Processing equipment of hydroxycamptothecin microbubbles for fibrosis and tumor targeted therapy

Abstract

The invention belongs to the technical field of medicines, and particularly relates to processing equipment of hydroxycamptothecin microbubbles for fibrosis and tumor targeted therapy. The device comprises a device framework, a medicine container, a lipid membrane generation mechanism, a hydration dispersion mechanism, a replacement oscillation mechanism, a conveying mechanism and an electric control system. The hydroxycamptothecin microbubble processing equipment disclosed by the invention is beneficial to improving the production efficiency and bubble forming quality of microbubble medicines.

Description

Technical Field

[0001] This application belongs to the field of pharmaceutical technology, specifically relating to processing equipment for hydroxycamptothecin microbubbles used in targeted therapy for fibrosis and tumors. Background Technology

[0002] Hydroxycamptothecin, an antitumor drug that inhibits DNA synthesis, has recently been found to significantly inhibit fibroblast proliferation. Fibrosis in various tissues and organs is essentially a process of repairing inflammatory damage, requiring the synthesis and secretion of large amounts of collagen fibers and extracellular matrix components, in which fibroblasts play a crucial role. By inhibiting fibroblast proliferation and inducing apoptosis through signaling pathways, hydroxycamptothecin can be used to treat diseases such as liver fibrosis and pathological scars. Please refer to [link to relevant documentation]. Figure 1 When the R group on C10 is H, it is camptothecin; when the R group on C10 is OH, it is 10-hydroxycamptothecin.

[0003] Microbubbles are liquids containing air bubbles with diameters in the micrometer range. Utilizing the strong backscattering property of bubble-containing liquids on ultrasound waves, they can be used as ultrasound contrast agents. They are used to enhance Doppler ultrasound signals related to blood flow and improve the clarity and resolution of ultrasound images, thereby increasing the detection and diagnostic rates of diseases. Currently, commonly used microbubbles are filled with inert gases, such as sulfur hexafluoride microbubbles and perfluoropropane microbubbles.

[0004] Existing hydroxycamptothecin formulations have the following technical problems: 1. Hydroxycamptothecin has low water solubility and, as an antitumor drug, possesses certain toxicity. During intravenous injection, it easily causes skin and vascular endothelial cell damage, as well as liver and kidney toxicity, leading to disease progression. 2. The closed α-hydroxylactone ring in the E-ring structure of hydroxycamptothecin is essential for maintaining its antitumor activity. However, the α-hydroxylactone ring is easily hydrolyzed in the human body to form a carboxylate structure. This open-ring form readily binds to human serum proteins, thus losing its antitumor activity. 3. Existing hydroxycamptothecin formulations have poor targeting, resulting in low blood concentrations at the lesion site, toxic side effects, and the therapeutic effect needs improvement. Summary of the Invention

[0005] In view of this, this application provides a processing apparatus for hydroxycamptothecin microbubbles for fibrosis and tumor targeted therapy, in order to solve the technical problems existing in the prior art.

[0006] The hydroxycamptothecin microbubble processing equipment disclosed in this application for the purpose of solving its technical problem is as follows: A hydroxycamptothecin microbubble processing device for fibrosis and tumor targeted therapy is characterized by comprising a device frame, a drug container, a lipid membrane generation mechanism, a hydration and dispersion mechanism, a displacement oscillation mechanism, a conveying mechanism, and an electrical control system. The lipid membrane generation mechanism, hydration and dispersion mechanism, displacement oscillation mechanism, and conveying mechanism are all disposed on and / or within the device frame. The drug container holds a lipid reserve solution and HCPT drug. The lipid membrane generation mechanism vortexes and mixes the lipid reserve solution and HCPT drug contained in the drug container, and introduces an inert gas to promote chloroform evaporation and form a dry drug lipid membrane. The hydration and dispersion mechanism hydrates and disperses the drug lipid membrane to form a uniform lipid suspension. The displacement oscillation mechanism performs gas displacement on the lipid suspension and oscillates the gas-displaced lipid suspension to form hydroxycamptothecin microbubbles. The conveying mechanism transfers the drug container between the lipid membrane generation mechanism, the hydration and dispersion mechanism, and the displacement oscillation mechanism.

[0007] Preferably, the lipid membrane generation mechanism includes a vortex oscillator, an oscillating plate, and an inflation device; the vortex oscillator is mounted on the device frame and electrically connected to the electronic control system, the oscillating plate is mounted on the vortex oscillator, and the oscillating plate is used to place the drug container; the inflation device includes an inflation gas source, an inflation pipeline, an inflation head, an inflation head drive mechanism, and an inflation electrically controlled valve; the inflation gas source is mounted on the device frame, the two ends of the inflation pipeline are respectively connected to the inflation gas source and the inflation head, the inflation electrically controlled valve is mounted on the inflation pipeline and electrically connected to the electronic control system, the inflation head is mounted on the inflation head drive mechanism, the inflation head drive mechanism is mounted on the device frame and electrically connected to the electronic control system, and the inflation head can extend into or out of the drug container placed on the oscillating plate under the action of the inflation head drive mechanism.

[0008] Preferably, the inflation head drive mechanism includes an inflation lifting screw, an inflation lifting motor, an inflation lifting slide, and an inflation head fixing frame. The inflation lifting screw and the inflation lifting motor are mounted on the equipment frame and are connected by transmission. The inflation lifting slide is threadedly connected to the inflation lifting screw and the inflation head fixing frame is mounted on the inflation lifting slide. The inflation lifting motor can drive the inflation lifting screw to rotate clockwise or counterclockwise, thereby causing the inflation lifting slide to drive the inflation head fixing frame to move up or down.

[0009] Preferably, the hydration and dispersion mechanism includes a heating device, an ultrasonic oscillator, and a hydration device. The heating device includes a container placement position, a heating component, and a temperature sensor. The container placement position is used to place the drug container. The heating component and the temperature sensor are located on the side of the container placement position and are electrically connected to the electronic control system. The ultrasonic oscillator is located at the bottom of the container placement position and is electrically connected to the electronic control system. The hydration device includes a hydration liquid container, a hydration liquid delivery pipe, a hydration head, a delivery pump, and a hydration head drive mechanism. The hydration liquid container is mounted on the equipment frame. The two ends of the hydration liquid delivery pipe are respectively connected to the hydration liquid container and the hydration head. The hydration head is mounted on the hydration head drive mechanism, which is mounted on the equipment frame and electrically connected to the electronic control system. The delivery pump is mounted on the hydration liquid delivery pipe and electrically connected to the electronic control system. The hydration head can extend into or out of the drug container placed in the container placement position under the drive of the hydration head drive mechanism. The delivery pump can deliver the hydration liquid stored in the hydration liquid container to the drug container.

[0010] Preferably, the hydration head drive mechanism includes a hydration lifting screw, a hydration lifting motor, a hydration lifting slide, and a hydration head fixing frame. The hydration lifting screw and the hydration lifting motor are mounted on the equipment frame and are connected by transmission. The hydration lifting slide is threadedly connected to the hydration lifting screw and the hydration head fixing frame is mounted on the hydration lifting slide. The hydration lifting motor can drive the hydration lifting screw to rotate clockwise or counterclockwise, thereby causing the hydration lifting slide to drive the hydration head fixing frame to move up or down.

[0011] Preferably, the displacement oscillation mechanism includes a displacement oscillation position, a displacement oscillator, a sealing device, and a ventilation device. The sealing device includes a sealing mold, a sealing mold lifting device, and a sealing mold rotating device. The sealing mold is mounted on the sealing mold lifting device, which is mounted on the sealing mold rotating device. The sealing mold can move up and down under the action of the sealing mold lifting device, and can also rotate together with the sealing mold lifting device under the action of the sealing mold rotating device. The ventilation device includes a displacement gas source, a ventilation pipeline, a ventilation head, a ventilation head drive device, and a ventilation head electrically controlled valve. The displacement gas source is mounted on the equipment frame. The two ends of the ventilation pipeline are connected to the displacement gas source and the ventilation head, respectively. The ventilation head is mounted on the ventilation head drive device, which is mounted on the equipment frame and electrically connected to the electrical control system. The ventilation head electrically controlled valve is mounted on the ventilation pipeline. The ventilation head can extend into or out of the drug container placed on the displacement oscillation position under the drive of the ventilation head drive device.

[0012] Preferably, the ventilation head drive mechanism includes a ventilation lifting screw, a ventilation lifting motor, a ventilation lifting slide, and a ventilation head fixing frame; the ventilation lifting screw and the ventilation lifting motor are connected by transmission and are both mounted on the equipment frame; the control end of the ventilation lifting motor is electrically connected to the electrical control system; the ventilation lifting slide is threaded onto the ventilation lifting screw; the ventilation head fixing frame is mounted on the ventilation lifting slide; and the ventilation head is mounted on the ventilation head fixing frame.

[0013] Preferably, the conveying mechanism includes a container clamp, an X-axis drive device, a Y-axis drive device, and a Z-axis drive device; the container clamp is an elastic clamp, which has an inlet and a clamping part; the container clamp is mounted on the Z-axis drive device, the Z-axis drive device is mounted on the X-axis drive device, and the X-axis drive device is mounted on the Y-axis drive device; the container clamp can reciprocate linearly along the Z-axis under the action of the Z-axis drive device, and can also reciprocate linearly along the X-axis together with the Z-axis drive device under the action of the X-axis drive device, and can also reciprocate linearly along the Y-axis together with the X-axis drive device and the Z-axis drive device under the action of the Y-axis drive device.

[0014] Preferably, the X-axis drive device includes an X-axis lead screw, an X-axis motor, and an X-axis slide; the Y-axis drive device includes a Y-axis lead screw, a Y-axis motor, and a Y-axis slide; and the Z-axis drive device includes a Z-axis lead screw, a Z-axis motor, and a Z-axis slide. The container clamp is mounted on the Z-axis slide, which is threaded onto the Z-axis lead screw, and the Z-axis lead screw and Z-axis motor are connected by a transmission connection. The Z-axis lead screw and Z-axis motor are mounted on the X-axis slide, which is threaded onto the X-axis lead screw, and the X-axis lead screw and X-axis motor are connected by a transmission connection. The X-axis lead screw and X-axis motor are mounted on the Y-axis slide, which is threaded onto the Y-axis lead screw, and the Y-axis lead screw and Y-axis motor are connected by a transmission connection. The Y-axis lead screw and Y-axis motor are mounted on the equipment frame.

[0015] Preferably, the container clamp is an elastic clamp, which has an inlet and a clamping part.

[0016] The hydroxycamptothecin microbubbles produced using the above-mentioned microbubble processing equipment for targeted therapy of fibrosis and tumors are as follows: A hydroxycamptothecin microbubble for targeted therapy of fibrosis and tumors is characterized by comprising, from the outside to the inside, a first encapsulation layer, a first drug layer, a second encapsulation layer, a spacer layer, a third encapsulation layer, a second drug layer, a fourth encapsulation layer, and a core layer; the first and second encapsulation layers are respectively the hydrophobic and hydrophilic layers of the outer liposomes, the second and third encapsulation layers are respectively the hydrophobic and hydrophilic layers of the inner liposomes, the spacer layer and the core layer are liquid-gas mixture spacer layers, and hydroxycamptothecin is disposed within the first and second drug layers.

[0017] Preferably, black phosphorus micro-nanosheets are also disposed in the first and second drug layers, with hydroxycamptothecin supported on the black phosphorus micro-nanosheets.

[0018] Preferably, the hydroxycamptothecin microbubbles used for fibrosis and tumor-targeted therapy also include the cell membrane at the lesion site, which is encapsulated on the outside of the hydroxycamptothecin microbubbles through self-assembly.

[0019] This application also relates to a method for increasing the drug concentration of hydroxycamptothecin at the target site, characterized in that: utilizing the lipophilic properties of hydroxycamptothecin, hydroxycamptothecin is encapsulated within liposomes to form hydroxycamptothecin microbubbles comprising a first encapsulation layer, a first drug layer, a second encapsulation layer, a spacer layer, a third encapsulation layer, a second drug layer, a fourth encapsulation layer, and a core layer; the first and second encapsulation layers are respectively the hydrophobic and hydrophilic layers of the outer liposomes, the second and third encapsulation layers are respectively the hydrophobic and hydrophilic layers of the inner liposomes, the spacer layer and the core layer are liquid-gas mixture spacer layers, and hydroxycamptothecin is disposed within the first and second drug layers.

[0020] This application also relates to the application of liposomes in increasing the drug concentration of hydroxycamptothecin at the target site, characterized in that: Taking advantage of the lipophilic properties of hydroxycamptothecin, hydroxycamptothecin is encapsulated within liposomes to form hydroxycamptothecin microvesicles comprising a first encapsulation layer, a first drug layer, a second encapsulation layer, a spacer layer, a third encapsulation layer, a second drug layer, a fourth encapsulation layer, and a core layer. The first and second encapsulation layers are respectively the hydrophobic and hydrophilic layers of the outer liposome, and the second and third encapsulation layers are respectively the hydrophobic and hydrophilic layers of the inner liposome. The spacer layer and the core layer are liquid-gas mixing spacer layers. Hydroxycamptothecin is disposed within the first and second drug layers.

[0021] This application also relates to a characterization model of hydroxycamptothecin microbubbles for targeted therapy of fibrosis and tumors: A hydroxycamptothecin microbubble characterization model for targeted therapy of fibrosis and tumors is characterized by using microbubble cluster mixing potential Eh, microbubble cluster mixing pH, and microbubble cluster concentration Rh as biological characteristic characterization parameters of hydroxycamptothecin microbubbles, and constructing a microbubble cluster medical model in which hydroxycamptothecin microbubbles can exert medical effects within an orthogonal coordinate system of Eh, pH, and Rh.

[0022] As a preferred embodiment, the microbubble cluster medical model includes upper and lower limits of microbubble cluster mixing potential (Eh1 and Eh2), upper and lower limits of microbubble cluster mixing pH (pH1 and pH2), and upper and lower limits of microbubble cluster concentration (Rh1 and Rh2).

[0023] Beneficial technical effects: The hydroxycamptothecin microbubbles prepared in this application for targeted therapy of fibrosis and tumors, through the nested encapsulation of hydroxycamptothecin with liposomes, can not only effectively improve the safety and targeting of the drug, but also help to increase the blood concentration of hydroxycamptothecin and prevent the loss of antitumor activity of hydroxycamptothecin in the human body.

[0024] The technical solution and technical effects of this application will be described in detail below with reference to the accompanying drawings and specific embodiments. Attached Figure Description

[0025] Figure 1 Schematic diagram of the molecular structure of hydroxycamptothecin; Figure 2 Schematic diagram of the microbubble structure of hydroxycamptothecin; Figure 3 : A three-dimensional schematic diagram of a microbubble cluster medical model; Figure 4 Layout plan of the hydroxycamptothecin microbubble processing equipment; Icon description: 1-First encapsulation layer, 2-First drug layer, 3-Second encapsulation layer, 4-Spacer layer, 5-Third encapsulation layer, 6-Second drug layer, 7-Fourth encapsulation layer, 8-Core layer; 10-Equipment skeleton, 20-Drug container, 30-Lipid membrane generation mechanism, 40-Hydration and dispersion mechanism, 50-Displacement and oscillation mechanism, 60-Transfer mechanism; 310 - Vortex oscillator; 320 - Oscillator plate; 3310-Inflation air source, 3320-Inflation pipeline, 3330-Inflation head, 3340-Inflation head drive mechanism, 3350-Inflation electric control valve; 3341-Inflatable lifting screw, 3342-Inflatable lifting motor, 3343-Inflatable lifting slide, 3344-Inflatable head fixing bracket; 410 - Heating device; 420 - Ultrasonic oscillator; 430 - Hydration device; 4110 - Container placement position; 4120 - Heating component; 4130 - Temperature sensor; 4310-Aqueous liquid container, 4320-Aqueous liquid conveying pipeline, 4330-Aqueous head, 4340-Transfer pump, 4350-Aqueous head drive mechanism; 510 - Displacement oscillation position, 520 - Displacement oscillator, 530 - Sealing device, 540 - Ventilation device; 5310 - Sealing mold, 5320 - Sealing mold lifting device, 5330 - Sealing mold rotating device; 5410 - Replacement air source, 5420 - Replacement pipeline, 5430 - Replacement head, 5440 - Replacement head drive device; 610 - Container clamp; 620 - X-axis drive unit; 630 - Y-axis drive unit; 640 - Z-axis drive unit. 6110 - Entrance section, 6120 - Clamping section. Detailed Implementation

[0026] In order to reduce the biotoxicity of hydroxycamptothecin in the human body, avoid the loss of antitumor activity due to drug hydrolysis, and improve the targeting accuracy of hydroxycamptothecin, this application discloses hydroxycamptothecin microbubbles for fibrosis and tumor targeted therapy, their characterization model and dedicated processing equipment.

[0027] Please see Figure 2 The hydroxycamptothecin microbubbles for fibrosis and tumor-targeted therapy comprise, from the outside in, a first encapsulation layer 1, a first drug layer 2, a second encapsulation layer 3, a spacer layer 4, a third encapsulation layer 5, a second drug layer 6, a fourth encapsulation layer 7, and a core layer 8. The first and second encapsulation layers 1 and 3 are respectively the hydrophobic and hydrophilic layers of the outer liposomes, and the second and third encapsulation layers 3 and 5 are respectively the hydrophobic and hydrophilic layers of the inner liposomes. The spacer layer 4 and core layer 8 are liquid-gas mixing spacer layers. Hydroxycamptothecin is disposed within the first and second drug layers 2 and 6. In a modified embodiment of this application, black phosphorus micro / nanosheets are further disposed within the first and second drug layers 2 and 6, with hydroxycamptothecin supported on the black phosphorus micro / nanosheets. In another modified embodiment of this application, the hydroxycamptothecin microbubbles for fibrosis and tumor-targeted therapy also include a lesion site cell membrane, which is self-assembled and encapsulated on the outside of the hydroxycamptothecin microbubbles.

[0028] The hydroxycamptothecin microbubbles disclosed in this application can be used to treat a variety of diseases, such as the treatment of multi-organ fibrosis (e.g., liver fibrosis) and the treatment of broad-spectrum anti-tumor drugs (liver cancer, colorectal cancer, lung cancer, leukemia). The inert gas of the microbubbles can also be changed according to the characteristics of the disease, such as perfluoropropane or sulfur hexafluoride, to achieve better therapeutic effects.

[0029] In this application, hydroxycamptothecin is organically combined with perfluoropropane microbubbles to form hydroxycamptothecin microbubbles, which not only retain the characteristics and functions of ultrasound contrast agents such as perfluoropropane microbubbles, but also expands its biological applications by utilizing the properties of hydroxycamptothecin.

[0030] The average particle size and number of hydroxycamptothecin microbubbles were not significantly different from those of perfluoropropane microbubbles (Table 1). This means that adding hydroxycamptothecin had almost no effect on the characterization of the microbubbles, indicating that hydroxycamptothecin microbubbles can retain the original characteristics and functions of microbubbles and can still be used for ultrasound contrast imaging.

[0031] Table 1. Particle size of different microbubbles

[0032] Furthermore, encapsulating hydroxycamptothecin can improve its safety. Hydroxycamptothecin has low water solubility and, as an antitumor drug, possesses certain toxicity. During intravenous injection, it can easily cause skin and vascular endothelial cell damage, as well as liver and kidney toxicity, leading to animal death. Hydroxycamptothecin microbubbles, encapsulating the drug with a lipid-soluble substance, are safer than pure hydroxycamptothecin solutions.

[0033] The lipophilic properties of hydroxycamptothecin allow it to bind to liposomes, achieving a large drug loading capacity. Under ultrasound, the liposomes explode locally, further increasing the local drug concentration, and the lesions are then treated after the explosion.

[0034] Therefore, this application also relates to a method for increasing the drug concentration of hydroxycamptothecin at a target site, and the application of liposomes in increasing the drug concentration of hydroxycamptothecin at a target site, characterized in that: utilizing the lipophilic properties of hydroxycamptothecin, hydroxycamptothecin is encapsulated in liposomes to form hydroxycamptothecin microbubbles comprising a first encapsulation layer, a first drug layer, a second encapsulation layer, a spacer layer, a third encapsulation layer, a second drug layer, a fourth encapsulation layer, and a core layer; the first and second encapsulation layers are respectively the hydrophobic and hydrophilic layers of the outer liposome, the second and third encapsulation layers are respectively the hydrophobic and hydrophilic layers of the inner liposome, the spacer layer and the core layer are liquid-gas mixture spacer layers, and hydroxycamptothecin is disposed within the first and second drug layers.

[0035] Additionally, please see Figure 3 This application also proposes a hydroxycamptothecin microbubble characterization model for targeted therapy of fibrosis and tumors. The model is characterized by using microbubble cluster mixing potential (Eh), microbubble cluster mixing pH, and microbubble cluster concentration (Rh) as biological characteristic characterization parameters for hydroxycamptothecin microbubbles. A microbubble cluster medical model is constructed within an orthogonal coordinate system of Eh, pH, and Rh to demonstrate the therapeutic effects of hydroxycamptothecin microbubbles. Specifically, the microbubble cluster medical model includes upper and lower limits of the microbubble cluster mixing potential (Eh1 and Eh2), upper and lower limits of the microbubble cluster mixing pH (pH1 and pH2), and upper and lower limits of the microbubble cluster concentration (Rh1 and Rh2). In practical applications, specific Eh, pH, and Rh values ​​of the microbubble cluster medical model can be determined according to different conditions of specific diseases, providing a reference for treatment plans. In one example based on an experimental model, Eh1 = -156 mV, Eh1 = 326 mV, pH1 = 6.44, pH2 = 7.23, Rh1 = 5053420035 / mL, and Rh2 = 5072946528 / mL.

[0036] Given the technical advantages of liposome encapsulation of hydroxycamptothecin drugs in terms of high targeting efficiency and low toxicity, this application also discloses a processing device for the automated production of hydroxycamptothecin microbubbles, to promote the production and application of hydroxycamptothecin microbubbles. Please refer to [link to relevant documentation]. Figure 4It includes an equipment frame 10, a drug container 20, a lipid membrane generation mechanism 30, a hydration and dispersion mechanism 40, a displacement and oscillation mechanism 50, a conveying mechanism 60, and an electrical control system. The lipid membrane generation mechanism 30, the hydration and dispersion mechanism 40, the displacement and oscillation mechanism 50, and the conveying mechanism 60 are all disposed on and / or within the equipment frame 10.

[0037] Drug container 20 is used to hold lipid stock solutions and HCPT drugs. It can be a test tube, reagent bottle, etc.

[0038] The lipid membrane generation mechanism 30 is used to vortex and mix the lipid stock solution and HCPT drug contained in the drug container 20 and pass inert gas to promote chloroform volatilization and form a dry drug lipid membrane.

[0039] The hydration and dispersion mechanism 40 is used to hydrate and disperse the drug lipid membrane to form a uniform lipid suspension.

[0040] The displacement oscillation mechanism 50 is used to perform gas displacement on the lipid suspension and then oscillate the gas-displaced lipid suspension to form hydroxycamptothecin microbubbles. The displacement gas can be selected from different inert gases depending on the application environment.

[0041] The transfer mechanism 60 is used to transfer the drug container 20 between the lipid membrane generation mechanism 30, the hydration dispersion mechanism 40, and the displacement oscillation mechanism 50.

[0042] The lipid membrane generation mechanism 30 includes a vortex oscillator 310, an oscillation plate 320, and an inflation device. The vortex oscillator 310 is mounted on the device frame 10 and electrically connected to the electronic control system. The oscillation plate 320 is mounted on the vortex oscillator 310 and is used to place the drug container 20. The oscillation plate 320 is generally provided with oscillation placement positions that match the shape and position of the container to be placed. The inflation device 330 includes an inflation gas source 3310, an inflation pipeline 3320, an inflation head 3330, an inflation head drive mechanism 3340, and an inflation electronic control valve 3350.

[0043] An inflation source 3310 is mounted on the equipment frame 10. The two ends of the inflation pipeline 3320 are connected to the inflation source 3310 and the inflation head 3330, respectively. An inflation electric control valve 3350 is mounted on the inflation pipeline 3320 and electrically connected to the electric control system. The inflation head 3330 is mounted on the inflation head drive mechanism 3340. The inflation head drive mechanism 3340 is mounted on the equipment frame 10 and electrically connected to the electric control system. The inflation head 3330 can extend into or out of the drug container 20 placed on the vibrating plate 320 under the action of the inflation head drive mechanism 3340.

[0044] The inflation head drive mechanism 3340 adopts a commercially available screw and slide module, which generally includes an inflation lifting screw 3341, an inflation lifting motor 3342, an inflation lifting slide 3343, and an inflation head fixing frame 3344. The inflation lifting screw 3341 and the inflation lifting motor 3342 are mounted on the equipment frame 10 and are connected by transmission. The inflation lifting slide 3343 is connected to the inflation lifting screw 3341 by threaded engagement. The inflation head fixing frame 3344 is mounted on the inflation lifting slide 3343. The inflation lifting motor 3342 can drive the inflation lifting screw 3341 to rotate clockwise or counterclockwise, thereby causing the inflation lifting slide 3343 to drive the inflation head fixing frame 3344 to move up or down.

[0045] The hydration and dispersion mechanism 40 includes a heating device 410, an ultrasonic oscillator 420, and a hydration device 430. The heating device 410 includes a container placement position 4110, a heating component 4120, and a temperature sensor 4130. The container placement position 4110 is used to place the drug container 10. The heating component 4120 and the temperature sensor 4130 are located on the side of the container placement position 4110 and are electrically connected to the electronic control system. The ultrasonic oscillator 420 is located at the bottom of the container placement position 4110 and is electrically connected to the electronic control system.

[0046] The hydration device 430 includes a hydration liquid container 4310, a hydration liquid delivery pipe 4320, a hydration head 4330, a delivery pump 4340, and a hydration head drive mechanism 4350. The hydration liquid container 4310 is mounted on the equipment frame 10. The two ends of the hydration liquid delivery pipe 4320 are respectively connected to the hydration liquid container 4310 and the hydration head 4330. The hydration head 4330 is mounted on the hydration head drive mechanism 4350, which is mounted on the equipment frame 10 and electrically connected to the electrical control system. The delivery pump 4340 is mounted on the hydration liquid delivery pipe 4320 and electrically connected to the electrical control system. The hydration head 4330 can extend into or out of the drug container 20 placed in the container placement position 4110 under the drive of the hydration head drive mechanism 4350. The delivery pump 4340 can deliver the hydration liquid stored in the hydration liquid container 4310 to the drug container 10.

[0047] The hydration head drive mechanism has a similar structure and function to the inflation head drive mechanism 3340, both using commercially available screw and slide modules. The hydration head drive mechanism includes a hydration lifting screw, a hydration lifting motor, a hydration lifting slide, and a hydration head mounting bracket. The hydration lifting screw and motor are mounted on the equipment frame and are connected by a transmission mechanism. The hydration lifting slide is threadedly connected to the hydration lifting screw for lifting and lowering. The hydration head mounting bracket is mounted on the hydration lifting slide, and the hydration head 4330 is mounted on the hydration head mounting bracket. The hydration lifting motor drives the hydration lifting screw to rotate clockwise or counterclockwise, thereby causing the hydration lifting slide to move the hydration head mounting bracket up or down.

[0048] The displacement oscillation mechanism 50 includes a displacement oscillation position 510, a displacement oscillator 520, a sealing device 530, and a ventilation device 540. The sealing device 530 includes a sealing mold 5310, a sealing mold lifting device 5320, and a sealing mold rotating device 5330. The sealing mold 5310 is mounted on the sealing mold lifting device 5320, and the sealing mold lifting device 5320 is mounted on the sealing mold rotating device 5330. The sealing mold 5310 can move up and down under the action of the sealing mold lifting device 5320, and can also rotate together with the sealing mold lifting device 5320 under the action of the sealing mold rotating device 5330. The sealing mold 5310 is provided with a placement position for sealing components (such as rubber plugs, aluminum caps, or sealing plates). The sealing mold rotating device 5330 uses an electric indexing plate, and the sealing mold lifting device 5320 uses a screw slide module similar to the inflation head drive mechanism 3340.

[0049] The ventilation device 540 includes a displacement air source 5410, a ventilation pipeline 5420, a ventilation head 5430, a ventilation head drive device 5440, and a ventilation head electrically controlled valve. The displacement air source 5410 is mounted on the equipment frame 10. Both ends of the ventilation pipeline 54240 are connected to the displacement air source 5410 and the ventilation head 5430, respectively. The ventilation head 5430 is mounted on the ventilation head drive device 5440, which is mounted on the equipment frame 10 and electrically connected to the electrical control system. The ventilation head electrically controlled valve is mounted on the ventilation pipeline 5420. The ventilation head 5430 can extend into or out of the drug container 20 placed on the displacement oscillation position 510 under the drive of the ventilation head drive device 5440. The ventilation head drive device 5440 adopts a screw-slide module similar to the inflation head drive mechanism 3340.

[0050] The conveying mechanism 60 includes a container clamp 610, an X-axis drive device 620, a Y-axis drive device 630, and a Z-axis drive device 640. The container clamp 610 is an elastic clamp, with an inlet 6110 and a clamping part 6120. The container clamp 610 is mounted on the Z-axis drive device 640, which is mounted on the X-axis drive device 620, and the X-axis drive device 620 is mounted on the Y-axis drive device 630. The container clamp 610 can move along the Z-axis (…) under the action of the Z-axis drive device. Figure 4 It can perform linear reciprocating motion in the direction perpendicular to the paper or perpendicular to the XY plane. It can also perform linear reciprocating motion along the X-axis together with the Z-axis drive device 640 under the action of the X-axis drive device 620, and can perform linear reciprocating motion along the Y-axis together with the X-axis drive device 620 and the Z-axis drive device 640 under the action of the Y-axis drive device 630.

[0051] The X-axis drive unit 620, Y-axis drive unit 630, and Z-axis drive unit 640 all employ a screw-slide module similar to that of the inflation head drive mechanism 3340. Specifically, the X-axis drive unit 620 includes an X-axis screw, an X-axis motor, and an X-axis slide; the Y-axis drive unit 630 includes a Y-axis screw, a Y-axis motor, and a Y-axis slide; and the Z-axis drive unit 640 includes a Z-axis screw, a Z-axis motor, and a Z-axis slide. The container clamp is mounted on the Z-axis slide, which is threaded onto the Z-axis screw, and a transmission connection is established between the Z-axis screw and the Z-axis motor. The Z-axis screw and Z-axis motor are mounted on the X-axis slide, which is threaded onto the X-axis screw, and a transmission connection is established between them. The X-axis screw and X-axis motor are mounted on the Y-axis slide, which is threaded onto the Y-axis screw, and a transmission connection is established between them. The Y-axis screw and Y-axis motor are mounted on the equipment frame.

[0052] Equipment principle description: A. The phospholipid stock solution and HCPT drug are placed in a specific ratio into the drug container 20, and the drug container 20 is placed in the vibration position on the vibration plate 320. The inflation head 3330, driven by the inflation head drive mechanism 3340, extends into the drug container 20 placed on the vibration plate 320. The inflation control valve 3350 is activated, and nitrogen gas flows into the mixture of phospholipid stock solution and HCPT drug. Simultaneously, the vortex shaker 310 is activated to generate vortex oscillation until chloroform completely evaporates and forms a thin film on the container wall.

[0053] B. Disconnect the inflation control valve 3350 to stop inflation. The inflation head 3330 moves away from the drug container 20 under the action of the inflation head drive mechanism 3340. The container clamp 610 extends towards the drug container 20 under the coordination of the X-axis drive device 620, the Y-axis drive device 630 and the Z-axis drive device 640 and clamps the drug container 20 in the clamping part 6120. The Z-axis drive device 640 drives the drug container 20 to rise away from the oscillation placement position on the oscillation plate 320 and is positioned above the container placement position 4110 on the hydration dispersion mechanism 40. The Z-axis drive device 640 drives the container clamp 610 and the drug container 20 to descend and place the drug container 20 in the container placement position 4110. Then, under the action of the X-axis drive device 620, it moves away from the drug container 20.

[0054] C. The hydration head 4330 enters the drug container 20 under the action of the hydration head drive mechanism 4350. The delivery pump 4340 delivers an appropriate amount of hydration liquid from the hydration liquid container 4310 to the drug container 20. The heating component 4120 and the temperature sensor 4130 maintain the temperature at a suitable level, while the ultrasonic oscillator 420 vibrates until a uniform suspension is formed. The hydration head 4330 rises and leaves the drug container 20. The conveying mechanism 60 transfers the drug container 20 to the displacement oscillation position 510 of the displacement oscillation mechanism 50 (see the description in Title B for the mechanism of action).

[0055] D. The sealing mold 5310 rotates to above the drug container 20 under the action of the sealing mold rotating device 5330, and then descends under the action of the sealing mold lifting device 5320 to assemble the sealing component onto the drug container 20. After completing the assembly of the sealing component, the sealing mold 5310 rotates in the opposite direction to reset to one side of the displacement oscillation position 510. The gas exchange head 5430 descends under the action of the gas exchange head driving device 5440 and partially passes through the sealing component, such as a rubber stopper, into the drug container 20. The gas exchange head 20 can be an injection needle. The gas exchange head's electrically controlled valve is turned on, and inert gas enters the drug container 20. At the same time, the displacement oscillator 520 is started to form stable and uniform hydroxycamptothecin microbubbles.

[0056] The technical solutions and effects of this application have been described in detail above with reference to the accompanying drawings and specific embodiments. It should be noted that the specific embodiments disclosed in the specification are only preferred embodiments of this application, and those skilled in the art can develop other embodiments based on them; any simple modifications and equivalent substitutions that do not depart from the innovative concept of this application are covered by this application and fall within the protection scope of this patent.

Claims

1. A processing device for hydroxycamptothecin microbubbles used in fibrosis and tumor targeted therapy, characterized in that: The device includes a frame (10), a drug container (20), a lipid membrane generation mechanism (30), a hydration and dispersion mechanism (40), a displacement and oscillation mechanism (50), a conveying mechanism (60), and an electrical control system; the lipid membrane generation mechanism (30), the hydration and dispersion mechanism (40), the displacement and oscillation mechanism (50), and the conveying mechanism (60) are all disposed on and / or within the frame (10), and the drug container (20) is used to hold the lipid stock solution and HCPT drug; The lipid membrane generation mechanism (30) is used to vortex and mix the lipid reserve liquid and HCPT drug contained in the drug container (20) and pass inert gas to promote chloroform volatilization and form a dry drug lipid membrane. The hydration and dispersion mechanism (40) is used to hydrate and disperse the drug lipid membrane to form a uniform lipid suspension; The displacement oscillation mechanism (50) is used to gas-displace the lipid suspension and oscillate the gas-displaced lipid suspension to form hydroxycamptothecin microbubbles. The transfer mechanism (60) is used to transfer the drug container (20) between the lipid membrane generation mechanism (30), the hydration dispersion mechanism (40), and the displacement oscillation mechanism (50).

2. The processing equipment for hydroxycamptothecin microbubbles for targeted therapy of fibrosis and tumors according to claim 1, characterized in that: The lipid membrane generation mechanism (30) includes a vortex oscillator (310), an oscillation plate (320), and an inflation device (330); the vortex oscillator (310) is mounted on the device frame (10) and electrically connected to the electronic control system; the oscillation plate (320) is mounted on the vortex oscillator (310) and is used to place the drug container (20); the inflation device (330) includes an inflation gas source (3310), an inflation pipeline (3320), an inflation head (3330), an inflation head drive mechanism (3340), and an inflation electronic control valve (3350); The inflation gas source (3310) is mounted on the equipment frame (10). The two ends of the inflation pipeline (3320) are respectively connected to the inflation gas source (3310) and the inflation head (3330). The inflation electric control valve (3350) is mounted on the inflation pipeline (3320) and electrically connected to the electric control system. The inflation head (3330) is mounted on the inflation head drive mechanism (3340). The inflation head drive mechanism (3340) is mounted on the equipment frame (10) and electrically connected to the electric control system. The inflation head (3330) can extend into or leave the drug container (20) placed on the oscillating plate (320) under the action of the inflation head drive mechanism (3340).

3. The processing equipment for hydroxycamptothecin microbubbles for targeted therapy of fibrosis and tumors according to claim 2, characterized in that: The inflation head drive mechanism (3340) includes an inflation lifting screw (3341), an inflation lifting motor (3342), an inflation lifting slide (3343), and an inflation head fixing frame (3344). The inflation lifting screw (3341) and the inflation lifting motor (3342) are mounted on the equipment frame (10) and are connected by transmission between them. The inflation lifting slide (3343) is connected to the inflation lifting screw (3341) by threaded connection. The inflation head fixing bracket (3344) is mounted on the inflation lifting slide (3343). The inflation lifting motor (3342) can drive the inflation lifting screw (3341) to rotate clockwise or counterclockwise, thereby causing the inflation lifting slide (3343) to drive the inflation head fixing bracket (3344) to move up or down.

4. The processing equipment for hydroxycamptothecin microbubbles for targeted therapy of fibrosis and tumors according to claim 1, characterized in that: The hydration dispersion mechanism (40) includes a heating device (410), an ultrasonic oscillator (420), and a hydration device (430); The heating device (410) includes a container placement position (4110), a heating component (4120), and a temperature sensor (4130). The container placement position (4110) is used to place the drug container (10). The heating component (4120) and the temperature sensor (4130) are disposed on the side of the container placement position (4110) and are electrically connected to the electronic control system. The ultrasonic oscillator (420) is disposed at the bottom of the container placement position (4110) and is electrically connected to the electronic control system. The hydration device (430) includes a hydration liquid container (4310), a hydration liquid conveying pipeline (4320), a hydration head (4330), a conveying pump (4340), and a hydration head drive mechanism (4350); The hydrated liquid container (4310) is mounted on the equipment frame (10). The two ends of the hydrated liquid conveying pipe (4320) are respectively connected to the hydrated liquid container (4310) and the hydrated head (4330). The hydrated head (4330) is mounted on the hydrated head driving mechanism (4350). The hydrated head driving mechanism (4350) is mounted on the equipment frame (10) and electrically connected to the electrical control system. The conveying pump (4340) is mounted on the hydrated liquid conveying pipe (4320) and electrically connected to the electrical control system. The hydration head (4330) can extend into or leave the drug container (20) placed in the container placement position (4110) under the drive of the hydration head drive mechanism (4350), and the delivery pump (4340) can deliver the hydration liquid stored in the hydration liquid container (4310) to the drug container (10).

5. The processing equipment for hydroxycamptothecin microbubbles for targeted therapy of fibrosis and tumors according to claim 1, characterized in that: The displacement oscillation mechanism (50) includes a displacement oscillation position (510), a displacement oscillator (520), a sealing device (530), and a ventilation device (540); The sealing device (530) includes a sealing mold (5310), a sealing mold lifting device (5320), and a sealing mold rotating device (5330). The sealing mold (5310) is mounted on the sealing mold lifting device (5320), and the sealing mold lifting device (5320) is mounted on the sealing mold rotating device (5330). The sealing mold (5310) can move up and down under the action of the sealing mold lifting device (5320), and can also rotate together with the sealing mold lifting device (5320) under the action of the sealing mold rotating device (5330). The ventilation device (540) includes a displacement air source (5410), a ventilation pipeline (5420), a ventilation head (5430), a ventilation head drive device (5440), and a ventilation head electrically controlled valve. The displacement air source (5410) is mounted on the equipment frame (10). The two ends of the ventilation pipeline (5240) are respectively connected to the displacement air source (5410) and the ventilation head (5430). The ventilation head (5430) is mounted on the ventilation head drive device (5440). The ventilation head drive device (5440) is mounted on the equipment frame (10) and electrically connected to the electrical control system. The ventilation head electrically controlled valve is mounted on the ventilation pipeline (5420). The ventilation head (5430) can extend into or out of the drug container (20) placed on the displacement oscillation position (510) under the drive of the ventilation head drive device (5440).

6. The processing equipment for hydroxycamptothecin microbubbles for targeted therapy of fibrosis and tumors according to claim 1, characterized in that: The conveying mechanism (60) includes a container clamp (610), an X-axis drive device (620), a Y-axis drive device (630), and a Z-axis drive device (640); The container clamp (610) is an elastic clamp, which is provided with an inlet (6110) and a clamping part (6120). The container clamp (610) is mounted on the Z-axis drive device (640), which is mounted on the X-axis drive device (620) and the Y-axis drive device (630). The container clamp (610) can reciprocate linearly along the Z-axis under the action of the Z-axis drive device (640), and can also reciprocate linearly along the X-axis together with the Z-axis drive device (640) under the action of the X-axis drive device (620), and can also reciprocate linearly along the Y-axis together with the X-axis drive device (620) and the Z-axis drive device (640) under the action of the Y-axis drive device (630).

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