A composition of tranilast for topical administration

Abstract

The present invention relates to a composition for topical administration of tranilast, characterized in that said composition comprises tranilast and a solubilizing agent, said solubilizing agent being meglumine, said composition having a molar ratio of tranilast to meglumine comprised between 1 :0.5 and 1 :3, preferably any of the ranges comprised between 1 :0.5 and 2.5, 1 :0.5 and 2, 1 :1 and 2, 1 :0.5 and 1.5, 1 :0.6 and 1.5, 1 :0.7 and 1.5, 1 :0.5 and 1.5, 1 :0.6 and 1.5, 1 :0.7 and 1.5, 1 :0.8 and 1.2, 1 :0.9 and 1.2, 1 :1 and 1.5, most preferably 1 :1. The present invention further provides the use of said composition, or of a cream or gel or foam based on said composition, for the manufacture of a medicament for the treatment or amelioration of a dermatological disease.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical formulations, and more specifically to a topical tranilast composition. Background Technology

[0002] Tranilast, chemically known as N-(3,4-dimethoxycinnamoyl)aminoanisic acid, is an anti-allergy drug jointly developed by Gifu Pharmaceutical University and Kissei Pharmaceutical in Japan in 1976. Tranilast capsules were approved for marketing in Japan in 1982 for the treatment of bronchial asthma. In 1985, the drug was approved for the treatment of atopic dermatitis and allergic rhinitis. In 1993, it was approved for the treatment of keloids and hypertrophic scars.

[0003] Currently, tranilast is used clinically to treat or improve keloids and hypertrophic scars via oral administration. However, oral systemic administration can lead to insufficient local blood drug concentrations, requiring multiple long-term doses. Therefore, the therapeutic effect of oral administration for dermatological diseases such as scars often fails to meet expectations.

[0004] The biggest challenge in applying tranilast to external administration is that tranilast is extremely difficult to dissolve in water.

[0005] Therefore, some related technologies propose using organic amines as solubilizers to improve the water solubility of tranilast. For example, JP2002234837A relates to an aqueous topical formulation containing tranilast, wherein the solubilizer is preferably an amine having an alcohol hydroxyl group, particularly selected from meglumine, monoethanolamine, diethanolamine, triethanolamine, aminobutanetriol, diisopropanolamine, and triisopropanolamine. In the specific examples, diisopropanolamine is used.

[0006] Some related technologies also mention using meglumine as a solubilizer for tranilast. For example, JP2001122776A describes dissolving tranilast or its pharmacologically acceptable salt in an aqueous solution of an alkanolamine, wherein the alkanolamine is monoethanolamine, diethanolamine, triethanolamine, isopropanolamine, or diisopropanolamine, selected from triisopropanolamine, tromethamine, and meglumine. Specifically, meglumine is used in the nasal drops of Example 3 and the injection of Example 6. CN100388915C provides a tranilast eye drop solution, in which meglumine is used as a solubilizer. Moreover, except for the injection in JP2001122776A, the other two dosage forms use a relatively large amount of meglumine (the amount of meglumine in the CN100388915C formulation is 100-300g / 5000ml).

[0007] When administered topically, the concentration of meglumine was not properly optimized within the recommended range, resulting in insufficient improvement in drug solubility, low therapeutic efficiency, and accompanying stability and safety defects when used in excess: 1. Safety issues, causing erythema, desquamation, or burning sensation, especially for patients with broken skin (such as eczema, ulcers) or sensitive skin, and sensitization; 2. Formulation stability defects, excessive meglumine may lead to excessively high alkalinity in topical semi-solid preparations (such as creams, gels), resulting in phase separation or decreased viscosity. Summary of the Invention

[0008] To address the problems existing in the prior art, the present invention relates to a tranilast composition for topical administration, the composition of which can significantly improve the solubility of tranilast, thereby significantly improving the therapeutic effect of topical administration of tranilast for dermatological diseases.

[0009] According to an embodiment of the present invention, the composition contains tranilast and a solubilizer, wherein the solubilizer is meglumine.

[0010] According to an embodiment of the present invention, the chemical name of the tranilast is N-(3,4-dimethoxycinnamoyl)o-aminobenzoic acid, the molecular weight is 327.33, and it has the following structure:

[0011]

[0012] According to an embodiment of the present invention, the N-methylglucamine has the chemical name 1-deoxy-1-(methylamino)-D-sorbitol, a molecular weight of 195.21, and the following structure:

[0013]

[0014] According to embodiments of the present invention, the molar ratio of tranilast to meglumine in the composition is 1:0.5 to 1:3, preferably any range from 1:0.5 to 2.5, 1:0.5 to 2, 1:1 to 2, 1:0.5 to 1.5, 1:0.6 to 1.5, 1:0.7 to 1.5, 1:0.5 to 1.5, 1:0.6 to 1.5, 1:0.7 to 1.5, 1:0.8 to 1.2, 1:0.9 to 1.2, and 1:1 to 1.5, with 1:1 being the most preferred.

[0015] According to embodiments of the present invention, the amount of tranilast added to the composition is 0.5%-15% of the total mass of the composition, preferably 1%-10% or 2%-8%.

[0016] According to embodiments of the present invention, the composition further comprises at least one pharmaceutically acceptable excipient selected from at least one of emulsifiers, thickeners, co-emulsifiers, humectants, preservatives, stabilizers, pH adjusters, defoamers, antioxidants, chelating agents, and solvents.

[0017] According to embodiments of the present invention, the emulsifier is selected from nonionic surfactants, and the nonionic surfactant is selected from at least one of the following categories:

[0018] (a) Glycerides, including glycerides mono- and di-stearate;

[0019] (b) Alcohol ethers, including cetearyl alcohol polyether, cetearyl alcohol polyether, lauryl alcohol polyether, methyl glucanol polyether, stearyl alcohol polyether;

[0020] (c) Polyoxyethylene derivatives, including polyoxyethylene fatty acid esters, polyoxyethylene castor oil, polyoxyethylene hydrogenated castor oil, polyoxyethylene stearate, and polyoxyethylene glyceryl stearate;

[0021] (d) Polysorbates, including polysorbates;

[0022] (e) Propylene glycol esters, including propylene glycol diacetate, propylene glycol dioctanoate, and propylene glycol monostearate;

[0023] (f) Other nonionic emulsifiers, including poloxamer and diethylene glycol alkyl ethers.

[0024] According to embodiments of the present invention, the thickener is selected from at least one of the following categories:

[0025] (a) Synthesizing high molecular weight polymers, including acrylate copolymers, carbomer and its copolymers, carboxyvinyl copolymers, sodium carboxymethyl cellulose, and carboxypolymethylene;

[0026] (b) Natural colloids and their derivatives, including carrageenan and guar gum;

[0027] (c) Cellulose derivatives, including hydroxyethyl cellulose, hydroxypropyl cellulose, and methyl cellulose;

[0028] (d) Fatty alcohols, including hexadecyl alcohol and octadecanol.

[0029] According to embodiments of the present invention, the co-emulsifier is selected from at least one of the following categories:

[0030] (a) A monohydric alcohol, which is an alkanol having 1 to 4 carbon atoms, selected from at least one of methanol, ethanol, n-propanol and isopropanol;

[0031] (b) A polyol selected from at least one of ethylene glycol, propylene glycol, and glycerol.

[0032] According to embodiments of the present invention, the pH adjuster is selected from at least one of the following categories:

[0033] (a) Organic acids and their salts, including acetic acid, sodium acetate, potassium acetate, citric acid, sodium citrate, potassium citrate, fumaric acid, malic acid, succinic acid, and tartaric acid;

[0034] (b) Inorganic acids and their salts, including hydrochloric acid, sulfuric acid, nitric acid, boric acid, sodium borate, sodium carbonate, sodium bicarbonate, potassium carbonate, and potassium bicarbonate;

[0035] (c) Organic bases, including triethylamine, triethanolamine, diethanolamine, and tromethamine;

[0036] (d) Inorganic bases, including sodium hydroxide, ammonium hydroxide, and ammonium carbonate.

[0037] According to embodiments of the present invention, the antioxidant is selected from at least one of the following categories:

[0038] (a) Fat-soluble antioxidants, including butylated hydroxyanisole (BHA), 2,6-di-tert-butyl-p-cresol (BHT), and butylated hydroxytoluene;

[0039] (b) Water-soluble antioxidants, including ascorbic acid and its ester derivatives, and α-tocopherol succinate.

[0040] According to an embodiment of the present invention, the solvent is selected from at least one of C1-C3 alcohol solvents and water, wherein the C1-C3 alcohol solvents include methanol, ethanol, propylene glycol, and isopropanol.

[0041] According to embodiments of the present invention, the dosage form of the composition is selected from at least one of creams, suspensions, gels, sprays, oils, ointments, creams, pastes, foams, patches, or solutions.

[0042] According to embodiments of the present invention, the composition further comprises at least one of the following adjuvant activators: desloratadine, epinastine, levocetirizine, isotretinoin, and benzoyl peroxide.

[0043] A second aspect of the invention relates to the use of any of the above compositions in the manufacture of a medicament for the treatment or improvement of dermatological diseases.

[0044] According to an embodiment of the present invention, the skin disease is selected from at least one of the following categories:

[0045] (a) Fibrotic diseases, including scleroderma, keloids, and sclerosing panniculitis;

[0046] (b) Inflammatory diseases, including atopic dermatitis, chronic urticaria, psoriasis, herpetic dermatitis, and polymorphic light eruption;

[0047] (c) Proliferative diseases, including cutaneous sarcoidosis and mast cell hyperplasia;

[0048] (d) Immune-related skin diseases, including pemphigus vulgaris and linear bullous dermatitis;

[0049] (e) Other skin conditions, including acne, granuloma annulare, lichen scintillans, pruritus, and progressive pigmented purpuric dermatosis.

[0050] A third aspect of the present invention relates to a gelling agent prepared from the above-described tranilast composition, comprising a gel matrix selected from at least one of the following categories:

[0051] (a) Synthetic polymer materials, including polyvinyl alcohol, polyvinylpyrrolidone, sodium carboxymethyl cellulose, hydroxypropyl methylcellulose, methylcellulose, and carbomer;

[0052] (b) Natural colloids and their derivatives, including sodium alginate and xanthan gum;

[0053] (c) Polyols, including glycerol;

[0054] The gel matrix is ​​preferably carbomer and / or xanthan gum.

[0055] A fourth aspect of the present invention relates to a foaming agent prepared from the above-described tranilast composition, comprising:

[0056] (a) A gelling agent selected from at least one of synthetic polymers (polyvinyl alcohol, polyvinylpyrrolidone, sodium carboxymethyl cellulose, hydroxypropyl methylcellulose, methylcellulose, carbomer) and natural colloids (sodium alginate, xanthan gum), preferably carbomer and / or xanthan gum;

[0057] (b) Foaming agent selected from C16-C20 fatty alcohols and fatty acids, including at least one of cetyl alcohol, stearyl alcohol, arachidyl alcohol, stearic acid, arachidic acid, and oleyl alcohol.

[0058] According to an embodiment of the present invention, the foaming agent further comprises a propellant, the propellant being selected from:

[0059] (a) Liquefied hydrocarbon gases, including propane, butane, isobutane and mixtures thereof;

[0060] (b) Hydrofluoroalkane (HFA) liquefied gases, including at least one of HFA-134a (tetrafluoroethane), HFA-227ea (heptafluoropropane), and dimethyl ether.

[0061] A fifth aspect of the present invention relates to a cream prepared from the above-described tranilast composition, comprising a cream base selected from:

[0062] (a) Hydrocarbon matrices, including petrolatum and paraffin;

[0063] (b) Waxy matrices, including beeswax;

[0064] (c) Ester matrices, including squalane and palmitic acid derivatives;

[0065] (d) Silicone oil-based matrices, including dimethyl silicone oil;

[0066] (e) Fatty alcohol matrix, including hexadecyl alcohol and octadecanol;

[0067] (f) Polyethylene glycol matrix, including mixtures of PEGs of different molecular weights;

[0068] According to an embodiment of the present invention, the tranilast cream comprises the following components by weight percentage:

[0069] Trinilast: 0.5%-15%;

[0070] The solubilizer is meglumine; the molar ratio of tranilast to meglumine in the composition is 1:0.5 to 1:3, preferably any range from 1:0.5 to 2.5, 1:0.5 to 2, 1:1 to 2, 1:0.5 to 1.5, 1:0.6 to 1.5, 1:0.7 to 1.5, 1:0.5 to 1.5, 1:0.6 to 1.5, 1:0.7 to 1.5, 1:0.8 to 1.2, 1:0.9 to 1.2, 1:1 to 1.5, with 1:1 being the most preferred.

[0071] Emulsifier: 0.5%-15%;

[0072] Thickener: 1%-15%;

[0073] Cream base: 10%-80%;

[0074] Solvent: Make up to 100% w / w.

[0075] According to an embodiment of the present invention, the tranilast cream comprises the following components by weight percentage:

[0076] The content of tranilast is 2%-8%;

[0077] The solubilizer is meglumine; the molar ratio of tranilast to meglumine in the composition is 1:0.5 to 1:3, preferably any range from 1:0.5 to 2.5, 1:0.5 to 2, 1:1 to 2, 1:0.5 to 1.5, 1:0.6 to 1.5, 1:0.7 to 1.5, 1:0.5 to 1.5, 1:0.6 to 1.5, 1:0.7 to 1.5, 1:0.8 to 1.2, 1:0.9 to 1.2, 1:1 to 1.5, with 1:1 being the most preferred.

[0078] The emulsifier content is 1%-10%;

[0079] The thickener content is 0.5%-5%;

[0080] The cream base content is 10%-50%;

[0081] The solvent content is: the balance is made up to 100% w / w.

[0082] According to an embodiment of the present invention, the tranilast cream comprises the following components:

[0083] The emulsifier is selected from glycerides, including glyceryl monostearate and glyceryl distearate;

[0084] The thickener is selected from fatty alcohols, including at least one of hexadecyl alcohol and octadecyl alcohol;

[0085] The cream base is a combination of petrolatum, paraffin and beeswax, more preferably a mixture of white petrolatum and paraffin;

[0086] The beneficial effects of this invention are that, when administered topically, the molar ratio of tranilast to meglumine is 1:0.5 to 1:3, preferably any range from 1:0.5 to 2.5, 1:0.5 to 2, 1:1 to 2, 1:0.5 to 1.5, 1:0.6 to 1.5, 1:0.7 to 1.5, 1:0.5 to 1.5, 1:0.6 to 1.5, 1:0.7 to 1.5, 1:0.8 to 1.2, 1:0.9 to 1.2, and 1:1 to 1.5, with 1:1 being the most preferred, as this results in optimal solubility. Consequently, when the tranilast composition, gel, foam, or cream involved is used to treat dermatological diseases, the therapeutic effect is also optimal. Attached Figure Description

[0087] Figure 1 The reduction in rabbit ear scar thickness after 14 days of drug administration in each group of the efficacy experiment of cream A.

[0088] Figure 2 The reduction in rabbit ear scar thickness after 21 days of drug administration in each group of the efficacy experiment of cream A.

[0089] Figure 3The reduction in rabbit ear scar thickness after 28 days of drug administration in each group of the efficacy experiment of cream A.

[0090] Figure 4 Efficacy experiment of cream A: Collagen fiber area ratio experiment of each group

[0091] Figure 5 : Detection of Collagen I content in tissues of each group in the efficacy experiment of cream A

[0092] Figure 6 After two weeks of treatment with cream B, a comparison was made between the 4% scar reduction in the cream B group and the positive control group.

[0093] Figure 7 After three weeks of treatment with cream B, a comparison was made between the 4% scar reduction in the cream B group and the positive control group.

[0094] Figure 8 : After four weeks of treatment with cream B, a comparison of scar reduction in 4% of the cream B group and the positive control group. Detailed Implementation

[0095] To make the objectives, technical solutions, and advantages of this invention clearer, the invention will be further described in detail below with reference to the accompanying drawings and embodiments. It should be understood that the specific embodiments described herein are merely illustrative and not intended to limit the invention.

[0096] Example 1: Solubilizer Screening

[0097] Weigh tranilast and the materials in Table 1 at a molar ratio of 1:1, place them in a beaker, add an appropriate amount of solvent (such as ethanol or methanol), heat and stir, cool to room temperature, and vacuum dry overnight to obtain a tranilast salt mixture.

[0098] Take an appropriate amount of ultrapure water, transfer 1 mL of ultrapure water into a 5 mL centrifuge tube, and number them sequentially. Add the tranilast salt mixture from Table 1 to the centrifuge tube according to the order in the table, and shake the resulting slurry at 25°C. Observe the solubility, ensuring that there are always excess solid particles during the experiment. Shake the slurry for 24 hours, take the sample aqueous solution after 24 hours of shaking, filter, centrifuge the supernatant, dilute with methanol, and inject to detect the solubility of tranilast. The results are shown in Table 1.

[0099] The detection method is as follows:

[0100] Chromatographic conditions: C18 (4.6×250mm, 5µm), flow rate: 1.0mL / min, injection volume: 5µl, column temperature: 30℃, detection wavelength: 308nm

[0101] Mobile phase: methanol:acetonitrile:ammonium acetate solution (0.02 mol / L) = 1:1:2 (adjust pH to 4.0 with glacial acetic acid)

[0102] Accurately measure the test solution and the control solution, inject them separately into the liquid chromatograph, record the chromatograms, and calculate the solubility.

[0103] Content calculation formula:

[0104]

[0105] Table 1

[0106] sample Solubility determination results in pure water (mg / mL) Trinister 0.0012 meglumine 349.67 Diethylamine 16.39 potassium hydroxide 48.04 diethanolamine 325.33 Triethanolamine 165.68 meglumine 168.02 Tromethamine 13.91 Niacinamide 0.26

[0107] As shown in Table 1, the solubility test data shows that the combination of tranilast and meglumine has significantly better solubility in organic amine systems than other organic amine systems (such as nicotinamide).

[0108] Example 2: Screening of molar ratio of tranilast to meglumine

[0109] The solubility of tranilast at different molar ratios of tranilast and meglumine was tested using the experimental method of Example 1, and the results are shown in Table 2.

[0110] Table 2

[0111] Trinister - weighing value Meglumine - Weighing value molar ratio of tranilast to meglumine Solubility determination results in pure water (mg / mL) 500mg 150mg 1:0.5 175.57 500mg 300mg 1:1 319.83 500mg 600mg 1:2 314.55 500mg 900mg 1:3 201.48

[0112] As shown in Table 2, when the molar ratio of tranilast to meglumine was 1:1 and 1:2, the saturated solubility of tranilast in pure water reached 319.83 mg / mL and 314.55 mg / mL, respectively. When the molar ratio of tranilast to meglumine increased to 1:3, its solubility decreased to 201.48 mg / mL. When the molar ratio of tranilast to meglumine decreased to 1:0.5, its solubility significantly decreased to 175.5 mg / mL.

[0113] Example 3: In vitro release experiment of tranilast-meglumine solutions with different molar ratios

[0114] The artificial filter membrane was immersed in pure water for 30 minutes, then removed and dried. Approximately 300 μL of sample was loaded for each sample (see Table 3). The diffusion cell was then assembled and placed on the transdermal analyzer. The receiving solution was 0.5% SDS (sodium dodecyl sulfate), the stirring speed was 600 rpm, and the temperature was 32℃. Samples were taken at 0.5, 1, 2, 3, 4, and 6 hours for analysis. After sampling, 0.5% SDS was added. After 6 hours, the remaining tranilast solution and filter membrane were transferred to a 50 ml centrifuge tube containing 25 ml of 0.5% SDS for vortexing to dissolve. 1 mL of the supernatant was collected by centrifugation, diluted with 9 mL of mobile phase, filtered through the membrane, and then injected.

[0115] The content detection conditions are as follows:

[0116] Chromatographic column: Yuexu Ultimate LP-C18 (4.6*250mm, 5μm)

[0117] Detection wavelength: 308nm

[0118] Injection volume: 20 μL

[0119] Column temperature: 30℃

[0120] Flow rate: 1 mL / min

[0121] Mobile phase: methanol / acetonitrile / 0.02 mol·L ammonium acetate solution = 1 / 1 / 2 (adjust pH to 4.0 with glacial acetic acid)

[0122] Based on the test results, the cumulative release per unit area (μg / cm²) for different groups was calculated. 2 The results are shown in Table 4.

[0123] Table 3

[0124] Tranilast meglumine suspension group molar ratio of tranilast to meglumine Trinister weighing value (g) Meglumine weighing value (g) 1 1:0.5 2 0.6 2 1:1 2 1.2 3 1:2 2 2.4 4 1:3 2 3.6

[0125] Table 4

[0126] Group 1 Group 2 Group 3 Group 4 Infiltration time (h) 1:0.5 1:1 1:2 1:3 0.5 2.8 4.4 3.5 2.8 1 3.4 5.4 4.3 3.3 2 3.5 5.7 4.5 3.5 3 3.6 5.9 4.6 3.6 4 3.7 6.0 4.7 3.7 6 3.7 6.1 4.8 3.7 Permeability % 5.50 9.02 7.09 5.51 In vitro release rate 0.45 0.84 0.66 0.51

[0127] Table 4 shows the cumulative release per unit area (μg / cm²) when the molar ratio of tranilast to meglumine was 1:1. 2 The permeation rate and in vitro release rate of this group were significantly higher than those of other groups. The above technical effects indicate that this molar ratio range can significantly enhance the release efficiency of the active ingredient.

[0128] Example 4: Preparation of gelling agent

[0129] A gel formulation with a molar ratio of tranilast to meglumine of 1:1 was prepared according to the formulation ratio in Table 5.

[0130] The preparation process is as follows:

[0131] (1) Preparation of phase A: Weigh the prescribed amounts of anhydrous ethanol, propylene glycol and methyl hydroxypropyl, mix them, heat to 55–65℃ in a water bath and stir until completely dissolved to obtain a clear phase A solution;

[0132] (2) Preparation of phase B: Weigh the prescribed amount of purified water, disodium edetate, allantoin, poloxamer 188, tranilast, meglumine, and triethanolamine, mix them, heat to 50–60°C, and stir until uniformly dissolved to form phase B solution;

[0133] (3) Mixing and neutralization: Slowly add phase A solution to phase B solution, maintain temperature at 45–60℃ and stir continuously until homogeneous; then add phase C – a gel matrix formed by pre-swelling of the prescribed amount of carbomer and purified water, mix evenly and adjust pH to 6.5–7.5, then fill into the container.

[0134] Table 5

[0135]

[0136] Example 5: Preparation of foaming agent

[0137] A foaming agent with a molar ratio of tranilast to meglumine of 1:1 was prepared according to the formulation ratio in Table 6.

[0138] The preparation process is as follows:

[0139] (1) Alcohol phase preparation: Mix anhydrous ethanol, propylene glycol, octadecanol and hexadecyl alcohol according to the prescription amount, and stir in a water bath at 55–65℃ until a clear and homogeneous phase is formed;

[0140] (2) Aqueous phase preparation: Mix the prescribed amount of purified water, meglumine, xanthan gum and tranilast, and stir until completely dissolved;

[0141] (3) Mixing and filling: Slowly add the aqueous phase to the alcohol phase while stirring to form a homogeneous solution; fill the solution into a pressure-resistant aerosol can (made of aluminum or tin-plated steel), seal it, and then inject the propellant (heptafluoropropane); install the valve and seal it, and finally conduct quality inspection to ensure the airtightness of the product.

[0142] Table 6

[0143]

[0144] Example 6: Preparation of Cream A

[0145] Creams with molar ratios of tranilast to meglumine of 1:0.5, 1:1, and 1:2 were prepared according to the formulation ratios in Table 7. The preparation process is as follows:

[0146] Preparation of the oil phase: Weigh out the prescribed amounts of butylated hydroxyanisole, white petrolatum, paraffin, cetyl alcohol (hexadecyl alcohol), polysorbate 60, and glycerin 85 in sequence, heat until melted, and stir evenly.

[0147] Preparation of the aqueous phase: Weigh triethanolamine and meglumine, add a mixture of hydrochloric acid and purified water, control the pH at around 9.5, set the water bath temperature to 65℃, and heat the aqueous phase to 65℃.

[0148] Add the aqueous phase to the oil phase, stir, homogenize, and cool. Weigh the prescribed amounts of diethylene glycol monoethyl ether, menthol, and potassium sorbate, add them to the mixed matrix, stir, homogenize, and mix well. Add the remaining hydrochloric acid and the remaining purified water, stir and mix well, measure the pH value of the sample, and cool to room temperature for filling.

[0149] Table 7

[0150]

[0151] Example 7: Efficacy Experiment of Cream A

[0152] The therapeutic effects of creams prepared with different molar ratios of tranilast and meglumine in Table 7 of Example 6 on a rabbit ear hypertrophic scar model were investigated.

[0153] Experimental Methods: Six 1.0 cm diameter prototype wounds were imprinted at six locations on the ventral side of rabbit ears using a punch, with a 1.0 cm interval between each wound, avoiding blood vessels. The superficial skin was removed with a scalpel, and the perichondrium was completely removed, preserving the cartilage. The wounds were allowed to heal naturally, with povidone-iodine applied twice daily for disinfection until scarring occurred, thus establishing a rabbit ear hypertrophic scar model. After successful modeling, medications were applied to the hypertrophic scars in each group. The medications applied were: model (blank ointment), positive control medication (Centella asiatica cream ointment, silicone scar gel), and test medications (S230401, S230402, S230403), for 4 weeks. At the experimental endpoint, scar hyperplasia tissue was collected for scar hyperplasia index (SEI) measurement. Scar tissue was stained with HE and Masson staining and observed under a light microscope to examine morphological changes. Immunohistochemistry was used to detect the expression of collagen I protein in the tissue.

[0154] Keloids typically present as raised, thickened scars, often significantly thicker than normal skin. Changes in scar thickness are a key indicator of treatment effectiveness. A significant reduction in scar thickness after treatment usually indicates effective treatment. Figure 1-3As shown, the reduction in rabbit ear scar thickness was evaluated in each treatment group, and comparisons were made with the normal control group at 14, 21, and 28 days after administration. The results showed that the reduction in rabbit ear scar thickness was significantly higher in the model group (blank ointment). Compared with the model group, the reduction in rabbit ear scar thickness was lower in the S230401 and S230403 treatment groups, while it was significantly higher in the S230402 treatment group. For example, after 28 days of administration, the reduction in rabbit ear scar thickness in the S230402 group (0.841 mm) was statistically significantly different from that in the S230401 group (0.342 mm) and the S230403 group (0.351 mm) (p < 0.05). This indicates that S230402 can effectively reduce rabbit ear scar thickness, significantly better than other treatment groups, demonstrating the optimal effect of S230402 in the treatment of rabbit ear scars.

[0155] Excessive deposition of collagen fibers is a major cause of scar formation. Reducing the area of ​​collagen fibers can lessen the formation and severity of scars. Figure 4 As shown, in the collagen fiber area ratio experiment, compared with the blank ointment control group without active ingredients, all experimental drug compositions showed a significant decrease in the percentage of collagen fiber cross-sectional area. In particular, the collagen fiber area ratio of S230402 decreased to 0.625, which was significantly different from S230401 (0.771) and S230403 (0.715) (p<0.05), demonstrating the best collagen deposition inhibition activity.

[0156] Excessive deposition of Collagen I (type I collagen) is an important pathological basis for keloid formation, and its high expression can serve as a diagnostic marker for keloids. Figure 5 As shown, in the test of Collagen I content in tissues, the Collagen I content in all treatment groups decreased significantly compared with the blank ointment group. Among them, the silicone scar gel in the positive control group showed the best therapeutic effect, while among the test drugs, S230402 had the most significant effect, reducing the Collagen I content in tissues to 0.450, which was statistically significantly different from S230401 (0.511) and S230403 (0.604) (p<0.05), indicating that S230402 was more effective than other test drugs in reducing Collagen I content.

[0157] Example 8: Preparation of Cream B

[0158] Following the preparation method in Example 6, creams with a molar ratio of tranilast to meglumine of 1:1 were prepared according to the formulation ratios in Table 8.

[0159] Table 8

[0160] raw materials Proportion Dosage effect Trinister 4% 40 Active ingredients cetyl alcohol 5% 50 Thickener Stearyl alcohol 5% 50 Thickener paraffin 10% 100 Cream base Vaseline 10% 100 Cream base meglumine 2.4% 24 Solubilizer Glyceryl monostearate and glyceryl distearate 4% 40 emulsifier Purified water Add to 100% Add to 1000 solvent hydrochloric acid Appropriate amount Appropriate amount pH adjuster Triethanolamine Appropriate amount Appropriate amount pH adjuster total 100% 1000 /

[0161] Example 9: Efficacy Experiment of Cream B

[0162] This study aimed to evaluate the efficacy of the test drug in treating hypertrophic scars in rabbit ears.

[0163] Study ID: ZHBY-CRO-2024-202-1

[0164] Breed: New Zealand White Rabbit

[0165] Formulation information:

[0166] Blank cream formulation (except for lacking active ingredients, all other ingredients are the same as cream B).

[0167] 4% Cream B (Example 8, batch number: S-240516, specification: 4% (10 g : 0.4 g);

[0168] Tranilast capsules (batch number: 230416, specification: 0.1 g / capsule);

[0169] Centella asiatica cream (batch number: 231004);

[0170] Silicone scar gel (batch number: 20221202).

[0171] Dosage and administration method:

[0172] Grouping

[0173] 1 Model group (right ear model, left ear as normal control group, no intervention) (N=2 birds) 2 Model + blank cream preparation group (blank cream preparation treatment, single dose: 20 mg / wound, once a day / animal, applied topically to scar wounds, continuous treatment for 3 weeks) (N=2 animals) 3 Model + positive drug group 1 (silicone scar gel treatment, single dose: 20 mg / wound, twice / wound / day / animal, topical application to scar wound, continuous treatment for 3 weeks) (N=2 animals) 4 Two groups were established: a model group and a positive control group (treated with Centella asiatica cream ointment, single dose: 20 mg / wound, twice / wound / day / animal, topical application to scarred wounds, continuous treatment for 3 weeks) (N=2 animals). 5 Model + test cream formulation group (4% cream B treatment, single dose: 20 mg / wound, once / wound / day / animal, topical application to scarred wounds, continuous treatment for 3 weeks) (N=2 animals) 6 Model + Test drug group B (trenilast capsules, single dose: 5.75 mg / kg, twice a day / animal, administered by gavage, for 3 consecutive weeks) (N=4 animals)

[0174] Modeling: All animals were weighed and numbered. After anesthesia, the right ear was modeled. Six sites were taken on the inner side of the right ear. A circular wound with a diameter of 1 cm was made using a punch. The superficial skin and perichondrium were completely removed. Each wound was spaced 1 cm apart. The six wounds on the left and right ears were numbered A, B, C, D, E, and F respectively.

[0175] Photos were taken on the weekends of each week before and after drug administration, on day 1 (the day of modeling), day 5, day 10, day 15, day 20, and day 25, respectively. Scar thickness (mm) was measured and recorded, and the reduction in scar thickness before and after drug administration was calculated for each group.

[0176] The results are as follows Figure 6As shown, after two weeks of treatment, the scar thickness in all groups except the normal group gradually decreased with increasing treatment time. Specifically, compared with the positive control group, the scar reduction in the 4% cream B group was 0.670 mm, which was significantly better than that of Centella Asiatica ointment (0.235 mm), silicone scar gel (0.518 mm), and tranilast capsules (0.394 mm).

[0177] like Figure 7 As shown, after three weeks of treatment, the scar thickness in all groups except the normal group gradually decreased with increasing treatment time. Specifically, compared with the positive control group, the scar reduction in the 4% cream B group was 0.800 mm, which was significantly better than the 0.362 mm reduction in the Centella Asiatica ointment, and better than the 0.655 mm reduction in the silicone scar gel and the 0.684 mm reduction in the tranilast capsules.

[0178] like Figure 8 As shown, after four weeks of treatment, the scar thickness in all groups except the normal group gradually decreased with increasing treatment time. Specifically, compared with the positive control group, the scar reduction in the 4% cream B group was 0.790 mm, which was significantly better than the 0.556 mm reduction in the Centella Asiatica ointment, and better than the 0.695 mm reduction in the silicone scar gel and the 0.739 mm reduction in the tranilast capsule.

[0179] The embodiments described above are merely illustrative of several implementations of the present invention, and while the descriptions are relatively specific and detailed, they should not be construed as limiting the scope of the invention patent. It should be noted that those skilled in the art can make various modifications and controls without departing from the concept of the present invention, and these all fall within the protection scope of the present invention. Therefore, the protection scope of this invention patent should be determined by the appended claims.

Claims

1. A topically administered tranilast composition, characterized in that, The composition comprises tranilast and a solubilizer, wherein the solubilizer is meglumine, and the molar ratio of tranilast to meglumine in the composition is from 1:0.5 to 1:3, preferably any range from 1:0.5 to 2.5, 1:0.5 to 2, 1:1 to 2, 1:0.5 to 1.5, 1:0.6 to 1.5, 1:0.7 to 1.5, 1:0.5 to 1.5, 1:0.6 to 1.5, 1:0.7 to 1.5, 1:0.8 to 1.2, 1:0.9 to 1.2, to 1:1 to 1.5, with 1:1 being the most preferred.

2. The composition according to claim 1, characterized in that, The amount of tranilast added to the composition is 0.5%-15% of the total mass of the composition, preferably 1%-10% or 2%-8%.

3. The composition according to claim 2, characterized in that, The composition further comprises a pharmaceutically acceptable excipient selected from at least one of emulsifiers, thickeners, co-emulsifiers, humectants, preservatives, stabilizers, pH adjusters, defoamers, antioxidants, chelating agents, and solvents.

4. The composition according to claim 3, characterized in that, The emulsifier is selected from nonionic surfactants, and the nonionic surfactant is selected from at least one of the following categories: (a) Glycerides, including glycerides mono- and di-stearate; (b) Alcohol ethers, including cetearyl alcohol polyether, cetearyl alcohol polyether, lauryl alcohol polyether, methyl glucanol polyether, stearyl alcohol polyether; (c) Polyoxyethylene derivatives, including polyoxyethylene fatty acid esters, polyoxyethylene castor oil, polyoxyethylene hydrogenated castor oil, polyoxyethylene stearate, and polyoxyethylene glyceryl stearate; (d) Polysorbates, including polysorbates; (e) Propylene glycol esters, including propylene glycol diacetate, propylene glycol dioctanoate, and propylene glycol monostearate; (f) Other nonionic emulsifiers, including poloxamer and diethylene glycol alkyl ethers.

5. The composition according to claim 3, characterized in that, The thickener is selected from at least one of the following categories: (a) Synthesizing high molecular weight polymers, including acrylate copolymers, carbomer and its copolymers, carboxyvinyl copolymers, sodium carboxymethyl cellulose, and carboxypolymethylene; (b) Natural colloids and their derivatives, including carrageenan and guar gum; (c) Cellulose derivatives, including hydroxyethyl cellulose, hydroxypropyl cellulose, and methyl cellulose; (d) Fatty alcohols, including hexadecyl alcohol and octadecanol.

6. The composition according to claim 3, characterized in that, The co-emulsifier is selected from at least one of the following categories: (a) A monohydric alcohol, which is an alkanol having 1 to 4 carbon atoms, selected from at least one of methanol, ethanol, n-propanol and isopropanol; (b) A polyol selected from at least one of ethylene glycol, propylene glycol, and glycerol.

7. The composition according to claim 3, characterized in that, The pH adjuster is selected from at least one of the following categories: (a) Organic acids and their salts, including acetic acid, sodium acetate, potassium acetate, citric acid, sodium citrate, potassium citrate, fumaric acid, malic acid, succinic acid, and tartaric acid; (b) Inorganic acids and their salts, including hydrochloric acid, sulfuric acid, nitric acid, boric acid, sodium borate, sodium carbonate, sodium bicarbonate, potassium carbonate, and potassium bicarbonate; (c) Organic bases, including triethylamine, triethanolamine, diethanolamine, and tromethamine; (d) Inorganic bases, including sodium hydroxide, ammonium hydroxide, and ammonium carbonate.

8. The composition according to claim 3, characterized in that, The antioxidant is selected from at least one of the following categories: (a) Fat-soluble antioxidants, including butylated hydroxyanisole (BHA), 2,6-di-tert-butyl-p-cresol (BHT), and butylated hydroxytoluene; (b) Water-soluble antioxidants, including ascorbic acid and its ester derivatives, vitamin E and its derivatives such as α-tocopherol succinate.

9. The composition according to claim 3, characterized in that, The solvent is selected from at least one of C1-C3 alcohol solvents and water, wherein the C1-C3 alcohol solvents include methanol, ethanol, propylene glycol, and isopropanol.

10. The composition according to any one of claims 1 to 9, characterized in that, The dosage form of the composition is selected from at least one of creams, suspensions, gels, sprays, oils, ointments, creams, pastes, foams, patches, microneedle patches, solutions, and solid dispersions.

11. The composition according to any one of claims 1 to 9, characterized in that, The composition further comprises at least one of the following adjuvant active agents: desloratadine, epinastine, levocetirizine, isotretinoin, benzoyl peroxide, and asengeprast.

12. Use of the composition according to any one of claims 1 to 9 for the production of a medicament for the treatment or improvement of dermatological diseases.

13. The use as described in claim 12, characterized in that, The skin disease is selected from at least one of the following categories: (a) Fibrotic diseases, including scleroderma, keloids, and sclerosing panniculitis; (b) Inflammatory diseases, including atopic dermatitis, chronic urticaria, psoriasis, herpetic dermatitis, and polymorphic light eruption; (c) Proliferative diseases, including cutaneous sarcoidosis and mast cell hyperplasia; (d) Immune-related skin diseases, including pemphigus vulgaris and linear bullous dermatitis; (e) Other skin conditions, including acne, granuloma annulare, lichen scintillans, pruritus, and progressive pigmented purpuric dermatosis.

14. The composition according to claim 10, characterized in that, The dosage form is a gel, comprising a gel matrix, wherein the gel matrix is ​​selected from at least one of the following categories: (a) Synthetic polymer materials, including polyvinyl alcohol, polyvinylpyrrolidone, sodium carboxymethyl cellulose, hydroxypropyl methylcellulose, methylcellulose, and carbomer; (b) Natural colloids and their derivatives, including sodium alginate and xanthan gum; (c) Polyols, including glycerol; The gel matrix is ​​preferably carbomer and / or xanthan gum.

15. The composition according to claim 10, characterized in that, The dosage form is a foaming agent, comprising: (a) A gelling agent selected from at least one of synthetic polymers (polyvinyl alcohol, polyvinylpyrrolidone, sodium carboxymethyl cellulose, hydroxypropyl methylcellulose, methylcellulose, carbomer) and natural colloids (sodium alginate, xanthan gum), preferably carbomer and / or xanthan gum; (b) Foaming agent selected from C16-C20 fatty alcohols and fatty acids, including at least one of cetyl alcohol, stearyl alcohol, arachidyl alcohol, stearic acid, arachidic acid, and oleyl alcohol.

16. The composition according to claim 15, characterized in that, The foaming agent further comprises a propellant, the propellant being selected from: (a) Liquefied hydrocarbon gases, including propane, butane, isobutane and mixtures thereof; (b) Hydrofluoroalkane (HFA) liquefied gases, including at least one of HFA-134a (tetrafluoroethane), HFA-227ea (heptafluoropropane), and dimethyl ether.

17. The composition according to claim 10, characterized in that, The dosage form is a cream, comprising a cream base, wherein the cream base is selected from: (a) Hydrocarbon matrices, including petrolatum and paraffin; (b) Waxy matrices, including beeswax; (c) Ester matrices, including squalane and palmitic acid derivatives; (d) Silicone oil-based matrices, including dimethyl silicone oil; (e) Fatty alcohol matrix, including hexadecyl alcohol and octadecanol; (f) Polyethylene glycol matrix, including mixtures of PEGs of different molecular weights; At least one of the following, preferably a combination of petrolatum, paraffin and beeswax, more preferably a mixture of white petrolatum and paraffin.

18. A tranilast cream, comprising the following components by weight percentage: Trinilast: 0.5%-15%; The solubilizer is meglumine; the molar ratio of tranilast to meglumine in the composition is 1:0.5 to 1:3, preferably any range from 1:0.5 to 2.5, 1:0.5 to 2, 1:1 to 2, 1:0.5 to 1.5, 1:0.6 to 1.5, 1:0.7 to 1.5, 1:0.5 to 1.5, 1:0.6 to 1.5, 1:0.7 to 1.5, 1:0.8 to 1.2, 1:0.9 to 1.2, 1:1 to 1.5, with 1:1 being the most preferred. Emulsifier: 0.5%-15%; Thickener: 1%-15%; Cream base: 10%-80%; Solvent: Make up to 100% w / w.

19. The tranilast cream according to claim 18, characterized in that, By weight percentage, it contains the following components: The content of tranilast is 1%-10%; The solubilizer is meglumine; the molar ratio of tranilast to meglumine in the composition is 1:0.5 to 1:3, preferably any range from 1:0.5 to 2.5, 1:0.5 to 2, 1:1 to 2, 1:0.5 to 1.5, 1:0.6 to 1.5, 1:0.7 to 1.5, 1:0.5 to 1.5, 1:0.6 to 1.5, 1:0.7 to 1.5, 1:0.8 to 1.2, 1:0.9 to 1.2, 1:1 to 1.5, with 1:1 being the most preferred. The emulsifier content is 1%-10%; The thickener content is 0.5%-5%; The cream base content is 10%-50%; The solvent content is: the balance is made up to 100% w / w.

20. The tranilast cream according to claim 19, characterized in that: The emulsifier is selected from glycerides, including glyceryl monostearate and glyceryl distearate; The thickener is selected from fatty alcohols, including at least one of hexadecyl alcohol and octadecyl alcohol; The cream base is a combination of petrolatum, paraffin and beeswax, more preferably a mixture of white petrolatum and paraffin; The solvent is water.

Images