Pharmaceutical compositions of phenol derivatives with improved stability and their uses

Abstract

This disclosure discloses a pharmaceutical composition of a phenol derivative and its use. The pharmaceutical composition comprises the following components: an active ingredient, a thickener, an emulsifier, a humectant, a chelating agent, a pH adjuster, an oil phase matrix, and water. The active ingredient is selected from at least one compound of formula (I) and its pharmaceutically acceptable salts. The active ingredient is dispersed in a uniform and homogeneous droplet form, exhibiting good physical and chemical stability. This composition is suitable for the treatment of atopic dermatitis, psoriasis, and seborrheic dermatitis, especially in children with atopic dermatitis and seborrheic dermatitis, while possessing good safety, stability, efficacy, and uniform morphological characteristics. (I)

Description

[0001] This application is a divisional application of Chinese patent application No. 202411537158.2, filed on October 30, 2024, entitled "Pharmaceutical Composition of Phenol Derivative with Improved Stability and Use Thereof". Technical Field

[0002] This disclosure pertains to the field of pharmaceutical compositions, and specifically relates to a pharmaceutical composition of a phenol derivative with improved stability and its use. Background Technology

[0003] Atopic dermatitis (AD) is a chronic, relapsing, 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, but it may be related to multiple factors such as genetics, skin barrier defects, immunity, environment, and microbial colonization. Currently, the treatment of mild to moderate childhood AD usually focuses on topical corticosteroids and calcineurin inhibitors. However, the treatment of moderate to severe or refractory childhood AD is more challenging and requires individualized treatment. There is currently no systematic, universally applicable drug treatment; otherwise, it will seriously affect the quality of life and mental health of affected children.

[0004] Seborrheic dermatitis (SD) is a chronic, papulosquamous, superficial inflammatory skin disease occurring in areas of excessive sebum production. The typical rash consists of dark red or yellowish-red patches formed by the merging of follicular papules, covered with greasy scales or crusts, and may be accompanied by varying degrees of itching. SD is a chronic, relapsing inflammatory skin disease, usually presenting as red, scaly rashes. The incidence rate in the healthy population is 5%, with 70.3% occurring on the scalp, commonly seen in infants, adolescents, and adults. Seborrheic dermatitis refers to a disease of the scalp that differs from simple dandruff in that it presents with erythema as a sign of inflammation, more extensive scalp peeling, and sometimes itching and burning sensations, as well as eczema on other parts of the body. The disease can occur in plaques, but often affects the entire scalp and extends beyond the hairline, frequently including the forehead, around the neck, and both ears. In severe cases, secondary infections may occur on the scalp, with changes manifesting as a spongy texture, the formation of blisters and crusts, and possible oozing. Seborrheic dermatitis also frequently occurs in infancy and usually resolves spontaneously by 8-12 months of age. Scalp changes in infants include erythema, scalp peeling, and occasional blisters and crusts, which may resolve spontaneously within 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 puberty and can persist throughout life, sometimes even becoming more severe. Approximately 1-3% of the population has this condition. The etiology and pathogenesis of SD are not fully understood, but the complex interactions of Malassezia, keratinocytes, and the immune response play a crucial role in its pathogenesis. Seborrheic dermatitis shares some of the pathogenic factors with other inflammatory skin diseases such as atopic dermatitis, such as the regulation of factors stimulating keratinocyte proliferation and differentiation, and disruption of the skin barrier. Atopic dermatitis typically presents as a Th2 immune response, with elevated levels of interleukin (IL)-4 and IL-13; 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 and calcineurin inhibitors) supplemented with skin moisturizing products, but the effectiveness is low; and symptoms are prone to relapse after discontinuation of medication.

[0006] Although CN108066279A and CN113797159A disclose research on topical creams for benzenemod, the samples had poor properties, with a large proportion of lumpy oily substances, affecting product performance. Furthermore, examples in CN114042041A show that the white petrolatum in its formulation leads to the formation of waxy substances; even formulations containing low levels of white petrolatum result in uneven emulsions, while formulations without petrolatum oil have uniform emulsions.

[0007] Therefore, providing a drug composition / formulation for treating childhood Alzheimer's disease (AD) and symptomatic disease (SD) that can eliminate the anxiety and fear caused by hormonal drugs in children, while taking into account safety, stability, efficacy, and uniform morphological characteristics, remains an urgent technical problem to be solved in this field. Summary of the Invention

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

[0009]

[0010] (I).

[0011] According to embodiments of this disclosure, the compound represented by formula (I) can be an E-type or Z-type isomer, preferably an E-type isomer represented by formula (I-1):

[0012]

[0013] (I-1).

[0014] According to a preferred embodiment of this disclosure, the compound represented by formula (I-1) is benvitimod.

[0015] According to embodiments of this disclosure, the pharmaceutically acceptable salt may be selected from the addition salt of a compound of formula (I) and a base.

[0016] In a preferred embodiment, the pharmaceutical composition uses only the compound represented by formula (I) as the active ingredient, and more preferably only the E-isomer represented by formula (I-1) (i.e., benvitimod) as the active ingredient.

[0017] According to embodiments of this disclosure, in the pharmaceutical composition, the active ingredient is present in the form of droplets, preferably with a diameter of less than 10 μm, for example, less than 5 μm.

[0018] According to embodiments of this disclosure, the active ingredient in the pharmaceutical composition is present in a weight ratio of 0.1 to 8 parts, for example 0.5 to 5 parts, such as 0.5 parts, 0.75 parts, 1 part, 1.25 parts, 1.5 parts, 2 parts, 2.5 parts, 3 parts, 3.5 parts, or 4 parts.

[0019] According to embodiments of this disclosure, the thickener is selected from one or more of hexadecyl alcohol, octadecyl alcohol, and hexadecyloctadecyl alcohol.

[0020] According to embodiments of this disclosure, the thickener in the pharmaceutical composition is 2 to 15 parts by weight, for example 5 to 10 parts, exemplarily 6, 7 or 8 parts.

[0021] According to embodiments of this disclosure, the emulsifier is selected from one or more of polyethylene glycol hexadecyl ether, glyceryl monostearate and glyceryl distearate, 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 hexadecyl ether, glyceryl monostearate and glyceryl distearate, and polysorbate 80; in other embodiments, the emulsifier is polyethylene glycol hexadecyl ether and glyceryl monostearate and glyceryl distearate; and in still other embodiments, the emulsifier is polyethylene glycol-7 stearate and polysorbate 80. Preferably, the emulsifier comprises at least polyethylene glycol hexadecyl ether and glyceryl monostearate and glyceryl distearate, for example, the emulsifier is composed of polyethylene glycol hexadecyl ether and glyceryl monostearate and glyceryl distearate, or is composed of polyethylene glycol hexadecyl ether, glyceryl monostearate and glyceryl distearate, and polysorbate 80.

[0022] According to embodiments of this disclosure, the emulsifier in the pharmaceutical composition is 2 to 25 parts by weight, for example 5 to 20 parts, such as 6 parts, 6.5 parts, 7 parts, 7.5 parts, 8 parts, 10 parts, 12 parts or 16 parts.

[0023] According to embodiments of this 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), or (1~1.2):(1.2~1), with specific examples being 3:3.5, 3.5:3, or 1:1. For example, when the emulsifier is polyethylene glycol hexadecyl ether and glyceryl mono- and di-stearate, the weight ratio of polyethylene glycol hexadecyl ether and glyceryl mono- and di-stearate can be (1~3):(3~1), for example (1~2):(2~1), such as (1~1.5):(1.5~1), or (1~1.2):(1.2~1), with specific examples being 3:3.5, 3.5:3, or 1:1.

[0024] According to embodiments of this disclosure, in the pharmaceutical composition, when there are three types of emulsifiers, the proportion of each emulsifier in the total weight of the emulsifiers can be independently selected from 1 / 5 to 1 / 2, for example 1 / 4 to 1 / 3, such as 2 / 7 to 1 / 3.

[0025] In some embodiments, when the emulsifier comprises three types, 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, or, for example, 3.5:3:1.5. For example, the emulsifier may be composed of polyethylene glycol hexadecyl ether, glyceryl mono- and glyceryl di- and polysorbate 80, and the weight ratio of these components can be (1.5~3):(1.5~3):1, for example (1.7~2.5):(1.7~2.5):1, or, for example, 3.5:3:1.5.

[0026] According to embodiments of this disclosure, the moisturizer is selected from one or more of propylene glycol, glycerin, and polyethylene glycol, preferably propylene glycol.

[0027] According to embodiments of this disclosure, the humectant in the pharmaceutical composition is 3 to 15 parts by weight, for example 5 to 12 parts, exemplarily 6, 7, 8, 9 or 10 parts.

[0028] According to embodiments of this disclosure, the chelating agent is selected from metal ion chelating agents, such as ethylenediaminetetraacetic acid, sodium gluconate, ethylenetriacetic acid, tartaric acid, citric acid and one or more of their salts; preferably, the salt is a sodium salt, potassium salt or ammonium salt; in some embodiments, the chelating agent is selected from disodium ethylenediaminetetraacetic acid (also known as disodium edetate).

[0029] According to embodiments of this disclosure, the chelating agent in the pharmaceutical composition is 0.01 to 1 part by weight, for example 0.05 to 0.5 parts, such as 0.05 parts, 0.1 parts, 0.2 parts or 0.5 parts.

[0030] According to embodiments of this disclosure, the pH adjuster is selected from pH buffers, preferably organic acid and / or its salt pH buffers, such as one or more of citric acid / sodium citrate buffer, tartrate buffer, malic acid buffer, and acetate / sodium acetate buffer, preferably citric acid / sodium citrate buffer.

[0031] According to embodiments of this disclosure, the oil phase matrix may comprise one or more selected from petrolatum, medium-chain triglycerides, and paraffin, for example, the oil phase matrix may comprise one or both of petrolatum and medium-chain triglycerides. The petrolatum is preferably white petrolatum. Preferably, the oil phase matrix comprises petrolatum and one or both of medium-chain triglycerides and paraffin, optionally present or absent; more preferably, the oil phase matrix is ​​petrolatum and medium-chain triglycerides.

[0032] According to embodiments of this disclosure, the total weight parts of the oil phase matrix in the pharmaceutical composition are 5 to 25 parts, for example 8 to 20 parts, and exemplary parts are 9, 10, 12, 13, 14, 15, 16 or 17 parts.

[0033] According to the embodiments of this disclosure, the pharmaceutical composition contains 1 to 9 parts by weight of petrolatum (preferably white petrolatum), such as 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. Examples include 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 more than 1 part, more than 1.5 parts, more than 2 parts, more than 2.5 parts, more than 3 parts, more than 3.5 parts, more than 4 parts, more than 4.5 parts, more than 5 parts, more than 5.5 parts, or more than 6 parts.

[0034] According to an embodiment of this disclosure, the water is preferably purified water.

[0035] According to embodiments of this disclosure, the water in the pharmaceutical composition is 40-70 parts by weight, for example 45-60 parts or 50-65 parts, such as 45, 46, 47, 48, 49, 50, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64 or 65 parts.

[0036] According to embodiments of this disclosure, the pharmaceutical composition may also contain antioxidants, preservatives, and / or penetration enhancers.

[0037] According to embodiments of this disclosure, the antioxidant is selected from one or more of propyl gallate and butylated hydroxytoluene (BHT); preferably, the antioxidant is butylated hydroxytoluene.

[0038] According to embodiments of this disclosure, the antioxidant in the pharmaceutical composition is 0.01 to 0.2 parts by weight, for example 0.05 to 0.15 parts, such as 0.05 parts, 0.1 parts, or 0.12 parts.

[0039] According to embodiments of this disclosure, the preservative is selected from one or more of methylparaben, ethylparaben, and propylparaben, preferably ethylparaben.

[0040] According to the embodiments of this disclosure, the preservative in the pharmaceutical composition is 0.01 to 0.3 parts by weight, for example 0.05 to 0.15 parts, such as 0.1, 0.1, 0.15 or 0.2 parts.

[0041] According to embodiments of this disclosure, the penetration enhancer is selected from one or more of diethylene glycol monoethyl ether, isopropyl myristate, isopropyl palmitate, menthol, polyethylene glycol glycerol ester, N-methylpyrrolidone, propylene carbonate, and isosorbide dimethyl ether, preferably diethylene glycol monoethyl ether.

[0042] According to embodiments of this disclosure, the penetration enhancer in the pharmaceutical composition is 0.1 to 5 parts by weight, for example 0.5 to 3 parts, exemplarily 1 part, 2 parts, 3 parts or 4 parts.

[0043] According to embodiments of this disclosure, the pH of the pharmaceutical composition is 4 to 6.5, for example 4.5, 5, 5.2, 5.5 or 6.

[0044] In some implementations, the aforementioned humectants and penetration enhancers also function as solvents in the oil phase formulation.

[0045] According to an embodiment of this disclosure, the pharmaceutical composition comprises the following components in parts by weight: 0.1-8 parts of active ingredient, 2-15 parts of thickener, 2-25 parts of emulsifier, 3-15 parts of humectant, 0.01-1 part of chelating agent, 0.01-0.2 parts of antioxidant, 0.01-0.3 parts of preservative, 0-5 parts of penetration enhancer, 5-25 parts of oil phase matrix, 40-65 parts of water, and an appropriate amount of pH adjuster;

[0046] The active ingredient is a compound represented by formula (I), preferably the E-type isomer represented by formula (I-1) above as the active ingredient;

[0047] Preferably, the thickener is octadecyl alcohol or hexadecyl alcohol;

[0048] Preferably, the emulsifier is selected from any one of the following combinations: polyethylene glycol hexadecyl ether, glyceryl mono- and glyceryl di- and polysorbate 80, polyethylene glycol hexadecyl ether and glyceryl mono- and glyceryl di- and polysorbate 80, or polyethylene glycol-7 stearate and polysorbate 80.

[0049] Preferably, the humectant is selected from propylene glycol;

[0050] Preferably, the chelating agent is selected from disodium ethylenediaminetetraacetate;

[0051] Preferably, the oil phase matrix is ​​selected from one, two, or three of petrolatum, medium-chain triglycerides, and paraffin, and is preferably white petrolatum and medium-chain triglycerides;

[0052] Preferably, the pH adjuster is selected from citrate / sodium citrate buffer or acetate / sodium acetate buffer;

[0053] Preferably, the antioxidant is selected from butylated hydroxytoluene;

[0054] Preferably, the preservative is ethylparaben;

[0055] Preferably, the penetration enhancer is diethylene glycol monoethyl ether;

[0056] Preferably, the pH of the pharmaceutical composition is 4 to 6.5.

[0057] Preferably, in each embodiment of the pharmaceutical composition, the sum of the weight parts of the components in the pharmaceutical composition is 100 parts.

[0058] In some embodiments, the pharmaceutical composition comprises the following components in parts by weight:

[0059] The compound represented by formula (I) contains 0.5-5 parts of the E-isomer, 5-10 parts of cetearyl alcohol, 5-20 parts of emulsifier, 5-12 parts of propylene glycol, 0.05-0.5 parts of chelating agent, 0.01-0.2 parts of antioxidant, 0.01-0.3 parts of preservative, 0-5 parts of penetration enhancer, 8-20 parts of oil phase matrix, 40-65 parts of water, and an appropriate amount of pH adjuster.

[0060] Preferably, the emulsifier is composed of polyethylene glycol hexadecyl ether, glyceryl mono- and di-stearate and polysorbate 80 in a weight ratio of (1.5~3):(1.5~3):1;

[0061] Preferably, the oil phase matrix is ​​composed of white petrolatum and medium-chain triglycerides, wherein the amount of white petrolatum is 1 to 9 parts.

[0062] In some embodiments, the pharmaceutical composition is selected from any one of the following formulations in parts by weight:

[0063] Formula 1: 1 part of the E isomer of the compound shown in Formula (I), 2 parts of white petrolatum, 7 parts of cetearyl alcohol, 3.5 parts of polyethylene glycol cetearyl ether, 10 parts of medium-chain triglycerides, 3 parts of glyceryl mono- and di-stearates, 0.1 parts 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 appropriate amounts of citric acid / sodium citrate;

[0064] Formula 2: 1 part of the E isomer of the compound shown in Formula (I), 2 parts of white petrolatum, 7 parts of cetearyl alcohol, 3.5 parts of polyethylene glycol cetearyl ether, 10 parts of medium-chain triglycerides, 3 parts of glyceryl mono- and di-stearates, 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, 61.7 parts of water, and an appropriate amount of citric acid / sodium citrate;

[0065] Formula 3: 4 parts of the E isomer of the compound shown in Formula (I), 2 parts of white petrolatum, 7 parts of cetearyl alcohol, 3.5 parts of polyethylene glycol cetearyl ether, 10 parts of medium-chain triglycerides, 3 parts of glyceryl mono- and di-stearates, 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 appropriate amounts of citric acid / sodium citrate;

[0066] Formula 4: 0.5 parts of the E isomer of the compound shown in Formula (I), 2 parts of white petrolatum, 7 parts of cetearyl alcohol, 3.5 parts of polyethylene glycol cetearyl ether, 10 parts of medium-chain triglycerides, 3 parts of glyceryl mono- and di-stearates, 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 appropriate amounts of citric acid / sodium citrate;

[0067] Formula 5: 2 parts of the E isomer of the compound shown in Formula (I), 2 parts of white petrolatum, 7 parts of cetearyl alcohol, 3.5 parts of polyethylene glycol cetearyl ether, 10 parts of medium-chain triglycerides, 3 parts of glyceryl mono- and distearates, 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 appropriate amounts of citric acid / sodium citrate;

[0068] Formula 6: 3 parts of the E isomer of the compound shown in Formula (I), 2 parts of white petrolatum, 7 parts of cetearyl alcohol, 3.5 parts of polyethylene glycol cetearyl ether, 10 parts of medium-chain triglycerides, 3 parts of glyceryl mono- and di-stearates, 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 appropriate amounts of citric acid / sodium citrate.

[0069] In some embodiments, the pharmaceutical composition may also contain a second active ingredient.

[0070] This disclosure also provides a method for preparing the above-described pharmaceutical composition, comprising mixing the components to obtain the composition.

[0071] In one embodiment, the preparation method includes the following steps:

[0072] (A1) Mix the chelating agent, pH adjuster and water, and heat to obtain an aqueous solution;

[0073] (A2) Mix the oil phase matrix, emulsifier, thickener, and optional preservatives and antioxidants, and heat to dissolve them to obtain an oil phase solution;

[0074] (A3) The active ingredient is mixed with a moisturizer and a penetration enhancer, which may or may not be present, and heated to dissolve, thus obtaining a third-phase solution;

[0075] (A4) Transfer the aqueous solution to the oil phase solution, emulsify, and cool;

[0076] (A5) Add the third phase solution to the emulsion system of step (A4), emulsify, cool, and obtain the pharmaceutical composition.

[0077] According to embodiments of this disclosure, the pH of the aqueous solution is 4 to 6.5, for example, 5 to 6.

[0078] According to the embodiments of this disclosure, in step (A1) or step (A2), the heating temperature is 60~90°C, for example 70~80°C.

[0079] According to the embodiments of this disclosure, the heating temperature in step (A3) is 50~65°C, for example 55~60°C.

[0080] According to the embodiments of this disclosure, the temperature to which the temperature is cooled in step (A4) is 50~65°C, for example, 55~60°C.

[0081] According to the embodiments of this disclosure, the emulsification time in step (A4) or step (A5) is 10 to 25 minutes, for example, 15 minutes or 20 minutes.

[0082] In another embodiment, the preparation method includes the following steps:

[0083] (B1) Mix the chelating agent, pH adjuster and water, and heat to obtain an aqueous solution;

[0084] (B2) Mix the oil phase matrix, emulsifier, thickener, and optional preservatives and antioxidants, and heat to dissolve them to obtain an oil phase solution;

[0085] (B3) The active ingredient is mixed with a moisturizer and a penetration enhancer, which may or may not be present, and heated to dissolve, thus obtaining a third-phase solution;

[0086] (B4) Transfer the third phase solution to the oil phase solution, keep it warm, and stir;

[0087] (B5) Add the aqueous solution to the mixture from step (B4), emulsify, cool, re-emulsify, and cool again to obtain the pharmaceutical composition.

[0088] According to embodiments of this disclosure, the pH of the aqueous solution is 4 to 6.5, for example, 5 to 6.

[0089] According to the embodiments of this disclosure, in step (B1) or step (B2), the heating temperature is 60~90°C, for example 70~80°C.

[0090] According to the embodiments of this disclosure, the heating temperature in step (B3) is 50~65°C, for example 55~60°C.

[0091] According to the embodiments of this disclosure, in step (B5), the time for the first emulsification is longer than the time for the second emulsification; for example, the time for the first emulsification is 10 to 25 minutes, such as 15 minutes or 20 minutes.

[0092] According to the implementation scheme of this disclosure, in step (B5), the first cooling is to reduce the temperature to 48~52°C.

[0093] In one embodiment, the preparation method includes the following steps:

[0094] (C1) Mix the chelating agent, pH adjuster and water, and heat to obtain an aqueous solution;

[0095] (C2) Mix the active ingredients, oil phase matrix, emulsifier, thickener, moisturizer, and optional preservatives, antioxidants, and penetration enhancers, and heat to dissolve them to obtain an oil phase solution;

[0096] (C3) The oil phase solution is added to the aqueous phase solution, emulsified, and cooled to obtain the pharmaceutical composition.

[0097] According to the embodiments of this disclosure, the pH of the aqueous solution is 4 to 6.5.

[0098] According to the embodiments of this disclosure, in step (C1) or step (C2), the heating temperature is 60~90°C, for example 70~80°C.

[0099] According to the embodiments of this disclosure, the emulsification time in step (C3) is 5 to 20 minutes, for example, 10 minutes or 15 minutes.

[0100] This disclosure also provides the use of the above-described pharmaceutical composition in the preparation of pharmaceutical formulations, preferably, the pharmaceutical formulation being an ointment.

[0101] This disclosure also provides a pharmaceutical preparation, preferably a cream, containing the above-described pharmaceutical composition.

[0102] According to embodiments of this disclosure, in the pharmaceutical formulation, the mass percentage of the active ingredient (i.e., at least one of the compounds represented by formula (I) and its pharmaceutically acceptable salts) is 0.1-8%, for example 0.5-5%, exemplarily 0.5%, 0.75%, 1%, 1.25%, 1.5%, 1.75%, 2%, 2.5%, 3%, 3.5% or 4%.

[0103] According to embodiments of this disclosure, the pharmaceutical composition or pharmaceutical preparation is used to treat atopic dermatitis and psoriasis, wherein the atopic dermatitis is preferably childhood atopic dermatitis, such as mild, moderate, severe or refractory childhood atopic dermatitis.

[0104] On the other hand, this disclosure relates to the use of the above-described pharmaceutical composition in the preparation of a medicament for the treatment and / or prevention of atopic dermatitis and psoriasis; wherein the atopic dermatitis is preferably childhood atopic dermatitis, more preferably mild, moderate, severe or refractory childhood atopic dermatitis.

[0105] On the other hand, this disclosure relates to the use of the above-described pharmaceutical composition in the preparation of a medicament for treating and / or preventing seborrheic dermatitis; wherein the seborrheic dermatitis is preferably seborrheic dermatitis.

[0106] In one embodiment, the route of administration of the pharmaceutical composition or the pharmaceutical preparation is local administration, or further in combination with an oral administration preparation or other local administration preparation.

[0107] This 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 childhood atopic dermatitis; and the seborrheic dermatitis is preferably seborrheic dermatitis.

[0108] Terminology Definitions and Explanations

[0109] Unless otherwise stated, the definitions of terms recorded in this application specification and claims, including definitions as examples, exemplary definitions, preferred definitions, definitions recorded in tables, and definitions of specific compounds in the examples, can be arbitrarily combined and combined with each other. Such combinations and combinations shall fall within the scope of this application specification.

[0110] The term "effective amount" or "therapeutic effective amount" refers to the amount of the compound described in this disclosure sufficient to achieve the intended application (including, but not limited to, the treatment of diseases as defined below). Therapeutic effective amounts may vary depending on factors such as the intended application (in vitro or in vivo), the subject being treated, and the condition of the disease, such as the subject's weight and age, the severity of the disease, and the route of administration, which can be readily determined by those skilled in the art. Specific dosages will vary depending on factors such as the particular compound selected, the administration regimen, whether it is administered in combination with other compounds, the timing of administration, the tissue to which the drug is administered, and the physical delivery system used.

[0111] The term "patient" refers to a person who requires preventive or treatment for a disease associated with anaerobic bacteria, where the patient is a mammal, such as a rodent, cow, pig, dog, cat, or primate, and especially a human.

[0112] The term "child" refers to patients aged 3 months or older, such as 3 months to 18 years, preferably 3 months to 14 years.

[0113] Beneficial effects

[0114] This disclosure provides a cream-like pharmaceutical composition / formulation in which the active ingredient is dispersed in a uniform and homogeneous droplet form, exhibiting good physical and chemical stability. This composition is suitable for the treatment of atopic dermatitis and seborrheic dermatitis, particularly in children, offering both good safety and efficacy. Attached Figure Description

[0115] Figure 1 This is an image showing the appearance of Example 1 after one week of storage;

[0116] Figure 2 This is a microscope image of Example 2;

[0117] Figure 3 This is a microscope image of Example 3;

[0118] Figure 4 This is a microscope image of Example 6;

[0119] Figure 5 Microscopic image of commercially available Benvitimod cream;

[0120] Figure 6 Polarized light micrograph of commercially available benvitamin Bactroban cream;

[0121] Figure 7This is a comparison chart of the skin retention amount in the in vitro transdermal test of Example 6 and the control example (commercially available benzoyl peroxide). In the bar chart 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.

[0122] Figure 8 This is a comparison graph of the skin penetration amount in an in vitro transdermal test of Example 6 and commercially available benvitimod;

[0123] Figure 9 The clinical effect of changes in erythema index in the treatment of seborrheic dermatitis in Example 6;

[0124] Figure 10 This is the clinical effect of the desquamation index change in Example 6 for treating seborrheic dermatitis.

[0125] Figure 11 This is a comparison chart of the skin retention amount in the in vitro transdermal test of Example 6 and Sample C. Detailed Implementation

[0126] The technical solutions of this disclosure will be further described in detail below with reference to specific embodiments. It should be understood that the following embodiments are merely illustrative and explanatory of this disclosure and should not be construed as limiting the scope of protection of this disclosure. All technologies implemented based on the above content of this disclosure are covered within the scope of protection intended by this disclosure.

[0127] Unless otherwise stated, the raw materials and reagents used in the following examples are commercially available products or can be prepared by known methods.

[0128] Commercially available Benvitimod cream: Manufactured by Guangdong Zhonghao Pharmaceutical Co., Ltd., trade name: Xinbike ® Benvitimod content: 1%.

[0129] Example 1 Initial Formulation

[0130] By comparing the formulations disclosed in the product instructions of commercially available Benvitimod creams, it is found that the cream consists of an aqueous phase, an oil phase, an emulsifier, a solvent, and a preservative. The specific formulations are shown in Table 1-1 below:

[0131] Table 1-1

[0132]

[0133] Referring to Table 1-1, the preliminary formulation of this application is the prescription of Example 1 and Example 2, wherein the prescription of Example 1 is shown in Table 1:

[0134] Table 1

[0135]

[0136] The preparation method of the cream is as follows:

[0137] 1. Aqueous phase: Add disodium edetate, sodium acetate, polysorbate 80 and purified water to a beaker, heat to 70-80℃, stir to dissolve, adjust the pH to about 5-6 to obtain the aqueous phase;

[0138] 2. Oil phase: Add light liquid paraffin, white petrolatum, polyethylene glycol-7 stearate, octadecanol, ethylparaben, and butylated hydroxytoluene to a beaker, bring the temperature to 70-80℃, stir to dissolve, and obtain the oil phase;

[0139] 3. Third phase: Diethylene glycol monoethyl ether and propylene glycol are heated to 55-60°C, and the E-type isomer of the compound shown in formula (I) is added to dissolve it, thus obtaining the third phase;

[0140] 4. Transfer the aqueous phase to the oil phase and emulsify for 15 minutes; then cool to 55-60℃;

[0141] 5. Add the third phase to the emulsification system in step 4, emulsify for 15 minutes, cool down, and obtain the cream.

[0142] Examples 2-4 Initial Formulation Optimization

[0143] The prescriptions for Examples 2-4 are shown in Table 2:

[0144] Table 2

[0145]

[0146] The preparation method of the cream is as follows:

[0147] 1. Aqueous phase: Add disodium edetate, anhydrous sodium acetate and purified water to a beaker, heat to 70-80℃, stir to dissolve, adjust the pH to about 5-6 to obtain the aqueous phase;

[0148] 2. Oil phase: Light liquid paraffin, white petrolatum, polyethylene glycol cetearyl ether, cetearyl alcohol, glyceryl mono- and di-stearyl esters, ethylparaben, polyoxyethylene (54) hydrogenated castor oil and dibutylhydroxytoluene are added to a beaker and stirred to 70-80℃ to dissolve, thus obtaining the oil phase;

[0149] 3. Third phase: Diethylene glycol monoethyl ether and propylene glycol are heated to 55-65°C, and the E-type isomer of the compound shown in formula (I) is added to dissolve it, thus obtaining the third phase;

[0150] 4. Transfer the third phase to the oil phase, keep warm, and stir for 10 minutes;

[0151] 5. Add the mixture from step 4 to the aqueous phase, emulsify for 10 minutes, then slowly cool to 48-52℃, emulsify for another 5 minutes, cool down to obtain the cream.

[0152] Example 5: Study on the physicochemical properties of Examples 1-4

[0153] Example 1: A white cream, with uniform droplets as seen under a microscope, but the cream had poor spreadability and a rather hard texture; after being placed at 30℃ / RH65% for one week, the cream underwent a significant discoloration, changing from white to pale yellow. Figure 1 .

[0154] Example 2: A whitish cream, microscopically observed to contain large patches of oily material, with unevenly distributed droplets, resulting in poor spreadability. See related micrographs for details. Figure 2 .

[0155] Examples 3 and 4: By comparing Examples 2-4, the effect of white petrolatum in the formulation on the product droplets was investigated. Microscopic observation showed that as the proportion of white petrolatum decreased, the droplet size in the sample decreased. Detailed micrographs of Example 3 can be found in [link to example]. Figure 3 .

[0156] Examples 5-7: Formulation Optimization

[0157] Based on the physicochemical properties of Examples 1-4, the applicant considered further optimizing the formulation. After extensive creative work, by adjusting the types and contents of factors such as the oil phase matrix, thickener, and pH adjuster, the optimized formulation was finally obtained as shown in Table 3.

[0158] Table 3

[0159]

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

[0161] Step 1: Aqueous phase preparation. Dissolve disodium edetate, sodium citrate, and citric acid in purified water, heat to 70-80℃, maintain the temperature, and adjust the pH to 4.5-6.5 to obtain the aqueous phase.

[0162] Step 2: Preparation of the oil phase: The E-type isomer of the compound shown in formula (I), white petrolatum, cetearyl alcohol, polyethylene glycol cetearyl ether, glyceryl mono- and di-stearyl esters, medium-chain triglycerides, dibutylhydroxytoluene, polysorbate 80, propylene glycol and ethylparaben are heated to 70-80℃ to melt, and kept at this temperature to obtain the oil phase.

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

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

[0165] Step 1: Aqueous phase preparation. Dissolve disodium edetate, sodium citrate, and citric acid in purified water, heat to 70-80℃, maintain the temperature, and adjust the pH to 4.5-6.5 to obtain the aqueous phase.

[0166] Step 2: Oil phase preparation: The E-type isomer of the compound shown in formula (I), white petrolatum, cetearyl alcohol, polyethylene glycol cetearyl ether, glyceryl mono- and di-stearyl esters, medium-chain triglycerides, dibutylhydroxytoluene, polysorbate 80, diethylene glycol monoethyl ether, propylene glycol and ethylparaben are heated to 70-80℃ to melt and kept at that temperature.

[0167] Step 3: Add the oil phase to the aqueous 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 uniformly dispersed in the form of droplets, and the droplets were of uniform size, all less than 5 μm. (See microscope image). Figure 4 .

[0170] Example 9 In vitro transdermal test

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

[0172] 1) Experimental steps:

[0173] The formulations prepared in Examples 5 and 6 were subjected to in vitro transdermal tests to evaluate the average retention of benvitimod in the epidermis and dermis. Pigskin (0.8–1.0 mm thick) was mounted on a LOGAN System 918 vertical diffusion cell, exposed at a depth of 1.77 cm. 2 The surface area of ​​the skin was measured. A diffusion cell was connected to a multichannel pump at 600 rpm, with PBS (phosphate-buffered saline) at pH 7.4 as the receiving solution. Each cell was placed in a heated manifold to equilibrate the temperature, ensuring the skin surface temperature was 32°C (at least 30 min before administration). A dose of 10 mg test sample per square centimeter was added. Receiving solutions were collected at 2, 4, 8, 20, and 24 hours to measure the active ingredient permeated through the skin. After 24 hours of sampling, the skin was swab-swab-washed to remove any residual sample deemed impermeable to the skin, and the epidermis and dermis were separated by heating. The skin layer was minced, and the drug was extracted by sonication with methanol. The concentration of benvitimod was determined by high-performance liquid chromatography (HPLC). The recovered drug concentration was used to calculate the average retention of benvitimod in the skin.

[0174] 2) Test Results

[0175] In the formulation prepared in Example 5, the average retention of benvitimide in the skin was 1.85 μg / cm³. 2 In the formulation prepared in Example 6, the average retention of benvitimide in the skin was 2.91 μg / cm³. 2 Transdermal assay results showed that adding the penetration enhancer diethylene glycol monoethyl ether significantly increased the total amount retained in the skin.

[0176] Example 10 Stimulation Test

[0177] Sixty healthy adult guinea pigs (30 females / 30 males) and forty healthy young guinea pigs (20 females / 20 males) were randomly divided into four groups according to sex and weight using TOXSTAT 2006 software: a negative control group, a positive control group, a low-dose adult animal test product group (Example 6, 1%), a high-dose adult animal test product group (Example 7, 4%), a low-dose young animal test product group (Example 6, 1%), and a high-dose young animal test product group (Example 7, 4%). Each negative and positive control group contained 10 guinea pigs (5 females / 5 males), and each test product group contained 20 guinea pigs (10 females / 10 males).

[0178] Hair preparation: Before administration, the animal is first trimmed with electric clippers, removing the skin and hair on both sides of the spine on the back, 3×3cm on each side. 2 .

[0179] Sensitization: On days 0, 7, and 14, 0.2 g / animal (0.2 mL / animal for negative / positive control groups) of the test substance was administered to the left side of the hair-removed area. Cellophane or filter paper was placed in the groove of a blank plaster, and the test substance was placed on the cellophane or contained in the filter paper and applied to the administration site. The plaster was then sealed and fixed with non-irritating medical tape. The blank plaster and filter paper were removed after approximately 6 hours. Animals in the negative control group were given 0.9% sodium chloride injection, and animals in the positive control group were given 2% 2,4-dinitrochlorobenzene (prepared by ultrasonication with 80% ethanol). Animals in the low- and high-dose groups of the test substance were given the corresponding concentrations of the formulations prepared in Examples 6 and 7 (containing 1% and 4% benvitimide, respectively).

[0180] Challenge: On day 14 after the last sensitization, 0.2 g / animal of the test substance was administered to the right side of the bald area of ​​each group of guinea pigs (0.2 mL / animal for the positive control group, prepared with 0.2% 2,4-dinitrochlorobenzene in acetone solution; 0.2 mL / animal for the negative control group, prepared with 0.9% sodium chloride injection solution), and the test substance was removed after about 6 hours.

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

[0182] The results showed that under the experimental conditions, the Buehler test results were negative after guinea pigs were repeatedly given the formulations prepared in Examples 6 and 7, indicating that no sensitizing effect on the skin was observed even with the increase of the content of the active ingredient benvitimod.

[0183] Example 11 Stability Test

[0184] Six groups of the same amount of the cream from Example 6 were weighed into sealed aluminum tubes. The samples were placed at room temperature and 40°C, and their physicochemical stability was observed and determined using liquid chromatography at 0 days, 40°C–5 days, 40°C–10 days, 40°C–30 days, 40°C–3 months, and 40°C–6 months. The specific results are shown in Table 4. The results show that the cream from Example 6 did not oxidize or discolor after long-term storage, the active ingredients remained stable, still uniformly dispersed in droplet form without crystallization, and the impurity content remained almost unchanged, demonstrating excellent stability.

[0185] Impurity and content determination by liquid chromatography: Octadecylsilane-bonded silica gel was used as the packing material; water was used as mobile phase A and acetonitrile as mobile phase B, with gradient elution; elution gradient: 0 min 80% A → 20–30 min 10% A → 32–40 min 80% A; flow rate was 1.0 ml per minute; column temperature was 35℃; detection wavelength was 220 nm; injection volume was 10 μl.

[0186] Table 4

[0187]

[0188] Example 12: Comparison of the formulation prepared in Example 6 and commercially available benvitimide cream (control example).

[0189] 1) Morphology: Under microscopic conditions, commercially available Benvitimod cream exhibits uneven droplets and large oily substances (see...). Figure 5 Solid crystals were observed under polarized light microscopy (see...) Figure 6 ).

[0190] 2) In vitro transdermal assay: to examine the retention and penetration of the active ingredient benvitimod in the skin.

[0191] The in vitro transdermal test was performed following the experimental steps described in Example 9. Six groups (n=6) were tested in parallel with the control and example cases. The results are shown in Table 5. Figures 7 to 8 .

[0192] Table 5. Skin retention (μg / cm³) 2 )

[0193]

[0194] From Table 5 and the average data of skin retention, both Example 6 and the control showed that the retention of benvitimod in the dermis was greater than that in the epidermis; and in Example 6, the retention of benvitimod in both the dermis and skin was greater than that in the control group. Furthermore, from... Figure 7 It can be seen that the skin retention (dermis and epidermis) in each group of Example 6 is more uniform and stable than that in each group of control examples, with smaller fluctuations in the skin retention. Figure 8 Based on the skin penetration data, the skin penetration of Example 6 was comparable to that of the control example, indicating better parallelism, higher skin retention, and better efficacy.

[0195] Example 13

[0196] The cream prepared in Example 6 was applied topically to the skin of subjects aged 3 months to 14 years with atopic dermatitis (AD), twice daily. Significant improvement was observed in some patients within 5 to 7 days, with symptoms continuing to lessen over a month.

[0197] Example 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 daily. The control group received the base ingredients of Example 6 without benvitimod, applied twice daily. Significant improvements in erythema index and desquamation index were observed in the second week, persisting into the eighth week. By week 8, the treatment group showed an 81.81% reduction in erythema index and an 83.70% reduction in desquamation index; while the control group showed a 38.46% reduction in erythema index and a 37.44% reduction in desquamation index. (See Table 6 and...) Figure 9 and Figure 10 This study can demonstrate the clinical efficacy of the AhR agonist benvitimide in treating patients with seborrheic dermatitis.

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

[0200]

[0201] Example 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 influence of the sample composition on the cream products was evaluated.

[0203] The preparation method for the cream sample is as follows:

[0204] Step 1: Aqueous phase preparation. Dissolve disodium edetate, sodium citrate, and citric acid in purified water, heat to 70-80℃, keep warm, and adjust the pH to 4.5-5.5 to obtain the aqueous phase.

[0205] Step 2: Oil phase preparation. Mix the E-type isomer of the compound shown in formula (I) with other components, heat to 70-80℃ to melt, and keep warm to obtain the oil phase.

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

[0207] Table 7

[0208]

[0209] Table 8

[0210]

[0211] The results show that:

[0212] In Table 7, samples 1 and 2 had an oily substance on the upper layer and failed to form a uniform paste. Samples 3-10 could all be prepared into creams, but when the amount of white petrolatum decreased, the appearance of the cream changed from a slightly pinkish color to a white cream. Samples 3 and 4 were observed under a microscope to have small, flaky oily substances instead of regular droplets. Samples 5 and 6 were observed under a microscope to have round droplets formed in the oil phase, indicating that when the amount of white petrolatum is controlled below 6%, samples with uniform droplets can be prepared.

[0213] In Table 8, the creams of samples 11 and 12 showed large, blocky oil droplets under a microscope, while sample 13 could be prepared into a white cream with small droplets, indicating that the emulsifier polyethylene glycol hexadecyl ether has a good emulsifying ability for medium-chain triglycerides and white petrolatum oil phase matrix.

[0214] Samples 14-19 can be prepared into a white, uniform, and fine cream without oil-water separation. However, Sample 14, which does not contain polysorbate 80, has uneven droplet size; Sample 15 has smaller, round droplets, indicating that the addition of polysorbate 80 can improve the droplet size. Sample 18, which does not contain glyceryl monostearate or glyceryl distearate, has uneven droplet size and large oil droplets, while this phenomenon was not observed in other samples containing glyceryl monostearate or glyceryl distearate.

[0215] Furthermore, during the application process, it was observed that the creams containing a high proportion of polysorbate 80 or polyethylene glycol hexadecyl ether (PEG 80) exhibited a whitening effect with repeated application. Viscosity testing results showed that the creams with a high proportion of PEG 80 and a high proportion of glyceryl mono- and glyceryl di-stearate had a higher viscosity than those with a lower proportion, indicating that PEG 80 and glyceryl mono- and glyceryl di-stearate have a certain thickening effect.

[0216] In summary, the preferred sample of this invention has moderate viscosity, is uniform and delicate, and has a good coating effect.

[0217] Example 16

[0218] Based on 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 effect of the active ingredient content in the samples on the cream products was evaluated. 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 content of other components constant.

[0219] Table 9

[0220]

[0221] The preparation method for the cream sample is as follows:

[0222] Step 1: Aqueous phase preparation. Dissolve disodium edetate, sodium citrate, and citric acid in purified water, heat to 70-80℃, keep warm, and adjust the pH to 4.5-5.5 to obtain the aqueous phase.

[0223] Step 2: Oil phase preparation. Mix the E-type isomer of the compound shown in formula (I) with other components, heat to 70-80℃ to melt, and keep warm to obtain the oil phase.

[0224] Step 3: Add the oil phase to the aqueous phase, emulsify for 10 minutes, cool down, and obtain the cream sample.

[0225] The results showed that the compositions of samples 20-22 and Example 7 could both be used to prepare off-white creams with droplet diameters less than 10 μm, indicating that the cream formulation of the present invention can be applied to different contents of active ingredients.

[0226] Example 17

[0227] Sample C was prepared according to the composition of formulation 21 in Table 8 of the specification of patent CN114042041A. The formulation consists of an oil phase (active ingredient, propylene glycol, diethylene glycol monoethyl ether, butylated hydroxytoluene, benzoic acid, emulsified wax, medium-chain triglycerides, polysorbate 80, stearyl alcohol polyether 2, stearyl alcohol polyether 20) and an aqueous phase (disodium edetate, citric acid, sodium citrate, purified water). The preparation method is as follows: the oil phase components are mixed and heated to 70-80℃, and mixing is continued until the active ingredient is dissolved and the appearance is uniform; the aqueous phase components are mixed and heated to 70-80℃, and mixing is continued until all substances are completely dissolved and the aqueous phase has a uniform appearance; the oil phase is added to water, the temperature is maintained between 70-80℃, and mixing is carried out for 5-10 minutes, followed by cooling.

[0228] The in vitro transdermal test was conducted following the experimental steps described in Example 9. A comparison was made between the sample from Example 6 of this application and sample C. The results showed that, with the same active ingredient content, the intradermal retention of the cream sample from Example 6 of this application was higher than that of sample C (see...). Figure 11 ).

[0229] The specific embodiments of the present invention have been described above by way of example. However, the scope of protection of the present invention is not limited to the above exemplary embodiments. Any modifications, equivalent substitutions, improvements, etc., made by those skilled in the art within the spirit and principles of the present invention should be included within the scope of protection of the claims of the present invention.

Claims

1. A pharmaceutical composition, characterized in that, The pharmaceutical composition comprises the following components: an active ingredient, a thickener, an emulsifier, a humectant, a chelating agent, a pH adjuster, an oil phase matrix, and water, wherein the active ingredient is selected from at least one of the compounds represented by formula (I) and their pharmaceutically acceptable salts; （I） in, The oil phase matrix is ​​petrolatum and medium-chain triglycerides; The sum of the weight parts of each component in the pharmaceutical composition is 100 parts; The petroleum jelly is present in 1-6 parts by weight; The emulsifier is composed of polyethylene glycol hexadecyl ether and glyceryl mono- and di-stearate, or of polyethylene glycol hexadecyl ether, glyceryl mono- and di-stearate, and polysorbate 80.

2. The pharmaceutical composition according to claim 1, characterized in that, The compound represented by formula (I) is the E-type isomer represented by formula (I-1): （I-1） Or, the pharmaceutically acceptable salt is selected from the addition salt of the E or Z isomer of the compound of formula (I) with a base; Or, in the pharmaceutical composition, the active ingredient is present in the form of emulsion droplets; Or, in the pharmaceutical composition, the active ingredient is 0.1-8 parts by weight.

3. The pharmaceutical composition according to claim 1, characterized in that, The thickener is selected from one or both of octadecyl alcohol and hexadecyl alcohol; And / or, in the pharmaceutical composition, the thickener is present in parts by weight of 2 to 15 parts; And / or, in the pharmaceutical composition, the emulsifier is present in parts by weight of 2 to 25 parts; When there are two types of emulsifiers, the weight ratio of the two emulsifiers is (1~3):(3~1); when there are three types of emulsifiers, the weight ratio of the three emulsifiers is (1~3):(3~1):

1. And / or, the moisturizer is selected from one or more of propylene glycol, glycerin, and polyethylene glycol; And / or, in the pharmaceutical composition, the humectant is present in parts by weight of 3 to 15 parts; And / or, the chelating agent is selected from metal ion chelating agents; And / or, in the pharmaceutical composition, the chelating agent is present in a weight fraction of 0.01 to 1 part; And / or, the pH adjuster is selected from organic acids or their salts pH buffers; And / or, in the pharmaceutical composition, the oil phase matrix is ​​5 to 25 parts by weight; And / or, the water is purified water; And / or, in the pharmaceutical composition, the water comprises 40 to 65 parts by weight.

4. The pharmaceutical composition according to claim 1, characterized in that, The pharmaceutical composition also contains antioxidants, preservatives, and / or penetration enhancers; And / or, the antioxidant is selected from one or both of propyl gallate and butylated hydroxytoluene; And / or, in the pharmaceutical composition, the antioxidant is present in an amount of 0.01 to 0.2 parts by weight; And / or, the preservative is selected from one or more of methylparaben, ethylparaben, and propylparaben; And / or, in the pharmaceutical composition, the preservative is present in an amount of 0.01 to 0.3 parts by weight; And / or, the penetration enhancer is selected from one or more of diethylene glycol monoethyl ether, isopropyl myristate, isopropyl palmitate, menthol, polyethylene glycol glycerol caprylate / capric acid, N-methylpyrrolidone, propylene carbonate, and isosorbide dimethyl ether; And / or, in the pharmaceutical composition, the penetration enhancer is present in an amount of 0.1 to 5 parts by weight; and / or, the pH of the pharmaceutical composition is 4 to 6.5; And / or, the pharmaceutical composition further comprises a second active ingredient.

5. The pharmaceutical composition according to claim 1, characterized in that, The pharmaceutical composition comprises the following components in parts by weight: 0.1-8 parts of active ingredient, 2-15 parts of thickener, 2-25 parts of emulsifier, 3-15 parts of humectant, 0.01-1 part of chelating agent, 0.01-0.2 parts of antioxidant, 0.01-0.3 parts of preservative, 0-5 parts of penetration enhancer, 5-25 parts of oil phase matrix, 40-65 parts of water, and pH adjuster; The active ingredient is the E-type isomer shown in formula (I-1); the pH of the pharmaceutical composition is 4 to 6.

5.

6. The pharmaceutical composition according to claim 1, characterized in that, The pharmaceutical composition comprises the following components in parts by weight: The compound represented by formula (I) contains 0.5-5 parts of its E-type isomer, 5-10 parts of cetearyl alcohol, 5-20 parts of emulsifier, 5-12 parts of propylene glycol, 0.05-0.5 parts of chelating agent, 0.01-0.2 parts of antioxidant, 0.01-0.3 parts of preservative, 0-5 parts of penetration enhancer, 8-20 parts of oil phase matrix, 40-65 parts of water, and an appropriate amount of pH adjuster; The emulsifier is composed of polyethylene glycol hexadecyl ether, glyceryl mono- and di-stearate, and polysorbate 80 in a weight ratio of (1.5~3):(1.5~3):

1.

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

8. The preparation method according to claim 7, characterized in that, The preparation method is selected from any one of the following methods: Method 1, the preparation method includes the following steps: (A1) Mix the chelating agent, pH adjuster and water, and heat to obtain an aqueous solution; (A2) Mix the oil phase matrix, emulsifier, thickener, and optional preservatives and antioxidants, and heat to dissolve them to obtain an oil phase solution; (A3) The active ingredient is mixed with a moisturizer and a penetration enhancer, which may or may not be present, and heated to dissolve, thus obtaining a third-phase solution; (A4) Transfer the aqueous solution to the oil phase solution, emulsify, and cool; (A5) Add a third-phase solution to the emulsion system of step (A4), emulsify, and cool to obtain the pharmaceutical composition; Method 2, the preparation method includes the following steps: (B1) Mix the chelating agent, pH adjuster and water, and heat to obtain an aqueous solution; (B2) Mix the oil phase matrix, emulsifier, thickener, and optional preservatives and antioxidants, and heat to dissolve them to obtain an oil phase solution; (B3) The active ingredient is mixed with a moisturizer and a penetration enhancer, which may or may not be present, and heated to dissolve, thus obtaining a third-phase solution; (B4) Transfer the third phase solution to the oil phase solution, keep it warm, and stir; (B5) Add an aqueous solution to the mixture from step (B4), emulsify, cool, re-emulsify, and cool again to obtain the pharmaceutical composition; Method 3, the preparation method includes the following steps: (C1) Mix the chelating agent, pH adjuster and water, and heat to obtain an aqueous solution; (C2) The active ingredients, oil phase matrix, emulsifier, thickener, humectant, and optional preservatives, antioxidants, and penetration enhancers are mixed and heated to dissolve, thus obtaining an oil phase solution; (C3) The oil phase solution is added to the aqueous phase solution, emulsified, and cooled to obtain the pharmaceutical composition.

9. A pharmaceutical preparation, characterized in that, The pharmaceutical preparation contains the pharmaceutical composition as described in any one of claims 1 to 6; the pharmaceutical preparation is preferably a cream.

10. Use of a pharmaceutical composition according to any one of claims 1 to 6 in the preparation of a medicament for treating a disease, wherein, The disease is selected from atopic dermatitis, psoriasis, or seborrheic dermatitis; the atopic dermatitis is preferably pediatric atopic dermatitis, and the seborrheic dermatitis is preferably seborrheic dermatitis.

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