Tranexamic acid tablet for improving bioavailability and preparation method of tranexamic acid tablet

Abstract

The invention relates to the technical field of pharmaceutical preparations, and particularly discloses a tranexamic acid tablet capable of improving bioavailability and a preparation method of the tranexamic acid tablet. The tranexamic acid tablet is prepared from the following components in parts by weight: 50 to 65 parts of tranexamic acid, 15 to 25 parts of hydroxypropyl-beta-cyclodextrin, 5 to 8 parts of poloxamer 407, 3 to 5 parts of sodium alginate microspheres, 2 to 4 parts of carboxymethyl starch sodium and 0.5 to 1 part of stabilizer. The structure of the stabilizer is as follows: # imgabs0: tranexamic acid and hydroxypropyl-beta-cyclodextrin form an inclusion compound through a molecular inclusion technology, and the dissolution rate of the medicine is synergistically improved by combining the micelle solubilization effect of poloxamer 407. 0.5%-1% of magnesium stearate pre-coated sodium alginate microspheres are adopted to construct a pH response controlled release system, and the stability of the medicine is guaranteed through the anti-oxidation effect in cooperation with an independently researched and developed stabilizer. Animal experiments show that the bioavailability reaches 71.6%-83.2% and is improved by 40% or above compared with a traditional preparation, and the technical problems that an existing tablet is serious in oxidative degradation and low in absorption efficiency are solved.

Description

Technical Field

[0001] The present invention relates to the technical field of improving drug bioavailability, and in particular to a tranexamic acid tablet with improved bioavailability and a preparation method thereof. Background Art

[0002] Tranexamic acid, a commonly used antifibrinolytic drug in clinical practice, has significant efficacy in treating various bleeding disorders. However, existing tranexamic acid tablets have many problems in use, which limit their full efficacy.

[0003] First, tablets are susceptible to oxidation during storage and use. Tranexamic acid contains easily oxidizable groups in its molecular structure. When exposed to air or in contact with oxidizing substances, oxidation reactions can occur, leading to a decrease in the active ingredient content and, in turn, affecting the stability of the drug's efficacy. This not only shortens the drug's shelf life but also may produce harmful oxidation products, increasing the risk of toxic side effects.

[0004] Secondly, bioavailability is a key indicator for measuring drug absorption efficiency. Currently, most tranexamic acid tablets on the market have low bioavailability, primarily due to the drug's slow dissolution in the body, making it difficult to quickly release sufficient active ingredients to achieve the desired therapeutic effect. Furthermore, drug absorption in the gastrointestinal tract is restricted by various factors, such as the destructive effects of gastric acid on the drug and the limited contact area between the drug and the gastrointestinal mucosa. These factors hinder the effective absorption of tranexamic acid, requiring patients to take higher doses to achieve the desired therapeutic effect, thereby increasing treatment costs and potential risks.

[0005] Therefore, developing a novel tablet and a preparation method thereof that can improve the stability and bioavailability of tranexamic acid tablets is of great significance for improving the clinical application effect of tranexamic acid and enhancing the safety and effectiveness of treatment. Summary of the Invention

[0006] The purpose of the present invention is to provide a tranexamic acid tablet with improved bioavailability and a preparation method thereof in response to the problems existing in the prior art, wherein the tablet has high bioavailability and strong stability and a preparation method thereof.

[0007] To achieve the above object, the technical solution adopted by the present invention is: a tranexamic acid tablet with improved bioavailability, comprising the following components in percentage by weight: 50-65 parts of tranexamic acid, 15-25 parts of hydroxypropyl-β-cyclodextrin, 5-8 parts of poloxamer 407, 3-5 parts of sodium alginate microspheres, 2-4 parts of sodium starch glycolate, and 0.5-1 part of a stabilizer;

[0008] The structure of the stabilizer is a compound shown in Formula 1:

[0009]

[0010] Further, the structure of the tranexamic acid is:

[0011] Furthermore, the synthesis method of the stabilizer is:

[0012]

[0013] Step 1: Under a nitrogen atmosphere, dimethyl sulfoxide, potassium phosphate trihydrate, pyridine-2-carboxylic acid, CuI, raw material 1 and raw material 2 were added to the reaction system, heated to 85-90°C and reacted for 16-18 hours. After the reaction, intermediate 1 was obtained through post-treatment;

[0014] Step 2: Under a nitrogen atmosphere, aluminum chloride, thiourea, intermediate 1 and dichloromethane were added to the reaction system, heated to 85-90°C and reacted for 5-8 hours. After the reaction was completed, the stabilizer was obtained through post-treatment.

[0015] Furthermore, the molar ratio of potassium phosphate trihydrate, pyridine-2-carboxylic acid, CuI, raw material 1 and raw material 2 is 2:0.01:0.05:1:1.2.

[0016] Furthermore, the molar ratio of the aluminum chloride, thiourea and intermediate 1 is 14:7:1.

[0017] Furthermore, the added amount of dimethyl sulfoxide is 10-15 times the mass of raw material 1.

[0018] Furthermore, the added amount of dichloromethane is 13-15 times the mass of the intermediate 1.

[0019] Furthermore, the mass ratio of the hydroxypropyl-β-cyclodextrin to poloxamer 407 is (3-5):1.

[0020] Furthermore, the sodium alginate microspheres are pre-coated with 0.5%-1% magnesium stearate.

[0021] A method for preparing a tranexamic acid tablet with improved bioavailability comprises the following steps:

[0022] S1. The tranexamic acid and hydroxypropyl-β-cyclodextrin are molecularly included at 60-70 ° C to form an inclusion complex;

[0023] S2. The inclusion complex and poloxamer 407, sodium alginate microspheres, sodium carboxymethyl starch and a stabilizer were layered and granulated using an ethanol solution of sodium carboxymethyl starch to form tablets;

[0024] S3. The tablets are dried to a moisture content of ≤1.8%.

[0025] Furthermore, the drying temperature in S3 is 70-80°C.

[0026] Furthermore, the mass content of sodium carboxymethyl starch in the sodium carboxymethyl starch ethanol solution is 3%-5%.

[0027] Furthermore, the S3 was dried under a nitrogen atmosphere.

[0028] Furthermore, the tablets have an in vitro dissolution rate that meets the following requirements: ≥85% dissolution in 0.1N HCl medium within 15 minutes; and ≥95% dissolution in pH 6.8 phosphate buffer within 30 minutes.

[0029] The present invention discloses a tranexamic acid tablet with enhanced bioavailability. The core approach to improving bioavailability is based on multi-component synergy and delivery system optimization. The specific mechanisms are as follows: ①. Molecular inclusion technology: By forming an inclusion complex between tranexamic acid and hydroxypropyl-β-cyclodextrin (HP-β-CD) at 60-70°C, drug solubility is significantly improved. The hollow structure of HP-β-CD hydrophobically encapsulates tranexamic acid molecules, reducing crystallinity and increasing the amorphous fraction, thereby accelerating dissolution rate. ②. Surfactant synergistic solubilization: As a nonionic surfactant, poloxamer 407 improves drug dispersibility in gastrointestinal fluids by reducing interfacial tension. Its mass ratio to HP-β-CD (3-5:1) optimizes micelle formation, further enhancing dissolution efficiency. ③. Controlled-release delivery system: Sodium alginate microspheres are pre-coated with 0.5%-1% magnesium stearate to form a pH-responsive release system. In the gastric acid environment (pH ≈ 1.2), magnesium stearate delays the swelling of microspheres; after entering the intestine (pH ≥ 6.8), sodium alginate quickly dissolves and releases the drug, achieving targeted intestinal absorption. ④. Stabilizer Antioxidant Protection: The hydroxyl structure of the stabilizer scavenges free radicals and chelates metal ions (such as Fe 3+ 、Cu 2+ ), blocking the oxidative degradation pathway of tranexamic acid, ensuring the chemical stability of the drug during storage and in vivo environment, and maintaining the activity of the active ingredient.

[0030] The synergistic effect of the stabilizer described in this invention and other excipients is reflected in the cascade optimization of drug stability, release, and absorption: 1. Synergy with HP-β-CD: The inclusion complexation of HP-β-CD increases the surface area of tranexamic acid, but also exposes more oxidation-sensitive sites. The stabilizer protects the drug molecules from oxidation through localized antioxidant activity (enrichment at the inclusion complex interface), maintaining the integrity of the inclusion structure. 2. Synergy with Poloxamer 407: The micellar solubilization effect of Poloxamer 407 can increase drug concentration, but molecular collisions at high concentrations exacerbate the risk of oxidation. The stabilizer achieves a balance between solubilization and stability by reducing the oxidative microenvironment of the micelle core (the lipid-soluble portion is embedded in the micelle). 3. Synergy with sodium alginate microspheres: The controlled release of pre-coated microspheres relies on time-dependent swelling. If the drug degrades before release, the controlled release is lost. The stabilizer's sustained antioxidant effect (especially under nitrogen protection during the drying process) ensures long-term drug stability within the microspheres. ④. Indispensability: Without a stabilizer, tranexamic acid undergoes N-dealkylation and aromatic ring oxidation during granulation, drying (70-80°C), and storage, generating inactive metabolites that decrease bioavailability. Furthermore, these oxidation products may trigger allergic reactions, reducing medication safety.

[0031] Compared with the prior art, the present invention has the following beneficial effects:

[0032] 1. Significantly improved bioavailability: By adopting the synergistic effects of multiple components such as molecular inclusion technology, surfactant solubilization, and optimized delivery system, the tranexamic acid tablets of the present invention have high in vitro solubility and can quickly release the active ingredients in vivo, significantly improving the bioavailability of the drug.

[0033] 2. Enhanced drug stability: The added stabilizer effectively scavenges free radicals and chelates metal ions, blocking the oxidative degradation pathway of tranexamic acid. This allows it to maintain excellent chemical stability during storage and in vivo, preserving the activity of the active ingredient, extending the drug's shelf life, and reducing the risk of toxic side effects from oxidation products. The stabilizer's synthesis method precisely controls the molar ratio of each raw material and reaction conditions, ensuring its quality and effectiveness.

[0034] 3. Optimized preparation process: The preparation method is simple, efficient, and amenable to industrial production. Molecular inclusion is performed first, followed by layered granulation, and finally drying. Each step has clear parameters and strong operability. The use of a nitrogen atmosphere during the drying process further ensures tablet quality and stability.

[0035] 4. Improve drug safety and effectiveness: Stabilizers work synergistically with other excipients to not only improve the stability and release effect of drugs, but also reduce the risk of drug degradation in the body, ensure the accuracy of drug dosage and the reliability of therapeutic effects, and improve the safety and effectiveness of medication. DETAILED DESCRIPTION

[0036] The following will clearly and completely describe the technical solution of the present invention in conjunction with the inventive content of the present invention. Obviously, the embodiments described are only some embodiments of the present invention, not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without making creative efforts are within the scope of protection of the present invention.

[0037] Synthesis example 1

[0038] Synthesis of stabilizer:

[0039]

[0040] Step 1: Under a nitrogen atmosphere, 200 g of dimethyl sulfoxide, 35.04 g of potassium phosphate trihydrate, 0.1 g of pyridine-2-carboxylic acid, 0.8 g of CuI, 20 g of raw material 1, and 35 g of raw material 2 were added to the reaction system, heated to 90°C and reacted for 17 hours. After the reaction, 40.74 g of intermediate 1 was obtained through post-treatment.

[0041] The post-treatment of the first step is as follows: after the reaction is completed, the reaction mixture is cooled to room temperature, and then extracted with an aqueous ammonia solution and methyl tert-butyl ether. The organic phase is washed five times with water and then twice with a saturated NaCl solution. Finally, the combined organic phase is dried over anhydrous magnesium sulfate and spin-dried to obtain a solid. The solid is purified by a silica gel column using a mixed solution of ethyl acetate / petroleum ether as an eluent, and the solution is spin-dried to obtain an intermediate 1. The MS [MS+1] of the intermediate 1 is 626.

[0042] The intermediate 1 1 HNMR (deuterated chloroform) is: δ6.81 (d, 1H), 6.62 (dd, 1H), 6.37 (d, 1H), 5.69 (d, 1H), 5.51 (dd, 2H), 4.43 (dd, 1H), 4.38-4.16 (m, 4H), 4.11 (dd, 1H), 3.87 (s, 6H), 3.72 (s, 6H), 3.56 (dd, 1H), 3.48-3.37 (m, 1H), 3.37-3.29 (m, 10H), 1.77-1.63 (m, 1H), 0.90 (m, 6H);

[0043] Step 2: Under a nitrogen atmosphere, 121.55 g of aluminum chloride, 34.69 g of thiourea, 40.74 g of intermediate 1, and 600 g of dichloromethane were added to the reaction system, heated to 90° C., and reacted for 5 h. After the reaction, 28.96 g of a stabilizer was obtained after post-treatment; MS [MS+1] of the stabilizer was 528;

[0044] The post-treatment of the second step is as follows: after the reaction is completed, the reaction mixture is cooled to room temperature, the pH is adjusted to neutral with 0.1 mol / L HCl, the organic phase is retained after purification, the aqueous phase is washed three times with dichloromethane, the organic phases are combined, the organic phases are dried over anhydrous magnesium sulfate, and the solid is obtained by spin drying. The solid is purified by silica gel column, and a mixed solution of ethyl acetate / petroleum ether is used as eluent, and the solution is spin dried to obtain a stabilizer;

[0045] The stabilizer 1 HNMR (deuterated chloroform) is: δ9.82 (s, 2H), 9.73 (s, 2H), 6.80 (d, 1H), 6.62 (dd, 1H), 6.37 (d, 1H), 5.65 (d, 1H), 5.21 (d, 1H), 5.17-5.08 (m, 1H), 4.39-4.25 (m, 4H), 4.15-4.06 (m, 2H), 4.06-3.98 (m, 2H), 3.80 (m, 1H), 3.55 (m, 1H), 3.46 (t, 1H), 3.37 (m, 1H), 1.84-1.69 (m, 1H), 0.90 (m, 6H).

[0046] Synthetic example performance test:

[0047] 1. Use MTT colorimetry to test the biological toxicity of the synthesis example. The specific steps are as follows:

[0048] HepG2 cells were cultured in a 37°C, 5% CO2 saturated humidity incubator using Dulbecco's Modified Eagle Medium (DMEM). Dulbecco's Modified Eagle Medium (DMEM) was purchased from Wuhan Punosai Life Science Co., Ltd.; HepG2 liver cancer cells were purchased from the Cell Bank of the Chinese Academy of Sciences in Shanghai. 5×10 cells were seeded in each well of a 96-well plate using 180 μL of culture medium. 3 cells, and then cultured with a series of concentrations of the compound prepared in the synthesis example at 37°C for 48 h. After that, 20 μL of MTT solution (5 mg / mL) was added and cultured for 4 h. After that, all the solution was removed, and 150 μL of DMSO was added to each well to dissolve the formed formazan crystals. After shaking in a constant temperature water shaker (37°C, 100 rpm) for 10 min, the absorbance at 490 nm was measured, and the cell growth inhibition rate was calculated using the following formula.

[0049] The calculation formula for cell growth inhibition rate is:

[0050] In the concentration range of 10-100 μM, the growth inhibition rate of HepG2 cells treated with stabilizers was less than (2.3±0.5)%, indicating that the cells were non-toxic.

[0051] 2. Evaluation of the in vitro antioxidant activity of the compounds prepared in the synthesis examples The in vitro antioxidant capacity of the compounds prepared in the synthesis examples was determined by the DPPH method and ABTS method described in GB / T 39100-2020. The results were as follows: IC 50 IC for scavenging ABTS free radicals: 2.1 μM 50 is: 1.3μM.

[0052] Example 1

[0053] A tranexamic acid tablet for improving bioavailability, comprising the following components in percentage by mass: 65 parts of tranexamic acid, 25 parts of hydroxypropyl-β-cyclodextrin, 8 parts of poloxamer 407, 5 parts of sodium alginate microspheres, 4 parts of sodium starch glycolate, and 1 part of a stabilizer;

[0054] Preparation of a tranexamic acid tablet with improved bioavailability:

[0055] S1. molecular inclusion complexing tranexamic acid with hydroxypropyl-β-cyclodextrin at 70° C. to form an inclusion complex;

[0056] S2. The inclusion complex was layered with poloxamer 407, sodium alginate microspheres, sodium carboxymethyl starch and a stabilizer using a 5% sodium carboxymethyl starch ethanol solution to form tablets;

[0057] S3. The tablets were dried at 80°C under nitrogen atmosphere until the moisture content was ≤1.8%.

[0058] Example 2

[0059] A tranexamic acid tablet for improving bioavailability, comprising the following components in percentage by mass: 50 parts of tranexamic acid, 15 parts of hydroxypropyl-β-cyclodextrin, 5 parts of poloxamer 407, 3 parts of sodium alginate microspheres, 2 parts of sodium starch glycolate, and 0.5 parts of a stabilizer;

[0060] The preparation method of a tranexamic acid tablet with improved bioavailability is the same as that in the examples.

[0061] Example 3

[0062] Referring to the preparation of a tranexamic acid tablet with improved bioavailability in Example 1, the 5% sodium starch glycolate ethanol solution was replaced with a 3% sodium starch glycolate ethanol solution, and the rest remained the same as in Example 1.

[0063] Comparative Example 1

[0064] The preparation of a tranexamic acid tablet with improved bioavailability was carried out with reference to Example 1, except that no stabilizer was added, and the rest of the preparation was the same as in Example 1.

[0065] Comparative Example 2

[0066] The preparation of a tranexamic acid tablet with improved bioavailability was carried out with reference to Example 1, except that the sodium alginate microspheres were not added, and the rest of the preparation was the same as in Example 1.

[0067] Performance testing:

[0068] Pharmacokinetics and oral bioavailability were tested in SD rats. Depending on drug solubility, single doses were administered orally, intravenously, or intraperitoneally. Blood samples were collected at different time points (0, 0.5, 1, 2, 4, 6, 8, and 24 hours), anticoagulated with heparin, and centrifuged to obtain the supernatant. The blood samples were analyzed by HPLC-MS, and data were analyzed to determine bioavailability (BA). The results are shown in the following table:

[0069] sample Bioavailability (BA) Example 1 77.3％ Example 2 71.6％ Example 3 83.2％ Comparative Example 1 48.5％ Comparative Example 3 58.9％

[0070] While embodiments of the present invention have been shown and described, it will be appreciated by those skilled in the art that various changes, modifications, substitutions, and variations may be made to these embodiments without departing from the principles and spirit of the invention, and that the scope of the invention is defined by the appended claims and their equivalents.

Claims

1. A tranexamic acid tablet for improving bioavailability, characterized in that, The invention is composed of the following components in percentage by mass: 50-65 parts of tranexamic acid, 15-25 parts of hydroxypropyl-β-cyclodextrin, 5-8 parts of poloxamer 407, 3-5 parts of sodium alginate microspheres, 2-4 parts of sodium starch glycolate, and 0.5-1 part of a stabilizer; The structure of the stabilizer is a compound shown in Formula 1:

2. A tranexamic acid tablet for improving bioavailability according to claim 1, characterized in that, The synthesis method of the stabilizer is: Step 1: Under a nitrogen atmosphere, dimethyl sulfoxide, potassium phosphate trihydrate, pyridine-2-carboxylic acid, CuI, raw material 1 and raw material 2 were added to the reaction system, heated to 85-90°C and reacted for 16-18 hours. After the reaction, intermediate 1 was obtained through post-treatment; Step 2: Under a nitrogen atmosphere, aluminum chloride, thiourea, intermediate 1 and dichloromethane were added to the reaction system, heated to 85-90°C and reacted for 5-8 hours. After the reaction was completed, the stabilizer was obtained through post-treatment.

3. A tranexamic acid tablet for improving bioavailability according to claim 2, characterized in that, The molar ratio of potassium phosphate trihydrate, pyridine-2-carboxylic acid, CuI, raw material 1 and raw material 2 is 2:0.01:0.05:1:1.2; The molar ratio of aluminum chloride, thiourea and intermediate 1 is 14:7:1; The amount of dimethyl sulfoxide added is 10-15 times the mass of raw material 1; The amount of dichloromethane added is 13-15 times the mass of the intermediate 1.

4. A tranexamic acid tablet for improving bioavailability according to claim 1, characterized in that The mass ratio of the hydroxypropyl-β-cyclodextrin to poloxamer 407 is (3-5):

1.

5. A tranexamic acid tablet for improving bioavailability according to claim 1, characterized in that, The sodium alginate microspheres are pre-coated with 0.5%-1% magnesium stearate.

6. A method for preparing a tranexamic acid tablet with improved bioavailability according to any one of claims 1 to 5, characterized in that: The following steps are involved: S1. The tranexamic acid and hydroxypropyl-β-cyclodextrin are molecularly included at 60-70 ° C to form an inclusion complex; S2. The inclusion complex and poloxamer 407, sodium alginate microspheres, sodium carboxymethyl starch and a stabilizer were layered and granulated using an ethanol solution of sodium carboxymethyl starch to form tablets; S3. The tablets are dried to a moisture content of ≤1.8%.

7. A method for preparing a tranexamic acid tablet that improves bioavailability according to claim 6, characterized in that, The drying temperature in S3 is 70-80°C.

8. A method for preparing a tranexamic acid tablet that improves bioavailability according to claim 6, characterized in that, The mass content of sodium carboxymethyl starch in the sodium carboxymethyl starch ethanol solution is 3%-5%.

9. A method for preparing a tranexamic acid tablet that improves bioavailability according to claim 6, characterized in that, The S3 was dried under a nitrogen atmosphere.

10. A tranexamic acid tablet for improving bioavailability according to claim 1, characterized in that, The tablets have an in vitro dissolution rate that meets the following requirements: ≥85% dissolution in 0.1N HCl medium within 15 minutes; and ≥95% dissolution in pH 6.8 phosphate buffer within 30 minutes.

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