Preparation method of antibacterial ointment

Abstract

The invention discloses a preparation method of an antibacterial ointment. The preparation method comprises the following steps: 1) auxiliary material treatment: heating a prescription amount of auxiliary materials under a 55-65 DEG C water bath condition, and stirring until the auxiliary materials are completely molten; 2) raw material treatment: under a 55-65 DEG C water bath condition, adding the raw materials into the mixture obtained in the step 1), and completely dissolving to obtain a raw and auxiliary material mixture; 3) cooling: under a vacuum condition, adopting water bath stepped cooling; 4) heat preservation: after the step 3) is finished, continuing water bath heat preservation to obtain a final product; (5) filling; the antibacterial ointment prepared by the invention has rheological properties and a good absorption effect.

Description

Technical Field

[0001] The present application belongs to the technical field of pharmaceutical preparations, and in particular relates to a method for preparing an antibacterial ointment. Background Art

[0002] Mupirocin is chemically named 9-{4-[5-(2,3-epoxy-5-hydroxy-4-methylhexyl)-3,4-dihydroxytetrahydropyran-2-yl]-3-methylbut-2-enoyloxy, with a CAS number of 12650-69-0. It is a new antibiotic produced by fermentation of Pseudomonas fluorescens. Mupirocin inhibits isoleucyl transfer RNA synthetase, thereby preventing bacterial protein synthesis. Mupirocin has antibacterial properties at the minimum inhibitory concentration and has bactericidal properties when it reaches higher concentrations when applied topically. The chemical structure is as follows:

[0003]

[0004] Mupirocin Ointment was developed by GlaxoSmithKline under the trade name Bactroban. It is a topical antimicrobial agent that is active against organisms that cause most 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 furunculosis.

[0005] Patent CN110787128A discloses a mupirocin ointment and a preparation method thereof. The stability of mupirocin is increased by adding vitamin E, and the problem of the thin ointment base being thin when the temperature is high in summer is improved by adjusting the ratio of polyethylene glycol 3350, polyethylene glycol 400 and propylene glycol and reducing the proportion of polyethylene glycol 400. The problem of the ointment base being very hard when the temperature is low in winter is improved by adding an appropriate amount of propylene glycol in combination with polyethylene glycol 3350 and polyethylene glycol 400.

[0006] Patent CN110772479A discloses a mupirocin ointment and a preparation method thereof, in which polyethylene glycol-4000 is substituted for polyethylene glycol-3350, so that the mupirocin ointment has a low impurity content and a release rate better than the products on the market.

[0007] Patent CN105412000A discloses a method for preparing mupirocin ointment. By opening a high-speed emulsifying head and maintaining a high-speed shear state until the material is cooled to 38°C, polyethylene glycol 3500 can be prevented from quickly agglomerating and precipitating, ensuring that 95% of the material particle size is less than 50um, ensuring that the material is fine, and avoiding the problem of uncontrollable filling volume during the filling process caused by rough material and excessive consistency. The final product of the material has qualified properties.

[0008] Patent CN102335122A A mupirocin ointment and its preparation method Since the mupirocin ointment provided contains an organic acid as a stabilizer, compared with the existing mupirocin ointment, it has high stability and low related substances, so it has 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] In order to solve 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°C and stir until completely melted;

[0012] 2) Raw material processing: adding the raw materials to the mixture obtained in step 1) under a water bath condition of 55-65° C. and dissolving them completely to obtain a mixture of raw materials and auxiliary materials;

[0013] 3) Cooling: Under vacuum conditions, use a water bath to cool down the temperature;

[0014] 4) Insulation: After step 3), continue to insulate in a water bath to obtain the final product;

[0015] 5) Filling.

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

[0017] A. gradually cooling the raw material mixture to 45-52° C. in a water bath at 40-50° C., and then homogenizing;

[0018] B. After the completion of stage A, the mixture of raw materials and auxiliary materials is gradually cooled to 40-46° C. in a water bath at 35-42° C., and then homogenized;

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

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

[0021] Furthermore, the homogenization conditions in step 3) are: homogenization time is 1 to 3 minutes, and homogenization speed is 10000 to 12000 rpm.

[0022] Furthermore, the cooling time of stage A is 5 to 10 minutes; the cooling time of stage B is 10 to 40 minutes; and the cooling time of stage C is 5 to 30 minutes.

[0023] Furthermore, the homogenization treatment in step 3) is followed by a stirring treatment, the stirring time being 5 to 15 minutes and the stirring speed being 50 to 150 rpm.

[0024] Furthermore, the water bath temperature in the step 4) is 40-50°C.

[0025] Furthermore, in step 4), the mixture is stirred while being kept warm, with a stirring time of 5 to 15 minutes and a stirring speed of 50 to 150 rpm.

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

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

[0028] In another aspect, the present invention provides an antibacterial ointment prepared according to the above method, wherein the antibacterial ointment is preferably mupirocin ointment.

[0029] Compared with the prior art, 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, and its shear thinning properties are obvious, and the ointment can quickly return to its original state after shearing. This good thixotropic property not only improves the comfort during use, but also greatly optimizes the user experience. Secondly, the viscosity range of mupirocin ointment is suitable, which not only ensures good spreadability, but also avoids the problem of difficulty in spreading due to excessive viscosity.

[0030] More importantly, the mupirocin ointment obtained by the present invention has a highly efficient transdermal absorption capacity, and the active ingredient mupirocin can quickly penetrate the skin surface layer and enter the deep layer of the skin to exert its effect. At the same time, the transdermal amount 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. In addition, the entire preparation process is simple and efficient, has strong operability, and is easy to produce and use. BRIEF DESCRIPTION OF THE DRAWINGS

[0031] Figure 1 This is the flow curve of Bactroban-viscosity and shear stress changing with shear rate.

[0032] Figure 2This is a flow curve diagram of Example 1 showing the change of viscosity and shear stress with shear rate.

[0033] Figure 3 This is a flow curve diagram of Example 2 showing the change of viscosity and shear stress with shear rate.

[0034] Figure 4 This is a flow curve diagram of Example 3 showing the change of viscosity and shear stress with shear rate.

[0035] Figure 5 This is a flow curve diagram of Example 4 showing the change of viscosity and shear stress with shear rate.

[0036] Figure 6 This is a flow curve diagram of comparative example 1 showing the change of viscosity and shear stress with shear rate.

[0037] Figure 7 This is a flow curve diagram of comparative example 2 showing the change of viscosity and shear stress with shear rate.

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

[0039] Fig. 9 This is a flow curve diagram of comparative example 4 showing the change of viscosity and shear stress with shear rate.

[0040] Fig.10 This is a flow curve diagram of comparative example 5 showing the change of viscosity and shear stress with shear rate.

[0041] Fig.11 This is a flow curve diagram of comparative example 6 showing the change of viscosity and shear stress with shear rate.

[0042] Fig.12 This is a flow curve diagram of comparative example 7 showing the change of viscosity and shear stress with shear rate.

[0043] Fig.13 This is a flow curve diagram of Comparative Example 8 showing the change of viscosity and shear stress with shear rate.

[0044] Fig.14 This is the Bactroban viscosity change curve over time (thixotropic properties).

[0045] Fig.15 This is a graph of Example 1 - viscosity change over time (thixotropic properties).

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

[0047] Fig.17 This is Example 3 - Viscosity change over time (thixotropic properties).

[0048] Fig.18 This is a graph of Example 4 - viscosity change over time (thixotropic properties).

[0049] Fig.19 This is a graph showing the viscosity change over time for comparative example 1 (thixotropic properties).

[0050] Fig. 20 This is a graph showing the viscosity change over time in Comparative Example 2 (thixotropic properties).

[0051] Fig.21 This is a graph showing the viscosity change over time in Comparative Example 3 (thixotropic properties).

[0052] Fig. 22 This is a graph showing the viscosity change over time of Comparative Example 4 (thixotropic properties).

[0053] Fig.23 This is a graph showing the viscosity change over time for Comparative Example 5 (thixotropic properties).

[0054] Fig.24 This is a graph showing the viscosity change over time of Comparative Example 6 (thixotropic properties).

[0055] Fig.25 This is a graph showing the viscosity change over time of Comparative Example 7 (thixotropic properties).

[0056] Fig.26 This is a graph showing the viscosity change over time of Comparative Example 8 (thixotropic properties). DETAILED DESCRIPTION

[0057] The following will be combined with the drawings in the embodiments of the present application to clearly describe the technical solutions in the embodiments of the present application. Obviously, the described embodiments are part of the embodiments of the present application, rather than all the embodiments. All other embodiments obtained by ordinary technicians in this field based on the embodiments in the present application belong to the scope of protection of this application.

[0058] The terms "first", "second", etc. in the specification and claims of the present application are used to distinguish similar objects, and are not used to describe a specific order or sequence. It should be understood that the data used in this way can be interchangeable under appropriate circumstances, so that the embodiments of the present application can be implemented in an order other than those illustrated or described here, and the objects distinguished by "first", "second", etc. are generally of one type, and the number of objects is not limited. For example, the first object can be one or more. In addition, "and / or" in the specification and claims represents at least one of the connected objects, and the character " / " generally indicates that the objects associated with each other are in an "or" relationship.

[0059] The inventors of the present application have found that by controlling the key processes in the preparation method of mupirocin ointment, the consistency of the performance of mupirocin ointment with commercial products can be significantly improved, especially in terms of rheological properties and in vitro absorption effects, which are consistent with the level of commercial products and better than commercial products. The whole process includes the following main steps:

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

[0061] In one embodiment of the present invention, the stirring speed is 50-150 rpm, such as 50 rpm, 100 rpm or 150 rpm, but is not limited to the listed values, and other values ​​not listed within the numerical range are also applicable. In one embodiment of the present invention, the auxiliary material is an aqueous matrix; in a specific embodiment of the present invention, the aqueous matrix is ​​polyethylene glycol 400 and polyethylene glycol 3350, and the amount is polyethylene glycol 40050.0-65.0% (w / w) and polyethylene glycol 335030.0-49.0% (w / w), preferably polyethylene glycol 40055.0-60.0% (w / w) and polyethylene glycol 335035.0-40.0% (w / w).

[0062] 2) Raw material processing: add the raw material to the mixture obtained in step 1) under a water bath condition of 55-65°C and dissolve completely to obtain a mixture of raw materials and auxiliary materials; 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, and other values ​​not listed within the numerical range are also applicable.

[0063] 3) Cooling: Under vacuum conditions, use a water bath to cool down the temperature;

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

[0065] A. gradually cooling the raw material mixture to 45-52° C. in a water bath at 40-50° C., and then homogenizing;

[0066] In one embodiment of the present invention, the water bath temperature in stage A is preferably 43-45°C, such as 43°C, 44°C or 45°C, but is not limited to the listed values, and other unlisted values ​​within the numerical range are also applicable.

[0067] In one embodiment of the present invention, the material temperature in stage A is preferably 49-51°C, such as 49°C, 50°C or 51°C, but is not limited to the listed values, and other unlisted values ​​within the numerical range are also applicable.

[0068] B. After the completion of stage A, the mixture of raw materials and auxiliary materials is gradually cooled to 40-46° C. in 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 37-39°C, such as 37°C, 38°C or 39°C, but is not limited to the listed values, and other unlisted values ​​within the numerical range are also applicable.

[0070] In one embodiment of the present invention, the material temperature in stage B is preferably 43-45°C, such as 43°C, 44°C or 45°C, but is not limited to the listed values, and other unlisted values ​​within the numerical range are also applicable.

[0071] C. After stage B is completed, the raw material and auxiliary material mixture is gradually cooled to 35-45° C. in 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 33-35°C, such as 33°C, 34°C or 35°C, but is not limited to the listed values, and other unlisted values ​​within the numerical range are also applicable.

[0073] In one embodiment of the present invention, the material temperature in stage C is preferably 40-42°C, such as 40°C, 41°C or 42°C, but is not limited to the listed values, and other unlisted values ​​within the numerical range are also applicable.

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

[0075] In one embodiment of the present invention, the water bath temperature in stage D is preferably 33-35°C, such as 33°C, 34°C or 35°C, but is not limited to the listed values, and other unlisted values ​​within the numerical range are also applicable.

[0076] In one embodiment of the present invention, the conditions for the homogenization treatment in step 3) are: the homogenization time is 1 to 3 minutes, for example, 1 minute, 2 minutes or 3 minutes, but is not limited to the listed values, and other values ​​not listed within the numerical range are also applicable; the homogenization speed is 10000 to 12000 rpm, for example, 10000 rpm, 11000 rpm or 12000 rpm, but is not limited to the listed values, and other values ​​not listed within the numerical range are also applicable.

[0077] Homogenization in the present invention refers to the process of refining and uniformly distributing particles in a mixture by physical forces (such as shear force, impact force and cavitation). The present invention does not limit the homogenization method, and a high-pressure pump, a colloid mill, an ultrasonic device or other special 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 min, for example, 5 min, 5.5 min, 6 min, 6.5 min, 7 min, 7.5 min, 8 min, 8.5 min, 9 min, 9.5 min or 10 min, but is not limited to the listed values, and other unlisted values ​​within the numerical range are equally applicable; the cooling time of stage B is 10 to 40 min, for example, 10 min, 15 min, 20 min, 25 min, 30 min, 35 min or 40 min, but is not limited to the listed values, and other unlisted values ​​within the numerical range are equally applicable; the cooling time of stage C is 5 to 30 min, for example, 5 min, 10 min, 15 min, 20 min, 25 min or 30 min, but is not limited to the listed values, and other unlisted values ​​within the numerical range are equally applicable.

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

[0080] 4) Insulation: After step 3), continue to insulate in a water bath to obtain the final product;

[0081] In one embodiment of the present invention, the water bath temperature in step 4) is 40-50°C, such as 40°C, 45°C or 50°C, but is not limited to the listed values, and other unlisted values ​​within the numerical range are also applicable.

[0082] In one embodiment of the present invention, in step 4), stirring is performed while keeping warm, and the stirring time is 5 to 15 minutes, for example, 5 minutes, 10 minutes or 15 minutes, but is not limited to the listed values, and other values ​​not listed within the numerical range are also applicable; the stirring speed is 50 to 150 rpm, for example, 50 rpm, 100 rpm or 150 rpm, but is not limited to the listed values, and other values ​​not listed within the numerical range are also applicable.

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

[0084] In the preparation process of mupirocin ointment, the inventors found that the whole cooling process was finely controlled by using a step-by-step cooling method, the temperature was gradually reduced, and the temperature and processing conditions at different stages were set, which not only facilitated the full mixing of the active ingredient (mupirocin) and other components, but also promoted the formation of a more uniform dispersion system. This treatment method significantly improved the stability of the ointment and gave it good fluidity and easy-to-apply properties. In addition, precise temperature control also has an important influence on the penetration performance of the ointment.

[0085] More importantly, in the preparation of mupirocin ointment, reasonable step cooling technology combined with appropriate homogenization and stirring treatment is the key to effectively regulate the product's rheological properties and in vitro absorption effect within an appropriate temperature range. Homogenization and stirring treatments play a vital role in achieving uniform mixing and dispersion of the various components. As the temperature gradually decreases, continuous homogenization and stirring operations help maintain the uniformity of the ointment and avoid stratification or agglomeration. This series of carefully designed operating steps work together to form a stable emulsion structure, optimize the product's rheological properties, and make it easier to apply. Through a specific step cooling strategy, combined with appropriate homogenization and stirring conditions, it can be ensured that the ointment has excellent rheological properties, efficient in vitro absorption effect and long-term stability.

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

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

[0088] Table 1

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

[0090] Example 1

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

[0092] Table 2 Mupirocin prescription composition

[0093]

[0094] Preparation method:

[0095] 1) Excipient treatment: Heat and stir the prescribed amount 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: Add the prescribed amount of mupirocin to the mixture of polyethylene glycol 400 and polyethylene glycol 3350 obtained in step 1) in a 60° C. water bath and dissolve completely.

[0097] 3) Cooling: Turn on the vacuum pump (-0.08mpa) and adopt a water bath step cooling method, including the following stages:

[0098] A. Turn on the cooling, gradually cool the mixture obtained in step 2) to 50°C in a 45°C water bath, the cooling time is 6min29s, turn off the cooling, homogenize for 1min, the homogenization speed is 10000rpm, and then stir for 10min, the stirring speed is 100rpm;

[0099] B. After stage A, turn on the cooling, 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 10,000 rpm, and then stir for 10 min at a stirring speed of 100 rpm;

[0100] C. After stage B, turn on the cooling, gradually cool the mixture to 41°C in a 35°C water bath for 22min50s, turn off the cooling, homogenize for 1min at a homogenization speed of 10000rpm, and then stir for 10min at a stirring speed of 100rpm;

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

[0102] 4) Insulation: After step 3), cooling was started, and stirring was performed for 10 min in a 45° C. water bath at a stirring speed of 100 rpm to obtain the final product.

[0103] 5) Filling: The filling amount is 15g / tube.

[0104] Example 2

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

[0106] 3) Cooling: Turn on the vacuum pump (-0.08mpa) and adopt a water bath step cooling method, including the following stages:

[0107] A. Turn on the cooling, gradually cool the mixture obtained in step 2) to 49°C in a 43°C water bath, the cooling time is 6min29s, turn off the cooling, homogenize for 1min, the homogenization speed is 10000rpm, and then stir for 10min, the stirring speed is 100rpm;

[0108] B. After stage A, turn on the cooling, gradually cool the mixture to 43°C in a 37°C water bath, the cooling time is 17min21s, turn off the cooling, homogenize for 1min, the homogenization speed is 10000rpm, and then stir for 10min, the stirring speed is 100rpm;

[0109] C. After stage B, turn on cooling, gradually cool the mixture to 40°C in a 33°C water bath for 22min50s, turn off cooling, homogenize for 1min at a homogenization speed of 10000rpm, and then stir for 10min at a stirring speed of 100rpm;

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

[0111] Example 3

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

[0113] 3) Cooling: Turn on the vacuum pump (-0.08mpa) and adopt a water bath step cooling method, including the following stages:

[0114] A. Turn on the cooling, gradually cool the mixture obtained in step 2) to 51°C in a 45°C water bath, the cooling time is 6min11s, turn off the cooling, homogenize for 3min, the homogenization speed is 10000rpm, and then stir for 10min, the stirring speed is 100rpm;

[0115] B. After stage A, turn on the cooling, gradually cool the mixture to 45°C in a 39°C water bath for 13min20s, turn off the cooling, homogenize for 3min at a homogenization speed of 10000rpm, and then stir for 10min at a stirring speed of 100rpm;

[0116] C. After stage B, turn on the cooling, gradually cool the mixture to 42°C in a 35°C water bath for 8min20s, turn off the cooling, homogenize for 3min at a homogenization speed of 10000rpm, and then stir for 10min at a stirring speed of 100rpm;

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

[0118] Example 4

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

[0120] 3) Cooling: Turn on the vacuum pump (-0.08mpa) and adopt a water bath step cooling method, including the following stages:

[0121] A. Turn on the cooling, gradually cool the mixture obtained in step 2) to 50°C in a 45°C water bath, the cooling time is 6min29s, turn off the cooling, homogenize for 1min, the homogenization speed is 12000rpm, and then stir for 10min, the stirring speed is 100rpm;

[0122] B. After stage A, turn on the cooling, gradually cool the mixture to 44°C in a 39°C water bath, the cooling time is 17min21s, turn off the cooling, homogenize for 1min, the homogenization speed is 12000rpm, and then stir for 10min, the stirring speed is 100rpm;

[0123] C. After stage B, turn on the cooling, gradually cool the mixture to 41°C in a 35°C water bath for 22min50s, turn off the cooling, homogenize for 1min at a homogenization speed of 12000rpm, and then stir for 10min at a stirring speed of 100rpm;

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

[0125] Comparative Example 1

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

[0127] 3) Cooling: Turn on the vacuum pump (-0.08mpa) and adopt a water bath step cooling method, including the following stages:

[0128] A. Turn on the cooling, gradually cool the mixture obtained in step 2) to 50°C in a 25°C water bath, the cooling time is 2min20s, turn off the cooling, homogenize for 1min, the homogenization speed is 10000rpm, and then stir for 10min, the stirring speed is 100rpm;

[0129] B. After stage A, turn on the cooling, gradually cool the mixture to 44°C in a 25°C water bath for 1 min, turn off the cooling, homogenize for 1 min at a homogenization speed of 10,000 rpm, and then stir for 10 min at a stirring speed of 100 rpm;

[0130] C. After stage B, turn on the cooling, gradually cool the mixture to 41°C in a 25°C water bath for 3min20s, turn off the cooling, homogenize for 1min at a homogenization speed of 10000rpm, and then stir for 10min at a stirring speed of 100rpm;

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

[0132] Comparative Example 2

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

[0134] 3) Cooling: Turn on the vacuum pump (-0.08mpa) and adopt a water bath step cooling method, including the following stages:

[0135] A. Turn on cooling, gradually cool the mixture obtained in step 2) to 50°C in a 25°C water bath, the cooling time is 1min30s, turn off cooling, homogenize for 1min, and the homogenization speed is 10000rpm;

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

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

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

[0139] Comparative Example 3

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

[0141] 3) Cooling: Turn on the vacuum pump (-0.08mpa) and adopt a water bath step cooling method, including the following stages:

[0142] A. Turn on the cooling, gradually cool the mixture obtained in step 2) to 50°C in a 45°C water bath, the cooling time is 6min11s, turn off the cooling, homogenize for 1min, the homogenization speed is 10000rpm, and then stir for 10min, the stirring speed is 100rpm;

[0143] B. After stage A, turn on the cooling, gradually cool the mixture to 44°C in a 39°C water bath for 13min20s, turn off the cooling, homogenize for 1min at a homogenization speed of 10000rpm, and then stir for 10min at a stirring speed of 100rpm;

[0144] C. After stage B, turn on the cooling, gradually cool the mixture to 41°C in a 20°C water bath, the cooling time is 8min20s, turn off the cooling, homogenize for 1min, the homogenization speed is 10000rpm, and then stir for 10min, the stirring speed is 100rpm;

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

[0146] Comparative Example 4

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

[0148] 3) Cooling: Turn on the vacuum pump (-0.08mpa) and adopt a water bath step cooling method, including the following stages:

[0149] A. Turn on the cooling, gradually cool the mixture obtained in step 2) to 50°C in a 45°C water bath, the cooling time is 6min30s, turn off the cooling, homogenize for 1min, the homogenization speed is 10000rpm, and then stir for 10min, the stirring speed is 100rpm;

[0150] B. After stage A, turn on the cooling, gradually cool the mixture to 44°C in a 30°C water bath for 7min20s, turn off the cooling, homogenize for 1min at a homogenization speed of 10000rpm, and then stir for 10min at a stirring speed of 100rpm;

[0151] C. After stage B, turn on the cooling, 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 homogenization speed of 10000 rpm, and then stir for 10 min at a stirring speed of 100 rpm;

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

[0153] Comparative Example 5

[0154] The water bath temperatures of the three stages in step 3) are adjusted as follows. The formulation composition, other process steps and conditions are the same as those in Example 1.

[0155] 3) Cooling: Turn on the vacuum pump (-0.08mpa) and adopt a water bath step cooling method, including the following stages:

[0156] A. Turn on the cooling, gradually cool the mixture obtained in step 2) to 50°C in a 35°C water bath, the cooling time is 4min30s, turn off the cooling, homogenize for 1min, the homogenization speed is 10000rpm, and then stir for 10min, the stirring speed is 100rpm;

[0157] B. After stage A, turn on the cooling, 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, turn on the cooling, 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 step C is completed, cool in a 20°C water bath for 30 minutes and then end cooling.

[0160] Comparative Example 6

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

[0162] 3) Cooling: Turn on the vacuum pump (-0.08mpa) and adopt a water bath step cooling method, including the following stages:

[0163] A. Turn on the cooling, gradually cool the mixture obtained in step 2) to 50°C in a 45°C water bath, the cooling time is 5min40s, turn off the cooling, homogenize for 5min, the homogenization speed is 10000rpm, and then stir for 10min, the stirring speed is 100rpm;

[0164] B. After stage A, turn on the cooling, gradually cool the mixture to 44°C in a 39°C water bath for 14 min, turn off the cooling, homogenize for 5 min at a homogenization speed of 10,000 rpm, and then stir for 10 min at a stirring speed of 100 rpm;

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

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

[0167] Comparative Example 7

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

[0169] 3) Cooling: Turn on the vacuum pump (-0.08mpa) and adopt a water bath step cooling method, including the following stages:

[0170] A. Turn on the cooling, gradually cool the mixture obtained in step 2) to 50°C in a 45°C water bath, the cooling time is 6min29s, turn off the cooling, homogenize for 1min, the homogenization speed is 8000rpm, and then stir for 10min, the stirring speed is 100rpm;

[0171] B. After stage A, turn on the cooling, 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, turn on the cooling, gradually cool the mixture to 41°C in a 35°C water bath for 22min50s, turn off the cooling, homogenize for 1min at a homogenization speed of 8000rpm, and then stir for 10min at a stirring speed of 100rpm;

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

[0174] Comparative Example 8

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

[0176] 3) Cooling: Turn on the vacuum pump (-0.08mpa) and adopt a water bath step cooling method, including the following stages:

[0177] A. Turn on the cooling, gradually cool the mixture obtained in step 2) to 50°C in a 45°C water bath, the cooling time is 6min41s, turn off the cooling, homogenize for 1min, the homogenization speed is 13000rpm, and then stir for 10min, the stirring speed is 100rpm;

[0178] B. After stage A, turn on the cooling, 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, turn on cooling, gradually cool the mixture to 41°C in a 35°C water bath for 7 min 40 s, turn off 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 step C is completed, cool in a 35°C water bath for 30 minutes and then end cooling.

[0181] Determination of the products obtained in Examples 1 to 4 and Comparative Examples 1 to 8 and the commercially available products (Certificate holder: Beecham Groupplc batch number: UJ4L) flow curve, thixotropy, viscosity and transdermal absorption.

[0182] Flow curve measurement parameters :

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

[0184] Thixotropic measurement parameters:

[0185] Test rotor PP25 / S Test temperature 32℃ Insulation time 1min Sample gap 0.5mm Data processing model Three-stage Thixotropy Test (3ITT) Static stage <![CDATA[30 data points, 4 s / point, shear strain: 0.02%, angular frequency 15 S -1 > Shearing stage <![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 rheological properties test results are shown in Table 3 :

[0187] Table 3

[0188]

[0189]

[0190] Viscosity determination method:

[0191] Take this product and measure it according to the viscosity measurement method (Method 3 of 0633 of Part IV of the Chinese Pharmacopoeia 2020 Edition), using a DVNext RV or DV2TRVTJ0 viscometer. The specific parameters are as 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. The same instrument and PP25 / S rotor were used under the same test conditions to compare the products obtained in Examples 1 to 4 and Comparative Examples 1 to 8 with the commercially available products. Viscosity.

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

[0195] Table 4

[0196]

[0197]

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

[0199] Consistency index: b is also called 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 index: p is the flow behavior index or non-Newtonian index, which is a temperature-related parameter. The greater the degree of p deviation from 1, the stronger the non-Newtonian property of the material. When p>1, it is a generalized Bingham fluid shear thickening; when p<1, it is a generalized Bingham fluid shear thinning; when p=1, it is an ideal Bingham fluid.

[0201] Yield stress τ0, flow occurs only when the external force exceeds this stress;

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

[0203] Attached Figures 14 to 26 This is the three-stage thixotropy test of mupirocin ointment and Bactroban of Examples 1 to 4 and Comparative Examples 1 to 8. The three-stage thixotropy test refers to observing the destruction of the internal structure of the sample at a constant shear rate, using a dynamic oscillation test or a time method to observe and determine the reconstruction of the sample structure after waiting for different times, that is, a time curve mode and a three-stage measurement mode (dynamic oscillation + steady-state shear + dynamic oscillation). A simpler description is the use of three-stage constant shear rates of "low-high-low" to examine the viscosity changes of the material at different shear rate stages. In the three-stage thixotropy experiment, the sample structure is not destroyed at the beginning of low shear, the subsequent high shear destroys the initial structure of the sample, and the sample structure is restored at the last low shear. Under the same measurement conditions, different preparations have different degrees of recovery.

[0204] According to Table 3 and Appendix Figures 1 to 13 The rheological curve data of the mupirocin ointment and Bactroban of Examples 1 to 4 and Comparative Examples 1 to 8 show that Examples 1 to 4 and Bactroban show similarities in yield stress, b value, p value and viscosity. Figures 14 to 26 The thixotropic curves show that the 60S recovery rate of the mupirocin ointment of Examples 1 to 4 is maintained above 60%, which is close to that of Bactroban. Combining the rheological and thixotropic results, it can be seen that the mupirocin ointment obtained in Examples 1 to 4 has good spreading properties and can be evenly applied to the skin.

[0205] In contrast, the mupirocin ointment obtained in Comparative Examples 1, 2, and 4 to 8 are quite different from Bactroban in yield stress, b value, p value, and viscosity, and the 60S recovery rate of Comparative Examples 1 to 6 and 8 is relatively low. Therefore, the mupirocin ointment obtained in Comparative Examples 1 to 8 is quite different from Bactroban in rheological properties, which indicates that the fluidity and elasticity of the ointment are poor, making it not meet the requirements of the pharmacopoeia that the ointment should have appropriate viscosity and be easy to apply to the skin or mucous membrane.

[0206] In order to further evaluate the flow state of the mupirocin ointment of each embodiment and comparative example, the inventors measured the viscosity at 60 seconds. It can be seen from the data in Table 4 that the viscosity at 60 seconds of the mupirocin ointment of Examples 1 to 4 is similar to that of Bactroban, showing good fluidity and stability, while the viscosity at 60 seconds of the mupirocin ointment of Comparative Examples 1 to 8 is significantly higher (Comparative Examples 1 to 5 and Comparative Example 7) or lower (Comparative Examples 6 and 8) than that of Bactroban, and the viscosity of Comparative Examples 1 and 2 exceeds the limit of 800000 to 1800000 mPa·s, indicating that their fluidity and stability are poor.

[0207] In vitro transdermal test (IVPT test)

[0208] In order to investigate the skin permeability of the mupirocin ointment obtained in Examples 1 to 4 and Comparative Examples 1 to 8, a transdermal test was performed as follows:

[0209] Test conditions

[0210] Temperature and humidity: The temperature in the laboratory is controlled at 25℃±2℃ and the relative humidity is controlled 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 influence of light on the experimental results.

[0212] Equipment and instruments: A vertical Franz diffusion cell was used as the transdermal test device, equipped with a high performance liquid chromatography (HPLC) analysis device.

[0213] Skin selection, source and treatment

[0214] Selection: Pig skin as an ex vivo skin model.

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

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

[0217] Fixation: Fix the cut pig skin between the dosing chamber and the receiving chamber of the Franz diffusion cell, making sure that the stratum corneum faces the dosing chamber.

[0218] Process of in vitro porcine skin permeation test

[0219]

[0220] Drug concentration determination:

[0221] (1) The calculation process of the cumulative drug permeation 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 pool, and A is the drug administration area)

[0224] (2) Absorption rate (J): J = (QQ 0 ) / (hh 0 )

[0225] (Q is the cumulative permeability per unit area at the sampling time point (μg·cm -2 ),Q 0 is the cumulative permeability per unit area at the previous sampling time point (μg·cm-2 ); h is the sampling time point, h 0 is 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 = detection concentration of drug in residue × pre-treatment dilution volume

[0228] (5) Permeation rate: Cumulative permeation rate = Cumulative permeation rate / dose × 100%

[0229] (6) Absorption percentage: Absorption percentage % = intradermal retention / dosage × 100%

[0230] (7) Residual percentage: Residual percentage % = drug residue / dose × 100%

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

[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 90% confidence interval significance level coefficient, S is the standard deviation, n is the sample size, and the Excel function CONFIDENCE(0.1,S,n) is used.

[0234] Acceptable criteria:

[0235] In order to present the test results intuitively, the permeation curve was drawn based on the cumulative permeation per unit area (Q) and the corresponding time. The maximum absorption rate (Jmax (μg / cm 2 / h))T / R and the total amount of permeation per unit area at the end of the experiment (Atotal (μg / cm 2 ))The 90% confidence intervals of the T / R, Jmax, and Atotal ratios should all be between 80.00% and 125.00%.

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

[0237] Table 5

[0238]

[0239] The present invention statistically calculates the 90% confidence interval of the ratio of the maximum absorption rate (Jmax) of the embodiments and comparative examples to Bactroban and the 90% confidence interval of the ratio of the total amount permeated per unit area (Atotal) at the end of the experiment. As can be seen from Table 5, the 90% confidence intervals of the maximum absorption rate (Jmax) and the total amount permeated per unit area (Atotal) of embodiments 1 to 4 and comparative examples 1 to 8 are all between 80.00% and 125.00%, indicating that these mupirocin ointments are consistent with the in vitro release behavior of Bactroban.

[0240] However, for topical drugs, the permeation and absorption of the skin directly affects the safety and efficacy evaluation of the drug. The cumulative permeation (percentage of permeation) refers to the cumulative amount of the ointment that permeates the skin. For topical preparations for skin, excessive percutaneous absorption is likely to cause systemic adverse reactions. On the other hand, the retention (percentage of absorption) is the amount of ointment retained in the skin. A higher intradermal retention indicates better drug effectiveness, but too high a retention may also lead to other adverse reactions. Therefore, an ideal ointment should have a retention equivalent to that of a commercially available reference preparation.

[0241] As can be seen from Table 5, the cumulative permeation and retention levels of Examples 1 to 4 are close to those of Bactroban, indicating that the mupirocin ointment obtained therefrom has good efficacy and safety. In contrast, the transdermal permeation and absorption effect of the mupirocin ointment obtained in the comparative examples is unstable, such as the retention amounts of Comparative Examples 1, 2, 4, 5 and 6 are lower than those of Bactroban, and their drug efficacy is poor, while the retention amounts of Comparative Examples 3, 7 and 8 are too high compared to Bactroban, and there may be risks of other adverse reactions; the cumulative permeation amount of Comparative Example 5 is too high, which may cause safety issues.

[0242] In summary, a reasonable process can ensure that the transdermal absorption and retention of mupirocin ointment are within an ideal range, which not only ensures the effectiveness of the drug, but also avoids adverse reactions caused by excessive transdermal absorption or excessive retention. The preparation methods of Examples 1 to 4 successfully achieve this balance and provide 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, which improves the user experience, but also has excellent absorption properties, ensuring the effectiveness and safety of the drug.

[0244] Good rheological properties make the ointment easy to apply and not easy to flow, which improves the patient's comfort. Excellent absorption properties ensure that the drug can properly penetrate the skin to achieve the best therapeutic effect while avoiding unnecessary side effects.

[0245] In short, the present invention improves the user experience while ensuring the effectiveness and safety of the drug.

[0246] The embodiments of the present application are described above in conjunction with the accompanying drawings, but the present application is not limited to the above-mentioned specific implementation methods. The above-mentioned specific implementation methods are merely illustrative and not restrictive. Under the guidance of the present application, ordinary technicians in this field can also make many forms without departing from the purpose of the present application and the scope of protection of the claims, all of which are within the protection of the present application.

Claims

1. A method for preparing an antibacterial ointment, characterized in that: The steps include: 1) Excipient processing: Heat the prescribed amount of excipients in a water bath at 55-65°C and stir until completely melted; 2) Raw material processing: adding the raw materials to the mixture obtained in step 1) under a water bath condition of 55-65° C. and dissolving them completely to obtain a mixture of raw materials and auxiliary materials; 3) Cooling: Under vacuum conditions, use a water bath to cool down the temperature; 4) Insulation: After step 3), continue to insulate in a water bath to obtain the final product; 5) Filling.

2. The method for preparing the antibacterial ointment according to claim 1, wherein The step 3) cooling comprises the following stages: A. gradually cooling the raw material mixture to 45-52° C. in a water bath at 40-50° C., and then homogenizing; B. After the completion of stage A, the mixture of raw materials and auxiliary materials is gradually cooled to 40-46° C. in a water bath at 35-42° C., and then homogenized; C. After stage B is completed, the raw material and auxiliary material mixture is gradually cooled to 35-45° C. in a water bath at 25-42° C., and then homogenized; D. After stage C is completed, cool in a water bath at 25-42°C for 20-40 minutes to end cooling.

3. The method for preparing the antibacterial ointment according to claim 2, characterized in that: The homogenization conditions in step 3) are: homogenization time is 1 to 3 minutes, and homogenization speed is 10000 to 12000 rpm.

4. The method for preparing the antibacterial ointment according to claim 3, characterized in that: The cooling time of the stage A is 5 to 10 minutes; the cooling time of the stage B is 10 to 40 minutes; and the cooling time of the stage C is 5 to 30 minutes.

5. The method for preparing the antibacterial ointment according to claim 4, characterized in that: The homogenization treatment in step 3) is followed by stirring, the stirring time is 5 to 15 minutes, and the stirring speed is 50 to 150 rpm.

6. The method for preparing the antibacterial ointment according to claim 5, characterized in that: The water bath temperature in the step 4) is 40-50°C.

7. The method for preparing the antibacterial ointment according to claim 6, characterized in that: In the step 4), the mixture is stirred while being kept warm, the stirring time is 5 to 15 minutes, and the stirring speed is 50 to 150 rpm.

8. The method for preparing the antibacterial ointment according to claim 7, characterized in that: The stirring speed of the auxiliary material treatment in step 1) is 50-150 rpm.

9. The method for preparing an antibacterial ointment according to claims 1 to 8, characterized in that: The mupirocin ointment comprises: 1.0-5.0% (w / w) of mupirocin and 95.0-99.0% (w / w) of auxiliary materials, wherein the auxiliary materials are 0.0-65.0% (w / w) of polyethylene glycol 400 and 30.0-49.0% (w / w) of polyethylene glycol 3350.

10. The antibacterial ointment prepared by the method according to any one of claims 1 to 9, wherein the antibacterial ointment is preferably mupirocin ointment.

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