A kind of tranexamic acid gel composition and its preparation method and application

Abstract

The present invention provides a tranexamic acid gel composition and a preparation method and application thereof. The tranexamic acid gel composition comprises the following components by mass: 5-15 parts of tranexamic acid drugs, 1-10 parts of maltitol, 1-10 parts of polyols, and 2-10 parts of gel matrix materials; the polyols are selected from any one or a combination of at least two of chain-like small molecule polyols with a functionality of ≥4. The present invention, through the design of maltitol and a specific type of polyols and their compounding with tranexamic acid drugs, synergistically improves the skin permeability, absorbability and stability of the tranexamic acid gel composition, inhibits the crystallization and oxidative deterioration of the tranexamic acid drug without adding an alkaline regulator and an antioxidant, reduces the generation of impurities, obtains the effect of comprehensively improving transdermal absorbability and stability, and has an excellent and stable white appearance, so that the tranexamic acid gel plaster containing the maltitol and the polyols has better storage performance and therapeutic effect.

Description

Technical Field

[0001] The invention belongs to the technical field of pharmaceutical preparations, and in particular relates to a tranexamic acid gel composition and a preparation method and application thereof. Background Art

[0002] Chloasma is an acquired chronic hyperpigmented skin disease, more common in women, with clinical manifestations of symmetrical brown or gray-brown irregular shaped adverse reactions, mostly occurring on exposed parts such as the forehead, cheeks, temples, upper lip, and chin. Chloasma affects appearance, has limited treatment effects, has a very high recurrence rate, and has a great psychological impact on patients.

[0003] Tranexamic acid, also known as tranexamic acid, tranexamic acid, and hemostatic acid, is a derivative of aminobenzoic acid. It is an antifibrinolytic hemostatic drug and has been widely used in the beauty industry in recent years as an active ingredient for whitening and removing freckles. Tranexamic acid has a certain therapeutic effect on chloasma. Literature reports that the efficacy of tranexamic acid in removing melasma and freckles is about 50 times higher than that of vitamin C and nearly 10 times that of fruit acid. The possible mechanisms of action of tranexamic acid include: (1) It has a similar chemical structure to tyrosine and can directly compete with tyrosine, interfering with the catalytic effect of tyrosinase on tyrosine metabolism and reducing melanin production; (2) It interferes with the interaction between keratinocytes and melanocytes, inhibits the release of prostaglandin E2 by keratinocytes, and reduces the activity of melanocyte tyrosinase induced by ultraviolet light, thereby reducing melanin production; (3) It reduces tyrosinase activity and interferes with melanin production by inhibiting the activation of vascular endothelial growth factor receptors and the expression of melanogenic proteins in normal human melanocytes.

[0004] The commercially available preparation of tranexamic acid for freckle treatment is a Class I OTC drug from Daiichi Sankyo Co., Ltd., which has tranexamic acid and conventional vitamin C as the main active ingredients and is an oral compound tablet; however, the treatment of chloasma requires long-term medication, and tranexamic acid is a coagulant. Long-term use will produce a series of adverse reactions, especially gastrointestinal reactions, which can easily cause nausea, vomiting, diarrhea, etc., and can cause side effects such as menstrual blood coagulation and thrombosis. In clinical practice, tranexamic acid injection can also be used for subcutaneous injection or external application. Subcutaneous injection can allow the drug to effectively reach the local subcutaneous position, solve the problem of transdermal absorption, and reduce the side effects caused by the systemic application of drugs, but this method is also prone to cause local allergies and irritation, causing local discomfort.

[0005] Compared with other modes of administration, topical application has higher biosafety and is convenient for patients to use. Therefore, the development of tranexamic acid topical preparations is a research focus in the industry. For example, CN116370401A discloses a tranexamic acid topical preparation, specifically a tranexamic acid gel, comprising the following components: 1-3% tranexamic acid or its salt, 15-50% diethylene glycol monoethyl ether (first penetration enhancer), 5-35% propylene glycol and / or ethanol (second penetration enhancer), 0.1-2% carbomer, and 100% aqueous phase; the topical preparation has good percutaneous permeability, good stability, and is not easy to crystallize. CN116531353A discloses a tranexamic acid composition, comprising the following components: 0.01-15 parts of tranexamic acid or a pharmaceutically acceptable salt thereof, 0.5-50 parts of a gel skeleton component, 5-60 parts of a moisturizer, 0.01-4 parts of a cross-linking agent, 0.1-10 parts of an alkaline compound, 0.1-4 parts of a pH regulator, and 10-90 parts of a solvent; wherein the alkaline compound comprises a combination of one or more of diethylamine, triethylamine, triethanolamine, sodium hydroxide, and potassium hydroxide; and by introducing the alkaline compound and a plurality of transdermal penetration enhancers, the drug permeability and drug absorption in the tranexamic acid composition are improved.

[0006] Because tranexamic acid has strong hydrophilicity, it is difficult to pass through the stratum corneum barrier of the skin, and the transdermal rate is poor; moreover, tranexamic acid has very high crystallinity and poor stability. During production, storage and use, there are problems such as easy precipitation of crystals, easy oxidation and generation of oxidative impurities, which affect the effect and safety of the preparation. Transdermal penetration enhancers such as diethylene glycol monoethyl ether, propylene glycol, glycerol, ethanol, alkaline compounds, etc. are usually added to existing topical preparations, but their improvement effects on transdermal absorption are not obvious; moreover, the introduction of alkaline compounds will also reduce the stability of tranexamic acid preparations, which are easy to turn yellow / yellowish brown. In addition, researchers have tried to add antioxidants such as ascorbic acid to tranexamic acid preparations, but the effect of such antioxidants is not ideal. The tranexamic acid preparations containing them will still undergo obvious yellowing after storage, affecting the effect of the preparation and the user experience.

[0007] Therefore, how to improve the transdermal performance, absorbability and stability of tranexamic acid preparations is a problem to be solved urgently in the art. Summary of the invention

[0008] In view of the deficiencies in the prior art, the object of the present invention is to provide a tranexamic acid gel composition and a preparation method and application thereof. Through the design of maltitol and a specific polyol and the mutual compounding of maltitol and a tranexamic acid drug, the skin permeability, absorbability and stability of the tranexamic acid gel composition are significantly improved, the crystallization and oxidative deterioration of tranexamic acid are effectively inhibited, the generation of impurities is avoided or reduced, and the tranexamic acid gel composition and the tranexamic acid gel patch containing the tranexamic acid gel composition have higher stability and transdermal absorbability.

[0009] In order to achieve the purpose of the invention, the present invention adopts the following technical solutions:

[0010] In a first aspect, the present invention provides a tranexamic acid gel composition, wherein the tranexamic acid gel composition comprises the following components in parts by mass:

[0011]

[0012] The polyol is selected from any one or a combination of at least two of chain small molecule polyols with a functionality of ≥4.

[0013] The invention introduces maltitol and a specific type of polyol, which are compounded with a tranexamic acid drug to synergistically improve the transdermal performance, absorbability and stability of the tranexamic acid gel composition. In the case of no external alkaline regulator (alkaline compound) and no external antioxidant (such as ascorbic acid), the crystallization and oxidative deterioration of the tranexamic acid drug are effectively inhibited, and the generation of impurities is avoided or reduced, so that the transdermal performance and stability are comprehensively improved, and the tranexamic acid gel composition has an excellent white appearance, and can still maintain the stability of the properties and appearance after long-term storage, and will not have yellow / yellow-brown conversion, so that the tranexamic acid gel composition and the tranexamic acid gel patch containing the tranexamic acid gel composition have excellent stability and transdermal absorbability.

[0014] The following are preferred technical solutions of the present invention, but are not intended to limit the technical solutions provided by the present invention. Through the following preferred technical solutions, the objectives and beneficial effects of the present invention can be better achieved and realized.

[0015] In the tranexamic acid gel composition of the present invention, the mass parts of the tranexamic acid drug are 5-15 parts, for example, 6 parts, 7 parts, 8 parts, 9 parts, 10 parts, 11 parts, 12 parts, 13 parts or 14 parts, as well as specific point values ​​between the above point values. Due to space limitations and for the sake of simplicity, the present invention no longer exhaustively enumerates the specific point values ​​included in the range.

[0016] The mass proportion of the maltitol is 1-10 parts, for example, it can be 2 parts, 3 parts, 4 parts, 5 parts, 6 parts, 7 parts, 8 parts or 9 parts, as well as specific point values ​​between the above point values. Due to space limitations and for the sake of simplicity, the present invention no longer exhaustively lists the specific point values ​​included in the range.

[0017] The mass parts of the polyol are 1-10 parts, for example, 2 parts, 3 parts, 4 parts, 5 parts, 6 parts, 7 parts, 8 parts or 9 parts, as well as specific point values ​​between the above point values. Due to space limitations and for the sake of simplicity, the present invention no longer exhaustively lists the specific point values ​​included in the range.

[0018] The mass fraction of the gel matrix material is 2-10 parts, for example, it can be 3 parts, 4 parts, 5 parts, 6 parts, 7 parts, 8 parts or 9 parts, as well as specific values ​​between the above points. Due to space limitations and for the sake of simplicity, the present invention no longer exhaustively lists the specific points included in the range.

[0019] The “parts” and “parts by mass” involved in the present invention are all calculated based on the solid content, that is, the solvent, dispersant, etc. are not included.

[0020] Preferably, the tranexamic acid drug comprises tranexamic acid and / or tranexamic acid salt; wherein the tranexamic acid salt is a pharmaceutically acceptable salt of tranexamic acid.

[0021] In the present invention, the polyol is selected from any one or a combination of at least two of the chain small molecule polyols with a functionality ≥4 (for example, 4, 5, 6, 7, 8, etc.), wherein "functionality ≥4" means that 1 mol of the polyol molecule contains ≥4 mol (for example, 4 mol, 5 mol, 6 mol, 7 mol, 8 mol, etc.) of hydroxyl groups.

[0022] Preferably, the polyol comprises sorbitol and / or xylitol.

[0023] Preferably, the mass ratio of maltitol to polyol is 1:(0.2-5), for example, it can be 1:0.22, 1:0.25, 1:0.3, 1:0.4, 1:0.5, 1:0.6, 1:0.8, 1:1, 1:1.2, 1:1.5, 1:1.8, 1:2, 1:2.2, 1:2.5, 1:2.8, 1:3, 1:3.2, 1:3.5, 1:3.8, 1:4, 1:4.2, 1:4.5 or 1:4.8, and more preferably 1:(0.25-4).

[0024] As the preferred technical scheme of the present invention, the mass ratio of the design described maltitol and polyol is 1:4-4:1, and the two are compatible with the tranexamic acid drug and synergistically enhanced, so that the described tranexamic acid gel composition can effectively suppress the oxidation deterioration of the tranexamic acid drug while having better skin permeability and absorbability, reduce or avoid the generation of oxidative impurities, and significantly improve the stability of the described tranexamic acid gel composition. If the mass ratio of maltitol and polyol exceeds the preferred range of the present invention, the synergistic compatibility of the two will be weakened, affecting the stability and transdermal absorption performance of the tranexamic acid gel composition.

[0025] Preferably, the gel matrix material comprises any one of sodium polyacrylate, polyvinyl alcohol, carbomer, gelatin, and gum arabic, or a combination of at least two thereof.

[0026] Exemplarily, the sodium polyacrylate includes partially neutralized sodium polyacrylate (pharmaceutical excipient).

[0027] Preferably, the tranexamic acid gel composition further comprises 45-65 parts of solvent in parts by mass, and the mass parts of the solvent can be 46 parts, 48 ​​parts, 50 parts, 52 parts, 55 parts, 58 parts, 60 parts, 62 parts or 64 parts, as well as specific point values ​​between the above point values. Due to space limitations and for the sake of simplicity, the present invention no longer exhaustively enumerates the specific point values ​​included in the range.

[0028] Preferably, the solvent comprises water.

[0029] Preferably, the solvent further includes an optional organic solvent, and the organic solvent illustratively includes but is not limited to: any one of ethanol, N-methylpyrrolidone, propanol, or a combination of at least two thereof.

[0030] Preferably, the solvent is water.

[0031] Preferably, the tranexamic acid gel composition further includes 0.01-0.5 parts of a pH regulator by mass, and the mass parts of the pH regulator can be 0.02 parts, 0.05 parts, 0.08 parts, 0.1 parts, 0.12 parts, 0.15 parts, 0.18 parts, 0.2 parts, 0.22 parts, 0.25 parts, 0.28 parts, 0.3 parts, 0.32 parts, 0.35 parts, 0.38 parts, 0.4 parts, 0.42 parts, 0.45 parts or 0.48 parts, as well as specific point values ​​between the above point values. Due to space limitations and for the sake of simplicity, the present invention no longer exhaustively enumerates the specific point values ​​included in the range.

[0032] Preferably, the pH adjuster is an acidic pH adjuster.

[0033] Preferably, the pH adjuster includes any one of citric acid, tartaric acid, lactic acid, oleic acid, phosphoric acid, fumaric acid, malic acid, and ethylenediaminetetraacetic acid, or a combination of at least two thereof.

[0034] Preferably, the tranexamic acid gel composition further comprises 1-10 parts of a penetration enhancer by mass, and the mass portion of the penetration enhancer can be 2 parts, 3 parts, 4 parts, 5 parts, 6 parts, 7 parts, 8 parts or 9 parts, as well as specific values ​​between the above-mentioned points. Due to space limitations and for the sake of simplicity, the present invention no longer exhaustively enumerates the specific points included in the range.

[0035] Preferably, the penetration enhancer includes any one of diethylene glycol monoethyl ether, menthol, laurocapram, isopropyl myristate, or a combination of at least two thereof.

[0036] Preferably, the tranexamic acid gel composition further comprises 6-20 parts of humectant by mass, and the mass parts of the humectant can be 7 parts, 8 parts, 9 parts, 10 parts, 11 parts, 12 parts, 13 parts, 14 parts, 15 parts, 16 parts, 17 parts, 18 parts or 19 parts, as well as specific point values ​​between the above point values. Due to space limitations and for simplicity, the present invention no longer exhaustively enumerates the specific point values ​​included in the range.

[0037] Preferably, the moisturizing agent includes any one of glycerin, propylene glycol, and polyethylene glycol, or a combination of at least two of them.

[0038] Preferably, the tranexamic acid gel composition further comprises 0.05-1 parts of a cross-linking agent by mass, and the mass parts of the cross-linking agent can be 0.08 parts, 0.1 parts, 0.2 parts, 0.3 parts, 0.4 parts, 0.5 parts, 0.6 parts, 0.7 parts, 0.8 parts or 0.9 parts, as well as specific values ​​between the above points. Due to space limitations and for the sake of simplicity, the present invention no longer exhaustively enumerates the specific points included in the range.

[0039] Preferably, the cross-linking agent includes any one of aluminum glycolate, aluminum chloride, and aluminum hydroxide, or a combination of at least two thereof, and aluminum glycolate is further preferred.

[0040] Preferably, the tranexamic acid gel composition further comprises 0.05-1 parts of a cross-linking regulator by mass, and the mass parts of the cross-linking regulator can be 0.08 parts, 0.1 parts, 0.2 parts, 0.3 parts, 0.4 parts, 0.5 parts, 0.6 parts, 0.7 parts, 0.8 parts or 0.9 parts, as well as specific values ​​between the above points. Due to space limitations and for the sake of simplicity, the present invention no longer exhaustively enumerates the specific points included in the range.

[0041] Preferably, the cross-linking regulator comprises disodium edetate (disodium ethylenediaminetetraacetic acid).

[0042] Preferably, the tranexamic acid gel composition also includes a binder, and the mass portion of the binder is ≤8 parts, for example, it can be 0, 0.1 parts, 0.5 parts, 1 parts, 1.5 parts, 2 parts, 2.5 parts, 3 parts, 3.5 parts, 4 parts, 4.5 parts, 5 parts, 5.5 parts, 6 parts, 6.5 parts, 7 parts or 7.5 parts, as well as specific point values ​​between the above point values. Due to space limitations and for the sake of simplicity, the present invention no longer exhaustively enumerates the specific point values ​​included in the range.

[0043] Preferably, the adhesive includes any one of sodium carboxymethyl cellulose, methyl cellulose, polyacrylic acid, povidone, and grafted starch, or a combination of at least two thereof.

[0044] Preferably, the tranexamic acid gel composition further comprises other auxiliary agents that a person skilled in the art is motivated to add, such as a filler and / or an antibacterial agent.

[0045] In a preferred technical solution, the tranexamic acid gel composition comprises the following components in parts by mass:

[0046]

[0047] The polyol is selected from any one or a combination of at least two of chain small molecule polyols with a functionality of ≥4.

[0048] Preferably, the pH value of the tranexamic acid gel composition is 5.0-7.0, for example, it can be 5.2, 5.5, 5.8, 6.0, 6.2, 6.5 or 6.8, as well as specific values ​​between the above points. Due to space limitations and for the sake of simplicity, the present invention no longer exhaustively lists the specific points included in the range.

[0049] In a second aspect, the present invention provides a method for preparing the tranexamic acid gel composition as described in the first aspect, the preparation method comprising: uniformly mixing tranexamic acid drug, maltitol, polyol and gel matrix material to obtain the tranexamic acid gel composition.

[0050] Preferably, the mixed material further comprises any one of a solvent, a pH regulator, a penetration enhancer, a moisturizer, a cross-linking agent, a cross-linking regulator, and an adhesive, or a combination of at least two thereof.

[0051] Preferably, the preparation method comprises the following steps:

[0052] The tranexamic acid drug, maltitol, polyol, solvent and pH adjuster are uniformly mixed to obtain a phase A mixture;

[0053] Mixing the gel matrix material, the penetration enhancer, the moisturizer, the cross-linking agent, the cross-linking regulator and the optional binder to obtain a phase B mixture;

[0054] The phase A mixture and the phase B mixture are mixed evenly to obtain the tranexamic acid gel composition.

[0055] Preferably, the preparation method of the phase A mixture comprises: mixing tranexamic acid, a pH regulator and a solvent to obtain a solution; and uniformly mixing the solution with maltitol and a polyol to obtain the phase A mixture.

[0056] It should be noted that the tranexamic acid gel composition provided by the present invention can be used as an external preparation in any specific dosage form known in the art, including but not limited to ointments, gels, and patches.

[0057] In a third aspect, the present invention provides a tranexamic acid gel patch, comprising a backing layer, a drug storage layer and a protective layer arranged in sequence, wherein the drug storage layer comprises the tranexamic acid gel composition as described in the first aspect.

[0058] Preferably, the backing layer comprises a nonwoven fabric.

[0059] Preferably, the protective layer comprises a release film, such as a polyethylene terephthalate (PET) film.

[0060] Illustratively, the preparation method of the tranexamic acid gel patch includes: coating the tranexamic acid gel composition on a backing layer to form a drug storage layer; and compounding a protective layer on the drug storage layer to obtain the tranexamic acid gel patch.

[0061] Compared with the prior art, the present invention has the following beneficial effects:

[0062] (1) In the tranexamic acid gel composition provided by the present invention, by the design of maltitol and a specific type of polyol and its mutual compounding with the tranexamic acid drug, the skin permeability, absorbability and stability of the tranexamic acid gel composition are synergistically improved, and when no alkaline regulator or antioxidants such as ascorbic acid are added, the crystallization and oxidative deterioration of the tranexamic acid drug are effectively suppressed, and the generation of impurities is avoided or reduced, and the effect of comprehensively improving the transdermal absorbability and stability is obtained. Meanwhile, the tranexamic acid gel composition has an excellent white appearance, and can still maintain the stability of properties and appearance after long-term storage, and no yellowing phenomenon occurs, so that the tranexamic acid gel plaster comprising it has higher stability and transdermal absorbability.

[0063] (2) The present invention designs and further optimizes components such as maltitol and polyols, so that the tranexamic acid gel composition and the tranexamic acid gel patch containing the same have significantly improved transdermal absorbability and stability, inhibit oxidative deterioration and reduce impurity content, and can make the cumulative permeation amount of 24h>10000ng / cm2 After storage at 50°C for 30 days, the impurity C content is ≤0.2%, and the total impurity content is ≤0.26%. After storage at room temperature for 30 days, it still maintains an excellent white appearance without yellow / yellowish brown transformation, which improves the storage performance and therapeutic effect of tranexamic acid gel patch. BRIEF DESCRIPTION OF THE DRAWINGS

[0064] Figure 1 This is the HPLC test spectrum of the tranexamic acid gel patch provided in Example 12 after being stored at 50° C. for 30 days. DETAILED DESCRIPTION

[0065] The technical solution of the present invention is further described below by specific implementation methods. It should be understood by those skilled in the art that the embodiments are only to help understand the present invention and should not be regarded as specific limitations of the present invention.

[0066] As used herein, the terms "comprises," "including," "having," "containing," or any other variation thereof, are intended to cover a non-exclusive inclusion. For example, a composition, process, method, article, or apparatus that comprises the listed elements is not necessarily limited to only those elements but may include other elements not expressly listed or inherent to such composition, process, method, article, or apparatus.

[0067] "Optionally", "optionally" or "either" means that the subsequently described matter or event can or cannot occur, and that the description includes cases where the event occurs and cases where it does not.

[0068] In the following specific embodiments of the present invention, the materials, reagents, etc. used can all be conventional commercially available raw materials obtained from commercial channels. Among them, the gel matrix material is partially neutralized sodium polyacrylate, model AH-105X, purchased from East Asia Synthetic.

[0069] Example 1

[0070] A tranexamic acid gel composition comprises the following components in parts by mass:

[0071]

[0072] A tranexamic acid gel patch comprises a backing layer, a drug storage layer and a protective layer which are arranged in sequence, wherein the drug storage layer adopts the tranexamic acid gel composition provided in this embodiment; and the specific preparation method is as follows:

[0073] (1) according to the above formula, tranexamic acid, tartaric acid (pH regulator) and water are mixed, stirred and dissolved, and maltitol and sorbitol (polyol) are added thereto, and the mixture is stirred and mixed to obtain a phase A mixture;

[0074] According to the above formula, partially neutralized sodium polyacrylate (gel matrix material), diethylene glycol monoethyl ether (penetration enhancer), glycerin (humectant), aluminum glycolate (crosslinking agent), disodium edetate (crosslinking regulator) and sodium carboxymethylcellulose (binder) are mixed and stirred to obtain a phase B mixture;

[0075] (2) pouring the phase A mixture obtained in step (1) into the phase B mixture and stirring for 30 min to obtain the tranexamic acid gel composition;

[0076] (3) coating the tranexamic acid gel composition obtained in step (2) on a backing layer using a gel patch coating machine to form a drug storage layer; and then compounding a protective layer and cutting to obtain the tranexamic acid gel patch.

[0077] Examples 2-12, Comparative Examples 1-11

[0078] A tranexamic acid gel composition and a tranexamic acid gel patch comprising the same, which are different from those in Example 1 in that the formula of the tranexamic acid gel composition is different, as specifically shown in Table 1 and Table 2; wherein the dosage units of each component are all "parts by mass"; and the preparation method of the tranexamic acid gel patch is the same as that in Example 1.

[0079] Table 1

[0080]

[0081]

[0082] Table 2

[0083]

[0084]

[0085] Table 3

[0086]

[0087] The tranexamic acid gel composition and tranexamic acid gel patch provided in Examples 1-12 and Comparative Examples 1-11 were subjected to performance tests, and the specific methods are as follows:

[0088] (1) Stability test: impurity content before and after high temperature storage

[0089] The tranexamic acid gel patch to be tested was stored in a high temperature environment of 50°C, and the impurity content before storage (0 day) and after storage for 30 days was tested by high performance liquid chromatography (HPLC). The chromatographic conditions were as follows: chromatographic column: Inertsil ODS-3V (4.6mm×250mm, 5μm) (up); column temperature 40°C; flow rate: 1.2mL / min; injection volume: 40μL; detection wavelength: 210nm; mobile phase: mobile phase A: 25mmol sodium dihydrogen phosphate buffer solution (pH=2.3), mobile phase B: acetonitrile; elution conditions: isocratic elution; and the HPLC test spectra of each tranexamic acid gel patch were obtained. Among them, impurity C (structure is

[0090] The peak of ) is located at 14.840min in the HPLC test spectrum. The total impurity (total impurity) content is the sum of the masses of impurity C and other unknown impurities. The impurity content is calculated by the self-control method, impurity content = 1.0% × A 杂 / A 对 , where A 杂 Represents the area of ​​the impurity peak in the HPLC spectrum, A 对 It represents the main peak area in the chromatogram of the control solution. The preparation method of the control solution is as follows: take 1 mL of the test solution and dilute it to 100 mL with a diluent.

[0091] Taking Example 12 as an example, its HPLC test spectrum is as follows Figure 1 As shown, the peak corresponding to 14.840min is the peak of impurity C, and the total impurity is impurity C plus other unknown impurities; calculation shows that the impurity C content of the tranexamic acid gel patch of Example 12 after storage at 50°C for 30 days is 0.20%, and the total impurity content is 0.20%; the test data of other embodiments and comparative examples are shown in Table 4.

[0092] (2) Skin permeability test

[0093] The tranexamic acid gel patch to be tested was cut into 1.54 cm pieces using a mold. 2 The disc was used for transdermal investigation on pig skin and liquid chromatography-mass spectrometry (LC-MS) was used for detection. The specific method was as follows: the tranexamic acid gel patch to be tested was applied to the skin of a one-month-old Bama miniature pig with a thickness of about 1.0 mm; samples were taken from the physiological saline receiving solution after 1h, 2h, 4h, 8h, 12h, 16h, and 24h, and the LC-MS / MS method was used to detect the content of tranexamic acid in the samples taken at different time points, and the retention amount of the drug in the pig skin after the test was detected. The cumulative permeation amount was calculated according to the drug concentration in the samples taken at different time points and the size of the patch (effective permeation area). The in vitro permeation ability of the drug in the tranexamic acid gel patch was evaluated by the cumulative permeation amount.

[0094] The cumulative permeation calculation formula is:

[0095] Where Q is the cumulative amount of permeation per unit area per time t (ng / cm 2 ), C is the volume of the solution in the receiving tank, Cn is the measured concentration of the nth sample, and S is the effective penetration area.

[0096] (3) Appearance stability

[0097] The tranexamic acid gel patch to be tested was sealed in a paper aluminum bag and placed at room temperature. The appearance of the patch (drug storage layer) was observed after 30 days.

[0098] The test results are shown in Table 4:

[0099] Table 4

[0100]

[0101]

[0102] According to the above table data, in the tranexamic acid gel composition provided by the present invention, the skin permeability, absorbability and stability of the tranexamic acid gel composition can be improved by designing maltitol and a specific type of polyol and compounding them with components such as tranexamic acid drugs, so that the cumulative permeation amount of the tranexamic acid gel patch provided in Examples 1-12 for 24 hours is 10061-12341 ng / cm 2 After storage at 50°C for 30 days, the impurity C content is 0.07-0.20%, and the total impurity content is 0.07-0.26%. After storage at room temperature for 30 days, it still maintains an excellent white appearance without yellow / yellowish brown transformation, which improves the room temperature and high temperature storage performance and therapeutic effect of tranexamic acid gel patch.

[0103] In Comparative Examples 1 and 2, maltitol or sorbitol is used alone. After storage at 50°C for 30 days, the impurities increase significantly, the 24h cumulative permeability is relatively low, and the transdermal absorbability and storage stability decrease. Comparative Examples 3 and 4 do not contain a combination of maltitol and sorbitol, but replace one of maltitol or sorbitol with other polyols (such as glycerol). After storage, the impurity content is still very high. Although the skin permeability is improved to a certain extent compared with Comparative Examples 1-2, there is still no significant improvement. In Comparative Examples 5-11, when an alkaline regulator or an antioxidant (ascorbic acid) is added to the prescription, the impurities do not increase significantly after storage at 50°C for 30 days, and there is no significant difference in the 24h cumulative permeability, but the appearance will appear yellow / yellow-brown transformation under room temperature storage.

[0104] The applicant states that the present invention illustrates tranexamic acid gel composition of the present invention and its preparation method and application through the above-mentioned embodiments, but the present invention is not limited to the above-mentioned process steps, that is, it does not mean that the present invention must rely on the above-mentioned process steps to be implemented. Those skilled in the art should understand that any improvement of the present invention, the equivalent replacement of the raw materials selected by the present invention, the addition of auxiliary components, the selection of specific methods, etc., all fall within the protection scope of the present invention and the disclosure scope.

Claims

1. A tranexamic acid gel composition, characterized in that, The tranexamic acid gel composition comprises the following components in parts by mass: 5-15 copies of tranexamic acid Maltitol 1-10 parts Polyol 1-10 parts 2-10 parts of gel matrix material Solvent 45-65 parts Acidic pH regulator 0.01-0.5 parts Penetration enhancer 1-10 parts Moisturizer 6-20 parts Crosslinking agent 0.05-1 part Cross-linking regulator 0.05-1 part Adhesive 0-8 parts; The polyol is sorbitol and / or xylitol, and the mass ratio of maltitol to the polyol is 1:(0.2-5).

2. The tranexamic acid gel composition according to claim 1, wherein The tranexamic acid drug includes tranexamic acid and / or tranexamic acid salt.

3. The tranexamic acid gel composition according to claim 1 or 2, characterized in that The mass ratio of the maltitol to the polyol is 1:(0.25-4).

4. The tranexamic acid gel composition according to claim 1, characterized in that The gel matrix material includes any one of sodium polyacrylate, polyvinyl alcohol, carbomer, gelatin, and gum arabic, or a combination of at least two of them.

5. The tranexamic acid gel composition according to claim 1, characterized in that The solvent includes water.

6. The tranexamic acid gel composition according to claim 1, characterized in that The acidic pH regulator includes any one of citric acid, tartaric acid, lactic acid, oleic acid, phosphoric acid, fumaric acid, malic acid, and ethylenediaminetetraacetic acid, or a combination of at least two thereof.

7. The tranexamic acid gel composition according to claim 1, characterized in that The penetration enhancer includes any one of diethylene glycol monoethyl ether, menthol, laurocapram, and isopropyl myristate, or a combination of at least two of them.

8. The tranexamic acid gel composition according to claim 1, characterized in that The moisturizing agent includes any one of glycerin, propylene glycol, and polyethylene glycol, or a combination of at least two of them.

9. The tranexamic acid gel composition according to claim 1, characterized in that The cross-linking agent includes any one of aluminum glycolate, aluminum chloride, and aluminum hydroxide, or a combination of at least two of them.

10. The tranexamic acid gel composition according to claim 1, characterized in that The cross-linking regulator includes disodium edetate.

11. The tranexamic acid gel composition according to claim 1, characterized in that The adhesive includes any one of sodium carboxymethyl cellulose, methyl cellulose, polyacrylic acid, povidone, and grafted starch, or a combination of at least two of them.

12. The tranexamic acid gel composition according to claim 1, characterized in that The pH value of the tranexamic acid gel composition is 5.0-7.

0.

13. A method for preparing a tranexamic acid gel composition as claimed in any one of claims 1 to 12, characterized in that: The preparation method comprises the following steps: The tranexamic acid drug, maltitol, polyol, solvent and acidic pH regulator are uniformly mixed to obtain a phase A mixture; The gel matrix material, the penetration enhancer, the moisturizer, the cross-linking agent and the cross-linking regulator are mixed uniformly to obtain a phase B mixture; The phase A mixture and the phase B mixture are mixed evenly to obtain the tranexamic acid gel composition.

14. The preparation method according to claim 13, characterized in that: The preparation method comprises the following steps: The tranexamic acid drug, maltitol, polyol, solvent and acidic pH regulator are uniformly mixed to obtain a phase A mixture; The gel matrix material, the penetration enhancer, the moisturizer, the cross-linking agent, the cross-linking regulator and the adhesive are uniformly mixed to obtain a phase B mixture; The phase A mixture and the phase B mixture are mixed evenly to obtain the tranexamic acid gel composition.

15. A tranexamic acid gel patch, characterized in that: The tranexamic acid gel patch comprises a backing layer, a drug storage layer and a protective layer which are arranged in sequence, and the drug storage layer comprises the tranexamic acid gel composition according to any one of claims 1 to 12.

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