Temperature-sensitive gel production device

Abstract

The utility model discloses a production device of temperature-sensitive gel. The production device comprises a first preparation tank, a reaction tank, a feeding tool, a second preparation tank, a purification tank and a plurality of sterilization filters, wherein the first preparation tank and the reaction tank are respectively provided with a first discharge port and a second discharge port, and the reaction tank and the purification tank are respectively provided with a second feed port and a fourth feed port; a first discharge port of the first preparation tank is connected with the reaction tank through a pipeline, and at least two sterilization filters are mounted in the middle of a connecting pipeline of the first preparation tank and the reaction tank; the feeding tool is connected with the second feeding hole of the reaction tank through a pipeline, and at least two sterilization filters are connected between the feeding tool and the reaction tank; the second preparation tank is provided with a third discharge port, and the second discharge port and the third discharge port are respectively connected with a fourth feed port of the purification tank through pipelines. According to the invention, the whole-process sterile production of the temperature-sensitive gel is realized.

Description

Technical Field

[0001] The utility model relates to the technical field of material processing, in particular to a production device for temperature-sensitive gel. Background Art

[0002] 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 periphery to the large blood vessels.

[0003] 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.

[0004] Existing sterility control methods for medical devices include irradiation sterilization and moist heat sterilization. Irradiation sterilization can cause crosslinking of polymer materials, altering their properties. Moist heat sterilization can cause a dramatic phase transition in thermosensitive gels, making it difficult to restore them to their pre-phase transition state, resulting in a significant loss of thermosensitive properties. These sterility control methods are difficult to meet the application requirements of the production and preparation of thermosensitive gel embolic agents.

[0005] 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.

[0006] There are two common methods for removing residual monomers:

[0007] The first is dialysis, 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.

[0008] The second method involves adding a precipitant to the reaction solution, filtering out the clear solution containing residual monomers, and obtaining a thermosensitive gel precipitate. The precipitate is then dried and crushed to obtain a thermosensitive gel powder. This method, for example, is disclosed in CN103224586B. However, in this method, the gel precipitate before the drying and crushing steps forms a monolithic, block-shaped precipitate. In large-scale production, the volume of the gel precipitate is larger than that of laboratory-grade production, and the organic solvent within the gel is difficult to completely dry, which can introduce impurities into the next step and ultimately into the product. Furthermore, incompletely dried gel blocks are sticky, affecting the effectiveness of the crushing step.

[0009] The drawback of the two aforementioned methods for removing residual monomers is that they are difficult to implement on a large scale. Furthermore, both purification methods involve the transfer of solid materials. During production, liquid materials can be transferred through sealed pipes, while solid materials are typically transferred manually in open spaces, increasing the risk of product contamination.

[0010] In view of this, there is an urgent need to improve the existing production equipment of temperature-sensitive gel. Utility Model Content

[0011] The purpose of this utility model is to overcome the shortcomings of the existing technology and provide a production device for thermosensitive gel, which realizes the full-process aseptic production of thermosensitive gel. All raw materials are sterilized and filtered before participating in the next process, and all processes are carried out in a closed system, so the materials do not come into contact with people or the environment. This is achieved through the following technical solutions:

[0012] A production device for a temperature-sensitive gel comprises a first preparation tank, a reaction tank, a feeding tool, a second preparation tank, a purification tank and several sterilizing filters; wherein, the first preparation tank and the reaction tank are respectively provided with a first discharge port and a second discharge port, and the reaction tank and the purification tank are respectively provided with a second feed port and a fourth feed port; the first discharge port of the first preparation tank is connected to the reaction tank by a pipeline, and at least two sterilizing filters are installed in the middle of the connecting pipeline between the first preparation tank and the reaction tank; the feeding tool comprises a feeding discharge port and a feeding air inlet, the feeding discharge port is connected to the second feed port of the reaction tank by a pipeline, and at least two sterilizing filters are connected between the feeding discharge port and the reaction tank; the second preparation tank is provided with a third discharge port, the second discharge port and the third discharge port are respectively connected to the fourth feed port of the purification tank by pipelines, and at least one sterilizing filter is respectively provided between the second discharge port, the third discharge port and the fourth feed port.

[0013] Preferably, the first preparation tank is used to prepare the polymerization reaction material, and further comprises:

[0014] a first feed port, located at the upper portion of the first preparation tank;

[0015] a first stirring blade rotatably mounted in the first preparation tank to promote mixing and dissolving of materials;

[0016] A first jacketed heat exchanger is disposed around the outer periphery of the first preparation tank;

[0017] The first water inlet is used to add water for injection;

[0018] The first spray ball is used for cleaning inside the equipment;

[0019] 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 the sterilizing filter;

[0020] The first respirator is used to balance the internal and external air pressures of the first preparation tank when it is turned on, and can maintain the internal pressure of the first preparation tank when it is turned off.

[0021] Preferably, the reaction tank is used for polymerization reaction and further comprises:

[0022] The second feed port is connected to the first discharge port through a pipeline and is used to receive the material prepared in the first preparation tank; as well as a second stirring blade, a second jacketed heat exchanger, a second water inlet, a second spray ball, a second air inlet and a second respirator.

[0023] Preferably, the second preparation tank is used for preparing the precipitant, and further comprises: a third feed port, a third stirring blade, a third jacketed heat exchanger, a third water inlet, a third spray ball, a third air inlet and a third respirator.

[0024] Preferably, the purification tank is used to remove residual raw materials and impurities, and also includes a fourth stirring blade, a fourth jacketed heat exchanger, a fourth water inlet, a fourth spray ball, a fourth centrifugal drum, a fourth discharge port, a fourth air inlet and a fourth respirator.

[0025] Preferably, the first spray ball, the second spray ball, the third spray ball and the fourth spray ball are respectively composed of a water pipe and a small ball with a hole. The water pipe terminal is movably connected to the small ball with a hole. After the injection water enters the water pipe, it drives the small ball to rotate and spray water, thereby achieving dead-angle cleaning inside the equipment.

[0026] Preferably, the first stirring blade, the second stirring blade, the third stirring blade and the fourth stirring blade are all connected to the output shaft of the motor through a rotating shaft and rotated by the drive of the motor.

[0027] Preferably, the fourth centrifugal drum is rotatably connected to the bottom of the purification tank, and its surface layer is a mesh structure with a mesh diameter of 0.4 mm, and its inner layer is a cavity.

[0028] Preferably, the first preparation tank, reaction tank, second preparation tank and purification tank are all provided with a weighing module, a liquid level sensor, a temperature sensor and a timing module.

[0029] Preferably, it further comprises a PLC control module, which is electrically connected to the first preparation tank, the second preparation tank, the reaction tank and the purification tank respectively.

[0030] Compared with the existing technology, the present invention has the following beneficial effects:

[0031] The device protected by this technical solution includes a first preparation tank, a reaction tank, a feeding tooling, a second preparation tank, a purification tank and several sterilizing filters, which realizes the full-process aseptic production of temperature-sensitive gel. All raw materials are sterilized and filtered before participating in the next process. After the sterilization and filtration of the liquid, the subsequent process (such as polymerization, purification and material transfer involved in each process) is carried out in a closed system, and the materials do not come into contact with personnel or the environment.

[0032] Therefore, the production device of the present application can ensure the sterile production of the product without using a terminal sterilization device, thereby avoiding the loss of product performance caused by traditional sterilization processes and devices. BRIEF DESCRIPTION OF THE DRAWINGS

[0033] Figure 1 It is a structural schematic diagram of a temperature-sensitive gel preparation system of the utility model.

[0034] Description of reference numerals:

[0035] First preparation tank 1, first feed port 11, first stirring blade 12, first jacket 13, first water inlet 14, first spray ball 15, first discharge port 16, first air inlet 17, first respirator 18;

[0036] Reactor 2, second feed port 21, second stirring blade 22, second jacket 23, second water inlet 24, second spray ball 25, second discharge port 26, second air inlet 27, second respirator 28

[0037] Feeding tool 3, feeding outlet 31, feeding air inlet 32

[0038] Second preparation tank 4, third feed port 41, third stirring blade 42, third jacket 43, third water inlet 44, third spray ball 45, third discharge port 46, third air inlet 47, third respirator 48;

[0039] Purification tank 5, fourth feed port 51, fourth jacket 53, fourth water inlet 54, fourth spray ball 55, fourth centrifugal drum 56, fourth discharge port 57, fourth air inlet 58, fourth respirator 59;

[0040] Sterilizing filter 6, PLC control module 7. DETAILED DESCRIPTION

[0041] The technical solutions in the embodiments of the present invention will be clearly and completely described below in conjunction with the drawings in the embodiments of the present invention; it is obvious that the described embodiments are only part of the embodiments of the present invention, rather than all the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without making creative work are within the scope of protection of the present invention.

[0042] In the description of this utility model, it should be noted that the terms "upper," "lower," "inner," "outer," "top / bottom," and the like, indicating orientations or positional relationships, are based on the orientations or positional relationships shown in the accompanying drawings and are intended solely to facilitate the description of this utility model and simplify the description. They are not intended to indicate or imply that the devices or components referred to must have a specific orientation, be constructed, or operate in a specific orientation. Therefore, they should not be construed as limitations on this utility model. Furthermore, the terms "first" and "second" are used for descriptive purposes only and should not be construed as indicating or implying relative importance.

[0043] In the description of this utility model, it should be noted that, unless otherwise expressly specified or limited, the terms "installed," "provided with," "mounted / connected," and "connected" should be understood in a broad sense. For example, "connected" can mean a fixed connection, a detachable connection, or an integral connection; it can be a mechanical connection or an electrical connection; it can be a direct connection or an indirect connection through an intermediate medium, or it can be internal communication between two components. For those skilled in the art, the specific meanings of the above terms in this utility model can be understood according to the specific circumstances.

[0044] A preferred embodiment of the present invention is as follows Figure 1 As shown, a production device for a temperature-sensitive gel is provided, comprising a first preparation tank 1, a reaction tank 2, a feeding tool 3, a second preparation tank 4, a purification tank 5 and several sterilizing filters 6; wherein, the first preparation tank 1 and the reaction tank 2 are respectively provided with a first discharge port 16 and a second discharge port 26, and the reaction tank 2 and the purification tank 5 are respectively provided with a second feed port 21 and a fourth feed port 51; the first discharge port 16 of the first preparation tank 1 is connected to the reaction tank 2 through a pipe, and at least two sterilizing filters 6 are installed in the middle of the connecting pipe between the first preparation tank 1 and the reaction tank 2, that is, the material is transferred from the first preparation tank 1 to the reaction tank 2. At least two filtration processes are performed during the reaction tank 2; the feeding tool 3 is connected to the second feeding port 21 of the reaction tank 2 through a pipeline, which is used to feed the initiator into the reaction tank 2, and at least two sterilizing filters 6 are connected between the feeding tool 3 and the reaction tank 2; the second preparation tank 4 is provided with a third discharge port 46, and the second discharge port 26 and the third discharge port 46 are respectively connected to the fourth feeding port 51 of the purification tank 5 through pipelines, and at least one sterilizing filter 6 is respectively provided between the second discharge port 26, the third discharge port 46 and the fourth feeding port 51, preferably two sterilizing filters.

[0045] Specifically, the first preparation tank 1 is used to prepare polymerization reaction materials, and further includes:

[0046] A first feed port 11, located at the upper portion of the first preparation tank 1, for feeding raw materials;

[0047] A first stirring blade 12 is rotatably mounted in the first preparation tank 1 to promote mixing and dissolving of materials;

[0048] A first jacketed heat exchanger 13 is disposed around the outer periphery of the first preparation tank 1 and is used to control the temperature inside the tank;

[0049] The first water inlet 14 is used to add water for injection;

[0050] The first spray ball 15 is used for cleaning inside the equipment. In this example, the first spray ball 15 consists of a water pipe and a small ball with a hole. The terminal end of the water pipe is movably connected to the small ball with a hole. After the pressurized injection water enters the water pipe, it drives the small ball to rotate and spray water, achieving a complete cleaning of the tank.

[0051] 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 the sterilizing filter 6;

[0052] The first respirator 18 is used to balance the internal and external air pressures of the first preparation tank 1 when it is turned on, and can maintain the internal pressure of the first preparation tank 1 when it is turned off.

[0053] Specifically, the feeding fixture 3 includes a feeding outlet 31 and a feeding air inlet 32. The feeding outlet 31 is connected to the second feeding port 21 of the reaction tank 2 via a pipe. Furthermore, the feeding outlet 31 is used for discharging materials; the feeding fixture 3 may also include a feeding respirator (not shown).

[0054] The feeding air inlet 32 ​​can be fed with compressed air to assist in discharging or transferring the material. The feeding air inlet 32 ​​is connected to the air source through a sterilizing filter 6. The feeding respirator (not shown) is used to balance the internal and external air pressure when it is turned on. When it is closed, it can maintain the pressure in the tank and is connected to the external environment through a sterilizing filter 6.

[0055] Specifically, the reaction tank 2 is used for polymerization reaction and further comprises:

[0056] The second feed port 21 is connected to the first discharge port 16 through a pipeline and is used to receive the prepared material in the first preparation tank 1; as well as a second stirring blade 22, a second jacketed heat exchanger 23, a second water inlet 24, a second spray ball 25, a second air inlet 27 and a second respirator 28.

[0057] It should be noted that the second feed port 21 is used to receive the materials configured in the first preparation tank 1 and the initiator in the feeding tooling 3; the second stirring blade 22 is used to mix the materials; the second jacketed heat exchanger 23 is used to control the temperature in the tank; the second water inlet 24 is used to add water for injection; the second spray ball 25 is used for cleaning inside the equipment, and adopts the same structure as the first spray ball 15; the second air inlet 27 can be used to introduce compressed air to assist in discharging or transferring materials, and it is connected to the air source through the sterilizing filter 6; the second respirator 28 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; the second respirator 28 is connected to the external environment through the sterilizing filter 6.

[0058] Specifically, the second preparation tank 4 is used to prepare the precipitant, and also includes: a third feed port 41, a third stirring blade 42, a third jacketed heat exchanger 43, a third water inlet 44, a third spray ball 45, a third air inlet 47 and a third respirator 48. The third discharge port 46 is used for discharging the prepared precipitant into the purification tank 5; the function of the third respirator 48 is the same as that of the first respirator 18 and the second respirator 28, and will not be repeated.

[0059] Specifically, the purification tank 5 is used to remove residual raw materials and impurities, and also includes a fourth stirring blade, a fourth jacketed heat exchanger 53, a fourth water inlet 54, a fourth spray ball 55, a fourth centrifugal drum 56, a fourth discharge port 57, a fourth air inlet 58, and a fourth respirator 59. The fourth centrifugal drum 56 is used to mix the materials at a low speed and to separate the precipitate and the washing liquid at a high speed.

[0060] Furthermore, the first preparation tank 1, reaction tank 2, second preparation tank 4, and purification tank 5 are each equipped with a weighing module, a liquid level sensor, a temperature sensor, and a timing module. The device also includes a PLC control module 7, which is electrically connected to the first preparation tank 1, the second preparation tank 4, the reaction tank 2, and the purification tank 5, respectively. The PLC control module 7 is directly obtained from the prior art. The specific connection method for the PLC control module 7 to the first preparation tank 1, the second preparation tank 4, the reaction tank 2, and the purification tank 5, respectively, is derived from the prior art. Since it is not the inventive point of this application, it will not be described in detail, but this does not mean that it cannot be implemented.

[0061] Specifically, the first stirring blade 12 , the second stirring blade 22 , the third stirring blade 42 and the fourth stirring blade are all connected to the output shaft of the motor via a rotating shaft and are rotated by the drive of the motor.

[0062] Specifically, 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 its inner layer is a cavity.

[0063] The following example illustrates the working principle of the thermosensitive gel production device, as follows:

[0064] First, weigh N-isopropylacrylamide, acrylic acid, N,N'-methylenebisacrylamide, and sodium stearoyl glutamate and add them to the first preparation tank 1. Add water for injection to a volume of 100 L and stir to dissolve at 50°C to prepare the polymerization reaction material. Also, pre-fill the feeding tool 3 with an aqueous solution of azobisisobutyramidine hydrochloride.

[0065] 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 through the pipeline and the sterilizing filter 6 to the reaction tank 2. Under the protection of argon, the temperature of the material in the tank is raised to 65°C.

[0066] The initiator solution (aqueous solution of azobisisobutylamidine hydrochloride) in feeding tool 3 was added to reaction tank 2 after sterile filtration, and stirred and mixed with the polymer reaction materials added previously. The reaction was carried out under argon protection at a temperature of 65° C. for 4 hours.

[0067] The remaining initiator solution in the feeding tool 3 was added to the reaction tank 2 after sterilization filtration, stirred and mixed, and reacted for 4 hours at 65° C. under the same argon atmosphere to obtain a reaction solution.

[0068] Open the valve of the second discharge port 26 of the reaction tank 2, and pressurize the tank 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.

[0069] Weigh calcium chloride and put it into the second preparation tank 4, add water for injection, and stir and dissolve at 30°C to obtain a precipitant solution.

[0070] Open the valve of the third discharge port 46 of the second preparation tank 4, pressurize the tank through the third air inlet 47, set the pressure to 0.3 MPa, and transfer the precipitant solution through the pipeline and the sterilizing filter 6 to the purification tank 5.

[0071] 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 precipitate.

[0072] The valve of the fourth discharge port 57 of the purification tank 5 was opened, the centrifugal drum speed was set to 1500 rpm, and the supernatant was discharged by centrifugation in the tank to remove the residual monomers and precipitant.

[0073] The valve of the fourth discharge port 57 of the purification tank 5 is kept open, the centrifugal drum speed is 1500 rpm, and 70° C. water for injection is added to the purification tank 5 while the clear liquid is discharged through centrifugation in the tank.

[0074] The valve of the fourth discharge port 57 is kept open, water is stopped from entering, the centrifugal drum speed is set at 1500 rpm, and the liquid in the tank is emptied by centrifugation, leaving gel precipitate in the tank.

[0075] Add water for injection to the purification tank 5 and stir to redissolve the gel precipitate. Thus, a sterile thermosensitive nanogel dispersion is obtained.

[0076] The above are only preferred embodiments of the present invention; however, the scope of protection of the present invention is not limited thereto. Any person skilled in the art who, within the technical scope disclosed in the present invention, makes equivalent substitutions or modifications based on the technical solutions and improved concepts of the present invention shall be covered by the scope of protection of the present invention.

Claims

1. A production device for a thermosensitive gel, characterized in that: It includes a first preparation tank, a reaction tank, a feeding tool, a second preparation tank, a purification tank and several sterilizing filters; The first preparation tank and the reaction tank are respectively provided with a first discharge port and a second discharge port, and the reaction tank and the purification tank are respectively provided with a second feed port and a fourth feed port; The first discharge port of the first preparation tank is connected to the reaction tank through a pipeline, and at least two sterilizing filters are installed in the middle of the connecting pipeline between the first preparation tank and the reaction tank; The feeding tooling includes a feeding outlet and a feeding air inlet, the feeding outlet is connected to the second feeding port of the reaction tank through a pipeline, and at least two sterilizing filters are connected between the feeding outlet and the reaction tank; The second preparation tank is provided with a third discharge port, and the second discharge port and the third discharge port are respectively connected to the fourth feed port of the purification tank through pipelines, and at least one sterilizing filter is respectively provided between the second discharge port, the third discharge port and the fourth feed port.

2. The production device of the thermosensitive gel according to claim 1, characterized in that: The first preparation tank is used to prepare polymerization reaction materials, and further comprises: a first feed port, located at the upper portion of the first preparation tank; a first stirring blade rotatably mounted in the first preparation tank to promote mixing and dissolving of materials; A first jacketed heat exchanger is disposed around the outer periphery of the first preparation tank; The first water inlet is used to add water for injection; The first spray ball is used for cleaning inside the equipment; 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 the sterilizing filter; The first respirator is used to balance the internal and external air pressures of the first preparation tank when it is turned on, and can maintain the internal pressure of the first preparation tank when it is turned off.

3. The production device of the thermosensitive gel according to claim 2, characterized in that: The reaction tank is used for polymerization reaction and also includes: The second feed port is connected to the first discharge port through a pipeline and is used to receive the material prepared in the first preparation tank; as well as a second stirring blade, a second jacketed heat exchanger, a second water inlet, a second spray ball, a second air inlet and a second respirator.

4. The production device of the thermosensitive gel according to claim 3, characterized in that: The second preparation tank is used for preparing the precipitant and further comprises: a third feed port, a third stirring blade, a third jacketed heat exchanger, a third water inlet, a third spray ball, a third air inlet and a third respirator.

5. The production device of the thermosensitive gel according to claim 4, characterized in that: The purification tank is used to remove residual raw materials and impurities, and also includes a fourth stirring blade, a fourth jacketed heat exchanger, a fourth water inlet, a fourth spray ball, a fourth centrifugal drum, a fourth discharge port, a fourth air inlet and a fourth respirator.

6. The production device of the thermosensitive gel according to claim 5, characterized in that: The first spray ball, the second spray ball, the third spray ball and the fourth spray ball are respectively composed of a water pipe and a small ball with a hole, and the terminal of the water pipe is movably connected to the small ball with a hole.

7. The production device of the thermosensitive gel according to claim 6, characterized in that: The first stirring blade, the second stirring blade, the third stirring blade and the fourth stirring blade are all connected to the output shaft of the motor through a rotating shaft and rotated by the drive of the motor.

8. The production device of the thermosensitive gel according to claim 6, characterized in that: The fourth centrifugal drum is rotatably connected to the bottom of the purification tank, and its surface layer is a mesh structure with a mesh diameter of 0.4 mm, and its inner layer is a cavity.

9. The production device of a thermosensitive gel according to claim 1, characterized in that: The first preparation tank, reaction tank, second preparation tank and purification tank are all provided with a weighing module, a liquid level sensor, a temperature sensor and a timing module.

10. The production device of the temperature-sensitive gel according to claim 1, characterized in that: It also includes a PLC control module, which is electrically connected to the first preparation tank, the second preparation tank, the reaction tank and the purification tank respectively.

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