A method for preparing an antiseptic ointment

Abstract

The application discloses a preparation method of an antibacterial ointment, which comprises the following steps: 1) auxiliary material treatment: heating the auxiliary material in a prescribed amount under the condition of a water bath at 55-65 DEG C, and stirring until complete melting; 2) raw material treatment: dissolving the raw material into the mixture obtained in step 1) under the condition of a water bath at 55-65 DEG C until complete dissolution, to obtain a raw material and auxiliary material mixture; 3) cooling: under vacuum, adopting water bath step cooling; 4) heat preservation: after the end of step 3), continuing water bath heat preservation to obtain a final product; and 5) filling; the antibacterial ointment prepared by the method has good rheological properties and absorption effect.

Description

Technical Field

[0001] This application belongs to the field of pharmaceutical preparation technology, and specifically relates to a method for preparing an antibacterial ointment. Background Technology

[0002] Mupirocin, chemically named 9-{4-[5-(2,3-epoxy-5-hydroxy-4-methylhexyl)-3,4-dihydroxytetrahydropyran-2-yl]-3-methylbut-2-enoyloxy, CAS number 12650-69-0, is a novel antibiotic produced by fermentation of *Pseudomonas fluorescens*. Mupirocin inhibits isoleucyl transfer RNA synthase, thereby preventing bacterial protein synthesis. Mupirocin exhibits bacteriostatic properties at its minimum inhibitory concentration (MIC), and bactericidal properties at higher concentrations when applied topically. Its chemical structure is as follows:

[0003]

[0004] Mupirocin ointment, developed by GlaxoSmithKline and marketed as Bactroban, is a topical antibacterial agent active against most organisms causing skin infections, such as Staphylococcus aureus, including methicillin-resistant strains, other staphylococci, and streptococci. It is also active against Gram-negative organisms such as Escherichia coli and Haemophilus influenzae. It can be used for skin infections such as impetigo, folliculitis, and furuncles.

[0005] Patent CN110787128A describes a mupirocin ointment and its preparation method. By adding vitamin E, the stability of mupirocin is increased. By adjusting the ratio of polyethylene glycol 3350, polyethylene glycol 400, and propylene glycol, the proportion of polyethylene glycol 400 is reduced to improve the problem of the ointment base being too thin in summer when the temperature is high. Furthermore, by adding an appropriate amount of propylene glycol to work with polyethylene glycol 3350 and polyethylene glycol 400, the problem of the ointment base being too hard in winter when the temperature is low is improved.

[0006] Patent CN110772479A describes a mupirocin ointment and its preparation method, which uses polyethylene glycol-4000 to replace polyethylene glycol-3350, resulting in a mupirocin ointment with low impurity content and better release than commercially available products.

[0007] Patent CN105412000A describes a method for preparing mupirocin ointment. By turning on a high-speed emulsifying head and maintaining a high-speed shearing state until the material cools to 38°C, it can prevent polyethylene glycol 3500 from rapidly precipitating into lumps, ensuring that 95% of the material particles are less than 50μm, ensuring the material is fine, and avoiding the problem of uncontrollable filling volume during the filling process caused by the coarseness and excessive viscosity of the material. The final product obtained is qualified in terms of properties.

[0008] Patent CN102335122A describes a mupirocin ointment and its preparation method. Because the mupirocin ointment contains organic acids as stabilizers, it exhibits high stability and low levels of related substances compared to existing mupirocin ointments, resulting in better efficacy in clinical use.

[0009] The contents described in the above patents are all aimed at solving the quality problem of mupirocin ointment, but the effects they can achieve are limited and the operation is complicated. Summary of the Invention

[0010] To address the problems existing in the prior art, the present invention provides a method for preparing an antibacterial ointment, comprising the following steps:

[0011] 1) Excipient processing: Heat the prescribed amount of excipients in a water bath at 55-65℃ and stir until completely melted;

[0012] 2) Raw material processing: Under water bath conditions of 55-65℃, the raw materials are added to the mixture obtained in step 1) and dissolved completely to obtain a mixture of raw materials and auxiliary materials;

[0013] 3) Cooling: Under vacuum conditions, water bath stepped cooling is used to lower the temperature;

[0014] 4) Heat preservation: After step 3) is completed, continue water bath heat preservation to obtain the final product;

[0015] 5) Filling.

[0016] Furthermore, step 3) cooling includes the following stages:

[0017] A. The raw material mixture is gradually cooled to 45-52°C under a water bath at 40-50°C, and then homogenized.

[0018] B. After stage A is completed, the raw material mixture is gradually cooled to 40-46°C under a water bath at 35-42°C, and then homogenized.

[0019] C. After stage B is completed, the raw material mixture is gradually cooled to 35-45°C under a water bath at 25-42°C, and then homogenized.

[0020] D. After stage C is completed, cool with a water bath at 25-42°C for 20-40 minutes to end the cooling process.

[0021] Further, the homogenization conditions in step 3) are: homogenization time of 1 to 3 minutes and homogenization speed of 10,000 to 12,000 rpm.

[0022] Furthermore, the cooling time for stage A is 5–10 min; the cooling time for stage B is 10–40 min; and the cooling time for stage C is 5–30 min.

[0023] Further, after the homogenization process described in step 3), a stirring process is performed for 5 to 15 minutes at a stirring speed of 50 to 150 rpm.

[0024] Furthermore, the water bath temperature in step 4) of heat preservation is 40-50℃.

[0025] Furthermore, in step 4), while maintaining the temperature, a stirring process is carried out for 5 to 15 minutes and at a stirring speed of 50 to 150 rpm.

[0026] Furthermore, the stirring speed for the auxiliary material treatment in step 1) is 50-150 rpm.

[0027] Furthermore, the composition of the mupirocin ointment includes: 0.1 to 0.5 parts of mupirocin and 2 to 35 parts of excipients, wherein the excipients are 5 to 15 parts of polyethylene glycol 400 and 2 to 10 parts of polyethylene glycol 3350.

[0028] On the other hand, the present invention provides an antibacterial ointment prepared according to the above method, wherein the antibacterial ointment is preferably mupirocin ointment.

[0029] Compared with existing technologies, the preparation method of the antibacterial ointment (hereinafter referred to as "mupirocin ointment") of the present invention has the following advantages: First, the mupirocin ointment obtained by the present invention exhibits excellent rheological properties, with significant shear-thinning characteristics. Furthermore, after shearing, the ointment can quickly recover to its original state. This excellent thixotropic property not only improves the comfort of use but also greatly optimizes the user experience. Second, the viscosity range of the mupirocin ointment is suitable, ensuring good spreadability while avoiding the problem of difficulty in application caused by excessively high viscosity.

[0030] More importantly, the mupirocin ointment obtained by this invention has a highly efficient transdermal absorption capacity. The active ingredient, mupirocin, can rapidly penetrate the skin surface and reach the deep layers of the skin to exert its effect. Simultaneously, the transdermal dosage of the ointment is precisely controlled within a safe and reasonable range, which not only significantly enhances the therapeutic effect but also ensures the safety of medication use. Furthermore, the entire preparation process is simple, efficient, easy to operate, and readily available for production and application. Attached Figure Description

[0031] Figure 1 This is a flow curve of Bactroban-viscosity and shear stress as a function of shear rate.

[0032] Figure 2This is a flow curve of viscosity and shear stress as a function of shear rate, as shown in Example 1.

[0033] Figure 3 This is Example 2 - flow curves showing the variation of viscosity and shear stress with shear rate.

[0034] Figure 4 This is Example 3 - flow curves showing the variation of viscosity and shear stress with shear rate.

[0035] Figure 5 This is Example 4 - flow curves showing the variation of viscosity and shear stress with shear rate.

[0036] Figure 6 This is a flow curve of viscosity and shear stress as a function of shear rate, as shown in Comparative Example 1.

[0037] Figure 7 This is a flow curve diagram showing the variation of viscosity and shear stress with shear rate in Comparative Example 2.

[0038] Figure 8 This is a flow curve of comparative example 3, showing the changes in viscosity and shear stress with shear rate.

[0039] Figure 9 This is a flow curve of viscosity and shear stress as a function of shear rate, as shown in Comparative Example 4.

[0040] Figure 10 This is a flow curve of viscosity and shear stress as a function of shear rate, as shown in Comparative Example 5.

[0041] Figure 11 This is a flow curve of viscosity and shear stress as a function of shear rate, as shown in Comparative Example 6.

[0042] Figure 12 This is a flow curve diagram showing the variation of viscosity and shear stress with shear rate, as shown in Comparative Example 7.

[0043] Figure 13 This is a flow curve of viscosity and shear stress as a function of shear rate, as shown in Comparative Example 8.

[0044] Figure 14 This is a graph showing the viscosity of Bactroban over time (thixotropic properties).

[0045] Figure 15 This is Example 1 - Viscosity versus time curve (thixotropic properties).

[0046] Figure 16 This is Example 2 - Viscosity versus time curve (thixotropic properties).

[0047] Figure 17 This is Example 3 - Viscosity versus time curve (thixotropic properties).

[0048] Figure 18 This is Example 4 - Viscosity versus time curve (thixotropic properties).

[0049] Figure 19 This is a comparative example 1 – viscosity versus time curve (thixotropic properties).

[0050] Figure 20 This is Comparative Example 2 - Viscosity versus time curve (thixotropic properties).

[0051] Figure 21 This is Comparative Example 3 - Viscosity versus time curve (thixotropic properties).

[0052] Figure 22 This is Comparative Example 4 - Viscosity versus time curve (thixotropic properties).

[0053] Figure 23 This is Comparative Example 5 - Viscosity versus time curve (thixotropic properties).

[0054] Figure 24 This is Comparative Example 6 - Viscosity versus time curve (thixotropic properties).

[0055] Figure 25 This is Comparative Example 7 - Viscosity versus time curve (thixotropic properties).

[0056] Figure 26 This is Comparative Example 8 - Viscosity versus time curve (thixotropic properties). Detailed Implementation

[0057] The technical solutions of the embodiments of this application will be clearly described below with reference to the accompanying drawings. Obviously, the described embodiments are only some, not all, of the embodiments of this application. All other embodiments obtained by those skilled in the art based on the embodiments of this application are within the scope of protection of this application.

[0058] The terms "first," "second," etc., used in the specification and claims of this application are used to distinguish similar objects and not to describe a specific order or sequence. It should be understood that such use of data can be interchanged where appropriate so that embodiments of this application can be implemented in orders other than those illustrated or described herein, and the objects distinguished by "first," "second," etc., are generally of the same class and the number of objects is not limited; for example, a first object can be one or more. Furthermore, in the specification and claims, "and / or" indicates at least one of the connected objects, and the character " / " generally indicates that the preceding and following objects are in an "or" relationship.

[0059] The inventors of this application have discovered that by controlling the key steps in the preparation method of mupirocin ointment, the consistency of the performance of mupirocin ointment with commercially available products can be significantly improved, especially in terms of rheological properties and in vitro absorption, achieving the same level as commercially available products and even surpassing them. The entire process includes the following main steps:

[0060] 1) Excipient processing: Heat the prescribed amount of excipients in a water bath at 55-65℃ and stir until completely melted;

[0061] In one embodiment of the invention, the stirring speed is 50-150 rpm, for example 50 rpm, 100 rpm, or 150 rpm, but is not limited to the listed values; other unlisted values ​​within this range are also applicable. In one embodiment of the invention, the excipient is an aqueous matrix; in a specific embodiment of the invention, the aqueous matrix is ​​polyethylene glycol 400 and polyethylene glycol 3350, and the amount used is 50.0-65.0% (w / w) of polyethylene glycol 400 and 30.0-49.0% (w / w) of polyethylene glycol 3350, preferably 55.0-60.0% (w / w) of polyethylene glycol 400 and 35.0-40.0% (w / w) of polyethylene glycol 3350.

[0062] 2) Raw material processing: Under water bath conditions of 55–65°C, the raw material is added to the mixture obtained in step 1) and dissolved completely to obtain a raw material and auxiliary material mixture. In one embodiment of the present invention, the raw material is mupirocin. In a specific embodiment of the present invention, the amount of mupirocin is 1.0–5.0% (w / w), preferably 2.0–2.5% (w / w). In one embodiment of the present invention, the water bath temperature is 55–65°C, for example 55°C, 60°C, or 65°C, but is not limited to the listed values; other unlisted values ​​within this range are also applicable.

[0063] 3) Cooling: Under vacuum conditions, water bath stepped cooling is used to lower the temperature;

[0064] In one embodiment of the present invention, step 3) cooling includes the following stages:

[0065] A. The raw material mixture is gradually cooled to 45-52°C under a water bath at 40-50°C, and then homogenized.

[0066] In one embodiment of the present invention, the water bath temperature in stage A is preferably 43 to 45°C, for example 43°C, 44°C or 45°C, but is not limited to the listed values. Other unlisted values ​​within this range are also applicable.

[0067] In one embodiment of the present invention, the material temperature in stage A is preferably 49 to 51°C, for example 49°C, 50°C or 51°C, but is not limited to the listed values. Other unlisted values ​​within this range are also applicable.

[0068] B. After stage A is completed, the raw material mixture is gradually cooled to 40-46°C under a water bath at 35-42°C, and then homogenized.

[0069] In one embodiment of the present invention, the water bath temperature in stage B is preferably 37 to 39°C, for example 37°C, 38°C or 39°C, but is not limited to the listed values. Other unlisted values ​​within this range are also applicable.

[0070] In one embodiment of the present invention, the material temperature in stage B is preferably 43 to 45°C, for example 43°C, 44°C or 45°C, but is not limited to the listed values. Other unlisted values ​​within this range are also applicable.

[0071] C. After stage B is completed, the raw material mixture is gradually cooled to 35-45°C under a water bath at 25-42°C, and then homogenized.

[0072] In one embodiment of the present invention, the water bath temperature in stage C is preferably 33 to 35°C, for example 33°C, 34°C or 35°C, but is not limited to the listed values. Other unlisted values ​​within this range are also applicable.

[0073] In one embodiment of the present invention, the material temperature in stage C is preferably 40 to 42°C, for example 40°C, 41°C or 42°C, but is not limited to the listed values. Other unlisted values ​​within this range are also applicable.

[0074] D. After stage C is completed, cool with a water bath at 25-42°C for 20-40 minutes to end the cooling process.

[0075] In one embodiment of the present invention, the water bath temperature in stage D is preferably 33 to 35°C, for example 33°C, 34°C or 35°C, but is not limited to the listed values. Other unlisted values ​​within this range are also applicable.

[0076] In one embodiment of the present invention, the conditions for homogenization in step 3) are as follows: the homogenization time is 1 to 3 minutes, for example, 1 minute, 2 minutes or 3 minutes, but not limited to the listed values, and other unlisted values ​​within this range are also applicable; the homogenization speed is 10,000 to 12,000 rpm, for example, 10,000 rpm, 11,000 rpm or 12,000 rpm, but not limited to the listed values, and other unlisted values ​​within this range are also applicable.

[0077] The homogenization described in this invention refers to the process of refining and uniformly distributing particles in a mixture through physical forces (such as shear force, impact force, and cavitation). This invention does not limit the homogenization method; high-pressure pumps, colloid mills, ultrasonic equipment, or other specialized homogenization equipment can be used to disperse different components in the mixture into smaller particles, thereby achieving the purpose of uniform mixing.

[0078] In one embodiment of the present invention, the cooling time of stage A is 5 to 10 minutes, for example, 5 minutes, 5.5 minutes, 6 minutes, 6.5 minutes, 7 minutes, 7.5 minutes, 8 minutes, 8.5 minutes, 9 minutes, 9.5 minutes, or 10 minutes, but is not limited to the listed values; other unlisted values ​​within this range are also applicable. The cooling time of stage B is 10 to 40 minutes, for example, 10 minutes, 15 minutes, 20 minutes, 25 minutes, 30 minutes, 35 minutes, or 40 minutes, but is not limited to the listed values; other unlisted values ​​within this range are also applicable. The cooling time of stage C is 5 to 30 minutes, for example, 5 minutes, 10 minutes, 15 minutes, 20 minutes, 25 minutes, or 30 minutes, but is not limited to the listed values; other unlisted values ​​within this range are also applicable.

[0079] In one embodiment of the present invention, the homogenization process is followed by a further stirring process, the stirring time being 5 to 15 minutes, for example 5 minutes, 10 minutes or 15 minutes, but not limited to the listed values, other unlisted values ​​within this range are also applicable; the stirring speed is 50 to 150 rpm, for example 50 rpm, 100 rpm or 150 rpm, but not limited to the listed values, other unlisted values ​​within this range are also applicable;

[0080] 4) Heat preservation: After step 3) is completed, continue water bath heat preservation to obtain the final product;

[0081] In one embodiment of the present invention, the water bath temperature in step 4) heat preservation is 40 to 50°C, for example 40°C, 45°C or 50°C, but is not limited to the listed values. Other unlisted values ​​within this range are also applicable.

[0082] In one embodiment of the present invention, in step 4), the stirring process is carried out while the temperature is maintained. The stirring time is 5 to 15 minutes, for example, 5 minutes, 10 minutes or 15 minutes, but it is not limited to the listed values. Other unlisted values ​​within this range are also applicable. The stirring speed is 50 to 150 rpm, for example, 50 rpm, 100 rpm or 150 rpm, but it is not limited to the listed values. Other unlisted values ​​within this range are also applicable.

[0083] 5) Filling: Filling is performed using common filling equipment and methods in the field, such as piston filling machines, screw filling machines, volumetric filling machines, gravity filling machines, vacuum filling machines, etc. Common filling equipment in the field is also applicable.

[0084] In the preparation of mupirocin ointment, the inventors discovered that employing a stepped cooling method to precisely control the entire cooling process, gradually reducing the temperature and setting different temperatures and processing conditions at different stages, not only facilitates thorough mixing of the active ingredient (mupirocin) with other components but also promotes the formation of a more uniform dispersion system. This treatment method significantly improves the stability of the ointment and imparts good flowability and ease of application. Furthermore, precise temperature control also has a significant impact on the ointment's penetration properties.

[0085] More importantly, in the preparation of mupirocin ointment, the combination of a reasonable step-cooling technique with appropriate homogenization and stirring is key to effectively controlling the product's rheological properties and in vitro absorption within a suitable temperature range. Homogenization and stirring play a crucial role in achieving uniform mixing and dispersion of the various components. As the temperature gradually decreases, continuous homogenization and stirring help maintain the ointment's homogeneity, preventing layering or clumping. This series of carefully designed steps works together to form a stable emulsion structure, optimizing the product's rheological properties and making it easier to apply. Through a specific step-cooling strategy, combined with suitable homogenization and stirring conditions, the ointment can be ensured to possess excellent rheological properties, efficient in vitro absorption, and long-term stability.

[0086] The specific embodiments and comparative examples of the present invention are listed below, but the present invention is not limited to the following examples.

[0087] The instruments used in the examples and comparative examples are shown in Table 1:

[0088] Table 1

[0089] name model factory Fluke Mixed Set Reaction Fisco-1S Shanghai Fluke Technology Development Co., Ltd.

[0090] Example 1

[0091] The prescription composition is shown in Table 2:

[0092] Table 2. Composition of Mupirocin Prescription

[0093]

[0094] Preparation method:

[0095] 1) Excipient processing: Heat and stir the prescribed amounts of polyethylene glycol 400 and polyethylene glycol 3350 in a 60°C water bath at a stirring speed of 100 rpm until they are completely melted.

[0096] 2) Raw material processing: Under 60°C water bath conditions, the prescribed amount of mupirocin was added to the mixture of polyethylene glycol 400 and polyethylene glycol 3350 obtained in step 1) and completely dissolved.

[0097] 3) Cooling: Activate vacuum (-0.08 MPa) and use a water bath for stepped cooling, including the following stages:

[0098] A. Turn on the cooling and gradually cool the mixture obtained in step 2) to 50°C under a 45°C water bath for 6 min 29 s. Turn off the cooling and homogenize for 1 min at a speed of 10000 rpm. Then stir for 10 min at a speed of 100 rpm.

[0099] B. After stage A is completed, turn on the cooling and gradually cool the mixture to 44°C in a 39°C water bath for 17 min 21 s. Turn off the cooling, homogenize for 1 min at a homogenization speed of 10000 rpm, and then stir for 10 min at a stirring speed of 100 rpm.

[0100] C. After stage B is completed, turn on the cooling and gradually cool the mixture to 41°C in a 35°C water bath for 22 min 50 s. Turn off the cooling, homogenize for 1 min at a homogenization speed of 10000 rpm, and then stir for 10 min at a stirring speed of 100 rpm.

[0101] D. After process C is completed, cool in a 35°C water bath for 30 minutes, and then end the cooling process.

[0102] 4) Heat preservation: After step 3), turn on the cooling and stir for 10 minutes at a stirring speed of 100 rpm in a 45℃ water bath to obtain the final product.

[0103] 5) Filling: Filled in 15g / tube.

[0104] Example 2

[0105] Adjust the water bath temperature and material temperature in step 3). The specific operation is as follows: the prescription composition, other process steps and conditions are the same as in Example 1.

[0106] 3) Cooling: Activate vacuum (-0.08 MPa) and use a water bath for stepped cooling, including the following stages:

[0107] A. Turn on the cooling and gradually cool the mixture obtained in step 2) to 49°C under a 43°C water bath for 6 min 29 s. Turn off the cooling and homogenize for 1 min at a speed of 10000 rpm. Then stir for 10 min at a speed of 100 rpm.

[0108] B. After stage A is completed, turn on the cooling and gradually cool the mixture to 43°C in a 37°C water bath for 17 min 21 s. Turn off the cooling, homogenize for 1 min at a speed of 10000 rpm, and then stir for 10 min at a speed of 100 rpm.

[0109] C. After stage B is completed, turn on the cooling and gradually cool the mixture to 40°C in a 33°C water bath for 22 min 50 s. Turn off the cooling, homogenize for 1 min at a speed of 10000 rpm, and then stir for 10 min at a speed of 100 rpm.

[0110] D. After process C is completed, cool in a 33°C water bath for 30 minutes, and then end the cooling process.

[0111] Example 3

[0112] Adjust the homogenization time and material temperature in step 3). The specific operation is as follows: the prescription composition, other process steps and conditions are the same as in Example 1.

[0113] 3) Cooling: Activate vacuum (-0.08 MPa) and use a water bath for stepped cooling, including the following stages:

[0114] A. Turn on the cooling and gradually cool the mixture obtained in step 2) to 51°C under a 45°C water bath for 6 min 11 s. Turn off the cooling and homogenize for 3 min at a speed of 10000 rpm. Then stir for 10 min at a speed of 100 rpm.

[0115] B. After stage A is completed, turn on the cooling and gradually cool the mixture to 45°C in a 39°C water bath for 13 min 20 s. Turn off the cooling and homogenize for 3 min at a speed of 10000 rpm. Then stir for 10 min at a speed of 100 rpm.

[0116] C. After stage B is completed, turn on the cooling and gradually cool the mixture to 42°C in a 35°C water bath for 8 min 20 s. Turn off the cooling and homogenize for 3 min at a speed of 10000 rpm. Then stir for 10 min at a speed of 100 rpm.

[0117] D. After process C is completed, cool in a 35°C water bath for 30 minutes, and then end the cooling process.

[0118] Example 4

[0119] Adjust the homogenization speed in step 3). The specific operation is as follows: the prescription composition, other process steps and conditions are the same as in Example 1.

[0120] 3) Cooling: Activate vacuum (-0.08 MPa) and use a water bath for stepped cooling, including the following stages:

[0121] A. Turn on the cooling and gradually cool the mixture obtained in step 2) to 50°C under a 45°C water bath for 6 min 29 s. Turn off the cooling and homogenize for 1 min at a speed of 12000 rpm. Then stir for 10 min at a speed of 100 rpm.

[0122] B. After stage A is completed, turn on the cooling and gradually cool the mixture to 44°C in a 39°C water bath for 17 min 21 s. Turn off the cooling, homogenize for 1 min at a homogenization speed of 12000 rpm, and then stir for 10 min at a stirring speed of 100 rpm.

[0123] C. After stage B is completed, turn on the cooling and gradually cool the mixture to 41°C in a 35°C water bath for 22 min 50 s. Turn off the cooling, homogenize for 1 min at a homogenization speed of 12000 rpm, and then stir for 10 min at a stirring speed of 100 rpm.

[0124] D. After process C is completed, cool in a 35°C water bath for 30 minutes, and then end the cooling process.

[0125] Comparative Example 1

[0126] The cooling method in step 3) is adjusted to staged cooling. The specific operation is as follows: the prescription composition, other process steps and conditions are the same as in Example 1.

[0127] 3) Cooling: Activate vacuum (-0.08 MPa) and use a water bath for stepped cooling, including the following stages:

[0128] A. Turn on the cooling and gradually cool the mixture obtained in step 2) to 50°C under a 25°C water bath for 2 min 20 s. Turn off the cooling and homogenize for 1 min at a speed of 10000 rpm. Then stir for 10 min at a speed of 100 rpm.

[0129] B. After stage A is completed, turn on the cooling and gradually cool the mixture to 44°C in a 25°C water bath for 1 minute. Turn off the cooling and homogenize for 1 minute at a speed of 10,000 rpm. Then stir for 10 minutes at a speed of 100 rpm.

[0130] C. After stage B is completed, turn on the cooling and gradually cool the mixture to 41°C in a 25°C water bath for 3 min 20 s. Turn off the cooling, homogenize for 1 min at a homogenization speed of 10000 rpm, and then stir for 10 min at a stirring speed of 100 rpm.

[0131] D. After process C is completed, cool in a 25°C water bath for 30 minutes, and then end the cooling process.

[0132] Comparative Example 2

[0133] The cooling method in step 3) is adjusted to full-speed cooling. The specific operation is as follows: the prescription composition, other process steps and conditions are the same as in Example 1.

[0134] 3) Cooling: Activate vacuum (-0.08 MPa) and use a water bath for stepped cooling, including the following stages:

[0135] A. Turn on the cooling and gradually cool the mixture obtained in step 2) to 50°C under a 25°C water bath for 1 min 30 s. Turn off the cooling and homogenize for 1 min at a homogenization speed of 10000 rpm.

[0136] B. After stage A is completed, turn on the cooling and gradually cool the mixture to 44°C in a 25°C water bath for 11 minutes. Turn off the cooling and homogenize for 1 minute at a homogenization speed of 10,000 rpm.

[0137] C. After stage B is completed, turn on the cooling and gradually cool the mixture to 41°C in a 25°C water bath for 7 minutes. Then turn off the cooling and homogenize for 1 minute at a speed of 10,000 rpm.

[0138] D. After step C is completed, stir and cool for 30 minutes, then end the cooling process.

[0139] Comparative Example 3

[0140] Adjust the water bath temperature in stage C of step 3). The specific operation is as follows: the prescription composition, other process steps and conditions are the same as in Example 1.

[0141] 3) Cooling: Activate vacuum (-0.08 MPa) and use a water bath for stepped cooling, including the following stages:

[0142] A. Turn on the cooling and gradually cool the mixture obtained in step 2) to 50°C under a 45°C water bath for 6 min 11 s. Turn off the cooling and homogenize for 1 min at a speed of 10000 rpm. Then stir for 10 min at a speed of 100 rpm.

[0143] B. After stage A is completed, turn on the cooling and gradually cool the mixture to 44°C in a 39°C water bath for 13 min 20 s. Turn off the cooling, homogenize for 1 min at a homogenization speed of 10000 rpm, and then stir for 10 min at a stirring speed of 100 rpm.

[0144] C. After stage B is completed, turn on the cooling and gradually cool the mixture to 41°C in a 20°C water bath for 8 min 20 s. Turn off the cooling, homogenize for 1 min at a homogenization speed of 10000 rpm, and then stir for 10 min at a stirring speed of 100 rpm.

[0145] D. After process C is completed, cool in a 20°C water bath for 30 minutes, and then end the cooling process.

[0146] Comparative Example 4

[0147] Adjust the water bath temperature in stages B and C of step 3). The specific operation is as follows: the prescription composition, other process steps and conditions are the same as in Example 1.

[0148] 3) Cooling: Activate vacuum (-0.08 MPa) and use a water bath for stepped cooling, including the following stages:

[0149] A. Turn on the cooling and gradually cool the mixture obtained in step 2) to 50°C under a 45°C water bath for 6 min 30 s. Turn off the cooling and homogenize for 1 min at a speed of 10000 rpm. Then stir for 10 min at a speed of 100 rpm.

[0150] B. After stage A is completed, turn on the cooling and gradually cool the mixture to 44°C in a 30°C water bath for 7 min 20 s. Turn off the cooling, homogenize for 1 min at a homogenization speed of 10000 rpm, and then stir for 10 min at a stirring speed of 100 rpm.

[0151] C. After stage B is completed, turn on the cooling and gradually cool the mixture to 41°C in a 20°C water bath for 6 min 10 s. Turn off the cooling, homogenize for 1 min at a speed of 10000 rpm, and then stir for 10 min at a speed of 100 rpm.

[0152] D. After process C is completed, cool in a 20°C water bath for 30 minutes, and then end the cooling process.

[0153] Comparative Example 5

[0154] Adjust the water bath temperature in the three stages of step 3). The specific operation is as follows: the prescription composition, other process steps and conditions are the same as in Example 1.

[0155] 3) Cooling: Activate vacuum (-0.08 MPa) and use a water bath for stepped cooling, including the following stages:

[0156] A. Turn on the cooling and gradually cool the mixture obtained in step 2) to 50°C under a 35°C water bath for 4 min 30 s. Turn off the cooling and homogenize for 1 min at a speed of 10000 rpm. Then stir for 10 min at a speed of 100 rpm.

[0157] B. After stage A is completed, turn on the cooling and gradually cool the mixture to 44°C in a 30°C water bath for 5 min 15 s. Turn off the cooling, homogenize for 1 min at a homogenization speed of 10000 rpm, and then stir for 10 min at a stirring speed of 100 rpm.

[0158] C. After stage B is completed, turn on the cooling and gradually cool the mixture to 41°C in a 20°C water bath for 6 min 20 s. Turn off the cooling, homogenize for 1 min at a homogenization speed of 10000 rpm, and then stir for 10 min at a stirring speed of 100 rpm.

[0159] D. After process C is completed, cool in a 20°C water bath for 30 minutes, and then end the cooling process.

[0160] Comparative Example 6

[0161] Adjust the homogenization time in step 3). The specific operation is as follows: the prescription composition, other process steps and conditions are the same as in Example 1.

[0162] 3) Cooling: Activate vacuum (-0.08 MPa) and use a water bath for stepped cooling, including the following stages:

[0163] A. Turn on the cooling and gradually cool the mixture obtained in step 2) to 50°C under a 45°C water bath for 5 min 40 s. Turn off the cooling and homogenize for 5 min at a speed of 10000 rpm. Then stir for 10 min at a speed of 100 rpm.

[0164] B. After stage A is completed, turn on the cooling and gradually cool the mixture to 44°C in a 39°C water bath for 14 minutes. Turn off the cooling and homogenize for 5 minutes at a speed of 10,000 rpm. Then stir for 10 minutes at a speed of 100 rpm.

[0165] C. After stage B is completed, turn on the cooling and gradually cool the mixture to 41°C in a 35°C water bath for 9 min 40 s. Turn off the cooling and homogenize for 5 min at a speed of 10000 rpm. Then stir for 10 min at a speed of 100 rpm.

[0166] D. After process C is completed, cool in a 35°C water bath for 30 minutes, and then end the cooling process.

[0167] Comparative Example 7

[0168] Adjust the homogenization speed in step 3). The specific operation is as follows: the prescription composition, other process steps and conditions are the same as in Example 1.

[0169] 3) Cooling: Activate vacuum (-0.08 MPa) and use a water bath for stepped cooling, including the following stages:

[0170] A. Turn on the cooling and gradually cool the mixture obtained in step 2) to 50°C under a 45°C water bath for 6 min 29 s. Turn off the cooling and homogenize for 1 min at a homogenization speed of 8000 rpm. Then stir for 10 min at a stirring speed of 100 rpm.

[0171] B. After stage A is completed, turn on the cooling and gradually cool the mixture to 44°C in a 39°C water bath for 17 min 21 s. Turn off the cooling, homogenize for 1 min at a homogenization speed of 8000 rpm, and then stir for 10 min at a stirring speed of 100 rpm.

[0172] C. After stage B is completed, turn on the cooling and gradually cool the mixture to 41°C in a 35°C water bath for 22 min 50 s. Turn off the cooling, homogenize for 1 min at a homogenization speed of 8000 rpm, and then stir for 10 min at a stirring speed of 100 rpm.

[0173] D. After process C is completed, cool in a 35°C water bath for 30 minutes, and then end the cooling process.

[0174] Comparative Example 8

[0175] Adjust the homogenization speed in step 3). The specific operation is as follows: the prescription composition, other process steps and conditions are the same as in Example 1.

[0176] 3) Cooling: Activate vacuum (-0.08 MPa) and use a water bath for stepped cooling, including the following stages:

[0177] A. Turn on the cooling and gradually cool the mixture obtained in step 2) to 50°C under a 45°C water bath for 6 min 41 s. Turn off the cooling and homogenize for 1 min at a speed of 13000 rpm. Then stir for 10 min at a speed of 100 rpm.

[0178] B. After stage A is completed, turn on the cooling and gradually cool the mixture to 44°C in a 39°C water bath for 36 min 30 s. Turn off the cooling, homogenize for 1 min at a homogenization speed of 13000 rpm, and then stir for 10 min at a stirring speed of 100 rpm.

[0179] C. After stage B is completed, turn on the cooling and gradually cool the mixture to 41°C in a 35°C water bath for 7 min 40 s. Turn off the cooling, homogenize for 1 min at a homogenization speed of 13000 rpm, and then stir for 10 min at a stirring speed of 100 rpm.

[0180] D. After process C is completed, cool in a 35°C water bath for 30 minutes, and then end the cooling process.

[0181] The products obtained in Examples 1-4, Comparative Examples 1-8, and commercially available products were measured. (Certified Trader: Beecham) The flow profile, thixotropy, viscosity, and transdermal absorption of Groupplc (batch number: UJ4L).

[0182] Flow curve measurement parameters :

[0183] Detection mode Logarithmic shear rate scan Test rotor PP25 / S Test temperature 25℃ Insulation time 1min Sample gap 0.5mm Pre-shear rate <![CDATA[0.1S -1 ]]> Pre-shearing time 60S Shear rate <![CDATA[0.1-200S -1 ]]> Data start value and end value 10-1S Data points 21 Data processing model Herschel-Bulkley

[0184] Thixometry measurement parameters:

[0185] Test rotor PP25 / S Test temperature 32℃ Insulation time 1min Sample gap 0.5mm Data processing model Three-stage thixotropic test (3ITT) Settling stage <![CDATA[30 data points, 4 s / point, shear strain: 0.02%, angular frequency 15 S -1 > Shearing phase <![CDATA[30 data points, 4 s / point, shear rate: 100 S -1 > Recovery phase <![CDATA[30 data points, 3 s / point, shear strain: 0.02%, angular frequency 15 S -1 >

[0186] The results of the rheological property test are shown in Table 3. :

[0187] Table 3

[0188]

[0189]

[0190] Methods for measuring viscosity:

[0191] Take this product and determine its viscosity according to the viscosity determination method (Chinese Pharmacopoeia 2020 Edition, Part IV, General Chapter 0633, Method III). Use a DVNext RV or DV2TRVTJ0 viscometer. The specific parameters are shown in the table below. The measured viscosity should be 800,000 to 1,800,000 mPa·s.

[0192]

[0193] The rheological properties of the paste were tested using an MCR-92 rheometer. Using the same instrument and PP25 / S rotor under the same testing conditions, the products obtained from Examples 1-4 and Comparative Examples 1-8 were compared with commercially available products. The viscosity.

[0194] The viscosity test results are shown in Table 4:

[0195] Table 4

[0196]

[0197]

[0198] Appendix Figures 1-13 The figures show the rheological curves of mupirocin ointment and Bactroban from Examples 1-4 and Comparative Examples 1-8, measured using an Anton Paar rheometer and represented by the Herschel-Bulkley model (a mathematical model commonly used to describe the rheological behavior of non-Newtonian fluids). The fluid shear stress in the figures is proportional to the shear rate; that is, as the shear rate increases, the shear stress also increases accordingly. The viscosity of the fluid gradually decreases with increasing shear rate (from left to right). The meanings of each parameter are as follows:

[0199] Consistency index: b, also known as the consistency coefficient. The b value is a measure of viscosity, but it is not equal to the viscosity value. The higher the viscosity, the higher the b value.

[0200] Power-law exponent: p is the flow behavior exponent or non-Newtonian exponent, which is a temperature-related parameter. The greater the deviation of p from 1, the stronger the non-Newtonian property of the material. When p>1, it is a generalized Bingham fluid that is shear-thickened; when p<1, it is a generalized Bingham fluid that is shear-thinned; when p=1, it is an ideal Bingham fluid.

[0201] The yield stress τ0 is the stress that causes flow to occur only when the external force exceeds this stress.

[0202] Comparative Examples 2 and 5, with p>1, exhibit shear-thickening rheological behavior, which is significantly different from the rheological behavior of the Bactroban formulation. Under the same shear-thinning fluid condition, the higher the viscosity of the formulation, the higher the b-value, and the greater the required yield stress.

[0203] Appendix Figures 14-26 This section describes the three-stage thixotropic testing of mupirocin ointment and Bactroban in Examples 1-4 and Comparative Examples 1-8. The three-stage thixotropic test involves observing the destruction of the internal structure of a sample at a constant shear rate, using dynamic oscillation testing or a time-based method. After waiting for different time periods, the reconstruction of the sample structure is observed and determined; this is represented by a time-curve mode and a three-stage measurement mode (dynamic oscillation + steady-state shear + dynamic oscillation). More simply, it can be described as examining the viscosity change of a material at different shear rates using a "low-high-low" three-stage constant shear rate. In the three-stage thixotropic experiment, the sample structure is not destroyed at the beginning at low shear, the initial structure is destroyed at the subsequent high shear, and the sample structure is restored at the final low shear. Under the same measurement conditions, the degree of recovery varies among different formulations.

[0204] According to Table 3 and appendix Figures 1-13 The rheological data of Mupirocin ointment and Bactroban from Examples 1-4 and Comparative Examples 1-8 show that Examples 1-4 and Bactroban exhibit similarities in yield stress, b-value, p-value, and viscosity. (See Table 3 and Appendix...) Figures 14-26 The thixotropic curves show that the 60S recovery rate of mupirocin ointment in Examples 1-4 remains above 60%, which is close to that of Bactroban. Based on the combined rheological and thixotropic results, the mupirocin ointment obtained in Examples 1-4 has good application properties and can be evenly applied to the skin.

[0205] In contrast, the mupirocin ointments obtained in Comparative Examples 1, 2, and 4–8 showed significant differences from Bactroban in terms of yield stress, b-value, p-value, and viscosity. Comparative Examples 1–6 and Example 8 also exhibited lower 60S recovery rates. Therefore, overall, the mupirocin ointments obtained in Comparative Examples 1–8 differed significantly from Bactroban in their rheological properties, indicating poor flowability and elasticity, which fails to meet the pharmacopoeia's requirements for ointments to have appropriate viscosity and be easily applied to skin or mucous membranes.

[0206] To further evaluate the flow properties of the mupirocin ointments in the examples and comparative examples, the inventors measured the viscosity at 60 seconds. As can be seen from the data in Table 4, the 60-second viscosity of the mupirocin ointments in Examples 1-4 was similar to that of Bactroban, indicating good flowability and stability. However, the 60-second viscosity of the mupirocin ointments in Comparative Examples 1-8 was significantly higher than that of (Comparative Examples 1-5 and Comparative Example 7) or lower than that of (Comparative Examples 6 and 8) Bactroban. Furthermore, the viscosity of Comparative Examples 1 and 2 exceeded the limit of 800,000-1,800,000 mPa·s, indicating poor flowability and stability.

[0207] In vitro transdermal test (IVPT)

[0208] To investigate the skin permeability of the mupirocin ointments obtained in Examples 1-4 and Comparative Examples 1-8 above, a transdermal test was conducted, as follows:

[0209] Test conditions

[0210] Temperature and humidity: The temperature in the laboratory is controlled at 25℃±2℃ and the relative humidity at 50%±10% to simulate the normal environment of human skin.

[0211] Lighting conditions: Avoid direct sunlight and keep the light in the experimental area soft to prevent the light from affecting the experimental results.

[0212] Equipment and Instruments: A vertical Franz diffusion cell was used as the transdermal testing device, equipped with a high-performance liquid chromatograph (HPLC) for analysis.

[0213] Skin selection, source and treatment

[0214] Selection: Pigskin was chosen as the ex vivo skin model.

[0215] Cleaning: Clean the pigskin sample with physiological saline or sterile water for injection to remove surface grease, dirt and hair.

[0216] Cutting: Cut the pigskin into circles to fit the size of the Franz diffusion cell.

[0217] Fixation: Fix the cut pigskin between the administration chamber and the receiving chamber of the Franz diffusion cell, ensuring that the cuticle faces the administration chamber.

[0218] The process of isolated pig skin permeability test

[0219]

[0220] Drug concentration determination:

[0221] (1) The calculation process of the cumulative permeation of drug per unit area (Q) is as follows:

[0222]

[0223] (Cn represents the drug concentration measured at the nth sampling point, V is the volume of the receiving cell, and A is the drug delivery area)

[0224] (2) Absorption rate (J): J=(Q-Q0) / (h-h0)

[0225] (Q is the cumulative permeability per unit area at the sampling time point (μg·cm)) -2 Q0 represents the cumulative permeability per unit area at the previous sampling time point (μg·cm³). -2 (h represents the sampling time point, and h0 represents the previous sampling time point)

[0226] (3) Intradermal retention: Intradermal retention = Detection concentration of drug in skin homogenate × Homogenate dilution volume

[0227] (4) Drug residue: Drug residue = Detected drug concentration in residue × Pretreatment dilution volume

[0228] (5) Permeability: Cumulative permeability percentage % = Cumulative permeability / Dosage administered × 100%

[0229] (6) Absorption percentage: Absorption percentage % = Intradermal retention volume / Administered volume × 100%

[0230] (7) Residual percentage: Residual percentage % = Drug residue amount / Dosage administered × 100%

[0231] (8) Overall recovery rate: Overall recovery rate % = Permeation rate % + Absorption rate % + Residual rate %

[0232] (9) 90% confidence interval: (X-CONFIDENCE(0.1,S,n)—X+CONFIDENCE(0.1,S,n))

[0233] Note: x is the mean, 0.1 is the significance level coefficient for the 90% confidence interval, S is the standard deviation, and n is the sample size. The Excel function CONFIDENCE(0.1,S,n) is used.

[0234] Acceptable standards:

[0235] To facilitate a clear presentation of the experimental results, permeation curves were plotted based on the cumulative permeation per unit area (Q) versus the corresponding time. The maximum absorption rate (Jmax (μg / cm³)) for each test formulation and reference formulation was calculated. 2 / h))T / R and the total amount of infiltration per unit area at the end of the experiment (Atotal (μg / cm) 2 The 90% confidence intervals for the T / R, Jmax, and Atotal ratios should all be between 80.00% and 125.00%.

[0236] The results of Examples 1-4 and Comparative Examples 1-8 are shown in Table 5:

[0237] Table 5

[0238]

[0239] This invention statistically analyzed the 90% confidence intervals of the ratio of the maximum absorption rate (Jmax) of the examples and comparative examples to that of Bactroban, as well as the 90% confidence interval of the ratio of the total amount of permeation per unit area (Atotal) at the end of the experiment. As shown in Table 5, the 90% confidence intervals of the maximum absorption rate (Jmax) and the total amount of permeation per unit area (Atotal) for Examples 1-4 and Comparative Examples 1-8 are all between 80.00% and 125.00%, indicating that these mupirocin ointments exhibit consistent in vitro release behavior with Bactroban.

[0240] However, for topical medications, skin penetration and absorption directly affect the safety and efficacy of the drug. Cumulative permeation (permeation percentage) refers to the cumulative amount of drug that has passed through the skin. For topical preparations, excessive transdermal absorption can easily cause systemic adverse reactions. On the other hand, retention (absorption percentage) is the amount of drug remaining in the skin. A higher intradermal retention indicates better drug efficacy, but excessive retention may also lead to other adverse reactions. Therefore, an ideal ointment should have a retention rate comparable to that of a commercially available reference formulation.

[0241] As shown in Table 5, the cumulative permeation and retention levels of Examples 1-4 are close to those of Bactroban, indicating that the resulting mupirocin ointment has good efficacy and safety. In contrast, the transdermal absorption of the mupirocin ointment obtained in the comparative examples is unstable. For example, the retention levels of Comparative Examples 1, 2, 4, 5, and 6 are lower than those of Bactroban, indicating poorer drug efficacy. Comparative Examples 3, 7, and 8 have excessively high retention levels compared to Bactroban, which may pose a risk of other adverse reactions. The excessively high cumulative permeation level of Comparative Example 5 may cause safety issues.

[0242] In summary, a reasonable process can ensure that the transdermal absorption and retention of mupirocin ointment are within the ideal range, guaranteeing the drug's effectiveness while avoiding adverse reactions caused by excessive transdermal absorption or retention. The preparation methods in Examples 1-4 successfully achieved this balance, providing a reliable treatment plan for clinical application.

[0243] The mupirocin ointment prepared by the technical solution of the present invention not only has good rheological properties, improving the user experience, but also has excellent absorption properties, ensuring the efficacy and safety of the drug.

[0244] The ointment's excellent rheological properties make it easy to apply and prevent it from dripping, improving patient comfort. Its superior absorption properties ensure that the medication can penetrate the skin appropriately to achieve the best therapeutic effect while avoiding unnecessary side effects.

[0245] In summary, this invention enhances the user experience while ensuring the efficacy and safety of the drug.

[0246] The embodiments of this application have been described above with reference to the accompanying drawings. However, this application is not limited to the specific embodiments described above. The specific embodiments described above are merely illustrative and not restrictive. Those skilled in the art can make many other forms under the guidance of this application without departing from the spirit and scope of the claims, and all of these forms are within the protection scope of this application.

Claims

1. A method of preparing an antiseptic ointment, characterized by, The method comprises the following steps: 1) excipient treatment: heat the prescribed amount of excipient in a water bath at 55-65℃, and stir until completely melted; 2) raw material treatment: add the raw material to the mixture obtained in step 1) under the condition of a water bath at 55-65℃, and dissolve completely to obtain a raw material and excipient mixture; 3) cooling: under vacuum, adopt step cooling by water bath; 4) incubation: after the end of step 3), continue water bath incubation to obtain the final product; 5) filling; The step 3) cooling comprises the following stages: A. gradually cool the raw material and excipient mixture to 45-52℃ under the condition of a water bath at 40-50℃, and then perform homogenization treatment; B. after the end of stage A, gradually cool the raw material and excipient mixture to 40-46℃ under the condition of a water bath at 35-42℃, and then perform homogenization treatment; C. after the end of stage B, gradually cool the raw material and excipient mixture to 35-45℃ under the condition of a water bath at 25-42℃, and then perform homogenization treatment; D. after the end of stage C, cool for 20-40 min under the condition of a water bath at 25-42℃, and end the cooling; The raw material is mupirocin, and the excipient is polyethylene glycol 400 and polyethylene glycol 3350.

2. The method of preparing an antiseptic ointment according to claim 1, characterized in that, The homogenization treatment in step 3) is performed under the following conditions: homogenization time is 1-3 min, and homogenization speed is 10,000-12,000 rpm.

3. The method of making an antiseptic ointment according to claim 2, wherein, The temperature decreasing time in stage A is 5-10 min, the temperature decreasing time in stage B is 10-40 min, and the temperature decreasing time in stage C is 5-30 min.

4. The method for preparing the antibacterial ointment according to claim 3, characterized in that, After the homogenization treatment in step 3), perform stirring treatment, the stirring time is 5-15 min, and the stirring speed is 50-150 rpm.

5. The method of claim 4, wherein the antimicrobial ointment is prepared by mixing the antimicrobial agent and the base in a ratio of 1 : 10 to 10:

1. 5 The water bath temperature in the incubation in step 4) is 40-50℃.

6. The method of claim 5, wherein the antimicrobial ointment is prepared by, The stirring treatment is performed simultaneously with the incubation in step 4), the stirring time is 5-15 min, and the stirring speed is 50-150 rpm.

7. The method of claim 6, wherein the antimicrobial ointment is prepared by, The stirring speed in the excipient treatment in step 1) is 50-150 rpm.

8. The method of claim 1-7, wherein the method further comprises, The composition of the antibacterial ointment comprises: mupirocin 1.0-5.0% w / w and excipient 95.0-99.0% w / w, the excipient is polyethylene glycol 400 50.0-65.0% w / w and polyethylene glycol 3350 30.0-49.0% w / w.

9. The antibacterial ointment prepared by the method in any one of claims 1-8, wherein the antibacterial ointment is a mupirocin ointment.

Images