Compound nystatin ointment and preparation method thereof

Abstract

The invention provides a compound nystatin ointment and a preparation method thereof, and relates to the technical field of medicine preparation, the compound nystatin ointment comprises active ingredients of nystatin, neomycin sulfate, triamcinolone acetonide and permethrin, and the formula comprises liquid paraffin, white vaseline, wool fat, hexadecanol, PEG-30 dipolyhydroxystearate and glyceryl monoisostearate. According to the compound nystatin ointment preparation prescription process disclosed by the invention, the phenomenon of ointment matrix layering in the use process of commercially available products is mainly solved. According to a pharmaceutical research test, the stability of the compound nystatin ointment is superior to that of a commercially available original development agent, the ointment body character and the stability of active ingredients can be kept under the conditions of high temperature, high humidity, low temperature, freeze thawing and illumination, the maximum single impurity content and the total impurity content in the product are not obviously increased, and the quality is controllable. And meanwhile, an in-vitro transdermal test (IVPT) accidentally finds that the retention amount of related active ingredients is higher than that of the original development agent, and the drug effect is obviously improved. Through clinical test research, the compound nystatin ointment disclosed by the invention can be used for effectively treating external otitis caused by bacteria sensitive to neomycin, fungi sensitive to nystatin and ear mites sensitive to permethrin of dogs and cats.

Description

Technical Field

[0001] The present invention relates to the technical field of pharmaceutical chemistry, and in particular to a compound nystatin ointment and a preparation method thereof. Technical Background

[0002] Compound nystatin ointment is used to treat otitis externa in dogs and cats caused by bacteria, yeasts, and parasites. The commercial product was launched in China in May 2012. Otitis externa is a common ear disease in dogs and cats, especially during hot, humid summer months. It causes itching and an unpleasant odor in the ears. In severe cases, it can lead to suppuration, a foul odor, and even hyperplastic ear canal obstruction. Clinically, the disease has a long course and is prone to relapse. Literature reports indicate that the incidence of otitis externa in dogs ranges from 5-20%, while that in cats is approximately 2%. The causes of otitis externa in dogs and cats are complex, primarily due to parasites, fungi, cross-infection with bacteria, or allergies. Problems with the existing technology: Clinical drug use data indicates that the original formulation developed by Vilon Pharmaceuticals Co., Ltd. in France exhibits ointment separation after opening, coupled with frequent dosing during the treatment cycle. (Approximately 0.3g of ointment should be applied daily to the ear, gently massaging the base of the ear to remove excess. Dosage should be repeated every other day until recovery is complete. The recommended dosing cycle is 21 days.) Therefore, developing more stable preparations and reducing the number of dosing times during the treatment cycle are of great significance for improving the convenience of clinical medication and therapeutic effects.

[0003] To this end, the applicants set out to develop a relatively stable and evenly dispersed compound nystatin ointment. During the development process, they discovered that by pre-treating the ingredients and controlling the cooling rate to a low level, the ingredients, particularly triamcinolone acetonide, were evenly dispersed in the ointment base. Furthermore, through screening the formulation, the ointment's stratification problem was resolved. The applicants unexpectedly discovered that the formulation used a composite emulsifier, PEG-30 dipolyhydroxystearate and glyceryl monoisostearate. PEG-30 dipolyhydroxystearate is an ABA-type block copolymer. Its structure, consisting of two fixed, bulky, long chains, forms a unique, non-rotatable three-dimensional structure at the emulsion interface. Because this polymeric surfactant irreversibly adsorbs to the oil surface, glyceryl monoisostearate assists the emulsifier in stabilizing the emulsion, helping to form a uniform cream system, preventing separation of the oil and water phases, and forming a strong emulsion film. This results in a stable ointment that also increases skin retention and prolongs drug efficacy. Summary of the Invention

[0004] (1) Technical problems solved

[0005] In view of the shortcomings of the existing technology, the present invention provides a compound nystatin ointment and a preparation method thereof, which solves the problems of poor dispersibility of multiple active ingredients and stratification stability of the ointment matrix, and reduces the number of drug administrations during the treatment cycle.

[0006] (II) Technical Solution

[0007] To achieve the above object, the present application is implemented by the following technical solution:

[0008] A compound nystatin ointment, characterized in that:

[0009] The ointment is composed of active ingredients nystatin, neomycin sulfate, triamcinolone acetonide, permethrin and a base, and the base is composed of liquid paraffin, white vaseline, lanolin, cetyl alcohol, PEG-30 dipolyhydroxystearate and glyceryl monoisostearate:

[0010] By pre-dispersing the active ingredients and controlling the cooling process of the base, the three active ingredients nystatin, neomycin sulfate and triamcinolone acetonide are uniformly dispersed in the base in a suspended state.

[0011] Further, in the ointment, the content of nystatin is 1.6% to 3.5% by mass, the content of neomycin sulfate is 0.53% to 1.0% by mass, the content of permethrin is 1% to 3% by mass, the content of triamcinolone acetonide is 0.1% to 0.3% by mass, the content of liquid paraffin is 14% to 40% by mass, the content of lanolin is 4.6% to 15% by mass, the content of cetyl alcohol is 0.4% to 2% by mass, the content of PEG-30 dipolyhydroxystearate is 2.6% to 3.0% by mass, the content of glyceryl monoisostearate is 2.6% to 3.0% by mass, and the rest is vaseline.

[0012] Among them, the liquid paraffin can also be light liquid paraffin; the vaseline can be yellow vaseline or white vaseline.

[0013] The present application also provides a preparation method of the above-mentioned compound nystatin ointment, characterized in that the method comprises the following steps:

[0014] S1, base preparation, heating vaseline to above melting point and completely melting in a vacuum homogenizing emulsifier;

[0015] S2, active ingredient preparation, adding liquid paraffin, nystatin, neomycin sulfate, triamcinolone acetonide and permethrin in a premix tank, and shearing to obtain a suspension liquid;

[0016] S3, mixing, cooling the melted vaseline obtained in step S1 to the melting point, then adding PEG-30 dipolyhydroxystearate, glyceryl monoisostearate, lanolin and cetyl alcohol in sequence, and adding the suspension liquid obtained in step S2 into the vacuum homogenizing emulsifier for homogenizing and mixing until uniform;

[0017] S4, cooling, stirring the mixture obtained in step S3 to room temperature;

[0018] S5, canning.

[0019] Furthermore, in step S1, the vaseline is heated to 80-90°C, in step S3, the vaseline is cooled to 50-70°C; and in step S4, the mixed material is cooled to 22-35°C.

[0020] Furthermore, in step S2, the homogenization parameters are as follows: triamcinolone acetonide, neomycin sulfate, permethrin, and nystatin are taken in the prescribed amount in order and added to the liquid paraffin. After each raw material is added, a shearing machine is used for shearing, and the shearing time should be no less than 3 to 5 minutes, 5 to 8 minutes, 3 to 5 minutes, and 10 to 15 minutes, respectively.

[0021] Furthermore, in step S3, the homogenization mixing parameters are as follows: stirring speed 20-50 rpm, homogenization speed 1500-5000 rpm, homogenization temperature 50-60° C., and homogenization time 10-30 min.

[0022] Furthermore, in step S4, the cooling and stirring parameters are as follows: the stirring speed is 20 to 50 rpm, and the cooling rate is 0.5 to 0.8°C / min.

[0023] (3) Beneficial effects

[0024] The present invention has the following beneficial effects:

[0025] (1) The compound nystatin ointment of the present invention has doubled the amount of active ingredient retained in the skin compared to commercially available products, and has a good therapeutic effect on animal otitis externa;

[0026] (2) The compound nystatin ointment of the present invention has good stability;

[0027] (3) The compound nystatin ointment of the present invention uses pharmaceutical grade excipients in the ointment matrix composition, which improves the stability of the ointment matrix system. The original preparation has a stratification phenomenon after opening.

[0028] (4) The compound nystatin ointment of the present invention has a simple preparation method, and the active ingredients are easily and evenly dispersed in the matrix, making it easier to industrialize. DETAILED DESCRIPTION

[0029] To make the objectives, technical solutions, and advantages of the embodiments of the present invention more clear, the technical solutions in the embodiments of the present invention are clearly and completely described below. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of them. All other embodiments obtained by ordinary technicians in this field based on the embodiments of the present invention without making any creative efforts shall fall within the scope of protection of the present invention.

[0030] Example 1

[0031] The compound nystatin composition in this embodiment includes 1.6 wt % of nystatin, 0.53 wt % of neomycin sulfate, 1 wt % of permethrin, 0.1 wt % of triamcinolone acetonide, 20 wt % of liquid paraffin, 4.6 wt % of lanolin, 0.5 wt % of cetyl alcohol, 2.8 wt % of PEG-30 dipolyhydroxystearate, 2.8 wt % of glyceryl monoisostearate, and 66.07 wt % of petrolatum.

[0032] The preparation process is as follows:

[0033] S1. Matrix preparation: Heat vaseline to 85°C in a vacuum homogenizer and melt it completely;

[0034] S2. Prepare the active ingredient phase by adding liquid paraffin to a premixing tank, and sequentially adding triamcinolone acetonide and shearing for 3 minutes, neomycin sulfate and shearing for 5 minutes, permethrin and shearing for 3 minutes, and nystatin and shearing for 10 minutes at a shearing speed of 11600 rpm to obtain a suspension;

[0035] S3, mixing, after cooling the molten vaseline obtained in step S1 to 60°C, PEG-30 dipolyhydroxystearate, glyceryl monoisostearate, lanolin and cetyl alcohol are added in sequence, and the suspension obtained in step S2 is added to a vacuum homogenizer and homogenized until uniform. The homogenization mixing parameters are as follows: homogenization temperature 60°C, stirring speed 35 rpm, homogenization speed 3000 rpm, and homogenization time 10 min;

[0036] S4, cooling, stirring the mixture obtained in step S3 to room temperature, the cooling and stirring parameters are as follows: stirring speed 25 rpm, cooling to 30.0 ° C, cooling rate 0.6 ° C / min;

[0037] S5. Canned.

[0038] Example 2

[0039] The compound nystatin composition in this embodiment includes 2.4 wt % of nystatin, 0.8 wt % of neomycin sulfate, 1.5 wt % of permethrin, 0.15 wt % of triamcinolone acetonide, 30 wt % of liquid paraffin, 4.6 wt % of lanolin, 0.5 wt % of cetyl alcohol, 2.8 wt % of PEG-30 dipolyhydroxystearate, 2.8 wt % of glyceryl monoisostearate, and 54.45 wt % of petrolatum.

[0040] The preparation process is the same as that of Example 1.

[0041] Example 3

[0042] The compound nystatin composition in the present embodiment comprises nystatin 3.2 wt%, neomycin sulfate 1.06 wt%, permethrin 1.5 wt%, triamcinolone acetonide 0.2 wt%, liquid paraffin 30 wt%, lanolin 4.6 wt%, cetyl alcohol 0.5 wt%, PEG-30 dipolyhydroxystearate 2.8%, glyceryl monoisostearate 2.8%, and vaseline 54.45 wt%.

[0043] The preparation process is the same as that in Example 1.

[0044] Comparative Example

[0045] The product comparative example is a commercially available compound nystatin ointment. Reverse research shows that the product comprises nystatin 1.6 wt%, neomycin sulfate 0.53 wt%, permethrin 1 wt%, triamcinolone acetonide 0.1 wt%, polyethylene wax 4.12 wt%, and liquid paraffin 92.65 wt%.

[0046] Stability comparison test

[0047] Accelerated condition: 30±2℃ / 65±5%RH

[0048] Stability test method

[0049] 1. Appearance: The product is a light yellow ointment.

[0050] 2. Related substances:

[0051] Determination method: high performance liquid chromatography (Chinese Veterinary Pharmacopoeia Appendix 0512).

[0052] Instruments and tools: high performance liquid chromatograph, electronic balance, volumetric flask, pipette, ear suction ball, measuring cylinder, mobile phase filter, ultrasonic cleaner, C18 chromatographic column.

[0053] Reagents: acetonitrile, phosphoric acid, purified water.

[0054] Chromatographic conditions:

[0055] Chromatographic column: octadecylsilane bonded silica gel as filler (Nucleosil 120-3C18, 4mm×125mm, 3μm);

[0056] Mobile phase A: 0.01 mol / L phosphoric acid solution (take 1.15 g of phosphoric acid and add 1000 ml of water, shake well);

[0057] Mobile phase B: acetonitrile;

[0058] Detection wavelength: 240 nm;

[0059] Flow rate: 1.0 ml / min;

[0060] Column temperature: 30℃;

[0061] Injection volume: 10 μl;

[0062] Gradient elution program: Time (minutes) A(％) B(％) 0 80 20 30 5 95 32 80 20 37 80 20

[0063] Test solution: Take about 2.5g of this product, accurately weigh it, put it into a 50ml volumetric flask, add phosphoric acid solution to the scale, ultrasonicate for 5 minutes to dissolve it, let it cool, dilute it to the scale with phosphoric acid solution, shake well, filter, and you are done.

[0064] Control solution: Accurately measure 1 ml of the reference solution under the content determination item, transfer it to a 100 ml volumetric flask, dilute it to the scale with phosphoric acid solution (take 0.1 g of phosphoric acid, add 1000 ml of acetonitrile, and shake well), shake well, accurately measure 10 ml, transfer it to a 50 ml volumetric flask, dilute it to the scale with the above phosphoric acid solution, and shake well.

[0065] Reference solution: Take approximately 10 mg each of 3-phenoxybenzyl alcohol reference substance and 3-phenoxybenzoic acid reference substance, accurately weigh them, and transfer them to a 100 ml volumetric flask. Dilute to the mark with the above phosphoric acid solution and shake well.

[0066] 3. Viscosity: According to the third method of viscosity determination (rotational viscometer determination method) in the general chapter 0633 of the 2020 edition of the Chinese Pharmacopoeia, the NDJ-5S coaxial cylinder rotational viscometer produced by Shanghai Fangrui Instrument Co., Ltd. was used for testing.

[0067] 4. Content determination

[0068] 4.1 Nystatin

[0069] Determination method: Antibiotic microbial assay (Appendix 1201 of the Chinese Veterinary Pharmacopoeia).

[0070] Instruments and equipment: clean workbench, incubator, refrigerator, medicine refrigerator, drying oven, electric constant temperature water bath, pipette, biological safety cabinet, analytical balance, steam sterilizer, vortex oscillator, vernier caliper.

[0071] Reagents, consumables and culture medium: test tubes, blue-cap bottles, disposable sterile pipette tips, disposable sterile double-plate culture dishes, four-piece Oxford cups, Oxford cups (7.8*6*10mm), nystatin test medium, phosphate buffer (pH 6.0), dimethylformamide, methanol.

[0072] Test strains and standards: Saccharomyces cerevisiae, nystatin.

[0073] Test operation:

[0074] Take 0.5g of this product, accurately weigh it, add 10ml of n-hexane, stir to disperse it evenly, accurately add 100ml of water-methanol-dimethylformamide (30:55:15), stir for 20 minutes, separate the lower layer, and dilute it with phosphate buffer (pH 6.0) containing 5% dimethylformamide to a concentration range of 30.0-120.0 units per 1ml. Determine it according to the antibiotic microbiological test method (Appendix 1201 of the Chinese Veterinary Pharmacopoeia).

[0075] 4.2 Neomycin Sulfate

[0076] Determination method: Antibiotic microbial assay (Appendix 1201 of the Chinese Veterinary Pharmacopoeia).

[0077] Instruments and equipment: clean workbench, biochemical incubator, refrigerator, drying oven, electric constant temperature water bath, pipette, biological safety cabinet, analytical balance, steam sterilizer, vernier caliper.

[0078] Reagents, consumables and culture media: test tubes, blue-cap bottles, disposable sterile pipette tips, disposable sterile double-disc culture dishes, four-piece Oxford cups, Oxford cups (7.8*6*10mm), antibiotic assay medium No. II (high pH), antibiotic assay medium No. II (pH7.8-8.0), phosphate buffer (pH8.0), 0.9% sodium chloride solution, nutrient agar.

[0079] Test strains and standards: Staphylococcus aureus, neomycin.

[0080] Test operation:

[0081] Take about 1.15g of this product, accurately weigh it, add 75ml of petroleum ether, stir to disperse evenly, transfer it to a separatory funnel, extract it twice with phosphate buffer (pH8.0), 25ml each time, combine the aqueous layers, place it in a 100ml volumetric flask, dilute it to the scale with phosphate buffer (pH8.0), shake well, and determine it according to the antibiotic microbiological test method (Appendix 1201 of the current Chinese Veterinary Pharmacopoeia).

[0082] 4.3 Triamcinolone acetonide and permethrin

[0083] Determination method: High performance liquid chromatography (Appendix 0512 of the Chinese Veterinary Pharmacopoeia).

[0084] Instruments and equipment: high performance liquid chromatograph, electronic balance, volumetric flask, pipette, ear bulb, measuring cylinder, mobile phase filter, ultrasonic cleaner, C18 chromatographic column.

[0085] Reagents: acetonitrile, phosphoric acid, purified water.

[0086] Chromatographic conditions:

[0087] Chromatographic column: octadecylsilane bonded silica gel as filler (Nucleosil 120-3C18, 4 mm × 125 mm, 3 μm);

[0088] Mobile phase A: 0.01 mol / L phosphoric acid solution (1.15 g of phosphoric acid, add 1000 ml of water, and shake well);

[0089] Mobile phase B: acetonitrile;

[0090] Detection wavelength: 240nm;

[0091] Flow rate: 1.0 ml / min;

[0092] Column temperature: 30°C;

[0093] Injection volume: 10 μl;

[0094] Gradient elution program: Time (minutes) A(％) B(％) 0 80 20 30 5 95 32 80 20 37 80 20

[0095] Test operation:

[0096] Internal standard solution: Take about 250 mg of prednisolone acetate, accurately weigh it, put it into a 250 ml volumetric flask, dissolve it in phosphoric acid solution (take 0.1 g of phosphoric acid, add 1000 ml of acetonitrile, shake well) and dilute it to the scale, shake well, and obtain the internal standard solution.

[0097] Test solution: Take about 2.5g of this product, accurately weigh it, put it into a 50ml volumetric flask, accurately add 5ml of internal standard solution, add phosphoric acid solution to nearly the scale, ultrasonicate for 5 minutes to dissolve it, let it cool, dilute it to the scale with phosphoric acid solution, shake well, filter, and you are done.

[0098] Triamcinolone acetonide reference substance stock solution: Take about 50 mg of triamcinolone acetonide reference substance, accurately weigh it, put it into a 100 ml volumetric flask, dilute it to the scale with phosphoric acid solution, shake well, and obtain it.

[0099] Reference solution: Take about 50 mg of permethrin reference substance, accurately weigh it, and put it into a 100 ml volumetric flask. Accurately add 10 ml each of triamcinolone acetonide reference substance stock solution and internal standard solution, dilute to the scale with phosphoric acid solution, shake well, and obtain.

[0100] 1. A stability test was conducted on the compound nystatin composition of Example 1. The results are as follows:

[0101] The results show that the compound nystatin composition of Example 1 has good stability after 6 months of accelerated treatment. The triamcinolone acetonide component accounts for the lowest proportion and has good mixing uniformity.

[0102] 2. A stability test was conducted on the compound nystatin composition of Example 2. The results are as follows:

[0103] The results show that the compound nystatin composition of Example 2 has good stability after accelerated 6 months, has the lowest proportion of triamcinolone acetonide, and has good mixing uniformity.

[0104] 3. A stability test was conducted on the compound nystatin composition of Example 3. The results are as follows:

[0105] The results show that the compound nystatin composition of Example 3 has good stability after accelerated 6 months, has the lowest proportion of triamcinolone acetonide, and has good mixing uniformity.

[0106] In vitro permeation test

[0107] Detection method

[0108] Determined by high performance liquid chromatography (Chinese Pharmacopoeia 2020 Edition, Part IV, General Chapter 0512). Solvent: 70% ethanol-0.9% sodium chloride solution.

[0109] The test solution is prepared by transdermal release test. After the transdermal release test, the collected solution is filtered and the filtrate is taken.

[0110] Reference solution: Take about 12.5 mg of triamcinolone acetonide reference substance, accurately weigh it, place it in a 50 ml volumetric flask, dissolve it and dilute it to the scale with ethanol, shake it well, and use it as the triamcinolone acetonide reference substance stock solution; take about 80 mg of nystatin, accurately weigh it, place it in a 20 ml volumetric flask, dissolve it and dilute it to the scale with N,N-dimethylformamide (N,N-dimethylformamide), shake it well, and use it as the nystatin stock solution; take about 12.5 mg of neomycin sulfate reference substance, accurately weigh it, place it in a 50 ml volumetric flask, accurately add 5 ml of triamcinolone acetonide reference substance stock solution and 5 ml of nystatin stock solution, dilute it to the scale with solvent, and shake it well. Chromatographic conditions: Octadecylsilane bonded silica gel was used as the filler (e.g., Nucleosil 120-3C18, 4 mm × 125 mm, 3 μm or a chromatographic column of equivalent performance); the mobile phase was 0.01 mol / L phosphoric acid solution (1.15 g of phosphoric acid was added to 1000 ml of water and shaken well)-acetonitrile (80:20); the flow rate was 1.0 ml per minute; the column temperature was 30°C; and the detection wavelength was 240 nm.

[0111] Receiving solution: 70% ethanol-0.9% sodium chloride solution

[0112] Skin selection: Artificial skin membrane (Strat-MTMMembrane); Batch number: 0000210147; Specification: 25 mm; Manufacturer: Merck Chemical Technology (Shanghai) Co., Ltd.

[0113] Sampling time: 2h, 4h, 8h, 16h, 24h, 48h

[0114] Collection of residual solution on the epidermis

[0115] Place the test sample on the membrane after transdermal release test in a 50ml centrifuge tube, add 10ml of N,N-dimethylformamide, and ultrasonicate for 20 minutes, shake well, and filter.

[0116] Intradermal retention solution extraction

[0117] After the transdermal release test, the membrane was cut into pieces and weighed. After weighing, the strips were placed in a grinding cup and frozen in liquid nitrogen for at least 2 hours. 10 ml of N, N-dimethylformamide was added and ultrasonicated for 20 minutes. The mixture was shaken and filtered.

[0118] The 48-hour intradermal retention of the compositions of Examples 1 to 3 and Comparative Example 1 was compared in vitro, and the results are as follows:

[0119] Conclusion: Examples 1 to 3 significantly increase the skin retention amount compared to Comparative Example 1.

[0120] Pharmacodynamic studies

[0121] In order to verify the therapeutic effect of the present invention on otitis media caused by cat ear mite infection, a grouped, blinded, randomized pharmacodynamic study was conducted. This study included 20 adult cats, aged between 1 and 7 years old. The body weight on the day of dosing ranged from 2.5 to 5 kg. Before recruitment, all cats had a confirmed natural ear mite infection in one or both ears. The experimental animals were randomly assigned to two study groups, with 10 cats in each group. On day 0, after cleaning the external ear, the experimental cats applied about 0.3g of ointment (about the size of a pea) to the ears each time, gently massaging the base of the ear to wash off the excess medicine. The medicine was applied once every other day until recovery. Observation was performed daily until day 30. Ear mite assessments were performed on days 7 and 30. The results showed that after 7 days of dosing, the ear mite clearance rate in the dosing group was 100%, and that in the blank control group was 10%. After 30 days of dosing, the ear mite clearance rate in the dosing group was 100%, and that in the blank control group was 20%.

[0122] Local visual observation of the drug administration site (Example 1): No irritation reaction was observed during the drug administration process and after the disease was cured.

[0123] Observation of the drug administration site with naked eyes (commercial product of comparative example): mild erythema appeared during the drug administration.

[0124] Conclusion: The treatment effects of both the case group and the commercial product group in Example 1 reached the efficacy standard during the treatment period. The compound nystatin ointment in Example 1 was less irritating to the skin at the administration site than the commercial product.

[0125] In order to more clearly illustrate the technical solutions of the embodiments of the present invention, the following briefly introduces the drawings required for clinical experiments. BRIEF DESCRIPTION OF THE DRAWINGS

[0126] Figure 1 This is a picture of a case with more ear canal secretions.

[0127] Figure 2 The case of ear mites (eggs) was observed during otoscopy.

[0128] Figure 3 Cases were selected in which fungi or bacteria were observed under microscopic examination of ear canal secretions.

[0129] Figure 4 This is a case diagram before administration of the test product in Example 1.

[0130] Figure 5 This is a case diagram after administration of the test product in Example 1.

[0131] Figure 6 This is a picture of the case before administration of the comparative test product.

[0132] Figure 7 This is a case diagram after administration of the comparative test product.

[0133] Figure 8 This is a graph showing the properties of the sample from Example 1 after long-term storage for 36 months.

[0134] Figure 9 This is the performance diagram of the commercially available product at the end of its efficacy period.

[0135] It should be noted that, in this article, the above embodiments are only used to illustrate the technical solutions of the present invention, rather than to limit it. Although the present invention has been described in detail with reference to the aforementioned embodiments, those skilled in the art should understand that they can still modify the technical solutions described in the aforementioned embodiments, or make equivalent replacements for some of the technical features therein. However, these modifications or replacements do not deviate the essence of the corresponding technical solutions from the spirit and scope of the technical solutions of the various embodiments of the present invention.

Claims

1. A compound nystatin ointment, characterized in that: Compound nystatin ointment is composed of active ingredients nystatin, neomycin sulfate, triamcinolone acetonide, permethrin and a matrix. The matrix is ​​composed of a thickener, a stabilizer, an emulsifier and a carrier. By pre-dispersing the active ingredients and controlling the cooling of the matrix, the three active ingredients, nystatin, neomycin sulfate and triamcinolone acetonide, are evenly dispersed in the matrix in a suspended state.

2. The preparation according to claim 1, wherein the thickener is selected from at least one of lanolin, sodium carboxymethyl cellulose, and polyethylene glycol; the stabilizer is selected from at least one of glyceryl monoisostearate, polyethylene glycol, disodium edetate, beeswax, and spermaceti; the emulsifier is selected from at least one of cetyl alcohol, stearyl alcohol, PEG-30 dipolyhydroxystearate, glyceryl monoisostearate, coconut diethanolamide, and lauryl polyoxyethylene ether, preferably a composite emulsifier combination of glyceryl monoisostearate and PEG-30 dipolyhydroxystearate; and the carrier is selected from at least one of vaseline and paraffin.

3. The compound nystatin ointment according to claim 1, characterized in that: The ointment comprises, by mass percentage, 16% to 20% by weight of nystatin, 5.6% to 15% by weight of neomycin sulfate, 1% to 3% by weight of permethrin, 0.1% to 0.3% by weight of triamcinolone acetonide, 14% to 40% by weight of liquid paraffin, 4.6% to 15% by weight of lanolin, 0.4% to 2% by weight of cetyl alcohol, 2.6% to 3.0% of PEG-30 dipolyhydroxystearate, 2.6% to 3.0% of glyceryl monoisostearate, and the remainder being vaseline.

4. The method for preparing the compound nystatin ointment according to claim 1 or 2, wherein: The method comprises the following steps: S1. Matrix preparation: In a vacuum homogenizer, vaseline is heated to a temperature exceeding the melting point and completely melted; S2. Prepare the active ingredients by adding liquid paraffin, nystatin, neomycin sulfate, triamcinolone acetonide, and permethrin into a premixing tank, and shearing the mixture using a shearing machine to obtain a suspension; S3, mixing, cooling the molten vaseline obtained in step S1 to the melting point, adding PEG-30 dipolyhydroxystearate, glyceryl monoisostearate, lanolin and cetyl alcohol in sequence, and then adding the suspension obtained in step S2 to a vacuum homogenizer and homogenizing and mixing until uniform; S4, cooling the mixture obtained in step S3 by stirring and cooling to room temperature; S5. Canned.

5. The preparation method according to claim 3, wherein In step S1, the vaseline is heated to 80-90° C., in step S3, the vaseline is cooled to 50-70° C.; and in step S4, the mixed material is cooled to 22-35° C.

6. The preparation method according to claim 3, wherein In step S2, the homogenization parameters are as follows: triamcinolone acetonide, neomycin sulfate, permethrin, and nystatin are taken in the prescribed amount in order and added to liquid paraffin. After each raw material is added, a shearing machine is used for shearing. The shearing time should be no less than 3 to 5 minutes, 5 to 8 minutes, 3 to 5 minutes, and 10 to 15 minutes, respectively.

7. The preparation method according to claim 3, wherein In step S3, the homogenization mixing parameters are as follows: stirring speed 20-50 rpm, homogenization speed 1500-5000 rpm, homogenization temperature 50-60° C., and homogenization time 10-30 min.

8. The preparation method according to claim 3, wherein In step S4, the cooling and stirring parameters are as follows: the stirring speed is 20-50 rpm, and the cooling rate is 0.5-0.8°C / min.

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