Dual closed-loop insulin delivery system, use thereof, and medical product thereof

Abstract

The present invention belongs to the technical field of medical devices and particularly relates to a dual closed-loop insulin delivery system, use thereof, and a medical product thereof. Disclosed is a dual closed-loop insulin delivery system, specifically comprising a continuous glucose monitoring system, a dual closed-loop control algorithm, an insulin pump, and a specific glucose-responsive insulin analog. The present invention controls blood glucose in a dual closed-loop mode and can achieve a high time-in-range and more stable, safer, and simpler blood glucose control. Moreover, no human intervention is required during the use of the system. The present invention provides a more intelligent and user-friendlier treatment scheme for diabetic patients.

Description

A dual closed-loop insulin delivery system and its applications and medical products Technical Field

[0001] This invention belongs to the field of medical device technology, specifically relating to a dual closed-loop insulin delivery system and its applications and medical products. Background Technology

[0002] Diabetes is a chronic metabolic disease characterized by high blood sugar. Currently, more than 100 million people with diabetes must use exogenous insulin to control their blood sugar.

[0003] Most closed-loop insulin delivery systems currently used in clinical practice employ a single closed-loop control system. This system monitors the patient's blood glucose levels through a continuous glucose monitoring system, is equipped with different control algorithms, and calculates the corresponding insulin delivery volume based on blood glucose levels and preset parameters, ultimately controlling the insulin pump to deliver insulin subcutaneously. Traditional insulin pumps use rapid-acting human insulin analogs or short-acting human insulin, mimicking basal insulin secretion in an adjustable pulsatile subcutaneous infusion mode. Simultaneously, during meals, the type and total amount of food are manually input, and pre-meal insulin and infusion mode are set to control postprandial blood glucose. This type of closed-loop insulin delivery system has certain limitations. First, such systems require human intervention. In actual use, patients need to manually input parameters such as carbohydrate intake based on factors like diet and exercise so that the system can more accurately calculate the required insulin dose. This reliance on patient self-monitoring and input not only increases the patient's burden but may also lead to poor blood glucose control due to improper operation or forgetfulness. Second, because most of these closed-loop systems cannot fully predict and adapt to complex changes in the patient's internal environment, such as sudden increases in exercise or changes in food intake, it is difficult to completely avoid hypoglycemic events. Furthermore, most existing control algorithms are based on preset parameters such as insulin sensitivity and carbohydrate coefficient, which vary significantly between individuals and may fluctuate over time and with changes in the patient's condition. Therefore, a single algorithm cannot meet the needs of all patients, resulting in inconsistent glycemic control outcomes.

[0004] Current closed-loop insulin delivery systems are not yet capable of fully autonomous blood glucose control and struggle to adapt to sudden blood glucose fluctuations. The key challenge is to develop a fully automated, highly safe closed-loop blood glucose management system without relying on additional medications (such as glucagon) to achieve complete closed-loop blood glucose management while significantly reducing the risk of hypoglycemia. Summary of the Invention

[0005] In view of this, the purpose of this invention is to provide a dual closed-loop insulin delivery system and its applications and medical products, providing a more intelligent and humane treatment option for diabetic patients.

[0006] To achieve the above-mentioned objectives, the technical solution of the present invention is as follows:

[0007] On one hand, the present invention provides a dual closed-loop insulin delivery system, comprising: a dynamic blood glucose monitoring system, a dual closed-loop control algorithm, an insulin pump, and a glucose-responsive insulin analog;

[0008] In this process, a glucose-responsive insulin analog is filled into the insulin pump; the insulin pump injection is controlled by a dual closed-loop control algorithm, which includes: a dynamic blood glucose monitoring system acquiring blood glucose information, and then calculating and sending instructions through the dual closed-loop control algorithm; the dual closed-loop control algorithm includes: transmitting blood glucose information to an open-source mobile application and using a custom algorithm to calculate the infusion volume, and sending instructions to the insulin pump for infusion.

[0009] The dual closed-loop mechanism of this invention includes: glucose feedback regulation by insulin analogs and glucose feedback regulation by insulin pumps.

[0010] Specifically, the dynamic blood glucose monitoring system is selected from any one of xDrip+, NSClient blood glucose, Medtronic 640g, Glimp, BYODA Kangde patch version, Poctech, GlucoRx Aidex, Glunovo, random blood glucose, and silicon-based research.

[0011] Specifically, the dual closed-loop control algorithm is a custom setting of the built-in algorithm module of Android APS. The setting parameters include insulin dosing interval, insulin delivery dose, and the set range of blood glucose values ​​for insulin delivery.

[0012] Specifically, the insulin dosing interval is 0-24 hours.

[0013] Preferably, the insulin dosing interval is 0.5-12 hours.

[0014] In some embodiments, the insulin dosing interval is 2 hours.

[0015] Specifically, the insulin delivery dose is 0-10 mg.

[0016] Preferably, the insulin delivery dose is 0-2 mg.

[0017] In some embodiments, the insulin delivery dose is 0.2 mg, 0.3 mg, or 0.4 mg.

[0018] Specifically, the range of blood glucose levels for insulin delivery is set at 70-180 mg / dL.

[0019] Preferably, the range of blood glucose levels for insulin delivery is 100-180 mg / dL.

[0020] In some embodiments, the insulin delivery blood glucose level is 150 mg / dL.

[0021] The conditions for insulin to deliver blood glucose are that the blood glucose value must be greater than a certain value twice consecutively and the interval between the previous administration must be greater than or equal to the set administration interval.

[0022] Specifically, the insulin pump is selected from any one of Dana R, Dana R Korean version, Dana Rv2, Dana-iRS, Accu-Chek Insight, Accu-Chek Comb, Omnipod, Dash, Medtronic, Diaconn G8, or a virtual pump.

[0023] Preferably, the insulin pump is selected from Dana® (Korean version).

[0024] Specifically, the structure of the sugar-responsive insulin analog is shown below:

[0025] Wherein, R1, R2, and R3 are each independently selected from H or the structure shown in formula (I), and at least one group among R1, R2, and R3 is the structure shown in formula (I);

[0026] In formula (I), R4 is selected from halogen, hydrocarbon, nitro, amide, ester, hydroxyl, or nitrile groups. More specifically, formula (I) is selected from any of the following structures:

[0027] Specifically, the R mentioned 1 It is 3-fluoro-1-phenylboronic acid-4-acyl, R 2 For H, R 3 It is a 3-fluoro-1-phenylboronic acid-4-acyl group.

[0028] Specifically, the R mentioned 4 Selected from halogens, C1-C 20 Alkyl, C1-C 20 cycloalkyl, C1-C 20 alkenyl, C1-C 20 alkynyl group, C1-C 20 Cycloalkenyl, C1-C 20 Cycloalkynyl, nitro, amide, ester, C1-C20 Any one of alkoxy or nitrile groups.

[0029] More specifically, the halogen is selected from any one of fluorine, chlorine, or bromine.

[0030] On the other hand, this invention discloses the application of a dual closed-loop insulin delivery system in the preparation of drugs for treating diabetes.

[0031] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0032] This invention employs a dual closed-loop control system. By integrating an advanced dynamic blood glucose monitoring system and intelligent algorithms, it can monitor a patient's blood glucose levels in real time and, based on real-time data, automatically deliver glucose-responsive insulin using a customized delivery algorithm. After entering the bloodstream, the glucose-responsive insulin's built-in phenylboronic acid groups form stable borate ester bonds with plasma proteins and some membrane proteins. When blood glucose rises, the glucose-responsive insulin breaks these bonds, thus lowering blood glucose. When blood glucose falls to a safe range, the insulin can bind to plasma proteins and some membrane proteins, significantly reducing the risk of hypoglycemia. This dual closed-loop insulin delivery system prolongs the time blood glucose remains within the target range and significantly improves treatment safety, requiring no manual intervention in insulin delivery. Furthermore, the customized delivery algorithm of this invention has simple logic, runs quickly, simplifies algorithm complexity, and reduces computational load. Attached Figure Description

[0033] Figure 1 is a schematic diagram of a dual closed-loop insulin delivery system;

[0034] Figure 2 shows the blood glucose levels and dosage of insulin pump-fed glucose-responsive insulin therapy in type 1 diabetic pigs.

[0035] Figure 3 shows the blood glucose levels and dosage of type 1 diabetic pigs treated with insulin pump-fed commercially available rapid-acting insulin lispro injection.

[0036] Figure 4 shows the statistics of time within the target glucose range (TIR), time above the target glucose range (TAR), and time below the target glucose range (TBR).

[0037] Figure 5 shows the glucose variation coefficient during the treatment cycle of the glucose-responsive insulin dual closed-loop delivery system and the lispro insulin delivery system.

[0038] Figure 6 shows the area under the time-glucose curve during the treatment cycle for the glucose-responsive insulin dual closed-loop delivery system and the lispro insulin delivery system. Detailed Implementation

[0039] The present invention will be further illustrated below with reference to specific embodiments. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the invention. Experimental methods in the following embodiments that do not specify specific conditions are generally performed according to conventional methods and conditions or as selected in the product instructions.

[0040] The manufacturers or models of the reagents or instruments used in the following examples are shown in Table 1.

[0041] Table 1

[0042] Example 1

[0043] 1. Setting the delivery algorithm for the dual closed-loop insulin delivery system

[0044] The Android APS algorithm module was custom-coded with the following main parameters set: Insulin dosing interval: 2 hours; Insulin delivery dose: 0.2 mg; Blood glucose level delivered by insulin: 150 mg / dL. That is, if two consecutive blood glucose levels obtained by the continuous glucose monitoring system are greater than 150 mg / dL, and the interval between the last dosing is more than 2 hours, the insulin pump will deliver 0.2 mg of glucose-responsive insulin. Otherwise, no insulin will be delivered, and the sampling time of the continuous glucose monitoring system is 5 minutes.

[0045] 2. Construction of a dual closed-loop insulin delivery system device

[0046] Using a silicon-based motion sensor as the blood glucose source system, it can acquire blood glucose data in real time and upload it to the host device; the host device is a Google mobile phone with Android APS software installed and a built-in custom delivery algorithm, which serves as the control system; the Dana R Korean version insulin pump is used as the delivery system, receiving instructions from the control system to deliver the glucose.

[0047] 3. Application of glucose-responsive insulin analogs

[0048] The glucose-responsive insulin analog was dissolved and diluted with phosphate buffer to a concentration of 3 mg / mL, filled into the insulin pump reservoir, and connected to the insulin pump infusion set. The infusion set needle could then be attached to the skin of a type 1 diabetic pig model.

[0049] 4. Start-up of the dual closed-loop insulin delivery system

[0050] Activate and start the dynamic blood glucose monitoring system according to the manufacturer's instructions. After the blood glucose reading stabilizes, turn on the closed-loop mode. The glucose-responsive insulin will be infused according to the set program. The system will automatically record the blood glucose, dosing interval and dosage every five minutes.

[0051] Example 2

[0052] In “1. Setting the delivery algorithm of the dual closed-loop insulin delivery system”, the insulin delivery dose is changed to 0.3mg. Other than that, the steps and conditions are the same as in Example 1.

[0053] Example 3

[0054] In “1. Setting the delivery algorithm of the dual closed-loop insulin delivery system”, the insulin delivery dose is changed to 0.4 mg. Other than that, the steps and conditions are the same as in Example 1.

[0055] Comparative Example 1

[0056] 1. Setting the delivery algorithm for a single closed-loop insulin delivery system

[0057] The Android APS algorithm module was custom-coded, with the main parameters set as follows: Insulin dose (IU) delivered every 5 minutes = intensity coefficient (set to 0.3 or 0.4) * (current blood glucose level / 18 - 4.4) / 6.7. Furthermore, if the blood glucose level is below 200 mg / dL and the current blood glucose level is lower than the average blood glucose level of the previous 5 time points, insulin will not be injected.

[0058] 2. Construction of a single closed-loop insulin delivery system device

[0059] Using a silicon-based motion sensor as the blood glucose source system, it can acquire blood glucose data in real time and upload it to the host device; the host device is a Google mobile phone with Android APS software installed and a built-in custom delivery algorithm, which serves as the control system; the Dana R Korean version insulin pump is used as the delivery system, receiving instructions from the control system to deliver the glucose.

[0060] 3. Application of lispro insulin

[0061] Commercially available rapid-acting insulin lispro is filled into an insulin pump, and the insulin pump infusion set is connected. The infusion set needle can then be attached to the skin of a type 1 diabetic pig model.

[0062] 4. Start-up of the dual closed-loop insulin delivery system

[0063] Activate the silicon-based dynamic blood glucose monitoring system according to the manufacturer's instructions. After the blood glucose reading stabilizes, switch to closed-loop mode and infuse lispro insulin according to the set program. The system automatically records the blood glucose, dosing interval, and dosage every five minutes.

[0064] Example of effect

[0065] Experimental subjects: Six-month-old male Bama miniature pigs were selected and intravenously injected with streptozotocin (STZ, 150 mg / kg) to induce a type 1 diabetes model.

[0066] Experimental pretreatment: Miniature pigs were fed twice daily, and their blood glucose levels were monitored using a dynamic blood glucose monitoring system (silicon-based dynamic system, Shenzhen Silicon-based Bionic). Pigs with blood glucose levels greater than 250 mg / dL were selected for the study. Glucose was routinely controlled with insulin glargine injection. After discontinuing insulin glargine for 48 hours, a dual closed-loop insulin delivery system was implemented to study its glycemic control effect.

[0067] The experimental steps are as follows:

[0068] (1) The main parameters of the custom delivery algorithm for Android APS are set as follows: Insulin dosing interval: 2 hours; Insulin delivery dose: 0.2, 0.3, or 0.4 mg; Blood glucose level delivered by insulin: 150 mg / dL. The self-developed glucose-responsive insulin analog was filled into the insulin pump using the insulin pump reservoir, and the insulin pump infusion set was connected. The infusion set needle could be attached to the skin of the miniature pig's leg to start the dual closed-loop system. Blood glucose levels were selected for 48 consecutive hours. The results are shown in Figure 2. It can be seen that blood glucose control is stable, and the number of times and the duration of blood glucose levels below 50 mg / dL in the animals are significantly less. The system's dosing execution rate is >95%.

[0069] (2) The control group had its Android APS algorithm module custom-coded. The algorithm was set as follows: the dose administered every five minutes = intensity coefficient (set to 0.3 or 0.4) * (current blood glucose / 18 - 4.4) / 6.7. Furthermore, if the blood glucose level was below 200 mg / dL and the current blood glucose value was lower than the average of the previous five five-minute intervals, no injection would be given. Commercially available rapid-acting insulin lispro was used to fill the insulin pump. The insulin pump infusion set was connected, and the infusion needle was attached to the skin of the miniature pig's leg. The system was then started. Blood glucose levels were collected over a continuous 48-hour period. The results are shown in Figure 3. It can be seen that blood glucose fluctuations were large, the blood glucose control effect was poor, and the number of times and duration of blood glucose levels below 50 mg / dL were both high.

[0070] (3) The glucose control effects of the dual closed-loop delivery system in experimental step (1) and the single closed-loop delivery system in experimental step (2) were further compared, and the time within the glucose target range (TIR, 70-180 mg / dL), the time above the glucose target range (TAR, >180 mg / dL), and the time below the glucose target range (TBR, <70 mg / dL) were statistically analyzed. The results are shown in Figure 4. The results show that the glucose TIR (mean 81.6 ± 8.7%) of the dual closed-loop insulin delivery system using glucose-responsive insulin was significantly higher than that of the single closed-loop insulin delivery system using lispro insulin (mean 46.0 ± 6.9%), ***P = 0.0007; the TBR (mean 13.7 ± 4.5%) of the dual closed-loop insulin delivery system using glucose-responsive insulin was significantly lower than that of the single closed-loop insulin delivery system using lispro insulin (mean 40.8 ± 4.8%), ***P = 0.0002; there was no significant difference in TAR. The coefficient of variation for glucose was calculated for both delivery systems, and the results are shown in Figure 5. The results indicate that the blood glucose fluctuation in the dual-loop insulin delivery system was significantly lower than that in the control group (single-loop insulin delivery system), ***P = 0.0006. The area under the curve (AUC) of the time-glucose curves for both delivery systems was calculated, and the results are shown in Figure 6. The results indicate that there was no significant difference in the cumulative blood glucose level between the dual-loop and single-loop insulin delivery systems.

[0071] All of the above demonstrates that the constructed dual-closed-loop insulin delivery system not only achieves fully closed-loop blood glucose management, but also ensures a high proportion of time with glucose within the target range, a low incidence of hypoglycemia, and reduced blood glucose fluctuations. It solves the problems of single-closed-loop systems, such as the need for human intervention, high risk of hypoglycemia, and algorithmic complexity, and provides a safer, more convenient, and more effective treatment method.

Claims

1. A dual closed-loop insulin delivery system, characterized in that, The dual closed-loop insulin delivery system includes: a dynamic blood glucose monitoring system, a dual closed-loop control algorithm, an insulin pump, and a glucose-responsive insulin analog. The glucose-responsive insulin analogue is filled into the insulin pump; The insulin pump's injection is controlled by a dual closed-loop control algorithm, including: The dynamic blood glucose monitoring system acquires blood glucose information, then calculates and sends instructions through a dual closed-loop control algorithm; The aforementioned dual closed-loop control algorithm includes: transmitting blood glucose information to an open-source mobile application and using a custom algorithm to calculate the infusion volume, and sending instructions to the insulin pump for infusion.

2. The dual closed-loop insulin delivery system according to claim 1, characterized in that, The dynamic blood glucose monitoring system is selected from any one of xDrip+, NSClient blood glucose, Medtronic 640g, Glimp, BYODA Kangde patch version, Poctech, GlucoRx Aidex, Glunovo, random blood glucose, and silicon-based research.

3. The dual closed-loop insulin delivery system according to claim 1, characterized in that, The aforementioned dual closed-loop control algorithm is a custom setting of the built-in algorithm module of Android APS. The setting parameters include insulin dosing interval, insulin delivery dose, and the set range of blood glucose values ​​delivered by insulin.

4. The dual closed-loop insulin delivery system according to claim 3, characterized in that, The insulin dosing interval is 0.5-12 hours.

5. The dual closed-loop insulin delivery system according to claim 3, characterized in that, The insulin delivery dose is 0-2 mg.

6. The dual closed-loop insulin delivery system according to claim 3, characterized in that, The set range for the blood glucose level delivered by insulin is 100-180 mg / dL.

7. The dual closed-loop insulin delivery system according to claim 1, characterized in that, The insulin pump is selected from any one of Dana R, Dana R Korean version, Dana Rv2, Dana-iRS, Accu-Chek Insight, Accu-Chek Comb, Omnipod, Dash, Medtronic, Diaconn G8, or a virtual pump.

8. The dual closed-loop insulin delivery system according to claim 1, characterized in that, The structure of the sugar-responsive insulin analog is shown below: Wherein, R1, R2, and R3 are each independently selected from H or the structure shown in formula (I), and at least one group among R1, R2, and R3 is the structure shown in formula (I); R4 in formula (I) is selected from halogen, hydrocarbon, nitro, amide, ester, hydroxyl, or nitrile groups.

9. The dual closed-loop insulin delivery system according to claim 8, characterized in that, The formula (I) is selected from any of the following structures:

10. The dual closed-loop insulin delivery system according to claim 8, characterized in that, The R mentioned 1 It is 3-fluoro-1-phenylboronic acid-4-acyl, R 2 For H, R 3 It is a 3-fluoro-1-phenylboronic acid-4-acyl group.

11. The dual closed-loop insulin delivery system according to claim 8, characterized in that, The R mentioned 4 Selected from halogens, C1-C 20 Alkyl, C1-C 20 cycloalkyl, C1-C 20 alkenyl, C1-C 20 Alkyne group, C1-C 20 Cycloalkenyl, C1-C 20 Cycloalkynyl, nitro, amide, ester, C1-C 20 Any one of alkoxy or nitrile groups.

12. The dual closed-loop insulin delivery system according to claim 11, characterized in that, The halogen is selected from any one of fluorine, chlorine or bromine.

13. The use of the dual closed-loop insulin delivery system according to any one of claims 1-12 in the preparation of a drug for treating diabetes.

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