Gas emulsification composition as well as preparation method and application thereof

Abstract

The invention belongs to the technical field of pharmaceutical preparations, and particularly relates to a gas emulsification composition as well as a preparation method and application thereof. The gas emulsification composition is prepared from the following components in percentage by mass: 0.1%-2.0% of a compound X, 5%-20% of a solvent, 1%-10% of a nonionic surfactant, 0.5%-5% of an anionic surfactant, 0.3%-0.8% of a rheology modifier, 3%-15% of a propellant and the balance of water, totaling 100%, wherein the compound X is {1-(ethylsulfonyl)-3-[4-(7H-pyrrolo [2, 3-d] pyrimidine-4-yl)-1H-pyrazol-1-yl] azetidine-3-yl} acetonitrile, and the compound X is a compound R2, a compound R3 and a compound R4, the mass ratio of the nonionic surfactant to the anionic surfactant is (1-4): 1. The gas emulsion composition prepared by the invention has excellent foam performance, high skin permeation efficiency and good stability.

Description

Technical Field

[0001] The present invention belongs to the technical field of pharmaceutical preparations, and in particular relates to a gas emulsion composition, a preparation method and an application thereof. Background Art

[0002] In the pharmaceutical field, pyrrolo[2,3-d]pyrimidines, a class of highly effective Janus kinase (JAK) inhibitors, have demonstrated significant advantages in the treatment of autoimmune and inflammatory diseases. For example, in conditions such as atopic dermatitis and psoriasis, these compounds precisely target pathogenic targets, effectively alleviating inflammatory responses and regulating immune imbalances, demonstrating broad clinical application prospects.

[0003] Compound X, abbreviated as {1-(ethylsulfonyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile, is a key topical formulation for pyrrolo[2,3-d]pyrimidine active ingredients, such as Compound X. This allows the drug to act directly on affected skin, increasing local drug concentration while reducing the risk of systemic side effects associated with systemic administration. Currently, traditional ointments and creams containing Compound X have a strong greasy feel due to the matrix properties, impacting the patient experience. Furthermore, the drug's transdermal absorption efficiency is limited, making it difficult to effectively penetrate deep into the skin to exert its effects. Furthermore, the drug is unstable and susceptible to degradation or deterioration due to the influence of the matrix components.

[0004] In recent years, gaseous emulsions have attracted considerable attention as a novel topical drug delivery method due to their excellent spreadability, refreshing skin feel, and high patient compliance. However, developing a gaseous emulsion suitable for Compound X remains a significant challenge.

[0005] Because Compound X contains polycyclic aromatic heterocycles and lipophilic groups, the solubilizing ability of conventional surfactants, such as polysorbate 20 or sorbitan monooleate, is insufficient to achieve the desired solubility. This can lead to drug crystallization, particularly at high drug concentrations, directly impacting formulation stability and bioavailability. Furthermore, aerosol emulsion compositions require a stable foam structure, but conventional excipients that promote foam stability, such as sodium dodecyl sulfate and sodium dodecylbenzenesulfonate, can form ion pairs or aggregates with Compound X molecules, altering the drug's solubility and thus affecting its thermodynamic stability. Summary of the Invention

[0006] To address the technical issues of compound X solubility at high drug concentrations, foam stability, and compatibility with drug stability, the present invention provides a gaseous emulsion composition, its preparation method, and application. This gaseous emulsion composition can improve the skin permeability of compound X, enhance the stability of compound X in the formulation, and exhibit excellent foam properties and patient compliance.

[0007] The present invention utilizes a nonionic surfactant to form micelles to encapsulate compound X, and controls the mass ratio of the nonionic surfactant to the anionic surfactant to be 1 to 4:1. Through the synergistic solubilization effect of the nonionic surfactant, the anionic surfactant, and the solvent, the solubility of compound X in the aqueous phase is significantly improved while minimizing skin irritation. A rheology modifier is utilized to stabilize the foam structure through physical thickening. This physical thickening mechanism does not react with the chemical structure of compound X, thereby avoiding the technical contradiction between foam stability and drug chemical stability.

[0008] The first object of the present invention is to provide a gas emulsion composition, which is prepared from the following components, calculated by mass percentage: 0.1% to 2.0% of compound X, 5% to 20% of solvent, 1% to 10% of nonionic surfactant, 0.5% to 5% of anionic surfactant, 0.3% to 0.8% of rheology modifier, 3% to 15% of propellant, and the balance being water, totaling 100%; wherein the structural formula of compound X is as follows: ; Preferably, the mass ratio of the nonionic surfactant to the anionic surfactant is 1 to 4:1.

[0009] Preferably, the nonionic surfactant is one of fatty acid polyoxyethylene esters, polyethers and alkylphenol polyoxyethylene ethers.

[0010] Preferably, the anionic surfactant is a carboxylate or a phosphate.

[0011] Preferably, the pH value of the gas emulsion composition is 4.5 to 6.5.

[0012] It should be noted that the present invention utilizes nonionic surfactants to form micelles to encapsulate compound X. Simultaneously, the solubilizing effect of anionic surfactants is utilized. When the mass ratio of nonionic surfactant to anionic surfactant is 1 to 4:1, a synergistic solubilization effect occurs between the two, thereby significantly improving the solubility of compound X in the aqueous phase. The specific mechanism is as follows: the charged head of the anionic surfactant and the non-charged head of the nonionic surfactant together form stable mixed micelles. The internal environment of this mixed micelle is more friendly to the dissolution of compound X, and the micelle structure is more stable, capable of accommodating more drugs. At the same time, the anionic surfactant may help the nonionic surfactant to spread and penetrate better by reducing interfacial tension.

[0013] Nonionic surfactants typically produce fine, stable foam, but their foaming power is inferior to that of anionic surfactants. Anionic surfactants, on the other hand, possess extremely strong foaming power and can rapidly produce large amounts of foam. When the mass ratio of nonionic surfactant to anionic surfactant is 1 to 4:1, the two surfactants form a tougher and more elastic liquid film. The nonionic surfactant fills the gaps between the anionic surfactant molecules, enhancing the strength and elasticity of the liquid film and reducing water drainage. This improves the durability and fineness of the foam and prevents it from collapsing too quickly or becoming too coarse.

[0014] Using high concentrations of anionic surfactants alone can cause skin irritation due to their strong degreasing ability, which can disrupt the skin barrier. Compounding anionic surfactants with mild nonionic surfactants can significantly reduce the skin irritation of the anionic surfactant while maintaining the foaming ability of both the nonionic and anionic surfactants. Furthermore, the buffering effect and mild properties of the nonionic surfactant can alleviate the irritation of the anionic surfactant to a certain extent, making the entire combination more skin-friendly and improving patient compliance.

[0015] Surfactants also have a certain permeation-promoting effect; they can temporarily alter the lipid arrangement in the skin's stratum corneum, reducing the skin barrier's electrical resistance and creating favorable conditions for the penetration of Compound X. This synergistic effect of nonionic and anionic surfactants promotes the transdermal absorption of Compound X more effectively than a single type of surfactant alone.

[0016] Preferably, the nonionic surfactant is one of polysorbate 80, poloxamer 188 and octylphenol polyoxyethylene ether.

[0017] Preferably, the anionic surfactant is sodium N-lauroyl sarcosinate or sodium laureth sulfate.

[0018] The present invention ensures the full dissolution of compound X while minimizing skin irritation through the synergistic effect of surfactants and solvents. Preferably, the solvent is at least one of propylene glycol, glycerol, and polyethylene glycol 400.

[0019] Preferably, the rheology modifier is one of carbomer 980, hydroxypropyl methylcellulose, and xanthan gum. The present invention utilizes a rheology modifier to control the viscosity of the formulation through physical thickening. When the rheology modifier accounts for 0.3% to 0.8% of the total mass of the gas emulsion composition, a moderately cross-linked three-dimensional network is formed within the formulation. This network effectively "traps" bubbles, restricting their coalescence and rise, preventing the foam film from rapidly thinning and breaking, thereby significantly improving the durability of the foam. Furthermore, an appropriate viscosity helps form more uniform and smaller bubbles, resulting in a finer foam with a better feel. A rheology modifier concentration below 0.3% results in excessively low viscosity, a thin formulation, and a fragile, easily collapsed foam film. This not only leads to unstable foam but also may cause premature or uneven drug release, compromising skin absorption efficiency. A rheology modifier concentration above 0.8% results in excessively high viscosity, making the formulation overly viscous. This makes the foam difficult to spread and creates a strong dragging sensation during application, impacting the patient experience. The drug is trapped in the viscous matrix, which limits its diffusion and release rates, thereby reducing the in vitro skin permeation rate and permeation amount of Compound X.

[0020] Preferably, the propellant is a hydrofluoroalkane or a hydrocarbon.

[0021] A second object of the present invention is to provide a method for preparing the above-mentioned gas emulsion composition, comprising the following steps: Compound X and a solvent are mixed under stirring to obtain a drug solution; a nonionic surfactant, an anionic surfactant, and a portion of water are mixed, a rheology modifier is added, and the mixture is stirred until completely swollen and uniform to obtain a matrix; the drug solution and the matrix are mixed, the pH value is adjusted to 4.5 to 6.5, and the remaining water is added to obtain a feed liquid; the feed liquid is encapsulated with a propellant to obtain a gas emulsion composition.

[0022] Preferably, the mass of the water accounts for 60% to 70% of the total mass of the gas emulsion composition.

[0023] The third object of the present invention is to provide the use of the above-mentioned gas emulsion composition in the preparation of a pharmaceutical preparation for treating inflammatory skin diseases.

[0024] Compared with the prior art, the present invention has the following technical effects: The present invention utilizes a nonionic surfactant to form micelles to encapsulate compound X, and controls the mass ratio of the nonionic surfactant to the anionic surfactant to be 1 to 4:1. Through the synergistic solubilization effect of the nonionic surfactant, the anionic surfactant, and the solvent, the solubility of compound X in the aqueous phase is significantly improved, while minimizing skin irritation. The present invention utilizes a rheology modifier to stabilize the foam structure through physical thickening. This physical thickening mechanism does not react with the chemical structure of compound X, thus avoiding the technical contradiction between foam stability and drug chemical stability.

[0025] By controlling the rheology modifier dosage to 0.3% to 0.8%, the present invention stabilizes the foam while ensuring good spreadability of the formulation, enabling the drug to be effectively released from the matrix and penetrate the skin. Furthermore, the appropriate viscosity provided by the rheology modifier effectively inhibits the sedimentation or crystallization of solid particles in the formulation and limits the stratification of liquid components; this helps maintain the uniformity and physical stability of the entire formulation, thereby extending the product's shelf life.

[0026] The gas emulsified composition prepared by the invention has excellent foaming performance, high skin penetration efficiency and good stability. DETAILED DESCRIPTION

[0027] As described in the background art, as a new type of topical drug delivery formulation, gas emulsion compositions have advantages such as good spreadability and refreshing skin feel. However, the development of gas emulsion compositions suitable for compound X faces the following key technical bottlenecks: (1) The polycyclic aromatic heterocyclic structure and strong hydrophobicity of compound X require excipients with extraordinary solubilization ability, but traditional surfactants such as polysorbate 20 and sorbitan monooleate are difficult to maintain their solubility at high drug concentrations, which can easily lead to drug crystallization and precipitation, directly affecting the stability and bioavailability of the formulation. (2) Gas emulsion compositions rely on surfactants such as sodium dodecyl sulfate and sodium dodecylbenzene sulfonate to construct a stable foam structure, but the strong ionicity of such excipients may form ion pairs or aggregates with compound X molecules. This interaction may change the solubility state of the drug and trigger drug degradation or precipitation under certain conditions, thereby affecting the thermodynamic and chemical stability of the formulation; that is, it is difficult to maintain the stability of the foam structure and the chemical stability of compound X while ensuring the quality of the foam. (3) Some excipients may also cause irritation to the skin, increasing the difficulty of formulation development. For example, high concentrations of sodium lauryl sulfate are highly irritating to the skin. Ethanol or isopropyl alcohol, although they can be used as solvents or penetration enhancers at certain concentrations, can cause irritation reactions such as dryness, redness, and stinging of the skin at high concentrations, making them unsuitable for long-term or large-area use.

[0028] Based on this, the present invention provides a gas emulsion composition, a preparation method, and an application thereof. The gas emulsion composition can improve the skin permeability of compound X, enhance the stability of compound X in a formulation, and has excellent foaming properties and patient compliance.

[0029] In order to enable those skilled in the art to better understand and implement the technical solution of the present invention, the present invention is further described below with reference to specific embodiments.

[0030] In the description of the present invention, unless otherwise specified, all reagents used are commercially available and all methods used are conventional techniques in the art.

[0031] It should be noted that the sources of the raw materials used in the following examples are as follows: Compound X was provided by Shandong Nuomingkang Pharmaceutical Research Institute Co., Ltd.; propylene glycol was provided by Nanjing Well Pharmaceutical Group Co., Ltd.; polysorbate 80 was provided by Croda Inc.; sodium N-lauroylsarcosinate was provided by Jiangsu Southeast Nanomaterials Co., Ltd.; carbomer 980 was provided by The Noveon Inc.; citric acid was provided by Nanjing Chemical Reagent Co., Ltd.; sodium hydroxide was provided by Nanjing Chemical Reagent Co., Ltd.; and propane / butane / isobutane were provided by Tianjin Aohong Environmental Protection Materials Co., Ltd.

[0032] Example 1 A gas emulsion composition is prepared from the following components, calculated by mass percentage: 1.0% compound X, 15.0% solvent, 4.0% nonionic surfactant, 2.0% anionic surfactant, 0.5% rheology modifier, 8.0% propellant, and the balance being water, totaling 100%; wherein the solvent is propylene glycol, the nonionic surfactant is polysorbate 80, the anionic surfactant is sodium N-lauroyl sarcosinate, the rheology modifier is carbomer 980, and the propellant is a mixture of propane, butane, and isobutane, wherein the mass ratio of propane, butane, and isobutane is 55:27:18.

[0033] The specific preparation method of the gas emulsion composition is as follows: Under stirring conditions, 1.0 g of compound X and 15.0 g of propylene glycol were mixed and stirred until completely dissolved to obtain a drug solution.

[0034] 4.0 g of polysorbate 80, 2.0 g of sodium N-lauroyl sarcosinate and 60.0 g of purified water were mixed and stirred evenly, and then 0.5 g of carbomer 980 was slowly added and stirred until the mixture was completely swollen and evenly dissolved to obtain a matrix.

[0035] The drug solution and the matrix were stirred evenly, citric acid and sodium hydroxide were added to adjust the pH value to 5.5, the remaining purified water was added, and the mixture was stirred evenly to obtain a feed solution.

[0036] The feed liquid was packed together with 4.4 g of propane, 2.16 g of butane, and 1.44 g of isobutane in a pressure-resistant container to obtain a gas emulsion composition.

[0037] Example 2 A gas emulsion composition is prepared from the following components, calculated by mass percentage: 0.5% of compound X, 10.0% of solvent, 3.0% of nonionic surfactant, 1.0% of anionic surfactant, 0.3% of rheology modifier, 9.0% of propellant, and the balance being water, totaling 100%; wherein the solvent is propylene glycol, the nonionic surfactant is polysorbate 80, the anionic surfactant is sodium N-lauroyl sarcosinate, the rheology modifier is carbomer 980, and the propellant is a mixture of propane, butane, and isobutane, wherein the mass ratio of propane, butane, and isobutane is 55:27:18.

[0038] The specific preparation method of the gas emulsion composition is as follows: Under stirring conditions, 0.5 g of compound X and 10.0 g of propylene glycol were mixed and stirred until completely dissolved to obtain a drug solution.

[0039] 3.0 g of polysorbate 80, 1.0 g of sodium N-lauroyl sarcosinate and 60.0 g of purified water were mixed and stirred evenly, and then 0.3 g of carbomer 980 was slowly added and stirred until the mixture was completely swollen and evenly dissolved to obtain a matrix.

[0040] The drug solution and the matrix were stirred evenly, citric acid and sodium hydroxide were added to adjust the pH value to 5.2, the remaining purified water was added, and the mixture was stirred evenly to obtain a feed solution.

[0041] The feed liquid was packed together with 4.95 g of propane, 2.43 g of butane, and 1.62 g of isobutane in a pressure-resistant container to obtain a gas emulsion composition.

[0042] Example 3 A gas emulsion composition is prepared from the following components, calculated by mass percentage: 1.5% of compound X, 12.0% of solvent, 5.0% of nonionic surfactant, 2.5% of anionic surfactant, 0.7% of rheology modifier, 10.0% of propellant, and the balance being water, totaling 100%; wherein the solvent is propylene glycol, the nonionic surfactant is polysorbate 80, the anionic surfactant is sodium N-lauroyl sarcosinate, the rheology modifier is carbomer 980, and the propellant is a mixture of propane, butane, and isobutane, wherein the mass ratio of propane, butane, and isobutane is 55:27:18.

[0043] The specific preparation method of the gas emulsion composition is as follows: Under stirring conditions, 1.5 g of compound X and 12.0 g of propylene glycol were mixed and stirred until completely dissolved to obtain a drug solution.

[0044] 5.0 g of polysorbate 80, 2.5 g of sodium N-lauroyl sarcosinate and 60.0 g of purified water were mixed and stirred evenly, and then 0.7 g of carbomer 980 was slowly added and stirred until the mixture was completely swollen and evenly dissolved to obtain a matrix.

[0045] The drug solution and the matrix were stirred evenly, citric acid and sodium hydroxide were added to adjust the pH value to 5.8, the remaining purified water was added, and the mixture was stirred evenly to obtain a feed solution.

[0046] The feed liquid was packed together with 5.5 g of propane, 2.7 g of butane, and 1.8 g of isobutane in a pressure-resistant container to obtain a gas emulsion composition.

[0047] Comparative Example 1 A gas emulsion composition is prepared from the following components, calculated by mass percentage: 1.0% of compound X, 15.0% of solvent, 4.0% of nonionic surfactant, 2.0% of anionic surfactant, 0.5% of rheology modifier, 8.0% of propellant, and the balance being water, totaling 100%; wherein the solvent is propylene glycol, the nonionic surfactant is polyoxyethylene (40) hydrogenated castor oil, the anionic surfactant is sodium N-lauroyl sarcosinate, the rheology modifier is carbomer 980, and the propellant is a mixture of propane, butane, and isobutane, wherein the mass ratio of propane, butane, and isobutane is 55:27:18.

[0048] The preparation method of the gas emulsion composition refers to the preparation method of Example 1.

[0049] The difference from Example 1 is: Polyoxyethylene (40) hydrogenated castor oil was used instead of polysorbate 80.

[0050] Comparative Example 2 A gas emulsion composition is prepared from the following components, calculated by mass percentage: 1.0% compound X, 15.0% solvent, 4.0% nonionic surfactant, 2.0% anionic surfactant, 0.5% rheology modifier, 8.0% propellant, and the balance being water, totaling 100%; wherein the solvent is propylene glycol, the nonionic surfactant is polysorbate 80, the anionic surfactant is sodium lauryl sulfate, the rheology modifier is carbomer 980, and the propellant is a mixture of propane, butane, and isobutane, wherein the mass ratio of propane, butane, and isobutane is 55:27:18.

[0051] The preparation method of the gas emulsion composition refers to the preparation method of Example 1.

[0052] The difference from Example 1 is: Sodium lauryl sulfate was used to replace sodium N-lauroyl sarcosinate.

[0053] Comparative Example 3 A gas emulsion composition is prepared from the following components, calculated by mass percentage: 1.0% compound X, 15.0% solvent, 1.0% nonionic surfactant, 3.0% anionic surfactant, 0.5% rheology modifier, 8.0% propellant, and the balance being water, totaling 100%; wherein the solvent is propylene glycol, the nonionic surfactant is polysorbate 80, the anionic surfactant is sodium N-lauroyl sarcosinate, the rheology modifier is carbomer 980, and the propellant is a mixture of propane, butane, and isobutane, wherein the mass ratio of propane, butane, and isobutane is 55:27:18.

[0054] The preparation method of the gas emulsion composition refers to the preparation method of Example 1.

[0055] The difference from Example 1 is: The mass ratio of nonionic surfactant to anionic surfactant is 1:3.

[0056] Comparative Example 4 A gas emulsion composition is prepared from the following components, calculated by mass percentage: 1.0% compound X, 15.0% solvent, 4.0% nonionic surfactant, 2.0% anionic surfactant, 0.05% rheology modifier, 8.0% propellant, and the balance being water, totaling 100%; wherein the solvent is propylene glycol, the nonionic surfactant is polysorbate 80, the anionic surfactant is sodium N-lauroyl sarcosinate, the rheology modifier is carbomer 980, and the propellant is a mixture of propane, butane, and isobutane, wherein the mass ratio of propane, butane, and isobutane is 55:27:18.

[0057] The preparation method of the gas emulsion composition refers to the preparation method of Example 1.

[0058] The difference from Example 1 is: The amount of rheology modifier used was 0.05 g.

[0059] Comparative Example 5 A gas emulsion composition is prepared from the following components, calculated by mass percentage: 1.0% compound X, 15.0% solvent, 4.0% nonionic surfactant, 2.0% anionic surfactant, 2.0% rheology modifier, 8.0% propellant, and the balance being water, totaling 100%; wherein the solvent is propylene glycol, the nonionic surfactant is polysorbate 80, the anionic surfactant is sodium N-lauroyl sarcosinate, the rheology modifier is carbomer 980, and the propellant is a mixture of propane, butane, and isobutane, wherein the mass ratio of propane, butane, and isobutane is 55:27:18.

[0060] The preparation method of the gas emulsion composition refers to the preparation method of Example 1.

[0061] The difference from Example 1 is: The amount of rheology modifier used was 2.0 g.

[0062] Comparative Example 6 A gas emulsion composition is prepared from the following components, calculated by mass percentage: 1.0% compound X, 15.0% solvent, 4.0% nonionic surfactant, 2.0% anionic surfactant, 0.5% rheology modifier, 8.0% propellant, and the balance being water, totaling 100%; wherein the solvent is propylene glycol, the nonionic surfactant is polysorbate 80, the anionic surfactant is sodium N-lauroyl sarcosinate, the rheology modifier is carbomer 980, and the propellant is a mixture of propane, butane, and isobutane, wherein the mass ratio of propane, butane, and isobutane is 55:27:18.

[0063] The specific preparation method of the gas emulsion composition is as follows: After mixing 4.0 g of polysorbate 80, 2.0 g of sodium N-lauroyl sarcosinate and 60.0 g of purified water, 1.0 g of compound X was added, followed by 15.0 g of propylene glycol, and the mixture was stirred evenly. Then, 0.5 g of carbomer 980 was slowly added and stirred thoroughly. Citric acid and sodium hydroxide were added to adjust the pH to 5.5, and the remaining purified water was added and stirred evenly to obtain a feed solution.

[0064] The feed liquid was packed together with 4.4 g of propane, 2.16 g of butane, and 1.44 g of ethanol in a pressure-resistant container to obtain a gas emulsion composition.

[0065] Experimental test: 1. Foam morphology and stability test.

[0066] The gas emulsion compositions prepared in Examples 1 to 3 and Comparative Examples 1 to 6 were subjected to observation of foam morphology and the collapse time of the foam. The foam emulsion compositions were allowed to stand at room temperature for 24 hours to allow for the collapse of the foam. The specific testing method was as follows: the temperature of the gas emulsion composition was balanced; before use, the gas emulsion composition was thoroughly shaken; and before the first spray, several pre-sprays of air were performed to expel air from the nozzle. A 250 mL graduated cylinder was placed on a stable platform; the nozzle of the pressure-resistant container containing the gas emulsion composition was aligned with the container opening of the graduated cylinder, maintaining a fixed spray distance of 15 cm. The nozzle was pressed quickly and completely three times, each press lasting 2 seconds, to spray the foam into the graduated cylinder. After spraying, the initial foam height (from the liquid surface to the top of the foam) was immediately recorded. The initial foam morphology was also observed and recorded. The initial foam morphology was classified as fine, uniform, long-lasting, relatively rough, and with a small number of large bubbles. After stopping the spraying, start the stopwatch immediately and continue to observe the collapse process of the foam. When the foam height collapses to half of the initial height, record the time on the stopwatch, which is the FCT value.

[0067] Table 1 Foam morphology and foam collapse time of the gas emulsion compositions prepared in Examples 1 to 3 and Comparative Examples 1 to 6 As can be seen from Table 2, the foams of the gas emulsion compositions prepared in Examples 1 to 3 are fine and uniform, and their stability is significantly improved. The foam of the gas emulsion composition prepared in Comparative Example 1 using polyoxyethylene (40) hydrogenated castor oil as a nonionic surfactant is relatively coarse, with a small number of large bubbles and average stability. The foam structure of the gas emulsion composition prepared in Comparative Example 2 using sodium lauryl sulfate as an anionic surfactant is acceptable, because the anionic surfactant has a very strong foaming ability and can quickly produce a large amount of foam. When the mass ratio of the nonionic surfactant to the anionic surfactant in Comparative Example 3 is 1:3, the foam is slightly sparse and the stability is slightly poor. When the amount of the rheology modifier in Comparative Example 4 is too low, the foam of the gas emulsion composition is thin and collapses quickly. When the amount of the rheology modifier in Comparative Example 5 is too high, the foam of the gas emulsion composition is too viscous and difficult to extrude and spread.

[0068] This shows that the present invention controls the mass ratio of nonionic surfactant to anionic surfactant to be 1 to 4:1, utilizes nonionic surfactant to fill the gaps between anionic surfactant molecules, enhances the strength and elasticity of the liquid film, reduces liquid film drainage, thereby improving the durability and fineness of the foam, and preventing the foam from collapsing too quickly or becoming too coarse. The amount of rheology modifier is controlled to be 0.3% to 0.8%, stabilizes the foam, and provides a suitable viscosity, thereby forming a tougher and more elastic liquid film.

[0069] 2. In vitro skin permeability test.

[0070] The instrument used is: Franz diffusion cell is used as the in vitro skin permeability test instrument, and the effective diffusion area of ​​Franz diffusion cell is 1.77cm 2 The constant temperature water bath had a temperature control accuracy of ±0.5°C. The experimental medium was sterile excised porcine skin, 500 ± 50 μm thick, obtained from the dorsal side of healthy pigs. The receiving solution was phosphate buffered saline (pH 7.4).

[0071] The specific testing method is as follows: cut the ex vivo pig skin into circular samples suitable for the size of the Franz diffusion cell, rinse the skin surface with sterile saline to remove residual tissue fluid; place the skin sample between the donor cell and the receptor cell of the Franz diffusion cell to ensure that the skin fits tightly with the cell body without bubbles. Add 10mL of pH=7.4 phosphate buffer as the receiving liquid to the receptor cell of the Franz diffusion cell; place the Franz diffusion cell in a constant temperature water bath and keep the temperature at 32±0.5°C to simulate the surface temperature of human skin. Turn on the magnetic stirrer and set the stirring speed to 600rpm to ensure that the receiving liquid is evenly mixed. Spray 100mg of the gas emulsion composition of Example 1 and Comparative Example 1 on the surface of two groups of ex vivo pig skin, respectively, and cover the donor cell with sterile gauze to prevent sample volatilization.

[0072] Sample Collection: Remove 1 mL of receiving solution from the receptor reservoir at 1, 2, 4, 6, 8, 12, and 24 hours after the start of the experiment. Immediately replace with an equal volume of fresh phosphate buffer. Filter the removed receiving solution through a 0.22 μm filter and store in a refrigerator at 4°C until analysis by HPLC.

[0073] Sample Analysis: The concentration of Compound X in the receiving solution was determined using a high-performance liquid chromatograph. The chromatographic column was a C18 column (250 mm × 4.6 mm, 5 μm); the mobile phase consisted of acetonitrile and water in a 50:50 volume ratio; the flow rate was 1.0 mL / min; and the detection wavelength was 254 nm. The 24-hour cumulative transdermal dose and transdermal rate were calculated using the following formula:

[0074] ; in, Q The cumulative transdermal dose in 24 hours, expressed in μg / cm 2 ; is the concentration of compound X at the nth sampling time, in μg / mL; is the volume of the receptor pool, in mL; For the The concentration of compound X in the subsample is in µg / mL; For the The volume of the sub-sampling, in mL; is the diffusion area in cm 2 ; For the first to n -1 is the sum of the product of the concentration and volume of compound X in the first sampling, in µg; n -The sum of the contents of compound X in one sampling, in µg.

[0075] The calculation is performed using the following formula for transdermal rate: ; in, J is the transdermal rate, in μg / cm 2 / h; t For 24 hours.

[0076] Table 2 Transdermal performance test results of the gas emulsion compositions prepared in Example 1 and Comparative Example 1 As shown in Table 2, the in vitro cumulative skin permeation of Compound X in Example 1 was significantly higher than that in Comparative Example 1, demonstrating that the present invention, using a combination of polysorbate 80 as a nonionic surfactant and sodium N-lauroylsarcosinate as an anionic surfactant, significantly improves the skin permeation efficiency of Compound X. This is due to the fact that surfactants have a certain permeation-promoting effect; by temporarily altering the lipid arrangement of the stratum corneum, they reduce the resistance of the skin barrier and create favorable conditions for the penetration of Compound X. Furthermore, the synergistic effect of the nonionic and anionic surfactants promotes the transdermal absorption of Compound X more effectively than using a single surfactant type.

[0077] 3. Stability test.

[0078] The gas emulsion composition prepared in Example 1 was stored at a temperature of 40°C ± 2°C and a humidity of 75% ± 5% for 3 months. The appearance and the content of Compound X in the gas emulsion composition were examined. The pH value was measured using a three-point calibration of a Mettler FE28 pH meter.

[0079] Table 3 Stability data of the gas emulsion composition prepared in Example 1 As shown in Table 3, Example 1 exhibited good stability under accelerated conditions, with the content of Compound X and changes in related substances within acceptable ranges, and no significant change in the foam appearance. This further demonstrates the superiority of the composition of the present invention.

[0080] It should be noted that when numerical ranges are mentioned in the present invention, it should be understood that both endpoints of each numerical range and any value between the two endpoints may be selected. Since the steps and methods used are the same as those in the embodiments, the present invention describes preferred embodiments to avoid redundancy. Although preferred embodiments of the present invention have been described, those skilled in the art may make additional changes and modifications to these embodiments once they understand the basic inventive concepts, and such changes and modifications fall within the scope of the present invention.

[0081] Obviously, those skilled in the art can make various changes and modifications to the present invention without departing from the spirit and scope of the present invention. If these modifications and variations of the present invention fall within the scope of the equivalent technology of the present invention, the present invention is also intended to include these modifications and variations.

Claims

1. A gas emulsion composition, characterized in that: The composition is prepared from the following components by mass percentage: 0.1% to 2.0% of compound X, 5% to 20% of solvent, 1% to 10% of nonionic surfactant, 0.5% to 5% of anionic surfactant, 0.3% to 0.8% of rheology modifier, 3% to 15% of propellant, and the balance is water, totaling 100%; wherein the structural formula of compound X is as follows: ； The mass ratio of nonionic surfactant to anionic surfactant is 1 to 4:1; The nonionic surfactant is one of fatty acid polyoxyethylene esters, polyethers and alkylphenol polyoxyethylene ethers; Anionic surfactants are carboxylates or phosphates.

2. The gas emulsion composition according to claim 1, characterized in that The nonionic surfactant is one of polysorbate 80, poloxamer 188 and octylphenol polyoxyethylene ether.

3. The gas emulsion composition according to claim 1, characterized in that The anionic surfactant is sodium N-lauroyl sarcosinate or sodium laureth sulfate.

4. The gas emulsion composition according to claim 1, characterized in that The rheology modifier is one of carbomer 980, hydroxypropyl methylcellulose and xanthan gum.

5. The gas emulsion composition according to claim 1, characterized in that The solvent is at least one of propylene glycol, glycerol and polyethylene glycol 400.

6. The gas emulsion composition according to claim 1, characterized in that The pH value of the gas emulsion composition is 4.5 to 6.

5.

7. The gas emulsion composition according to claim 1, characterized in that The propellant is a hydrofluoroalkane or a hydrocarbon.

8. A method for preparing the gas emulsion composition according to any one of claims 1 to 7, characterized in that: The following steps are involved: Mixing compound X and a solvent under stirring conditions to obtain a drug solution; After mixing a nonionic surfactant, anionic surfactant and a portion of water, a rheology modifier is added and stirred until the mixture is completely swollen and uniform to obtain a matrix; After mixing the drug solution and the matrix, the pH value is adjusted to 4.5 to 6.5, and the remaining water is added to obtain a feed solution; The feed liquid and the propellant are packaged to obtain a gas emulsion composition.

9. The method for preparing a gas emulsion composition according to claim 8, wherein: The mass of the water accounts for 60% to 70% of the total mass of the gas emulsion composition.

10. Use of a gas emulsion composition in preparing a pharmaceutical preparation for treating skin inflammatory diseases, characterized in that: The gas emulsion composition is the gas emulsion composition according to any one of claims 1 to 7.

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