A tranexamic acid composition and a method of preparing the same

Abstract

The present application relates to the technical field of pharmaceutical preparation, in particular to a tranexamic acid composition and a preparation method thereof, according to weight parts, the tranexamic acid composition comprises: tranexamic acid 100 parts, polyvinyl alcohol 5-9 parts, corn starch 1-3 parts, low-substituted hydroxypropyl cellulose 4-8 parts and lubricant 1-4 parts; the lubricant comprises glyceryl behenate. The tranexamic acid composition has less impurities than a reference preparation, and there is no obvious change in dissolution under high-temperature conditions; through accelerated and long-term test research, evaluation indexes such as dissolution curve, content, dissolution rate and related substances all meet the requirements, and there is no significant change compared with 0 days, the quality is stable, the quality is consistent with that of the reference preparation, and the bioequivalence in vivo is achieved, the clinical substitution with the reference preparation is realized, the price is lower, the accessibility is high, and the medication burden of the public is reduced.

Description

Technical Field

[0001] The present invention relates to a tranexamic acid composition and a preparation method thereof, belonging to the technical field of pharmaceutical preparations. Background Art

[0002] Tranexamic acid (C8H 15 NO2) structural formula: Molecular weight: 157.21. It is a lysine derivative and an antifibrinolytic agent. It reversibly binds to the lysine site on plasmin, hindering the binding of plasminogen to fibrin, exerting an antifibrinolytic effect and thus achieving a hemostatic effect. Tranexamic acid tablets are originally developed and listed by Daiichi Sankyo Co., Ltd. in Japan. Available in 250mg and 500mg strengths, they are listed as a reference preparation in the 20th batch of generic drug reference preparations.

[0003] Currently, the domestically marketed dosage forms of tranexamic acid include ordinary tablets, capsules, powder for injection, and injection, which are generally used to stop bleeding.

[0004] Patent publication CN102525878A discloses a tranexamic acid sustained-release solid composition and its preparation method. The composition uses tranexamic acid as a raw material, and the weight ratios of tranexamic acid, hydrophilic gel sustained-release matrix material, filler, binder, glidant, and lubricant are 50-70%, 7-20%, 10-40%, 0-10%, 0-2%, and 0.5-2%, respectively. The resulting sustained-release solid preparation achieves zero-order release within 3 hours and maintains a stable blood drug concentration.

[0005] Patent publication CN104414991A discloses a solid sustained-release tablet of tranexamic acid and a preparation method thereof, which comprises, by weight, 40% to 60% tranexamic acid, 35% to 55% insoluble sustained-release matrix material, and 0.5% to 5% lubricant, and is granulated by wet granulation, dry granulation, or melt granulation process and then tableted.

[0006] Patent publication CN104490752A discloses a freeze-dried tablet of a tranexamic acid composition and a preparation method thereof, which comprises tranexamic acid, starch, and sucrose. Starch and sucrose are used as auxiliary materials. By heating ordinary corn starch, the adhesion and disintegration effects of the starch in the tablet can be improved, thereby improving the tablet forming process.

[0007] Patent publication CN103054861A discloses a compound solid preparation containing tranexamic acid, which contains tranexamic acid, vitamin C, vitamin B6, L-cysteine, calcium pantothenate and pharmaceutical excipients suitable for making solid preparations, and is a compound solid preparation made through formulation technology.

[0008] Patent publication CN106265581A discloses a tranexamic acid tablet comprising: 2.5 kg of tranexamic acid, 0.3-0.8 kg of microcrystalline cellulose, 0.1-0.4 kg of low-substituted hydroxypropyl cellulose, 0.01-0.05 kg of hypromellose (HPMC), 0.05-0.2 kg of sodium lauryl sulfate (K12), and 0.3-0.7 kg of ethanol (30-70%). The tablets are prepared by dissolving sodium lauryl sulfate in a binder slurry, spray granulating the micronized tranexamic acid, and then mixing with magnesium stearate to form tablets.

[0009] Patent publication CN110721169A discloses a method for preparing tranexamic acid tablets, comprising 100 parts tranexamic acid, 1.2-4 parts polyvinyl alcohol, 1.2-4 parts low-substituted hydroxypropyl cellulose, 1.2-4 parts sodium starch glycolate, 4-12 parts hydrogenated vegetable oil, 12-40 parts purified water, 4-12 parts corn starch, and 1.2-4 parts magnesium stearate. The tablets are prepared by weighing the raw materials, screening them, wet granulating them, drying the granules, mixing them, and tableting them.

[0010] Although there are numerous patents published for tranexamic acid formulations, none of these have been reported to have passed consistency evaluations, and no product has demonstrated in vitro and in vivo equivalence to the original formulation (Daiichi Sankyo Co., Ltd., Japan). Based on the CFDA's "Guidelines for Human Bioequivalence Study Exemptions," an analysis of the solubility and permeability of tranexamic acid suggests that tranexamic acid is a highly soluble, low-permeability drug, thus belonging to BCS Class 3.

[0011] Tranexamic acid is an extremely water-soluble drug, but as a low-permeability drug, achieving in vivo equivalence with the original drug requires that the developed product be similar to the original drug in all media (similarity factor f2 ≥ 50). Only by achieving similarity in dissolution profiles in various media can bioequivalence with the original drug be achieved in vivo.

[0012] The original research tablets of tranexamic acid (specification 250mg, tablet weight 290mg) have a large proportion of raw materials (86.2%) and a small proportion of excipients. The properties of the prepared preparations mostly depend on the properties of the raw materials. After preliminary attempts, tranexamic acid tablets alone have severe stickiness and astringency and cannot be formed. The compressibility and fluidity of the mixed powder of raw materials and excipients are poor, and the friability is easily exceeded, which cannot meet the requirements of the direct powder tableting process.

[0013] During research on tranexamic acid tablets, it was discovered that the dissolution profile of the reference formulation showed a downward trend after 10 days at 60°C, differing from the 0-day dissolution profile. Although the dissolution profile is not a test item in the quality specification, it is particularly important as a key indicator of in vivo bioequivalence. To address the stability issues of tranexamic acid tablets under high temperature conditions while ensuring comparable quality and in vivo bioequivalence with the reference formulation, the formulation and process optimization of this product were conducted. Summary of the Invention

[0014] The present invention addresses the deficiencies in the prior art and provides a tranexamic acid composition and a preparation method thereof. The tranexamic acid composition has similar dissolution in vitro to a reference preparation in different media and is bioequivalent to the reference preparation in vivo, thereby achieving clinical substitutability with the reference preparation and reducing treatment costs.

[0015] The technical solution of the present invention for solving the above technical problems is as follows: a tranexamic acid composition, which comprises, by weight, 100 parts of tranexamic acid, 5 to 9 parts of polyvinyl alcohol, 1 to 3 parts of corn starch, 4 to 8 parts of low-substituted hydroxypropyl cellulose and 1 to 4 parts of a lubricant; the lubricant comprises glyceryl behenate.

[0016] On the basis of the above technical solution, the present invention can also be improved as follows:

[0017] Furthermore, the lubricant is glyceryl behenate or a combination of glyceryl behenate and magnesium stearate.

[0018] Furthermore, the particle size of the tranexamic acid is 60-100 mesh.

[0019] Preferably, the particle size of the tranexamic acid is 60-80 mesh.

[0020] Furthermore, the low-substituted hydroxypropyl cellulose may be any one or a combination of LH-B1, LH11, LH22 and LH21, but is not limited to these types.

[0021] The polyvinyl alcohol models are 05-88, 03-88, and 17-88, but are not limited to these.

[0022] The present invention also discloses a preparation method of the tranexamic acid composition. The preparation method comprises the following steps: adding sieved tranexamic acid into a high-efficiency mixing granulator, adding corn starch and polyvinyl alcohol into the high-efficiency mixing granulator, stirring and mixing uniformly, adding a binder solution, stirring and wet granulating, drying, and granulating, adding low-substituted hydroxypropyl cellulose and a lubricant into a three-dimensional mixer for mixing, and then compressing the obtained mixed powder into tablets or filling capsules.

[0023] Furthermore, the adhesive solution is one or a combination of polyvinyl alcohol solution or starch slurry.

[0024] The mass concentration of the polyvinyl alcohol solution and the starch slurry is 5%-10%, that is, the polyvinyl alcohol or corn starch is prepared into a solution as the adhesive solution; the amount of polyvinyl alcohol or corn starch used as the adhesive is 50%-100% of the total weight of the polyvinyl alcohol or corn starch, that is, the amount of polyvinyl alcohol used as the adhesive is 50%-100% of the total weight of the polyvinyl alcohol in the formula raw material components, and the amount of corn starch used as the adhesive is 50%-100% of the total weight of the corn starch in the formula raw material components.

[0025] Furthermore, the sieved tranexamic acid is added to a high-efficiency mixing granulator, and corn starch and polyvinyl alcohol are added to the high-efficiency mixing granulator. After stirring and mixing at 100-150 rpm, a binder solution is added, and wet granulation is performed by stirring at 100-150 rpm and shearing at 800-1000 rpm for 3-5 minutes. The mixture is dried at 50-70° C., granulated into 20 mesh pieces, and low-substituted hydroxypropyl cellulose and a lubricant are added to a three-dimensional mixer and mixed for 3-5 minutes. After obtaining the total mixed powder, tablets are pressed or capsules are filled.

[0026] The beneficial effects of the present invention are:

[0027] (1) The tranexamic acid composition of the present invention has fewer impurities than the reference preparation, and has no significant change in dissolution under high temperature conditions; through research on accelerated and long-term tests, evaluation indicators such as dissolution curve, content, solubility, and related substances all meet the requirements, and there is no significant change compared with day 0, and the quality is stable.

[0028] (2) The tranexamic acid composition provided by the present invention has passed the BE test (currently there is no report of other manufacturers passing the test), is consistent in quality with the reference preparation and is bioequivalent to it in vivo, achieving clinical substitutability with the reference preparation, with lower price and high accessibility, thus reducing the medication burden on the general public.

[0029] (3) The hydrophilic gel skeleton material polyvinyl alcohol is used as a binder and thickener in the tranexamic acid composition of the present invention, and a hydrophilic gel layer is formed when it comes into contact with water. At the same time, the dissolution behavior of tranexamic acid is controlled by optimizing the ratio of prescription components, adjusting the amount of binder and process parameters, and the dissolution is slowly released, which reduces gastric irritation, thereby solving the problem that tranexamic acid is easily soluble in water and dissolves too quickly in water, making it difficult to maintain a stable blood drug concentration.

[0030] (4) The use of glyceryl behenate in the tranexamic acid composition of the present invention solves the problems of stickiness and astringency in tableting, ensuring the smooth progress of large-scale tableting production. The synergistic effect of glyceryl behenate and polyvinyl alcohol regulates the dissolution behavior of tranexamic acid, which can not only make tranexamic acid have good solubility, but also prevent tranexamic acid from dissolving too quickly and causing irritation to the stomach.

[0031] (5) the tranexamic acid in the tranexamic acid composition of the present invention is 60-100 mesh, so that the final product has more suitable dissolution, and ensures the smooth progress of the preparation process. If the mesh number of tranexamic acid is too small, the particle size of tranexamic acid is too large, which easily causes uneven mixing and ultimately affects the quality of the product; if the mesh number of tranexamic acid is too large, the particle size of tranexamic acid is too small, which easily causes dissolution to be affected. In addition, the preparation process is easily affected by static electricity, and the original drug of tranexamic acid is relatively astringent. If the particle size is too small, the punch will be very astringent and the process cannot be smoothly carried out. BRIEF DESCRIPTION OF THE DRAWINGS

[0032] Figure 1 Concentration-time curves of tranexamic acid in plasma after oral administration of the test preparation Example 1 and the reference preparation;

[0033] Figure 2 Concentration-time curves of tranexamic acid in plasma after oral administration of the test preparation Example 2 and the reference preparation;

[0034] Figure 3 Concentration-time curves of tranexamic acid in plasma after oral administration of the test preparation Example 3 and the reference preparation;

[0035] Figure 4 Concentration-time curves of tranexamic acid in plasma after oral administration of test preparation Example 4 and reference preparation. DETAILED DESCRIPTION

[0036] The present invention can be implemented in many other ways than those described herein, and those skilled in the art can make similar improvements without violating the scope of the present invention. Therefore, the present invention is not limited to the specific embodiments disclosed.

[0037] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those commonly understood by those skilled in the art to which the present invention belongs. The terms used are only for describing specific embodiments and are not intended to limit the present invention.

[0038] 1. Preparation Example

[0039] Example 1

[0040] The raw material composition of the tranexamic acid composition in this embodiment is as follows: 100 parts of tranexamic acid, 5 parts of polyvinyl alcohol (17-88), 3 parts of corn starch, 4 parts of low-substituted hydroxypropyl cellulose (LH-B1), 2.5 parts of magnesium stearate, and 1.5 parts of glyceryl behenate, in parts by weight, wherein the particle size of the tranexamic acid is 60 mesh.

[0041] The specific process steps are as follows:

[0042] Tranexamic acid is sieved through 60 mesh and added to a high-efficiency mixing granulator. Then, corn starch and polyvinyl alcohol are added to the high-efficiency mixing granulator. The speed is set at 100 rpm and stirred and mixed uniformly. Then, a starch slurry with a binder is added (the mass concentration of the starch slurry is 5%; the amount of corn starch used as a binder is 80% of the total weight of the corn starch in the raw material composition). The mixture is stirred at 100 rpm and sheared at 800 rpm for 3 minutes to perform wet granulation. The mixture is dried at 50° C. and granulated into 20 mesh pieces. Then, low-substituted hydroxypropyl cellulose, magnesium stearate, and glyceryl behenate are added to a three-dimensional mixer and mixed for 3 minutes to obtain a total mixed powder tablet.

[0043] Example 2

[0044] The raw materials of the tranexamic acid composition in this embodiment are as follows: 100 parts by weight of tranexamic acid, 7 parts of polyvinyl alcohol (05-88), 2 parts of corn starch, 6 parts of low-substituted hydroxypropyl cellulose (LH-11), and 2.5 parts of glyceryl behenate, wherein the particle size of the tranexamic acid is 80 mesh. The specific process steps are as follows:

[0045] Tranexamic acid is sieved through 80 mesh and added to a high-efficiency mixing granulator. Corn starch and polyvinyl alcohol are then added to the high-efficiency mixing granulator. The mixture is stirred and mixed uniformly at a rotation speed of 120 rpm. A polyvinyl alcohol solution as a binder is added (the mass concentration of the polyvinyl alcohol solution is 10%; the amount of polyvinyl alcohol used as a binder is 50% of the total weight of polyvinyl alcohol in the raw material composition). The mixture is stirred at 120 rpm and sheared at 900 rpm for 4 minutes to perform wet granulation. The mixture is dried at 60° C. and granulated into 20 mesh pieces. Low-substituted hydroxypropyl cellulose and glyceryl behenate are then added to a three-dimensional mixer and mixed for 4 minutes to obtain the total mixed powder for filling capsules.

[0046] Example 3

[0047] The raw materials of the tranexamic acid composition in this embodiment are as follows: 100 parts by weight of tranexamic acid, 9 parts of polyvinyl alcohol (03-88), 1 part of corn starch, 8 parts of low-substituted hydroxypropyl cellulose (LH-22), 1 part of magnesium stearate, and 3 parts of glyceryl behenate, wherein the particle size of the tranexamic acid is 100 mesh. The specific process steps are as follows:

[0048] After sieving 100 mesh tranexamic acid, the mixture was added into a high-efficiency mixing granulator. Corn starch and polyvinyl alcohol were then added into the high-efficiency mixing granulator. After the rotating speed was set at 150 rev / mins and the mixture was evenly mixed, an aqueous solution of polyvinyl alcohol (the mass concentration of the polyvinyl alcohol solution was 5%; the polyvinyl alcohol was 50% of the total weight of the polyvinyl alcohol in the raw material composition as the binder) was added. The mixture was stirred at 150 rev / mins and sheared at 1000 rev / min for 5 min for wet granulation. The mixture was dried at 70°C. A starch slurry (the mass concentration of the starch slurry was 10%; the corn starch was 50% of the total weight of the corn starch in the raw material composition as the binder) was added again. The above-mentioned wet granulation process was repeated. After drying for 20 mesh granules, low-substituted hydroxypropyl cellulose, magnesium stearate and glyceryl behenate were added into a three-dimensional mixer and mixed for 5 min to obtain a total mixed powder tablet.

[0049] Example 4

[0050] The raw material composition of the tranexamic acid composition in this embodiment is as follows: 100 parts of tranexamic acid, 8 parts of polyvinyl alcohol (03-88), 3 parts of corn starch, 7 parts of low-substituted hydroxypropyl cellulose (LH-21), and 1 part of glyceryl behenate, calculated by weight, wherein the particle size of the tranexamic acid is 80 mesh.

[0051] The specific process steps are as follows:

[0052] Tranexamic acid is sieved through 80 mesh and added to a high-efficiency mixing granulator. Corn starch and polyvinyl alcohol are then added to the high-efficiency mixing granulator. The mixture is stirred and mixed uniformly at a rotation speed of 150 rpm. A starch slurry as a binder is added (the mass concentration of the starch slurry is 5%; the amount of corn starch used as a binder is 60% of the total weight of the corn starch in the raw material composition). The mixture is stirred at 100 rpm and sheared at 900 rpm for 5 minutes to perform wet granulation. The mixture is dried at 60° C. and granulated into 20 mesh pieces. Low-substituted hydroxypropyl cellulose and glyceryl behenate are then added to a three-dimensional mixer and mixed for 3 minutes to obtain a total mixed powder for tableting.

[0053] Comparative Example 1

[0054] The tranexamic acid composition was prepared by the same method as in Example 1, except that 2 parts of hydrogenated vegetable oil were added to the formula. The specific method is as follows:

[0055] The raw materials of the tranexamic acid composition in this comparative example are as follows: 100 parts by weight of tranexamic acid, 5 parts of polyvinyl alcohol (17-88), 3 parts of corn starch, 4 parts of low-substituted hydroxypropyl cellulose (LH-B1), 2 parts of hydrogenated vegetable oil, 2.5 parts of magnesium stearate, and 1.5 parts of glyceryl behenate, wherein the particle size of the tranexamic acid is 60 mesh. The specific process steps are as follows:

[0056] Tranexamic acid is sieved through 60 mesh and added to a high-efficiency mixing granulator. Corn starch, polyvinyl alcohol, and hydrogenated vegetable oil are then added to the high-efficiency mixing granulator. The mixture is stirred and mixed uniformly at a speed of 100 rpm. A starch slurry as a binder is added (the mass concentration of the starch slurry is 5%; the amount of corn starch used as a binder is 80% of the total weight of the corn starch in the raw material composition). The mixture is stirred at 100 rpm and sheared at 800 rpm for 3 minutes to perform wet granulation. The mixture is dried at 50° C. and granulated into 20 mesh pieces. Low-substituted hydroxypropyl cellulose, magnesium stearate, and glyceryl behenate are then added to a three-dimensional mixer and mixed for 3 minutes to obtain a total mixed powder for tableting.

[0057] Comparative Example 2

[0058] The raw material composition of the tranexamic acid composition in this comparative example is as follows: in parts by weight, 100 parts of tranexamic acid, 2.6 parts of polyvinyl alcohol (17-88), 2.6 parts of low-substituted hydroxypropyl cellulose (LH-B1), 2.6 parts of sodium carboxymethyl starch, 8 parts of hydrogenated vegetable oil, 28 parts of purified water, 8 parts of corn starch, and 2.6 parts of magnesium stearate.

[0059] The sieved tranexamic acid, sodium starch glycolate, low-substituted hydroxypropyl cellulose, and hydrogenated vegetable oil were stirred and mixed at 200 rpm for 5 minutes until uniformly mixed. A starch slurry as a binder was added (the mass concentration of the starch slurry was 5%; the weight of corn starch as a binder was 80% of the weight of corn starch in the raw material composition). The stirring speed was 250 rpm, the shear rate was 400 rpm, and the granulation time was 4 minutes. The wet granules were 18-mesh granulated by swing granulation, and the whole granules were fluidized-bed dried. Corn starch and magnesium stearate were added successively and the whole mixture was compressed into tablets.

[0060] Comparative Example 3

[0061] The tranexamic acid composition was prepared by the same method as in Example 1, except that glyceryl behenate was not added to the prescription. The specific method was as follows:

[0062] The raw material composition of the tranexamic acid composition in this comparative example is as follows: 100 parts of tranexamic acid, 5 parts of polyvinyl alcohol (17-88), 3 parts of corn starch, 4 parts of low-substituted hydroxypropyl cellulose (LH-B1), and 2.5 parts of magnesium stearate are weighed in parts by weight, wherein the particle size of the tranexamic acid is 60 mesh. The specific process steps are as follows:

[0063] Tranexamic acid is sieved through 60 mesh and added to a high-efficiency mixing granulator. Then, corn starch and polyvinyl alcohol are added to the high-efficiency mixing granulator. The speed is set at 100 rpm and stirred and mixed evenly. Then, a starch slurry with a 5% mass concentration of the starch slurry and the weight of the corn starch as the binder is 80% of the weight of the corn starch in the raw material composition is added. The mixture is stirred at 100 rpm and sheared at 800 rpm for 3 minutes to perform wet granulation. The mixture is dried at 50° C. and granulated into 20 mesh pieces. Then, low-substituted hydroxypropyl cellulose and magnesium stearate are added to a three-dimensional mixer and mixed for 3 minutes to obtain a total mixed powder tablet.

[0064] The comparative example had severe astringency during tableting, and the lower punch could not fall back smoothly, so a large number of tablets could not be pressed smoothly.

[0065] Comparative Example 4

[0066] The tranexamic acid composition was prepared by the same method as in Example 1, except that 1.5 parts of glyceryl behenate was replaced with 1.5 parts of hydrogenated vegetable oil. The specific method is as follows:

[0067] The raw material composition of the tranexamic acid composition in this comparative example is as follows: in parts by weight, 100 parts of tranexamic acid, 5 parts of polyvinyl alcohol (17-88), 3 parts of corn starch, 4 parts of low-substituted hydroxypropyl cellulose (LH-B1), 2.5 parts of magnesium stearate, and 1.5 parts of hydrogenated vegetable oil, wherein the particle size of the tranexamic acid is 60 mesh.

[0068] The specific process steps are as follows:

[0069] Tranexamic acid is sieved through 60 mesh and added to a high-efficiency mixing granulator. Then, corn starch and polyvinyl alcohol are added to the high-efficiency mixing granulator. The speed is set at 100 rpm and stirred and mixed uniformly. Then, a starch slurry with a 5% mass concentration of the starch slurry and the weight of the corn starch as the binder is 80% of the weight of the corn starch in the raw material composition is added. The mixture is stirred at 100 rpm and sheared at 800 rpm for 3 minutes to perform wet granulation. The mixture is dried at 50° C. and granulated into 20 mesh pieces. Then, low-substituted hydroxypropyl cellulose, magnesium stearate, and hydrogenated vegetable oil are added to a three-dimensional mixer and mixed for 3 minutes to obtain a total mixed powder tablet.

[0070] Comparative Example 5

[0071] Adopt the identical method of embodiment 1 to prepare tranexamic acid composition, difference is: do not add glyceryl behenate, but in order to guarantee that the total raw material weight is identical with that of embodiment 1, " 2.5 parts of magnesium stearates " are replaced with " 4 parts of magnesium stearates " (guaranteeing that the consumption of lubricant is identical with the consumption of embodiment 1), concrete grammar is as follows:

[0072] The raw material composition of the tranexamic acid composition in this comparative example is as follows: in parts by weight, 100 parts of tranexamic acid, 5 parts of polyvinyl alcohol (17-88), 3 parts of corn starch, 4 parts of low-substituted hydroxypropyl cellulose (LH-B1), and 4 parts of magnesium stearate, wherein the selected particle size of the tranexamic acid is 60 mesh.

[0073] The specific process steps are as follows:

[0074] Tranexamic acid is sieved through 60 mesh and added to a high-efficiency mixing granulator. Then, corn starch and polyvinyl alcohol are added to the high-efficiency mixing granulator. The speed is set at 100 rpm and stirred and mixed evenly. Then, a starch slurry with a 5% mass concentration of the starch slurry and the weight of the corn starch as the binder is 80% of the weight of the corn starch in the raw material composition is added. The mixture is stirred at 100 rpm and sheared at 800 rpm for 3 minutes to perform wet granulation. The mixture is dried at 50° C. and granulated into 20 mesh pieces. Then, low-substituted hydroxypropyl cellulose and magnesium stearate are added to a three-dimensional mixer and mixed for 3 minutes to obtain a total mixed powder tablet.

[0075] Comparative Example 6

[0076] The tranexamic acid composition was prepared by the same method as in Example 1, except that polyvinyl alcohol was not added. However, in order to ensure that the total weight of the raw materials was the same as that in Example 1, 3 parts of corn starch was replaced with 8 parts of corn starch. The specific method was as follows:

[0077] The raw material composition of the tranexamic acid composition in this comparative example is as follows: 100 parts of tranexamic acid, 8 parts of corn starch, 4 parts of low-substituted hydroxypropyl cellulose (LH-B1), 2.5 parts of magnesium stearate, and 1.5 parts of glyceryl behenate, in parts by weight, wherein the particle size of the tranexamic acid is 60 mesh.

[0078] The specific process steps are as follows:

[0079] Tranexamic acid is sieved through 60 mesh and added to a high-efficiency mixing granulator. Corn starch is then added to the high-efficiency mixing granulator. The speed is set at 100 rpm and the mixture is stirred and mixed uniformly. Then, a starch slurry with a 5% mass concentration of the starch slurry and the weight of the corn starch as the binder is 80% of the weight of the corn starch in the raw material composition is added. The mixture is stirred at 100 rpm and sheared at 800 rpm for 3 minutes to perform wet granulation. The mixture is dried at 50° C. and granulated into 20 mesh pieces. Low-substituted hydroxypropyl cellulose, magnesium stearate, and glyceryl behenate are added to a three-dimensional mixer and mixed for 3 minutes to obtain a total mixed powder tablet.

[0080] Comparative Example 7

[0081] The same method as in Example 1 was used to prepare a tranexamic acid composition, except that the tranexamic acid was sieved through a 40-mesh screen. In this comparative example, the bulk drug and other excipients had large particle sizes that resulted in uneven mixing and stratification.

[0082] Comparative Example 8

[0083] The same method as Example 1 was used to prepare the tranexamic acid composition, except that the tranexamic acid was sieved through 120 mesh. During tableting operation, the comparative example had a rough punching phenomenon, and the underpunch could not fall back smoothly, so a large amount of tableting could not be carried out smoothly.

[0084] 2. Dissolution curve test

[0085] In vitro dissolution profile testing is commonly used to evaluate the consistency of quality between pharmaceutical products. The similarity factor (f2) method for comparing dissolution profiles compares the average dissolution volume of the test sample with the average dissolution volume of the reference sample. When using the similarity factor (f2) method for similarity comparison, dissolution profiles are generally considered similar when the similarity factor (f2) value is ≥50.

[0086] The dissolution conditions of the tranexamic acid compositions of Examples 1-4 and Comparative Examples 1-8 in a pH 6.8 medium at high temperature (60° C.) are shown in Table 1.

[0087] Table 1 Changes in dissolution curves of tranexamic acid preparations in pH 6.8 medium under high temperature conditions

[0088]

[0089] The dissolution curves of Examples 1 to 4 in a pH 6.8 medium at day 0 were very similar to those of the reference preparation (f2≥82), which provided a guarantee for their bioequivalence with the reference preparation in vivo.

[0090] After 10 days at 60°C, compared to the same batch at day 0, Examples 1 to 4 showed no significant change (f2 ≥ 85), indicating good stability. The dissolution curve of the reference preparation showed a downward trend (f2 = 72). Comparative Example 1 added hydrogenated vegetable oil to Example 1. After the high temperature test, the dissolution curve showed a downward trend compared to day 0 (f2 = 55). Comparative Example 2 also contained hydrogenated vegetable oil in the formulation, and the validation test found that this also affected dissolution, showing a downward trend (f2 = 51). Comparative Example 3 was adjusted based on Example 1, but without glyceryl behenate in the formulation. During tableting, the astringency was severe, the undershoot could not be smoothly recovered, and large-scale tableting could not be smoothly performed.

[0091] In Comparative Example 4, glyceryl behenate was replaced with hydrogenated vegetable oil. After the high temperature test, the dissolution curve showed a downward trend compared with that on day 0, and there was also a slight astringent phenomenon during the tableting operation; in Comparative Example 5, glyceryl behenate was not used in the lubricant, only magnesium stearate was used, and the amount of glyceryl behenate in the original prescription was made up. After the high temperature test, the dissolution curve showed a downward trend compared with that on day 0, and there was also a slight astringent phenomenon during the tableting operation; in Comparative Example 6, no polyvinyl alcohol was added. After the high temperature test, the dissolution curve also showed a downward trend compared with that on day 0.

[0092] The data of Example 1, Comparative Example 3, Comparative Example 4, and Comparative Example 5 show that the addition of glyceryl behenate during the preparation of the tranexamic acid composition can provide a good lubricating effect, ensuring that the tableting process proceeds smoothly. In addition, the data of Example 1, Comparative Example 5, and Comparative Example 6 show that when glyceryl behenate and polyvinyl alcohol are present simultaneously in the formulation, the dissolution curve is similar to that of the reference preparation and has good dissolution stability.

[0093] By comparing the experimental data of Example 1 and Comparative Examples 7 and 8, it can be seen that the use of tranexamic acid with the mesh size of the present invention is more conducive to obtaining a tranexamic acid composition preparation with good dissolution behavior, and ensures that the tableting process is smooth, thereby ensuring the smooth progress of the process.

[0094] 3. Stability test

[0095] Examples 1-4 were subjected to stability testing according to the Pharmacopoeia of the People's Republic of China 2020 edition, Part IV, General Rules 9001, "Guidance for Stability Testing of Pharmaceutical Ingredients and Preparations." Accelerated testing: 40±2°C, RH 75%±5%; long-term testing: 30±2°C, RH 65%±5%. The results are shown in Tables 2, 3, and 4.

[0096] Table 2 Accelerated test data

[0097]

[0098]

[0099] Table 3 Long-term test data

[0100]

[0101] Table 4 Stability test pH 6.8 medium dissolution curve data

[0102]

[0103]

[0104] The results of the accelerated and long-term stability test data show that, after being placed under accelerated and long-term conditions for 6 months and 24 months, respectively, the in vitro dissolution curve behavior of Examples 1 to 4 in a pH 6.8 medium is similar to that on day 0 (f2 ≥ 80), and there is no significant change in the solubility, content and other data, no related substances are detected, and the drug stability is good.

[0105] 4. Bioequivalence Evaluation

[0106] The bioequivalence study of the test preparations Examples 1-4 prepared by the present invention and the reference preparation was conducted, and the pharmacokinetic parameter results after oral administration of the test preparations and the reference preparation were summarized. The preparations prepared in Examples 1-4 were bioequivalent to the reference preparation. The specific comparison curves are shown in FIG. Figures 1-4 .

[0107] The technical features of the above-described embodiments can be combined arbitrarily. To make the description concise, not all possible combinations of the technical features in the above-described embodiments are exhaustively listed. However, as long as there is no contradiction in the combination of these technical features, they should be considered to be within the scope of this specification.

[0108] For those skilled in the art, several variations and improvements may be made without departing from the scope of the present invention, which all fall within the scope of protection of the present invention. The scope of protection of the present invention shall be based on the appended claims.

Claims

1. A tranexamic acid composition, characterized in that, The tranexamic acid composition comprises, by weight, 100 parts of tranexamic acid, 5 to 9 parts of polyvinyl alcohol, 1 to 3 parts of corn starch, 4 to 8 parts of low-substituted hydroxypropyl cellulose, and 1 to 4 parts of a lubricant. The lubricant is glyceryl behenate or a combination of glyceryl behenate and magnesium stearate.

2. A tranexamic acid composition according to claim 1, characterized in that The particle size of the tranexamic acid is 60-100 meshes.

3. A tranexamic acid composition according to claim 1, characterized in that, The particle size of the tranexamic acid is 60-80 meshes.

4. A tranexamic acid composition according to claim 1, characterized in that, The low-substituted hydroxypropyl cellulose is of any one or a combination of LH-B1, LH-11, LH-22 and LH-21.

5. A method for preparing a tranexamic acid composition according to any one of claims 1 to 4, characterized in that: The preparation method comprises the following steps: adding sieved tranexamic acid into a high-efficiency mixing granulator, adding corn starch and polyvinyl alcohol into the high-efficiency mixing granulator, stirring and mixing evenly, adding a binder solution, stirring and wet granulating, drying, and granulating, adding low-substituted hydroxypropyl cellulose and a lubricant into a three-dimensional mixer, mixing, obtaining a total mixed powder, and then compressing the mixed powder into tablets or filling the mixed powder into capsules.

6. The method for preparing a tranexamic acid composition according to claim 5, wherein The adhesive solution is one of polyvinyl alcohol solution and starch slurry or a combination of the two.

7. The method for preparing a tranexamic acid composition according to claim 5, wherein The sieved tranexamic acid is added to a high-efficiency mixing granulator, and corn starch and polyvinyl alcohol are added to the high-efficiency mixing granulator. After stirring and mixing at 100-150 rpm, the binder solution is added, and wet granulation is performed by stirring at 100-150 rpm and shearing at 800-1000 rpm for 3-5 minutes. The mixture is dried at 50-70°C, granulated into 20 mesh granules, and low-substituted hydroxypropyl cellulose and a lubricant are added to a three-dimensional mixer and mixed for 3-5 minutes. The total mixed powder is then compressed into tablets or filled into capsules.

Images