Preparation method of mupirocin ointment

Abstract

The preparation method of the mupirocin ointment comprises the following steps: mixing and stirring polyethylene glycol 3350, mupirocin, polyethylene glycol 400 and glycerol, and heating the materials to 80-90 DEG C until the materials are molten and clarified; cooling to 50 DEG C to 55 DEG C; the stirring speed is reduced to 18-22 r / min, stirring is carried out, and after the temperature of the materials is reduced to 45-50 DEG C, homogenizing is carried out; then the stirring speed is increased to 75-85 r / min, stirring is conducted for 55-65 min, and then homogenizing is conducted; cooling the materials to 40-45 DEG C, stirring for 280-320 minutes at the rotating speed of 75-85 r / min, and homogenizing when the temperature reaches 38-42 DEG C; the stirring speed is adjusted to be 9-11 r / min, stirring is conducted for 110-130 min at the temperature of 40-42 DEG C, and after curing is conducted, the product is obtained. The rheological property of the mupirocin ointment prepared by the invention can be consistent with that of the original ointment.

Description

Technical Field

[0001] The invention relates to the technical field of organic synthesis, and in particular to a method for preparing mupirocin ointment. Background Art

[0002] Mupirocin ointment is a topical drug widely used in the treatment of skin infections. It is mainly used to prevent and treat skin infections caused by Gram-positive cocci, such as primary skin infections such as impetigo, furuncle, folliculitis, and secondary skin infections such as eczema combined with infection and superficial trauma combined with infection. The main mechanism of the antibacterial effect of mupirocin is to inhibit protein synthesis in bacteria. It acts on the binding site of isoleucine-tRNA synthetase and isoleucine in bacteria, hinders the synthesis of amino acids, and consumes tRNA in cells, so that the synthesis of RNA and protein is stopped.

[0003] Patent CN110772479A provides a mupirocin ointment and a preparation method thereof, wherein the mupirocin ointment comprises the following components in weight percentage: polyethylene glycol-400: 70% to 85%, polyethylene glycol-4000: 10% to 28% and mupirocin: 1% to 4%. Compared with the prior art, the beneficial effects of the present invention are: (1) polyethylene glycol-4000 replaces polyethylene glycol-3350, and medical-grade polyethylene glycol-4000 is more readily available, thereby reducing the cost of the raw materials for preparation; (2) the mupirocin ointment of the present invention has a low impurity content and a release rate that is superior to that of products on the market.

[0004] Patent CN110787128A discloses a mupirocin ointment, the raw materials of which include by weight: 20-100 parts of mupirocin, 500-700 parts of polyethylene glycol 3350, 400-600 parts of polyethylene glycol 400, 1-2 parts of vitamin E, and 39-58 parts of propylene glycol. The present invention also discloses a preparation method of the mupirocin ointment, comprising the following steps: taking polyethylene glycol 400, adding polyethylene glycol 3350 and propylene glycol to mix to obtain solution A; taking polyethylene glycol 400, adding mupirocin and vitamin E to mix to obtain suspension B; mixing solution A and suspension B at 55-65°C, then cooling to 35-45°C, grinding, cooling to room temperature, and canning. The active ingredients of the present invention are evenly distributed, the consistency is suitable, it is easy to apply, and it is convenient for patients to use.

[0005] In the existing mupirocin ointment preparation technology, although attempts have been made to improve the rheological properties of the ointment by adjusting the matrix components, optimizing the preparation process and other means, there are still problems. For example, the rheological properties are unstable. Due to slight changes in factors such as raw material ratio, temperature control, and stirring speed during the preparation process, the rheological properties of the ointment may fluctuate significantly, thereby affecting its use effect and efficacy. There are also many methods for preparing products that are very different from the original research products. The mupirocin ointment prepared in part has significant differences in rheological properties from the original research products, which not only affects the patient's use experience, but also may affect the absorption and release of the drug, thereby affecting the efficacy. Based on this, the present invention provides a method for preparing mupirocin ointment. Summary of the invention

[0006] The invention aims to provide a method for preparing mupirocin ointment, which has the advantages of safe and controllable continuous preparation process, high conversion efficiency, high purity, small impurities and high production capacity.

[0007] The present invention provides a method for preparing mupirocin ointment, the steps comprising: (1) Melting: Mix polyethylene glycol 3350, mupirocin, polyethylene glycol 400 and glycerol, and heat the materials to 80°C-90°C until they are melted and clarified; (2) Cooling: cool the material to 50℃-55℃; (3) Cooling stage 1: Reduce the stirring speed to 18-22 r / min and stir until the material is cooled to 45℃-50℃, then homogenize; then increase the stirring speed to 75-85 r / min and stir for 55-65 minutes, then homogenize; (4) Cooling stage 2: Cool the material to 40-45°C, stir at 75-85 r / min for 280-320 min, and homogenize when the temperature reaches 38-42°C; (5) Cooling stage three: Adjust the stirring speed to 9-11 r / min, stir at a temperature of 40℃-42℃ for 110-130 minutes, and mature.

[0008] Furthermore, in step (1), the weight ratio of polyethylene glycol 3350, mupirocin, polyethylene glycol 400 and glycerol is (50-60): (1.5-2.5): (40-45): (3-8).

[0009] Furthermore, in step (1), the stirring speed is 75-85 r / min.

[0010] Furthermore, the cooling method in step (2) is to use cooling water circulation for cooling.

[0011] Furthermore, during the cooling process in step (2), the stirring speed is maintained at 75-85 r / min.

[0012] Furthermore, in step (3), the cooling rate is 28-32 min / °C.

[0013] Furthermore, in step (4), the cooling rate is 55-65 min / °C.

[0014] Furthermore, in step (3), the homogenization speed is 2500-3500 r / min, and the homogenization time is 25-35 min.

[0015] Furthermore, in step (4), the homogenization speed is 2500-3500 r / min, and the homogenization time is 25-35 min.

[0016] The beneficial effects of the present invention are: (1) The present invention controls the cooling rate, stirring rate, homogenization rate and time in the cooling stage 1 to achieve uniform particle size and pore size of polyethylene glycol precipitation.

[0017] (2) The present invention controls the cooling rate, stirring rate, homogenization rate and time in the second cooling stage to achieve a dynamic balance between the precipitation and melting of polyethylene glycol, thereby making the texture uniform and soft.

[0018] (3) The present invention controls the temperature and stirring rate in the cooling stage 3 to achieve the maturation of the matrix, releases the energy fluctuations in the melting and precipitation process of polyethylene glycol, and achieves a dynamic stable state, so that the rheological properties of the mupirocin ointment can be stable and uniform.

[0019] (4) The present invention provides a method for preparing mupirocin ointment, and the rheological properties of the prepared mupirocin ointment can be consistent with the original research fitting. BRIEF DESCRIPTION OF THE DRAWINGS

[0020] In order to more clearly illustrate the technical solutions of the embodiments of the present application, the drawings required for use in the embodiments will be briefly introduced below. It should be understood that the following drawings only show certain embodiments of the present application and therefore should not be regarded as limiting the scope. For ordinary technicians in this field, other related drawings can be obtained based on these drawings without paying creative work.

[0021] Figure 1 This is a microscope inspection picture after the second cooling stage in Example 1; Figure 2 This is a microscope inspection picture after the second cooling stage in Example 2; Figure 3 This is a microscope detection image after the second cooling stage in Example 3 is completed. DETAILED DESCRIPTION

[0022] The technical solution of the present invention is described clearly and completely below. Obviously, the described embodiments are part of the embodiments of the present invention, rather than all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in the field without creative work are within the scope of protection of the present invention. It should be noted that mupirocin was purchased from Sino-US Huadong, polyethylene glycol 3350 was purchased from Dow Chemical, polyethylene glycol 400 was purchased from Nanjing Well, and glycerol was purchased from Wuxi Huatai.

[0023] The present invention provides a method for preparing mupirocin ointment, the steps comprising: (1) Melting: Add polyethylene glycol 3350, mupirocin, polyethylene glycol 400 and glycerol into an emulsification tank and mix and stir at a stirring speed of 75-85 r / min. Heat the materials to 80°C-90°C until they are melted and clarified. The weight ratio of polyethylene glycol 3350, mupirocin, polyethylene glycol 400 and glycerol is (50-60): (1.5-2.5): (40-45): (3-8), and the total amount is 100; (2) Cooling: Use cooling water circulation to cool down, maintain the stirring speed at 75-85r / min, and cool the material to 50℃-55℃; (3) Cooling stage 1: Reduce the stirring speed to 18-22 r / min, adjust the cooling speed to 28-32 min / ℃, wait for the material to cool to 45℃-50℃, then homogenize at a speed of 2500-3500 r / min for 25-35 min; then increase the stirring speed to 75-85 r / min for 55-65 min, then homogenize at a speed of 2500-3500 r / min for 25-35 min; (4) Cooling stage 2: Adjust the cooling rate to 55-65min / ℃, cool the material to 40℃-45℃, stir at 75-85r / min for 280-320min, and homogenize when the temperature reaches 38-42℃, with a speed of 2500-3500 r / min and a homogenization time of 25-35min; (5) Cooling stage three: Adjust the stirring speed to 9-11 r / min, stir at a temperature of 40℃-42℃ for 110-130 minutes, and mature.

[0024] The present invention will be further explained below with examples: Example 1

[0025] This embodiment provides a method for preparing mupirocin ointment, the steps comprising: (1) Melting: Add polyethylene glycol 3350, mupirocin, polyethylene glycol 400 and glycerol into an emulsification tank and mix and stir at a stirring speed of 80 r / min. Heat the materials to 85°C until they are melted and clarified. The weight ratio of polyethylene glycol 3350, mupirocin, polyethylene glycol 400 and glycerol is 52:2:40:6; (2) Cooling: Use cooling water circulation to cool down, maintain the stirring speed at 80r / min, and cool the material to 52°C; (3) Cooling stage 1: Reduce the stirring speed to 20 r / min and adjust the cooling speed to 30 min / °C. When the material is cooled to 47°C, homogenize at a speed of 3000 r / min for 30 min. Then increase the stirring speed to 80 r / min for 60 min, and then homogenize at a speed of 3000 r / min for 30 min. (4) Cooling stage 2: Adjust the cooling rate to 60 min / °C, cool the material to 42°C, stir at 80 r / min for 300 min, and homogenize when the temperature reaches 40°C, with a speed of 3000 r / min and a homogenization time of 30 min; After the second cooling stage, samples were taken and the particle size was tested under a microscope. The evaluation standard was that no particles larger than 180 μm should be detected. The results were as follows: Figure 1 As shown, the results show that the maximum particle size detected by microscope scanning is 54.18um, which is less than 180um and meets the particle size requirements.

[0026] (5) Cooling stage three: Adjust the stirring speed to 10 r / min, stir at a temperature of 41°C for 120 minutes, and mature to obtain the product.

[0027] Example 2

[0028] This embodiment provides a method for preparing mupirocin ointment, the steps comprising: (1) Melting: Add polyethylene glycol 3350, mupirocin, polyethylene glycol 400 and glycerol into an emulsification tank and mix and stir at a stirring speed of 75 r / min. Heat the materials to 80°C until they are melted and clarified. The weight ratio of polyethylene glycol 3350, mupirocin, polyethylene glycol 400 and glycerol is 50:1.5:41.5:7; (2) Cooling: Use cooling water circulation to cool down, maintain the stirring speed at 75r / min, and cool the material to 50°C; (3) Cooling stage 1: Reduce the stirring speed to 18 r / min and adjust the cooling speed to 28 min / °C. When the material is cooled to 45°C, homogenize it at a speed of 2500 r / min for 25 min. Then increase the stirring speed to 75 r / min for 55 min, and then homogenize it at a speed of 2500 r / min for 25 min. (4) Cooling stage 2: Adjust the cooling rate to 55 min / °C, cool the material to 40°C, stir at 75 r / min for 280 min, and homogenize when the temperature reaches 38°C, with a speed of 2500 r / min and a homogenization time of 25 min; After the second cooling stage, samples were taken and the particle size was tested under a microscope. The evaluation standard was that no particles larger than 180 μm should be detected. The results were as follows: Figure 2 As shown, the results show that the maximum particle size detected by microscope scanning is 28.29um, which is less than 180um and meets the particle size requirements.

[0029] (5) Cooling stage three: Adjust the stirring speed to 9 r / min, stir at 40°C for 110 minutes, and mature to obtain the product.

[0030] Example 3

[0031] This embodiment provides a method for preparing mupirocin ointment, the steps comprising: (1) Melting: Add polyethylene glycol 3350, mupirocin, polyethylene glycol 400 and glycerol into an emulsification tank and mix and stir at a stirring speed of 85 r / min. Heat the materials to 90°C until they are melted and clarified. The weight ratio of polyethylene glycol 3350, mupirocin, polyethylene glycol 400 and glycerol is 51:2.5:42.5:4; (2) Cooling: Use cooling water circulation to cool down, maintain the stirring speed at 85r / min, and cool the material to 55°C; (3) Cooling stage 1: Reduce the stirring speed to 22 r / min and adjust the cooling rate to 32 min / °C. When the material is cooled to 50°C, homogenize it at a speed of 3500 r / min for 35 min. Then increase the stirring speed to 85 r / min for 65 min, and then homogenize it at a speed of 3500 r / min for 35 min. (4) Cooling stage 2: Adjust the cooling rate to 65 min / °C, cool the material to 45°C, stir at 85 r / min for 320 min, and homogenize when the temperature reaches 42°C, with a speed of 3500 r / min and a homogenization time of 35 min; After the second cooling stage, samples were taken and the particle size was tested under a microscope. The evaluation standard was that no particles larger than 180 μm should be detected. The results were as follows: Figure 3 As shown, the results show that the maximum particle size detected by microscope scanning is 59.86um, which is less than 180um and meets the particle size requirements.

[0032] (5) Cooling stage three: Adjust the stirring speed to 11 r / min, stir at a temperature of 42°C for 130 minutes, and mature to obtain the product.

[0033] A rotational rheometer was used to conduct flow curve test, yield stress test and thixotropy test. The evaluation criteria were to compare the self-made product with the original product by T test to determine whether the physical properties were consistent with the original product. The evaluation criteria was P value > 0.05.

[0034] The performance test of the mupirocin ointment prepared in Examples 1-3 of the present invention is shown in Table 1 below:

[0035] The results showed that after the flow curves of the product prepared in Example 1 and the original reference preparation (batch numbers: M53B, VU3T, N76P, Shenzhen Huaxin Pharmaceutical Technology Co., Ltd.) were fitted, the yield stress, storage modulus and loss modulus were calculated using the T-test statistical analysis method, and the two-sample equal variance assumption was used, and the P values ​​were all greater than 0.05, proving that the rheological properties of the product prepared in Example 1 were consistent with the reference preparation.

[0036] Comparative Example 1 This comparative example provides a method for preparing mupirocin ointment, the steps comprising: (1) Melting: Add polyethylene glycol 3350, mupirocin, polyethylene glycol 400 and glycerol into an emulsification tank and mix and stir at a stirring speed of 80 r / min. Heat the materials to 85°C until they are melted and clarified. The weight ratio of polyethylene glycol 3350, mupirocin, polyethylene glycol 400 and glycerol is 52:2:40:6; (2) Cooling: Use cooling water circulation to cool down, maintain the stirring speed at 80r / min, and cool the material to 52°C; (3) Cooling stage 1: Adjust the cooling rate to 60 min / °C, cool the material to 42°C, stir at 80 r / min for 300 min, and homogenize when the temperature reaches 40°C, with a speed of 3000 r / min and a homogenization time of 30 min; (4) Cooling stage 2: Adjust the stirring speed to 10 r / min, stir at a temperature of 41°C for 120 minutes, and then mature to obtain the product.

[0037] Comparative Example 2 This comparative example provides a method for preparing mupirocin ointment, the steps comprising: (1) Melting: Add polyethylene glycol 3350, mupirocin, polyethylene glycol 400 and glycerol into an emulsification tank and mix and stir at a stirring speed of 80 r / min. Heat the materials to 85°C until they are melted and clarified. The weight ratio of polyethylene glycol 3350, mupirocin, polyethylene glycol 400 and glycerol is 52:2:40:6; (2) Cooling: Use cooling water circulation to cool down, maintain the stirring speed at 80r / min, and cool the material to 52°C; (3) Cooling stage 1: Reduce the stirring speed to 20 r / min and adjust the cooling speed to 30 min / °C. When the material is cooled to 47°C, homogenize at a speed of 3000 r / min for 30 min. Then increase the stirring speed to 80 r / min for 60 min, and then homogenize at a speed of 3000 r / min for 30 min. (4) Cooling stage 2: Adjust the stirring speed to 10 r / min, stir at a temperature of 41°C for 120 minutes, and then mature to obtain the product.

[0038] Comparative Example 3 This comparative example provides a method for preparing mupirocin ointment, the steps comprising: (1) Melting: Add polyethylene glycol 3350, mupirocin, polyethylene glycol 400 and glycerol into an emulsification tank and mix and stir at a stirring speed of 80 r / min. Heat the materials to 85°C until they are melted and clarified. The weight ratio of polyethylene glycol 3350, mupirocin, polyethylene glycol 400 and glycerol is 52:2:40:6; (2) Cooling: Use cooling water circulation to cool down, maintain the stirring speed at 80r / min, and cool the material to 52°C; (3) Cooling stage 1: Reduce the stirring speed to 20 r / min and adjust the cooling speed to 30 min / °C. When the material is cooled to 47°C, homogenize at a speed of 3000 r / min for 30 min. Then increase the stirring speed to 80 r / min for 60 min, and then homogenize at a speed of 3000 r / min for 30 min. (4) Cooling stage 2: Adjust the cooling rate to 60 min / ℃, cool the material to 42℃, stir at 80 r / min for 300 min, and homogenize when the temperature reaches 40℃. The speed is 3000 r / min and the homogenization time is 30 min. Stir for 120 min at a temperature of 41℃ and the mixture is ready after maturation.

[0039] The performance test of the products prepared in Comparative Examples 1-3 of the present invention is shown in Table 2 below:

[0040] Finally, it should be noted that the above embodiments are only used to illustrate the present invention and are not intended to limit the technical solutions described in the present invention. Those skilled in the art should understand that the present invention can still be modified or replaced by equivalents. All technical solutions and improvements that do not depart from the spirit and scope of the present invention should be included in the scope of the claims of the present invention.

Claims

1. A method for preparing mupirocin ointment, characterized in that the steps include: (1) Melting: Mix polyethylene glycol 3350, mupirocin, polyethylene glycol 400 and glycerol, and heat the materials to 80°C-90°C until they are melted and clear; (2) Cooling: cool the material to 50℃-55℃; (3) Cooling stage 1: Reduce the stirring speed to 18-22 r / min and stir until the material is cooled to 45℃-50℃, then homogenize; then increase the stirring speed to 75-85 r / min and stir for 55-65 minutes, then homogenize; (4) Cooling stage 2: Cool the material to 40-45°C, stir at 75-85 r / min for 280-320 min, and homogenize when the temperature reaches 38-42°C; (5) Cooling stage three: Adjust the stirring speed to 9-11 r / min, stir at a temperature of 40℃-42℃ for 110-130 minutes, and mature.

2. The method for preparing mupirocin ointment according to claim 1, characterized in that: In the step (1), the weight ratio of polyethylene glycol 3350, mupirocin, polyethylene glycol 400 and glycerol is (50-60): (1.5-2.5): (40-45): (3-8).

3. The method for preparing mupirocin ointment according to claim 1, characterized in that: The stirring speed in step (1) is 75-85 r / min.

4. The method for preparing mupirocin ointment according to claim 3, characterized in that: The cooling method in step (2) is to use cooling water circulation to cool down.

5. The method for preparing mupirocin ointment according to claim 3, characterized in that: During the cooling process in step (2), the stirring speed is maintained at 75-85 r / min.

6. The method for preparing mupirocin ointment according to claim 1, characterized in that: The cooling rate in step (3) is 28-32 min / °C.

7. The method for preparing mupirocin ointment according to claim 1, characterized in that: The cooling rate in step (4) is 55-65 min / °C.

8. The method for preparing mupirocin ointment according to claim 1, characterized in that: The homogenization speed in step (3) is 2500-3500 r / min, and the homogenization time is 25-35 min.

9. The method for preparing mupirocin ointment according to claim 1, characterized in that: The homogenization speed in step (4) is 2500-3500 r / min, and the homogenization time is 25-35 min.

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