A preparation method of mupirocin ointment

Abstract

The present invention provides a method for preparing mupirocin ointment, comprising the steps of: mixing polyethylene glycol 3350, mupirocin, polyethylene glycol 400 and glycerol, heating the material to 80-90°C until melting and clarifying; cooling to 50-55°C; reducing the stirring speed to 18-22r / min and stirring, and homogenizing the material after the material cools to 45-50°C; increasing the stirring speed to 75-85 r / min and stirring for 55-65min, and then homogenizing; cooling the material to 40-45°C, stirring at 75-85 r / min for 280-320min, and homogenizing when the temperature reaches 38-42°C; regulating the stirring speed to 9-11 r / min, stirring for 110-130min at a temperature of 40-42°C, and obtaining the desired result after aging. The rheological properties of the mupirocin ointment prepared by the present invention can reach the same consistency as the original research fitting.

Description

Technical Field

[0001] The present 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 medication widely used to treat skin infections. It is primarily used to prevent and treat skin infections caused by Gram-positive cocci, such as primary skin infections like impetigo, furuncle, and folliculitis, as well as secondary skin infections like eczema and superficial wound infections. Mupirocin's antibacterial effect primarily stems from its ability to inhibit protein synthesis in bacteria. It acts on the binding site of isoleucine-tRNA synthetase to isoleucine, hindering amino acid synthesis and consuming intracellular tRNA, halting RNA and protein synthesis.

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

[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 method for preparing the mupirocin ointment, comprising the following steps: taking polyethylene glycol 400, adding polyethylene glycol 3350 and propylene glycol, and mixing to obtain solution A; taking polyethylene glycol 400, adding mupirocin and vitamin E, and mixing 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, and it is easy to apply and 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 the 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 may also affect the absorption and release of the drug, thereby affecting the efficacy. Based on this, the present invention provides a preparation method for mupirocin ointment. Summary of the Invention

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

[0007] The present invention provides a method for preparing mupirocin ointment, comprising the following steps:

[0008] (1) Melting: Mix polyethylene glycol 3350, mupirocin, polyethylene glycol 400 and glycerol, and heat the mixture to 80-90°C until it melts and becomes clear.

[0009] (2) Cooling: Cool the material to 50℃-55℃;

[0010] (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;

[0011] (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;

[0012] (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 then mature.

[0013] 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).

[0014] Furthermore, the stirring speed in step (1) is 75-85 r / min.

[0015] Furthermore, the cooling method in step (2) is to use cooling water circulation to cool down.

[0016] Furthermore, the stirring speed is maintained at 75-85 r / min during the cooling process in step (2).

[0017] Furthermore, the cooling rate in step (3) is 28-32 min / °C.

[0018] Furthermore, the cooling rate in step (4) is 55-65 min / °C.

[0019] Furthermore, in step (3), the homogenization speed is 2500-3500 r / min, and the homogenization time is 25-35 min.

[0020] Furthermore, in step (4), the homogenization speed is 2500-3500 r / min, and the homogenization time is 25-35 min.

[0021] The beneficial effects of the present invention are:

[0022] (1) The present invention controls the cooling rate, stirring rate, homogenization rate and time in the first cooling stage to achieve uniform particle size and pore size of polyethylene glycol precipitation.

[0023] (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, making the texture uniform and soft.

[0024] (3) The present invention controls the temperature and stirring rate in the third cooling stage 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.

[0025] (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

[0026] In order to more clearly illustrate the technical solutions of the embodiments of the present application, the following is a brief introduction to the drawings required for use in the embodiments. 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 relevant drawings can be obtained based on these drawings without creative work.

[0027] Figure 1 This is a microscope inspection image after the second cooling stage in Example 1;

[0028] Figure 2 This is a microscope inspection image after the second cooling stage in Example 2;

[0029] Figure 3 This is a microscope inspection image after the second cooling stage in Example 3. DETAILED DESCRIPTION

[0030] The technical solution of the present invention is described clearly and completely below. Obviously, the embodiments described 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 making creative work are within the scope of protection of the present invention. It should be noted that mupirocin was purchased from Zhongmei Huadong, polyethylene glycol 3350 was purchased from Dow Chemical, polyethylene glycol 400 was purchased from Nanjing Well, and glycerol was purchased from Wuxi Huatai.

[0031] The present invention provides a method for preparing mupirocin ointment, comprising the steps of:

[0032] (1) Melting: Add polyethylene glycol 3350, mupirocin, polyethylene glycol 400 and glycerol into an emulsification tank and mix at a stirring speed of 75-85 r / min. Heat the material to 80℃-90℃ until it melts and becomes clear.

[0033] 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;

[0034] (2) Cooling: Use cooling water circulation to cool down, maintain the stirring speed at 75-85r / min, and cool the material to 50℃-55℃;

[0035] (3) Cooling stage 1: Reduce the stirring speed to 18-22 r / min and adjust the cooling rate to 28-32 min / ℃. Wait until the material is cooled 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 and stir for 55-65 min. Then homogenize at a speed of 2500-3500 r / min for 25-35 min.

[0036] (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;

[0037] (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 then mature.

[0038] The present invention will be further explained below with examples:

[0039] Example 1

[0040] This embodiment provides a method for preparing mupirocin ointment, comprising the following steps:

[0041] (1) Melting: Add polyethylene glycol 3350, mupirocin, polyethylene glycol 400 and glycerol into an emulsification tank and mix at a stirring speed of 80 r / min. Heat the material to 85°C until it melts and becomes clear.

[0042] The weight ratio of polyethylene glycol 3350, mupirocin, polyethylene glycol 400 and glycerol is 52:2:40:6;

[0043] (2) Cooling: Use cooling water circulation to cool down, maintain the stirring speed at 80r / min, and cool the material to 52℃;

[0044] (3) Cooling stage 1: Reduce the stirring speed to 20 r / min and adjust the cooling rate to 30 min / °C. After 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 and stir for 60 min. Then homogenize at a speed of 3000 r / min for 30 min.

[0045] (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℃, with a speed of 3000 r / min and a homogenization time of 30 min;

[0046] 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.

[0047] (5) Cooling stage three: Adjust the stirring speed to 10 r / min, stir at a temperature of 41°C for 120 minutes, and then mature.

[0048] Example 2

[0049] This embodiment provides a method for preparing mupirocin ointment, comprising the following steps:

[0050] (1) Melting: Add polyethylene glycol 3350, mupirocin, polyethylene glycol 400 and glycerol into an emulsification tank and mix at a stirring speed of 75 r / min. Heat the material to 80°C until it melts and becomes clear.

[0051] The weight ratio of polyethylene glycol 3350, mupirocin, polyethylene glycol 400 and glycerol is 50:1.5:41.5:7;

[0052] (2) Cooling: Use cooling water circulation to cool down, maintain the stirring speed at 75r / min, and cool the material to 50℃;

[0053] (3) Cooling stage 1: Reduce the stirring speed to 18 r / min and adjust the cooling rate to 28 min / ℃. Wait until the material is cooled to 45℃, then homogenize at a speed of 2500 r / min for 25 min. Then increase the stirring speed to 75 r / min and stir for 55 min. Then homogenize at a speed of 2500 r / min for 25 min.

[0054] (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. The speed is 2500 r / min and the homogenization time is 25 min.

[0055] 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.

[0056] (5) Cooling stage three: Adjust the stirring speed to 9 r / min, stir at a temperature of 40°C for 110 minutes, and then mature to obtain the product.

[0057] Example 3

[0058] This embodiment provides a method for preparing mupirocin ointment, comprising the following steps:

[0059] (1) Melting: Add polyethylene glycol 3350, mupirocin, polyethylene glycol 400 and glycerol into an emulsification tank and mix at a stirring speed of 85 r / min. Heat the material to 90°C until it melts and becomes clear.

[0060] The weight ratio of polyethylene glycol 3350, mupirocin, polyethylene glycol 400 and glycerol is 51:2.5:42.5:4;

[0061] (2) Cooling: Use cooling water circulation to cool down, maintain the stirring speed at 85r / min, and cool the material to 55℃;

[0062] (3) Cooling stage 1: Reduce the stirring speed to 22 r / min and adjust the cooling rate to 32 min / °C. After the material is cooled to 50°C, homogenize at a speed of 3500 r / min for 35 min. Then increase the stirring speed to 85 r / min and stir for 65 min. Then homogenize at a speed of 3500 r / min for 35 min.

[0063] (4) Cooling stage 2: Adjust the cooling rate to 65 min / ℃, cool the material to 45℃, stir at 85 r / min for 320 min, and homogenize when the temperature reaches 42℃, with a speed of 3500 r / min and a homogenization time of 35 min;

[0064] 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.

[0065] (5) Cooling stage three: Adjust the stirring speed to 11 r / min, stir at a temperature of 42°C for 130 minutes, and then mature.

[0066] A rotational rheometer was used to conduct flow curve tests, yield stress tests, and thixotropy tests. The evaluation criteria were to compare the self-made product with the original research product using the T-test method to determine whether the physical properties were consistent with the original research product. The evaluation criteria was a P value > 0.05.

[0067] The performance test of the mupirocin ointment prepared in Examples 1-3 of the present invention is shown in Table 1 below:

[0068]

[0069] The results showed that after the flow curves of the product prepared in Example 1 and the original reference preparation (Batch No.: 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. Using the two-sample equal variance assumption, the P values ​​were all greater than 0.05, demonstrating that the rheological properties of the product prepared in Example 1 were consistent with those of the reference preparation.

[0070] Comparative Example 1

[0071] This comparative example provides a method for preparing mupirocin ointment, comprising the following steps:

[0072] (1) Melting: Add polyethylene glycol 3350, mupirocin, polyethylene glycol 400 and glycerol into an emulsification tank and mix at a stirring speed of 80 r / min. Heat the material to 85°C until it melts and becomes clear.

[0073] The weight ratio of polyethylene glycol 3350, mupirocin, polyethylene glycol 400 and glycerol is 52:2:40:6;

[0074] (2) Cooling: Use cooling water circulation to cool down, maintain the stirring speed at 80r / min, and cool the material to 52℃;

[0075] (3) Cooling stage 1: 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℃, with a speed of 3000 r / min and a homogenization time of 30 min;

[0076] (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.

[0077] Comparative Example 2

[0078] This comparative example provides a method for preparing mupirocin ointment, comprising the following steps:

[0079] (1) Melting: Add polyethylene glycol 3350, mupirocin, polyethylene glycol 400 and glycerol into an emulsification tank and mix at a stirring speed of 80 r / min. Heat the material to 85°C until it melts and becomes clear.

[0080] The weight ratio of polyethylene glycol 3350, mupirocin, polyethylene glycol 400 and glycerol is 52:2:40:6;

[0081] (2) Cooling: Use cooling water circulation to cool down, maintain the stirring speed at 80r / min, and cool the material to 52℃;

[0082] (3) Cooling stage 1: Reduce the stirring speed to 20 r / min and adjust the cooling rate to 30 min / °C. After 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 and stir for 60 min. Then homogenize at a speed of 3000 r / min for 30 min.

[0083] (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.

[0084] Comparative Example 3

[0085] This comparative example provides a method for preparing mupirocin ointment, comprising the following steps:

[0086] (1) Melting: Add polyethylene glycol 3350, mupirocin, polyethylene glycol 400 and glycerol into an emulsification tank and mix at a stirring speed of 80 r / min. Heat the material to 85°C until it melts and becomes clear.

[0087] The weight ratio of polyethylene glycol 3350, mupirocin, polyethylene glycol 400 and glycerol is 52:2:40:6;

[0088] (2) Cooling: Use cooling water circulation to cool down, maintain the stirring speed at 80r / min, and cool the material to 52℃;

[0089] (3) Cooling stage 1: Reduce the stirring speed to 20 r / min and adjust the cooling rate to 30 min / °C. After 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 and stir for 60 min. Then homogenize at a speed of 3000 r / min for 30 min.

[0090] (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℃, with a speed of 3000 r / min and a homogenization time of 30 min. Stir at a temperature of 41℃ for 120 min and mature.

[0091] The performance tests of the products prepared in Comparative Examples 1-3 of the present invention are shown in Table 2 below:

[0092]

[0093] 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 mixture to 80°C-90°C until the mixture is melted and clear; the weight ratio of polyethylene glycol 3350, mupirocin, polyethylene glycol 400 and glycerol is 50-60: 1.5-2.5：40-45：3-8； (2) Cooling: Cool the material to 50-55°C; keep the stirring speed at 75-85r / min during the cooling process; (3) Cooling stage 1: Reduce the stirring speed to 18-22 r / min and stir until the material is cooled to 45°C-50°C at a cooling rate of 28-32 min / °C, 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 at a cooling rate of 55-65 min / °C, stir at a speed of 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 to obtain the product.

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

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

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

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

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