Tranexamic acid tablet and preparation method thereof

Abstract

The invention discloses a tranexamic acid tablet and a preparation method thereof. The tranexamic acid tablet comprises tranexamic acid, corn starch, polyvinyl alcohol, low-substituted hydroxypropyl cellulose and hydrogenated castor oil. The preparation method of the tranexamic acid tablet comprises the following steps: preparing a polyvinyl alcohol aqueous solution as an adhesive, adding hydrogenated castor oil into the polyvinyl alcohol aqueous solution, carrying out wet granule preparation, fluidized drying and granule finishing on tranexamic acid, corn starch and low-substituted hydroxypropyl cellulose by using the adhesive in a fluidized granulation coating machine, mixing dry granules with magnesium stearate, and tabletting. The tranexamic acid tablet prepared by the preparation method disclosed by the invention is free from sticking and astringent rushing problems, solves the problem that the tranexamic acid medicine is relatively fast to dissolve out and release, and relieves the irritation to gastrointestinal tracts; the technological operation is simple, the production efficiency is high, and industrial production is facilitated; the quality is consistent with that of a reference preparation, clinical substitution of the reference preparation is realized, the treatment cost is reduced, and the accessibility of a patient is improved.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical preparations, and relates to a pharmaceutical preparation with tranexamic acid as the active ingredient, and particularly to a tranexamic acid tablet and its preparation method. Background Technology

[0002] Postpartum hemorrhage is a major obstetric complication and a leading cause of maternal death worldwide, including in my country. On average, one woman dies from postpartum hemorrhage every seven minutes. It primarily manifests as vaginal bleeding after childbirth, and in severe cases, can lead to hemorrhagic shock, severe anemia, and other related symptoms. If a woman experiences prolonged postpartum hemorrhage and shock, even if she survives, she may still suffer from serious secondary hypopituitarism. Therefore, postpartum hemostasis is of paramount importance. Nearly 20 million patients in my country require hemostasis annually, primarily in surgical and some internal medicine departments. Hemostatic drugs are the most widely used method of hemostasis in emergency treatment of sudden accidents, surgical wound hemostasis, and in cases requiring rapid and effective local hemostasis in patients.

[0003] Tranexamic acid, also known as tranexamic acid, has the chemical name (E)-4-aminomethylcyclohexanecarboxylic acid and the molecular formula C8H12. 15 NO2. Molecular weight: 157.21. Chemical structural formula:

[0004]

[0005] Tranexamic acid, as a hemostatic agent, has been widely used since its introduction in Japan in the 1960s. Due to its antifibrinolytic effect in the body, tranexamic acid can shorten bleeding time and increase the rate of thrombus formation, effectively reducing blood loss. It can also be used in combination with other clinical drugs, playing a significant role in controlling bleeding during cardiac surgery, excessive bleeding from thrombolysis, and postpartum hemorrhage. To date, there are no strong substitutes. As a highly practical hemostatic drug, tranexamic acid is structurally stable, reliable in quality, has definite efficacy, and few side effects, and has been included in the pharmacopoeias of many countries. Tranexamic acid also has whitening, spot-fading, and anti-inflammatory effects, and is widely used in the pharmaceutical and cosmetic fields.

[0006] Currently, tranexamic acid is available in China in the form of ordinary tablets, capsules, powder for injection, and injections. In the 20th batch of the generic drug reference preparation list, tranexamic acid tablets in 250mg and 500mg strengths manufactured by Daiichi Sankyo Co., Ltd. of Japan have been published as reference preparations.

[0007] Tranexamic acid original tablets (250mg, tablet weight 290mg) have a high proportion of active pharmaceutical ingredient (API) (86.2%) and a low proportion of excipients. The properties of the prepared formulation largely depend on the properties of the API. When tranexamic acid is used alone for tableting, severe sticking and brittleness occur, making it impossible to compress the tablets into shape. The compressibility and flowability of the mixed API and excipient powder are poor, and the brittleness easily exceeds the standard. Furthermore, the tablet weight difference is prone to exceed the limit, which can easily lead to unqualified drug content uniformity. Chinese invention patent applications CN106265581A and CN110721169A both disclose a tranexamic acid tablet and its preparation method, which involves granulation by wet granulation or fluidized bed granulation before tableting to obtain the finished product.

[0008] Tranexamic acid is readily soluble in water and dissolves rapidly, releasing quickly into the body, but its absorption rate is slow. It easily irritates the gastrointestinal tract, causing adverse reactions such as heartburn, nausea, vomiting, and diarrhea. Existing patented technologies all contain large amounts of disintegrants and solubilizers, which can easily increase gastrointestinal irritation.

[0009] Therefore, under the premise of ensuring drug quality, selecting appropriate excipients and suitable preparation processes to control the dissolution rate of tranexamic acid tablets, while solving problems such as large differences in tablet weight, excessive brittleness, and sticking and astringency during tablet compression, is of positive significance for ensuring the efficacy and safety of clinical use. Summary of the Invention

[0010] To address the aforementioned technical problems, this invention provides tranexamic acid tablets and their preparation process. The prepared tranexamic acid tablets are free from sticking and astringency issues, and simultaneously solve the problem of rapid drug dissolution and release, reducing gastrointestinal irritation. Furthermore, the process is simple to operate, highly efficient, and conducive to industrial production; it maintains consistent quality with the reference formulation, achieving clinical substitutability for the reference formulation, reducing treatment costs, and improving patient accessibility.

[0011] The technical solution provided by this invention is as follows:

[0012] In a first aspect, the present invention provides a tranexamic acid tablet, which is obtained by a fluidized bed spray granulation process. The raw materials for preparation include: tranexamic acid, filler, binder, disintegrant and lubricant; the weight parts of each component are as follows: 100 parts of tranexamic acid, 1-4 parts of filler, 4-6 parts of binder, 4-6 parts of disintegrant and 2-6 parts of lubricant.

[0013] The filler is selected from one or a combination of corn starch, microcrystalline cellulose, lactose, mannitol, dextrin, and polyethylene glycol; the filler is further preferably corn starch.

[0014] The adhesive is one or a combination of polyvinyl alcohol, starch, polyvinyl ketone, hydroxypropyl methylcellulose, and hydroxypropyl cellulose; the adhesive is further preferably polyvinyl alcohol; further, the polyvinyl alcohol is of type 05-88 or 18-88, but is not limited to these types.

[0015] The disintegrant is one or a combination of several of low-substituted hydroxypropyl cellulose, croscarmellose sodium, and croscarmellose polyvinylpyrrolidone; the disintegrant is further preferably low-substituted hydroxypropyl cellulose; furthermore, the low-substituted hydroxypropyl cellulose is of any one or a combination of several of LH-B1, LH11, LH22 and LH21, including but not limited to LH-B1, LH11, LH22 and LH21.

[0016] The lubricant is one or a combination of several of hydrogenated castor oil, glyceryl behenate, glyceryl distearate, stearic acid, sodium stearate fumarate, and magnesium stearate; the lubricant is further preferably a combination of hydrogenated castor oil and magnesium stearate.

[0017] Preferably, the raw materials are composed of the following components by weight: 100 parts tranexamic acid, 2.4 parts filler, 6 parts binder, 4 parts disintegrant, and 3.6 parts lubricant.

[0018] More preferably, the ingredients are 100 parts tranexamic acid, 2.4 parts corn starch, 6 parts polyvinyl alcohol, 4 parts low-substituted hydroxypropyl cellulose, 3 parts hydrogenated castor oil, and 0.6 parts magnesium stearate.

[0019] Secondly, the method for preparing tranexamic acid tablets provided by the present invention includes the following steps:

[0020] (1) Add tranexamic acid, filler, and disintegrant to the fluidized granulation coating pot, mix evenly, and preheat;

[0021] (2) Dissolve the adhesive and lubricant (hydrogenated castor oil) in water to obtain an adhesive solution;

[0022] (3) Spray the solution from step (2) into the solution and dry it to obtain dry granules;

[0023] (4) Granulate the dry granules;

[0024] (5) Add lubricant (magnesium stearate) to the dry granules and mix evenly to obtain total mixed granules;

[0025] (6) Compress the total mixture of particles into tablets.

[0026] Furthermore, in step (1), the preheating temperature is 50±5℃.

[0027] Furthermore, in step (2), the mass concentration of the adhesive solution is 2-10%.

[0028] Furthermore, in step (3), the adhesive solution is sprayed in using either top spraying or side spraying.

[0029] Furthermore, in step (3), the spraying speed is 8-30 g / min, the material temperature is 35-55℃, the drying temperature is 60℃, and the drying endpoint LOD is ≤2.0%.

[0030] Furthermore, in step (4), the mesh size of the dry granules is 1.0 to 2.5 mm.

[0031] Furthermore, in step (6), the tableting standards are: disintegration time > 10 min, tablet weight difference ≤ 5%, friability ≤ 1.0%, and hardness 40-100 N.

[0032] Compared with the prior art, the present invention has the following beneficial effects:

[0033] (1) The present invention uses hydrogenated castor oil and polyvinyl alcohol to prepare an aqueous solution, which can synergistically solve the problem of rapid dissolution and release caused by the high water solubility of tranexamic acid, and reduce the irritation to the gastrointestinal tract.

[0034] (2) The tranexamic acid tablets of the present invention use oil-based lubricating excipients such as glyceryl distearate, glyceryl behenate, or hydrogenated castor oil, preferably hydrogenated castor oil, as a lubricant in the formulation. When used in combination with magnesium stearate, it solves the sticking and jerk problems generated during the tableting process of tranexamic acid, ensuring the smooth progress of commercial production of the product.

[0035] (3) The present invention uses fluidized bed granulation process to prepare tranexamic acid drug. Compared with wet granulation process, the one-step granulation process produces a better uniformity of total mixed particles, which solves the problem of weight difference in tablet production and has high feasibility. At the same time, it is simple to operate, has high production efficiency, and is conducive to industrial production.

[0036] (4) The dissolution behavior of the tranexamic acid tablets provided by the present invention is consistent with that of the reference preparation, and the quality is consistent with that of the reference preparation. The reference preparation is clinically replaceable, reducing treatment costs and improving patient accessibility. Detailed Implementation

[0037] The technical solutions of various embodiments of the present invention will be clearly and completely described below. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. The following content is merely an exemplary description of the scope of protection claimed by the present invention. Those skilled in the art can make various changes and modifications to the invention based on the disclosed content, and such changes should also fall within the scope of protection claimed by the present invention.

[0038] Example 1:

[0039] The formulation of the tranexamic acid composition in this embodiment is as follows:

[0040]

[0041] Note: / indicates no addition, the same applies below.

[0042] Formulas 1-4 are prepared using fluidized bed granulation process as follows:

[0043] Preheating: Set the air inlet temperature to 50±5℃, add tranexamic acid, corn starch, and low-substituted hydroxypropyl cellulose to the fluidized granulation coating machine, mix and preheat for 10 minutes.

[0044] Adhesive solution preparation (5% by mass): Add polyvinyl alcohol to the prescribed amount of water, heat to 90℃ and hold for 5 minutes to dissolve, then cool to room temperature for later use. Spraying: Spray the adhesive solution in at a speed of 8–30 g / min and a material temperature of 40℃. After spraying, set the inlet air temperature to 60℃ for drying, with a drying endpoint LOD ≤ 2.0%.

[0045] Mixing: The dry granules are sized through a 2.0 mm sieve, then mixed with hydrogenated castor oil or glyceryl behenate for 10 min, and then magnesium stearate is added to a three-dimensional mixer and mixed for 5 min to obtain the total mixed granules;

[0046] Tableting: Using a rotary tablet press, the tablet weight is calculated according to the theoretical weight, and the pressure is adjusted to obtain tranexamic acid tablets (the tableting standards are as follows: disintegration time > 10 minutes, tablet weight difference ≤ 5%, friability ≤ 1.0%, hardness 40-100N).

[0047] Formula 5 uses the same formula as Formula 3, but the method of adding hydrogenated castor oil is changed from adding it after granulation and mixing to dissolving it in the binder solution and granulating it together. The specific process is as follows: Preheating: The inlet air temperature is set to 50±5℃. Tranexamic acid, corn starch, and low-substituted hydroxypropyl cellulose are added to the fluidized granulation and coating machine and mixed and preheated for 10 minutes.

[0048] Preparation of adhesive solution (5% by mass): Add polyvinyl alcohol to the prescribed amount of water, heat to 90°C and maintain for 5 minutes to dissolve, then cool to room temperature. While the adhesive solution is cooling, add the prescribed amount of hydrogenated castor oil and stir to dissolve.

[0049] Spraying: Spray in the adhesive solution at a speed of 8-30 g / min and a material temperature of 40℃. After spraying, set the inlet air temperature to 60℃ for drying, with a drying endpoint LOD ≤ 2.0%.

[0050] Mixing: The dry granules are sized through a 2.0 mm sieve, and then mixed with the prescribed amount of magnesium stearate for 5 min to obtain total mixed granules;

[0051] Tableting: Using a rotary tablet press, the tablet weight is calculated according to the theoretical weight, and the pressure is adjusted to obtain tranexamic acid tablets (the tableting standards are as follows: disintegration time > 10 minutes, tablet weight difference ≤ 5%, friability ≤ 1.0%, hardness 40-100N).

[0052] Example 2: Adhesion and roughness during tableting of prescriptions 1-5 The adhesion and roughness during tableting of prescriptions 1-5 are shown in the table below:

[0053]

[0054] The results above show that: Formula 1 exhibits significant sticking and jerking during tableting, making continuous tableting impossible; Formula 2, even with increased magnesium stearate content, still fails to meet the product's lubrication requirements; Formulas 3-5 utilize oil-based lubricants such as glyceryl behenate or hydrogenated castor oil in combination with magnesium stearate, which can counteract the sticking and jerking of tranexamic acid and ensure smooth tableting; Formula 5 shows better particle flowability than Formulas 3 and 4.

[0055] Example 2: Dissolution profiles of tranexamic acid tablets of formulations 3-5 and the reference formulation in pH 1.2 medium.

[0056] The dissolution profiles of the tranexamic acid tablets of formulations 3-5 above and the reference formulation were tested in a medium at pH 1.2. The results are shown in the table below:

[0057]

[0058] As can be seen from the table above, formulations 3 and 4, which use physical mixing to add oil-based lubricants, exhibited similar dissolution rates to the reference formulation, but their dissolution and release were all faster. Formulation 5, which adds hydrogenated castor oil to the binder solution, effectively synergistically regulated the dissolution and release of tranexamic acid, achieving a dissolution level similar to or even better than the reference formulation (similarity factor f2 > 80).

[0059] Adding glyceryl behenate and hydrogenated castor oil, among other oil-based lubricants, during the preparation of tranexamic acid tablets provides excellent lubrication, ensuring smooth tableting. Furthermore, data from Formulation 5 shows that hydrogenated castor oil, by dissolving in a polyvinyl alcohol aqueous solution, effectively and synergistically regulates the dissolution and release of tranexamic acid, resulting in tranexamic acid tablets with better dissolution behavior. This also ensures smooth tableting and guarantees the successful execution of the manufacturing process.

[0060] The technical features of the above embodiments can be combined in any way. For the sake of brevity, not all possible combinations of the technical features in the above 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.

[0061] For those skilled in the art, various modifications and improvements can be made without departing from the concept of the present invention, and these modifications and improvements are all within the scope of protection of the present invention. The scope of protection of the present invention is defined by the appended claims.

Claims

1. A tablet of tranexamic acid characterized in that, The raw and auxiliary materials are composed of the following components by weight: tranexamic acid 100 parts, filler 1-4 parts, binder 4-6 parts, disintegrant 4-6 parts.

2. The tranexamic acid tablet of claim 1, characterized by The filler is selected from one or more of corn starch, microcrystalline cellulose, lactose, mannitol, dextrin, and polyethylene glycol; the binder is one or more of polyvinyl alcohol, starch, povidone, hypromellose, and hydroxypropyl cellulose; the disintegrant is one or more of low-substituted hydroxypropyl cellulose, cross-linked sodium carboxymethyl cellulose, and cross-linked polyvinyl pyrrolidone; and the lubricant is one or more of hydrogenated castor oil, glyceryl behenate, glyceryl bis-stearate, stearic acid, sodium stearyl fumarate, and magnesium stearate.

3. The tranexamic acid tablet of claim 2, wherein, The filler is corn starch; the binder is polyvinyl alcohol; the disintegrant is low-substituted hydroxypropyl cellulose; and the lubricant is hydrogenated castor oil and / or magnesium stearate.

4. The tranexamic acid tablet of claim 3, wherein, The polyvinyl alcohol is of any one or more of types 05-88 and 18-88; and the low-substituted hydroxypropyl cellulose is of any one or more of types LH-B1, LH11, LH22, and LH21.

5. The tranexamic acid tablet according to claims 1 to 4, characterized by The raw and auxiliary materials are composed of the following components by weight:

6. A process for the preparation of a tablet of tranexamic acid characterized in that, tranexamic acid 100 parts, corn starch 1-2.4 parts, polyvinyl alcohol 6 parts, low-substituted hydroxypropyl cellulose 4 parts, hydrogenated castor oil 3 parts, and magnesium stearate 0.6 parts. The tranexamic acid tablets are prepared by a fluidized bed spray granulation process, which comprises the following steps:

7. The manufacturing process of claim 6, wherein, (1) mixing tranexamic acid, filler, and disintegrant in a fluidized granulation and coating pot and preheating; (2) dissolving the binder and lubricant in water to obtain a binder solution; (3) spraying the binder solution obtained in step (2) and drying to obtain dry granules; (4) sizing the dry granules; (5) mixing the lubricant with the dry granules to obtain total mixed granules; (6) tabletting the total mixed granules. In step (1), the preheating temperature is 50±5℃; in step (2), the mass concentration of the binder solution is 2-10%; in step (3), the spraying of the binder solution is performed by top spraying or side spraying; in step (3), the spraying speed is 8-30 g / min, and the material temperature is 35-55℃; the drying temperature is 60℃, and the LOD at the end of drying is ≤2.0%; in step (4), the sizing of the dry granules is performed to a mesh size of 1.0-2.5 mm; and in step (6), the tabletting is performed according to the following standards: disintegration time >10 min, tablet weight difference ≤5%, friability ≤1.0%, and hardness 40-100 N.

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