CN112500997B - Auxiliary device for online culture fluid supplementation of antibacterial drug in-vitro PK/PD model and use method thereof - Google Patents
Auxiliary device for online culture fluid supplementation of antibacterial drug in-vitro PK/PD model and use method thereof Download PDFInfo
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- C12M—APPARATUS FOR ENZYMOLOGY OR MICROBIOLOGY; APPARATUS FOR CULTURING MICROORGANISMS FOR PRODUCING BIOMASS, FOR GROWING CELLS OR FOR OBTAINING FERMENTATION OR METABOLIC PRODUCTS, i.e. BIOREACTORS OR FERMENTERS
- C12M23/00—Constructional details, e.g. recesses, hinges
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- C12M23/00—Constructional details, e.g. recesses, hinges
- C12M23/38—Caps; Covers; Plugs; Pouring means
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- C12M29/00—Means for introduction, extraction or recirculation of materials, e.g. pumps
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- C12M29/00—Means for introduction, extraction or recirculation of materials, e.g. pumps
- C12M29/06—Nozzles; Sprayers; Spargers; Diffusers
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- C12M33/00—Means for introduction, transport, positioning, extraction, harvesting, peeling or sampling of biological material in or from the apparatus
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Abstract
The invention provides an auxiliary device for online culture fluid supplementation of an antibacterial drug in-vitro PK/PD model, and belongs to the technical field of antibacterial drug in-vitro efficacy research. The auxiliary device comprises a donor bottle cap for capping the donor bottle in the PK/PD model and a receptor bottle cap for capping the receptor bottle in the PK/PD model; the donor bottle cap is hermetically penetrated with a donor bottle gas inlet pipeline and a donor bottle liquid outlet pipeline, one ends of the gas inlet pipeline and the donor bottle liquid outlet pipeline, which extend out of the donor bottle, are respectively provided with a first luer connector and a second luer connector, and the first luer connector is provided with a first filter; the receptor bottle cap is hermetically penetrated with a receptor bottle liquid inlet pipeline, a receptor bottle gas outlet pipeline and a receptor bottle liquid outlet pipeline, one ends of the receptor bottle liquid inlet pipeline and the receptor bottle gas outlet pipeline, which extend out of the receptor bottle, are respectively provided with a third luer connector and a fourth luer connector, and the fourth luer connector is provided with a second filter. The auxiliary device for on-line culture fluid supplementation of the antibacterial agent in-vitro PK/PD model provided by the invention can realize on-line culture fluid supplementation for a fresh culture fluid storage container of the in-vitro PK/PD model.
Description
Technical Field
The invention relates to the technical field of in-vitro drug effect research of antibacterial drugs, in particular to an auxiliary device for online culture fluid supplementation of an in-vitro PK/PD model of an antibacterial drug and a use method thereof.
Background
The in vitro PK/PD technology of antibacterial medicine is a research technology integrating pharmacokinetic factors and antibacterial activity of medicine, and is characterized by that it is an in vitro device which simulates the pharmacokinetic process of medicine in human body and observes the killing action of antibacterial medicine on bacteria in the course. The technology can be used for carrying out PK/PD research of antibacterial drugs, and further provides reference for preparing clinical schemes of antibacterial new drugs.
The technology is adopted internationally at present, and the technology needs to be completed based on a set of special equipment. The hardware architecture of the general in vitro PK/PD model includes: the fresh culture medium container, the central chamber, the waste liquid storage container, the peristaltic pump, the stirrer and the like, wherein the fresh culture medium container, the central chamber and the waste liquid storage container are connected through a silica gel tube to form a liquid path, the peristaltic pump is used as a liquid path to drive the fresh culture liquid to be pumped into the central chamber from the storage container, and the volume of the liquid in the central chamber needs to be kept stable, so that equal amount of liquid can be pumped out of the central chamber into the waste liquid storage container synchronously. In the process, the drug introduced into the central chamber can form exponential decay, the pharmacokinetic process of the drug in the body can be simulated through the adjustment of the liquid flow rate, and meanwhile, if bacteria are connected into the central chamber, the antibacterial effect of the drug on the bacteria in the dynamic change of the concentration can be examined.
In vitro PK/PD models require a larger amount of fresh medium during the run, especially when the dosing period to be investigated is longer or the dosing frequency is higher, a larger amount of culture medium is consumed. Second, when multiple models are run simultaneously, it is often an option to connect multiple models to the same fresh medium storage vessel for simplicity and increased controllability. Therefore, the volume of the fresh medium storage container is greatly required in the in vitro PK/PD model technology. Often researchers choose to purchase high temperature resistant bulk plastic pails from the market and configure special bottle caps to meet this requirement. However, large volume storage vessels require the addition of large volumes of culture broth at once and autoclaving during use, the broth requiring a pre-heating treatment before being pumped into the central chamber, and excessive volumes and weights can cause significant inconvenience to these treatments or procedures.
Disclosure of Invention
In view of the above, the present invention aims to provide an auxiliary device for on-line replenishment of culture fluid for an in-vitro PK/PD model of an antibacterial agent and a method for using the same, so as to solve the problem that in the prior art, a large amount of culture fluid needs to be added at one time and autoclaved in use, the culture fluid needs to be preheated before being pumped into a central chamber, and the excessive volume and weight cause great inconvenience to the processes or operations.
In order to achieve the above purpose, the present invention provides the following technical solutions:
an auxiliary device for online culture medium replenishment of an antibacterial drug in-vitro PK/PD model comprises a donor bottle cap for covering a donor bottle in the PK/PD model and a receptor bottle cap for covering a receptor bottle in the PK/PD model;
the donor bottle cap is hermetically penetrated with a donor bottle gas inlet pipeline and a donor bottle liquid outlet pipeline, a first luer connector and a second luer connector are respectively arranged at one end of the gas inlet pipeline and the donor bottle liquid outlet pipeline, which extends out of the donor bottle, and a first filter is arranged on the first luer connector;
the receptor bottle cap is hermetically penetrated with a receptor bottle liquid inlet pipeline, a receptor bottle gas outlet pipeline and a receptor bottle liquid outlet pipeline, one ends of the receptor bottle liquid inlet pipeline and the receptor bottle gas outlet pipeline, which extend out of the receptor bottle, are respectively provided with a third luer connector and a fourth luer connector, and the fourth luer connector is provided with a second filter.
Preferably, the donor bottle cap and the acceptor bottle cap are integrally formed.
Preferably, the first filter and the second filter are 0.22 micron filters.
Preferably, the donor bottle gas introduction pipe, the donor bottle liquid discharge pipe, the acceptor bottle liquid introduction pipe, the acceptor bottle gas discharge pipe, and the acceptor bottle liquid discharge pipe are made of silica gel or rubber.
The invention also provides a use method of the auxiliary device for on-line culture fluid supplementation of the antibacterial drug in-vitro PK/PD model, which comprises the following steps:
s1, covering the donor bottle cap on a donor bottle with a culture solution prepared inside, connecting the first luer connector with the second luer connector, and then carrying out integral disinfection treatment;
s2, after the third luer connector and the fourth luer connector are plugged by a first luer plug and a second luer plug respectively, the bottle cap of the receptor bottle is disinfected, the receptor bottle after the disinfection is covered on the receptor bottle after the disinfection treatment is finished, and the liquid leading-out pipeline is connected to a central chamber in the PK/PD model;
s3, after the first luer plug and the second luer plug are detached respectively, the second luer connector is connected with the third luer connector, the first filter and the second filter are connected at the first luer connector and the fourth luer connector respectively, and the first filter is connected with a syringe;
s4, rapidly injecting air into a donor bottle in the PK/PD model by using the injector.
Compared with the prior art, the invention has the following beneficial effects:
the auxiliary device for the antibacterial external PK/PD model for the online culture fluid supplementation of the antibacterial external PK/PD model and the use method thereof can realize the online culture fluid supplementation purpose for a fresh culture fluid storage container of the external PK/PD model, and simultaneously, the preparation of the culture fluid by bottle separation is greatly convenient for the preparation, disinfection, preheating and other treatment processes of the culture fluid. In addition, the convenient butt joint measure and the filtration measure can achieve good sterile control.
Drawings
FIG. 1 is a schematic structural diagram of an auxiliary device for on-line culture fluid replenishment of an antibacterial agent in-vitro PK/PD model;
FIG. 2 is a schematic diagram showing a standby state of an auxiliary device for on-line culture fluid replenishment of an antibacterial agent in-vitro PK/PD model;
FIG. 3 is a schematic diagram showing the starting state of an auxiliary device for on-line culture fluid replenishment of an antibacterial agent in-vitro PK/PD model;
FIG. 4 is a schematic illustration of the fluid supplementation of the PK/PD model in vitro for intravenous administration;
FIG. 5 is a schematic illustration of fluid supplementation of an in vitro PK/PD model for intravenous infusion administration;
in the drawings, 1, a donor bottle cap, 2, a donor bottle gas introduction line, 3, a donor bottle liquid introduction line, 4, a first luer fitting, 5, a second luer fitting, 6, a third luer fitting, 7, a fourth luer fitting, 8, a recipient bottle gas introduction line, 9, a recipient bottle liquid introduction line, 10, a recipient bottle liquid introduction line, 11, a donor bottle, 12, a recipient bottle, 13, a luer fitting, 14, a second luer plug, 15, a syringe, 16, a first filter, 17, a donor bottle, 18, a peristaltic pump, 19, a central chamber, 20, a stirrer, 21, a stirrer, 22, a waste liquid bottle, 23, a sampling hole passage, 24, a recipient bottle cap, 25, a waste liquid introduction line, 26, a first luer plug, and 27.
Detailed Description
For the purpose of making the objects, technical solutions and advantages of the embodiments of the present invention more apparent, the technical solutions of the embodiments of the present invention will be clearly and completely described below with reference to the accompanying drawings in the embodiments of the present invention, and it is apparent that the described embodiments are some embodiments of the present invention, but not all embodiments. All other embodiments, based on the embodiments of the invention, which a person of ordinary skill in the art would achieve without inventive faculty, are within the scope of the invention. Thus, the following detailed description of the embodiments of the invention, as presented in the figures, is not intended to limit the scope of the invention, as claimed, but is merely representative of selected embodiments of the invention.
As shown in fig. 1, the present invention provides an auxiliary device for on-line replenishment of culture medium for an in-vitro PK/PD model of an antibacterial agent, comprising a donor bottle cap 1 for capping a donor bottle 11 in the PK/PD model and a recipient bottle cap 24 for capping a recipient bottle 12 in the PK/PD model;
a donor bottle gas inlet pipeline 2 and a donor bottle liquid outlet pipeline 3 are hermetically penetrated through the donor bottle cap 1, a first luer connector 4 and a second luer connector 5 are respectively arranged at one end of the gas inlet pipeline 2 and the donor bottle liquid outlet pipeline 3 extending out of the donor bottle 11, and a first filter 16 is arranged on the first luer connector 4;
the receptor bottle cap 24 is provided with a receptor bottle liquid inlet pipeline 10, a receptor bottle gas outlet pipeline 8 and a receptor bottle liquid outlet pipeline 9 in a sealing and penetrating manner, one ends of the receptor bottle liquid inlet pipeline 10 and the receptor bottle gas outlet pipeline 8, which extend out of the receptor bottle 12, are respectively provided with a third luer connector 6 and a fourth luer connector 7, and the fourth luer connector 7 is provided with a second filter 27.
The above technical solution of the present invention is described as follows, as shown in fig. 1 to 3:
1. the donor bottle cap 1 is preferably provided with round holes corresponding to the donor bottle gas inlet pipeline 2 and the donor bottle liquid outlet pipeline 3, the diameters of the round holes can penetrate through the donor bottle gas inlet pipeline 2 and the donor bottle liquid outlet pipeline 3, and sufficient tightness between the donor bottle gas inlet pipeline 2 and the donor bottle liquid outlet pipeline 3 and the hole wall is ensured to ensure the tightness of the top end of the donor bottle cap 1, so that the diameters of the holes are smaller than the diameters of the donor bottle gas inlet pipeline 2 and the donor bottle liquid outlet pipeline 3, the diameter difference is ensured to be more than 0.1mm for ensuring the tightness, the donor bottle cap and the acceptor bottle cap can be manufactured through an integral molding process, the pipeline is ensured to penetrate through the bottle cap in a sealing way, and the pipeline is preferably provided with round holes in a sealing way, and the pipeline is ensured to be convenient to replace in the sealing way.
2. The donor bottle gas inlet pipeline 2 and the donor bottle liquid outlet pipeline 3 have proper lengths above the donor bottle cap 1 so as to ensure convenient operation;
3. the donor bottle gas inlet pipe 2 and the donor bottle liquid outlet pipe 3 can be used as donor bottle liquid outlet pipes, in the invention, the reference numeral 3 in fig. 1 is taken as a liquid outlet pipe for illustration, and the length of the donor bottle liquid outlet pipe 3 below the bottle cap is preferably that the bottom of the donor bottle 11 can be contacted;
4. the donor bottle gas introduction line 2 and the donor bottle liquid discharge line 3 can be used as the lines for introducing the donor bottle gas, in the present invention, the reference numeral 2 in fig. 1 is taken as the donor bottle gas introduction line 2, and the length of the donor bottle gas introduction line 2 below the donor bottle cap 1 can be any length, but preferably is 2-10cm, so that the lower end of the line does not touch the liquid surface in the donor bottle 11;
5. preferably, a round hole corresponding to the receptor bottle liquid inlet pipe 10, the receptor bottle gas outlet pipe 8 and the receptor bottle liquid outlet pipe 9 is formed at the top of the receptor bottle cap 24, the diameter of the round hole should be capable of penetrating the receptor bottle liquid inlet pipe 10, the receptor bottle gas outlet pipe 8 and the receptor bottle liquid outlet pipe 9, and sufficient tightness between the receptor bottle liquid inlet pipe 10, the receptor bottle gas outlet pipe 8 and the receptor bottle liquid outlet pipe 9 and the hole wall should be ensured to ensure tightness of the top end of the receptor bottle cap 24, so the diameter of the round hole should be smaller than the diameters of the receptor bottle liquid inlet pipe 10, the receptor bottle gas outlet pipe 8 and the receptor bottle liquid outlet pipe 9, and the diameter difference should be ensured to be more than 0.1mm in order to ensure tightness;
6. as shown in fig. 1, at least 3 sections of the pipeline on the bottle cap 24 of the receptor bottle are needed, wherein one pipeline is responsible for introducing liquid, the invention is illustrated by taking reference numeral 10 in fig. 1 as a pipeline for introducing the liquid into the receptor bottle, one pipeline is responsible for introducing the gas, the invention is illustrated by taking reference numeral 8 in fig. 1 as a pipeline for introducing the gas into the receptor bottle, one pipeline is responsible for introducing the liquid, the invention is illustrated by taking reference numeral 9 in fig. 1 as a pipeline for introducing the liquid into the receptor bottle, and the invention can be selected according to actual needs, for example: the pipe 9 for guiding the liquid from the receptor bottle shown by reference numeral 9 in fig. 1 may be used as a pipe 10 for guiding the liquid from the receptor bottle, and will not be described here;
7. the length of the above-mentioned recipient bottle gas outlet pipe 8 for gas outlet below the recipient bottle cap 24 is preferably such that the lower end of the pipe does not touch the liquid surface in the recipient bottle 12, the above-mentioned recipient bottle liquid inlet pipe 10 for liquid inlet should touch the bottom as much as possible to form an effective liquid surface difference between the donor bottle 11 and the recipient bottle 12 as much as possible, and the above-mentioned recipient bottle liquid outlet pipe 9 for liquid outlet should touch the bottom as much as possible to discharge the maximum volume of liquid as much as possible.
8. The sex of the luer connector and the matching of the pipelines are arbitrary, and the sex of the luer connector is not distinguished. As shown in fig. 2, in the non-activated state of the present invention, the third luer fitting 6 and the fourth luer fitting 7 should be closed with the first luer plug 26 and the second luer plug 14, respectively, and the first luer fitting 4 and the second luer fitting 5 are mated to form a luer fitting mating body 13 for closing; as shown in fig. 3, the present invention is used by releasing the first luer fitting 4 and the fourth luer fitting 5, and then mating the second luer fitting 5 with the third luer fitting 6 with the first luer plug 26 removed to complete the connection.
In the present invention, the manufacturing method of the donor bottle cap and the acceptor bottle cap is not limited, and there is no special requirement on the materials thereof, preferably, the manufacturing method of the donor bottle cap and the acceptor bottle cap by adopting integrated molding is adopted, the materials are preferably plastic materials, and other materials in the art may be, for example: rubber material.
In the present invention, the first filter 16 and the second filter 27 are 0.22 micron filters to constitute an effective bacteria-shielding environment.
In the present invention, the donor bottle gas introduction line 2, the donor bottle liquid discharge line 3, the acceptor bottle liquid introduction line 10, the acceptor bottle gas discharge line 8, and the acceptor bottle liquid discharge line 9 are made of a silicone rubber material or a rubber material.
The invention also provides a use method of the auxiliary device for on-line culture fluid supplementation of the antibacterial drug in-vitro PK/PD model, which comprises the following steps:
s1, covering the donor bottle cap 1 on a donor bottle 11 with a culture solution prepared inside, connecting the first luer connector 4 with the second luer connector 5, and then carrying out integral disinfection treatment;
s2, after plugging the third luer fitting 6 and the fourth luer fitting 7 with the first luer plug 26 and the second luer plug 14, respectively, sterilizing the receptor bottle cap 24, capping the sterilized receptor bottle 12, and connecting the liquid outlet line 9 to the central chamber 19 in the PK/PD model;
s3, after the first luer plug 26 and the second luer plug 14 are removed, the second luer connector 5 is connected with the third luer connector 6, the first filter 16 and the second filter 27 are connected at the first luer connector 4 and the fourth luer connector 7 respectively, and the first filter 16 is connected with a syringe 15;
s4 rapid air injection into the donor flask in the PK/PD model was performed using the syringe 15.
In one embodiment of the invention, the in vitro PK/PD model fluid supplementation for intravenous administration is shown:
as shown in fig. 4, when the fresh culture solution in the recipient bottle 12 is nearly consumed, after the connection of the above-mentioned auxiliary device for online replenishment of culture solution for external PK/PD model of antibacterial agent is completed, after the air is pumped by the large-volume syringe 15, air is rapidly injected into the donor bottle 11 to make the culture solution in the donor bottle 11 flow into the recipient bottle 12, then the donor bottle and the recipient bottle form a connected state, under the action of gravity and peristaltic pump 18, the culture solution flows into the central chamber 19 through the recipient bottle liquid outlet pipeline 9 in sealed connection with the central chamber 19 in PK/PD model, the central chamber 19 is arranged on the stirrer 20, and the stirrer 21 is contained in the central chamber 19, the stirrer 20 drives the stirrer 21 to mix the culture solution in the central chamber 19, the bottle cap of the central chamber 19 is further provided with a sampling hole channel 23 and a waste liquid outlet pipeline 25, the antibacterial agent is added into the central chamber 19 through the sampling hole channel 23, one end of the waste liquid outlet pipeline 25 is connected with the central chamber 19, and the other end of the waste liquid outlet pipeline 25 is connected with the waste liquid 22, and the waste liquid produced in the central chamber 19 is taken into the waste liquid bottle 22 through the waste liquid outlet pipeline 25.
In one embodiment of the invention, a protocol for intravenous infusion administration of liquid supplementation of an in vitro PK/PD model is shown:
as shown in fig. 5, when the fresh culture solution in the recipient bottle 12 is nearly consumed, after the above-mentioned auxiliary device for supplementing the culture solution on-line for the external PK/PD model of the antibacterial drug is connected, the air is rapidly injected into the donor bottle 11 after the large-volume syringe 15 is filled with air, the culture solution in the donor bottle 11 flows into the recipient bottle 12, then the donor bottle and the recipient bottle are in a connected state, under the action of gravity and the peristaltic pump 18, the culture solution flows into the central chamber 19 through the recipient bottle liquid outlet pipeline 9 which is in sealed connection with the central chamber 19 in the PK/PD model, the central chamber 19 is arranged on the stirrer 20, the stirrer 21 is contained in the central chamber 19, the stirrer 20 drives the stirrer 21 to uniformly mix the culture solution in the central chamber 19, the antibacterial drug is injected into the introduction tube 17 which is connected with the recipient bottle liquid outlet pipeline 9 through the pipeline, the gas pipeline with a filter is also in sealed connection with the bottle cap of the introduction tube 17, the antibacterial drug is injected into the central chamber 19 through the syringe and the peristaltic pump is in the peristaltic pump 18 under the action of the central chamber 19. The bottle cap of the central chamber 19 is also provided with a sampling hole channel 23 and a waste liquid guiding pipeline 25, one end of the waste liquid guiding pipeline 25 is communicated with the central chamber 19, the other end of the waste liquid guiding pipeline 25 is connected with a waste liquid bottle 22, and waste liquid generated in the central chamber 19 is brought into the waste liquid bottle 22 through the waste liquid guiding pipeline 25.
In the above two embodiments, the lower end of the waste liquid outlet tube 25 is preferably close to the bottom end of the central chamber 19, and the waste liquid outlet tube 25 and the sampling hole channel 23 are both made of silica gel or rubber.
It should be further noted that the donor bottle, recipient bottle, donor bottle cap and recipient bottle cap described in the present invention may be common reagent bottles and reagent caps or may be assembled with corresponding container caps and tubing by using nonstandard or specialty containers to achieve the same purpose.
The above description is only of the preferred embodiments of the present invention and is not intended to limit the present invention, and various modifications and variations may be made to the present invention by those skilled in the art. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (4)
1. A method for on-line supplementing culture solution for antibacterial in-vitro PK/PD model by using auxiliary device is characterized by that,
the auxiliary device includes: the device comprises a donor bottle cap for covering a donor bottle in the PK/PD model and an acceptor bottle cap for covering an acceptor bottle in the PK/PD model, wherein a donor bottle gas inlet pipeline and a donor bottle liquid outlet pipeline are hermetically penetrated on the donor bottle cap, a first luer connector and a second luer connector are respectively arranged at one ends of the gas inlet pipeline and the donor bottle liquid outlet pipeline, which extend out of the donor bottle, a first filter is arranged on the first luer connector, an acceptor bottle liquid inlet pipeline, an acceptor bottle gas outlet pipeline and an acceptor bottle liquid outlet pipeline are hermetically penetrated on the acceptor bottle cap, a third luer connector and a fourth luer connector are respectively arranged at one ends of the acceptor bottle liquid inlet pipeline and the acceptor bottle gas outlet pipeline, and a second filter is arranged on the fourth luer connector;
the method comprises the following steps:
1) The donor bottle cap is covered on the donor bottle with the culture solution prepared inside, and the first luer connector and the second luer connector are connected and then subjected to integral disinfection treatment;
2) Plugging the third luer connector and the fourth luer connector by a first luer plug and a second luer plug respectively, then sterilizing the bottle cap of the receptor bottle, covering the receptor bottle after sterilization, and connecting the liquid lead-out pipeline to a central chamber in the PK/PD model;
3) Removing the first luer plug and the second luer plug, connecting the second luer connector with the third luer connector, connecting the first filter and the second filter at the first luer connector and the fourth luer connector respectively, and connecting the first filter with a syringe;
4) When fresh culture solution in the receptor bottle is nearly consumed, air is rapidly injected into the donor bottle by adopting the injector, so that the culture solution in the donor bottle flows into the receptor bottle, the donor bottle and the receptor bottle form a communicating state, the receptor bottle supplements the culture solution on line, and then the culture solution flows into a central chamber in the PK/PD model through a receptor bottle liquid outlet pipeline under the action of gravity and a peristaltic pump.
2. The method of claim 1, wherein the donor vial cap and the recipient vial cap are integrally formed.
3. The method of claim 1, wherein the first filter and the second filter are 0.22 micron filters.
4. The method of claim 1, wherein the donor bottle gas introduction line, the donor bottle liquid introduction line, the recipient bottle gas introduction line, and the recipient bottle liquid introduction line are of a silicone material or a rubber material.
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