Pharmaceutical composition of phenol derivative with improved stability and use thereof

Abstract

Pharmaceutical compositions of phenol derivatives with improved stability and uses thereof. The invention discloses a pharmaceutical composition of a phenol derivative and application of the pharmaceutical composition. The pharmaceutical composition comprises the following components: an active component, a thickening agent, an emulsifier, a humectant, a chelating agent, a pH regulator, an oil phase matrix and water, wherein the active component is selected from at least one of a compound as shown in a formula (I) and pharmaceutically acceptable salts thereof; wherein the active ingredients are dispersed in the form of uniform emulsion droplets, and have good physical and chemical stability. The composition is suitable for treating atopic dermatitis, psoriasis and seborrheic dermatitis, especially children atopic dermatitis and dermatoseborrheic dermatitis, and has good safety, stability, effectiveness and uniform morphology characteristics. # imgabs0 #

Description

[0001] This application claims priority to a prior application with patent application number 20231 1442719.6 filed on November 2, 2023, entitled “Pharmaceutical composition of phenol derivatives with improved stability and use thereof”. The entire text of the prior application is incorporated into this application by reference. Technical Field

[0002] The present disclosure belongs to the field of pharmaceutical compositions, and in particular relates to a pharmaceutical composition of a phenol derivative with improved stability and uses thereof. Background Art

[0003] Atopic dermatitis (AD) is a chronic, recurrent, inflammatory skin disease. In recent years, the incidence of AD has been on the rise worldwide. The etiology and pathogenesis of AD are still unclear and may be related to multiple factors such as genetics, skin barrier defects, immunity, environment, and microbial colonization. At present, the treatment of mild to moderate AD in children is usually based on topical glucocorticoids and calcineurin inhibitors, while the treatment of moderate, severe or refractory AD in children is more difficult and requires individualized treatment. There is no systematic and universal drug treatment, otherwise it will seriously affect the quality of life and mental health of children.

[0004] Seborrheic dermatitis (SD) is a chronic papulosquamous, superficial inflammatory skin disease that occurs in the area of ​​sebum secretion. The typical rash is dark red, yellow-red spots formed by the fusion of follicular papules, covered with greasy scales or scabs, and may be accompanied by varying degrees of itching. SD is a chronic, recurrent inflammatory skin disease, usually manifested as a red scaly rash. The incidence rate in healthy people is 5%, of which 70.3% occurs on the head, common in infants, adolescents and adults. Seborrheic dermatitis refers to a disease of the scalp. The difference between this disease and simple dandruff is that it has erythema as a sign of inflammation, the degree of scalp flaking is greater and sometimes accompanied by itching and burning, and eczema occurs in other parts of the body. The disease can occur in the form of plaques, but often affects the entire scalp and exceeds the hairline, often including the forehead, around the neck and both ears. In severe cases, the scalp may become secondary infected, and changes may appear as a spongy texture, with blisters and crusts that may ooze. Seborrheic dermatitis also frequently occurs in infancy and usually resolves spontaneously at 8-12 months of age. Scalp changes in infants include erythema, flaking of the scalp, and occasional blisters and crusts that may resolve spontaneously within a few weeks, recur intermittently, or persist throughout childhood. These changes are often accompanied by similar lesions around the eyelids, nose, and ears. The condition then frequently recurs after adolescence and can persist throughout life, even with the potential for more severe symptoms. Approximately 1-3% of the population suffers from the disease. The etiology and pathogenesis of SD are still unclear, with the complex interaction of Malassezia, keratinocytes, and immune responses playing a crucial role in the onset of SD. Seborrheic dermatitis shares some of the same pathogenic factors as inflammatory skin diseases such as atopic dermatitis, such as the regulation of factors that stimulate keratinocyte proliferation and differentiation, and disruption of the skin barrier. Atopic dermatitis usually manifests as a Th2 immune response, with elevated levels of interleukin (IL)-4 and IL-13, while seborrheic dermatitis is mainly a Th2 and Th17 response, with elevated levels of IL-4, IL-17, and IL-8.

[0005] Current treatments for seborrheic dermatitis include simple anti-inflammatory drugs (such as topical hormone preparations, calcineurin inhibitors), supplemented with skin moisturizing skin care products, but the efficacy is low; and symptoms are prone to recurrence after drug discontinuation.

[0006] Although CN108066279A and CN113797159A disclose research on benzophenone mod external cream, the properties of the samples are poor, and there is still a large proportion of blocky oily substances, which affects the product performance. Moreover, the examples of CN114042041A show that the white vaseline in its preparation leads to the formation of waxy substances, and even the preparation containing a lower level of white vaseline will lead to uneven emulsion, but the preparation without vaseline oil has a uniform emulsion.

[0007] Therefore, providing a pharmaceutical composition / preparation for treating AD in children and a pharmaceutical combination / preparation for treating SD that can eliminate the anxiety and fear caused by hormone drugs to children and take into account safety, stability, effectiveness and uniform morphological characteristics is still a technical problem that needs to be urgently solved in this field. Summary of the invention

[0008] In order to improve the above technical problems, the present disclosure provides a pharmaceutical composition, comprising the following components: an active ingredient, a thickener, an emulsifier, a humectant, a chelating agent, a pH regulator, an oil phase matrix and water, wherein the active ingredient is selected from at least one of the compounds represented by formula (I) and pharmaceutically acceptable salts thereof;

[0009]

[0010] According to the embodiments of the present disclosure, the compound represented by formula (I) may be an E-type or Z-type isomer, preferably an E-type isomer represented by the following formula (I-1):

[0011]

[0012] According to a preferred embodiment of the present disclosure, the compound represented by formula (I-1) is benvimod.

[0013] According to an embodiment of the present disclosure, the pharmaceutically acceptable salt may be selected from addition salts of the compound of formula (I) and a base.

[0014] In a preferred embodiment, the pharmaceutical composition contains only the compound represented by formula (I) as the active ingredient, and preferably contains only the E-isomer represented by formula (I-1) (i.e., bevimod) as the active ingredient.

[0015] According to an embodiment of the present disclosure, in the pharmaceutical composition, the active ingredient is present in the form of emulsion droplets, and preferably the diameter of the emulsion droplets is less than 10 μm, such as less than 5 μm.

[0016] According to an embodiment of the present disclosure, in the pharmaceutical composition, the weight portion of the active ingredient is 0.1 to 8 parts, such as 0.5 to 5 parts, and exemplified by 0.5 parts, 0.75 parts, 1 parts, 1.25 parts, 1.5 parts, 2 parts, 2.5 parts, 3 parts, 3.5 parts or 4 parts.

[0017] According to an embodiment of the present disclosure, the thickener is selected from one or more of cetyl alcohol, stearyl alcohol and cetostearyl alcohol.

[0018] According to an embodiment of the present disclosure, in the pharmaceutical composition, the weight portion of the thickener is 2 to 15 parts, such as 5 to 10 parts, exemplified by 6 parts, 7 parts or 8 parts.

[0019] According to an embodiment of the present disclosure, the emulsifier is selected from one or more of polyethylene glycol cetearyl ether, mono- and distearic glyceryl, polyethylene glycol stearate (e.g., polyethylene glycol-7 stearate), polyoxyethylene hydrogenated castor oil (polyoxyethylene (54) hydrogenated castor oil), and polysorbate 80. In some embodiments, the emulsifier is polyethylene glycol cetearyl ether, mono- and distearic glyceryl, and polysorbate 80; in other embodiments, the emulsifier is polyethylene glycol cetearyl ether and mono- and distearic glyceryl; in yet other embodiments, the emulsifier is polyethylene glycol-7 stearate and polysorbate 80. Preferably, the emulsifier contains at least polyethylene glycol cetearyl ether and mono- and distearic glyceryl, for example, the emulsifier consists of polyethylene glycol cetearyl ether and mono- and distearic glyceryl, or consists of polyethylene glycol cetearyl ether, mono- and distearic glyceryl, and polysorbate 80.

[0020] According to an embodiment of the present disclosure, in the pharmaceutical composition, the weight portion of the emulsifier is 2 to 25 parts, such as 5 to 20 parts, exemplified by 6 parts, 6.5 parts, 7 parts, 7.5 parts, 8 parts, 10 parts, 12 parts or 16 parts.

[0021] According to an embodiment of the present disclosure, in the pharmaceutical composition, when there are two emulsifiers, the weight ratio of the two emulsifiers can be (1-3): (3-1), for example (1-2): (2-1), such as (1-1.5): (1.5-1), and (1-1.2): (1.2-1), and specific examples are 3:3.5, 3.5:3 or 1:1. Exemplarily, when the emulsifier is polyethylene glycol cetostearyl ether and mono- and distearic acid glyceryl, the weight ratio of polyethylene glycol cetostearyl ether and mono- and distearic acid glyceryl can be (1-3): (3-1), for example (1-2): (2-1), such as (1-1.5): (1.5-1), and (1-1.2): (1.2-1), and specific examples are 3:3.5, 3.5:3 or 1:1.

[0022] According to an embodiment of the present disclosure, in the pharmaceutical composition, when there are three emulsifiers, based on the total weight of the emulsifiers, the proportion of each emulsifier in the total weight of the emulsifiers can be independently selected from 1 / 5 to 1 / 2, such as 1 / 4 to 1 / 3, such as 2 / 7 to 1 / 3.

[0023] In some embodiments, when there are three emulsifiers, the weight ratio of the three emulsifiers can be (1.5-3): (1.5-3): 1, for example (1.7-2.5): (1.7-2.5): 1, and exemplarily 3.5: 3: 1.5. For example, the emulsifier is composed of polyethylene glycol cetostearyl ether, glyceryl mono- and distearate, and polysorbate 80, and the weight ratio of polyethylene glycol cetostearyl ether, glyceryl mono- and distearate, and polysorbate 80 can be (1.5-3): (1.5-3): 1, for example (1.7-2.5): (1.7-2.5): 1, and exemplarily 3.5: 3: 1.5.

[0024] According to an embodiment of the present disclosure, the moisturizing agent is selected from one or more of propylene glycol, glycerol, polyethylene glycol, etc., preferably propylene glycol.

[0025] According to an embodiment of the present disclosure, in the pharmaceutical composition, the weight portion of the moisturizer is 3 to 15 parts, such as 5 to 12 parts, exemplified by 6 parts, 7 parts, 8 parts, 9 parts or 10 parts.

[0026] According to an embodiment of the present disclosure, the chelating agent is selected from metal ion chelating agents, such as one or more of ethylenediaminetetraacetic acid, sodium gluconate, nitrilotriacetic acid, tartaric acid, citric acid and salts thereof; preferably, the salt is a sodium salt, a potassium salt or an ammonium salt; in some embodiments, the chelating agent is selected from disodium ethylenediaminetetraacetic acid (also known as disodium edetate).

[0027] According to an embodiment of the present disclosure, in the pharmaceutical composition, the weight portion of the chelating agent is 0.01 to 1 part, such as 0.05 to 0.5 part, exemplified by 0.05 part, 0.1 part, 0.2 part or 0.5 part.

[0028] According to an embodiment of the present disclosure, the pH adjuster is selected from a pH buffer, preferably an organic acid and / or its salt pH buffer, such as one or more of citric acid / sodium citrate buffer, tartrate buffer, malic acid buffer, acetic acid / sodium acetate buffer, preferably citric acid / sodium citrate buffer.

[0029] According to an embodiment of the present disclosure, the oil phase matrix may include one or more selected from vaseline, medium chain triglycerides and paraffin, for example, the oil phase matrix includes one or two selected from vaseline and medium chain triglycerides. The vaseline is preferably white vaseline. Preferably, the oil phase matrix includes vaseline and one or two selected from medium chain triglycerides and paraffin, which may be present or absent; more preferably, the oil phase matrix is ​​vaseline and medium chain triglycerides.

[0030] According to an embodiment of the present disclosure, in the pharmaceutical composition, the total weight proportion of the oil phase matrix is ​​5 to 25 parts, such as 8 to 20 parts, exemplified by 9 parts, 10 parts, 12 parts, 13 parts, 14 parts, 15 parts, 16 parts or 17 parts.

[0031] According to an embodiment of the present disclosure, in the pharmaceutical composition, the weight portion of the vaseline (preferably white vaseline) is 1 to 9 parts, for example, 1 to 8 parts, 1 to 7 parts or 1 to 6 parts, such as 1 to 5 parts, 2 to 6 parts, 3 to 6 parts or 4 to 6 parts, exemplified by 1 part, 1.5 parts, 2 parts, 2.5 parts, 3 parts, 3.5 parts, 4 parts, 4.5 parts, 5 parts, 5.5 parts or 6 parts, or greater than 1 part, greater than 1.5 parts, greater than 2 parts, greater than 2.5 parts, greater than 3 parts, greater than 3.5 parts, greater than 4 parts, greater than 4.5 parts, greater than 5 parts, greater than 5.5 parts or greater than 6 parts.

[0032] According to an embodiment of the present disclosure, the water is preferably purified water.

[0033] According to an embodiment of the present disclosure, in the pharmaceutical composition, the weight proportion of water is 40 to 70 parts, for example 45 to 60 parts or 50 to 65 parts, such as 45, 46, 47, 48, 49, 50, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64 or 65 parts.

[0034] According to an embodiment of the present disclosure, the pharmaceutical composition may further contain an antioxidant, a preservative and / or a permeation enhancer.

[0035] According to an embodiment of the present disclosure, the antioxidant is selected from one or more of propyl gallate and butylated hydroxytoluene (BHT), etc.; preferably, the antioxidant is butylated hydroxytoluene.

[0036] According to an embodiment of the present disclosure, in the pharmaceutical composition, the weight portion of the antioxidant is 0.01 to 0.2 parts, such as 0.05 to 0.15 parts, exemplified by 0.05 parts, 0.1 parts or 0.12 parts.

[0037] According to an embodiment of the present disclosure, the preservative is selected from one or more of methylparaben, ethylparaben and propylparaben, preferably ethylparaben.

[0038] According to an embodiment of the present disclosure, in the pharmaceutical composition, the weight portion of the preservative is 0.01 to 0.3 parts, such as 0.05 to 0.15 parts, and exemplified by 0.1, 0.1, 0.15 parts or 0.2 parts.

[0039] According to an embodiment of the present disclosure, the penetration enhancer is selected from one or more of diethylene glycol monoethyl ether, isopropyl myristate, isopropyl palmitate, menthol, caprylic acid capric acid macrogol glyceride, N-methyl pyrrolidone, propylene carbonate and dimethyl isosorbide, preferably diethylene glycol monoethyl ether.

[0040] According to an embodiment of the present disclosure, in the pharmaceutical composition, the weight portion of the permeation enhancer is 0.1 to 5 parts, such as 0.5 to 3 parts, exemplified by 1 part, 2 parts, 3 parts or 4 parts.

[0041] According to an embodiment of the present disclosure, the pH of the pharmaceutical composition is 4 to 6.5, for example 4.5, 5, 5.2, 5.5 or 6.

[0042] In some embodiments, the above-mentioned moisturizers and penetration enhancers also serve as solvents for the oil phase formulation.

[0043] According to an embodiment of the present disclosure, the pharmaceutical composition includes the following components in parts by weight: 0.1 to 8 parts of active ingredient, 2 to 15 parts of thickener, 2 to 25 parts of emulsifier, 3 to 15 parts of moisturizer, 0.01 to 1 part of chelating agent, 0.01 to 0.2 parts of antioxidant, 0.01 to 0.3 parts of preservative, 0 to 5 parts of penetration enhancer, 5 to 25 parts of oil phase matrix, 40 to 65 parts of water and an appropriate amount of pH adjuster;

[0044] The active ingredient is a compound represented by formula (I), preferably the E-type isomer represented by the above formula (I-1) as the active ingredient;

[0045] Preferably, the thickener is stearyl alcohol or cetostearyl alcohol;

[0046] Preferably, the emulsifier is selected from any one of the following combinations: polyethylene glycol cetearyl ether, glyceryl mono- and distearate and polysorbate 80, polyethylene glycol cetearyl ether and glyceryl mono- and distearate, or polyethylene glycol-7 stearate and polysorbate 80;

[0047] Preferably, the humectant is selected from propylene glycol;

[0048] Preferably, the chelating agent is selected from disodium ethylenediaminetetraacetate;

[0049] Preferably, the oil phase matrix is ​​selected from one, two or three of vaseline, medium chain triglycerides and paraffin, preferably white vaseline and medium chain triglycerides;

[0050] Preferably, the pH regulator is selected from citric acid / sodium citrate buffer or acetic acid / sodium acetate buffer;

[0051] Preferably, the antioxidant is selected from butylated hydroxytoluene;

[0052] Preferably, the preservative is ethylparaben;

[0053] Preferably, the penetration enhancer is diethylene glycol monoethyl ether;

[0054] Preferably, the pH of the pharmaceutical composition is 4-6.5.

[0055] Preferably, in each embodiment of the pharmaceutical composition, the sum of the weight parts of each component in the pharmaceutical composition is 100 parts.

[0056] In some embodiments, the pharmaceutical composition comprises the following components in parts by weight:

[0057] 0.5-5 parts of the E-isomer of the compound represented by formula (I), 5-10 parts of cetostearyl alcohol, 5-20 parts of an emulsifier, 5-12 parts of propylene glycol, 0.05-0.5 parts of a chelating agent, 0.01-0.2 parts of an antioxidant, 0.01-0.3 parts of a preservative, 0-5 parts of a penetration enhancer, 8-20 parts of an oil phase base, 40-65 parts of water, and an appropriate amount of a pH adjuster;

[0058] Preferably, the emulsifier is composed of polyethylene glycol cetearyl ether, glyceryl mono- and distearate, and polysorbate 80 in a weight ratio of (1.5-3): (1.5-3): 1;

[0059] Preferably, the oil phase matrix consists of white vaseline and medium-chain triglycerides, wherein the proportion of white vaseline is 1 to 9 parts.

[0060] In some embodiments, the pharmaceutical composition is selected from any one of the following formulations by weight:

[0061] Formula 1: 1 part of the E-type isomer of the compound represented by formula (I), 2 parts of white vaseline, 7 parts of cetostearyl alcohol, 3.5 parts of polyethylene glycol cetostearyl ether, 10 parts of medium chain triglycerides, 3 parts of mono- and distearic glyceryl, 0.1 part of butylated hydroxytoluene, 0.15 parts of ethylparaben, 1.5 parts of polysorbate 80, 10 parts of propylene glycol, 0.05 parts of disodium edetate, 61.7 parts of water and an appropriate amount of citric acid / sodium citrate;

[0062] Formula 2: 1 part of the E-type isomer of the compound represented by formula (I), 2 parts of white vaseline, 7 parts of cetostearyl alcohol, 3.5 parts of polyethylene glycol cetostearyl ether, 10 parts of medium chain triglycerides, 3 parts of mono- and distearic glyceryl, 0.1 part of butylated hydroxytoluene, 0.15 parts of ethylparaben, 1.5 parts of polysorbate 80, 2 parts of diethylene glycol monoethyl ether, 8 parts of propylene glycol, 0.05 parts of disodium edetate, 61.7 parts of water and an appropriate amount of citric acid / sodium citrate;

[0063] Formula 3: 4 parts of the E-type isomer of the compound represented by formula (I), 2 parts of white vaseline, 7 parts of cetostearyl alcohol, 3.5 parts of polyethylene glycol cetostearyl ether, 10 parts of medium chain triglycerides, 3 parts of mono- and distearic glyceryl, 0.1 parts of butylated hydroxytoluene, 0.15 parts of ethylparaben, 1.5 parts of polysorbate 80, 2 parts of diethylene glycol monoethyl ether, 8 parts of propylene glycol, 0.05 parts of disodium edetate, 58.7 parts of water and an appropriate amount of citric acid / sodium citrate;

[0064] Formula 4: 0.5 parts of the E-isomer of the compound represented by formula (I), 2 parts of white vaseline, 7 parts of cetostearyl alcohol, 3.5 parts of polyethylene glycol cetostearyl ether, 10 parts of medium chain triglycerides, 3 parts of mono- and distearic glyceryl, 0.1 parts of butylated hydroxytoluene, 0.15 parts of ethylparaben, 1.5 parts of polysorbate 80, 2 parts of diethylene glycol monoethyl ether, 8 parts of propylene glycol, 0.05 parts of disodium edetate, 62.2 parts of water and an appropriate amount of citric acid / sodium citrate;

[0065] Formula 5: 2 parts of the E-type isomer of the compound represented by formula (I), 2 parts of white vaseline, 7 parts of cetostearyl alcohol, 3.5 parts of polyethylene glycol cetostearyl ether, 10 parts of medium chain triglycerides, 3 parts of mono- and distearic glyceryl, 0.1 parts of butylated hydroxytoluene, 0.15 parts of ethylparaben, 1.5 parts of polysorbate 80, 2 parts of diethylene glycol monoethyl ether, 8 parts of propylene glycol, 0.05 parts of disodium edetate, 60.7 parts of water and an appropriate amount of citric acid / sodium citrate;

[0066] Formula 6: 3 parts of the E-isomer of the compound represented by formula (I), 2 parts of white vaseline, 7 parts of cetostearyl alcohol, 3.5 parts of polyethylene glycol cetostearyl ether, 10 parts of medium chain triglycerides, 3 parts of mono- and distearic glyceryl, 0.1 parts of butylated hydroxytoluene, 0.15 parts of ethylparaben, 1.5 parts of polysorbate 80, 2 parts of diethylene glycol monoethyl ether, 8 parts of propylene glycol, 0.05 parts of disodium edetate, 59.7 parts of water and an appropriate amount of citric acid / sodium citrate.

[0067] In some embodiments, the pharmaceutical composition may further comprise a second active ingredient.

[0068] The present disclosure also provides a method for preparing the above pharmaceutical composition, comprising mixing the components.

[0069] In one embodiment, the preparation method comprises the steps of:

[0070] (A1) mixing a chelating agent, a pH adjusting agent and water, and heating the mixture to obtain an aqueous solution;

[0071] (A2) mixing an oil phase base, an emulsifier, a thickener, and optionally a preservative and an antioxidant, and heating and dissolving them to obtain an oil phase solution;

[0072] (A3) mixing the active ingredient with a moisturizer and optionally a penetration enhancer, heating and dissolving the mixture to obtain a third phase solution;

[0073] (A4) transferring the aqueous phase solution to the oil phase solution, emulsifying, and cooling;

[0074] (A5) adding the third phase solution to the emulsified system of step (A4), emulsifying, and cooling to obtain the pharmaceutical composition.

[0075] According to an embodiment of the present disclosure, the pH of the aqueous solution is 4-6.5, for example, 5-6.

[0076] According to an embodiment of the present disclosure, in step (A1) or step (A2), the heating temperature is 60 to 90°C, such as 70 to 80°C.

[0077] According to an embodiment of the present disclosure, the heating temperature in step (A3) is 50 to 65°C, such as 55 to 60°C.

[0078] According to an embodiment of the present disclosure, the temperature to which the temperature is lowered in step (A4) is 50 to 65°C, for example 55 to 60°C.

[0079] According to an embodiment of the present disclosure, the emulsification time in step (A4) or step (A5) is 10 to 25 minutes, for example, 15 minutes or 20 minutes.

[0080] In another embodiment, the preparation method comprises the steps of:

[0081] (B1) mixing a chelating agent, a pH adjusting agent and water, and heating the mixture to obtain an aqueous solution;

[0082] (B2) mixing an oil phase base, an emulsifier, a thickener, and optionally a preservative and an antioxidant, and heating and dissolving them to obtain an oil phase solution;

[0083] (B3) mixing the active ingredient with a moisturizer and optionally a penetration enhancer, heating and dissolving the mixture to obtain a third phase solution;

[0084] (B4) transferring the third phase solution into the oil phase solution, keeping warm and stirring;

[0085] (B5) adding the aqueous phase solution to the mixed system of step (B4), emulsifying, cooling, re-emulsifying, and cooling again to obtain the pharmaceutical composition.

[0086] According to an embodiment of the present disclosure, the pH of the aqueous solution is 4-6.5, for example, 5-6.

[0087] According to an embodiment of the present disclosure, in step (B1) or step (B2), the heating temperature is 60 to 90°C, such as 70 to 80°C.

[0088] According to an embodiment of the present disclosure, the heating temperature in step (B3) is 50 to 65°C, such as 55 to 60°C.

[0089] According to an embodiment of the present disclosure, in step (B5), the time of the first emulsification is longer than the time of the second emulsification; for example, the time of the first emulsification is 10 to 25 minutes, such as 15 minutes or 20 minutes.

[0090] According to an embodiment of the present disclosure, in step (B5), the first cooling is to reduce the temperature to 48-52°C.

[0091] In one embodiment, the preparation method comprises the steps of:

[0092] (C1) mixing a chelating agent, a pH adjusting agent and water, and heating the mixture to obtain an aqueous solution;

[0093] (C2) mixing the active ingredient, the oil phase base, the emulsifier, the thickener, the humectant, and the optional preservatives, antioxidants, and permeation enhancers, and heating and dissolving them to obtain an oil phase solution;

[0094] (C3) adding the oil phase solution to the water phase solution, emulsifying, and cooling to obtain the pharmaceutical composition.

[0095] According to an embodiment of the present disclosure, the pH of the aqueous solution is 4 to 6.5.

[0096] According to an embodiment of the present disclosure, in step (C1) or step (C2), the heating temperature is 60 to 90°C, such as 70 to 80°C.

[0097] According to an embodiment of the present disclosure, the emulsification time in step (C3) is 5 to 20 minutes, for example, 10 minutes or 15 minutes.

[0098] The present disclosure also provides use of the above-mentioned pharmaceutical composition in preparing a pharmaceutical preparation. Preferably, the pharmaceutical preparation is a cream.

[0099] The present disclosure also provides a pharmaceutical preparation, preferably a cream, containing the above-mentioned pharmaceutical composition.

[0100] According to an embodiment of the present disclosure, in the pharmaceutical preparation, the mass percentage of the active ingredient (i.e., the compound represented by formula (I) and at least one of its pharmaceutically acceptable salts) is 0.1-8%, for example, 0.5-5%, and exemplified by 0.5%, 0.75%, 1%, 1.25%, 1.5%, 1.75%, 2%, 2.5%, 3%, 3.5% or 4%.

[0101] According to an embodiment of the present disclosure, the pharmaceutical composition or pharmaceutical preparation is used to treat atopic dermatitis and psoriasis, and the atopic dermatitis is preferably pediatric atopic dermatitis, such as mild, moderate, severe or refractory pediatric atopic dermatitis.

[0102] On the other hand, the present disclosure relates to the use of the above-mentioned pharmaceutical composition in the preparation of a medicament for treating and / or preventing atopic dermatitis and psoriasis; wherein the atopic dermatitis is preferably pediatric atopic dermatitis, more preferably mild, moderate, severe or refractory pediatric atopic dermatitis.

[0103] In another aspect, the present disclosure relates to use of the above pharmaceutical composition in preparing a medicament for treating and / or preventing seborrheic dermatitis; wherein the seborrheic dermatitis is preferably seborrheic dermatitis.

[0104] In one embodiment, the pharmaceutical composition or the pharmaceutical preparation is administered topically, or is further combined with an oral administration preparation or other topical administration preparations.

[0105] The present disclosure also provides a method for treating and / or preventing atopic dermatitis, psoriasis and / or seborrheic dermatitis, comprising administering to a patient an effective amount or a therapeutically effective amount of the pharmaceutical composition or the pharmaceutical preparation; wherein the atopic dermatitis is preferably pediatric atopic dermatitis; and the seborrheic dermatitis is preferably seborrheic dermatitis.

[0106] Definitions and explanations of terms

[0107] Unless otherwise specified, the definitions of terms recorded in the specification and claims of this application, including their definitions as examples, exemplary definitions, preferred definitions, definitions recorded in tables, definitions of specific compounds in examples, etc., may be arbitrarily combined and coupled with each other. Such combinations and couplings shall fall within the scope of the description of this application.

[0108] The term "effective amount" or "therapeutically effective amount" refers to an amount of the compound of the present disclosure sufficient to achieve the intended application (including but not limited to the treatment of diseases as defined below). The therapeutically effective amount may vary depending on the intended application (in vitro or in vivo), or the subject and the disease condition being treated, such as the weight and age of the subject, the severity of the disease condition, and the mode of administration, which can be easily determined by a person of ordinary skill in the art. The specific dosage will vary depending on the specific compound selected, the dosage regimen relied upon, whether it is administered in combination with other compounds, the timing of administration, the tissue to which it is administered, and the physical delivery system carried.

[0109] The term "patient" refers to a patient who needs to prevent or treat a disease associated with anaerobic bacteria, wherein the patient is a mammal, for example selected from rodents, cattle, pigs, dogs, cats and primates, in particular humans.

[0110] The term "child" refers to patients aged 3 months and above, such as patients aged 3 months to 18 years, preferably 3 months to 14 years.

[0111] Beneficial Effects

[0112] The present invention discloses a cream-like pharmaceutical composition / preparation, in which the active ingredient is dispersed in a uniform and uniform emulsion droplet form, and has good physical and chemical stability. The composition is suitable for treating atopic dermatitis and seborrheic dermatitis, especially atopic dermatitis and seborrheic dermatitis in children, and has good safety and effectiveness. BRIEF DESCRIPTION OF THE DRAWINGS

[0113] Figure 1 This is the appearance of Example 1 after being placed for one week;

[0114] Figure 2 It is the microscope picture of Example 2;

[0115] Figure 3 It is the microscope picture of Example 3;

[0116] Figure 4 is a microscope image of Example 6;

[0117] Figure 5 This is a microscopic picture of the commercially available Benvimod cream;

[0118] Figure 6 This is a polarized light micrograph of the commercially available Benvimod cream;

[0119] Figure 7It is a comparison chart of the skin retention of in vitro permeation test of Example 6 and the control example (commercially available Benvimod), wherein in the bar graphs of the control example and Example 6, the 1st, 2nd, 3rd, 4th, 5th, and 6th "bars" from left to right correspond to the 1st, 2nd, 3rd, 4th, 5th, and 6th experimental results of the control example or Example 6, respectively;

[0120] Figure 8 This is a comparison chart of the skin permeation amount of Example 6 and commercially available Benvimod in an in vitro transdermal test;

[0121] Fig. 9 The clinical effect of the change of erythema index in treating seborrheic dermatitis in Example 6;

[0122] Fig.10 This is the clinical effect of Example 6 on the change of desquamation index in treating seborrheic dermatitis.

[0123] Fig.11 This is a comparison chart of the skin retention amounts of Example 6 and Sample C in the in vitro transdermal test. DETAILED DESCRIPTION

[0124] The technical solution of the present disclosure will be further described in detail below in conjunction with specific embodiments. It should be understood that the following embodiments are only exemplary illustrations and explanations of the present disclosure and should not be construed as limiting the scope of protection of the present disclosure. All technologies implemented based on the above content of the present disclosure are included in the scope of protection intended by the present disclosure.

[0125] Unless otherwise specified, the raw materials and reagents used in the following examples are commercially available or can be prepared by known methods.

[0126] Commercially available Benvimod cream: produced by Guangdong Zhonghao Pharmaceutical Co., Ltd., trade name: Benvimod content: 1%.

[0127] Example 1 Initial Formulation

[0128] By comparing the formula disclosed in the product instructions of the commercially available Benvimod cream, it is composed of water phase, oil phase, emulsifier, solvent, and preservative. The specific formula is shown in Table 1-1 below:

[0129] Table 1-1

[0130]

[0131] Referring to Table 1-1, the preliminary formulation of the present application is composed of the prescriptions of Example 1 and Example 2, wherein the prescription of Example 1 is shown in Table 1:

[0132] Table 1

[0133] Element Percentage % (w / w) E-isomer of the compound represented by formula (I) 1.00 White Vaseline 2.00 Octadecanol 6.00 PEG-7 Stearate 15.00 Light liquid paraffin 12.00 Butylated Hydroxytoluene 0.10 Ethylparaben 0.10 Polysorbate 80 1.00 Diethylene glycol monoethyl ether 2.00 Propylene glycol 10.00 Edetate Disodium 0.05 acetic acid Moderate Sodium acetate Moderate Purified water About 50.75 Total weight 100

[0134] The preparation method of the cream is as follows:

[0135] 1. Aqueous phase: Add disodium edetate, sodium acetate, polysorbate 80 and purified water into a beaker, heat to 70-80°C, stir to dissolve, and adjust the pH to about 5-6 to obtain an aqueous phase;

[0136] 2. Oil phase: Add light liquid paraffin, white vaseline, polyethylene glycol-7 stearate, stearyl alcohol, ethyl hydroxybenzoate and butylated hydroxytoluene into a beaker, heat to 70-80°C, stir and dissolve to obtain an oil phase;

[0137] 3. Third phase: heat diethylene glycol monoethyl ether and propylene glycol to 55-60° C., add the E-type isomer of the compound represented by formula (I) to dissolve, and obtain the third phase;

[0138] 4. Transfer the water phase to the oil phase and emulsify for 15 minutes; then cool to 55-60°C;

[0139] 5. Add the third phase into the emulsified system in step 4, emulsify for 15 minutes, cool down, and obtain a cream.

[0140] Example 2-4 Initial formulation optimization

[0141] The prescription of Example 2-4 is shown in Table 2:

[0142] Table 2

[0143]

[0144]

[0145] The preparation method of the cream is as follows:

[0146] 1. Aqueous phase: Add disodium edetate, anhydrous sodium acetate and purified water into a beaker, heat to 70-80°C, stir to dissolve, and adjust the pH value to about 5-6 to obtain an aqueous phase;

[0147] 2. Oil phase: add light liquid paraffin, white vaseline, polyethylene glycol cetearyl ether, cetearyl alcohol, glyceryl mono- and distearate, ethyl hydroxybenzoate, polyoxyethylene (54) hydrogenated castor oil and butylated hydroxytoluene into a beaker, add to 70-80° C., stir and dissolve to obtain an oil phase;

[0148] 3. Third phase: heat diethylene glycol monoethyl ether and propylene glycol to 55-65° C., add the E-type isomer of the compound represented by formula (I) to dissolve, and obtain the third phase;

[0149] 4. Transfer the third phase to the oil phase, keep warm and stir for 10 minutes;

[0150] 5. Add the mixture in step 4 to the aqueous phase, emulsify for 10 minutes, then slowly cool to 48-52°C, emulsify for another 5 minutes, and cool to obtain a cream.

[0151] Example 5 Study on the physicochemical properties of Examples 1-4

[0152] Example 1: Off-white cream, the droplets are uniform under the microscope, but the cream has poor application feeling and hard texture; after being placed under 30℃ / RH65% for one week, the cream changes color significantly from off-white to light yellow. Figure 1 .

[0153] Example 2: Off-white cream, under the microscope, there are large pieces of oily substances, the emulsion droplets are not uniform, and the cream has a poor application feel. Figure 2 .

[0154] Example 3 and Example 4: By comparing Examples 2-4, the effect of white vaseline in the prescription on the product emulsion droplets was investigated. It can be observed through a microscope that as the proportion of white vaseline decreases, the emulsion droplet size in the sample decreases. The relevant micrographs of Example 3 are detailed in Figure 3 .

[0155] Example 5-7 Formulation Optimization

[0156] According to the results of the physical and chemical properties of Examples 1-4, the applicant considered further optimizing the formula, and after a lot of creative work, by adjusting the types and contents of factors such as the oil phase matrix, thickener, and pH regulator, the optimized formula finally obtained is shown in Table 3:

[0157] Table 3

[0158]

[0159]

[0160] The preparation method of the cream of embodiment 5 is as follows:

[0161] Step 1: preparing the aqueous phase, dissolving edetate disodium, sodium citrate and citric acid in purified water, heating to 70-80°C, keeping warm, and adjusting the pH value to 4.5-6.5 to obtain an aqueous phase;

[0162] Step 2: preparing the oil phase, heating the E-type isomer of the compound represented by formula (I), white vaseline, cetostearyl alcohol, polyethylene glycol cetostearyl ether, glyceryl mono- and distearate, medium chain triglycerides, butylated hydroxytoluene, polysorbate 80, propylene glycol and ethylparaben to 70-80° C. to melt, and keeping the temperature to obtain the oil phase;

[0163] Step 3: Add the oil phase to the water phase, emulsify for 10 minutes, cool down, and form a cream.

[0164] The preparation method of the cream of Example 6-7 is as follows:

[0165] Step 1: preparing the aqueous phase, dissolving edetate disodium, sodium citrate and citric acid in purified water, heating to 70-80°C, keeping warm, and adjusting the pH value to 4.5-6.5 to obtain an aqueous phase;

[0166] Step 2: preparing the oil phase, heating the E-type isomer of the compound represented by formula (I), white vaseline, cetostearyl alcohol, polyethylene glycol cetostearyl ether, glyceryl mono- and distearate, medium chain triglycerides, butylated hydroxytoluene, polysorbate 80, diethylene glycol monoethyl ether, propylene glycol and ethylparaben to 70-80° C. to melt, and keeping the temperature;

[0167] Step 3: Add the oil phase to the water phase, emulsify for 10 minutes, cool down, and form a cream.

[0168] Example 8 Morphology Test

[0169] The cream obtained in Example 6 was observed under a microscope, and it was found that the active ingredients were evenly dispersed in the form of emulsion droplets, and the particle size of the emulsion droplets was uniform, and the particle size was less than 5 μm. Figure 4 .

[0170] Example 9 In vitro skin permeation test

[0171] The effect of diethylene glycol monoethyl ether on skin retention was investigated using in vitro transdermal test (IVPT).

[0172] 1) Experimental steps:

[0173] The preparations prepared in Example 5 and Example 6 were subjected to an in vitro permeation test to evaluate the average retention of benvimod in the epidermis and dermis. Porcine skin (thickness 0.8-1.0 mm) was mounted on a LOGAN System 918 vertical diffusion cell, exposing 1.77 cm 2 surface area. The diffusion cell was connected to a multichannel pump at a speed of 600 rpm, and the receiving fluid was PBS (phosphate buffered saline) at pH 7.4. Each cell was placed in a heating manifold to balance the temperature and ensure that the skin surface temperature was 32°C (at least 30 minutes before administration). The sample was added at a dose of 10 mg of the test sample per square centimeter. The receiving fluid was collected at 2, 4, 8, 20, and 24 hours to measure the active ingredients that penetrated the skin. After the 24-hour sampling, the skin was wiped with a cotton swab to remove any residual sample that was considered not to penetrate the skin, and the epidermis and dermis were separated by heating. The skin layer was cut into pieces and methanol was added to ultrasonically extract the drug, and the concentration of benvimod was detected by high performance liquid chromatography. The recovered drug concentration was used to calculate the average retention of benvimod in the skin.

[0174] 2) Test results

[0175] In the preparation prepared in Example 5, the average retention of benvimod in the skin was 1.85 μg / cm 2 In the preparation prepared in Example 6, the average retention amount of benvimod in the skin was 2.91 μg / cm 2 The results of the transdermal test showed that adding the penetration enhancer diethylene glycol monoethyl ether could significantly increase the total amount of retention in the skin.

[0176] Example 10 Irritation Test

[0177] 60 healthy adult guinea pigs were selected, 30♀ / 30 , 40 healthy young guinea pigs, 20♀ / 20 The animals were randomly divided into negative control group, positive control group, adult animal test sample low-dose group (Example 6, 1%), adult animal test sample high-dose group (Example 7, 4%), young animal test sample low-dose group (Example 6, 1%) and young animal test sample high-dose group (Example 7, 4%) according to sex and weight using TOXSTAT2006 software. There were 10 animals in each negative control group and positive control group (5♀ / 5 ), 20 mice in each test group (10♀ / 10 ).

[0178] Hair preparation: Before administration, the animals were prepared with electric clippers to trim the hair on both sides of the spine, 3×3 cm on each side. 2 .

[0179] Sensitization: On the 0th, 7th and 14th days, the test substance was administered to the left side of the hair removal area at 0.2 g / animal (0.2 mL / animal in the negative / positive control groups), and cellophane or filter paper was attached to the groove of the blank plaster. The test substance was placed on the cellophane or contained in the filter paper and applied to the administration site, and then sealed and fixed with non-irritating medical adhesive tape. The blank plaster and filter paper were removed after about 6 hours. The animals in the negative control group were administered with 0.9% sodium chloride injection, the animals in the positive control group were administered with 2% 2,4-dinitrochlorobenzene (ultrasonic preparation with 80% ethanol), and the animals in the low- and high-dose groups of the test substance were administered with the preparations prepared in Examples 6 and 7 of corresponding concentrations (the content of benvimod was 1% and 4%, respectively).

[0180] Challenge: On the 14th day after the last sensitization, 0.2 g / guinea pig of each group was given the test substance on the right side of the hair removal area (0.2 mL / guinea pig of the positive control group, 0.2% 2,4-dinitrochlorobenzene, prepared in acetone solution; 0.2 mL / guinea pig of the negative control group, 0.9% sodium chloride injection), and the test substance was removed after about 6 hours.

[0181] Observation: Observe and record the allergic reaction symptoms 1h and 24h after sensitization, as well as 24h and 48h after stimulation.

[0182] The results showed that under the experimental conditions, the Buehler test evaluation results were negative after guinea pigs were given the preparations prepared in Example 6 and Example 7 multiple times, indicating that as the content of the active ingredient benvimod increased, there was still no sensitizing effect on the skin.

[0183] Example 11 Stability Test

[0184] The same amount of Example 6 cream was weighed into an aluminum tube (sealed), and a total of 6 groups were set up. They were placed in room temperature and 40°C environments, and the physical and chemical stability of the samples at 0 days, 40°C-5 days, 40°C-10 days, 40°C-30 days, 40°C-3 months, and 40°C-6 months was observed and measured using liquid phase. The specific results are shown in Table 4. The results show that the cream of Example 6 will not oxidize and discolor after long-term placement, the active ingredients are stable, and it is still uniformly dispersed in the form of emulsion droplets without crystallization, and the impurity content is almost unchanged, with excellent stability.

[0185] Liquid phase determination method for impurities and content: octadecylsilane bonded silica gel is used as filler; water is used as mobile phase A, acetonitrile is used as mobile phase B, and gradient elution is performed; elution gradient: 0min 80% A-→20~30min 10% A→32~40min 80% A; flow rate is 1.0ml per minute; column temperature is 35°C; detection wavelength is 220nm; injection volume is 10μl.

[0186] Table 4

[0187]

[0188] Example 12 Comparison of the preparation prepared in Example 6 and commercially available Benvimod cream (control example)

[0189] 1) Appearance: Under microscopic conditions, the emulsion droplets of the commercially available Benvimod cream are uneven and contain large oily substances (see Figure 5 ), solid crystals were observed under polarized light microscopy (see Figure 6 ).

[0190] 2) In vitro transdermal test: to investigate the retention and penetration of the active ingredient benvimod in the skin

[0191] The in vitro permeation test was performed according to the experimental steps in Example 9. Six groups (n=6) were tested in parallel with the control and examples. The test results are shown in Tables 5 and Figures 7 and 8 .

[0192] Table 5 Skin retention (μg / cm 2 )

[0193]

[0194] From Table 5 and the average data of skin retention, both Example 6 and the control example show that the retention of bevimod in the dermis is greater than that in the epidermis; and the retention of bevimod in the dermis and skin in Example 6 is greater than that in the control group. Figure 7 It can be seen that the skin retention amount (dermis and epidermis) of each group of Example 6 is more uniform and stable than that of each group of control examples, and the skin retention amount of each group of Example 6 fluctuates slightly; Figure 8 From the skin permeation data, the skin permeation of Example 6 is comparable to that of the control example, and Example 6 has better parallelism, high skin retention, and better efficacy.

[0195] Embodiment 13

[0196] The cream prepared in Example 6 was topically applied to the skin of subjects with atopic dermatitis (AD) aged 3 months to 14 years old, twice a day. In some patients, significant improvement was observed within 5 to 7 days, and the symptoms continued to be alleviated within one month.

[0197] Embodiment 14

[0198] In a prospective, randomized, 8-week clinical trial, the cream prepared in Example 6 (treatment group) was applied to the skin of subjects with seborrheic dermatitis twice a day. The control group used the matrix component of Example 6 without benvimod and applied it to the affected area twice a day. The changes in the erythema index and desquamation index of seborrheic dermatitis were significantly improved in the second week and continued until the 8th week. By the 8th week, the changes in the erythema index of the treatment group decreased by 81.81%, and the changes in the desquamation index decreased by 83.70%; while the changes in the erythema index of the control group decreased by 38.46%, and the changes in the desquamation index decreased by 37.44%. As shown in Table 6 and Fig. 9 and Fig.10 The clinical efficacy of the AhR agonist benvimod in the treatment of patients with seborrheic dermatitis can be shown.

[0199] Table 6 Clinical efficacy of the cream of Example 6 in treating seborrheic dermatitis

[0200]

[0201] Embodiment 15

[0202] Based on the composition of Example 6, creams were prepared according to the compositions of cream samples 1-10 (the composition of sample 9 is the same as that of Example 6) shown in Table 7 below, and cream samples 11-19 shown in Table 8 below, and the effects of the sample compositions on the cream products were evaluated.

[0203] Wherein, the preparation method of the cream sample is as follows:

[0204] Step 1: preparing the aqueous phase, dissolving edetate disodium, sodium citrate and citric acid in purified water, heating to 70-80°C, keeping warm, and adjusting the pH value to 4.5-5.5 to obtain an aqueous phase;

[0205] Step 2: preparing the oil phase, mixing the E-type isomer of the compound represented by formula (I) and other components, heating to 70-80° C. to melt, and keeping the temperature to obtain the oil phase;

[0206] Step 3: Add the oil phase into the water phase, emulsify for 10 minutes, cool down, and obtain a cream sample.

[0207]

[0208]

[0209] The results show that:

[0210] In Table 7, the upper layers of Samples 1 and 2 contained oily substances, and a uniform paste could not be formed. Samples 3-10 could all be prepared into creams, but when the amount of white vaseline was reduced, the appearance color of the creams changed from slightly pink to white creams. Microscopic observation showed that Samples 3 and 4 did not form regular emulsion droplets, but presented small pieces of flaky oily substances. Microscopic observation showed that the oil phase of Samples 5 and 6 could form round emulsion droplets, indicating that when the amount of white vaseline was controlled below 6%, samples with uniform emulsion droplets could be prepared.

[0211] In Table 8, the creams of Samples 11 and 12 showed large blocky oil droplets under microscopy, while Sample 13 could prepare a white cream with small droplets, indicating that the emulsifier polyethylene glycol ceteareth-8 has a good emulsifying ability for medium-chain triglycerides and white vaseline oil phase matrix.

[0212] Samples 14-19 can be prepared into off-white uniform and delicate creams without oil-water separation. However, the droplet size of sample 14 without polysorbate 80 is uneven; the droplets of sample 15 become smaller and present round droplets, indicating that the addition of polysorbate 80 can improve the droplet size. Sample 18 without mono- and distearic glyceryl has uneven droplet size and large oil droplets, while other samples containing mono- and distearic glyceryl have no such phenomenon.

[0213] Furthermore, during the application process, it was observed that the creams of samples 13 and 15 containing a high proportion of polysorbate 80 or glyceryl stearate became whiter the more they were applied. The viscosity test results showed that the viscosity of the creams with a high proportion of glyceryl stearate and glyceryl mono- and distearate was greater than that of the creams with a low proportion, and glyceryl stearate and glyceryl mono- and distearate had a certain thickening effect.

[0214] In summary, the preferred samples of the present invention have moderate viscosity, are uniform and delicate, and have a good spreading effect.

[0215] Example 16

[0216] On the basis of the composition of the cream in Example 7, creams were prepared according to the compositions of cream samples 20-22 shown in Table 9 below, and the influence of the active ingredient content in the samples on the cream products was evaluated, wherein the difference in the active ingredient content in samples 20-22 relative to that in Example 7 was adjusted by the purified water content to keep the contents of other ingredients unchanged.

[0217] Table 9

[0218]

[0219]

[0220] Wherein, the preparation method of the cream sample is as follows:

[0221] Step 1: preparing the aqueous phase, dissolving edetate disodium, sodium citrate and citric acid in purified water, heating to 70-80°C, keeping warm, and adjusting the pH value to 4.5-5.5 to obtain an aqueous phase;

[0222] Step 2: preparing the oil phase, mixing the E-type isomer of the compound represented by formula (I) and other components, heating to 70-80° C. to melt, and keeping the temperature to obtain the oil phase;

[0223] Step 3: Add the oil phase into the water phase, emulsify for 10 minutes, cool down, and obtain a cream sample.

[0224] The results show that the compositions of samples 20-22 and Example 7 can be used to prepare off-white creams, and the diameter of the droplets is less than 10 μm, indicating that the cream of the present invention can be applied to active ingredients with different contents.

[0225] Embodiment 17

[0226] Sample C was prepared with reference to the composition of preparation 21 in Table 8 of the specification of patent CN114042041A. The prescription composition was oil phase (active ingredient, propylene glycol, diethylene glycol monoethyl ether, butylated hydroxytoluene, benzoic acid, emulsifying wax, medium chain triglyceride, polysorbate 80, steareth 2, steareth 20) and water phase (disodium edetate, citric acid, sodium citrate, purified water). The preparation method was as follows: the oil phase components were mixed and heated to 70-80°C, and continued to mix until the active ingredient was dissolved and the appearance was uniform; the water phase components were mixed and heated to 70-80°C, and mixed until all substances were completely dissolved and the water phase had a uniform appearance; the oil phase was added to water, the temperature was maintained between 70-80°C, mixed for 5-10 minutes, and cooled.

[0227] In vitro transdermal test operation Referring to the experimental steps under Example 9, the sample of Example 6 of the present application was compared with Sample C, indicating that under the same content of active ingredients, the intradermal retention of the cream sample of Example 6 of the present application was higher than that of Sample C (see Fig.11 ).

[0228] The above examples are used to illustrate the specific implementation of the present invention. However, the protection scope of the present invention is not limited to the above exemplary implementation. Any modification, equivalent substitution, improvement, etc. made by those skilled in the art within the spirit and principle of the present invention shall be included in the protection scope of the claims of the present invention.

Claims

1. A pharmaceutical composition, comprising the following components: an active ingredient, a thickener, an emulsifier, a humectant, a chelating agent, a pH regulator, an oil phase matrix and water, wherein the active ingredient is selected from at least one of the compounds represented by formula (I) and pharmaceutically acceptable salts thereof; in, The oil phase matrix comprises vaseline and one or two selected from medium chain triglycerides and paraffin, which are optionally present or absent; Preferably, the oil phase matrix is ​​vaseline and medium chain triglycerides; Preferably, in the pharmaceutical composition, the weight portion of the vaseline (preferably white vaseline) is 1 to 9 parts, such as 1 to 6 parts.

2. The pharmaceutical composition according to claim 1, wherein The compound represented by formula (I) is an E-type or Z-type isomer, preferably an E-type isomer represented by formula (I-1): Preferably, the pharmaceutically acceptable salt is selected from addition salts of the compound of formula (I) and a base; Preferably, the pharmaceutical composition contains only the compound represented by formula (I) as the active ingredient, and preferably contains only the E-type isomer represented by formula (I-1) as the active ingredient; Preferably, in the pharmaceutical composition, the active ingredient is present in the form of emulsion droplets, and preferably the diameter of the emulsion droplets is less than 10 μm; Preferably, in the pharmaceutical composition, the weight portion of the active ingredient is 0.1 to 8 parts.

3. The pharmaceutical composition according to claim 1 or 2, wherein The thickener is selected from one or both of stearyl alcohol and cetostearyl alcohol; Preferably, in the pharmaceutical composition, the weight portion of the thickener is 2 to 15 parts; Preferably, the emulsifier is selected from one or more of polyethylene glycol cetearyl ether, glyceryl mono- and distearate, polyethylene glycol stearate, polyoxyethylene hydrogenated castor oil and polysorbate 80; preferably, the emulsifier contains at least polyethylene glycol cetearyl ether and glyceryl mono- and distearate, for example, the emulsifier consists of polyethylene glycol cetearyl ether and glyceryl mono- and distearate or consists of polyethylene glycol cetearyl ether, glyceryl mono- and distearate and polysorbate 80; Preferably, in the pharmaceutical composition, the weight portion of the emulsifier is 2 to 25 parts; when there are two emulsifiers, the weight ratio of the two emulsifiers is (1 to 3): (3 to 1); when there are three emulsifiers, the weight ratio of the three emulsifiers is (1 to 3): (3 to 1): 1; Preferably, the humectant is selected from one or more of propylene glycol, glycerol and polyethylene glycol; Preferably, in the pharmaceutical composition, the weight portion of the moisturizer is 3 to 15 parts; Preferably, the chelating agent is selected from metal ion chelating agents, such as one or more of ethylenediaminetetraacetic acid, sodium gluconate, nitrilotriacetic acid, tartaric acid, citric acid and salts thereof; Preferably, in the pharmaceutical composition, the weight portion of the chelating agent is 0.01 to 1 part; Preferably, the pH regulator is selected from a pH buffer, preferably an organic acid or its salt pH buffer, such as one or more of citric acid / sodium citrate buffer, tartrate buffer, malic acid buffer, acetic acid / sodium acetate buffer; Preferably, the oil phase matrix is ​​selected from one or more of vaseline, medium chain triglycerides, and paraffin; Preferably, in the pharmaceutical composition, the weight portion of the oil phase matrix is ​​5 to 25 parts; Preferably, the water is purified water; Preferably, in the pharmaceutical composition, the weight portion of water is 40 to 65 parts.

4. The pharmaceutical composition according to any one of claims 1 to 3, wherein The pharmaceutical composition further contains an antioxidant, a preservative and / or a permeation enhancer; Preferably, the antioxidant is selected from one or both of propyl gallate and butylated hydroxytoluene; Preferably, in the pharmaceutical composition, the antioxidant is present in an amount of 0.01 to 0.2 parts by weight; Preferably, the preservative is selected from one or more of methylparaben, ethylparaben and propylparaben; Preferably, in the pharmaceutical composition, the weight portion of the preservative is 0.01 to 0.3 parts; Preferably, the penetration enhancer is selected from one or more of diethylene glycol monoethyl ether, isopropyl myristate, isopropyl palmitate, menthol, caprylic acid capric acid macrogol glyceride, N-methyl pyrrolidone, propylene carbonate and isosorbide dimethyl ether; Preferably, in the pharmaceutical composition, the weight portion of the penetration enhancer is 0.1 to 5 parts; Preferably, the pH of the pharmaceutical composition is 4 to 6.5; Preferably, the pharmaceutical composition further comprises a second active ingredient.

5. The pharmaceutical composition according to any one of claims 1 to 4, wherein The pharmaceutical composition comprises the following components in parts by weight: 0.1 to 8 parts of active ingredient, 2 to 15 parts of thickener, 2 to 25 parts of emulsifier, 3 to 15 parts of moisturizer, 0.01 to 1 part of chelating agent, 0.01 to 0.2 parts of antioxidant, 0.01 to 0.3 parts of preservative, 0 to 5 parts of penetration enhancer, 5 to 25 parts of oil phase matrix, 40 to 65 parts of water and pH regulator; The active ingredient is a compound of formula (I), preferably the E-type isomer represented by the above formula (I-1) as the active ingredient; preferably, the pH of the pharmaceutical composition is 4 to 6.5; Preferably, the pharmaceutical composition comprises the following components in parts by weight: 0.5-5 parts of the E-isomer of the compound represented by formula (I), 5-10 parts of cetostearyl alcohol, 5-20 parts of an emulsifier, 5-12 parts of propylene glycol, 0.05-0.5 parts of a chelating agent, 0.01-0.2 parts of an antioxidant, 0.01-0.3 parts of a preservative, 0-5 parts of a penetration enhancer, 8-20 parts of an oil phase base, 40-65 parts of water, and an appropriate amount of a pH adjuster; Preferably, the emulsifier is composed of polyethylene glycol cetearyl ether, glyceryl mono- and distearate, and polysorbate 80 in a weight ratio of (1.5-3):(1.5-3):1; Preferably, the oil phase matrix consists of white vaseline and medium-chain triglycerides, wherein the proportion of white vaseline is 1 to 9 parts.

6. A method for preparing the pharmaceutical composition according to any one of claims 1 to 5, comprising mixing the components.

7. The preparation method according to claim 6, wherein: The preparation method is selected from any one of the following methods: Method 1, the preparation method comprises the following steps: (A1) mixing a chelating agent, a pH adjusting agent and water, and heating the mixture to obtain an aqueous solution; (A2) mixing an oil phase base, an emulsifier, a thickener, and optionally a preservative and an antioxidant, and heating and dissolving them to obtain an oil phase solution; (A3) mixing the active ingredient with a moisturizer and optionally a penetration enhancer, heating and dissolving the mixture to obtain a third phase solution; (A4) transferring the aqueous phase solution to the oil phase solution, emulsifying, and cooling; (A5) adding the third phase solution to the emulsified system of step (A4), emulsifying, and cooling to obtain the pharmaceutical composition; Method 2, the preparation method comprises the following steps: (B1) mixing a chelating agent, a pH adjusting agent and water, and heating the mixture to obtain an aqueous solution; (B2) mixing an oil phase base, an emulsifier, a thickener, and optionally a preservative and an antioxidant, and heating and dissolving them to obtain an oil phase solution; (B3) mixing the active ingredient with a moisturizer and optionally a penetration enhancer, heating and dissolving the mixture to obtain a third phase solution; (B4) transferring the third phase solution into the oil phase solution, keeping warm and stirring; (B5) adding the aqueous solution to the mixed system of step (B4), emulsifying, cooling, re-emulsifying, and cooling again to obtain the pharmaceutical composition; Method three, the preparation method comprises the following steps: (C1) mixing a chelating agent, a pH adjusting agent and water, and heating the mixture to obtain an aqueous solution; (C2) mixing the active ingredient, the oil phase base, the emulsifier, the thickener, the humectant, and the optional preservatives, antioxidants, and permeation enhancers, and heating and dissolving them to obtain an oil phase solution; (C3) adding the oil phase solution to the water phase solution, emulsifying, and cooling to obtain the pharmaceutical composition.

8. A pharmaceutical preparation, wherein the pharmaceutical preparation contains the pharmaceutical composition according to any one of claims 1 to 5; preferably, the pharmaceutical preparation is a cream.

9. Use of the pharmaceutical composition according to any one of claims 1 to 5 in the preparation of a medicament for treating and / or preventing atopic dermatitis and psoriasis; wherein the atopic dermatitis is preferably childhood atopic dermatitis, more preferably mild, moderate, severe or refractory childhood atopic dermatitis.

10. Use of the pharmaceutical composition according to any one of claims 1 to 5 in the preparation of a medicament for treating and / or preventing seborrheic dermatitis; wherein the seborrheic dermatitis is preferably seborrheic dermatitis.

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