Oxytetracycline injection and preparation method thereof

Abstract

The invention provides an oxytetracycline injection and a preparation method thereof, and belongs to the technical field of medicine preparation, the oxytetracycline injection is prepared by the following steps: uniformly mixing N-methyl pyrrolidone and deionized water, sequentially adding sodium formaldehyde sulfoxylate and magnesium oxide, dispersing, heating, adding an oxytetracycline raw material, heating, carrying out a complexation reaction, filtering, washing, and drying to obtain the oxytetracycline injection. Adding monoethanolamine to adjust the pH value for the first time, performing ultrafiltration on the obtained solution by using a PS-20 membrane, adding monoethanolamine to the obtained filtrate for the second time to adjust the pH value, fixing the volume, and filtering to obtain the oxytetracycline injection. The oxytetracycline injection disclosed by the invention is simple in preparation process, low in oxytetracycline loss, high in yield of finished products and suitable for industrial production.

Description

Technical Field

[0001] The invention belongs to the technical field of drug preparation, and in particular relates to oxytetracycline injection and a preparation method thereof. Background Art

[0002] Oxytetracycline injection is an antibiotic drug, and its main component is oxytetracycline, which belongs to tetracycline antibiotics. The mechanism of action is mainly to prevent aminoacyl-tRNA from entering the A position by binding to the bacterial ribosome 30S subunit, thereby inhibiting the synthesis of bacterial proteins and exerting an antibacterial effect. However, the prior art is to produce oxytetracycline by fermentation. In the post-process of producing oxytetracycline by fermentation, the product quality is often improved by optimizing the process conditions. However, the existing oxytetracycline raw materials often have insufficient product purity. Direct preparation of oxytetracycline injection will result in a large amount of impurities such as protein, metal ions, organic byproducts and other visible foreign matter, resulting in poor overall quality and high impurity content. After purifying the oxytetracycline raw material, preparing oxytetracycline injection will result in a large loss of oxytetracycline, and there is still a large unqualified rate in the oxytetracycline injection finished product, so how to improve the oxytetracycline finished product rate and reduce production costs is one of the important topics in the current oxytetracycline injection research and development process. Summary of the invention

[0003] In view of the above problems, the present invention provides an oxytetracycline injection and a preparation method thereof.

[0004] To achieve the above purpose, the technical solution adopted by the present invention is:

[0005] A method for preparing oxytetracycline injection, wherein the oxytetracycline injection is prepared by mixing N-methylpyrrolidone and deionized water, adding sodium formaldehyde sulfoxylate and magnesium oxide in sequence, dispersing and heating, then adding oxytetracycline raw material, heating again for complexation reaction, adding monoethanolamine for the first time to adjust the pH value, ultrafiltration of the obtained solution using a PS-20 membrane, adding monoethanolamine for the second time to adjust the pH value of the obtained filtrate, fixing the volume, filtering, and obtaining the oxytetracycline injection.

[0006] Furthermore, the ultrafiltration pressure is 0.1-0.13 MPa.

[0007] Furthermore, the pH value after the first addition of monoethanolamine is 5.3-5.8.

[0008] Furthermore, the weight ratio of oxytetracycline, N-methylpyrrolidone, sodium formaldehyde sulfoxylate and magnesium oxide is 4-6:25-35:0.4-0.6:0.4-0.5.

[0009] Furthermore, during the mixing process of N-methylpyrrolidone and deionized water, the weight ratio of the total weight of N-methylpyrrolidone and deionized water to the weight of oxytetracycline is 85-87:4-6.

[0010] Furthermore, the pH value after the second addition of monoethanolamine is 8.4-8.6.

[0011] Furthermore, the temperature of the complexation reaction is 60-65°C.

[0012] Furthermore, when oxytetracycline is added, the temperature of the system is 45-55°C.

[0013] Furthermore, the complexation reaction time is 15 to 20 minutes.

[0014] A oxytetracycline injection prepared by the above preparation method.

[0015] The beneficial effects of the oxytetracycline injection and the preparation method thereof of the present invention are:

[0016] The present invention uses oxytetracycline raw materials without further purification to directly prepare oxytetracycline injection, and by selecting a specific ultrafiltration membrane and ultrafiltration pressure to filter at a specific pH value, impurities in the oxytetracycline injection can be effectively removed, thereby improving the oxytetracycline injection finished product rate;

[0017] The oxytetracycline injection of the present invention has a simple preparation process, a small amount of oxytetracycline loss, a high rate of finished products, and is suitable for industrial production.

[0018] The oxytetracycline injection product prepared by the present invention has high purity, low visible foreign matter content, and a small amount of pyrrolidone used overall, so the irritation is low. DETAILED DESCRIPTION

[0019] The technical solutions in the embodiments of the present invention are described clearly and completely below. In the following description, many specific details are set forth to facilitate a full understanding of the present invention, but the present invention can also be implemented in other ways different from those described herein, and those skilled in the art can make similar generalizations without violating the connotation of the present invention, so the present invention is not limited by the specific embodiments disclosed below.

[0020] Example 1 A method for preparing oxytetracycline injection

[0021] The preparation method of oxytetracycline injection in this embodiment specifically comprises the following steps:

[0022] Take 30kg of N-methylpyrrolidone and 55kg of deionized water and mix them, then add 0.5kg of sodium formaldehyde sulfoxylate and 0.5kg of magnesium oxide in turn, stir and disperse at a speed of 1200rpm and heat to 50°C, then add 5.35kg of oxytetracycline raw material (97.46%, equivalent to 5.21kg of oxytetracycline net content), and then heat to 60°C for complexation reaction for 15min. After the first addition of monoethanolamine, adjust the pH value to 5.5. The resulting solution is stirred at 0 .Ultrafiltration was performed using a PS-20 membrane under 13MPa conditions. Monoethanolamine was added to the filtrate for the second time to adjust the pH value to 8.5. A small amount of deionized water was added to make the volume 100 L. The solution was filtered through a 0.22 μm filter membrane and aseptically filled to obtain oxytetracycline injection, which was marked as T1. The net content of oxytetracycline was 50.0 mg / mL, the number of visible foreign matter was 163, the impurity content was 0.0009 mg / mL, the amniotic fluid yield was 99.62%, and the oxytetracycline utilization rate was 95.89%.

[0023] Among them, the utilization rate of oxytetracycline (%) = (oxytetracycline net content × 100) / (oxytetracycline raw material amount × oxytetracycline raw material purity) × 100%.

[0024] Embodiment 2-5 A method for preparing oxytetracycline injection

[0025] Examples 2 to 5 are respectively a method for preparing oxytetracycline injection. According to the optimized method given in Example 1, the range of oxytetracycline and its injection that can be prepared is further explored to obtain the preparation methods in Examples 2 to 5, wherein the preparation methods of oxytetracycline injection in Examples 2 to 5 are basically the same as those in Example 1, except that some process parameters are different, as shown in Table 1 for details:

[0026] Table 1 List of process parameters in Examples 2 to 5

[0027]

[0028] The contents and results of other parts of Examples 2 to 5 are basically the same as those of Example 1 and will not be repeated here.

[0029] Comparative Examples 1 to 5 Comparison of Oxytetracycline Preparation Process

[0030] Comparative Examples 1 to 5 are comparative tests of the preparation method of oxytetracycline injection in Example 1, and the steps are basically the same as those in Example 1, and the same batch of oxytetracycline raw materials (purity of 97.46%) in Example 1 are used, except that:

[0031] The steps of Comparative Example 1 are as follows:

[0032] Take 30kg of N-methylpyrrolidone and 55kg of deionized water and mix them, then add 0.5kg of sodium formaldehyde sulfoxylate and 0.5kg of magnesium oxide in turn, stir and disperse at a speed of 1200rpm and heat to 50°C, then add 5.30kg of oxytetracycline raw material (97.46%, equivalent to a net content of oxytetracycline of 5.21kg), and then heat to 60°C for complexation reaction for 15min, add monoethanolamine to adjust the pH value to 8.5, add a small amount of deionized water to make the volume 100L, filter with 0.22μm filter membrane, and aseptically fill to obtain oxytetracycline injection, marked as DT1, wherein the net content of oxytetracycline contained is 51.7mg / mL, the number of visible foreign matter is 23357, the impurity content is 1.3447mg / mL, the amniotic fluid yield is 94.3%, and the oxytetracycline utilization rate is 99.15%.

[0033] The steps of Comparative Example 2 are as follows:

[0034] Take 30kg of N-methylpyrrolidone and 55kg of deionized water and mix them, then add 0.5kg of sodium formaldehyde sulfoxylate and 0.5kg of magnesium oxide, stir and disperse at a speed of 1200rpm and heat to 50℃, then add 5.35kg of oxytetracycline raw material (97.46%, equivalent to 5.21kg of oxytetracycline net content), and then heat to 60℃ for complexation reaction for 15min. After the first addition of monoethanolamine, adjust the pH value to 5.5. The resulting solution is 0. Ultrafiltration was performed using a PS-20 membrane under 2MPa conditions, and monoethanolamine was added to the filtrate for the second time to adjust the pH value to 8.5. A small amount of deionized water was added to make the volume 100 L, and the solution was filtered through a 0.22 μm filter membrane and aseptically filled to obtain oxytetracycline injection, which was marked as DT2. The net content of oxytetracycline was 50.7 mg / mL, the number of visible foreign matter was 14325, the impurity content was 0.8562 mg / mL, the amniotic fluid yield was 96.7%, and the oxytetracycline utilization rate was 97.23%.

[0035] The steps of Comparative Example 3 are as follows:

[0036] Take 30kg of N-methylpyrrolidone and 55kg of deionized water and mix them, then add 0.5kg of sodium formaldehyde sulfoxylate and 0.5kg of magnesium oxide in turn, stir and disperse at a speed of 1200rpm and heat to 50°C, then add 5.35kg of oxytetracycline raw material (97.46%, equivalent to a net content of oxytetracycline of 5.21kg), and then heat to 60°C for complexation reaction for 15min. After adding monoethanolamine, the pH value is adjusted to 8.5, and the resulting solution is ultrafiltered using a PS-20 membrane under 0.13MPa conditions. A small amount of deionized water is added to the obtained filtrate to make the volume 100L, filtered through a 0.22μm filter membrane, and aseptically filled to obtain oxytetracycline injection, marked as DT3, wherein the net content of oxytetracycline contained is 50.4mg / mL, the number of visible foreign matter is 12875, the impurity content is 0.7953mg / mL, the amniotic yield is 97.3%, and the oxytetracycline utilization rate is 96.66%.

[0037] The steps of Comparative Example 4 are as follows:

[0038] Take 30kg of N-methylpyrrolidone and 55kg of deionized water and mix them, then add 0.5kg of sodium formaldehyde sulfoxylate and 0.5kg of magnesium oxide in turn, stir and disperse at a speed of 1200rpm and heat to 50°C, then add 5.35kg of oxytetracycline raw material (97.46%, equivalent to a net content of oxytetracycline of 5.21kg), and then heat to 60°C for complexation reaction for 15min. The resulting solution is ultrafiltered using a PS-20 membrane under 0.13MPa conditions, and the filtrate is added with monoethanolamine to adjust the pH value to 8.5. A small amount of deionized water is added to make the volume 100L, filtered with a 0.22μm filter membrane, and aseptically filled to obtain oxytetracycline injection, marked as DT4, wherein the net content of oxytetracycline contained is 50.8mg / mL, the number of visible foreign matter is 17961, the impurity content is 0.9354mg / mL, the amniotic yield is 95.2%, and the utilization rate of oxytetracycline is 97.43%.

[0039] The steps of Comparative Example 5 are as follows:

[0040] Take 30kg of N-methylpyrrolidone and 55kg of deionized water and mix them, then add 0.5kg of sodium formaldehyde sulfoxylate and 0.5kg of magnesium oxide, stir and disperse at a speed of 1200rpm and heat to 50℃, then add 5.35kg of oxytetracycline raw material (97.46%, equivalent to 5.21kg of oxytetracycline net content), and then heat to 60℃ for complexation reaction for 15min. After the first addition of monoethanolamine, adjust the pH value to 5.5. The resulting solution is 0. Ultrafiltration was performed using a PS-60 membrane under 13 MPa conditions, and monoethanolamine was added to the filtrate for the second time to adjust the pH value to 8.5. A small amount of deionized water was added to make the volume 100 L, and the solution was filtered through a 0.22 μm filter membrane and aseptically filled to obtain oxytetracycline injection, which was marked as DT5. The net content of oxytetracycline was 51.3 mg / mL, the number of visible foreign matters was 20156, the impurity content was 1.1256 mg / mL, the amniotic fluid yield was 94.6%, and the oxytetracycline utilization rate was 98.39%.

[0041] In summary, it can be seen that the present invention can effectively remove impurities in oxytetracycline injection and improve the oxytetracycline injection dialysis yield rate by selecting a specific ultrafiltration membrane and ultrafiltration pressure to filter at a specific pH value. However, changing the ultrafiltration membrane, ultrafiltration pressure or pH value will lead to an increase in the impurity content and visible foreign matter in oxytetracycline injection, and a decrease in the dialysis yield rate.

[0042] Obviously, the described embodiments are only some embodiments of the present invention, not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

Claims

1. A method for preparing oxytetracycline injection, characterized in that: The oxytetracycline injection is prepared by mixing N-methylpyrrolidone and deionized water, adding sodium formaldehyde sulfoxylate and magnesium oxide in sequence, dispersing and heating, then adding oxytetracycline raw material, heating again for complexation reaction, adding monoethanolamine for the first time to adjust the pH value, ultrafiltering the obtained solution using a PS-20 membrane, adding monoethanolamine for the second time to adjust the pH value of the obtained filtrate, fixing the volume, and filtering to obtain the oxytetracycline injection.

2. The method for preparing oxytetracycline injection according to claim 1, characterized in that: The ultrafiltration pressure is 0.1~0.13MPa.

3. The method for preparing oxytetracycline injection according to claim 1 or 2, characterized in that: The pH value after the first addition of monoethanolamine was 5.3-5.

8.

4. The method for preparing oxytetracycline injection according to claim 1 or 2, characterized in that: The weight ratio of oxytetracycline, N-methylpyrrolidone, sodium formaldehyde sulfoxylate and magnesium oxide is 4-6:25-35:0.4-0.6:0.4-0.

5.

5. The method for preparing oxytetracycline injection according to claim 1 or 2, characterized in that: During the mixing process of N-methylpyrrolidone and deionized water, the weight ratio of the total weight of N-methylpyrrolidone and deionized water to the weight of oxytetracycline is 85-87:4-6.

6. The method for preparing oxytetracycline injection according to claim 1 or 2, characterized in that: The pH value after the second addition of monoethanolamine was 8.4-8.

6.

7. The method for preparing oxytetracycline injection according to claim 1 or 2, characterized in that: The temperature of the complexation reaction is 60-65°C.

8. The method for preparing oxytetracycline injection according to claim 1 or 2, characterized in that: The temperature of the system obtained when oxytetracycline is added is 45-55°C.

9. The method for preparing oxytetracycline injection according to claim 1 or 2, characterized in that: The complexation reaction time is 15 to 20 minutes.

10. Oxytetracycline injection prepared by the preparation method according to any one of claims 1 to 9.

Images