A catalytic preparation device and preparation process of a light ischemic stroke treatment drug composition based on tenecteplase

Abstract

The present application relates to the technical field of pharmaceutical production device, specifically, it relates to a catalytic preparation device of a light ischemic stroke treatment drug composition based on tenecteplase and a preparation process thereof, which comprises a reactor, a stirring assembly is arranged in the reactor, the stirring assembly comprises a rotating shaft, a plurality of stirring blades and a plurality of cleaning plates, the reactor is provided with an adjusting structure for changing the angle of the stirring blade and a plurality of sweeping structures for driving the cleaning plates to clean the surface of the corresponding stirring blade; the adjusting structure comprises a base and an electric motor; the sweeping structure comprises a sweeping rod in transmission connection with a transmission structure, a guide rod located above the corresponding cleaning plate and a second connecting rod fixed to the middle part of the inner side wall of the cleaning plate. The device can adjust the deflection angle of the stirring blade to adapt to different periods of reaction by setting the adjusting structure during the reaction process, and the stirring blade is cleaned during the reaction process by setting the cleaning plate, so that the influence of denatured protein aggregation on the reaction is avoided.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical manufacturing equipment technology, specifically a catalytic preparation device and its preparation process for a drug composition for the treatment of mild ischemic stroke based on tenecteplase. Background Technology

[0002] Mild ischemic stroke is a type of acute stroke with milder symptoms. It is typically treated with a compound drug formulation containing tenecteplase as the core component, combined with stabilizers and buffers as excipients. This formulation dissolves blood clots in blood vessels and reduces the risk of bleeding. The preparation of tenecteplase generally involves several stages, including gene recombination, cell culture, protein purification, and formulation development. During protein purification, the tenecteplase expressed in prokaryotic cells needs to undergo protein folding to ensure it exhibits the correct structural expression activity. A propeller-driven stirred reactor is used to mix and catalyze the reaction of denatured protein solution and refolding buffer. The resulting reaction solution is then subjected to shearing to obtain the active tenecteplase.

[0003] For example, invention application CN120227837A discloses a preparation apparatus and method for sodium isophthalic acid-5-sulfonate in the field of sodium isophthalic acid-5-sulfonate preparation technology. The apparatus includes a reaction vessel body with a top cover, a jacket inside, and a discharge pipe and a heat transfer medium inlet pipe at the bottom, with the discharge pipe connected to the interior of the reaction vessel body. It also discloses a preparation method. This invention, through the rotation of the stirring shaft, not only achieves mixing and stirring but also drives the annular feeding seat to rotate. The entire process requires no multiple manual operations; the entire amount of isophthalic acid needed is added to the reaction vessel at once, achieving automatic material distribution and batch feeding. This not only simplifies operation and improves work efficiency but also ensures safety, minimizing harm to the human body. Furthermore, it meets the requirements for automated feeding, making the entire production process more precise.

[0004] Based on the above cases and actual situations, we have identified the following issues: In the catalytic reaction of denatured protein solution and refolding buffer, the functional focus of the impeller differs in the early, middle, and late stages of the reaction. In the early stage, the denatured protein solution needs to be rapidly dispersed in the refolding buffer; in the middle stage, a relatively stable solution environment is required for the reaction; and in the late stage, it is necessary to avoid excessive shear force generated by the impeller rotation exceeding the threshold of protein folding. However, existing propeller reactors are difficult to adjust in angle and adapt to different reaction stages. Furthermore, since denatured protein solutions typically have a certain viscosity, the impeller needs to rotate at a relatively slow speed during stirring to avoid shear force generated during stirring damaging the protein. Therefore, denatured protein solution may adhere to the impeller, forming a thin film that leads to protein aggregation, affecting the reaction rate and quality. Summary of the Invention

[0005] The purpose of this invention is to provide a catalytic preparation device and preparation process for a drug composition for the treatment of mild ischemic stroke based on tenecteplase. By setting an adjustment structure to adjust the deflection angle of the stirring blade to adapt to the needs of different reaction stages, and by setting a sweeping structure to drive a cleaning plate to clean the stirring blade, the above-mentioned problems of the prior art are solved.

[0006] To achieve the above objectives, the present invention provides a catalytic preparation apparatus for a drug composition for the treatment of mild ischemic stroke based on tenecteplase, comprising a reactor, wherein a stirring assembly is provided in the reactor, the stirring assembly comprising a rotating shaft, a plurality of stirring blades regularly and alternately installed on the rotating shaft, and a plurality of cleaning plates corresponding one-to-one with the plurality of stirring blades, and the reactor is provided with an adjustment structure for changing the angle of the stirring blades and a plurality of sweeping structures for driving the cleaning plates to clean the surface of the corresponding stirring blades.

[0007] The adjustment structure includes a base fixed to the top of the rotating shaft and an electric motor fixed on the base. An adjustment shaft is coaxially rotatably connected inside the rotating shaft. The output end of the electric motor passes through the base and the rotating shaft in sequence and is connected to the adjustment shaft through a second gear set. A first connecting rod is fixed in the middle of the inner side of the cleaning plate. The inner end of the first connecting rod passes through the rotating shaft and is connected to the adjustment shaft through a first gear set.

[0008] The reactor is equipped with several transmission structures for driving several sweeping structures to reciprocate. Each sweeping structure includes a sweeping rod that is connected to the transmission structure, a guide rod located above the corresponding cleaning plate, and a second connecting rod fixed in the middle of the inner wall of the cleaning plate. The guide rod has a guide groove in the middle of its outer wall, and the inner end of the cleaning plate is inserted into the corresponding guide groove and the two are slidably connected.

[0009] This design takes into account the protein catalytic folding required in tenecteplase production. The denatured protein solution containing tenecteplase is mixed with a refolding buffer for catalysis. In existing propeller reactors, mixing is done directly by stirring with the blades. The blades require different functional focuses in the early, middle, and late stages of the reaction. In the early stage, rapid dispersion of the denatured protein solution in the refolding buffer is needed; in the middle stage, a relatively stable solution environment is required for the reaction; and in the late stage, excessive shear force generated by the blade rotation needs to be avoided, which could exceed the protein folding threshold. However, existing propeller reactors make it difficult to change the blade angle. Furthermore, since denatured protein solutions typically have a certain viscosity, the blades need to rotate at a slower speed during stirring to prevent shear force from damaging the protein. Therefore, denatured protein solution may adhere to the blades, forming a film that leads to protein aggregation, affecting the reaction rate and quality. This device, through an adjustable structure, can adjust the blade deflection angle during the reaction to adapt to different stages. Simultaneously, a cleaning plate cleans the blades during the reaction, preventing denatured protein aggregation from affecting the reaction.

[0010] In the technical solution of the present invention, the reactor consists of an inner tank containing the reaction liquid and an outer circulating water jacket that maintains the reaction temperature. The top of the inner tank is provided with a sealing cover, and the sealing cover is provided with a first feed inlet and a second feed inlet on the left and right sides respectively. The outer wall of the circulating water jacket is fixed by a bracket.

[0011] In this setup, a circulating water jacket is used to control the temperature of the reaction liquid inside the inner tank, thereby maintaining a constant reaction temperature and reducing the generation of byproducts. The first and second feed inlets are filled with packing materials.

[0012] In the technical solution of the present invention, the top end of the rotating shaft extends through the sealing cover and is provided with a servo motor. The servo motor is fixed on the sealing cover by a mounting bracket. The output shaft of the servo motor is coaxially and fixedly connected to the rotating shaft. The adjustment structure is installed on the outer wall of the rotating shaft located above the sealing cover.

[0013] In this setting, a servo motor is used to drive the rotating shaft, which in turn drives the stirring blades to stir.

[0014] In the technical solution of the present invention, the transmission structure includes a gear ring fixed on the inner wall of the inner liner, a planetary gear meshing with the inner side of the gear ring, and a fixing plate. The outer end of the fixing plate is rotatably connected to the planetary gear, and the inner end is fixed to the side wall of the rotating shaft.

[0015] In this setup, by incorporating planetary gears and a gear ring, when the shaft rotates, the shaft drives the fixed plate to rotate, which in turn drives the planetary gears to revolve around the sun, and the gear ring causes the planetary gears to rotate on their own axis.

[0016] In the technical solution of the present invention, the planetary gear is provided with a first transmission rod, the outer end of the first transmission rod is rotatably connected to the upper surface of the planetary gear, and the inner end is hinged to a movable rod. The fixed plate is provided with a movable groove, and the movable rod is engaged in the movable groove and the two are slidably connected.

[0017] In this configuration, by setting up a first transmission rod and a movable rod, when the planetary gear rotates, it drives the first transmission rod and the movable rod to reciprocate along the movable groove.

[0018] In the technical solution of the present invention, the movable rod is provided with a second transmission rod, the outer end of the second transmission rod is hinged to the movable rod, and the inner end is hinged to a rotating sleeve, the rotating sleeve is sleeved outside the adjusting shaft and the two are rotatably connected.

[0019] In this setup, by setting a second transmission rod and a rotating sleeve, when the movable rod moves back and forth along the movable groove, it drives the second transmission rod to move back and forth, which in turn drives the sweeping rod to sweep back and forth, thereby causing the cleaning plate to move back and forth along the guide groove to clean the surface of the stirring blade.

[0020] In the technical solution of the present invention, the inner end of the sweeping rod passes through the rotating shaft and is fixedly connected to the lower part of the rotating sleeve. The front end of the sweeping rod is L-shaped and bent downwards. The front end of the sweeping rod is provided with a locking rod. The top end of the locking rod is slidably connected to the front end of the sweeping rod, and the bottom end is hemispherical and is engaged with the top surface of the corresponding cleaning plate. The rotating shaft is provided with an opening for the second transmission rod and the sweeping rod to rotate.

[0021] In this setup, by using a locking rod, the cleaning plate will not only move up and down but also twist as it slides along the guide groove. The hemispherical structure at the bottom of the locking rod ensures the connection with the cleaning plate and prevents the cleaning plate from twisting. The reserved opening prevents the second transmission rod and the sweeping rod from being blocked from rotating.

[0022] In the technical solution of the present invention, the guide rod, the guide groove and the stirring blade are all the same spiral shape, and the extension line of the inner end of the sweeping rod passes through the axis of the rotating shaft.

[0023] In this configuration, the guide rod, the guide groove, and the stirring blade are all spiral-shaped, ensuring that the cleaning plate remains in contact with the surface of the stirring blade when it slides along the guide groove. The extension line of the inner end of the sweeping rod passes through the axis of the rotating shaft, ensuring that the sweeping rod rotates around the rotating shaft when it drives the cleaning plate to rotate, thus preventing the cleaning plate from shifting and failing to clean the stirring blade.

[0024] In the technical solution of the present invention, the second connecting rod is located directly above the first connecting rod, and both the first and second connecting rods have side rods fixed to their side walls at the front and back. The corresponding side rods on the first and second connecting rods are hinged together by a vertical rod. The second connecting rod has a mounting plate in the middle, and the top of the mounting plate is fixedly connected to the side wall of the rotating shaft. The second connecting rod passes through the mounting plate and the two are rotatably connected.

[0025] In this setup, by setting up side rods and vertical rods, since the side rods on the first connecting rod, the side rods on the second connecting rod, and the vertical rod form a parallelogram structure, when the stirring blade changes its deflection angle, the first connecting rod drives the second connecting rod to rotate synchronously and at the same angle, thereby ensuring that the guide rod and the stirring blade move synchronously, and thus ensuring that the cleaning plate and the stirring blade always fit together.

[0026] On the other hand, the present invention also provides a catalytic preparation process for a tenecteplase-based pharmaceutical composition for the treatment of mild ischemic stroke, employing the aforementioned catalytic preparation apparatus for the tenecteplase-based pharmaceutical composition for the treatment of mild ischemic stroke, comprising the following steps:

[0027] S1. First, the refolding buffer is fed into the first inlet, and then the denatured protein solution is slowly and quantitatively added to the second inlet through a peristaltic pump. At the same time, the servo motor is started to drive the shaft to rotate, which in turn drives the stirring blade to rotate and stir slowly.

[0028] S2. During the mixing process, the rotating shaft drives the fixed plate to rotate, which in turn drives the planetary gear to revolve. Under the action of the gear ring, the planetary gear rotates on its own axis, which drives the first transmission rod and the movable rod to move back and forth. This in turn drives the second transmission rod to move back and forth, causing the rotating sleeve to rotate back and forth, which in turn drives the sweeping rod to sweep back and forth. This causes the cleaning plate to move back and forth along the guide groove to clean the surface of the mixing blade.

[0029] S3. When protein folding catalysis reaches the middle and end stages, turn off the servo motor and start the electric motor to drive the second gear set to rotate, which in turn drives the adjustment shaft to rotate. This, in turn, drives the first connecting rod and stirring blade to rotate through the first gear set, reducing the tilt angle of the stirring blade. After adjustment, start the servo motor again.

[0030] S4. After the catalytic protein has folded, open the reactor outlet to proceed with subsequent processes.

[0031] In summary, due to the adoption of the above technical solution, the beneficial effects of the present invention are:

[0032] 1. In this invention, by setting an adjustment structure, during the reaction process, the electric motor is started to drive the second gear set to rotate, which in turn drives the adjustment shaft to rotate. Then, the first gear set drives the first connecting rod and the stirring blade to rotate, changing the tilt angle of the stirring blade to adapt to the needs of different stages of the reaction.

[0033] 2. In this invention, by setting a transmission structure and a sweeping structure, during the stirring process, the rotating shaft drives the fixed plate to rotate, which in turn drives the planetary gear to revolve. Under the action of the gear ring, the planetary gear rotates, which drives the first transmission rod and the movable rod to move back and forth along the movable groove, thereby driving the second transmission rod to move back and forth, causing the rotating sleeve to rotate back and forth, which in turn drives the sweeping rod to sweep back and forth, thereby causing the cleaning plate to move back and forth along the guide groove to clean the surface of the stirring blade.

[0034] 3. In this invention, the side rod and the vertical rod form a parallelogram structure. Therefore, when the stirring blade changes its deflection angle, the first connecting rod drives the second connecting rod to rotate synchronously at the same angle, thereby ensuring that the guide rod and the stirring blade move synchronously, and thus ensuring that the cleaning plate and the stirring blade are always in contact. Attached Figure Description

[0035] Figure 1 This is a simplified schematic diagram of the overall structure of the present invention;

[0036] Figure 2 This is an exploded view of the reactor of the present invention;

[0037] Figure 3 This is a schematic diagram of the interior of the inner liner in this invention;

[0038] Figure 4 This is a cross-sectional view of the inner liner in this invention;

[0039] Figure 5 This is a schematic diagram of the rotating shaft in this invention;

[0040] Figure 6 This is a cross-sectional view of the rotating shaft in this invention;

[0041] Figure 7 This is a schematic diagram of the transmission structure in this invention;

[0042] Figure 8 This is a schematic diagram of the sweeping structure in this invention;

[0043] Figure 9 This is a schematic diagram of the sweeping rod in this invention;

[0044] Figure 10 This is a schematic diagram of the first connecting rod and the second connecting rod in this invention;

[0045] Figure 11 This is a schematic diagram of the adjustment structure in this invention;

[0046] Explanation of reference numerals in the attached figures:

[0047] 1. Reactor; 101. Inner tank; 102. First feed inlet; 103. Second feed inlet; 104. Support frame; 105. Circulating water jacket;

[0048] 2. Stirring assembly; 201. Servo motor; 2011. Mounting bracket; 202. Rotating shaft; 203. Stirring blade; 2031. First connecting rod; 204. Cleaning plate; 205. Adjusting shaft; 206. First gear set; 207. Second gear set; 210. Transmission structure; 211. Gear ring; 212. Planetary gear; 213. Fixing plate; 214. First transmission rod; 215. Movable rod; 216. Second transmission rod; 217. Rotating sleeve; 218. Movable groove; 220. Sweeping structure; 221. Sweeping rod; 222. Locking rod; 223. Guide rod; 2231. Guide groove; 224. Mounting plate; 225. Second connecting rod; 226. Vertical rod; 227. Side rod; 230. Adjusting structure; 231. Electric motor; 232. Base. Detailed Implementation

[0049] The specific embodiments of the present invention will now be described in detail with reference to the accompanying drawings, but it should be understood that the scope of protection of the present invention is not limited to the specific embodiments.

[0050] Unless otherwise expressly stated, throughout this specification, the term "comprising" or its variations such as "including" or "comprises" shall be understood to include the stated elements or components without excluding other elements or other components.

[0051] Reference Figures 1-11 As shown, this embodiment provides a technical solution:

[0052] A catalytic preparation device for a pharmaceutical composition for the treatment of mild ischemic stroke based on tenecteplase includes a reactor 1. The reactor 1 is equipped with a stirring assembly 2, which includes a rotating shaft 202, a plurality of stirring blades 203 regularly and alternately installed on the rotating shaft 202, and a plurality of cleaning plates 204 corresponding to the stirring blades 203. The stirring blades 203 are used to stir and mix the reaction solution to accelerate the reaction and improve the reaction quality. Since denatured protein solutions usually have a certain viscosity, the stirring blades 203 need to rotate at a relatively slow speed during the stirring process to avoid the shear force generated during the stirring process from damaging the protein. Therefore, denatured protein solutions may adhere to the stirring blades 203 to form a film, which may lead to protein aggregation and affect the reaction rate and reaction quality. By setting up cleaning plates 204, the surface of the stirring blades 203 is continuously cleaned during the catalytic reaction to avoid protein aggregation. The reactor 1 is equipped with an adjustment structure 230 for changing the angle of the stirring blades 203 and a plurality of sweeping structures 220 for driving the cleaning plates 204 to clean the surface of the corresponding stirring blades 203.

[0053] The adjustment structure 230 includes a base 232 fixed to the top of the rotating shaft 202 and an electric motor 231 fixed to the base 232. An adjustment shaft 205 is coaxially rotatably connected inside the rotating shaft 202. The output end of the electric motor 231 passes through the base 232 and the rotating shaft 202 in sequence and is connected to the adjustment shaft 205 via a second gear set 207. A first connecting rod 2031 is fixed to the middle of the inner side of the cleaning plate 204. The inner end of the first connecting rod 2031 passes through the rotating shaft 202 and is connected to the adjustment shaft 205 via a first gear set 206. At the beginning of the catalytic reaction, there is a large amount of denatured protein solution. The stirring blade 203 deflects at its maximum angle of 30°. The vertical thrust along the axial direction of the rotating shaft 202 is small, while the radial thrust perpendicular to the rotating shaft 202 is large, allowing the denatured protein solution and the refolding buffer to disperse and mix rapidly. As the reaction proceeds, more and more proteins are folded. To prevent the folded proteins from being subjected to excessive impact, the electric motor 231 is started, which drives the adjusting shaft 205 to rotate counterclockwise through the second gear set 207, and in turn drives the first connecting rod 2031 to rotate through the first gear set 206. This causes the stirring blade 203 to gradually deflect at an angle of 15°, increasing the proportion of axial force and decreasing the proportion of radial force, so that the deformed protein solution and the refolding buffer can circulate up and down, while reducing horizontal diffusion impact and ensuring a balanced and stable reaction. Towards the end of the reaction, the electric motor 231 is started again to reduce the deflection angle of the stirring blade 203 to 5°. At this point, the proportion of axial force is the largest and the proportion of radial force is the smallest, which improves the circulation of the entire reaction solution and prevents excessive aggregation of folded proteins. At the same time, it reduces the shear effect generated by the radial force during the rotation of the stirring blade 203, preventing the folded protein tolerance threshold from being exceeded.

[0054] The reactor 1 is equipped with several transmission structures 210 for driving several sweeping structures 220 to reciprocate. Each sweeping structure 220 includes a sweeping rod 221 that is connected to the transmission structure 210, a guide rod 223 located above the corresponding cleaning plate 204, and a second connecting rod 225 fixed in the middle of the inner side wall of the cleaning plate 204. The guide rod 223 has a guide groove 2231 in the middle of its outer wall. The inner end of the cleaning plate 204 is inserted into the corresponding guide groove 2231 and the two are slidably connected. During the reaction, the sweeping rod 221 drives the cleaning plate 204 to slide along the guide groove 2231 to clean the surface of the stirring blade 203, reducing protein aggregation and affecting the reaction efficiency. It should be noted that the sweeping structure 220 and the stirring blade 203 are one-to-one. The sweeping structure 220 is located above the corresponding stirring blade 203. The minimum distance between adjacent stirring blades 203 should be greater than the maximum vertical height difference of the sweeping structure 220 to leave enough space for the sweeping structure 220 to be installed.

[0055] Please see Figures 1-2As shown, reactor 1 consists of an inner tank 101 containing the reaction liquid and an outer circulating water jacket 105 that maintains the reaction temperature. The circulating water jacket 105 controls the temperature of the reaction liquid in the inner tank 101 to maintain a constant reaction temperature and reduce the generation of by-products. The circulating water jacket 105 is provided with an inlet pipe and an outlet pipe, which are not shown in the figure. This is prior art in the field and will not be described in detail here. The top of the inner tank 101 is provided with a sealing cover. The sealing cover is provided with a first feed port 102 and a second feed port 103 on the left and right sides, respectively. The first feed port 102 and the second feed port 103 are filled with materials. The outer wall of the circulating water jacket 105 is fixed by a bracket 104.

[0056] Please see Figures 2-3 As shown, the top of the rotating shaft 202 extends through the sealing cover and is equipped with a servo motor 201. The servo motor 201 drives the rotating shaft 202 to rotate, thereby driving the stirring blade 203 to stir. The servo motor 201 is fixed to the sealing cover by bolts through the mounting bracket 2011. The output shaft of the servo motor 201 is coaxially and fixedly connected to the rotating shaft 202. The adjustment structure 230 is installed on the outer wall of the rotating shaft 202 located above the sealing cover.

[0057] Please see Figures 4-8 As shown, the transmission structure 210 includes a gear ring 211 fixed on the inner wall of the inner liner 101, a planetary gear 212 meshing with the inner side of the gear ring 211, and a fixing plate 213. The outer end of the fixing plate 213 is rotatably connected to the planetary gear 212, and the inner end is fixed to the side wall of the rotating shaft 202. When the rotating shaft 202 rotates, the rotating shaft 202 drives the fixing plate 213 to rotate, which in turn drives the planetary gear 212 to revolve. Under the action of the gear ring 211, the planetary gear 212 rotates on its own axis.

[0058] Specifically, the planetary gear 212 is provided with a first transmission rod 214. The outer end of the first transmission rod 214 is rotatably connected to the upper surface of the planetary gear 212, and the inner end is hinged to a movable rod 215. The fixed plate 213 is provided with a movable groove 218. The movable rod 215 is engaged in the movable groove 218 and the two are slidably connected. When the planetary gear 212 rotates, it drives the first transmission rod 214 and the movable rod 215 to move back and forth along the movable groove 218.

[0059] Furthermore, the movable rod 215 is provided with a second transmission rod 216. The outer end of the second transmission rod 216 is hinged to the movable rod 215, and the inner end is hinged to a rotating sleeve 217. The rotating sleeve 217 is sleeved on the outside of the adjusting shaft 205. The inner wall of the rotating sleeve 217 is embedded in the outer wall of the adjusting shaft 205 and the two are rotatably connected. When the movable rod 215 moves back and forth along the movable groove 218, it drives the second transmission rod 216 to move back and forth and pushes and pulls the rotating sleeve 217 to rotate back and forth, thereby driving the sweeping rod 221 to sweep back and forth, thereby causing the cleaning plate 204 to move back and forth along the guide groove 2231 to clean the surface of the stirring blade 203.

[0060] Please see Figures 8-9 As shown, the inner end of the sweeping rod 221 passes through the rotating shaft 202 and is fixedly connected to the lower part of the rotating sleeve 217. The front end of the sweeping rod 221 is L-shaped with a downward bend. A locking rod 222 is provided at the front end of the sweeping rod 221. The top end of the locking rod 222 is slidably connected to the front end of the sweeping rod 221, and the bottom end is hemispherical and is engaged with the top surface of the corresponding cleaning plate 204. The bottom end of the locking rod 222 is hemispherically embedded in the top surface of the cleaning plate 204. Since the cleaning plate 204 will not only move up and down but also twist when sliding along the guide groove 2231, the hemispherical joint at the bottom end of the locking rod 222... The structure ensures the connection with the cleaning plate 204 and prevents the cleaning plate 204 from twisting. The clamping rod 222 can extend and retract vertically, and the extension and retraction distance should be greater than the vertical distance from the highest end to the lowest end when the stirring blade 203 deflects at its maximum angle. This prevents the clamping rod 222 from failing to drive the cleaning plate 204 to rotate due to insufficient downward movement, which would prevent the cleaning plate 204 from performing cleaning operations. The rotating shaft 202 is provided with an opening for the second transmission rod 216 and the sweeping rod 221 to rotate. The reserved opening prevents the second transmission rod 216 and the sweeping rod 221 from being blocked from rotating.

[0061] Specifically, the guide rod 223, guide groove 2231, and stirring blade 203 are all the same spiral shape, ensuring that when the cleaning plate 204 slides along the guide groove 2231, the cleaning plate 204 is always in contact with the surface of the stirring blade 203. The extension line of the inner end of the sweeping rod 221 passes through the axis of the rotating shaft 202, ensuring that when the sweeping rod 221 drives the cleaning plate 204 to rotate, it rotates around the rotating shaft 202, thereby ensuring that the cleaning plate 204 will not deviate and thus fail to clean the stirring blade 203.

[0062] Please see Figures 10-11 As shown, the second connecting rod 225 is located directly above the first connecting rod 2031, and both the first connecting rod 2031 and the second connecting rod 225 have side rods 227 fixed to their side walls at the front and rear. The corresponding side rods 227 on the first connecting rod 2031 and the second connecting rod 225 are hinged together by a vertical rod 226. A mounting plate 224 is provided in the middle of the second connecting rod 225, and the top of the mounting plate 224 is fixedly connected to the side wall of the rotating shaft 202. The second connecting rod 225 passes through the mounting plate 224 and the two are rotatably connected. Due to the first connecting rod 2031... The side rod 227, the side rod 227 on the second connecting rod 225, and the vertical rod 226 form a parallelogram structure. Therefore, when the stirring blade 203 changes its deflection angle, the first connecting rod 2031 drives the second connecting rod 225 to rotate synchronously and at the same angle, thereby ensuring that the guide rod 223 and the stirring blade 203 move synchronously, and thus ensuring that the cleaning plate 204 and the stirring blade 203 are always in contact. It should be noted that, due to the presence of the locking rod 222, the sweeping rod 221 will not form an obstruction when the guide rod 223 deflects.

[0063] This invention also provides a catalytic preparation process for a tenecteplase-based pharmaceutical composition for the treatment of mild ischemic stroke, employing the aforementioned catalytic preparation apparatus for the tenecteplase-based pharmaceutical composition for the treatment of mild ischemic stroke, comprising the following steps:

[0064] Before protein catalytic folding, the recombinant cells were cultured at high density to express tenecteplase in the cells. Then, the cells were denatured and washed to make the internal proteins have a linear structure. After centrifugation and filtration, the denatured protein solution containing tenecteplase was obtained, and a refolding buffer was prepared.

[0065] S1. First, the refolding buffer is fed into the first feed port 102, and then the denatured protein solution is slowly and quantitatively added to the second feed port 103 by a peristaltic pump. At the same time, the servo motor 201 is started to drive the rotating shaft 202 to rotate, which in turn drives the stirring blade 203 to rotate and stir slowly.

[0066] S2. During the stirring process, the rotating shaft 202 drives the fixed plate 213 to rotate, which in turn drives the planetary gear 212 to revolve. Under the action of the gear ring 211, the planetary gear 212 rotates on its own axis, which drives the first transmission rod 214 and the movable rod 215 to move back and forth. This in turn drives the second transmission rod 216 to move back and forth, causing the rotating sleeve 217 to rotate back and forth, which in turn drives the sweeping rod 221 to sweep back and forth. This in turn causes the cleaning plate 204 to move back and forth along the guide groove 2231 to clean the surface of the stirring blade 203.

[0067] S3. When protein folding catalysis reaches the middle and end stages, turn off the servo motor 201 and start the electric motor 231 to drive the second gear set 207 to rotate, which in turn drives the adjustment shaft 205 to rotate. This, in turn, drives the first connecting rod 2031 and the stirring blade 203 to rotate through the first gear set 206, reducing the tilt angle of the stirring blade 203. After adjustment, start the servo motor 201 again.

[0068] S4. After the catalytic protein has folded, open the outlet of reactor 1 to proceed with the subsequent process.

[0069] The foregoing description of specific exemplary embodiments of the invention is for illustrative and explanatory purposes. These descriptions are not intended to limit the invention to the precise forms disclosed, and it will be apparent that many changes and variations can be made in accordance with the foregoing teachings. The exemplary embodiments were chosen and described in order to explain the specific principles of the invention and its practical application, thereby enabling those skilled in the art to implement and utilize various different exemplary embodiments of the invention, as well as various different choices and variations. The scope of the invention is intended to be defined by the specification and its equivalents.

Claims

1. A catalytic preparation apparatus for a pharmaceutical composition for the treatment of mild ischemic stroke based on tenecteplase, comprising a reactor, characterized in that: The reactor is equipped with a stirring assembly, which includes a rotating shaft, a number of stirring blades regularly and alternately installed on the rotating shaft, and a number of cleaning plates corresponding to the stirring blades. The reactor is equipped with an adjustment structure for changing the angle of the stirring blades and a number of sweeping structures for driving the cleaning plates to clean the surface of the corresponding stirring blades. The adjustment structure includes a base fixed to the top of the rotating shaft and an electric motor fixed on the base. An adjustment shaft is coaxially rotatably connected inside the rotating shaft. The output end of the electric motor passes through the base and the rotating shaft in sequence and is connected to the adjustment shaft through a second gear set. A first connecting rod is fixed in the middle of the inner side of the cleaning plate. The inner end of the first connecting rod passes through the rotating shaft and is connected to the adjustment shaft through a first gear set. The reactor is equipped with several transmission structures for driving several sweeping structures to reciprocate. The sweeping structure includes a sweeping rod that is connected to the transmission structure, a guide rod located above the corresponding cleaning plate, and a second connecting rod fixed in the middle of the inner side wall of the cleaning plate. The guide rod has a guide groove in the middle of its outer wall, and the inner end of the cleaning plate is inserted into the corresponding guide groove and the two are slidably connected. The reactor consists of an inner tank that holds the reaction liquid and an outer circulating water jacket that maintains the reaction temperature. The transmission structure includes a gear ring fixed to the inner wall of the inner liner, a planetary gear meshing with the inner side of the gear ring, and a fixing plate. The outer end of the fixing plate is rotatably connected to the planetary gear, and the inner end is fixed to the side wall of the rotating shaft. The planetary gear is provided with a first transmission rod, the outer end of the first transmission rod is rotatably connected to the upper surface of the planetary gear, and the inner end is hinged to a movable rod. The fixed plate is provided with a movable groove, and the movable rod is engaged in the movable groove and the two are slidably connected. The movable rod is provided with a second transmission rod, the outer end of the second transmission rod is hinged to the movable rod, and the inner end is hinged to a rotating sleeve. The rotating sleeve is sleeved outside the adjusting shaft and the two are rotatably connected. The inner end of the sweeping rod passes through the rotating shaft and is fixedly connected to the lower part of the rotating sleeve. The front end of the sweeping rod is L-shaped and bent downwards. The front end of the sweeping rod is provided with a locking rod. The top end of the locking rod is slidably connected to the front end of the sweeping rod, and the bottom end is hemispherical and is engaged with the top surface of the corresponding cleaning plate. The rotating shaft is provided with an opening for the second transmission rod and the sweeping rod to rotate. The guide rod, the guide groove, and the stirring blade are all the same spiral shape, and the extension line of the inner end of the sweeping rod passes through the axis of the rotating shaft; The second connecting rod is located directly above the first connecting rod, and both the first and second connecting rods have side rods fixed to their side walls at the front and back. The corresponding side rods on the first and second connecting rods are hinged together by vertical rods. The second connecting rod has a mounting plate in the middle, and the top of the mounting plate is fixedly connected to the side wall of the rotating shaft. The second connecting rod passes through the mounting plate and the two are rotatably connected.

2. The catalytic preparation apparatus for the pharmaceutical composition for the treatment of mild ischemic stroke based on tenecteplase as described in claim 1, characterized in that: The inner tank is provided with a sealing cover at the top, and the sealing cover is provided with a first feed port and a second feed port on the left and right sides respectively. The outer wall of the circulating water jacket is fixed by a bracket.

3. The catalytic preparation apparatus for the pharmaceutical composition for the treatment of mild ischemic stroke based on tenecteplase as described in claim 2, characterized in that: The top of the rotating shaft extends through the sealing cover and is equipped with a servo motor. The servo motor is fixed to the sealing cover by a mounting bracket. The output shaft of the servo motor is coaxially and fixedly connected to the rotating shaft. The adjustment structure is installed on the outer wall of the rotating shaft located above the sealing cover.

4. A catalytic preparation process for a pharmaceutical composition for the treatment of mild ischemic stroke based on tenecteplase, employing the catalytic preparation apparatus for the pharmaceutical composition for the treatment of mild ischemic stroke based on tenecteplase as described in claim 3, characterized in that... Includes the following steps: S1. First, the refolding buffer is fed into the first inlet, and then the denatured protein solution is slowly and quantitatively added to the second inlet through a peristaltic pump. At the same time, the servo motor is started to drive the shaft to rotate, which in turn drives the stirring blade to rotate and stir slowly. S2. During the mixing process, the rotating shaft drives the fixed plate to rotate, which in turn drives the planetary gear to revolve. Under the action of the gear ring, the planetary gear rotates on its own axis, which drives the first transmission rod and the movable rod to move back and forth. This in turn drives the second transmission rod to move back and forth, causing the rotating sleeve to rotate back and forth, which in turn drives the sweeping rod to sweep back and forth. This causes the cleaning plate to move back and forth along the guide groove to clean the surface of the mixing blade. S3. When protein folding catalysis reaches the middle and end stages, turn off the servo motor and start the electric motor to drive the second gear set to rotate, which in turn drives the adjustment shaft to rotate. This, in turn, drives the first connecting rod and stirring blade to rotate through the first gear set, reducing the tilt angle of the stirring blade. After adjustment, start the servo motor again. S4. After the catalytic protein has folded, open the reactor outlet to proceed with subsequent processes.

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