RU2605792C2 - Device for compensation of hyperglycemia in diabetic patients - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: invention relates to medical equipment. Device for compensation of hyperglycemia in diabetic patients is made in form of portable device and includes unit for diagnostics of expired air, configured to generate signal on volume of exhaled air and concentration of glucose in condensate of exhaled air, electronic unit configured to output sound alarm signal and visual information and unit for dosed injection of therapeutic aerosol. Unit of exhaled air diagnostics contains serially connected labial exhaled air intake with spirometry apparatus, concentrator of taken aerosol, throttle and capacitor-detector with replaceable cartridge with cooling mixture or cooling ring and measuring electrochemical cell for detecting concentration of glucose in exhaled air condensate. Electronic unit has series-connected recorder of detected signal, memory device, comparator circuit of detected and reference signals, circuit of assessment of amount of corrective action and display panel for visual display of information on content of glucose in air condensate. Unit for dosed injection of therapeutic aerosol comprises guide nozzle, aerosol can with liquid drug, equipped with spraying piston head. Cartridge is fixed in mounting seat in device housing and has possibility of manual activation by pressing on spraying piston head.

EFFECT: invention provides efficient and safe compensation of hyperglycemia in diabetic patients.

3 cl, 7 dwg

Description

The invention relates to medicine, namely to the field of diagnostics and devices for administering drugs to the body with giving drugs a certain physical or other form for consumption. The rapid growth of patients with diabetes mellitus, 5% of the population (including identified patients and patients with undiagnosed diabetes) is accompanied by an increase in cases of infection with infections in cases of invasive diagnosis of glucose in the patient’s blood and individual administration of drugs into the patient’s body. At present, almost all practical healthcare institutions in Russia use blood sampling for glucometer, and specialized retail chains supply the population with individual portable glucometers with test strips, the effect of which is also based on blood sampling from the patient’s finger.

In the general case, the relevance of non-invasive diagnostics is due to the gentle methods of taking material for analysis, when the patient does not experience pain, physical and emotional discomfort; safety studies because of the impossibility of infection with infections transmitted through blood or tools. Therefore, in recent years, federal and regional scientific and technical programs and projects for the development and creation of non-invasive glucometers have begun to be created and implemented.

An analysis of publications and patents indicates the following areas in the development of non-invasive glucometers (Pavlov A.F., Novak A.S. Problems and prospects of creating non-invasive glucometers. - Bulletin of medical Internet conferences (ISSN2224-6150), 2013, Volume 3, No. 2 ):

- optical methods of measurements in the near infrared range;

- electrical methods, such as impendanceometry;

- thermometry;

- ultrasonic measurements in combination with thermometry;

- the use of other biological objects (saliva, retina, head vessels).

However, until now, the efforts of developers have not led to the emergence of non-invasive glucometers on sale.

In the last decade, the attention of researchers and developers to such a biological object for diagnosis as exhaled air (BB) has increased, see, for example, a brief overview of the staff of Kharkov National Medical University V.A. Klimenko and Krivorotko D.N. (article “Analysis of expired air as a marker of biochemical processes in the body” in the journal “Child Health”, 1 (81), 2011).

It is known that lung functions contain, in addition to respiratory, metabolic and excretory functions. The lungs play an important role in regulating the state of aggregation of blood. Chemical compounds are released through the lungs, primarily volatile ones, which are formed during metabolic reactions occurring both in the lung tissue and throughout the human body. By changing the amount and ratio of substances released during breathing, conclusions can be drawn about metabolic changes and the presence of the disease.

In the mid-twentieth century, about 400 volatile metabolites were determined by mass spectrometry and chromatography in explosives, many of which are disease markers. In modern practice, capnographs are used - devices for recording carbon dioxide (CO2); nitric oxide (NO) detectors; Breathalyzers - measuring the content of ethyl alcohol (C2H5OH) in human blood.

Modern gas and liquid chromatography methods determine up to 1000 substances in the explosive condensate (Raed A. Dwink, Anton Amann. Exhaled breath analysis: the new frontier in medical testing J. Breath. Res. - 2008. - No. 2; doj: 10.1088 / 1752-7163 / 2/3/030301).

The explosive aerosol is saturated with water vapor, the amount of which is 7 ml / kg of human body weight. An adult releases about 400 ml of water per day through the lungs. Water vapor serves as a carrier of many volatile and non-volatile compounds through the dissolution of molecules (according to the dissolution coefficient) and the formation of new chemicals inside an aerosol particle (Klimanov I.A. Condensation formation mechanisms) of exhaled air and oxidative stress markers in respiratory tract pathologies // Pulmanology. - 2009 - No. 2. - from. 113-119).

The average diameter of aerosol particles in explosives normally under normal breathing in an adult is about 0.3 μm, and contains 1 cm ^{3 of} explosives - up to 4 particles (Fairchild CD, Stemfer JE Practicle concentration in exhaled breath // Am. Industr. Hyg Assoc. J. - 1987 - No. 48 - P. 948-949). When air is cooled, water vapor and the substances contained in them condense, which makes their quantitative analysis possible.

Having established the fundamental possibility of operative glycometry on the basis of a diagnosed bioobject every 4 seconds - BB, which is well concentrated from liter volumes to the size of a condensate drop (SBC), it is necessary to determine the possibility of a corrective effect on the human body in order to compensate for hyperglycemia. To do this, we give a brief overview of technical analogues that determine the current level of technology in this direction.

Invasive methods of glycometry and their technical devices based on taking blood from the human body before and after eating are known (Emanuel V.A., Karyachina I.Yu., Emanuel Yu.V. Portable self-monitoring systems and laboratory analysis of blood glucose concentration. Comparative study // Labor. Med. 2009; 20-30), which have such disadvantages as discomfort and the risk of infection.

Examples of non-invasive glycometry, especially those based on commercially available glucometers, are very few.

The most famous methodology and devices developed by MD Elbaev A.D. in the dissertation research “Arterial hypertension and diabetes mellitus: modeling the relationship, new approaches to diagnosis and complex therapy” - 2005, Nalchik and in inventions protected by RF patents No. 2198586; 2,138,875; 2368303, as well as those published in the monograph “Diabetes mellitus and arterial hypertension: mechanisms of interconnection and ways of correction”. - Moscow - Stavropol. - 2003. - 136 p. / Author: Elbaev A.D., Kurdanov. HA.

The diagnostic technique is based on the experimentally established correlation of the blood pressure in a patient with type 2 diabetes and the level of glucose in his blood.

So, in the "Method for determining the concentration of glucose in the blood" (according to RU 2198586) in the morning, on an empty stomach, the patient is measured systolic blood pressure and diastolic blood pressure on the left and right hands, determine the correlation coefficient, which is the ratio of the largest of the measured values of systolic blood pressure on left and right hands to the smallest of the measured values of diastolic blood pressure on the left right hands, and the glucose content in the blood is calculated by the formula.

The “Method for the treatment of type 2 diabetes patients” (according to RU2193875) also uses a stable relationship between glycemia levels and blood pressure parameters, which is described by a mathematical model based on regression equations.

In the “Method for the non-invasive determination of carbohydrate metabolism disorders” (according to RU 2368303), systolic blood pressure and diastolic blood pressure are measured on an empty stomach and after eating, carbohydrate metabolism is determined by comparing the results with diabetes compensation criteria taken, for example, from Dreval A source .AT. Treatment of uncomplicated non-insulin-dependent diabetes mellitus // Problems of endocrinology. - 1995. - No. 14 - p. 28.

The invention of other authors is also known according to RU 2444279, improving the above methods in terms of calibration characteristics.

The main common disadvantages of these known methods are the indirectness of glycometry and the impossibility of their use for the diagnosis and treatment of insulin-dependent patients with diabetes mellitus.

Other non-invasive indirect methods of glycometry are also known, for example, “A method for non-invasive determination of blood glucose by the voice of a person” according to patent RU 2295915. This method is also based on the experimentally established fact that a change in the frequency and intensity of oscillations in the spoken area of a person 100- 20,000 Hz at 60 ± 5 dB. The disadvantage of this method is the exposure of the vocal apparatus of a person to other influences that interfere with glycometry (sleep, food, colds, infections, etc.).

The source of information RU 2368312 presents invasive and non-invasive methods for determining blood glucose.

The essence of the technical solution according to patent RU 2368312 is the operation of periodically injecting insulin through the intradermal port and "in addition, an electrochemical sensor (electrode) that is sensitive to glucose is periodically immersed through the intradermal port in the subcutaneous environment."

According to paragraph 1 of the claims, in the monitoring method “use the difference in the measurement results that occurs after each pulsed dose of insulin to determine the current glucose level” and, accordingly, the value of the “current glucose level” determined during monitoring belongs to the diseased organism in one of its parametric points (pos. 3 fig. on p. 9), where the “intradermal port” is located and in one temporary gate - for several minutes “of a complete short-term blockage of glucose in the vicinity of the“ intradermal port ”.

Information source Pooja Singal M D et al. "Intra-Individual Variability of C02 Breath Isotope Enrichment Compared to Blood Glucose in the Oral Glucose Tolerance Test." Diabetes Technol Ther. 2010 Dec; 12 (12): 947-953, Full Text, found from PubMed PMCID: PMC014756 indicates the prior art's ability to perform comparative glycemic control by examining blood glucose tolerance before and after meals (bolus injection of 75 g glucose) followed by regular monitoring every 30 minutes for the level of glycemia for 3 hours (i.e. 180 minutes) in healthy people, which allows us to conclude that the obtained results of glycemic measurement are correlated by invasive and non-invasive methods, as in the claimed m method.

In the aforementioned work, an original technique for the experimental study of glycemia is given by the marker ratio of carbon isotopes in carbon dioxide exhaled with air ( ¹³ C / ¹² C) and the results of experiments using the standard OGTT test and isotope mass spectrometry make a conclusion on the correlation of the results of invasive and non-invasive methods (p. 1-8).

The disadvantage of this technical solution is the indirect measurement of the CO ₂ metabolite ( ¹³ C / ¹² C) with a poorly taken into account error due to the secondary carbon source (except ¹³ C - glucose plasma) from fatty acids (p. 6).

From a source of information Novae B.J. et al. "Exhaled methyl nitrate as a noninvasive marker of hyperglycemic in type 1 diabetes." Proc Natl Acad Sci USA. 2007 Oct 2; 104 (40): 15613-15618, Full text, found from PubMed PMCID: PMC1994136 known comparative regression analysis in healthy people and patients with diabetes mellitus in order to assess the correlation of the results of non-invasive and invasive glycemic studies with an appropriate choice of normative corridors for a non-invasive study and the possibility of using a non-invasive study to monitor hyperglycemia therapy in patients with diabetes mellitus.

The document contains information on the experimental verification of the hypothesis of non-invasive control of hyperglycemia that occurs spontaneously in children with type 1 diabetes by measuring one of the components of volatile organic compounds (VOC _s ) in the air exhaled by the child, namely CH ₃ ONO ₂ methyl nitrate gas. Based on the results of the discussion of experimental results, a conclusion is made on the correlation of the results of non-invasive and invasive control and the possibility of using this non-invasive method to control the treatment of hyperglycemia in patients with diabetes mellitus (p. 1-8).

The disadvantage of this solution is indirect measurements of the metabolite-methyl nitrate, which forms spontaneously (p. 1) and is not a permanent glucose marker.

Source of information Kuraeva T.P. et al. “A Full Life with Diabetes in Children and Adolescents” (a book for parents and children with diabetes), M., 2014 (see p. 16-18, p. 21-22, p. 27-28, p. 46, p. 49-53, p. 58-59) contains digital indicators of diabetes compensation criteria - glucose indicators (glucose level in capillary blood) on an empty stomach 5.0-8.0 mmol / l (glucose level in capillary blood ) after meals (postprandial glycemia 2 hours after eating) 5.0-10.0 mmol / L. From the source it is also known that in case of detection of hyperglycemia in patients with diabetes mellitus, measures should be taken to reduce blood sugar, that is, to introduce a fast-acting sugar-lowering drug (for example, short-acting insulin), the dose of which varies depending on the level of hyperglycemia with subsequent monitoring the level of hyperglycemia, which involves a comparison of the results obtained in a particular patient with the norms of glycemia in a healthy person.

The disadvantage of this technical solution is that as the basic criteria, the results of only two glucose measurements are used - on an empty stomach and after eating, however, as you know, an infinite number of curves can be drawn through two points - this means that from the fasting glucose level to the glycemic level through two hours after eating, the patient's body can go through a state of hypoglycemia and / or hyperglycemia, provoked, for example, by stressful situations.

Information source Balabolkin M.I. “Diabetology”, M .: “Medicine”, 2000 (see p. 541, Fig. 6.1) indicates the popularity of the regression analysis of glycemia levels using the graphical method.

засоби, мережiта системи», 2010, №9, стр. 62-71 (см.стр. 62-68) информация о том, что с целью гликометрии конденсат выдыхаемого воздуха исследуют электрохимическим методом, в том числе для определения уровня гликемии у больных сахарным диабетом. В источнике представлена информация об изучении выдыхаемых газов человека в состоянии гипергликемии. При этом использовалось мультигазовое моделирование летучих органических соединений (VOC_s), которые «представляют собой идеальные маркеры эндогенного метаболизма и должны быть использованы в неинвазивных измерениях вариабельности глюкозы в циркулирующей плазме (крови)».Known from the source of information Lukash S.I. “Problems in the diagnosis of certain diseases by exhaled air” // “

hassle, reduce the system ”, 2010, No. 9, pp. 62-71 (see pages 62-68) information that, for the purpose of glycometry, the condensate of exhaled air is examined by the electrochemical method, including to determine the level of glycemia in patients with sugar diabetes. The source provides information on the study of human exhaled gases in a state of hyperglycemia. We used multigas modeling of volatile organic compounds (VOC _s ), which "are ideal markers of endogenous metabolism and should be used in non-invasive measurements of glucose variability in circulating plasma (blood)."

Since volatile organic compounds (VOC _s ) are, by definition, unstable (unstable) correlations of glucose in human blood, in fact, indirect identifiers of glucose, since they are metabolites of biochemical processes, the above information does not implement the claimed invention, in which the process of “glycometry” aerosol / expiratory condensate ”includes direct measurement of glucose structures.

From information source Lee J et al. “Improved predictive models for plasma glucose estimation from multi-linear regression analysis of exhaled volatile organic compounds)). J Appl Phisiol (1985). 2009 Jul; 107 (1): 155-60, Full Text, found from PubMed PMCID: PMC2711799 a known study of expiratory condensate prepared for diagnosis.

The source contains information that “light gases ... are formed in the body, are present in exhaled air in the form of traces (concentration less than 10 ^-6 %) and are signs or markers of ongoing biochemical processes” (p. 62).

In Table 1 on p. 63 sources, among other “diseases and associated gases in a person’s exhalation, include pancreatic diseases and diabetes mellitus, marker gases acetone and acetaldehyde in concentrations of 4-20 ppm”.

Acetone C ₃ H ₆ O, being a product of the metabolism of free fatty acids, is formed in decompensated diabetes mellitus. “A certain amount of acetone is excreted from the body unchanged with exhaled air and through the skin, creating the so-called faint smell of“ maple syrup ”, and some with urine” (p. 65).

In the measurement range of 0-2-20 mg / m ^3, acetone can be measured using electrochemical or semiconductor sensors with an absolute error of ± 0.5 mg / m ³ and a relative error of ± 25% (Table 2, p. 67).

The disadvantage of this solution is the measurement of the concentration of metabolites of biochemical processes (acetonometry), and not glucose.

From the work of Barnett A.N. et al. “An open, randomized, parallel-group study to compare the efficacy and safety profile of inhaled human insulin (Exubera) with glibenclamide as adjunctive therapy in patients with type 2 diabetes poorly controlled on metformin)). Diabetes Care. 2006 Aug; 29 (8): 1818-25, abstract, found 07/07/2016 from PubMed PMID: 16873786 inhaled administration of insulin and metformin for the treatment of diabetes is known.

This paper compares the results of the treatment of type 2 diabetes in two groups of patients through inhaled human insulin (Exubera) and metphorine tablets.

The mentioned preparations were used during the 24-week experiment in the usual form, according to the usual scheme - for basic therapy of some patients with metformin and for basic therapy of other patients with Exubera aerosol.

The technical level in the field of devices for implementing the invention can be represented by the following technical solutions.

According to the website kakmed.com/15217/, 2015, in 2005, scientists from the University of Syracuse (USA) attempted to create a laser glucometer based on the Raman spectrometry method. However, a non-invasive glucometer was not prepared.

Information about the pilot test of a laser glucometer at Princeton University (USA) was published in the Biomedical Optics Expess.

The principle of operation of the device is based on the fact that a quantum cascade beam of a mid-infrared laser is directed to the palm of the hand, its absorption and scattering in the interstitial fluid of the skin is measured, the state of which strictly correlates with the desired level of monosaccharides in the blood. So far, the achieved accuracy of the device is small - 84%, but work continues to create a portable laser generator.

Almost the only non-invasive glucometer, commercially available in Russia, is the Omelon V-2 portable device (omelon2@yandex.ru). in fact, it is a tonometer with a modified electronic unit that measures the blood pressure of the patient on the left and right hands with an indication, automatically determined by calculation, of the blood glucose level (patent application No. 2004136942 of November 21, 2004. “A portable device for determining glucose concentration in blood ”/ Auth .: Elbaev A.D. et al.).

There is a well-known proposal by Dr. Joon Hu of the University of Akron, Ohio, USA (2012) for the use of eye contact lenses, including the substance he invented, for glycometry by indicating the intensity of redness of the lenses depending on the level of sugar in the tear fluid.

There is information (yalo.su/zdorove/3695) that GOOGL and the Swiss pharmaceutical company NOVARTIS filed a patent application with the Patent Office in 2012 for the invention of glucometric contact eye lenses. The engineers of these applicants created lenses equipped with sensors, a microchip and a transmitting device of superminiature sizes. All electronics are located between several layers of transparent polymer material, and ring sensors are in contact with a tear fluid containing sugar impurities. An algorithm has been created to automatically convert an analog signal from sensors to numbers. In 2015, "glucometer lenses" were officially authorized for sale.

Breathalyzers and breathalyzers are known - portable devices for non-invasive control of alcohol in human blood (alcotester / by / meyu / info / html # content). Breathalyzers (for example, Chinese ones with an electrochemical sensor of the Satellite; Pluto; Stopcar; MARK V brands) are technical devices for a qualitative assessment of ethanol concentration in exhaled air or in human blood by explosives; have a non-standardized error and are not subject to metrological verification.

Breathalyzers (for example, companies Lion Laboratories LTD., Great Britain such as Lion Alcobiow, Lion Alcometer 500, Lion Alcometr SD-400 or the Russian company Breathalyzer type Alcotector Jupiter) - technical means of measuring the concentration of alcohol in explosives or human blood by explosives; have a nominated error and are subject to metrological verification. Electrochemical sensors allow up to 100 measurements per day.

Currently, devices for serial production (EcoScreen - Jaeger Tomies Hoechberg, Germany: Rtube-Respiratory Reseach, Inc., USA) and home-made devices, for example, the device of Kharkiv National Medical University, Ukraine, application U are used for diagnostic tests 201005878 from 05/10/2010. All these devices work according to one principle: the patient makes forced exhalations into a container (vessel, flask, tube), in which water vapor contained in the explosive condenses upon cooling (with liquid or dry ice or liquid nitrogen).

A device for collecting HVAC (RU 6661), including a U-shaped tube-condenser made of stainless steel, titanium or aluminum alloy, lined with polyurethane from the inside, a mouthpiece and a cooling chamber, is placed in a heat-insulating foam casing.

A device for collecting HVS according to SU 694180 is known, consisting of a U-shaped glass condenser tube with a diameter of 15-20 mm and a knee height of 200 mm connected to a mouthpiece and placed in a refrigerator at a temperature of 0 to -5 ° C.

It is known “Device for collecting condensate of exhaled air in animals” (RU 134772), containing a replaceable polypropylene storage container KVV, a spirometer, a respiratory mask (latex, rubber) with inhalation and expiration valves, a cooling chamber with a cooling mixture (ice with water or ice with table salt), insulating casing of the refrigerator.

The device disclosed in the application US 2014144431 is intended to control hyperglycemia in spontaneously falling asleep diabetics in an automatic mode (abstract, formula). Moreover, the device according to the application US 2014144431 has external elements (pos. 10, 20, 80, 100 Fig. 1-3).

In addition, diagnostic unit 80, in fact, is a transdermal blood sugar level detector ([0018] p. 2), which deprives the opposed device of the status of a device that uses only non-invasive methods for controlling hyperglycemia.

In the source of information RU 2481129 C2 05/10/2013 (see page 1 - abstract, page 33 lines 45, 50-52 - description of the invention) “an inhaler is proposed ... with many blisters, each blister contains a punctured lid and holds a dose of the drug a device for inhalation by the user, a mouthpiece through which the dose of the drug is inhaled by the user ... so that when the user takes a breath through the mouthpiece, an air stream is created through the blister to entrain the dose contained in the blister and its removal from the blister and through the mouthpiece into the breath user’s personal paths ”(p. 1), and harmonic-insulin analogue (p. 45 p. 33) and hypoglycemic agents — metformin, pioglitazone, rosiglitazone, etc. (p. 50-52 p. 33) can be used as medications. )

The proposed inhaler implements the physical effect of “ejection” - absorption into the inhaled air stream of a dispersed drug. At the same time, inhalation suction does not provide a controlled ratio of the dispersed dose / dispersed medium characteristic of aerosols.

Information sources (US 5743250; WO 2009/135729) present technical solutions for metered injection of therapeutic aerosol, which also have their drawbacks. For example, with respect to the device of US Pat. No. 5,743,250, the following can be noted. In common with the claimed device of the achieved goal, the known device is significantly structurally different by the presence of microporous membranes (pos. 3 of Fig. 1-4), a vibration mechanism (pos. 20-24, 28 of Fig. 4) and its layout of components (Fig. 4) . Also, this device is significantly limited in the parameters of its functioning, for example, the vibration range of microporous membranes 575-17000 kHz; micropore range 2.25-6.0 microns; the value of viscosity, forced through the liquid membrane - from 25 to 1000% relative to the viscosity of water; operating intervals of pressure, temperature, fluid consistency (paragraphs 4-14 of the formula).

As can be seen from the brief overview of analog devices presented, they can be divided into groups according to their functional purpose: indirect glycometry devices (according to informative features in the form of voice, condition of the skin, imbalance in blood pressure); devices for collecting and preparing for the diagnosis of bioobject samples; contact glucometers in the form of eye lenses; portable testers and measuring instruments of ingredients in BB / KVV. Each group of devices has its own drawbacks, which are more pronounced when preparing them for mass production.

The task is to propose a technical solution to compensate for hyperglycemia in patients with diabetes mellitus, implemented in a device with greater efficiency, ergonomics, comfort and safety.

The problem is solved by using the respiratory activity of the patient by diagnosing exhaled aerosol and corrective effects of the inhaled therapeutic aerosol in the following claims.

1. Device for compensating for hyperglycemia in patients with diabetes mellitus, made in the form of a portable device and including a diagnostic unit for exhaled air, configured to issue a signal about the volume of exhaled air and glucose concentration in the condensate of exhaled air, an electronic unit configured to issue an audible warning signal and visual information, and a unit for metered injection of therapeutic aerosol, while

the exhaled air diagnostic unit contains a serrated inlet of exhaled air with a spirometer, a withdrawn aerosol concentrator, a throttle and a condenser-detector containing a replaceable cartridge with a cooling mixture or a cooling ring and an electrochemical measuring cell for detecting glucose concentration in the exhaled air condensate,

the electronic unit contains a serially connected detector of the detected signal, a storage device, a circuit for comparing the detected and reference signals, a circuit for estimating the magnitude of the corrective action, and a display panel for visually displaying information about the glucose content in the air condensate,

The metered-dose injection aerosol injection unit contains a guiding mouthpiece, an aerosol can of liquid medicine equipped with a spraying piston head, while the spraying can is fixed in the seat in the device housing and is made with the possibility of manual activation by pressing the spraying piston head.

2. The device according to claim 1, characterized in that the concentrator of the aerosol withdrawn with exhaled air is made in the form of an aerocyclone.

3. The device according to p. 1, characterized in that the throttle is made in the form of a Laval nozzle.

The methodological basis of the technical solution is two theoretical and practical provisions - one from the field of non-invasive diagnosis of the state of the human body, the other from the field of control of dynamic systems.

The diagnostic capabilities of the BB / CVB study are based on the proposition that changes in the concentration of chemicals in the BB / CVB, blood serum, lung tissue, bronchoalveolar lavage fluid are unidirectional (Read A. Dweik, Anton Amann, 2008; Scherbakova N.V., Nacharov P.V., Yanov, Yu.K., 2005).

The possibility of tactical compensation for incipient or developing hyperglycemia is based on the effectiveness of small control actions on the process during the initial phase of the detected deviation from the calculated or regulated values of the parameters of the dynamic system.

Briefly comment on these provisions.

Glucose enters the lungs with venous blood flowing in a large circle of blood circulation from the stomach, duodenum, liver to the heart, and then in the small (pulmonary) circle of blood circulation. In the lungs, arteries branch into increasingly thinner ones, approach the pulmonary vesicles-alveoli and branch into capillaries, braiding around the thin walls of the alveolar vesicles. Oxygen diffuses from the alveolar air into the blood, and carbon dioxide and some glucose molecules escape from the venous blood into the alveolar air. Moreover, it was found that the amount of glucose evaporated into the exhaled air from the blood is proportional to its concentration in the venous blood, according to the consequence of Henry's law - this justifies the possibility of using explosives / explosives as a diagnosed bioobject.

The article "Non-invasive diagnostics", available at http://mllsk.narod.ru/med/neinvaz.html, reports on studies at the Research Institute of Physical and Chemical Medicine of the Ministry of Health of the Russian Federation on monitoring glucose using biosensors in sweat, urine, feces, saliva , tears, explosives, sebum, hair. Among these research works is the development of a device for non-invasive glycometry by measuring glucose in the composition of sweat based on a modified Clark electrode. Information is provided on experimental evidence of the presence of glucose in the amount of 0.01–0.03 mmol / L in CVB, that is, two orders of magnitude less than in blood (3.9–5.5 mmol / L). Thus, the fact of the presence of glucose in the explosive / CVB is established despite the fact that the protein molecules are non-volatile and their removal from the explosive is difficult to explain.

We will illustrate the second position with a concrete example well known from the media. When launching orbiting spacecraft, rockets with powerful booster blocks are used, usually with third and second detachable steps. A spacecraft - a satellite of the Earth, launched into a given orbit over time, begins to deviate from a given orbit. In order to prevent the satellite from burning out in dense atmospheric layers or falling to the ground before the planned time, its orbit is corrected using small rods of standard microreactive units, the power of which is several orders of magnitude lower than the power of the upper stages, which ensure the satellite is put into a given orbit (V. Levantovsky. The mechanics of space flight in an elementary presentation - M .: Nauka. - 1980 [paragraph 9, chapter 5]).

Based on these provisions, it can be concluded that by diagnosing the non-invasive route of the microquantity of glucose in BB / CVB in a patient with diabetes mellitus and detecting signs of hyperglycemia, it is advisable to compensate it already at the initial stage with minimal doses of a fast-acting drug.

The claimed technical solution involves the implementation of several common with traditional invasive methods and non-invasive methods similar to operations:

- instrumental determination of the glucose level in the patient’s blood before meals (on an empty stomach) and after meals;

- comparison of certain glucose levels with corridors of generally accepted values for similar levels of glucose in the patient’s blood from the accepted value of the glucose level in a healthy person;

- identification, in the General case, the deviation of glucose in the blood of the patient from the accepted value of the glucose level of a healthy person;

- if a deviation of a significant value, which is a sign of hyperglycemia, is detected, a corrective effect is made on the body in order to compensate for hyperglycemic or hypoglycemic deviation;

- the magnitude of the corrective effect - its dose and / or its duration is proportional to the magnitude of the deviation.

Significant differences in the operation of the claimed device, improving known technical solutions, are the following operations:

- plotting the function of the response of a healthy person to a standard glycemic effect;

- the choice of the logistic curve of this graph as a reference target graduated dependence of the glucose level in the blood of a sick patient;

- non-invasive diagnostic glycometry in the first half of the logistic curve;

- a consistent comparison of each glycometric reading with the corresponding value of the reference target calibration dependence;

- Compensation of the first detected hyperglycemic deviation with a minidose of a fast-acting drug;

- Evaluation by subsequent diagnostic measurements of the effectiveness of incipient hyperglycemia;

- carrying out, if necessary, a repeated mini-dose correction with a corresponding check of the effectiveness of the impact;

- ensuring the coincidence of the diagnostic logistic curve of the graph of the response function of the patient’s organism with the logistic curve of the graph of the reference target calibration dependence.

In the explanatory drawings, we illustrate some of the distinguishing features of the claimed invention.

FIG. 1 clearly demonstrates the second basic position underlying the claimed solution, taken from the fundamentals of cybernetics in the field of control of dynamic systems, here it is indicated: 1 - a given trajectory of motion or a given course of the process from point A to point B (line AB); 2 - curve AB, deviating from a given condition for the functioning of the system; D1 - the minimum deviation of the curve AB in the initial section; D2 - a significant deviation of the curve AB in the final section from the line AB. Obviously, the sooner the deviation of the AB curve from the AB line is reliably detected, the less effort it will be possible to correct the deviation.

In FIG. Figure 2A shows a typical graph of the function of the response of a healthy person to glycemic effect - curve 3, it can be seen that in the initial section the function has a gentle slope, then the curve at the inflection point in the developmental area of the blood glucose growth process goes into a steep slope and then reaches its maximum value response function.

In FIG. 2B presents the standardized part of curve 3 in the form of an S-shaped section or a logistic curve in the terminology accepted in mathematics. The standardization of obtaining the logistic curve 4 is necessary for its use as a reference target calibration dependence in the process of diagnostic glycometry of a sick patient.

The components of the standardization of the logical curve 4 are the following conditions:

- providing a standard glycemic effect during meals, equivalent to, for example, taking 75 mg of glucose;

- providing a standard procedure for regular, with an interval of 10-15 minutes, measurements of blood glucose by an invasive glucometer (7-8 measurements for 1-1.5 hours);

- ensuring that curve 4 is within the standard range of accepted values of fasting blood glucose levels (5.0-7.0 mmol / L) and after meals (8.0-10.0 mmol / L).

In mathematics, the logistic curve 4 is described by the Verhulst equation, which is used to study a large number of processes characterized by slow development in the initial phase, avalanche-like development in the middle phase and a slow approach to the maximum in the final phase (for example, the growth of plant and animal populations )

In FIG. 3 shows the different course of the logistic curves of a healthy person - 4 and a patient - 5. Similarly to the figure in FIG. Figure 1 shows that it is more advisable to correct the level of glucose in the patient’s blood at the initial site (d1 << d2), since the compensation of the growth rate of the glucose level in the blood can be achieved by taking the minimum dose of the drug.

In FIG. 4 illustrates the fundamental difference between the order of operation of the claimed device from the traditional invasive and non-invasive methods according to the prototype analogue, which consists in the fact that in the known solutions hyperglycemia is compensated ex-post (2 hours after eating) in terms of the absolute value of the blood glucose level under the conditions developed hyperglycemia (D2) with large doses of the drug, and in the claimed method compensate for the small deviation of D1 with the minimum dose of the drug. As a result of this small, but timely effect, the growth rate of the glucose level in the blood of a sick patient changes, which corresponds to the convergence of the left halves of the logistic curves 5 → 4: tgα ₂ → tgα ₁ and tgβ ₂ → tgβ ₁ . In this case, at the final phase, the logistic curve 5 does not go beyond the upper level (10 mmol / L) of the corridor of accepted values, that is, hyperglycemia was compensated.

Since the operating procedure described above involves the implementation of operational actions and manipulations with the bioobject of diagnostic non-invasive glycometry and a drug, a portable device with a working substance in the form of an aerosol, the most mobile and finely dispersed state of a condensed substance (including that contained in explosives), is used for its implementation )

The use of the electrochemical method of glucometry of HVC is due to its sufficient practical development in non-invasive portable devices, high reliability, relatively high speed.

The proposal for the use of a drug in the form of insulin for insulin-dependent patients of the first type is justified by the recommendations of the FDA advisory light to allow the use of the aerosol form of the Exhubera insulin preparation, developed jointly by Pfizer, zSanafi-Aventis and Nevtar Therapeutics (www.pharmvestnik.ru 2015).

The use of second-type drugs for insulin-dependent patients in the form of finely dispersed systems (suspensions, emulsions, sols) based on metformin, glitazone, nateglinide is due to the possibility of their micronanodispersion and rapid penetration into the alveoli when taking the drug in the form of an aerosol. In addition, these drugs when used together provide a synergistic effect and increase the duration of the drug.

The process of natural addiction and dulling of the reaction of the patient’s body suggests a known variability in doses, exposure time and use of previously unused drugs.

Device description

In FIG. 5 shows a block diagram of a device that implements the claimed method, with the following notation: 6 - block diagnosis of exhaled air (BB); 7 - electronic unit; 8 - block metered injection therapeutic aerosol (AE). The structure of the block 6, issuing a detectable signal, includes serially connected oblique intake BB, spirometer, intake aerosol concentrator in the BB, throttle, capacitor-detector. The block 7 that produces the control signal includes a series-connected recorder of the detected signal, a storage device, a circuit for estimating the magnitude of the corrected effect, and a display panel (display). Block 8 contains a guiding mouthpiece mounted on an aerosol can with liquid medicine and a spraying dosing piston head, a seat in the housing of the device for fixing the can.

In FIG. 6 is a block diagram of a portable device showing the arrangement of blocks 6-8. It can be seen that the dimensions of the device’s body allow it to be held in the palm of your hand, while the explosives are taken in and the aircraft are sprayed from opposite sides - this ensures ease of use of the device.

In FIG. 7 shows the internal structure of the BB-6 diagnostics unit with the accepted position designations: 9 — explosive lip intake; 10 - spirometer; 11 - concentrator of the taken aerosol; 12 - throttle; 13 - capacitor detector; 14 - layer CVB; 15 - replaceable cartridge with a cooling mixture.

The nodes involved in the preparation of explosives for diagnostic glycometry, namely, 11, 12, and 13, can be made in the form of an aerocyclone (11), a Laval nozzle (12), and a cooling ring in an electrochemical measuring cell (13, 15).

The device operates as follows. The patient makes a forced exhalation into the BB-9 oblique intake, a spirometer 10 in the form of, for example, a rotating impeller, controls the exhalation depth, and registers the volume of the explosive. It is known that the most informative part of explosives is contained in the alveolar air exhaled by the lungs in the last phase of exhalation, after exhalation of 1.0-1.5 l of explosives. For a patient with diabetes mellitus with pathology of the heart and lungs, a forced deep breath may be difficult and, if the spirometer - 10 detects a similar case, then the electronic unit 7 generates a warning sound signal to the patient to produce a repeated series of shallow exhalations (3-5 exhalations) to obtain the analyzed quantity KVV.

After passing through the spirometer 10, the explosive flow under pressure tangentially enters the concentrator of the aerosol withdrawn as part of the explosive, which is made in the form of a conical aerocyclone 11, where it is compressed along a spiral path with the simultaneous separation of heavier aerosol drops in the near-wall region of the lower, narrower part of the aerocyclone, and more the light molecules of the gases that make up the explosive are concentrated in the upper, wider part of the aerocyclone and in its center. Then, the swirling flow of explosives falls into the narrowest place along the path of its movement in block 6- into the throttle 12, made, for example, in the form of a Laval nozzle, known and widely used in aerohydrodynamics of the assembly. In the throttle 12, the throttle effect (or the Joule-Thompson effect) is realized, which consists in the adiabatic expansion of the gas after a narrow passage with a change in temperature and pressure.

In the case under consideration, a positive choke effect is realized when, after passing through the choke 12, the temperature and pressure of the BB / HVB mixture fall in the wide chamber and in the condenser-detector made in the form of a cooling ring in the measuring electrochemical cell 13, settles on the walls and electrodes in the interelectrode space KVV film 14, and explosive gases freed from aerosol through the central part of the capacitor-detector 13 enter the external atmosphere.

In the above case, when the patient is not able to provide exhalation in the composition of the explosive air of the alveolar air, a replaceable cartridge 15 with a cooling mixture is used to cool the HFB from the unforced and shallow exhaled mixture. As a cooling mixture, for example, a combination of dry ice (solid carbon dioxide) and ethyl alcohol, or gasoline, or acetone, or diethyl ether can be used.

Similar to the technical solution GOOGLE and NOVARTIS for tear fluid glycometry mentioned in the review, the measuring cell 13 detects a signal about the content of glucose impurities in the HFB, the detector of the detected signal in the electronic unit 7 automatically normalizes the value of the recorded signal by a proportionality coefficient (increasing by three orders of magnitude), leading measured signal value from the relative to the absolute value of the glucose level in the patient’s blood in mol / l, which is stored in the storage device e, then, in the comparison scheme, the reference signal measured and previously memorized is compared; when the reference signal is exceeded above the set threshold, the value of the corrective effect, which is induced on the display and is a signal to the patient’s action, is estimated.

The patient, having recorded information visually displayed on the display, accompanied by an audible signal, performs mini-LA injection through the mouthpiece by pressing the spraying metering piston head of the aerosol can fixed in the seat slot of unit 8. The replaceable can can be disposable, similarly, for example, to aerosol cans “ Nitromint, Pharmaceutical Plant Egis CJSC, Budapest, Hungary and Berodual N, Beringer Ungelheim Pharma GmbH and Co. KG, Germany or refillable filling, for example, according to patent RU 2493081.

After 10-15 minutes after injection of the LA into the oral cavity and the patient’s lungs with repeated procedural glycometry, the effectiveness of the corrective effect of the LA is checked and, if necessary, the correction is repeated, ensuring that the obtained section of the logistic curve 5 is aligned with the same section of the left half of the logistic curve 4. If combined of these sections, a further part of the graph of the response function of the human body 5 will not reach the upper value of 10 mmol / L of the corridor of accepted values, which means the implementation of compensation for sugar diabetes mellitus.

Thus, the application of the proposed device will have the following features. A method is being implemented to compensate for hyperglycemia in patients with diabetes mellitus, including non-invasively determining the level of glucose in the patient’s blood before and after eating with a measuring device, comparing the established glucose levels with the corridor of the accepted values of the glucose level in a healthy person, and detecting the excess of the glucose level in the patient’s blood over the accepted value glucose level in a healthy person, a patient taking a drug that compensates for hyperglycemia, in a dose proportional to a value higher than the level of glucose in the patient’s blood above the accepted value of the glucose level in a healthy person, while initially, by means of regular, with an interval of 10-15 minutes, measurements of the glucose level in the blood of a healthy person, before and after a meal, a graph of the body’s response to standard glycemic is plotted for 120 minutes exposure to food, equivalent to taking 75 mg of glucose, then, as a reference target calibration dependence of the blood glucose level of a patient with diabetes mellitus, a logistic curve is taken - S-shaped section to the graph of the functions of the response of a healthy person’s body to standard glycemic effects in the range of the corridor of accepted values of glucose levels in a healthy person’s blood, namely, from fasting glucose levels of 5.0-7.0 mmol / l to glycemia after eating 8.0-10.0 mmol / l, after which diagnostic glycometry in a patient with an interval of 10-15 minutes, on an empty stomach and then after eating, each obtained indication is successively compared with the corresponding value of the reference target calibration dependence, at the first detection of hype glycemia, the patient takes a fast-acting drug that compensates for the onset of hyperglycemia in a minimal correcting dose, evaluates the effectiveness of hyperglycemia compensation with subsequent measurements, and, if necessary, re-performs a mini-dose correction of developing hyperglycemia with a fast-acting drug, ensuring that the logistic curve of the patient's response function graph with the logistic curve of the reference curve of the patient target calibration dependence.

In the processes of glycometry and dosing of a fast-acting drug, the same portable device is used, using aerosols absorbed during glycometry and injected during hyperglycemia as a working substance.

As an aerosol diagnosed in the course of glycometry, the air exhaled by a person and / or the condensate of exhaled air prepared for physical, chemical or physico-chemical diagnosis is used.

For glycometry of exhaled air condensate, the electrochemical method is used.

As a corrective aerosol for insulin-dependent patients with type 1 diabetes mellitus, insulin is used.

As ingredients for hypergikemia-correcting aerosol for insulin-dependent patients with type 2 diabetes, metformin or metformin is used in combination with another fast-acting antidiabetic agent, for example, from the group of glitazones.

With long-term compensation of hyperglycemia, the minimum corrective dose of the drug for each patient is selected experimentally individually and, with a decrease in the effectiveness of the corrective effect, the dose gradually increases or switches to taking a new type of drug.

The technical result achieved by the invention can be characterized by the following provisions:

- compensation of hyperglycemia is carried out by minidoses of drugs, the value of which is ten times less than the values of the traditionally used corrective doses;

- the efficiency of compensation for hyperglycemia has been achieved - the effect can be achieved within 10-30 minutes from the moment of detection of the first sign (increase in the threshold level);

- the patient’s safety was ensured during the diagnosis of hyperglycemia and its compensation due to non-invasive glucometry and the use of mini-doses of a quick-acting corrective drug in aerosol form;

- the proposed portable device is ergonomic and comfortable, can be used both by patients at home and by medical personnel in health facilities;

- the functionality of the device allows you to use it in scientific research and pharmacopeia tests of the effectiveness of new antidiabetic drugs.

Claims (3)

1. Device for compensating for hyperglycemia in patients with diabetes mellitus, made in the form of a portable device and including a diagnostic unit for exhaled air, configured to issue a signal about the volume of exhaled air and glucose concentration in the condensate of exhaled air, an electronic unit configured to issue an audible warning signal and visual information, and a unit for metered injection of therapeutic aerosol, while
the exhaled air diagnostics unit contains a serrated inlet of exhaled air with a spirometer, a withdrawn aerosol concentrator, a throttle and a condenser-detector containing a replaceable cartridge with a cooling mixture or a cooling ring and an electrochemical measuring cell for detecting glucose concentration in the exhaled air condensate,
the electronic unit contains a serially connected detector of the detected signal, a storage device, a circuit for comparing the detected and reference signals, a circuit for estimating the magnitude of the corrective action and a display panel for visually displaying information about the glucose content in the air condensate,
The metered-dose injection aerosol injection unit contains a guiding mouthpiece, an aerosol can of liquid medicine equipped with a spraying piston head, while the spraying can is fixed in the seat in the device housing and is made with the possibility of manual activation by pressing the spraying piston head. 2. The device according to claim 1, characterized in that the concentrator of the aerosol withdrawn with exhaled air is made in the form of an aerocyclone. 3. The device according to p. 1, characterized in that the throttle is made in the form of a Laval nozzle.

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