External antibacterial pharmaceutical composition as well as preparation method and application thereof

Abstract

The invention discloses an external antibacterial medicine composition as well as a preparation method and application thereof, and belongs to the technical field of antibacterial medicines. The external antibacterial pharmaceutical composition provided by the invention comprises a medicinal active component and a pharmaceutically acceptable carrier, wherein the medicinal active component comprises polymyxin B sulfate, trimethoprim sulfate and lidocaine; every 10 g of the antibacterial pharmaceutical composition for external use is prepared from the following components in parts by weight: 40000 to 60000 U of polymyxin B sulfate, 0.08 to 0.16 g of trimethoprim sulfate and 0.30 to 0.35 g of lidocaine. The pharmaceutical composition disclosed by the invention has broad-spectrum inhibition on multiple drug-resistant bacteria such as common gram-negative drug-resistant bacteria and acinetobacter baumannii on a wound surface, synchronously plays a synergistic role in relieving inflammatory response of the wound surface and relieving local pain, and remarkably improves the medication safety and the comprehensive treatment effect while ensuring excellent antibacterial activity.

Description

Technical Field

[0001] This invention relates to the field of antibacterial drug technology, and in particular to a topical antibacterial drug composition, its preparation method, and its application. Background Technology

[0002] Skin wound infections are very common in clinical practice, and their treatment is becoming increasingly difficult due to the continuously rising detection rate of multidrug-resistant bacteria. Polymyxin B has a strong bactericidal effect against common Gram-negative drug-resistant bacteria in wounds, and its combination with trimethoprim shows a clear synergistic antibacterial effect, demonstrating potential for the development of topical antibacterial drugs. However, current formulations of this combination are mainly concentrated in eye drops or systemic administration, with insufficient development of topical semi-solid formulations for local skin application. Furthermore, its own antibacterial spectrum has limited activity against multidrug-resistant bacteria such as Acinetobacter baumannii, making it difficult to meet clinical needs.

[0003] To compensate for deficiencies in the antibacterial spectrum, existing topical preparations containing polymyxin B often combine multiple antibiotics (such as neomycin and bacitracin). However, this leads to complex formulations, increases the risk of bacterial resistance, and introduces safety hazards such as ototoxicity, nephrotoxicity, and sensitization. Furthermore, skin wound infections are often accompanied by significant inflammatory responses and pain. Existing combinations lack anti-inflammatory and local analgesic functions, and adding additional anti-inflammatory or analgesic ingredients further complicates formulation and increases the risk of irritation. Summary of the Invention

[0004] In view of this, the present invention provides a topical antibacterial drug composition, its preparation method and application, which avoids the complex formulation, increased risk of bacterial resistance, and safety hazards such as ototoxicity, nephrotoxicity and sensitization caused by the combined use of multiple antibiotics, and significantly improves the safety of medication while ensuring antibacterial activity.

[0005] In a first aspect, the present invention provides a topical antibacterial drug composition comprising a pharmaceutically active ingredient and a pharmaceutically acceptable carrier, wherein the pharmaceutically active ingredient comprises polymyxin B sulfate, trimethoprim sulfate, and lidocaine; and each 10g of the topical antibacterial drug composition contains 40,000-60,000U of polymyxin B sulfate, 0.08-0.16g of trimethoprim sulfate, and 0.30-0.35g of lidocaine.

[0006] Preferably, each 10g of the topical antibacterial drug composition contains 48,000-52,000U of polymyxin B sulfate, 0.10-0.14g of trimethoprim sulfate, and 0.31-0.33g of lidocaine.

[0007] Preferably, the dosage form of the topical antibacterial drug composition is any one of ointment, cream, or gel.

[0008] Furthermore, when the topical antibacterial drug composition is an ointment, the pharmaceutically acceptable carrier includes an ointment base; the ointment base includes a solid oily base and a liquid oily base, and the mass ratio of the solid oily base to the liquid oily base is 90:10 to 60:40.

[0009] Furthermore, the solid oily matrix includes at least one of white petrolatum and lanolin; the liquid oily matrix includes at least one of silicone oil, liquid paraffin, and squalane.

[0010] Preferably, when the topical antibacterial drug composition is a cream, the pharmaceutically acceptable carrier includes an oil phase component, an aqueous phase component, and an emulsifier.

[0011] Furthermore, the oil phase component includes at least one of octadecyl alcohol, hexadecyl alcohol, liquid paraffin, isopropyl myristate, and white petrolatum; the aqueous phase component includes glycerol and purified water; and the emulsifier includes polysorbate 80.

[0012] Preferably, when the topical antibacterial drug composition is a gel, the pharmaceutically acceptable carrier includes a gel matrix, a humectant, and a solvent; the gel matrix includes at least one of carbomer and sodium hyaluronate, the humectant includes glycerin, and the solvent includes anhydrous ethanol and purified water.

[0013] Secondly, the present invention provides a method for preparing the above-mentioned topical antibacterial drug composition, comprising the following steps: mixing the pharmaceutically active ingredient with a pharmaceutically acceptable carrier until uniform, thereby obtaining the topical antibacterial drug composition.

[0014] Thirdly, the present invention provides the use of the above-mentioned topical antibacterial drug composition in the preparation of a drug for treating skin wound infections.

[0015] Fourthly, the present invention provides the use of the above-mentioned topical antibacterial drug composition in the preparation of antibacterial, anti-inflammatory and / or analgesic topical drugs.

[0016] Compared with the prior art, the present invention has achieved the following beneficial effects: The topical antibacterial composition provided by this invention, by combining polymyxin B sulfate, trimethoprim sulfate, and lidocaine in specific amounts, can achieve broad-spectrum inhibition of common Gram-negative drug-resistant bacteria and multidrug-resistant bacteria such as Acinetobacter baumannii in wounds without the need for combined use of multiple antibiotics such as neomycin and bacitracin. Simultaneously, it exerts a synergistic effect in relieving wound inflammation and local analgesia. This composition overcomes the safety risks associated with multi-antibiotic combinations, such as complex formulations, increased risk of bacterial resistance, ototoxicity, nephrotoxicity, and sensitization. While ensuring excellent antibacterial activity, it significantly improves medication safety and overall therapeutic efficacy. Detailed Implementation

[0017] It should be noted that the following detailed descriptions are exemplary and intended to provide further illustration of the invention. Unless otherwise specified, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains.

[0018] This invention provides a topical antibacterial pharmaceutical composition comprising a pharmaceutically active ingredient and a pharmaceutically acceptable carrier. The pharmaceutically active ingredient includes polymyxin B sulfate, trimethoprim sulfate, and lidocaine.

[0019] In the composition of the present invention, based on 10 g of the topical antibacterial drug composition, it contains 40,000 to 60,000 U of polymyxin B sulfate, 0.08 to 0.16 g of trimethoprim sulfate, and 0.30 to 0.35 g of lidocaine. This ratio range was determined through extensive formulation screening and pharmacodynamic experiments.

[0020] It should be noted that polymyxin B sulfate is a polypeptide antibiotic, and its dosage is expressed in biological activity units "U" (unit), which is the internationally accepted standard unit for measuring antibiotic potency in the art. Different batches or sources of polymyxin B sulfate raw materials may have different potency (U / mg) per milligram, but those skilled in the art can obtain the required mass to achieve the specified number of units through simple conversion based on the actual potency of the raw material. For example, when using a raw material with a potency of 8000 U / mg, 50000 U is equivalent to 6.25 mg. Any dosage of polymyxin B sulfate that can provide the stated number of units of biological activity falls within the scope of protection of this invention.

[0021] In this invention, polymyxin B sulfate and trimethoprim sulfate exhibit a clear synergistic antibacterial effect within the aforementioned range: polymyxin B sulfate acts on the bacterial cell membrane, increasing its permeability and leading to leakage of bacterial contents; trimethoprim sulfate inhibits bacterial dihydrofolate reductase, blocking folic acid metabolism. When used in combination, polymyxin B sulfate disrupts the cell membrane, promoting the entry of trimethoprim sulfate into the bacteria, thereby enhancing the latter's antibacterial activity. Simultaneously, the inhibition of bacterial metabolism by trimethoprim sulfate reduces bacterial resistance to polymyxin B sulfate. The introduction of lidocaine does not merely provide local anesthesia; experiments show that lidocaine, when used in combination with the two antibiotics mentioned above, can synergistically reduce wound inflammation. The combined use of these three antibiotics achieves an integrated effect of antibacterial, anti-inflammatory, and analgesic effects, while avoiding the safety issues associated with multiple antibiotic combinations.

[0022] As a preferred embodiment, each 10 g of the topical antibacterial drug composition contains 48,000-52,000 U of polymyxin B sulfate, 0.10-0.14 g of trimethoprim sulfate, and 0.31-0.33 g of lidocaine. More preferably, each 10 g of the composition contains 50,000 U of polymyxin B sulfate, 0.12 g of trimethoprim sulfate, and 0.32 g of lidocaine. This preferred range ensures optimal formulation stability and skin compatibility while maintaining antibacterial activity.

[0023] The topical antibacterial drug composition of the present invention can be prepared into various semi-solid dosage forms, including but not limited to ointments, creams, or gels. The choice of different dosage forms depends on clinical usage habits and patient compliance, and those skilled in the art can select appropriate dosage forms according to actual needs.

[0024] When the topical antibacterial drug composition is an ointment, the pharmaceutically acceptable carrier includes an ointment base. The ointment base consists of a solid oily base and a liquid oily base, with a mass ratio of solid oily base to liquid oily base of 90:10 to 60:40. This ratio range is crucial to ensuring good spreadability, stability, and uniform drug dispersion of the ointment. If the proportion of solid base is too high, the ointment becomes too viscous and difficult to spread; if the proportion of liquid base is too high, the ointment is prone to separation and its stability decreases.

[0025] The solid oily matrix includes at least one of white petrolatum and lanolin. White petrolatum is a classic hydrophobic ointment matrix with good occlusive and lubricating properties; lanolin has good water absorption and skin compatibility. The liquid oily matrix includes at least one of silicone oil, liquid paraffin, and squalane. Silicone oil has excellent lubricity and hydrophobicity, liquid paraffin can adjust the consistency of the ointment, and squalane has good skin affinity. In actual formulation, suitable single or mixed components can be selected according to the desired viscosity, greasiness, and skin absorption characteristics of the ointment. For example, the solid oily matrix can use white petrolatum alone or a mixture of white petrolatum and lanolin; the liquid oily matrix can use silicone oil alone or a mixture of silicone oil and liquid paraffin.

[0026] This invention does not impose any special restrictions on the preparation method of the ointment, but the following method is preferred: (1) Matrix heating: Add the prescribed amount of solid oily matrix and liquid oily matrix to a mixing pot, heat to 45~55℃, keep stirring, and evacuate to -0.04~-0.08 MPa. The preferred heating temperature is 48~52℃, for example, 50℃.

[0027] (2) Addition: Add the prescribed amount of lidocaine in multiple batches. After each addition, start stirring (preferably at a stirring speed of 10-20 rpm, for example, 15 rpm) and homogenizing (preferably at a homogenization speed of 1500-2500 rpm, for example, 2000 rpm) until completely dispersed. Then add polymyxin B sulfate and trimethoprim sulfate in sequence, stirring and homogenizing until evenly dispersed after each addition. Adding in batches helps the active ingredients to be evenly distributed in the matrix and avoids excessively high local concentrations.

[0028] (3) Dispersion: After feeding, maintain a vacuum environment (-0.04~-0.08 MPa), adjust the stirring speed to 20~30 rpm, and the homogenization speed to 1500~2500 rpm. Continue stirring and homogenizing for 10~30 minutes, preferably 15~25 minutes, for example, 20 minutes. Vacuum conditions can remove air bubbles and improve the density of the paste.

[0029] (4) Filling: Stop homogenization, cool down to 30~35℃ while stirring, stop stirring, and fill into aluminum tubes or other suitable containers to obtain the product.

[0030] When the topical antibacterial drug composition is a cream, the pharmaceutically acceptable carrier includes an oil phase component, an aqueous phase component, and an emulsifier. The cream is an oil-in-water (O / W) or water-in-oil (W / O) emulsion, with oil-in-water creams being the preferred type as they are easier to wash off and have a better feel on the skin.

[0031] The oil phase component includes at least one of octadecanol, hexadecyl alcohol, liquid paraffin, isopropyl myristate, and white petrolatum. These components together constitute the oil phase of the cream, giving it suitable consistency and occlusive properties. Octadecanol and hexadecyl alcohol also have auxiliary emulsifying effects, increasing the cream's stability. The aqueous phase component includes glycerin and purified water. Glycerin acts as a moisturizer to retain skin moisture and also as a solubilizer. The emulsifier includes polysorbate 80 (Tween 80), with a hydrophilic-lipophilic balance (HLB) of approximately 15, suitable for preparing oil-in-water creams. If necessary, other emulsifiers such as the Span series can be added to adjust the HLB value. The amounts of each component in the cream can be adjusted according to conventional cream preparation principles; for example, per 10 g of cream, the total oil phase is approximately 3-6 g, the total aqueous phase is approximately 3-5 g, and the emulsifier is approximately 0.3-0.6 g.

[0032] This invention does not impose any special restrictions on the preparation method of the cream, but the following method is preferred: (1) Aqueous phase preparation: Place the prescribed amount of purified water and glycerin in a water bath and heat to 70~80℃. Then add polymyxin B sulfate and trimethoprim sulfate and stir to dissolve.

[0033] (2) Preparation of oil phase: Mix the prescribed amounts of cetyl alcohol, octadecanol, isopropyl myristate, liquid paraffin and white petrolatum, heat to 70~80℃, and stir until completely melted and mixed evenly.

[0034] (3) Emulsification: Add the emulsifier to the aqueous phase and stir to dissolve. While stirring, slowly add the oil phase to the aqueous phase. Then turn on the homogenizer and homogenize at a speed of 3000~5000 rpm for 20~40 minutes (e.g., 30 minutes) to form a uniform cream.

[0035] (4) Cooling and filling: Cool down to room temperature while stirring, and fill into aluminum tubes to obtain the product.

[0036] When the topical antibacterial drug composition is a gel, the pharmaceutically acceptable carrier includes a gel matrix, a humectant, and a solvent. The gel matrix includes at least one of carbomer and sodium hyaluronate. Carbomer is a cross-linked acrylic acid polymer that swells in water to form a transparent gel, exhibiting good biocompatibility and drug release properties; sodium hyaluronate is a natural polysaccharide with moisturizing and repairing effects. The humectant includes glycerin, which prevents the gel from drying and enhances skin permeability. The solvent includes anhydrous ethanol and purified water. Anhydrous ethanol can be used to dissolve lidocaine and acts as a transdermal penetration enhancer. The amounts of each component in the gel can be, for example,: carbomer 0.8–1.2 g / 10 g, sodium hyaluronate 0.8–1.2 g / 10 g, glycerin 0.8–1.2 g / 10 g, anhydrous ethanol 0.4–0.6 g / 10 g, with the remainder being purified water. During preparation, carbomer should first be fully swollen with an appropriate amount of water, and then the pH should be adjusted to neutral or weakly acidic to form a gel.

[0037] This invention does not impose any special restrictions on the preparation method of the gelling agent, but the following method is preferred: (1) Weigh out 40% to 60% of the total amount of purified water, add the prescribed amount of carbomer and sodium hyaluronate, mix well, stir overnight to allow it to fully swell, and obtain a gel matrix solution.

[0038] (2) Weigh lidocaine and anhydrous ethanol, mix them evenly to obtain solution A.

[0039] (3) Weigh polymyxin B sulfate and trimethoprim sulfate, add water equal to 40% to 60% of the total purified water, stir well, then add the prescribed amount of glycerin, stir and mix well to obtain solution B.

[0040] (4) Mix solution A and solution B evenly, add the remaining purified water to make up the volume, stir evenly, and obtain the compound gel.

[0041] (5) Fill it into an aluminum tube to obtain the product.

[0042] This invention also provides a method for preparing the above-mentioned topical antibacterial drug composition, comprising the following steps: uniformly mixing the pharmaceutically active ingredient with a pharmaceutically acceptable carrier to obtain the topical antibacterial drug composition. Depending on the dosage form, the specific mixing and dispersion processes vary, as described in the preparation methods for ointments, creams, and gels above. This invention does not impose any special restrictions on the source of any raw materials; commercially available materials are acceptable. All operations should be performed in a clean environment that meets GMP requirements.

[0043] This invention also provides the application of the above-mentioned topical antibacterial drug composition in the preparation of a medicament for treating skin wound infections. The skin wound infections include, but are not limited to, bacterial infections secondary to traumatic wounds, surgical incisions, burn wounds, and chronic ulcers, and are particularly suitable for infections caused by multidrug-resistant bacteria (such as Acinetobacter baumannii).

[0044] The present invention provides the use of the above-mentioned topical antibacterial drug composition in the preparation of antibacterial, anti-inflammatory and / or analgesic topical drugs.

[0045] Experiments have confirmed that the topical antibacterial drug composition of the present invention, through the synergistic effect of polymyxin B sulfate, trimethoprim sulfate, and lidocaine, has significant effects in inhibiting Staphylococcus aureus, Pseudomonas aeruginosa, Acinetobacter baumannii, and Candida albicans. Simultaneously, it can synergistically reduce local inflammatory responses (such as redness and ulceration in an ear swelling model) and significantly increase the pain threshold, thus exerting a local analgesic effect. Therefore, this composition can be used to prepare topical drugs with multiple effects of antibacterial, anti-inflammatory, and analgesic properties, and is particularly suitable for skin wound infections accompanied by pain and inflammation.

[0046] The technical solution of the present invention will be further described below with reference to specific embodiments. The present invention does not impose any special restrictions on the source of reagents used in the following embodiments; commercially available products well known to those skilled in the art can be used.

[0047] Example 1 This embodiment provides ointments with different active ingredient ratios.

[0048] The composition of prescriptions 1-1 to 1-7 is shown in Table 1. Each component is weighed per 10g of ointment.

[0049] Table 1. Formulation of Example 1 Components Prescription 1-1 Prescription 1-2 Prescription 1-3 Prescriptions 1-4 Prescriptions 1-5 Prescriptions 1-6 Prescriptions 1-7 Polymyxin B (U) sulfate 50000 50000 50000 50000 50000 50000 50000 Trimethoprim sulfate (g) 0.6 0.8 1.0 1.2 1.4 1.6 1.8 Lidocaine (g) 0.32 0.32 0.32 0.32 0.32 0.32 0.32 White petrolatum (g) 8.2 8.0 7.8 7.6 7.4 7.2 7.0 Silicone oil (g) 0.88 0.88 0.88 0.88 0.88 0.88 0.88 Note: The potency of this batch of polymyxin B sulfate raw material is 8000 U / mg, and 50000 U is equivalent to 6.25 mg.

[0050] The preparation method is as follows: (1) Matrix heating: Add the prescribed amount of white petrolatum and silicone oil to a mixing pot, heat to 50°C, keep stirring, and evacuate to about -0.06 MPa.

[0051] (2) Adding: Add the prescribed amount of lidocaine in four batches. After each addition, start stirring (stirring speed 15 rpm) and homogenizing (homogenization speed 2000 rpm) until completely dispersed. Then add polymyxin B sulfate and trimethoprim sulfate in sequence. After each addition, stir and homogenize until evenly dispersed.

[0052] (3) Dispersion: After feeding, maintain a vacuum environment (-0.06 MPa), adjust the stirring speed to 25 rpm, the homogenization speed to 2000 rpm, and continue stirring, homogenizing and dispersing for 20 min (stop the machine every 5 min to observe).

[0053] (4) Filling: Stop homogenization, cool down to 30~35℃ while stirring, stop stirring, and fill into aluminum tubes, 10g per tube.

[0054] The results are as follows: Appearance: All prescriptions 1-1 to 1-7 are off-white ointments.

[0055] Spreadability and skin feel test: Formulas 1-1 to 1-7 have uniform color, smooth application, and are easy to spread.

[0056] Centrifugation stability test (3000 rpm, 30 min): Formulas 1-1 to 1-6 showed no stratification and uniform color; Formula 1-7 showed stratification and uneven color.

[0057] The above results indicate that an ointment with good properties and stability can be obtained when the dosage of trimethoprim sulfate is in the range of 0.6~1.6g / 10g, but the stability fails when the dosage is increased to 1.8g / 10g.

[0058] Example 2 This embodiment provides ointments with different types of excipients.

[0059] The composition of prescriptions 2-1 to 2-3 is shown in Table 2. Each component is weighed per 10g of ointment.

[0060] Table 2. Formulation composition of Example 2

[0061] The preparation method is the same as in Example 1.

[0062] The results are as follows: Appearance: Prescriptions 2-1 to 2-3 are all off-white ointments.

[0063] Spreadability and skin feel tests: Formulas 2-1 to 2-3 all showed uniform color, smooth application, and easy spreadability.

[0064] Centrifugation stability test (3000 rpm, 30 min): Formulas 2-1 to 2-3 did not separate into layers and had uniform color.

[0065] The results showed that ointments with good properties and stability could be obtained by using white petrolatum or lanolin as the solid matrix and squalane, silicone oil or liquid paraffin as the liquid matrix.

[0066] Example 3 This embodiment provides ointments with different excipient ratios.

[0067] The compositions of prescriptions 3-1 to 3-5 are shown in Table 3. Each component is weighed per 10g of ointment. The solid base is white petrolatum, and the liquid base is silicone oil.

[0068] Table 3. Formulation composition of Example 3 Components Prescription 3-1 Prescription 3-2 Prescription 3-3 Prescription 3-4 Prescription 3-5 Polymyxin B (U) sulfate 50000 50000 50000 50000 50000 Trimethoprim sulfate (g) 1.2 1.2 1.2 1.2 1.2 Lidocaine (g) 0.32 0.32 0.32 0.32 0.32 White petrolatum (g) 8.48 6.78 5.94 5.08 4.24 Silicone oil (g) 0 1.70 2.54 3.40 4.24 Solid: Liquid (mass ratio) 100:0 80:20 70:30 60:40 50:50 The preparation method is the same as in Example 1.

[0069] The results are as follows: Appearance: Prescriptions 3-1 to 3-5 are all off-white ointments.

[0070] Spreadability and skin feel test: Formula 3-1 has uniform color, is smooth to apply, and is not easy to spread; Formulas 3-2 to 3-5 have uniform color, are smooth to apply, and are easy to spread.

[0071] Centrifugation stability test (3000 rpm, 30 min): Formulas 3-1 to 3-4 showed no stratification and uniform color; Formula 3-5 showed stratification and uneven color.

[0072] The above results, combined with the results of Example 2, indicate that when the mass ratio of solid matrix to liquid matrix is ​​in the range of 90:10 to 60:40, the ointment exhibits good properties and stability; outside this range (100:0 or 50:50), the spreadability is poor or it separates into layers.

[0073] Example 4 This embodiment provides a method for preparing an ointment.

[0074] The composition of prescription 4-1 is shown in Table 4. Weigh each component per 10g of cream.

[0075] Table 4. Formulation of Example 4

[0076] The preparation method is as follows: (1) Aqueous phase preparation: Place the prescribed amount of purified water and glycerin in a water bath and heat to 75°C. Then add polymyxin B sulfate and trimethoprim sulfate and stir to dissolve.

[0077] (2) Oil phase preparation: Mix the prescribed amounts of hexadecyl alcohol, octadecanol, isopropyl myristate, liquid paraffin and white petrolatum, heat to 70~75℃, and stir until completely melted and evenly mixed.

[0078] (3) Emulsification: Polysorbate 80 is added to the aqueous phase and stirred to dissolve. The oil phase is slowly added to the aqueous phase while stirring. Then, the homogenizer is turned on and the homogenization rate is 4000 rpm. Emulsification is carried out for 30 min to form a uniform cream.

[0079] (4) Cooling and filling: Cool down to room temperature while stirring, and fill into aluminum tubes, 10 g per tube.

[0080] The results are as follows: The product is an off-white cream. The spreadability and skin feel tests showed that it was uniform in color, smooth to apply, and easy to spread. The centrifugal stability test (3000 rpm, 30 min) showed that it did not separate into layers and had a uniform color.

[0081] Example 5 This embodiment provides a method for preparing a gelling agent.

[0082] The composition of prescription 5-1 is shown in Table 5. Weigh each component per 10g of gel.

[0083] Table 5. Formulation of Example 5

[0084] The preparation method is as follows: (1) Weigh out 40% of the total amount of purified water, add the prescribed amount of carbomer and sodium hyaluronate, mix well, stir overnight to allow it to fully swell, and obtain a gel matrix solution.

[0085] (2) Weigh lidocaine and anhydrous ethanol, mix them evenly to obtain solution A.

[0086] (3) Weigh polymyxin B sulfate and trimethoprim sulfate, add water equal to 50% of the total amount of purified water, stir well, then add the prescribed amount of glycerol, stir and mix well to obtain solution B.

[0087] (4) Mix solution A and solution B evenly, add the remaining 10% purified water to make up the volume, stir evenly, and obtain the compound gel.

[0088] (5) Fill into aluminum tubes, 10 g per tube.

[0089] The results are as follows: The product is a pale yellow transparent gel. Spreading and skin feel tests showed that the color was uniform, the application was smooth, and it was easy to spread. Centrifugation stability test (3000 rpm, 30 min) showed that it did not separate into layers and the color was uniform.

[0090] Comparative Examples 1-3 Comparative Examples 1-3 are ointments, and their formulations are named Formulation D-1, Formulation D-2 and Formulation D-3, respectively. Their compositions are shown in Table 6. The mass ratio of the fixed solid matrix (white petrolatum) to the liquid matrix (silicone oil) is 90:10. Each component is weighed per 10g of ointment, and the preparation method is the same as in Example 1.

[0091] Table 6. Prescription composition of Comparative Examples 1-3

[0092] In the table, " / " indicates that the component is not added.

[0093] Comparative Example 4 This comparative example is commercially available polymyxin B compound ointment (a commercially available drug, brand name Funo). ® Each gram contains 5000 U of polymyxin B sulfate, 3500 U of neomycin sulfate, 500 U of bacitracin, and 40 mg of lidocaine hydrochloride. This serves as a positive control.

[0094] Test case 1. Antibacterial efficacy test (1) Test method The test was conducted according to Section 1127, "Test Method for Antibacterial Efficacy," of the 2020 edition of the Chinese Pharmacopoeia, Part IV. Ointment samples from formulations 1-1 to 1-6 of Example 1 (formulations 1-7 were not included due to stability issues) were inoculated with Staphylococcus aureus. Staphylococcus aureus ATCC 25923), Pseudomonas aeruginosa ( Pseudomonas aeruginosa ATCC9027), Acinetobacter baumannii ( Acinetobacter baumannii ATCC 19606), Candida albicans ( Candida albicans According to ATCC 10231, the number of surviving bacteria was measured at different time points, and the logarithmic decrease in bacterial count was calculated. Judgment criteria: the decrease in bacterial logarithm should not be less than 1.0 within 7 days, and not less than 3.0 within 14 days; the decrease in fungal logarithm should not increase within 7 days, 14 days, or 28 days.

[0095] (2) Test results The results are shown in Table 7.

[0096] Table 7 Results of antibacterial efficacy test

[0097] Note: + indicates fungal growth, - indicates no fungal growth. (3) Results Analysis As shown in Table 7, Formula 1-1 (trimethoprim sulfate 0.6g / 10g) had insufficient antibacterial efficacy; Staphylococcus aureus, Pseudomonas aeruginosa, and Acinetobacter baumannii resumed growth after 28 days, and there was no inhibitory effect on Candida albicans. Formulas 1-2 to 1-6 (trimethoprim sulfate 0.8~1.6g / 10g) showed good antibacterial efficacy against all tested bacteria, with no resurgence of growth within 28 days, and significant inhibitory effect against the fungus Candida albicans. Comparative Examples 1 and 2 showed poor inhibitory effects against Staphylococcus aureus and Acinetobacter baumannii, respectively. Comparative Example 3, with both components, showed good inhibitory effects against Staphylococcus aureus, Pseudomonas aeruginosa, and Acinetobacter baumannii, and also showed good inhibitory effects against the fungus Candida albicans. The positive control contains three antibiotics and has the same antibacterial effect as the two-component antibiotic composition of this invention.

[0098] 2. Skin irritation test (1) Test method Seventy rabbits were selected, and the hair on both sides of the spine on the back was removed using 3% sodium sulfide 24 hours before the test. The rabbits were randomly divided into 7 groups of 10 rabbits each: normal control group (physiological saline), positive control group (comparative example 4 commercially available compound polymyxin B ointment), and test sample group (formulas 1-2 and 1-6 of Example 1, formula D-1 of comparative example 1, formula D-2 of comparative example 2, and formula D-3 of comparative example 3). The test sample was applied using a closed patch method, administered for 24 hours daily for 7 consecutive days. On the 8th day, the test sample was washed off. After drug withdrawal, the rabbits were observed for 3 days, and the erythema and edema at the application site were observed daily. The skin irritation response was scored according to the skin irritation response scoring standard, and the irritation intensity was calculated.

[0099] The skin irritation response scoring criteria are as follows: no erythema 0 points, mild erythema (barely visible) 1 point, moderate erythema (clearly visible) 2 points, severe erythema 3 points, purplish-red erythema to mild eschar formation 4 points; no edema 0 points, mild edema (barely visible) 1 point, moderate edema (clearly raised) 2 points, severe edema (skin raised 1mm, clear outline) 3 points, severe edema (skin raised more than 1mm and enlarging) 4 points, with a maximum total score of 8 points. After calculating the average score for each group, the skin irritation intensity was evaluated according to the skin irritation intensity scoring criteria as follows: 0~0.49, no irritation; 0.5~2.99, mild irritation; 3.0~5.99, moderate irritation; 6.0~8.0, strong irritation.

[0100] (2) Test results The results are shown in Table 8.

[0101] Table 8 Results of skin irritation test (n=10)

[0102] (3) Results Analysis The ointments of formulations 1-2 and 1-6 in Example 1 of this invention are non-irritating to rabbit skin, while commercially available compound polymyxin B ointment (containing neomycin and bacitracin) shows mild irritation. This indicates that the compositions of this invention have better skin compatibility.

[0103] 3. Animal efficacy tests (1) Animal model An acute ear swelling model was induced in mice using croton oil. 30 μL of croton oil was applied to both the upper and lower surfaces of the right auricle of Kunming mice and left for 30 min to establish the ear swelling model.

[0104] (2) Grouping and administration Seventy-two hours after modeling, mice that had successfully developed the model were selected and evenly divided into eight groups of six mice each, based on their ear swelling scores: normal control group (saline), model group (saline), positive control group (comparative example 4), and test sample group (formulas 1-2 and 1-6 of Example 1, formula D-1 of Comparative example 1, formula D-2 of Comparative example 2, and formula D-3 of Comparative example 3). The drugs were administered transdermally three times daily for seven consecutive days.

[0105] (3) Detection indicators Ear swelling score: Scored (0-8 points) based on ulcer area and degree of redness and swelling on days 0, 3, and 7 after drug administration. The grading criteria are as follows: Ulcers: Ulcers covering more than 70% of the mouse ear: 5 points; 50% to less than 70%: 4 points; 30% to less than 50%: 3 points; 20% to less than 30%: 2 points; 1% to less than 20%: 1 point; No ulcers: 0 points. Redness and swelling: Severe swelling (shiny skin or blisters): 3 points; Moderate swelling (significant tightness, possibly accompanied by pain): 2 points; Mild swelling (visible bulges on the skin but no tightness): 1 point; No swelling: 0 points.

[0106] Pain threshold: The pain threshold was determined by the hot plate method, with the time it took for the mouse to lick its hind paw for the first time. The temperature of the hot plate was kept constant at 55±0.5℃. The pain response time of the mice was measured on days 0, 3 and 7 after drug administration (with 60 s as the upper limit to avoid burning the mice).

[0107] (4) Test results The ear swelling score results are shown in Table 9, and the pain threshold results are shown in Table 10.

[0108] Table 9 Ear swelling score (x±s, n=6) Group 0 d 3 d 7 d normal control group 0 0 0 Model group 7.8±1.5 7.4±1.2 6.9±2.1 Positive control group 7.9±1.7 5.0±2.3 3.8±1.2* Prescription 1-2 7.7±2.0 4.3±1.8* 2.0±0.6** Prescriptions 1-6 7.7±1.2 4.1±1.9* 1.8±0.9** Prescription D-1 7.6±2.1 6.3±2.0 5.3±2.0 Prescription D-2 7.9±1.8 6.0±1.8 5.1±1.7 Prescription D-3 8.0±1.6 4.8±1.6* 2.4±0.7** Note: In Table 9, * indicates p < 0.05, and ** indicates p < 0.01, compared with the model group.

[0109] Prescriptions 1-2 and 1-6 showed a significant reduction in scores starting from day 3 of administration (p < 0.05), and the effect was extremely significant at day 7 (p < 0.01), superior to the positive control group. Prescriptions D-1 and D-2 (lacking trimethoprim or polymyxin B) had poor anti-inflammatory effects, while prescription D-3 (without lidocaine) also showed anti-inflammatory effects, but not as significant as prescriptions 1-2 and 1-6, indicating that the combined use of lidocaine with polymyxin B sulfate or trimethoprim sulfate can further enhance the anti-inflammatory effect.

[0110] Table 10 Pain threshold (s, x±s, n=6) Group 0 d 3 d 7 d Model group 6.8±1.5 6.4±1.2 6.9±2.1 Positive control group 6.6±2.3 9.1±2.3* 11.3±1.2** Prescription 1-2 6.7±2.0 9.3±1.8* 11.5±0.6** Prescriptions 1-6 6.5±1.2 9.1±1.9* 11.3±1.0** Prescription D-1 6.6±2.1 8.3±2.0 9.0±2.0 Prescription D-2 6.9±1.8 8.0±1.6 9.1±1.1 Prescription D-3 6.3±1.6 6.8±1.6 6.4±0.7 Note: In Table 10, * indicates p < 0.05, and ** indicates p < 0.01, compared with the model group.

[0111] It can be seen that the pain threshold of prescriptions 1-2 and 1-6 and the positive control group was significantly increased after 3 days of administration (p<0.05), and extremely significantly increased after 7 days (p<0.01); prescription D-3 (without lidocaine) in comparative example 3 had no analgesic effect.

[0112] The above description is merely a preferred embodiment of the present invention and is not intended to limit the invention. Various modifications and variations can be made to the present invention by those skilled in the art. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the scope of protection of the present invention.

Claims

1. A topical antibacterial drug composition, characterized in that, The product comprises a pharmaceutically active ingredient and a pharmaceutically acceptable carrier, wherein the pharmaceutically active ingredient includes polymyxin B sulfate, trimethoprim sulfate, and lidocaine; each 10g of the topical antibacterial composition contains 40,000-60,000U of polymyxin B sulfate, 0.08-0.16g of trimethoprim sulfate, and 0.30-0.35g of lidocaine.

2. The topical antibacterial drug composition according to claim 1, characterized in that, The dosage form of the topical antibacterial drug composition is any one of ointment, cream, or gel.

3. The topical antibacterial drug composition according to claim 2, characterized in that, When the topical antibacterial drug composition is an ointment, the pharmaceutically acceptable carrier includes an ointment base; the ointment base includes a solid oily base and a liquid oily base, and the mass ratio of the solid oily base to the liquid oily base is 90:10 to 60:

40.

4. The topical antibacterial drug composition according to claim 3, characterized in that, The solid oily matrix includes at least one of white petrolatum and lanolin; the liquid oily matrix includes at least one of silicone oil, liquid paraffin, and squalane.

5. The topical antibacterial drug composition according to claim 2, characterized in that, When the topical antibacterial drug composition is a cream, the pharmaceutically acceptable carrier includes an oil phase component, an aqueous phase component, and an emulsifier.

6. The topical antibacterial drug composition according to claim 5, characterized in that, The oil phase component includes at least one of octadecyl alcohol, hexadecyl alcohol, liquid paraffin, isopropyl myristate, and white petrolatum; the aqueous phase component includes glycerol and purified water; and the emulsifier includes polysorbate 80.

7. The topical antibacterial drug composition according to claim 2, characterized in that, When the topical antibacterial drug composition is a gel, the pharmaceutically acceptable carrier includes a gel matrix, a humectant, and a solvent; the gel matrix includes at least one of carbomer and sodium hyaluronate, the humectant includes glycerin, and the solvent includes anhydrous ethanol and purified water.

8. The method for preparing the topical antibacterial drug composition according to any one of claims 1 to 7, characterized in that, The process includes the following steps: mixing the pharmaceutically active ingredient with a pharmaceutically acceptable carrier until homogeneous to obtain the topical antibacterial drug composition.

9. The use of the topical antibacterial pharmaceutical composition according to any one of claims 1 to 7 in the preparation of a medicament for treating skin wound infections.

10. The use of the topical antibacterial pharmaceutical composition according to any one of claims 1 to 7 in the preparation of antibacterial, anti-inflammatory and / or analgesic topical pharmaceuticals.

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