CN103589636A - System and method for simulating in-vivo atrioventricular model - Google Patents
System and method for simulating in-vivo atrioventricular model Download PDFInfo
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Abstract
The invention relates to a system and method for simulating an in-vivo atrioventricular model. The system comprises a fresh culture solution storage tank, a central chamber simulating container for bacterial injection, an absorption chamber simulating container, a waste solution collecting tank and a stirrer, wherein the stirrer is a constant-temperature magnetic stirrer, and is used for stirring liquid in the central chamber simulating container and controlling the temperature; the central chamber simulating container is communicated with the waste solution collecting tank through a waste solution conduit; the storage tank is communicated with the absorption chamber simulating container through a culture solution conduit; the absorption chamber simulating container is communicated with the central chamber simulating container through a drug-containing culture solution conduit; a peristaltic pump is arranged on each conduit. The system has the characteristics of uniform stirring and constant system temperature; the system adopts a dynamic environment of continuous flow of liquid; the absorption chamber simulating container is provided for simulating in-vivo drug administration from a drug administering part to an acting part through absorptive transfer, so that the in-vivo atrioventricular model can be simulated more vividly.
Description
Technical field
The present invention relates to analog machine and the analogy method of pharmacokinetics, specifically refer to system and the analogy method thereof of the interior compartment model of analogue body of drug transport in a kind of analogue body in vitro.
Background technology
Medicine absorption in body, distribution, metabolism and excretion change with time are called pharmacokinetics.Pharmacokinetics is simulated human body with chamber conventionally, as long as interior some position of body is accepted or the speed of elimination medicine is similar, can be included into a chamber.Compartment model is only a kind of abstract concept of carrying out pharmacokinetic analysis, might not represent a certain anatomical site.Body is divided into one or more separate units, and the characteristic can absorb in vivo medicine, distributing, eliminate is made mode chart, to set up mathematical model, discloses its dynamic rule.Suppose after body administration, medicine reaches running balance at each position of whole body immediately, at this moment whole body is considered as to a chamber, is called one-compartment model or one compartment model.Suppose that medicine enters after body, instantaneously just can distribute and to reach running balance at the abundant tissue of blood supply (as blood, liver, kidney etc.), and then tissue (as fat, skin, bone etc.) distribution less in blood supply or that blood flow is slower reaches running balance, now these tissues can be called to central compartment and periphery compartment, i.e. two-compartment model.In addition, two-compartment model can reflect the physiological disposition feature of medicine exactly, although a compartment model accuracy is slightly poor, fairly simple, be convenient to understand, promote, application, and some medicine processes and can meet the demands with one compartment model, so its importance not second to two-compartment model.
For most of antibacterials, its antibacterial effect is relevant to drug level.Too low drug level is not enough to suppress or kill bacteria, and too high drug level may cause toxic side effect or cause bacterial resistance sudden change.Therefore, determining of antibacterials dosage, must be according to this medicine killing curve.With the dull and stereotyped measured static killing curve of pastille, can not correctly reflect that medicine transports the dynamic process with metabolism in vivo, the growth of Endophytic bacteria is also non-to be carried out under static condition.Therefore the sterilization effect that, the static killing curve of vitro Drug can not actual response medicine.
It is CNL03077296A that State Intellectual Property Office of the People's Republic of China discloses publication number on May 1st, 2013, denomination of invention is the patent of invention of the in-vitro simulated method of the intravenous injection pharmacokinetics model based on flow rate regulation, the equipment that this invents intravenous injection pharmacokinetics model used, comprises fresh container for storing liquid, reaction chamber, waste liquid cylinder, peristaltic pump, silicone tube and agitator etc.; Described reaction chamber is the space that drug level dynamic change, medicine and action target react to each other; Because drug efficacy study needs, reaction chamber is often placed in specific environment, or structurally has special modification; Peristaltic pump pumps into reaction chamber from container for storing liquid by certain flow rate by liquid as drive system, thereby the quantity of fluid such as in simultaneous reactions chamber, has again under pressure to discharge the specific change that forms reaction chamber drug level; Described silicone tube is as the connecting tube of each parts, and agitator acts on the liquid system in reaction chamber, makes drug distribution and to being uniformly dispersed in the whole system of acting on of target.There is following defect in above-mentioned disclosed technical scheme: the one, there is no temperature control device, and its agitator used is in fact a cage chair, only has the function of stirring, thus can not guarantee that the temperature of the liquid in model approaches the temperature of human body, therefore the precision of simulation is low, the 2nd, only on the nutrient solution input tube of reaction chamber (central compartment), established peristaltic pump, and do not set up peristaltic pump on waste liquid output tube, the environment of explanation simulation is static environment thus, that is to say, liquid is not continuous flow, therefore the effect of simulation is very undesirable, while using test tube or culture dish culturing bacterium, there will be nutrition exhausted and cause the problem of bacterium death, in addition, discharge when waste liquid can not the utmost point, can not guarantee that bacterium can grow sustainedly and stably, and simulated environment and actual environment are come in and gone out too large, so sterilization effect that the static killing curve of the vitro Drug forming can not actual response medicine.
In addition, for the similar mould unit of external foundation, the cost of existence is high, temperature control is uneven, stir the problems such as inhomogeneous.
Summary of the invention
The object of the invention is to overcome the deficiencies in the prior art, provide a kind of and simulate that tolerance range is high, the system of compartment model in the analogue body of convenient operation.
Another object of the present invention is to provide the analogy method of the system of compartment model in a kind of above-mentioned analogue body, by the method, more can reproduce realistically the compartment model in human body, thereby provide guarantee for setting up accurate killing curve.
The present invention is achieved through the following technical solutions: the system of compartment model in a kind of analogue body, include fresh medium hold tank, the container of the simulation central compartment of injecting in order to bacterium, waste collection cylinder and agitator, the container of simulation central compartment is communicated with waste collection cylinder by waste liquid conduit, also comprise the container in order to the simulation absorption chamber of infusion of medicine, described fresh medium hold tank is communicated with the container of simulation absorption chamber by nutrient solution conduit, the container of simulation absorption chamber is communicated with the container of simulation central compartment by pastille nutrient solution conduit, described nutrient solution conduit, on pastille nutrient solution conduit and waste liquid conduit, be respectively equipped with peristaltic pump, described agitator is constant temperature blender with magnetic force, in order to the liquid in containers of simulation central compartment is stirred and temperature control.
Compared with prior art there are three large features in technique scheme: the one, set up the container in order to the simulation absorption chamber of infusion of medicine, in order to simulate drug disposition from medicine-feeding part absorption and transport to site of action, thus more true to nature to the simulation of compartment model in body; The 2nd, on nutrient solution conduit, pastille nutrient solution conduit and waste liquid conduit, be respectively equipped with peristaltic pump, liquid in system be do not arrhea moving, thereby by traditional static environment, change dynamic environment into, in the time of guaranteeing like this utmost point of waste liquid, discharge, bacterium can be grown sustainedly and stably; The 3rd, adopted constant temperature blender with magnetic force, not only make to simulate more even that medicine, bacterium and nutrient solution in the liquid in containers of central compartment mixes, but also guaranteed that liquid has the temperature close with human body.Above-mentioned three large features, can correctly reflect that medicine transports the dynamic process with metabolism in vivo, thereby provide guarantee for setting up accurate killing curve.
Also comprise constant temperature blender with magnetic force and thermostat water bath, described fresh medium hold tank is located in thermostat water bath, and the container of described simulation absorption chamber is located in constant temperature blender with magnetic force.This technical scheme, is that the temperature of liquid in containers in simulation central compartment keeps on constant basis, makes the temperature of the liquid in the container of fresh nutrient solution hold tank and simulation absorption chamber also keep constant, thereby has further improved the precision of compartment model in analogue body.
The one or both ends of described waste liquid conduit are provided with filter membrane, this structure can prevent the discharge of bacterium, especially adopts two ends to set up the structure formation of filter membrane, and effect is better, can guarantee that central indoor bacteria is not subject to extraneous living contaminants, the bacterium in central compartment can not discharged by waste liquid conduit yet.
One end of described pastille nutrient solution conduit is provided with filter membrane.
It is the filter membrane of 0.22 μ m that described filter membrane adopts aperture.
Described nutrient solution conduit, pastille nutrient solution conduit and waste liquid conduit are all to be made by silica gel material.The conduit made from silica gel material is more close with the blood vessel of human body.
The container of the container of described simulation central compartment and simulation absorption chamber is all narrow-mouthed bottle or the Erlenmeyer flask that adopts glass material.Adopting narrow-mouthed bottle or Erlenmeyer flask is in fact all small-bore experimental apparatus, can effectively prevent the volatilization of liquid.
The analogy method of the system of compartment model in analogue body, comprise the following steps: the sterilizing of A, system and installation: container, nutrient solution conduit, pastille nutrient solution conduit and the waste liquid conduit of the container of fresh medium hold tank, simulation absorption chamber, simulation central compartment and fresh medium are put into respectively to 121 ℃ of above high-pressure steam sterilizing pans, sterilizing 20 minutes; Then in sterilisable chamber, above-mentioned each parts are connected, finally the system of compartment model in mounted analogue body is put in stink cupboard and prepares to move; B, adjustment flow velocity: open each peristaltic pump, adjust flow velocity; C, Temperature Setting: open thermostat water bath and two constant temperature blender with magnetic force, design temperature is 36.6～37.4 ℃; D, bacterium are injected: to simulating the bacterium of injecting certain turbidity in the container of central compartment; E, infusion of medicine: above-mentioned microbial culture is after the regular hour, to the medicine that injects doses in the container of simulation absorption chamber, has now just created the interior compartment model of body of aids drug dynamic metabolism.
In described step B, the rotating speed of each peristaltic pump is identical, to simulate the constant of the container of absorption chamber and the liquid in containers volume of simulation central compartment in keeping system.
In described step C, the temperature setting is 37 ℃.
The present invention is with respect to prior art, there is following advantageous effect: (1) inputs fresh medium and output waste liquid by peristaltic pump, bacterium can be grown sustainedly and stably, overcome and use test tube or culture dish culturing bacterium because of the exhausted problem that causes bacterium death of nutrition; (2) by peristaltic pump, control transhipment drug transport speed, make it meet the Absorption And Metabolism process in body as far as possible, thereby can simulate the sterilization effect in body in vitro, overcome and can not describe in real time the sterilization effect problem of medicine in body; (3) utilize native system, by bacterial counting and high-efficiency liquid chromatography method for detecting, can measure bacterial growth situation under different pharmaceutical concentration, take the time formulates killing curve as the longitudinal axis as transverse axis, the bacterial colony units of take, in conjunction with medicine curve in a period of time, can determine the rational dosage regimen of medicine.Meanwhile, by for some time, measure the MIC value of bacterium, can judge whether bacterium produces resistance under the effect of medicine; (4) the present invention has successfully set up compartment model device in analogue body, can be used for the research of pharmacokinetics, pharmacodynamics and pharmacokinetics and efficacy combination model, also can be used for the research that bacterial drug resistance produces, therefore range of application is very extensive; (5) the present invention has overcome that the cost existing while setting up with class model abroad is at present high, temperature control is uneven, stir the problems such as inhomogeneous, has cost feature low, easy to use, simple to operate.
Accompanying drawing explanation
Fig. 1 is structural representation of the present invention.
Fig. 2 is the schema of analogy method of the present invention.
In figure: 1, thermostat water bath; 2, fresh medium hold tank; 3, nutrient solution conduit; 4, peristaltic pump; 5, constant temperature blender with magnetic force; 6, the container of simulation absorption chamber; 7, pastille nutrient solution conduit; 8, peristaltic pump; 9, agitator; 10, the container of simulation central compartment; 11, waste liquid conduit; 12, peristaltic pump; 13, waste collection cylinder; 14, filter membrane; 15, filter membrane; 16, filter membrane.
Embodiment
Below in conjunction with embodiment and accompanying drawing, the present invention is described in further detail, but embodiments of the present invention are not limited to this.
Embodiment 1: as shown in Figure 1, the system of compartment model in a kind of analogue body, it is mainly by fresh medium hold tank 2, the container 10 of the simulation central compartment of injecting in order to bacterium, waste collection cylinder 13, constant temperature blender with magnetic force 5, thermostat water bath 1 and agitator 9 form, described agitator 9 is constant temperature blender with magnetic force, the container 10 of simulation central compartment is located in constant temperature blender with magnetic force 9, the container 10 of simulation central compartment is communicated with waste collection cylinder 13 by waste liquid conduit 11, also comprise the container 6 in order to the simulation absorption chamber of infusion of medicine, described fresh medium hold tank 2 is communicated with the container 6 of simulation absorption chamber by nutrient solution conduit 3, the container 6 of simulation absorption chamber is communicated with the container 10 of simulation central compartment by pastille nutrient solution conduit 7, described nutrient solution conduit 3, pastille nutrient solution conduit 7 and waste liquid conduit 11 are all to be made by silica gel material, on above-mentioned pipeline, be respectively equipped with peristaltic pump 4, peristaltic pump 8, peristaltic pump 12, described fresh medium hold tank 2 is located in thermostat water bath 1, and the container 6 of described simulation absorption chamber is located in constant temperature blender with magnetic force 5.The container 6 of the container 10 of above-mentioned simulation central compartment and simulation absorption chamber is all narrow-mouthed bottle or the Erlenmeyer flask that adopts glass material.The two ends of waste liquid conduit 11 are respectively equipped with filter membrane 15 and filter membrane 16, and one end of described pastille nutrient solution conduit 7 is provided with filter membrane filter membrane 14, and above-mentioned each filter membrane is the filter membrane of 0.22 μ m.
The feature of constant temperature blender with magnetic force: speed range (rpm) is: 0-1500; Module rotating speed deviation: 5%; Temperature-control range: 20-400 ℃; Temperature control deviation: ± 0.1 ℃.Temperature-control range is in organic synthesis scope, and temperature stability, at the magnetic stirring apparatus of ± 1 ℃, is called constant temperature blender with magnetic force.It is compared with common magnetic stirring apparatus, and constant temperature blender with magnetic force has highly sensitive, and controllability is strong, the feature that temperature-control range is wide.Be widely used in Advanced Organic Chemistry compound experiment.Chemical experiment stirring automatization being stepped and go a step further, is the ideal tools of supporting various analyzer agitator solution.Feature: this class agitator can be processed a plurality of heating simultaneously, stirs temperature control step process.Speed reaches workstation rank, and operation is also relatively very safe, convenient.
As shown in Figure 1 and Figure 2, the analogy method of the system of compartment model in analogue body, comprise the following steps: the sterilizing of A, system and installation: container 10, nutrient solution conduit 3, pastille nutrient solution conduit 7 and the waste liquid conduit 11 of the container 6 of fresh medium hold tank 2, simulation absorption chamber, simulation central compartment and fresh medium are put into respectively to 121 ℃ of above high-pressure steam sterilizing pans, sterilizing 20 minutes; Then in sterilisable chamber, above-mentioned each parts are connected, finally the system of compartment model in mounted analogue body is put in stink cupboard and prepares to move; B, adjust flow velocity: open successively peristaltic pump 4, peristaltic pump 8, peristaltic pump 12, adjust flow velocity, the rotating speed of each peristaltic pump is identical, to simulate the constant of liquid volume in the container 6 of absorption chamber and the container 10 of simulation central compartment in keeping system; C, Temperature Setting: open thermostat water bath and two constant temperature blender with magnetic force, design temperature is 36.6 ℃; D, bacterium are injected: to the bacterium of simulating the certain turbidity of the interior injection of container 10 of central compartment; E, infusion of medicine: above-mentioned microbial culture, after the regular hour, to the medicine of simulating the interior injection doses of container 6 of absorption chamber, has now just created the interior compartment model of body of aids drug dynamic metabolism.
Embodiment 2: as shown in Figure 1 and Figure 2, the analogy method of the system of compartment model in analogue body, comprise the following steps: the sterilizing of A, system and installation: container 10, nutrient solution conduit 3, pastille nutrient solution conduit 7 and the waste liquid conduit 11 of the container 6 of fresh medium hold tank 2, simulation absorption chamber, simulation central compartment and fresh medium are put into respectively to 121 ℃ of above high-pressure steam sterilizing pans, sterilizing 20 minutes; Then in sterilisable chamber, above-mentioned each parts are connected, finally the system of compartment model in mounted analogue body is put in stink cupboard and prepares to move; B, adjust flow velocity: open successively peristaltic pump 4, peristaltic pump 8, peristaltic pump 12, adjust flow velocity, the rotating speed of each peristaltic pump is identical, to simulate the constant of liquid volume in the container 6 of absorption chamber and the container 10 of simulation central compartment in keeping system; C, Temperature Setting: open thermostat water bath and two constant temperature blender with magnetic force, design temperature is 37 ℃; D, bacterium are injected: to the bacterium of simulating the certain turbidity of the interior injection of container 10 of central compartment; E, infusion of medicine: above-mentioned microbial culture, after the regular hour, to the medicine of simulating the interior injection doses of container 6 of absorption chamber, has now just created the interior compartment model of body of aids drug dynamic metabolism.
Embodiment 3: as shown in Figure 1 and Figure 2, the analogy method of the system of compartment model in analogue body, comprise the following steps: the sterilizing of A, system and installation: container 10, nutrient solution conduit 3, pastille nutrient solution conduit 7 and the waste liquid conduit 11 of the container 6 of fresh medium hold tank 2, simulation absorption chamber, simulation central compartment and fresh medium are put into respectively to 121 ℃ of above high-pressure steam sterilizing pans, sterilizing 20 minutes; Then in sterilisable chamber, above-mentioned each parts are connected, finally the system of compartment model in mounted analogue body is put in stink cupboard and prepares to move; B, adjust flow velocity: open successively peristaltic pump 4, peristaltic pump 8, peristaltic pump 12, adjust flow velocity, the rotating speed of each peristaltic pump is identical, to simulate the constant of liquid volume in the container 6 of absorption chamber and the container 10 of simulation central compartment in keeping system; C, Temperature Setting: open thermostat water bath and two constant temperature blender with magnetic force, design temperature is 37.4 ℃; D, bacterium are injected: to the bacterium of simulating the certain turbidity of the interior injection of container 10 of central compartment; E, infusion of medicine: above-mentioned microbial culture, after the regular hour, to the medicine of simulating the interior injection doses of container 6 of absorption chamber, has now just created the interior compartment model of body of aids drug dynamic metabolism.
The principle of work of the various embodiments described above: native system is the operating mode of a continuous flow, with certain speed, constantly add fresh medium, with same speed, constantly discharge old nutrient solution again simultaneously, to guarantee the demand of bacterium to nutritive substance, and the harmful meta-bolites of exclusive segment, make microorganism keep the high-speed rapid growth of long period, regulate the speed of three peristaltic pump transhipment nutrient solutions, to simulate medicine transport velocity in vivo, make it to there is identical absorption halftime, eliminate the transformation period, area under the drug-time curve (AUC), clearance rate etc., in addition, by the bacterium in the container of bacterial count method and high efficiency liquid phase chromatographic analysis method monitoring simulation central compartment and the content of medicine, set up the killing curve of dynamicmodel Chinese traditional medicine, in order to evaluate the antibacterial effect of this medicine.
As mentioned above, just can realize preferably the present invention, above-described embodiment is only preferred embodiment of the present invention, is not used for limiting practical range of the present invention; Be that all equalizations of doing according to content of the present invention change and modify, all by the claims in the present invention scope required for protection, contained.
Claims (9)
1. the system of compartment model in an analogue body, include fresh medium hold tank, the container of the simulation central compartment of injecting in order to bacterium, waste collection cylinder and agitator, the container of simulation central compartment is communicated with waste collection cylinder by waste liquid conduit, it is characterized in that: also comprise the container in order to the simulation absorption chamber of infusion of medicine, described fresh medium hold tank is communicated with the container of simulation absorption chamber by nutrient solution conduit, the container of simulation absorption chamber is communicated with the container of simulation central compartment by pastille nutrient solution conduit, described nutrient solution conduit, on pastille nutrient solution conduit and waste liquid conduit, be respectively equipped with peristaltic pump, described agitator is constant temperature blender with magnetic force, in order to the liquid in containers of simulation central compartment is stirred and temperature control.
2. the system of compartment model in analogue body according to claim 1, it is characterized in that: also comprise constant temperature blender with magnetic force and thermostat water bath, described fresh medium hold tank is located in thermostat water bath, and the container of described simulation absorption chamber is located in constant temperature blender with magnetic force.
3. the system of compartment model in analogue body according to claim 1 and 2, is characterized in that: the one or both ends of described waste liquid conduit are provided with filter membrane.
4. the system of compartment model in analogue body according to claim 3, is characterized in that: one end of described pastille nutrient solution conduit is provided with filter membrane.
5. the system of compartment model in analogue body according to claim 3, is characterized in that: described nutrient solution conduit, pastille nutrient solution conduit and waste liquid conduit are all to be made by silica gel material.
6. the system of compartment model in analogue body according to claim 3, is characterized in that: the container of the container of described simulation central compartment and simulation absorption chamber is all narrow-mouthed bottle or the Erlenmeyer flask that adopts glass material.
7. according to the analogy method of the system of compartment model in analogue body described in claim 1～6 any one, it is characterized in that, comprise the following steps: the sterilizing of A, system and installation: container, nutrient solution conduit, pastille nutrient solution conduit and the waste liquid conduit of the container of fresh medium hold tank, simulation absorption chamber, simulation central compartment and fresh medium are put into respectively to 121 ℃ of above high-pressure steam sterilizing pans, sterilizing 20 minutes; Then in sterilisable chamber, above-mentioned each parts are connected, finally the system of compartment model in mounted analogue body is put in stink cupboard and prepares to move; B, adjustment flow velocity: open each peristaltic pump, adjust flow velocity; C, Temperature Setting: open thermostat water bath and two constant temperature blender with magnetic force, design temperature is 36.6～37.4 ℃; D, bacterium are injected: to simulating the bacterium of injecting certain turbidity in the container of central compartment; E, infusion of medicine: above-mentioned microbial culture is after the regular hour, to the medicine that injects doses in the container of simulation absorption chamber, has now just created the interior compartment model of body of aids drug dynamic metabolism.
8. the analogy method of the system of compartment model in analogue body according to claim 7, it is characterized in that: in described step B, the rotating speed of each peristaltic pump is identical, to simulate the constant of the container of absorption chamber and the liquid in containers volume of simulation central compartment in keeping system.
9. the analogy method of the system of compartment model in analogue body according to claim 7, is characterized in that: in described step C, the temperature setting is 37 ℃.
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Application publication date: 20140219 |