Benvitimod nanoemulsion composition, pharmaceutical preparation containing the same, and preparation method and application thereof

Abstract

The present invention belongs to the field of pharmaceutical technology, and specifically relates to a bemotrizinol nanoemulsion composition, a pharmaceutical preparation containing the same, and a preparation method and application thereof. The nanoemulsion composition comprises bemotrizinol or a pharmaceutically acceptable salt thereof, an emulsifying component 1, an emulsifying component 2, an oil phase, and an aqueous phase, as well as an optional penetration enhancer, an antioxidant, an antibacterial agent, a chelating agent, a pH regulator, and a gelling agent. The nanoemulsion of the present invention is clear and transparent, has excellent physical stability and chemical stability, can improve the solubility of the drug, reduce skin irritation, and has a good drug release rate and skin permeability, can promote the continuous penetration of the drug through the stratum corneum, and can also effectively relieve the symptoms of inflammatory skin diseases and has an obvious improvement effect on skin damage.

Description

Technical Field

[0001] The present invention belongs to the field of pharmaceutical technology, and particularly relates to a benvitimod nanoemulsion composition, a pharmaceutical preparation containing the same, and a preparation method and application thereof. Background Art

[0002] Benvitimod (also known as benzene ethenemod) is a globally innovative new generation of non-hormonal small molecule chemical drug for the treatment of inflammatory and autoimmune diseases, with a CAS number of 79338-84-4 and a chemical name of 5-[(E)-2-styryl]-2-isopropyl-1,3-benzenediol or (E)-2-isopropyl-5-styrylbenzene-1,3-diol. Benvitimod was isolated from the metabolites of a symbiotic bacterium of a soil nematode and is the first therapeutic aryl hydrocarbon receptor modulating agent (TAMA). Pharmacological studies have shown that benvitimod can inhibit the activity of lymphocyte protein tyrosine kinase and has inhibitory effects on the release of inflammatory cytokines related to psoriasis, the migration and infiltration of inflammatory cells, the abnormal differentiation and proliferation of keratinocytes, the formation of new blood vessels, and vasodilation.

[0003] In 2019, benvitimod cream was approved for marketing in China for the topical treatment of mild to moderate stable plaque psoriasis in adults. In 2018, Dermavant Company obtained the R & D rights of benvitimod. In 2022, the US FDA officially approved the benvitimod cream developed by Dermavant Company for marketing for the treatment of plaque psoriasis in adults. And has different prescription compositions.

[0004] CN107666902A is a corresponding formulation patent for which discloses a benvitimod topical drug emulsion composition containing benvitimod, an oil phase, an aqueous phase, a surfactant, and an antioxidant, and the composition is formulated into a cream preparation. CN113797159A discloses a benvitimod cream which contains benvitimod, an oil-soluble matrix, a solvent, an emulsifier, a preservative, a pH regulator, water, and optionally a chelating agent and an antioxidant. However, the benvitimod preparations and marketed products disclosed in the above prior arts are all in cream dosage forms, with a thick texture, obvious greasiness, difficult to penetrate the hair cutin layer, low skin retention, and unfavorable for drug absorption and the continuous action of drug efficacy.

[0005] Nanoemulsion refers to a transparent or semi-transparent homogeneous dispersion system spontaneously formed by components such as emulsifying components (for example, it can be a single emulsifier or a combination of two or more emulsifiers, or a combination of at least one emulsifier and at least one co-emulsifier), oil phase and water phase. It is also called micro-emulsion, which has thermodynamic stability and kinetic stability, generally referring to a homogeneous dispersion system with an emulsion droplet particle size of 10 - 200 nm. Nanoemulsion preparations can increase the drug loading and stability, prolong the action time of the drug, and increase the bioavailability of the drug. Nanoemulsion can also promote some poorly soluble drugs or drugs with poor skin penetration ability to effectively penetrate the stratum corneum of the skin, enhance the transdermal penetration of the drug, and has broad application prospects in both local transdermal drug delivery and transdermal systemic drug delivery.

[0006] The emulsifying components in nanoemulsion play an important role in the interfacial stability of nanoemulsion. Emulsifiers can reduce the interfacial tension, form an interfacial film, promote the formation of nanoemulsion and maintain its dispersion and stability. The hydrophilic or lipophilic degree of emulsifiers can be judged according to the size of the hydrophilic-lipophilic balance value (HLB); conversely, the required emulsifier can also be screened according to the HLB value. Generally, a single emulsifier is difficult to reduce the interfacial tension to the required range, so a second emulsifier or co-emulsifier is often added to further stabilize the nanoemulsion. This second emulsifier or co-emulsifier can assist the first emulsifier to further reduce the interfacial tension, increase the fluidity of the interfacial film, adjust the overall HLB value of the emulsifying components, enable the nanoemulsion droplets to form spontaneously and enhance the strength of the emulsifying film, preventing the emulsion droplets from coalescing. The oil phase is an important component of nanoemulsion. The solubility of the drug in the oil phase determines the drug loading of nanoemulsion. The type and content of the oil phase can directly affect the phase-forming ability, solubilization effect and stability of the nanoemulsion system. Thus, the selection of emulsifying components and oil phase has an important impact on the formulation of nanoemulsion. In addition, factors such as the physicochemical properties, specifications, solubility, stability, etc. of API also have an important impact on the formulation of nanoemulsion. Therefore, a rigorous formulation screening is required to obtain a stable nanoemulsion.

[0007] CN103315958A discloses a bemotrizinol nanoemulsion and its preparation method. The nanoemulsion is made from an oil phase, an aqueous phase, a surfactant, a co-surfactant, and deionized water. The surfactant used is a compound surfactant with an HLB value of 13 - 14, and the particle size range of the prepared nanoemulsion is 10 - 50 nm. Moreover, this nanoemulsion uses two types of surfactants, Tween and Span, for compounding, and it is necessary to strictly control the weight ratios of the compound surfactant, the co-surfactant, and the oil phase. Otherwise, problems will occur in the emulsification area and particle size of the nanoemulsion, affecting the appearance and stability of the nanoemulsion. At the same time, this nanoemulsion is prepared by the PIT (phase inversion temperature) method, which requires controlling the temperature and stirring speed, and the process is complex, making it not conducive to large-scale industrialization.

[0008] The master's thesis "Research on Benvitimod Nanoemulsion" (Guo Peidong, Hebei University of Science and Technology, May 2017) discloses the screening experiment of the oil-in-water (O / W) benvitimod nanoemulsion formulation. Finally, it is determined to prepare the benvitimod nanoemulsion with EL40 as the surfactant, absolute ethanol as the co-surfactant, and pumpkin seed oil as the oil phase. This preparation uses ethanol as the co-surfactant, which is prone to cause skin irritation, increasing irritating adverse reactions such as skin erythema and itching, further affecting the compliance of patients. Moreover, the nanoemulsion containing ethanol is not easy to foam, which is not conducive to the further preparation of a stable foam agent.

[0009] Therefore, in view of the above-mentioned technical problems faced, there is an urgent need in the art to develop a stable bemotrizinol nanoemulsion that is particularly suitable for effectively penetrating the thick stratum corneum of the skin and is not prone to cause skin irritation, so as to promote drug absorption, improve the bioavailability of the drug, improve the compliance of patients, and maintain the stable and continuous action of the drug effect. Summary of the Invention

[0010] Problems to be Solved by the Invention

[0011] The present invention aims to provide a bemotrizinol nanoemulsion composition, a pharmaceutical preparation containing the same, and its preparation method and application. The bemotrizinol nanoemulsion of the present invention is easy to apply, has good stability, a fast onset time, has a greater skin penetration and skin retention amount than ordinary cream agents, and improves the bioavailability. At the same time, it has a light greasy feeling, small irritation, does not adhere to hair, does not cause itching, is simple and convenient for clinical use, and is particularly suitable for scalp psoriasis patients with skin lesions such as itching and desquamation, and can significantly improve the compliance of patients.

[0012] Solutions for Solving the Problems

[0013] In the first aspect, the present invention provides a nanoemulsion composition, which may comprise bemotrizinol or a pharmaceutically acceptable salt thereof, emulsifying component 1, emulsifying component 2, an oil phase, and an aqueous phase.

[0014] In one embodiment, the nanoemulsion composition of the present invention may comprise benvitimod, emulsifying component 1, emulsifying component 2, an oil phase, and an aqueous phase.

[0015] The nanoemulsion composition in the present invention can be an oil-in-water (O / W) nanoemulsion or a water-in-oil (W / O) nanoemulsion, preferably an oil-in-water (O / W) nanoemulsion.

[0016] In the nanoemulsion composition of the present invention, based on the total weight of the composition, the content of benvitimod or its pharmaceutically acceptable salt can be 0.1% - 5%, preferably 0.5% - 5%, more preferably 1% - 5%, further preferably 1% - 3%, and most preferably 1% - 2%.

[0017] In one embodiment, in the nanoemulsion composition of the present invention, based on the total weight of the composition, the content of benvitimod can be 0.1% - 5%, preferably 0.5% - 5%, more preferably 1% - 5%, further preferably 1% - 3%, and most preferably 1% - 2%.

[0018] In the nanoemulsion composition of the present invention, emulsifying component 1 can be a nonionic surfactant with an HLB value of 10 - 30. Nonionic surfactants do not dissociate in water, and their molecular structure includes a hydrophilic group and a lipophilic group. The hydrophilic group is formed by one or more of polyethylene glycol, polyhydric alcohols (such as sorbitol, glycerol, pentaerythritol, sucrose, glucose, etc.), and the lipophilic group is formed by one or more of fatty acids, fatty alcohols, phenols, or alkylphenols. The hydrophilic group and the lipophilic group are bonded by an ester bond or an ether bond. According to the different hydrophilic groups, nonionic surfactants can be divided into polyethylene glycol type (also known as polyoxyethylene type) and polyhydric alcohol type.

[0019] In one embodiment, emulsifying component 1 in the nanoemulsion composition of the present invention can be selected from one or more of polyoxyethylene type nonionic surfactants with an HLB value of 10 - 30 and polyhydric alcohol type nonionic surfactants with an HLB value of 10 - 30.

[0020] In one embodiment, emulsifying component 1 in the nanoemulsion composition of the present invention can be selected from one or more of polyoxyethylene type nonionic surfactants with an HLB value of 10 - 30.

[0021] In one embodiment, emulsifying component 1 in the nanoemulsion composition of the present invention can be selected from one or more of polyoxyethylene castor oil derivatives, polyethylene glycol vitamin E succinate, polyoxyethylene fatty alcohol ethers, polyoxyethylene fatty acid esters, poloxamers, tweens, and sucrose fatty acid esters.

[0022] In one embodiment, the emulsifying component 1 in the nanoemulsion composition of the present invention may be selected from one or more of Tween, polyoxyethylene castor oil derivatives, and polyethylene glycol vitamin E succinate.

[0023] In one embodiment, the emulsifying component 1 in the nanoemulsion composition of the present invention may be selected from one or more of polyoxyethylene castor oil derivatives and polyethylene glycol vitamin E succinate.

[0024] In one embodiment, the emulsifying component 1 in the nanoemulsion composition of the present invention may be selected from one or more of polyoxyethylene castor oil derivatives with an HLB value of 10 - 30 and polyethylene glycol vitamin E succinate.

[0025] In one embodiment, the emulsifying component 1 in the nanoemulsion composition of the present invention may be selected from one or more of polyoxyethylene castor oil derivatives with 30 - 60 polyoxyethylene units and polyethylene glycol vitamin E succinate with an average molecular weight of 500 - 2000.

[0026] In one embodiment, the emulsifying component 1 in the nanoemulsion composition of the present invention may be selected from one or more of polyoxyethylene castor oil derivatives with 30 - 50 polyoxyethylene units and polyethylene glycol vitamin E succinate with an average molecular weight of 500 - 1500.

[0027] In one embodiment, the emulsifying component 1 in the nanoemulsion composition of the present invention may be selected from one or more of polyoxyethylene castor oil derivatives with 30 - 40 polyoxyethylene units and polyethylene glycol vitamin E succinate with an average molecular weight of 800 - 1200.

[0028] In one embodiment, the emulsifying component 1 in the nanoemulsion composition of the present invention may be selected from one or more of polyoxyethylene castor oil with 30 - 60 polyoxyethylene units, polyoxyethylene hydrogenated castor oil with 30 - 60 polyoxyethylene units, and polyethylene glycol vitamin E succinate with an average molecular weight of 500 - 2000.

[0029] In one embodiment, the emulsifying component 1 in the nanoemulsion composition of the present invention may be selected from one or more of polyoxyethylene castor oil with 30 - 50 polyoxyethylene units, polyoxyethylene hydrogenated castor oil with 30 - 50 polyoxyethylene units, and polyethylene glycol vitamin E succinate with an average molecular weight of 500 - 1500.

[0030] In one embodiment, the emulsifying component 1 in the nanoemulsion composition of the present invention may be selected from one or more of polyoxyethylene castor oil with 30 - 40 units of polyoxyethylene, polyoxyethylene hydrogenated castor oil with 30 - 40 units of polyoxyethylene, and polyethylene glycol vitamin E succinate with an average molecular weight of 800 - 1200.

[0031] In one embodiment, the emulsifying component 1 in the nanoemulsion composition of the present invention may be selected from one or more of polyoxyethylene 35 castor oil, polyoxyethylene 40 hydrogenated castor oil, and polyethylene glycol vitamin E succinate 1000.

[0032] In the nanoemulsion composition of the present invention, based on the total weight of the composition, the content of the emulsifying component 1 may be 5% - 30%, preferably 10% - 25%, more preferably 10% - 20%, and most preferably 12% - 20%.

[0033] In the nanoemulsion composition of the present invention, the emulsifying component 2 may be selected from one or more of short-chain alcohols having 2 - 6 carbon atoms or their fatty alcohol ethers or fatty acid esters, polyethylene glycol glycerides, and polyethylene glycols.

[0034] In one embodiment, the emulsifying component 2 in the nanoemulsion composition of the present invention may be selected from one or more of monohydric alcohols having 2 - 6 carbon atoms or their fatty alcohol ethers or fatty acid esters, polyhydric alcohols having 2 - 6 carbon atoms or their fatty alcohol ethers or fatty acid esters, polyethylene glycol glycerides, and polyethylene glycols.

[0035] In one embodiment, the emulsifying component 2 in the nanoemulsion composition of the present invention may be selected from one or more of polyhydric alcohols having 2 - 6 carbon atoms or their fatty alcohol ethers or fatty acid esters, polyethylene glycol glycerides, and polyethylene glycols.

[0036] In one embodiment, the emulsifying component 2 in the nanoemulsion composition of the present invention may be selected from one or more of polyhydric alcohols having 2 - 6 carbon atoms or their fatty alcohol ethers, polyethylene glycol glycerides, and polyethylene glycols.

[0037] In one embodiment, the emulsifying component 2 in the nanoemulsion composition of the present invention may be selected from one or more of polyhydric alcohols having 2 - 6 carbon atoms or their fatty alcohol ethers, polyethylene glycol glycerides, and polyethylene glycols with an average molecular weight of 200 - 400.

[0038] In one embodiment, the monohydric alcohol having 2 - 6 carbon atoms or its fatty alcohol ether or fatty acid ester may be selected from one or more of ethanol and n-butanol.

[0039] In one embodiment, the polyol having 2 to 6 carbon atoms or its fatty alcohol ether or fatty acid ester may be selected from one or more of propylene glycol, butylene glycol, pentylene glycol, glycerol, diethylene glycol monoethyl ether, propylene glycol monolaurate, propylene glycol monocaprylate, and glycerol monocaprylate, preferably propylene glycol or diethylene glycol monoethyl ether.

[0040] In one embodiment, the polyol having 2 to 6 carbon atoms or its fatty alcohol ether may be selected from one or more of propylene glycol, butylene glycol, pentylene glycol, glycerol, and diethylene glycol monoethyl ether, preferably propylene glycol or diethylene glycol monoethyl ether.

[0041] In one embodiment, the polyethylene glycol glyceride may be selected from one or more of polyethylene glycol glyceride caprylate / caprate, polyethylene glycol glyceride lauroyl, polyethylene glycol glyceride linoleyl, polyethylene glycol glyceride oleyl, polyethylene glycol glyceride stearoyl, and polyethylene glycol glyceride caprate, preferably polyethylene glycol glyceride caprylate / caprate.

[0042] In one embodiment, the polyethylene glycol of the present invention may be polyethylene glycol with an average molecular weight of 200 to 400.

[0043] In one embodiment, the polyethylene glycol may be selected from one or more of polyethylene glycol 200, polyethylene glycol 300, and polyethylene glycol 400, preferably polyethylene glycol 400.

[0044] In one embodiment, the emulsifying component 2 in the nanoemulsion composition of the present invention may be selected from one or more of polyethylene glycol glyceride caprylate / caprate, propylene glycol, diethylene glycol monoethyl ether, and polyethylene glycol 400.

[0045] In one embodiment, the emulsifying component 2 in the nanoemulsion composition of the present invention may be selected from one or more of polyethylene glycol glyceride caprylate / caprate, diethylene glycol monoethyl ether, and polyethylene glycol 400.

[0046] In one embodiment, the emulsifying component 2 in the nanoemulsion composition of the present invention may be selected from one or more of polyethylene glycol glyceride caprylate / caprate and diethylene glycol monoethyl ether.

[0047] In the nanoemulsion composition of the present invention, based on the total weight of the composition, the content of the emulsifying component 2 may be 3% - 25%, preferably 3% - 20%, more preferably 5 - 20%, and most preferably 5 - 12%.

[0048] In one embodiment, when the emulsifying component 1 is polyoxyethylene hydrogenated castor oil with 30 to 60 ethylene oxide units, the emulsifying component 2 is not a polyol having 2 to 6 carbon atoms and / or polyethylene glycol.

[0049] In one embodiment, when the emulsifying component 1 is polyoxyethylene hydrogenated castor oil with 30 - 50 polyoxyethylene units, the emulsifying component 2 is not a polyhydric alcohol and / or polyethylene glycol containing 2 - 6 carbon atoms.

[0050] In one embodiment, when the emulsifying component 1 is polyoxyethylene hydrogenated castor oil with 30 - 40 polyoxyethylene units, the emulsifying component 2 is not a polyhydric alcohol and / or polyethylene glycol containing 2 - 6 carbon atoms.

[0051] In one embodiment, when the emulsifying component 1 is polyoxyethylene 40 hydrogenated castor oil, the emulsifying component 2 is not a polyhydric alcohol and / or polyethylene glycol containing 2 - 6 carbon atoms.

[0052] In one embodiment, the polyhydric alcohol containing 2 - 6 carbon atoms described above may be propylene glycol.

[0053] In one embodiment, the polyethylene glycol described above may be polyethylene glycol with an average molecular weight of 200 - 400, such as polyethylene glycol 400.

[0054] In one embodiment, when the emulsifying component 1 in the nanoemulsion composition of the present invention is polyoxyethylene hydrogenated castor oil with 30 - 60 polyoxyethylene units, the emulsifying component 2 is not propylene glycol and / or polyethylene glycol 400.

[0055] In one embodiment, when the emulsifying component 1 in the nanoemulsion composition of the present invention is polyoxyethylene hydrogenated castor oil with 30 - 50 polyoxyethylene units, the emulsifying component 2 is not propylene glycol and / or polyethylene glycol 400.

[0056] In one embodiment, when the emulsifying component 1 in the nanoemulsion composition of the present invention is polyoxyethylene hydrogenated castor oil with 30 - 40 polyoxyethylene units, the emulsifying component 2 is not propylene glycol and / or polyethylene glycol 400.

[0057] In one embodiment, when the emulsifying component 1 in the nanoemulsion composition of the present invention is polyoxyethylene 40 hydrogenated castor oil, the emulsifying component 2 is not propylene glycol and / or polyethylene glycol 400.

[0058] In one embodiment, the emulsifying component 1 is selected from one or more of polyoxyethylene castor oil with 30 - 60 units of polyoxyethylene, polyoxyethylene hydrogenated castor oil with 30 - 60 units of polyoxyethylene, and polyethylene glycol vitamin E succinate with an average molecular weight of 500 - 2000. The emulsifying component 2 is selected from one or more of monohydric alcohols having 2 - 6 carbon atoms or their fatty alcohol ethers or fatty acid esters, polyhydric alcohols having 2 - 6 carbon atoms or their fatty alcohol ethers or fatty acid esters, polyethylene glycol glycerol esters, and polyethylene glycol with an average molecular weight of 200 - 400, preferably one or more of polyhydric alcohols having 2 - 6 carbon atoms or their fatty alcohol ethers or fatty acid esters, polyethylene glycol glycerol esters, and polyethylene glycol with an average molecular weight of 200 - 400.

[0059] In one embodiment, the emulsifying component 1 is selected from one or more of polyoxyethylene castor oil with 30 - 50 units of polyoxyethylene, polyoxyethylene hydrogenated castor oil with 30 - 50 units of polyoxyethylene, and polyethylene glycol vitamin E succinate with an average molecular weight of 500 - 1500. The emulsifying component 2 is selected from one or more of monohydric alcohols having 2 - 6 carbon atoms or their fatty alcohol ethers or fatty acid esters, polyhydric alcohols having 2 - 6 carbon atoms or their fatty alcohol ethers or fatty acid esters, polyethylene glycol glycerol esters, and polyethylene glycol with an average molecular weight of 200 - 400, preferably one or more of polyhydric alcohols having 2 - 6 carbon atoms or their fatty alcohol ethers or fatty acid esters, polyethylene glycol glycerol esters, and polyethylene glycol with an average molecular weight of 200 - 400.

[0060] In one embodiment, the emulsifying component 1 is selected from one or more of polyoxyethylene castor oil with 30 - 40 units of polyoxyethylene, polyoxyethylene hydrogenated castor oil with 30 - 40 units of polyoxyethylene, and polyethylene glycol vitamin E succinate with an average molecular weight of 800 - 1200. The emulsifying component 2 is selected from one or more of monohydric alcohols having 2 - 6 carbon atoms or their fatty alcohol ethers or fatty acid esters, polyhydric alcohols having 2 - 6 carbon atoms or their fatty alcohol ethers or fatty acid esters, polyethylene glycol glycerol esters, and polyethylene glycol with an average molecular weight of 200 - 400, preferably one or more of polyhydric alcohols having 2 - 6 carbon atoms or their fatty alcohol ethers or fatty acid esters, polyethylene glycol glycerol esters, and polyethylene glycol with an average molecular weight of 200 - 400.

[0061] In one embodiment, the emulsifying component 1 is selected from one or more of polyoxyethylene 35 castor oil, polyoxyethylene 40 hydrogenated castor oil, and polyethylene glycol 1000 vitamin E succinate, and the emulsifying component 2 is selected from one or more of a monohydric alcohol having 2 to 6 carbon atoms or its fatty alcohol ether or fatty acid ester, a polyhydric alcohol having 2 to 6 carbon atoms or its fatty alcohol ether or fatty acid ester, polyethylene glycol glyceride, and polyethylene glycol having an average molecular weight of 200 to 400, preferably one or more of a polyhydric alcohol having 2 to 6 carbon atoms or its fatty alcohol ether or fatty acid ester, polyethylene glycol glyceride, and polyethylene glycol having an average molecular weight of 200 to 400.

[0062] In one embodiment, the emulsifying component 1 is selected from one or more of polyoxyethylene 35 castor oil, polyoxyethylene 40 hydrogenated castor oil, and polyethylene glycol 1000 vitamin E succinate, and the emulsifying component 2 is selected from one or more of a monohydric alcohol having 2 to 6 carbon atoms or its fatty alcohol ether or fatty acid ester, a polyhydric alcohol having 2 to 6 carbon atoms or its fatty alcohol ether or fatty acid ester, polyethylene glycol glyceride, and polyethylene glycol having an average molecular weight of 200 to 400, preferably one or more of a polyhydric alcohol having 2 to 6 carbon atoms or its fatty alcohol ether or fatty acid ester, polyethylene glycol glyceride, and polyethylene glycol having an average molecular weight of 200 to 400.

[0063] In one embodiment, the emulsifying component 1 is selected from one or more of polyoxyethylene 35 castor oil, polyoxyethylene 40 hydrogenated castor oil, and polyethylene glycol 1000 vitamin E succinate, and the emulsifying component 2 is selected from one or more of a polyhydric alcohol having 2 to 6 carbon atoms or its fatty alcohol ether, polyethylene glycol glyceride, and polyethylene glycol having an average molecular weight of 200 to 400.

[0064] In one embodiment, the emulsifying component 1 is selected from one or more of polyoxyethylene 35 castor oil, polyoxyethylene 40 hydrogenated castor oil, and polyethylene glycol 1000 vitamin E succinate, and the emulsifying component 2 is selected from one or more of a fatty alcohol ether of a polyhydric alcohol having 2 to 6 carbon atoms, polyethylene glycol glyceride, and polyethylene glycol having an average molecular weight of 200 to 400.

[0065] In one embodiment, the emulsifying component 1 is selected from one or more of polyoxyethylene 35 castor oil, polyoxyethylene 40 hydrogenated castor oil, and polyethylene glycol 1000 vitamin E succinate, and the emulsifying component 2 is selected from one or more of polyethylene glycol 400, polyethylene glycol glyceride caprylic / capric acid, and diethylene glycol monoethyl ether.

[0066] In one embodiment, the emulsifying component 1 is selected from one or more of polyoxyethylene 35 castor oil, polyoxyethylene 40 hydrogenated castor oil, and polyethylene glycol 1000 vitamin E succinate, and the emulsifying component 2 is selected from one or more of polyethylene glycol glycerol caprylate / caprate and diethylene glycol monoethyl ether.

[0067] In one embodiment, when the emulsifying component 1 is polyoxyethylene castor oil with 30 - 60 ethylene oxide units, the emulsifying component 2 can be selected from one or more of polyols having 2 - 6 carbon atoms or their fatty alcohol ethers, polyethylene glycol glycerol esters, and polyethylene glycols with an average molecular weight of 200 - 400, preferably one or more of fatty alcohol ethers of polyols having 2 - 6 carbon atoms, polyethylene glycol glycerol esters, and polyethylene glycols with an average molecular weight of 200 - 400, and most preferably one or more of polyethylene glycol 400, polyethylene glycol glycerol caprylate / caprate, and diethylene glycol monoethyl ether.

[0068] In one embodiment, when the emulsifying component 1 is polyoxyethylene castor oil with 30 - 50 ethylene oxide units, the emulsifying component 2 can be selected from one or more of polyols having 2 - 6 carbon atoms or their fatty alcohol ethers, polyethylene glycol glycerol esters, and polyethylene glycols with an average molecular weight of 200 - 400, preferably one or more of fatty alcohol ethers of polyols having 2 - 6 carbon atoms, polyethylene glycol glycerol esters, and polyethylene glycols with an average molecular weight of 200 - 400, and most preferably one or more of polyethylene glycol 400, polyethylene glycol glycerol caprylate / caprate, and diethylene glycol monoethyl ether.

[0069] In one embodiment, when the emulsifying component 1 is polyoxyethylene castor oil with 30 - 40 ethylene oxide units, the emulsifying component 2 can be selected from one or more of polyols having 2 - 6 carbon atoms or their fatty alcohol ethers, polyethylene glycol glycerol esters, and polyethylene glycols with an average molecular weight of 200 - 400, preferably one or more of fatty alcohol ethers of polyols having 2 - 6 carbon atoms, polyethylene glycol glycerol esters, and polyethylene glycols with an average molecular weight of 200 - 400, and most preferably one or more of polyethylene glycol 400, polyethylene glycol glycerol caprylate / caprate, and diethylene glycol monoethyl ether.

[0070] In one embodiment, the emulsifying component 1 in the nanoemulsion composition of the present invention can be polyoxyethylene 35 castor oil, and the emulsifying component 2 can be selected from one or more of monohydric alcohols having 2 - 6 carbon atoms or their fatty alcohol ethers or fatty acid esters, polyols having 2 - 6 carbon atoms or their fatty alcohol ethers or fatty acid esters, polyethylene glycol glycerol esters, and polyethylene glycols with an average molecular weight of 200 - 400.

[0071] In one embodiment, the emulsifying component 1 in the nanoemulsion composition of the present invention may be polyoxyethylene 35 castor oil, and the emulsifying component 2 may be selected from one or more of polyols having 2 to 6 carbon atoms or their fatty alcohol ethers or fatty acid esters, polyethylene glycol glycerol esters, and polyethylene glycols having an average molecular weight of 200 to 400.

[0072] In one embodiment, the emulsifying component 1 in the nanoemulsion composition of the present invention may be polyoxyethylene 35 castor oil, and the emulsifying component 2 may be selected from one or more of polyols having 2 to 6 carbon atoms or their fatty alcohol ethers, polyethylene glycol glycerol esters, and polyethylene glycols having an average molecular weight of 200 to 400.

[0073] In one embodiment, the emulsifying component 1 in the nanoemulsion composition of the present invention may be polyoxyethylene 35 castor oil, and the emulsifying component 2 may be selected from one or more of fatty alcohol ethers of polyols having 2 to 6 carbon atoms, polyethylene glycol glycerol esters, and polyethylene glycols having an average molecular weight of 200 to 400.

[0074] In one embodiment, the emulsifying component 1 in the nanoemulsion composition of the present invention may be polyoxyethylene 35 castor oil, and the emulsifying component 2 may be selected from one or more of polyethylene glycol glycerol caprylate / caprate, diethylene glycol monoethyl ether, and polyethylene glycol 400.

[0075] In one embodiment, when the emulsifying component 1 is polyoxyethylene hydrogenated castor oil with 30 to 60 polyoxyethylene units, the emulsifying component 2 may be selected from one or more of fatty alcohol ethers of polyols having 2 to 6 carbon atoms and polyethylene glycol glycerol esters, preferably one or more of polyethylene glycol glycerol caprylate / caprate and diethylene glycol monoethyl ether.

[0076] In one embodiment, when the emulsifying component 1 is polyoxyethylene hydrogenated castor oil with 30 to 50 polyoxyethylene units, the emulsifying component 2 may be selected from one or more of fatty alcohol ethers of polyols having 2 to 6 carbon atoms and polyethylene glycol glycerol esters, preferably one or more of polyethylene glycol glycerol caprylate / caprate and diethylene glycol monoethyl ether.

[0077] In one embodiment, when the emulsifying component 1 is polyoxyethylene hydrogenated castor oil with 30 to 40 polyoxyethylene units, the emulsifying component 2 may be selected from one or more of fatty alcohol ethers of polyols having 2 to 6 carbon atoms and polyethylene glycol glycerol esters, preferably one or more of polyethylene glycol glycerol caprylate / caprate and diethylene glycol monoethyl ether.

[0078] In one embodiment, the emulsifying component 1 in the nanoemulsion composition of the present invention may be polyoxyl 40 hydrogenated castor oil, and the emulsifying component 2 may be selected from one or more of monohydric alcohols having 2-6 carbon atoms or their fatty alcohol ethers or fatty acid esters, fatty alcohol ethers or fatty acid esters of polyhydric alcohols having 2-6 carbon atoms, and polyethylene glycol glycerol esters.

[0079] In one embodiment, the emulsifying component 1 in the nanoemulsion composition of the present invention may be polyoxyl 40 hydrogenated castor oil, and the emulsifying component 2 may be selected from one or more of fatty alcohol ethers or fatty acid esters of polyhydric alcohols having 2-6 carbon atoms and polyethylene glycol glycerol esters.

[0080] In one embodiment, the emulsifying component 1 in the nanoemulsion composition of the present invention may be polyoxyl 40 hydrogenated castor oil, and the emulsifying component 2 may be selected from one or more of fatty alcohol ethers of polyhydric alcohols having 2-6 carbon atoms and polyethylene glycol glycerol esters.

[0081] In one embodiment, the emulsifying component 1 in the nanoemulsion composition of the present invention may be polyoxyl 40 hydrogenated castor oil, and the emulsifying component 2 may be selected from one or more of polyethylene glycol glycerol caprylate / caprate and diethylene glycol monoethyl ether.

[0082] In one embodiment, when the emulsifying component 1 is polyethylene glycol vitamin E succinate with an average molecular weight of 500-2000, the emulsifying component 2 may be selected from one or more of fatty alcohol ethers of polyhydric alcohols having 2-6 carbon atoms and polyethylene glycol glycerol esters, preferably one or more of polyethylene glycol glycerol caprylate / caprate and diethylene glycol monoethyl ether, and most preferably polyethylene glycol glycerol caprylate / caprate and diethylene glycol monoethyl ether.

[0083] In one embodiment, when the emulsifying component 1 is polyethylene glycol vitamin E succinate with an average molecular weight of 500-1500, the emulsifying component 2 may be selected from one or more of fatty alcohol ethers of polyhydric alcohols having 2-6 carbon atoms and polyethylene glycol glycerol esters, preferably one or more of polyethylene glycol glycerol caprylate / caprate and diethylene glycol monoethyl ether, and most preferably polyethylene glycol glycerol caprylate / caprate and diethylene glycol monoethyl ether.

[0084] In one embodiment, when the emulsifying component 1 is polyethylene glycol vitamin E succinate with an average molecular weight of 800-1200, the emulsifying component 2 may be selected from one or more of fatty alcohol ethers of polyhydric alcohols having 2-6 carbon atoms and polyethylene glycol glycerol esters, preferably one or more of polyethylene glycol glycerol caprylate / caprate and diethylene glycol monoethyl ether, and most preferably polyethylene glycol glycerol caprylate / caprate and diethylene glycol monoethyl ether.

[0085] In one embodiment, the emulsifying component 1 in the nanoemulsion composition of the present invention can be polyethylene glycol 1000 vitamin E succinate, and the emulsifying component 2 can be selected from one or more of monohydric alcohols containing 2 to 6 carbon atoms or their fatty alcohol ethers or fatty acid esters, polyhydric alcohols containing 2 to 6 carbon atoms or their fatty alcohol ethers or fatty acid esters, polyethylene glycol glycerol esters, and polyethylene glycols with an average molecular weight of 200 to 400.

[0086] In one embodiment, the emulsifying component 1 in the nanoemulsion composition of the present invention can be polyethylene glycol 1000 vitamin E succinate, and the emulsifying component 2 can be selected from one or more of polyhydric alcohols containing 2 to 6 carbon atoms or their fatty alcohol ethers or fatty acid esters, polyethylene glycol glycerol esters, and polyethylene glycols with an average molecular weight of 200 to 400.

[0087] In one embodiment, the emulsifying component 1 in the nanoemulsion composition of the present invention can be polyethylene glycol 1000 vitamin E succinate, and the emulsifying component 2 can be selected from one or more of polyhydric alcohols containing 2 to 6 carbon atoms or their fatty alcohol ethers or fatty acid esters and polyethylene glycol glycerol esters.

[0088] In one embodiment, the emulsifying component 1 in the nanoemulsion composition of the present invention can be polyethylene glycol 1000 vitamin E succinate, and the emulsifying component 2 can be selected from one or more of polyhydric alcohols containing 2 to 6 carbon atoms or their fatty alcohol ethers and polyethylene glycol glycerol esters.

[0089] In one embodiment, the emulsifying component 1 in the nanoemulsion composition of the present invention can be polyethylene glycol 1000 vitamin E succinate, and the emulsifying component 2 can be selected from one or more of fatty alcohol ethers of polyhydric alcohols containing 2 to 6 carbon atoms and polyethylene glycol glycerol esters.

[0090] In one embodiment, the emulsifying component 1 in the nanoemulsion composition of the present invention can be polyethylene glycol 1000 vitamin E succinate, and the emulsifying component 2 can be selected from one or more of polyethylene glycol glycerol caprylic / capric acid esters and diethylene glycol monoethyl ether.

[0091] In one embodiment, the emulsifying component 1 in the nanoemulsion composition of the present invention can be polyethylene glycol 1000 vitamin E succinate, and the emulsifying component 2 can be selected from polyethylene glycol glycerol caprylic / capric acid esters and diethylene glycol monoethyl ether.

[0092] In one embodiment, the emulsifying component 1 in the nanoemulsion composition of the present invention can be polyoxyethylene 35 castor oil, and the emulsifying component 2 can be polyethylene glycol glycerol caprylic / capric acid esters.

[0093] In one embodiment, the emulsifying component 1 in the nanoemulsion composition of the present invention may be polyoxyl 35 castor oil, and the emulsifying component 2 may be polyethylene glycol 400.

[0094] In one embodiment, the emulsifying component 1 in the nanoemulsion composition of the present invention may be polyoxyl 35 castor oil, and the emulsifying component 2 may be diethylene glycol monoethyl ether.

[0095] In one embodiment, the emulsifying component 1 in the nanoemulsion composition of the present invention may be polyethylene glycol 1000 vitamin E succinate, and the emulsifying component 2 may be polyethylene glycol glycerol caprylate / caprate and diethylene glycol monoethyl ether.

[0096] In one embodiment, the emulsifying component 1 in the nanoemulsion composition of the present invention may be polyoxyl 40 hydrogenated castor oil, and the emulsifying component 2 may be polyethylene glycol glycerol caprylate / caprate.

[0097] In one embodiment, the emulsifying component 1 in the nanoemulsion composition of the present invention may be polyoxyl 40 hydrogenated castor oil, and the emulsifying component 2 may be diethylene glycol monoethyl ether.

[0098] In the nanoemulsion composition of the present invention, the oil phase may be selected from one or more of liquid vegetable oils, liquid mineral oils, liquid fatty acids, liquid fatty alcohols, and liquid fatty acid esters.

[0099] Preferably, the liquid vegetable oil may be selected from one or more of corn oil, peanut oil, olive oil, soybean oil, sesame oil, peppermint oil, and clove oil.

[0100] Preferably, the liquid mineral oil may be selected from one or more of liquid paraffin and light liquid paraffin.

[0101] Preferably, the liquid fatty acid may be selected from one or more of oleic acid, linoleic acid, linolenic acid, myristic acid, lauric acid, and ricinoleic acid.

[0102] Preferably, the liquid fatty alcohol may be selected from one or more of oleyl alcohol, octanol, decanol, octyldecanol, lauryl alcohol, and octyldodecanol.

[0103] Preferably, the liquid fatty acid ester may be selected from one or more of liquid fatty acid monohydric alcohol esters, liquid fatty acid dihydric alcohol esters, and liquid fatty acid glycerol esters.

[0104] More preferably, the liquid fatty acid monohydric alcohol ester may be selected from one or more of ethyl oleate, isopropyl myristate, isopropyl palmitate, diisopropyl oxalate, isopropyl stearate, and isopropyl laurate.

[0105] More preferably, the liquid fatty acid diol ester may be selected from one or more of propylene glycol dicaprylate / dicaprate (also known as propylene glycol dioctanoate / didecanoate) and propylene glycol monocaprylate.

[0106] More preferably, the liquid fatty acid glyceride may be selected from one or more of glycerol monooleate, glycerol monolinoleate, medium-chain triglycerides, caprylic / capric acid mono- and diglycerides, and oleoyl polyoxyethylene glycerol ester (also known as oleoyl polyethyleneglycol glycerol ester).

[0107] In one embodiment, the oil phase in the nanoemulsion composition of the present invention may be a liquid fatty acid ester.

[0108] In one embodiment, the oil phase in the nanoemulsion composition of the present invention may be selected from one or more of liquid fatty acid monoalcohol esters, liquid fatty acid diol esters, and liquid fatty acid glycerides.

[0109] In one embodiment, the oil phase in the nanoemulsion composition of the present invention may be selected from one or more of liquid fatty acid diol esters and liquid fatty acid glycerides.

[0110] In one embodiment, the oil phase in the nanoemulsion composition of the present invention may be selected from one or more of medium-chain triglycerides, caprylic / capric acid mono- and diglycerides, isopropyl myristate, oleoyl polyoxyethylene glycerol ester, diisopropyl oxalate, ethyl oleate, and propylene glycol monocaprylate.

[0111] In one embodiment, the oil phase in the nanoemulsion composition of the present invention may be selected from one or more of medium-chain triglycerides, caprylic / capric acid mono- and diglycerides, oleoyl polyoxyethylene glycerol ester, and propylene glycol monocaprylate.

[0112] In the nanoemulsion composition of the present invention, based on the total weight of the composition, the content of the oil phase may be 1% - 25%, preferably 3% - 20%, more preferably 3% - 15%, and most preferably 4% - 8%.

[0113] In one embodiment, the oil phase in the nanoemulsion composition of the present invention may be a mixed oil phase.

[0114] In one embodiment, the oil phase in the nanoemulsion composition of the present invention may be selected from any combination of two of medium-chain triglycerides, caprylic / capric acid mono- and diglycerides, oleoyl polyoxyethylene glycerol ester, and propylene glycol monocaprylate.

[0115] In a specific embodiment, the oil phase in the nanoemulsion composition of the present invention can be a combination of medium-chain triglycerides and polyoxyethylene glyceryl oleate, a combination of medium-chain triglycerides and propylene glycol monocaprylate, a combination of medium-chain triglycerides and caprylic / capric glycerides, a combination of caprylic / capric glycerides and polyoxyethylene glyceryl oleate, a combination of caprylic / capric glycerides and propylene glycol monocaprylate, or a combination of polyoxyethylene glyceryl oleate and propylene glycol monocaprylate.

[0116] In a specific embodiment, the oil phase in the nanoemulsion composition of the present invention can be a mixed oil phase of medium-chain triglycerides and polyoxyethylene glyceryl oleate. The weight ratio of the medium-chain triglycerides in the mixed oil phase can be 10% - 90%, preferably 20% - 80%, more preferably 20% - 70%, and most preferably 40% - 60%.

[0117] In a specific embodiment, the oil phase in the nanoemulsion composition of the present invention can be a mixed oil phase of medium-chain triglycerides and propylene glycol monocaprylate. The weight ratio of the medium-chain triglycerides in the mixed oil phase can be 10% - 90%, preferably 20% - 80%, more preferably 20% - 70%, and most preferably 40% - 60%.

[0118] In a specific embodiment, the oil phase in the nanoemulsion composition of the present invention can be a mixed oil phase of medium-chain triglycerides and caprylic / capric glycerides. The weight ratio of the medium-chain triglycerides in the mixed oil phase can be 10% - 90%, preferably 20% - 80%, more preferably 20% - 70%, and most preferably 40% - 60%.

[0119] In a specific embodiment, the oil phase in the nanoemulsion composition of the present invention can be a mixed oil phase of caprylic / capric glycerides and polyoxyethylene glyceryl oleate. The weight ratio of the caprylic / capric glycerides in the mixed oil phase can be 10% - 90%, preferably 20% - 80%, more preferably 20% - 70%, and most preferably 40% - 60%.

[0120] In a specific embodiment, the oil phase in the nanoemulsion composition of the present invention can be a mixed oil phase of caprylic / capric glycerides and propylene glycol monocaprylate. The weight ratio of the caprylic / capric glycerides in the mixed oil phase can be 10% - 90%, preferably 20% - 80%, more preferably 20% - 70%, and most preferably 40% - 60%.

[0121] In a specific embodiment, the oil phase in the nanoemulsion composition of the present invention can be a mixed oil phase of polyoxyethylene glyceryl oleate and propylene glycol monocaprylate. The weight ratio of the polyoxyethylene glyceryl oleate in the mixed oil phase can be 10% - 90%, preferably 20% - 80%, more preferably 20% - 70%, and most preferably 40% - 60%.

[0122] In the nanoemulsion composition of the present invention, the aqueous phase may contain water and an optional humectant.

[0123] There is no particular limitation on the water that can be used in the present invention, and it can be purified water, distilled water, deionized water, water for injection, or any combination thereof.

[0124] In one embodiment, the humectant in the nanoemulsion composition of the present invention may be a hydrophilic or water-miscible substance.

[0125] In one embodiment, the humectant in the nanoemulsion composition of the present invention may be a short-chain alcohol containing 2 to 6 carbon atoms, such as one or more of glycerol, sorbitol, propylene glycol, isopropyl alcohol, ethanol, butylene glycol, hexylene glycol, and pentylene glycol, preferably propylene glycol.

[0126] In the nanoemulsion composition of the present invention, based on the total weight of the composition, the content of the aqueous phase may be 30% - 85%, preferably 30% - 75%, more preferably 45% - 75%, and most preferably 58% - 72%.

[0127] In the nanoemulsion composition of the present invention, based on the total weight of the composition, the content of the humectant may be 0 - 10%, preferably 5% - 10%, and more preferably 7% - 10%.

[0128] In one embodiment, based on the total weight of the composition, the weight percentages of the components in the nanoemulsion composition of the present invention may be as follows: benvitimod or a pharmaceutically acceptable salt thereof is 0.1% - 5%, emulsifying component 1 is 5% - 30%, emulsifying component 2 is 3% - 25%, the oil phase is 1% - 25%, and the aqueous phase is 30% - 85%.

[0129] In one embodiment, based on the total weight of the composition, the weight percentages of the components in the nanoemulsion composition of the present invention may be as follows: benvitimod or a pharmaceutically acceptable salt thereof is 1% - 5%, emulsifying component 1 is 10% - 25%, emulsifying component 2 is 3% - 20%, the oil phase is 3% - 20%, and the aqueous phase is 30% - 75%.

[0130] In one embodiment, based on the total weight of the composition, the weight percentages of the components in the nanoemulsion composition of the present invention may be as follows: benvitimod or a pharmaceutically acceptable salt thereof is 1% - 3%, emulsifying component 1 is 10% - 20%, emulsifying component 2 is 5% - 20%, the oil phase is 3% - 15%, and the aqueous phase is 45% - 75%.

[0131] In one embodiment, based on the total weight of the composition, the weight percentages of the components in the nanoemulsion composition of the present invention may be as follows: bemotrizinol or a pharmaceutically acceptable salt thereof is 1%-2%, emulsifying component 1 is 12%-20%, emulsifying component 2 is 5%-12%, the oil phase is 4%-8%, and the aqueous phase is 58%-72%.

[0132] In one embodiment, emulsifying component 1 in the nanoemulsion composition of the present invention may be selected from one or more of polyoxyethylene castor oil derivatives with 30-60 polyoxyethylene units and polyethylene glycol vitamin E succinate esters with an average molecular weight of 500-2000, emulsifying component 2 may be selected from one or more of polyhydric alcohols with 2-6 carbon atoms or their fatty alcohol ethers, polyethylene glycol glycerol esters, and polyethylene glycols, and the oil phase may be selected from one or more of liquid fatty acid monohydric alcohol esters, liquid fatty acid dihydric alcohol esters, and liquid fatty acid glycerol esters.

[0133] In one embodiment, emulsifying component 1 in the nanoemulsion composition of the present invention may be selected from one or more of polyoxyethylene castor oil derivatives with 30-50 polyoxyethylene units and polyethylene glycol vitamin E succinate esters with an average molecular weight of 500-1500, emulsifying component 2 may be selected from one or more of polyhydric alcohols with 2-6 carbon atoms or their fatty alcohol ethers, polyethylene glycol glycerol esters, and polyethylene glycols, and the oil phase may be selected from one or more of liquid fatty acid monohydric alcohol esters, liquid fatty acid dihydric alcohol esters, and liquid fatty acid glycerol esters.

[0134] In one embodiment, emulsifying component 1 in the nanoemulsion composition of the present invention may be selected from one or more of polyoxyethylene castor oil derivatives with 30-40 polyoxyethylene units and polyethylene glycol vitamin E succinate esters with an average molecular weight of 800-1200, emulsifying component 2 may be selected from one or more of polyhydric alcohols with 2-6 carbon atoms or their fatty alcohol ethers, polyethylene glycol glycerol esters, and polyethylene glycols, and the oil phase may be selected from one or more of liquid fatty acid monohydric alcohol esters, liquid fatty acid dihydric alcohol esters, and liquid fatty acid glycerol esters.

[0135] In one embodiment, emulsifying component 1 in the nanoemulsion composition of the present invention may be selected from one or more of polyoxyethylene castor oil with 30-60 polyoxyethylene units, polyoxyethylene hydrogenated castor oil with 30-60 polyoxyethylene units, and polyethylene glycol vitamin E succinate esters with an average molecular weight of 500-2000, emulsifying component 2 may be selected from one or more of fatty alcohol ethers of polyhydric alcohols with 2-6 carbon atoms, polyethylene glycol glycerol esters, and polyethylene glycols with an average molecular weight of 200-400, and the oil phase may be selected from one or more of liquid fatty acid dihydric alcohol esters and liquid fatty acid glycerol esters.

[0136] In one embodiment, the emulsifying component 1 in the nanoemulsion composition of the present invention may be selected from one or more of polyoxyethylene castor oil with 30 - 50 units of polyoxyethylene, polyoxyethylene hydrogenated castor oil with 30 - 50 units of polyoxyethylene, and polyethylene glycol vitamin E succinate with an average molecular weight of 500 - 1500. The emulsifying component 2 may be selected from one or more of fatty alcohol ethers of polyhydric alcohols containing 2 - 6 carbon atoms, polyethylene glycol glycerol esters, and polyethylene glycol with an average molecular weight of 200 - 400. The oil phase may be selected from one or more of liquid fatty acid diol esters and liquid fatty acid glycerol esters.

[0137] In one embodiment, the emulsifying component 1 in the nanoemulsion composition of the present invention may be selected from one or more of polyoxyethylene castor oil with 30 - 40 units of polyoxyethylene, polyoxyethylene hydrogenated castor oil with 30 - 40 units of polyoxyethylene, and polyethylene glycol vitamin E succinate with an average molecular weight of 800 - 1200. The emulsifying component 2 may be selected from one or more of fatty alcohol ethers of polyhydric alcohols containing 2 - 6 carbon atoms, polyethylene glycol glycerol esters, and polyethylene glycol with an average molecular weight of 200 - 400. The oil phase may be selected from one or more of liquid fatty acid diol esters and liquid fatty acid glycerol esters.

[0138] In one embodiment, the emulsifying component 1 in the nanoemulsion composition of the present invention may be selected from one or more of polyoxyethylene 35 castor oil, polyoxyethylene 40 hydrogenated castor oil, and polyethylene glycol vitamin E succinate 1000. The emulsifying component 2 may be selected from one or more of polyethylene glycol 400, polyethylene glycol glycerol caprylate / caprate, and diethylene glycol monoethyl ether. The oil phase may be selected from one or more of medium-chain triglycerides, polyoxyethylene glyceryl oleate, caprylate / caprate mono- and diglycerides, and propylene glycol monocaprylate.

[0139] In one embodiment, the emulsifying component 1 in the nanoemulsion composition of the present invention may be polyoxyethylene 35 castor oil or polyethylene glycol vitamin E succinate 1000. The emulsifying component 2 may be one or more of polyethylene glycol glycerol caprylate / caprate, polyethylene glycol 400, and diethylene glycol monoethyl ether. The oil phase may be selected from one or more of medium-chain triglycerides, polyoxyethylene glyceryl oleate, caprylate / caprate mono- and diglycerides, and propylene glycol monocaprylate.

[0140] In one embodiment, the emulsifying component 1 in the nanoemulsion composition of the present invention may be polyoxyethylene 35 castor oil. The emulsifying component 2 may be one or more of polyethylene glycol glycerol caprylate / caprate, polyethylene glycol 400, and diethylene glycol monoethyl ether. The oil phase may be selected from one or more of medium-chain triglycerides, polyoxyethylene glyceryl oleate, caprylate / caprate mono- and diglycerides, and propylene glycol monocaprylate.

[0141] In one embodiment, the emulsifying component 1 in the nanoemulsion composition of the present invention may be polyoxyethylene 35 castor oil, the emulsifying component 2 may be polyethylene glycol caprylic / capric glycerides, and the oil phase may be selected from one or more of medium-chain triglycerides, polyoxyethylene glyceryl oleate, caprylic / capric monoglyceride and propylene glycol monocaprylate.

[0142] In one embodiment, the emulsifying component 1 in the nanoemulsion composition of the present invention may be polyoxyethylene 35 castor oil, the emulsifying component 2 may be polyethylene glycol 400, and the oil phase may be selected from one or more of medium-chain triglycerides, polyoxyethylene glyceryl oleate, caprylic / capric monoglyceride and propylene glycol monocaprylate.

[0143] In one embodiment, the emulsifying component 1 in the nanoemulsion composition of the present invention may be polyoxyethylene 35 castor oil, the emulsifying component 2 may be diethylene glycol monoethyl ether, and the oil phase may be selected from one or more of medium-chain triglycerides, polyoxyethylene glyceryl oleate, caprylic / capric monoglyceride and propylene glycol monocaprylate.

[0144] In one embodiment, the emulsifying component 1 in the nanoemulsion composition of the present invention may be polyethylene glycol 1000 vitamin E succinate, the emulsifying component 2 may be polyethylene glycol caprylic / capric glycerides and diethylene glycol monoethyl ether, and the oil phase may be selected from one or more of medium-chain triglycerides, polyoxyethylene glyceryl oleate, caprylic / capric monoglyceride and propylene glycol monocaprylate.

[0145] In one embodiment, the emulsifying component 1 in the nanoemulsion composition of the present invention may be polyoxyethylene 40 hydrogenated castor oil, the emulsifying component 2 may not be propylene glycol and / or polyethylene glycol 400, and the oil phase may be selected from one or more of medium-chain triglycerides, polyoxyethylene glyceryl oleate, caprylic / capric monoglyceride and propylene glycol monocaprylate.

[0146] In one embodiment, the emulsifying component 1 in the nanoemulsion composition of the present invention may be polyoxyethylene 40 hydrogenated castor oil, the emulsifying component 2 may be selected from one or more of polyethylene glycol caprylic / capric glycerides and diethylene glycol monoethyl ether, and the oil phase may be selected from one or more of medium-chain triglycerides, polyoxyethylene glyceryl oleate, caprylic / capric monoglyceride and propylene glycol monocaprylate.

[0147] In one embodiment, the emulsifying component 1 in the nanoemulsion composition of the present invention may be polyoxyethylene 40 hydrogenated castor oil, the emulsifying component 2 may be polyethylene glycol caprylic / capric glycerides, and the oil phase may be selected from one or more of medium-chain triglycerides, polyoxyethylene glyceryl oleate, caprylic / capric monoglyceride and propylene glycol monocaprylate.

[0148] In one embodiment, the emulsifying component 1 in the nanoemulsion composition of the present invention may be polyoxyl 40 hydrogenated castor oil, the emulsifying component 2 may be diethylene glycol monoethyl ether, and the oil phase may be selected from one or more of medium-chain triglycerides, polyoxyl oleoyl glyceride, caprylic / capric mono- and diglycerides, and propylene glycol monocaprylate.

[0149] In one embodiment, based on the total weight of the composition, the weight percentages of the components in the nanoemulsion composition of the present invention may be as follows: the emulsifying component 1 is 10%-20%, the emulsifying component 2 is 5%-20%, the oil phase is 3%-15%, and the aqueous phase is 45%-75%; the emulsifying component 1 may be polyoxyl 35 castor oil, the emulsifying component 2 may be one or more of diethylene glycol monoethyl ether, polyethylene glycol 400, and polyethylene glycol glycerol caprylic / capric acid esters, and the oil phase may be selected from one or more of medium-chain triglycerides, polyoxyl oleoyl glyceride, caprylic / capric mono- and diglycerides, and propylene glycol monocaprylate.

[0150] In one embodiment, based on the total weight of the composition, the weight percentages of the components in the nanoemulsion composition of the present invention may be as follows: the emulsifying component 1 is 12%-20%, the emulsifying component 2 is 5%-20%, the oil phase is 3%-15%, and the aqueous phase is 45%-75%; the emulsifying component 1 may be polyoxyl 35 castor oil, the emulsifying component 2 may be diethylene glycol monoethyl ether, and the oil phase may be selected from one or more of medium-chain triglycerides, polyoxyl oleoyl glyceride, caprylic / capric mono- and diglycerides, and propylene glycol monocaprylate.

[0151] In one embodiment, based on the total weight of the composition, the weight percentages of the components in the nanoemulsion composition of the present invention may be as follows: the emulsifying component 1 is 12%-20%, the emulsifying component 2 is 5%-20%, the oil phase is 3%-15%, and the aqueous phase is 45%-75%; the emulsifying component 1 may be polyoxyl 35 castor oil, the emulsifying component 2 may be polyethylene glycol 400, and the oil phase may be selected from one or more of medium-chain triglycerides, polyoxyl oleoyl glyceride, caprylic / capric mono- and diglycerides, and propylene glycol monocaprylate.

[0152] In one embodiment, based on the total weight of the composition, the weight percentages of the components in the nanoemulsion composition of the present invention may be as follows: the emulsifying component 1 is 10%-20%, the emulsifying component 2 is 5%-10%, the oil phase is 3%-15%, and the aqueous phase is 60%-75%; the emulsifying component 1 may be polyoxyl 35 castor oil, the emulsifying component 2 may be polyethylene glycol glycerol caprylic / capric acid esters, and the oil phase may be selected from one or more of medium-chain triglycerides, polyoxyl oleoyl glyceride, caprylic / capric mono- and diglycerides, and propylene glycol monocaprylate.

[0153] In one embodiment, based on the total weight of the composition, the weight percentages of the components in the nanoemulsion composition of the present invention can be as follows: emulsifying component 1 is 10%-20%, emulsifying component 2 is 5%-20%, the oil phase is 3%-15%, and the aqueous phase is 45%-75%; the emulsifying component 1 can be polyethylene glycol 1000 vitamin E succinate, the emulsifying component 2 can be polyethylene glycol glycerol caprylate / caprate and diethylene glycol monoethyl ether, and the oil phase can be selected from one or more of medium-chain triglycerides, polyoxyethylene glyceryl oleate, mono- and diglycerides of caprylic / capric acid, and propylene glycol monocaprylate.

[0154] In one embodiment, based on the total weight of the composition, the weight percentages of the components in the nanoemulsion composition of the present invention can be as follows: emulsifying component 1 is 10%-18%, emulsifying component 2 is 8%-15%, the oil phase is 3%-7%, and the aqueous phase is 60%-75%; the emulsifying component 1 can be polyethylene glycol 1000 vitamin E succinate, the emulsifying component 2 can be polyethylene glycol glycerol caprylate / caprate and diethylene glycol monoethyl ether, and the oil phase can be selected from one or more of medium-chain triglycerides, polyoxyethylene glyceryl oleate, mono- and diglycerides of caprylic / capric acid, and propylene glycol monocaprylate.

[0155] In one embodiment, based on the total weight of the composition, the weight percentages of the components in the nanoemulsion composition of the present invention can be as follows: emulsifying component 1 is 10%-20%, emulsifying component 2 is 5%-20%, the oil phase is 3%-15%, and the aqueous phase is 45%-75%; the emulsifying component 1 can be polyoxyethylene (40) hydrogenated castor oil, the emulsifying component 2 can be one or more of polyethylene glycol glycerol caprylate / caprate and diethylene glycol monoethyl ether, and the oil phase can be selected from one or more of medium-chain triglycerides, polyoxyethylene glyceryl oleate, mono- and diglycerides of caprylic / capric acid, and propylene glycol monocaprylate.

[0156] In one embodiment, based on the total weight of the composition, the weight percentages of the components in the nanoemulsion composition of the present invention can be as follows: emulsifying component 1 is 12%-20%, emulsifying component 2 is 5%-20%, the oil phase is 3%-10%, and the aqueous phase is 45%-75%; the emulsifying component 1 can be polyoxyethylene (40) hydrogenated castor oil, the emulsifying component 2 can be diethylene glycol monoethyl ether, and the oil phase can be selected from one or more of medium-chain triglycerides, polyoxyethylene glyceryl oleate, mono- and diglycerides of caprylic / capric acid, and propylene glycol monocaprylate.

[0157] In one embodiment, based on the total weight of the composition, the weight percentages of the components in the nanoemulsion composition of the present invention can be as follows: the emulsifying component 1 is 12% - 20%, the emulsifying component 2 is 5% - 15%, the oil phase is 3% - 10%, and the aqueous phase is 55% - 75%; the emulsifying component 1 can be polyoxyethylene 40 hydrogenated castor oil, the emulsifying component 2 can be polyethylene glycol glycerol caprylate / caprate, and the oil phase can be selected from one or more of medium-chain triglycerides, polyoxyethylene glyceryl oleate, mono- and diglycerides of caprylic / capric acid, and propylene glycol monocaprylate.

[0158] In addition to bemotrizinol or its pharmaceutically acceptable salts, emulsifying component 1, emulsifying component 2, the oil phase, and the aqueous phase, the nanoemulsion composition of the present invention may further comprise pharmaceutically acceptable excipients.

[0159] In one embodiment, the pharmaceutically acceptable excipients may include penetration enhancers.

[0160] In one embodiment, the penetration enhancers in the nanoemulsion composition of the present invention can be selected from one or more of diethylene glycol monoethyl ether, oleic acid, stearic acid, isostearic acid, lactic acid, lauric acid, polyethylene glycol, isopropyl myristate, isopropyl palmitate, dimethylacetamide, triglyceride, menthol, menthol crystal, propylene glycol, borneol, cnidium fruit oil, azone, sodium lauryl sulfate, geraniol, anethole, and decyl methyl sulfoxide.

[0161] In a specific embodiment, the penetration enhancer in the nanoemulsion composition of the present invention can be diethylene glycol monoethyl ether.

[0162] In the nanoemulsion composition of the present invention, based on the total weight of the composition, the content of the penetration enhancer can be 0 - 15%, preferably 1% - 10%, more preferably 1% - 8%, and most preferably 2% - 5%.

[0163] In one embodiment, the pharmaceutically acceptable excipients may further include one or more of conventional thickeners, solubilizers, mucoadhesives, pH regulators, antioxidants, osmotic pressure regulators, bacteriostatic agents (or preservatives), and chelating agents in the art.

[0164] Preferably, the pharmaceutically acceptable excipients may further include one or more of antioxidants, bacteriostatic agents, chelating agents, and pH regulators.

[0165] In one embodiment, the antioxidants in the nanoemulsion composition of the present invention can be selected from one or more of synthetic antioxidants such as butylated hydroxyanisole, dibutylhydroxytoluene, tert-butylhydroquinone, propyl gallate, L-ascorbyl palmitate, ethoxyquinoline, sodium metabisulfite, dilauryl thiodipropionate, and natural antioxidants such as tea polyphenols, tocopherols, and grape seed extracts.

[0166] In a specific embodiment, the antioxidant in the nanoemulsion composition of the present invention may be selected from one or more of butylated hydroxyanisole and dibutylhydroxytoluene.

[0167] In the nanoemulsion composition of the present invention, based on the total weight of the composition, the content of the antioxidant may be 0 - 2%, preferably 0.01% - 1%, more preferably 0.05% - 0.5%, and most preferably 0.1% - 0.2%.

[0168] In one embodiment, the bacteriostatic agent in the nanoemulsion composition of the present invention may be selected from one or more of benzyl alcohol, phenoxyethanol, sorbic acid or its salts (such as potassium sorbate), parabens (also known as nipagin esters, such as methyl paraben, ethyl paraben, propyl paraben, butyl paraben), benzalkonium chloride, benzalkonium bromide, chlorobutanol, benzoic acid or its salts (such as sodium benzoate), citric acid or its salts (such as sodium citrate), and ascorbic acid or its salts (such as sodium ascorbate).

[0169] In a specific embodiment, the bacteriostatic agent in the nanoemulsion composition of the present invention may be benzoic acid.

[0170] In the nanoemulsion composition of the present invention, based on the total weight of the composition, the content of the bacteriostatic agent may be 0 - 2%, preferably 0.01% - 1%, more preferably 0.1% - 0.5%, and most preferably 0.2% - 0.3%.

[0171] In one embodiment, the chelating agent in the nanoemulsion composition of the present invention may be selected from one or more of citric acid, glucuronic acid, sodium hexametaphosphate, zinc hexametaphosphate, edetic acid or its derivatives (such as disodium edetate), and phosphonates.

[0172] In a specific embodiment, the chelating agent in the nanoemulsion composition of the present invention may be disodium edetate.

[0173] In the nanoemulsion composition of the present invention, based on the total weight of the composition, the content of the chelating agent may be 0 - 2%, preferably 0.01% - 1%, more preferably 0.05% - 0.5%, and most preferably 0.1% - 0.2%.

[0174] In one embodiment, the pH regulator in the nanoemulsion composition of the present invention is a conventional pH regulator in the art, and it may be selected from one or more of inorganic or organic acids, inorganic or organic bases, and buffer salts.

[0175] In one embodiment, the acid in the nanoemulsion composition of the present invention may be selected from one or more of hydrochloric acid, phosphoric acid, acetic acid, citric acid, lactic acid, and boric acid.

[0176] In one embodiment, the base in the nanoemulsion composition of the present invention may be selected from one or more of ethylenediamine, ethanolamine, basic amino acids, sodium hydroxide, calcium hydroxide, potassium hydroxide, and aqueous ammonia solution.

[0177] In one embodiment, the buffer salt in the nanoemulsion composition of the present invention may be selected from one or more of boric acid-borax buffer salt, citric acid-sodium citrate buffer salt, phosphoric acid-sodium phosphate buffer salt, and acetic acid-sodium acetate buffer salt.

[0178] In a specific embodiment, the pH regulator in the nanoemulsion composition of the present invention may be a buffer salt.

[0179] In a more specific embodiment, the pH regulator in the nanoemulsion composition of the present invention may be citric acid-sodium citrate buffer salt.

[0180] In the nanoemulsion composition of the present invention, based on the total weight of the composition, the content of the pH regulator may be 0-2%, preferably 0.01%-1%, more preferably 0.1%-0.5%, and most preferably 0.2%-0.3%.

[0181] In one embodiment, the nanoemulsion composition of the present invention may comprise benvitimod or a pharmaceutically acceptable salt thereof, an emulsifying component 1, an emulsifying component 2, an oil phase, an aqueous phase, an antioxidant, an antibacterial agent, a chelating agent, a pH regulator, and optionally a penetration enhancer.

[0182] In one embodiment, the nanoemulsion composition of the present invention may consist of benvitimod or a pharmaceutically acceptable salt thereof, an emulsifying component 1, an emulsifying component 2, an oil phase, an aqueous phase, an antioxidant, an antibacterial agent, a chelating agent, a pH regulator, and optionally a penetration enhancer.

[0183] In one embodiment, the nanoemulsion composition of the present invention may comprise benvitimod or a pharmaceutically acceptable salt thereof, an emulsifying component 1, an emulsifying component 2, an oil phase, an aqueous phase, optionally diethylene glycol monoethyl ether, an antioxidant, benzoic acid, disodium edetate, citric acid, and sodium citrate; the emulsifying component 1 may be one or more of polyoxyethylene 35 castor oil and polyethylene glycol 1000 vitamin E succinate, the emulsifying component 2 may be one or more of polyethylene glycol glycerol caprylate / caprate, polyethylene glycol 400, and diethylene glycol monoethyl ether, the oil phase may be selected from one or more of medium-chain triglycerides, polyoxyethylene glyceryl oleate, glycerol caprylate / caprate, and propylene glycol monocaprylate, the aqueous phase may be water and / or propylene glycol, and the antioxidant may be butylated hydroxyanisole or dibutylhydroxytoluene or a combination of both.

[0184] In one embodiment, the nanoemulsion composition of the present invention may comprise benvitimod or a pharmaceutically acceptable salt thereof, emulsifying component 1, emulsifying component 2, oil phase, water phase, optional diethylene glycol monoethyl ether, antioxidant, benzoic acid, disodium edetate, citric acid and sodium citrate; the emulsifying component 1 may be polyoxyl 40 hydrogenated castor oil, and the emulsifying component 2 may be one or more of polyethylene glycol glycerol caprylate / caprate and diethylene glycol monoethyl ether. The oil phase may be selected from one or more of medium-chain triglycerides, polyoxyl oleate glycerol, glycerol caprylate / caprate and propylene glycol monocaprylate, and the water phase may be water and / or propylene glycol. The antioxidant may be butylated hydroxyanisole or dibutylhydroxytoluene or a combination of both.

[0185] In one embodiment, based on the total weight of the composition, the weight percentages of the components in the nanoemulsion composition of the present invention may be as follows: benvitimod or a pharmaceutically acceptable salt thereof is 0.1%-5%, emulsifying component 1 is 5%-30%, emulsifying component 2 is 3%-25%, oil phase is 1%-25%, water phase is 30%-85%, penetration enhancer is 0-15%, antioxidant is 0-2%, bacteriostatic agent is 0-2%, chelating agent is 0-2%, and pH regulator is 0-2%.

[0186] In one embodiment, the nanoemulsion composition of the present invention may further comprise a gelling agent.

[0187] In one embodiment, the gelling agent in the nanoemulsion composition of the present invention may be selected from one or more of xanthan gum, carbomer, sodium carboxymethyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl cellulose, methylcellulose, sodium hyaluronate (also known as sodium hyaluronate), polyvinyl alcohol, xyloglucan, polyvinylpyrrolidone, hydroxyethyl cellulose, gellan gum and sodium alginate.

[0188] Preferably, the gelling agent may be selected from one or more of polyvinylpyrrolidone, xanthan gum, carbomer, hydroxypropyl methylcellulose, sodium alginate and sodium hyaluronate.

[0189] More preferably, the gelling agent may be selected from one or more of polyvinylpyrrolidone, xanthan gum, sodium alginate and sodium hyaluronate.

[0190] Most preferably, the gelling agent may be selected from one or more of xanthan gum, sodium alginate and sodium hyaluronate.

[0191] In the nanoemulsion composition of the present invention, based on the total weight of the composition, the content of the gelling agent may be 0-5%, preferably 0.05%-5%, more preferably 0.05%-2%, and most preferably 0.1%-1.5%.

[0192] In one embodiment, the nanoemulsion composition of the present invention may comprise benvitimod or a pharmaceutically acceptable salt thereof, an emulsifying component 1, an emulsifying component 2, an oil phase, an aqueous phase, an antioxidant, an antibacterial agent, a chelating agent, a pH regulator, a gelling agent, and an optional penetration enhancer.

[0193] In one embodiment, the nanoemulsion composition of the present invention may consist of benvitimod or a pharmaceutically acceptable salt thereof, an emulsifying component 1, an emulsifying component 2, an oil phase, an aqueous phase, an antioxidant, an antibacterial agent, a chelating agent, a pH regulator, a gelling agent, and an optional penetration enhancer.

[0194] Unless otherwise specified, the term "particle size" in the present invention refers to the average particle size value, usually expressed as "Z-Average", which is applicable to the particles in the dispersion or the molecules in the solution.

[0195] In one embodiment, the particle size of the nanoemulsion composition of the present invention may be 5 - 200 nm, preferably 5 - 100 nm, more preferably 5 - 80 nm, further preferably 10 - 60 nm, and most preferably 10 - 30 nm.

[0196] In one embodiment, the pH value of the nanoemulsion composition of the present invention may be 4 - 9.5, preferably 4 - 8, more preferably 4.5 - 7, and most preferably 4.5 - 6.

[0197] In a second aspect, the present invention provides a method for preparing the benvitimod nanoemulsion composition described in the first aspect, which may include the following steps:

[0198] (1) Mix benvitimod or a pharmaceutically acceptable salt thereof, an emulsifying component 1, an emulsifying component 2, an oil phase, an optional antioxidant, and an optional antibacterial agent uniformly to obtain phase A;

[0199] (2) Mix the aqueous phase, an optional penetration enhancer, an optional chelating agent, and an optional pH regulator uniformly to obtain phase B;

[0200] (3) Mix phase A, phase B, and an optional gelling agent uniformly to prepare the nanoemulsion composition of the present invention.

[0201] In one embodiment, in step (3), first mix phase A and phase B uniformly, and then add the gelling agent and mix uniformly again.

[0202] In one embodiment, in any one of steps (1) to (3), the mixing is carried out under heating, for example, by water bath heating, and the water bath temperature may be 0 - 90 °C, preferably 30 - 70 °C, and most preferably 40 - 60 °C.

[0203] In one embodiment, in any one of steps (1) to (3), the mixing method may be a stirring method, an ultrasonic method, a homogenization method or a microfluidization method, preferably a stirring method.

[0204] In one embodiment, in any one of steps (1) to (3), the mixing method may be a stirring method under water bath heating at 40 - 60°C.

[0205] In one embodiment, in step (1), the mixing is carried out under water bath heating at 40 - 60°C and stirring.

[0206] In one embodiment, in step (2), the mixing is carried out under water bath heating at 40 - 60°C and stirring.

[0207] In one embodiment, in step (3), the mixing is carried out under water bath heating at 40 - 60°C and stirring.

[0208] In one embodiment, in step (3), after the A phase and the B phase are stirred evenly at 40 - 60°C in a water bath, a gelling agent is added and stirred evenly again to prepare the bemotrizinol nanoemulsion composition containing the gelling agent.

[0209] In a third aspect, the present invention also provides a topical pharmaceutical preparation, which comprises the bemotrizinol nanoemulsion composition described in the first aspect.

[0210] The nanoemulsion composition of the present invention can be directly applied to the affected area, or can be prepared into other topical pharmaceutical dosage forms. Therefore, the present invention also provides a topical pharmaceutical preparation comprising the bemotrizinol nanoemulsion composition as described above, such as liniments, foams, sprays, films, ointments, creams, gels, patches, cataplasms, etc.

[0211] In one embodiment, the topical pharmaceutical preparation of the present invention can be a liniment or a foam.

[0212] In one embodiment, the topical pharmaceutical preparation of the present invention can be a foam.

[0213] In one embodiment, the foam of the present invention may comprise the bemotrizinol nanoemulsion composition described in the first aspect and a propellant.

[0214] Preferably, the propellant may be selected from one or more of hydrofluoroalkanes (such as difluoroethane, tetrafluoroethane, hexafluoropropane or heptafluoropropane), hydrofluoroolefins (such as trifluoropropene or tetrafluoropropene), alkanes (such as propane, isobutane, butane, pentane or isopentane) and alkyl ethers (such as dimethyl ether or methyl ethyl ether).

[0215] More preferably, the propellant can be selected from one or more of tetrafluoroethane, hexafluoropropane, heptafluoropropane, tetrafluoropropene, propane, isobutane, butane, pentane, isopentane, dimethyl ether, and methyl ethyl ether.

[0216] Most preferably, the propellant can be selected from one or more of butane and tetrafluoroethane.

[0217] In a fourth aspect, the present invention also provides the use of the benvitimod nanoemulsion composition described in the first aspect or the topical pharmaceutical preparation (such as a liniment or a foam) described in the third aspect in the preparation of a medicament for preventing and / or treating inflammatory skin diseases.

[0218] Preferably, the inflammatory skin disease can be selected from one or more of psoriasis, eczema, palmoplantar pustulosis, and atopic dermatitis.

[0219] More preferably, the inflammatory skin disease can be scalp psoriasis.

[0220] Terms

[0221] In the present invention, the numerical range represented by "numerical value A to numerical value B" refers to a range including the endpoint numerical values A and B.

[0222] In the present invention, when using "normal temperature" or "room temperature", the temperature can be 10 - 40°C, or can also be 10 - 30°C or 15 - 30°C, such as 25°C.

[0223] In the present invention, "optional" means that the listed components can be selected (if there are multiple listed components, one component can be selected, or multiple components can be selected), or the listed components can also not be selected.

[0224] Unless otherwise specified, the term "polyoxyethylene castor oil derivative" in the present invention is a polyoxyethylene type nonionic surfactant obtained by reacting polyethylene glycol with castor oil or hydrogenated castor oil, and it can be selected from one or more of polyoxyethylene castor oil (such as polyoxyethylene 5 castor oil, polyoxyethylene 9 castor oil, polyoxyethylene 15 castor oil, polyoxyethylene 35 castor oil, polyoxyethylene 40 castor oil) and polyoxyethylene hydrogenated castor oil (such as polyoxyethylene 40 hydrogenated castor oil, polyoxyethylene 54 hydrogenated castor oil, and polyoxyethylene 60 hydrogenated castor oil), preferably polyoxyethylene 35 castor oil or polyoxyethylene 40 hydrogenated castor oil.

[0225] Unless otherwise specified, the term "polyethylene glycol ester of vitamin E succinate" in the present invention refers to a polyethylene glycol-based nonionic surfactant formed by esterifying the carboxyl group of D-α-tocopherol succinate with polyethylene glycol, which can be selected from one or more of polyethylene glycol ester of vitamin E succinate 200, polyethylene glycol ester of vitamin E succinate 400, polyethylene glycol ester of vitamin E succinate 1000, polyethylene glycol ester of vitamin E succinate 1500, polyethylene glycol ester of vitamin E succinate 2000, and polyethylene glycol ester of vitamin E succinate 4000, preferably polyethylene glycol ester of vitamin E succinate 1000.

[0226] Unless otherwise specified, the term "polyoxyethylene fatty alcohol ether" in the present invention refers to a polyethylene glycol-based nonionic surfactant formed by etherifying polyethylene glycol with fatty alcohols (such as lauryl alcohol, oleyl alcohol, myristyl alcohol, cetyl alcohol, stearyl alcohol, etc.), which can be selected from one or more of polyoxyethylene stearyl alcohol ethers (such as polyoxyethylene 2 stearyl alcohol ether, polyoxyethylene 10 stearyl alcohol ether, polyoxyethylene 21 stearyl alcohol ether), polyoxyethylene cetyl alcohol ethers (such as polyoxyethylene 10 cetyl alcohol ether, polyoxyethylene 20 cetyl alcohol ether), polyoxyethylene lauryl alcohol ethers (such as polyoxyethylene 4 lauryl alcohol ether, polyoxyethylene 9 lauryl alcohol ether, polyoxyethylene 23 lauryl alcohol ether), polyoxyethylene oleyl alcohol ethers (polyoxyethylene 10 oleyl alcohol ether, polyoxyethylene 20 oleyl alcohol ether), polyoxyethylene cetyl stearyl alcohol ethers (such as polyoxyethylene 6 cetyl stearyl alcohol ether, polyoxyethylene 20 cetyl stearyl alcohol ether, polyoxyethylene 25 cetyl stearyl alcohol ether), polyoxyethylene myristyl alcohol ether, polyoxyethylene tridecyl alcohol ether, polyoxyethylene behenyl alcohol ether, and polyoxyethylene cholesteryl ether, preferably polyoxyethylene stearyl alcohol ether, polyoxyethylene cetyl alcohol ether, or polyoxyethylene lauryl alcohol ether.

[0227] Unless otherwise specified, the term "polyoxyethylene fatty acid ester" in the present invention refers to a polyethylene glycol-based nonionic surfactant formed by esterifying polyethylene glycol with fatty acids (such as stearic acid, hydroxystearic acid, etc.), which can be selected from one or more of polyoxyethylene stearic acid esters (such as polyoxyethylene 2 stearic acid ester, polyoxyethylene 4 stearic acid ester, polyoxyethylene 6 stearic acid ester, polyoxyethylene 8 stearic acid ester, polyoxyethylene 12 stearic acid ester, polyoxyethylene 20 stearic acid ester, polyoxyethylene 30 stearic acid ester, polyoxyethylene 40 stearic acid ester, polyoxyethylene 50 stearic acid ester, polyoxyethylene 100 stearic acid ester), polyoxyethylene distearic acid esters (such as polyoxyethylene 8 distearic acid ester, polyoxyethylene 12 distearic acid ester, polyoxyethylene 32 distearic acid ester, polyoxyethylene 150 distearic acid ester), and polyoxyethylene hydroxystearic acid esters (such as polyoxyethylene 15 hydroxystearic acid ester), preferably polyoxyethylene 40 stearic acid ester.

[0228] Unless otherwise specified, the term "poloxamer" in the present invention refers to a polyethylene glycol type non-ionic surfactant formed by copolymerization of polyoxyethylene and polypropylene, and it can be selected from one or more of poloxamer 124, poloxamer 181, poloxamer 182, poloxamer 184, poloxamer 188, poloxamer 237, poloxamer 331, poloxamer 338 and poloxamer 407, preferably poloxamer 188.

[0229] Unless otherwise specified, the term "Tween" in the present invention, also known as "polyoxyethylene sorbitan fatty acid ester" or "polysorbate", is a polyhydric alcohol type non-ionic surfactant, and it can be selected from one or more of Tween 20, Tween 40, Tween 60, Tween 80 and Tween 85, preferably Tween 80.

[0230] Unless otherwise specified, the term "sucrose fatty acid ester" in the present invention is a polyhydric alcohol type non-ionic surfactant, and it can be selected from one or more of sucrose fatty acid monoesters, sucrose fatty acid diesters and sucrose fatty acid triesters, preferably sucrose fatty acid monoesters.

[0231] In the present invention, "polyhydric alcohol" refers to alcohols containing more than 2 hydroxyl groups in the molecule, such as dihydric alcohols, trihydric alcohols, etc., specifically such as propylene glycol, butylene glycol, pentylene glycol, diethylene glycol, glycerol, etc. For example, in "polyhydric alcohol containing 2-6 carbon atoms", the "containing 2-6 carbon atoms" is used to modify the number of carbon atoms in the polyhydric alcohol, and it refers to alcohols containing 2-6 carbon atoms and more than 2 hydroxyl groups in the molecule.

[0232] In the present invention, "polyhydric alcohol or its fatty alcohol ether or fatty acid ester" includes polyhydric alcohol, fatty alcohol ether of polyhydric alcohol and fatty acid ester of polyhydric alcohol; "polyhydric alcohol or its fatty alcohol ether" includes polyhydric alcohol and fatty alcohol ether of polyhydric alcohol. Among them, "fatty alcohol ether of polyhydric alcohol" refers to an ether formed by one or more hydroxyl groups in the polyhydric alcohol and hydroxyl groups in another molecule or multiple molecules of fatty alcohol, and the fatty alcohol can be, for example, a monohydric alcohol containing 1-6 carbon atoms, or a monohydric alcohol containing 2-4 carbon atoms, or a monohydric alcohol containing 2-3 carbon atoms; "fatty acid ester of polyhydric alcohol" refers to an ester formed by one or more hydroxyl groups in the polyhydric alcohol and carboxyl groups in another molecule or multiple molecules of fatty acid, and the fatty acid can be, for example, a monobasic fatty acid containing 6-18 carbon atoms, or a monobasic fatty acid containing 6-12 carbon atoms, or a monobasic fatty acid containing 6-10 carbon atoms. For example, in "fatty alcohol ether of polyhydric alcohol containing 2-6 carbon atoms", the "containing 2-6 carbon atoms" is used to modify the number of carbon atoms in the polyhydric alcohol, and it refers to an ether formed by one or more hydroxyl groups in an alcohol containing 2-6 carbon atoms and containing more than 2 hydroxyl groups and hydroxyl groups in another molecule or multiple molecules of fatty alcohol.

[0233] In the present invention, "Macrogolglycerides", also known as Polyoxylglycerides, can be prepared by partial alcoholysis of triglycerides of saturated or unsaturated fatty acids with polyethylene glycol, or by esterification of glycerol and polyethylene glycol with saturated or unsaturated fatty acids, or by mixing glycerol esters and ethylene oxide condensates with saturated or unsaturated fatty acids. Macrogolglycerides generally refer to a mixture of glycerol monoesters, diesters and triesters, as well as polyethylene glycol monoesters and diesters. According to the types of fatty acid moieties in Macrogolglycerides, Macrogolglycerides include polyethylene glycol glycerol caprylate / caprate, polyethylene glycol glycerol laurate, polyethylene glycol glycerol linoleate, polyethylene glycol glycerol oleate, polyethylene glycol glycerol stearate, polyethylene glycol glycerol caprate, etc.

[0234] In the present invention, the "number of polyoxyethylene units" refers to the average degree of polymerization of the polyoxyethylene moiety (i.e., the polyethylene glycol moiety) in the molecule. For example, "polyoxyethylene castor oil with the number of polyoxyethylene units of 30 - 40" means that the average degree of polymerization of the polyoxyethylene moiety in the defined polyoxyethylene castor oil is 30 - 40; "polyoxyethylene 35 castor oil" means that the average degree of polymerization of the polyoxyethylene moiety in the defined polyoxyethylene castor oil is 35.

[0235] In the present invention, the "average molecular weight of polyethylene glycol" refers to the average molecular weight of the polyethylene glycol moiety (i.e., the polyoxyethylene moiety) in the defined molecule. For example, "polyethylene glycol vitamin E succinate with an average molecular weight of polyethylene glycol of 500 - 1500" means that the average molecular weight of the polyethylene glycol moiety in the defined polyethylene glycol vitamin E succinate is 500 - 1500; "polyethylene glycol vitamin E succinate 1000" means that the average molecular weight of the polyethylene glycol moiety in the defined polyethylene glycol vitamin E succinate is 1000.

[0236] In the present invention, the "emulsifying component" plays an important role in the interfacial stability of the nanoemulsion. The emulsifying component can be a single emulsifier or a combination of two or more emulsifiers, or a combination of at least one emulsifier and at least one co - emulsifier. The emulsifier can reduce the interfacial tension, form an interfacial film, promote the formation of the nanoemulsion and maintain its dispersion and stability. The hydrophilic or lipophilic degree of the emulsifier can be judged according to the value of the hydrophilic - lipophilic balance (HLB); conversely, the required emulsifier can also be screened according to the HLB value.

[0237] Generally, a single emulsifier (i.e., "emulsifying component 1" in the present invention) is difficult to reduce the interfacial tension to the required range. Therefore, a second emulsifier or co-emulsifier (i.e., "emulsifying component 2" in the present invention) is often added to further stabilize the nanoemulsion. "Emulsifying component 2" can assist "emulsifying component 1" to further reduce the interfacial tension, increase the fluidity of the interfacial film, adjust the overall HLB value of the emulsifying components, enable the nanoemulsion droplets to form spontaneously, and enhance the strength of the emulsifying film, prevent the droplets from coalescing, and enhance the physical stability of the nanoemulsion.

[0238] Effects of the Invention

[0239] When the benvitimod or its pharmaceutically acceptable salt, emulsifying component 1, emulsifying component 2, oil phase, water phase and optional penetration enhancer, antioxidant, bacteriostatic agent, chelating agent, pH regulator and gelling agent in the benvitimod nanoemulsion composition of the present invention are mixed together at appropriate concentrations, an oil-in-water nanoemulsion will form spontaneously, and the formed nanoemulsion is clear, transparent and thermodynamically stable. This nanoemulsion can improve the solubility of the drug, reduce skin irritation, and promote the continuous penetration of the drug through the stratum corneum.

[0240] The nanoemulsion of the present invention has excellent physical and chemical stability. After the nanoemulsion is stored for at least 1 week, or at least 2 weeks, or at least 1 month, or at least 3 months, or at least 4 months, or at least 6 months, or at least 9 months, or at least 12 months, it contains less than 1%, or less than 0.5%, or less than 0.2%, or less than 0.1% of impurities. After being stored under accelerated conditions of 40°C / 75% RH for at least one week, at least two weeks, at least one month or at least four months, the content of individual impurities in the nanoemulsion composition is less than about 0.3% by weight, or less than about 0.2% by weight, and the total impurity content is less than about 1% by weight, or less than about 0.8% by weight, or less than about 0.6% by weight, or less than about 0.4% by weight. The stability of the nanoemulsion of the present invention is at least not inferior to or is superior to the control drug.

[0241] The nanoemulsion of the present invention has good in vitro release effect and skin permeability, and its effect in in vitro release studies and in vitro transdermal studies within 24 hours is significantly superior to that of the control drug. and

[0242] The nanoemulsion of the present invention can also be prepared into a benvitimod foam agent. The foam agent has stable foam, uniform dispersion, is delicate and soft, has strong adhesiveness, is easy to apply, is conducive to the drug to exert a stable and continuous therapeutic effect, and reduces the chemical and physical stimulation to the inflamed part.

[0243] The nanoemulsion of the present invention can effectively relieve the symptoms of inflammatory skin diseases and has an obvious improvement effect on skin damage. The PASI score of the severity of skin lesions in the psoriasis mouse model of the nanoemulsion is relative to and Both showed statistical differences in drug efficacy and had better therapeutic effects. Description of the Drawings

[0244] Figure 1 It is the in vitro cumulative release percentage of the nanoemulsion and the control drug in Example 10 of the present invention.

[0245] Figure 2 It is the in vitro cumulative penetration amount per unit area of the nanoemulsion and the control drug in Example 10 of the present invention.

[0246] Figure 3 It is the change curve of the PASI score of the severity of skin lesions induced by imiquimod in BALB / c mice. Detailed Embodiments

[0247] The abbreviations, trade names and their meanings of some technical terms in the present invention are as follows:

[0248] Abbreviations or Trade Names Meanings API Benvitimod ELP35 Polyoxyethylene 35 Castor Oil RH40 Polyoxyethylene 40 Hydrogenated Castor Oil TPGS1000 Polyethylene Glycol Vitamin E Succinate 1000 TP Diethylene Glycol Monoethyl Ether Labrasol Caprylic / Capric PEG Glycerol Esters PEG400 Polyethylene Glycol 400 MCT Medium Chain Triglycerides MCM Caprylic / Capric Mono- and Diglycerides IPM Isopropyl Myristate Labrafil M1944CS Oleoyl Polyoxyethylene Glycerol Ester Capryol 90 Propylene Glycol Monocaprylate BHT Butylated Hydroxytoluene BHA Butylated Hydroxyanisole HLB Hydrophilic-Lipophilic Balance Value

[0249] The reagents and raw materials used in the present invention are all commercially available. Among them, the control drugs are purchased from China (manufacturer: Guangdong Zhonghao Pharmaceutical Co., Ltd.) and the composition is: bemotrizinol (1%), cetyl alcohol, white petrolatum, light liquid paraffin, mono- and diglycerides of fatty acids, propylene glycol, Tween 80, ethylparaben and purified water; are purchased from the United States (manufacturer: Dermavant Sciences) and the composition is: bemotrizinol (1%), benzoic acid, butylated hydroxytoluene, citric acid monohydrate, diethylene glycol monoethyl ether, disodium edetate, emulsifying wax, medium-chain triglycerides, polyoxyethylene 2 stearyl ether, polyoxyethylene 20 stearyl ether, Tween 80, propylene glycol, purified water and sodium citrate dihydrate.

[0250] The determination methods adopted in the examples of the present invention are as follows:

[0251] Centrifugal stratification: Take 5 g of the nanoemulsion and place it in a centrifuge. Centrifuge at 12,000 rpm for 30 min and observe whether stratification occurs.

[0252] Freeze-thaw: Take 5 g of the nanoemulsion and conduct a physical stability investigation of one freeze-thaw cycle. Each cycle is to first place it at -20 to -10 °C for 2 days, then place it at 40 °C for 2 days, and then take samples to observe whether stratification or turbidity occurs.

[0253] Stability determination: The chemical stability of the sample was analyzed by HPLC: Filler: octadecylsilyl-bonded silica gel (Shimadzu Shim-pack GIST C18, 4.6 mm × 100 mm, 3 μm or a chromatographic column with equivalent efficiency); Column temperature: 35 °C; Autosampler temperature: ambient temperature; Flow rate: 0.7 ml / min; Injection volume: 10 μl; Detection wavelength: 220 nm; Run time: 70 minutes; Mobile phase A: phosphoric acid solution (take an appropriate amount of water and adjust the pH value to 3.0 with phosphoric acid), Mobile phase B: methanol-acetonitrile (2:1); The HPLC elution gradient was:

[0254] Time (minutes) Mobile Phase A (%) Mobile Phase B (%) 0 65 35 25 30 70 40 5 95 60 5 95 61 65 35 70 65 35

[0255] Particle size determination: Take an appropriate amount of nanoemulsion, dilute it 10 times or 100 times with purified water, and measure the particle size, Zeta potential and polydispersity index PDI on a Malvern particle size and zeta potential analyzer. The Zeta potential is a measure of the strength of the repulsive or attractive forces between particles and can be used to detect the surface charge properties of emulsion droplets. Its value is related to the stability of the emulsion system. The PDI is the particle size distribution coefficient, and its value is related to the degree of uniform dispersion of the emulsion system.

[0256] In vitro release: The vemurafenib nanoemulsion was evaluated by in vitro release test (IVRT). This study aimed to determine the rate at which the drug is released from the nanoemulsion into the medium. Determination method: Install a hydrophilic polytetrafluoroethylene artificial membrane (diameter 25 mm, pore size 0.45 μm) on a Franz vertical diffusion cell, use a donor block to provide a leak-proof seal, and expose a surface area of 1.766 cm 2 . The receiving solution was 30% ethanol solution (at a constant temperature of 32 °C); Take an appropriate amount of the test article and apply it on the artificial membrane. Collect the receiving solution at 30 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 10 hours, 16 hours and 24 hours, and use liquid chromatography to detect the amount of vemurafenib that permeates through the artificial membrane. The cumulative amount of vemurafenib measured in the receiving solution is the average of three repeated IVRT measurements. This average is divided by the area of the artificial membrane in contact with the drug, and the cumulative release amount per unit area (μg / cm 2 ) is obtained; This average is divided by the amount of drug in the test article applied to the artificial membrane, and the cumulative release rate (%) is obtained. Plot the cumulative release amount per unit area (μg / cm 2 ) against the square root of time (h -1 / 2 ). The slope (regression) of the resulting straight line is the release rate of the test article.

[0257] In vitro transdermal: The vemurafenib nanoemulsion was evaluated using an in vitro skin penetration test (IVPT). This study aimed to determine the retention amount of the drug in the epidermis and dermis layers and the cumulative penetration amount in the receiving fluid. Determination method: Skin was taken from the abdomen of Bama minipigs aged 1 - 3 months thawed at -20°C to a thickness of approximately 800 - 1300 μm and mounted on a Franz vertical diffusion cell. A donor block was used to provide a leak-proof seal, exposing a surface area of 1.766 cm 2 . The receiving fluid was 0.9% normal saline (maintained at a constant temperature of 32°C). The transdermal water loss value of the skin was measured using a transdermal water loss meter (<50 g·m -2 ·h -1 was considered qualified). The test article was applied to each skin section. The receiving fluid was collected at 1, 3, 6, 9, 12, 15, and 18 hours after application. The cumulative amount of vemurafenib that penetrated through the skin in the receiving fluid was measured using liquid chromatography / mass spectrometry. At 18 hours after application, the skin surface was wiped with a cotton swab and tape-stripped three times to remove any residual test article. The drug residue amount of this residual test article collected from the skin surface was determined using liquid chromatography. The value of the obtained drug residue amount was divided by the contact area of the skin section with the drug to obtain the residue amount per unit area (skin surface residue) (μg / cm 2 ). The skin layers (epidermis and dermis layers) were placed in separate homogenization bottles, the drug was extracted, and the cumulative amount of vemurafenib in the skin layers was detected using liquid chromatography. The cumulative amount of vemurafenib measured in the skin layers was divided by the contact area of the skin section with the drug to obtain the residue amount per unit area (skin retention) (μg / cm 2 ). The cumulative amount of vemurafenib measured in the receiving fluid was divided by the contact area of the skin section with the drug to obtain the cumulative penetration amount per unit area (ng / cm 2 ). The sum of the cumulative amount of vemurafenib in the skin layers, the residual amount of vemurafenib on the skin surface, and the cumulative amount of vemurafenib in the receiving fluid was divided by the amount of drug in the test article applied to the skin to obtain the recovery rate (%).

[0258] Examples

[0259] The present invention will be further illustrated by the following examples, but the present invention is not limited to the scope of the described examples. For the experimental methods without specific conditions noted in the following examples, they are carried out according to conventional methods and conditions, or selected according to the product specifications. For the reagents or instruments without the manufacturer noted, they are all conventional products that can be obtained commercially.

[0260] Example 1: Solubility experiment of vemurafenib

[0261] Based on the characteristics of the excipients (such as HLB value), the key excipients such as emulsifying component 1, emulsifying component 2, and oil phase were initially selected as the screening objects, and the solubility of bemotrizinol in each excipient was preliminarily investigated. Take 1 g of the test excipient. If it is solid at room temperature, heat it to 30 - 40 °C to make it completely liquefy, and add bemotrizinol at this temperature for solubility testing; if it is liquid at room temperature, add bemotrizinol at room temperature for solubility testing. Add bemotrizinol in batches. First, use vortex to promote dissolution. If the effect of vortex is not good, then use ultrasound to promote dissolution until the solution is saturated. The measurement results are shown in Table 1:

[0262] Table 1 Solubility of bemotrizinol in different excipients

[0263]

[0264] The results show that: taking the exemplary drug loading of the bemotrizinol nanoemulsion composition as 1% as the measurement standard, the solubility should preferably reach at least 100 mg / g. According to the solubility test results, polyglyceryl oleate does not meet the requirements, the solubility of TPGS1000 is slightly low, and the solubility properties of the remaining excipients are relatively ideal.

[0265] Example 2: Screening of the type of emulsifying component 1 for blank nanoemulsion

[0266] According to the solubility measurement results of Example 1, the emulsifying component 1 was screened with physical stability as the index. The results are shown in Table 2:

[0267] Preparation of blank nanoemulsion: Phase A: Mix emulsifying component 1, emulsifying component 2, and oil phase, heat in a water bath at 40 - 60 °C, and stir evenly; Phase B: Mix the aqueous phase (water and optional humectant) with the optional penetration enhancer, heat in a water bath at 40 - 60 °C, and stir evenly; Mix Phase A and Phase B, heat in a water bath at 40 - 60 °C, and stir evenly to prepare the blank nanoemulsion.

[0268] Table 2 Screening of the type of emulsifying component 1 for blank nanoemulsion

[0269]

[0270] Continued Table 2 Screening of the type of emulsifying component 1 for blank nanoemulsion

[0271]

[0272] The results show that: when the emulsifying component 1 is Tween 80, the blank nanoemulsion forms a white emulsion after stirring or becomes turbid after freeze-thawing, and a stable nanoemulsion cannot be formed; when the emulsifying component 1 is ELP35, RH40, or TPGS1000, the stability of the blank nanoemulsion is good, and the drug-loaded nanoemulsion can be formulated.

[0273] Example 3: Screening of the type of emulsifying component 2 for blank nanoemulsion

[0274] Prepare the blank nanoemulsion by the same method as in Example 2, and investigate the effect of different emulsifying components 2 on the physical stability of the nanoemulsion. The results are shown in Table 3 in detail:

[0275] Table 3 Screening of the type of emulsifying component 2 for blank nanoemulsion

[0276]

[0277] The results show that when the emulsifying component 2 is PEG400, TP, or Labrasol, stable nanoemulsions can be formed, and the preparation of nanoemulsions containing drugs can be carried out.

[0278] Example 4: Screening of the type of oil phase for blank nanoemulsion (ELP / TP system)

[0279] Prepare the blank nanoemulsion by the same method as in Example 2, and investigate the effect of the oil phase on the physical stability of the nanoemulsion in the ELP / TP system. The results are shown in Table 4-1 in detail:

[0280] Table 4-1 Screening of the type of oil phase for blank nanoemulsion (ELP / TP system)

[0281]

[0282] Continued Table 4-1 Screening of the type of oil phase for blank nanoemulsion (ELP / TP system)

[0283]

[0284] Increase the proportion of the oil phase to 6%, and at the same time adjust the proportion of each component in the mixed oil phase, and investigate the physical stability of the blank nanoemulsion. The results are shown in Table 4-2 in detail:

[0285] Table 4-2 Screening of the proportion of oil phase for blank nanoemulsion

[0286]

[0287] Continued Table 4-2 Screening of the proportion of oil phase for blank nanoemulsion

[0288]

[0289] The results show that in the ELP / TP system, except for IPM, the blank nanoemulsions formed by the other oil phases have good stability, and the preparation of nanoemulsions containing drugs can be carried out.

[0290] Example 5: Screening of the type of oil phase for blank nanoemulsion (ELP / Labrasol system)

[0291] The blank nanoemulsion was prepared by the same method as in Example 2, and the effect of the oil phase on the physical stability of the nanoemulsion in the ELP / Labrasol system was investigated. The results are shown in Table 5 as follows:

[0292] Table 5 Screening of oil phase types for blank nanoemulsion (ELP / Labrasol system)

[0293]

[0294] Continued Table 5 Screening of oil phase types for blank nanoemulsion (ELP / Labrasol system)

[0295]

[0296] The results showed that the blank nanoemulsion formed by the above formulation had good physical stability and could be used for the preparation of nanoemulsion containing drugs.

[0297] Example 6: Screening of oil phase types for blank nanoemulsion (TPGS / Labrasol / TP system)

[0298] The blank nanoemulsion was prepared by the same method as in Example 2, and the effect of the oil phase on the physical stability of the nanoemulsion in the TPGS / Labrasol / TP system was investigated. The results are shown in Table 6 as follows:

[0299] Table 6 Screening of oil phase types for blank nanoemulsion (TPGS / Labrasol / TP system)

[0300]

[0301] The results showed that the blank nanoemulsion formed by the above formulation had good physical stability and could be used for the preparation of nanoemulsion containing drugs.

[0302] Example 7: Screening of formulation for nanoemulsion containing drugs (without gelling agent)

[0303] According to the screening results of the blank nanoemulsion in the above examples, excipients such as antioxidants, bacteriostatic agents, chelating agents and pH regulators were additionally added to prepare the formulation of nanoemulsion containing drugs, and the physical stability of the nanoemulsion containing drugs was investigated.

[0304] Preparation of comparative example: The comparative example was prepared according to the formulation composition and preparation method of Example 2 in Patent CN103315958A.

[0305] Preparation of drug-loaded nanoemulsion: Phase A: Mix API, emulsifying component 1, emulsifying component 2, oil phase, and optional antioxidant and bacteriostatic agent, heat in a water bath at 40 - 60 °C, and stir evenly; Phase B: Mix aqueous phase, optional penetration enhancer, chelating agent, and pH regulator, heat in a water bath at 40 - 60 °C, and stir evenly; Mix Phase A and Phase B, heat in a water bath at 40 - 60 °C, and stir evenly to obtain the drug-loaded nanoemulsion. Alternatively, it can also be added to Phase A or Phase B according to the specific properties of the excipients. For example, when the antioxidant and bacteriostatic agent have good water solubility, they can be added to Phase B.

[0306] The screening results of the drug-loaded nanoemulsion formulation are shown in Table 7 as follows:

[0307] Table 7 Screening of the drug-loaded nanoemulsion formulation

[0308]

[0309] Continued Table 7 Screening of the drug-loaded nanoemulsion formulation

[0310]

[0311] Continued Table 7 Screening of the drug-loaded nanoemulsion formulation

[0312]

[0313] Continued Table 7 Screening of the drug-loaded nanoemulsion formulation

[0314]

[0315] Continued Table 7 Screening of the drug-loaded nanoemulsion formulation

[0316]

[0317] The results show that: The average particle size of the nanoemulsion prepared in the comparative example was measured to be 109 nm, and a clear and transparent nanoemulsion could not be formed. In the drug-loaded nanoemulsion of the present invention, when RH40 was used as emulsifying component 1 and PEG400 or propylene glycol was used as emulsifying component 2, a physically stable drug-loaded nanoemulsion could not be formed; the remaining formulations could all form physically stable drug-loaded nanoemulsions, and nanoemulsions containing gelling agents could be prepared to investigate quality attributes such as stability and in vitro transdermal permeation.

[0318] Example 8: Screening of gelling agent for drug-loaded nanoemulsion (ELP / Labrasol system)

[0319] In this example, aqueous solutions of gelling agents with different types and concentrations were prepared. Using Formulation 7.1 as an exemplary drug-loaded nanoemulsion, it was mixed with the aqueous solution of the gelling agent, and a drug-loaded nanoemulsion containing the gelling agent was prepared by the same method as in Example 7 to investigate the appearance and physical stability. The results are shown in Table 8 as follows:

[0320] Screening of drug-loaded nanoemulsion gels

[0321]

[0322] [1] This ratio refers to the concentration of the gelling agent in the aqueous solution of the gelling agent.

[0323] [2] This ratio refers to the concentration of the gelling agent in the final composition.

[0324] Continued Table 8 Screening of drug-loaded nanoemulsion gels

[0325]

[0326] Continued Table 8 Screening of drug-loaded nanoemulsion gels

[0327]

[0328] The results showed that drug-loaded nanoemulsions containing gelling agents with good physical stability could be obtained using PVP, sodium alginate, sodium hyaluronate, and xanthan gum as gelling agents.

[0329] Example 9: Screening of drug-loaded nanoemulsion formulations containing gelling agents (ELP35 / PEG400, ELP / TP, and TPGS / Labrasol / TP systems)

[0330] In this example, nanoemulsion formulations 7.4 (ELP / PEG400 system), 7.5 (ELP / TP system), and 7.6 (TPGS / Labrasol / TP system) were mixed with sodium alginate or PVP K30, and the appearance and physical stability of the nanoemulsions were investigated. The results are shown in Table 9:

[0331] Table 9 Screening of drug-loaded nanoemulsion gels

[0332]

[0333] [1] This ratio refers to the concentration of the gelling agent in the aqueous solution of the gelling agent.

[0334] [2] This ratio refers to the concentration of the gelling agent in the final composition.

[0335] Continued Table 9 Screening of drug-loaded nanoemulsion gels

[0336]

[0337] The results showed that the physical stabilities of the drug-loaded nanoemulsions and gelling agent mixtures of Formulation 7.4 (ELP / PEG400 system), Formulation 7.5 (ELP / TP), and Formulation 7.6 (TPGS / Labrasol / TP) were good, and they could be formulated with the gelling agent into drug-loaded nanoemulsions containing the gelling agent.

[0338] Example 10: Investigation of the stability and in vitro properties of drug-loaded nanoemulsions containing a gelling agent (ELP / Labrasol system)

[0339] (1) Preparation of the formulation of drug-loaded nanoemulsions containing a gelling agent (ELP / Labrasol system)

[0340] The drug-loaded nanoemulsions containing a gelling agent (ELP / Labrasol system) were prepared according to the formulation components in Table 10, and the results were as follows:

[0341] Table 10 Formulation components of drug-loaded nanoemulsions containing a gelling agent

[0342]

[0343] Continued Table 10 Formulation components of drug-loaded nanoemulsions containing a gelling agent

[0344]

[0345] The results showed that in the ELP / Labrasol system, the nanoemulsions with xanthan gum, sodium alginate, and PVP K30 as gelling agents all had good physical stabilities.

[0346] (2) Accelerated stability test

[0347] The patented prescription 1 (containing 1% bemotrizinol) was prepared according to the formulation of Preparation 21 in Table 8 of Example 7 of Patent CN107666902A, and BHT in the patented prescription 1 was replaced with BHA to prepare the patented prescription 2 (containing 1% bemotrizinol). The creams of the patented prescriptions 1-2 were compared with the nanoemulsions of Formulation 7.1 and Formulations 10.1-10.3 for stability. The samples were placed under accelerated conditions for 1 month or 4 months, and the stability determination results are shown in detail in Table 11:

[0348] Table 11 Accelerated stability test of drug-loaded nanoemulsions containing a gelling agent

[0349]

[0350] The results showed that compared with the creams of the patented prescriptions, the accelerated stability of the nanoemulsions of the present invention was significantly better, the particle size and particle size distribution were both ideal, and the stability was good.

[0351] (3) In vitro release results

[0352] The nanoemulsions of Formulas 10.1 - 10.3 were compared with the creams marketed in China the creams marketed in the United States and the nanoemulsions of Patent Formulas 1 - 2 in terms of in vitro release with different sample loading amounts. The results are shown in Tables 12, 13 and Figure 1 :

[0353] Table 12 Comparative Data of In Vitro Release between the Nanoemulsions of the Present Invention and the Control Drugs

[0354]

[0355] Table 13 Comparative Data of In Vitro Release of the Nanoemulsions of the Present Invention

[0356] Sample Sample Loading Amount mg Cumulative Release Rate % <![CDATA[Cumulative release amount per unit area μg / cm 2 > Release Rate Formulation 10.1 134 27.8(24h) 211.0(24h) 42.2 Formulation 10.2 150 55.4(24h) 427.0(24h) 219.7 Formulation 10.3 100 88.4(24h) 495.6(24h) 491.3

[0357] The results showed that: under the condition of the same sample loading amount, the in vitro release effect of the nanoemulsions of the present invention was significantly better than that of the creams of Patent Formulas 1 - 2

[0358] (4) Results of In Vitro Transdermal Penetration

[0359] A comparative study on in vitro transdermal penetration was carried out between Formula 10.1 (xanthan gum 0.56%) and the creams of Patent Formulas 1 - 2 (with sample loading amounts of 150 mg or 20 mg). The results are shown in Tables 14, 15 and Figure 2 :

[0360] Table 14 Skin Integrity Results and Sample Loading Amounts

[0361] Skin Serial Number <![CDATA[Transdermal water loss (g·m -2 ·h -1 )]]> Thickness (mm) Weight (g) Sample Loading Amount (mg) 1 37.2 0.802 0.7615 155.70 2 36.9 0.891 0.8024 149.29 3 24.0 0.790 0.6914 159.49 4 36.0 0.903 0.8375 144.06 5 94.9 0.845 0.7063 139.26 6 30.2 0.990 0.8647 141.33 7 20.0 0.935 0.7994 145.49 8 43.4 0.998 0.8942 143.97 9 27.6 0.943 0.8063 150.16 10 24.3 0.986 0.9210 21.93 11 42.5 1.038 0.8895 19.35 12 47.2 1.029 0.9007 21.71

[0362] Table 15 Skin Retention and Skin Surface Residue Results

[0363]

[0364] [1] Measure the residual amount per unit area (skin retention) 3 times and take the average value

[0365] [2] Measure the residual amount per unit area (skin surface residue) 3 times and take the average value

[0366] The results showed that: the residual amount per unit area in the skin (skin retention) of the nanoemulsion of Formula 10.1 (0.56% xanthan gum) was better than that of and As can be seen from Figure 2 the cumulative penetration amount per unit area in vitro of the nanoemulsion of Formula 10.1 was significantly better than that of and Example 11: Investigation of the stability and in vitro properties of a drug-loaded nanoemulsion containing a gelling agent (ELP / TP system) (1) Preparation of the formulation of the drug-loaded nanoemulsion containing a gelling agent (ELP / TP system) The drug-loaded nanoemulsions with and without a gelling agent were prepared according to the formulation components in Table 16, and the results are as follows:

[0367] Table 16 Formulation components of the drug-loaded nanoemulsion

[0368]

[0369] Continued Table 16 Formulation components of the drug-loaded nanoemulsion

[0370]

[0371] Continued Table 16 Formulation components of the drug-loaded nanoemulsion

[0372]

[0373] Continued Table 16 Formulation components of the drug-loaded nanoemulsion

[0374]

[0375] (2) Accelerated stability test

[0376] The nanoemulsion of the present invention and were subjected to an accelerated stability test. The samples were placed under accelerated conditions for 1 month, and the stability determination results are shown in Table 17 in detail:

[0377] Table 17 Accelerated stability test of the drug-loaded nanoemulsion of the present invention

[0378]

[0379] The results showed that the accelerated stabilities of Formulations 11.4, 11.8, and 11.9 were at least not inferior to or better than those of other formulations.

[0380] (3) In vitro transdermal results

[0381] Formulations 11.8, 11.9, and 10.1 and were subjected to in vitro transdermal studies (the sample loading amount was 150 mg), and the results are shown in Tables 18 and 19 in detail:

[0382] Table 18 Skin integrity results and drug loading amount

[0383] Skin Serial Number <![CDATA[Transdermal water loss (g·m -2 ·h -1 )]]> Thickness (mm) Weight (g) Sample Loading Amount (mg) 1 17.3 1.169 1.0614 149.15 2 41.5 1.276 1.0966 151.20 3 18.4 1.157 1.0598 148.80 4 22.4 1.195 1.1026 150.83 5 18.0 1.286 1.1601 151.10 6 18.4 1.119 1.0484 144.48 7 30.0 1.183 0.9822 159.59 8 33.3 1.203 1.2068 144.39 9 20.6 1.218 1.0319 150.51 10 31.6 1.171 1.0026 142.98 11 14.1 1.170 1.0013 146.83 12 12.5 1.273 1.1664 145.16

[0384] Table 19 Skin retention and skin surface residue results

[0385]

[0386] [1] Measure the residual amount per unit area (skin retention) three times and take the average value.

[0387] [2] Measure the residual amount per unit area (skin surface residue) three times and take the average value.

[0388] The results showed that the skin retention of Formulations 10.1, 11.8, and 11.9 was better than

[0389] Example 12: Investigate the stability and in vitro properties of drug-loaded nanoemulsions containing gelling agents (RH40 / TP or RH40 / Labrasol systems)

[0390] (1) Preparation of the formulation of drug-loaded nanoemulsions containing gelling agents (RH40 / TP or RH40 / Labrasol systems)

[0391] Prepare drug-loaded nanoemulsions containing gelling agents according to the formulation components in Table 20. The results are as follows:

[0392] Table 20 Formulation components of drug-loaded nanoemulsions

[0393]

[0394] Continued Table 20 Formulation components of drug-loaded nanoemulsions

[0395]

[0396] The results showed that the physical stability was good after mixing the drug-loaded nanoemulsions and gelling agents composed of the formulation components in Table 20, and stable drug-loaded nanoemulsions containing gelling agents could be formulated with gelling agents.

[0397] (2) Accelerated stability test

[0398] Subject the nanoemulsion of the present invention and conduct an accelerated stability test. The samples are placed under accelerated conditions for 1 month. The results of the stability determination are shown in Table 21 in detail:

[0399] Table 21 Accelerated stability test of the drug-loaded nanoemulsion of the present invention

[0400]

[0401] The results showed that the accelerated stability of Formulations 12.1 - 12.4 and 12.6 was at least not inferior to or better than

[0402] (3) In vitro transdermal results

[0403] Mix Formulation 12.1, Formulation 12.3, and Formulation 12.4 with In vitro transdermal studies were carried out (the sample loading amount was about 150 mg), and the results are shown in Tables 22 and 23:

[0404] Table 22 Skin integrity results and sample loading amount

[0405] Skin Serial Number <![CDATA[Transdermal water loss (g·m -2 ·h -1 )]]> Thickness (mm) Weight (g) Sample Loading Amount (mg) 1 17.8 0.986 0.8957 136.4 2 20.7 0.956 0.8465 146.7 3 16.3 0.891 0.7855 153.0 4 3.3 1.093 0.8565 145.3 5 7.0 1.171 0.9036 155.9 6 27.3 1.131 0.8982 163.5 7 24.6 0.984 1.1097 154.5 8 37.7 0.966 0.8173 159.1 9 16.8 0.988 0.7826 149.7 10 18.4 0.895 0.7973 154.8 11 27.8 0.772 0.7025 157.9 12 29.9 0.960 0.9017 156.5

[0406] Table 23 Skin retention and skin surface residue results

[0407]

[0408] [1] Measure the residue amount per unit area (skin retention) 3 times and take the average value.

[0409] [2] Measure the residue amount per unit area (skin surface residue) 3 times and take the average value.

[0410] The results showed that the skin retention amounts of Formulations 12.1, 12.3 and 12.4 were all better than

[0411] Example 13: Preparation of foam agent

[0412] Select Formulation 10.2, Formulation 11.4, Formulation 11.8 and Formulation 11.9 to prepare nanoemulsion, and the propellant is pure butane or tetrafluoroethane. Design to fill 50 g of nanoemulsion with different weights of propellant to prepare different concentrations of bemotrizinol foam agent. The results are shown in Table 24:

[0413] Table 24 Preparation of foam agent

[0414]

[0415] Continued Table 24 Preparation of foam agent

[0416]

[0417] The results showed that the nanoemulsion of the present invention can be made into a foam agent, and the foam agent is stable, delicate and soft, easy to apply, and can be used for special parts attached to the scalp and hair.

[0418] Example 14: Pharmacodynamic study of the nanoemulsion of the present invention in a psoriasis-like model of BALB / c mice induced by imiquimod

[0419] A psoriasis-like model of BALB / c mice was established, and the nanoemulsion of the present invention was administered by topical application to investigate the therapeutic and improvement effects of the test substance on psoriasis induced by imiquimod in mice.

[0420] (1) Main experimental materials

[0421] Animals: Specific pathogen-free (SPF) grade BALB / c mice, female, 9 weeks old, weighing 18 g - 22 g, purchased from Beijing Vital River Laboratory Animal Technology Co., Ltd.

[0422] Drugs and reagents: The nanoemulsion test articles of the present invention (Formulation 11.8 and Formulation 12.1), cream, cream, imiquimod cream (purchased from Sichuan Mingxin Pharmaceutical Co., Ltd.).

[0423] (2) Experimental methods

[0424] Take SPF grade BALB / c mice with qualified quarantine. One day before modeling, the hair on the back of the animals was removed with depilatory cream in an area of about 2 cm × 3 cm until the skin was completely exposed. After the experiment started, all the animals were randomly divided into a blank control group, a model control group, a positive control group 1 ( cream), a positive control group 2 ( cream), a test article group 1 (Formulation 11.8) and a test article group 2 (Formulation 12.1) according to their body weights. On the day of the experiment, 6 hours after administration, except for the blank control group, the mice in the other groups were smeared with about 5% imiquimod cream at 83 mg / animal / day on the back. The mice in the blank control group were smeared with the same dose of vaseline on the back for 8 consecutive days. The number of animals in each group was 10. After the modeling started, they were raised individually in cages. The specific grouping and drug administration are shown in Table 25:

[0425] Table 25 Experimental grouping and dose design table

[0426]

[0427] [1] refers to the control group that does not give any treatment to the animals and does not add any control drugs.

[0428] [2] That is, the animal pathological model group, which refers to the control group treated with the modeling drug (imiquimod cream).

[0429] [3] refers to the drug administration group that gives positive reagents or test articles (solvent / test article) on the basis of imiquimod modeling.

[0430] (3) Observation indicators

[0431] The Psoriasis Area and Severity Index (PASI) was used to score the skin lesions on the backs of the mice. During the period of animal administration, each mouse was photographed with a digital camera before drug administration every day, and the PASI scoring method was used to score the severity of skin lesions in mice with three indicators: erythema, scale, and skin thickness. PASI scoring criteria: 0 - 4 points, corresponding to none, mild, moderate, severe, and extremely severe according to the severity, and the total score is the sum of the scores of the three indicators (0 - 12 points). The PASI scoring form is shown in Table 26:

[0432] Table 26 PASI Scoring Form

[0433]

[0434] (4) Data Statistics

[0435] The data were expressed as Mean ± SEM. If it conformed to the normal distribution, a two-sample equal-variance two-tailed T-test was used; if it did not conform to the normal distribution, a non-parametric test was used.

[0436] (5) Experimental Results

[0437] After the administration and treatment of the female BALB / c mouse model induced by imiquimod, the changes in the severity scores of skin lesions in each group are shown in Table 27. The change curve of the PASI score for the severity of skin lesions can be seen in Figure 3 .

[0438] Table 27 Severity Scores of Skin Lesions at Different Time Points in Each Group

[0439]

[0440] △: Indicates a statistically significant difference compared with the cream, P < 0.05.

[0441] *: Indicates a statistically significant difference compared with the cream, P < 0.05.

[0442] The results showed that: there were no changes such as scales and erythema in the skin of the mice in the normal control group. In the model control group, after 2 - 3 days of imiquimod application, fine scales and mild wrinkles appeared on the skin. On the 8th day, the skin turned dark red in a large area, covered with layered scales that were easy to fall off, the skin was highly thickened, and the elevation was obvious. In the mice treated with the cream, Prescription 11.8, and Prescription 12.1, the mental state improved compared with the model control group on the 8th day of drug administration. A little scale was visible on the skin, the high thickening of the skin improved, the elevation decreased significantly, and there were mild wrinkles. A two-sample equal-variance two-tailed T-test was used for statistical analysis. Among them, compared with Cream. The skin PASI scores of Formulation 11.8 and Formulation 12.1 showed a significant decrease on the 6th, 7th, and 8th days of continuous topical administration, and the effects were better than cream; furthermore, Formulation 11.8 showed a statistically significant difference in drug efficacy compared to cream on the 8th day at the end of the trial, and Formulation 12.1 showed a statistically significant difference in drug efficacy compared to cream on the 6th, 7th, and 8th days. Compared to cream, the skin PASI scores of Formulation 11.8 and Formulation 12.1 were significantly lower than cream on the 5th, 6th, 7th, and 8th days of continuous topical administration, and showed a statistically significant difference in drug efficacy compared to cream on the 5th, 6th, 7th, and 8th days. The above results indicate that the composition of the present invention can significantly improve imiquimod-induced psoriatic-like skin lesions in BALB / c mice, and has better therapeutic effects compared to cream, cream.

Claims

1. A nanoemulsion composition, which comprises benvitimod or a pharmaceutically acceptable salt thereof, an emulsifying component 1, an emulsifying component 2, an oil phase and an aqueous phase; The emulsifying component 1 is polyoxyl castor oil with 30 - 60 units of polyethylene oxide, and the emulsifying component 2 is selected from: fatty alcohol ethers of polyhydric alcohols containing 2 - 6 carbon atoms, a combination of fatty alcohol ethers of polyhydric alcohols containing 2 - 6 carbon atoms and polyethylene glycol glycerol esters, a combination of fatty alcohol ethers of polyhydric alcohols containing 2 - 6 carbon atoms and polyethylene glycol with an average molecular weight of 200 - 400, and a combination of fatty alcohol ethers of polyhydric alcohols containing 2 - 6 carbon atoms, polyethylene glycol glycerol esters and polyethylene glycol with an average molecular weight of 200 - 400; Alternatively, the emulsifying component 1 is polyoxyl hydrogenated castor oil with 30 - 60 units of polyethylene oxide, and the emulsifying component 2 is selected from: fatty alcohol ethers of polyhydric alcohols containing 2 - 6 carbon atoms, and a combination of fatty alcohol ethers of polyhydric alcohols containing 2 - 6 carbon atoms and polyethylene glycol glycerol esters; Alternatively, the emulsifying component 1 is polyethylene glycol vitamin E succinate with an average molecular weight of 500 - 2000, and the emulsifying component 2 is a combination of fatty alcohol ethers of polyhydric alcohols containing 2 - 6 carbon atoms and polyethylene glycol glycerol esters; The fatty alcohol ether of polyhydric alcohols containing 2 - 6 carbon atoms is diethylene glycol monoethyl ether; the polyethylene glycol glycerol ester is polyethylene glycol glycerol caprylate / caprate; The oil phase is selected from one or more of medium-chain triglycerides, caprylic / capric monoglyceride and diglyceride, polyoxyl glyceryl oleate and propylene glycol monocaprylate; Based on the total weight of the composition, the content of benvitimod or a pharmaceutically acceptable salt thereof is 1% - 3%, the content of the emulsifying component 1 is 5% - 30%, the content of the emulsifying component 2 is 3% - 25%, the content of the oil phase is 1% - 25%, and the content of the aqueous phase is 30% - 85%.

2. The nanoemulsion composition according to claim 1, wherein the nanoemulsion composition is an oil-in-water nanoemulsion.

3. The nanoemulsion composition according to claim 1, wherein based on the total weight of the composition, the content of benvitimod or a pharmaceutically acceptable salt thereof is 1% - 2%.

4. The nanoemulsion composition according to claim 1, wherein the emulsifying component 1 is polyoxyl castor oil with 30 - 50 units of polyethylene oxide, and the emulsifying component 2 is selected from: fatty alcohol ethers of polyhydric alcohols containing 2 - 6 carbon atoms, a combination of fatty alcohol ethers of polyhydric alcohols containing 2 - 6 carbon atoms and polyethylene glycol glycerol esters, a combination of fatty alcohol ethers of polyhydric alcohols containing 2 - 6 carbon atoms and polyethylene glycol with an average molecular weight of 200 - 400, and a combination of fatty alcohol ethers of polyhydric alcohols containing 2 - 6 carbon atoms, polyethylene glycol glycerol esters and polyethylene glycol with an average molecular weight of 200 - 400; Alternatively, the emulsifying component 1 is polyoxyl hydrogenated castor oil with 30 - 50 units of polyethylene oxide, and the emulsifying component 2 is selected from: fatty alcohol ethers of polyhydric alcohols containing 2 - 6 carbon atoms, and A combination of fatty alcohol ethers of polyols having 2 to 6 carbon atoms and polyethylene glycol glycerol esters; Alternatively, the emulsifying component 1 is polyethylene glycol vitamin E succinate with an average molecular weight of 500 - 1500, and the emulsifying component 2 is a combination of fatty alcohol ethers of polyols having 2 to 6 carbon atoms and polyethylene glycol glycerol esters.

5. The nanoemulsion composition according to claim 4, characterized in that the emulsifying component 1 is polyoxyethylene castor oil with 30 - 40 units of polyoxyethylene, and the emulsifying component 2 is selected from: fatty alcohol ethers of polyols having 2 to 6 carbon atoms, a combination of fatty alcohol ethers of polyols having 2 to 6 carbon atoms and polyethylene glycol glycerol esters, a combination of fatty alcohol ethers of polyols having 2 to 6 carbon atoms and polyethylene glycol with an average molecular weight of 200 - 400, and a combination of fatty alcohol ethers of polyols having 2 to 6 carbon atoms, polyethylene glycol glycerol esters and polyethylene glycol with an average molecular weight of 200 - 400; Alternatively, the emulsifying component 1 is polyoxyethylene hydrogenated castor oil with 30 - 40 units of polyoxyethylene, and the emulsifying component 2 is selected from: fatty alcohol ethers of polyols having 2 to 6 carbon atoms, and a combination of fatty alcohol ethers of polyols having 2 to 6 carbon atoms and polyethylene glycol glycerol esters; Alternatively, the emulsifying component 1 is polyethylene glycol vitamin E succinate with an average molecular weight of 800 - 1200, and the emulsifying component 2 is a combination of fatty alcohol ethers of polyols having 2 to 6 carbon atoms and polyethylene glycol glycerol esters.

6. The nanoemulsion composition according to claim 5, characterized in that the emulsifying component 1 is polyoxyethylene 35 castor oil, and the emulsifying component 2 is selected from: fatty alcohol ethers of polyols having 2 to 6 carbon atoms, a combination of fatty alcohol ethers of polyols having 2 to 6 carbon atoms and polyethylene glycol glycerol esters, a combination of fatty alcohol ethers of polyols having 2 to 6 carbon atoms and polyethylene glycol with an average molecular weight of 200 - 400, and a combination of fatty alcohol ethers of polyols having 2 to 6 carbon atoms, polyethylene glycol glycerol esters and polyethylene glycol with an average molecular weight of 200 - 400; Alternatively, the emulsifying component 1 is polyoxyethylene 40 hydrogenated castor oil, and the emulsifying component 2 is selected from: fatty alcohol ethers of polyols having 2 to 6 carbon atoms, and a combination of fatty alcohol ethers of polyols having 2 to 6 carbon atoms and polyethylene glycol glycerol esters; Alternatively, the emulsifying component 1 is vitamin E succinate polyethylene glycol ester 1000, and the emulsifying component 2 is a combination of fatty alcohol ethers of polyols having 2 to 6 carbon atoms and polyethylene glycol glycerol esters.

7. The nanoemulsion composition according to claim 1, characterized in that based on the total weight of the composition, the content of the emulsifying component 1 is 10% - 25%.

8. The nanoemulsion composition according to claim 7, characterized in that based on the total weight of the composition, the content of the emulsifying component 1 is 10% - 20%.

9. The nanoemulsion composition according to claim 8, characterized in that based on the total weight of the composition, the content of the emulsifying component 1 is 12% - 20%.

10. The nanoemulsion composition according to claim 1, wherein the emulsifying component 1 is polyoxyl castor oil with 30 - 60 units of polyethylene oxide, and the emulsifying component 2 is selected from: diethylene glycol monoethyl ether, a combination of polyethylene glycol glyceryl caprylate / caprate and diethylene glycol monoethyl ether, a combination of diethylene glycol monoethyl ether and polyethylene glycol 400, and a combination of polyethylene glycol glyceryl caprylate / caprate, diethylene glycol monoethyl ether and polyethylene glycol 400.

11. The nanoemulsion composition according to claim 10, wherein the emulsifying component 2 is selected from: diethylene glycol monoethyl ether, and a combination of polyethylene glycol glyceryl caprylate / caprate and diethylene glycol monoethyl ether.

12. The nanoemulsion composition according to claim 1, wherein based on the total weight of the composition, the content of the emulsifying component 2 is 3% - 20%.

13. The nanoemulsion composition according to claim 12, wherein based on the total weight of the composition, the content of the emulsifying component 2 is 5% - 20%.

14. The nanoemulsion composition according to claim 13, wherein based on the total weight of the composition, the content of the emulsifying component 2 is 5% - 12%.

15. The nanoemulsion composition according to claim 1, wherein the oil phase is selected from any combination of two of medium-chain triglycerides, caprylic / capric monoglyceride / diglyceride, polyoxyl glyceryl oleate and propylene glycol monocaprylate.

16. The nanoemulsion composition according to claim 1, wherein based on the total weight of the composition, the content of the oil phase is 3% - 20%.

17. The nanoemulsion composition according to claim 16, wherein based on the total weight of the composition, the content of the oil phase is 3% - 15%.

18. The nanoemulsion composition according to claim 17, wherein based on the total weight of the composition, the content of the oil phase is 4% - 8%.

19. The nanoemulsion composition according to any one of claims 1 - 18, wherein the aqueous phase contains water and an optional humectant; the humectant is a short-chain alcohol containing 2 - 6 carbon atoms.

20. The nanoemulsion composition according to claim 19, wherein the humectant is selected from one or more of glycerol, sorbitol, propylene glycol, isopropyl alcohol, ethanol, butylene glycol, hexylene glycol and pentylene glycol.

21. The nanoemulsion composition according to claim 20, wherein the humectant is propylene glycol.

22. The nanoemulsion composition according to claim 19, wherein based on the total weight of the composition, the content of the humectant is 0 - 10%.

23. The nanoemulsion composition according to claim 22, wherein based on the total weight of the composition, the content of the aqueous phase is 30% - 75%, and the content of the humectant is 5% - 10%.

24. The nanoemulsion composition according to claim 23, wherein based on the total weight of the composition, the content of the aqueous phase is 45% - 75%, and the content of the humectant is 5% - 10%.

25. The nanoemulsion composition according to claim 24, wherein based on the total weight of the composition, the content of the aqueous phase is 58%-72%, and the content of the humectant is 7%-10%.

26. The nanoemulsion composition according to any one of claims 1-18, wherein the nanoemulsion composition further comprises a penetration enhancer; the penetration enhancer is selected from one or more of diethylene glycol monoethyl ether, oleic acid, stearic acid, isostearic acid, lactic acid, lauric acid, polyethylene glycol, isopropyl myristate, isopropyl palmitate, dimethylacetamide, triglyceride, menthol, menthol crystal, propylene glycol, borneol, cnidium fruit oil, azone, sodium tetradecyl sulfate, geraniol, anethole, and decyl methyl sulfoxide; based on the total weight of the composition, the content of the penetration enhancer is 0-15%.

27. The nanoemulsion composition according to claim 26, wherein the penetration enhancer is diethylene glycol monoethyl ether; based on the total weight of the composition, the content of the penetration enhancer is 1%-10%.

28. The nanoemulsion composition according to any one of claims 1-18, wherein the nanoemulsion composition further comprises one or more of an antioxidant, an antibacterial agent, a chelating agent, and a pH regulator.

29. The nanoemulsion composition according to claim 28, wherein the antioxidant is selected from one or more of butylated hydroxyanisole, dibutylhydroxytoluene, tert-butylhydroquinone, propyl gallate, L-ascorbyl palmitate, ethoxyquin, sodium metabisulfite, dilauryl thiodipropionate, tea polyphenols, tocopherol, and grape seed extract; based on the total weight of the composition, the content of the antioxidant is 0-2%; the antibacterial agent is selected from one or more of benzyl alcohol, phenoxyethanol, sorbic acid or its salts, parabens, benzalkonium chloride, benzalkonium bromide, chlorobutanol, benzoic acid or its salts, citric acid or its salts, and ascorbic acid or its salts; based on the total weight of the composition, the content of the antibacterial agent is 0-2%; the chelating agent is selected from one or more of citric acid, glucuronic acid, sodium hexametaphosphate, zinc hexametaphosphate, edetic acid or its derivatives, and phosphonates; based on the total weight of the composition, the content of the chelating agent is 0-2%; the pH regulator is selected from one or more of inorganic or organic acids, inorganic or organic bases, and buffer salts; based on the total weight of the composition, the content of the pH regulator is 0-2%.

30. The nanoemulsion composition according to claim 29, wherein the antioxidant is selected from one or more of butylated hydroxyanisole and dibutylhydroxytoluene; the antibacterial agent is benzoic acid; the chelating agent is disodium edetate; the pH regulator is citric acid-sodium citrate buffer salt; based on the total weight of the composition, the content of the antioxidant is 0.1%-0.2%; the content of the antibacterial agent is 0.2%-0.3%; the content of the chelating agent is 0.1%-0.2%; the content of the pH regulator is 0.2%-0.3%.

31. The nanoemulsion composition according to any one of claims 1-18, wherein The nanoemulsion composition further comprises a gelling agent; The gelling agent is selected from one or more of xanthan gum, sodium hyaluronate, povidone, and sodium alginate; Based on the total weight of the composition, the content of the gelling agent is 0-5%.

32. The nanoemulsion composition according to claim 31, wherein The gelling agent is selected from one or more of xanthan gum, sodium alginate, and sodium hyaluronate; Based on the total weight of the composition, the content of the gelling agent is 0.05%-2%.

33. The nanoemulsion composition according to any one of claims 1-18, wherein The particle size of the nanoemulsion composition is 5-200 nm; The pH value of the nanoemulsion composition is 4-9.

5.

34. The nanoemulsion composition according to claim 33, wherein The particle size of the nanoemulsion composition is 5-80 nm; The pH value of the nanoemulsion composition is 4.5-7.

35. An external pharmaceutical preparation, which comprises the nanoemulsion composition according to any one of claims 1-34; The external pharmaceutical preparation is a liniment, foam agent, spray, film, ointment, cream, gel, patch, or cataplasm.

36. The application of the nanoemulsion composition according to any one of claims 1-34 or the external pharmaceutical preparation according to claim 35 in the preparation of a drug for preventing and / or treating inflammatory skin diseases.

37. The application according to claim 36, wherein The inflammatory skin disease is selected from one or more of psoriasis, eczema, palmoplantar pustulosis, and atopic dermatitis.

38. The application according to claim 37, wherein The inflammatory skin disease is scalp psoriasis.

Images