A clobetasol propionate liniment and a preparation method thereof

Abstract

This invention discloses a clobetasol propionate liniment and its preparation method, belonging to the field of pharmaceutical formulation technology. The clobetasol propionate liniment provided by this invention consists of the active ingredient clobetasol propionate, dipotassium glycyrrhizate, anhydrous ethanol as a co-solvent, and a novel eutectic solvent aqueous solution. This eutectic solvent aqueous solution is prepared by heating an aqueous solution of citric acid and an aqueous solution of tartaric acid under specific conditions. This invention also provides a method for preparing the clobetasol propionate liniment. By using the eutectic solvent formed by citric acid and tartaric acid as the main solvent, the amount of anhydrous ethanol used is reduced, thus reducing skin irritation. The liniment of this invention improves the solubility and stability of clobetasol propionate, which is extremely difficult to dissolve in water, in the liniment system. Simultaneously, the formulation system is mild, reducing skin irritation caused by ethanol, and exhibits good safety and application prospects.

Description

Technical Field

[0001] This invention relates to a clobetasol propionate topical solution and its preparation method, belonging to the field of pharmaceutical formulation technology. Background Technology

[0002] Clobetasol propionate is a potent topical corticosteroid widely used due to its significant anti-inflammatory, antipruritic, and vasoconstrictive effects. It is widely used to treat various pruritic and non-infectious inflammatory skin diseases that are sensitive to corticosteroids, such as chronic eczema, neurodermatitis, psoriasis, palmoplantar pustulosis, lichen planus, and discoid lupus erythematosus.

[0003] Currently, commercially available topical formulations of clobetasol propionate are mostly creams, ointments, and lotions. Among them, lotions are particularly suitable for areas with dense hair, such as the scalp, due to their good transdermal absorption and non-greasy finish. However, existing clobetasol propionate lotions have the following significant drawbacks, limiting their clinical application and industrial development:

[0004] (1) It is highly irritating. Clobetasol propionate is extremely insoluble in water. Conventional topical medications usually rely on high concentrations of ethanol (usually >50% by volume) and propylene glycol as solvent systems to ensure drug dissolution. This high-concentration organic solvent system comes into direct contact with the skin. Especially when the skin has minor ulcers, erosions, or is in an acute inflammatory phase, applying topical medications with high alcohol content will produce obvious burning and stinging sensations, seriously affecting patients' medication compliance. At the same time, the evaporation of high-concentration alcohol will take away moisture and sebum from the skin surface. Long-term use will make the skin dry and flaky, aggravating damage to the skin barrier.

[0005] (2) Poor stability: Clobetasol propionate is easily degraded under light and high temperature conditions, and the complex liquid system is more likely to exacerbate the growth of related substances, affecting product safety and shelf life; at the same time, the simple alcohol-water solution system is an unstable thermodynamic system. When the ambient temperature decreases, the solubility of the drug will decrease, and tiny crystals may precipitate from the solution. These are not easily noticeable to the naked eye, but they will lead to a decrease in the actual effective drug concentration of the liniment, reducing the efficacy, and may even cause irritation due to direct contact of the crystals with the skin.

[0006] (3) The preparation process is complex. Traditional preparation methods, such as emulsification, involve many steps and require precise control and mixing of emulsifiers, solubilizers, acids, etc., as well as homogenization and cooling. These steps place high demands on the production equipment and the skills of the operators, increasing the difficulty and cost of process scale-up and quality control.

[0007] Therefore, the industry has been seeking solutions, and existing improvement attempts mostly focus on dosage form conversion, such as developing new creams, compound ointments, or film-forming agents. For example, patent CN109833291A discloses a stable clobetasol propionate compound ointment that reduces shelf-life impurities by adding emulsifiers, solubilizers, and stabilizers. Alternatively, drug delivery technologies such as latex or liposome hydrogels are employed. Patent CN102327273 discloses a compound clobetasol propionate nanomedicine that improves the stability, solubility, and irritation of the formulation through nanoemulsion technology. However, these solutions either cannot replace the application scenarios of liniments due to their dosage form characteristics, or are difficult to industrialize due to technical complexity and high costs, and have not fundamentally solved the core problems of traditional liniments.

[0008] It is evident that developing a clobetasol propionate topical solution that can balance low irritation, high stability, and bioavailability while having a simple preparation process has significant application value and market prospects. Summary of the Invention

[0009] [Technical Issues]

[0010] To develop a clobetasol propionate topical solution that balances low irritation, high stability, and bioavailability with a simple preparation process.

[0011] [Technical Solution]

[0012] To address the aforementioned problems, this invention provides a clobetasol propionate liniment and its preparation method. Specifically, this invention first prepares a eutectic solvent aqueous solution using citric acid solution and tartaric acid solution, and then prepares the clobetasol propionate liniment together with anhydrous ethanol, dipotassium glycyrrhizate, and clobetasol propionate. The clobetasol propionate liniment prepared by this invention is homogeneous, stable, low in irritation, and has high bioavailability.

[0013] The first objective of this invention is to provide a clobetasol propionate liniment composed of an aqueous solution of a eutectic solvent, anhydrous ethanol, dipotassium glycyrrhizate, and clobetasol propionate.

[0014] In one embodiment of the present invention, the method for preparing the eutectic solvent aqueous solution is as follows:

[0015] A citric acid aqueous solution with a concentration of 0.05-0.1 mol / L and a tartaric acid aqueous solution with a concentration of 0.05-0.1 mol / L are mixed at a volume ratio of (1-3):(1-3) and heated at 60-80℃ and 800-1500 rpm for 1-5 hours to obtain a eutectic solvent aqueous solution. For example, the concentration of the citric acid aqueous solution can be 0.05, 0.06, 0.07, 0.08, 0.09, or 0.1 mol / L, as well as specific values ​​between the above values. Due to space limitations and for the sake of brevity, this invention will not exhaustively list the specific values ​​included in the range. The concentration of the tartaric acid aqueous solution can be 0.05, 0.06, 0.07, 0.08, 0.09, or 0.1 mol / L; the volume ratio can be 1:1, 1:2, 1:3, 2:3, 3:1, or 3:1. 2. The specific values ​​between the above-mentioned point values ​​are not exhaustively listed here due to space limitations and for the sake of brevity. The temperature can be selected as 60, 70, or 80°C. The specific values ​​between the above-mentioned point values ​​are not exhaustively listed here due to space limitations and for the sake of brevity. The rotation speed can be selected as 800, 900, 1000, 1100, 1200, 1300, 1400, or 1500 rpm. The specific values ​​between the above-mentioned point values ​​are not exhaustively listed here due to space limitations and for the sake of brevity. The heating time can be selected as 1, 2, 3, 4, or 5 hours. The specific values ​​between the above-mentioned point values ​​are not exhaustively listed here due to space limitations and for the sake of brevity.

[0016] The mass ratio of the eutectic solvent aqueous solution, anhydrous ethanol, dipotassium glycyrrhizate, and clobetasol propionate is (85-95):(1-10):(0.005-0.01):(0.01-0.05); for example, it can be 85:10:0.005:0.01, 90:5:0.01:0.05, 95:1:0.005:0.01, and specific values ​​between the above values. Due to space limitations and for the sake of brevity, this invention will not exhaustively list the specific values ​​included in the range.

[0017] A second objective of this invention is to provide a method for preparing clobetasol propionate liniment, comprising the following steps:

[0018] (1) Dissolve citric acid and tartaric acid in water to prepare citric acid aqueous solution and tartaric acid aqueous solution respectively;

[0019] (2) Mix citric acid aqueous solution and tartaric acid aqueous solution in a volume ratio of (1-3):(1-3) to obtain a eutectic solvent aqueous solution;

[0020] (3) Dissolve clobetasol propionate in anhydrous ethanol to form a clobetasol propionate-ethanol mixture;

[0021] (4) Mix the clobetasol propionate-ethanol mixture with an aqueous solution of a eutectic solvent to form a homogeneous mixture;

[0022] (5) Add dipotassium glycyrrhizate to the mixture and mix well to obtain clobetasol propionate liniment.

[0023] The concentrations of the citric acid aqueous solution and the tartaric acid aqueous solution are 0.05-0.1 mol / L; for example, they can be 0.05, 0.06, 0.07, 0.08, 0.09, 0.1 mol / L, as well as specific values ​​between the above values. Due to space limitations and for the sake of brevity, this invention will not exhaustively list all the specific values ​​included in the range.

[0024] In one embodiment of the present invention, in step (2), heating is performed at 40-90℃ and 500-1500rpm for 1-10 hours; the temperature can be selected from 40, 50, 60, 70, 80, 90℃, and specific values ​​between the above points. Due to space limitations and for the sake of brevity, the present invention will not exhaustively list the specific values ​​included in the range; the rotation speed can be selected from 500, 600, 700, 800, 900, 1000, 1100, 1200, 1300, 1400, 1500rpm, and specific values ​​between the above points. Due to space limitations and for the sake of brevity, the present invention will not exhaustively list the specific values ​​included in the range; the heating time can be selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 hours, and specific values ​​between the above points. Due to space limitations and for the sake of brevity, the present invention will not exhaustively list the specific values ​​included in the range.

[0025] Preferably, in step (2), heating is performed at 60-90℃ and 800-1500rpm for 1-5 hours; the temperature can be selected from 60, 70, 80, 90℃, and specific values ​​between the above points. Due to space limitations and for the sake of brevity, the present invention will not exhaustively list the specific values ​​included in the range; the rotation speed can be selected from 800, 900, 1000, 1100, 1200, 1300, 1400, 1500rpm, and specific values ​​between the above points. Due to space limitations and for the sake of brevity, the present invention will not exhaustively list the specific values ​​included in the range; the heating time can be selected from 1, 2, 3, 4, 5 hours, and specific values ​​between the above points. Due to space limitations and for the sake of brevity, the present invention will not exhaustively list the specific values ​​included in the range.

[0026] In one embodiment of the present invention, the mass ratio of the eutectic solvent aqueous solution, anhydrous ethanol, dipotassium glycyrrhizate, and clobetasol propionate is (85-95):(1-10):(0.005-0.01):(0.01-0.05); for example, it can be 85:10:0.005:0.01, 90:5:0.01:0.05, 95:1:0.005:0.01, and specific values ​​between the above values. Due to space limitations and for the sake of brevity, the present invention will not exhaustively list the specific values ​​included in the range.

[0027] In one embodiment of the present invention, in step (4), the mixing conditions are 1000-5000 rpm for 10-30 min; the speed can be selected from 1000, 1100, 1200, 1300, 1400, 1500, 1600, 1700, 1800, 1900, 2000, 2100, 2200, 2300, 2400, 2500, 2600, 2700, 2800, 2900, 3000, 3100, 3200, 3300, 3400, 3500, 3600 rpm. The specific values ​​within the ranges of 3700, 3800, 3900, 4000, 4100, 4200, 4300, 4400, 4500, 4600, 1700, 4800, 4900, and 5000 rpm, as well as specific values ​​between the above values, are not exhaustively listed here due to space limitations and for the sake of brevity. The heating time can be selected as 10, 20, or 30 minutes, and the specific values ​​between the above values ​​are not exhaustively listed here due to space limitations and for the sake of brevity.

[0028] A third object of the present invention is to provide a medicine containing the clobetasol propionate topical solution.

[0029] A fourth objective of this invention is to provide the application of the clobetasol propionate topical solution in the pharmaceutical field.

[0030] A fifth object of the present invention is to provide the use of the clobetasol propionate liniment in the preparation of pharmaceuticals.

[0031] [Beneficial Effects]

[0032] (1) Improving the solubility and stability of clobetasol propionate: Clobetasol propionate is a compound that is extremely difficult to dissolve in water. Conventional water-based topical preparation methods cannot effectively dissolve and maintain the long-term stability of clobetasol propionate. This invention uses an aqueous solution of a eutectic solvent (DES) composed of citric acid and tartaric acid as the main solvent system, which significantly improves the solubility of clobetasol propionate in the aqueous medium, avoids crystallization of the drug during storage or use, and thus ensures the homogeneity and stability of the formulation.

[0033] (2) Reduced skin irritation: Traditional topical ointments often require high concentrations of cosolvents such as ethanol and propylene glycol during preparation, which can easily lead to adverse reactions such as stinging, burning, and dryness at the application site. This invention uses water as the main carrier, and the citric acid and tartaric acid used are natural organic acids with good biocompatibility and high safety. This significantly reduces the amount of organic solvents such as anhydrous ethanol, making the entire formulation milder, less irritating to the skin, and improving patient compliance. It is especially suitable for sensitive skin.

[0034] (3) Synergistic effect and reduced skin irritation: The topical solution of this invention contains dipotassium glycyrrhizate, which is an excellent anti-inflammatory and anti-allergic agent. It can assist the potent corticosteroid clobetasol propionate in exerting its effects, while alleviating the local reactions that hormones may cause. In addition, citric acid and tartaric acid, as solvent components, belong to fruit acids (AHAs). At appropriate concentrations, they can promote stratum corneum renewal and enhance drug penetration into the skin, which is expected to further improve the bioavailability and efficacy of the active ingredient.

[0035] (4) Simple preparation process: The preparation method of the present invention is simple, involving only dissolution, mixing and heating operations. The conditions are mild and controllable, and no special or expensive equipment is required, making it easy to achieve industrial production. At the same time, since the formulation system is mainly water, the use of volatile organic solvents is greatly reduced, making the production process more green and environmentally friendly, which is in line with the development direction of modern pharmaceutics. Detailed Implementation

[0036] The preferred embodiments of the present invention are described below. It should be understood that the embodiments are for the purpose of better explaining the present invention. The present invention can be implemented in many different forms and is not limited to the implementation methods described herein.

[0037] Unless otherwise specified, the experimental methods used in the following embodiments are all conventional methods.

[0038] General terms and definitions

[0039] The terms "preferred," "more preferably," etc., used in this invention refer to embodiments of the invention that provide certain beneficial effects under certain circumstances. However, other embodiments may also be preferred under the same or other circumstances. Furthermore, the description of one or more preferred embodiments does not imply that other embodiments are unavailable, nor is it intended to exclude other embodiments from the scope of this invention.

[0040] When a numerical range is disclosed herein, the range is considered continuous and includes the minimum and maximum values ​​of the range, as well as every value between the minimum and maximum values. Furthermore, when the range refers to integers, it includes every integer between the minimum and maximum values ​​of the range. Additionally, when multiple ranges are provided to describe a feature or characteristic, the ranges may be combined. In other words, unless otherwise specified, all ranges disclosed herein should be understood to include any and all subranges to which they are incorporated.

[0041] Unless otherwise specified, all percentages, fractions, and ratios are calculated based on the total mass of the compositions of the present invention. Unless otherwise specified, all masses of the listed ingredients are given as the content of the active substance, and therefore do not include solvents or byproducts that may be present in commercially available materials. The term "percentage by mass" herein may be expressed by the symbol "%". Unless otherwise specified, all molecular weights herein are weight-average molecular weights expressed in Daltons. Unless otherwise specified, all formulations and tests herein are conducted at 25°C. The terms "comprising," "including," "containing," "containing," "having," or other variations herein are intended to cover non-closed inclusions, and no distinction is made between these terms. The term "comprising" means additional steps and ingredients that may be added without affecting the final result. The compositions and methods / processes of the present invention comprise, consist of, and substantially consist of the essential elements and limitations described herein, as well as any additional or optional ingredients, components, steps, or limitations described herein. No distinction is made between the terms "efficacy," "performance," "effect," and "potency" herein.

[0042] The term "liniment" refers to a liquid medicine applied to the skin by friction (e.g., rubbing). The liniment of this invention is composed of an aqueous eutectic solvent, anhydrous ethanol, dipotassium glycyrrhizate, and clobetasol propionate; wherein the mass ratio of the aqueous eutectic solvent, anhydrous ethanol, dipotassium glycyrrhizate, and clobetasol propionate is (85-95):(1-10):(0.005-0.01):(0.01-0.05); for example, it can be 85:10:0.005:0.01, 90:5:0.01:0.05, 95:1:0.005:0.01, and specific values ​​between these values. Due to space limitations and for the sake of brevity, this invention will not exhaustively list all the specific values ​​included in the range.

[0043] The term "clobetasol propionate" refers to a synthetic, highly potent glucocorticoid, CAS number 25122-46-7. It should be understood that clobetasol propionate as used in this invention is not limited to a specific purity or physical form (e.g., anhydrous, hydrated, crystalline, or amorphous powder). Furthermore, the term "clobetasol propionate" as used herein is intended to encompass all its stereoisomers, isotopically labeled forms (such as those in which some atoms are replaced by their radioactive or stable isotopes), and any other pharmaceutically acceptable form in the dosage forms described in this invention. In the liniment of this invention, clobetasol propionate, as the active pharmaceutical ingredient, primarily provides anti-inflammatory, anti-allergic, anti-proliferative, and / or vasoconstrictive pharmacological effects, but its therapeutic use should not be absolutely limited thereto.

[0044] The term "dipotassium glycyrrhizate" refers to the salt formed by glycyrrhizic acid and potassium ions, obtained from the root of the legume licorice. Its chemical name is dipotassium glycyrrhizate, CAS number 68797-35-3, and it includes its various isomers, hydrates, and pharmaceutically acceptable salt forms. It should be understood that the dipotassium glycyrrhizate used in this invention is not limited to a specific purity or crystalline form, and it can be used in any commercially available specification (e.g., powder, granules, etc.). Furthermore, the term "dipotassium glycyrrhizate" as used herein is also intended to include its various hydrates, solvates, and pharmaceutically or cosmetically acceptable equivalents at different purities. In the compositions of this invention, dipotassium glycyrrhizate primarily functions as an anti-inflammatory and soothing agent, but its function should not be limited thereto.

[0045] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. The terminology used herein in the description of the invention is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention. The term "and / or" as used herein includes any and all combinations of one or more of the associated listed items.

[0046] The raw materials used in the following examples:

[0047] Unless otherwise specified, all materials and reagents used in the following examples can be purchased from biological or chemical reagent companies.

[0048] Clobetasol propionate: CAS No. 25122-46-7, 99%;

[0049] Citric acid: Anhydrous citric acid, CAS number 77-92-9, 99% purity;

[0050] Tartaric acid (D(-)-Tartaric acid): CAS No. 526-83-0, 99%;

[0051] Anhydrous ethanol (Ethanol): CAS No. 64-17-5, 99%;

[0052] Dipotassium glycyrrhizinate: CAS No. 68797-35-3, 99%;

[0053] Salicylic acid: CAS number 69-72-7, 99%;

[0054] Malic acid: CAS number 6915-15-7, 99%.

[0055] All of the above raw materials are pharmaceutical grade.

[0056] Example 1

[0057] A clobetasol propionate liniment, prepared by the following steps:

[0058] (1) Preparation of natural eutectic solvent (DES) compatibilization system: 0.1 mol / L citric acid aqueous solution and 0.1 mol / L tartaric acid aqueous solution were mixed at a volume ratio of 1:3 and heated and stirred at 60℃ and 1500 rpm for 1 h to obtain eutectic solvent aqueous solution.

[0059] (2) Preparation of the active pharmaceutical ingredient solution: Weigh 0.1g of clobetasol propionate and add it to 50g of anhydrous ethanol. Stir until completely dissolved to obtain a clobetasol propionate-ethanol mixture.

[0060] (3) Mixing and preparation: Under continuous stirring, the clobetasol propionate-ethanol mixture prepared in step (2) is slowly added to the eutectic solvent aqueous solution prepared in step (1) so that the clobetasol propionate content is 0.01wt%. The mixture is mixed and homogenized at 5000rpm for 10min to form a homogeneous mixture.

[0061] (4) Addition and volume adjustment of functional ingredients: Add 0.1g of dipotassium glycyrrhizate to the mixture in step (3) and mix evenly to obtain clobetasol propionate liniment;

[0062] (5) Filtration and filling: The final clobetasol propionate liniment is filtered through a 0.22μm microporous membrane for sterilization, and then aseptically filled to obtain a clear, stable and non-irritating clobetasol propionate liniment product.

[0063] Example 2

[0064] A clobetasol propionate liniment, prepared by the following steps:

[0065] (1) Preparation of natural eutectic solvent (DES) compatibilization system: 0.1 mol / L citric acid aqueous solution and 0.1 mol / L tartaric acid aqueous solution were mixed at a volume ratio of 1:1 and heated and stirred at 80℃ and 500 rpm for 3 h to obtain eutectic solvent aqueous solution.

[0066] (2) Preparation of the active pharmaceutical ingredient solution: Weigh 0.5g of clobetasol propionate and add it to 100g of anhydrous ethanol. Stir until completely dissolved to obtain a clobetasol propionate-ethanol mixture.

[0067] (3) Mixing and preparation: Under continuous stirring, the clobetasol propionate-ethanol mixture prepared in step (2) is slowly added to the eutectic solvent aqueous solution prepared in step (1) at a mass ratio of 1:10, so that the clobetasol propionate content is 0.05wt%. The mixture is mixed and homogenized at 3000rpm for 10min to form a homogeneous mixture.

[0068] (4) Addition and volume adjustment of functional ingredients: Add 0.5g of dipotassium glycyrrhizate to the mixture in step (3) and mix evenly to obtain clobetasol propionate liniment;

[0069] (5) Filtration and filling: The final clobetasol propionate liniment is filtered through a 0.22μm microporous membrane for sterilization, and then aseptically filled to obtain a clear, stable and non-irritating clobetasol propionate liniment product.

[0070] Example 3

[0071] A method for preparing a clobetasol propionate liniment includes the following steps:

[0072] (1) Preparation of natural eutectic solvent (DES) compatibilization system: 0.05 mol / L citric acid aqueous solution and 0.05 mol / L tartaric acid aqueous solution were mixed at a volume ratio of 3:1 and heated and stirred at 60℃ and 1500 rpm for 1 h to obtain eutectic solvent aqueous solution.

[0073] (2) Preparation of the active pharmaceutical ingredient solution: Weigh 0.5g of clobetasol propionate and add it to 50g of anhydrous ethanol. Stir until completely dissolved to obtain a clobetasol propionate-ethanol mixture.

[0074] (3) Mixing and preparation: Under continuous stirring, the clobetasol propionate-ethanol mixture prepared in step (2) is slowly added to the eutectic solvent aqueous solution prepared in step (1) at a mass ratio of 1:10, so that the clobetasol propionate content is 0.05wt%. The mixture is mixed and homogenized at 1000rpm for 10min to form a homogeneous mixture.

[0075] (4) Addition and volume adjustment of functional ingredients: Add 0.05g of dipotassium glycyrrhizate to the mixture in step (3) and mix evenly to obtain clobetasol propionate liniment;

[0076] (5) Filtration and filling: The final clobetasol propionate liniment is filtered through a 0.22μm microporous membrane for sterilization, and then aseptically filled to obtain a clear, stable and non-irritating clobetasol propionate liniment product.

[0077] Example 4

[0078] A method for preparing a clobetasol propionate liniment includes the following steps:

[0079] (1) Preparation of natural eutectic solvent (DES) compatibilization system: 0.05 mol / L citric acid aqueous solution and 0.05 mol / L tartaric acid aqueous solution were mixed at a volume ratio of 1:3 and heated and stirred at 60℃ and 1500 rpm for 1 h to obtain eutectic solvent aqueous solution.

[0080] (2) Preparation of the active pharmaceutical ingredient solution: Weigh 0.1g of clobetasol propionate and add it to 10g of anhydrous ethanol. Stir until completely dissolved to obtain a clobetasol propionate-ethanol mixture.

[0081] (3) Mixing and preparation: Under continuous stirring, the clobetasol propionate-ethanol mixture prepared in step (2) is slowly added to the eutectic solvent aqueous solution prepared in step (1) so that the clobetasol propionate content is 0.01wt%. The mixture is mixed and homogenized at 1000rpm for 30min to form a homogeneous mixture.

[0082] (4) Addition and volume adjustment of functional ingredients: Add 0.01g of dipotassium glycyrrhizate to the mixture in step (3) and mix evenly to obtain clobetasol propionate liniment;

[0083] (5) Filtration and filling: The final clobetasol propionate liniment is filtered through a 0.22μm microporous membrane for sterilization, and then aseptically filled to obtain a clear, stable and non-irritating clobetasol propionate liniment product.

[0084] Comparative Example 1

[0085] Compared to Example 1, the difference is that an aqueous solution of eutectic solvent is not used; instead, an aqueous solution of citric acid and an aqueous solution of tartaric acid are directly mixed.

[0086] (1) Preparation of natural eutectic solvent (DES) compatibilization system: 0.1 mol / L citric acid aqueous solution and 0.1 mol / L tartaric acid aqueous solution were directly mixed at a volume ratio of 1:3 to obtain mixture I;

[0087] (2) Preparation of the active pharmaceutical ingredient solution: Weigh 0.1g of clobetasol propionate and add it to 50g of anhydrous ethanol. Stir until completely dissolved to obtain a clobetasol propionate-ethanol mixture.

[0088] (3) Mixing and preparation: Under continuous stirring, the clobetasol propionate-ethanol mixture prepared in step (2) was slowly added to the mixture prepared in step (1) at a mass ratio of 1:10. The mixture was mixed and homogenized at 5000 rpm for 10 min to form a homogeneous mixture II.

[0089] (4) Addition and volume adjustment of functional ingredients: Add 0.1g of dipotassium glycyrrhizate to the mixture II in step (3) and mix evenly to obtain clobetasol propionate liniment;

[0090] (5) Filtration and filling: The final clobetasol propionate liniment is filtered through a 0.22μm microporous membrane for sterilization, and then aseptically filled to obtain a clear, stable and non-irritating clobetasol propionate liniment product.

[0091] Comparative Example 2

[0092] Compared to Example 1, the difference is that tartaric acid is replaced with salicylic acid:

[0093] (1) Preparation of natural eutectic solvent (DES) compatibilization system: 0.1 mol / L citric acid aqueous solution and 0.1 mol / L salicylic acid aqueous solution were mixed at a volume ratio of 1:3 and heated and stirred at 60℃ and 1500 rpm for 1 h to obtain eutectic solvent aqueous solution;

[0094] (2) Preparation of the active pharmaceutical ingredient solution: Weigh 0.1g of clobetasol propionate and add it to 50g of anhydrous ethanol. Stir until completely dissolved to obtain a clobetasol propionate-ethanol mixture.

[0095] (3) Mixing and preparation: Under continuous stirring, the clobetasol propionate-ethanol mixture prepared in step (2) is slowly added to the eutectic solvent aqueous solution prepared in step (1) at a mass ratio of 1:10. The mixture is mixed and homogenized at 5000 rpm for 10 min to form a homogeneous mixture.

[0096] (4) Addition and volume adjustment of functional ingredients: Add 0.1g of dipotassium glycyrrhizate to the mixture in step (3) and mix evenly to obtain clobetasol propionate liniment;

[0097] (5) Filtration and filling: The final clobetasol propionate liniment is filtered through a 0.22μm microporous membrane for sterilization, and then aseptically filled to obtain a clear, stable and non-irritating clobetasol propionate liniment product.

[0098] Comparative Example 3

[0099] Compared to Example 1, the difference is that tartaric acid is replaced with malic acid:

[0100] A clobetasol propionate liniment, prepared by the following steps:

[0101] (1) Preparation of natural eutectic solvent (DES) compatibilization system: 0.1 mol / L citric acid aqueous solution and 0.1 mol / L malic acid aqueous solution were mixed at a volume ratio of 1:3 and heated and stirred at 60℃ and 1500 rpm for 1 h to obtain eutectic solvent aqueous solution;

[0102] (2) Preparation of the active pharmaceutical ingredient solution: Weigh 0.1g of clobetasol propionate and add it to 50g of anhydrous ethanol. Stir until completely dissolved to obtain a clobetasol propionate-ethanol mixture.

[0103] (3) Mixing and preparation: Under continuous stirring, the clobetasol propionate-ethanol mixture prepared in step (2) is slowly added to the eutectic solvent aqueous solution prepared in step (1) at a mass ratio of 1:10. The mixture is mixed and homogenized at 5000 rpm for 10 min to form a homogeneous mixture.

[0104] (4) Addition and volume adjustment of functional ingredients: Add 0.1g of dipotassium glycyrrhizate to the mixture in step (3) and mix evenly to obtain clobetasol propionate liniment;

[0105] (5) Filtration and filling: The final clobetasol propionate liniment is filtered through a 0.22μm microporous membrane for sterilization, and then aseptically filled to obtain a clear, stable and non-irritating clobetasol propionate liniment product.

[0106] Comparative Example 4

[0107] Citric acid, tartaric acid, clobetasol propionate, anhydrous ethanol, and dipotassium glycyrrhizate were added to water in a mass ratio of 0.01:0.03:0.05:5:0.01, and the final volume was adjusted to 100g. The mixture was stirred and mixed evenly at 60℃ and 1500rpm for 10min. Then, it was filtered through a 0.22μm microporous membrane for sterilization and aseptically filled to obtain the clobetasol propionate liniment.

[0108] Comparative Example 5

[0109] Compared to Example 1, the difference is that anhydrous ethanol and clobetasol propionate do not form a mixture and are added directly:

[0110] (1) Preparation of natural eutectic solvent (DES) compatibilization system: 0.1 mol / L citric acid aqueous solution and 0.1 mol / L tartaric acid aqueous solution were mixed at a volume ratio of 1:3 and heated and stirred at 60℃ and 1500 rpm for 1 h to obtain eutectic solvent aqueous solution.

[0111] (2) Mixing and preparation: Under continuous stirring, 0.1g of clobetasol propionate and 50g of anhydrous ethanol were slowly added to the eutectic solvent aqueous solution prepared in step (1), and the mixture was homogenized at 5000rpm for 10min to form a homogeneous mixture.

[0112] (3) Addition and volume adjustment of functional ingredients: Add 0.1g of dipotassium glycyrrhizate to the mixture in step (2) and mix evenly to obtain clobetasol propionate liniment;

[0113] (4) Filtration and filling: The final clobetasol propionate liniment is filtered through a 0.22μm microporous membrane for sterilization, and then aseptically filled to obtain a clear, stable and non-irritating clobetasol propionate liniment product.

[0114] Comparative Example 6

[0115] The difference from Example 1 is that dipotassium glycyrrhizate and clobetasol propionate were added to anhydrous ethanol simultaneously:

[0116] (1) Preparation of natural eutectic solvent (DES) compatibilization system: 0.1 mol / L citric acid aqueous solution and 0.1 mol / L tartaric acid aqueous solution were mixed at a volume ratio of 1:3 and heated and stirred at 60℃ and 1500 rpm for 1 h to obtain eutectic solvent aqueous solution.

[0117] (2) Preparation of the main drug solution: Weigh 0.1g clobetasol propionate and 0.1g dipotassium glycyrrhizate, add them to 50g anhydrous ethanol, stir until completely dissolved, and obtain a clobetasol propionate-dipotassium glycyrrhizate-ethanol mixture;

[0118] (3) Mixing and preparation: Under continuous stirring, the clobetasol propionate-dipotassium glycyrrhizate-ethanol mixture prepared in step (2) was slowly added to the eutectic solvent aqueous solution prepared in step (1) at a mass ratio of 1:10. The mixture was mixed and homogenized at 5000 rpm for 10 min to form a homogeneous mixture.

[0119] (4) Filtration and filling: The final clobetasol propionate liniment is filtered through a 0.22μm microporous membrane for sterilization, and then aseptically filled to obtain a clear, stable and non-irritating clobetasol propionate liniment product.

[0120] Stability test:

[0121] The conditions and methods for stability testing are mainly based on the requirements of the Guidelines for Stability Testing of Raw Materials and Preparations in Part IV of the 2025 Edition of the Chinese Pharmacopoeia. The solution is placed in a 50 mL container, sealed, and kept in the dark at 30°C and 60% humidity for 12 months. Every 3 months, the contents of the bottle are observed for turbidity or precipitation. The sample droplets are also checked to see if they can be spread evenly. Impurity A is quantitatively determined (the detection method is based on the application document with publication number CN116593612A).

[0122] The results are shown in Table 1.

[0123] Table 1 Storage Stability

[0124]

[0125]

[0126] The results showed that the clobetasol propionate liniments prepared in Examples 1-4 exhibited good stability after being stored in the dark for 12 months at 30°C and 60% humidity. In contrast, Comparative Examples 1-6 showed problems such as discoloration, precipitation, and the detection of impurity A after 12 months.

[0127] Stimulation tests:

[0128] The skin irritation test was conducted in accordance with the requirements of the skin irritation / corrosion test in the "Cosmetic Hygiene Standard" (2015 edition).

[0129] Experimental animals: 5 three-month-old white rabbits per group.

[0130] Experimental Method: 24 hours prior to the experiment, the hair on both sides of the spine on the animal's back was shaved, with a shaved area of ​​3cm × 3cm on each side, taking care not to damage the epidermis. Approximately 0.5mL of the liniment prepared in Examples 1-4 and the comparative examples was applied to one side of the skin, with an application area of ​​2.5cm × 2.5cm, twice daily for one week. The other side of the skin served as the control group (when the test substance was prepared using a non-irritating solvent, the solvent was applied as a control). Starting from the second day, the hair was shaved before each application, and the results were observed 1 hour later. Scoring was performed according to Table 2 of the Skin Irritation / Corrosion Test in the "Cosmetic Hygiene Standard" (2015 edition). The control and test areas were treated in the same way. After the experiment, the average score for each animal per day was calculated to determine the intensity of skin irritation.

[0131] Skin irritation response scoring criteria:

[0132] Erythema and eschar formation: 0 = no erythema, 1 = very slight erythema, 2 = moderate erythema, 3 = severe erythema, 4 = purplish-red erythema with slight eschar formation;

[0133] Edema formation: 0 = no edema, 1 = very slight edema (barely visible), 2 = edema with a clear outline, 3 = edema that is raised about 1 mm above the skin, 4 = edema that is raised more than 1 mm above the skin and the area is expanded.

[0134] Table 2 Skin Irritation Studies

[0135]

[0136] Efficacy testing (in vitro transdermal assay):

[0137] 1. Preparation of isolated mouse skin

[0138] Male SD rats were sacrificed, their abdominal fur was shaved off, and the abdominal skin was peeled off. Subcutaneous adipose tissue and adhesions were carefully removed using cotton balls on a glass dish, and then the rats were washed with PBS before use.

[0139] 2. Transdermal test

[0140] A vertical Franz transdermal diffusion cell was used, with the upper chamber serving as the drug delivery chamber and the lower chamber as the receiving chamber; the effective diffusion area was 1.13 cm². 2 The volume was 15 mL. Isolated mouse skin was fixed between the drug delivery chamber and the receiving chamber in the diffusion pool. Epidermal drug delivery was performed, ensuring close contact between the dermis and the receiving solution (glacial acetic acid). Air bubbles were removed, and the surface of the receiving solution was brought into contact with the mouse skin. The skin was placed in an intelligent transdermal absorption instrument, first kept at temperature and equilibrated for 10 minutes, then a magnetic stirrer was set to 300 rpm at 37°C. The transdermal process was maintained at a constant temperature and speed for 16 hours. At regular intervals, 1 mL of the receiving solution was collected, and an equal volume of fresh receiving solution was added. The solution was filtered through a 0.45 μm microporous membrane to obtain the permeate. The concentration of clobetasol propionate in the permeate was determined by liquid chromatography.

[0141] Cumulative permeability = (Clobetasol propionate concentration in permeate / Clobetasol propionate concentration in dosing chamber) × 100%

[0142] The results are shown in Table 3.

[0143] Table 3 Transmittance (%)

[0144]

[0145]

[0146] The results showed that Examples 1-4 had higher permeability within 16 hours, and their effects were much better than those of Comparative Examples 1-6, indicating that they had better efficacy.

[0147] Although the present invention has been disclosed above with reference to preferred embodiments, it is not intended to limit the present invention. Anyone skilled in the art can make various modifications and alterations without departing from the spirit and scope of the present invention. Therefore, the scope of protection of the present invention should be determined by the claims.

Claims

1. A clobetasol propionate topical solution, characterized in that, It consists of the following components: clobetasol propionate, dipotassium glycyrrhizate, anhydrous ethanol, and an aqueous solution of a eutectic solvent; The mass ratio of the eutectic solvent aqueous solution, anhydrous ethanol, dipotassium glycyrrhizate, and clobetasol propionate is (85-95):(1-10):(0.005-0.01):(0.01-0.05). The method for preparing the eutectic solvent aqueous solution is as follows: 0.05-0.1 mol / L citric acid aqueous solution and 0.05-0.1 mol / L tartaric acid aqueous solution are mixed at a volume ratio of (1-3):(1-3) and heated at 60-80℃ and 800-1500rpm for 1-5 h to obtain the eutectic solvent aqueous solution.

2. A method for preparing the clobetasol propionate liniment according to claim 1, characterized in that, Includes the following steps: (1) Dissolve citric acid and tartaric acid in water respectively to prepare citric acid aqueous solution and tartaric acid aqueous solution; (2) Mix citric acid aqueous solution and tartaric acid aqueous solution, heat and stir to obtain eutectic solvent aqueous solution; (3) Dissolve clobetasol propionate in anhydrous ethanol to obtain a clobetasol propionate-ethanol mixture; (4) Mix the clobetasol propionate-ethanol mixture with an aqueous solution of a eutectic solvent to obtain a mixed solution; (5) Add dipotassium glycyrrhizate to the mixture and mix well to obtain clobetasol propionate liniment.

3. The method according to claim 2, characterized in that, In step (2), citric acid aqueous solution and tartaric acid aqueous solution are mixed in a volume ratio of (1-3):(1-3), and the concentrations of citric acid aqueous solution and tartaric acid aqueous solution are 0.05-0.1 mol / L.

4. The method according to claim 2, characterized in that, In step (2), the heating and stirring conditions are: heating at 60-80℃ and 800-1500 rpm for 1-5 h.

5. The method according to claim 2, characterized in that, The mass ratio of the eutectic solvent aqueous solution, anhydrous ethanol, dipotassium glycyrrhizate, and clobetasol propionate is (85-95):(1-10):(0.005-0.01):(0.01-0.05).

6. A medicine, characterized in that, The medicine contains the clobetasol propionate liniment as described in claim 1.

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