Compound composition of adapalene and dapsone, preparation method therefor, and use thereof

Abstract

The present disclosure belongs to the field of pharmaceutical formulations, and particularly relates to a compound composition of adapalene and dapsone for topical dermal use, a preparation method therefor, and use thereof. The composition of the present disclosure has at least one of the following excellent characteristics: high solubility of drug active ingredients in a carrier, small particle size of drug particles, stable particle size, good skin absorption, high in-vitro release efficiency, small particle size of composition oil drops, good stability, good therapeutic effect, small skin irritation, and good placement stability. The composition of the present disclosure can be directly used as a formulation, or can be further prepared into formulations of different dosage forms after other carriers are added.

Description

A compound composition of adapalene and dapsone, and its preparation method and use

[0001] Citation of Related Applications

[0002] This application claims all rights and interests in the invention patent application with application number 202311832033.8 filed with the State Intellectual Property Office of the People's Republic of China on December 28, 2023, and incorporates its entire contents into this application by reference. Technical Field

[0003] The present invention belongs to the field of pharmaceutical preparations, and particularly relates to a compound composition of adapalene and dapsone for topical skin application, a preparation method thereof, and uses thereof. Technical Background

[0004] Adapalene and dapsone are commonly used drugs for treating acne. Currently, the marketed products of adapalene include 0.1% and 0.3% gels and 0.1% cream, and the marketed products of dapsone include 5% and 7.5% gels.

[0005] Adapalene is a poorly water-soluble and oil-soluble drug. Due to its strong hydrophobicity, adapalene has low solubility in the matrix and is often dispersed in a crystalline state within the gel matrix, resulting in poor drug absorption and bioavailability. Previous studies have shown that adapalene has a very low absorption rate, whether in the form of a gel or cream, and is prone to skin allergies and irritation. Furthermore, adapalene creams also have the problem of poor skin comfort when applied.

[0006] The marketed dapsone gel suffers from storage instability and large particle size. After long-term storage, the dapsone particles in the gel gradually increase in size, affecting product stability and causing a gritty feel during use. Furthermore, particle size instability in topical preparations can lead to significant variations in release and absorption rates during use, impairing drug efficacy.

[0007] Therefore, existing topical acne treatment products, such as dapsone and adapalene, each have their own challenges, such as low drug solubility in the carrier, large particle size, particle size growth during storage, poor stability, and poor skin absorption. There is a need to develop a topical product that addresses these issues and achieves improved stability, compliance, and bioavailability. Summary of the Invention

[0008] To produce a topical acne product with excellent drug solubility, a suitable and stable particle size, and good bioavailability, the present disclosure provides a compound composition of adapalene and dapsone. This composition exhibits at least one of the following excellent properties: high solubility of the active pharmaceutical ingredient in the carrier, small and stable drug particle size, good skin absorption, high in vitro release efficiency, small oil droplet size, good stability, good therapeutic effect, low skin irritation, and good shelf stability. The disclosed composition can be used directly as a preparation or further prepared into various dosage forms by adding other carriers.

[0009] In one aspect of the present disclosure, a compound composition of adapalene and dapsone is provided. The compound composition comprises, by weight of the total composition, 1%-15% of dapsone, 0.05%-0.5% of adapalene, 0.25%-20% of a carboxylic acid ester oily solvent, 0.5%-20% of a polyoxyethylene nonionic surfactant, 5%-50% of diethylene glycol monoethyl ether, and other pharmaceutically acceptable carriers.

[0010] In a preferred technical solution of the present disclosure, the composition comprises 0.25-15% of a carboxylic acid ester oily solvent based on the total weight of the composition.

[0011] In some embodiments, the composition comprises 0.25%-10%, 0.25%-5%, 0.25%-4%, 0.25%-3%, 0.25%-2%, 0.25%-1%, 0.5%-10%, 0.5%-5%, 0.5%-1%, 1%-10%, 1%-5%, 5%-10% or 10%-15% of a carboxylic acid ester oily solvent, based on the total weight of the composition.

[0012] In some embodiments, the composition comprises 0.25%, 0.3%, 0.35%, 0.4%, 0.45%, 0.5%, 0.55%, 0.6%, 0.65%, 0.7%, 0.75%, 0.8%, 0.85%, 0.9%, 0.95%, 1%, 1.5%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5%, 5%, 5.5%, 6%, 6.5%, 7%, 7.5%, 8%, 8.5%, 9%, 9.5%, 10%, 10.5%, 11%, 11.5%, 12%, 12.5%, 13%, 13.5%, 14%, 14.5%, 15% of a carboxylic acid ester oily solvent based on the total weight of the composition.

[0013] In the preferred technical solution of the present disclosure, the carboxylate oily solvent is selected from any one of monocarboxylate, dicarboxylate, tricarboxylate or a mixture thereof; preferably, the oily solvent is monocarboxylate.

[0014] In some embodiments, the monocarboxylic acid ester is selected from any one of propylene glycol monocaprylate, propylene glycol monolaurate, propylene glycol oleate, propylene glycol myristate, isopropyl palmitate, lauryl lactate, isopropyl myristate, ethyl oleate, ethyl linoleate, glyceryl monolinoleate, glyceryl monostearate, and glyceryl monooleate, or a mixture thereof; the dicarboxylic acid ester is selected from any one of propylene glycol dicaprylate, diisopropyl adipate, diethyl sebacate, propylene glycol dicaprate, and di-n-butyl adipate, or a mixture thereof; the tricarboxylic acid ester is selected from any one of medium chain triglycerides, glyceryl triacetate, and caprylic capric triglyceride, or a mixture thereof;

[0015] Furthermore, the carboxylic acid ester oily solvent is selected from any one of propylene glycol monocaprylate and propylene glycol monolaurate, or a mixture thereof.

[0016] In some embodiments, the carboxylic acid ester oily solvent is propylene glycol monocaprylate.

[0017] In some embodiments, the propylene glycol monocaprylate is the commercially available product Capryol.

[0018] In some embodiments, the propylene glycol monocaprylate is the commercially available product Capryol 90, a mixture of propylene glycol monoester and propylene glycol diester with a ratio of >90% monoester and <10% diester.

[0019] In some embodiments, the carboxylic acid ester oily solvent is propylene glycol monolaurate.

[0020] In some embodiments, the propylene glycol monolaurate is a commercially available product of the Lauroglycol series.

[0021] In some embodiments, the propylene glycol monolaurate is the commercially available product Lauroglycol 90, a mixture of propylene glycol monoester and propylene glycol diester with a ratio of >90% monoester and <10% diester.

[0022] In a preferred technical solution of the present disclosure, the composition comprises 0.5-15% of a polyoxyethylene nonionic surfactant based on the total weight of the composition.

[0023] In some embodiments, the composition comprises 0.5-10%, 0.5%-5%, 0.5%-4%, 0.5%-3%, 0.5%-2%, 0.5%-1%, 1%-10%, 1%-5%, 5%-10% or 10%-15% of a polyoxyethylene nonionic surfactant, based on the total weight of the composition.

[0024] In some embodiments, the composition comprises 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1%, 1.5%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5%, 5%, 5.5%, 6%, 6.5%, 7%, 7.5%, 8%, 8.5%, 9%, 9.5%, 10%, 10.5%, 11%, 11.5%, 12%, 12.5%, 13%, 13.5%, 14.%, 14.5%, 15% of a polyoxyethylene nonionic surfactant based on the total weight of the composition.

[0025] In the preferred technical solution of the present invention, the polyoxyethylene nonionic surfactant is selected from any one of polyoxyethylene castor oil, fatty alcohol polyoxyethylene ether, polyol polyoxyethylene ether fatty acid ester, alkylphenol polyoxyethylene ether, fatty acid polyoxyethylene ester and fatty amine polyoxyethylene ether, or a mixture thereof.

[0026] Furthermore, the polyoxyethylene nonionic surfactant is polyoxyethylene castor oil.

[0027] In some embodiments, the polyoxyethylene castor oil is selected from any one of polyoxyethylene 35 castor oil, polyoxyethylene 40 hydrogenated castor oil, polyoxyethylene 54 hydrogenated castor oil and polyoxyethylene 60 hydrogenated castor oil, or a mixture thereof.

[0028] Furthermore, the polyoxyethylene castor oil is selected from any one of polyoxyethylene 35 castor oil and polyoxyethylene 40 hydrogenated castor oil or a mixture thereof.

[0029] In some embodiments, the polyoxyethylene nonionic surfactant is polyoxyethylene 35 castor oil.

[0030] In some embodiments, the polyoxyethylene nonionic surfactant is polyoxyethylene 40 hydrogenated castor oil.

[0031] In a preferred technical solution of the present disclosure, the composition comprises 10%-50% of diethylene glycol monoethyl ether, further 15%-45%, based on the total weight of the composition.

[0032] In some embodiments, the composition comprises 20%-45%, 20%-40%, 20%-35%, 20%-30%, 25%-45%, 25%-40%, 25%-35%, 30%-45%, 30%-40%, 35%-45%, or 40%-45% of diethylene glycol monoethyl ether, based on the total weight of the composition.

[0033] In some embodiments, the composition comprises 10%, 15%, 20%, 25%, 30%, 35%, 40% or 45% diethylene glycol monoethyl ether by weight of the total composition.

[0034] In a preferred technical solution of the present disclosure, the composition comprises 2% to 12% of dapsone based on the total weight of the composition;

[0035] In some embodiments, the composition comprises, based on the total weight of the composition, 2%-11%, 2%-10%, 2%-9%, 2%-8%, 2%-7%, 2%-6%, 2%-5%, 2%-4%, 2%-3%, 3%-11%, 3%-10%, 3%-9%, 3%-8%, 3%-7%, 3%-6%, 3%-5%, 3%-4%, 4%-11%, 4%-10%, 4%-9.0%, 4%-8 %, 4%-7%, 4%-6%, 5%-11%, 5%-10%, 5%-9%, 5%-8%, 5%-7%, 5%-6%, 6%-11%, 6%-10%, 6%-9%, 6%-8%, 6%-7%, 7%-11%, 7%-10%, 7%-9%, 7%-8%, 8%-11%, 8%-10%, 8.0%-9%, 9%-11%, 9%-10%, or 10%-11% dapsone.

[0036] In some embodiments, the composition comprises 2%, 2.5%, 3%, 3.5%, 4%, 4.5%, 5%, 5.5%, 6%, 6.5%, 7%, 7.5%, 8%, 8.5%, 9%, 9.5%, 10%, 10.5%, 11%, 11.5% or 12% dapsone by total weight of the composition.

[0037] In some embodiments, the composition comprises 0.05%-0.4%, 0.05%-0.3%, 0.05%-0.2%, 0.05%-0.1%, 0.1%-0.4%, 0.1%-0.3%, 0.1%-0.2%, 0.2%-0.4%, 0.2%-0.3%, or 0.3%-0.4% adapalene, based on the total weight of the composition.

[0038] In some embodiments, the composition comprises 0.05%, 0.075%, 0.1%, 0.15%, 0.2%, 0.25%, 0.3%, 0.35%, 0.4%, 0.45% or 0.5% adapalene by total weight of the composition.

[0039] In some embodiments, the amounts of dapsone and adapalene in the composition are 7.5% and 0.1%, 6.0% and 0.1%, 5.0% and 0.1%, 7.5% and 0.15%, 6.0% and 0.15%, 5.0% and 0.15%, 7.5% and 2.0%, 6.0% and 2.0%, 5.0% and 2.0%, 7.5% and 3.0%, 6.0% and 3.0%, 5.0% and 3.0%, 12% and 0.3%, or 3% and 0.075%, respectively, based on the total weight of the composition.

[0040] In a preferred technical solution of the present disclosure, the mass ratio of the polyoxyethylene nonionic surfactant to the carboxylate oily solvent in the composition is ≥1:1 ​​or >1:1.

[0041] Furthermore, the mass ratio of the polyoxyethylene nonionic surfactant to the carboxylate oily solvent is ≤5:1, for example ≤4:1 or ≤3:1.

[0042] In some embodiments, the mass ratio of the polyoxyethylene nonionic surfactant to the carboxylate oily solvent is 1.5:1, 2:1, 2.5:1, 3:1, 3.5:1, 4:1 or 4.5:1.

[0043] In a preferred technical solution of the present disclosure, the other pharmaceutically acceptable carriers include a crystallization inhibitor, and the composition contains 0.5%-4% of the crystallization inhibitor based on the total weight of the composition.

[0044] In some embodiments, the composition comprises 0.5%-3.5%, 0.5%-3%, 0.5%-2.5%, 0.5%-2%, 0.5%-1.5%, 1%-3.5%, 1%-3%, 1%-2.5%, 1%-2%, 1.5%-3.5%, 1.5%-3%, or 1.5%-2.5% of a crystallization inhibitor, based on the total weight of the composition.

[0045] In some embodiments, the composition comprises 0.5%, 1%, 1.5%, 2%, 2.5%, 3%, 3.5%, or 4% of a crystallization inhibitor, based on the total weight of the composition.

[0046] Furthermore, the crystallization inhibitor is selected from any one of povidone (PVP), polyvinyl alcohol (PVA) and hydroxypropyl cellulose (HPC) or a combination thereof.

[0047] In some embodiments, the crystallization inhibitor is PVP.

[0048] Furthermore, the polyvidone (PVP) is selected from any one of PVP-K12, PVP-K17, PVP-K25, PVP-K30, PVP-K60, and PVP K-90, or a combination thereof.

[0049] In some embodiments, the crystallization inhibitor is PVP-K30.

[0050] In a preferred technical solution of the present disclosure, the pharmaceutically acceptable carrier further comprises a polymer copolymer emulsifier. Based on the total weight of the composition, the composition comprises 0.05-6% of the polymer copolymer emulsifier.

[0051] Furthermore, the composition comprises 0.05%-1% of a high molecular weight copolymer emulsifier based on the total weight of the composition.

[0052] In some embodiments, the composition comprises, based on the total weight of the composition, 0.05%-0.9%, 0.05%-0.8%, 0.05%-0.7%, 0.05%-0.6%, 0.05%-0.5%, 0.05%-0.4%, 0.05%-0.3%, 0.05%-0.2%, 0.05%-0.1%, 0.1%-0.9%, 0.1%-0.8%, 0.1%-0.7%, 0.1%-0.6%, 0.1%-0.5%, 0.1%-0.4%, 0.1%-0.3%, 0.1%-0.2%, 0.2%-0.9%, 0.2%-0.8%, 0.2%-0.7%, 0.2%-0.6%, 0.2%-0. %-0.5%, 0.2%-0.4%, 0.2%-0.3%, 0.3%-0.9%, 0.3%-0.8%, 0.3%-0.7%, 0.3%-0.6%, 0.3%-0.5%, 0.3%-0.4%, 0.4%-0.9%, 0.4%-0.8%, 0.4%-0.7%, 0.4%-0.6%, 0.4%-0.5%, 0.5%-0.9%, 0.5%-0.8%, 0.5%-0.7%, 0.5%-0.6%, 0.6%-0.9%, 0.6%-0.8%, 0.6%-0.7%, 0.7%-0.9%, 0.7%-0.8% or 0.8%-0.9% of a high molecular weight copolymer emulsifier.

[0053] Furthermore, the composition comprises 0.05%, 0.1%, 0.15%, 0.2%, 0.25%, 0.3%, 0.35%, 0.4%, 0.45%, 0.5%, 0.55%, 0.6%, 0.65%, 0.7%, 0.75%, 0.8%, 0.85%, 0.9%, 0.95% or 1% of a high molecular weight copolymer emulsifier based on the total weight of the composition.

[0054] Furthermore, the high molecular weight copolymer emulsifier is a carbomer copolymer.

[0055] Furthermore, the carbomer copolymer is an acrylic acid (ester) / (C10-30) alkyl acrylate cross-linked copolymer.

[0056] In some embodiments, the acrylic acid (esters) / (C10-30) alkyl acrylate cross-linked copolymer is selected from any one of the commercially available products PEMULEN TR-1, PEMULEN TR-2, and PEMULEN EZ-4U, or a combination thereof.

[0057] In some embodiments, the high molecular weight copolymer emulsifier is PEMULEN TR-1.

[0058] In a preferred technical solution of the present disclosure, the pharmaceutically acceptable carrier further comprises a thickener. Based on the total weight of the composition, the composition comprises 0.1%-4% of the thickener.

[0059] Furthermore, the thickener is selected from any one of polyacrylamide and carbomer homopolymer or a combination thereof.

[0060] In some embodiments, the polyacrylamide is a mixture of acrylamide / sodium acryloyldimethyltaurate copolymer / isohexadecane / polysorbate 80 (Sepineo P600).

[0061] In some embodiments, the carbomer homopolymer is carbomer 981.

[0062] Furthermore, the thickener is selected from any one of Sepineo P600 and Carbomer 981 or a combination thereof.

[0063] In some embodiments, the thickening agent is a combination of Sepineo P600 and Carbomer 981.

[0064] In some embodiments, the composition comprises 1%-3% Sepineo P600 and 0.1%-1% Carbomer 981, based on the total weight of the composition.

[0065] In some embodiments, the composition comprises 1%, 1.5%, 2%, 2.5%, or 3% Sepineo P600, based on the total weight of the composition.

[0066] In some embodiments, the composition comprises 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9% or 1% Carbomer 981 based on the total weight of the composition.

[0067] In some embodiments, the composition comprises 1.5% Sepineo P600 and 0.2% Carbomer 981, based on the total weight of the composition.

[0068] In a preferred technical solution of the present disclosure, the solubility of adapalene in the composition is at least 10 times higher than its solubility in water at the same temperature, for example, more than 100 times higher.

[0069] In a preferred technical solution of the present disclosure, the oil droplet diameter of the composition is ≤300 nm; for example, ≤250 nm.

[0070] In some embodiments, the composition has an oil droplet size of ≤ 240 nm, 220 nm, 200 nm, 180 nm, 160 nm, 140 nm, 120 nm, 100 nm, 80 nm, 60 nm, 50 nm, 40 nm, or 30 nm.

[0071] In a preferred technical solution of the present disclosure, the transparency of the composition is not less than 50%, for example, not less than 80%.

[0072] In the preferred technical solution of the present disclosure, when the content of Adapalene is 0.10% of the total weight of the composition, at least 10% of the Adapalene is in a dissolved state.

[0073] In a preferred technical solution of the present disclosure, when the content of dapsone is 7.5% by weight of the total weight of the pharmaceutical composition for topical skin application, at least 50% of the dapsone is in a dissolved state.

[0074] In the preferred technical solution of the present disclosure, the composition can be directly applied to the skin, or can be added with other pharmaceutically acceptable carriers to prepare other local pharmaceutical preparations.

[0075] In the preferred technical solution of the present disclosure, the composition is an emulsion or latex.

[0076] In some embodiments, the composition is an emulsion, such as a microemulsion.

[0077] In some embodiments, the composition is an emulsion, such as a microemulsion gel.

[0078] In the preferred technical solution of the present disclosure, the pharmaceutically acceptable carrier may further comprise any one or a combination of a preservative, an antioxidant, a chelating agent and a pH regulator.

[0079] In the technical solution provided by the present disclosure, the stability of the composition or the topical pharmaceutical preparation prepared therefrom is further improved by adding preservatives, antioxidants, chelating agents and pH regulators, and the specific addition amounts are added according to the commonly used concentration range of excipients.

[0080] In some embodiments, the preservative is selected from any one of methylparaben (methylparaben), benzyl alcohol, sodium benzoate, ethylparaben, propylparaben, potassium sorbate, phenoxyethanol, or a combination thereof.

[0081] In some embodiments, the preservative is methylparaben (methylparaben).

[0082] In some embodiments, the antioxidant comprises any one or a combination thereof selected from butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), propyl gallate, and α-tocopherol.

[0083] In some embodiments, the antioxidant is butylated hydroxytoluene (BHT).

[0084] In the preferred technical solution of the present invention, the chelating agent is selected from any one or a combination of ethylenediaminetetraacetic acid (EDTA), diethylenetriaminepentaacetic acid (DTPA), ethylenediamine-bis(o-hydroxyphenyl)acetic acid (EDDHA), hydroxy-2-ethylenediaminetriacetic acid (HEDTA), ethylenediamine-bis(o-hydroxy-p-methylphenyl)acetic acid (EDDHMA) and ethylenediamine-bis(5-carboxy-2-hydroxyphenyl)acetic acid (EDDCHA).

[0085] In some embodiments, the chelating agent is edetate disodium.

[0086] In a preferred technical solution of the present disclosure, the pH regulator comprises any one selected from sodium hydroxide and triethanolamine or a combination thereof.

[0087] In some embodiments, the pH adjuster is sodium hydroxide.

[0088] In a preferred technical solution of the present disclosure, the pH range of the composition is between 5.0-7.0.

[0089] In some embodiments, the composition has a pH range of 5.0-6.5.

[0090] In some embodiments, the composition has a pH range of 5.0-6.0.

[0091] Another aspect of the present disclosure is to provide a method for preparing a compound composition of adapalene and dapsone, the preparation method comprising the following steps:

[0092] 1) preparing an oil phase: adding dapsone and adapalene to a mixed solution of a carboxylic acid ester oily solvent, a polyoxyethylene nonionic surfactant, and diethylene glycol monoethyl ether to form an oil phase;

[0093] 2) Preparing the aqueous phase: uniformly dispersing other pharmaceutically acceptable carriers in water and mixing to form an aqueous phase; or directly using water as the aqueous phase;

[0094] 3) Emulsification: Add the oil phase from step 1) to the water phase from step 2), adjust the pH to 5.0-6.0, mix well, and add water to 100%.

[0095] According to a preferred technical solution of the present disclosure, the other pharmaceutically acceptable carrier in step 2) is any one of a polymer emulsifier, a thickener and a crystallization inhibitor, or a combination thereof.

[0096] Furthermore, in step 2), other pharmaceutically acceptable carriers are polymer emulsifiers, thickeners and crystallization inhibitors.

[0097] Furthermore, in step 2), a thickener may be added after the high molecular weight copolymer emulsifier is added.

[0098] Furthermore, in step 2), a crystallization inhibitor may be added before adding the high molecular weight copolymer emulsifier.

[0099] According to a preferred technical solution of the present disclosure, any one or a combination of a penetration enhancer, an antioxidant, a preservative and a chelating agent may be added to the steps 1) and / or 2).

[0100] Another aspect of the present disclosure provides use of a compound composition of adapalene and dapsone in preparing a medicament for treating skin diseases.

[0101] According to an embodiment of the present disclosure, the skin disease is acne vulgaris, rosacea, rosacea, chronic wounds, bedsores, keratosis, sebaceous cysts, post-inflammatory hyperpigmentation, eczema, xerosis, pruritus, lichen planus, dermatitis, atopic dermatitis, prurigo nodularis, or prickly heat.

[0102] Furthermore, the skin disease is acne vulgaris.

[0103] According to an embodiment of the present disclosure, the acne vulgaris is mild, moderate, moderately severe or severe acne;

[0104] Moderate or moderately severe acne is preferred.

[0105] Another aspect of the present disclosure provides a use of a compound composition of adapalene and dapsone in preparing a pharmaceutical preparation for topical administration.

[0106] According to an embodiment of the present disclosure, the topically administered pharmaceutical formulation is selected from an emulsion, an emulgel, or a cream.

[0107] Another aspect of the present disclosure provides a method for treating skin diseases, comprising administering a therapeutically effective amount of the compound composition of adapalene and dapsone of the present disclosure to a subject in need thereof.

[0108] According to an embodiment of the present disclosure, the skin disease is acne vulgaris, rosacea, rosacea, chronic wounds, bedsores, keratosis, sebaceous cysts, post-inflammatory hyperpigmentation, eczema, xerosis, pruritus, lichen planus, dermatitis, atopic dermatitis, prurigo nodularis, or prickly heat.

[0109] According to an embodiment of the present disclosure, the skin disease is acne vulgaris.

[0110] In the present disclosure, acne vulgaris can occur on the face, chest, back, and sometimes even more extensively. Depending on the severity, acne vulgaris can be mild, moderate, or severe, with mild acne typically being categorized by the appearance of blackheads and whiteheads, but also including papules and pustules; moderate acne being characterized by the appearance of more painful, deep, inflamed lesions that may lead to scarring; and severe acne being characterized by the appearance of deep, inflamed lesions, including cysts and nodules, which may be painful and may produce scars.

[0111] The topical pharmaceutical composition for skin application disclosed herein has the following beneficial effects:

[0112] 1) The present invention utilizes a combination of a specific type of oily solvent, a surfactant, and a co-surfactant to prepare a clear, non-stratified, transparent microemulsion system of a compound composition of adapalene and dapsone with excellent stability. Furthermore, the adapalene and dapsone compound emulsion prepared using the microemulsion system maintains no significant changes in properties, pH, viscosity, particle size, active ingredient content, and related substances for at least 12 months when stored under conditions of 25±2°C / 60±5% RH, 30±2°C / 65%±5% RH, and 40±2°C / 75%±5% RH, demonstrating excellent stability.

[0113] 2) In the composition provided by the present disclosure, the solubility of adapalene in the composition carrier is increased by more than 100 times compared with that in water, which is beneficial to improving the absorption of adapalene.

[0114] 3) In the compositions provided herein, the inventors, after multiple screenings, surprisingly discovered that when the weight ratio of the polyoxyethylene nonionic surfactant to the oily solvent is controlled to be greater than 1:1, even at relatively low amounts of the polyoxyethylene nonionic surfactant and the oily solvent, a clear, non-stratified, and highly transparent microemulsion system can still be prepared, while also reducing the stickiness, odor, and irritation of the system.

[0115] 4) The composition provided by the present disclosure contains a crystallization inhibitor, which greatly reduces the particle size of the drug particles, inhibits the growth of the drug particles, and reduces the grittiness felt by patients during application.

[0116] 5) In the composition provided by the present disclosure, the oil droplet size is less than 300 nm, which is conducive to the rapid absorption of the active pharmaceutical ingredient by the skin.

[0117] 6) In the composition provided by the present disclosure, the release rate of dapsone can be increased by 1.5 times compared with the prior art, and the amount of skin absorption in the epithelium and dermis can be increased by 1.9 times compared with the prior art, which is beneficial to improving the efficacy of the drug.

[0118] 7) The composition provided by the present disclosure has a good therapeutic effect on diseases such as acne.

[0119] 8) The composition provided by the present disclosure can reduce the irritation of drugs to the skin and has good tolerance and safety.

[0120] 9) The composition provided by the present disclosure is non-greasy and easy to spread. BRIEF DESCRIPTION OF THE DRAWINGS

[0121] FIG1 is a PLM spectrum of the E15 sample in Experimental Example 2;

[0122] FIG2 is a PLM spectrum of sample E2 in Experimental Example 2;

[0123] FIG3 is a PLM spectrum of the E11 sample in Experimental Example 2;

[0124] FIG4 is a PLM spectrum of the R2 sample in Experimental Example 2;

[0125] FIG5 is an overlay of XRD patterns of samples E2, E11, E15, and R2 in Experimental Example 2;

[0126] Figure 6 shows the change rate of total skin lesions in rabbit ears compared to the baseline in each drug-treated group on days 11 and 14 of Experimental Example 5;

[0127] FIG7 shows the change rate of inflammatory lesions in the rabbit ears of each administration group at day 11 and day 14 compared with the baseline in Experimental Example 5. DETAILED DESCRIPTION

[0128] Hereinafter, the present disclosure will be explained in detail through the following examples in order to better understand the various aspects and advantages of the present disclosure. However, it should be understood that the following examples are non-limiting and are only used to illustrate certain embodiments of the present disclosure.

[0129] In the present disclosure, an emulsion is an emulsified system formed by two immiscible phases through a specific emulsifier (surfactant), in which fine droplets of one liquid are uniformly dispersed in the other liquid, the former being called the dispersed phase and the latter being called the continuous phase. Conventionally, the organic liquid constituting the emulsion is referred to as "oil (O)", and oil (O) dispersed in water (W) is called an oil-in-water emulsion (O / W); conversely, it is called a water-in-oil emulsion (W / O). In order to improve the solubility and transdermal absorption of hydrophobic drugs, a uniform and stable O / W emulsion is formed by dissolving the raw drug in oil phase droplets, which are then dispersed in the water phase. An emulsion with an oil droplet size of less than 300 nm is called a microemulsion.

[0130] In this disclosure, latex or latexes are emulsion-type gels. Gels or latexes refer to thick liquid or semisolid preparations with gel properties, made from a drug substance and a gel-forming excipient. Latexes or latexes refer to thick liquid or semisolid preparations with gel properties, made from a drug substance dissolved / dispersed in oil phase droplets, which are then dispersed in a gel-forming excipient.

[0131] In the present disclosure, creams or ointments are uniform semi-solid topical preparations made by mixing raw drug substances with oily or water-soluble bases. Creams can be divided into oil-in-water creams and water-in-oil creams due to different bases.

[0132] In the present disclosure, nonionic surfactants are surfactants that do not dissociate into ions in water and are insensitive to pH changes.

[0133] In this disclosure, a "poorly water-soluble drug" refers to a drug known to be used in the pharmaceutical field and having low solubility in water relative to its effective dosage. Specifically, it refers to a drug for which the amount of solvent (water) required to dissolve 1 g or 1 mL of solute is 100 mL or more (at a concentration of 1% or less), preferably 1000 mL or more (at a concentration of 0.1% or less), and more preferably 10,000 mL or more (at a concentration of 0.01% or less).

[0134] In this disclosure, "pharmaceutically acceptable carrier" refers to any pharmaceutically acceptable ingredient known to those skilled in the art, which is generally regarded as an inactive ingredient.

[0135] In the present disclosure, the content of adapalene is detected by HPLC, mobile phase A: 0.05% TFA / acetonitrile (95%), mobile phase B: water (5%), detection wavelength: 270 nm.

[0136] Screening Example 1: Screening of oily solvents, surfactants, and cosurfactants

[0137] (1) Solubility of adapalene in various media.

[0138] Solubility test method: Take 2-3 mL of the medium in Table 1, add an excess of adapalene to obtain a suspension, stir at room temperature for 24 hours, filter, and take the clarified filtrate for testing.

[0139] In the present disclosure, when the solubility of adapalene in the medium reaches about 400 μg / ml or more, it is considered that the solubility requirement can be met.

[0140] The results are shown in Table 1:

[0141] Table 1

[0142] * Note: Polyoxyethylene (35) castor oil, polyoxyethylene (40) hydrogenated castor oil and polyethylene glycol (15)-hydroxystearate are solid or semi-solid at room temperature. They need to be dissolved in diethylene glycol monoethyl ether before measuring the solubility of adapalene in the mixed medium.

[0143] The results in Table 1 show that in oily solvents, the solubility of adapalene in propylene glycol monocaprylate, propylene glycol monolaurate, diisopropyl adipate and diethyl sebacic acid is above 400 μg / ml, which can meet the solubility requirements.

[0144] Among surfactants, the solubility of adapalene in diethylene glycol monoethyl ether / polyoxyethylene (35) castor oil (2 / 1), diethylene glycol monoethyl ether / polyoxyethylene (40) hydrogenated castor oil (2 / 1), and diethylene glycol monoethyl ether / polyethylene glycol (15)-hydroxystearate (2 / 1) is above 3000 μg / ml, the solubility in caprylic / capric macrogol glyceride is above 1000 μg / ml, and the solubility in monoolein is close to 400 μg / ml, all of which can meet the solubility requirements;

[0145] Among the co-surfactants, the solubility of adapalene in diethylene glycol monoethyl ether is above 2000 μg / ml, which can meet the solubility requirements.

[0146] (2) Further screening of surfactant types

[0147] Using propylene glycol monocaprylate as the oily solvent and diethylene glycol monoethyl ether as the cosurfactant, the appearance, transparency, stability and solubility of adapalene in the systems formed by different surfactant combinations listed in Table 2 were investigated.

[0148] Test method:

[0149] At room temperature, 5% propylene glycol monooctanoate, 30% diethylene glycol monoethyl ether, and 15% surfactant were added to a beaker and stirred thoroughly. Purified water was then added dropwise to the beaker while stirring (making the total volume 100%) to form a system sample. The following parameters were evaluated, with the results shown in Table 2.

[0150] a) Appearance: Let it stand and observe whether it is clear and has layers.

[0151] b) Transparency: For samples that did not delaminate after standing at room temperature for one day, the transparency of the composition was tested using UV-Vis spectroscopy (transmittance at 650 nm (with water as blank)).

[0152] c) Stability: For samples that have not separated after being placed at room temperature for one day, centrifuge at 8000 rpm for 15 min to observe whether separation occurs.

[0153] d) Adapalene solubility: 2-3 mL of sample was added with an excess of adapalene to obtain a suspension. The suspension was stirred at room temperature for 24 h, filtered, and the clear filtrate was assayed.

[0154] Table 2

[0155] The results in Table 2 show that when the oily solvent is propylene glycol monocaprylate and the co-surfactant is diethylene glycol monoethyl ether, polyoxyethylene (35) castor oil and polyoxyethylene (40) hydrogenated castor oil are selected as surfactants, the obtained samples have a clear and transparent appearance, a transparency of more than 99%, good phase stability, and are not prone to oil-water separation, and adapalene has a high solubility; while when polyethylene glycol glyceride caprylate, monooleate glyceride and polyethylene glycol (15)-hydroxystearate are selected as surfactants, the obtained samples are turbid, indicating that the droplet size is large, oil-water separation is prone to occur, and there is a risk of poor stability.

[0156] (3) Further screening of oily solvent types

[0157] Using diethylene glycol monoethyl ether as a cosurfactant and polyoxyethylene (35) castor oil as a surfactant, the appearance, clarity, stability and solubility of adapalene in the systems formed by different oily solvents in Table 3 were investigated.

[0158] Test method:

[0159] At room temperature, 15% polyoxyethylene (35) castor oil, 30% diethylene glycol monoethyl ether, and 5% oily solvent were added to a beaker and stirred to mix. Purified water was added dropwise to the beaker while stirring (to 100%) to form a system sample, which was evaluated using the following parameters.

[0160] a) Appearance: Let the sample stand and observe whether it is clear and stratified.

[0161] b) Transparency: For samples that did not delaminate after being stored at room temperature for one day, their transparency (transmittance at 650 nm (with water as blank)) was tested using UV-Vis spectroscopy.

[0162] c) Stability: For samples that have not separated after being placed at room temperature for one day, centrifuge at 8000 rpm for 15 min to observe whether separation occurs.

[0163] d) Adapalene solubility: 2-3 mL of different samples were added with an excess of adapalene to obtain a suspension. The suspension was stirred at room temperature for 24 h, filtered, and the clarified filtrate was tested.

[0164] The results are shown in Table 3.

[0165] Table 3

[0166] The results in Table 3 show that when the cosurfactant is diethylene glycol monoethyl ether and the surfactant is polyoxyethylene (35) castor oil, propylene glycol monocaprylate and propylene glycol monolaurate are selected as the oily solvents, respectively, and the obtained samples have a transparent and clear appearance, good stability, a transparency of more than 96%, and a high solubility of adapalene; while when diisopropyl adipate, diethyl sebacate, medium-chain triglycerides and soybean oil are used as oily solvents, the obtained samples are turbid, indicating that the droplet size in the system is large, oil-water separation is easy to occur, and there is a risk of poor stability.

[0167] Screening Example 2: Investigation of the Ratio of Oily Solvent and Nonionic Surfactant

[0168] Based on the results of screening example 1, this screening example used propylene glycol monocaprylate as the oily solvent, diethylene glycol monoethyl ether as the cosurfactant and polyoxyethylene (35) castor oil as the surfactant to prepare a compound composition of adapalene and dapsone, and investigated the effects of compositions formed by different proportions of oily solvent and surfactant on the appearance, clarity, stability and solubility of adapalene droplets.

[0169] Test method:

[0170] At room temperature, according to the prescription in Table 4, adapalene, dapsone, propylene glycol monocaprylate, polyoxyethylene (35) castor oil and diethylene glycol monoethyl ether were mixed and stirred to obtain an oil phase solution, and then purified water was added to the oil phase solution and stirred to obtain a compound composition of adapalene and dapsone.

[0171] Table 4

[0172] The composition samples prepared above were evaluated using the following parameters.

[0173] Appearance: After the composition has been allowed to stand at room temperature for 1 day, observe whether it is turbid or has separated into layers.

[0174] Stability: For the composition sample that has not separated into layers after being placed at room temperature for one day, centrifuge it at 8000 rpm for 15 minutes to observe whether it separates into layers.

[0175] Transparency: For the composition sample that was not delaminated after standing at room temperature for one day, the transparency of the composition was tested using UV-Vis spectroscopy (transmittance at 650 nm (with water as blank)).

[0176] Oil droplet size: Take a sample of the composition and measure it three times using a laser particle size analyzer to calculate the average value.

[0177] pH: Take a sample of the composition and measure it three times using a pH meter to calculate the average value.

[0178] The results are shown in Table 5.

[0179] Table 5

[0180] The results in Table 5 show that: 1) when the ratio of polyoxyethylene (35) castor oil / propylene glycol monocaprylate is greater than 1:1, such as 1.5:1, 2:1 or 3:1 (M2, M3, M6, M10-M15), the prepared composition is a colorless and transparent microemulsion with an oil droplet size of less than 100 nm and good stability without turbidity or stratification.

[0181] 2) When the ratio of polyoxyethylene (35) castor oil / propylene glycol monocaprylate is 1:1 and the content is 15% or 10% (M9, M5), the prepared composition is a colorless and transparent microemulsion with an oil droplet size of less than 250 nm and good stability without turbidity or stratification.

[0182] 3) When the ratio of polyoxyethylene (35) castor oil / propylene glycol monocaprylate is 1:1 and the content accounts for 5% (M1), the prepared composition is milky white and stratification occurs during the storage process.

[0183] 4) When the ratio of polyoxyethylene (35) castor oil / propylene glycol monocaprylate is less than 1:1 (M4, M7, M8), the prepared composition is milky white and stratification occurs during storage.

[0184] In summary, when the mass ratio of polyoxyethylene (35) castor oil / propylene glycol monocaprylate is greater than 1:1, or when the mass ratio of polyoxyethylene (35) castor oil / propylene glycol monocaprylate is 1:1 and a relatively high content of surfactant is maintained at the same time, a compound composition of adapalene and dapsone with good stability, high transparency and small oil droplet size can be obtained; when the mass ratio of polyoxyethylene (35) castor oil / propylene glycol monocaprylate is 1:1 and the content of surfactant is low, or when the mass ratio of polyoxyethylene (35) castor oil / propylene glycol monocaprylate is less than 1:1, or, the obtained composition is milky white and turbid, and stratification will occur, and the stability is poor.

[0185] Example 1: Preparation of a compound composition of adapalene and dapsone (emulsion)

[0186] According to the prescriptions in Table 6 and Table 7, the latex of the present disclosure was prepared.

[0187] Table 6

[0188] Table 7

[0189] According to the prescriptions in Tables 6 and 7:

[0190] a) Preparation of aqueous phase:

[0191] Take an appropriate amount of purified water into the aqueous phase bucket, add disodium edetate, and stir until dissolved; then add Carbomer 981 and PEMULEN TR-1, stir to disperse them evenly, and obtain an aqueous phase solution.

[0192] b) Preparation of oil phase:

[0193] Add diethylene glycol monoethyl ether to the oil phase barrel, add PVP-K30, methyl hydroxybenzoate and butylated hydroxytoluene, and stir until dissolved; then add dapsone and stir until dissolved to obtain an oil phase solution 1 containing dapsone.

[0194] Add polyoxyethylene (35) castor oil to another oil phase barrel, heat and stir at 50-60°C to obtain a yellow clear liquid, then add propylene glycol monocaprylate and stir until mixed evenly to obtain oil phase solution 2.

[0195] Add the oil phase solution 2 to the oil phase solution 1 and stir evenly; then add adapalene and stir to obtain a suspended oil phase solution containing the active ingredient.

[0196] c) Preparation of sodium hydroxide solution

[0197] Mix sodium hydroxide and an appropriate amount of purified water and stir until fully dissolved.

[0198] d) Mixing and emulsification

[0199] The aqueous phase solution is added to the suspended oil phase solution, stirred, and homogenized; then sodium hydroxide solution and SEPINEO P 600 are added, stirred, and homogenized to obtain the latex of the present disclosure.

[0200] Comparative Example 1: Preparation of gel

[0201] Adapalene gel R1 was prepared according to Example 1 of US7838558, and dapsone gel R2 was prepared according to Example 1 of CN105246457B. The specific prescriptions are shown in Table 8.

[0202] Table 8

[0203] Preparation method of comparative example R1:

[0204] According to the prescription in Table 8, phenoxyethanol, methyl parahydroxybenzoate, poloxamer, and edetate disodium were added to water and dissolved, and then carbomer was added and mixed uniformly to obtain an aqueous phase; adapalene was added to propylene glycol and mixed uniformly to obtain an organic phase; the organic phase was slowly added to the aqueous phase under stirring, uniformly dispersed, and homogenized to obtain the adapalene hydrogel of Comparative Example 1.

[0205] Preparation method of comparative example R2:

[0206] According to the prescription in Table 8, methyl parahydroxybenzoate was added to water and dissolved to obtain an aqueous phase; dapsone was added to diethylene glycol monoethyl ether and mixed uniformly to obtain an organic phase; the organic phase was slowly added to the aqueous phase under stirring, and finally SEPINEO P600 was added and uniformly dispersed and homogenized to obtain the dapsone hydrogel of Comparative Example 2.

[0207] Test Example 1: Comparative study of in vitro release and skin absorption.

[0208] The in vitro release and skin absorption of dapsone from the emulsions provided by the present disclosure (Examples E2 and E3) and the prior art hydrogel (Comparative Example R2) were compared.

[0209] Test method:

[0210] In vitro release: A vertical diffusion cell was used, and a solution of isopropyl alcohol:cyclodextrin:potassium dihydrogen phosphate:water (30:5:0.6:64.4) was used as the receiving medium for dapsone. A PVDF filter membrane was fixed between the supply chamber and the receiving chamber of the diffusion cell. The diffusion cell was fixed in a transdermal absorption diffusion instrument. In vitro release experiments were conducted at 32°C and 600 rpm. The dapsone content in the diffusion cell was detected by HPLC, and the release rate of dapsone within 6 hours was calculated.

[0211] Skin absorption: A vertical diffusion cell was used, and a solution of isopropyl alcohol:cyclodextrin:potassium dihydrogen phosphate:water (30:5:0.6:64.4) was used as the receiving medium for dapsone. Pig skin was used as a filter membrane and fixed between the supply chamber and the receiving chamber of the diffusion cell. The diffusion cell was fixed in a transdermal absorption diffusion instrument, and the skin absorption experiment was carried out at 32°C and 600 rpm. After 24 hours, the pig skin was removed, and the residual sample on the surface of the pig skin was wiped off with a cotton swab. The stratum corneum was then peeled off with tape, and the remaining epithelial and dermal tissues were cut into pieces. The dapsone in the tissues was extracted with methanol. The dapsone content was detected by HPLC, and the total absorption of dapsone in the epithelial and dermal tissues was calculated.

[0212] The results are shown in Table 9.

[0213] Table 9

[0214] The results in Table 9 show that the in vitro release rate of dapsone from the emulsion of the present disclosure is significantly higher than that from the hydrogel of the prior art, with the in vitro release rates of dapsone in Examples E2 and E3 being 1.2 times and 1.5 times that of Comparative Example R2, respectively. The skin absorption of dapsone from the emulsion of the present disclosure is significantly higher than that from the hydrogel, with the absorption of dapsone in the epithelium and dermis in Examples E2 and E3 being 1.9 times and 1.5 times that of Comparative Example R2, respectively.

[0215] Test Example 2: Comparative Study of Particle Size and Dispersion State

[0216] Optical microscopy (PLM) and X-ray diffractometer (XRD) were used to compare the particle size and dispersion state of the crystal particles in the latex of the present disclosure (Examples E2, E11, E15) and the prior art hydrogel (Comparative Example R2).

[0217] Test method:

[0218] The PLM spectrum was collected from an XPV-990E polarized light microscope; a small amount of sample was placed on a glass slide, covered with a coverslip, and placed on a stage for observation, photography, and particle size statistics.

[0219] XRD data were collected from a Bruker D8 Advance diffractometer; parameters were as follows: Cu target; wavelength Current and voltage: 40kV, 40mA; Angle range: 3-40°2θ.

[0220] The results are shown in Figures 1-5.

[0221] The results in Figures 1-4 show that in the emulsion examples E2 and E15 provided by the present disclosure containing PVP-K30, the drug particles have a small particle size (D90 <30 μm), and no large particles with a particle size exceeding 50 μm were found; in the emulsion example E11 provided by the present disclosure without PVP-K30, a small amount of large particles with a particle size exceeding 100 μm were found; and in the dapsone hydrogel preparation R2, which also does not contain PVPPK30, a large number of large particles with particle sizes exceeding 50 μm and 100 μm were found.

[0222] The results in Figure 5 show that no crystal diffraction peaks appeared in the latex examples E2 and E15 containing PVP-K30 provided by the present disclosure, indicating that the drug particles in the preparations were small in size and well dispersed; a crystal diffraction peak appeared in the latex example E11 not containing PVP-K30 provided by the present disclosure, but the peak intensity was weak; and a strong dapsone crystal diffraction peak was found in the dapsone hydrogel preparation R2 not containing PVP-K30, indicating that the dapsone particles in the hydrogel were large in size and poorly dispersed.

[0223] Test Example 3: Skin touch test

[0224] Since the particle size of the particles in the topical preparation will affect the user experience of applying the product, the inventors of the present disclosure further investigated the skin feel of the latex examples E2, E11 and E15 and the hydrogel comparative example R2 of the present disclosure when applied.

[0225] The results show that: the latex examples E2 and E15 provided by the present disclosure containing PVP-K30 did not have a gritty feeling during application, and the latex example E11 not containing PVP-K30 had a slight gritty feeling; and the comparative example R2 of the dapsone hydrogel formulation not containing PVP-K30 had a significant gritty feeling during application.

[0226] It can be seen that the addition of PVP-K30 to the compound composition of adapalene and dapsone can inhibit the growth of drug particles, reduce the particle size, and reduce the gritty feeling produced during the application process.

[0227] Test Example 4: Stability Study

[0228] The latex provided by the present disclosure was subjected to a long-term (25±2°C / 60±5%RH) stability test, and the following indicators were examined: appearance, pH, PLM particle size, viscosity, HPLC content, and related substances. The results are shown in Tables 10-14.

[0229] Table 10

[0230] The results in Table 10 show that the properties and appearance of the latexes of Examples E2, E3 and E15 remained unchanged for 12 months when placed under 25±2°C / 60±5%RH, respectively, and the latexes had good stability.

[0231] Table 11

[0232] The results in Table 11 show that the pH of the latexes of Examples E2, E2 and E15 were kept at 25±2°C / 60±5%RH for 1 month without significant changes, indicating good stability.

[0233] Table 12

[0234] Viscosity determination method: Method 1: Test using a Brookfield viscometer with a TC (93) rotor, a rotation speed of 5 rpm, and a test time of 1 minute. Method 2: Test using a Brookfield viscometer with a TD (94) rotor, a rotation speed of 40 rpm, and a test time of 1 minute.

[0235] The results in Table 12 show that the viscosity of the latex of Example E15 remained essentially unchanged after being placed under 25±2°C / 60±5%RH for one month, indicating good stability.

[0236] Table 13

[0237] The results in Table 13 show that the particle size (D90) of the latex of Example E3 remains essentially unchanged after being placed under the conditions of 25±2°C / 60±5%RH for 6 months.

[0238] Table 14

[0239] Notes: [1] Percentage of the product's labeled amount; [2] Percentage of total impurities;

[0240] The results in Table 14 show that the latexes of Examples E2, E3 and E15 remained stable with respect to the active ingredient content and the content of related substances when placed under conditions of 25±2°C / 60±5%RH for 12 months, respectively.

[0241] In summary, the latex prepared in the present invention is a white latex. When placed under 25±2°C / 60±5%RH, its properties, pH, viscosity, drug particle size (D90), active ingredient content and related substance content can remain unchanged for at least 12 months. All quality indicators meet the product quality standards and have good stability.

[0242] In addition, the inventors of the present disclosure also studied the storage stability of the latex (Examples E2, E3 and E15) under 40±2°C / 75%±5%RH and 30±2°C / 65%±5%RH conditions, and also showed good stability.

[0243] Test Example 5: Comparative Study of Drug Efficacy

[0244] The rabbit ear acne model was used to compare the therapeutic effects of the latex of the present disclosure (Examples E15 and E16), the adapalene hydrogel of the prior art (Comparative Example R1), and the dapsone hydrogel (Comparative Example R2) on acne.

[0245] Test method:

[0246] Modeling: 2% coal tar was applied daily to a 2 cm x 2 cm area at the outlet of the right ear canal of New Zealand white rabbits (0.5-1 ml / rabbit) for 18 consecutive days. Starting on the eighth day, Propionibacterium acnes was injected intradermally into the right ear at 7-8 sites per rabbit, 30 μL / site, every other day for a total of 6 injections. Twenty-four hours after the last injection, all rabbit ears were photographed and observed, and the number of comedones, papules, and pustules was counted.

[0247] Grouping: The modeled animals were randomly divided into a model group, an Example E15 administration group, an Example E16 administration group, a Comparative Example R1 administration group, and a Comparative Example R2 administration group.

[0248] Drug administration: After grouping, drug administration was started. 0.4 mL / rabbit / day of the test drug was applied to the rabbit ear model for 2 consecutive weeks.

[0249] The numbers of comedones, papules and pustules in each group were counted before administration (Day 0), 11 days and 14 days after administration.

[0250] 24 hours after the last administration, the right ear was collected and fixed with 4% paraformaldehyde. The ears were routinely paraffin-embedded and sectioned. The pathological morphological changes of the ear tissues were observed under a light microscope using HE staining (including general observation indicators: keratin hyperplasia, thickening of the stratum spinosum, dilation of hair follicles, hyperplasia of sebaceous glands, inflammatory cell infiltration, and histological determination of experimental comedones).

[0251] The results are shown in Figures 6 and 7.

[0252] The results showed that after 11 and 14 days of administration, the rates of change of total skin lesions (acne + papules + pustules) and the rates of change of inflammatory skin lesions (papules + pustules) compared to the baseline of the emulsions of the present invention (Examples E15 and E16) were lower than those of the dapsone hydrogel (Comparative Example R2) and the adapalene hydrogel (Comparative Example R1), indicating that the therapeutic effects of the emulsions of the present invention on total acne lesions and inflammatory skin lesions are superior to those of the dapsone hydrogel and adapalene hydrogel of the prior art.

[0253] In addition, in terms of pathological structure, 14 days after administration, the latex of the present invention (Examples E15 and E16) was superior to the prior art dapsone hydrogel (Comparative Example R2) and adapalene hydrogel (Comparative Example R1) in improving hyperkeratosis of the rabbit ear epidermis, keratinized material filling, hair follicle expansion, sebaceous gland hyperplasia, and inflammatory cell infiltration.

[0254] Test Example 6: Toxicity Study

[0255] The toxicity of the emulsions Example E19 (0.15% adapalene and 6% dapsone compound emulsion) and Example E20 (0.30% adapalene / 12% dapsone compound emulsion) of the present disclosure was studied.

[0256] (1) Guinea pig active skin allergy test

[0257] Test method:

[0258] Grouping: British guinea pigs were randomly divided into a negative control group, a positive control group, a blank latex control group (without adapa and lindapsone, and the other components were the same as the drug-treated group), an Example E19 drug-treated group, and an Example E20 drug-treated group.

[0259] Dosage

[0260] Sensitization drug

[0261] Preparation before administration: Before administration, the skin on the left side of the guinea pig's back was removed with a skin preparation area of ​​approximately 5 cm × 5 cm.

[0262] On the 1st, 8th and 15th days of the experiment, the negative control group was given sterile water for injection percutaneously at 0.2 mL / animal, the positive control group was applied with 1% 1-chloro-2,4-dinitrobenzene at 0.2 mL / animal, and the remaining groups were given the corresponding test substance at 0.5 g / animal. The rats were covered with cellophane (approximately 4 cm × 4 cm) and gauze, sealed and fixed with medical tape for about 6 hours, and then the dressing was removed.

[0263] Provocative drug administration

[0264] Preparation before administration: Before administration, the skin on the right side of the guinea pig's back was removed, and the skin preparation area was approximately 5 cm × 5 cm;

[0265] On the 29th day of the experiment, the negative control group was given sterile water for injection percutaneously at 0.2 mL / animal, the positive control group was applied with 0.5% 1-chloro-2,4-dinitrobenzene at 0.2 mL / animal, and the remaining groups were given the corresponding test substance at 0.5 g / animal. The rats were covered with cellophane (approximately 4 cm × 4 cm) and gauze, sealed and fixed with medical tape for approximately 6 hours, and then the dressing was removed.

[0266] Observational scoring

[0267] Observation time: 1 hour (±30 minutes), 24 hours (±2 hours) after each sensitization and 1 hour (±30 minutes), 24 hours (±1 hour), 48 hours (±2 hours), and 72 hours (±2 hours) after each challenge.

[0268] Observed animals: All surviving guinea pigs in each group;

[0269] Observation Details: Observe and score the skin at the administration site. Calculate the total score for each side of the skin at each examination time point and the average score for each dose group. After challenge, observe the animal for systemic allergic reactions such as asthma, unsteadiness, or shock.

[0270] The results showed that, except for the positive drugs, no obvious skin and systemic allergic reactions occurred in the guinea pigs in each group, indicating that the latex agent disclosed herein is non-allergenic.

[0271] (2) Long-term toxicity study in miniature pigs

[0272] Test method:

[0273] Grouping: Bama miniature pigs were randomly divided into a blank control group, a blank latex control group (excluding adapalene and dapsone, and the other components were the same as the drug-administered group), an Example E19 drug-administered group, and an Example E20 drug-administered group.

[0274] Dosage

[0275] Apply transdermally on the back, once a day for 28 consecutive days;

[0276] Preparation before dosing: Before dosing, remove the fur from the back of the miniature pigs and prepare the skin. The preparation area should be slightly larger than the application area of ​​each animal. The frequency of skin preparation should be at least once a week. Before dosing, mark the application area with a marker and pay attention to the skin condition to avoid skin damage. Clean the application area with drinking water before dosing every 2 to 28 days. Dry the test area with gauze or a clean towel before dosing.

[0277] Dosing: Weigh the required amount of test article and apply it evenly to the depilated area on the back of miniature pigs. The dosage and application area of ​​each animal are calculated based on the most recent weight. Application area = dosage ÷ application volume.

[0278] The results showed that: during the administration period, the pigs in each group were in good condition, with normal autonomous activities, no death or dying, and no other obvious toxic symptoms; the irritation score of the administration site of the pigs in each group was 0 points, no abnormal manifestations such as erythema and edema were observed, and there was no irritation to the skin at the administration site; there were no obvious abnormal changes in the weight and food intake of the pigs in each group; at the end of the administration, there were no obvious abnormal changes in the hematological indicators such as WBC and various classification counts and percentages, RBC, HGB, HCT, MCV, MCH, MCHC, PLT, RET, RET%, APTT, PT, etc. of the pigs in each group; there were no obvious abnormal changes in the ALT, AST, ALP, LDH, GGT, UREA, No obvious abnormal changes were found in the blood biochemical indicators such as CREA, CHOL, TP, ALB, GLB, TG, TBIL, CK, GLU, A / G, K+, Na+, and Cl-; no obvious abnormal changes were found in the weights of the brain, liver, kidney, adrenal gland, heart, spleen, thyroid gland, thymus / parathyroid gland, epididymis, testis, ovary, uterus / cervix, and viscera-brain coefficients of the pigs in each group; gross dissection and naked eye observation of the remaining organs or tissues of the pigs in each group showed no abnormal changes in their size, shape, color, and texture related to the test article; no abnormal histopathological changes related to the test article were found in the skin and subcutaneous tissues of the pigs in each group at the administration site.

[0279] Test Example 7: User Experience Comparison

[0280] Comparison of the skin use experience of the latex provided by the present disclosure (Example E2) and the hydrogel of the prior art (Comparative Example R2)

[0281] Test method:

[0282] This study was conducted on 10-20 healthy subjects to evaluate functional and cosmetic properties. The test products (Example E2, Comparative Example R2) were identified by a blinded identification code, thereby preventing the subjects from knowing the identity of the applied test product. The subjects were randomly applied to their left and right arms. The age range of the subject population was between 20 and 40 years old.

[0283] The following properties were evaluated during and after application: ease of application, foreign body sensation during application, sticky sensation after application, odor, rate of absorption after application, drying time of the skin, skin feel after application, overall cosmetic preference and usability of the product.

[0284] The results showed that: all subjects said that the application experience of Example E2 and Comparative Example R2 was not much different, and generally reflected that Example E2 had the advantages of being easy to apply, having no foreign body feeling, being non-sticky, having no unpleasant odor, and being absorbed quickly.

Claims

1. A compound composition of adapalene and dapsone. Based on the total weight of the composition, the composition contains 1% - 15% of dapsone, 0.05% - 0.5% of adapalene, 0.25% - 20% of carboxylic acid ester-based oily solvent, 0.5% - 20% of polyoxyethylene-based nonionic surfactant, 5% - 50% of diethylene glycol monoethyl ether, and other pharmaceutically acceptable carriers.

2. The composition according to claim 1, characterized in that, Based on the total weight of the composition, the composition contains 0.25 - 15% of carboxylic acid ester-based oily solvent.

3. The composition according to claim 2, characterized in that, Based on the total weight of the composition, the composition contains 0.25 - 5% of carboxylic acid ester-based oily solvent.

4. The composition according to claim 3, wherein Based on the total weight of the composition, the composition contains 0.25 - 1% of carboxylic acid ester-based oily solvent.

5. The composition according to claim 1, characterized in that, The carboxylic acid ester-based oily solvent is selected from any one or a mixture of monocarboxylic acid esters, dicarboxylic acid esters, and tricarboxylic acid esters.

6. The composition according to claim 5, wherein The carboxylic acid ester-based oily solvent is a monocarboxylic acid ester-based oily solvent.

7. The composition according to claim 5 or 6, characterized in that, The monocarboxylic acid ester-based oily solvent is selected from any one or a mixture of propylene glycol monocaprylate and propylene glycol monolaurate.

8. The composition according to any one of claims 5 - 7, characterized in that, The carboxylic acid ester-based oily solvent is propylene glycol monocaprylate.

9. The composition according to claim 1, wherein Based on the total weight of the composition, the composition contains 0.5 - 15% of polyoxyethylene-based nonionic surfactant.

10. The composition according to claim 9, wherein Based on the total weight of the composition, the composition contains 0.5 - 10% of polyoxyethylene-based nonionic surfactant.

11. The composition according to claim 10, wherein Based on the total weight of the composition, the composition contains 0.5 - 5% of polyoxyethylene-based nonionic surfactant.

12. The composition according to claim 1, wherein The polyoxyethylene-based nonionic surfactant is selected from any one or a mixture of polyoxyethylene castor oil, fatty alcohol polyoxyethylene ether, polyol polyoxyethylene ether fatty acid ester, alkylphenol polyoxyethylene ether, fatty acid polyoxyethylene ester, and fatty amine polyoxyethylene ether.

13. The composition according to claim 12, wherein The polyoxyethylene-based nonionic surfactant is selected from polyoxyethylene castor oil.

14. The composition according to claim 13, wherein The polyoxyethylene-based nonionic surfactant is selected from any one or a mixture of polyoxyethylene 35 castor oil or polyoxyethylene 40 hydrogenated castor oil.

15. The composition according to claim 14, characterized in that, The polyoxyethylene-based nonionic surfactant is polyoxyethylene 35 castor oil.

16. The composition according to claim 1, wherein Based on the total weight of the composition, the composition contains 10% - 50% of diethylene glycol monoethyl ether.

17. The composition according to claim 16, wherein Based on the total weight of the composition, the composition contains 15% - 45% of diethylene glycol monoethyl ether.

18. The composition according to claim 17, wherein Based on the total weight of the composition, the composition contains 30% - 45% of diethylene glycol monoethyl ether.

19. The composition according to claim 1, wherein Based on the total weight of the composition, the composition contains 5% - 10% of dapsone and 0.1% - 0.3% of adapalene.

20. The composition according to claim 19, wherein Based on the total weight of the composition, the composition contains 7.5% of dapsone and 0.1% of adapalene.

21. The composition according to claim 19, wherein Based on the total weight of the composition, the composition contains 6% of dapsone and 0.1% of adapalene.

22. The composition according to claim 19, characterized in that, Based on the total weight of the composition, the composition contains 5% of dapsone and 0.1% of adapalene.

23. The composition according to claim 1, wherein In the composition, the mass ratio of the polyoxyethylene-based nonionic surfactant to the carboxylic acid ester-based oily solvent is ≥1:1 or >1:

1.

24. The composition according to claim 23, characterized in that, In the composition, the mass ratio of the polyoxyethylene-based nonionic surfactant to the carboxylic acid ester-based oily solvent is ≤3:

1.

25. The composition according to claim 1, wherein The other pharmaceutically acceptable carriers contain a crystallization inhibitor, and the composition contains 0.5%-4% of the crystallization inhibitor based on the total weight of the composition.

26. The composition according to claim 25, wherein The composition contains 1%-3% of the crystallization inhibitor based on the total weight of the composition.

27. The composition according to claim 25, characterized in that, The crystallization inhibitor is selected from any one or a combination of PVP, PVA, and HPC.

28. The composition according to claim 27, wherein The crystallization inhibitor is PVP.

29. The composition according to claim 28, wherein The PVP is PVP-K30.

30. The composition according to claim 1, characterized in that, The pharmaceutically acceptable carrier further contains a high molecular weight copolymer emulsifier, and the composition contains 0.05-6% of the high molecular weight copolymer emulsifier based on the total weight of the composition.

31. The composition according to claim 30, wherein The composition contains 0.05%-1% of the high molecular weight copolymer emulsifier based on the total weight of the composition.

32. The composition according to claim 31, wherein The composition contains 0.1%-0.5% of the high molecular weight copolymer emulsifier based on the total weight of the composition.

33. The composition according to claim 30, wherein The high molecular weight copolymer emulsifier is a carbomer copolymer.

34. The composition according to claim 33, wherein The carbomer copolymer is an acrylic acid (ester) / C10-30 alkanol acrylate cross-linked copolymer.

35. The composition according to claim 1, wherein The pharmaceutically acceptable carrier further contains a thickener, and the composition contains 0.1%-4% of the thickener based on the total weight of the composition.

36. The composition according to claim 35, characterized in that, The thickener is a combination of Sepineo P600 and carbomer 981.

37. The composition according to claim 36, wherein The composition contains 1%-3% of Sepineo P600 and 0.1%-1% of carbomer 981 respectively based on the total weight of the composition.

38. The composition according to claim 1, wherein The oil droplet size of the composition is ≤300 nm.

39. The composition according to claim 1, wherein The composition is a latex.

40. The composition according to claim 1, wherein The composition is an emulsion.

41. The composition according to claim 1, wherein The pharmaceutically acceptable carrier further contains any one or a combination selected from preservatives, antioxidants, chelating agents, and pH regulators.

42. The composition according to claim 41, characterized in that, The preservative is methyl paraben.

43. The composition according to claim 41, characterized in that, The antioxidant is dibutylhydroxytoluene.

44. The composition according to claim 41, characterized in that, The chelating agent is disodium edetate.

45. The composition according to claim 41, characterized in that, The pH regulator is sodium hydroxide.

46. The composition according to claim 1, wherein The pH range of the composition is between 5.0-7.

0. Preferably 5.0-6.5, more preferably 5.0-6.

0.

47. The method for preparing the composition according to any one of claims 1-46, characterized in that, The preparation method includes the following steps: 1) Prepare the oil phase: Add dapsone and adapalene to a mixed solution of a carboxylic acid ester-based oily solvent, a polyoxyethylene-based nonionic surfactant, and diethylene glycol monoethyl ether to form the oil phase; 2) Prepare the water phase: After uniformly dispersing the other pharmaceutically acceptable carriers in water and mixing evenly, form the water phase; or directly use water as the water phase; 3) Emulsify: Add the oil phase from step 1) to the water phase from step 2), adjust the pH to 5.0-6.0, mix evenly, and make up the water to 100%. Preferably, the other pharmaceutically acceptable carriers in step 2) are any one or a combination of a high molecular weight polymer emulsifier, a thickener, and a crystallization inhibitor. Preferably, the other pharmaceutically acceptable carriers in step 2) are a high molecular weight polymer emulsifier, a thickener, and a crystallization inhibitor. Preferably, the thickener can be added after adding the high molecular weight copolymer emulsifier in step 2). Preferably, the crystallization inhibitor can be added before adding the high molecular weight copolymer emulsifier in step 2). Preferably, any one or a combination of a penetration enhancer, an antioxidant, a preservative, and a chelating agent may also be added in the step 1) or / and 2).

48. Use of a compound composition of adapalene and dapsone in the preparation of a medicament for treating skin diseases.

49. The use according to claim 48, wherein, The skin diseases are selected from the group consisting of acne vulgaris, rosacea, acne rosacea, chronic wounds, pressure sores, keratosis, sebaceous cysts, post-inflammatory hyperpigmentation, eczema, xerosis, pruritus, lichen planus, dermatitis, atopic dermatitis, prurigo nodularis, and miliaria.

50. The use according to claim 48 or 49, characterized in that, The skin disease is acne vulgaris.

51. Use of a compound composition of adapalene and dapsone in the preparation of a topically administered pharmaceutical preparation.

52. The use according to claim 51, characterized in that, The topically administered pharmaceutical preparation is selected from the group consisting of lotions, latexes, or creams.

53. A method for treating a skin disease, which comprises administering a therapeutically effective amount of the compound composition of adapalene and dapsone according to any one of claims 1-46 to a subject in need thereof.

54. The treatment method according to claim 53, characterized in that, The skin diseases are selected from the group consisting of acne vulgaris, rosacea, acne rosacea, chronic wounds, pressure sores, keratosis, sebaceous cysts, post-inflammatory hyperpigmentation, eczema, xerosis, pruritus, lichen planus, dermatitis, atopic dermatitis, prurigo nodularis, and miliaria.

55. The treatment method according to claim 53 or 54, characterized in that, The skin disease is acne vulgaris.

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