Production process of acute ischemic stroke neuroprotective agent

Abstract

The invention provides a production process of an acute ischemic stroke neuroprotective agent, and particularly relates to a method for preparing an edaravone dextroborneol concentrated solution for injection, and the method comprises the following steps: adding a liquid medicine containing propylene glycol, edaravone, dextroborneol and sodium pyrosulfite into a liquid preparation tank; the temperature of the liquid medicine is controlled to be 0-50 DEG C, the pH value of the liquid medicine is adjusted to be 3.0-7.0, the liquid medicine is conveyed into an ampoule bottle through a conveying pipeline, the conveying pipeline is a pipe, and the ampoule bottle is filled with the liquid medicine through the pipe through a pump. According to the preparation method, the loss of effective components in the production and storage process of the liquid medicine is greatly reduced, the stability of the liquid medicine can be remarkably improved, and the preparation process is good in consistency, repeatable and suitable for industrial production.

Description

Technical Field

[0001] The present invention belongs to the technical field of the production process of pharmaceutical preparations, and specifically relates to a production process of a neuroprotective agent for acute ischemic stroke. Background Art

[0002] The original research company of edaravone dexborneol concentrated injection solution is Simcere Pharmaceutical Group. The National Medical Products Administration (NMPA) approved its listing in July 2020, and the trade name is Xianbixin ® , with the specification of 5 ml: edaravone 10 mg and dexborneol 2.5 mg. Each milliliter of the liquid medicine in the prescription contains edaravone 2 mg, dexborneol 0.5 mg, sodium metabisulfite 1.0 mg, propylene glycol (for injection) 0.8 ml, and hydrochloric acid and / or sodium hydroxide (for adjusting pH value) in appropriate amounts. In the field of drug production, silica gel materials are widely used due to their excellent chemical stability and mechanical strength. However, there are a large number of hydroxyl (-OH) groups on the surface of silica gel, which makes silica gel show strong adsorption to drug components rich in polar groups. Polar groups in the dexborneol molecule, such as hydroxyl groups, can adsorb to the hydroxyl groups on the surface of silica gel through hydrogen bonds, van der Waals forces or electrostatic interactions. At the same time, the microporous structure of silica gel is extremely likely to physically intercept dexborneol molecules, further aggravating the adsorption phenomenon.

[0003] Taking the preparation of Xianbixin ® as an example, the adsorption rate of dexborneol as the main component often exceeds 90% during the production process. This situation results in a significant reduction in the effective components of the drug, seriously affecting the drug efficacy and batch consistency. In addition, the active groups on the surface of silica gel may also react chemically with dexborneol molecules, such as condensation reactions, to generate unknown impurities, greatly increasing the safety risk of the drug.

[0004] Therefore, there is an urgent need in the art to develop a production process of edaravone dexborneol concentrated injection solution with a low drug adsorption rate and high drug safety. Summary of the Invention

[0005] The present invention aims to provide a production process of edaravone dexborneol concentrated injection solution with a low drug adsorption rate and high drug safety, and specifically relates to a method for preparing edaravone dexborneol concentrated injection solution.

[0006] In the first aspect of the present invention, a method for preparing edaravone dexborneol concentrated injection solution is provided, including the following steps: S1: Add a liquid medicine containing propylene glycol, edaravone, dexborneol and sodium metabisulfite into a liquid preparation tank; S2: Control the liquid medicine to be at 0 - 50 °C and adjust the pH to 3.0 - 7.0, then send it to the ampoule through a delivery pipeline, where the delivery pipeline is made of tubing, and a pump fills the liquid medicine into the ampoule through the tubing; Wherein, the tubing is selected from the following group: platinum - cured silicone tube, platinum - cured silicone tube with a super - smooth inner surface, polytetrafluoroethylene (PTFE) tube, plasma - treated PTFE tube, thermoplastic elastomer (TPE) tube, fluorinated ethylene propylene copolymer (FEP) tube, polyethylene (PE) tube, polyether ether ketone (PEEK) tube, polyimide (PI) tube; The liquid - preparation tank is selected from a stainless - steel tank or a passivated stainless - steel tank.

[0007] In another preferred example, the liquid - preparation tank is a passivated stainless - steel tank.

[0008] In another preferred example, the tubing is selected from a plasma - treated polytetrafluoroethylene (PTFE) tube or a platinum - cured silicone tube with a super - smooth inner surface.

[0009] In another preferred example, the tubing is a plasma - treated polytetrafluoroethylene tube.

[0010] In another preferred example, the tubing is a platinum - cured silicone tube with a super - smooth inner surface.

[0011] In another preferred example, the method comprises the following steps: S1: Add propylene glycol, edaravone, dextrorotatory borneol and sodium metabisulfite solution into a liquid - preparation tank, and stir to form a liquid medicine; S2: Take the liquid medicine obtained in step S1, adjust the temperature and pH, and then send it to the ampoule through a delivery pipeline, where the delivery pipeline is made of tubing, and a pump fills the liquid medicine into the ampoule through the tubing; Wherein, the tubing is a platinum - cured silicone tube with a super - smooth inner surface; The liquid - preparation tank is selected from a stainless - steel tank or a passivated stainless - steel tank.

[0012] In another preferred example, the surface of the platinum - cured silicone tube with a super - smooth inner surface is coated with a polydimethylsiloxane or fluorosilane coating.

[0013] In another preferred example, the surface of the platinum - cured silicone tube with a super - smooth inner surface is coated with a polydimethylsiloxane coating.

[0014] In another preferred example, the thickness of the surface coating of the platinum - cured silicone tube with a super - smooth inner surface is 0 - 30 nm.

[0015] In another preferred example, the thickness of the surface coating of the platinum - cured silicone tube with a super - smooth inner surface is 5 - 25 nm.

[0016] In another preferred example, the thickness of the surface coating of the platinum-cured silicone tube with a super-smooth inner surface is 10 - 25 nm.

[0017] In another preferred example, the thickness of the surface coating of the platinum-cured silicone tube with a super-smooth inner surface is 15 - 25 nm.

[0018] In another preferred example, the thickness of the surface coating of the platinum-cured silicone tube with a super-smooth inner surface is selected from 10 nm or 20 nm, preferably 20 nm.

[0019] In another preferred example, the preparation method of the liquid medicine in step S1 is as follows: S1-1: Add propylene glycol, edaravone, and dextrorbencidol into the liquid preparation tank A in sequence, and stir to form solution A; S1-2: Add sodium metabisulfite and injection water into the liquid preparation tank B, and stir to form solution B; S1-3: Add solution B into solution A, and stir to form the liquid medicine.

[0020] In another preferred example, solution B is a freshly prepared sodium metabisulfite solution.

[0021] In another preferred example, step S2 further includes: adjusting the pH using a dilute hydrochloric acid solution or a dilute sodium hydroxide solution.

[0022] In another preferred example, in step S2, the pH is adjusted using a 0.05 - 0.2 mol / L hydrochloric acid solution.

[0023] In another preferred example, in step S2, the pH is adjusted using a 0.05 - 0.2 mol / L sodium hydroxide solution.

[0024] In another preferred example, the pH of the liquid medicine in step S2 is 4.0 - 6.0.

[0025] In another preferred example, the pH of the liquid medicine in step S2 is 4.5 - 5.5.

[0026] In another preferred example, in step S2, the temperature of the liquid medicine is controlled at 0 - 40 °C.

[0027] In another preferred example, the temperature in step S2 is 0 - 25 °C.

[0028] In another preferred example, the temperature in step S2 is 0 - 15 °C.

[0029] In another preferred example, the temperature in step S2 is 0 - 10 °C.

[0030] In another preferred example, the temperature in step S2 is 4 - 25 °C, preferably 4 - 10 °C, more preferably 4 °C.

[0031] In another preferred example, the reduction rate of the adsorption rate of the pipe material described in step S2 compared with the traditional pipe material is greater than 50%.

[0032] In another preferred example, hydrophilic groups are introduced into the pipe material described in step S2 to reduce hydrophobic interactions.

[0033] In another preferred example, step S2 further includes: filtering the liquid medicine through a filter membrane before feeding it into an ampoule bottle for filling.

[0034] In another preferred example, the filling speed of the liquid medicine described in step S2 is 1.0 - 12.0 mL / s.

[0035] In another preferred example, the filling speed of the liquid medicine described in step S2 is 5.0 - 12.0 mL / s, preferably 8.0 - 12.0 mL / s, and more preferably 10.0 mL / s.

[0036] In another preferred example, after the liquid medicine is filled into the ampoule bottle, it is sealed by nitrogen melting.

[0037] It should be understood that within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features specifically described below (such as in the embodiments) can be combined with each other to form new or preferred technical solutions. Due to space limitations, they will not be elaborated one by one here. Detailed implementation manners

[0038] Through extensive and in-depth research and a large number of experimental screenings, the inventor of the present invention unexpectedly found for the first time that in the preparation of edaravone dextrorotatory camphor injection concentrated solution, the dispensing tank is selected from passivated stainless steel tanks, and the pipe material of the conveying pipeline is selected from super-smooth inner surface platinum-vulcanized silica gel pipes. Especially after the super-smooth inner surface platinum-vulcanized silica gel pipe is coated, the adsorption rate of dextrorotatory camphor is significantly reduced; secondly, the preparation, filling and storage are carried out at low temperature and in an environment with a relatively high pH, which further inhibits the adsorption rate of dextrorotatory camphor. Due to the low adsorption rate of the preparation method of the present invention, the loss of the active ingredient of the liquid medicine during production and storage is greatly reduced, and the stability of the liquid medicine can be significantly improved. In addition, the preparation process of the present invention has consistency and repeatability, and the adsorption rate is continuously maintained below 0.40%, ensuring the high efficiency of the product during use; at the same time, the main component content of each batch reaches or exceeds the standard specified in the quality standard (minimum 98.9%), laying a solid foundation for subsequent large-scale production and having significant economic and social benefits. On this basis, the inventor of the present invention completed the present invention.

[0039] Term description The method for preparing edaravone dextrorotatory camphor injection concentrated solution of the present invention During the production process of pharmaceutical preparations, the adsorption rate of drugs is related to the following factors: 1) Material type: Traditional pharmaceutical container materials such as silica gel tubes, polyethylene (PE), and polytetrafluoroethylene (PTFE) perform well in terms of chemical stability and mechanical properties, but they are insufficient in anti-adsorption.

[0040] 2) Surface treatment of materials: Surface treatment technology is a key means to improve the anti-drug adsorption performance of materials. By methods such as plasma treatment and passivation treatment, the chemical properties of the material surface can be changed, reducing the interaction between drugs and the material surface, thereby reducing the drug adsorption rate.

[0041] 3) Pharmaceutical preparation production process: Environmental factors such as temperature and pH can affect the charge state and diffusion rate of drug molecules, and thus affect the adsorption behavior of drugs on the material surface.

[0042] In the present invention, a method for preparing a concentrated solution of edaravone and dextrorotatory camphor alcohol for injection is provided, which includes the following steps: S1: Add propylene glycol, edaravone, dextrorotatory camphor alcohol, and sodium metabisulfite solution into a liquid preparation tank, and stir to form a liquid medicine; S2: Adjust the temperature and pH of the liquid medicine obtained in step S1, and then send it to an ampoule through a conveying pipeline, where the conveying pipeline is a pipe material, and a pump fills the liquid medicine into the ampoule through the pipe material; Among them, the pipe material is selected from the following group: a platinum-vulcanized silica gel tube with a super-smooth inner surface, a polytetrafluoroethylene tube, and a plasma-treated PTFE tube; The liquid preparation tank is selected from a stainless steel tank or a passivated stainless steel tank.

[0043] Preferably, the liquid preparation tank is a passivated stainless steel tank.

[0044] Preferably, the pipe material is a plasma-treated polytetrafluoroethylene tube or a platinum-vulcanized silica gel tube with a super-smooth inner surface.

[0045] Preferably, the pipe material is a plasma-treated polytetrafluoroethylene tube.

[0046] Preferably, the pipe material is a platinum-vulcanized silica gel tube with a super-smooth inner surface.

[0047] Preferably, the method includes the following steps: S1: Add propylene glycol, edaravone, dextrorotatory camphor alcohol, and sodium metabisulfite solution into a liquid preparation tank, and stir to form a liquid medicine; S2: Adjust the temperature and pH of the liquid medicine obtained in step S1, and then send it to an ampoule through a conveying pipeline, where the conveying pipeline is a pipe material, and a pump fills the liquid medicine into the ampoule through the pipe material; Among them, the pipe is a platinum-cured silicone tube with a super-smooth inner surface; The liquid dispensing tank is selected from a stainless steel tank or a passivated stainless steel tank.

[0048] In the preparation method of the present invention, the adsorption rates of the plasma-treated polytetrafluoroethylene (PTFE) and the platinum-cured silicone tube with a super-smooth inner surface are significantly decreased compared with those of traditional pipes, and the decrease rates are both greater than 50%.

[0049] In the preparation method of the present invention, the decrease rate of the adsorption rate of the plasma-treated PTFE tube compared with that of the traditional platinum-cured silicone tube is 99.99%, and the decrease rate compared with that of the polytetrafluoroethylene (PTFE) tube is 99.9%.

[0050] In the preparation method of the present invention, the decrease rate of the adsorption rate of the platinum-cured silicone tube with a super-smooth inner surface compared with that of the traditional platinum-cured silicone tube is 94.8%, and the decrease rate compared with that of the polytetrafluoroethylene (PTFE) tube is 53.8%.

[0051] In the preparation method of the present invention, the 24-hour adsorption rate of the passivated stainless steel liquid dispensing tank is 0.01%, and the decrease rate compared with that of the ordinary stainless steel pipe is as high as 99.9%. Therefore, the passivated stainless steel is an ideal choice for anti-adsorption.

[0052] In the present invention, the adsorption rate of camphene is further inhibited by carrying out preparation, canning and storage at low temperature and in an environment with a relatively high pH. In particular, the pH of the liquid medicine is relatively high (such as pH 5.0), and the low temperature (such as 4°C) environment is helpful for maintaining the stability of camphene and reducing the adsorption loss on the silica gel material.

[0053] In the present invention, the adsorption rate of camphene is significantly reduced by coating the platinum-cured silicone tube with a super-smooth inner surface. Among them, at a coating thickness of 20 nm, the adsorption rate of the polydimethylsiloxane (PDMS) coating slightly increases from 0.1% at 4 h to 0.5% at 24 h, proving that coating the platinum-cured silicone tube with a super-smooth inner surface can significantly reduce the adsorption rate.

[0054] The term "passivation" in the "passivated stainless steel tank" used in the present invention refers to a common means in the workshop, and its steps are as follows: 1) Surface cleaning: Before passivation treatment, the stainless steel surface must be thoroughly cleaned to remove grease, dirt, oxides and other pollutants. 2) Passivation treatment: Immerse the stainless steel in a special passivation solution (nitrate) to form a uniform and dense oxide film on its surface. The passivated stainless steel tank can be directly purchased on the market.

[0055] The term "plasma-treated polytetrafluoroethylene tube" used in the present invention refers to the process of surface modification of a polytetrafluoroethylene tube by exciting gas molecules through an electric field or current in a low-temperature and high-pressure environment to generate highly energetic particles such as ions, free radicals, and electrons. Plasma-treated polytetrafluoroethylene tubes can be directly purchased on the market.

[0056] The term "ultra-smooth inner surface platinum-cured silicone tube" used in the present invention means that the smoothness of the inner surface of the platinum-cured silicone tube can reach more than three times that of the inner surface of ordinary platinum-cured silicone tubes. Ultra-smooth inner surface platinum-cured silicone tubes can be directly purchased on the market.

[0057] Compared with the prior art, the beneficial effects of the present invention are as follows: 1. Significantly reduce the adsorption rate of the active ingredient camphene Using a passivated stainless steel tank and an ultra-smooth inner surface platinum-cured silicone tube, or an ultra-smooth inner surface platinum-cured silicone tube with a surface coating, in the production process can significantly reduce the adsorption rate of camphene on the container surface. Preparation and storage at low temperature (4°C) and in an environment with a relatively high pH (pH 5.0) can also inhibit the adsorption of camphene.

[0058] 2. Improve the stability of the liquid medicine A low adsorption rate means that during the production and storage of the liquid medicine, the loss of the active ingredient is greatly reduced, thereby improving the stability of the liquid medicine.

[0059] 3. The production process has consistency and repeatability In the production of different batches, the quality of the liquid medicine remains consistent, and the adsorption rate is continuously maintained below 0.40%, ensuring the high efficiency of the product during use; at the same time, the main component content of each batch reaches or exceeds the standard specified in the quality standard (minimum 98.9%). Therefore, the production process has consistency and repeatability, laying a solid foundation for subsequent large-scale production and having significant economic and social benefits.

[0060] The following further elaborates the present invention in conjunction with specific embodiments. It should be understood that these embodiments are only used to illustrate the present invention and not to limit the scope of the present invention. The experimental methods without specific conditions indicated in the following embodiments are generally carried out under conventional conditions or according to the conditions recommended by the manufacturer. Unless otherwise stated, percentages and parts are by weight.

[0061] The sources of the materials used in the experiments are as follows: The platinum-cured silicone tubes were purchased from Hebei Linaier Rubber and Plastic Products Co., Ltd.; The polytetrafluoroethylene (PTFE) tubes and fluorinated ethylene propylene copolymer (FEP) tubes were purchased from Bona (Shanghai) Biotechnology Co., Ltd.; The polyethylene (PE) pipe was purchased from Cangzhou Hengyun Pipeline Equipment Manufacturing Co., Ltd.; The thermoplastic elastomer (TPE) pipe and polyimide (PI) pipe were purchased from DuPont Company, USA; The polyetheretherketone (PEEK) pipe was purchased from Zhangjiagang Youcheng High-Tech Materials Co., Ltd.; The plasma-treated PTFE pipe was purchased from Shenzhen Jinlai Plasma Technology Co., Ltd.; The super-smooth inner surface platinum-cured silicone tube was purchased from Saint-Gobain (China) Investment Co., Ltd.; Both the ordinary stainless steel tank and the passivated stainless steel tank were purchased from Nanjing Nuohe Machinery Manufacturing Co., Ltd.

[0062] Edaravone raw material drug (batch number: S-XS02A-240102, purchased from Jiangsu Xiansheng Biopharmaceutical Co., Ltd.), D-camphor-10-sulfonic acid raw material drug (batch number: S-XS03A-231202, purchased from Jiangsu Xiansheng Biopharmaceutical Co., Ltd.), sodium metabisulfite (batch number: 10220240302, Hunan Erkang Pharmaceutical Co., Ltd.), injection water, propylene glycol (for injection) (batch number: 20230503, purchased from Nanjing Weier Pharmaceutical Co., Ltd.), hydrochloric acid (Shanghai Hushi), sodium hydroxide (Shanghai Hushi) Example 1 Preparation of Edaravone and (+)-Camphorol Concentrated Injection Solution 1. Purpose: This experiment aims to demonstrate the complete preparation process of edaravone D-camphor-10-sulfonic acid concentrated injection solution, and to reflect the key role of anti-adsorption pipes in the production process, ensuring the stability and purity of the medicinal liquid during preparation and storage.

[0063] 2. Materials and Equipment 1) Materials: Edaravone raw material drug, D-camphor-10-sulfonic acid raw material drug, sodium metabisulfite, injection water, propylene glycol (for injection), hydrochloric acid, sodium hydroxide, anti-adsorption pipes 2) Equipment: Gas chromatograph (GC), pH meter, electronic balance, peristaltic pump 3. Preparation Process 1) Preparation of the medicinal liquid: ① Weighing: Weigh the raw material drugs and excipients according to the prescription amount (the same as the Xianbixin ® prescription); ② Add the prescription amount of propylene glycol (for injection) to stainless steel liquid preparation tank A, start stirring, heat to 60 °C, add edaravone, and stir to dissolve it completely; ③ Control the temperature of the medicinal liquid in liquid preparation tank A to ≤25 °C, add D-camphor-10-sulfonic acid, and stir to dissolve; ④ Preparation of the sodium metabisulfite solution: Add sodium metabisulfite to stainless steel bucket B, add about 1% of the injection water for preparation (the water temperature ≤25 °C), and stir until completely dissolved; ⑤ Slowly add the prepared sodium metabisulfite solution to mixing tank A while stirring. Rinse stainless steel bucket B with an appropriate amount of injection water (water temperature ≤ 25°C), and add the rinsing solution to mixing tank A. Repeat this process three times. Then, continue to add injection water (water temperature ≤ 25°C) while stirring until 95% of the total preparation volume is reached. ⑥ After the liquid medicine is stirred evenly, take a sample to measure the pH value. The pH of the liquid medicine should be controlled within 3.0 - 5.0. If it is not within this range, adjust the pH with an appropriate amount of 0.1 mol / L hydrochloric acid solution or 0.1 mol / L sodium hydroxide solution. After the pH of the liquid medicine is qualified, add injection water (water temperature ≤ 25°C) to make up the weight to the total preparation volume.

[0064] 2) Filtration: Filter the liquid medicine through a 0.22 μm PVDF filter membrane in two stages.

[0065] 3) Low-temperature filling: Use anti-adsorption tubing as the transfer pipeline, and slowly and evenly fill the filtered liquid medicine into ampoules at a flow rate of 5.0 mL / s through a peristaltic pump, and then conduct nitrogen filling and melting sealing.

[0066] Example 2 Screening Test of Anti-Adsorption Pipe Materials for Filling and Materials of Solution Preparation Tanks 1. Purpose: This experiment aims to evaluate the anti-adsorption performance of different materials of tubing on the main component, dextrancamphor in the concentrated solution of edaravone dextrancamphor for injection, by screening different materials of tubing. By comparing the adsorption rates of traditional materials and new materials, it provides a scientific basis for subsequent material optimization and application. In this experiment, the drug is filled into the tubing / tank to be tested and sealed. Each material is tested separately to select the tubing with the best effect, and then the best mixing tank is selected.

[0067] 2. Materials and methods 1) Material group Anti-adsorption tubing: Traditional materials include: platinum-vulcanized silica gel tubing, polytetrafluoroethylene ( PTFE ) tubing 、 polyethylene ( PE ) tubing 、 fluorinated ethylene propylene copolymer (FEP) tubing 、 thermoplastic elastomer (TPE) tubing; New materials include: polyether ether ketone (PEEK) tubing, polyimide (PI) tubing, plasma-treated PTFE tubing, and super-smooth inner surface platinum-vulcanized silica gel tubing; Mixing tank materials: ordinary stainless steel tank, passivated stainless steel tank.

[0068] 2) Detection equipment and methods Detection equipment: gas chromatograph (GC, Agilent7890B).

[0069] Chromatographic conditions: A capillary column with β-cyclodextrin as the stationary liquid was used as the chromatographic column (cyclosil-B 30m×0.250mm×0.25μm or a chromatographic column with equivalent efficiency); Program temperature rise: The initial temperature was 120°C, and it was heated to 140°C at a rate of 1°C per minute and maintained for 7 minutes, then heated to 230°C at a rate of 40°C per minute and maintained for 10 minutes; Injector temperature: 250°C; The detector was a flame ionization detector (FID) temperature: 250°C; Carrier gas (N2) flow rate: 1ml / min, split ratio was 5:1, injection volume 1μl.

[0070] 3. Experimental procedures 1) Sample preparation: Prepare the concentrated solution of edaravone dextrorotatory camphor alcohol for injection (same as the prescription of Xianbixin ® ), fill it into the test material tube / can, seal it, and sample and detect it at 4 time points (2h, 4h, 8h, 24h). The results are shown in Table 1.

[0071] 2) Calculation of adsorption rate: Adsorption rate = (1 - measured concentration / initial concentration) × 100% 4. Results Table 1 Results of the screening test for anti-adsorption new composite materials

[0072] Note: The calculation of the adsorption rate decrease rate is

[0073] As can be seen from Table 1, the adsorption rate of the plasma-treated polytetrafluoroethylene (PTFE) tube is extremely low, and the 24-hour adsorption rate is only 0.01%. The adsorption rate of the super-smooth inner surface platinum vulcanized silica gel tube is relatively low, and the 24-hour adsorption rate is 4.9%. The decrease rate of the adsorption rate of the plasma-treated PTFE tube compared with the traditional platinum vulcanized silica gel tube is 99.99%, and the decrease rate compared with the polytetrafluoroethylene (PTFE) tube is 99.9%. The decrease rate of the adsorption rate of the super-smooth inner surface platinum vulcanized silica gel tube compared with the traditional platinum vulcanized silica gel tube is 94.8%, and the decrease rate compared with the polytetrafluoroethylene (PTFE) tube is 53.8%. The adsorption rates of the plasma-treated polytetrafluoroethylene (PTFE) and the super-smooth inner surface platinum vulcanized silica gel tube are significantly decreased compared with the traditional pipes, and the decrease rates are both greater than 50%.

[0074] For the liquid preparation tank, the 24-hour adsorption rate of the passivated stainless steel is 0.01%, and the decrease rate of the adsorption rate compared with the ordinary stainless steel pipe is as high as 99.9%. Therefore, the passivated stainless steel is an ideal choice for anti-adsorption.

[0075] Conclusion: Importance of Surface Treatment: The adsorption rates of plasma-treated PTFE and passivated stainless steel are extremely low, indicating that the surface treatment of the pipe can significantly improve the anti-adsorption performance of the material. Among them, plasma treatment can introduce hydrophilic groups and reduce hydrophobic interactions; passivation treatment can form a dense oxide layer to prevent the penetration of the liquid medicine.

[0076] Considerations in Material Selection: Plasma-treated PTFE has excellent anti-adsorption effect, but the PTFE material has a relatively high hardness and is not suitable for use with common peristaltic pumps, which limits its application in co-line production lines. Therefore, the super-smooth inner surface platinum-vulcanized silica gel tube and passivated stainless steel tank after surface treatment become better choices. The super-smooth inner surface platinum-vulcanized silica gel tube introduces hydrophilic groups through chemical modification to reduce hydrophobic interactions. These materials not only have good anti-adsorption performance but also can be compatible with common equipment such as peristaltic pumps to ensure the smooth progress of the production process.

[0077] Example 3 Influence of Ultra-Smooth Inner Surface Platinum-Cured Silicone Rubber Tube Materials on the Adsorption of (+)-Camphorol at Different Temperatures and pH Values 1. Purpose: This experiment aims to study the differences in the adsorption rates of the super-smooth inner surface platinum-vulcanized silica gel tube material for camphene solution under different temperature and pH conditions. By systematically changing the temperature (4°C, 25°C, 40°C) and pH value (3.0, 4.0, 5.0), the influence of environmental factors on the camphene adsorption rate is evaluated to provide a scientific basis for optimizing the preparation process.

[0078] 2. Materials and Methods: Silica Gel Material: Super-smooth inner surface platinum-vulcanized silica gel tube.

[0079] Experimental Equipment: Includes a constant temperature water bath, pH meter, electronic balance 3. Experimental Procedures: 1) Sample Preparation Wash the super-smooth inner surface platinum-vulcanized silica gel tube material with deionized water to remove surface impurities and dry for later use.

[0080] Prepare edaravone camphene concentrated injection solutions with different pH values (3.0, 4.0, 5.0) and place them in a constant temperature water bath at different temperatures (4°C, 25°C, 40°C) respectively.

[0081] 2) Adsorption Rate Detection: Seal the edaravone camphene concentrated injection solutions with different pH values in the super-smooth inner surface platinum-vulcanized silica gel tube and place them in a constant temperature water bath at different temperatures (4°C, 25°C, 40°C) respectively. Sampling is carried out after 4 hours, 8 hours, and 24 hours of adsorption to measure the change in the concentration of camphene. The adsorption rate results at different temperatures and different pH values are shown in Tables 2 and 3.

[0082] 4. Detection Method: The detection equipment and detection method are the same as in Example 1 5. Results: The test results are shown in Table 2 and Table 3.

[0083] Table 2 Investigation Results of Adsorption Rates at Different Temperatures

[0084] Table 3 Investigation Results of Adsorption Rates under Different pH Conditions

[0085] Result Analysis: 1) Temperature effect: Low temperature (4°C) can significantly inhibit the adsorption of camphene on the platinum-vulcanized silica gel tube with a super-smooth inner surface. The adsorption rate after 24 hours is only 1.7%. While high temperature (40°C) significantly promotes adsorption, and the adsorption rate after 24 hours is as high as 10.1%. This may be related to the intensified molecular movement and accelerated diffusion rate at high temperatures. In addition, it is difficult to control the large-scale production process at lower temperatures, and the main component camphene will precipitate at too low temperatures. Therefore, considering comprehensively, the optimal temperature is about 4°C.

[0086] 2) pH effect: An environment with a lower pH (pH 3.0) significantly promotes the adsorption of camphene, while an environment with a higher pH (pH 5.0) inhibits adsorption. This may be related to the chemical properties of the silica gel surface and the charge state of camphene molecules. In an environment with a lower pH, the silica gel surface may carry a positive charge and undergo electrostatic attraction with the negatively charged camphene molecules; while in an environment with a higher pH, this electrostatic attraction weakens, but when the pH exceeds 6, it exceeds the standard range of the injection solution, and in addition, the product becomes unstable when the pH exceeds 6.

[0087] Conclusion: To reduce the adsorption rate of camphene, it is recommended to control the pH of the liquid medicine to be relatively high (such as pH 5.0) and a low-temperature (such as 4°C) environment. This will help maintain the stability of camphene and reduce the adsorption loss on the silica gel material.

[0088] Example 4 Influence of Ultra-Smooth Inner Surface Platinum-Cured Silicone Rubber Tube Materials on the Adsorption of (+)-Camphorol at Different Filling Speeds 1. Purpose: This experiment aims to study the differences in the adsorption rates of camphene solution by the platinum-vulcanized silica gel tube material with a super-smooth inner surface under different filling speeds. By systematically changing the filling speeds (1.0 mL / s, 5.0 mL / s, 10.0 mL / s), the effect of the filling speed on the adsorption rate of camphene is evaluated to provide a scientific basis for optimizing the preparation process.

[0089] 2. Materials: Peristaltic pump, platinum-vulcanized silica gel tube with a super-smooth inner surface 3. Experimental Procedures: 1) Sample Preparation Wash the platinum-vulcanized silica gel tube material with a super-smooth inner surface with deionized water to remove surface impurities and dry it for standby.

[0090] Prepare the concentrated solution of edaravone and dextrorotatory borneol for injection according to Example 1 2) Adsorption rate detection: Use a platinum-vulcanized silica gel tube with a super-smooth inner surface as the delivery pipeline. After filtering the medicinal liquid, slowly and evenly fill it into ampoules at a flow rate of 1.0 mL / s, 5.0 mL / s, and 10.0 mL / s through a peristaltic pump, and then sample to detect the content of dextrorotatory borneol. The adsorption conditions at different flow rates are shown in Table 4

[0091] 4. Detection method: The detection equipment and method are the same as those in Example 1 5. Results Table 4 Results of the investigation of the adsorption rate at different flow rates

[0092] Result analysis: In this experiment, by testing the adsorption rate of dextrorotatory borneol on the anti-adsorption pipe material at different flow rates (1.0 mL / s, 5.0 mL / s, 10.0 mL / s), it was found that the adsorption rate showed a significant downward trend with the increase of the flow rate (1.2% → 0.5% → 0.3%), which confirmed that increasing the flow rate could shorten the contact time between the medicinal liquid and the pipe material and thus reduce the adsorption amount

[0093] Conclusion: When the anti-adsorption pipe material is under high-speed filling, that is, when the workshop production is running normally (such as 10.0 mL / s), it can maintain a low adsorption rate of 0.3%. It not only meets the high-efficiency requirements of industrial production but also effectively guarantees the integrity of the active ingredients of the medicinal liquid

[0094] Example 5 Influence of Surface Coating of Ultra-Smooth Inner Surface Platinum-Cured Silicone Rubber Tube on the Adsorption of (+)-Camphorol 1. Experimental purpose: This experiment aims to study the anti-adsorption properties of different coating materials (polydimethylsiloxane (PDMS) and fluorosilane) and thicknesses (10 nm and 20 nm)

[0095] 2. Experimental procedures 1) Substrate treatment: Perform the following treatments on the platinum-vulcanized silica gel tube with a super-smooth inner surface (delivery pipeline): a. Clean with isopropanol to remove surface impurities

[0096] b. Perform ultrasonic cleaning with deionized water to ensure the surface is clean

[0097] c. Dry with nitrogen to avoid surface residual moisture

[0098] d. Perform oxygen plasma treatment (100 W, 5 min) to activate the surface and enhance the coating adhesion 2) Coating preparation: ①PDMS coating: a. Mix the PDMS prepolymer (Dow Corning Sylgard 184) with the curing agent in a ratio of 10:1.

[0099] b. Uniformly coat the mixed solution on the surface of the pretreated silica gel tube.

[0100] c. Cure at 80 °C for 2 hours to form a uniform PDMS coating.

[0101] ②Fluorosilane coating: a. Use perfluorooctyltriethoxysilane (Sigma) as the coating material.

[0102] b. Coat the silane solution on the surface of the platinum-cured silica gel tube with a super-smooth inner surface after pretreatment.

[0103] c. Crosslink at 60 °C for 1 hour to form a stable fluorosilane coating.

[0104] 3) Preparation of the medicinal solution: Use a passivated stainless steel solution preparation tank to prepare the concentrated solution of edaravone dextrorotatory borneol for injection (same as the prescription of Xianbixin ® ), and adjust the pH of the medicinal solution to 4.0.

[0105] 4) Adsorption rate detection: Seal the medicinal solution in pipelines with different coating materials and soak for different times (4 hours, 8 hours, and 24 hours) at room temperature. After the soaking ends, take samples and detect the content of dextrorotatory borneol in them.

[0106] 3. Detection method: The detection equipment and detection method are the same as in Example 1 4. The experimental results are shown in Table 5, which shows the adsorption rates at 4 °C for 4 hours, 8 hours, and 24 hours.

[0107] Table 5 Adsorption rates of different coatings and thicknesses

[0108] Result analysis: 1) The adsorption rates of PDMS and fluorosilane coatings with different thicknesses (10 nm and 20 nm) increase with the increase of time (from 4 h, 8 h to 24 h). Among them, the 10-nm-thick fluorosilane coating has the highest adsorption rate, rising from 2.1% at 4 h to 3.4% at 24 h; while the 20-nm-thick PDMS coating has the lowest adsorption rate, slightly rising from 0.1% at 4 h to 0.5% at 24 h. This indicates that the thicker polydimethylsiloxane (PDMS) coating has better adsorption performance over a long time.

[0109] Conclusion. The results of this example show that through the optimization treatment of the surface coating, a relatively thick 20-nm-thick polydimethylsiloxane (PDMS) coating exhibits the best anti-adsorption performance over a long period, which can significantly reduce the adsorption rate of the liquid medicine on the container surface, providing an important reference for subsequent experiments and applications.

[0110] Example 6 Synergistic Effect of Preparation Process (Optimization of Combined Parameters) 1. Experimental purpose: This experiment aims to verify the synergistic effect in reducing the adsorption of liquid medicine under different preparation process parameters to determine the optimal process combination.

[0111] 2. Scheme design: To comprehensively evaluate the influence of each process parameter and determine whether to use passivated stainless steel, whether to use a platinum-cured silicone tube with a 20-nm PDMS coating, temperature, pH, etc. as process parameters, an L8(2 7 ) orthogonal experiment was designed. The factor level table is shown in Table 6 for details.

[0112] Table 6 Process factor level table

[0113] 3. Experimental steps: 1) Clean and passivate the stainless steel tank to ensure the surface is smooth and free of impurities. Perform surface treatment (PDMS coating) on the silicone tube to enhance its anti-adsorption performance. Calibrate the temperature control equipment to ensure the accuracy of the filling temperature.

[0114] 2) Preparation of liquid medicine Prepare the concentrated solution of edaravone dextrorotatory camphor alcohol for injection in the tank according to the prescription and store it temporarily for 4 h.

[0115] 3) Detection of adsorption rate According to the conditions of each process group, after taking out the liquid medicine from the tank, seal it in pipelines of different materials and let it stand sealed for 8 hours. Take samples to measure the concentration of dextrorotatory camphor alcohol in the liquid medicine and calculate the adsorption rate.

[0116] 4. Detection method: The detection equipment and detection method are the same as those in Example 1.

[0117] 5. The results of the orthogonal experiment are shown in Table 7, and the results of the variance analysis are shown in Table 8.

[0118] Table 7 Orthogonal test result table

[0119] Table 8 Variance analysis table

[0120] Note: F 0.05 (1,3)=10.13 Result analysis: From the results of the analysis of variance of the adsorption rate of camphene, factors A and B have significant effects on the adsorption rate (p<0.05), and there is no significant difference in factors (C, D). Through comprehensive analysis of the experimental results, it is known that the order of the influence of each factor on the experimental results is B>A>D>C, and factor C (temperature) has the least influence on the adsorption rate of camphene.

[0121] From the investigation of the orthogonal design results: The optimal combination is: (Passivation tank) + (PDMS coating) + (4°C) + (pH5) and (Passivation tank) + (PDMS coating) + (25°C) + (pH5). In experimental group 2, the adsorption rate of camphene of the combination is 0.4%. To further optimize the process parameters, a confirmation experiment with increased factor levels was carried out for the combination. The specific operation steps are the same as [Experimental Step 3]. Samples were prepared using the process parameter combination of (Passivation tank), (PDMS-coated tube), (4°C) and (pH5). After sampling, the concentration of camphene in the liquid medicine was measured, and its adsorption rate was calculated. The test results showed that the adsorption rate of camphene of this combination was 0.2%, slightly lower than the adsorption rate of the combination. Therefore, the optimal combination was determined as .

[0122] Test Example 1 Verification of Process Consistency 1. Experimental purpose: To verify the anti-adsorption performance and stability of production components during continuous use.

[0123] 2. Scheme design: In this study, the present invention adopted a passivated stainless steel tank and a platinum-cured silicone rubber tube assembly with a PDMS coating (20 nm) to ensure the stability and low adsorption of the production environment. During the liquid preparation and filling processes, the temperature of the liquid medicine was strictly controlled at 4°C, the pH of the liquid medicine was 5.0, and the filling flow rate was maintained at 5.0 mL / s to 10.0 mL / s to keep the physicochemical properties of edaravone camphene concentrated injection solution stable. The experiment was carried out for 6 consecutive batches of production, and the adsorption rate and the content of the main component camphene in the solution of each batch of products were detected to evaluate the consistency of the production process and the stability of product quality.

[0124] 3. The experimental results are shown in Table 9, which shows the results of measuring the concentration of camphene and calculating the adsorption rate for different batches of liquid medicine.

[0125] Table 9 Adsorption Rate and Content of Camphene in Different Batches

[0126] Results: 1) Stability of adsorption rate: The experimental results show that in six consecutive production batches, the adsorption rate remained at a low level, with a maximum of 0.40%, a minimum of 0.10%, and an average adsorption rate of 0.22%. The stable performance of the adsorption rate (SD = 0.11) indicates that the production process has good consistency and repeatability in controlling adsorption.

[0127] 2) Compliance of main component content: The main component content of each batch is between 98.9% and 99.8%, far higher than the minimum content requirement (≥90%) specified in the quality standard.

[0128] 3) Verification of process reliability: The stability of the adsorption rate and the compliance of the main component content jointly verify the reliability of the production process. These results provide strong support for subsequent scale-up production and commercial application, indicating that the process has the potential for large-scale production.

[0129] Conclusion: Through the analysis of experimental data from consecutive production batches, the present invention verifies the reliability and stability of the production process. The adsorption rate remains continuously below 0.40%, ensuring the high efficiency of the product during use. At the same time, the main component content of each batch meets or exceeds the standard specified in the quality standard (minimum 98.9%), demonstrating the excellent performance of the production process in controlling the active ingredients. The consistency and compliance of these key quality parameters fully prove the reliability of the production process and lay a solid foundation for subsequent large-scale production.

[0130] All documents mentioned in the present invention are incorporated herein by reference as if each document was individually incorporated by reference. In addition, it should be understood that after reading the above teachings of the present invention, those skilled in the art can make various changes or modifications to the present invention, and these equivalent forms also fall within the scope defined by the appended claims of the present application.

Claims

1. A method for preparing edaravone dextrorotatory borneol concentrated solution for injection, characterized in that, It includes the following steps: S1: Add a liquid medicine containing propylene glycol, edaravone, dextrorbital and sodium metabisulfite into a liquid preparation tank; S2: Control the temperature of the liquid medicine at 0 - 50 °C and adjust the pH to 3.0 - 7.0, and send it to an ampoule through a conveying pipeline, wherein the conveying pipeline is a pipe material, and a pump fills the liquid medicine into the ampoule through the pipe material; Wherein, the pipe material is selected from the following group: platinum - cured silicone tube, platinum - cured silicone tube with a super - smooth inner surface, polytetrafluoroethylene (PTFE) tube, plasma - treated PTFE tube, thermoplastic elastomer (TPE) tube, fluorinated ethylene propylene copolymer (FEP) tube, polyethylene (PE) tube, polyether ether ketone (PEEK) tube, polyimide (PI) tube; The liquid preparation tank is selected from a stainless - steel tank or a passivated stainless - steel tank.

2. The method according to claim 1, characterized in that, The pipe material is selected from a plasma - treated polytetrafluoroethylene (PTFE) tube or a platinum - cured silicone tube with a super - smooth inner surface.

3. The method according to claim 1, characterized in that The method includes the following steps: S1: Add propylene glycol, edaravone, dextrorbital and sodium metabisulfite solution into a liquid preparation tank, and stir to form a liquid medicine; S2: Take the liquid medicine obtained in step S1, adjust the temperature and pH, and then send it to an ampoule through a conveying pipeline, wherein the conveying pipeline is a pipe material, and a pump fills the liquid medicine into the ampoule through the pipe material; Wherein, the pipe material is a platinum - cured silicone tube with a super - smooth inner surface; The liquid preparation tank is selected from a stainless - steel tank or a passivated stainless - steel tank.

4. The method according to claim 1, wherein The surface of the platinum - cured silicone tube with a super - smooth inner surface is coated with a polydimethylsiloxane or fluorosilane coating.

5. The method according to claim 1, characterized in that The thickness of the surface coating of the platinum - cured silicone tube with a super - smooth inner surface is 0 - 30 nm.

6. The method according to claim 1, wherein In step S2, it further includes: adjusting the pH using a dilute hydrochloric acid solution or a dilute sodium hydroxide solution.

7. The method according to claim 1, characterized in that, The pH of the liquid medicine in step S2 is 4.0 - 6.

0.

8. The method according to claim 1, characterized in that In step S2, control the temperature of the liquid medicine at 0 - 40 °C.

9. The method according to claim 1, wherein In step S2, it further includes: filtering the liquid medicine through a membrane filter before filling it into the ampoule.

10. The method according to claim 1, wherein The filling speed of the liquid medicine in step S2 is 1.0 - 12.0 mL / s.

Images