20 Dispositif de mesure de glycémie sans perforation par iontophorèse inverse Pending WO2024259501A1 (fr)

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Application Number Priority Date Filing Date Title
PCT/BR2023/050202 WO2024259501A1 (fr) 2023-06-20 2023-06-20 Dispositif de mesure de glycémie sans perforation par iontophorèse inverse

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Application Number Priority Date Filing Date Title
PCT/BR2023/050202 WO2024259501A1 (fr) 2023-06-20 2023-06-20 Dispositif de mesure de glycémie sans perforation par iontophorèse inverse

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6736777B2 (en) * 1998-03-13 2004-05-18 Cygnus, Inc. Biosensor, iontophoretic sampling system, and methods of use thereof
US7555337B2 (en) * 2001-06-22 2009-06-30 Richard Henry Guy Method for non-invasively determining the relative levels of two biological substances
GB2497726B (en) * 2011-12-09 2017-11-15 Dermal Diagnostics Ltd Determining the volume of a liquid in a reverse iontophoresis chamber
BR102022004984A2 (pt) * 2022-03-17 2023-09-26 Marcelo Martins Grasti Medidor de glicemia sem perfuração por iontoforese reversa

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6736777B2 (en) * 1998-03-13 2004-05-18 Cygnus, Inc. Biosensor, iontophoretic sampling system, and methods of use thereof
US7555337B2 (en) * 2001-06-22 2009-06-30 Richard Henry Guy Method for non-invasively determining the relative levels of two biological substances
GB2497726B (en) * 2011-12-09 2017-11-15 Dermal Diagnostics Ltd Determining the volume of a liquid in a reverse iontophoresis chamber
BR102022004984A2 (pt) * 2022-03-17 2023-09-26 Marcelo Martins Grasti Medidor de glicemia sem perfuração por iontoforese reversa

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