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

Abstract

The invention discloses a freeze-drying process preparation method of a latamoxef sodium powder injection for injection, and relates to the technical field of latamoxef sodium powder injection preparation. The latamoxef sodium powder injection for injection comprises the following components in parts by weight: 5000 to 10000 parts of latamoxef sodium, 250 to 2500 parts of mannitol, 250 to 2500 parts of sodium chloride and 25000 parts of water for injection. According to the freeze-drying process preparation method of the latamoxef sodium powder injection for injection, auxiliary materials of the product are prepared from mannitol and sodium chloride according to a matching ratio, and sodium ions dissociated from sodium chloride in an aqueous solution can enable latamoxef sodium to keep better stability in the solution; according to the latamoxef sodium powder injection for injection prepared by the process, the water content of the product can be effectively controlled at a lower level, the degradation of main components of the product is reduced, the effectiveness and stability of the main components of the product are ensured, 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 the preparation of latamoxef sodium for injection, and particularly to a freeze-drying process preparation method for latamoxef sodium for injection powder for injection. Background Art

[0002] Latamoxef sodium for injection is a semi-synthetic novel antibiotic of the oxacephem class. Years of clinical practice have shown that it has a broad antibacterial spectrum, strong antibacterial activity, dual antibacterial effects on aerobic and anaerobic bacteria, is highly stable to β-lactamase, and especially has the slowest development rate of resistance to extended-spectrum β-lactamase (ESBL). The indications are for various infectious diseases caused by sensitive bacteria, such as septicemia, meningitis, respiratory system infectious diseases (pneumonia, bronchitis, bronchiectasis, lung abscess, empyema, etc.), digestive system infectious diseases (cholangitis, cholecystitis, etc.), intra-abdominal infectious diseases (liver abscess, peritonitis, etc.), urinary and reproductive system infectious diseases (pyelonephritis, cystitis, urethritis, gonorrhea, epididymitis, intrauterine infection, adnexitis, pelvic inflammatory disease, etc.), skin and soft tissue infections, bone and joint infections, and wound infections.

[0003] Currently, the excipients used in the production of latamoxef sodium for injection freeze-dried powder are all single mannitol, which makes the viscosity of the product solution state too high, the water is difficult to sublimate quickly, the freeze-drying time is too long, the energy consumption is large, and the product is prone to collapse during the freeze-drying process. The water content of the obtained latamoxef sodium for injection is on the high side, and the impurities increase significantly during storage, and the quality is unstable.

[0004] Therefore, in view of this, research and improvement are carried out on the existing structure and deficiencies, and a freeze-drying process preparation method for latamoxef sodium for injection powder for injection is proposed. Summary of the Invention

[0005] In view of the deficiencies of the prior art, the present invention provides a freeze-drying process preparation method for latamoxef sodium for injection powder for injection, and solves the problems raised in the above background art.

[0006] To achieve the above objectives, the present invention is realized through the following technical solutions: A freeze-drying process preparation method for latamoxef sodium for injection powder for injection, the latamoxef sodium for injection powder for injection includes the following components by weight:

[0007] Latamoxef sodium: 5000 - 10000 parts, mannitol: 250 - 2500 parts, sodium chloride: 250 - 2500 parts, water for injection: 25000 parts.

[0008] Further, the freeze-drying process preparation method for latamoxef sodium for injection powder for injection includes the following operating steps:

[0009] S1. Stir and dissolve:

[0010] Weigh 250 - 2500 parts of mannitol and 250 - 2500 parts of sodium chloride, and add them to water for injection at a uniform speed while stirring until dissolved to obtain a mixed solution;

[0011] S2. pH value adjustment:

[0012] Adjust the pH value of the solution with sodium bicarbonate, add the remaining water for injection to the obtained solution, filter the liquid medicine through two microporous membranes to remove impurities in the solution, detect the content of the intermediate, and calculate the filling volume according to the production specifications to obtain the solution to be canned;

[0013] S3. Freeze - drying operation:

[0014] The solution to be canned is filled according to the detection requirements, and after semi - plugging, it is sent into a freeze - dryer. The temperature is lowered to - 35°C to - 45°C, the vacuum is pumped until the pressure in the freeze - drying chamber is lower than 10 Pa, and then the temperature is raised to - 5°C to 7°C, and sublimation drying is carried out under a vacuum degree of 7 Pa to 10 Pa, and keep warm for 30 h to 35 h;

[0015] S4. Secondary drying:

[0016] For secondary drying, use a temperature of 50°C to 58°C and keep warm for 6 h to thoroughly dry the residual moisture of the product. Finally, the freeze - dryer pre - releases nitrogen protective gas, plugs the vial, and takes the product out of the box. The product is protected by crimping an aluminum - plastic cap, thus obtaining the cefotaxime sodium for injection powder injection.

[0017] Furthermore, in the step S1, the temperature of the water for injection during addition is controlled at 70°C to 90°C.

[0018] Furthermore, in the step S1, after the mixed solution is cooled to - 5°C to 5°C, weigh 5000 - 10000 parts of cefotaxime sodium and add it to the mixed solution, and stir until completely dissolved.

[0019] Furthermore, in the step S2, the pH value is adjusted to 5.0 - 6.5.

[0020] Furthermore, in the step S2, the pore diameter of the microporous membrane is 0.22 μm.

[0021] Furthermore, in the step S3, during the process of raising the temperature to - 5°C to 7°C, the temperature is raised at a uniform speed of 2°C / h.

[0022] Furthermore, in the step S3, after cooling to - 35°C to - 45°C, it needs to be kept warm for 2 h to 6 h.

[0023] Furthermore, in the step S4, the pressure during secondary drying is controlled at 10 Pa to 17 Pa.

[0024] The present invention provides a freeze - drying process preparation method for cefotaxime sodium for injection powder injection, which has the following beneficial effects:

[0025] 1. The freeze-drying process preparation method of latamoxef sodium for injection powder injection, the product excipients use the combination of mannitol and sodium chloride. The sodium ions dissociated by sodium chloride in the aqueous solution can keep latamoxef sodium in better stability in the solution. Using the combination of mannitol and sodium chloride as excipients, without reducing the shaping effect of mannitol on the product during the freeze-drying process of latamoxef sodium for injection, sodium chloride is used as a stabilizer, and by designing the drying temperature and vacuum degree of the sublimation drying and secondary drying of the invented product, the water sublimation channel of latamoxef sodium in the product can be quickly opened during the freeze-drying process, ensuring that the product water can be effectively and quickly sublimated, thereby effectively preventing the product from shrinking and collapsing due to water accumulation. BRIEF DESCRIPTION OF THE DRAWINGS

[0026] Figure 1 It is the inspection data table of the product of Example 1 of the freeze-drying process preparation method of a latamoxef sodium for injection powder injection of the present invention;

[0027] Figure 2 It is the inspection data table of the product of Example 2 of the freeze-drying process preparation method of a latamoxef sodium for injection powder injection of the present invention;

[0028] Figure 3 It is the inspection data table of the product of Example 3 of the freeze-drying process preparation method of a latamoxef sodium for injection powder injection of the present invention. DETAILED DESCRIPTION OF THE INVENTION

[0029] The following further describes the embodiments of the present invention in detail with reference to the drawings and examples. The following examples are used to illustrate the present invention, but cannot be used to limit the scope of the present invention.

[0030] As Figures 1 to 3 shown, the present invention provides a technical solution: a freeze-drying process preparation method of a latamoxef sodium for injection powder injection, the latamoxef sodium for injection powder injection includes the following components by weight:

[0031] Latamoxef sodium: 5000 - 10000 parts, mannitol: 250 - 2500 parts, sodium chloride: 250 - 2500 parts, water for injection: 25000 parts.

[0032] The freeze-drying process preparation method of the latamoxef sodium for injection powder injection includes the following operating steps:

[0033] S1. Stir and dissolve:

[0034] Weigh 250 - 2500 parts of mannitol and 250 - 2500 parts of sodium chloride, slowly add a certain amount of injection water at 70℃ - 90℃ and stir until dissolved. After the solution cools down to -5℃ - 5℃, weigh 5000 - 10000 parts of latamoxef sodium and stir until completely dissolved to obtain a mixed solution;

[0035] S2. pH value adjustment:

[0036] Adjust the pH to 5.0 - 6.5 with sodium bicarbonate, add injection water to the obtained solution to the full volume, filter the liquid medicine through two 0.22μm microporous membranes to remove impurities in the solution, detect the content of the intermediate, calculate the filling volume according to the production specification, and obtain the solution to be canned;

[0037] S3. Freeze - drying operation:

[0038] The solution to be canned is filled according to the detection requirements, semi - stoppered and then sent into a freeze - dryer. Cool down to -35℃ - -45℃, keep warm for 2h - 6h, evacuate to a pressure in the freeze - drying chamber lower than 10Pa, then heat up to -5℃ - 7℃ at a rate of 2℃ / h and perform sublimation drying under a vacuum degree of 7Pa - 10Pa, keep warm for 30h - 35h;

[0039] S4. Secondary drying:

[0040] For secondary drying, use 50℃ - 58℃, control the pressure at 10Pa - 17Pa, keep warm for 6h to thoroughly dry the residual moisture of the product. Finally, pre - fill nitrogen protective gas in the freeze - dryer, stopper, take out of the box, and perform aluminum - plastic cap crimping protection on the product, thus obtaining the latamoxef sodium for injection powder injection;

[0041] Based on the above description, the product uses mannitol and sodium chloride as the auxiliary materials in a ratio combination. The sodium ions dissociated by sodium chloride in the aqueous solution can keep latamoxef sodium more stable in the solution. Using the combination of mannitol and sodium chloride as auxiliary materials, without reducing the shaping effect of mannitol on the product during the freeze - drying process of latamoxef sodium for injection, using sodium chloride as a stabilizer, and by designing the drying temperature and vacuum degree of the sublimation drying and secondary drying of the invented product, the moisture sublimation channel of latamoxef sodium can be quickly opened during the freeze - drying process of the product, ensuring that the moisture of the product can be effectively and quickly sublimated, thereby effectively preventing the product from shrinking and collapsing due to water accumulation. The latamoxef sodium for injection powder injection prepared by this process can effectively control the water content of the product at a low level, reduce the degradation of the main component of the product, ensure the effectiveness and stability of the main component of the product, extend the storage period of the product, and greatly improve the commercial value of the product.

[0042] To obtain the best raw material ingredient ratio, the following example operations were carried out:

[0043] Example 1:

[0044] Formulation process: Weigh 250 - 2500 parts of mannitol and 250 - 2500 parts of sodium chloride, slowly add a certain amount of injection water at 70℃ - 90℃ and stir until dissolved. After the solution cools down to -5℃ - 5℃, weigh 5000 - 10000 parts of latamoxef sodium in portions and stir until completely dissolved. Adjust the pH to 5.0 - 6.5 with sodium bicarbonate, add injection water to the resulting solution to the full volume, filter the liquid medicine through two 0.22μm microporous membranes to remove impurities in the solution, detect the intermediate content, and calculate the filling volume according to the production specifications.

[0045] Freeze-drying process: Fill according to the detection requirements, send it into the freeze-dryer after semi-plugging, cool down to -35℃ - -45℃, keep warm for 2h - 4h, evacuate to a pressure below 10Pa in the freeze-drying chamber, then heat up to -5℃ - 7℃ at a rate of 2℃ / h and conduct sublimation drying under a vacuum of 7Pa - 10Pa for 30h - 35h. For secondary drying, use 50℃ - 58℃, 10Pa - 17Pa, and keep warm for 6h to thoroughly dry the residual moisture of the product. Finally, pre-fill nitrogen protective gas in the freeze-dryer, plug, take out of the box, and protect the product with an aluminum-plastic cap crimping.

[0046] Example 2:

[0047] Formulation process: The excipient uses 500 - 5000 parts of mannitol. Weigh 500 - 5000 parts of mannitol, slowly add a certain amount of injection water at 70℃ - 90℃ and stir until dissolved. After the solution cools down to -5℃ - 5℃, weigh 5000 - 10000 parts of latamoxef sodium in portions and stir until completely dissolved. Adjust the pH to 5.0 - 6.5 with sodium bicarbonate, add injection water to the resulting solution to the full volume, filter the liquid medicine through two 0.22μm microporous membranes to remove impurities in the solution, detect the intermediate content, and calculate the filling volume according to the production specifications.

[0048] The freeze-drying process is the same as that in Example 1.

[0049] Example 3:

[0050] The formulation process is the same as that in Example 1;

[0051] Freeze-drying process: Fill according to the detection requirements, send it into the freeze-dryer at -5℃ - 5℃ after semi-plugging, use a cooling rate of -20℃ / h to cool the freeze-dryer to -35℃ ± 3℃, keep warm for 2h - 6h, evacuate to a pressure below 10Pa in the freeze-drying chamber; for sublimation drying, heat up to -5℃ ± 2℃ at a rate of 15℃ / h for sublimation drying, with a vacuum of 7Pa and keep warm for 50h. For secondary drying, heat up to 50℃ ± 2℃, with a vacuum of 10Pa and keep warm for 15h. Finally, pre-fill nitrogen protective gas in the freeze-dryer, plug, take out of the box, and protect the product with an aluminum-plastic cap crimping.

[0052] The inspection data of the products obtained based on the above examples at 30 °C are as follows Figures 1 - 3 For the product obtained in Example 1, it presented as a light beige loose mass, with good appearance, no shrinkage or melting

[0053] For the product obtained in Example 2, the moisture at the bottom could not be fully sublimated, and a large amount of shrinkage occurred

[0054] For the product obtained in Example 3, it presented as a light beige cake, but overall shrinkage occurred

[0055] By comparing Example 1, Example 2, and Example 3, it can be concluded that using the technical solution in Example 1 can obtain the product with the best quality. The latamoxef sodium for injection powder injection prepared by this process can effectively control the water content of the product at a low level, reduce the degradation of the main component of the product, ensure the effectiveness and stability of the main component of the product, extend the storage period of the product, and greatly improve the commercial value of the product

[0056] In summary, for the freeze-drying process preparation method of this latamoxef sodium for injection powder injection, during use, first weigh 250 - 2500 parts of mannitol and 250 - 2500 parts of sodium chloride, slowly add a certain amount of injection water at 70 °C - 90 °C and stir until dissolved. After the solution cools down to -5 °C - 5 °C; weigh 5000 - 10000 parts of latamoxef sodium and stir until completely dissolved to obtain a mixed solution

[0057] Adjust the pH to 5.0 - 6.5 with sodium bicarbonate, add injection water to the obtained solution to the full volume. The liquid medicine is filtered through two 0.22 μm microporous membranes to remove impurities in the solution, detect the intermediate content, calculate the filling volume according to the production specification, and obtain the solution to be canned

[0058] The solution to be canned is filled according to the detection requirements, semi-capped and then sent into a freeze dryer, cooled to -35 °C - -45 °C, kept warm for 2 h - 6 h, evacuated until the pressure in the freeze-drying chamber is lower than 10 Pa, and then heated at 2 °C / h to -5 °C - 7 °C, and sublimation drying is carried out at a vacuum degree of 7 Pa - 10 Pa, kept warm for 30 h - 35 h

[0059] For secondary drying, use 50 °C - 58 °C, control the pressure at 10 Pa - 17 Pa, and keep warm for 6 h to thoroughly dry the residual moisture of the product. Finally, the freeze dryer pre-injects nitrogen protective gas, capps, takes out of the chamber, and the product is protected by aluminum-plastic capping. Thus, the latamoxef sodium for injection powder injection is obtained

[0060] The embodiments of the present invention are provided for purposes of illustration and description, and are not intended to be exhaustive or to limit the invention to the disclosed forms. Many modifications and variations are obvious to those of ordinary skill in the art. The embodiments are chosen and described in order to best explain the principles of the invention and its practical application, and to enable those of ordinary skill in the art to understand the invention and design various embodiments with various modifications suitable for a particular purpose.

Claims

1. A freeze-drying process for preparing latamoxef sodium for injection powder injection, characterized in that: The latamoxef sodium for injection powder injection comprises the following components by weight: Latamoxef sodium: 5000 - 10000 parts, mannitol: 250 - 2500 parts, sodium chloride: 250 - 2500 parts, injection water: 25000 parts.

2. The freeze-drying process for preparing latamoxef sodium for injection powder injection according to claim 1, characterized in that: The freeze-drying process for preparing latamoxef sodium for injection powder injection comprises the following operating steps: S1. Stir and dissolve: Weigh 250 - 2500 parts of mannitol and 250 - 2500 parts of sodium chloride in portions, and add them to the injection water at a uniform speed and stir until dissolved to obtain a mixed solution; S2. Adjust the pH value: Adjust the pH value of the solution with sodium bicarbonate, add the remaining injection water to the obtained solution, filter the liquid medicine through two microporous membranes to remove impurities in the solution, detect the intermediate content, calculate the filling volume according to the production specification, and obtain the solution to be canned; S3. Freeze-drying operation: The solution to be canned is filled according to the detection requirements, semi-plugged and then sent into a freeze-dryer, cooled to -35°C to -45°C, evacuated until the pressure in the freeze-drying chamber is lower than 10 Pa, and then heated to -5°C to 7°C, and sublimation drying is carried out under a vacuum degree of 7 Pa to 10 Pa, and keep warm for 30 h to 35 h; S4. Secondary drying: The secondary drying is carried out at a temperature of 50°C to 58°C and keep warm for 6 h to thoroughly dry the residual moisture of the product. Finally, the freeze-dryer pre-injects nitrogen protective gas, plugs, takes out of the box, and the product is protected by aluminum-plastic cap crimping, thus obtaining the latamoxef sodium for injection powder injection.

3. The freeze-drying process for preparing latamoxef sodium for injection powder injection according to claim 2, characterized in that: In step S1, the temperature of the injection water is controlled at 70°C to 90°C when adding.

4. The freeze-drying process for preparing latamoxef sodium for injection powder injection according to claim 2, characterized in that: In step S1, after the mixed solution is cooled to -5 to 5°C, weigh 5000 - 10000 parts of latamoxef sodium and add it to the mixed solution, and stir until completely dissolved.

5. The freeze-drying process for preparing latamoxef sodium for injection powder injection according to claim 2, characterized in that: In step S2, the pH value is adjusted to 5.0 - 6.

5.

6. The freeze-drying process for preparing latamoxef sodium for injection powder injection according to claim 2, characterized in that: In step S2, the pore diameter of the microporous membrane is 0.22 μm.

7. The freeze-drying process for preparing latamoxef sodium for injection powder injection according to claim 2, characterized in that: In step S3, during the process of heating to -5°C to 7°C, the heating rate is 2°C / h and the temperature is raised uniformly.

8. The freeze-drying process for preparing latamoxef sodium for injection powder injection according to claim 2, characterized in that: In step S3, after cooling to -35°C to -45°C, it needs to be kept warm for 2 h to 6 h.

9. The freeze-drying process preparation method of a latamoxef sodium for injection powder injection according to claim 2, characterized in that: in the step S4, the pressure during secondary drying is controlled at 10 Pa to 17 Pa.

Images