An ivermectin external pharmaceutical composition, preparation method and application

Abstract

The application relates to the technical field of pharmaceutical preparations, and provides an ivermectin external pharmaceutical composition, a preparation method and application.The ivermectin external pharmaceutical composition is mainly composed of ivermectin, a permeation enhancer combination, oil ingredients, an emulsifier, a viscosity regulator and a carrier; the ivermectin content is 0.60%-1.00% w / w; the permeation enhancer combination is a combination of diethylene glycol monoethyl ether, decyl umbelliferrone polyoxyethylene ether 8 and farnesol, and the content is 10%-15% w / w.The application overcomes the defects of the prior art, the composition not only has improved skin permeability and retention, but also is stable and non-greasy, and meanwhile, the production process has scalability, and can ensure uniform dispersion of active ingredients and auxiliary materials.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical formulation technology, and in particular to a topical medicine with ivermectin as the active ingredient, specifically to an ivermectin topical medicine composition, preparation method and application. Background Technology

[0002] Ivermectin is a well-known antiparasitic drug with broad-spectrum activity against various parasites. Although ivermectin has been used topically, its efficacy has been less than ideal. This is because ivermectin has a high molecular weight, resulting in poor penetration into the skin and maximally remaining in the stratum corneum. Based on studies of SOOLANTRA (ivermectin) cream... TM A study using [ivermectin]cream evaluated the in vitro absorption of 1% [3H]-ivermectin cream using excised human skin, with a total permeation dose of 2.2%. Radioactivity was primarily recovered in the stratum corneum (1.6%), with only 0.03% recovered in the receptor fluid. The estimated absolute bioavailability after topical application of ivermectin to mice, rats, dogs, or miniature pigs was 4% for mice, 2% for rats, and 0.4% for dogs.

[0003] Therefore, we propose an ivermectin topical drug composition, its preparation method, and its application. Summary of the Invention

[0004] (a) Technical problems to be solved

[0005] To address the shortcomings of existing technologies, this invention provides an ivermectin topical pharmaceutical composition, preparation method, and application, which overcomes the deficiencies of existing technologies, improves skin permeability and retention, and does not affect the original efficacy and indications for treating rosacea, scabies, and other parasitic skin infections.

[0006] (II) Technical Solution

[0007] To achieve the above objectives, the present invention provides the following technical solution:

[0008] An ivermectin topical pharmaceutical composition, characterized in that it comprises:

[0009] The active ingredient, ivermectin, has a content of 0.60%–1.00% w / w.

[0010] The penetration enhancer combination is a combination of diethylene glycol monoethyl ether, decyl umbelliferone polyoxyethylene ether 8 (CAPRYLOCAPROYLPOLYOXYLGLYCERIDES 8) and farnesol, with a content of 10% to 15% w / w.

[0011] Oil component, content of which is 12.00% to 18.00% w / w;

[0012] Emulsifier, with a content of 2.00% to 5.00% w / w;

[0013] Viscosity modifier, with a content of 0.10% to 2.00% w / w;

[0014] The carrier is water, and its content is the balance or to make up to 100%.

[0015] Furthermore, in the penetrant, the mass ratio of diethylene glycol monoethyl ether, decyl umbelliferone polyoxyethylene ether 8, and farnesol is 5:5:1.

[0016] Furthermore, the emulsifier is a dual-gel emulsifier from Gaffars, France. Duo.

[0017] Furthermore, the oil component is a combination of medium-chain triglycerides, mineral oil, and olive oil, wherein the mass ratio of the medium-chain triglycerides, mineral oil, and olive oil is 1:1:1.

[0018] Furthermore, the viscosity modifier is a carbomer copolymer type B, and the composition does not contain an alkaline neutralizing agent, which includes sodium hydroxide, potassium hydroxide, triethanolamine, or ammonia.

[0019] Furthermore, the composition comprises:

[0020] Preservatives, with a content of 0.02% to 0.6 w / w;

[0021] Moisturizer, with a content of 8.00% to 10.00% w / w;

[0022] Chelating agent, with a content of 0.01% to 0.08% w / w.

[0023] Furthermore, the preservative is sodium benzoate;

[0024] The humectant is propylene glycol;

[0025] The chelating agent is disodium ethylenediaminetetraacetate.

[0026] Furthermore, in this composition,

[0027] Ivermectin (0.60% w / w): An active ingredient with antiparasitic and anti-inflammatory effects;

[0028] Diethylene glycol monoethyl ether (5.00% w / w): Improves the solubility and permeability of ivermectin in the skin;

[0029] Decyl Umbelliferone Polyoxyethylene Ether 8 (5.00% w / w): A nonionic surfactant that improves skin permeability;

[0030] Farnesol (1.00% w / w): A natural sesquiterpene alcohol that enhances permeability and provides antibacterial properties;

[0031] Medium-chain triglycerides (5.00% w / w): used as a solvent and emollient;

[0032] Mineral oil (5.00% w / w): Provides occlusive properties and enhances skin hydration;

[0033] Olive oil (5.00% w / w): a natural emollient with antioxidant properties;

[0034] Duo (3.00% w / w): A proprietary emulsifier that stabilizes the formulation and improves texture;

[0035] Sodium benzoate (0.50% w / w): It dissociates benzoic acid, inhibits the growth of microorganisms, and the released sodium ions can neutralize the acidic groups of carbomer, promote the hydration of its molecular chains and the formation of its three-dimensional network structure, thereby stabilizing the dosage form.

[0036] Propylene glycol (10.00% w / w): Maintains moisture and improves spreadability;

[0037] Disodium ethylenediaminetetraacetate (0.05% w / w): Improves stability by chelating metal ions;

[0038] Carbomer copolymer type B (1.00% w / w): Adjusts viscosity for easier application;

[0039] Water (to bring the total to 100%) is used as the substrate.

[0040] The present invention also provides a method for preparing the above-mentioned ivermectin topical pharmaceutical composition, characterized by comprising the following steps:

[0041] S1. Preparation of aqueous phase: The type B carbomer copolymer is dispersed in a mixed solution of disodium ethylenediaminetetraacetate and propylene glycol to prepare an aqueous phase, and then water is added for hydration to obtain the aqueous phase;

[0042] S2. Preparation of the oil phase: Medium-chain triglycerides, mineral oil, olive oil, decyl umbelliferone polyoxyethylene ether 8, farnesol, and... Duo-mixing yields the oil phase;

[0043] S3. Preparation of the drug phase: Ivermectin is added to diethylene glycol monoethyl ether and then mixed with the above oil phase to obtain the drug phase;

[0044] S4. Emulsifying the oil phase and aqueous phase: The above-mentioned drug phase is added to the aqueous phase and emulsified to obtain an emulsified intermediate;

[0045] S5. Add preservatives: Dissolve sodium benzoate in purified water and mix it with the above emulsification intermediate and homogenize it;

[0046] S6. Mix to obtain an ivermectin topical drug composition.

[0047] Further, S1, preparing the aqueous phase: At room temperature, disodium ethylenediaminetetraacetate is added to propylene glycol; under high-speed stirring, carbomer copolymer type B is dispersed in the above solution, taking care not to form powder clumps; at room temperature, purified water is added to the carbomer copolymer type B dispersion; the carbomer copolymer type B solution is hydrated for 60 minutes under stirring at room temperature; and then slowly homogenized at room temperature for 10 minutes to break up any clumps or fish eyes formed during the addition process to obtain the aqueous phase.

[0048] S2. Preparation of the oil phase: Add medium-chain triglycerides, mineral oil, decyl umbelliferone polyoxyethylene ether 8, farnesol, olive oil, and... to the oil phase container. Duo, stir at room temperature for 10 minutes to obtain the oil phase;

[0049] S3. Preparation of the drug phase: Ivermectin is added to diethylene glycol monoethyl ether, and the mixture is transferred to the oil phase under stirring; if necessary, it is heated at 50±2℃ and then cooled to room temperature to obtain the drug phase;

[0050] S4. Emulsification: Add the above drug phase to the aqueous phase and stir homogenize at room temperature for 30±10 minutes to obtain an emulsified intermediate.

[0051] S5. Add preservatives: Dissolve sodium benzoate in purified water at room temperature; add the aqueous solution of sodium benzoate to the above emulsification intermediate and homogenize at room temperature for 30±5 minutes.

[0052] S6. Mixing: Stir and mix at room temperature for 30±5 minutes to obtain the ivermectin topical drug composition.

[0053] A method of treating parasitic skin infections, rosacea, or other skin diseases, comprising applying the above-described ivermectin topical pharmaceutical composition to the affected area.

[0054] (III) Beneficial Effects

[0055] This invention provides an ivermectin topical pharmaceutical composition, its preparation method, and its application, which have the following beneficial effects:

[0056] 1. Due to the synergistic effect among the components of the improved ivermectin topical drug composition, the skin permeability of ivermectin is enhanced, and its retention in the skin is significantly increased;

[0057] 2. The improved ivermectin topical drug composition does not affect the original efficacy and indications, and remains effective against a variety of skin diseases, including parasitic infections and rosacea;

[0058] 3. The improved ivermectin topical drug composition can reduce the concentration of the active ingredient ivermectin and reduce the amount of various excipients, resulting in high cost-effectiveness, simple process, and scalability;

[0059] 4. The improved ivermectin topical drug combination has slightly improved formulation stability and shelf life;

[0060] 5. The improved ivermectin topical drug composition eliminates glycerin and uses different oil components, emulsifiers, and proportions, making the product non-greasy, easy to use, and suitable for local application. Detailed Implementation

[0061] To make the objectives, technical solutions, and advantages of the embodiments of the present invention clearer, the technical solutions in the embodiments of the present invention are described clearly and completely. Obviously, the described embodiments are only some embodiments of the present invention, not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0062] Example 1: Ivermectin topical gel 0.6w / w

[0063] Formula composition:

[0064] Table 1: Formulation composition of Example 1: Ivermectin topical latex 0.6 w / w

[0065]

[0066] Production process:

[0067] S1. Preparation of the aqueous phase: At room temperature (15-25℃, the same below), add disodium ethylenediaminetetraacetate to propylene glycol; disperse carbomer copolymer type B in the above solution under high-speed stirring, avoiding the formation of powder clumps; add purified water to the carbomer copolymer type B dispersion at room temperature; hydrate the carbomer copolymer type B solution for 60 minutes under stirring at room temperature; slowly homogenize at room temperature for 10 minutes to break up clumps or fish eyes formed during the addition process to obtain the aqueous phase;

[0068] S2. Preparation of the oil phase: Add medium-chain triglycerides, mineral oil, decyl umbelliferone polyoxyethylene ether 8, farnesol, olive oil, and... to the oil phase container. Duo, stir at room temperature for 10 minutes to obtain the oil phase;

[0069] S3. Preparation of the drug phase: Ivermectin is added to diethylene glycol monoethyl ether, and the mixture is transferred to the oil phase under stirring; if necessary, it is heated at 50±2℃ and then cooled to room temperature to obtain the drug phase;

[0070] S4. Emulsification: Add the above drug phase to the aqueous phase and stir homogenize at room temperature for 30±10 minutes to obtain an emulsified intermediate.

[0071] S5. Add preservatives: Dissolve sodium benzoate in purified water at room temperature; add the sodium benzoate aqueous solution to the above emulsification intermediate and homogenize at room temperature for 30±5 minutes.

[0072] S6. Mixing: Stir the homogenized solution from step S5 at room temperature for 30 ± 5 minutes.

[0073] An ivermectin topical pharmaceutical composition was obtained, specifically an ivermectin topical gel at 0.6 w / w.

[0074] Example 2: Ivermectin topical gel 1.0 w / w

[0075] Compared to Example 1, Example 2 differs from Example 1 except that the ivermectin concentration is changed from 0.6% to 1% w / w and the purified water content is adjusted to 58.45% w / w (to make up to 100%). The formulation composition and process of Example 2 are similar to those of Example 1, and the contents of other components and the production process are the same.

[0076] Example 3: Comparative formulation of ivermectin cream, 1% w / w

[0077] Formula composition:

[0078] Table 2: Formulation combination of ivermectin topical cream in Example 3 (1 w / w)

[0079]

[0080]

[0081] Production process:

[0082] Preparation of the aqueous phase: Mix purified water, propylene glycol, and glycerol under stirring to form a homogeneous solution. Heat the solution to 70±5℃. Add and dissolve citric acid, methyl benzoate, propylparaben, and disodium EDTA one-to-one ratio to the mixture of purified water, propylene glycol, and glycerol, maintaining a temperature of 70±5℃. Disperse the type B carbomer copolymer in the above solution under high-speed stirring, avoiding the formation of powder clumps. Hydrate the carbomer solution at 70±5℃ with stirring for 50 minutes. Homogenize slowly at 70±5℃ for 10 minutes to break up any agglomerates or fisheyes formed during the addition process.

[0083] Preparation of the oil phase: Cetyl alcohol, oleyl alcohol, stearyl alcohol, sorbitol monostearate, and polyoxyethylene 20 cetearyl ether are added to an oil phase container. The oil phase components are heated and melted at 70±5℃.

[0084] Emulsification: Add the oil phase to the aqueous phase, rinse the oil phase with hot water, and then add it in large quantities. Stir and homogenize at 70±5℃ for 30±10 minutes.

[0085] Intermediate cooling: The homogenized and stirred emulsion is cooled to the target temperature of 60±2℃ by circulating water at 18-25℃. Then, the stirred emulsion is cooled to the target temperature of 50±2℃ by circulating water at 18-25℃.

[0086] Preparation of the drug phase: Isopropyl palmitate and phenoxyethanol were mixed and stirred at 50±2℃. Ivermectin was dissolved in the mixture of isopropyl palmitate and phenoxyethanol at 50±2℃ with stirring. Stirring was continued until a clear solution was formed.

[0087] Adding the drug phase: Add the drug phase to the cooled emulsion, then rinse the drug container with a mixture of isopropyl palmitate and phenoxyethanol. Add the rinsed solution to the cooled emulsion. Add polydimethylsiloxane 200 20 CS with stirring, and homogenize at 50±2℃ for 20±5 minutes.

[0088] Final cooling: Cool the block to the target temperature of 40±2℃ by circulating water at 15-20℃ with stirring. Adjust the pH to 6.0±0.2 with sodium hydroxide solution. Cool the block to the target temperature of 30±2℃ by circulating water at 2-8℃ with stirring.

[0089] Example 4: In vitro release study

[0090] To evaluate the in vitro release rates of ivermectin emulsion and cream formulations, the following method was employed. A vertical Franz diffusion cell apparatus and a 0.45 μm polyvinylidene fluoride (Durapore HLVP) membrane were used, with water / ethanol (40 / 60, v / v) as the acceptor medium. The water bath conditions and medium temperature were maintained at 35 ± 1 °C to simulate skin temperature. Ivermectin was quantitatively analyzed using high-performance liquid chromatography (HPLC). A water / ethanol (40 / 60) mixture was prepared, filtered through a 0.45 μm filter, and degassed before use. The synthetic membrane was cut to the appropriate size for the Franz diffusion cell and hydrated in the acceptor medium for at least 1 hour before use. The hydrated synthetic membrane was placed between the donor and acceptor chambers. Degassed acceptor medium was injected into the acceptor chamber, and the system was equilibrated in a water bath to 35 ± 1 °C for 15–20 minutes. A measured amount of ivermectin formulation (300 mg) was uniformly applied to the membrane in the donor chamber, and the donor chamber was covered to prevent evaporation. Aliquots of samples were drawn at predetermined time intervals of 50, 100, 150, 200, 250, and 300 minutes, and 0.2 mL was aspirated from the acceptor chamber. Preheated acceptor medium was then added to maintain the water bath conditions. Samples were analyzed using a validated high-performance liquid chromatography (HPLC) method, and the amount of ivermectin released at each time point was quantified using a calibration curve. The cumulative amount of ivermectin released per unit area (μg / cm²) at each time point was calculated. 2 (See Table 3.) Compared to the cream in Example 3, the gels in Examples 1 and 2 showed a stable improvement in release efficiency, increasing by 3.89% and 6.92%, respectively.

[0091] Table 3: Results of in vitro release studies

[0092] time Example 1 Example 2 Example 3 30 minutes 23.7％ 25.7％ 24.3％ 60 minutes 41.5％ 43.8％ 42.4％ 90 minutes 58.3％ 60.5％ 59.5％ 120 minutes 71.4％ 74.5％ 73.2％ 180 minutes 82.8％ 85.6％ 84.6％ 240 minutes 91.1％ 94.5％ 87.9％ 300 minutes 96.1％ 98.9％ 92.5％

[0093] Example 5: In vitro permeation test

[0094] In vitro permeation testing (IVPT) of ivermectin was performed using Franz diffusion cells equipped with excised porcine skin to simulate permeation conditions. The recipient zone was filled with phosphate-buffered saline / ethanol (70 / 30 v / v) at pH 7.4, and the temperature was maintained at 32 ± 1 °C to simulate skin temperature, ensuring sedimentation conditions. A precise amount of 1000 mg of ivermectin was uniformly applied to the skin in the donor chamber and then sealed to prevent evaporation. Aliquots (e.g., 1 mL) were aspirated from the recipient zone every 1, 2, 4, 6, 8, and 24 hours, and the recipient medium was replaced with fresh medium to maintain volume. The samples were analyzed using LC-MS / MS to quantify ivermectin permeation. Permeability was calculated in multiple layers of skin and the recipient medium.

[0095] Table 4: Results of in vitro permeation studies

[0096]

[0097] Here, n represents the number of independent samples for example 1 / 2 / 3.

[0098] Referring to Table 4, the penetration rate of 0.6% ivermectin emulsion is similar to that of 1.0% ivermectin cream, while the penetration rate of 1.0% ivermectin emulsion is significantly higher than that of the cream formulation. However, the penetration rates of 1% ivermectin emulsion and ivermectin cream to receptor mediators are similar. This indicates that the skin permeability and retention in the skin of ivermectin emulsion formulation are significantly increased, and that when the ivermectin concentration is reduced, for example to 0.6%, it can maintain a similar penetration rate to 1.0% ivermectin cream while avoiding penetration into the systemic circulation. In addition, although adding a penetrant combination to Example 3 above can also improve the skin's permeability, the permeability of the corresponding receptor mediators also increases simultaneously, causing ivermectin to further penetrate into the systemic circulation. When ivermectin enters the bloodstream, it may be distributed throughout the body, which can cause some adverse reactions, such as abdominal pain, anorexia, constipation, diarrhea, nausea, vomiting, dizziness, drowsiness, vertigo, tremor, itching, rash, and urticaria.

[0099] Example 6: Skin irritation study

[0100] Skin irritation studies of topical ivermectin formulations using miniature pigs require animal acclimatization for at least 7 days, followed by shaving of the hair on the back or belly. Piglets are divided into experimental and control groups, and 1 gram of the finished ivermectin product is applied daily to the designated shaving area for 7–14 days, covered with sterile gauze to prevent shedding. Skin reactions (erythema, edema, etc.) are scored daily using a standard scale (such as the Draize system) at 1, 4, 24, 48, and 72 hours after application, and photographs are taken. Overall health and behavior are monitored to determine the presence of systemic toxicity. Data are analyzed, irritation scores are compared between groups, and statistical significance is determined.

[0101] Drez rating system reference:

[0102] Erythema and eschar formation: 0 = no erythema, 1 = very slight erythema, 2 = clear erythema, 3 = moderate to severe erythema, 4 = severe erythema with eschar formation

[0103] Edema formation: 0 = no edema, 1 = very slight edema, 2 = slight edema, 3 = moderate edema, 4 = severe edema.

[0104] The following is a template for a skin irritation study form comparing Examples 1, 2, and 3 using the Dresden scoring system. The form includes erythema and edema scores, as well as the overall likelihood of irritation.

[0105] Table 5: Results of Skin Irritation Studies

[0106]

[0107] See Table 5:

[0108] Example 1: No stimulation (scores below 1 at all time points).

[0109] Example 2: Mild irritation (erythema score of 2 points, edema score of 1 point).

[0110] Example 3: No irritation (no erythema or edema observed).

[0111] The redness in Example 2 may be attributed to the higher penetration rate of ivermectin in the skin compared to Examples 1 and 3.

[0112] When any type of carbomer is used in a formulation, it is accompanied by neutralizing agents such as sodium hydroxide, potassium hydroxide, triethanolamine, or ammonia, as in Example 3. These neutralizing agents are substances that can potentially irritate the skin. In clinical trials of ivermectin cream products, according to clinical data provided by the FDA, SOOLANTRA (ivermectin) cream... TM [(ivermectin)cream] also used carbomer type B and sodium hydroxide as a neutralizer. Patients have reported skin burning sensation and skin irritation symptoms. Among subjects treated with Suranta cream for at least 3 months, ≤1% reported adverse reactions including skin burning sensation and skin irritation symptoms.

[0113] Example 7: Microbial limit test

[0114] Microbial limit tests were performed according to Chapters 60, 61, and 62 of the United States Pharmacopeia (USP). Samples were prepared by homogenizing a 0.6% w / w solution of ivermectin latex gel from Example 1. Samples were rigorously inspected to ensure homogeneity, as microbial contamination is not uniformly dispersed throughout the batch or sample of the product. Conventional mechanical agitation was used without altering the original quantity and type of microorganisms in the product. Samples received were analyzed immediately after the study. The master container of each unit was visually inspected for integrity, noting any irregularities. The outer surface of the sample container was aseptically wiped with an effective antimicrobial agent and placed on a sterilized tray or surface in a properly sterilized laminar flow hood or biosafety cabinet. The container was allowed to dry. Where possible, the container was aseptically opened in a laminar flow hood or biosafety cabinet, and a weighing procedure was performed. Appropriate environmental controls, such as air exposure plates, were used according to local quality procedures. An appropriate negative control was used and run concurrently with the sample.

[0115] Table 6: Results of Microbial Limit Test in Example 1

[0116]

[0117] Referring to Table 6, the microbial limit test data for stability showed that no microbial growth occurred in the formulation containing 0.5% sodium benzoate preservative. Therefore, 0.5% sodium benzoate in topical latex can prevent microbial growth.

[0118] The original formulation (Example 3) contained three preservatives: phenoxyethanol, methylparaben, and propylparaben. Parabens are now rarely used because they can cause serious adverse reactions such as contact dermatitis, hypersensitivity, decreased immunity, hormonal imbalances, breast cancer, skin cancer, irritation, and developmental and reproductive toxicity. Phenoxyethanol can also cause skin allergies, redness, itching, or burning sensations. The combination of all these preservatives can potentially cause skin allergies, and people with sensitive or sensitized skin may be more prone to these reactions. Sodium benzoate is considered a safer preservative and can be used in oral, oral, intramuscular, intravenous, rectal, and topical formulations; therefore, sodium benzoate is used instead of the combination of the three preservatives mentioned above.

[0119] Example 8: Antibacterial efficacy test

[0120] The test was conducted in accordance with Chapter 51 of the United States Pharmacopeia General Principles. The standard test microbiome used in most methods included three bacterial strains (Staphylococcus aureus, Escherichia coli, and Pseudomonas aeruginosa), one mold strain (Aspergillus brasiliensis), and one yeast strain (Candida albicans). These standardized strains all met the standards of the United States Culture Collection (ATCC). The standard microbiome was added to the product formulation at 100,000 to 1,000,000 microorganisms per gram or milliliter, and then incubated for 28 days at controlled room temperature (20–25°C). After day 28, the formulation was re-inoculated with the same microorganisms for a second challenge, and the process was repeated for a total of 56 days. During incubation, microbial growth (or no growth) was counted at specific time intervals of 2, 7, 14, 28, and 56 days.

[0121] Table 7: Results of the antibacterial efficacy test in Example 1

[0122]

[0123] As shown in Table 7, the modified preservatives ensure that the formulation will not be accidentally inoculated with microorganisms. Therefore, 0.5% sodium benzoate replaces several preservatives in the formulation while maintaining the safe efficacy against microbial growth.

[0124] Example 9: Stability Study

[0125] The samples from Examples 1 and 3 underwent stability studies under accelerated storage conditions. Descriptive, pH, laboratory, and organic impurity analyses were performed on the samples at 0, 3, and 6 months.

[0126] Table 8: Stability results of Example 1

[0127]

[0128] Compared to Example 3, the test results and degradation products of Examples 1 and 2 were more stable over a period of time. Therefore, their stability is improved compared to existing formulations.

[0129] Conclusion: The topical latex formulation significantly improves drug penetration without compromising safety. The improved formulation reduces the dosage of ivermectin from 1% to 0.6%, thereby lowering costs and making the formulation more economical. Furthermore, the formulation is free of parabens, enhancing safety, and passed microbial limit and antimicrobial efficacy tests. In summary, this formulation composition reduces multiple excipients that may cause adverse reactions, lowering the cost of the finished product.

[0130] It should be noted that, in this document, the terms "comprising," "including," or any other variations thereof are intended to cover non-exclusive inclusion, such that a process, method, article, or apparatus that comprises a list of elements includes not only those elements but also other elements not expressly listed, or elements inherent to such a process, method, article, or apparatus. Unless otherwise specified, an element defined by the phrase "comprising one..." does not exclude the presence of other identical elements in the process, method, article, or apparatus that includes said element.

[0131] The above embodiments are only used to illustrate the technical solutions of the present invention, and are not intended to limit it. Although the present invention has been described in detail with reference to the foregoing embodiments, those skilled in the art should understand that modifications can still be made to the technical solutions described in the foregoing embodiments, or equivalent substitutions can be made to some of the technical features. Such modifications or substitutions do not cause the essence of the corresponding technical solutions to deviate from the spirit and scope of the technical solutions of the embodiments of the present invention.

Claims

1. An ivermectin pharmaceutical composition for external use, characterized by comprising: The composition comprises: Ivermectin 0.60% w / w; Diethylene glycol monoethyl ether 5.00% w / w; Caprylocaproyl polyoxylglycerides 8 5.00% w / w; Farnesol 1.00% w / w; Medium chain triglycerides 5.00% w / w; Mineral oil 5.00% w / w; Olive oil 5.00% w / w; Emulfree® Duo 3.00% w / w; Sodium benzoate 0.50% w / w; Propylene glycol 10.00% w / w; Disodium edetate 0.05% w / w; Carbomer copolymer type B 1.00% w / w; Pure water to 100%.

2. The method of preparing the external pharmaceutical composition of ivermectin according to claim 1, wherein, The method comprises the following steps: S1, preparing an aqueous phase: dispersing the carbomer copolymer type B in a mixed solution of disodium edetate and propylene glycol to prepare an aqueous phase, and then adding water to hydrate to obtain the aqueous phase; S2, preparing an oil phase: mixing medium chain triglycerides, mineral oil, olive oil, caprylocaproyl polyoxylglycerides 8, farnesol and Emulfree® Duo to obtain an oil phase; S3, preparing a drug phase: adding ivermectin to diethylene glycol monoethyl ether, and then mixing with the above oil phase to obtain a drug phase; S4, emulsifying the oil phase and the aqueous phase: adding the above drug phase to the aqueous phase and emulsifying to obtain an emulsified intermediate; S5, adding a preservative: dissolving sodium benzoate in pure water and mixing with the above emulsified intermediate and homogenizing; S6, mixing to obtain an ivermectin external use pharmaceutical composition.

3. The preparation method of claim 2, wherein, S1, preparing an aqueous phase: adding disodium edetate in propylene glycol at room temperature; dispersing carbomer copolymer type B in the above solution under high-speed stirring without forming powder lumps; adding pure water to the carbomer copolymer type B dispersion at room temperature; hydrating the carbomer copolymer type B solution under room temperature stirring for 60 minutes; and homogenizing at room temperature for 10 minutes at a slow speed to break the lumps or fish eyes formed during the addition process to obtain the aqueous phase; S2, preparing an oil phase: adding medium chain triglycerides, mineral oil, caprylocaproyl polyoxylglycerides 8, farnesol, olive oil and Emulfree® Duo in an oil phase container, and stirring at room temperature for 10 minutes to obtain an oil phase; S3, preparing a drug phase: adding ivermectin to diethylene glycol monoethyl ether, and transferring the mixture to the oil phase under stirring to obtain a drug phase; S4, emulsifying: adding the above drug phase to the aqueous phase, and homogenizing at room temperature for 30±10 minutes to obtain an emulsified intermediate; S5, adding a preservative: dissolving sodium benzoate in pure water at room temperature; and adding the aqueous solution of sodium benzoate to the above emulsified intermediate, and homogenizing at room temperature for 30±5 minutes; S6. Mixing: The solution homogenized in the above step S5 is mixed by stirring at room temperature for 30 ± 5 minutes.

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