A PHARMACEUTICAL COMPOSITION BASED ON A PHENOL DERIVATIVE WITH INCREASED STABILITY AND ITS APPLICATION

Abstract

A pharmaceutical composition of a phenol derivative and use thereof. The pharmaceutical composition comprises the following components: an active ingredient, a thickening agent, 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 a compound of formula (I) and a pharmaceutically acceptable salt thereof; the active ingredient is dispersed in a homogeneous and uniform emulsion drop form and has good physical and chemical stability. The composition is suitable for the treatment of atopic dermatitis, psoriasis and seborrheic dermatitis, especially for the treatment of atopic dermatitis and seborrheic dermatitis of children, and has good safety, stability, and effectiveness, and uniform morphology characteristics.

Description

Pharmaceutical compositions of phenol derivatives with improved stability and uses thereof

[0001] This application claims priority to a prior application, patent application number 202311442719.6, filed with the State Intellectual Property Office of China on November 2, 2023, entitled “Pharmaceutical compositions of phenol derivatives with improved stability and uses thereof.” The entire text of the prior application is incorporated herein by reference. Technical Field

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

[0003] Atopic dermatitis (AD) is a chronic, relapsing, inflammatory skin disease. The incidence of AD has been increasing worldwide in recent years. The etiology and pathogenesis of AD remain unclear and may be related to multiple factors, including genetics, skin barrier defects, immunity, environment, and microbial colonization. Currently, treatment for mild to moderate AD in children is typically based on topical glucocorticoids and calcineurin inhibitors. However, treatment for moderate, severe, or refractory AD in children is more challenging and requires individualized treatment. There is no systematic, universal drug therapy, otherwise it will seriously affect the quality of life and psychological well-being of children.

[0004] Seborrheic dermatitis (SD) is a chronic, papulosquamous, superficial inflammatory skin disease that occurs in areas of sebum secretion. The typical rash is dark red or yellow-red macules formed by the fusion of follicular papules, covered with greasy scales or crusts, and may be accompanied by varying degrees of itching. SD is a chronic, recurrent inflammatory skin disease that usually presents as a red, scaly rash. The incidence rate in healthy people is 5%, of which 70.3% occurs on the head, and is common in infants, adolescents and adults. Seborrheic dermatitis refers to a disease of the scalp. This disease differs from simple dandruff in that it has erythema as a sign of inflammation, the scalp is more flaky and sometimes accompanied by itching and burning, and eczema may appear in other parts of the body. The disease can occur in the form of plaques, but often affects the entire scalp and extends beyond the hairline, often including the forehead, around the neck and both ears. In severe cases, the scalp may become secondary infected, with changes that may manifest as a spongy texture, blistering, and crusting, which may ooze. Seborrheic dermatitis also frequently occurs in infancy and typically resolves spontaneously between 8 and 12 months of age. Scalp changes in infants include erythema, flaking, and occasional blisters and crusting. These changes 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 puberty and can persist throughout life, potentially becoming more severe. Approximately 1-3% of the population suffers from this condition. The etiology and pathogenesis of SD remain unclear, but a complex interplay between Malassezia, keratinocytes, and the immune response plays a crucial role in its development. Seborrheic dermatitis shares some of the same pathogenic factors with 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; 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 efficacy is low; and symptoms are prone to recurrence after discontinuation of the drugs.

[0006] Although CN108066279A and CN113797159A disclose research on benzophenonemod topical creams, their samples exhibit poor properties, with a significant proportion of lumpy, oily matter remaining, impacting product performance. Furthermore, the examples of CN114042041A demonstrate that the white vaseline in their formulations leads to the formation of a waxy substance. Even formulations containing relatively low levels of white vaseline result in uneven emulsions, whereas formulations without petrolatum oil produce uniform emulsions.

[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 remains a technical problem that needs to be solved urgently in this field.

[0008] Summary of the Invention

[0009] 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 compound represented by formula (I) and a pharmaceutically acceptable salt thereof;

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

[0012] 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.

[0013] 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-type isomer represented by formula (I-1) (i.e., benvimod) as the active ingredient.

[0014] 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.

[0015] 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, exemplified by 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.

[0016] According to an embodiment of the present disclosure, the thickener is selected from one or more of cetyl alcohol, stearyl alcohol and cetostearyl alcohol.

[0017] 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.

[0018] 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.

[0019] 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.

[0020] 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 further such as (1-1.2): (1.2-1), and specific examples are 3:3.5, 3.5:3 or 1:1. Exemplarily, when the emulsifiers are polyethylene glycol cetearyl ether and glyceryl mono- and distearate, the weight ratio of polyethylene glycol cetearyl ether and glyceryl mono- and distearate can be (1-3): (3-1), for example, (1-2): (2-1), such as (1-1.5): (1.5-1), and further such as (1-1.2): (1.2-1), and specific examples are 3:3.5, 3.5:3 or 1:1.

[0021] 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, for example, 1 / 4 to 1 / 3, such as 2 / 7 to 1 / 3.

[0022] 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 exemplified by 3.5: 3: 1.5. For example, the emulsifier is composed of polyethylene glycol cetearyl ether, glyceryl mono- and distearate, and polysorbate 80, and the weight ratio of polyethylene glycol cetearyl 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 exemplified by 3.5: 3: 1.5.

[0023] According to an embodiment of the present disclosure, the moisturizing agent is selected from one or more of propylene glycol, glycerin, polyethylene glycol, etc., preferably propylene glycol.

[0024] 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.

[0025] 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, nitrotriacetic 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).

[0026] 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.

[0027] According to an embodiment of the present disclosure, the pH regulator 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.

[0028] According to an embodiment of the present disclosure, the oil phase matrix may comprise one or more selected from petrolatum, medium-chain triglycerides, and paraffin wax. For example, the oil phase matrix comprises one or both of petrolatum and medium-chain triglycerides. The petrolatum is preferably white petrolatum. Preferably, the oil phase matrix comprises petrolatum and, optionally, one or both selected from medium-chain triglycerides and paraffin wax. More preferably, the oil phase matrix comprises petrolatum and medium-chain triglycerides.

[0029] According to an embodiment of the present disclosure, in the pharmaceutical composition, the total weight 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.

[0030] 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.

[0031] According to an embodiment of the present disclosure, the water is preferably purified water.

[0032] 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 parts, 46 parts, 47 parts, 48 ​​parts, 49 parts, 50 parts, 55 parts, 56 parts, 57 parts, 58 parts, 59 parts, 60 parts, 61 parts, 62 parts, 63 parts, 64 parts or 65 parts.

[0033] According to an embodiment of the present disclosure, the pharmaceutical composition may further contain an antioxidant, a preservative and / or a permeation enhancer.

[0034] According to an embodiment of the present disclosure, the antioxidant is selected from one or more of propyl gallate and butylated hydroxytoluene (BHT); preferably, the antioxidant is butylated hydroxytoluene.

[0035] 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.

[0036] According to an embodiment of the present disclosure, the preservative is selected from one or more of methylparaben, ethylparaben and propylparaben, preferably ethylparaben.

[0037] 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, exemplified by 0.1, 0.1, 0.15 or 0.2 parts.

[0038] 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 / capric macrogol glyceride, N-methyl pyrrolidone, propylene carbonate and dimethyl isosorbide, preferably diethylene glycol monoethyl ether.

[0039] 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.

[0040] 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.

[0041] In some embodiments, the aforementioned moisturizers and penetration enhancers also serve as solvents for the oil phase formulation.

[0042] According to an embodiment of the present disclosure, 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 base, 40 to 65 parts of water, and an appropriate amount of pH adjuster;

[0043] 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;

[0044] Preferably, the thickener is stearyl alcohol or cetostearyl alcohol;

[0045] 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;

[0046] Preferably, the humectant is selected from propylene glycol;

[0047] Preferably, the chelating agent is selected from disodium edetate;

[0048] Preferably, the oil phase matrix is ​​selected from one, two or three of petrolatum, medium chain triglycerides and paraffin, preferably white petrolatum and medium chain triglycerides;

[0049] Preferably, the pH regulator is selected from citric acid / sodium citrate buffer or acetic acid / sodium acetate buffer;

[0050] Preferably, the antioxidant is selected from butylated hydroxytoluene;

[0051] Preferably, the preservative is ethylparaben;

[0052] Preferably, the penetration enhancer is diethylene glycol monoethyl ether;

[0053] Preferably, the pH of the pharmaceutical composition is 4 to 6.5.

[0054] Preferably, in each embodiment of the pharmaceutical composition, the sum of the weight parts of each component in the pharmaceutical composition is 100 parts.

[0055] In some embodiments, the pharmaceutical composition includes the following components in parts by weight:

[0056] 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 oily base, 40-65 parts of water, and an appropriate amount of a pH adjuster;

[0057] 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;

[0058] Preferably, the oil phase matrix consists of white petrolatum and medium chain triglycerides, wherein the proportion of white petrolatum is 1 to 9 parts.

[0059] In some embodiments, the pharmaceutical composition is selected from any one of the following formulations in parts by weight:

[0060] Formula 1: 1 part of the E-isomer of the compound represented by formula (I), 2 parts of white petrolatum, 7 parts of cetostearyl alcohol, 3.5 parts of polyethylene glycol cetearyl ether, 10 parts of medium-chain triglycerides, 3 parts of mono- and distearic glycerides, 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;

[0061] Formula 2: 1 part of the E-isomer of the compound represented by formula (I), 2 parts of white petrolatum, 7 parts of cetostearyl alcohol, 3.5 parts of polyethylene glycol cetearyl ether, 10 parts of medium-chain triglycerides, 3 parts of glyceryl mono- and distearate, 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;

[0062] Formulation 3: 4 parts of the E-isomer of the compound represented by formula (I), 2 parts of white petrolatum, 7 parts of cetostearyl alcohol, 3.5 parts of polyethylene glycol cetearyl 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, 58.7 parts of water, and an appropriate amount of citric acid / sodium citrate;

[0063] Formula 4: 0.5 parts of the E-isomer of the compound represented by formula (I), 2 parts of white petrolatum, 7 parts of cetostearyl alcohol, 3.5 parts of polyethylene glycol cetearyl ether, 10 parts of medium-chain triglycerides, 3 parts of glyceryl mono- and distearate, 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;

[0064] Formulation 5: 2 parts of the E-isomer of the compound represented by formula (I), 2 parts of white petrolatum, 7 parts of cetostearyl alcohol, 3.5 parts of polyethylene glycol cetearyl ether, 10 parts of medium-chain triglycerides, 3 parts of mono- and distearic glycerides, 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, 60.7 parts of water, and an appropriate amount of citric acid / sodium citrate;

[0065] Formula 6: 3 parts of the E-isomer of the compound represented by formula (I), 2 parts of white petrolatum, 7 parts of cetostearyl alcohol, 3.5 parts of polyethylene glycol cetearyl ether, 10 parts of medium-chain triglycerides, 3 parts of mono- and distearic glycerides, 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, 59.7 parts of water, and an appropriate amount of citric acid / sodium citrate.

[0066] In some embodiments, the pharmaceutical composition may further comprise a second active ingredient.

[0067] The present disclosure also provides a method for preparing the above pharmaceutical composition, comprising mixing the components.

[0068] In one embodiment, the preparation method comprises the following steps:

[0069] (A1) mixing a chelating agent, a pH adjuster, and water, and heating the mixture to obtain an aqueous solution;

[0070] (A2) mixing an oil phase base, an emulsifier, a thickener, and optionally a preservative and an antioxidant, and heating and dissolving the mixture to obtain an oil phase solution;

[0071] (A3) mixing the active ingredient with a moisturizer and optionally a penetration enhancer, heating and dissolving the mixture to obtain a third phase solution;

[0072] (A4) transferring the aqueous phase solution to the oil phase solution, emulsifying, and cooling;

[0073] (A5) adding the third phase solution to the emulsified system of step (A4), emulsifying, and cooling to obtain the pharmaceutical composition.

[0074] According to an embodiment of the present disclosure, the pH of the aqueous solution is 4 to 6.5, for example, 5 to 6.

[0075] According to an embodiment of the present disclosure, in step (A1) or step (A2), the heating temperature is 60 to 90°C, for example, 70 to 80°C.

[0076] According to an embodiment of the present disclosure, the heating temperature in step (A3) is 50-65°C, for example 55-60°C.

[0077] According to an embodiment of the present disclosure, the temperature to which the temperature is lowered in step (A4) is 50-65°C, for example 55-60°C.

[0078] 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.

[0079] In another embodiment, the preparation method comprises the steps of:

[0080] (B1) mixing a chelating agent, a pH adjuster, and water, and heating the mixture to obtain an aqueous solution;

[0081] (B2) mixing an oil phase base, an emulsifier, a thickener, and optionally a preservative and an antioxidant, and heating and dissolving the mixture to obtain an oil phase solution;

[0082] (B3) mixing the active ingredient with a moisturizer and optionally a penetration enhancer, and heating to dissolve the mixture to obtain a third phase solution;

[0083] (B4) transferring the third phase solution into the oil phase solution, keeping warm, and stirring;

[0084] (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.

[0085] According to an embodiment of the present disclosure, the pH of the aqueous solution is 4 to 6.5, for example, 5 to 6.

[0086] According to an embodiment of the present disclosure, in step (B1) or step (B2), the heating temperature is 60 to 90°C, for example, 70 to 80°C.

[0087] According to an embodiment of the present disclosure, the heating temperature in step (B3) is 50-65°C, for example 55-60°C.

[0088] 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.

[0089] According to an embodiment of the present disclosure, in step (B5), the first cooling is to reduce the temperature to 48-52°C.

[0090] In one embodiment, the preparation method comprises the following steps:

[0091] (C1) mixing a chelating agent, a pH adjuster, and water, and heating the mixture to obtain an aqueous solution;

[0092] (C2) mixing the active ingredient, oil phase base, emulsifier, thickener, humectant, and optionally preservative, antioxidant, and penetration enhancer, and heating to dissolve to obtain an oil phase solution;

[0093] (C3) adding the oil phase solution to the aqueous phase solution, emulsifying, and cooling to obtain the pharmaceutical composition.

[0094] According to an embodiment of the present disclosure, the pH of the aqueous solution is 4 to 6.5.

[0095] According to an embodiment of the present disclosure, in step (C1) or step (C2), the heating temperature is 60 to 90°C, for example, 70 to 80°C.

[0096] 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.

[0097] The present disclosure also provides use of the above-mentioned pharmaceutical composition in preparing a pharmaceutical preparation. Preferably, the pharmaceutical preparation is a cream.

[0098] The present disclosure also provides a pharmaceutical preparation, preferably a cream, containing the above-mentioned pharmaceutical composition.

[0099] 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%, exemplified by 0.5%, 0.75%, 1%, 1.25%, 1.5%, 1.75%, 2%, 2.5%, 3%, 3.5% or 4%.

[0100] 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.

[0101] 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.

[0102] 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.

[0103] 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 preparation.

[0104] 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.

[0105] Definitions and Explanations of Terms

[0106] Unless otherwise indicated, the definitions of terms in this specification and claims, including definitions used as examples, exemplary definitions, preferred definitions, definitions in tables, and definitions of specific compounds in the Examples, may be arbitrarily combined and coupled with each other. Such combinations and couplings shall fall within the scope of this specification.

[0107] The term "effective amount" or "therapeutically effective amount" refers to an amount of a compound of the present disclosure sufficient to achieve the intended application (including but not limited to the treatment of a disease as defined below). The therapeutically effective amount may vary depending on factors such as the intended application (in vitro or in vivo), or the subject and 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 readily determined by one of ordinary skill in the art. The specific dosage will vary depending on factors such as the specific compound selected, the dosing regimen used, 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 used.

[0108] The term "patient" refers to a patient in need of prevention or treatment of a disease associated with anaerobic bacteria, wherein the patient is a mammal, for example, selected from rodents, cows, pigs, dogs, cats and primates, particularly humans.

[0109] The term "child" refers to a patient over the age of 3 months, such as a patient between the ages of 3 months and 18 years, preferably between the ages of 3 months and 14 years. Beneficial effects

[0110] The present disclosure provides a creamy pharmaceutical composition / formulation in which the active ingredient is dispersed in a uniform and evenly distributed emulsion droplet form, exhibiting excellent physical and chemical stability. The composition is suitable for treating atopic dermatitis and seborrheic dermatitis, particularly in children, and offers both safety and efficacy. BRIEF DESCRIPTION OF THE DRAWINGS

[0111] FIG1 is an appearance diagram of Example 1 after being placed for one week;

[0112] FIG2 is a microscope image of Example 2;

[0113] FIG3 is a microscope image of Example 3;

[0114] FIG4 is a microscope image of Example 6;

[0115] FIG5 is a microscopic image of commercially available benvimod cream;

[0116] Figure 6 is a polarized light micrograph of commercially available benvimod cream;

[0117] Figure 7 is a comparison of the skin retention amounts of in vitro permeation tests 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;

[0118] FIG8 is a comparison chart of the skin permeation amounts of Example 6 and commercially available benvimod in an in vitro transdermal test;

[0119] FIG9 shows the clinical effect of Example 6 on the changes in erythema index in treating seborrheic dermatitis;

[0120] FIG10 shows the clinical effect of Example 6 on the change of desquamation index in treating seborrheic dermatitis.

[0121] FIG11 is a comparison chart of the skin retention amounts of Example 6 and Sample C in an in vitro transdermal test. DETAILED DESCRIPTION

[0122] The technical solutions of the present 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 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 within the scope of protection intended by the present disclosure.

[0123] Unless otherwise specified, the raw materials and reagents used in the following examples are commercially available or can be prepared by known methods.

[0124] Commercially available Benvimod cream: produced by Guangdong Zhonghao Pharmaceutical Co., Ltd., trade name: Benvimod content: 1%.

[0125] Example 1 Initial Formulation

[0126] 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:

[0127] Table 1-1

[0128] With reference 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:

[0129] Table 1

[0130] The preparation method of the cream is as follows:

[0131] 1. Aqueous phase: Add disodium edetate, sodium acetate, polysorbate 80, and purified water to a beaker, heat to 70-80°C, stir to dissolve, and adjust the pH to about 5-6 to obtain an aqueous phase;

[0132] 2. Oil phase: Add light liquid paraffin, white petrolatum, polyethylene glycol-7 stearate, stearyl alcohol, ethyl hydroxybenzoate and butylated hydroxytoluene into a beaker, heat to 70-80°C, stir and dissolve to obtain the oil phase;

[0133] 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) and dissolve to obtain the third phase;

[0134] 4. Transfer the water phase to the oil phase and emulsify for 15 minutes; then cool to 55-60°C;

[0135] 5. Add the third phase to the emulsified system in step 4, emulsify for 15 minutes, and cool to obtain a cream.

[0136] Example 2-4 Initial formulation optimization

[0137] The prescriptions of Examples 2-4 are shown in Table 2:

[0138] Table 2

[0139] The preparation method of the cream is as follows:

[0140] 1. Aqueous phase: Add disodium edetate, anhydrous sodium acetate, and purified water to a beaker, heat to 70-80°C, stir to dissolve, and adjust the pH to about 5-6 to obtain an aqueous phase;

[0141] 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;

[0142] 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) and dissolve to obtain the third phase;

[0143] 4. Transfer the third phase to the oil phase, keep warm, and stir for 10 minutes;

[0144] 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.

[0145] Example 5 Study on the physicochemical properties of Examples 1-4

[0146] Example 1: The off-white cream showed uniform droplets under a microscope, but the cream had a poor application feel and a hard texture. After being placed under 30°C / RH65% for one week, the cream changed color significantly from off-white to light yellow, as shown in Figure 1.

[0147] Example 2: Off-white cream. Microscopic examination revealed the presence of large pieces of oily matter, uneven distribution of droplets, and poor application. See Figure 2 for details of the micrograph.

[0148] Examples 3 and 4: By comparing Examples 2-4, the effect of white vaseline in the formulation on the product droplets was investigated. Microscopic observations showed that as the proportion of white vaseline decreased, the droplet size in the sample decreased. The relevant micrographs of Example 3 are shown in Figure 3.

[0149] Example 5-7 Formulation Optimization

[0150] Based on the physicochemical property results of Examples 1-4, the applicant considered further optimizing the formula and, after a lot of creative work, adjusted the types and contents of factors such as the oil phase matrix, thickener, and pH regulator. The optimized formula was finally obtained as shown in Table 3:

[0151] Table 3

[0152] The preparation method of the cream of embodiment 5 is as follows:

[0153] Step 1: Preparation of aqueous phase: dissolve edetate disodium, sodium citrate and citric acid in purified water, heat to 70-80°C, keep warm, and adjust the pH to 4.5-6.5 to obtain an aqueous phase;

[0154] Step 2: preparing the oil phase, heating the E-type isomer of the compound represented by formula (I), white petrolatum, 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. and melting, and keeping the mixture warm to obtain the oil phase;

[0155] Step 3: Add the oil phase to the water phase, emulsify for 10 minutes, cool down, and form a cream.

[0156] The preparation method of the cream of Example 6-7 is as follows:

[0157] Step 1: Preparation of aqueous phase: dissolve edetate disodium, sodium citrate and citric acid in purified water, heat to 70-80°C, keep warm, and adjust the pH to 4.5-6.5 to obtain an aqueous phase;

[0158] Step 2: preparing the oil phase, heating the E-type isomer of the compound represented by formula (I), white petrolatum, 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. and melting, and keeping the mixture warm;

[0159] Step 3: Add the oil phase to the water phase, emulsify for 10 minutes, cool down, and form a cream.

[0160] Example 8 Morphology Test

[0161] Microscopic observation of the cream obtained in Example 6 revealed that the active ingredient was uniformly dispersed in the form of emulsion droplets, and the droplet particle size was uniform, all less than 5 μm. The microscopic image is shown in FIG4 .

[0162] Example 9 In vitro permeation test

[0163] The effect of diethylene glycol monoethyl ether on skin retention was investigated using in vitro transdermal permeation test (IVPT).

[0164] 1) Experimental steps:

[0165] The preparations prepared in Example 5 and Example 6 were subjected to an in vitro permeation test to evaluate the average retention of belimumab 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 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.

[0166] 2) Test results

[0167] 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 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.

[0168] Example 10 Irritation Test

[0169] Sixty healthy adult guinea pigs (30♀ / 30♂) and 40 healthy juvenile guinea pigs (20♀ / 20♂) were randomly divided into a negative control group, a positive control group, a low-dose adult test article group (Example 6, 1%), a high-dose adult test article group (Example 7, 4%), a low-dose juvenile test article group (Example 6, 1%), and a high-dose juvenile test article group (Example 7, 4%) according to sex and weight using TOXSTAT2006 software. The negative control group and the positive control group each had 10 animals (5♀ / 5♂), and the test article group each had 20 animals (10♀ / 10♂).

[0170] Hair preparation: Before administration, the animals were prepared with electric clippers. The skin on both sides of the spine on the back was trimmed to 3×3 cm on each side. 2 .

[0171] Sensitization: On days 0, 7, and 14, 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 and positive control groups). Cellophane or filter paper was applied to the groove of the blank plaster. The test substance was placed on the cellophane or contained within the filter paper and applied to the administration site. The area was then sealed and secured with non-irritating medical tape. The blank plaster and filter paper were removed approximately 6 hours later. The negative control group was administered 0.9% sodium chloride injection, and the positive control group was administered 2% 2,4-dinitrochlorobenzene (ultrasonicated in 80% ethanol). The low- and high-dose groups were administered the corresponding concentrations of the preparations prepared in Examples 6 and 7 (1% and 4% belimumab, respectively).

[0172] Challenge: On the 14th day after the last sensitization, the test substance was administered to the right side of the hair removal area of ​​each group of guinea pigs at a dose of 0.2 g / pig (0.2 mL / pig for the positive control group, prepared in 0.2% 2,4-dinitrochlorobenzene in acetone solution; 0.2 mL / pig for the negative control group, prepared in 0.9% sodium chloride injection). The test substance was removed approximately 6 hours later.

[0173] Observation: Observe and record the allergic reaction symptoms 1 hour and 24 hours after sensitization, as well as 24 hours and 48 hours after stimulation.

[0174] The results showed that under the experimental conditions, the Buehler test evaluation results were negative after guinea pigs were repeatedly administered the preparations prepared in Example 6 and Example 7, indicating that as the content of the active ingredient belimumab increased, there was still no sensitizing effect on the skin.

[0175] Example 11 Stability Test

[0176] The same amount of Example 6 cream was weighed into sealed aluminum tubes, with six groups prepared. The samples were placed at room temperature and 40°C, and the physicochemical stability of the samples was observed and measured using liquid chromatography for 0 days, 40°C for 5 days, 40°C for 10 days, 40°C for 30 days, 40°C for 3 months, and 40°C for 6 months. The results are shown in Table 4. The results show that the Example 6 cream does not oxidize or discolor after long-term storage. The active ingredient is stable and remains uniformly dispersed in the form of emulsion droplets with no crystallization. The impurity content remains virtually unchanged, demonstrating excellent stability.

[0177] Liquid phase determination method for impurities and content: octadecylsilane bonded silica gel was used as the filler; water was used as the mobile phase A, acetonitrile was used as the mobile phase B, and gradient elution was performed; the elution gradient was: 80% A at 0 min → 10% A at 20-30 min → 80% A at 32-40 min; the flow rate was 1.0 ml per minute; the column temperature was 35°C; the detection wavelength was 220 nm; and the injection volume was 10 μl.

[0178] Table 4

[0179] Example 12 Comparison of the preparation prepared in Example 6 and commercially available Benvimod cream (control example)

[0180] 1) Morphology: Under microscopic conditions, the commercially available benvimod cream had uneven droplets and contained large oily substances (see Figure 5 ). Solid crystals were observed under polarized light microscopy (see Figure 6 ).

[0181] 2) In vitro transdermal test: to investigate the retention and penetration of the active ingredient benvimod in the skin

[0182] The in vitro permeation test was performed according to the experimental steps in Example 9. Six groups (n=6) of control and example samples were tested in parallel. The test results are shown in Table 5 and Figures 7 to 8.

[0183] Table 5 Skin retention (μg / cm 2 )

[0184] From Table 5 and the average data of skin retention, both Example 6 and the control example showed that the retention of bevimod in the dermis was greater than that in the epidermis; and the retention of bevimod in the dermis and skin in Example 6 was greater than that in the control group. In addition, as can be seen from Figure 7, the skin retention (dermis and epidermis) of each group of Example 6 was more uniform and stable than that of each group of control examples, and the skin retention of each group of Example 6 fluctuated slightly; and from the skin permeation data in Figure 8, the skin permeation of Example 6 was comparable to that of the control example, and Example 6 had better parallelism, higher skin retention, and better efficacy.

[0185] Example 13

[0186] The cream prepared in Example 6 was topically applied to the skin of subjects with atopic dermatitis (AD) aged 3 months to 14 years, twice daily. In some patients, significant improvement was observed within 5 to 7 days, with continued symptom relief within a month.

[0187] Example 14

[0188] 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 used the base component of Example 6 without benvimod and applied it to the affected area twice daily. Significant improvements in the erythema index and desquamation index of seborrheic dermatitis were observed in the second week and persisted until the eighth week. By the eighth week, the erythema index change in the treatment group had decreased by 81.81%, and the desquamation index change had decreased by 83.70%. In contrast, the erythema index change in the control group had decreased by 38.46%, and the desquamation index change had decreased by 37.44%. Table 6 and Figures 9 and 10 demonstrate the clinical efficacy of the AhR agonist benvimod in treating patients with seborrheic dermatitis.

[0189] Table 6 Clinical efficacy of the cream of Example 6 in treating seborrheic dermatitis

[0190] Example 15

[0191] Based on the composition of Example 6, creams were prepared according to the compositions of cream samples 1-10 (the composition of sample 9 was the same as that of Example 6) shown in Table 7 below, and cream samples 11-19 shown in Table 8 below, and the effect of the sample composition on the cream products was evaluated.

[0192] The preparation method of the cream sample is as follows:

[0193] Step 1: Preparation of aqueous phase: dissolve edetate disodium, sodium citrate and citric acid in purified water, heat to 70-80°C, keep warm, and adjust the pH to 4.5-5.5 to obtain an aqueous phase;

[0194] 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;

[0195] Step 3: Add the oil phase to the water phase, emulsify for 10 minutes, cool down, and obtain a cream sample.

[0196] The results show that:

[0197] In Table 7, Samples 1 and 2 had an oily upper layer, failing to form a uniform paste. Samples 3-10 could all be prepared into creams, but when the amount of white vaseline was reduced, the cream's color changed from slightly pink to white. Microscopic observation revealed that Samples 3 and 4 did not form regular emulsion droplets, but rather small, flaky oily particles. Microscopic observation revealed that the oil phase of Samples 5 and 6 formed rounded emulsion droplets, indicating that when the amount of white vaseline was controlled below 6%, samples with uniform emulsion droplets could be prepared.

[0198] 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-24 has a good emulsifying ability for medium-chain triglycerides and white petrolatum oil phase matrix.

[0199] Samples 14-19 can be prepared into smooth, off-white creams with no oil-water separation. However, the droplet size of Sample 14, which does not contain polysorbate 80, is uneven; the droplets of Sample 15 are smaller, becoming round, indicating that the addition of polysorbate 80 can improve the droplet size. Sample 18, which does not contain glyceryl mono- and distearate, exhibits uneven droplet size and the presence of large oil droplets, while this phenomenon is not observed in the other samples containing glyceryl mono- and distearate.

[0200] Furthermore, during application, it was observed that the creams of Samples 13 and 15, which contained high proportions of polysorbate 80 or glyceryl mono- and distearate, became increasingly whiter with application. Viscosity testing showed that creams containing high proportions of glyceryl mono- and distearate had greater viscosity than those containing low proportions, suggesting that glyceryl mono- and distearate had a certain thickening effect.

[0201] In summary, the preferred sample of the present invention has moderate viscosity, is uniform and delicate, and has a good spreading effect.

[0202] Example 16

[0203] 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 contents of other ingredients unchanged.

[0204] Table 9

[0205] The preparation method of the cream sample is as follows:

[0206] Step 1: Preparation of aqueous phase: dissolve edetate disodium, sodium citrate and citric acid in purified water, heat to 70-80°C, keep warm, and adjust the pH to 4.5-5.5 to obtain an aqueous phase;

[0207] 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;

[0208] Step 3: Add the oil phase to the water phase, emulsify for 10 minutes, cool down, and obtain a cream sample.

[0209] The results showed that samples 20-22 and the composition of Example 7 could be used to prepare off-white creams with droplet diameters less than 10 μm, indicating that the cream of the present invention can be applied to different contents of active ingredients.

[0210] Example 17

[0211] Sample C was prepared with reference to the composition of Preparation 21 in Table 8 of the specification of patent CN114042041A. The formulation consisted of an oil phase (active ingredient, propylene glycol, diethylene glycol monoethyl ether, butylated hydroxytoluene, benzoic acid, emulsifying wax, medium-chain triglycerides, polysorbate 80, steareth 2, steareth 20) and an aqueous 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 mixing continued until the active ingredient was dissolved and the appearance was uniform; the aqueous phase components were mixed and heated to 70-80°C, and mixing continued until all substances were completely dissolved and the aqueous phase had a uniform appearance; the oil phase was added to water, maintained at 70-80°C, mixed for 5-10 minutes, and cooled.

[0212] The in vitro transdermal test was performed by referring to the experimental steps under Example 9, and the sample of Example 6 of the present application was compared with Sample C. It was shown that when the active ingredient content was the same, the intradermal retention amount of the cream sample of Example 6 of the present application was higher than that of Sample C (see Figure 11).

[0213] The above examples illustrate the specific embodiments of the present invention. However, the scope of protection of the present invention is not limited to the above-mentioned exemplary embodiments. Any modifications, equivalent substitutions, improvements, etc. made by those skilled in the art within the spirit and principles of the present invention shall be included in the scope of protection of the claims of the present invention.

Claims

1. A pharmaceutical composition comprising the following components: an active ingredient, a thickening agent, an emulsifier, a humectant, a chelating agent, a pH-regulating agent, an oil phase matrix and water, wherein the active ingredient is selected from at least one compound represented by formula (I) and its pharmaceutically acceptable salts; (I) wherein the oil phase matrix comprises petrolatum and optionally present or absent one or two compounds selected from medium chain triglycerides and paraffin; preferably the oil phase matrix is ​​petrolatum and medium chain triglycerides; Preferably, in the pharmaceutical composition, petrolatum (preferably white petrolatum) is present in an amount of 1-9 parts by weight, for example 1-6 parts by weight.

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

3. A pharmaceutical composition according to claim 1 or 2, characterized in that the thickener is selected from one or two compounds selected from stearyl alcohol and cetostearyl alcohol; preferably, in the pharmaceutical composition the thickener is present in an amount of 2-15 parts by weight; preferably, the emulsifier is selected from one or more compounds selected from polyethyleneglycol hexadecyl octyladecyl ether, glyceryl mono- and distearate, polyethyleneglycol stearate, polyoxyethylated hydrogenated castor oil and polysorbate 80; preferably, the emulsifier comprises at least polyethyleneglycol hexadecyl octyladecyl ether and glyceryl mono- and distearate, for example, the emulsifier consists of polyethyleneglycol hexadecyl octyladecyl ether and glyceryl mono- and distearate or consists of polyethyleneglycol hexadecyl octyladecyl ether, glyceryl mono- and distearate and polysorbate 80; Preferably, in the pharmaceutical composition, the emulsifier is present in an amount of 2-25 parts by weight; if there are two types of emulsifiers, the weight ratio of the two emulsifiers is (1-3):(3-1); if there are three types of emulsifiers, the weight ratio of the three emulsifiers is (1-3):(3-1):1; preferably the humectant is selected from one or more compounds selected from propylene glycol, glycerin and polyethylene glycol; preferably, in the pharmaceutical composition the humectant is present in an amount of 3-15 parts by weight; preferably the chelating agent is selected from a metal ion chelating agent, for example selected from one or more compounds selected from ethylenediaminetetraacetic acid, sodium gluconate, nitrilotriacetic acid, tartaric acid, citric acid and their salts; preferably, in the pharmaceutical composition the chelating agent is present in an amount of 0.01-1 parts by weight; preferably, the pH-regulating agent is selected from a pH buffer solution, and preferably a pH buffer solution of an organic acid or a salt thereof; for example, the pH-regulating agent is selected from one or more compounds selected from a citric acid / sodium citrate buffer solution, a tartrate buffer solution, a malate buffer solution, an acetic acid / sodium acetate buffer solution; preferably the oil phase matrix is ​​selected from one or more compounds selected from petrolatum, medium chain triglycerides and paraffin; preferably, in the pharmaceutical composition, the oil phase matrix is ​​present in an amount of 5-25 parts by weight; preferably the water is purified water; Preferably, water is present in the pharmaceutical composition in an amount of 40-65 parts by weight.

4. A pharmaceutical composition according to any one of paragraphs 1-3, characterized in that the pharmaceutical composition additionally includes an antioxidant, a preservative and / or a penetration enhancer; preferably the antioxidant is selected from one or two compounds selected from propyl gallate and butylhydroxytoluene; preferably, in the pharmaceutical composition the antioxidant is present in an amount of 0.01-0.2 parts by weight; preferably the preservative is selected from one or more compounds selected from methylparaben, ethylparaben and propylparaben; preferably, in the pharmaceutical composition the preservative is present in an amount of 0.01-0.3 parts by weight; preferably, the penetration enhancer is selected from one or more compounds selected from diethylene glycol monoethyl ether, isopropyl myristate, isopropyl palmitate, menthol, caprylocaproyl polyoxylglycerides, N-methylpyrrolidone, propylene carbonate and isosorbide dimethyl ether; preferably, in the pharmaceutical composition the penetration enhancer is present in an amount of 0.1-5 parts by weight; preferably the pharmaceutical composition has a pH of 4-6.5; Preferably, the pharmaceutical composition further comprises a second active ingredient.

5. A pharmaceutical composition according to any one of paragraphs. 1-4, characterized in that the pharmaceutical composition includes the following components in parts by weight: 0.1-8 parts by weight of an active ingredient, 2-15 parts by weight of a thickener, 2-25 parts by weight of an emulsifier, 3-15 parts by weight of a humectant, 0.01-1 part by weight of a chelating agent, 0.01-0.2 parts by weight of an antioxidant, 0.01-0.3 parts by weight of a preservative, 0-5 parts by weight of a penetration enhancer, 5-25 parts by weight of an oil phase matrix, 40-65 parts by weight of water and an appropriate amount of a pH-regulating agent; wherein the active ingredient is a compound represented by formula (I), preferably the E-isomer represented by formula (I-1), as an active ingredient; and preferably the pharmaceutical composition has a pH of 4-6.5; Preferably, the pharmaceutical composition comprises the following components in parts by weight: 0.5-5 parts by weight of the E-isomer of the compound represented by formula (I), 5-10 parts by weight of cetostearyl alcohol, 5-20 parts by weight of an emulsifier, 5-12 parts by weight of propylene glycol, 0.05-0.5 parts by weight of a chelating agent, 0.01-0.2 parts by weight of an antioxidant, 0.01-0.3 parts by weight of a preservative, 0-5 parts by weight of a penetration enhancer, 8-20 parts by weight of an oil phase matrix, 40-65 parts by weight of water and an appropriate amount of a pH-regulating agent; preferably the emulsifier consists of polyethyleneglycol hexadecyl octyl adecylate 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 petrolatum and medium chain triglycerides, with the white petrolatum present in an amount of 1-9 parts by weight.

6. A method for producing a pharmaceutical composition according to any one of paragraphs 1-5, comprising mixing the components to produce the pharmaceutical composition.

7. The method of production according to paragraph 6, characterized in that the method of production is selected from any one of the following methods: the first method, the method of preparation comprises the following steps: (A1) mixing a chelating agent, a pH-regulating agent and water, followed by heating to obtain an aqueous phase solution; (A2) mixing an oil phase matrix, an emulsifier, a thickener and optionally present or absent preservative and antioxidant, followed by heating until dissolution to obtain an oil phase solution; (A3) mixing an active ingredient, a humectant and optionally present or absent penetration enhancer, followed by heating until dissolution to obtain a third phase solution; (A4) transferring the aqueous phase solution to the oil phase solution, emulsifying and cooling; and (A5) adding the third phase solution to the emulsion system of step (A4), emulsifying and cooling to obtain a pharmaceutical composition; a second method, the production method comprises the following steps: (B1) mixing a chelating agent, a pH-regulating agent and water, followed by heating to obtain an aqueous phase solution; (B2) mixing an oil phase matrix, an emulsifier, a thickener and optionally present or absent preservative and antioxidant, followed by heating until dissolution to obtain an oil phase solution; (B3) mixing an active ingredient, a humectant and optionally present or absent penetration enhancer, followed by heating until dissolution to obtain a third phase solution; (B4) transferring the third phase solution to the oil phase solution and maintaining at a temperature with stirring; and (B5) adding an aqueous phase solution to the mixed system of step (B4), emulsifying and cooling, and re-emulsifying and re-cooling to obtain a pharmaceutical composition; a third method, the production method comprises the following steps: (C1) mixing a chelating agent, a pH-regulating agent and water, followed by heating to obtain an aqueous phase solution; (C2) mixing an active ingredient, an oil phase matrix, an emulsifier, a thickener, a humectant and optionally present or absent preservative, antioxidant and penetration enhancer, followed by heating until dissolution to obtain an oil phase solution; and (C3) transferring the oil phase solution into an aqueous phase solution, emulsifying and cooling to obtain a pharmaceutical composition.

8. A medicinal product comprising a pharmaceutical composition according to any one of claims 1-5, preferably the medicinal product is a product in the form of a cream.

9. The use of a pharmaceutical composition according to any one of claims 1-5 for the preparation of medicaments for the treatment and / or prevention of atopic dermatitis and psoriasis, wherein the atopic dermatitis is preferably childhood atopic dermatitis, and more preferably mild, moderate, severe or refractory childhood atopic dermatitis.

10. Use of a pharmaceutical composition according to any one of claims 1-5 for the production of medicinal products for the treatment and / or prevention of seborrheic dermatitis, wherein seborrheic dermatitis is preferably sebopsoriasis.

11. 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 a pharmaceutical composition according to any one of claims 1-5 or a medicinal product according to claim 8, wherein the atopic dermatitis is preferably childhood atopic dermatitis; the seborrheic dermatitis is preferably sebopsoriasis.

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