Anhydrous plant-based compound antibiotic self-emulsifying ointment and preparation method thereof

Abstract

The invention provides an anhydrous plant-based compound antibiotic self-emulsifying ointment and a preparation method thereof. The ointment comprises a compound antibiotic drug component and a plant-based semisolid self-emulsifying matrix, the compound antibiotic drug component comprises polymyxin antibiotics and a local anesthesia pain-relieving component, and the compound antibiotic drug component is dissolved and uniformly dispersed in the plant-based semisolid self-emulsifying matrix to form a solid solution; the plant-based semisolid self-emulsifying matrix comprises 20-70 wt% of plant-based oil, 10-30 wt% of an emulsifier, 10-35 wt% of a co-emulsifier and 10-20 wt% of a thickener, and the co-emulsifier comprises a small-molecule co-emulsifier with the molecular weight smaller than 100 and containing one or more active hydroxyl groups. The compound antibiotic drug component in the ointment can be well dissolved in a matrix to form a solid solution, and has good self-emulsifying property and shear thinning property, so that the rapid permeability and antibacterial property of the drug are synergistically improved.

Description

Technical Field

[0001] The invention belongs to the technical field of pharmaceutical preparations, and particularly relates to an anhydrous plant-based compound antibiotic self-emulsifying ointment and a preparation method thereof. Background Art

[0002] Antibiotics are a class of compounds that have the ability to inhibit or kill microorganisms. They are mainly used to prevent and treat bacterial infections, including β-lactam antibiotics, aminoglycoside antibiotics, tetracycline antibiotics, macrolide antibiotics, quinolone antibiotics, glycopeptide antibiotics, etc. Among them, polymyxin is a class of cyclic polypeptide antibiotics produced by Polymyxa bacteria. The antibacterial mechanism of polymyxin is to interact with bacterial cell membranes, destroy the integrity of cell membranes, and thus inhibit or kill bacteria. It has broad-spectrum antibacterial activity against Gram-negative bacteria such as Escherichia coli and Pseudomonas aeruginosa.

[0003] Ointment formulations (antibiotic ointments) prepared based on antibiotics have the advantages of easy use, long residence time, and good stability. They are one of the ideal dosage forms for the clinical treatment of local skin infections. However, currently, ointments mostly use vaseline and liquid paraffin as the main matrix to disperse polymyxin antibiotics. Since vaseline is an oily matrix, it feels greasy when applied and is not easy to clean. At the same time, considering that the effective drug ingredients of antibiotics and salt local anesthetic analgesic ingredients are generally water-soluble drugs, their solubility in low-polarity matrices such as vaseline or liquid paraffin is very poor, and crystals exist, which greatly limits the drug release ability, resulting in poor uniformity and poor efficacy. Therefore, it is urgent to develop a new type of compound antibiotic ointment preparation to improve its skin feel and improve its drug release ability. Summary of the invention

[0004] In order to solve all or part of the above technical problems, the present invention provides the following technical solutions: One of the purposes of the present invention is to provide an anhydrous plant-based compound antibiotic self-emulsifying ointment, the anhydrous plant-based compound antibiotic self-emulsifying ointment comprising a compound antibiotic drug component and a plant-based semisolid self-emulsifying matrix, the compound antibiotic drug component comprising a polymyxin antibiotic and a local anesthetic analgesic component, the compound antibiotic drug component being dissolved and uniformly dispersed in the plant-based semisolid self-emulsifying matrix to form a solid solution; The plant-based semisolid self-emulsifying matrix comprises plant-based oil, emulsifier, co-emulsifier and thickener, wherein the contents of the plant-based oil, emulsifier, co-emulsifier and thickener are 20-70wt%, 10-30wt%, 10-35wt% and 10-20wt% of the anhydrous plant-based compound antibiotic self-emulsifying ointment, respectively; and the co-emulsifier comprises a small molecule co-emulsifier having a molecular weight of less than 100 and containing one or more active hydroxyl groups.

[0005] The prior art generally uses a petroleum-based matrix (such as vaseline) to disperse polymyxin antibiotics to prepare antibiotic ointment dosage forms, but highly water-soluble compound antibiotic drug components (polymyxin antibiotics and salt local anesthetic analgesic components) cannot be completely dissolved in the petroleum-based matrix, resulting in them being dispersed in the petroleum-based matrix in the form of crystals, which is not conducive to the release of polymyxin antibiotics and absorption by organisms. The anhydrous plant-based compound antibiotic self-emulsifying ointment provided by the present invention contains a highly polar co-emulsifier (i.e., a small molecule co-emulsifier with a molecular weight of less than 100 and containing one or more active hydroxyl groups) to ensure that the highly water-soluble compound antibiotic drug components are well dissolved in the ointment to form a solid solution. The drug components in the obtained cream do not exist in the form of crystals, avoiding problems such as poor release effect caused by crystallization due to poor drug dissolution and dispersion, thereby improving the diffusion and penetration effect of the compound antibiotic drug components and making them easier to be absorbed by organisms.

[0006] The self-emulsifying matrix used in the present invention can self-emulsify to form smaller emulsion droplets when encountering an environmental solution (such as surface exudate of a wound), further improving the permeability. It is more delicate to apply and easy to apply evenly, and compared with the vaseline matrix, the greasy feeling is greatly improved. The excellent dispersibility and self-emulsifying properties of the compound antibiotic drug components of the ointment synergistically improve the diffusion and penetration effect of the compound antibiotic drug components in the ointment, thereby showing a good antibacterial effect. In addition, the self-emulsifying ointment provided by the present invention does not contain water, which on the one hand ensures the self-emulsifying effect of the ointment when applied, and on the other hand avoids the problem of degradation of polymyxin antibiotics in the presence of water.

[0007] In some embodiments, the content of the compound antibiotic drug component is 0.4-10wt%.

[0008] In some embodiments, the content of the polymyxin antibiotics is 0.1-2.5 wt %.

[0009] In some embodiments, the content of the local anesthetic analgesic component is 0.3-7.5wt%, preferably 4wt%.

[0010] In some embodiments, the polymyxin antibiotics include a combination of one or more of bacitracin, bacitracin zinc, neomycin sulfate, and polymyxin B sulfate.

[0011] In some embodiments, the polymyxin antibiotics include bacitracin and / or bacitracin zinc, neomycin sulfate and polymyxin B sulfate, and the contents of bacitracin and / or bacitracin zinc, neomycin sulfate and polymyxin B sulfate are 0.07wt%-1.6wt%, 0.03wt%-0.8wt% and 0.01wt%-0.25wt% of the anhydrous plant-based compound antibiotic self-emulsifying ointment, respectively.

[0012] In some preferred embodiments, the polymyxin antibiotics include bacitracin, neomycin sulfate and polymyxin B sulfate, and the contents of bacitracin, neomycin sulfate and polymyxin B sulfate are 0.83wt%, 0.35wt% and 0.12wt% of the anhydrous plant-based compound antibiotic self-emulsifying ointment, respectively.

[0013] In some embodiments, the salt-based local anesthetic analgesic component includes a caine-based drug.

[0014] In some embodiments, the salt local anesthetic analgesic component includes one or a combination of lidocaine, lidocaine hydrochloride, procaine hydrochloride or bupivacaine.

[0015] In some embodiments, the small molecule emulsifier is capable of dissolving the polymyxin antibiotics, and the small molecule emulsifier includes a combination of one or more of 1,2-propylene glycol (PG), 1,3-propylene glycol, ethanol, and glycerol.

[0016] In some embodiments, the mass of the small molecule emulsifier is greater than 30 wt %, for example, 30-100 wt %, of the total mass of the emulsifier.

[0017] In some embodiments, in addition to the above-mentioned small molecule emulsifiers, the emulsifiers may also include emulsifiers with lower polarity, such as polyethylene glycol 400, ethoxydiglycol, etc., to adjust the overall viscosity of the ointment.

[0018] In some embodiments, the plant-based oil includes one or a combination of more than one of oleyl alcohol (OA), medium chain triglycerides (GTCC), isopropyl myristate (IPM), cocoyl capryloyl caprate (3C) or glyceryl triacetate (GTA).

[0019] In some embodiments, the emulsifier includes a combination of one or more of polyoxyethylene 40 hydrogenated castor oil (RH40), polyoxyethylene (35) castor oil (ELP), polysorbate 20 (PS20), polysorbate 80 (PS80), polyethylene glycol cetearyl ether 20 (CS20) or poloxamer 188 (P188).

[0020] In some embodiments, the thickener includes a combination of one or more of glyceryl mono- and distearate II (GMS II), poloxamer 407 (P407), stearyl alcohol, or stearic acid.

[0021] In some embodiments, the anhydrous plant-based compound antibiotic self-emulsifying ointment is -1 The viscosity under shear rate conditions is 402-4638 , in 100 s -1 The viscosity under shear rate conditions is 1-6 That is, the ointment provided by the present invention has good shear thinning properties.

[0022] The second object of the present invention is to provide a method for preparing an anhydrous plant-based compound antibiotic self-emulsifying ointment, comprising: The plant-based oil, emulsifier, co-emulsifier and thickener are mixed and stirred at a temperature of 55° C. to 100° C. until a uniform phase is formed to obtain a plant-based semisolid self-emulsifying matrix; At least a compound antibiotic drug component is mixed with the plant-based semisolid self-emulsifying matrix, wherein the compound antibiotic drug component includes a polymyxin antibiotic and a local anesthetic analgesic component, so that the compound antibiotic drug component is dissolved in the plant-based semisolid self-emulsifying matrix to form a solid solution, and an anhydrous plant-based compound antibiotic self-emulsifying ointment is obtained; Among them, the amounts of the plant-based oil, emulsifier, co-emulsifier and thickener are 20-70wt%, 10-30wt%, 10-35wt% and 10-20wt% of the anhydrous plant-based compound antibiotic self-emulsifying ointment respectively; and the co-emulsifier includes a small molecule co-emulsifier with a molecular weight of less than 100 and containing one or more active hydroxyl groups.

[0023] In some embodiments, the stirring time at a temperature of 55° C.-100° C. is 20-60 min.

[0024] In some preferred embodiments, the preparation method comprises mixing the plant-based oil, the emulsifier, the co-emulsifier and the thickener, and stirring at 70° C. for 30 minutes to obtain a plant-based semisolid self-emulsifying matrix.

[0025] Compared with the prior art, the present invention has at least the following beneficial effects: the compound antibiotic drug ingredients (i.e., polymyxin antibiotics and local anesthetic analgesic ingredients) in the anhydrous plant-based compound antibiotic self-emulsifying ointment provided by the present invention can be dissolved in the plant-based semi-solid self-emulsifying matrix to form a solid solution without the presence of crystals, thereby improving the dispersion uniformity of the active ingredients and enabling them to be more easily absorbed by the organism, thereby solving the problem in the prior art that the petroleum-based matrix (e.g., vaseline) cannot completely dissolve active ingredients such as polymyxin antibiotics and the dosage is uncontrollable; the ointment provided by the present invention can spontaneously emulsify to generate small-sized emulsion droplets for rapid penetration, and the good dispersibility of the antibiotics and the self-emulsification of the ointment synergistically improve the drug diffusion and penetration effect. BRIEF DESCRIPTION OF THE DRAWINGS

[0026] In order to more clearly illustrate the embodiments of the present application or the technical solutions in the prior art, the drawings required for use in the embodiments or the description of the prior art will be briefly introduced below. Obviously, the drawings described below are only some embodiments recorded in the present application. For ordinary technicians in this field, other drawings can be obtained based on these drawings without paying creative work.

[0027] Figure 1 is a photograph of the anhydrous plant-based semisolid self-emulsifying matrix prepared in Examples 1-14 of the present invention; Figure 2 is a photograph of the anhydrous plant-based compound antibiotic self-emulsifying ointment prepared in Examples 1-14 of the present invention; Figure 3 , Figure 4 , Figure 5 They are photos of the anhydrous plant-based compound antibiotic self-emulsifying ointment prepared in Example 15, Example 16, and Example 17 of the present invention, respectively; Figure 6 are photos of the anhydrous plant-based semisolid self-emulsifying ointments prepared in Comparative Examples 1-3 of the present invention, in which only different co-emulsifiers were replaced compared with Example 1 (polyethylene glycol 400 in the left picture, PE / L 44 in the middle picture, and ethoxydiglycol in the right picture); Figure 7 These are optical microscope images of the commercially available Neosporin ointment in Comparative Example 5 of the present invention at 0 degrees (a) and 45 degrees (b) and corresponding polarizing microscope images (c, d); Figure 8 These are optical microscope images of the commercially available compound polymyxin B ointment in Comparative Example 6 of the present invention at 0 degrees (a) and 45 degrees (b) and corresponding polarizing microscope images (c, d); Fig. 9 These are optical microscope images of the anhydrous plant-based compound antibiotic self-emulsifying ointment of Example 1 of the present invention at 0 degrees (a) and 45 degrees (b) and corresponding polarizing microscope images (c, d); Fig.10 These are optical microscope images of the anhydrous plant-based compound antibiotic self-emulsifying ointment of Example 2 of the present invention at 0 degrees (a) and 45 degrees (b) and corresponding polarizing microscope images (c, d); Fig.11 These are optical microscope images of the anhydrous plant-based compound antibiotic self-emulsifying ointment of Example 3 of the present invention at 0 degrees (a) and 45 degrees (b) and corresponding polarizing microscope images (c, d); Fig.12 These are optical microscope images of the anhydrous plant-based compound antibiotic self-emulsifying ointment of Example 4 of the present invention at 0 degrees (a) and 45 degrees (b) and corresponding polarizing microscope images (c, d); Fig.13 These are optical microscope images of the anhydrous plant-based compound antibiotic self-emulsifying ointment of Example 5 of the present invention at 0 degrees (a) and 45 degrees (b) and corresponding polarizing microscope images (c, d); Fig.14 It is a "viscosity-shear rate" variation curve diagram of the samples of Examples 1-5, Comparative Example 5 and Comparative Example 6 of the present invention; Fig.15 It is a picture of the results of the antibacterial zone test on Escherichia coli of samples of Examples 1-5 of the present invention and Comparative Examples 4-6 (compound polymyxin-vaseline matrix, commercially available compound polymyxin B ointment and Neosporin); Fig.16 The pictures are the results of the antibacterial zone test of the samples of Examples 1-5 of the present invention and Comparative Examples 4-6 (compound polymyxin-vaseline matrix, commercially available compound polymyxin B ointment and Neosporin) on Staphylococcus aureus; Fig.17 The statistical results of the inhibition zone area of ​​Escherichia coli for samples of Examples 1-5 and Comparative Examples 4-6 (compound polymyxin-vaseline matrix, commercially available compound polymyxin B ointment and Neosporin); Fig.18 These are the statistical results of the inhibition zone areas of Staphylococcus aureus of samples of Examples 1-5 of the present invention and Comparative Examples 4-6 (compound polymyxin-vaseline matrix, commercially available compound polymyxin B ointment and Neosporin). DETAILED DESCRIPTION

[0028] The technical solution of the present invention is described in detail below in conjunction with specific embodiments so that those skilled in the art can better understand and implement the technical solution of the present invention. The specific functional details disclosed herein should not be interpreted as limiting, but only as the basis for the claims and as a representative basis for teaching those skilled in the art to adopt the present invention in different ways in any appropriate detailed embodiment.

[0029] Unless otherwise specified, the raw materials and reagents used in the present invention are all commercially available.

[0030] Example 1 Example 1 provides an anhydrous plant-based compound antibiotic self-emulsifying ointment and a preparation method thereof, which specifically comprises the following steps: Isopropyl myristate (IPM), 1,2-propylene glycol (PG), polyoxyethylene 40 hydrogenated castor oil (RH40) and glyceryl mono- and distearate II (GMS II) were weighed and mixed, heated and stirred at 70 °C for 30 min until a uniform phase was obtained to obtain a plant-based semisolid self-emulsifying matrix; The compound antibiotic drug ingredients of 0.83wt% bacitracin, 0.35wt% neomycin sulfate, 0.12wt% polymyxin B sulfate and 4wt% lidocaine hydrochloride are uniformly dispersed in the above-prepared plant-based semisolid self-emulsifying matrix, stirred until uniformly solidified, to obtain an anhydrous plant-based compound antibiotic self-emulsifying ointment; wherein the weight proportions of IPM, PG, RH40 and GMSⅡ in the ointment are 49.1wt%, 25.2wt%, 10.2wt% and 10.2wt%, respectively.

[0031] Embodiments 2 to 14 The only difference between Examples 2 to 14 and Example 1 is that the plant-based oil, emulsifier, co-emulsifier and thickener, as well as the weight percentage of the corresponding materials are changed as shown in Table 1, and the rest is implemented in the same way as Example 1.

[0032] Table 1 Components and weight percentages of the anhydrous plant-based compound antibiotic self-emulsifying ointment in Examples 1-14,

[0033] The photos of the plant-based semisolid self-emulsifying matrix and the anhydrous plant-based compound antibiotic self-emulsifying ointment prepared in all Examples 1 to 14 are shown in FIG. Figure 1 and Figure 2 As shown in the figure, all samples are in a uniform and stable solid paste state.

[0034] Embodiment 15 Weigh oleyl alcohol (OA), 1,2-propylene glycol (PG), polyoxyethylene (35) castor oil (ELP) and glyceryl mono- and distearate II (GMS II), mix them, heat and stir at 70 °C for 30 min until a uniform phase is obtained to obtain a plant-based semisolid self-emulsifying matrix; 0.075wt% of bacitracin, 0.03wt% of neomycin sulfate, 0.01wt% of polymyxin B sulfate and 0.36wt% of lidocaine hydrochloride are uniformly dispersed in the above-prepared plant-based semisolid self-emulsifying matrix, and stirred until uniformly solidified to obtain an anhydrous plant-based compound antibiotic self-emulsifying ointment; wherein the weight ratios of OA, PG, ELP and GMSⅡ in the ointment are 60.9%, 13.425%, 12.6% and 12.6%, respectively.

[0035] Figure 3 This is a photograph of the anhydrous plant-based compound antibiotic self-emulsifying ointment prepared in Example 15 of the present invention.

[0036] Example 16 Weigh oleyl alcohol (OA), 1,2-propylene glycol (PG), polyoxyethylene (35) castor oil (ELP) and glyceryl mono- and distearate II (GMS II), mix them, heat and stir at 70 °C for 30 min until a uniform phase is obtained to obtain a plant-based semisolid self-emulsifying matrix; 1.49wt% of bacitracin, 0.63wt% of neomycin sulfate, 0.22wt% of polymyxin B sulfate and 7.2wt% of lidocaine hydrochloride and other ingredients are evenly dispersed in the above-prepared plant-based semisolid self-emulsifying matrix, stirred until uniformly solidified, to obtain an anhydrous plant-based compound antibiotic self-emulsifying ointment; wherein the weight ratios of OA, PG, ELP and GMSⅡ in the ointment are 54.7%, 12.96%, 11.4% and 11.4%, respectively.

[0037] Figure 4 This is a photograph of the anhydrous plant-based compound antibiotic self-emulsifying ointment prepared in Example 16 of the present invention.

[0038] Embodiment 17 Weigh oleyl alcohol (OA), 1,2-propylene glycol (PG), polyoxyethylene (35) castor oil (ELP) and glyceryl mono- and distearate II (GMS II), mix them, heat and stir at 70 °C for 30 min until a uniform phase is obtained to obtain a plant-based semisolid self-emulsifying matrix; 0.75wt% of bacitracin, 0.32wt% of neomycin sulfate, 0.11wt% of polymyxin B sulfate and 3.6wt% of procaine hydrochloride are uniformly dispersed in the above-prepared plant-based semisolid self-emulsifying matrix, and stirred until uniformly solidified to obtain an anhydrous plant-based compound antibiotic self-emulsifying ointment; wherein the weight ratios of OA, PG, ELP and GMSⅡ in the ointment are 58.3%, 12.72%, 12.1% and 12.1%, respectively.

[0039] Figure 5 This is a photograph of the anhydrous plant-based compound antibiotic self-emulsifying ointment prepared in Example 17 of the present invention.

[0040] Comparative Example 1 The difference between Comparative Example 1 and Example 1 is that the highly polar small molecule emulsifier 1,2-propylene glycol (PG) in Example 1 is replaced by low polar polyethylene glycol 400, and the rest is the same as Example 1.

[0041] Comparative Example 2 The difference between Comparative Example 2 and Example 1 is that the highly polar small molecule emulsifier 1,2-propylene glycol (PG) in Example 1 is replaced by low polar PE / L 44 (an ethylene oxide / propylene oxide block copolymer), and the rest is the same as Example 1.

[0042] Comparative Example 3 The difference between Comparative Example 3 and Example 1 is that the highly polar small molecule co-emulsifier 1,2-propylene glycol (PG) in Example 1 is replaced by low polar ethoxydiglycol, and the rest is the same as Example 1.

[0043] Figure 6 The photos of the ointments prepared in Comparative Examples 1-3 show that after the strong polar emulsifier was replaced with a low polar emulsifier, the active pharmaceutical ingredient precipitated at the bottom and could not be evenly dissolved and dispersed.

[0044] Comparative Example 4 The only difference between Comparative Example 4 and Example 1 is that the plant-based semi-solid self-emulsifying matrix in Example 1 is replaced with vaseline, and the rest is the same as Example 1.

[0045] Comparative Example 5 Commercially available products: Neosporin: bacitracin zinc (0.7wt%), neomycin sulfate (0.35wt%), polymyxin B sulfate (0.12wt%), pramoxine hydrochloride (1wt%), and the rest is base vaseline.

[0046] Comparative Example 6 Commercially available products: Compound polymyxin B ointment: bacitracin (0.83wt%), neomycin sulfate (0.35wt%), polymyxin B sulfate (0.06wt%), lidocaine hydrochloride (4wt%), and the rest is base vaseline.

[0047] The present invention performs drug dispersibility evaluation, viscosity evaluation and antibacterial effect evaluation on the ointments of the above-mentioned embodiments and comparative examples. The evaluation methods and results are as follows: 1. Evaluation of the dispersibility of the samples of anhydrous plant-based compound antibiotic self-emulsifying ointment, comparative example 5, and comparative example 6 The anhydrous plant-based compound antibiotic self-emulsifying ointment samples prepared in Examples 1 to 5, the Neosporin of Comparative Example 5, and the compound polymyxin B ointment sample of Comparative Example 6 were observed using the optical mode and polarized light mode of the microscope.

[0048] Operation method: Take a small amount of the above sample, place it on a glass slide, gently cover it with a coverslip, and then place it under a microscope. Use the optical mode and polarization mode (0° and 45°) of the microscope to observe and take photos.

[0049] Figure 7 These are optical microscope images of the commercially available Neosporin ointment in Comparative Example 5 of the present invention at 0 degrees (a) and 45 degrees (b) and corresponding polarizing microscope images (c, d). Figure 8These are the optical microscope images of the commercially available compound polymyxin B ointment in Comparative Example 6 of the present invention at 0 degrees (a) and 45 degrees (b) and the corresponding polarizing microscope images (c, d). Fig. 9 , Fig.10 , Fig.11 , Fig.12 , Fig.13 The optical microscope images of the anhydrous plant-based compound antibiotic self-emulsifying ointment of Examples 1-5 of the present invention at 0 degrees (a) and 45 degrees (b) and the corresponding polarizing microscope images (c, d) are respectively shown. Figure 7 and Figure 8 As shown in the figure, the crystal particles of commercially available Neosporin and compound polymyxin B ointment are obvious under the microscope. At the same time, there is a clear difference in the alternation of light and dark when the polarization mode is changed from 0° to 45°, which proves the presence of drug crystals, that is, the drug has poor dispersion in the ointment preparation matrix. However, no light and dark changes were observed in the anhydrous plant-based compound antibiotic self-emulsifying ointment samples prepared based on Examples 1 to 5 when the polarization mode of the microscope was changed from 0° to 45°, as shown in the figure. Figures 9 to 13 As shown, it is proved that there is no crystal in the corresponding preparation matrix and the dispersion is good. The above phenomenon shows that the technical solution of the present invention can achieve good dispersion of antibiotic drugs, and the dispersion effect is better than that of commercial products.

[0050] 2. Evaluation of viscosity of the samples of anhydrous plant-based compound antibiotic self-emulsifying ointment, comparative example 5, and comparative example 6 The "viscosity-shear rate" changes of the anhydrous plant-based compound antibiotic self-emulsifying ointment samples prepared in Examples 1 to 5, Neosporin in Comparative Example 5, and the compound polymyxin B ointment in Comparative Example 6 were tested using a rotational rheometer.

[0051] Operation method: Take a small amount of the above sample and place it on a 20 mm 0° plate. Use the Flow-ramp mode, set the gap value to 500 μm, the temperature to 25 °C, and the shear rate to 0.1-100 s -1 The test yielded a “viscosity-shear rate” change curve.

[0052] Fig.14 It is the "viscosity-shear rate" change curve of the samples of Examples 1-5, Comparative Example 5 and Comparative Example 6 of the present invention. Fig.14 It can be seen that the viscosity of the anhydrous plant-based compound antibiotic self-emulsifying ointment samples prepared in Examples 1 to 5 can basically cover the two commercially available products. The viscosity at low shear rate reflects the storage stability of the sample. For example, when the shear rate is 0.1 s -1 When the viscosity of the anhydrous plant-based compound antibiotic self-emulsifying ointment samples prepared in Examples 1 to 5 was 402-4638 , the viscosity of Neosporin is 848 The viscosity of compound polymyxin B is 3518 ; The viscosity at high shear rate reflects the spreadability of the sample, such as when the shear rate is about 100 s -1 When the viscosity of the anhydrous plant-based compound antibiotic self-emulsifying ointment samples prepared in Examples 1 to 5 is 1-6 , the viscosity of Neosporin is 4 The viscosity of compound polymyxin B is 15 The sample of Example 5 has a higher viscosity than the commercial product under low shear rate conditions, and a lower viscosity than the commercial product under high shear rate conditions, making it easier to apply. (Determination of cosmetic viscosity: The shear rate for applying hand cream / lotion is described in the group standard of the rotational rheometer method as 10 2 ~10 4 s -1 ).

[0053] 3. Evaluation of the antibacterial effect of anhydrous plant-based compound antibiotic self-emulsifying ointment and comparative examples 4 to 6 The anhydrous plant-based compound antibiotic self-emulsifying ointment samples prepared in Examples 1 to 5, Neosporin in Comparative Example 5, and the compound polymyxin B ointment in Comparative Example 6 were subjected to an inhibition zone experiment, and antibacterial effect photos were collected and the inhibition zone area was calculated using Image J software.

[0054] Operation method: S1. Prepare sterilized TSA solid culture medium; S2. Activate the bacteria (Escherichia coli, E. coli and Staphylococcus aureus, S. aureus );S3. Test the OD value of the bacterial solution before use and dilute to 1×10 6 CFU / ml; S4. Pipette 100 μl of the diluted bacterial solution into TSA solid culture medium, use sterilized glass beads to disperse it evenly, and pour out the glass beads; S5. Use the sterilized pipette tip to dig a hole, fill it with the sample to ensure the same amount of sample added; S6. Place it in a 37 ℃ constant temperature incubator and culture it overnight, observe the inhibition zone results, collect photos and use ImageJ software to count the inhibition zone area.

[0055] Fig.15 It is a picture of the experimental results of the inhibition zone of Escherichia coli of the samples of Examples 1-5 and Comparative Examples 4-6. Fig.16 The pictures are the results of the antibacterial zone test of the samples of Examples 1-5 and Comparative Examples 4-6 on Staphylococcus aureus. Fig.15 and Fig.16 It can be seen that the samples prepared based on the technical solution of the present invention have stronger antibacterial ability against Escherichia coli and Staphylococcus aureus.

[0056] Fig.17 It is the statistical result of the inhibition zone area of ​​Escherichia coli of the samples of Examples 1-5 and Comparative Examples 4-6. Fig.18 The statistical results of the inhibition zone area of ​​Staphylococcus aureus for samples of Examples 1-5 and Comparative Examples 4-6 are shown in Table 1. Fig.17 and Fig.18 It can be seen that the antibacterial zone areas of the anhydrous plant-based compound antibiotic self-emulsifying ointment samples prepared based on Examples 1 to 5 for both strains are greater than those of Comparative Examples 4 to 6. The antibacterial zone area of ​​the compound polymyxin B ointment needle c of Comparative Example 5 for Escherichia coli is 1.8 cm 2 The inhibition zone area of ​​Neosporin in comparative example 6 against Escherichia coli was 1.3 cm 2 , while the inhibition zone areas of the anhydrous plant-based compound antibiotic self-emulsifying ointment samples prepared in Examples 1 to 5 were 4.9 cm 2 、5.7 cm 2 、4.9 cm 2 、4.4 cm 2 and 5.0 cm 2 The antibacterial zone area of ​​the compound polymyxin B ointment of comparative example 5 against Staphylococcus aureus was 2.4 cm 2 The inhibition zone area of ​​Neosporin in comparative example 6 against Staphylococcus aureus was 1.7 cm 2 , while the inhibition zone areas of the anhydrous plant-based compound antibiotic self-emulsifying ointment samples prepared in Examples 1 to 5 were 6.2 cm 2 、5.9 cm 2 , 5.0 cm 2 、6.0 cm 2 and 5.8 cm 2 The possible reason is that the self-emulsifying matrix can self-emulsify with the wound exudate, thereby promoting drug release, and thus showing better antibacterial effect than commercially available products.

[0057] The various aspects, embodiments, features and examples of the present invention should be considered as illustrative in all aspects and are not intended to limit the present invention, the scope of the present invention is defined only by the claims. Other embodiments, modifications and uses will be apparent to those skilled in the art without departing from the spirit and scope of the claimed invention.

[0058] In addition, the inventors of this case also referred to the aforementioned embodiments and conducted experiments with other raw materials, process operations, and process conditions described in this specification, and obtained relatively ideal results.

[0059] Although the present invention has been described with reference to illustrative embodiments, it will be appreciated by those skilled in the art that various other changes, omissions and / or additions may be made without departing from the spirit and scope of the present invention and that the elements of the embodiments may be replaced by substantial equivalents. In addition, many modifications may be made without departing from the scope of the present invention to adapt specific circumstances or materials to the teachings of the present invention. Therefore, it is not intended herein to limit the present invention to the disclosed specific embodiments for performing the present invention, but it is intended that the present invention will include all embodiments within the scope of the appended claims. In addition, unless specifically stated, any use of the terms first, second, etc. does not indicate any order or importance, but rather uses the terms first, second, etc. to distinguish one element from another element.

Claims

1. An anhydrous plant-based compound antibiotic self-emulsifying ointment, characterized in that: The anhydrous plant-based compound antibiotic self-emulsifying ointment comprises a compound antibiotic drug component and a plant-based semi-solid self-emulsifying matrix, wherein the compound antibiotic drug component comprises a polymyxin antibiotic and a local anesthetic analgesic component, and the compound antibiotic drug component is dissolved and uniformly dispersed in the plant-based semi-solid self-emulsifying matrix to form a solid solution; The plant-based semisolid self-emulsifying matrix comprises plant-based oil, emulsifier, co-emulsifier and thickener, wherein the contents of the plant-based oil, emulsifier, co-emulsifier and thickener are 20-70wt%, 10-30wt%, 10-35wt% and 10-20wt% of the anhydrous plant-based compound antibiotic self-emulsifying ointment, respectively; and the co-emulsifier comprises a small molecule co-emulsifier having a molecular weight of less than 100 and containing one or more active hydroxyl groups.

2. The anhydrous plant-based compound antibiotic self-emulsifying ointment according to claim 1, characterized in that: The content of the polymyxin antibiotic is 0.1-2.5 wt %, and / or the content of the local anesthetic analgesic component is 0.3-7.5 wt %.

3. The anhydrous plant-based compound antibiotic self-emulsifying ointment according to claim 1 or 2, characterized in that: The polymyxin antibiotics include one or more combinations of bacitracin, bacitracin zinc, neomycin sulfate, and polymyxin B sulfate.

4. The anhydrous plant-based compound antibiotic self-emulsifying ointment according to claim 3, characterized in that: The polymyxin antibiotics include bacitracin and / or bacitracin zinc, neomycin sulfate and polymyxin B sulfate, and the contents of bacitracin and / or bacitracin zinc, neomycin sulfate and polymyxin B sulfate are 0.07wt%-1.6wt%, 0.03wt%-0.8wt% and 0.01wt%-0.25wt% of the anhydrous plant-based compound antibiotic self-emulsifying ointment, respectively.

5. The anhydrous plant-based compound antibiotic self-emulsifying ointment according to claim 1 or 2, characterized in that: The local anesthetic analgesic ingredients include caine-type drugs.

6. The anhydrous plant-based compound antibiotic self-emulsifying ointment according to claim 5, characterized in that: The caine-based drugs include one or a combination of lidocaine, lidocaine hydrochloride, procaine hydrochloride or bupivacaine.

7. The anhydrous plant-based compound antibiotic self-emulsifying ointment according to claim 1, characterized in that: The small molecule emulsifier comprises a combination of one or more of 1,2-propylene glycol, 1,3-propylene glycol, ethanol, and glycerol; and / or, the mass of the small molecule emulsifier is more than 30wt% of the total mass of the emulsifier; And / or, the co-emulsifier further comprises ethoxydiglycol and / or PEG400.

8. The anhydrous plant-based compound antibiotic self-emulsifying ointment according to claim 1, characterized in that: The plant-based oil includes one or more of oleyl alcohol, medium-chain triglycerides, isopropyl myristate, cocoyl capryloyl caprate or triacetin; and / or, the emulsifier comprises a combination of one or more of polyoxyethylene 40 hydrogenated castor oil, polyoxyethylene (35) castor oil, polysorbate 20, polysorbate 80, macrogol cetostearyl ether 20 or poloxamer 188; And / or, the thickener includes a combination of one or more of glyceryl mono- and distearate II, poloxamer 407, stearyl alcohol or stearic acid.

9. The anhydrous plant-based compound antibiotic self-emulsifying ointment according to claim 1, characterized in that: The anhydrous plant-based compound antibiotic self-emulsifying ointment is -1 The viscosity under shear rate conditions is 402-4638 , in 100s -1 The viscosity under shear rate conditions is 1-6 .

10. A method for preparing an anhydrous plant-based compound antibiotic self-emulsifying ointment, characterized in that: include: The plant-based oil, emulsifier, co-emulsifier and thickener are mixed and stirred at a temperature of 55° C. to 100° C. until a uniform phase is formed to obtain a plant-based semisolid self-emulsifying matrix; At least a compound antibiotic drug component is mixed with the plant-based semisolid self-emulsifying matrix, wherein the compound antibiotic drug component includes a polymyxin antibiotic and a local anesthetic analgesic component, so that the compound antibiotic drug component is dissolved in the plant-based semisolid self-emulsifying matrix to form a solid solution, and an anhydrous plant-based compound antibiotic self-emulsifying ointment is obtained; Among them, the amounts of the plant-based oil, emulsifier, co-emulsifier and thickener are 20-70wt%, 10-30wt%, 10-35wt% and 10-20wt% of the anhydrous plant-based compound antibiotic self-emulsifying ointment respectively; and the co-emulsifier includes a small molecule co-emulsifier with a molecular weight of less than 100 and containing one or more active hydroxyl groups.

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