A preparation process and system for thermosensitive gel

Abstract

The present invention discloses a preparation process and system of a thermosensitive gel, which comprises the following steps: (1) preparing a polymerization reaction material in a first preparation tank; (2) the polymerization reaction material is transferred to a reaction tank after sterilization filtration; (3) the initiator is added to the reaction tank after sterilization filtration to react with the polymerization reaction material to obtain a reaction liquid; (4) the reaction liquid is transferred to a purification tank; or the reaction liquid is retained in the reaction tank, in which case the reaction tank is equivalent to the purification tank; (5) a precipitant is prepared in a second preparation tank; (6) the precipitant preparation liquid is transferred to a purification tank after sterilization filtration; (7) precipitation and purification are performed in the purification tank to obtain a thermosensitive gel dispersion. The present invention can ensure the sterility of the product without terminal sterilization, avoids the loss of product performance by traditional sterilization processes, and greatly enhances the temperature-sensitive performance of the product. The purification method in the preparation process of the present invention introduces a dynamic washing process, which can meet the industrial production of a scale of more than 100L.

Description

Technical Field

[0001] The invention relates to the technical field of polymer materials, in particular to a preparation process and system of a temperature-sensitive gel. Background Art

[0002] Interventional therapy is a technology that uses imaging diagnosis as a basis and medical imaging diagnostic equipment such as DSA, CT and MRI as a guide to diagnose and treat diseases. It has the characteristics of less trauma, accurate positioning, high efficacy, fewer complications, quick results and strong repeatability. In addition to medical treatment and surgical treatment, interventional therapy has become the third largest clinical treatment method.

[0003] Transcatheter arterial chemoembolization (TACE) is an interventional treatment method widely used in clinical practice, mainly used for the treatment of advanced tumors. This method can embolize the blood supply artery of the tumor, effectively blocking its blood supply, causing tumor ischemia and necrosis, but has little toxic side effects on tissue cells in other parts, and has obvious therapeutic effects.

[0004] Thermosensitive gel embolic agent is a new generation of intelligent responsive vascular embolic material. Compared with traditional embolic materials such as iodized oil and microspheres, it can effectively solve the contradiction between fluidity and embolic properties, and can achieve conformal embolization from the extremities to large blood vessels.

[0005] Since thermosensitive gel embolic agents are implantable medical devices, the product should be sterile to ensure safety, so sterile control measures must be adopted during the preparation process.

[0006] The existing sterility control methods for medical devices include irradiation sterilization and moist heat sterilization. Among them, irradiation sterilization will cause cross-linking of polymer materials and change their properties; moist heat sterilization will cause the thermosensitive gel to undergo a drastic phase change and it will be difficult to restore to the state before the phase change, resulting in a great loss of thermosensitive properties. The above sterility control methods are difficult to meet the application requirements of the production and preparation process of thermosensitive gel embolic agents.

[0007] In addition, since the polymer monomers used to prepare thermosensitive gels have certain biological toxicity, the residual monomers after the reaction need to be removed during the preparation process. Therefore, an effective and feasible process for removing residual monomers suitable for large-scale production is also an important technical point in the preparation process of thermosensitive gels.

[0008] There are usually two methods to remove residual monomers:

[0009] One is the dialysis method, which uses a dialysis membrane or dialyzer to remove small molecule impurities by utilizing the concentration gradient across the membrane. The reaction solution is dialyzed to remove small molecule impurities (residual monomers) and then freeze-dried to obtain purified thermosensitive gel freeze-dried powder. However, this method can only process small sample liquids and cannot meet the needs of large-scale production.

[0010] Another method is to add a precipitant to the reaction solution, filter out the clear solution containing residual monomers, obtain a thermosensitive gel precipitate, and obtain a thermosensitive gel powder after drying and crushing the precipitate. For example, CN103224586B discloses this method, but the gel precipitate before the drying and crushing process in this method is a whole block precipitate. In large-scale production, the volume of the gel precipitate is larger than the laboratory level, and the organic solvent inside the gel is difficult to achieve complete drying, which will introduce impurities into the next step and eventually into the product. In addition, the gel block that has not been thoroughly dried is sticky, which affects the effect of the crushing process.

[0011] The drawback of the above two methods for removing residual monomers is that it is difficult to achieve large-scale production. In addition, the above two purification methods involve the transfer of solid materials. During the production process, liquid materials can be transferred through sealed pipes, while the transfer of solid materials is usually carried out in an open space and is done manually, which increases the risk of product contamination. Summary of the invention

[0012] In view of the shortcomings of the prior art, the present invention provides a preparation process of a thermosensitive gel and a preparation system for realizing the process. The present invention creates an aseptic production process route suitable for thermosensitive gel, avoids the performance loss of the product caused by the existing sterilization technology, and can break through the limitation of the existing technology that is difficult to achieve industrial production and realize large-scale production.

[0013] In order to achieve the above object, the present invention adopts the following technical solutions:

[0014] A preparation process of a thermosensitive gel comprises the following steps:

[0015] (1) preparing a polymerization reaction material in a first preparation tank;

[0016] Weigh raw materials 1 to 4, dilute with injection water, set the temperature to 20 to 90° C., and stir until completely dissolved; wherein raw material 1 is N-isopropylacrylamide, and the molar concentration after diluting is 0.1 to 0.2 mol / L; raw material 2 is at least one of acrylic acid, acrylate, methacrylate, acrylamide and derivatives thereof, and the amount thereof accounts for 1% to 25% of the molar number of raw material 1; raw material 3 is a bisacrylamide compound or a derivative thereof, and the amount thereof accounts for 0.1% to 10% of the sum of the molar numbers of raw materials 1 and 2; raw material 4 is one of sodium stearoyl glutamate, glyceryl monostearate, glyceryl monoester, and polyoxyethylene stearate, and the molar concentration thereof after diluting is 0.1 to 10 mmol / L;

[0017] (2) The polymerization reaction materials are transferred to a reaction tank after sterilization filtration;

[0018] (3) the initiator is sterilized and filtered and then put into a reaction tank to carry out polymerization reaction with the polymerization reaction material to obtain a reaction liquid;

[0019] The initiator is one of azobisisobutylamidine hydrochloride, azobisisobutylimidazoline hydrochloride, azobisisobutylimidazoline, azobiscyanovaleric acid initiator, persulfate, and persulfate-sulfite. The molar concentration of the initiator in the entire reaction system is 1-10 mmol / L.

[0020] (4) The reaction liquid is transferred to a purification tank; or the reaction liquid is retained in the reaction tank, in which case the reaction tank is equivalent to the purification tank;

[0021] (5) preparing a precipitant in a second preparation tank;

[0022] The precipitant is at least one of ethanol, sodium chloride, potassium chloride, magnesium chloride, calcium chloride, sodium hydroxide and sodium sulfate; when a solid precipitant is selected, it needs to be prepared into a precipitant preparation liquid, which is prepared by diluting the precipitant with injection water at a preparation temperature of 10 to 75° C. to a concentration of 10 to 25 wt %, and stirring until it is completely dissolved; the amount of the precipitant is 5 to 20% of the total mass of the reaction solution and the precipitant preparation liquid;

[0023] (6) The precipitant solution is sterile filtered and transferred to a purification tank;

[0024] (7) Purify by precipitation in a purification tank to obtain a thermosensitive gel dispersion.

[0025] Preferably, the precipitation purification in step (7) specifically comprises the following steps:

[0026] (7.1) The reaction solution and the precipitant are stirred and mixed, and allowed to stand at a constant temperature of 50 to 90°C for 0.5 to 2 hours, and the gel is precipitated to form a flocculent precipitate.

[0027] (7.2) Open the discharge valve of the purification tank, set the centrifugal drum speed to 1000-1500 rpm, and discharge the clear liquid through centrifugation in the tank to remove residual monomers and precipitant;

[0028] (7.3) Keep the discharge valve of the purification tank open, the centrifugal drum speed is 1000-1500rpm, add 50-90°C water for injection into the purification tank and discharge the clear liquid through centrifugation in the tank, and control the water addition speed so that the weight in the tank reaches dynamic balance; the total amount of water for injection is 300-2000kg;

[0029] (7.4) Keep the discharge valve of the purification tank open, stop water inlet, set the centrifugal drum speed at 1000-1500 rpm, and empty the washing liquid in the tank by centrifugation;

[0030] (7.5) Add 5-30°C water for injection into the purification tank and stir for 4-48 hours to redissolve the gel precipitate to obtain a sterile thermosensitive nanogel dispersion; the amount of water for injection is 10-50 times the mass of the gel precipitate in the tank.

[0031] Wherein, the feeding of the initiator in step (3) is carried out in two steps, as follows:

[0032] (1) Under argon protection, the temperature of the material in the reaction tank is raised or lowered to a preset reaction temperature of 20 to 90° C., 70% volume of the initiator solution is added to the reaction tank after sterilization filtration, the reaction temperature is 20 to 90° C., and the reaction is continued for 2 to 4 hours under argon protection;

[0033] (2) The remaining initiator solution is sterile filtered and added to the reaction tank. The reaction temperature is kept constant and the reaction is continued for 2 to 20 hours under argon protection to obtain a reaction solution.

[0034] Preferably, the sterilizing filtration is achieved through a sterilizing filter, and a 0.22 μm pleated filter element is installed in the sterilizing filter.

[0035] The sterilizing filtration is specifically passing through at least one sterilizing filter. Preferably, the sterilizing filtration is specifically passing through two sterilizing filters.

[0036] The conveying in steps (2) and (4) is carried out by pressurizing the tank to 0.1-0.4 MPa and conveying the material or reaction liquid through a pipeline.

[0037] Another object of the present invention is to disclose a system for realizing the above-mentioned temperature-sensitive gel preparation process, including a first preparation tank, a reaction tank, a feeding tool, a second preparation tank, a purification tank, a plurality of sterilizing filters, and a PLC control module.

[0038] in:

[0039] The first preparation tank is used to prepare polymerization reaction materials, including:

[0040] The first feed port is used to feed raw materials;

[0041] The first stirring blade is used for mixing and dissolving materials;

[0042] A first jacket, used to control the temperature in the tank, the first jacket being connected to a cold medium and a hot medium;

[0043] A first water inlet, used for adding water for injection;

[0044] The first spray ball is used for cleaning inside the equipment;

[0045] A first discharge port, used for discharging materials;

[0046] The first air inlet is used to introduce compressed air to assist in discharging or transferring materials, and is connected to the air source through a sterilizing filter;

[0047] The first respirator is used to balance the internal and external air pressure when it is turned on, and can maintain the pressure in the tank when it is closed; it is connected to the external environment through a sterilizing filter.

[0048] The reaction tank is used for polymerization reaction, comprising:

[0049] A second feed port, connected to the first discharge port through a pipeline, for receiving the prepared material in the first preparation tank;

[0050] The second stirring blade is used for mixing materials;

[0051] A second jacket, used to control the temperature in the tank, the second jacket being connected to a cold medium and a hot medium;

[0052] The second water inlet is used to add water for injection;

[0053] The second spray ball is used for cleaning inside the equipment;

[0054] A second discharge port, used for discharging materials;

[0055] The second air inlet can be fed with compressed air to assist in discharging or transferring materials, and is connected to the air source through a sterilizing filter;

[0056] The second respirator is used to balance the internal and external air pressure when it is turned on, and can maintain the pressure inside the tank when it is closed; it is connected to the external environment through a sterilizing filter.

[0057] The feeding tool has a built-in initiator and is used to feed the initiator into the reaction tank.

[0058] The second preparation tank is used to prepare the precipitant, and comprises:

[0059] The third feed port is used to feed raw materials;

[0060] The third stirring blade is used for mixing and dissolving materials;

[0061] A third jacket, used to control the temperature in the tank, the third jacket being connected to cold and hot media;

[0062] The third water inlet is used to add water for injection;

[0063] The third spray ball is used for cleaning inside the equipment;

[0064] The third discharge port is used for discharging the prepared precipitant into the purification tank;

[0065] The third air inlet can be fed with compressed air to assist in discharging or transferring materials, and is connected to the air source through a sterilizing filter;

[0066] The third respirator is used to balance the internal and external air pressure when it is turned on. It can maintain the pressure inside the tank when it is closed and is connected to the external environment through a sterilizing filter.

[0067] The purification tank is used to remove small molecule residual raw materials and impurities, including:

[0068] The fourth feed port is connected to the second and third feed ports through pipelines and is used to receive materials from the reaction tank and the second preparation tank;

[0069] The fourth stirring blade is used to mix the materials;

[0070] A fourth jacket, used to control the temperature in the tank, the fourth jacket being connected to cold and hot media;

[0071] The fourth water inlet is used to add water for injection;

[0072] The fourth spray ball is used for cleaning inside the equipment;

[0073] The fourth centrifugal drum is used for mixing materials at a low speed and for separating precipitation and washing liquid at a high speed;

[0074] The fourth discharge port is used for discharging materials;

[0075] The fourth air inlet can be fed with compressed air to assist in discharging or transferring materials, and is connected to the air source through a sterilizing filter;

[0076] The fourth respirator is used to balance the internal and external air pressures when it is turned on, and can maintain the pressure in the tank when it is closed. The fourth respirator is connected to the external environment through a sterilizing filter.

[0077] Preferably, the feeding tool comprises:

[0078] A discharge port, used for discharging materials;

[0079] The air inlet can be fed with compressed air to assist in the discharge or transfer of materials, and is connected to the air source through a sterilizing filter;

[0080] The respirator is used to balance the internal and external air pressure when it is turned on. It can maintain the pressure inside the tank when it is closed and is connected to the external environment through a sterilizing filter.

[0081] Preferably, each tank body is provided with a weighing module, a liquid level sensor, a temperature sensor and a timing module, and the PLC control module is electrically connected to the first preparation tank, the second preparation tank, the reaction tank and the purification tank respectively, and is operated through a touch screen, and automatic control can be achieved by editing the program.

[0082] Preferably, the automated control specifically includes:

[0083] Automatic material addition and volume determination can be achieved by controlling the weighing module and liquid level sensor;

[0084] The temperature inside the tank is controlled by controlling the temperature sensor and the cold and hot medium of the jacket;

[0085] Adding materials is achieved by controlling the valves of the first feed inlet, the second feed inlet, the third feed inlet or the fourth feed inlet, and adding water is achieved by controlling the valves of the first water inlet, the second water inlet, the third water inlet or the fourth water inlet;

[0086] The tank is pressurized by controlling the valves of the first air inlet, the second air inlet, the third air inlet or the fourth air inlet, and the material is conveyed by controlling the valves of the first discharge port, the second discharge port, the third discharge port or the fourth discharge port.

[0087] Preferably, the fourth centrifugal drum is rotatably connected to the bottom of the purification tank, has a surface layer of a mesh structure, and has an inner layer of a cavity.

[0088] Compared with the prior art, the present invention has the following beneficial effects:

[0089] The preparation process of the thermosensitive gel of the present invention adopts full-process aseptic production, which is specifically manifested as follows:

[0090] (1) All raw materials are sterilized and filtered before participating in the process. After the sterilization and filtration, the subsequent process (polymerization, purification, and material transportation involved in each process) is carried out in a closed system and completed by a PLC automation system. The materials do not come into contact with personnel or the environment. Therefore, the preparation process of the present invention can ensure the sterility of the product without terminal sterilization, avoiding the loss of product performance caused by traditional sterilization processes, and greatly enhancing the embolic performance of the product.

[0091] (2) The purification method of dialysis-freeze drying is a laboratory small sample purification method and is not suitable for large-scale production; the process route of precipitation-drying-crushing has a reduced efficiency in removing impurities and process feasibility as the production scale is enlarged. The purification method in the preparation process of the present invention introduces a dynamic washing process, which can meet the industrial production of a scale of more than 100L. BRIEF DESCRIPTION OF THE DRAWINGS

[0092] Figure 1 It is a structural schematic diagram of a system for preparing a temperature-sensitive gel according to Example 1 of the present invention. DETAILED DESCRIPTION

[0093] The present invention is further described below in conjunction with specific embodiments, but the embodiments do not limit the present invention in any form. Unless otherwise specified, the raw materials and reagents used in the embodiments of the present invention are conventionally purchased raw materials and reagents.

[0094] Examples 1-3 of the present invention and Comparative Examples 1-2 are all 100 L systems.

[0095] Example 1

[0096] This embodiment provides a system for preparing a thermosensitive gel. Figure 1 As shown, it includes: a first preparation tank 1, a reaction tank 2, a feeding tool 3, a second preparation tank 4, a purification tank 5, a plurality of sterilizing filters 6 and a PLC control module 7.

[0097] Wherein: the first preparation tank 1 is used to prepare the polymerization reaction materials, including:

[0098] The first feed port 11 is used to feed raw materials;

[0099] The first stirring blade 12 is rotatably connected to the top of the tank body through a stirring member, and is used for mixing and dissolving materials;

[0100] A first jacket 13 is arranged around the outer periphery of the tank body and is used to control the temperature inside the tank. The first jacket is connected to the cold and hot media;

[0101] A first water inlet 14 is used to add water for injection;

[0102] The first spray ball 15 is used for cleaning inside the equipment. The spray ball is a small ball with a hole. A water pipe is inserted into the tank at the water inlet. The terminal of the water pipe is movably connected to the spray ball. After the pressurized injection water enters through the water inlet, the ball will rotate and spray water.

[0103] A first discharge port 16, for discharging materials;

[0104] The first air inlet 17 is used to introduce compressed air to assist in discharging or transferring materials, and is connected to the air source through a sterilizing filter;

[0105] The first respirator 18 is used to balance the internal and external air pressures when turned on, and can maintain the pressure in the tank when turned off; it is connected to the external environment through a sterilizing filter.

[0106] Reaction tank 2, used for polymerization reaction, comprising:

[0107] The second feed port 21 is connected to the first discharge port 16 and the discharge port 31 through a pipeline, and is used to receive the prepared material in the first preparation tank 1 and the initiator in the feeding tool 3;

[0108] The second stirring blade 22 is used for mixing materials;

[0109] A second jacket 23 is used to control the temperature in the tank, and the second jacket is connected to the cold and hot media;

[0110] A second water inlet 24 is used to add water for injection;

[0111] The second spray ball 25 is used for cleaning inside the equipment;

[0112] A second discharge port 26, for discharging materials;

[0113] The second air inlet 27 can be fed with compressed air to assist in discharging or transferring materials. The second air inlet 27 is connected to the air source through a sterilizing filter;

[0114] The second respirator 28 is used to balance the internal and external air pressures when it is turned on, and can maintain the pressure in the tank when it is turned off; it is connected to the external environment through a sterilizing filter.

[0115] The feeding tool 3, with a built-in initiator, is used to feed the initiator into the reaction tank 2, including:

[0116] A feeding and discharging port 31 is used for discharging materials;

[0117] The feeding air inlet 32 ​​can be fed with compressed air to assist in discharging or transferring materials, and is connected to the air source through a sterilizing filter;

[0118] The feeding respirator (not shown) is used to balance the internal and external air pressure when opened. It can maintain the pressure in the tank when closed and is connected to the external environment through a sterilizing filter.

[0119] The second preparation tank 4 is used to prepare the precipitant, including:

[0120] The third feed port 41 is used to feed raw materials;

[0121] The third stirring blade 42 is used for mixing and dissolving materials;

[0122] The third jacket 43 is used to control the temperature in the tank. The third jacket is connected to the cold and hot media; the cold and hot media can be passed into the jacket to achieve temperature control in the tank.

[0123] A third water inlet 44 is used to add water for injection;

[0124] The third spray ball 45 is used for cleaning inside the equipment;

[0125] The third discharge port 46 is used for discharging the prepared precipitant into the purification tank;

[0126] The third air inlet 47 can be fed with compressed air to assist in discharging or transferring materials, and is connected to the air source through a sterilizing filter;

[0127] The third respirator 48 is used to balance the internal and external air pressures when it is turned on, and can maintain the pressure in the tank when it is turned off, and is connected to the external environment through a sterilizing filter.

[0128] Purification tank 5, used to remove small molecule residual raw materials and impurities, including:

[0129] The fourth feed port 51 is connected to the second discharge port 26 and the third discharge port 46 through a pipeline, and is used to receive materials from the reaction tank 2 and the second preparation tank 4;

[0130] The fourth stirring blade (not shown) is used for mixing materials;

[0131] A fourth jacket 53, used to control the temperature in the tank, the fourth jacket being connected to cold and hot media;

[0132] A fourth water inlet 54, for adding water for injection;

[0133] The fourth spray ball 55 is used for cleaning inside the equipment;

[0134] The fourth centrifugal drum 56 is rotatably connected to the bottom of the purification tank 5, and its surface layer is a mesh structure with a mesh diameter of 0.4 mm, and the inner layer is a cavity. It is used for mixing materials at a low speed and for separating precipitation and washing liquid at a high speed;

[0135] A fourth discharge port 57, for discharging materials;

[0136] The fourth air inlet 58 can be fed with compressed air to assist in discharging or transferring materials, and is connected to the air source through a sterilizing filter;

[0137] The fourth respirator 59 is used to balance the internal and external air pressures when opened, and can maintain the pressure in the tank when closed. The fourth respirator is connected to the external environment through a sterilizing filter.

[0138] The first discharge port 16 of the first preparation tank 1 is connected to the reaction tank 2 through a pipeline, passing through at least two sterilizing filters 6, that is, two sterilizing filters 6 are installed in the middle of the pipeline connecting the first preparation tank 1 and the reaction tank 2, and the material is transmitted from the first preparation tank 1 to the reaction tank 2 through at least two filtering processes, preferably two.

[0139] The feeding tool 3 is connected to the second feeding port 21 of the reaction tank 2 through a pipeline, passing through two sterilizing filters 6 .

[0140] The second discharge port 26 of the reaction tank 2 is connected to the fourth feed port 51 of the purification tank 5 through a pipeline; the third discharge port 46 of the second preparation tank 4 is connected to the fourth feed port 51 of the purification tank 5 through a pipeline, passing through two sterilizing filters.

[0141] In the preparation system of the thermosensitive gel of the present invention, each tank body is also provided with a weighing module, a liquid level sensor, a timing module, and a temperature sensor. The preparation system of the thermosensitive gel of the present invention also includes a PLC control module 7, which is electrically connected to the first preparation tank, the second preparation tank, the reaction tank, and the purification tank, respectively, and is operated through a touch screen display. Automatic control can be achieved through editing programs: automatic volume setting is achieved by controlling the weighing module and the liquid level sensor; adding materials is achieved by controlling the valves of the first feed port, the second feed port, the third feed port, or the fourth feed port, and adding water is achieved by controlling the valves of the first water inlet, the second water inlet, the third water inlet, or the fourth water inlet; the first The valves at the air inlet, the second air inlet, the third air inlet or the fourth air inlet realize pressurization in the tank, and cooperate with the valves at the first outlet, the second outlet, the third outlet or the fourth outlet to realize material transmission; the timing dispersion, stirring or static sedimentation operation is completed by controlling the timing module; the temperature in the tank is controlled by controlling the temperature sensor and the cold and hot medium of the first jacket, the cold and hot medium of the second jacket, the cold and hot medium of the third jacket, and the cold and hot medium of the fourth jacket (the cold and hot medium are respectively introduced into the jacket to realize the connection between the cold and hot medium and the first jacket, the second jacket, the third jacket, and the fourth jacket).

[0142] Example 2

[0143] This embodiment provides a system for preparing a thermosensitive gel, which is the same as that of embodiment 1, except that:

[0144] The functions of the reaction tank 2 and the purification tank 5 are combined into the same tank body, that is, the system only includes: the first preparation tank 1, the reaction tank 2, the feeding tool 3, the second preparation tank 4, multiple sterilizing filters 6 and the PLC control module 7. After the reaction, the reaction liquid in the reaction tank 2 is not transferred to the purification tank 5, but remains in the reaction tank 2, and then the third discharge port 46 in the second preparation tank 4 is connected to the second feed port of the reaction tank 2 through a pipeline. At this time, the reaction tank is equivalent to the purification tank, and has the structure and function of the purification tank.

[0145] Example 3

[0146] Based on the temperature-sensitive gel preparation system of Example 1, this example provides a preparation process of a temperature-sensitive gel:

[0147] First, weigh 1131.6g (10mol) of N-isopropylacrylamide, 114.1g (2mol) of acrylic acid, 18.5g (0.12mol) of N,N'-methylenebisacrylamide, and 43.6g (0.1mol) of sodium stearoyl glutamate, add them to the first preparation tank 1, dilute to 100L with water for injection, stir and dissolve at 50°C to prepare the polymerization reaction material. And pre-install an aqueous solution of azobisisobutylamidine hydrochloride in the feeding tool 3, with a volume of 1.5L, which contains 54.2g (0.2mol) of azobisisobutylamidine hydrochloride.

[0148] Open the valve of the first outlet 16 of the first preparation tank 1, pressurize the tank through the first air inlet 17, set the pressure to 0.3 MPa, and transfer the material to the reaction tank 2 through the pipeline and the sterilizing filter 6. Under the protection of argon, raise the temperature of the material in the tank to 65°C.

[0149] 1.05 L of initiator solution (aqueous solution of azobisisobutylamidine hydrochloride) in feeding tool 3 was added to the reaction tank after sterilization filtration, and stirred and mixed with the polymer reaction materials added previously, and reacted under argon protection at a temperature of 65° C. for 4 hours.

[0150] The remaining 0.45 L of initiator solution in the feeding tool 3 was added to the reaction tank after sterilization filtration, stirred and mixed, and the reaction was continued for 4 hours at 65° C. in the same argon atmosphere to obtain a reaction solution.

[0151] The valve of the second discharge port 26 of the reaction tank 2 is opened, and the tank is pressurized through the second air inlet 27. The pressure is set to 0.3 MPa and the reaction liquid is transferred to the purification tank 5 through the pipeline.

[0152] Weigh 10 kg of calcium chloride and put it into the second preparation tank 4, add 30 kg of water for injection, and stir and dissolve at 30° C. to obtain a precipitant solution.

[0153] The valve of the third discharge port 46 of the second preparation tank 4 is opened, and the inside of the tank is pressurized through the third air inlet 47, and the pressure is set to 0.3 MPa, and the precipitant solution is transferred to the purification tank 5 through the pipeline and the sterilizing filter.

[0154] The reaction solution and the precipitant solution in the purification tank 5 are stirred and mixed, and the mixture of the reaction solution and the precipitant solution is allowed to stand at a constant temperature of 50° C. for 1 hour, and gel is precipitated to form flocculent precipitates.

[0155] The valve of the fourth discharge port 57 of the purification tank 5 is opened, the speed of the centrifugal drum 56 is set to 1500 rpm, and the clear liquid is discharged by centrifugation in the tank to remove the residual monomers and the precipitant.

[0156] The valve of the fourth discharge port 57 of the purification tank 5 is kept open, the speed of the centrifugal drum 56 is 1500rpm, and 70°C water for injection is added to the purification tank 5 while the clear liquid is discharged through centrifugation in the tank. The water adding speed is automatically adjusted by the PLC system according to the feedback of the weighing template to make the weight in the tank reach dynamic balance. The total amount of water for injection is 1500kg.

[0157] The valve of the fourth discharge port 57 was kept open, water was stopped, the speed of the centrifugal drum 56 was 1500 rpm, and the liquid in the tank was emptied by centrifugation. 4 kg of gel precipitate remained in the tank.

[0158] Add 50 kg of 20° C. injection water to the purification tank 5 and stir for 36 hours to redissolve the gel precipitate. Thus, a sterile thermosensitive nanogel dispersion is obtained.

[0159] In the above preparation process, except for weighing the polymerization reaction materials, weighing the initiator, and feeding, the rest of the operations are performed through the preset program of the PLC control module.

[0160] Example 4

[0161] Based on the temperature-sensitive gel preparation system of Example 1, this example provides a preparation process of a temperature-sensitive gel:

[0162] First, weigh 2263.2g (20mol) of N-isopropylacrylamide, 25.6g (0.2mol) of butyl acrylate, 3.08g (0.02mol) of N,N'-methylenebisacrylamide, and 314.5g (1mol) of polyoxyethylene stearate, add them to the first preparation tank 1, dilute to 100L with injection water, stir and dissolve at 60°C to prepare the polymerization reaction material. And pre-install the aqueous solution of azobisisobutylimidazoline in the feeding tool 3, the volume is 2L, which contains 161.6g (0.5mol) of azobisisobutylimidazoline.

[0163] Open the valve of the first outlet 16 of the first preparation tank 1, pressurize the tank through the first air inlet 17, set the pressure to 0.4 MPa, and transfer the material to the reaction tank 2 through the pipeline and the sterilizing filter 6. Under the protection of argon, raise the temperature of the material in the tank to 50°C.

[0164] 1.4 L of initiator solution (aqueous solution of azobisisobutylimidazoline) in feeding tool 3 was added to reaction tank 2 after sterilization filtration, and stirred and mixed with the polymer reaction materials added previously, and reacted under argon protection at a temperature of 50° C. for 3 hours.

[0165] The remaining 0.6 L initiator solution in the feeding tooling 3 was added into the reaction tank 2 after sterilization filtration, stirred and mixed, and the reaction was continued for 2 h at the same argon atmosphere and 50° C. to obtain a reaction solution.

[0166] The valve of the second discharge port 26 of the reaction tank 2 is opened, and the tank is pressurized through the second air inlet 27. The pressure is set to 0.4 MPa and the reaction liquid is transferred to the purification tank 5 through the pipeline.

[0167] Weigh 15 kg of sodium sulfate and put it into the second preparation tank 4, add 30 kg of water for injection, and stir and dissolve at 40° C. to obtain a precipitant solution.

[0168] The valve of the third discharge port 46 of the second preparation tank 4 is opened, and the inside of the tank is pressurized through the third air inlet 47, and the pressure is set to 0.4 MPa, and the precipitant solution is transferred to the purification tank 5 through the pipeline and the sterilizing filter 6.

[0169] The reaction solution and the precipitant solution in the purification tank 5 are stirred and mixed, and the mixture of the reaction solution and the precipitant solution is allowed to stand at a constant temperature of 60° C. for 2 hours, and gel is precipitated to form flocculent precipitates.

[0170] The valve of the fourth discharge port 57 of the purification tank 5 is opened, the speed of the centrifugal drum 56 is set to 1000 rpm, and the clear liquid is discharged by centrifugation in the tank to remove the residual monomers and the precipitant.

[0171] The valve of the fourth discharge port 57 of the purification tank 5 is kept open, the speed of the centrifugal drum 56 is 1000 rpm, and 50°C water for injection is added to the purification tank 5 while the clear liquid is discharged through centrifugation in the tank. The water adding speed is automatically adjusted by the PLC system according to the feedback of the weighing template to make the weight in the tank reach dynamic balance. The total amount of water for injection is 2000 kg.

[0172] The valve of the fourth discharge port 57 is kept open, water is stopped from entering, the speed of the centrifugal drum 56 is set at 1000 rpm, and the liquid in the tank is emptied by centrifugation, and 5 kg of gel precipitate remains in the tank.

[0173] Add 50 kg of 30° C. water for injection into the purification tank 5 and stir for 4 hours to redissolve the gel precipitate. Thus, a sterile thermosensitive nanogel dispersion is obtained.

[0174] In the above preparation process, except for weighing the polymerization reaction materials, weighing the initiator, and feeding, the rest of the operations are performed through the preset program of the PLC control module.

[0175] Example 5

[0176] Based on the temperature-sensitive gel preparation system of Example 1, this example provides a preparation process of a temperature-sensitive gel:

[0177] First, weigh 1697.4g (15mol) of N-isopropylacrylamide, 266.6g (3.75mol) of acrylamide, 289.1g (1.875mol) of N,N'-methylenebisacrylamide, and 3.6g (0.01mol) of glycerol monostearate, add them to the first preparation tank 1, dilute to 100L with injection water, stir and dissolve at 90°C to prepare the polymerization reaction material. And pre-install an aqueous solution of sodium persulfate in the feeding tool 3, with a volume of 1L, which contains 71.4g (0.3mol) of sodium persulfate.

[0178] The valve of the first discharge port 16 of the first preparation tank 1 was opened, and the tank was pressurized to set the pressure to 0.1 MPa, and the material was transferred to the reaction tank 2 through the pipeline and the sterilizing filter 6. Under the protection of argon, the temperature of the material in the tank was raised to 90°C.

[0179] 0.7 L of initiator solution (aqueous solution of sodium persulfate salt) in feeding tool 3 was added to reaction tank 2 after sterilization filtration, and mixed with the polymer reaction material added previously, and reacted under argon protection at a temperature of 90° C. for 2 hours.

[0180] The remaining 0.3 L initiator solution in the feeding tooling 3 was added into the reaction tank 2 after sterilization filtration, stirred and mixed, and the reaction was continued for 20 h at 90° C. in the same argon atmosphere to obtain a reaction solution.

[0181] The valve of the second discharge port 26 of the reaction tank 2 is opened, and the tank is pressurized through the second air inlet 27. The pressure is set to 0.1 MPa and the reaction liquid is transferred to the purification tank 5 through the pipeline.

[0182] Weigh 40 kg of anhydrous ethanol as a precipitant solution.

[0183] The valve of the third discharge port 46 of the second preparation tank 4 is opened, and the inside of the tank is pressurized through the third air inlet 47, and the pressure is set to 0.1 MPa, and the precipitant solution is transferred to the purification tank 5 through the pipeline and the sterilizing filter 6.

[0184] The reaction solution and the precipitant solution in the purification tank 5 are stirred and mixed, and the mixture of the reaction solution and the precipitant solution is allowed to stand at a constant temperature of 75° C. for 0.5 hours, and gel is precipitated to form flocculent precipitates.

[0185] The valve of the fourth discharge port 57 of the purification tank 5 is opened, the speed of the centrifugal drum 56 is set to 1200 rpm, and the clear liquid is discharged by centrifugation in the tank to remove residual monomers and precipitant.

[0186] The valve of the fourth discharge port 57 of the purification tank 5 is kept open, the speed of the centrifugal drum 56 is 1200rpm, and 90°C water for injection is added to the purification tank 5 while the clear liquid is discharged through centrifugation in the tank. The water adding speed is automatically adjusted by the PLC system according to the feedback of the weighing template to make the weight in the tank reach dynamic balance. The total amount of water for injection is 300kg.

[0187] The valve of the fourth discharge port 57 was kept open, water was stopped, the speed of the centrifugal drum 56 was 1200 rpm, and the liquid in the tank was emptied by centrifugation. 4.5 kg of gel precipitate remained in the tank.

[0188] Add 50 kg of 5° C. water for injection into the purification tank 5 and stir for 48 hours to redissolve the gel precipitate. Thus, a sterile thermosensitive nanogel dispersion is obtained.

[0189] In the above preparation process, except for weighing the polymerization reaction materials, weighing the initiator, and feeding, the rest of the operations are performed through the preset program of the PLC control module.

[0190] Comparative Example 1

[0191] Based on the thermosensitive gel preparation system of Example 1, the filter elements of all filters are removed, and only the filter housing (which functions as a transmission pipeline) is retained. This comparative example 1 provides a preparation process for thermosensitive gel, which is based on Example 3, but removes the sterilization filtration step.

[0192] First, weigh 1131.6g (10mol) of N-isopropylacrylamide, 114.1g (2mol) of acrylic acid, 18.5g (0.12mol) of N,N'-methylenebisacrylamide, and 43.6g (0.1mol) of sodium stearoyl glutamate, add them to the first preparation tank 1, dilute to 100L with water for injection, stir and dissolve at 50°C to prepare the polymerization reaction material. And pre-install an aqueous solution of azobisisobutylamidine hydrochloride in the feeding tool 3, with a volume of 1.5L, which contains 54.2g (0.2mol) of azobisisobutylamidine hydrochloride.

[0193] The valve of the first discharge port 16 of the first preparation tank 1 was opened, and the tank was pressurized through the first air inlet 17, and the pressure was set to 0.3 MPa, and the material was transferred to the reaction tank 2 through the pipeline. Under the protection of argon, the temperature of the material in the tank was raised to 65°C.

[0194] 1.05 L of initiator solution (aqueous solution of azobisisobutylamidine hydrochloride) in feeding tool 3 was added to the reaction tank, stirred and mixed with the polymer reaction materials added previously, and reacted under argon protection at a temperature of 65° C. for 4 hours.

[0195] The remaining 0.45 L of initiator solution in the feeding tool 3 was added into the reaction tank, stirred and mixed, and the reaction was continued for 4 h at 65° C. under the same argon atmosphere to obtain a reaction solution.

[0196] The valve of the second discharge port 26 of the reaction tank 2 is opened, and the tank is pressurized through the second air inlet 27. The pressure is set to 0.3 MPa and the reaction liquid is transferred to the purification tank 5 through the pipeline.

[0197] Weigh 10 kg of calcium chloride and put it into the second preparation tank 4, add 30 kg of water for injection, and stir and dissolve at 30° C. to obtain a precipitant solution.

[0198] The valve of the third discharge port 46 of the second preparation tank 4 is opened, and the inside of the tank is pressurized through the third air inlet 47, and the pressure is set to 0.3 MPa, and the precipitant solution is transferred to the purification tank 5 through the pipeline.

[0199] The reaction solution and the precipitant solution in the purification tank 5 are stirred and mixed, and the mixture of the reaction solution and the precipitant solution is allowed to stand at a constant temperature of 50° C. for 1 hour, and gel is precipitated to form flocculent precipitates.

[0200] The valve of the fourth discharge port 57 of the purification tank 5 is opened, the speed of the centrifugal drum 56 is set to 1500 rpm, and the clear liquid is discharged by centrifugation in the tank to remove the residual monomers and the precipitant.

[0201] The valve of the fourth discharge port 57 of the purification tank 5 is kept open, the speed of the centrifugal drum 56 is 1500rpm, and 70°C water for injection is added to the purification tank 5 while the clear liquid is discharged through centrifugation in the tank. The water adding speed is automatically adjusted by the PLC system according to the feedback of the weighing template to make the weight in the tank reach dynamic balance. The total amount of water for injection is 1500kg.

[0202] The valve of the fourth discharge port 57 was kept open, water was stopped, the speed of the centrifugal drum 56 was 1500 rpm, and the liquid in the tank was emptied by centrifugation. 4 kg of gel precipitate remained in the tank.

[0203] Add 50 kg of 20° C. injection water to the purification tank 5 and stir for 36 hours to redissolve the gel precipitate. Thus, a thermosensitive nanogel dispersion is obtained.

[0204] In the above preparation process, except for weighing the polymerization reaction materials, weighing the initiator, and feeding, the rest of the operations are performed through the preset program of the PLC control module.

[0205] Comparative Example 2

[0206] The preparation of the thermosensitive nanogel dispersion is the same as that of Comparative Example 1.

[0207] Based on the thermosensitive gel preparation system of comparative example 1, a terminal wet heat sterilization process is added, that is, after the thermosensitive nanogel dispersion is prepared, the temperature of the purification tank 5 is increased to 121° C. for 15 minutes to obtain a sterile thermosensitive nanogel dispersion.

[0208] Example and Comparative Example Test 1

[0209] Take the thermosensitive nanogel dispersions prepared in Examples 3-5 and Comparative Examples 1-2, and perform sterility testing with reference to the sterility test method in Part IV, 1101 of the 2020 edition of the Chinese Pharmacopoeia.

[0210] Sample processing: Take 18 samples, each 5 ml, thoroughly disinfect the surface of the sample container, and take the sample for inspection according to aseptic operation.

[0211] Test sample detection: Take 6 test samples, take half of each sample (2.5 ml), and inoculate them equally into 2 bottles of 500 ml thioglycollate fluid culture medium and 1 bottle of 500 ml tryptic soytone liquid culture medium. One tube of thioglycollate fluid culture medium and one tube of tryptic soytone liquid culture medium are used as the test sample group.

[0212] Negative control group: Take 2 tubes of 500 ml thioglycollate fluid culture medium and 1 tube of 500 ml tryptic soytone liquid culture medium as the negative control group.

[0213] Positive control of test article and positive control group: transfer one tube of thioglycollate fluid culture medium of test article and one tube of thioglycollate fluid culture medium of negative control group into positive room, add no more than 100 cfu of Staphylococcus aureus in the biosafety cabinet of positive room, respectively as positive control of test article and positive control group.

[0214] Culture observation: thioglycollate fluid culture medium is cultured at 30-35℃, and trypticase soy bean liquid culture medium is cultured at 20-25℃. The culture time of the test sample group and negative control group shall not be less than 14 days. The culture time of the test sample positive control and positive control shall not exceed 5 days, and the growth situation in the filter cartridge shall be recorded.

[0215] The test results are shown in Table 1.

[0216] Example and Comparative Example Test 2

[0217] Take 100 ml of each of the thermosensitive nanogel dispersions prepared in Examples 3-5 and Comparative Examples 1-2, add 0.9 g of sodium chloride and 64.8 g of iohexol, respectively, to obtain the corresponding thermosensitive nanogel embolic agents.

[0218] The complex shear modulus of the embolic agent at 25°C and 37°C was measured using a rotational rheometer and expressed as G*(25) and G*(37), respectively. * (37) / G * (25). The higher the ratio, the stronger the temperature sensitivity of the material.

[0219] The test conditions are as follows:

[0220] Frequency: 1Hz

[0221] Stress: 0.5Pa

[0222] Temperature: 25℃ / 37℃

[0223] Constant temperature condition: 5min

[0224] Rotor: 40mm flat plate

[0225] Board spacing: 0.8mm

[0226] The test results are shown in Table 1.

[0227] Table 1 Sterility and modulus test

[0228]

[0229] From Table 1, we can see that:

[0230] (1) The sterilization effect of the production process provided by Examples 1-3 of the present invention is equivalent to terminal sterilization and can meet the aseptic requirements;

[0231] (2) In comparative example 2 using the terminal sterilization process, the temperature-sensitive performance is greatly lost.

[0232] (3) The present invention can prepare a sterile thermosensitive nanogel embolic agent with good thermosensitive performance in a reaction system of more than 100 L, indicating that the preparation process and system of the thermosensitive gel of the present invention are suitable for large-scale production.

[0233] The embodiments provided in the purification process patent CN103224586A are all 1L systems, and the embodiments provided in the present invention are all 100L systems, which have been shown to be applicable to large-scale production.

[0234] The above embodiments have provided a detailed introduction to the technical solutions provided by the present invention. Specific examples are used herein to illustrate the principles and implementation methods of the embodiments of the present invention. The description of the above embodiments is only applicable to help understand the principles of the embodiments of the present invention. At the same time, for those skilled in the art, according to the embodiments of the present invention, there may be changes in the specific implementation methods and application scopes. In summary, the content of this specification should not be understood as limiting the present invention.

Claims

1. A process for preparing a thermosensitive gel, characterized in that: The following steps are involved: (1) preparing a polymerization reaction material in a first preparation tank; Weigh raw materials 1 to 4, dilute with injection water, set the temperature to 20 to 90° C., and stir until completely dissolved; wherein raw material 1 is N-isopropylacrylamide, and the molar concentration after diluting is 0.1 to 0.2 mol / L; raw material 2 is at least one of acrylic acid, acrylate, methacrylate, acrylamide and derivatives thereof, and the amount thereof accounts for 1% to 25% of the molar number of raw material 1; raw material 3 is a bisacrylamide compound or a derivative thereof, and the amount thereof accounts for 0.1% to 10% of the sum of the molar numbers of raw materials 1 and 2; raw material 4 is one of sodium stearoyl glutamate, glyceryl monostearate, glyceryl monoester, and polyoxyethylene stearate, and the molar concentration thereof after diluting is 0.1 to 10 mmol / L; (2) The polymerization reaction material is transferred to a reaction tank after sterilization filtration; (3) the initiator is sterilized and filtered and then put into a reaction tank to carry out polymerization reaction with the polymerization reaction material to obtain a reaction liquid; The initiator is one of azobisisobutylamidine hydrochloride, azobisisobutylimidazoline hydrochloride, azobisisobutylimidazoline, azobiscyanovaleric acid initiator, persulfate, and persulfate-sulfite, and the molar concentration of the initiator in the entire reaction system is 1 to 10 mmol / L; (4) The reaction liquid is transferred to a purification tank; or the reaction liquid is retained in a reaction tank, in which case the reaction tank is equivalent to the purification tank; (5) preparing a precipitant in a second preparation tank; The precipitant is at least one of ethanol, sodium chloride, potassium chloride, magnesium chloride, calcium chloride, sodium hydroxide and sodium sulfate; when a solid precipitant is selected, it needs to be prepared into a precipitant preparation liquid, which is prepared by diluting the precipitant with injection water at a preparation temperature of 10 to 75° C. so that the concentration of the precipitant in the precipitant preparation liquid is 10 to 25 wt %, and stirring until it is completely dissolved; the amount of the precipitant is 5 to 20% of the total mass of the reaction liquid and the precipitant preparation liquid; (6) The precipitant preparation solution is transferred to the purification tank after sterilization filtration; (7) Purifying by precipitation in the purification tank to obtain a thermosensitive gel dispersion.

2. The preparation process of a thermosensitive gel according to claim 1, characterized in that: The precipitation purification in step (7) specifically comprises the following steps: (7.1) stirring and mixing the reaction solution and the precipitant, and standing at a constant temperature of 50 to 90° C. for 0.5 to 2 hours, and the gel precipitates to form a flocculent precipitate; (7.2) Open the discharge valve of the purification tank, set the centrifugal drum speed to 1000-1500 rpm, and discharge the clear liquid through centrifugation in the tank to remove residual monomers and precipitant; (7.3) Keep the discharge valve of the purification tank open, the centrifugal drum speed is 1000-1500rpm, add 50-90°C water for injection into the purification tank, and discharge the clear liquid through centrifugation in the tank, and control the water addition speed so that the weight in the tank reaches dynamic balance; the total amount of the water for injection is 300-2000kg; (7.4) Keep the discharge valve of the purification tank open, stop water inlet, set the centrifugal drum speed at 1000-1500 rpm, and empty the washing liquid in the tank by centrifugation; (7.5) Add 5-30° C. water for injection to the purification tank and stir for 4-48 hours to redissolve the gel precipitate to obtain a sterile thermosensitive nanogel dispersion; the amount of the water for injection is 10-50 times the mass of the gel precipitate in the tank.

3. The preparation process of a thermosensitive gel according to claim 1, characterized in that: The feeding of the initiator in step (3) is carried out in two steps, as follows: (1) Under argon protection, the temperature of the material in the reaction tank is raised or lowered to a preset reaction temperature of 20 to 90° C., 70% volume of the initiator solution is added to the reaction tank after sterilization filtration, the reaction temperature is 20 to 90° C., and the reaction is continued for 2 to 4 hours under argon protection; (2) The remaining initiator solution is added to the reaction tank after sterilization filtration, the reaction temperature is kept constant, and the reaction is continued for 2 to 20 hours under argon protection to obtain the reaction solution.

4. The process for preparing a thermosensitive gel according to claim 1, characterized in that: The sterilizing filtration is achieved through a sterilizing filter, specifically through at least one sterilizing filter.

5. The process for preparing a thermosensitive gel according to claim 1, characterized in that: The conveying in steps (2) and (4) is carried out by pressurizing the tank to 0.1-0.4 MPa and conveying the material or reaction liquid through a pipeline.

6. A system for implementing the process for preparing the thermosensitive gel according to any one of claims 1 to 5, characterized in that: It includes a first preparation tank, a reaction tank, a feeding tool, a second preparation tank, a purification tank, several sterilizing filters, and a PLC control module; wherein: The first preparation tank is used to prepare polymerization reaction materials, including: The first feed port is used to feed raw materials; The first stirring blade is used for mixing and dissolving materials; A first jacket, used to control the temperature in the tank, the first jacket being connected to a cold medium and a hot medium; A first water inlet, used for adding water for injection; The first spray ball is used for cleaning inside the equipment; A first discharge port, used for discharging materials; The first air inlet is used to introduce compressed air to assist in discharging or transferring materials, and is connected to the air source through a sterilizing filter; The first respirator is used to balance the internal and external air pressure when it is turned on, and can maintain the pressure in the tank when it is turned off; it is connected to the external environment through a sterilizing filter; The reaction tank is used for polymerization reaction, comprising: A second feed port, connected to the first discharge port through a pipeline, for receiving the prepared material in the first preparation tank; The second stirring blade is used for mixing materials; A second jacket, used to control the temperature in the tank, the second jacket being connected to a cold medium and a hot medium; The second water inlet is used to add water for injection; The second spray ball is used for cleaning inside the equipment; A second discharge port, used for discharging materials; The second air inlet can be fed with compressed air to assist in discharging or transferring materials, and is connected to the air source through a sterilizing filter; The second respirator is used to balance the internal and external air pressure when it is turned on, and can maintain the pressure in the tank when it is turned off; it is connected to the external environment through a sterilizing filter; The feeding tool has a built-in initiator and is used to feed the initiator into the reaction tank; The second preparation tank is used to prepare the precipitant, and comprises: The third feed port is used to feed raw materials; The third stirring blade is used for mixing and dissolving materials; A third jacket, used to control the temperature in the tank, the third jacket being connected to cold and hot media; The third water inlet is used to add water for injection; The third spray ball is used for cleaning inside the equipment; The third discharge port is used for discharging the prepared precipitant into the purification tank; The third air inlet can be fed with compressed air to assist in discharging or transferring materials, and is connected to the air source through a sterilizing filter; The third respirator is used to balance the internal and external air pressure when it is turned on, and can maintain the pressure in the tank when it is closed, and is connected to the external environment through a sterilizing filter; The purification tank is used to remove small molecule residual raw materials and impurities, including: The fourth feed port is connected to the second and third feed ports through pipelines and is used to receive materials from the reaction tank and the second preparation tank; The fourth stirring blade is used to mix the materials; A fourth jacket, used to control the temperature in the tank, the fourth jacket being connected to cold and hot media; The fourth water inlet is used to add water for injection; The fourth spray ball is used for cleaning inside the equipment; The fourth centrifugal drum is used for mixing materials at a low speed and for separating precipitation and washing liquid at a high speed; The fourth discharge port is used for discharging materials; The fourth air inlet can be fed with compressed air to assist in discharging or transferring materials, and is connected to the air source through a sterilizing filter; The fourth respirator is used to balance the internal and external air pressures when it is turned on, and can maintain the pressure in the tank when it is closed. The fourth respirator is connected to the external environment through a sterilizing filter.

7. A system for preparing a thermosensitive gel according to claim 6, characterized in that: The feeding tooling comprises: Feeding and discharging port, used for discharging materials; The feeding air inlet can be fed with compressed air to assist in discharging or transferring materials, and is connected to the air source through a sterilizing filter; The feeding respirator is used to balance the internal and external air pressure when opened. It can maintain the pressure inside the tank when closed and is connected to the external environment through a sterilizing filter.

8. A system for preparing a thermosensitive gel according to claim 6, characterized in that: Each tank body is provided with a weighing module, a liquid level sensor, a temperature sensor and a timing module. The PLC control module is electrically connected to the first preparation tank, the second preparation tank, the reaction tank and the purification tank respectively. It is operated through a touch screen and automatic control can be achieved by editing the program.

9. A system for preparing a thermosensitive gel according to claim 8, characterized in that: The automatic control specifically includes: Automatic feeding and volume determination can be achieved by controlling the weighing module and liquid level sensor; The temperature inside the tank is controlled by controlling the temperature sensor and the cold and hot medium of the jacket; Adding materials by controlling the valves of the first feed inlet, the second feed inlet, the third feed inlet or the fourth feed inlet, and adding water by controlling the valves of the first water inlet, the second water inlet, the third water inlet or the fourth water inlet; The tank is pressurized by controlling the valves of the first air inlet, the second air inlet, the third air inlet or the fourth air inlet, and the material is conveyed by controlling the valves of the first discharge port, the second discharge port, the third discharge port or the fourth discharge port.

10. A system for preparing a thermosensitive gel according to claim 6, characterized in that: The fourth centrifugal drum is rotatably connected to the bottom of the purification tank, has a surface layer of a mesh structure, and an inner layer of a cavity.

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