Solution type pharmaceutical composition of phenol derivative as well as preparation and application of solution type pharmaceutical composition

Abstract

The invention discloses a solution type pharmaceutical composition of a phenol derivative as well as a preparation and application of the solution type pharmaceutical composition. The pharmaceutical composition comprises the following components: an active component, a humectant, a penetration enhancer, a chelating agent, a pH regulator and a solvent, and the active component is selected from at least one of a compound as shown in a formula (I) and pharmaceutically acceptable salts thereof; the composition has good physical and chemical stability, is suitable for treating autoimmune inflammations, is especially suitable for treating the diseases of hair parts, solves the problems of high administration difficulty and poor treatment effect of the hair parts, and remarkably improves the administration compliance and life quality of patients. # imgabs0 #

Description

[0001] This application claims priority to a prior application with patent application number 202311450168.8 filed with the State Intellectual Property Office of China on November 2, 2023, entitled “Solution-type pharmaceutical composition of phenol derivatives, preparations and uses thereof”. The entire text of the prior application is incorporated into this application by reference. Technical Field

[0002] The present invention belongs to the field of pharmaceutical compositions, and in particular 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 psoriasis, atopic dermatitis, seborrheic dermatitis and other skin diseases. Among them, psoriasis is commonly known as psoriasis. 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 of disease, is difficult to treat, and is prone to relapse. Some cases are almost lifelong and have a great impact on the patient's physical health and mental state. The common sites of onset are the scalp, sacrum, extensor side, flexor side and wrinkles of the limbs. Nearly 2 / 3 of the patients have onset of the disease in the hair area, especially the scalp is a common site for psoriasis. 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 that occurs in the area of ​​sebum secretion. The typical rash is dark red, yellow-red spots formed by the fusion of follicular papules, covered with greasy scales or scabs, and may be accompanied by varying degrees of itching. SD is a chronic, recurrent inflammatory skin disease, usually manifested as a red scaly rash. The incidence rate in healthy people is 5%, of which 70.3% occurs on the head, common in infants, adolescents and adults. Seborrheic dermatitis refers to a disease of the scalp. The difference between this disease and simple dandruff is that it has erythema as a sign of inflammation, the degree of scalp flaking is greater and sometimes accompanied by itching and burning, and eczema occurs in other parts of the body. The disease can occur in the form of plaques, but often affects the entire scalp and exceeds the hairline, often including the forehead, around the neck and both ears. In severe cases, the scalp may become secondary infected, and changes may appear as a spongy texture, with blisters and crusts that may ooze. Seborrheic dermatitis also frequently occurs in infancy and usually resolves spontaneously at 8-12 months of age. Scalp changes in infants include erythema, flaking of the scalp, and occasional blisters and crusts that may resolve spontaneously within a few weeks, recur intermittently, or persist throughout childhood. These changes are often accompanied by similar lesions around the eyelids, nose, and ears. The condition then frequently recurs after adolescence and can persist throughout life, even with the potential for more severe symptoms. Approximately 1-3% of the population suffers from the disease. The etiology and pathogenesis of SD are still unclear, with the complex interaction of Malassezia, keratinocytes, and immune responses playing a crucial role in the onset of SD. Seborrheic dermatitis shares some of the same pathogenic factors as inflammatory skin diseases such as atopic dermatitis, such as the regulation of factors that stimulate keratinocyte proliferation and differentiation, and disruption of the skin barrier. Atopic dermatitis usually manifests as a Th2 immune response, with elevated levels of interleukin (IL)-4 and IL-13, while seborrheic dermatitis is mainly a Th2 and Th17 response, with elevated levels of IL-4, IL-17, and IL-8.

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

[0006] The treatment of psoriasis aims to control symptoms and improve the quality of life, including topical medications, systemic medications and phototherapy. Topical medications are the first-line basic treatment and are suitable for more than 90% of patients. Topical preparations mainly include creams, ointments, gels, etc. However, the commonly used dosage forms of topical medications (creams, ointments, gels, etc.) are difficult to use due to the following reasons: the sebaceous glands of the scalp are dense and active, the bioavailability of lipophilic creams will be affected by the sebaceous glands and hair follicles, and the treatment effect is poor. In addition, due to the obstruction of hair, these preparations will inevitably be applied to the hair during medication, which not only causes a waste of drugs, but is also often difficult to wash, resulting in a greasy appearance of the hair, an unpleasant odor, etc., and poor patient compliance with medication; making it difficult to use topical medications at the site of hair disease and ineffective.

[0007] Therefore, providing a stable and / or safe pharmaceutical composition / preparation to improve the problems of difficulty in medication, poor therapeutic effect, poor patient medication compliance, etc. in treating the above-mentioned diseases is something that technicians in this field have long been committed to solving. Summary of the invention

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

[0009]

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

[0011]

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

[0013] 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):

[0014]

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

[0016] 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.

[0017] In some preferred embodiments of the present disclosure, in the pharmaceutical composition, only the compound represented by formula (I) is used as the active ingredient, and preferably only the E-type isomer represented by formula (I-1) (i.e., benvimod) is used as the active ingredient.

[0018] 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 parts, 1.5 parts, 2 parts, 3 parts or 4 parts.

[0019] According to an embodiment of the present disclosure, the moisturizing agent is selected from one or more of propylene glycol, glycerol, polyethylene glycol, etc., preferably propylene glycol.

[0020] According to an embodiment of the present disclosure, in the pharmaceutical composition, the weight portion of the moisturizer is 10 to 35 parts, such as 15 to 30 parts, exemplified by 15 parts, 18 parts, 20 parts, 22 parts, 25 parts, 27 parts or 30 parts.

[0021] According to an embodiment of the present 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 an embodiment of the present disclosure, in the pharmaceutical composition, the weight proportion of the permeation enhancer is 10 to 50 parts, such as 15 to 45 parts, exemplified by 20 parts, 22 parts, 25 parts, 27 parts, 30 parts, 35 parts, 40 parts or 41 parts.

[0023] According to an embodiment of the present disclosure, the chelating agent is selected from metal ion chelating agents, for example, one or more selected from ethylenediaminetetraacetic acid, sodium gluconate, nitrilotriacetic acid, tartaric acid, citric acid and salts thereof; preferably, the salt is a sodium salt, a potassium salt or an ammonium salt; in some embodiments, the chelating agent is selected from ethylenediaminetetraacetic acid and / or ethylenediaminetetraacetic acid disodium salt (i.e., disodium edetate).

[0024] 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.

[0025] According to an embodiment of the present disclosure, the pH adjuster is selected from a pH buffer, preferably an organic acid and / or its salt pH buffer, such as one or more of a citric acid / sodium citrate buffer, a tartrate buffer, an oxalate buffer and an acetic acid / acetate buffer, preferably a citric acid / sodium citrate buffer.

[0026] According to an embodiment of the present disclosure, the solvent is selected from water, preferably purified water.

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

[0028] According to an embodiment of the present disclosure, the pharmaceutical composition may further contain a thickener; and / or, may further contain an antioxidant; and / or, may further contain a preservative.

[0029] According to an embodiment of the present disclosure, the thickener is selected from one or more of sodium carboxymethylcellulose, hydroxypropyl methylcellulose, povidone and polyvinyl alcohol, preferably sodium carboxymethylcellulose.

[0030] According to an embodiment of the present disclosure, in the pharmaceutical composition, the weight portion of the thickener 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.

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

[0032] 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.

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

[0034] 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 parts, 0.1 parts or 0.15 parts.

[0035] According to an embodiment of the present disclosure, the pH of the pharmaceutical composition is 4 to 6, preferably 4.5 to 5.5, such as 4.5, 5, 5.1, 5.2 or 5.5.

[0036] In some embodiments, the moisturizer and permeation enhancer also serve as a solvent for the compound represented by formula (I) or formula (I-1) or a pharmaceutically acceptable salt thereof, an antioxidant and / or a preservative.

[0037] According to an embodiment of the present disclosure, the pharmaceutical composition includes the following components in parts by weight: 0.1 to 8 parts of active ingredient, 10 to 35 parts of moisturizer, 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 the above formula (I-1) as the active ingredient;

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

[0040] According to an embodiment of the present disclosure, the pharmaceutical composition includes the following components in parts by weight: 0.1 to 8 parts of active ingredient, 10 to 35 parts of moisturizer, 10 to 50 parts of penetration enhancer, 0.01 to 1 part of chelating agent, 0.01 to 1 part of thickening 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;

[0041] 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;

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

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

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

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

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

[0047] The active ingredient is a compound represented by formula (I), preferably the E-type isomer represented by the above formula (I-1) as the active ingredient;

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

[0049] In some embodiments, the pharmaceutical composition includes the following components in parts by weight: 0.1 to 8 parts of the E-isomer shown in 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 includes the following components in parts by weight: 0.1 to 8 parts of the E-isomer shown in 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 carboxymethylcellulose, 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 represented by 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 includes the following components in parts by weight: 0.5 to 5 parts of the E-isomer represented by 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 carboxymethylcellulose, 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 the present disclosure, the pharmaceutical composition includes the following components in parts by weight: 1 part of the E-type isomer shown in formula (I-1), 30 parts of propylene glycol, 25 parts of diethylene glycol monoethyl ether, 0.05 parts of disodium ethylenediaminetetraacetic acid, 0.05 parts of propyl gallate, 0.1 parts of methylparaben, 43.75 parts of water and a pH adjuster, preferably the pH adjuster is citric acid / sodium citrate buffer; preferably, the pH of the pharmaceutical composition is 4 to 6.

[0054] According to an exemplary embodiment of the present disclosure, the pharmaceutical composition includes the following components in parts by weight: 1 part of the E-type isomer shown in 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 carboxymethylcellulose, 0.05 parts of propyl gallate, 0.1 parts of methylparaben, 43.75 parts of water and a pH adjuster, preferably the pH adjuster is citric acid / sodium citrate buffer; preferably, the pH of the pharmaceutical composition is 4 to 6.

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

[0056] According to an exemplary embodiment of the present disclosure, the pharmaceutical composition includes the following components in parts by weight: 0.5 parts of the E-isomer shown in 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 carboxymethylcellulose, 0.05 parts of propyl gallate, 0.1 parts of methylparaben, 28.25 parts of water and a pH adjuster, preferably the pH adjuster is citric acid / sodium citrate buffer; preferably, the pH of the pharmaceutical composition is 4 to 6.

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

[0058] According to an exemplary embodiment of the present disclosure, the pharmaceutical composition includes the following components in parts by weight: 0.5 parts of the E-isomer shown in 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 carboxymethylcellulose, 0.05 parts of propyl gallate, 0.1 parts of methylparaben, 49.25 parts of water and a pH adjuster, preferably the pH adjuster is citric acid / sodium citrate buffer; preferably, the pH of the pharmaceutical composition is 4 to 6.

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

[0060] According to an exemplary embodiment of the present disclosure, the pharmaceutical composition includes the following components in parts by weight: 1 part of the E-type isomer represented by 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 carboxymethylcellulose, 0.05 parts of propyl gallate, 0.1 parts of methylparaben, 48.75 parts of water and a pH adjuster, preferably the pH adjuster is citric acid / sodium citrate buffer; preferably, the pH of the pharmaceutical composition is 4 to 6.

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

[0062] According to an exemplary embodiment of the present disclosure, the pharmaceutical composition includes the following components in parts by weight: 2 parts of the E-isomer shown in 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 carboxymethylcellulose, 0.05 parts of propyl gallate, 0.1 parts of methylparaben, 47.75 parts of water and a pH adjuster, preferably the pH adjuster is citric acid / sodium citrate buffer; 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 an embodiment of the present disclosure, the pharmaceutical composition may further include a second active ingredient.

[0065] The present disclosure also provides a method for preparing the above pharmaceutical composition, comprising mixing the components.

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

[0067] (1) mixing the active ingredient with a moisturizer and a penetration enhancer to form a solution containing the active ingredient;

[0068] Alternatively, the active ingredient, antioxidant, preservative, moisturizer, and permeation enhancer are mixed to form a solution containing the active ingredient;

[0069] (2) mixing a chelating agent, a thickener and a solvent to form a mixed solution; preferably, the chelating agent is first dissolved in the solvent, and then the thickener is added thereto for dispersion and dissolution;

[0070] (3) adding the mixed solution to the solution containing the active ingredient, mixing evenly, and then adding a pH adjuster to adjust the pH of the system, preferably to 4 to 6;

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

[0072] The present disclosure also provides use of the above-mentioned pharmaceutical composition in preparing a pharmaceutical preparation. Preferably, the pharmaceutical preparation is a solution-type preparation, such as a spray or an aerosol.

[0073] The present disclosure also provides a pharmaceutical preparation, preferably a solution preparation, and further preferably a spray or aerosol, containing the above-mentioned pharmaceutical composition.

[0074] 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%, 1.5%, 2%, 3% or 4%.

[0075] According to an embodiment of the present disclosure, the pharmaceutical composition or pharmaceutical preparation is used to treat autoimmune inflammatory diseases, preferably psoriasis, atopic dermatitis and / or seborrheic dermatitis;

[0076] Preferably, the pharmaceutical composition or pharmaceutical preparation is used to treat seborrheic dermatitis or the above diseases occurring in hair areas, and is particularly suitable for seborrheic dermatitis or psoriasis occurring in hair areas, such as the hair areas including but not limited to the scalp and axilla; preferably scalp psoriasis or seborrheic dermatitis.

[0077] The present disclosure provides use of the above-mentioned pharmaceutical composition in the preparation of a drug for treating and / or preventing an autoimmune inflammatory disease; wherein the autoimmune disease is preferably selected from psoriasis, atopic dermatitis and / or seborrheic dermatitis, more preferably seborrheic dermatitis or psoriasis occurring in the hair area, and most preferably seborrheic dermatitis or scalp psoriasis.

[0078] According to an embodiment of the present disclosure, the pharmaceutical preparation comprises a container for containing the pharmaceutical composition. Preferably, the container is a light-proof, airtight container.

[0079] In one embodiment, the pharmaceutical preparation further comprises a spray or aerosol device for spraying the pharmaceutical composition in the form of a spray or aerosol on the affected area. Preferably, the affected area is an affected area with hair, such as but not limited to the scalp and armpits.

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

[0081] In one embodiment, the pharmaceutical composition or the pharmaceutical preparation is administered topically, or is further combined with an oral administration preparation or other topical administration preparations.

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

[0083] The present disclosure also provides use of the pharmaceutical composition in preparing a drug for treating and / or preventing a disease caused by Pityrosporum ovale; further, the disease is seborrheic dermatitis caused by Pityrosporum ovale.

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

[0085] Definitions and explanations of terms

[0086] Unless otherwise specified, the definitions of terms recorded in the specification and claims of this application, including their definitions as examples, exemplary definitions, preferred definitions, definitions recorded in tables, definitions of specific compounds in examples, etc., may be arbitrarily combined and coupled with each other. Such combinations and couplings shall fall within the scope of the description of this application.

[0087] The term "effective amount" or "therapeutically effective amount" refers to an amount of the compound of the present disclosure sufficient to achieve the intended application (including but not limited to the treatment of diseases as defined below). The therapeutically effective amount may vary depending on the intended application (in vitro or in vivo), or the subject and the disease condition being treated, such as the weight and age of the subject, the severity of the disease condition, and the mode of administration, which can be easily determined by a person of ordinary skill in the art. The specific dosage will vary depending on the specific compound selected, the dosage regimen relied upon, whether it is administered in combination with other compounds, the timing of administration, the tissue to which it is administered, and the physical delivery system carried.

[0088] The term "optional" or "optional" means that the event or environment described later may but does not necessarily occur, and includes both the occurrence and non-occurrence of the event or environment. For example, "optionally containing an antioxidant" includes both the occurrence and non-occurrence of the antioxidant.

[0089] The term "patient" refers to a patient who needs to prevent or treat a disease associated with anaerobic bacteria, wherein the patient is a mammal, for example selected from rodents, cattle, pigs, dogs, cats and primates, in particular humans.

[0090] Beneficial Effects

[0091] The present disclosure provides a pharmaceutical composition for preparing a spray or an aerosol, which has good physical and chemical stability. The 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 above diseases that occur in the hair part (such as scalp psoriasis), has a good therapeutic effect on seborrheic dermatitis, and improves the problems of difficulty in medication in the hair part of scalp psoriasis, poor therapeutic effect, and pain and infection of conventional topical external medications, significantly improves patients' medication compliance and quality of life, improves clinical efficacy and safety, and contributes to the long-term management of autoimmune inflammatory diseases. BRIEF DESCRIPTION OF THE DRAWINGS

[0092] Figure 1 The experimental results of the intradermal retention of Examples 1-5 are as follows;

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

[0094] Figure 3 The experimental results of the cumulative permeation amount of Example 4 and the control group;

[0095] Figure 4 The experimental results of the average cumulative permeation amount of Example 4, Example 12 and the control group;

[0096] Figure 5 The experimental results of skin retention amount of Example 4, Example 12 and the control group;

[0097] Figure 6 The clinical effect of the change of erythema index in treating seborrheic dermatitis in Example 12;

[0098] Figure 7 This is the clinical effect of Example 12 on the change of desquamation index in treating seborrheic dermatitis. DETAILED DESCRIPTION

[0099] The technical solution of the present disclosure will be further described in detail below in conjunction with specific embodiments. It should be understood that the following embodiments are only exemplary illustrations and explanations of the present disclosure and should not be construed as limiting the scope of protection of the present disclosure. All technologies implemented based on the above content of the present disclosure are included in the scope of protection intended by the present disclosure.

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

[0101] Examples 1-5

[0102] The prescriptions of Examples 1-5 are shown in Table 1, and the preparation method of the pharmaceutical composition is as follows:

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

[0104] 2) dissolving edetate disodium in purified water, and then dispersing and dissolving sodium carboxymethyl cellulose to obtain a mixed solution;

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

[0106] 4) adding the mixed solution of step 2) to the drug-containing solution of step 1) and stirring to mix evenly, and adjusting the pH of the system to 4-6 with the buffer solution of step 3);

[0107] 5) Add purified water to make up the total weight to obtain a pharmaceutical composition.

[0108] Table 1

[0109]

[0110]

[0111] Example 6

[0112] The pharmaceutical compositions of Examples 1-5 were prepared into sprays, in which the active ingredients were sprayed out in the form of tiny mist particles and were evenly distributed.

[0113] Example 7

[0114] The pharmaceutical compositions of Examples 1-5 were prepared into aerosols, in which the active ingredients were sprayed out in the form of tiny mist particles and were evenly distributed.

[0115] Example 8 In vitro skin permeation test of Examples 1-5

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

[0117] Experimental methods:

[0118] Take the sample of Example 4 and the control group (commercially available Benvimod cream, Guangdong Zhonghao Pharmaceutical Co., Ltd., trade name: The in vitro permeation test of 1% belimumab was carried out to evaluate the intradermal retention and cumulative permeability. Porcine skin (thickness 0.8-1.0 mm) was mounted on a LOGAN System 918 vertical diffusion cell, with 1.77 cm exposed. 2 surface area. The diffusion cell was connected to a multichannel pump at a speed of 600 rpm, and the receiving fluid was normal saline (0.9% sodium chloride solution). Each cell was placed in a heating manifold to balance the temperature to ensure that the skin surface temperature was 32°C (at least 30 minutes before administration). The sample load was 0.3g. The receiving fluid was collected at 4, 8, 12, 16, and 24 hours to measure the active ingredients that penetrated through the skin. At the end of the 24-hour sampling, the skin was wiped with a cotton swab to remove any residual test sample that was considered not to penetrate the skin. The skin layer was cut into pieces and methanol was added for ultrasonic extraction of the drug. The recovered drug concentration was used to calculate the amount of retention in the skin.

[0119] Test results such as Figure 1 As shown, the intradermal retention amounts of Example 1, Example 2 and Example 3 were significantly lower than those of Example 4 and Example 5, and Example 4 was determined to be used as the optimized formula for subsequent screening.

[0120] Example 9 Optimization of Antioxidant

[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] The same amount of the composition of Example 4 and the composition of Example 9 were weighed into a liquid phase light-shielded sealed vial, and a total of 3 groups were set up. They were placed in room temperature and 60°C environments respectively, and the physical and chemical stability of the samples at 0 days, 60°C for five days, and 60°C for ten days was observed and measured by liquid phase. The specific results are shown in Table 3. The results show that the new impurities of RRT2.19 were detected in Example 9 at high temperature for 5 days and 10 days, while no new impurities appeared in Example 4. Example 4 has better stability than Example 9.

[0127] Table 3

[0128]

[0129] Determination method for related substances: use octadecylsilane bonded silica gel as filler; use water as mobile phase A, acetonitrile as mobile phase B, and perform gradient elution according to the table below; the flow rate is 1.0 ml per minute; the column temperature is 30°C; the detection wavelength is 220 nm; the injection volume is 25 μl.

[0130]

[0131]

[0132] Example 10 Stability Test

[0133] Weigh the same amount of the composition of Example 4 into a liquid phase light-shielded sealed vial, and set up 4 groups in total. Place them in room temperature, 60°C, and 40°C environments respectively, and observe and use liquid phase to measure the physical and chemical stability of the samples for 0 days, 60°C for 10 days, 60°C for 30 days, and 40°C for 3 months. The specific results are shown in Table 4. The results show that the composition of Example 4 has excellent stability. The test methods for related substances are as described in Example 9.

[0134] Table 4

[0135]

[0136] Example 11 Intradermal retention and cumulative permeation test

[0137] According to the following method, Example 4 and the control group (commercially available Benvimod cream, manufacturer: Guangdong Zhonghao Pharmaceutical Co., Ltd., trade name: Intradermal retention and cumulative permeation of belimumab (content: 1%).

[0138] Experimental methods:

[0139] The samples of Example 4 and the control group were subjected to in vitro permeation tests to evaluate the intradermal retention and cumulative permeability. 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 (pH 7.4). Each cell was placed in a heating manifold to balance the temperature to ensure that the skin surface temperature was 32°C (at least 30 minutes before administration). The sample was added at a dose of 10 mg of the test sample per square centimeter. The receiving fluid was collected at 2, 4, 8, 20, and 24 hours to measure the active ingredients that penetrated through the skin. At the end of the 24-hour sampling, the skin was wiped with a cotton swab to remove any residual test sample that was considered not to penetrate the skin. The skin layer was cut into pieces and methanol was added to ultrasonically extract the drug. The recovered drug concentration was used to calculate the amount of retention in the skin.

[0140] The test results are as follows Figure 2 and Figure 3 As shown, the intradermal retention and cumulative permeation amount of Example 4 are 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 may increase the viscosity of the drug solution and may affect the in vitro transdermal effect of the preparation, thereby affecting the patient's compliance with the preparation. The optimized prescription is shown in Table 5:

[0143] Table 5

[0144]

[0145] The viscosity of the formulation with sodium carboxymethylcellulose, i.e., Example 4, was significantly increased, and the patient compliance was poor; the formulation without sodium carboxymethylcellulose, i.e., Example 12, could be evenly dispersed on the skin, had low fluidity, and had good patient compliance.

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

[0147] Example 13 Stability Test

[0148] The same amount of the composition of Example 12 was weighed into a light-shielded sealed vial and subjected to an accelerated test (40°C ± 2°C / 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 had excellent stability.

[0149] Table 6

[0150]

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

[0152] Content determination method: Use octadecylsilane bonded silica gel as filler; use water as mobile phase A, acetonitrile as mobile phase B, and perform gradient elution according to the table below; the flow rate is 1.0 ml per minute; the column temperature is 30°C; the detection wavelength is 220 nm; and the injection volume is 25 μl.

[0153]

[0154] Example 14 Pharmacokinetic Test

[0155] Bama miniature pigs were percutaneously administered with the composition of Example 12 with a benvimod content of 1% and a control group (commercially available benvimod cream, Guangdong Zhonghao Pharmaceutical Co., Ltd., trade name: The skin pharmacokinetic properties of the common active ingredient benvimod in the two were investigated, and the differences between the two were compared.

[0156] Six Bama miniature pigs were selected, half male and half female. 10 μL / cm 2 Example 12 Composition and 10 mg / cm 2 After 2 doses in the control group (10h interval between doses), the skin of the dosing area was cut at 1, 2, 4, 6, 8, 12, 24, 36, 48, and 72h after the last dose (according to the design, the doses were given at different time points, and the dosing skin was cut after each group reached the end point at the same time). After wiping the surface ointment with alcohol, the stratum corneum was repeatedly removed with tape. The skin of the blank area was taken as the 0h point, the stratum corneum was repeatedly removed with tape, and stored at -20℃. The concentration of benvimod in the skin was determined by HPLC-MS / MS, and the PK parameters were calculated using the non-compartmental model of DAS3.3. Statistical analysis was performed using SPSS.

[0157] The results are shown in Table 7. After the Bama miniature pigs were topically administered with the composition of Example 12 having a bevimod content of 1% and the control group, the exposure of bevimod in the skin of the composition group of Example 12 was about 3.26 times that of the control group, and AUC (0-t) They were 669±187h*μg / g and 205±39.2h*μg / g respectively.

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

[0159]

[0160] Note: max is the median (minimum, maximum).

[0161] Example 15 Sensitization Test

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

[0163] Experimental methods:

[0164] 60 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 the software TOXSTAT2006. There were 10 guinea pigs in each of the negative control group and the positive control group (half male and half female), and 20 guinea pigs in each of the low-dose group and the high-dose group (half male and half female). Before administration, the animals were prepared with electric clippers to cut the skin and hair on both sides of the back spine, 3×3 cm on each side. 2 .

[0165] Sensitization: 0.2 mL / animal of the test substance was administered to the left side of the depilatory area on the 0th, 7th, and 14th days, respectively. Filter paper was attached to the groove of the blank plaster, and the test substance was contained in the filter paper and applied to the administration site, and then sealed and fixed with non-irritating medical adhesive tape. The blank plaster and filter paper were removed after about 6 hours. The animals in the negative control group were administered with 0.9% sodium chloride injection, the animals in the positive control group were administered with 2% 2,4-dinitrochlorobenzene (ultrasonic preparation with 80% ethanol), and the animals in the low-dose group (Example 4) and the high-dose group (Example 5) were administered with the corresponding concentrations of the Example composition (1%, 2%).

[0166] Challenge: On the 14th day after the last sensitization, 0.2 ml / guinea pig of each group was given the test substance on the right side of the hair removal area (prepared with 0.2% 2,4-dinitrochlorobenzene, acetone solution), and the test substance was removed about 6 hours later. The allergic reaction symptoms were observed and recorded 1 hour and 24 hours after sensitization and 24 hours and 48 hours after challenge.

[0167] The results showed that under the experimental conditions, after adult guinea pigs were given the composition at different concentrations (1%, 2%) for multiple times, the Buehler test evaluation results were negative, indicating that as the concentration increased, there was still no sensitization effect on the skin.

[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 a day. The control group used the matrix component of Example 12 without benvimod and applied it to the affected area twice a day. The changes in the erythema index and desquamation index of seborrheic dermatitis were significantly improved in the second week and continued until the 8th week. By the 8th week, the changes in the erythema index of the treatment group decreased by 81.81%, and the changes in the desquamation index decreased by 83.70%; while the changes in the erythema index of the control group decreased by 38.46%, and the changes in the desquamation index decreased by 37.44%. From Table 8 and Figure 6 and Figure 7 The clinical efficacy of the AhR agonist benvimod in the treatment of patients with seborrheic dermatitis can be shown.

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

[0171]

[0172] Based on the above experimental results, it can be known that the disclosed pharmaceutical composition and preparation have good stability, effectiveness and safety in the treatment of autoimmune inflammatory diseases, preferably psoriasis, atopic dermatitis and seborrheic dermatitis. In particular, sprays and aerosols not only improve the stability of active ingredients during use, extend the service life after unsealing, but also reduce the patient's treatment costs and potential chemical stability risks. In addition, the drug in the disclosed preparation is sprayed with tiny mist particles, uniformly distributed, easy to diffuse, and can reduce the irritation of the friction during the application process to the wound surface, reduce the pain and infection of the local application, and is particularly suitable for the treatment of the diseased condition in the hair part. These preparations improve the compliance of patients, improve clinical efficacy and safety, enhance the stability of the drug during use, and contribute to the long-term management of autoimmune inflammatory diseases, preferably psoriasis, seborrheic dermatitis and atopic dermatitis.

[0173] The above describes the implementation methods of the present disclosure. However, the present disclosure is not limited to the above implementation methods. Any modifications, equivalent replacements, improvements, etc. made within the spirit and principles of the present disclosure shall be included in the protection scope of the present disclosure.

Claims

1. A pharmaceutical composition, wherein the pharmaceutical composition comprises the following components: an active ingredient, a moisturizer, a penetration enhancer, a chelating agent, a pH regulator and a solvent, wherein the active ingredient is selected from at least one of the compounds represented by formula (I) and pharmaceutically acceptable salts thereof; 2. The pharmaceutical composition according to claim 1, wherein The pharmaceutical composition is a solution, preferably a solution-type pharmaceutical composition for spray or aerosol administration.

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

4. The pharmaceutical composition according to any one of claims 1 to 3, wherein The humectant is selected from one or more of propylene glycol, glycerol and polyethylene glycol; Preferably, in the pharmaceutical composition, the weight portion of the moisturizer is 10 to 35 parts; Preferably, 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, in the pharmaceutical composition, the weight portion of the penetration enhancer is 10 to 50 parts; Preferably, the chelating agent is selected from metal ion chelating agents, such as one or more of ethylenediaminetetraacetic acid, sodium gluconate, nitrilotriacetic acid, tartaric acid, citric acid and salts thereof; Preferably, in the pharmaceutical composition, the weight portion of the chelating agent is 0.01 to 1 part; Preferably, the pH regulator is selected from a pH buffer, preferably an organic acid and / or its salt pH buffer, such as one or more of a citric acid / sodium citrate buffer, a tartrate buffer, an oxalate buffer and an acetic acid / acetate buffer; Preferably, the solvent is selected from water; Preferably, in the pharmaceutical composition, the weight portion of the solvent is 20 to 60 parts.

5. The pharmaceutical composition according to any one of claims 1 to 4, wherein The pharmaceutical composition may further contain a thickener; and / or, may contain an antioxidant; and / or, may contain a preservative; Preferably, the thickener is selected from one or more of sodium carboxymethylcellulose, hypromellose, povidone and polyvinyl alcohol; Preferably, in the pharmaceutical composition, the weight portion of the thickener is 0.01 to 1 part; Preferably, the antioxidant is selected from one or both of propyl gallate and butylated hydroxytoluene; Preferably, in the pharmaceutical composition, the antioxidant is present in an amount of 0.01 to 0.2 parts by weight; Preferably, the preservative is selected from one or more of methylparaben, ethylparaben, propylparaben and benzalkonium chloride; Preferably, in the pharmaceutical composition, the weight portion of the preservative is 0.01 to 0.3 parts; Preferably, the pH of the pharmaceutical composition is 4 to 6; Preferably, the pharmaceutical composition further comprises a second active ingredient.

6. The pharmaceutical composition according to any one of claims 1 to 5, wherein The pharmaceutical composition comprises the following components in parts by weight: 0.1 to 8 parts of active ingredient, 10 to 35 parts of moisturizer, 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 regulator; 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; Preferably, the pH of the pharmaceutical composition is 4-6.

7. A method for preparing the pharmaceutical composition according to any one of claims 1 to 6, wherein: The preparation method comprises mixing the components to obtain; Preferably, the preparation method comprises the following steps: (1) mixing the active ingredient with a moisturizer and a penetration enhancer to form a solution containing the active ingredient; Alternatively, the active ingredient, antioxidant, preservative, moisturizer, and permeation enhancer are mixed to form a solution containing the active ingredient; (2) mixing a chelating agent, a thickener and a solvent to form a mixed solution; preferably, the chelating agent is first dissolved in the solvent, and then the thickener is added thereto for dispersion and dissolution; (3) adding the mixed solution to the solution containing the active ingredient, mixing evenly, and then adding a pH adjuster to adjust the pH of the system, preferably to 4 to 6; (5) adding a solvent to make up the weight to obtain the pharmaceutical composition.

8. Use of the pharmaceutical composition according to any one of claims 1 to 6 in the preparation of a pharmaceutical preparation; preferably, the pharmaceutical preparation is a solution preparation, such as a spray or an aerosol. Preferably, the pharmaceutical composition or pharmaceutical preparation is used to treat autoimmune inflammatory diseases, preferably psoriasis and / or atopic dermatitis; Preferably, the pharmaceutical composition or pharmaceutical preparation is used to treat the above diseases occurring in hair areas, and is particularly suitable for psoriasis occurring in hair areas, such as hair areas including but not limited to scalp and axilla; preferably scalp psoriasis.

9. A pharmaceutical preparation, wherein The pharmaceutical preparation contains the pharmaceutical composition according to any one of claims 1 to 6; Preferably, the pharmaceutical preparation is a solution preparation, preferably a spray or an aerosol; Preferably, the mass percentage of the active ingredient in the pharmaceutical preparation is 0.1 to 8%; Preferably, the pharmaceutical preparation is used to treat autoimmune inflammatory diseases, preferably psoriasis, atopic dermatitis and / or seborrheic dermatitis; Preferably, the pharmaceutical composition or pharmaceutical preparation is used to treat seborrheic dermatitis or the above diseases occurring in the hair area, and is particularly suitable for seborrheic dermatitis or psoriasis occurring in the hair area; preferably scalp psoriasis or seborrheic dermatitis.

10. Use of the pharmaceutical composition according to any one of claims 1 to 6 in the preparation of a medicament for treating and / or preventing autoimmune inflammatory diseases or diseases caused by Pityrosporum ovale; Preferably, the autoimmune disease is selected from psoriasis, atopic dermatitis and / or seborrheic dermatitis, more preferably seborrheic dermatitis or psoriasis occurring in the hair area, most preferably seborrheic dermatitis or scalp psoriasis; preferably, the disease caused by Pityrosporum ovale is seborrheic dermatitis caused by Pityrosporum ovale.

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