WO2010062211A2 - Methods and means for automatic treatment control - Google Patents

Abstract

The invention relates to pump technology in the intensive treatment of diabetes and other diseases. Means for automatically checking current measurements in a patient's body are proposed. The checking procedure uses a flow method and is integrated with the procedure for the basal and bolus programs for controlling the pump in the current treatment mode. Negative feedback algorithms are created for automatic treatment control. Flow means necessary for additional measurements carried out by external devices are used. The invention makes it unnecessary to take frequent blood samples for routine analysis.

Description

 Methods and tools for automatic therapy management

FIELD OF APPLICATION AND RELATED INVENTIONS The invention relates to medicine, namely, methods of control and intensive care used in critical situations or in emergency situations, for example, diabetes (hundreds of millions of patients). These include the international application PCT / RU2008 / 00057 "Method for monitoring the insulin therapy of diabetes" from 08/25/2008, and a similar application RU 2007132513 from 08/28/2007. Priority has been requested for both applications with respect to the figure and paragraphs 1-

3 claims incorporated by reference.

SOIL OF THE INVENTION

The intensity of therapy is determined by the frequency of medication, sometimes for life. This requires continuous monitoring of the effectiveness of medication, as well as ongoing monitoring of drug administration. The traditional diabetes intensive care method is based on manually injecting the patient under the skin

4 times a day of insulin of different brands in accordance with the doctor's recommendations and monitoring results.

Patients with diabetes mellitus monitor manually, taking blood samples up to 8 times a day for glucose analysis. This greatly complicates the life of the patient, but does not allow you to catch the dangerous fluctuations in glycemia due to the low frequency of measurements. This danger, the risk of infections and injuries during blood sampling are the main disadvantages of the above-described common method for monitoring diabetes therapy, which is an analogue of the present invention.

To reduce these deficiencies, electrochemical and optical glucose sensors are being developed. The current state of the development of new methods and means for continuous monitoring of glycemia is described in detail in the publication [1] Vepakta Radhakrtshpa Kopderati & H. Misheel Neisе, Resprogramgess, Apulutisipstrumptompolituspolitompolitompolitompolitompolitompolitompolitompolit. Apal. Bioapal. Chem. (2007) 388, 545-563.

All methods show good results in a few hours. But the gradually layering effects of a large number of random factors lead to a drift in glucose determinations. In the process of monitoring glycemia, it is necessary to produce still frequent (up to 5 times a day) blood samples.

Medtronic launched the world's first integrated Paradigm 722 system - an insulin pump with real-time electrochemical glucose monitoring. The system is protected by patents, for example AT363228T, WO0049941 and international application WO 2006/122048 Al. These documents relate to the prototypes of the proposed invention and are cited by reference.

The disadvantages of the system include the high cost of consumables (interchangeable sensor + interchangeable catheter, $ 100 for three days) and the need for a 4-fold daily blood sampling to calibrate the monitor. This equipment retains the main drawback of all known methods - the need for frequent blood sampling to assess the effectiveness of therapy.

SUBSTITUTE SHEET (RULE 26) SUMMARY OF THE DISCLOSURE OF THE INVENTION

The aim of this invention is the development of tools and methods that eliminate the above limitations in practice for various diseases and contribute to the creation of an automatic therapy system with negative feedback between the monitor and the pump. 5

The result is achieved by the fact that control methods and intensive care tools for diabetes and / or other diseases, including a programmable pump for infusion of a drug solution into a patient’s body through a connection device (see WO 2006/122048 Al double insert device) with an optical and / or electrochemical sensor body fluid or whole blood characteristics are characterized as follows. 10

In the case of the use of minimally invasive, subcutaneous, and / or intramuscular infusion through a double insert device, for example, a coaxial catheter, the means are designed so that:

• the base of the catheter has openings and is fixed on the patient’s skin,

• the catheter line is located under the skin, the sensor is located inside the tube.

• A catheter passes infusions, such as insulin, through passageways in the base and at the outlet end of the catheter.

• The side wall of the pipe contains a well-wettable porous material and / or holes for passing through, such as glucose.

fifteen

The catheter is designed so that the base contains a sensor washed by a fluid flowing from the flow cavity through the passage opening into a removable ampoule.

• Through the place of installation of the ampoule into the base, infusion of additional drugs, enzymes or other clinical solutions is carried out, for example, using a hand syringe.

twenty

The double insert is fixed to the lid of the intradermal port implanted under the patient’s skin.

• Mounting allows mounting and dismounting of the double insert.

• The hypodermic part of the port contains a stable base and an elastic mesh for circular protection of the double insert from spasms and other loads.

In the case of intravenous infusion, the double insert device is designed as an artificial shunt of a blood vessel, with the infusion site located at the beginning of the blood flow, and the measurement site, for example, optical, is located further. 25

The solution for infusion and / or perfusion contains glucose or another controlled biomarker with a target concentration, for example, equal to the average value for the prescribed range of therapy, or in particular equal to zero.

• The double insert device is designed so that infusions flow through the measurement site.

The signal of the Isign sensor (t) is connected to an analog-to-digital converter (ADC) at an Isig transformation frequency, for example, f = lHz.

• The ADC output is connected to a microcontroller (MCU). MCU contains conversion frequency divider for synchronization of the basal program

thirty • The divider divides each therapy session into intervals T ^k _n , p is the number of the current medication interval, k is the session number.

• The basal program distributes equal volumes of each infusion evenly, for example, during the day with an hourly interval T ^k _n .

5

The MCU contains a program for calculating in real time the average signal current ϊsign _n (τ) to estimate the duration τ and the effect of each infusion on the calculation result.

The microcontroller (MCU) is connected to a data input device from an external measurement source, for example, from a blood glucose meter.

• Contains a differential calibration program using traditional methods of pairwise measurements and linear calculation of calibration coefficients.

• Calculates the current levels of the managed biomarker at each interval T ^k _n , _m within each interval T ^k _in .

fifteen

If a controlled biomarker, such as a blood glucose level, above the target level of MCU therapy lowers the biomarker level, for example, using a bolus infusion of short (ultra) insulin.

• infuse drugs within the basal interval.

• A basal interval of medication, such as diabetes, for at least 30 minutes.

• The minimum medication interval is at least 15 minutes.

• All medications are equal: V _n ^{k = 1} basaI = V _n ^k basal = V bolus.

If a managed biomarker, such as blood glucose, is below the target range of therapy, the biomarker level is increased. For example, inform the patient: "Eat 15 grams of rapidly soluble carbohydrates (glucose tablets)." twenty

The average daily glucose coefficient ADGR of MCU is calculated as the ratio of the average daily glucose level to the middle of the target range. • Changes the basal infusion rate using the equation ADGR = T ^k _n / T ^{k "} V 15

BRIEF DESCRIPTION OF THE DRAWINGS

A detailed description of the variants of the invention is given with reference to the accompanying drawings, in which the same components are denoted by the same numbers.

Fig.l Minimally invasive system of intensive care control for the proposed variant of the invention.

Fig. 2 The subcutaneous portion of the double insert device.

Fig. 3 Intradermal port with double insert device.

Fig. 4 Intensive care monitoring system with negative feedback. twenty

DETAILED DESCRIPTION OF SUGGESTED OPTIONS

As illustrated in the figures, this invention relates to an intensive care control system, for example, diabetes, including a pump, sensor, and glucose monitor.

25 It provides continuous recording of data from the sensor over a period of time. These data are used to automatically generate real-time negative feedback between patient medication procedures and determine the level of a control biomarker. In the discussed embodiments of the invention, the sensor and monitor are a sensor and a monitor for determining the level of glucose in the blood and / or body fluid of the user. With diabetes, pump therapy has been widely used in recent years. LENHARD MJ. The RoIe of IPsulip Rumrs. Medsare Diabetes & Healthcare, 5 (1), 2003. and monitoring glucose levels, including in the tissue dialysis technique. Christorh Caritz et al. Optical Glucop Moporipg: Reliable Mezuremepts for u 4 to with SCGMl Sustem. Diabetes Technology & Therapy. 5 (4), 609-614, August 1 2003. For example, the concentration of glucose in the blood changes with diseases of the pancreas, thyroid gland, pituitary gland, adrenal glands, kidneys, liver, intestines, with traumatic, toxic irritation of the central nervous system and in a number of other pathological conditions.

5

Further embodiments of the invention may be used to determine other characteristics of the body, including analytes or agents, compounds or composition such as hormones, cholesterol, drug concentrations, and other similar intensive care purposes. The electrochemical sensor was originally designed for subcutaneous installation. However, in further embodiments, one or more of the same or different sensors can be placed in tissues of another type such as muscles, lymph glands, veins, arteries and the like.

Various types of intensive care are also used in emergency situations including field conditions and battles. Sometimes this is due to the presence of, for example, traumatic brain injuries in a patient. In such cases, neurometabolic monitoring and therapy are required, usually in a clinical setting. See, for example, Niléred L, Persson L, Ponten U, Ungerstedt U. Neurémetabolis mopitoripf of the ishumis humap uspg miсrodialusis. Asta Neuroshir (Wiep). - 1990 - 102 (3-4). - R. 91-7. See also: Timofeev I.C. Tissue microdialysis: principles and clinical application of the method in intensive care. Intensive Care, N ° l - 2007.

10

The principal design of the claimed method in the case of subcutaneous and / or intramuscular infusion is shown in Figure 1. Here: 1 - Patient's body; 2 - A patch for fixing 3 on the patient's body; 3 - Device for connecting a cannula of a catheter with a glucose sensor at the measurement site; 4 - catheter; 5 - Pump with a software and computing unit and a glucose monitor; 6 - Signal cable for glucose sensor.

Figure 1 is presented in PCT Priority Application, which is incorporated herein by reference. The catheter cannula connecting device to the sensor is called a double insert device, as described in WO 2006/122048 Al and is cited as a reference.

fifteen

The figure 2 shows the subcutaneous part of the double insert. The figure 3 shows a diagram of its input into the patient’s body through the intradermal port.

A double insert, such as a coaxial catheter, is designed so that: The base 16 of the catheter has passage holes for infusion and / or perfusion and is fixed to the patient’s skin. A catheter line 12 is placed under the skin.

2.0 The sensor 11 is placed inside the pipeline. The side wall 9 of the pipeline contains a well-wettable porous material '8 and / or holes through which passive diffusion of substances (for example, glucose) occurs along their concentration gradient.

An analysis using enzyme electrodes 10, 20 combines the high selectivity of biocatalysis and the perfect technique of electrochemical methods. Enzymes are immobilized, including in the film membrane 7, for example, from albumin. It is attached, for example, to the surface of the electrodes 10, 20. The body fluid 18 diffuses through the holes in the wall 9 into the layer 7 containing the enzyme, forming an electrically active substance detected by the sensor 11.

The permeability of membranes for most substances is determined by the size of the pores and / or holes (die cut-offsize). The flow cavity between the sensor 11 and the side wall 9 passes an infusion, for example, of insulin solution 14, through the passageways 13 at the outlet end of the catheter 12 and the passageways through base 16.

The catheter is designed so that the base 16 contains a sensor 20, washed by a fluid flowing through a passageway into a removable ampoule 21. The catheter is, for example, a polyurethane tube with an outer diameter of 1.5 mm and a length of 10 mm. A catheter is inserted into the patient's body using a penetrating needle. An isotonic solution for infusion enters through the orifice in the flow cavity. The liquid solution is passed through the infusion system 15 with a pump 5 at a speed of, for example, 0.5 microliters / min. For this purpose, it is preferable to use a specialized solution (CNS perfusion fluid, CMA Microdialysis, Solpa, Swedep), which in its ionic composition corresponds to tissue fluid, with the addition of the necessary drugs.

When the liquid reaches the membrane portion of the catheter, passive transport of substances occurs according to the concentration gradient from the intercellular fluid 18 to the flow cavity and the measuring channel 11. The catheter type CMA70, used for similar purposes in clinical practice, has pores of 20 kilodaltons in size. The portion of the solution containing the recovered substances flows along the side wall into the lid of the catheter. There it accumulates in a removable vial 21. The reaction time of the sensors 10 and 20 to diffusion, for example glucose, is approximately the same due to the well-wetted side wall. Thus, a catheter located in the extracellular fluid mimics the function of a blood vessel (capillary). Continuous renewal of the solution in the membrane area supports the transmembrane concentration gradient.

With the accumulation of sufficient dialysate for additional analyzes, the ampoule is replaced by the following. Express analysis of the main clinical markers (glucose, lactate, pyruvate, glutamate, glycerol and urea), including the prescribed medicine, is carried out, for example, by enzymatic methods. This analysis reflects the biochemical profile of the tissue fluid during dialysate collection and is therefore always retrospective. For this, it is necessary to take into account the accumulation time of dialysate in an ampoule with a volume of, for example, 30 microliters, which can be up to 100 minutes at a perfusion rate of 0.3 microliters / min.

Through the installation site of the ampoule 21, additional drugs, enzymes or other clinical solutions are infused into the base, for example, using a hand syringe. This method is used, for example, for adjunctive therapy or for enzymatic effects on bodily characteristics 25 liquids in a measurement zone. The next improvement in the therapy technique relates to the use of the intradermal port, as indicated in the priority application of claim 3 and is detailed in the proposed invention.

The double insert device is fixed in the cover 22 of the intradermal port implanted under the patient’s skin. The mount provides for mounting / dismounting of the double insert. The subcutaneous part of the port contains a stable base 17 and an elastic mesh 19 for circular protection of the double insert from spasms and other loads. An analogue of the proposed invention is intended for measuring glucose levels by optical methods and is cited as reference. G. G. Vosquet, Gerald L. Saute, Ashkod Gowda, Regg Ms Nisseskohls, Sokhi Rastegar METAL DETAILS DETAILS DETAILS DETAILS USED Date of Rathept: Aug. 20, 2002.

In the case of intravenous infusion, the double-insert device is designed as an artificial shunt of a blood vessel, and the place of infusion of the drug is located at the beginning of the blood flow, and the place of measurement, for example, optical, is located a little further.

An analogue of such an implantable therapy management system device is described in US6, 122, 536 and US 6,438,397 Bl and cited as reference. In the analogue, two different veins are used, one for the optical sensor, the other for the infusion of the drug. In the present invention, an artificial vessel, due to blood flow, provides a difference in the measurement results of the sensor covering it, which occurs after each infusion. This design uses the method described in cl. 1 of priority application PCT / RU2008 / 00057, and expands the possibilities of applying the claimed invention.

Additional detail of the priority method is contained in the following paragraphs of the claimed invention. Figure 4 illustrates the various possibilities of applying the main method of therapy management.

The infusion solution contains glucose or another control biomarker with a concentration, for example, corresponding to the middle of the prescribed target range of therapy, or equal to zero.

Since the insulin solution commonly used in the treatment of diabetes does not contain glucose, the priority method in paragraph 1 of the previous application repeats this rule, which is supported by the following rule.

The double insert device is configured so that all infusions flow through the measurement site.

The fulfillment of these two rules means that they use the method of flow measurements with periodic input of a given control environment. The method periodically eliminates stagnation. These and other phenomena occasionally occur in the measurement zone and disrupt the calibration.

With each infusion in the patient’s body, the previous volume is displaced from the measurement zone and replaced with the next volume of isotonic solution. Due to the concentration gradient that arises in this case, glucose molecules diffuse into the measurement zone until an equilibrium state is reached. Depending on the choice of the infusion method, the control biomarker and the design used, the duration of the process is units and tens of seconds. - -

At a particular concentration of a biomarker in solution, it is the carrier of physical information about this value at the measurement site during the production of each infusion. To use this factor in the further therapy control procedure, including during calibration of measurements, the following steps are proposed (Fig. 4).

The sensor signal Isign (t) is connected to a digital measurement transducer (ADC) at a conversion frequency of Isigп, for example, # = lrц. The ADC output is connected to a microcontroller (MCU).

(MCU) contains a conversion frequency divider to synchronize the basal program.

The MCU output is connected to a basal and bolus infusion administration program. The divider divides each therapy session into intervals T ^k _n , p is the number of the current medication interval, k is the session number.

The basal program distributes equal volumes of each infusion of the drug evenly, for example, during the day with an hourly interval T ^k n.

The uniform distribution of the basal dose and the equal volume of each bolus and basal infusion unify the measurement conditions. The measurement procedure is partially combined with the medication procedure. These circumstances are used for the working verification of current measurements at time intervals between the current infusion entries as described below.

The MCU contains a program for calculating the current average signal values ϊsign _n (t) and estimating the duration τ of the effect of each infusion on the measurement results результаты ^k sign (τ). It uses it to determine the duration of the intervals T ^k _n , _mj where t is the number of the current measurement interval on each interval T ^k _n .

(перепад в результатах измерений)

Δ^k(τ)n,m=ϊ^ksign_n,_m— ϊ^ksign(τ)_n>ш=i,Calculates the current average values of the signal ϊ ^k sign _ПjШ and the current difference Δ ^k ( ^τ ) n, m

(difference in measurement results)

Δ ^k (τ) n, m = ϊ ^k sign _n , _m - ϊ ^k sign (τ) _{n> w} = i,

The second input of the MCU is connected to a data input device from an external measurement source, for example, a home glucose meter. Inside, the MCU contains a differential calibration program using traditional pair measurement methods and linear calculation of calibration coefficients. Calculates the current levels of the managed biomarker at each interval T ^k _n , _m within each interval T _n .

The application of various l ^k sign calibration methods for an electrochemical glucose monitor is described in detail in AT363228T and WO0049941. In the present invention, similar methods are used to calibrate the difference Δ ^k _n , _m . The obtained values of the systematic mean deviation and scale factor are used to calculate the current levels of the biomarker, based on the calculated values of each current differential.

The above calculation of current differences is essentially a method of working verification of the current level of systematic average deviation in the results of electronic measurements. The means of verification is the infusion of the drug into the measurement area. The physicotechnical properties of such preparations are, as a rule, guaranteed by the manufacturer. Calibration is carried out with each infusion, which automatically eliminates the influence of all random factors on the value of the systematic average deviation in the results of determining the differential current of the sensor and, accordingly, the glucose level. During the entire treatment session, calibration coefficients are used, preferably determined by the point-to-point method. The duration of such a session depends on the need, for example, to replace the infusion system or reservoir with the solution, or other reasons that clearly change the measurement conditions and therefore require a new calibration. For systems like PARADIGM REAL TIME, the session lasts up to three days. At the same time, calibration reduces the number of blood samples for analysis, almost an order of magnitude.

Negative feedback algorithms significantly reduce the effect of possible changes in the scale of measurements on the control error relative to a given equilibrium point (for example, the middle of the target range of therapy). With the target width commonly practiced in diabetes, the accuracy requirements are a few mmol / L units.

As indicated above, the solution used in some applications contains glucose with a concentration equal to the middle of the target range. Such a solution improves the accuracy of glucose determinations in the middle of the target range and, accordingly, reduces the errors of the regulatory system. The discussed invention provides negative feedback algorithms described below.

If a controlled biomarker, for example, a blood glucose level, is automatically lowered above the target therapy level, for example, using short (ultra) insulin. again do the medication inside the basal interval. The basal interval of medication, for example, in diabetes, is at least 30 minutes. The minimum medication interval is at least 5 minutes. All medications are equal to each other. : V _n ^{k = 1} basal = V _n ^k basal = V bolus.

If a managed biomarker, such as blood glucose, is below the target range, its level is increased. For example, in diabetes, the MCU informs the patient: "Eat 15 grams of rapidly soluble carbohydrates (glucose tablets)." See figure 4, and, for example, Nuroglusemia update di-tebes: Buttre-lo-sugar (2008) Mauo Slip-retriev on Japan, 2009 form http: //www.mavoclшic.com/health/hypoglycemia/DA00063

The bolus rule provides additional verification of measurement results, essentially considering the patient’s current lifestyle.

τ^k _п/τ^k\In addition, the MCU calculates the daily average glucose coefficient ADGR as the ratio of the average daily glucose level to the middle of the target range. Change the basal infusion rate using the equation ADGR =

τ ^k _p / τ ^k \

The correction of the basal program by the proposed method automatically tracks slow pathological changes in the patient's body.

Claims

- -Claim 1. Automatic control methods and tools for the treatment of diabetes and / or other diseases, including a software-controlled pump for infusion of a drug solution into a patient’s body through a connection device (double insert) with an optical and / or electrochemical sensor of body fluid or whole blood characteristics, differ in , what: 2. In the case of using a minimally invasive subcutaneous, and / or intramuscular infusion through a double insert device, for example, a coaxial catheter, the means are designed so that: • the base of the catheter contains openings and is fixed on the patient’s skin, the catheter tubing is placed under the skin, and the body fluid characteristics sensor is located inside the catheter. • a catheter passes infusions, for example, of an insulin solution, through passageways in the base and at the outlet end of the catheter. • The side wall of the pipe contains a well-wettable porous material and / or micro-holes for diffusion, such as glucose. 3. The methods and means of automatic control of paragraph 1.2 are characterized in that: • the catheter is designed so that the base contains a sensor washed by a fluid flowing through a passageway into a removable ampoule. 4. Methods and means of automatic control p. 1,2,3 differ in that: • when the ampoule is removed, through the place of its installation in the base, infusion of additional drugs, enzymes or other clinical solutions is carried out, for example, using a hand syringe. 5. Methods and means of automatic therapy p. 1 - 4, characterized in that: • The double insert device is mounted on the lid of the intradermal port implanted under the patient’s skin. • Mounting allows mounting / dismounting of double insert. • The hypodermic part of the port contains a stable base and an elastic mesh for circular protection of the double insert from spasms and other loads. 6. Methods and means of automatic therapy management p. 1 in the case of intravenous infusion are different in that: • The double-insert device is designed as an artificial shunt of a blood vessel, where the place of infusion of the solution is located at the beginning of the blood flow, and the place of measurement, for example, optical, is located a little further. 7. Methods and means of automatic control p. 1, characterized in that: • the solution for infusion and / or perfusion contains glucose, or another biomarker, with a given concentration, for example, corresponding to the middle of the prescribed target range of therapy, or in particular equal to zero. • The double insert device is designed so that all infusions of the solution pass through the measurement site. 8. The methods and means of automatic control p. 7 are characterized in that: • The signal of the Isign sensor (t) is connected to an analog-to-digital converter (ADC) at an Isig transformation frequency, for example, f = lrc. • The ADC output is connected to a microcontroller (MCU). The MCU includes a conversion frequency divider to synchronize the basal infusion program. • The divider divides each therapy session into intervals T ^k _w and is the number of the current medication interval, k is the session number. • The basal program distributes equal volumes of each infusion of the solution evenly throughout the session, for example, a day with an hourly interval T ^k _n . . 9. Methods and means of automatic control p. 8, characterized in that: • MCU contains a program for calculating real-time average signal values

difference (difference in the measurement results) Δ ^k (τ) _n , _m = ϊ ^k sign _n , _m - ϊ ^k sign (τ) _n , _m = i, 10. Methods and means of automatic therapy management p. L and / or p. 9, characterized in that • The MCU is connected to an input device from an external measurement source, such as a blood glucose meter. • Contains a differential calibration program using traditional methods of pairwise measurements and linear calculation of calibration coefficients. • Calculates the current levels of the managed biomarker at each interval T _n , _m within each interval T ^k _n . 11. Methods and means of automatic therapy management p. 10 for intensive care of diabetes and / or other diseases, characterized in that: • If a controlled biomarker, such as a blood glucose level, is automatically lowered above the target range of therapy, for example, using short (ultra) insulin. • again do medication within the basal interval. • A basal interval of medication, such as diabetes, for at least 30 minutes. *> The minimum medication interval is at least 5 minutes. • All medicines are equal. VV ^ ¹ basal = V _n ^k basaI = V bolus. • If a managed biomarker, such as blood glucose, is below the target range, its level is increased. For example, inform the patient: "Eat 15 grams of rapidly soluble carbohydrates (glucose tablets)." 12. Methods and means of automatic control for intensive care of diabetes and related diseases differ in that: . The MCU calculates the daily average glucose coefficient ADGR as the ratio of the average daily glucose level to the middle of the target range. . Change the basal infusion rate using the equation ADGR = T ¹ VT * ^"1 ,,