WO2016082685A1 - 注射泵控制方法、控制单元及注射泵 - Google Patents

注射泵控制方法、控制单元及注射泵 Download PDF

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Publication number
WO2016082685A1
WO2016082685A1 PCT/CN2015/094538 CN2015094538W WO2016082685A1 WO 2016082685 A1 WO2016082685 A1 WO 2016082685A1 CN 2015094538 W CN2015094538 W CN 2015094538W WO 2016082685 A1 WO2016082685 A1 WO 2016082685A1
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Prior art keywords
insulin
injection
time
value
pump
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PCT/CN2015/094538
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English (en)
French (fr)
Inventor
周明东
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上海泽生科技开发有限公司
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Priority claimed from CN201410709653.7A external-priority patent/CN105688308A/zh
Application filed by 上海泽生科技开发有限公司 filed Critical 上海泽生科技开发有限公司
Priority to AU2015353267A priority Critical patent/AU2015353267A1/en
Priority to RU2017122443A priority patent/RU2017122443A/ru
Priority to EP15862852.9A priority patent/EP3225263A4/en
Priority to KR1020177015439A priority patent/KR20170089438A/ko
Priority to US15/529,314 priority patent/US20170258992A1/en
Priority to JP2017528949A priority patent/JP2017535383A/ja
Priority to BR112017011223A priority patent/BR112017011223A2/pt
Priority to CN201580061830.8A priority patent/CN107427630B/zh
Priority to CA2968480A priority patent/CA2968480A1/en
Publication of WO2016082685A1 publication Critical patent/WO2016082685A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M5/00—Devices for bringing media into the body in a subcutaneous, intra-vascular or intramuscular way; Accessories therefor, e.g. filling or cleaning devices, arm-rests
    • A61M5/14—Infusion devices, e.g. infusing by gravity; Blood infusion; Accessories therefor
    • A61M5/142—Pressure infusion, e.g. using pumps

Definitions

  • the invention relates to a control method for a syringe pump, and to an associated control unit and a syringe pump.
  • Diabetes is a chronic disease that seriously jeopardizes human health in modern society.
  • the use of insulin to control blood sugar and prevent various serious complications is most effective. Since insulin cannot be taken orally, a syringe is conventionally used to inject insulin. At present, the use of syringe pumps for injections is also increasing.
  • the syringe pump can accurately control the blood glucose concentration of diabetic patients, reduce the fluctuation of blood sugar, and reduce the incidence of hypoglycemia by regularly and accurately injecting insulin, thereby improving the quality of life of patients.
  • the emergence of a syringe pump was once considered a gospel for diabetics.
  • the current level of penetration of the syringe pump is not high.
  • the cumbersome procedure of setting the pump injection dose has caused problems for the medical staff and patients, and also limited the application and promotion of the syringe pump.
  • the current dose setting of the syringe pump follows the “total dose-base dose-additional dose” scheme, which calculates the total amount of insulin based on the patient's weight and condition, or previous insulin use and efficacy; the total dose is multiplied by the partition coefficient to obtain the base dose respectively. And add a dose before meals (meals).
  • this method does not allow the patient's blood glucose concentration to reach the expected range very quickly. It is usually necessary to monitor blood glucose four times a day, and the insulin dosage is continuously adjusted according to the blood glucose concentration.
  • the initial setting of the dose of the syringe pump is generally performed by the medical staff.
  • the diabetic patient In order to explore the optimal insulin dosage, the diabetic patient often needs to stay in the hospital for about one week; if the non-hospital method is selected, it takes longer to complete the dose setting of the syringe pump.
  • the pump user since the type and quantity of meals per patient may change, it is necessary for the pump user to master the calculation method of the pre-meal/meal amount, which imposes high requirements on the user's learning ability, and many patients cannot adapt to it. And mastered and gave up pump treatment.
  • clinicians have a variety of insulin preparations available for routine treatment, including fast-acting, short-acting, intermediate-acting, and long-acting insulins, each with its pharmacokinetic/pharmacodynamic characteristics and indications, but
  • the syringe pump only uses quick-acting or short-acting insulin.
  • This setting scheme is quite different from the daily treatment scheme.
  • the medical staff needs to be trained to master the setting method. At present, most medical personnel do not understand the setting scheme of such a syringe pump. This has also become a limiting factor in syringe pump applications.
  • the present invention proposes a solution.
  • the use of a quick-acting or short-acting preparation in combination with a syringe pump to simulate the pharmacokinetic/pharmacodynamic characteristics of a long-acting or intermediate-effect preparation greatly facilitates the use of a syringe pump by medical personnel and patients, thereby facilitating a syringe pump The promotion of the benefit of the majority of patients.
  • the present invention provides a control method for a syringe pump, and accordingly provides a control unit for a syringe pump and includes the control Unit of the syringe pump.
  • a method of controlling a syringe pump for injecting a formulation comprises: (1) obtaining a current first position preparation concentration value of a current moment of an individual of the preparation to be injected; (2) acquiring a desired concentration value in plasma at a predetermined next moment based on the first injection schedule; Obtaining an injection value at a current time based on a second injection protocol and a desired concentration value in plasma at the next time, and a current first position preparation concentration value; (4) injecting the individual by a pump according to the injection value Formulation; (5) Steps (1)-(4) are repeated until the time elapsed from the first injection reaches the duration of the first injection protocol.
  • the first position formulation concentration value is zero when no formulation is injected.
  • step (1) the current second position preparation concentration value of the current time is also acquired, and in step (3), the current injection time value is also obtained based on the current second position preparation concentration value.
  • the second site formulation concentration value is zero when no formulation is injected.
  • the first injection regimen is a long-acting or intermediate-effect injection regimen.
  • the second injection regimen is a short-acting or fast-acting injection regimen.
  • the first position is a subcutaneous position.
  • the second location is a tissue gap.
  • the formulation is insulin.
  • the amount of displacement of the pump is monitored in real time as the formulation is injected into the individual using a pump. This allows precise control of the pump injection volume.
  • a control unit for controlling a syringe pump injection preparation comprising: a current concentration value acquisition module configured to acquire a current first position preparation of a current time of an individual of the preparation to be injected a concentration value; a desired concentration value acquisition module configured to acquire a desired concentration value at a predetermined next time based on the first injection scenario; an injection value acquisition module configured to be based on the second injection plan, the next time The expected concentration value, and the current first position preparation concentration value, to obtain the current injection value; the injection instruction sending module is configured to send an instruction to use the pump to inject the preparation to the individual according to the injection value; A module is arranged to give a signal to stop the injection when the time elapsed since the first injection reaches the duration of the first injection protocol.
  • the desired concentration value acquisition module further acquires the current second position preparation concentration value of the current time
  • the should-injection value acquisition module further acquires the current injection time value based on the current second position preparation concentration value.
  • the timing module is implemented by a counter, wherein the timing module provides a signal to stop the injection when a predetermined number of injections is reached.
  • control unit further comprises a displacement sensor for monitoring the displacement of the pump in real time.
  • a syringe pump for an injection preparation comprising a pump And a control unit as described in the preceding paragraph, wherein the control unit is disposed in the pump body.
  • a method of controlling an insulin syringe pump comprises: (1) obtaining a current subcutaneous insulin value at a current moment of an individual to be injected with insulin and a current tissue interstitial insulin value; (2) acquiring a desired plasma insulin concentration at a predetermined next moment based on the first insulin injection protocol Value; (3) based on the second insulin injection protocol, the current subcutaneous insulin value and the current tissue interstitial insulin value, and the expected plasma insulin concentration value at the next moment, calculate the current injection value; (4) according to the injection value The individual is injected with insulin using a pump; (5) steps (1)-(4) are repeated until the time elapsed from the first injection reaches the duration of the first insulin injection protocol.
  • the subcutaneous insulin value and the interstitial insulin value are zero when there is no insulin injection.
  • the current subcutaneous insulin value at the current time is first acquired, and then the current interstitial insulin value is obtained based on the current subcutaneous insulin value.
  • the insulin value refers to a monomer/dimer insulin value.
  • the first injection regimen is a long-acting or intermediate-effect injection regimen.
  • the second injection regimen is a short-acting or fast-acting injection regimen.
  • the amount of displacement of the pump is monitored in real time when the individual is injected with insulin using a pump. This allows precise control of the pump injection volume.
  • a control unit for controlling an insulin injection pump comprising: a current concentration value acquisition module configured to take a current subcutaneous insulin value at a current time and a current tissue interstitial insulin value; a concentration value acquisition module configured to acquire a desired plasma insulin concentration value at a predetermined next moment based on the first insulin injection protocol; an injection value acquisition module configured to be based on the second insulin injection protocol, the next moment The desired plasma insulin concentration value, the current subcutaneous insulin value, and the current tissue interstitial insulin value to obtain an injection value at the current time; an injection instruction transmitting module configured to send an instruction to inject the individual with the pump according to the injection value Insulin; a timing module arranged to set a signal to stop the injection when the time elapsed since the first injection reached the duration of the first injection protocol.
  • the timing module is implemented by a counter, wherein the timing module provides a signal to stop the injection when a predetermined number of injections is reached.
  • control unit further comprises a displacement sensor for monitoring the displacement of the pump in real time.
  • a syringe pump for injecting insulin comprising a pump body and a control unit as described in the preceding paragraph, wherein the control unit is disposed in the pump body.
  • a method of controlling an insulin syringe pump comprises: (1) obtaining, based on a first insulin injection protocol, a first desired plasma insulin concentration value at a predetermined first time instant of an individual to be injected insulin; (2) based on a second insulin injection protocol and said first Expecting a plasma insulin concentration value, calculating an initial injection value at an initial time; (3) according to the initial injection value Injecting insulin into the individual using a pump; (4) obtaining a subcutaneous monomer/dimer insulin value and a first time tissue interstitial insulin value at the first moment of the first moment based on the second insulin injection protocol; (5) based on The first insulin injection protocol acquires a second desired plasma insulin concentration value at a predetermined second time instant; (6) based on the second insulin injection protocol, the second desired plasma insulin concentration value and the first The subcutaneous monomer/dimer insulin value and the first time tissue interstitial insulin value are calculated, and the first injection value at the first moment is calculated; (7) the individual
  • the interval between the first time and the initial time is equal to the interval between the second time and the first time.
  • the time interval between each injection is fixed.
  • the first injection regimen is a long-acting or intermediate-effect injection regimen.
  • the second injection regimen is a short-acting or fast-acting injection regimen.
  • a control unit for controlling an insulin syringe pump includes: a desired plasma insulin concentration value acquisition module configured to acquire a first desired plasma insulin concentration value at a predetermined first time, a predetermined second time instant of the individual to be injected with insulin based on the first insulin injection protocol a second desired plasma insulin concentration value up to a predetermined Nth expected plasma insulin concentration value; wherein N is a predetermined number of injections; and a current subcutaneous and interstitial insulin concentration value acquisition module configured to take the current time Current subcutaneous insulin value and current tissue interstitial insulin value; an injection value acquisition module configured to be based on a second insulin injection protocol, a desired plasma insulin concentration value at a next moment, the current subcutaneous insulin value, and the current interstitial insulin a value to obtain an injection value at the current time; an injection instruction sending module configured to send an instruction to inject insulin to the individual using the pump according to the injection value; and a counting module configured to be experienced from the first injection When the time reaches the
  • the timing module is implemented by a counter, wherein the timing module provides a signal to stop the injection when a predetermined number of injections is reached.
  • control unit further comprises a displacement sensor for monitoring the displacement of the pump in real time.
  • a syringe pump for injecting insulin comprising a pump body and a control unit as described in the preceding paragraph, wherein the control unit is disposed in the pump body.
  • FIG. 1 is a flow chart of a method of controlling a syringe pump in accordance with an embodiment of the present invention
  • Figure 2 is a graph showing changes in blood concentration after subcutaneous injection of 10 IU of NPH in a 70 kg body weight patient;
  • Figure 3 is a graph showing changes in blood concentration of pump-injected fast-acting insulin and one-injection of 10 IU of intermediate-acting insulin, wherein partial details are also shown in an enlarged view;
  • FIG. 4 is a functional block diagram of a control unit for a syringe pump in accordance with an embodiment of the present invention
  • FIG. 5 is a schematic illustration of a syringe pump in accordance with one embodiment of the present invention.
  • Figure 6 is an injection volume per 15 minutes and a theoretical expected value of a syringe pump in accordance with one embodiment of the present invention
  • Figure 7 is a PK comparison of a single subcutaneous injection of NPH, a continuous subcutaneous injection of a syringe pump, and a blank control group in one embodiment of the present invention.
  • systems and methods can include data signals transmitted over a network (eg, a local area network, a wide area network, the Internet, and combinations thereof, etc.), fiber optic media, carrier waves, wireless networks, etc., for communicating with one or more data processing devices .
  • the data signal can carry any or all of the data disclosed herein.
  • the methods and systems described herein can also be implemented on different types of processing devices, including program code including instructions that can be executed on the processing subsystems of such devices.
  • Software program instructions may include source code, object code, machine code, or other stored data that is operable to cause a processing system to perform the methods and operations described herein.
  • Other implementations are also possible, such as being configured to execute firmware or even suitable hardware of the methods and systems described herein.
  • Data for systems and methods may be stored and executed on one or more different kinds of non-transitory computer readable storage media,
  • the media can be located at a certain location or distributed in several locations.
  • the medium may include computer implemented data storage, such as different types of storage devices and programming structures (eg, RAM, ROM, flash memory, flat files, databases, programming data structures, programming variables, IF-THEN (or similar) declaration structures, etc.) ).
  • the data structure describes a format for organizing and storing data, databases, programs, memory or other computer readable media for use by a computer program.
  • Systems and methods can be provided on many different types of computer readable media, including computer storage mechanical structures (eg, CD-ROM, magnetic disks, RAM, flash memory, computer hard drives, etc.) containing instructions (eg, software) for use by a processor Execution to perform the operations of the methods described herein and implement the system.
  • computer storage mechanical structures eg, CD-ROM, magnetic disks, RAM, flash memory, computer hard drives, etc.
  • instructions eg, software
  • a module or processor includes, but is not limited to, a code unit that performs software operations and that can be, for example, as a subroutine unit, as a software functional unit of code, or as an object (in an object-oriented paradigm), or Implemented as a small application, or in a computer scripting language, or as another type of computer code.
  • Software components and/or functionality may be located on separate computers or distributed across multiple computers, depending on the circumstances.
  • the method includes five steps. First, at step 101, the current first position preparation concentration value of the current time of the individual of the preparation to be injected and the preparation concentration value of the current second position are obtained. Then, at step 102, based on the first injection scenario, a desired concentration value at a predetermined next time instant is acquired. Next, at step 103, the injection value at the current time is obtained based on the second injection protocol, the desired concentration value at the next time, the current first position preparation concentration value, and the current second position preparation concentration value. Again, at step 104, the formulation is injected into the individual using a pump based on the value of the injection.
  • step 105 it is judged whether the time elapsed from the first injection reaches the duration of the first injection plan, and if so, it ends; if not, then returns to step 101, and the execution is repeated, that is, repeated execution Steps 101-104, until the time elapsed since the first injection reaches the duration of the first injection protocol.
  • the duration of the first injection protocol refers to the duration of the effect of the preparation when injected according to the first injection protocol.
  • the first location may be a subcutaneous location and the second location may be a tissue gap
  • the first injection protocol is a long-acting injection regimen
  • the second injection regimen is a quick-acting injection regimen
  • the formulation is insulin.
  • the invention can be converted into a quick-acting injection solution suitable for injection by a syringe pump according to the conventional prescription of insulin, and fully utilizes the clinical drug regimen and clinical experience that the doctor has mastered to increase the medication. Accuracy and reliability; simplifies pump usage, reduces dose setting and adjustment time, and saves doctors and patients the time it takes to use insulin. Therefore, a very specific embodiment of the invention will be described below by taking insulin as an example.
  • the conventional treatment regimen was set at 10 IU NPH/day, while the patient's weight was 70 kg, and the insulin pump used fast-acting insulin, such as Novo Nordisk's Novo and Sharp.
  • the pharmacokinetic profile of the intermediate-acting insulin NPH (for example, Novo Nordisk's Nobel) is calculated.
  • NPH (t) total rate of intermediate-acting insulin NPH injection (mU/min);
  • NPH insulin injection rate (mU/min) in hexamer form
  • NPH insulin injection rate (mU/min) in monomer/dimer form
  • ⁇ NPH the ratio of crystalline form of insulin in NPH to the total amount of NPH
  • NPH NPH crystal dissolution rate (min -1 );
  • x h amount of hexamer insulin in the subcutaneous tissue (mU);
  • k 2 rate of transfer of dimer/monomer insulin from the subcutaneous to the interstitial space (min -1 );
  • k d rate at which hexamers, dimers, and monomers are depleted by diffusion (min -1 );
  • x dm hexamer insulin amount (mU);
  • k 3 rate of insulin transport from the interstitial space to the plasma (min -1 );
  • k d,i rate of loss from tissue gap loss, for example 0.0029 (min -1 );
  • I(t) plasma insulin concentration (mU/L);
  • n plasma insulin clearance rate, for example 0.16 (min -1 );
  • V i insulin plasma distribution volume, for example, 0.1421 (liter/kg);
  • m b body weight (kg), for example 70 kg;
  • I N exp(-(4*t)/25)*((1022699*exp((27*t)/200))/163961000+(50681673*exp((793*t)/5000))/4936028500- (2182714053*exp((953*t)/10000))/494945696200-(4449021*exp((1511*t)/10000))/327887000+1682730209/1141906519000) (8)
  • Figure 2 is a graph showing the change in blood concentration after subcutaneous injection of 10 IU of NPH in a 70 kg body weight patient.
  • u total, mono (t) total rate of rapid-acting insulin injection (mU/min);
  • I mt exp(-(4*t)/25)*((32489*x dm0 )/7156260-(613*x i0 )/9580+I m0 -exp((479*t)/5000)*(( 32489*x dm0 )/2567440-(613*x i0 )/9580)+(32489*x dm0 *exp((747*t)/5000))/4003920) (12)
  • x dm0 the amount of subcutaneous monomer/dimer fast-acting insulin (mU) at time 0;
  • x dmt the amount of subcutaneous monomer/dimer fast-acting insulin (mU) at time t;
  • I m0 0 time plasma fast-acting insulin concentration (mU / L);
  • I mt the concentration of plasma fast-acting insulin (mU/L) at time t;
  • the amount of insulin in the subcutaneous and interstitial spaces and the plasma insulin concentration at any time after the injection of the fast-acting insulin can be separately calculated.
  • the cyclically iterative method is used to analyze the equations composed of equations (10)-(12), and the pump-actual insulin injection amount can be calculated. Assume that the pump is injected every 3 minutes.
  • the specific calculation method is as follows:
  • 0.2605mU/L exp(-(4*3)/25)*((32489*(333.227mU+U 3 ))/7156260-(613*9.789mU)/9580+0.079874mU/L-exp((479 *3)/5000)*((32489*(333.227mU+U 3 ))/2567440-(613*9.789mU)/9580)+(32489*(333.227mU+U 3 ) + *exp((747*3 )/5000))/4003920)
  • the injection volume of the pump at each time point can be calculated, thereby realizing the conversion of the medium- or long-acting insulin injection protocol into a quick-acting insulin injection solution.
  • conversion of a medium or long-acting insulin injection regimen to a short-acting insulin injection regimen or other injection regimen conversions can be achieved.
  • Table 2 shows the various insulin kinetic parameter tables used for the simulation. Table 2 shows the kinetic parameters of each type of insulin product, the value of which is the median value, which can be used as a reference.
  • the fast-acting insulin content at each position may also be determined without a formula, but by an appropriate detection method (for example, ACS 180PLUS); the injection interval may not be set to 3 minutes, but may be set to other Suitable values are, for example, 2 minutes, 5 minutes, 10 minutes.
  • an appropriate detection method for example, ACS 180PLUS
  • the injection interval may not be set to 3 minutes, but may be set to other Suitable values are, for example, 2 minutes, 5 minutes, 10 minutes.
  • injection regimens for other formulations can also be converted to provide an injection regimen that is more advantageous for use on a syringe pump, thereby providing great convenience to the patient.
  • the control unit 200 includes a current density value acquisition module 201, a desired concentration value acquisition module 202, an injection value acquisition module 203, an injection instruction transmission module 204, and a timing module 205.
  • the current concentration value module 201 is used to obtain the current time of the individual to be injected into the preparation.
  • the desired concentration value acquisition module 202 acquires a desired plasma insulin concentration value at a predetermined next time based on the first insulin injection protocol.
  • the injection value acquisition module 203 acquires the injection value at the current time based on the second insulin injection protocol and the desired plasma insulin concentration value at the next moment, as well as the current subcutaneous insulin value and the current tissue interstitial insulin value.
  • the injection command transmitting module 204 sends an instruction to inject an individual into the preparation using a pump according to the value of the injection.
  • the timing module 205 performs timing and provides a signal to stop the injection when the time elapsed since the first injection reaches the duration of the first injection protocol.
  • the timing module 205 can be implemented, for example, by the system clock of the control unit. It can also be achieved, for example, by a counter; in this case, the counter gives a signal to stop the injection when the predetermined number of injections is reached. In some embodiments, the time interval for each injection is set to be constant, and the predetermined number of injections can be obtained by simply using the division from the duration of the first injection protocol.
  • FIG. 4 only functionally partitions the modules of the control unit 200 and does not represent a physical division of the control unit. In fact, the functionality of some modules may be integrated into one chip, and even the entire control unit is embodied as a single chip or as part of a single chip.
  • Fig. 5 schematically shows a syringe pump of one embodiment of the present invention.
  • the pump body of the syringe pump 300 includes a push rod assembly 301, a motor assembly 302, an injection chamber 303, and an injection head 304.
  • a motor assembly 302 is disposed at a rear end of the push rod assembly 301 for providing a power push to propel the push rod assembly 301.
  • the injection chamber 303 is disposed at the front end of the push rod assembly 301 in which the preparation is stored, and when subjected to the pressure of the push rod assembly 301, the preparation is injected outward from the injection head 304 located at the front end of the injection chamber 303.
  • a displacement sensor 309 can be disposed under the push rod assembly 301 for monitoring the displacement of the pump.
  • the syringe pump 300 further includes a battery chamber 305 located at a lower portion of the pump body and other electronic components, such as a centrally disposed liquid crystal panel 306 for information interaction with the user, and for example, a USB interface 307 disposed on one side of the liquid crystal panel 306. Used as a communication interface.
  • the syringe pump 300 also includes a detachably coupled alarm assembly 308 for transmitting an alarm under special circumstances.
  • a control unit 200 in the form of a control main board is provided inside the syringe pump 300.
  • the mat members mentioned above may be provided as separate components that are spatially separated from the control unit 200, or may be integrated on the control board as part of the control unit 200.
  • the invention is applied to experimental SD rats, the injection precision of the injection pump of the invention in animal experiments is studied, and the feasibility of the invention is further explored by comparing the pharmacokinetic curves between the injection pump and the subcutaneous injection of insulin. .
  • RESULTS RESULTS RESULTS RESULTS RESULTS RESULTS RESULTS RESULTS RESULTS RESULTS RESULTS RESULTS RESULTS RESULTS RESULTS RESULTS RESULTS RESULTS RESULTS RESULTS RESULTS RESULTS RESULTS RESULTS RESULTS RESULTS RESULTS RESULTS stasarcomas. RI injection pump continuous subcutaneous injection group and blank control group. During the 4 hours of the experiment, Samples were taken at each blood collection point and their insulin concentrations were measured. The syringe pump measures its injection amount every 15 minutes according to the set scheme and compares it with the theoretical expected value.
  • T1DM mice were randomly divided into NPH single subcutaneous injection group, RI injection pump continuous subcutaneous injection group and blank control group. During the 4 hours of the experiment, Samples were taken at each blood collection point and their insulin concentrations were measured. The sy
  • the feeding environment temperature is 20-25 degrees Celsius, the humidity is 40%-70%, free to eat and drink, and the rat cage is cleaned regularly.
  • SD rats weighing ⁇ 200 g were fasted for 24 h, and each group was administered by intraperitoneal injection at a dose of 70 mg/kg.
  • Modeling standard The blood glucose level of the tail vein of rats was measured 72 hours after administration by blood glucose meter, and the random blood glucose ⁇ 11.6mmol/L was used as the model standard for diabetic rats. The measured random blood glucose was more than 20mmol/L after modeling.
  • NPH single subcutaneous injection group was given a single subcutaneous injection of Novoline N at a dose of 5 IU/kg;
  • RI injection pump continuous subcutaneous injection group was given NPH-like kinetics of Novoling R subcutaneous continuous pumping; blank control group was given The syringe pump is continuously pumped under saline.
  • Insulin detection was performed using Roche electrochemical luminometer cobas e601, manufactured by Roche Diagnostics , tested by Guangzhou Jinyu Medical Testing Center.
  • the injection volume of the syringe pump was basically the same as the theoretical expectation, as shown in Figure 6.
  • the continuous subcutaneous injection group of the RI injection pump showed the reliability of controlling the insulin metabolism process in vitro.
  • the peak time is consistent with the peak concentration; the blank group proves the mechanical knot of the syringe pump. If it does not have any effect on insulin changes, see Figure 7 for details.
  • the in vivo concentration of insulin can be substantially controlled over time.

Abstract

一种控制胰岛素注射泵的方法、相关的控制单元（200）和注射泵（300）。控制单元（200）包括：期望血浆胰岛素浓度值获取模块（202）、当前皮下和组织间隙胰岛素浓度值获取模块（201）、应注射值获取模块（203）、注射指令发送模块（204）以及计数模块（205）。注射泵包括泵体和所述控制单元（200），其中控制单元（200）设置在泵体中。

Description

注射泵控制方法、控制单元及注射泵 技术领域
本发明涉及一种注射泵的控制方法，还涉及相关的控制单元以及注射泵。
背景技术
糖尿病是一种严重危害现代社会人类健康的慢性疾病。在实践中，使用胰岛素来控制血糖及防治各种严重并发症是最为有效的。由于胰岛素不能口服，传统上使用注射器来注射胰岛素。目前，使用注射泵来进行注射的情况也越来越多。
注射泵通过定时定量精确注射胰岛素，达到更好控制糖尿病患者血糖浓度，减小血糖波动，降低低血糖发生率的目的，从而提高患者生活质量。注射泵的出现一度被认为是糖尿病患者的福音。然而，当前注射泵的普及水平并不高，除费用昂贵等因素外，设置泵注射剂量的繁琐程序对医护人员和患者造成的困扰，也限制了注射泵的应用推广。
当前注射泵的剂量设置遵循“总剂量-基础剂量-追加剂量”方案，即根据患者体重和病情，或以往胰岛素使用情况和疗效，计算胰岛素总用量；总剂量乘以分配系数，分别得到基础剂量和餐前(餐时)追加剂量。然而，该方法无法使患者血糖浓度很快达到预期范围，通常需要每天4次监测血糖，根据血糖浓度不断调整胰岛素用量。注射泵的剂量初始设置操作一般由医护人员完成，为了摸索较为理想的胰岛素用量，糖尿病患者常常需住院一周左右；如果选择非住院方式，则需要花费更长时间才能完成注射泵的剂量设置。此外，由于患者每天用餐种类和数量可能发生改变，这就需要泵使用者必须掌握餐前/餐时追加量的计算方法，对使用者的学习能力提出了较高要求，而许多患者因为无法适应和掌握而放弃了泵治疗。另一方面，临床医生在常规治疗时有多种胰岛素制剂可供选择，包括速效、短效、中效和长效胰岛素，每种制剂有其药代/药效动力学特点和适应症，但注射泵仅采用速效或短效胰岛素，这种设置方案与日常治疗方案存在较大差异，医护人员需要经过培训才能掌握该设置方法，而目前多数医护人员并不了解此类注射泵的设置方案，这也成为注射泵应用的一个限制因素。
发明内容
针对上述问题，本发明提出了解决方案。根据本发明，使用速效或短效制剂并结合注射泵来模拟长效或中效制剂的药代/药效动力学特征，极大地方便了医护人员和患者对注射泵的使用，从而促进注射泵的推广，造福广大患者。本发明提供对注射泵的控制方法，还相应地提供用于注射泵的控制单元以及包括该控制 单元的注射泵。
根据本发明的一个主要方面，提供一种控制用于注射制剂的注射泵的方法。该方法包括：(1)获取待注射制剂的个体的当前时刻的当前第一位置制剂浓度值；(2)基于第一注射方案，获取在预定的下一时刻的血浆中期望浓度值；(3)基于第二注射方案和所述下一时刻的血浆中期望浓度值，以及当前第一位置制剂浓度值，获取当前时刻的应注射值；(4)根据所述应注射值利用泵对个体注射制剂；(5)重复执行步骤(1)-(4)，直至从第一次注射起所经历的时间达到第一注射方案的持续时长。
优选地，当没有制剂注射时，第一位置制剂浓度值为0。
优选地，在步骤(1)中，还获取当前时刻的当前第二位置制剂浓度值，并且在步骤(3)中，还基于当前第二位置制剂浓度值来获取当前时刻的应注射值。
优选地，当没有制剂注射时，第二位置制剂浓度值为0。
优选地，第一注射方案是长效或中效注射方案。
优选地，第二注射方案是短效或速效注射方案。
优选地，第一位置是皮下位置。
优选地，第二位置是组织间隙。
优选地，制剂是胰岛素。
优选地，在利用泵对个体注射制剂时，实时监控泵的位移量。这样可以精确控制泵的注射量。
根据本发明的另一个主要方法，提供一种用于控制注射泵注射制剂的控制单元，其包括：当前浓度值获取模块，其设置成获取待注射制剂的个体的当前时刻的当前第一位置制剂浓度值；期望浓度值获取模块，其设置成基于第一注射方案，获取在预定的下一时刻的期望浓度值；应注射值获取模块，其设置成基于第二注射方案、所述下一时刻的期望浓度值、以及所述当前第一位置制剂浓度值，来获取当前时刻的应注射值；注射指令发送模块，其设置成发送指令以根据所述应注射值利用泵对个体注射制剂；计时模块，其设置成在从第一次注射起所经历的时间达到第一注射方案的持续时长时，给出信号用以停止注射。
优选地，期望浓度值获取模块还获取当前时刻的当前第二位置制剂浓度值，并且应注射值获取模块还基于当前第二位置制剂浓度值来获取当前时刻的应注射值。
优选地，计时模块通过计数器来实现，其中当达到预定注射次数时，计时模块给出信号用以停止注射。
优选地，控制单元还包括位移传感器，用于实时监控泵的位移量。
根据本发明的又一个主要方面，提供一种用于注射制剂的注射泵，其包括泵 体和如前段所述的控制单元，其中所述控制单元设置在所述泵体中。
根据本发明的一个主要方面，提供一种控制胰岛素注射泵的方法。该方法包括：(1)获取待注射胰岛素的个体的当前时刻的当前皮下胰岛素值和当前组织间隙胰岛素值；(2)基于第一胰岛素注射方案，获取在预定的下一时刻的期望血浆胰岛素浓度值；(3)基于第二胰岛素注射方案，当前皮下胰岛素值和当前组织间隙胰岛素值，和下一时刻的期望血浆胰岛素浓度值，计算当前时刻的应注射值；(4)根据该应注射值利用泵对个体注射胰岛素；(5)重复执行步骤(1)-(4)，直至从第一次注射起所经历的时间达到第一胰岛素注射方案的持续时长。
优选地，当没有胰岛素注射时，皮下胰岛素值和组织间隙胰岛素值为0。
优选地，首先获取当前时刻的当前皮下胰岛素值，然后基于当前皮下胰岛素值来获取当前组织间隙胰岛素值。
优选地，胰岛素值是指单体/二聚体胰岛素值。
优选地，第一注射方案是长效或中效注射方案。
优选地，第二注射方案是短效或速效注射方案。
优选地，在利用泵对个体注射胰岛素时，实时监控泵的位移量。这样可以精确控制泵的注射量。
根据本发明的另一个主要方法，提供一种用于控制胰岛素注射泵的控制单元，其包括：当前浓度值获取模块，其设置成取当前时刻的当前皮下胰岛素值和当前组织间隙胰岛素值；期望浓度值获取模块，其设置成基于第一胰岛素注射方案，获取在预定的下一时刻的期望血浆胰岛素浓度值；应注射值获取模块，其设置成基于第二胰岛素注射方案、所述下一时刻的期望血浆胰岛素浓度值、当前皮下胰岛素值和当前组织间隙胰岛素值，来获取当前时刻的应注射值；注射指令发送模块，其设置成发送指令以根据该应注射值利用泵对所述个体注射胰岛素；计时模块，其设置成其设置成在从第一次注射起所经历的时间达到第一注射方案的持续时长时，给出信号用以停止注射。
优选地，计时模块通过计数器来实现，其中当达到预定注射次数时，计时模块给出信号用以停止注射。
优选地，控制单元还包括位移传感器，用于实时监控泵的位移量。
根据本发明的又一个主要方面，提供一种用于注射胰岛素的注射泵，其包括泵体和如前段所述的控制单元，其中所述控制单元设置在所述泵体中。
根据本发明的一个主要方面，提供一种控制胰岛素注射泵的方法。该方法包括：(1)基于第一胰岛素注射方案，获取待注射胰岛素的个体的在预定的第一时刻的第一期望血浆胰岛素浓度值；(2)基于第二胰岛素注射方案和所述第一期望血浆胰岛素浓度值，计算初始时刻的初始应注射值；(3)根据所述初始应注射值 利用泵对个体注射胰岛素；(4)基于第二胰岛素注射方案，获取在所述第一时刻的第一时刻皮下单体/二聚体胰岛素值和第一时刻组织间隙胰岛素值；(5)基于所述第一胰岛素注射方案，获取在预定的第二时刻的第二期望血浆胰岛素浓度值；(6)基于所述第二胰岛素注射方案，所述第二期望血浆胰岛素浓度值以及所述第一时刻皮下单体/二聚体胰岛素值和所述第一时刻组织间隙胰岛素值，计算第一时刻的第一应注射值；(7)根据所述第一应注射值利用泵对个体注射胰岛素；(8)基于步骤(4)-(7)，以迭代的方法获取每一时刻的应注射值并根据该应注射值利用泵对个体注射胰岛素，直到从第一次注射起所经历的时间达到第一胰岛素注射方案的持续时长。
优选地，第一时刻与初始时刻的间隔等于第二时刻与第一时刻的间隔。
优选地，每两次注射之间的时间间隔是固定的。
优选地，第一注射方案是长效或中效注射方案。
优选地，第二注射方案是短效或速效注射方案。
根据本发明的另一个主要方面，提供一种用于控制胰岛素注射泵的控制单元。该控制单元包括：期望血浆胰岛素浓度值获取模块，其设置成基于第一胰岛素注射方案，获取待注射胰岛素的个体的在预定的第一时刻的第一期望血浆胰岛素浓度值、预定的第二时刻的第二期望血浆胰岛素浓度值，直至预定的第N时刻的第N期望血浆胰岛素浓度值；其中N为预定注射次数；；当前皮下和组织间隙胰岛素浓度值获取模块，其设置成取当前时刻的当前皮下胰岛素值和当前组织间隙胰岛素值；应注射值获取模块，其设置成基于第二胰岛素注射方案、下一时刻的期望血浆胰岛素浓度值、所述当前皮下胰岛素值和所述当前组织间隙胰岛素值，来获取当前时刻的应注射值；注射指令发送模块，其设置成发送指令以根据该应注射值利用泵对个体注射胰岛素；以及计数模块，其设置成在从第一次注射起所经历的时间达到第一注射方案的持续时长时，给出信号用以停止注射。
优选地，计时模块通过计数器来实现，其中当达到预定注射次数时，计时模块给出信号用以停止注射。
优选地，控制单元还包括位移传感器，用于实时监控泵的位移量。
根据本发明的又一个主要方面，提供一种用于注射胰岛素的注射泵，其包括泵体和如前段所述的控制单元，其中所述控制单元设置在所述泵体中。
需要明白，本发明的技术方案并非仅限于所列出的以上各种。以上各主要技术方案和各优选方案的特征是可以自由结合的，只要被结合的特征之间并没有互相抵触。
附图说明
图1是根据本发明的一个实施方式的控制注射泵的方法的流程图；
图2是70kg体重患者皮下注射10IU NPH后血药浓度变化曲线图；
图3是泵注射速效胰岛素与一次注射10IU中效胰岛素血药浓度变化的曲线图，其中还以放大图的形式显示了局部细节；
图4是根据本发明的一个实施方式的用于注射泵的控制单元的功能框图；
图5是根据本发明的一个实施方式的注射泵的示意图；
图6是根据本发明的一个实施例的注射泵每15分钟注射量与理论预期值；
图7是本发明的一个实施例中NPH单次皮下注射、注射泵连续皮下注射与空白对照组的PK对比图。
下文将结合附图来阐述本发明的具体实施方式。需要明白，这些实施方式是示例性的，而非限制性的。
具体实施方案
说明书中使用了一些示例来描述本发明，其中包括一些优选实施方式。应当明白，本发明的保护范围还包括其他示例。
例如，系统和方法可以包括通过网络(例如，局域网、广域网、互联网，以及它们的结合等等)、光纤介质、载波、无线网络等传输的数据信号，用于与一个或多个数据处理装置通信。该数据信号能够承载本文中公开的任意或所有数据。另外，这里描述的方法与系统也可以在不同类型的处理装置上实现，通过能够在这些装置的处理子系统上执行的包括指令的程序代码。软件程序指令可以包括源代码、目标代码、机器代码或其它所储存的数据，其是可操作的以使处理系统执行此处描写的方法与操作。其它实现方式也是可行的，例如设置成能够执行本文所描写的方法和系统的固件或甚至合适的硬件。
系统和方法的数据(例如关联、映射、数据输入、数据输出、中间数据结果、最终数据结果等)可以在一个或多个不同种类的非易失性计算机可读存储介质上储存并执行，该介质可以是位于某一位置或者分布在几个位置。该介质可以包括计算机实现的数据存储器，例如不同类型的存储装置和编程结构(例如RAM、ROM、闪存、平面文件、数据库、编程数据结构、编程变量、IF-THEN(或类似的)声明结构等)。需要明白，数据结构描述了格式，用于组织和存储数据子啊数据库、程序、内存或其他由计算机程序使用的计算机可读介质。
系统和方法可以提供在许多不同类型的计算机可读介质上，包括计算机存储机械结构(例如CD-ROM、磁盘、RAM、闪存、计算机硬盘等)，其含有指令(例如软件)用于由处理器执行，以完成此处描述的方法的操作并实现该系统。
此处描述的计算机部件、软件模块、功能、数据存储以及数据结构可以直接或间接地彼此连接，以允许其工作所需的数据流动。还需明白，模块或者处理器包括但不限于这样的代码单元，其执行软件操作，并且可以例如作为子程序单元、作为代码的软件功能单元、或作为对象(在面向对象的范式中)、或作为小应用、或在计算机脚本语言中、或作为另一种类型的计算机代码来实现。软件组件和/或功能可以根据不同的情况位于单独的计算机上或分布在多个计算机上。
需要明白，在本说明书中使用的，以及在权利要求中提到的部件可以包括单数和复数的形式。同样，在本说明书中使用的，以及在权利要求中提到的，除非上下文特别指明，“在……中”包含“在……中”和“在……上”两层含义。最后，在本说明书中使用的，以及在权利要求中提到的，除非上下文特别指明，“和”与“或”包括连接性和分离性的含义两者，也可以互换使用，术语“排他的或”可以用来指明只应用分离性含义的情况。
图1显示了本发明的一个实施方式的控制注射泵的方法的流程图。如图所示，该方法包括五个步骤。首先，在步骤101处，获取待注射制剂的个体的当前时刻的当前第一位置制剂浓度值和当前第二位置的制剂浓度值。然后，在步骤102处，基于第一注射方案，获取在预定的下一时刻的期望浓度值。其次，在步骤103处基于第二注射方案、下一时刻的期望浓度值、当前第一位置制剂浓度值和当前第二位置的制剂浓度值，获取当前时刻的应注射值。再次，在步骤104处，根据应注射值利用泵对个体注射制剂。接着，在步骤105处，判断从第一次注射起所经历的时间是否达到第一注射方案的持续时长，如是，则结束；如否，则回到步骤101，重新依次执行，也即重复执行步骤101-104，直至从第一次注射起所经历的时间达到第一注射方案的持续时长。在这里，所谓第一注射方案的持续时长，指的是按照第一注射方案注射时，制剂所起效果的持续时长。
应当明白，在本发明的其他实施方式中，也可以只获取第一位置或第二位置的制剂浓度值，而不需要同时获取第一位置和第二位置的制剂浓度值。
在一个优选实施形式中，第一位置可以是皮下位置，而第二位置可以是组织间隙，第一注射方案是长效注射方案，第二注射方案是速效注射方案，而制剂是胰岛素。
尤其对于胰岛素注射来说，本发明能够依据胰岛素常规处方，通过药代动力学原理转换成适合以注射泵注射的速效注射方案，充分利用医生已掌握的胰岛素临床用药方案和临床经验，增加用药的准确性和可靠性；简化了泵的使用方法，减少了剂量设置和调整时间，节省医生和患者的使用胰岛素所花费的时间。因此，以下以胰岛素为例来描述本发明的一个非常具体的实施形式。
目前临床上使用的胰岛素有多种类型，常用给药方式是皮下注射，但作用时 效特征相差很大。短效胰岛素(RI)注射后15-60min起效，速效的10-15min起效，中效(NPH，lent)的2.5-3h起效，长效的(ultralente，glargine)2-3小时起效，可维持20-30小时。导致作用时间差异的主要因素是胰岛素皮下吸收过程的差异，该过程一般包括以下几个阶段：在皮下组织，晶体形态(crystalline)的胰岛素溶解为六聚体(hexameric)，六聚体可解聚为二聚体或单体(dimeric/monomeric)；后者从皮下进入组织间隙后可被吸收入血。每个吸收阶段遵循一级动力学模式。
在这个例子中，设定常规的治疗方案为10IU NPH/天，而患者的体重为70kg，胰岛素泵使用速效胰岛素，例如诺和诺德的诺和锐。
首先，计算中效胰岛素NPH(例如诺和诺德的诺和灵)的药代动力学特征。
用微分方程组描述NPH的皮下吸收过程：
utotal,NPH(t)＝uc,NPH(t)+uh,NPH(t)+um,NPH(t)              (1)
uc,NPH(t)＝αNPHutotal,NPH(t)                             (2)
Figure PCTCN2015094538-appb-000001
Figure PCTCN2015094538-appb-000002
Figure PCTCN2015094538-appb-000003
Figure PCTCN2015094538-appb-000004
Figure PCTCN2015094538-appb-000005
其中，
utotal,NPH(t)：中效胰岛素NPH注射总速率(mU/min)；
uc,NPH(t)：晶体形态的NPH胰岛素注射速率(mU/min)；
uh,NPH(t)：六聚体形态的NPH胰岛素注射速率(mU/min)；
um,NPH(t)：单体/二聚体形态的NPH胰岛素注射速率(mU/min)；
αNPH：NPH中晶体形态的胰岛素占NPH总量的比例；
CNPH(t)：皮下晶体形态NPH的量(mU)；
kcrys,NPH：NPH晶体溶解速率(min-1)；
xh：皮下组织六聚体胰岛素的量(mU)；
k1：六聚体解聚速率(min-1)；
k2：二聚体/单体胰岛素从皮下转运到组织间隙的速率(min-1)；
kd：六聚体、二聚体和单体因扩散而耗损的速率(min-1)；
xdm：六聚体胰岛素量(mU)；
k3：胰岛素从组织间隙转运到血浆的速率(min-1)；
kd,i：从组织间隙损耗丢失的速率，例如0.0029(min-1)；
I(t)：血浆胰岛素浓度(mU/L)；
n：血浆胰岛素清除速率，例如0.16(min-1)；
Vi：胰岛素血浆分布容积，例如0.1421(liter/kg)；
mb：体重(kg)，例如70kg；
通过求解上述方程组，可得到血浆NPH浓度IN关于时间t的解析解：
IN＝exp(-(4*t)/25)*((1022699*exp((27*t)/200))/163961000+(50681673*exp((793*t)/5000))/4936028500-(2182714053*exp((953*t)/10000))/494945696200-(4449021*exp((1511*t)/10000))/327887000+1682730209/1141906519000)          (8)
根据上式可计算一次注射中效胰岛素后任意时刻的血浆胰岛素浓度。图2示意性地显示了70kg体重患者皮下注射10IU NPH后血药浓度变化曲线。
其次，计算速效胰岛素的药代动力学特征。
用微分方程组描述速效胰岛素的皮下吸收过程：
utotal,mono(t)＝umono(t)                        (9)
Figure PCTCN2015094538-appb-000006
Figure PCTCN2015094538-appb-000007
Figure PCTCN2015094538-appb-000008
其中，
utotal,mono(t)：速效胰岛素注射总速率(mU/min)；
umono(t)：单体/二聚体形态的速效胰岛素注射速率(mU/min)；
其余参数见前文。
通过求解上述方程组，可得到以下计算公式：
xdmt＝xdm0*exp(-(53*t)/5000)           (10)
xit＝(20*exp(-(321*t)/5000)*((613*xi0)/20-(32489*xdm0)/5360+(32489*xdm0*exp((67*t)/1250))/5360))/613                    (11)
Imt＝exp(-(4*t)/25)*((32489*xdm0)/7156260-(613*xi0)/9580+Im0-exp((479*t)/5000)*((32489*xdm0)/2567440-(613*xi0)/9580)+(32489*xdm0*exp((747*t)/5000))/4003920)                     (12)
其中，
xdm0：0时刻皮下单体/二聚体速效胰岛素的量(mU)；
xdmt：t时刻皮下单体/二聚体速效胰岛素的量(mU)；
xi0：0时刻组织间隙速效胰岛素的量(mU)；
xit：t时刻组织间隙速效胰岛素的量(mU)；
Im0：0时刻血浆速效胰岛素的浓度(mU/L)；
Imt：t时刻血浆速效胰岛素的浓度(mU/L)；
通过以上公式，可分别计算一次注射速效胰岛素后任意时刻皮下和组织间隙胰岛素的量以及血浆胰岛素浓度。
接着，计算每个时点胰岛素泵注射量。
根据中效胰岛素NPH在各时点的浓度值，通过循环迭代法解析等式(10)-(12)组成的方程组，可计算泵速效胰岛素注射量。假定泵每3分钟注射一次，具体计算方法如下：
(a)根据公式(8)，计算3分钟中效胰岛素的血浆浓度为IN3＝0.07987mU/L；
(b)求0时刻各位置速效胰岛素含量；设0时刻注射速效胰岛素U0，则0时刻注入胰岛素U0瞬时皮下速效胰岛素量为xdm0 +＝U0；此刻速效胰岛素尚未达到组织间隙和血浆，因此，组织间隙xi0＝0，血浆中Im0＝0；
(c)欲使在第3分钟时血浆速效胰岛素浓度达到此刻中效胰岛素水平，则Im3＝IN3＝0.07987mU/L。将xdm0 +＝U0，xi0＝0，Im0＝0，Im3＝0.07987mU/L代入公式(12)，t取3min，得方程
0.07987mU/L＝exp(-(4*3)/25)*((32489*xdm0 +)/7156260-(613*0)/9580+0-exp((479*3)/5000)*((32489*xdm0 +)/2567440-(613*0)/9580)+(32489*xdm0 +*exp((747*3)/5000))/4003920)
此方程仅xdm0 +未知,解此方程，可得xdm0 +＝343.994mU,U0＝xdm0 +＝343.994mU，即0时刻胰岛素注射量为343.994mU；
(d)求第3分钟时各位置速效胰岛素含量；记第3分钟时泵第二次注射之前皮下速效胰岛素量为xdm3 -，根据公式(10)可得xdm3 -＝333.227mU；记第3分钟时组织间隙速效胰岛素量为xi3，根据公式(11)，可得xi3＝9.789mU；由步骤(c)可知Im3＝0.079874mU/L；
(e)根据公式(8)，计算第6分钟时中效胰岛素的血浆浓度为IN6＝0.2605mU/L；
(f)设第3分钟时速效胰岛素注射量为U3，则xdm3 +＝xdm3 -+U3＝333.227mU+U3；由步骤(d)可知xi3＝9.789mU，Im3＝0.079874mU/L；由步骤(e)计算3分钟后(即第6分钟时)速效胰岛素血浆浓度应为Im6＝IN6＝0.2605mU/L。在第3min各位置速效胰岛素含量基础上计算第6分钟时血浆胰岛素浓度，代入公式(12)，得方程
0.2605mU/L＝exp(-(4*3)/25)*((32489*(333.227mU+U3))/7156260-(613*9.789mU)/9580+0.079874mU/L-exp((479*3)/5000)*((32489*(333.227mU+U3))/2567440-(613*9.789mU)/9580)+(32489*(333.227mU+U3)+*exp((747*3)/5000))/4003920)
此方程仅U3未知,解此方程，可得U3＝20.2026mU，即第3分钟时应注射20.2026mu，注射后xdm3 +＝xdm3 -+U3＝353.4296mU；
(g)重复步骤(d)-(f)，可计算每3分钟胰岛素泵的注射量。见附表1，其中显示了胰岛素泵各时点速效胰岛素注射量。
表1 胰岛素泵各时点速效胰岛素注射量(mU)
Figure PCTCN2015094538-appb-000009
为了验证泵注射速效胰岛素与中效胰岛素一次注射两者血药浓度的吻合度，分别计算每6秒钟泵注射速效胰岛素与中效胰岛素一次注射两者血药浓度。结果显示，1分钟后两者差值小于1％，3分钟后两者差值小于0.1％。图3显示了两者的血药浓度曲线，显示了较高吻合度。
根据上面的例子，可计算出各个时点泵的注射量，从而实现用将中效或长效胰岛素注射方案转换为速效胰岛素注射方案。在其他实施形式中，可实现将中效或长效胰岛素注射方案转换为短效胰岛素注射方案，或实现其他的注射方案转换。附表2显示了用于模拟的各型胰岛素动力学参数表。附表2显示了各型胰岛素产品的动力学参数，其值为中位值，可作参考。
表2 各型胰岛素动力学参数表
Figure PCTCN2015094538-appb-000010
在上述例子中，各位置的速效胰岛素含量也可以不通过公式求得，而是通过适当的检测方法(例如，ACS 180PLUS)测得；注射间隔也可以不设置为3分钟，而是设置为其他合适的值，例如例如2分钟、5分钟、10分钟。
在进一步的例子中，还可以利用例如位移传感器来实时监控泵的位移量，从而监控注射量以达到精确注射的目的。
在本发明的一些其他实施方式中，还可以对其他制剂的注射方案进行转换，以得到更有利于在注射泵上使用的注射方案，从而给患者提供极大便利。
图4显示了根据本发明的一个实施方式的用于注射泵的控制单元的功能框图。如图所示，控制单元200包括当前浓度值获取模块201、期望浓度值获取模块202、应注射值获取模块203、注射指令发送模块204和计时模块205。还以胰岛素作为制剂举例，当前浓度值模块201用于获取待注射制剂的个体的当前时 刻的当前皮下胰岛素值和当前组织间隙胰岛素值。期望浓度值获取模块202基于第一胰岛素注射方案获取在预定的下一时刻的期望血浆胰岛素浓度值。应注射值获取模块203基于第二胰岛素注射方案和下一时刻的期望血浆胰岛素浓度值以及当前皮下胰岛素值和当前组织间隙胰岛素值，来获取当前时刻的应注射值。注射指令发送模块204发送指令以根据应注射值利用泵对个体进行注射制剂。计时模块205进行计时，并在从第一次注射起所经历的时间达到第一注射方案的持续时长时，给出信号用以停止注射。
计时模块205可以例如通过控制单元的系统时钟来实现。它还可以通过例如计数器来实现；则在这种情况下，当达到预定注射次数时，计数器给出信号用以停止注射。在一些实施方式中，设定每次注射的时间间隔是不变的，则可以简单地从第一注射方案的持续时长利用除法来得到预定注射次数。
应当明白，图4只是在功能上对控制单元200的各模块进行划分，而不代表对控制单元的物理划分。实际上，一些模块的功能可能集成在一个芯片中，甚至整个控制单元就只体现为一块芯片或者作为一部分集成在一个芯片中。
图5示意性地显示了本发明的一个实施方式的注射泵。如图所示，注射泵300的泵体包括推杆组件301、电机组件302、注射腔303和注射头304。电机组件302设置在推杆组件301的后端，用来提供动力推动以推动推杆组件301。注射腔303设置在推杆组件301的前端，其中储存制剂，在受到推杆组件301的压力时，制剂从位于注射腔303前端的注射头304向外注射。推杆组件301下方可以设置位移传感器309，用来监控泵的位移量。注射泵300还包括位于泵体下部的电池腔305和其他一些电子部件，例如居中设置的液晶面板306，用于和使用者进行信息交互，又例如设置在液晶面板306一侧的USB接口307，用作通信接口。注射泵300还包括可拆卸地连接的报警组件308，用于在特殊情况下发送警报。在注射泵300的内部，设置了形式为控制主板的控制单元200。以上提到的垫子部件既可以设置成与控制单元200在空间上分开的单独部件，也可以集成在控制主板上，作为控制单元200的一部分。
实施例1：
将本发明应用于实验用SD大鼠，研究本发明所述注射泵在动物实验中的注射精度，并通过对比其与皮下注射胰岛素之间的药代动力学曲线，进一步探讨本发明的可行性。
方法：采用SD大鼠，使用STZ一次性腹腔大剂量注射，一周后检测血糖值，大于11.6mmol/L则提示T1DM大鼠模型建立成功。T1DM鼠随机分为NPH单次皮下注射组、RI注射泵连续皮下注射组、空白对照组。在4小时的实验过程内， 分别于各采血点采样并检测其胰岛素浓度。注射泵按所设定方案另测定其每15min注射量并与理论预期值进行对照。
1.实验动物
1.1品系来源T1DM糖尿病SD大鼠，购自南京君科生物工程有限公司。
1.2性别周龄雄性，7-8周龄。
1.3饲养环境温度为20—25摄氏度，湿度40％-70％左右，自由进食饮水，定期打扫鼠笼。
2.受试注射泵
实验中使用注射泵，共8台，编码P001～P008，上海泽生科技开发股份有限公司生产。
3.实验材料
诺和灵R笔芯100IU/ml诺和诺德(中国)制药有限公司；诺和灵N笔芯100IU/ml诺和诺德(中国)制药有限公司
4.实验方法
4.1T1DM大鼠模型制备
将体重为～200g的SD大鼠禁食24h后,各组均分别按70mg/kg剂量一次性腹腔注射给药。
成模标准：采用血糖仪测给药后72h大鼠尾静脉血糖值，以随机血糖≥11.6mmol/L作为糖尿病大鼠成模标准。造模后实测随机血糖均在20mmol/L以上。
4.2分组与给药
成功建模后，T1DM鼠随机分入NPH单次皮下注射组、注射泵使用组、空白对照组。NPH单次皮下注射组使用诺和灵N单次皮下注射，给予剂量为5IU/kg；RI注射泵连续皮下注射组给予NPH样动力学过程的诺和灵R皮下连续泵注；空白对照组给予注射泵生理盐水皮下连续泵注。
4.3胰岛素测定
在给予治疗后的30min、45min、60min、75min、90min、105min、120min、135min、150min、180min、240min进行血样采集并检测胰岛素含量，胰岛素检测使用罗氏电化学发光仪cobas e601，罗氏诊断产品公司生产，由广州金域医学检验中心检测。
5.实验结果
实验中注射泵每15分钟注射量与理论预期基本一致，详见图6；与NPH单次皮下注射相比，RI注射泵连续皮下注射组显示出体外控制体内胰岛素代谢过程的可靠性，两者的达峰时间与达峰浓度基本一致；空白组则证明注射泵机械结 果不会对胰岛素变化产生任何影响，详见附图7。
6.结论
使用本专利所述注射泵后，胰岛素的体内浓度随时间变化曲线可以基本得到控制。
以上通过具体实施形式对本发明作了说明，需要理解，以上描述是说明性而不是限制性的。例如，上述内容中的特征既可以单独使用，也可以任意结合进行使用，只要其不超出本发明的范围。另外，在没有背离本发明的精神的情况下，可对实施形式进行修改以便适应具体情况。虽然本文所述的特定元素和过程定义了各个实施形式，但是它们决不是限制性的，而只是示范作用。通过阅读以上描述，许多其它实施例对于本领域的技术人员将是显而易见的。因此，本发明的范围应当参照权利要求连同这类权利要求涵盖的完整等效范围共同确定。

Claims (10)

  1. 一种控制胰岛素注射泵的方法，包括：
    (1)基于第一胰岛素注射方案，获取待注射胰岛素的个体的在预定的第一时刻的第一期望血浆胰岛素浓度值；
    (2)基于第二胰岛素注射方案和所述第一期望血浆胰岛素浓度值，计算初始时刻的初始应注射值；其中所述初始时刻与所述第一时刻的时间间隔定义为注射时间间隔；
    (3)根据所述初始应注射值利用泵对所述个体注射胰岛素；
    (4)基于第二胰岛素注射方案，获取在所述第一时刻的第一时刻皮下单体/二聚体胰岛素值和第一时刻组织间隙胰岛素值；
    (5)基于所述第一胰岛素注射方案，获取在预定的第二时刻的第二期望血浆胰岛素浓度值；其中所述第二时刻与所述第一时刻间隔等于所述注射时间间隔；
    (6)基于所述第二胰岛素注射方案，所述第二期望血浆胰岛素浓度值以及所述第一时刻皮下单体/二聚体胰岛素值和所述第一时刻组织间隙胰岛素值，计算第一时刻的第一应注射值；
    (7)根据所述第一应注射值利用泵对所述个体注射胰岛素；
    (8)基于步骤(4)-(7)，以迭代的方法获取每一时刻的应注射值并根据该应注射值利用泵对所述个体注射胰岛素，直到第N时刻的第N应注射值；其中N与所述注射时间间隔的乘积等于所述第一胰岛素注射方案的持续时长。
  2. 一种用于控制胰岛素注射泵的控制单元，其包括：
    期望血浆胰岛素浓度值获取模块，其设置成基于第一胰岛素注射方案，获取待注射胰岛素的个体的在预定的第一时刻的第一期望血浆胰岛素浓度值、预定的第二时刻的第二期望血浆胰岛素浓度值，直至预定的第N时刻的第N期望血浆胰岛素浓度值；其中初始时刻与所述第一时刻的时间间隔定义为注射时间间隔，所述第二时刻与所述第一时刻的时间间隔等于所述注射时间间隔，其后每一时刻与下一时刻的的时间间隔都等于所述注射时间间隔，而N与所述注射时间间隔的乘积等于所述第一胰岛素注射方案的持续时长；
    当前皮下和组织间隙胰岛素浓度值获取模块，其设置成取当前时刻的当前皮下胰岛素值和当前组织间隙胰岛素值；
    应注射值获取模块，其设置成基于第二胰岛素注射方案、下一时刻的期望血浆胰岛素浓度值、所述当前皮下胰岛素值和所述当前组织间隙胰岛素值，来获取当前时刻的应注射值；
    注射指令发送模块，其设置成发送指令以根据该应注射值利用泵对所述个体注射胰岛素；
    计数模块，其设置成在完成第N次注射时，给出信号用以停止注射。
  3. 根据权利要求2所述的控制单元，其特征在于，所述控制单元还包括位移传感器，用于实时监控泵的位移量。
  4. 一种用于注射胰岛素的注射泵，其包括泵体和如权利要求2-3中任一项所述的控制单元，其中所述控制单元设置在所述泵体中。
  5. 一种控制胰岛素注射泵的方法，包括：
    (1)基于第一胰岛素注射方案，获取待注射胰岛素的个体的在预定的第一时刻的第一期望血浆胰岛素浓度值；
    (2)基于第二胰岛素注射方案和所述第一期望血浆胰岛素浓度值，计算初始时刻的初始应注射值；
    (3)根据所述初始应注射值利用泵对所述个体注射胰岛素；
    (4)基于第二胰岛素注射方案，获取在所述第一时刻的第一时刻皮下单体/二聚体胰岛素值和第一时刻组织间隙胰岛素值；
    (5)基于所述第一胰岛素注射方案，获取在预定的第二时刻的第二期望血浆胰岛素浓度值；
    (6)基于所述第二胰岛素注射方案，所述第二期望血浆胰岛素浓度值以及所述第一时刻皮下单体/二聚体胰岛素值和所述第一时刻组织间隙胰岛素值，计算第一时刻的第一应注射值；
    (7)根据所述第一应注射值利用泵对所述个体注射胰岛素；
    (8)基于步骤(4)-(7)，以迭代的方法获取每一时刻的应注射值并根据该应注射值利用泵对所述个体注射胰岛素，直到从第一次注射起所经历的时间达到第一胰岛素注射方案的持续时长。
  6. 根据权利要求5所述的方法，其特征在于，所述第一时刻与所述初始时刻的间隔等于所述第二时刻与所述第一时刻的间隔。
  7. 根据权利要求5所述的方法，其特征在于，每两次注射之间的时间间隔是固定的。
  8. 一种用于控制胰岛素注射泵的控制单元，其包括：
    期望血浆胰岛素浓度值获取模块，其设置成基于第一胰岛素注射方案，获取待注射胰岛素的个体的在预定的第一时刻的第一期望血浆胰岛素浓度值、预定的第二时刻的第二期望血浆胰岛素浓度值，直至预定的第N时刻的第N期望血浆胰岛素浓度值；其中N为预定注射次数；
    当前皮下和组织间隙胰岛素浓度值获取模块，其设置成取当前时刻的当前皮下胰岛素值和当 前组织间隙胰岛素值；
    应注射值获取模块，其设置成基于第二胰岛素注射方案、下一时刻的期望血浆胰岛素浓度值、所述当前皮下胰岛素值和所述当前组织间隙胰岛素值，来获取当前时刻的应注射值；
    注射指令发送模块，其设置成发送指令以根据该应注射值利用泵对所述个体注射胰岛素；
    计时模块，其设置成在从第一次注射起所经历的时间达到第一注射方案的持续时长时，给出信号用以停止注射。
  9. 根据权利要求8所述的控制单元，其特征在于，所述计时模块通过计数器来实现，其中当达到预定注射次数时，所述计时模块给出信号用以停止注射。
  10. 一种用于注射胰岛素的注射泵，其包括泵体和如权利要求8-9中任一项所述的控制单元，其中所述控制单元设置在所述泵体中。
PCT/CN2015/094538 2014-11-13 2015-11-13 注射泵控制方法、控制单元及注射泵 WO2016082685A1 (zh)

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