Glycosaminoglycan derivative preparation device

Abstract

The utility model relates to the technical field of preparation of glycosaminoglycan derivatives, provides a preparation device of glycosaminoglycan derivatives, and particularly provides a preparation device suitable for preparing anti-tumor glycosaminoglycan derivatives and low-molecular-weight heparin. Heparin reacts in the first reaction tank to generate first reaction liquid, and the first reaction liquid dynamically flows through the first ultrafiltration device and is separated into first trapped liquid and first permeate liquid; the first permeate liquid enters a second reaction tank; and the first interception liquid returns to the first reaction tank to react again so as to reduce the molecular weight of the first interception liquid, and the process is repeated until the heparin in the first reaction tank is completely reacted. A reducing agent is added into the second reaction tank, so that the first permeate liquid is subjected to a reaction to generate a second reaction liquid, the second reaction liquid flows through the second ultrafiltration device and is separated into a second trapped liquid and a second permeate liquid, the second permeate liquid is discharged, and the second trapped liquid is used as a target product. Therefore, the utilization rate of the materials can be improved, and the product yield of the target product can also be improved.

Description

TECHNICAL FIELD

[0001] The utility model relates to the technical field of glycosaminoglycan derivative preparation, especially to a glycosaminoglycan derivative preparation device. BACKGROUND

[0002] Glycosaminoglycan derivatives have a wide range of biological activities, including anticoagulant, anti-thrombosis, anti-inflammatory and anti-tumor activities, etc. The molecular weight distribution of glycosaminoglycan derivatives has an important influence on their quality and activity.

[0003] Heparin is a linear polydisperse sulfated polysaccharide in the glycosaminoglycan family, which has anticoagulant and anti-thrombosis activity. The sugar chain of heparin is composed of alternating uronic acid and D-glucosamine, and the main repeating unit is 2-O-sulfated L-iduronic acid (IdoA2S) and alpha (1→4) N-, 6-O-disulfated D-glucosamine (GlcN6S); the less component is non-sulfated L-iduronic acid and D-glucuronic acid, and N-acetyl D-glucosamine and N-, 3-O-, 6-O-trisulfated D-glucosamine.

[0004] Heparin has strong anticoagulant activity, and can effectively inhibit heparanase and has anti-tumor activity. In the prior art, heparin sodium is used as a starting material to prepare low molecular weight heparin and anti-tumor glycosaminoglycan drugs.

[0005] Low molecular weight heparins such as dalteparin sodium and nartograstim are obtained by nitrous acid degradation of heparin sodium; anti-tumor glycosaminoglycan derivatives are also prepared by using heparin as a starting reactant and undergoing a series of reactions such as oxidation. However, the production process of low molecular weight heparin and anti-tumor glycosaminoglycan drugs has difficulty in controlling the weight average molecular weight and the molecular weight distribution. After heparin sodium is oxidized and degraded, it cannot directly form the target product meeting the requirements. The molecular weight distribution of the degradation product and the target product is very different, and the target product can be obtained only after a relatively harsh molecular weight modification means is used to remove a large amount of unnecessary molecular weight fragments, which not only causes a large amount of raw material waste but also affects the product yield.

[0006] Therefore, there is an urgent need for a glycosaminoglycan derivative preparation device to solve the above technical problems. UTILITY MODEL CONTENT

[0007] The utility model aims at providing a glycosaminoglycan derivative preparation device which can improve the utilization rate of raw materials and the product yield of the target product.

[0008] To achieve this purpose, the utility model adopts the following technical solutions:

[0009] The glycosaminoglycan derivative preparation device comprises:

[0010] a first reaction device comprising a first reaction tank for producing a first reaction liquid;

[0011] a first ultrafiltration device comprising a first ultrafiltration element, said first ultrafiltration element allowing passage of fluid having a molecular weight less than a first cut-off molecular weight, an output end A of said first reaction tank being capable of communicating with an input end B of said first ultrafiltration device, a first output end B of said first ultrafiltration device being formed upstream of said first ultrafiltration element and capable of communicating with a reflux end A of said first reaction tank, a second output end B of said first ultrafiltration device being formed downstream of said first ultrafiltration element;

[0012] a second reaction device comprising a second reaction tank, said second output end B of said first ultrafiltration device being capable of communicating with a first input end C of said second reaction tank, said first reaction liquid forming a second reaction liquid in said second reaction tank;

[0013] a second ultrafiltration device, an output end C of said second reaction device being capable of communicating with an input end D of said second ultrafiltration device, said second ultrafiltration device comprising a second ultrafiltration element, said second ultrafiltration element allowing passage of fluid having a molecular weight less than a second cut-off molecular weight, a first output end D of said second ultrafiltration device being formed upstream of said second ultrafiltration element and a second output end D of said second ultrafiltration device being formed downstream of said second ultrafiltration element, said first cut-off molecular weight being greater than said second cut-off molecular weight.

[0014] As a preferred technical solution of said glycosaminoglycan derivative preparation device, said first reaction device further comprises a first adjusting element, said first adjusting element being used for adjusting the flow rate of raw materials entering said first reaction tank, a plurality of said raw materials reacting to generate said first reaction liquid.

[0015] As a preferred technical solution of said glycosaminoglycan derivative preparation device, said first reaction device further comprises a first stirring mechanism, said first stirring mechanism being installed in said first reaction tank and being used for stirring a plurality of raw materials, said plurality of raw materials reacting to generate said first reaction liquid.

[0016] As a preferred technical solution of said glycosaminoglycan derivative preparation device, said first reaction device further comprises a condenser, said first output end B of said first ultrafiltration device being capable of communicating with said reflux end A of said first reaction tank through said condenser.

[0017] As a kind of preferred technical scheme of the above-mentioned glycosaminoglycan derivative preparation device, the first reaction device further includes first pH adjusting mechanism, the first pH adjusting mechanism includes first pH detection piece, first acidic solution output pipe and first alkaline solution output pipe;The first pH detection piece is used to obtain the pH value of the first reaction liquid in the first reaction tank, the first acidic solution output pipe is used to input acidic solution into the first reaction tank, and the first alkaline solution output pipe is used to input alkaline solution into the first reaction tank.

[0018] As a kind of preferred technical scheme of the above-mentioned glycosaminoglycan derivative preparation device, the second reaction device further includes second pH adjusting mechanism, the second pH adjusting mechanism includes second pH detection piece, second acidic solution output pipe and second alkaline solution output pipe;The second pH detection piece is used to obtain the pH value of the second reaction liquid in the second reaction tank, the second acidic solution output pipe is used to input acidic solution into the second reaction tank, and the second alkaline solution output pipe is used to input alkaline solution into the second reaction tank.

[0019] As a kind of preferred technical scheme of the above-mentioned glycosaminoglycan derivative preparation device, further including first pump group, the first pump group includes first pump body and second pump body, and the first pump body and / or the second pump body can be used to drive the first reaction liquid to flow to the first ultrafiltration device.

[0020] As a kind of preferred technical scheme of the above-mentioned glycosaminoglycan derivative preparation device, further including ultraviolet sterilizer, the first output end D of the second ultrafiltration device is communicated with the input end of the ultraviolet sterilizer.

[0021] As a kind of preferred technical scheme of the above-mentioned glycosaminoglycan derivative preparation device, further including drying device, the first output end D of the second ultrafiltration device can be communicated with the input end of the drying device.

[0022] As a kind of preferred technical scheme of the above-mentioned glycosaminoglycan derivative preparation device, further including third reaction device, the first output end D of the second ultrafiltration device can be communicated with the input end of the third reaction device, the first output end E of the third reaction device can be communicated with the input end of the drying device, and the second reaction liquid can generate precipitate in the third reaction device, and the precipitate enters the drying device.

[0023] The utility model has the advantages of:

[0024] The first reaction liquid in the first reaction tank flows from the output end A to the first ultrafiltration device, and the first reaction liquid passing through the first ultrafiltration device is separated into the first interception liquid and the first permeate liquid, wherein the molecular weight of the first interception liquid is greater than the first interception molecular weight, the molecular weight of the first permeate liquid is less than the first interception molecular weight, the first permeate liquid can pass through the first ultrafiltration piece into the second reaction tank, and the first interception liquid flows through the first output end B and the reflux end A in sequence and returns to the first reaction tank to react with the oxidant (such as sodium nitrite) again to reduce the molecular weight, and the process is repeated until the reaction of all heparin sodium in the first reaction tank is completed, and the first permeate liquid passes through the first ultrafiltration piece into the second reaction tank. The reducing agent (such as sodium borohydride) is added into the second reaction tank, so that the first permeate liquid generates the second reaction liquid through the reduction reaction, the second permeate liquid in the second reaction liquid can pass through the second ultrafiltration piece and be discharged, and the second interception liquid is intercepted by the second ultrafiltration piece as the target product. In this way, the utilization rate of raw materials can be improved, and the product yield of the target product can be improved. BRIEF DESCRIPTION OF DRAWINGS

[0025] Fig. 1 is a structural schematic diagram of a glycosaminoglycan derivative preparation device provided by an embodiment of the present application;

[0026] Fig. 2 is a connection schematic diagram of the first reaction device and the first ultrafiltration device provided by an embodiment of the present application;

[0027] Fig. 3 is a connection schematic diagram of the first ultrafiltration device and the second reaction device provided by an embodiment of the present application;

[0028] Fig. 4 is a connection schematic diagram of the second ultrafiltration device and the third reaction device provided by an embodiment of the present application.

[0029] In the drawings:

[0030] 10, first reaction device; 11, first reaction tank; 111, output end A; 112, reflux end A; 113, first input end A; 114, second input end A; 12, first adjusting piece; 13, first pH adjusting mechanism; 131, first pH detecting piece; 132, first acid solution output pipe; 14, condenser; 15, first valve body A; 16, second valve body A; 17, Y-shaped filter A;

[0031] 20, first ultrafiltration device; 21, input end B; 22, first output end B; 23, second output end B;

[0032] 30, second reaction device; 31, second reaction tank; 311, first input end C; 312, output end C; 313, second input end C; 32, second pH adjusting mechanism; 321, second pH detecting member; 322, second alkaline solution output pipe;

[0033] 40, second ultrafiltration device; 41, input end D; 42, first output end D; 43, second output end D;

[0034] 50, third reaction device; 51, first input end E; 52, second input end E; 53, first output end E; 54, third reaction tank; 55, second output end E;

[0035] 61, first pump group; 611, first pump body A; 612, second pump body A; 62, second pump group;

[0036] 70, ultraviolet sterilizer;

[0037] 80, third filtration device;

[0038] 90, drying device. DETAILED DESCRIPTION

[0039] The technical solutions of the present application will be described clearly and completely below in conjunction with the drawings. Obviously, the described embodiments are only some of the embodiments of the present application, rather than all the embodiments. Based on the embodiments in the present application, all other embodiments obtained by those skilled in the art without creative labor fall within the scope of protection of the present application.

[0040] In the description of the present application, it should be noted that the terms "center", "upper", "lower", "left", "right", "vertical", "horizontal", "inner", "outer" and the like indicate the orientation or positional relationship shown in the drawings, and are only for the convenience of describing the present application and simplifying the description, and do not indicate or imply that the devices or elements referred to must have a particular orientation, be constructed and operated in a particular orientation, and therefore cannot be understood as limiting the present application. In addition, the terms "first", "second", are only for the purpose of description, and cannot be understood as indicating or implying relative importance. Among them, the terms "first position" and "second position" are two different positions, and moreover, the "above", "above" and "above" of the first feature on the second feature include the first feature above and obliquely above the second feature, or only indicate that the horizontal height of the first feature is higher than that of the second feature. The "below", "below" and "below" of the first feature on the second feature include the first feature below and obliquely below the second feature, or only indicate that the horizontal height of the first feature is less than that of the second feature.

[0041] In the description of the utility model, it is necessary to explain, unless another explicit provision and limitation, the term "installation", "link", "connection" should do broad sense understanding, for example, can be fixed connection, also can be detachable connection, or integrally connected;Can be mechanical connection, also can be electrical connection;Can be directly connected, also can be indirectly connected through the intermediate medium, can be two elements inside the communication.For ordinary skilled in the art, the above-mentioned terms can be understood in the specific meaning of the utility model according to specific circumstances.

[0042] The embodiments of the utility model are described in detail below, the examples of the embodiments are shown in the drawings, wherein the same or similar reference numerals represent the same or similar elements or elements with the same or similar function throughout. The embodiments described below by referring to the drawings are exemplary, only for explaining the utility model, and cannot be understood as limiting the utility model.

[0043] As Figs. 1 to 4 The utility model provides a kind of glycosaminoglycan derivative preparation device, including first reaction device 10, first ultrafiltration device 20, second reaction device 30 and second ultrafiltration device 40.Therein, first reaction device 10 includes first reaction tank 11, for output first reaction liquid;First ultrafiltration device 20 includes first ultrafiltration piece, first ultrafiltration piece allows the fluid with molecular weight less than first cut-off molecular weight to pass through, the output end A111 of first reaction tank 11 can be communicated with the input end B21 of first ultrafiltration device 20, the first output end B22 of first ultrafiltration device 20 is formed in the upstream of first ultrafiltration piece, can be communicated with the backflow end A112 of first reaction tank 11;The second output end B23 of first ultrafiltration device 20 is formed in the downstream of first ultrafiltration piece;Second reaction device 30 includes second reaction tank 31, the second output end B23 of first ultrafiltration device 20 can be communicated with the first input end C311 of second reaction tank 31, and first reaction liquid forms second reaction liquid in second reaction tank 31;The output end C312 of second reaction device 30 can be communicated with the input end D41 of second ultrafiltration device 40, and second ultrafiltration device 40 includes second ultrafiltration piece, second ultrafiltration piece allows the fluid with molecular weight less than second cut-off molecular weight to pass through, the first output end D42 of second ultrafiltration device 40 is formed in the upstream of second ultrafiltration piece, and its second output end D43 is formed in the downstream of second ultrafiltration piece;First cut-off molecular weight is greater than second cut-off molecular weight.

[0044] In the present embodiment, when preparing dalteparin, the prepared heparin sodium solution is placed in the first reaction tank 11, an oxidizing agent is injected into the first reaction tank 11, and sodium nitrite is used as the oxidizing agent in the present embodiment. The heparin sodium reacts with the sodium nitrite to form a first reaction liquid, the first reaction liquid flows from the output end A111 to the first ultrafiltration device 20, and the first reaction liquid includes a first cut-off liquid and a first permeate liquid. The molecular weight of the first cut-off liquid is greater than the first cut-off molecular weight, and the molecular weight of the first permeate liquid is less than the first cut-off molecular weight. The first permeate liquid can pass through the first ultrafiltration member into the second reaction tank 31, and the first cut-off liquid flows through the first output end B22 and the reflux end A112 in turn and returns to the first reaction tank 11 to react with the sodium nitrite again to reduce the molecular weight. The process is repeated until all the heparin sodium solution in the first reaction tank 11 passes through the first ultrafiltration member into the second reaction tank 31. Sodium borohydride is injected into the second reaction tank 31 to make the first permeate liquid undergo a reduction reaction to form a second reaction liquid. After the second reaction liquid is discharged from the second reaction tank 31, it flows to the second ultrafiltration device 40 and is separated into a second cut-off liquid and a second permeate liquid. The second permeate liquid is discharged through the second ultrafiltration member, and the second cut-off liquid is intercepted by the second ultrafiltration member as the target product. In this way, the utilization rate of raw materials can be improved, and the product yield of the target product can be improved.

[0045] In the preparation process of dalteparin, the heparin sodium solution is dissolved in purified water, and the heparin sodium solution is adjusted to an acidic pH with an acidic solution. The heparin sodium is then placed in the first reaction tank 11.

[0046] In the present embodiment, the first reaction device 10 further includes a first input end A113 and a second input end A114. The heparin sodium and water can be injected into the first reaction tank 11 through the first input end A113, and the sodium nitrite can be injected into the first reaction tank 11 through the second input end A114.

[0047] In the present embodiment, the second reaction device 30 further includes a second input end C313. The sodium borohydride can be injected into the second reaction tank 31 through the second input end C313.

[0048] In the present embodiment, the first ultrafiltration member is an ultrafiltration membrane, and the first cut-off molecular weight is in the range of 9000-14000 Da. Preferably, the first cut-off molecular weight is 9000 Da.

[0049] In the present embodiment, the second ultrafiltration member is an ultrafiltration membrane, and the second cut-off molecular weight is in the range of 300-3000 Da. Preferably, the second cut-off molecular weight is 500 Da.

[0050] Due to the limited filtering area of the single second ultrafiltration device, the filtering of all the second reaction liquid cannot be completed at one time, so that the second permeated liquid is always mixed in the second intercept liquid, affecting the product quality.

[0051] To this end, in one embodiment, the second ultrafiltration device 40 further comprises a third output end D, which is arranged upstream of the second ultrafiltration device and can be in communication with the input end D41. Generally, therefore, in use, the first output end D42 is first closed, the second reaction liquid is separated by the second ultrafiltration device, part of the second permeated liquid is discharged from the second output end D43, and part of the second permeated liquid is mixed in the second intercept liquid and is intercepted upstream of the second ultrafiltration device and returned to the input end D41 through the third output end D to be filtered by the second ultrafiltration device again. If repeated multiple times, the content of the second permeated liquid in the second intercept liquid is further reduced, and after a specified number of cycles, the third output end D is closed and the first output end D42 is opened, and the second intercept liquid enters the next process through the first output end D42. In another embodiment, the second ultrafiltration device 40 is provided with multiple second ultrafiltration devices, and the multiple second ultrafiltration devices are connected in parallel. After the second reaction liquid enters the second ultrafiltration device 40 from the input end D41, it can contact the multiple second ultrafiltration devices. By connecting the multiple second ultrafiltration devices in parallel, the contact area of the second reaction liquid with the second ultrafiltration device is increased. In another embodiment, multiple second ultrafiltration devices 40 are provided, and the multiple second ultrafiltration devices 40 are connected in series in the flow direction of the second reaction liquid. The input end D41 of the second ultrafiltration device 40 located at the most upstream is connected with the output end C312 of the second reaction device 30, the first output end D42 thereof is connected with the input end D41 of the second ultrafiltration device 40 located downstream thereof, and the second intercept liquid is obtained from the first output end D42 of the second ultrafiltration device 40 located at the most downstream. In this way, the second reaction liquid flows through the multiple second ultrafiltration devices 40, the second intercept liquid discharged from the second ultrafiltration device 40 at the upstream is filtered again by the second ultrafiltration device 40 at the downstream, the second permeated liquid mixed therein is gradually discharged, and relatively pure second intercept liquid can be obtained.

[0052] Further, the glycosaminoglycan derivative preparation device further comprises a reaction degree detection mechanism, which comprises a quartz cuvette and a material taking device. The material taking device can obtain the enzyme liquid of the heparin substrate in the first reaction tank 11. Specifically, in use, 2.5 ml of Tris-HCl buffer solution (50 mM, containing 10 mM CaCl2, containing 1 mg / ml heparin, pH 7.0) is added to the quartz cuvette and preheated at 30°C. The material taking device removes 5-20 μL of enzyme liquid and places it in the quartz cuvette, shakes it uniformly, and then measures the absorbance at 232 nm. The absorbance change per minute is read. According to the molar extinction coefficient, the number of moles of double bonds produced per unit time is calculated, and the unit activity (1 U / ml) of the enzyme liquid is calculated.

[0053] Optionally, the first reaction device 10 further comprises a first adjusting member 12, the first adjusting member 12 is used for adjusting the flow of the raw materials into the first reaction tank 11, and the raw materials react to generate the first reaction liquid.

[0054] For example, in this embodiment, the first adjusting member 12 is a flow pump, and the sodium nitrite is injected into the first reaction tank 11 through the first adjusting member 12, so that the sodium nitrite and the heparin sodium can fully react.

[0055] In other embodiments, the first adjusting member 12 can also be a valve structure, which is a prior art, and its structure and principle will not be described here.

[0056] Optionally, the first reaction device 10 further comprises a first stirring mechanism, the first stirring mechanism is installed in the first reaction tank 11 and is used for stirring the raw materials, and the raw materials react to generate the first reaction liquid.

[0057] For example, in this embodiment, the first stirring mechanism comprises a stirring rod and a stirring paddle, the stirring rod is at least partially arranged in the first reaction tank 11, and the stirring paddle is fixed to the circumferential side of the stirring rod. When the first stirring rod rotates, the stirring paddle can rotate with it, and the stirring paddle is used to stir the raw materials in the first reaction tank 11, so that the raw materials in the first reaction tank 11 can fully contact and react.

[0058] In other embodiments, the first stirring mechanism can also use a magnetic stirring structure. According to the principle that like poles repel and unlike poles attract, a magnetic field is used to drive a magnetic stirring paddle placed in the container to rotate in a circle, thereby achieving the purpose of stirring the liquid. It is a prior art, and will not be described here.

[0059] During the generation of the first reaction liquid and / or during the subsequent transportation and filtration, heat will be generated. The first cut-off liquid of the first reaction liquid carries a large amount of heat back into the first reaction tank 11, which raises the overall temperature of the first reaction tank 11 and is not conducive to the reaction. Therefore, in this embodiment, the glycosaminoglycan derivative preparation device further comprises a condenser 14, and the first output end B22 of the first ultrafiltration device 20 can communicate with the reflux end A112 of the first reaction tank 11 through the condenser 14. The first cut-off liquid of the first reaction liquid discharged from the first output end B22 of the first ultrafiltration device 20 is cooled through the condenser 14, thereby maintaining the temperature of the first reaction tank 11, or further reducing the temperature of the first reaction tank 11.

[0060] Optionally, the first reaction device 10 further comprises a first pH adjusting mechanism 13, the first pH adjusting mechanism 13 comprises a first pH detecting member 131, a first acidic solution output pipe 132 and a first basic solution output pipe, the first pH detecting member 131 is used to obtain the pH value of the first reaction liquid in the first reaction tank 11, the first acidic solution output pipe 132 is used to input the acidic solution into the first reaction tank 11, and the first basic solution output pipe is used to input the basic solution into the first reaction tank 11.

[0061] In this way, the first reaction tank 11 can maintain the pH value of the reactant in the first reaction tank 11 at 2.0-5.5 by means of the first pH adjusting mechanism 13. In this embodiment, the acidic solution is hydrochloric acid.

[0062] Further, the first pH adjusting mechanism 13 further comprises a control unit, the first acidic solution output pipe 132 is provided with a first electric control valve A, the first basic solution output pipe is provided with a second electric control valve A, the first pH detecting member 131, the first electric control valve A and the second electric control valve A are in communication connection with the control unit, and the control unit is provided with a first pH threshold range: 2.0-5.5. The first electric control valve A and the second electric control valve A are in a normally closed state, the actual pH value of the first reaction tank 11 obtained by the first pH detecting member 131 is transmitted to the control unit, the control unit compares the actual pH value with the first pH threshold range, if the actual pH value < 2.0, the control unit commands the second electric control valve A to open, so that the first basic solution output pipe injects the basic solution into the first reaction tank 11, so as to increase the pH value of the first reaction liquid, until 2.0 < actual pH value < 5.5, and the second electric control valve A is closed. If the actual pH value > 5.5, the control unit commands the first electric control valve A to open, so that the first acidic solution output pipe 132 injects the acidic solution into the first reaction tank 11, so as to reduce the pH value of the first reaction liquid, until 2.0 < actual pH value < 5.5, and the first electric control valve A is closed.

[0063] Further, the first reaction device 10 further comprises a first valve body A15, the first valve body A15 is installed at the output end A111, and is used to adjust the output flow of the first reaction tank 11, and can also be used to control the opening or closing of the output end A111.

[0064] Further, the first reaction device 10 further comprises a second valve body A16, and the output end A111 of the first reaction device 10 can discharge the first reaction liquid outside the glycosaminoglycan derivative preparation device through the second valve body A16.

[0065] Further, the output end A111 of the first reaction device 10 is further provided with a Y-shaped filter A17, the Y-shaped filter A17 can preliminarily filter the first reaction liquid, so as to avoid that the particles wrapped therein damage the first ultrafiltration member when the particles contact the first ultrafiltration member.

[0066] Optionally, the second reaction device 30 further comprises a second pH adjusting mechanism 32, the second pH adjusting mechanism 32 comprises a second pH detection member 321, a second acidic solution output pipe and a second basic solution output pipe 322, the second pH detection member 321 is used to obtain the pH value of the second reaction liquid in the second reaction tank 31, the second acidic solution output pipe is used to input the acidic solution into the second reaction tank 31, and the second basic solution output pipe 322 is used to input the basic solution into the second reaction tank 31.

[0067] In this way, the second reaction tank 31 can maintain the pH value of the reactant in the internal thereof at 6.0-8.0 by means of the second pH adjusting mechanism 32. In the embodiment, the basic solution is sodium hydroxide.

[0068] Further, the second pH adjusting mechanism 32 further comprises a control unit, the second acidic solution output pipe is provided with a first electric control valve B, the second basic solution output pipe 322 is provided with a second electric control valve B, the second pH detection member 321, the first electric control valve B and the second electric control valve B are in communication connection with the control unit, and a second pH threshold range: 6.0-8.0 is set in the control unit. The first electric control valve B and the second electric control valve B are in a normally closed state, the actual pH value in the second reaction tank 31 obtained by the second pH detection member 321 is transmitted to the control unit, the control unit compares the actual pH value with the second pH threshold range, if the actual pH value < 6.0, the control unit commands the second electric control valve B to open, so that the second basic solution output pipe 322 injects the basic solution into the second reaction tank 31 to increase the pH value of the second reaction liquid, until 6.0 < actual pH value < 8.0 is satisfied, and the second electric control valve B is closed. If the actual pH value > 8.0, the control unit commands the first electric control valve B to open, so that the second acidic solution output pipe injects the acidic solution into the second reaction tank 31 to reduce the pH value of the first reaction liquid, until 6.0 < actual pH value < 8.0 is satisfied, and the first electric control valve B is closed.

[0069] Optionally, the glycosaminoglycan derivative preparation device further comprises a first pump group 61, the first pump group 61 comprises a first pump body A611 and a second pump body A612, and the first pump body A611 and / or the second pump body A612 can be used to drive the first reaction liquid to flow to the first ultrafiltration device 20.

[0070] Illustratively, the first reaction tank 11 is connected with the first ultrafiltration device 20 through the first pump group 61, and the first pump body A611 and / or the second pump body A612 can provide kinetic energy for the first reaction liquid.

[0071] Optionally, the GAG derivative preparation device further comprises a UV sterilizer 70, and the first output end D42 of the second ultrafiltration device 40 is in communication with the input end of the UV sterilizer 70. The UV sterilizer 70 is capable of emitting ultraviolet rays to sterilize and disinfect the second reaction solution.

[0072] Further, the GAG derivative preparation device further comprises a second pump set 62, and the second pump set 62 is used to drive the second reaction solution to flow to the second ultrafiltration device 40.

[0073] Optionally, the GAG derivative preparation device further comprises a drying device 90, and the first output end D42 of the second ultrafiltration device 40 is in communication with the input end of the drying device 90. Exemplarily, the drying device 90 is a freeze dryer, which is composed of a refrigeration system, a vacuum system, a heating system, and an electrical instrument control system. Main components include a drying box, a condenser, a refrigeration unit, a vacuum pump, a heating / cooling device, etc. Its working principle is to freeze the dried items below the triple point temperature first, and then make the solid water in the items (ice) sublimate into water vapor under vacuum conditions, so as to remove the water vapor from the items and dry the items.

[0074] It should be noted that the triple point is when the temperature is 0.01℃ and the water vapor pressure is 610.5Pa.

[0075] It should be noted that the freeze dryer is a prior art, and thus its specific mechanism will not be described here.

[0076] Optionally, the GAG derivative preparation device further comprises a third reaction device 50, the first output end D42 of the second ultrafiltration device 40 is in communication with the first input end E51 of the third reaction device 50, the first output end E53 of the third reaction device 50 is in communication with the input end of the drying device 90, and the second reaction solution can generate a precipitate in the third reaction device, and the precipitate enters the drying device 90.

[0077] Exemplarily, the third reaction device 50 comprises a third reaction tank 54, the second reaction solution with a molecular weight greater than 9000Da is discharged from the first output end D42 of the second ultrafiltration device 40 into the third reaction tank 54, ethanol is injected into the third reaction tank 54 through the second input end E52 to perform alcohol precipitation, and a precipitate, i.e., a crude heparin sodium product, is obtained. Then, saline is injected into the third reaction tank 54, the crude heparin sodium product is dissolved, and ethanol is added to perform alcohol precipitation, and a precipitate, i.e., a fine heparin sodium product, is obtained. Finally, purified water is injected to wash the precipitate, and the fine heparin sodium product is put into the drying device 90 for drying.

[0078] Exemplarily, the third reaction device 50 further comprises a second output end E55, and the waste liquid in the third reaction tank 54 can be discharged from the GAG derivative preparation device through the second output end E55.

[0079] Further, the sugar amine glycan derivative preparation device further comprises a third filtering device 80, the third filtering device 80 is installed between the third reaction device 50 and the drying device 90, and the filtered sodium heparin fine is introduced into the drying device 90 to be dried.

[0080] Obviously, the above embodiments of the present application are only examples for clearly illustrating the present application, and are not intended to limit the embodiments of the present application. For ordinary skilled in the art, other different forms of changes or variations can be made on the basis of the above description. Here, all the embodiments are not required to be exhausted. Any modification, equivalent replacement and improvement, etc. made within the spirit and principle of the present application shall be included in the protection scope of the claims of the present application.

Claims

1. A device for preparing a glycosaminoglycan derivative, characterized in that, The application relates to a reaction device for producing a reaction liquid, comprising: a first reaction device (10) comprising a first reaction tank (11) for producing a first reaction liquid; a first ultrafiltration device (20) comprising a first ultrafiltration element allowing fluid with a molecular weight less than a first cut-off molecular weight to pass through, an output end A (111) of the first reaction tank (11) being capable of communicating with an input end B (21) of the first ultrafiltration device (20), a first output end B (22) of the first ultrafiltration device (20) being formed upstream of the first ultrafiltration element and capable of communicating with a reflux end A (112) of the first reaction tank (11), and a second output end B (23) of the first ultrafiltration device (20) being formed downstream of the first ultrafiltration element; a second reaction device (30) comprising a second reaction tank (31), the second output end B (23) of the first ultrafiltration device (20) being capable of communicating with a first input end C (311) of the second reaction tank (31), the first reaction liquid forming a second reaction liquid in the second reaction tank (31); a second ultrafiltration device (40), an output end C (312) of the second reaction device (30) being capable of communicating with an input end D (41) of the second ultrafiltration device (40), the second ultrafiltration device (40) comprising a second ultrafiltration element allowing fluid with a molecular weight less than a second cut-off molecular weight to pass through, a first output end D (42) of the second ultrafiltration device (40) being formed upstream of the second ultrafiltration element and a second output end D (43) of the second ultrafiltration device (40) being formed downstream of the second ultrafiltration element; the first cut-off molecular weight being greater than the second cut-off molecular weight.

2. The device for preparing glycosaminoglycan derivatives according to claim 1, characterized in that, The first reaction device (10) further comprises a first regulating element (12) for regulating the flow rate of raw materials into the first reaction tank (11), the raw materials reacting to form the first reaction liquid.

3. The device for preparing glycosaminoglycan derivatives according to claim 1, characterized in that, The first reaction device (10) further comprises a first stirring mechanism installed in the first reaction tank (11) for stirring the raw materials, the raw materials reacting to form the first reaction liquid.

4. The device for preparing a glycosaminoglycan derivative according to claim 1, characterized in that, The application further comprises a condenser (14), the first output end B (22) of the first ultrafiltration device (20) being capable of communicating with the reflux end A (112) of the first reaction tank (11) through the condenser (14).

5. The glycosaminoglycan derivative preparation device according to claim 1, characterized in that, The first reaction device (10) further comprises a first pH regulating mechanism (13) comprising a first pH detection element (131), a first acid solution output pipe (132) and a first alkaline solution output pipe; the first pH detection element (131) being used for acquiring the pH value of the first reaction liquid in the first reaction tank (11), the first acid solution output pipe (132) being used for inputting an acid solution into the first reaction tank (11), and the first alkaline solution output pipe being used for inputting an alkaline solution into the first reaction tank (11).

6. The glycosaminoglycan derivative preparation device according to claim 1, characterized in that, The second reaction device (30) further comprises a second pH adjusting mechanism (32), the second pH adjusting mechanism (32) comprising a second pH detection piece (321), a second acidic solution output pipe and a second alkaline solution output pipe (322); the second pH detection piece (321) is used to obtain the pH value of the second reaction liquid in the second reaction tank (31), the second acidic solution output pipe is used to input acidic solution into the second reaction tank (31), and the second alkaline solution output pipe (322) is used to input alkaline solution into the second reaction tank (31).

7. The device for preparing glycosaminoglycan derivatives according to claim 1, characterized in that, Further comprising a first pump group (61), the first pump group (61) comprising a first pump body A (611) and a second pump body A (612), the first pump body A (611) and / or the second pump body A (612) can be used to drive the first reaction liquid to flow to the first ultrafiltration device (20).

8. The device for preparing glycosaminoglycan derivatives according to claim 1, characterized in that, Further comprising an ultraviolet sterilizer (70), a first output end D (42) of the second ultrafiltration device (40) communicates with an input end of the ultraviolet sterilizer (70).

9. The device for preparing glycosaminoglycan derivatives according to claim 1, characterized in that, Further comprising a drying device (90), the first output end D (42) of the second ultrafiltration device (40) can communicate with an input end of the drying device (90).

10. The device for preparing glycosaminoglycan derivatives according to claim 9, characterized in that, Further comprising a third reaction device (50), the first output end D (42) of the second ultrafiltration device (40) can communicate with an input end of the third reaction device (50), a first output end E (53) of the third reaction device (50) can communicate with an input end of the drying device (90), the second reaction liquid can generate precipitates in the third reaction device (50), and the precipitates enter the drying device (90).

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