Freeze-drying process preparation method of flomoxef sodium powder injection for injection

Abstract

The invention discloses a freeze-drying process preparation method of a flomoxef sodium powder injection for injection, and relates to the technical field of freeze-dried powder injections, the flomoxef sodium powder injection comprises the following raw material components by weight: 5000-10000 parts of flomoxef sodium; 250 to 500 parts of sodium chloride; 25000 parts of water for injection; the preparation method comprises the following specific steps: S1, preparing a sodium chloride solution; s2, mixing the flomoxef sodium; s3, liquid medicine treatment and detection; s4, performing freeze drying; and S5, finished product discharging. According to the freeze-drying process preparation method of the flomoxef sodium powder injection for injection, a single auxiliary material sodium chloride is used as a stabilizer of a product in a product preparation process, and sodium ions in the sodium chloride can reduce dissociation of flomoxef sodium, so that the stability of a product solution state is improved, and the generation of hydrolyzed impurities is reduced; the water content of the product can be effectively controlled at a low level, the effectiveness and stability of main components of the product can be better guaranteed, the storage life of the product is prolonged, and the commercial value of the product is greatly improved.

Description

Technical Field

[0001] The present invention relates to the technical field of freeze-dried powder injections, and specifically to a freeze-drying process preparation method for sodium flomoxef for injection powder injection. Background Technique

[0002] Sodium flomoxef for injection belongs to cephamycin antibiotics. Its antibacterial spectrum and antibacterial activity are similar to those of latamoxef, but it has a stronger effect on Staphylococcus aureus, especially MRSA, and has very low nephrotoxicity. However, the domestic self-developed freeze-dried powder injection of sodium flomoxef for injection has not been marketed yet. Therefore, sodium flomoxef for injection has important clinical value and commercial value.

[0003] Currently, the freeze-dried powder injections of sodium flomoxef for injection on the domestic market are all developed in Japan, and the original research products are expensive. The domestic process is to use the raw material drug of sterile sodium flomoxef for aseptic sub-packaging to make the powder injection of sodium flomoxef for injection. However, sodium flomoxef has strong hygroscopicity. During the aseptic sub-packaging process, due to the excessive exposure time of the raw material powder, it is easy to cause the water content of the product to exceed the standard, resulting in product degradation, excessive impurities, and a decrease in the content of the effective main component. Eventually, the safety and effectiveness of the product cannot reach the therapeutic effect, and the operation of aseptic sub-packaging requires a set of safe and effective environmental temperature and humidity control systems in the factory workshop, resulting in too high production costs.

[0004] Therefore, it is urgent to improve this shortcoming. The present invention studies and improves the existing structure and deficiencies, and provides a freeze-drying process preparation method for sodium flomoxef for injection powder injection. Summary of the Invention

[0005] The purpose of the present invention is to provide a freeze-drying process preparation method for sodium flomoxef for injection powder injection to solve the problems raised in the above background technique.

[0006] To achieve the above purpose, the present invention provides the following technical solution: A freeze-drying process preparation method for sodium flomoxef for injection powder injection, the preparation method comprising the following raw material components in parts by weight:

[0007] Sodium flomoxef 5000 - 10000 parts;

[0008] Sodium chloride 250 - 500 parts;

[0009] Water for injection 25000 parts.

[0010] Further, the preparation method includes the following specific steps:

[0011] S1. Preparation of sodium chloride solution:

[0012] After weighing 250 - 500 parts of sodium chloride according to the component amount of the raw materials, add it into the reaction kettle, and uniformly add injection water. Start the stirring mechanism and stir until the sodium chloride is completely dissolved to obtain a sodium chloride solution;

[0013] S2. Flomoxef Sodium Mixing:

[0014] After cooling the sodium chloride solution to -5 - 5°C, weigh 5000 - 10000 parts of flomoxef sodium according to the component amount of the raw materials, and add it into the reaction kettle. Start the stirring mechanism again and stir until it is completely dissolved;

[0015] S3. Liquid Medicine Treatment and Detection:

[0016] Adjust the pH of the solution with sodium bicarbonate, and add the remaining injection water to the obtained solution. After obtaining the liquid medicine, conduct filtration treatment on the obtained liquid medicine, and sample and detect the intermediate content until it is qualified;

[0017] S4. Freeze - drying:

[0018] Calculate the filling volume according to the production specification, and fill it according to the detection requirements. After semi - plugging, send it into a freeze - dryer at -5 - 5°C, set the parameters of the freeze - dryer, start the equipment operation, and sequentially conduct cooling and drying, sublimation drying, and moisture drying on the solution to make a freeze - dried product;

[0019] S5. Finished Product Out of the Box:

[0020] Pre - introduce nitrogen into the freeze - dryer as a protective gas. After plugging, conduct aluminum - plastic cap capping protection on the product to obtain the finished product and take it out of the box.

[0021] Further, in the step S1, the water temperature range of the injection water is controlled at 70 - 90°C, and the amount of the injection water is sufficient to completely dissolve the sodium chloride.

[0022] Further, in the step S1, the rotation speed of the stirring mechanism is controlled at 120 - 150 revolutions per minute, and the stirring duration is 25 minutes.

[0023] Further, in the step S2, start the cooling mechanism through a computer program to make the cooling mechanism in the reaction kettle conduct cooling work, and the cooling rate is controlled at 3 - 5°C / min.

[0024] Further, in the step S3, the adjusted solution pH range is controlled at 4.0 - 6.0.

[0025] Further, in the step S3, the filtration treatment adopts two microporous membranes, and the pore size of the microporous membrane is 0.22μm.

[0026] Further, in the step S4, the specific operation of cooling and drying is as follows: the freeze dryer is cooled to -55 to -45°C at a cooling rate of -20°C / h, held for 2 to 4 hours, and evacuated to a pressure below 10 Pa in the freeze dryer.

[0027] Further, in the step S4, the specific operation of sublimation drying is as follows: the freeze dryer is heated to -5 to 5°C, the pressure is adjusted to 1 to 5 Pa, and held under constant temperature and pressure for 68 to 75 hours.

[0028] Further, in the step S4, the specific operation of moisture drying is as follows: the product is heated to 30 to 35°C, the pressure is adjusted to 17 Pa, and held for 4 to 5 hours.

[0029] The present invention provides a freeze-drying process preparation method for flomoxef sodium for injection powder injection, which has the following beneficial effects:

[0030] In the process of product preparation of the present invention, a single auxiliary material sodium chloride is used as the stabilizer of the product. The sodium ions in sodium chloride can reduce the dissociation of flomoxef sodium, thereby improving the stability of the product in solution state, reducing the generation of hydrolysis impurities, and effectively controlling the water content of the product at a low level. In addition, due to the low solution viscosity of flomoxef sodium and no additional special freeze-drying auxiliary materials, by designing the pre-freezing temperature of the invented product and the temperature and vacuum degree of sublimation drying, the water channels can be quickly opened during the freeze-drying process of the product, so that the water in the product is fully sublimated during the drying process, ensuring the content of the main component of the product, and more importantly, ensuring the effectiveness and stability of the main component of the product, extending the storage period of the product, and greatly improving the commercial value of the product. Specific embodiments

[0031] The following further describes in detail the embodiments of the present invention in conjunction with the examples. The following examples are used to illustrate the present invention, but cannot be used to limit the scope of the present invention.

[0032] A freeze-drying process preparation method for flomoxef sodium for injection powder injection, the preparation method comprising the following raw material components in parts by weight:

[0033] Flomoxef sodium 5000 - 10000 parts;

[0034] Sodium chloride 250 - 500 parts;

[0035] Water for injection 25000 parts;

[0036] The preparation method includes the following specific steps:

[0037] S1. Preparation of sodium chloride solution:

[0038] After weighing 250 - 500 parts of sodium chloride according to the component amount of raw materials, add it into the reaction kettle, and uniformly add injection water. Start the stirring mechanism and stir until the sodium chloride is completely dissolved to obtain a sodium chloride solution;

[0039] In step S1, the water temperature range of the injection water is controlled at 70 - 90 °C, and the amount of injection water is sufficient to completely dissolve the sodium chloride;

[0040] In step S1, the rotation speed of the stirring mechanism is controlled at 120 - 150 revolutions per minute, and the stirring duration is 25 min;

[0041] S2. Mixing of flomoxef sodium:

[0042] After cooling the sodium chloride solution to - 5 - 5 °C, weigh 5000 - 10000 parts of flomoxef sodium according to the component amount of raw materials, and add it into the reaction kettle. Start the stirring mechanism again and stir until it is completely dissolved;

[0043] In step S2, start the cooling mechanism through computer program control, so that the cooling mechanism in the reaction kettle conducts cooling work, and the cooling rate is controlled at 3 - 5 °C / min;

[0044] S3. Liquid medicine treatment and detection:

[0045] Adjust the pH of the solution with sodium bicarbonate, and add the remaining injection water to the obtained solution. After obtaining the liquid medicine, conduct filtration treatment on the obtained liquid medicine, and sample and detect the intermediate content until it is qualified;

[0046] In step S3, the adjusted solution pH range is controlled at 4.0 - 6.0;

[0047] In step S3, the filtration treatment adopts two microporous membranes, and the pore size of the microporous membrane is 0.22 μm;

[0048] S4. Freeze - drying:

[0049] Calculate the filling volume according to the production specification, and fill according to the detection requirements. After semi - plugging, send it into a freeze - dryer at - 5 - 5 °C, set the parameters of the freeze - dryer, start the equipment operation, and sequentially conduct cooling and drying, sublimation drying, and moisture drying on the solution to make a freeze - dried product;

[0050] In step S4, the specific operation of cooling and drying is as follows: cool the freeze - dryer to - 55 - 45 °C at a cooling rate of - 20 °C / h, keep it warm for 2 - 4 h, and evacuate to make the pressure in the freeze - dryer lower than 10 Pa;

[0051] In step S4, the specific operation of sublimation drying is as follows: heat the freeze - dryer to - 5 - 5 °C, adjust the pressure to 1 - 5 Pa, and keep it warm and under pressure for 68 - 75 h;

[0052] In step S4, the specific operation of moisture drying is as follows: heat the product to 30 - 35°C, adjust the pressure to 17 Pa, and keep it warm for 4 - 5 h;

[0053] S5. Finished product out of the box:

[0054] Pre - introduce nitrogen into the freeze - dryer as a protective gas. After pressing the plug, perform aluminum - plastic cap capping protection on the product to obtain the finished product and take it out of the box.

[0055] Example 1:

[0056] The preparation method includes the following raw material components by weight:

[0057] Cefozopran sodium: 5000 parts;

[0058] Sodium chloride: 250 parts;

[0059] Water for injection: 25000 parts;

[0060] The preparation method includes the following specific steps:

[0061] S1. Preparation of sodium chloride solution:

[0062] Weigh 250 parts of sodium chloride according to the amount of raw materials, add it into the reaction kettle, and uniformly add water for injection. The water temperature range of the water for injection is controlled at 80°C, and the amount of water for injection should be sufficient to completely dissolve sodium chloride. Start the stirring mechanism and stir until sodium chloride is completely dissolved. The rotation speed of the stirring mechanism is controlled at 120 revolutions per minute, and the stirring time is 25 min to obtain a sodium chloride solution;

[0063] S2. Mixing of cefozopran sodium:

[0064] Start the cooling mechanism through computer program control, so that the cooling mechanism in the reaction kettle conducts cooling work, and the cooling rate is controlled at 5°C / min. After cooling the sodium chloride solution to 5°C, weigh 5000 parts of cefozopran sodium according to the amount of raw materials and add it into the reaction kettle, and start the stirring mechanism again and stir until it is completely dissolved;

[0065] S3. Liquid medicine treatment and detection:

[0066] Adjust the pH of the solution to 5.0 with sodium bicarbonate, add the remaining water for injection to the obtained solution, obtain the liquid medicine, then perform filtration treatment on the obtained liquid medicine. The filtration treatment uses two microporous membranes, and the pore size of the microporous membrane is 0.22 μm. Take samples to detect the intermediate content until it is qualified;

[0067] S4. Freeze - drying:

[0068] Calculate the filling volume according to the production specifications, fill according to the detection requirements, send it into a freeze dryer at 5°C after semi-plugging, set the parameters of the freeze dryer, start the equipment operation, cool the freeze dryer to -50°C at a cooling rate of -20°C / h, keep it warm for 3 hours, evacuate to a pressure below 10 Pa in the freeze dryer for cooling and drying, then heat the freeze dryer to 5°C, adjust the pressure to 2 Pa, and keep it warm and pressurized for 70 hours for sublimation drying, then heat the product to 35°C, adjust the pressure to 17 Pa, and keep it warm for 4.5 hours for moisture drying to make a freeze-dried product;

[0069] S5. Finished product out of the box:

[0070] Pre-inject nitrogen into the freeze dryer as a protective gas. After plugging, apply aluminum-plastic cap capping protection to the product to obtain the finished product and take it out of the box.

[0071] Example 2:

[0072] The preparation method includes the following raw material components in parts by weight:

[0073] Flomoxef sodium 5000 parts;

[0074] Sodium chloride 250 parts;

[0075] Water for injection 25000 parts;

[0076] The preparation method includes the following specific steps:

[0077] S1 - S3 are the same as in Example 1;

[0078] S4. Freeze drying:

[0079] Calculate the filling volume according to the production specifications, fill according to the detection requirements, send it into a freeze dryer at 5°C after semi-plugging, set the parameters of the freeze dryer, start the equipment operation, cool the freeze dryer to -40°C at a cooling rate of -20°C / h, keep it warm for 3 hours, evacuate to a pressure below 10 Pa in the freeze dryer for cooling and drying, then heat it to -15°C at a rate of 2°C / h for sublimation drying, and keep it warm for 50 hours, then heat it to 45°C ± 2°C, keep it warm for 6 hours for moisture drying to make a freeze-dried product;

[0080] S5. Finished product out of the box:

[0081] Pre-inject nitrogen into the freeze dryer as a protective gas. After plugging, apply aluminum-plastic cap capping protection to the product to obtain the finished product and take it out of the box.

[0082] Example 3:

[0083] The preparation method includes the following raw material components in parts by weight:

[0084] Flomoxef sodium 5000 parts;

[0085] 250 parts of sodium chloride;

[0086] 25,000 parts of water for injection;

[0087] 250 parts of macromolecular chitosan;

[0088] The preparation method includes the following specific steps:

[0089] S1. Preparation of sodium chloride solution:

[0090] Weigh 250 parts of sodium chloride and 250 parts of macromolecular chitosan according to the component amounts of the raw materials, add them into the reaction kettle, and uniformly add water for injection. The water temperature range of the water for injection is controlled at 80 °C, and the amount of the water for injection should be sufficient to completely dissolve the sodium chloride. Start the stirring mechanism and stir until the sodium chloride is completely dissolved. The rotation speed of the stirring mechanism is controlled at 120 revolutions per minute, and the stirring duration is 25 minutes to obtain a sodium chloride solution;

[0091] S2 - S5 are the same as in Example 1.

[0092] The results of Examples 1 - 3 are compared as follows:

[0093] Example 1: The product presents a light - white loose block, with good appearance, no shrinkage or melting;

[0094] Example 2: The product presents a shrunk shape, and a large number of products show shrinkage;

[0095] Example 3: The product presents yellow melted lumps, and a large number of products show melting;

[0096] Place the products prepared in Examples 1 - 3 under the temperature condition of 40 °C for investigation, and record the investigation data in a table. The investigation data of Example 1 are shown in Table 1, the investigation data of Example 2 are shown in Table 2, and the investigation data of Example 1 are shown in Table 3.

[0097] Example 1 Cefozopran content Water content Largest single impurity Total impurities 0 months 99.8％ 0.12％ 0.05％ 1.0％ 1 month 99.3％ 0.15％ 0.08％ 1.3％ 2 months 98.7％ 0.2％ 0.11％ 1.8％

[0098] Table 1

[0099] Example 2 Cefozopran content Water content Largest single impurity Total impurities 0 months 98.5％ 1.0％ 0.10％ 1.5％ 1 month 98.3％ 1.6％ 0.15％ 1.9％ 2 months 97.9％ 2.1％ 0.19％ 2.2％

[0100] Table 2

[0101] Example 3 Cefozopran content Water content Largest single impurity Total impurities 0 months 98.0％ 2.0％ 0.15％ 2.5％ 1 month 97.8％ 2.4％ 0.18％ 2.9％ 2 months 97.5％ 3.0％ 0.21％ 3.3％

[0102] Table 3

[0103] As shown in Tables 1 to 3: When placed at a temperature of 40 °C for 2 months, the flomoxef content of the product prepared in Example 1 is higher than that of the products prepared in Example 2 and Example 3, and the moisture content, maximum single impurity and total impurity of the product prepared in Example 1 are lower than those of the products prepared in Example 2 and Example 3; It can be seen from this that: The product prepared in Example 1 is significantly superior to Example 2 and Example 3.

[0104] In summary, a freeze-drying process preparation method for flomoxef sodium for injection, when used, the freeze-drying process preparation method for flomoxef sodium for injection comprises the following raw material components in parts by weight:

[0105] Flomoxef sodium 5000 - 10000 parts;

[0106] Sodium chloride 250 - 500 parts;

[0107] Injection water 25000 parts;

[0108] The preparation method comprises the following specific steps:

[0109] S1. Preparation of sodium chloride solution:

[0110] After weighing 250 - 500 parts of sodium chloride according to the component amount of the raw materials, add it to the reaction kettle, and uniformly add injection water. The water temperature range of the injection water is controlled at 70 - 90 °C, and the amount of injection water is sufficient to completely dissolve the sodium chloride. Start the stirring mechanism and stir until the sodium chloride is completely dissolved. The rotation speed of the stirring mechanism is controlled at 120 - 150 revolutions per minute, and the stirring duration is 25 min to obtain a sodium chloride solution;

[0111] S2. Mixing of flomoxef sodium:

[0112] Start the cooling mechanism through computer program control, so that the cooling mechanism in the reaction kettle conducts cooling work, and the cooling rate is controlled at 3 - 5 °C / min. After cooling the sodium chloride solution to -5 - 5 °C, weigh 5000 - 10000 parts of flomoxef sodium according to the component amount of the raw materials, and add it to the reaction kettle, and start the stirring mechanism again and stir until it is completely dissolved;

[0113] S3. Liquid medicine treatment and detection:

[0114] Adjust the pH of the solution with sodium bicarbonate, and the pH range of the adjusted solution is controlled at 4.0 - 6.0. Add the remaining injection water to the obtained solution. After obtaining the liquid medicine, conduct filtration treatment on the obtained liquid medicine. The filtration treatment adopts two microporous membranes, and the pore size of the microporous membrane is 0.22 μm, and sample and detect the intermediate content until it is qualified;

[0115] S4. Freeze-drying:

[0116] Calculate the filling volume according to the production specifications, fill according to the detection requirements, send it into a freeze dryer at -5 to 5°C after semi-plugging, set the parameters of the freeze dryer, start the equipment operation, cool the freeze dryer to -55 to -45°C at a cooling rate of -20°C / h, keep warm for 2 to 4 hours, evacuate to a pressure below 10 Pa in the freeze dryer for cooling and drying, then heat the freeze dryer to -5 to 5°C, adjust the pressure to 1 to 5 Pa, and keep warm and pressurized for 68 to 75 hours for sublimation drying, and then heat the product to 30 to 35°C, adjust the pressure to 17 Pa, and keep warm for 4 to 5 hours for moisture drying to make a freeze-dried product;

[0117] S5. Finished product out of the box:

[0118] Pre-inject nitrogen into the freeze dryer as a protective gas. After plugging, perform aluminum-plastic cap capping protection on the product to obtain the finished product and out of the box.

[0119] The embodiments of the present invention are given for purposes of illustration and description, and are not exhaustive or limit the invention to the disclosed form. Many modifications and variations are obvious to those of ordinary skill in the art. The embodiments are selected and described to better illustrate the principles and practical applications of the present invention, and to enable those of ordinary skill in the art to understand the present invention and thus design various embodiments with various modifications suitable for specific purposes.

Claims

1. A freeze-drying process for preparing flomoxef sodium for injection powder injection, characterized in that, The preparation method comprises the following raw material components in parts by weight: Flomoxef Sodium 5000 - 10000 parts; Sodium Chloride 250 - 500 parts; Water for Injection 25000 parts.

2. The freeze-drying process preparation method of flomoxef sodium powder for injection according to claim 1, characterized in that, The preparation method includes the following specific steps: S1. Preparation of Sodium Chloride Solution: After weighing 250 - 500 parts of sodium chloride according to the component quantity of the raw materials, add it into the reaction kettle, and uniformly add water for injection, then start the stirring mechanism to stir until the sodium chloride is completely dissolved to obtain a sodium chloride solution; S2. Mixing of Flomoxef Sodium: After cooling the sodium chloride solution to -5 - 5°C, weigh 5000 - 10000 parts of flomoxef sodium according to the component quantity of the raw materials, and add it into the reaction kettle, then start the stirring mechanism again to stir until it is completely dissolved; S3. Treatment and Detection of the Medicinal Solution: Adjust the pH of the solution with sodium bicarbonate, add the remaining water for injection to the obtained solution, after obtaining the medicinal solution, conduct filtration treatment on the obtained medicinal solution, and sample and detect the intermediate content until it is qualified; S4. Freeze - drying: Calculate the filling volume according to the production specification, and fill it according to the detection requirements. After semi - plugging, send it into a freeze - dryer at -5 - 5°C, set the parameters of the freeze - dryer, start the equipment operation, and sequentially conduct cooling and drying, sublimation drying, and moisture drying on the solution to make a freeze - dried product; S5. Taking the Finished Product out of the Box: Pre - introduce nitrogen into the freeze - dryer as a protective gas. After plugging, conduct aluminum - plastic cap capping protection on the product to obtain the finished product and take it out of the box.

3. The lyophilization process preparation method of a flomoxef sodium for injection powder injection according to claim 2, characterized in that, In the step S1, the water temperature range of the water for injection is controlled at 70 - 90°C, and the amount of water for injection is sufficient to completely dissolve the sodium chloride.

4. The freeze-drying process preparation method of a flomoxef sodium for injection powder injection according to claim 2, characterized in that, In the step S1, the rotation speed of the stirring mechanism is controlled at 120 - 150 revolutions per minute, and the stirring duration is 25 minutes.

5. The freeze-drying process preparation method of a flomoxef sodium for injection powder injection according to claim 2, characterized in that, In the step S2, start the cooling mechanism through computer program control to make the cooling mechanism in the reaction kettle conduct cooling work, and the cooling rate is controlled at 3 - 5°C / min.

6. The freeze-drying process preparation method of a flomoxef sodium for injection powder injection according to claim 2, characterized in that, In the step S3, the adjusted solution pH range is controlled at 4.0 - 6.

0.

7. The freeze-drying process preparation method of a flomoxef sodium for injection powder injection according to claim 2, characterized in that, In the step S3, the filtration treatment adopts two microporous membranes, and the pore size of the microporous membrane is 0.22μm.

8. The lyophilization process preparation method of flomoxef sodium for injection according to claim 2, characterized in that, In the step S4, the specific operation of cooling and drying is as follows: Cool the freeze - dryer to -55 - -45°C at a cooling rate of -20°C / h, keep it warm for 2 - 4 hours, and evacuate to make the pressure in the freeze - dryer lower than 10 Pa.

9. The lyophilization process preparation method of flomoxef sodium for injection powder injection according to claim 2, characterized in that, In the step S4, the specific operation of sublimation drying is as follows: Heat the freeze - dryer to -5 - 5°C, adjust the pressure to 1 - 5 Pa, and keep it warm and under pressure for 68 - 75 hours.

10. The freeze-drying process preparation method of a flomoxef sodium for injection powder injection according to claim 2, characterized in that, In the step S4, the specific operation of moisture drying is as follows: Heat the product to 30 - 35°C, adjust the pressure to 17 Pa, and keep it warm for 4 - 5 hours.