Ivermectin external pharmaceutical composition, preparation method and application

Abstract

The invention 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, an oil component, an emulsifier, a viscosity modifier and a carrier; the content of the ivermectin is 0.60% w / w to 1.00% w / w; the permeation enhancer combination is a combination of diethylene glycol monoethyl ether, decyl umbelliferone polyoxyethylene ether 8 and farnesyl alcohol, and the content of the permeation enhancer combination is 10-15% w / w. According to the composition, the defects in the prior art are overcome, the skin permeability and retention performance of the composition are improved, the product is stable and not greasy, meanwhile, the production process has expandability, and it can be ensured that active ingredients and auxiliary materials are evenly dispersed.

Description

Technical Field

[0001] The present invention relates to the technical field of pharmaceutical preparations, and particularly to an external drug with ivermectin as an active ingredient, and specifically relates to an ivermectin external drug composition, a preparation method and an application. Background Art

[0002] Ivermectin is a well-known anti-parasitic drug with broad-spectrum activity against various parasites. Although ivermectin has been used externally, its efficacy is not ideal. The reason is that the molecular weight of ivermectin is relatively high, resulting in poor permeability in the skin and being retained in the stratum corneum to the greatest extent. According to the research on [SOOLANTRA TM (ivermectin) cream, the in vitro absorption of [3H]-ivermectin 1% cream was evaluated using human excised skin, and the total permeation dose was 2.2%. The radioactivity was mainly recovered in the stratum corneum (1.6%), and only 0.03% was recovered in the receptor fluid. After local application of ivermectin to mice, rats, dogs or minipigs, the estimated absolute bioavailability was: 4% for mice, 2% for rats, and 0.4% for dogs.

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

[0004] (1) Technical Problems to be Solved

[0005] Aiming at the deficiencies of the prior art, the present invention provides an ivermectin external drug composition, a preparation method and an application, which overcome the deficiencies of the prior art, improve skin permeability and retention, and do not affect the original efficacy and indications of treating rosacea, scabies and other parasitic skin infections.

[0006] (2) Technical Solutions

[0007] To achieve the above object, the present invention is realized through the following technical solutions:

[0008] An ivermectin external drug composition, characterized by comprising:

[0009] An active ingredient, ivermectin, with a content of 0.60% - 1.00% w / w;

[0010] A penetration enhancer combination, which is a combination of diethylene glycol monoethyl ether, caprylocaproyloxyl glycerides 8 (CAPRYLOCAPROYLPOLYOXYLGLYCERIDES 8) and farnesol, and the content of this penetration enhancer combination is 10% - 15% w / w;

[0011] Oil component, content is 12.00% - 18.00% w / w;

[0012] Emulsifier, content is 2.00% - 5.00% w / w;

[0013] Viscosity regulator, content is 0.10% - 2.00% w / w;

[0014] Carrier is water, content is the balance or made 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 the double gel emulsifier Duo from Gattefosse, France Duo.

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

[0018] Furthermore, the viscosity regulator is carbomer copolymer type B, and the composition does not contain alkaline neutralizing reagents, and the alkaline neutralizing reagents include sodium hydroxide, potassium hydroxide, triethanolamine or ammonia water.

[0019] Furthermore, the composition includes:

[0020] Preservative, content is 0.02% - 0.6 w / w;

[0021] Humectant, content is 8.00% - 10.00% w / w;

[0022] Chelating agent, content is 0.01% - 0.08% w / w.

[0023] Even further, the preservative is sodium benzoate;

[0024] The humectant is propylene glycol;

[0025] The chelating agent is disodium ethylenediaminetetraacetate.

[0026] Furthermore, in the composition,

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

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

[0029] Decylumbelliferone polyoxyethylene ether 8 (5.00% w / w): A non-ionic surfactant that can enhance skin permeability;

[0030] Farnesol (1.00% w / w): A natural sesquiterpenol that can enhance permeability and provide 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 can stabilize the formulation and improve the texture;

[0035] Sodium benzoate (0.50% w / w): Dissociates into benzoic acid to inhibit microbial growth. The released sodium ions can neutralize the acidic groups of carbomer, promoting the hydration and three-dimensional network structure formation of its molecular chains, thus stabilizing the dosage form;

[0036] Propylene glycol (10.00% w / w): Maintains humidity 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): Regulates viscosity for easy application;

[0039] Water (up to 100%), as the matrix.

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

[0041] S1. Prepare the aqueous phase: Disperse the carbomer copolymer type B in a mixed solution of disodium ethylenediaminetetraacetate and propylene glycol to prepare the aqueous phase, and then add water for hydration to obtain the aqueous phase;

[0042] S2. Prepare the oil phase: Mix medium-chain triglycerides, mineral oil, olive oil, decylumbelliferone polyoxyethylene ether 8, farnesol and Duo to obtain the oil phase;

[0043] S3. Prepare the drug phase: Add ivermectin to diethylene glycol monoethyl ether, and then mix it with the above-mentioned oil phase to obtain the drug phase;

[0044] S4. Emulsify the oil phase and the water phase: Add the above-mentioned drug phase to the water phase and emulsify to obtain an emulsified intermediate;

[0045] S5. Add a preservative: Dissolve sodium benzoate in purified water and then mix and homogenize with the above-mentioned emulsified intermediate;

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

[0047] Furthermore, S1. Prepare the water phase: At room temperature, add disodium ethylenediaminetetraacetate to propylene glycol; under high-speed stirring, disperse Carbomer copolymer type B in the above solution without forming powder agglomerates; at room temperature, add purified water to the Carbomer copolymer type B dispersion; under stirring at room temperature, hydrate the Carbomer copolymer type B solution for 60 minutes; homogenize slowly at room temperature for 10 minutes to break up the lumps or fish eyes formed during the addition process to obtain the water phase;

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

[0049] S3. Prepare the drug phase: Add ivermectin to diethylene glycol monoethyl ether and transfer the mixture to the oil phase under stirring; heat at 50 ± 2 °C if necessary, and then cool to room temperature to obtain the drug phase; obtain the drug phase;

[0050] S4. Emulsify: Add the above-mentioned drug phase to the water phase and stir and homogenize at room temperature for 30 ± 10 minutes to obtain an emulsified intermediate;

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

[0052] S6. Mix: Stir and mix at room temperature for 30 ± 5 minutes to obtain an ivermectin topical pharmaceutical composition.

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

[0054] (III) Beneficial effects

[0055] The present invention provides an ivermectin topical pharmaceutical composition, a preparation method and an application, having the following beneficial effects:

[0056] 1. Due to the synergistic effect among the components of the penetrant combination, the improved ivermectin topical pharmaceutical composition enhances the skin permeability of ivermectin and significantly increases its retention in the skin;

[0057] 2. The improved ivermectin topical pharmaceutical composition does not affect the original efficacy and indications and is still effective against various skin diseases, including parasitic infections and rosacea;

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

[0059] 4. The stability and shelf - life of the preparation of the improved ivermectin topical pharmaceutical composition are slightly improved;

[0060] 5. The improved ivermectin topical pharmaceutical composition deletes glycerol and adopts different oil components, emulsifiers, and proportioning relationships, making the product texture non - greasy, easy to use, and suitable for topical use. Detailed implementation mode

[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 clearly and completely described. Obviously, the described embodiments are part of the embodiments of the present invention, rather than all of them. Based on the embodiments of the present invention, all other embodiments obtained by those of ordinary skill in the art without creative efforts belong to the scope of protection of the present invention.

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

[0063] Formulation composition:

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

[0065]

[0066] Production procedure:

[0067] S1. Prepare the aqueous phase: At room temperature (15 - 25 °C, the same below), add disodium ethylenediaminetetraacetate to propylene glycol; under high - speed stirring, disperse Carbomer copolymer type B in the above solution without forming powder agglomerates; at room temperature, add pure water to the Carbomer copolymer type B dispersion; under stirring at room temperature, hydrate the Carbomer copolymer type B solution for 60 minutes; homogenize slowly at room temperature for 10 minutes to break the agglomerates or fisheyes formed during the addition process to obtain the aqueous phase;

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

[0069] S3. Preparation of the drug phase: Add ivermectin into diethylene glycol monoethyl ether, and transfer the mixture to the oil phase under stirring; heat at 50 ± 2 °C if necessary, and then cool to room temperature to obtain the drug phase; obtain the drug phase;

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

[0071] S5. Adding preservative: Dissolve sodium benzoate in pure water at room temperature; add the aqueous solution of sodium benzoate to the above emulsified intermediate, and homogenize at room temperature for 30 ± 5 minutes;

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

[0073] An ivermectin topical pharmaceutical composition is obtained, specifically ivermectin topical gelatin 0.6 w / w.

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

[0075] Compared with Example 1, in Example 2, except that the ivermectin concentration changes from 0.6% to 1% w / w and the pure water content is adjusted to 58.45% w / w (to make up 100%), the formulation components and processes of Example 2 are similar to those of Example 1, and the contents of other components and the production process procedures are the same.

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

[0077] Formulation composition:

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

[0079]

[0080]

[0081] Production procedure:

[0082] Preparation of the aqueous phase: Mix purified water, propylene glycol, and glycerin under stirring to form a homogeneous solution. Heat the solution to a temperature of 70 ± 5 °C. Add and dissolve citric acid, methyl benzoate, propyl p-hydroxybenzoate, and disodium ethylenediaminetetraacetate one by one in the mixture of purified water, propylene glycol, and glycerin at a temperature of 70 ± 5 °C. Under high-speed stirring, disperse the Carbomer B copolymer in the above solution without forming powder agglomerates. Hydrate the Carbomer solution with stirring at a temperature of 70 ± 5 °C for 50 minutes. Homogenize slowly for 10 minutes at a temperature of 70 ± 5 °C to break up the lumps or fish eyes formed during the addition process.

[0083] Preparation of the oil phase: Add cetyl alcohol, oleyl alcohol, stearyl alcohol, sorbitan monostearate, and polyoxyethylene 20 cetostearyl ether to the oil phase container. Heat and melt the oil phase components at a temperature of 70 ± 5 °C.

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

[0085] Intermediate cooling: Cool the homogenized and stirred emulsion to a target temperature of 60 ± 2 °C by circulating water at 18 - 25 °C. Then, cool the stirred emulsion to a target temperature of 50 ± 2 °C by circulating water at 18 - 25 °C.

[0086] Preparation of the drug phase: Stir and mix isopropyl palmitate and phenoxyethanol at 50 ± 2 °C. Dissolve ivermectin in the mixture of isopropyl palmitate and phenoxyethanol under stirring at 50 ± 2 °C. Continue stirring until a transparent solution is formed.

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

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

[0089] Example 4: In vitro release study

[0090] To evaluate the in vitro release rates of ivermectin latex and cream formulations, the following method was adopted. A vertical Franz diffusion cell apparatus and a 0.45 μm polyvinylidene fluoride (Durapore HLVP) membrane were used, and the receptor medium was water / ethanol (40 / 60, v / v). The sink conditions and the medium temperature were maintained at 35 ± 1 °C to simulate skin temperature. High-performance liquid chromatography was used for the quantitative analysis of ivermectin. A water / ethanol (40 / 60) mixture was prepared, filtered through a 0.45 μm filter membrane, and degassed before use. The synthetic membrane was cut into a size suitable for the Franz diffusion cell and hydrated in the receptor medium for at least 1 hour before use. The hydrated synthetic membrane was placed between the donor chamber and the receptor chamber. The degassed receptor medium was injected into the receptor chamber, and the system was allowed to equilibrate in a water bath at 35 ± 1 °C for 15 - 20 minutes. A certain amount of 300 mg of the ivermectin formulation was evenly applied onto the membrane in the donor chamber, and the donor chamber was covered to prevent evaporation. Aliquot samples were withdrawn at predetermined time intervals of 50, 100, 150, 200, 250, and 300 minutes, and 0.2 mL was withdrawn from the receptor chamber, and then the preheated receptor medium was replaced to maintain the sink conditions. The samples were analyzed by a validated high-performance liquid chromatography 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 at each time point (μg / cm 2 ) was calculated. Referring to Table 3, the release effects of the latex formulations in Examples 1 and 2 showed a stable improvement compared to the cream formulation in Example 3, with increases of 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] The in vitro permeation test (IVPT) of the ivermectin formulation was carried out using a Franz diffusion cell equipped with excised porcine skin to simulate the permeation conditions. The receptor region was filled with phosphate buffer / ethanol (70 / 30 v / v) at pH 7.4, and the temperature was maintained at 32 ± 1 °C to simulate skin temperature, ensuring the sedimentation conditions. An exact amount of 1000 mg of the ivermectin formulation was evenly applied onto the skin in the donor chamber, and then sealed to prevent evaporation. At intervals of 1, 2, 4, 6, 8, and 24 hours, aliquot samples (such as 1 mL) were withdrawn from the receptor region, and fresh receptor medium was replaced to maintain the volume. The samples were analyzed using an LC-MS / MS method to quantify the permeation of ivermectin. The permeation rates in the multi-layer skin and the receptor medium were calculated.

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

[0096]

[0097] Among them, n is the number of independent samples in 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 into the receptor medium are similar. This indicates that the skin permeability and retention of the ivermectin emulsion dosage form are significantly increased, and when the ivermectin concentration is reduced, for example, reduced to 0.6%, it can avoid penetration into the systemic circulation while maintaining a similar penetration rate to 1.0% ivermectin cream. In addition, although adding a penetration enhancer combination based on Example 3 above can also improve the skin penetration rate, the penetration rate of the corresponding receptor medium also increases synchronously, resulting in further penetration of ivermectin into the systemic circulation. When ivermectin enters the blood, 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, tremors, itching, rash, and urticaria.

[0099] Example 6: Skin irritation study

[0100] For the skin irritation study of ivermectin topical preparations using minipigs, the animals need to be acclimated for at least 7 days, and then the hair on the dorsal or ventral side is shaved off. The piglets are divided into a test group and a control group, and 1 gram of the finished ivermectin product is applied to the specified depilated area every day. This is continued for 7 - 14 days, and it is covered with a sterile gauze to prevent shedding. At 1, 4, 24, 48, and 72 hours after application, the skin reactions (erythema, edema, etc.) are scored daily using a standard scale (such as the Draize system), and photographs are taken for recording. The overall health status and behavior are monitored to determine whether there is systemic toxicity. The data is analyzed to compare the irritation scores between groups and to determine statistical significance.

[0101] Reference for the Draize scoring system:

[0102] Erythema and eschar formation: 0 = no erythema, 1 = very slight erythema, 2 = distinct 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 table template for comparing the skin irritation studies of Example 1, Example 2, and Example 3 using the Draize scoring system. The table includes erythema and edema scores and the overall likelihood of irritation.

[0105] Table 5: Results of skin irritation study

[0106]

[0107] See Table 5:

[0108] Example 1: Non-irritating (scores at all time points are less than 1 point).

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

[0110] Example 3: Non-irritating (no erythema or edema was observed).

[0111] This reddening phenomenon in Example 2 may be attributed to a higher penetration rate of ivermectin in the skin, which is higher than that in Examples 1 and 3.

[0112] When using any type of carbomer in the formulation, neutralizing agents such as sodium hydroxide, potassium hydroxide, triethanolamine, or ammonia water are accompanied. For example, in Example 3, these neutralizing reagents are substances that have potential irritation to the skin. In the clinical test of ivermectin cream products, according to the clinical data provided by the US Food and Drug Administration, Soolantra (ivermectin) cream TM (ivermectin) cream] also uses carbomer type B and uses sodium hydroxide as a neutralizing agent. Patients have reported skin burning sensations and skin irritation symptoms. Among the subjects who used Soolantra cream for at least 3 months, ≤1% of the people reported adverse reactions including skin burning sensations and skin irritation symptoms.

[0113] Example 7: Microbial limit test

[0114] The microbial limit test was carried out according to Chapters 60, 61, and 62 of the United States Pharmacopeia (USP). The sample preparation method was to make a homogeneous solution of 0.6% w / w of ivermectin latex gel in Example 1. The samples were strictly examined to ensure the uniformity of the solution because microbial contamination is not evenly dispersed in batches or samples of the product. A traditional mechanical oscillation method was used without changing the original quantity and type of microorganisms in the product. Immediately after the study ended, the received samples were analyzed. Visually inspect each unit of the primary container for integrity and note any irregularities. Use an effective antibacterial agent to wipe the outer surface of the sample container aseptically and place it on a sterilized tray or surface in a properly sterilized laminar flow hood or biosafety cabinet. Let the container dry. Open the container aseptically in the laminar flow hood or biosafety cabinet as much as possible and perform the weighing procedure. Use appropriate environmental controls, such as air exposure plates, in accordance with local quality procedures. Use appropriate negative controls and run them simultaneously with the samples.

[0115] Table 6: Results of the microbial limit test for Example 1

[0116]

[0117] See Table 6. The microbial limit test data on stability shows that there is no microbial growth in the formulation containing 0.5% sodium benzoate preservative. Therefore, 0.5% sodium benzoate in the topical emulsion can prevent microbial growth.

[0118] The original formulation (Example 3) contained three preservatives: phenoxyethanol, methyl benzoate, and propyl paraben. Parabens are currently less used because they can cause serious adverse reactions such as contact dermatitis, hypersensitivity reactions, decreased immunity, hormonal disorders, breast cancer, skin cancer, irritation, and developmental and reproductive toxicity. Phenoxyethanol can also cause skin allergies, redness, itching, or a burning sensation. The combination of all these preservatives may cause skin allergies, and people with sensitive or allergic skin may be more prone to these reactions. Sodium benzoate is considered a safer preservative and can be used in oral, oral cavity, intramuscular, intravenous, rectal, and topical preparations. Therefore, sodium benzoate was used to replace the combination of the above three preservatives.

[0119] Example 8: Antimicrobial Efficacy Test

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

[0121] Table 7: Antimicrobial Efficacy Test Results of Example 1

[0122]

[0123] See Table 7. The modified preservative can ensure that the formulation is not accidentally inoculated with microorganisms. Therefore, 0.5% sodium benzoate replaced multiple preservatives in the formulation and maintained the safe efficacy of preventing microbial growth.

[0124] Example 9: Stability Study

[0125] The samples of Example 1 and Example 3 were subjected to stability studies under accelerated storage conditions. The samples were described, pH values, assays, and organic impurity analyses were performed at time points such as 0 months, 3 months, and 6 months.

[0126] Table 8: Stability Results of Example 1

[0127]

[0128] Compared with Example 3, the assay results and degradation products of Examples 1 and 2 were more stable over a period of time. Therefore, its stability was improved compared with the existing formulations.

[0129] Conclusion: The topical emulsion formulation can significantly improve drug permeability without affecting the safety of the formulation. The improved formulation reduced the dose of ivermectin from 1% to 0.6%, thus reducing the cost and making the formulation more economical. In addition, the formulation does not contain parabens, thus improving safety and passing the microbial limit test and antibacterial efficacy test. In short, the formulation composition reduces various excipients that may cause adverse reactions and reduces the cost of the finished product.

[0130] It should be noted that in this article, the terms "including", "comprising", or any other variants thereof are intended to cover non-exclusive inclusion, so that a process, method, article, or device including a series of elements not only includes those elements, but also includes other elements not expressly listed, or also includes elements inherent to such process, method, article, or device. Without further limitation, an element defined by the statement "including one..." does not exclude the existence of additional identical elements in the process, method, article, or device including the said element.

[0131] The above embodiments are only used to illustrate the technical solutions of the present invention and are not intended to limit them; although the present invention has been described in detail with reference to the foregoing embodiments, those of ordinary skill in the art should understand that they can still modify the technical solutions described in the foregoing embodiments, or perform equivalent replacements for some of the technical features; and these modifications or replacements 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 external pharmaceutical composition, characterized in that: include: The active ingredient, ivermectin, is present in an amount of 0.60% to 1.00% w / w; A penetration enhancer combination, which is a combination of diethylene glycol monoethyl ether, decyl umbelliferone polyoxyethylene ether 8 and farnesol, wherein the content of the penetration enhancer combination is 10% to 15% w / w; Oil component, content is 12.00% to 18.00% w / w; Emulsifier, content of 2.00% to 5.00% w / w; Viscosity modifier, content of 0.10% to 2.00% w / w; The carrier is water, and its content is the balance or makes up to 100%.

2. The ivermectin external pharmaceutical composition according to claim 1, characterized in that: In the penetrant, the mass ratio of diethylene glycol monoethyl ether, decyl umbelliferyl polyoxyethylene ether 8 and farnesol is 5:5:

1.

3. The ivermectin external pharmaceutical composition according to claim 1, characterized in that: The emulsifier is a double gel emulsifier from Gattefossé, France Duo.

4. The ivermectin external pharmaceutical composition according to claim 1, characterized in that: The oil component is a combination of medium-chain triglycerides, mineral oil and olive oil, and the mass ratio of the medium-chain triglycerides, mineral oil and olive oil is 1:1:

1.

5. The ivermectin external pharmaceutical composition according to claim 1, characterized in that: The viscosity modifier is carbomer copolymer type B. The composition does not contain an alkaline neutralizing agent, and the alkaline neutralizing agent includes sodium hydroxide, potassium hydroxide, triethanolamine or ammonia water.

6. The ivermectin external pharmaceutical composition according to claim 1, characterized in that: The composition comprises: Preservatives, content 0.02% to 0.6w / w; Moisturizer, content of 8.00% to 10.00% w / w; Chelating agent, content is 0.01% to 0.08% w / w.

7. The ivermectin external pharmaceutical composition according to claim 6, characterized in that: The preservative is sodium benzoate; The moisturizing agent is propylene glycol; The chelating agent is disodium ethylenediaminetetraacetate.

8. The ivermectin external pharmaceutical composition according to claim 1, characterized in that: The composition: Ivermectin 0.60% w / w; Diethylene glycol monoethyl ether 5.00% w / w; Decylumbelliferone polyoxyethylene ether 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; Duo 3.00%w / w; Sodium benzoate 0.50% w / w; Propylene glycol 10.00% w / w; Disodium EDTA 0.05% w / w; Carbomer Copolymer Type B 1.00% w / w; Make up to 100% with purified water.

9. The method for preparing the ivermectin external pharmaceutical composition according to claim 8, characterized in that: The following steps are involved: S1, preparing an aqueous phase: dispersing the type B carbomer copolymer in a mixed solution of disodium ethylenediaminetetraacetate and propylene glycol to prepare an aqueous phase, and then adding water for hydration to obtain an aqueous phase; S2, prepare the oil phase: medium chain triglyceride, mineral oil, olive oil, decyl umbelliferyl polyoxyethylene ether 8, farnesol and Duo mixing to obtain oil phase; S3, preparing a drug phase: adding ivermectin to diethylene glycol monoethyl ether, and then mixing it with the oil phase to obtain a drug phase; S4, emulsifying the oil phase and the water phase: adding the above-mentioned drug phase to the water phase and emulsifying to obtain an emulsified intermediate; S5. Adding preservatives: dissolving sodium benzoate in purified water and mixing with the emulsified intermediate to homogenize; S6. Mix to obtain an ivermectin external pharmaceutical composition.

10. The preparation method according to claim 9, characterized in that: S1. Prepare the aqueous phase: add disodium ethylenediaminetetraacetate to propylene glycol at room temperature; disperse the carbomer copolymer type B in the above solution under high-speed stirring without forming powder lumps; 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; homogenize slowly at room temperature for 10 minutes to break up lumps or fish eyes formed during the addition process to obtain the aqueous phase; S2. Prepare the oil phase: Add medium chain triglycerides, mineral oil, decyl umbelliferone polyoxyethylene ether 8, farnesol, olive oil and Duo, stirred 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 an oil phase under stirring to obtain a drug phase; S4, emulsification: adding the above drug phase to the aqueous phase, stirring and homogenizing at room temperature for 30±10 minutes to obtain an emulsified intermediate; S5. Adding preservatives: dissolving sodium benzoate in purified water at room temperature; 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 step S5 is stirred and mixed at room temperature for 30±5 minutes.

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