Solution pharmaceutical compositions of phenol derivatives, their formulation and use

Abstract

The present disclosure discloses a solution type pharmaceutical composition of phenol derivatives, and its preparation and use. The pharmaceutical composition comprises the following components: active ingredients selected from at least one of the compounds represented by formula (I) and pharmaceutically acceptable salts thereof; humectants; penetration enhancers; chelating agents; pH regulators; solvents. The composition has good physical and chemical stability, is suitable for treating autoimmune inflammatory diseases, especially for treating the above-mentioned diseases occurring in the hair part, improves the problems of difficult drug use and poor treatment effect in the hair part, and significantly improves the drug compliance and life quality of patients.

Description

[0001] This application claims priority to the prior patent application filed with the China National Intellectual Property Administration on November 2, 2023, with application number 202311450168.8 and titled "Solution-type pharmaceutical composition of phenol derivative, preparation thereof and use thereof". The full text of said prior application is incorporated into this application by reference. Technical Field

[0002] The present disclosure belongs to the field of pharmaceutical compositions, and specifically relates to a solution-type pharmaceutical composition of a phenol derivative, a preparation thereof and a use thereof. Background Art

[0003] Autoimmune inflammatory diseases, such as skin diseases including psoriasis, atopic dermatitis and seborrheic dermatitis. Among them, psoriasis is commonly known as "niupixuan". Psoriasis is a common chronic, inflammatory, systemic disease induced by the interaction of multiple factors such as genetic factors, environmental factors and immune factors. It has a long course, is difficult to treat, and prone to relapse. Some cases are almost incurable for the whole life, which has a great impact on the physical health and mental state of patients. The onset sites are commonly seen in the scalp, sacral region, extensor sides, flexor sides and folds of the extremities, etc. Nearly 2 / 3 of patients have onset in hair-bearing areas, and the scalp in particular is a predilection site for psoriasis. Existing studies have shown that 50% to 80% of psoriasis patients have skin lesions involving the scalp.

[0004] Seborrheic dermatitis (SD) is a chronic, papulosquamous, superficial inflammatory skin disease occurring in areas of high 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 steroid 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] Treatment for psoriasis aims primarily at controlling symptoms and improving quality of life, including topical medications, systemic drugs, and phototherapy. Topical medications are the first-line, basic treatment, suitable for over 90% of patients. Topical preparations mainly include creams, ointments, and gels. However, common formulations of topical medications (creams, ointments, gels, etc.) suffer from several drawbacks: the scalp has a dense concentration of active sebaceous glands, and the bioavailability of lipophilic creams is affected by the sebaceous glands and hair follicles, resulting in poor treatment efficacy. Furthermore, due to the obstruction of hair, these preparations inevitably end up on the hair during application, leading to drug waste, difficulty in rinsing, and an oily appearance and unpleasant odor, resulting in poor patient adherence. These factors also make it difficult to apply topical medications effectively to affected hair areas.

[0007] Therefore, providing a stable and / or safe pharmaceutical composition / formulation to improve the problems of difficult medication use, poor treatment effect, and poor patient medication compliance in the treatment of the above-mentioned diseases is something that those skilled in the art have long been committed to solving. 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 humectant, a penetration enhancer, a chelating agent, a pH adjuster, and a solvent, wherein the active ingredient is selected from at least one of the compounds represented by formula (I) and their pharmaceutically acceptable salts;

[0009]

[0010] On the other hand, this disclosure provides a pharmaceutical composition comprising: an active ingredient, a humectant, a penetration enhancer, a chelating agent, a thickener, a pH adjuster, and a solvent, wherein the active ingredient is selected from at least one of the compounds represented by formula (I) and their pharmaceutically acceptable salts;

[0011]

[0012] In some embodiments of this disclosure, the pharmaceutical composition is a solution, preferably a solution-type pharmaceutical composition for spray or aerosol application.

[0013] 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):

[0014]

[0015] According to a preferred embodiment of this disclosure, the compound represented by formula (I-1) is benvimod.

[0016] 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.

[0017] In some preferred embodiments of this disclosure, 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., benvitide) as the active ingredient.

[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, 0.75, 1, 1.5, 2, 3 or 4 parts.

[0019] According to embodiments of this disclosure, the moisturizer is selected from one or more of propylene glycol, glycerin, and polyethylene glycol, preferably propylene glycol.

[0020] According to embodiments of this disclosure, the humectant in the pharmaceutical composition is 10 to 35 parts by weight, for example 15 to 30 parts, such as 15, 18, 20, 22, 25, 27 or 30 parts.

[0021] According to embodiments of this disclosure, the penetration enhancer is selected from one or more of diethylene glycol monoethyl ether, ethanol, menthol, N-methylpyrrolidone, propylene carbonate, and isosorbide dimethyl ether, preferably diethylene glycol monoethyl ether.

[0022] According to embodiments of this disclosure, the penetration enhancer in the pharmaceutical composition is 10 to 50 parts by weight, for example 15 to 45 parts, such as 20, 22, 25, 27, 30, 35, 40, or 41 parts.

[0023] According to embodiments of this disclosure, the chelating agent is selected from metal ion chelating agents, such as one or more selected from ethylenediaminetetraacetic acid, sodium gluconate, ethylenediaminetriacetic acid, tartaric acid, citric acid and their salts; preferably, the salt is a sodium salt, potassium salt or ammonium salt; in some embodiments, the chelating agent is selected from ethylenediaminetetraacetic acid and / or disodium ethylenediaminetetraacetic acid (i.e., disodium edetate).

[0024] 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, exemplarily 0.05 parts, 0.1 parts, 0.2 parts or 0.5 parts.

[0025] 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 citrate / sodium citrate buffer, tartrate buffer, oxalate buffer and acetate / acetate buffer, preferably citrate / sodium citrate buffer.

[0026] According to embodiments of this disclosure, the solvent is selected from water, preferably purified water.

[0027] According to embodiments of this disclosure, in the pharmaceutical composition, the solvent is present in parts by weight of 20 to 60, for example 25 to 55, such as 28, 28.75, 30, 35, 40, 45, 47.75, 48.75, or 49.25.

[0028] According to embodiments of this disclosure, the pharmaceutical composition may optionally contain a thickener; and / or, optionally, an antioxidant; and / or, optionally, a preservative.

[0029] According to embodiments of this disclosure, the thickener is selected from one or more of sodium carboxymethyl cellulose, hydroxypropyl methylcellulose, polyvinyl alcohol, and polyvinyl alcohol, preferably sodium carboxymethyl cellulose.

[0030] According to embodiments of this disclosure, the thickener in the pharmaceutical composition is 0.01 to 1 part by weight, for example 0.05 to 0.5 parts, exemplarily 0.05 parts, 0.1 parts, 0.2 parts or 0.5 parts.

[0031] According to embodiments of this disclosure, the antioxidant is selected from one or both of propyl gallate and butylated hydroxytoluene (BHT).

[0032] 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.

[0033] According to embodiments of this disclosure, the preservative is selected from one or more of methylparaben, ethylparaben, propylparaben, and benzalkonium chloride, preferably methylparaben.

[0034] According to 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 or 0.15 parts.

[0035] According to embodiments of this disclosure, the pH of the pharmaceutical composition is 4 to 6, preferably 4.5 to 5.5, for example 4.5, 5, 5.1, 5.2 or 5.5.

[0036] In some embodiments, the aforementioned humectants and penetration enhancers also function as solvents for compounds of formula (I) or (I-1) or their pharmaceutically acceptable salts, antioxidants, and / or preservatives.

[0037] According to an embodiment of this disclosure, the pharmaceutical composition comprises the following components in parts by weight: 0.1 to 8 parts of active ingredient, 10 to 35 parts of humectant, 10 to 50 parts of penetration enhancer, 0.01 to 1 part of chelating agent, 0.01 to 0.2 parts of antioxidant, 0.01 to 0.3 parts of preservative, 20 to 60 parts of solvent, and pH adjuster;

[0038] 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;

[0039] Preferably, the pH of the pharmaceutical composition is 4 to 6.

[0040] According to embodiments of this disclosure, the pharmaceutical composition comprises the following components in parts by weight: 0.1 to 8 parts of active ingredient, 10 to 35 parts of humectant, 10 to 50 parts of penetration enhancer, 0.01 to 1 part of chelating agent, 0.01 to 1 part of thickener, 0.01 to 0.2 parts of antioxidant, 0.01 to 0.3 parts of preservative, 20 to 60 parts of solvent, and pH adjuster;

[0041] 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;

[0042] Preferably, the pH of the pharmaceutical composition is 4 to 6.

[0043] In some embodiments, the pharmaceutical composition comprises the following components in parts by weight: 0.5 to 5 parts of active ingredient, 15 to 30 parts of humectant, 15 to 45 parts of penetration enhancer, 0.05 to 0.5 parts of chelating agent, 0.05 to 0.15 parts of antioxidant, 0.05 to 0.15 parts of preservative, 25 to 55 parts of solvent, and pH adjuster;

[0044] 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;

[0045] Preferably, the pH of the pharmaceutical composition is 4 to 6.

[0046] In some embodiments, the pharmaceutical composition comprises the following components in parts by weight: 0.5 to 5 parts of active ingredient, 15 to 30 parts of humectant, 15 to 45 parts of penetration enhancer, 0.05 to 0.5 parts of chelating agent, 0.05 to 0.5 parts of thickener, 0.05 to 0.15 parts of antioxidant, 0.05 to 0.15 parts of preservative, 25 to 55 parts of solvent, and pH adjuster;

[0047] 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;

[0048] Preferably, the pH of the pharmaceutical composition is 4 to 6.

[0049] In some embodiments, the pharmaceutical composition comprises the following components in parts by weight: 0.1 to 8 parts of the E isomer of formula (I-1), 10 to 35 parts of propylene glycol, 10 to 50 parts of diethylene glycol monoethyl ether, 0.01 to 1 part of disodium ethylenediaminetetraacetate, 0.01 to 0.2 parts of propyl gallate, 0.01 to 0.3 parts of methylparaben, 20 to 60 parts of water, and a pH adjuster; preferably, the pH of the pharmaceutical composition is 4 to 6.

[0050] In some embodiments, the pharmaceutical composition comprises the following components in parts by weight: 0.1 to 8 parts of the E isomer of formula (I-1), 10 to 35 parts of propylene glycol, 10 to 50 parts of diethylene glycol monoethyl ether, 0.01 to 1 part of disodium ethylenediaminetetraacetate, 0.01 to 1 part of sodium carboxymethyl cellulose, 0.01 to 0.2 parts of propyl gallate, 0.01 to 0.3 parts of methylparaben, 20 to 60 parts of water, and a pH adjuster; preferably, the pH of the pharmaceutical composition is 4 to 6.

[0051] In some embodiments, the pharmaceutical composition comprises the following components in parts by weight: 0.5 to 5 parts of the E isomer of formula (I-1), 15 to 30 parts of propylene glycol, 15 to 45 parts of diethylene glycol monoethyl ether, 0.05 to 0.15 parts of disodium ethylenediaminetetraacetate, 0.05 to 0.15 parts of propyl gallate, 0.05 to 0.15 parts of methylparaben, 25 to 55 parts of water, and a pH adjuster; preferably, the pH of the pharmaceutical composition is 4 to 6.

[0052] In some embodiments, the pharmaceutical composition comprises the following components in parts by weight: 0.5 to 5 parts of the E isomer of formula (I-1), 15 to 30 parts of propylene glycol, 15 to 45 parts of diethylene glycol monoethyl ether, 0.05 to 0.15 parts of disodium ethylenediaminetetraacetate, 0.05 to 0.15 parts of sodium carboxymethyl cellulose, 0.05 to 0.15 parts of propyl gallate, 0.05 to 0.15 parts of methylparaben, 25 to 55 parts of water, and a pH adjuster; preferably, the pH of the pharmaceutical composition is 4 to 6.

[0053] According to an exemplary embodiment of this disclosure, the pharmaceutical composition comprises the following components in parts by weight: 1 part of the E isomer of formula (I-1), 30 parts of propylene glycol, 25 parts of diethylene glycol monoethyl ether, 0.05 parts of disodium ethylenediaminetetraacetate, 0.05 parts of propyl gallate, 0.1 parts of methylparaben, 43.75 parts of water, and a pH adjuster, preferably a citrate / sodium citrate buffer solution; preferably, the pH of the pharmaceutical composition is 4 to 6.

[0054] According to an exemplary embodiment of this disclosure, the pharmaceutical composition comprises the following components in parts by weight: 1 part of the E isomer of formula (I-1), 30 parts of propylene glycol, 25 parts of diethylene glycol monoethyl ether, 0.05 parts of disodium ethylenediaminetetraacetate, 0.05 parts of sodium carboxymethyl cellulose, 0.05 parts of propyl gallate, 0.1 parts of methylparaben, 43.75 parts of water, and a pH adjuster, preferably a citrate / sodium citrate buffer solution; preferably, the pH of the pharmaceutical composition is 4 to 6.

[0055] According to an exemplary embodiment of this disclosure, the pharmaceutical composition comprises the following components in parts by weight: 0.5 parts of the E isomer of formula (I-1), 30 parts of propylene glycol, 41 parts of diethylene glycol monoethyl ether, 0.05 parts of disodium ethylenediaminetetraacetate, 0.05 parts of propyl gallate, 0.1 parts of methylparaben, 28.25 parts of water, and a pH adjuster, preferably a citrate / sodium citrate buffer solution; preferably, the pH of the pharmaceutical composition is 4 to 6.

[0056] According to an exemplary embodiment of this disclosure, the pharmaceutical composition comprises the following components in parts by weight: 0.5 parts of the E isomer of formula (I-1), 30 parts of propylene glycol, 41 parts of diethylene glycol monoethyl ether, 0.05 parts of disodium ethylenediaminetetraacetate, 0.05 parts of sodium carboxymethyl cellulose, 0.05 parts of propyl gallate, 0.1 parts of methylparaben, 28.25 parts of water, and a pH adjuster, preferably a citrate / sodium citrate buffer solution; preferably, the pH of the pharmaceutical composition is 4 to 6.

[0057] According to an exemplary embodiment of this disclosure, the pharmaceutical composition comprises the following components in parts by weight: 0.5 parts of the E isomer of formula (I-1), 25 parts of propylene glycol, 25 parts of diethylene glycol monoethyl ether, 0.05 parts of disodium ethylenediaminetetraacetate, 0.05 parts of propyl gallate, 0.1 parts of methylparaben, 49.25 parts of water, and a pH adjuster, preferably a citrate / sodium citrate buffer solution; preferably, the pH of the pharmaceutical composition is 4 to 6.

[0058] According to an exemplary embodiment of this disclosure, the pharmaceutical composition comprises the following components in parts by weight: 0.5 parts of the E isomer of formula (I-1), 25 parts of propylene glycol, 25 parts of diethylene glycol monoethyl ether, 0.05 parts of disodium ethylenediaminetetraacetate, 0.05 parts of sodium carboxymethyl cellulose, 0.05 parts of propyl gallate, 0.1 parts of methylparaben, 49.25 parts of water, and a pH adjuster, preferably a citrate / sodium citrate buffer solution; preferably, the pH of the pharmaceutical composition is 4 to 6.

[0059] According to an exemplary embodiment of this disclosure, the pharmaceutical composition comprises the following components in parts by weight: 1 part of the E isomer of formula (I-1), 25 parts of propylene glycol, 25 parts of diethylene glycol monoethyl ether, 0.05 parts of disodium ethylenediaminetetraacetate, 0.05 parts of propyl gallate, 0.1 parts of methylparaben, 48.75 parts of water, and a pH adjuster, preferably a citrate / sodium citrate buffer solution; preferably, the pH of the pharmaceutical composition is 4 to 6.

[0060] According to an exemplary embodiment of this disclosure, the pharmaceutical composition comprises the following components in parts by weight: 1 part of the E isomer of formula (I-1), 25 parts of propylene glycol, 25 parts of diethylene glycol monoethyl ether, 0.05 parts of disodium ethylenediaminetetraacetate, 0.05 parts of sodium carboxymethyl cellulose, 0.05 parts of propyl gallate, 0.1 parts of methylparaben, 48.75 parts of water, and a pH adjuster, preferably a citrate / sodium citrate buffer solution; preferably, the pH of the pharmaceutical composition is 4 to 6.

[0061] According to an exemplary embodiment of this disclosure, the pharmaceutical composition comprises the following components in parts by weight: 2 parts of the E isomer of formula (I-1), 25 parts of propylene glycol, 25 parts of diethylene glycol monoethyl ether, 0.05 parts of disodium ethylenediaminetetraacetate, 0.05 parts of propyl gallate, 0.1 parts of methylparaben, 47.75 parts of water, and a pH adjuster, preferably a citrate / sodium citrate buffer solution; preferably, the pH of the pharmaceutical composition is 4 to 6.

[0062] According to an exemplary embodiment of this disclosure, the pharmaceutical composition comprises the following components in parts by weight: 2 parts of the E isomer of formula (I-1), 25 parts of propylene glycol, 25 parts of diethylene glycol monoethyl ether, 0.05 parts of disodium ethylenediaminetetraacetate, 0.05 parts of sodium carboxymethyl cellulose, 0.05 parts of propyl gallate, 0.1 parts of methylparaben, 47.75 parts of water, and a pH adjuster, preferably a citrate / sodium citrate buffer solution; preferably, the pH of the pharmaceutical composition is 4 to 6.

[0063] Preferably, the sum of the weight parts of the above components is 100 parts.

[0064] According to embodiments of this disclosure, the pharmaceutical composition may further include a second active ingredient.

[0065] This disclosure also provides a method for preparing the above-described pharmaceutical composition, comprising mixing the components to obtain the composition.

[0066] Preferably, the preparation method includes the following steps:

[0067] (1) Mix the active ingredients with moisturizers and penetration enhancers to form a solution containing the active ingredients;

[0068] Alternatively, active ingredients, antioxidants, preservatives, humectants, and penetration enhancers can be mixed to form a solution containing active ingredients;

[0069] (2) Mix the chelating agent, thickener and solvent to form a mixed solution; preferably, dissolve the chelating agent in the solvent first, and then add the thickener to disperse and dissolve it.

[0070] (3) Add the mixed solution to the solution containing the active ingredient, mix well, and then add a pH adjuster to adjust the pH of the system, preferably to 4-6;

[0071] (5) Add solvent to make up the weight to obtain the pharmaceutical composition.

[0072] This disclosure also provides the use of the above-described pharmaceutical composition in the preparation of pharmaceutical formulations, preferably, the pharmaceutical formulation being a solution formulation, such as a spray or aerosol.

[0073] This disclosure also provides a pharmaceutical formulation, preferably a solution, and even more preferably a spray or aerosol, containing the above-described pharmaceutical composition.

[0074] 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 their pharmaceutically acceptable salts) is 0.1% to 8%, for example 0.5% to 5%, exemplarily 0.5%, 0.75%, 1%, 1.5%, 2%, 3% or 4%.

[0075] According to embodiments of this disclosure, the pharmaceutical composition or pharmaceutical preparation is used to treat autoimmune inflammatory diseases, preferably psoriasis, atopic dermatitis and / or seborrheic dermatitis, etc.

[0076] Preferably, the pharmaceutical composition or pharmaceutical preparation is used to treat the above-mentioned diseases of seborrheic dermatitis or hair-related diseases, especially seborrheic dermatitis or psoriasis of hair-related diseases, such as hair-related diseases including but not limited to the scalp and armpits; preferably scalp psoriasis or seborrheic dermatitis.

[0077] This disclosure provides the use of the above-described pharmaceutical composition in the preparation of a medicament for treating and / or preventing autoimmune inflammatory diseases; wherein the autoimmune disease is preferably selected from psoriasis, atopic dermatitis and / or seborrheic dermatitis, more preferably seborrheic dermatitis or psoriasis occurring on hair follicles, and most preferably seborrheic dermatitis or scalp psoriasis.

[0078] According to embodiments of this disclosure, the pharmaceutical preparation includes a container for holding the pharmaceutical composition. Preferably, the container is a light-proof, airtight container.

[0079] In one embodiment, the pharmaceutical preparation further includes a spray or aerosol device for spraying the pharmaceutical composition onto the affected area in the form of a spray or aerosol, preferably the affected area being a hairy area, such as, but not limited to, the scalp and armpits.

[0080] In one embodiment, the pharmaceutical formulation further includes a propellant.

[0081] 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.

[0082] This disclosure also provides a method for treating autoimmune inflammatory diseases, preferably psoriasis, atopic dermatitis, and seborrheic dermatitis, especially those occurring in hair-bearing areas, comprising administering to a patient an effective or therapeutically effective amount of the pharmaceutical composition or the pharmaceutical preparation.

[0083] This disclosure also provides the use of the above-described pharmaceutical composition in the preparation of a medicament for treating and / or preventing diseases caused by Malassezia furfur; further, said disease is seborrheic dermatitis caused by Malassezia furfur.

[0084] The present invention also provides a method for treating and / or preventing diseases caused by Malassezia furfur, comprising administering to a patient an effective amount or a therapeutically effective amount of the pharmaceutical composition or the pharmaceutical preparation.

[0085] Terminology Definitions and Explanations

[0086] 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.

[0087] 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.

[0088] The term "optional" or "optional" means that the event or environment subsequently described may but is not necessarily to occur, including both the possibility that the event or environment may or may not occur. For example, "optionally contains antioxidants" includes both the possibility that it contains antioxidants and the possibility that it does not contain antioxidants.

[0089] 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.

[0090] Beneficial effects

[0091] This disclosure provides a pharmaceutical composition for preparing a spray or aerosol, exhibiting good physical and chemical stability. This composition / spray is used to treat autoimmune inflammatory diseases, preferably psoriasis, atopic dermatitis, and seborrheic dermatitis, and is particularly suitable for treating seborrheic dermatitis and the aforementioned diseases affecting hair follicles (such as scalp psoriasis). It has a good therapeutic effect on seborrheic dermatitis and improves the difficulties in applying medication to hair follicles in scalp psoriasis, the poor treatment effect, and the pain and infection associated with conventional topical medications. It significantly improves patient medication adherence and quality of life, enhances clinical efficacy and safety, and contributes to the long-term management of autoimmune inflammatory diseases. Attached Figure Description

[0092] Figure 1 The results of the intradermal retention in Examples 1-5;

[0093] Figure 2 The results of the intradermal retention amount in Example 4 and the control group;

[0094] Figure 3 The results show the cumulative permeation of Example 4 and the control group.

[0095] Figure 4 The experimental results show the average cumulative permeability of Examples 4, 12, and the control group;

[0096] Figure 5 The results are for the skin retention amounts in Examples 4, 12, and the control group.

[0097] Figure 6 The clinical efficacy of changes in erythema index in the treatment of seborrheic dermatitis in Example 12;

[0098] Figure 7 This is the clinical effect of the desquamation index change in Example 12 for the treatment of seborrheic dermatitis. Detailed Implementation

[0099] 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.

[0100] Unless otherwise stated, the raw materials and reagents used in the following examples are commercially available products or can be prepared by known methods.

[0101] Examples 1-5

[0102] The formulations for Examples 1-5 are shown in Table 1, and the preparation methods of the pharmaceutical compositions are as follows:

[0103] 1) Dissolve the E-isomer of the compound shown in formula (I), methylparaben, and propyl gallate in a mixed solvent of propylene glycol and diethylene glycol monoethyl ether;

[0104] 2) Dissolve disodium edetate in purified water, then disperse and dissolve sodium carboxymethyl cellulose to obtain a mixture;

[0105] 3) Prepare a buffer solution of citric acid and sodium citrate;

[0106] 4) Add the mixture from step 2) to the drug-containing solution from step 1) and stir until well mixed. Adjust the pH of the system to 4-6 using the buffer solution from step 3).

[0107] 5) Add purified water to bring the total weight up to obtain the drug composition.

[0108] Table 1

[0109]

[0110]

[0111] Example 6

[0112] The pharmaceutical compositions of Examples 1-5 were used to prepare a spray. The active ingredient in the spray was atomized as fine mist particles with uniform distribution.

[0113] Example 7

[0114] The pharmaceutical compositions of Examples 1-5 were used to prepare aerosols. The active ingredients in the aerosols were sprayed out as tiny droplets with uniform distribution.

[0115] Example 8: In vitro transdermal detection of Examples 1-5

[0116] The intradermal retention of Examples 1-5 was tested according to the following method.

[0117] Experimental methods:

[0118] Take the sample from Example 4 and the control group (commercially available Benvitimod cream, Guangdong Zhonghao Pharmaceutical Co., Ltd., trade name: In vitro transdermal tests were conducted to assess intradermal retention and cumulative permeability of benvimide (1%). Pigskin (0.8–1.0 mm thick) was mounted on a LOGAN System 918 vertical diffusion chamber, exposed at a depth of 1.77 cm. 2 The surface area of ​​the diffusion cell was determined. The diffusion cell was connected to a multichannel pump at 600 rpm, and the receiving solution was physiological saline (0.9% sodium chloride solution). Each cell was placed in a heated manifold to equilibrate the temperature, ensuring the skin surface temperature was 32°C (at least 30 minutes before administration). A sample loading volume of 0.3 g was used. Receiving solutions were collected at 4, 8, 12, 16, and 24 hours to measure the amount of active ingredient that had penetrated the skin. After 24 hours of sampling, the skin was wiped with a cotton swab to remove any residual test sample deemed impermeable to the skin. The skin layer was minced and subjected to ultrasonic extraction with methanol. The recovered drug concentration was used to calculate the intradermal retention.

[0119] Test results are as follows Figure 1 As shown, the intradermal retention of Examples 1, 2, and 3 was significantly lower than that of Examples 4 and 5, thus Example 4 was selected as the optimized formulation for subsequent screening.

[0120] Example 9: Optimization of Antioxidants

[0121] The antioxidant propyl gallate in Example 4 was replaced with butylated hydroxytoluene, and the stability of the new formulation was further observed. The specific formulation is shown in Table 2 below:

[0122] Table 2

[0123]

[0124]

[0125] a) Stability comparison:

[0126] Equal amounts of the compositions from Example 4 and Example 9 were weighed into sealed, light-shielded vials for liquid chromatography, resulting in three groups. The samples were placed at room temperature and 60°C, and their physicochemical stability was observed and determined using liquid chromatography after 0 days, 5 days at 60°C, and 10 days. Specific results are shown in Table 3. The results show that Example 9 exhibited a new impurity of RRT2.19 at 5 and 10 days at high temperature, while Example 4 did not show any new impurity. Example 4 demonstrates superior stability compared to Example 9.

[0127] Table 3

[0128]

[0129] Related substances determination method: Octadecylsilane-bonded silica gel was used as the packing material; water was used as mobile phase A and acetonitrile as mobile phase B, and gradient elution was performed according to the table below; the flow rate was 1.0 ml per minute; the column temperature was 30℃; the detection wavelength was 220 nm; and the injection volume was 25 μl.

[0130]

[0131]

[0132] Example 10 Stability Test

[0133] Equal amounts of the composition from Example 4 were weighed into four sealed vials for liquid chromatography, shielded from light. The samples were placed at room temperature, 60°C, and 40°C, and their physicochemical stability was observed and determined using liquid chromatography for 0 days, 10 days at 60°C, 30 days at 60°C, and 3 months at 40°C. The specific results are shown in Table 4. The results show that the composition from Example 4 exhibits excellent stability. The relevant substance testing methods are as described in Example 9.

[0134] Table 4

[0135]

[0136] Example 11 Intradermal Retention and Cumulative Permeability Test

[0137] The following method was used to test Example 4 and the control group (commercially available Benvitimod cream, manufacturer: Guangdong Zhonghao Pharmaceutical Co., Ltd., product name: Intradermal retention and cumulative permeation of benvitimod (content: 1%).

[0138] Experimental methods:

[0139] In vitro transdermal tests were conducted on samples from Example 4 and the control group to evaluate intradermal retention and cumulative permeability. Pigskin (0.8–1.0 mm thick) was mounted on a LOGAN System 918 vertical diffusion chamber, exposed at a depth of 1.77 cm. 2 The surface area of ​​the skin was measured. The diffusion cell was connected to a multichannel pump at 600 rpm, with PBS (pH 7.4) as the receiving solution. Each cell was placed in a heated manifold to equilibrate the temperature, ensuring a skin surface temperature of 32°C (at least 30 minutes before administration). A dose of 10 mg test sample per square centimeter was added. The receiving solution was collected at 2, 4, 8, 20, and 24 hours to measure the amount of active ingredient that had permeated the skin. After 24 hours of sampling, the skin was wiped clean with a cotton swab to remove any residual test sample deemed impermeable to the skin. The skin layer was minced and subjected to ultrasonic extraction with methanol. The recovered drug concentration was used to calculate the intradermal retention.

[0140] Test results are as follows Figure 2 and Figure 3 As shown, the intradermal retention and cumulative permeation of Example 4 were both superior to those of the control group.

[0141] Example 12 Optimization of Thickener

[0142] The applicant considered that the use of thickeners in the prescription might increase the viscosity of the drug solution, which could affect the in vitro transdermal efficacy of the formulation, thereby impacting patient compliance. The optimized prescription is shown in Table 5:

[0143] Table 5

[0144]

[0145] The formulation with added sodium carboxymethyl cellulose, i.e. Example 4, showed a significant increase in viscosity and poor patient compliance; the formulation without added sodium carboxymethyl cellulose, i.e. Example 12, could be evenly dispersed on the skin, had low fluidity, and good patient compliance.

[0146] Using the in vitro transdermal experimental procedure in Example 11, the in vitro transdermal effects of Examples 4 and 12 were observed (including average cumulative permeation and skin retention per unit mass). The experimental results are shown below. Figure 4 and Figure 5 Therefore, it can be seen that the retention amounts in the in vitro transdermal experiments of Examples 4 and 12 are similar, both slightly higher than the control group (commercially available Benvitimod cream, Guangdong Zhonghao Pharmaceutical Co., Ltd., trade name: Benvitimod content: 1%), while the average cumulative permeation of Example 12 (sample without sodium carboxymethyl cellulose) was lower than that of Example 4 and the control group, and only half that of the control group. Therefore, the safety risk of the Example 12 sample was reduced.

[0147] Example 13 Stability Test

[0148] The same amount of the composition of Example 12 was weighed into a light-protected, sealed vial and subjected to accelerated testing (40℃±2℃ / 75%±5%RH). The specific results are shown in Table 6. The results show that the composition of Example 12 met the quality standards after 6 months of accelerated testing and exhibited excellent stability.

[0149] Table 6

[0150]

[0151] The method for determining the relevant substances is as described in Example 9.

[0152] Content determination method: Octadecylsilane-bonded silica gel was used as the packing material; water was used as mobile phase A and acetonitrile as mobile phase B, and gradient elution was performed according to the table below; the flow rate was 1.0 ml per minute; the column temperature was 30℃; the detection wavelength was 220 nm; and the injection volume was 25 μl.

[0153]

[0154] Example 14 Pharmacokinetic Study

[0155] Example 12 composition and control group were administered transdermally to Bama miniature pigs with a content of 1% benvitimod (commercially available benvitimod cream, Guangdong Zhonghao Pharmaceutical Co., Ltd., trade name: After examining the skin pharmacokinetic characteristics of the common active ingredient benvitimod (1%), the differences between the two were compared.

[0156] Six Bama miniature pigs, half male and half female, were selected. A 10 μL / cm² dose was applied transdermally to both sides of the pigs' backs. 2 Example 12 Composition and 10 mg / cm 2 In the control group, after two administrations (10-hour interval), skin samples were taken from the treatment area at 1, 2, 4, 6, 8, 12, 24, 36, 48, and 72 hours after the last administration (as designed, administration was performed at different time points, and skin samples were taken after all groups reached the endpoint simultaneously). The surface ointment was wiped clean with alcohol, and the stratum corneum was repeatedly removed using adhesive tape. A blank area of ​​skin was taken as the 0-hour mark, and the stratum corneum was repeatedly removed using adhesive tape and stored at -20°C. The concentration of benvomod in the skin was determined by HPLC-MS / MS, and p-values ​​were calculated using a non-compartmental model of DAS 3.3. Statistical analysis was performed using SPSS.

[0157] The results are shown in Table 7. After topical administration of the 1% benvomod content composition of Example 12 to Bama miniature pigs and to the control group, the exposure of benvomod in the skin of the Example 12 composition group was approximately 3.26 times that of the control group, with AUC... (0-t) The values ​​were 669±187h*μg / g and 205±39.2h*μg / g, respectively.

[0158] Table 7. Pharmacokinetic parameters of skin in Bama miniature pigs after transdermal administration of Example 12 / control group.

[0159]

[0160] Note: T max This represents the median (minimum and maximum values).

[0161] Example 15 Sensitization Test

[0162] The Buehler test was performed in adult guinea pigs to evaluate the potential local sensitization of the pharmaceutical compositions of Examples 4 and 5.

[0163] Experimental methods:

[0164] Sixty healthy adult guinea pigs, half male and half female, were randomly divided into a negative control group, a positive control group, a low-dose group (Example 4, 1%), and a high-dose group (Example 5, 2%) according to sex and weight using TOXSTAT 2006 software. The negative and positive control groups each contained 10 animals (half male and half female), while the low-dose and high-dose groups each contained 20 animals (half male and half female). Before administration, the animals were trimmed with electric clippers, removing the skin and hair on both sides of the spine on the back, with each side measuring 3×3 cm. 2 .

[0165] Sensitization: On days 0, 7, and 14, 0.2 mL / animal of the test substance was administered to the left side of the hair-removing area. Filter paper was placed in the groove of a blank plaster, and the test substance was placed 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 sonication in 80% ethanol). Animals in the low-dose group (Example 4) and the high-dose group (Example 5) were given the corresponding concentrations of the combination from the examples (1% and 2%).

[0166] Challenge: On day 14 after the last sensitization, 0.2 ml / guinea pig (prepared with 0.2% 2,4-dinitrochlorobenzene in acetone solution) was administered to the right side of the bald area of ​​each group of guinea pigs. The test substance was removed after about 6 hours. Allergic reaction symptoms were observed and recorded at 1 hour and 24 hours after sensitization, as well as at 24 hours and 48 hours after challenge.

[0167] The results showed that under the experimental conditions, adult guinea pigs were repeatedly given different concentrations (1%, 2%) of the composition and the Buehler test results were negative, indicating that there was no skin sensitization effect as the concentration increased.

[0168] Example 16: Clinical efficacy of seborrheic dermatitis

[0169] In a prospective, randomized, 8-week clinical trial, the spray composition prepared in Example 12 (treatment group) was applied to the skin of subjects with seborrheic dermatitis twice daily. The control group received the benvitimod-free base composition of Example 12, 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 8 and...) Figure 6 and Figure 7 This study can demonstrate the clinical efficacy of the AhR agonist benvitimide in treating patients with seborrheic dermatitis.

[0170] Table 8. Clinical efficacy of the spray composition in treating seborrheic dermatitis in Example 12.

[0171]

[0172] Based on the above experimental results, the pharmaceutical compositions and formulations disclosed herein demonstrate good stability, efficacy, and safety in treating autoimmune inflammatory diseases, particularly psoriasis, atopic dermatitis, and seborrheic dermatitis. In particular, the sprays and aerosols not only improve the stability of the active ingredients during use and extend the shelf life after opening, but also reduce treatment costs for patients and potential chemical stability risks. Furthermore, the drugs in the formulations of this disclosure are sprayed as fine mist particles, resulting in uniform distribution and easy diffusion. This also reduces friction during application, minimizing irritation to the affected area and reducing pain and infection associated with topical application, making it especially suitable for treating conditions affecting hair follicles. These formulations improve patient compliance, enhance clinical efficacy and safety, and improve drug stability during use, contributing to the long-term management of autoimmune inflammatory diseases, particularly psoriasis, seborrheic dermatitis, and atopic dermatitis.

[0173] The embodiments of this disclosure have been described above. However, this disclosure is not limited to the above embodiments. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of this disclosure should be included within the protection scope of this disclosure.

Claims

1. A pharmaceutical composition comprising: an active ingredient, propylene glycol, diethylene glycol monoethyl ether, disodium ethylenediaminetetraacetate, a pH adjuster, and water, wherein the active ingredient is selected from at least one compound of formula (I-1) and its pharmaceutically acceptable salts. （I-1）， The active ingredient is present in parts by weight of 0.1 to 8 parts. The propylene glycol is present in parts by weight of 10-35. The diethylene glycol monoethyl ether is present in parts by weight of 10 to 50. The disodium ethylenediaminetetraacetate is present in a weight ratio of 0.01 to 1 part. The water is in the form of 20-60 parts by weight. The pharmaceutical composition is a solution.

2. The pharmaceutical composition according to claim 1, wherein, The composition is a solution-type pharmaceutical composition for spray or aerosol application, wherein the pH adjuster is selected from pH buffer solutions.

3. The pharmaceutical composition according to claim 2, wherein, The pH buffer is selected from one or more of citrate / sodium citrate buffer, tartrate buffer, oxalate buffer, and acetate / acetate buffer.

4. The pharmaceutical composition according to any one of claims 1-3, wherein the water comprises 25 to 55 parts by weight.

5. The pharmaceutical composition according to any one of claims 1-3, wherein, The pharmaceutical composition may optionally contain a thickener, and / or, optionally, an antioxidant, and / or, optionally, a preservative, wherein the thickener is selected from one or more of sodium carboxymethyl cellulose, hydroxypropyl methylcellulose, povidone, and polyvinyl alcohol; the antioxidant is selected from one or two of propyl gallate and butylated hydroxytoluene; and the preservative is selected from one or more of methylparaben, ethylparaben, propylparaben, and benzalkonium chloride.

6. The method for preparing the pharmaceutical composition according to claim 1, wherein, The preparation method includes mixing the components.

7. The use of the pharmaceutical composition according to any one of claims 1-5 in the preparation of a pharmaceutical formulation, wherein the pharmaceutical formulation is a solution formulation, and the pharmaceutical formulation is used to treat psoriasis, atopic dermatitis and / or seborrheic dermatitis.

8. The application according to claim 7, wherein the pharmaceutical preparation is used for psoriasis, atopic dermatitis and / or seborrheic dermatitis occurring in hair-bearing areas.

9. The application according to claim 8, wherein the hair-bearing area is the scalp and / or armpit.

10. The application according to claim 9, wherein the psoriasis is scalp psoriasis.

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