Drug encapsulation production monitoring device and use method
By integrating monitoring components and impedance detection structures, the efficiency bottleneck of traditional drug encapsulation production monitoring devices in microfluidic chip scenarios has been solved, enabling continuous detection and timely diversion of drug component ratios, thus ensuring the quality and stability of drug products.
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- GUANGZHOU INSTITUTES OF BIOMEDICINE AND HEALTH CHINESE ACADEMY OF SCIENCES
- Filing Date
- 2026-01-28
- Publication Date
- 2026-05-08
AI Technical Summary
Traditional drug encapsulation production monitoring devices are difficult to adapt to the miniaturized and integrated production scenarios of microfluidic chips, resulting in low efficiency in monitoring and subsequent product control, easy accumulation of unqualified products and cross-contamination, and affecting product quality stability.
It adopts integrated monitoring components, including conveying components, mixing units and monitoring components. It monitors the proportion of drug components in real time through an impedance detection structure and switches the output pipeline according to the detection results to ensure that unqualified products are diverted in a timely manner, which is compatible with traditional large-scale production lines.
It enables continuous detection and timely diversion of drug component ratios, ensuring the quality and yield of drug products, reducing the risk of cross-contamination, and meeting the needs of microfluidic chip production.
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Figure CN121994875A_ABST
Abstract
Description
Technical Field
[0001] This application relates to the field of biomedical technology, and in particular to a drug encapsulation production monitoring device and its usage method. Background Technology
[0002] Nucleic acid nanomedicines have attracted much attention as a novel biotherapy approach. The efficiency of nucleic acid nanomedicine preparation and real-time quality monitoring are crucial for their successful transition from early development to clinical application. Drug encapsulation technology is one of the core processes in the biopharmaceutical field, and the component ratios of the encapsulated product directly determine the drug's activity, stability, and safety during administration.
[0003] Traditional drug encapsulation production relies on multi-unit systems, typically including multiple functional units such as material handling, proportion detection, and material diversion. The overall design of traditional monitoring devices is difficult to match the miniaturized and integrated production scenarios such as microfluidic chips. Traditional technologies have efficiency bottlenecks in the connection between monitoring and subsequent product control, which can easily lead to the accumulation of unqualified products due to control lag. At the same time, the complex material flow path also increases the risk of cross-contamination, thereby affecting the reliability of monitoring results and the quality stability of the final product. Summary of the Invention
[0004] To solve at least one of the above-mentioned technical problems, this application provides a drug packaging production monitoring device and a method of using it, and the technical solution adopted is as follows.
[0005] The drug encapsulation production monitoring device provided in this application includes:
[0006] A delivery assembly for independently delivering the components of a target drug; A mixing unit connected to the delivery assembly, the mixing unit being used to mix the components delivered by the delivery assembly into the target drug; A monitoring component is connected to the mixing unit and is used to detect the target drug. The monitoring component includes two independent output lines, which are used to output unqualified waste liquid and qualified samples, respectively. The monitoring component is used to switch the conduction state of the two output lines according to the detection results of the component ratio of the target drug.
[0007] In some embodiments of this application, the monitoring component has an input terminal, a first output terminal, a second output terminal, a third output terminal, and a detection structure. The input terminal is used to input a target drug, the first output terminal is used to output waste liquid, and the second output terminal is used to output a sample. The detection structure is used to detect the component ratio of the target drug. The third output terminal is connected to the inlet terminal of the detection structure, and the outlet terminal of the detection structure is connected to the outlet terminal of the first output terminal.
[0008] In some embodiments of this application, the third output terminal is disposed between the input port of the first output terminal and the input port of the second output terminal.
[0009] In some embodiments of this application, the detection structure is a microfluidic chip, and the microfluidic chip includes an impedance detection structure.
[0010] In some embodiments of this application, the conveying assembly has at least two sets of fluid pumps, each of which is connected to the mixing unit and is used to convey raw materials; the mixing unit has a combined output terminal, which is connected to the monitoring assembly.
[0011] In some embodiments of this application, a flow meter is provided between each of the fluid pumps and the mixing unit.
[0012] In some embodiments of this application, the delivery assembly includes two sets of the fluid pumps.
[0013] This application also provides a method for using the drug encapsulation production monitoring device as described above, including the following steps: Input the raw materials according to the preset component ratio; Connect the monitoring component to the output pipeline between it and the waste liquid that fails to meet the standards. The monitoring component performs random checks on the target drug at preset intervals. When the deviation of the detected component ratio exceeds the preset error range, the output pipeline between the monitoring component and the qualified sample is closed, and the output pipeline between the monitoring component and the unqualified waste liquid is opened. Correct the input component ratio and repeat the above steps until the deviation of the detected component ratio is within the preset error range. Then, close the output pipeline between the monitoring component and the unqualified waste liquid, and open the pipeline between the monitoring component and the qualified sample.
[0014] In some embodiments of this application, the error range is the error between the actual proportion of each component and the target proportion, and the preset error range is -5% to 5%.
[0015] In some embodiments of this application, the preset interval time is 500ms.
[0016] This application has at least the following beneficial effects: The drug encapsulation production monitoring device provided by this application adopts an integrated monitoring component. The monitoring component can perform multiple repeated tests and achieve continuous detection of the component ratio of the target drug. It can switch the conduction state of the two output pipelines according to the test results, continuously monitor, and can be adapted to traditional large-scale drug encapsulation production lines to ensure timely diversion of unqualified products and effectively guarantee the quality and yield of the final product.
[0017] Additional aspects and advantages of this application will be set forth in part in the description which follows, and in part will be obvious from the description, or may be learned by practice of this application. Attached Figure Description
[0018] The present application will be further illustrated below with reference to the accompanying drawings and embodiments. It should be noted that the embodiments illustrated in the following drawings are exemplary and are only used to explain the present application, and should not be construed as limiting the present application.
[0019] Figure 1 This is a schematic diagram of a drug encapsulation production monitoring device in one embodiment of this application; Figure 2 This is a current diagram under different preset component ratios in a certain embodiment of this application; Figure 3 This is a polymer molecular weight distribution index diagram in one embodiment of this application; Figure 4 This is a cryo-electron microscopy image of a sample from one embodiment of this application; Figure 5 This is a comparison diagram of the lattice radii of nucleic acid nanomedicines produced and monitored using the device of this application in a certain embodiment of the present application; Figure 6 This is a comparison chart showing the copy frequency of nucleic acid nanomedicines produced and monitored using the device described in this application in a certain embodiment of the present application. Figure 7 This is a comparison chart of the encapsulation efficiency and empty load rate of nucleic acid nanomedicines produced and monitored using the device of this application in a certain embodiment of the present application. Figure 8 This is a comparison chart of the encapsulation rates of nucleic acid nanomedicines produced and monitored using the device described in this application, based on reagent kit detection, in a certain embodiment of this application. Figure 9 This is a comparison chart showing the in vivo infectious efficiency of nucleic acid nanomedicines produced and monitored using the device of this application in a certain embodiment of the present application. Figure 10 This is a comparison chart of the relative fluorescence intensity values of nucleic acid nanomedicines produced and monitored using the device of this application in a certain embodiment of this application in mice.
[0020] Reference numeral: Base 100; Monitoring component 200; first output terminal 210; first valve 211; second output terminal 220; second valve 221; third output terminal 230; third valve 231; detection structure 240; Waste liquid collection unit 300; Sample collection unit 400; Conveying assembly 500; first fluid pump 511; second fluid pump 512; first flow meter 521; second flow meter 522; Hybrid Unit 600. Detailed Implementation
[0021] The following is combined Figures 1 to 10 The embodiments of this application are described in detail below, wherein the same or similar reference numerals denote the same or similar elements or elements having the same or similar functions throughout. The embodiments described below with reference to the accompanying drawings are exemplary and are only used to explain this application, and should not be construed as limiting this application.
[0022] In the description of this application, it should be understood that the terms "center", "middle", "longitudinal", "transverse", "length", "width", "thickness", "upper", "lower", "front", "rear", "left", "right", "vertical", "horizontal", "top", "bottom", "inner", "outer", "axial", "radial", "circumferential", etc., indicating the orientation or positional relationship based on the orientation or positional relationship shown in the accompanying drawings, are only for the convenience of describing this application and simplifying the description, and do not indicate or imply that the device or element referred to must have a specific orientation, or be constructed and operated in a specific orientation, and therefore should not be construed as a limitation of this application.
[0023] In the description of this application, "several" means one or more, "multiple" means two or more, "greater than," "less than," and "exceeding" are understood to exclude the stated number, while "above," "below," and "within" are understood to include the stated number. The use of "first" and "second" in the description is merely for distinguishing technical features and should not be construed as indicating or implying relative importance, or implicitly indicating the number of indicated technical features, or implicitly indicating the order of the indicated technical features.
[0024] In the description of this application, unless otherwise expressly specified and limited, the terms "set up," "install," "connect," and "link" should be interpreted broadly. For example, they can refer to a fixed connection, a detachable connection, or an integral connection; they can refer to a mechanical connection or an electrical connection; they can refer to a direct connection or an indirect connection through an intermediate medium; and they can refer to the internal connection of two components. Those skilled in the art can understand the specific meaning of the above terms in this application based on the specific circumstances.
[0025] In the description of this application, the use of terms such as "one embodiment," "some embodiments," "an example," "some instances," "some embodiments," "illustrative embodiment," "example," "specific example," and "some examples" indicates that the specific feature, structure, material, or characteristic described in connection with that embodiment or example is included in at least one embodiment or example of this application. In this specification, the illustrative expressions of the above terms do not necessarily refer to the same embodiment or example. Furthermore, the specific features, structures, materials, or characteristics described may be combined in any suitable manner in one or more embodiments or examples.
[0026] Taking the fabrication of nucleic acid nanomedicines using this application as an example, with nucleic acid nanomedicine as the target drug, the drug encapsulation production monitoring device and its usage method of this application are described. The drug encapsulation production monitoring device provided by this application includes a base 100, a waste liquid collection section 300, and a sample collection section 400. Switchable output pipelines are respectively provided between the monitoring component 200 and the waste liquid collection section 300 and the sample collection section 400. The monitoring component 200 is used to receive the target drug and detect the component ratio of the target drug; the monitoring component 200 is used to switch the conduction state of the two output pipelines according to the detection result of the component ratio of the target drug. The monitoring component 200, the waste liquid collection section 300, and the sample collection section 400 are all mounted on the base 100.
[0027] Combination Figure 1 As shown, the drug packaging production monitoring device provided in this application includes: Delivery assembly 500, which is used to independently deliver the components of the target drug; A mixing unit 600 is connected to the delivery assembly and is used to mix the components delivered by the delivery assembly 500 into the target drug. The monitoring component 200 is connected to the mixing unit and is used to detect the target drug. The monitoring component 200 includes two independent output lines, which are used to output unqualified waste liquid and qualified samples, respectively. The monitoring component 200 is used to switch the conduction state of the two output lines according to the detection results of the component ratio of the target drug.
[0028] The core of the nucleic acid nanomedicines monitored in this application is the encapsulation structure of "nucleic acid encapsulated by a carrier," such as nucleic acid encapsulated by liposomes or polymers. The carrier serves as the outer shell of the drug, corresponding to the organic phase raw material in subsequent production, while the nucleic acid is the core content possessing the therapeutic effect, corresponding to the aqueous phase raw material in subsequent production. The core monitoring target of this device is the ratio of carrier to nucleic acid components in the nucleic acid nanomedicine. This ratio directly determines the encapsulation efficiency, stability, and efficacy of the nucleic acid nanomedicine, and is a core quality indicator that needs to be precisely controlled during the production process of nucleic acid nanomedicines.
[0029] The sample collection section 400 has a bottle-like structure and is used to collect qualified drug samples. The waste liquid collection section 300 has a bottle-like structure and is used to collect unqualified drug samples. The waste liquid collection section 300 is also used to collect the tested drugs. The tops of the containers of the waste liquid collection section 300 and the sample collection section 400 are equipped with standard sealing interfaces, which can achieve leak-free connection with subsequent output pipelines and avoid external contamination, thus meeting the clean production requirements of nucleic acid nanomedicines.
[0030] The monitoring component 200 is an integrated core component. The monitoring component 200 operates on the principle of impedance detection to monitor component ratios. Due to the significant difference in dielectric constant between the organic phase of the carrier and the aqueous phase of the nucleic acid, when the target drug with different carrier-to-nucleic acid ratios flows through the detection module, it causes a regular change in the impedance value between the electrodes within the detection module. The detection module collects this impedance signal and converts it into component ratio data to monitor the core quality indicators of the nucleic acid nanomedicine. The difference from the preset component ratio is used as the standard for acceptance. If the error is greater than the preset component ratio range, it is considered unacceptable; if the error is less than or equal to the preset component ratio range, it is considered acceptable.
[0031] A first output pipe is provided between the monitoring component 200 and the waste liquid collection unit 300, and a second output pipe is provided between the monitoring component 200 and the sample collection unit 400. At most one of the first output pipe and the second output pipe is connected, and both the first output pipe and the second output pipe are closed when the device is not in use. When the drug encapsulation production monitoring device is started, untested drugs are transported from the first output pipeline to the waste liquid collection section 300. The monitoring component 200 receives the target drug and continuously detects the component ratio of the target drug. After passing the test, the first output pipeline is closed, and the second output pipeline is opened to transport the qualified drug to the sample collection section 400. During this process, the monitoring component 200 receives the target drug and detects the component ratio of the target drug. If a test fails, the second output pipeline is closed, and the first output pipeline is opened to transport the drug from the first output pipeline to the waste liquid collection section 300. During this process, the monitoring component 200 receives the target drug and detects the component ratio of the target drug. If the test passes, the first output pipeline is closed again, and the second output pipeline is opened to transport the qualified drug to the sample collection section 400. Drug samples tested by the monitoring component 200 are all transported to the waste liquid collection section 300 to prevent untested drugs from being transported to the sample collection section 400.
[0032] The drug encapsulation production monitoring device provided in this application adopts an integrated monitoring component 200. The monitoring component 200 can perform multiple repeated tests and continuously detect the component ratio of the target drug. It can switch the conduction state of the two output pipelines according to the test results, continuously monitor, and can be adapted to traditional large-scale drug encapsulation production lines to ensure that unqualified products are diverted in a timely manner, effectively guaranteeing the quality and yield of the final product.
[0033] Specifically, the monitoring component 200 has an input terminal, a first output terminal 210, a second output terminal 220, a third output terminal 230, and a detection structure 240. The input terminal is used to input the target drug. The first output terminal 210 is connected to the waste liquid collection section 300 and is used to output waste liquid. The second output terminal 220 is used to output the sample and is connected to the sample collection section 400. The detection structure 240 is used to detect the component ratio of the target drug. The third output terminal 230 is connected to the inlet end of the detection structure 240, and the outlet end of the detection structure 240 is connected to the outlet end of the first output terminal 210 or the waste liquid collection section 300.
[0034] It is understood that both the first output terminal 210 and the second output terminal 220 are equipped with valves, the detection structure 240 is used to detect the component ratio of the target drug, and the monitoring component 200 is used to switch the opening and closing states of the two valves according to the detection results of the component ratio of the target drug.
[0035] The monitoring component 200 has an input terminal for inputting the target drug; a first output terminal 210 is located on a first output pipeline, and a first valve 211 is located at the output position of the first output terminal 210; a second output terminal 220 is located on a second output pipeline, and a second valve 221 is located at the output position of the second output terminal 220. The drug encapsulation production monitoring device has a control system, which is electrically connected to the first valve 211 and the second valve 221, and electrically connected to the detection structure 240. The detection structure 240 monitors the component ratio of the carrier and nucleic acid using the principle of electrical impedance to directly transmit the monitoring signal to the control system; the control system, based on the signal determination result, instructs the two valves to switch between open and closed states. When the device is first used, the first valve 211 is open and the second valve 221 is closed; the detection structure 240 detects the target drug. If the component ratio is qualified and continuously within the preset component ratio range, the second valve 221 is opened and the first valve 211 is closed; if the component ratio exceeds the preset component ratio range, the second valve 221 is closed and the first valve 211 is opened.
[0036] The monitoring component 200 is equipped with multiple ports and corresponding parts to ensure a high pass rate for the output drug samples. At the same time, the device is easy to maintain, reducing the difficulty of device assembly and subsequent maintenance.
[0037] The third output terminal 230 is connected to the inlet terminal of the detection structure 240, and the outlet terminal of the detection structure 240 is connected to the outlet terminal of the first output terminal 210 or the waste liquid collection section 300. The third output terminal 230 is independent of the first output terminal 210 and the second output terminal 220. The third output terminal 230 is used by the detection structure 240 to sample the target drug input to the monitoring component 200. A third valve 231 is also provided at the output position of the third output terminal 230. After the nucleic acid nanoparticle to be detected flows into the built-in flow channel of the monitoring component 200 through the inlet terminal, a portion of the nucleic acid nanoparticle to be detected enters the detection structure 240 through the pipeline of the third output terminal 230 for component ratio monitoring, avoiding interference with the flow of the main material. After the detection is completed, the sampled material can be directly input into the waste liquid collection section 300 through the outlet pipeline of the detection structure 240 or merge into the outflow pipeline of the first output terminal 210, flowing into the waste liquid collection section 300 along with the unqualified products, thus achieving the discharge of the sampled material. The third valve 231 is connected to the control system. When using the device, the third valve 231 opens at preset intervals for multiple sampling checks. The second valve 221 and the first valve 211 selectively open and conduct based on the test results. Closing the third valve 231 facilitates disassembly and maintenance without contamination. The use of a third output terminal 230 for sampling checks reduces drug loss and improves the efficiency of outputting drug samples. The sampled material flows through an independent guide path, avoiding contact with qualified materials in the main path, thus preventing potential contamination during sampling and ensuring the smooth flow of materials in the main path.
[0038] Furthermore, the third output terminal 230 is located between the input port of the first output terminal 210 and the input port of the second output terminal 220. The detection structure 240 is located at the branch point between the first output terminal 210 and the second output terminal 220, ensuring that when unqualified waste liquid is detected, the output to the second output terminal 220 is stopped, and the output is sent to the first output terminal 210 instead, thus avoiding the problem of delayed missed detection caused by the separation of the detection position and the branch point.
[0039] Specifically, the detection structure 240 is a microfluidic chip, which includes an impedance detection structure. The impedance detection structure is embedded in the shunt junction region of the microfluidic chip. Its electrode structure is a three-electrode system, including a source, drain, and gate, symmetrically distributed on the inner wall of the microchannel. A conductive functional layer covers the electrode surface; the conductivity of this layer changes with the content of charged substances in the nucleic acid nanomedicine flowing through the channel, thereby achieving real-time detection of component proportions. By placing the microfluidic chip and impedance detection structure at the shunt junction, there is no need for additional sampling branches or extended channels, reducing the internal space occupied by the component, maintaining the compactness of the device, and matching miniaturized and integrated application scenarios such as microfluidic chip production lines. In the nucleic acid nanomedicine to be detected, different ratios of the carrier organic phase to the nucleic acid aqueous phase will lead to differences in the content of charged substances in the intermediates. Nucleic acid itself is a charged molecule, and the binding state between the carrier and nucleic acid also affects the ion release amount. When different proportions of the nucleic acid nanomedicine to be detected flow through the detection structure 240, the conductivity state of the conductive functional layer will change to varying degrees, thereby forming differentiated current signals, such as... Figure 2 As shown, the corresponding carrier and nucleic acid component ratio data are finally obtained through signal conversion, providing a precise basis for pipeline switching. The detection structure 240 includes an impedance detection structure, which can achieve continuous multiple sampling and monitoring without replacing the detection component. The detection process is achieved only through the interaction between voltage and charged substances in the intermediate, without the addition of chemical reagents or mechanical contact, thus not damaging the encapsulation structure and activity of the nucleic acid nanomedicine, and avoiding contamination of the intermediate by the detection component, which meets the clean production requirements of biopharmaceuticals.
[0040] Specifically, the delivery assembly 500 includes at least two sets of fluid pumps, each connected to the mixing unit 600, which are used to deliver raw materials. The mixing unit 600 has a combined output terminal connected to the monitoring assembly 200. The mixing unit 600 is a fluid mixing chip. The delivery assembly 500 is connected to the monitoring assembly and is used to input the target drug into the monitoring assembly 200. By setting up the delivery assembly 500, the stability of inputting the target drug into the monitoring assembly 200 is improved, thus enhancing the continuity of production.
[0041] Specifically, the delivery assembly 500 includes two sets of fluid pumps. A first fluid pump 511 delivers aqueous phase raw materials to the mixing unit 600, and a second fluid pump 512 delivers organic phase raw materials to the mixing unit 600. The fluid pumps can precisely control the delivery volume of the two raw materials. The mixing unit 600 mixes the received raw materials and outputs the target drug from the combined output end to the monitoring assembly 200. The fluid pumps allow for strict control of the ratio of aqueous to organic phase raw materials. After mixing, the raw materials are directly delivered to the monitoring assembly 200 without intermediate transfer links, shortening the flow path of intermediates, reducing the possibility of pipeline residue and cross-contamination, and avoiding activity loss of intermediates during transfer.
[0042] Specifically, each fluid pump is equipped with a flow meter between itself and the mixing unit 600. A first flow meter 521 is installed between the first fluid pump 511 and the mixing unit 600, and a second flow meter 522 is installed between the second fluid pump 512 and the mixing unit 600. The flow meters are connected to the control system. The flow rate is set to be less than 10 mL / min. The ratio of raw material flow rates is monitored by the two flow meters to ensure the accuracy of the aqueous and organic phase ratio. A preset flow rate ratio is set according to the preset component ratio. If either flow meter exceeds its preset flow rate range, or if the raw material flow rate ratio monitored by both flow meters exceeds the preset flow rate ratio range, the second valve 221 is closed and the first valve 211 is opened. This further reduces flow deviation, ensures the accurate ratio of the aqueous and organic phases, and improves the quality of nucleic acid nanomedicines.
[0043] This application also provides a method for using the drug encapsulation production monitoring device as described above, comprising the following steps: Input the raw materials according to the preset component ratio; Connect the output pipeline between the monitoring component 200 and the waste liquid that fails to meet the output requirements; The monitoring component 200 performs random sampling tests on the target drug at preset intervals. When the deviation of the detected component ratio exceeds the preset error range, the output pipeline between the monitoring component 200 and the qualified sample is closed, and the output pipeline between the monitoring component 200 and the unqualified waste liquid is opened. Correct the input component ratio and repeat the above steps until the deviation of the detected component ratio is within the preset error range. Then, close the output pipeline between the monitoring component 200 and the unqualified waste liquid, and open the pipeline between the monitoring component 200 and the qualified sample.
[0044] The raw materials include an aqueous phase and an organic phase. When starting the drug encapsulation production monitoring device, the aqueous and organic phases are first mixed and then input into the monitoring component 200. The first valve 211 is opened and the second valve 221 is closed, connecting the output pipeline between the monitoring component 200 and the waste liquid collection unit 300. Simultaneously, the monitoring component 200 samples the target drug at preset intervals. If the deviation of the component ratio detected multiple times is within the preset error range, the second valve 221 is opened and the first valve 211 is closed. If the deviation of the component ratio detected exceeds the preset error range, the second valve 221 is closed and the first valve 211 is opened. At the same time, the input component ratio is checked and corrected, and the process restarts by mixing the aqueous and organic phases before inputting them into the monitoring component 200 and the waste liquid collection unit 300. Simultaneously, the monitoring component 200 samples the target drug at preset intervals.
[0045] Specifically, a first fluid pump 511 is used to deliver aqueous phase raw materials to a mixing unit 600, and a second fluid pump 512 is used to deliver organic phase raw materials to the mixing unit 600. Aqueous nucleic acid and organic phase raw materials are delivered according to a preset component ratio. After mixing in the mixing unit 600, the raw materials form the nucleic acid nanomedicine to be detected and are continuously delivered to the input end of the monitoring component 200. The control system controls the opening of the first valve 211 and the third valve 231. The detection structure 240 detects the nucleic acid nanomedicine to be detected. The third valve 231 opens at preset intervals. When the deviation of the component ratio detected multiple times is within and stabilizes within a preset error range, the second valve 221 is opened and the first valve 211 is closed. When using a drug encapsulation production monitoring device, the third valve 231 opens at preset intervals. The flow rate is continuously monitored by the first flow meter 521 and the second flow meter 522. If either flow meter exceeds its preset flow range, or if the ratio of raw material flow monitored by the two flow meters exceeds the preset flow ratio range, the second valve 221 is closed and the first valve 211 is opened. If the deviation of the detected component ratio exceeds the preset error range, close the second valve 221, open the first valve 211, correct the input rate of the first fluid pump 511 and the second fluid pump 512, adjust the ratio of the two flow meters back to the preset flow ratio, and when the deviation of the component ratio is detected multiple times and is within and stable within the preset error range, open the second valve 221 and close the first valve 211.
[0046] In the method of use of this application, the design of the initial conductive waste liquid pipeline can eliminate the initial unstable intermediates, ensure the purity of qualified samples, and link sampling and correction to promptly detect and quickly adjust the raw material ratio deviation. The operation objectives of each step are clear, requiring no complex manual intervention and achieving automation.
[0047] Specifically, the preset component ratio is aqueous phase:organic phase = 1:3. Figure 3As shown, when the device of the present application is used for multiple tests, when the preset component ratio is aqueous phase: organic phase = 1:3, the polymer molecular weight distribution index is the lowest and the effect is the best.
[0048] Specifically, the error range is the error of the actual proportion of each component compared to the target proportion, and the preset error range is -5% to 5%. The detection structure 240 detects the target drug. By comparing the monitored data with the preset component ratio, subtract the preset component ratio 1 / 3 from the detection ratio, then divide by 1 / 3, and multiply by 100% to obtain the error ratio. When the deviation value is greater than -5% and less than 5%, it is judged as qualified; when the absolute value of the deviation value is greater than or equal to 5%, it is judged as unqualified. This ensures that the collected samples can be used to prepare drug products that meet clinical requirements, avoiding insufficient drug efficacy caused by too wide judgment criteria or raw material waste caused by too strict criteria.
[0049] Specifically, the preset interval time is 500 ms, that is, the third valve 231 is opened every 500 ms, and the detection structure 240 detects the target drug. The impedance signal of the detection structure 240 is collected, and immediately converted into component ratio data and transmitted to the control system every time a signal collection is completed; every time the control system receives data, a spot check judgment is completed. If the spot check results of a continuous preset number of times are within the preset error range, it can be judged that the quality of the target drug is stable, and the pipeline of the sample collection part is kept open; if the spot check result of a certain time exceeds the range, immediately switch to the pipeline of the waste liquid collection part 300 and trigger the raw material ratio correction process. High-frequency spot checks can quickly feedback the ratio deviation data, making the correction of the raw material ratio more timely, shortening the duration of the unstable quality of the target drug, and further improving the stability and yield of nucleic acid nanodrug production.
[0050] Combined with Figure 4 As shown, based on the device of the present application, nucleic acid nanodrugs are produced, and nucleic acid nanoparticles under different fluid fluxes are obtained. The samples encapsulated at different flow rates are imaged by cryo-electron microscopy. The results show that lipid nanoparticles with a hexagonal lattice structure can be synthesized by this device. Nanoparticles with this structure have good in vivo transfection effects. The results show that the lattice radius of the nanoparticles is between 5.3 - 5.5 nm, and the particle size of the nanoparticles is 95 ± 5 nm, and the particle size distribution is uniform.
[0051] Combined with Figure 5 As shown, based on Figure 4 The cryo-electron microscopy statistical data compares the lattice radius differences of the nanoparticles produced with and without using this device. The left side is the nanoparticles produced without using this device, and the right side is the nanoparticles produced using this device. Figure 5The results show that the nucleic acid nanomedicines produced using this device have a smaller particle lattice radius dispersion, indicating that the nanomedicines produced using this device have a more uniform quality.
[0052] Combination Figure 6 As shown, the copy number of nucleic acid nanoparticles produced using the device described in this application is compared. The left side represents nanoparticles produced without this device, and the right side represents nanoparticles produced using this device. The nucleic acid nanoparticles produced by this device have a higher nucleic acid copy number per nanoparticle. This indicates that products produced using this device will have better transfection efficiency.
[0053] Combination Figure 7 As shown, the encapsulation efficiency and empty loading rate of nucleic acid nanoparticles produced using the device of this application are compared. The left side shows nanoparticles produced without the device, and the right side shows nanoparticles produced using the device. The nucleic acid empty loading rate of the nucleic acid nanoparticles produced by this device is lower, less than 10%, indicating that the samples produced using this device are of better quality.
[0054] Combination Figure 8 As shown, based on the test kit, the encapsulation efficiency of nucleic acid nanomedicines produced by the device of this application was compared with that produced by the device. The nucleic acid encapsulation efficiency of the nucleic acid nanomedicines produced by this device was higher, greater than 95%, and the products produced by this device will have better transfection effect.
[0055] Combination Figure 9 , Figure 10 As shown, the in vivo transfection experiment in mice based on luciferase compared the differences in in vivo transfection efficiency between nucleic acid nanomedicines produced by the device of this application and those produced by luciferase. The results showed that the nucleic acid nanomedicines produced by this device had stronger fluorescence intensity in mice, indicating that the products produced by this device do indeed have better in vivo transfection efficiency.
[0056] The embodiments of this application have been described in detail above with reference to the accompanying drawings. However, this application is not limited to the above embodiments. Within the scope of knowledge possessed by those skilled in the art, various changes can be made without departing from the spirit of this application. Furthermore, unless otherwise specified, the embodiments and features described in the embodiments of this application can be combined with each other.
Claims
1. A drug encapsulation production monitoring device, characterized in that, include: A delivery assembly for independently delivering the components of a target drug; A mixing unit connected to the delivery assembly, the mixing unit being used to mix the components delivered by the delivery assembly into the target drug; A monitoring component is connected to the mixing unit and is used to detect the target drug. The monitoring component includes two independent output lines, which are used to output unqualified waste liquid and qualified samples, respectively. The monitoring component is used to switch the conduction state of the two output lines according to the detection results of the component ratio of the target drug.
2. The drug encapsulation production monitoring device according to claim 1, characterized in that: The monitoring component has an input terminal, a first output terminal, a second output terminal, a third output terminal, and a detection structure. The input terminal is used to input the target drug, the first output terminal is used to output waste liquid, and the second output terminal is used to output the sample. The detection structure is used to detect the component ratio of the target drug. The third output terminal is connected to the inlet terminal of the detection structure, and the outlet terminal of the detection structure is connected to the output port terminal of the first output terminal.
3. The drug encapsulation production monitoring device according to claim 2, characterized in that: The third output terminal is located between the input port of the first output terminal and the input port of the second output terminal.
4. The drug encapsulation production monitoring device according to claim 3, characterized in that: The detection structure is a microfluidic chip, which includes an impedance detection structure.
5. The drug encapsulation production monitoring device according to claim 1, characterized in that: The conveying assembly has at least two sets of fluid pumps, each of which is connected to the mixing unit and is used to convey raw materials; the mixing unit has a combined output terminal, which is connected to the monitoring assembly.
6. The drug encapsulation production monitoring device according to claim 5, characterized in that: Each of the fluid pumps is equipped with a flow meter between itself and the mixing unit.
7. The drug encapsulation production monitoring device according to claim 5, characterized in that: The delivery assembly includes two sets of the fluid pumps.
8. A method of using the drug encapsulation production monitoring device as described in any one of claims 1 to 7, characterized in that, Includes the following steps: Input the raw materials according to the preset component ratio; Connect the monitoring component to the output pipeline between it and the waste liquid that fails to meet the standards. The monitoring component performs random checks on the target drug at preset intervals. When the deviation of the detected component ratio exceeds the preset error range, the output pipeline between the monitoring component and the qualified sample is closed, and the output pipeline between the monitoring component and the unqualified waste liquid is opened. Correct the input component ratio and repeat the above steps until the deviation of the detected component ratio is within the preset error range. Then, close the output pipeline between the monitoring component and the unqualified waste liquid, and open the pipeline between the monitoring component and the qualified sample.
9. The method of use according to claim 8, characterized in that: The error range is the difference between the actual proportion of each component and the target proportion, and the preset error range is -5% to 5%.
10. The method of use according to claim 8, characterized in that: The preset interval is 500ms.