Tranexamic acid compression-coated sustained-release tablet, preparation process therefor, and use thereof

Abstract

A compression-coated sustained-release tablet comprising tranexamic acid, a preparation process therefor, and use thereof. The sustained-release tablet comprises a tablet core layer and an outer coating layer which are of an asymmetric dual-depot structure. The tablet core layer and the outer coating layer both contain tranexamic acid and a sustained-release material, and drug release is controlled by means of a compression-coated structure and the sustained-release material.

Description

A compressed coated sustained-release tablet of tranexamic acid and its preparation process and use Technical Field

[0001] The present disclosure relates to the field of pharmaceutical preparations, and in particular to a compressed, coated sustained-release tablet of tranexamic acid, and a preparation process and use thereof. Background Art

[0002] Melasma is a chronic, acquired facial hyperpigmentation skin disease, clinically manifested by light brown or dark brown patches of varying shades and unclear boundaries symmetrically distributed on the cheeks, forehead, and jaw. The incidence rate among Asian women of childbearing age is as high as 30%. It is prone to recurrence and difficult to cure. Tranexamic acid, also known as trans-4-(aminomethyl)cyclohexanecarboxylic acid, tranexamic acid, tranexamic acid, or tranexamic acid, has a molecular formula of C8H 15 NO2, with a molecular weight of 157.21, is a synthetic lysine derivative originally used as a hemostatic agent. It competitively binds to lysine's binding site on the plasminogen molecule, thereby inhibiting the conversion of plasminogen activators to plasmin. In 1979, Japanese researchers first discovered that low-dose tranexamic acid could treat melasma and other skin diseases characterized by hyperpigmentation. The primary mechanisms of tranexamic acid in treating melasma include inhibiting angiogenesis, inhibiting mast cell proliferation and activation, protecting the basement membrane zone, inhibiting melanin synthesis and transport, and promoting skin barrier repair. Recent studies have confirmed that tranexamic acid can act on multiple aspects of melasma's pathogenesis, demonstrating promising clinical efficacy.

[0003] Currently, tranexamic acid is available in oral, injectable, and topical dosage forms. However, when used to treat chloasma, it suffers from severe gastrointestinal reactions and poor patient compliance. Hydrophilic gel matrix sustained-release tablets are one of the main types of oral sustained-release preparations. Their drug release process is a comprehensive process of matrix dissolution and drug diffusion. When the matrix material encounters an aqueous medium (digestive fluid), the surface is first moistened to form a gel layer. The surface drug diffuses into the digestive fluid, the gel layer continues to hydrate, the matrix swells, and the gel layer thickens, delaying drug release. The tablet matrix dissolves at the same time, and water penetrates into the tablet core until the matrix is ​​completely dissolved, and all the drug is released.

[0004] It is currently believed that the mechanism of drug release from polymer backbones follows the Ritger-Peppas equation: t / M ∞ =kt n , M t 、M ∞, the cumulative release amounts at times t and ∞ respectively; k is the geometric characteristic constant of the skeleton structure; n is the release exponent, and there are the following three cases: ① When n = 0.5, the drug dissolves and diffuses outwards through the gel skeleton formed by the polymer, that is, "Fickian release". ② When 0.5 < n < 1, it is non-"Fickian release" or abnormal transport. ③ When n = 1, it is "zero-order rate release" or Case II transport, swelling control. The Peppas model believes that when the penetration rate of the dissolution medium is greater than the rate of the drug passing through the gel layer, the movement of the drug plays a decisive role, conforming to the diffusion control process; while when the movement rate of the medium is less than the movement rate of the drug, the movement of the medium controls the whole process, presenting Case II transport, with the drug releasing at a constant rate, being zero-order kinetics. Therefore, zero-order release is only easily achieved when the proportion of the sustained-release material is large enough and the proportion of the drug is small enough.

[0005] Existing studies have shown that the dosage of tranexamic acid in the preparation needs to be greater than 500 mg to reach the effective dose for treating melasma, and clinically, it is necessary to extend the administration cycle of tranexamic acid to treat melasma more effectively. Therefore, there is an urgent need to develop a tranexamic acid sustained-release tablet that can achieve zero-order release for a long time and improve the patient's medication compliance to meet the clinical medication needs. Summary of the Invention

[0006] The purpose of the present disclosure is to provide a tranexamic acid compression-coated sustained-release tablet, its preparation process and uses. Using tranexamic acid as the active ingredient, applying a gel skeleton material, adopting a compression-coating technique, and making a compression-coated tablet through an asymmetric double reservoir form. By maximizing the drug content in the core layer and the outer coating layer reservoirs, increasing the powder proportion of the inner and outer layer reservoirs, and adjusting the types and dosages of the sustained-release materials in each reservoir, the skeleton sustained release of highly water-soluble drugs with high drug loading is achieved, the dose and content of tranexamic acid per tablet are increased, the drug maintains zero-order release, the action time is extended, the stable blood drug concentration is maintained for a long time, the bioavailability of tranexamic acid is improved, the gastrointestinal reaction is reduced, the administration frequency is reduced, it is easy to be swallowed by the human body, and the patient's medication compliance is improved. In addition to being used for treating bleeding caused by hyperfibrinolysis, it is also applicable to the treatment of melasma.

[0007] To solve the above technical problems, the present disclosure proposes the following technical solutions:

[0008] On the one hand, the present disclosure provides a tranexamic acid compression-coated sustained-release tablet, which includes a core layer and an outer coating layer. The core layer includes raw materials with the following mass percentages: tranexamic acid 70%-85%, sustained-release material 17%-19%, binder 0.5%-2%, filler 0.5%-8%, lubricant 0.5%-2.5%;

[0009] The outer coating layer comprises the following raw materials in percentage by weight: 52%-54% tranexamic acid, 20%-30% sustained-release material, 4%-6% binder, 9%-21% filler, and 1%-2.5% lubricant;

[0010] Among them, the raw materials of tranexamic acid compressed coated sustained-release tablets do not contain water.

[0011] The sustained-release material accounts for 19%-28% of the total mass percentage of the tranexamic acid compressed coated sustained-release tablets, preferably 26.5%. Preferably, the sustained-release material is selected from hydroxypropyl cellulose, hydroxypropyl methylcellulose and mixtures thereof. Preferably, the sustained-release material of the core layer is selected from hydroxypropyl cellulose-L, hydroxypropyl cellulose-M and mixtures thereof, more preferably hydroxypropyl cellulose-L. Preferably, the sustained-release material of the outer coating layer is selected from hydroxypropyl cellulose-M, hydroxypropyl methylcellulose HS-K4M, hydroxypropyl methylcellulose HS-K15M and mixtures thereof, more preferably hydroxypropyl methylcellulose HS-K4M.

[0012] Preferably, the mass percentage of the core layer in the tranexamic acid compressed-coated sustained-release tablet is 23%-30%, and the mass percentage of the outer coating layer is 70%-77%. More preferably, the mass percentage of the core layer is 29.4%, and the mass percentage of the outer coating layer is 70.6%.

[0013] Preferably, the drug loading of the tranexamic acid compressed coated sustained-release tablets is not less than 58.8%, the mass of each tranexamic acid compressed coated sustained-release tablet is not higher than 850 mg, and the total dose of tranexamic acid in each tranexamic acid compressed coated sustained-release tablet is not less than 500 mg.

[0014] Preferably, the mass of tranexamic acid in the core layer of the tranexamic acid compressed-coated sustained-release tablet accounts for 32%-36% of the total mass of tranexamic acid, and the mass of tranexamic acid in the outer coating layer accounts for 64%-68% of the total mass of tranexamic acid. More preferably, the mass of tranexamic acid in the core layer accounts for 36% of the total mass of tranexamic acid, and the mass of tranexamic acid in the outer coating layer accounts for 64% of the total mass of tranexamic acid.

[0015] Preferably, the hardness of the core layer is 20-70 N, and the hardness of the tranexamic acid compressed coated sustained-release tablet is 30-155 N. More preferably, the hardness of the core layer is 40-60 N, and the hardness of the tranexamic acid compressed coated sustained-release tablet is 130-140 N.

[0016] Preferably, the core layer has a minor diameter no greater than 10 mm and a thickness no greater than 5 mm; the outer coating layer has a minor diameter no greater than 13 mm and a thickness no greater than 9 mm. More preferably, the core layer has a minor diameter of 6 mm and a thickness of 3.87 mm; the outer coating layer has a minor diameter of 9 mm and a thickness of 5.96 mm. Their structure and dimensions are shown in Figure 2.

[0017] Preferably, the binder accounts for 3%-5% of the total mass percentage of the tranexamic acid compressed coated sustained-release tablets, more preferably 3.8%. Preferably, the binder is selected from povidone K30, povidone VA and a mixture thereof, more preferably povidone VA.

[0018] Preferably, the filler accounts for 8%-17% of the total mass percentage of the tranexamic acid compressed coated sustained-release tablets, more preferably 8.7%. Preferably, the filler is selected from lactose, microcrystalline cellulose and a mixture thereof, more preferably microcrystalline cellulose KG802.

[0019] Preferably, the lubricant accounts for 0.5%-2.5% of the total mass percentage of the tranexamic acid compressed coated sustained-release tablets, more preferably 2.2%. Preferably, the lubricant is selected from micropowder silica gel, magnesium stearate, stearic acid and a mixture thereof, more preferably a mixture of micropowder silica gel, magnesium stearate and stearic acid.

[0020] On the other hand, the present disclosure provides a method for preparing the tranexamic acid compressed coated sustained-release tablets, comprising the following steps:

[0021] Tranexamic acid granules were prepared using a dry granulation method;

[0022] The core layer particles are mixed with other raw materials and pressed to obtain the core layer;

[0023] Mixing the outer coating layer particles with other raw materials to obtain an outer coating layer mixed powder;

[0024] Filling the first portion of the outer coating layer mixed powder into a mold, placing the core layer in the middle of the first portion of the outer coating layer mixed powder, filling the second portion of the outer coating layer mixed powder, and performing tableting to obtain the tranexamic acid compressed coated sustained-release tablets;

[0025] The tranexamic acid is made into granules to improve its fluidity, wherein the tranexamic acid granules do not contain auxiliary materials and skeleton materials other than tranexamic acid;

[0026] The core layer should be placed in the middle of the first part of the outer coating layer mixed powder, with a deviation distance of less than 0.5 mm in the short diameter direction and less than 1 mm in the long diameter direction;

[0027] The mass ratio of the first part of the outer coating layer mixed powder to the second part of the outer coating layer mixed powder is 1:1.

[0028] The tranexamic acid granules prepared by the dry granulation method have good particle uniformity, which is conducive to the smooth release of the drug.

[0029] On the other hand, the present disclosure provides a clinical application of a compressed, coated sustained-release tablet of tranexamic acid, including but not limited to bleeding caused by hyperfibrinolysis, chloasma, etc.

[0030] Compared with the prior art, the present disclosure has at least the following beneficial effects:

[0031] Since tranexamic acid has good water solubility and dissolves quickly in water, it is difficult for ordinary single-layer tranexamic acid sustained-release tablets to adjust the amount and type of sustained-release materials to achieve a high drug content while releasing tranexamic acid at a slow and constant rate for a long time. Compression coating technology can allow the inner layer drug to experience a double layer of sustained-release material to reduce the drug release rate. Among them, the compressed coated tablets in the form of an asymmetric double-reservoir gel matrix absorb water, swell, and dissolve in the outer controlled-release layer at the initial stage of drug release, so that the outer layer drug is gradually released into the gastrointestinal tract. After that, the tablet core controlled-release layer absorbs water, swells, and dissolves, and the inner layer drug is gradually released into the outer layer and then further released into the gastrointestinal tract. The drug release process is shown in Figure 1. In addition to adjusting the type and dosage of sustained-release materials to control the drug release rate, the drug release rate is also controlled by adjusting the powder ratio between the two reservoirs and the drug loading percentage of each reservoir, so that the drug is slowly and constantly released into the gastrointestinal tract, achieving long-term zero-order release, better sustained-release effect, longer sustained-release time, stable blood drug concentration, less prone to sudden release, reduced toxic and side effects, better safety, and higher reliability.

[0032] In addition, since tranexamic acid sustained-release tablets require a large drug content per tablet and the dissolution rate of tranexamic acid in water is much greater than the dissolution rate of the gel skeleton material, a compression coating technology in the form of an asymmetric double-reservoir gel skeleton can be used to prepare a core layer and an outer coating layer with a high drug loading density to achieve a high drug loading of tranexamic acid sustained-release tablets. By adjusting the drug loading of each layer and the drug ratio between the two layers, the type and amount of the sustained-release material can be adjusted to ultimately obtain a smooth and balanced zero-order drug release behavior.

[0033] The disclosed preparation method compresses and coats the tablet cores by compressing granules and powders. The production process is rational, simple, low-cost, environmentally friendly, and suitable for industrial production. The disclosed tranexamic acid compressed and coated sustained-release tablets contain no water in their raw materials, and the preparation process utilizes a dry granulation method, resulting in good granule uniformity. In addition to being used to treat bleeding caused by hyperfibrinolysis, the disclosed tranexamic acid compressed and coated sustained-release tablets can also be used to treat chloasma, reducing toxic side effects and improving patient medication compliance. These tablets can better meet patients' medication needs and are suitable for a wide range of patients. BRIEF DESCRIPTION OF THE DRAWINGS

[0034] FIG1 is a diagram showing the drug release process of a compressed, coated sustained-release tablet in the form of an asymmetric double-reservoir gel matrix.

[0035] Figure 2 is a diagram showing the structure and dimensions of tranexamic acid compressed coated sustained-release tablets.

[0036] FIG3 is a dissolution curve of the tranexamic acid compressed coated sustained-release tablets of Examples 1-4.

[0037] FIG4 is a dissolution curve of the tranexamic acid compressed coated sustained-release tablets of Examples 5-7.

[0038] FIG5 is a dissolution curve of the tranexamic acid compressed coated sustained-release tablets of Examples 8-10.

[0039] FIG6 is a dissolution curve of different batches of tranexamic acid compressed coated sustained-release tablets of Example 12.

[0040] FIG7 is a dissolution curve of the tranexamic acid compressed coated sustained-release tablets of Examples 13-15.

[0041] FIG8 is a dissolution curve of different batches of tranexamic acid compressed coated sustained-release tablets of Example 16.

[0042] FIG9 is a dissolution curve of the tranexamic acid compressed coated sustained-release tablets of Comparative Example 13. DETAILED DESCRIPTION

[0043] In order to more clearly illustrate the embodiments of the present disclosure or the technical solutions in the prior art, the terms and implementation methods required for use in the embodiments or the description of the prior art will be briefly introduced below. Obviously, the implementation method described below is only one implementation method of the present disclosure. For ordinary technicians in this field, other implementation methods can also be obtained based on these drawings.

[0044] I. Terminology

[0045] In order to make the present disclosure more easily understood, certain technical and scientific terms are specifically defined below. Unless otherwise clearly defined elsewhere in this document, all other technical and scientific terms used herein have the meaning commonly understood by those skilled in the art to which the present disclosure belongs.

[0046] As used herein, the articles "a" and "an" refer to one or more than one (ie, to at least one) of the grammatical object to which the article refers. For example, "an element" means one element or more than one element.

[0047] As used herein, the term "about" refers to and encompasses a specified value and a range greater than or less than that value. In certain embodiments, the term "about" can refer to a variation of ±0.1%, ±0.5%, ±1%, ±2%, ±3%, ±4%, ±5%, ±6%, ±7%, ±8%, ±9%, or ±10%. In certain embodiments, where applicable, the term "about" refers to a specified value ± one standard deviation of that value.

[0048] The endpoints of the ranges and any values ​​disclosed herein are not limited to the precise ranges or values, and these ranges or values ​​should be understood to include values ​​close to these ranges or values. For numerical ranges, the endpoints of each range, the endpoints of each range and individual point values, and the individual point values ​​can be combined with each other to obtain one or more new numerical ranges, which should be considered to be specifically disclosed herein.

[0049] The terms "comprising," "consisting essentially of," or variations thereof, used throughout the specification and claims mean that all recited elements or groups of elements are included, and optionally, other elements of similar or different properties to the recited elements that do not significantly alter the basic or novel properties of a specified dosage regimen, method, or composition.

[0050] "Optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs and where it does not.

[0051] II. Detailed description of specific implementation plan

[0052] In one aspect, the present disclosure provides a compressed, coated sustained-release tablet of tranexamic acid, comprising a core layer and an outer coating layer. The core layer comprises the following raw materials by weight: 70%-85% tranexamic acid, 17%-19% sustained-release material, 0.5%-2% binder, 0.5%-8% filler, and 0.5%-2.5% lubricant;

[0053] The tranexamic acid content of the core layer is preferably about 70.0%-85.0%, 70.0%-84.5%, 70.0%-84.0%, 70.0%-83.5%, 70.0%-83.0%70.0%-82.5%, 70.0%-82.0%, 71.5%-81.5%, 72.0%-80%, 72.5%-79.5%, 73.0%-79.0%, 73.5%-78.5%, 74.0%-78.0%, 74.5%-77.5%, 75.0%-77.0%, 75.5%-76.5%, 76%-80%.More preferably, it is 70.1%, 70.2%, 70.3%, 70.4%, 70.5%, 70.6%, 70.7%, 70.8%, 70.9%, 71.0%, 71.1%, 71.2%, 71.3%, 71.4%, 71.5%, 71.6%, 71.7%, 71.8%, 71.9%, 72.0%, 72.1%, 72.2%, 72.3%, 72.4%, 72.5%, 72.6%, 72.7%, 72.8%, 72.9%, 73.0%, 73.1%, 73.2%, 73.3%, 73.4%, 73.5%, 73.6%, 73.7 %, 73.8%, 73.9%, 74.0%, 74.1%, 74.2%, 74.3%, 74.4%, 74.5%, 74.6%, 74.7%, 74.8%, 74.9%, 75.0%, 75.1%, 75.2%, 75.3%, 75.4%, 75.5%, 75.6%, 75.7%, 75.8%, 75.9%, 76.0%, 76.1%, 76.2%, 76.3%, 76.4%, 76.5%, 76.6%, 76.7%, 76.8%, 76.9%, 77.0%, 77.1%, 77.2%, 77.3%, 77.4%, 77. 5%, 77.6%, 77.7%, 77.8%, 77.9%, 78.0%, 78.1%, 78.2%, 78.3%, 78.4%, 78.5%, 78.6%, 78.7%, 78.8%, 78.9%, 79.0%, 79.1%, 79.2%, 79.3%, 79.4%, 79.5%, 79.6%, 79.7%, 79.8%, 79.9%, 80.0%, 80.1%, 80.2%, 80.3%, 80.4%, 80.5%, 80.6%, 80.7%, 80.8%, 80.9%, 81.0%, 81.1%, 81.2%, 8 1.3%, 81.4%, 81.5%, 81.6%, 81.7%, 81.8%, 81.9%, 82.0%, 82.1%, 82.2%, 82.3%, 82.4%, 82.5%, 82.6%, 82.7%, 82.8%, 82.9%, 83.0%, 83.1%, 83.2%, 83.3%, 83.4%, 83.5%, 83.6%, 83.7%, 83.8%, 83.9%, 84.0%, 84.1%, 84.2%, 84.3%, 84.4%, 84.5%, 84.6%, 84.7%, 84.8%, 84.9%, 85.0%.

[0054] The content of sustained-release material in the core layer is preferably about 17.0%, 17.1%, 17.2%, 17.3%, 17.4%, 17.5%, 17.6%, 17.7%, 17.8%, 17.9%, 18.0%, 18.1%, 18.2%, 18.3%, 18.4%, 18.5%, 18.6%, 18.7%, 18.8%, 18.9%, 19.0%.

[0055] The amount of binder in the core layer is preferably about 0.6%-1.9%, 0.7%-1.8%, 0.8%-1.7%, 0.9%-1.6%, 1.0%-1.5%, 1.1%-1.4%, 1.2%-1.3%.

[0056] The amount of lubricant in the core layer is preferably about 0.6%-2.4%, 0.7%-2.3%, 0.8%-2.2%, 0.9%-2.1%, 1.0%-2.0%, 1.1%-1.9%, 1.2%-1.8%, 1.3%-1.9%, 1.4%-1.8%, 1.5%-1.7%, 1.6-2.5%.

[0057] The outer coating layer comprises the following raw materials in percentage by weight: 52%-54% tranexamic acid, 20%-30% sustained-release material, 4%-6% binder, 9%-21% filler, and 1%-2.5% lubricant;

[0058] The content of tranexamic acid in the outer coating layer is preferably about 52.5%-53.5%, preferably 52%, 52.1%, 52.2%, 52.3%, 52.4%, 52.5%, 52.6%, 52.7%, 52.8%, 52.9%, 53.0%, 53.1%, 53.2%, 53.3%, 53.4%, 53.5%, 53.6%, 53.7%, 53.8%, 53.9%, 54.0%.

[0059] The content of sustained-release material in the outer coating layer is preferably about 20.5%-29.5%, 21.0%-29.0%, 21.5%-28.5%, 22.0%-28.0%, 22.5%-27.5%, 23.0%-27.0%, 23.5%-26.5%, 24.0%-26.0%, 24.5%-25.5%, 24.0%-25.0%, 24.5%-30%.

[0060] The binder content in the outer coating layer is preferably about 4.1%-5.9%, 4.2%-5.8%, 4.3%-5.7%, 4.4%-5.6%, 4.5%-5.5%, 4.6%-5.4%, 4.7%-5.3%, 4.8%-5.2%, 4.9%-5.1%, 5.0%-6.0%.

[0061] The content of filler in the outer coating layer is preferably about 9.5%-20.5%, 10.0%-20.0%, 10.5%-19.5%, 11.0%-19.0%, 11.5%-18.5%, 12.0%-18.0%, 12.5%-17.5%, 13.0%-17.0%, 13.5%-16.5%, 14.0%-16.0%, 14.5%-15.5%, 15.0%-21.0%.

[0062] The lubricant content in the outer coating layer is preferably about 1.1%-2.4%, 1.2%-2.3%, 1.3%-2.2%, 1.4%-2.1%, 1.5%-2.0%, 1.6%-1.9%, 1.7%-1.8%.

[0063] The sustained-release material accounts for 19%-28% of the total mass percentage of the tranexamic acid compressed coated sustained-release tablets, preferably 19.5%-27.5%, more preferably 20%-27%, further preferably 23%-27%, more preferably 23.5%, 24%, 24.5%, 25%, 25.5%, 26%, 26.5%, 27%.

[0064] The sustained-release material is selected from: cellulose derivatives: such as methyl cellulose (MC), sodium carboxymethyl cellulose (CMC-Na), hydroxypropyl cellulose (HPC), hydroxypropyl methyl cellulose (HPMC), hydroxyethyl cellulose (HEC), etc.

[0065] The sustained-release material is preferably hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose (HPMC), or a mixture thereof. The core layer sustained-release material is preferably selected from hydroxypropyl cellulose-L, hydroxypropyl cellulose-M, and mixtures thereof, more preferably hydroxypropyl cellulose-L. The outer coating layer sustained-release material is preferably selected from hydroxypropyl cellulose-M, hydroxypropyl methylcellulose HS-K4M, hydroxypropyl methylcellulose HS-K15M, and mixtures thereof, more preferably hydroxypropyl methylcellulose HS-K4M.

[0066] In the present disclosure, the drug loading of the tranexamic acid compressed coated sustained-release tablets is not less than 58.8%, the mass of each tranexamic acid compressed coated sustained-release tablet is not higher than 850 mg, and the total dose of tranexamic acid in each tranexamic acid compressed coated sustained-release tablet is not less than 500 mg.

[0067] The disclosed compressed, coated sustained-release tablets of tranexamic acid include a core layer; the core layer comprises 23% to 30% by weight, preferably 29.4% by weight. In some embodiments, the mass of tranexamic acid in the core layer accounts for 32% to 36% of the total mass of tranexamic acid, preferably 36%. In some embodiments, the core layer has a hardness of 20 to 70 N, preferably 40 to 60 N. In some embodiments, the core layer has a minor diameter of no greater than 10 mm and a thickness of no greater than 5 mm, preferably a minor diameter of 6.00 mm and a thickness of 3.87 mm.

[0068] In some embodiments, the core layer comprises the following raw materials in the following weight percentages: tranexamic acid 72%-80%, sustained-release material 17%-19%, binder 0.5%-2%, filler 0.5%-8%, and lubricant 0.5%-2.5%.

[0069] In some embodiments, the raw materials of the core layer include 72%-80% by weight of tranexamic acid, preferably 72%.

[0070] In some embodiments, the raw materials of the core layer include 17-19% by weight of sustained-release material, preferably 18%. In the present invention, the sustained-release material of the core layer is selected from hydroxypropyl cellulose-L, hydroxypropyl cellulose-M and a mixture thereof, further preferably hydroxypropyl cellulose-L.

[0071] In some embodiments, the raw materials of the core layer include 0.5%-2% binder by weight, preferably 0.8%. In the present invention, the binder is selected from povidone K30, povidone VA and a mixture thereof, and is further preferably povidone VA.

[0072] In some embodiments, the raw materials of the core layer include 0.5%-8% filler by weight, preferably 7%. In the present invention, the filler is selected from lactose, microcrystalline cellulose and a mixture thereof, and more preferably microcrystalline cellulose.

[0073] In some embodiments, the core layer comprises 0.5% to 2.5% by weight of a lubricant, preferably 2.2%. In some embodiments, the lubricant is selected from micropowdered silica gel, magnesium stearate, stearic acid, and mixtures thereof, more preferably a mixture of micropowdered silica gel, magnesium stearate, and stearic acid.

[0074] The disclosed compressed-coated sustained-release tablets of tranexamic acid include an outer coating layer; the mass percentage of the outer coating layer in the compressed-coated sustained-release tablets of tranexamic acid is preferably 70%-77%, more preferably 70.6%. In some embodiments, the mass of tranexamic acid in the outer coating layer accounts for 64%-68%, preferably 64%, of the total amount of tranexamic acid. In some embodiments, the hardness of the compressed-coated sustained-release tablets of tranexamic acid is 30-155N, preferably 125-155N, more preferably 130-140N. In the present invention, the outer coating layer has a minor diameter of no greater than 13 mm and a thickness of no greater than 9 mm, preferably a minor diameter of 9.00 mm and a thickness of 5.96 mm.

[0075] In some embodiments, the outer coating layer comprises the following raw materials in the following weight percentages: tranexamic acid 52%-54%, sustained-release material 20%-30%, binder 4%-6%, filler 9%-21%, and lubricant 1%-2.5%.

[0076] In some embodiments, the raw materials of the outer coating layer include 52%-54% by weight of tranexamic acid, preferably 53.3%.

[0077] In some embodiments, the raw materials of the outer coating layer include 20%-30% by weight of sustained-release material, preferably 30%. In the present invention, the sustained-release material of the outer coating layer is selected from hydroxypropyl cellulose-M, hydroxypropyl methylcellulose HS-K4M, hydroxypropyl methylcellulose HS-K15M and a mixture thereof, further preferably hydroxypropyl methylcellulose HS-K4M.

[0078] In some embodiments, the raw materials of the outer coating layer include 4%-6% by weight of an adhesive, preferably 5%. In the present invention, the type of the adhesive is preferably consistent with the above technical solution and will not be repeated here.

[0079] In some embodiments, the raw materials of the outer coating layer include 9%-21% filler by weight, preferably 9.5%. In the present invention, the type of the filler is preferably consistent with the above technical solution and will not be repeated here.

[0080] In some embodiments, the raw materials of the outer coating layer include 1%-2.5% lubricant by weight, preferably 2.2%. In the present invention, the type of the lubricant is preferably consistent with the above technical solution and will not be repeated here.

[0081] The present disclosure also provides a method for preparing the compressed, coated sustained-release tablets of tranexamic acid described in the above technical solution, comprising the following steps:

[0082] Tranexamic acid granules were prepared using a dry granulation method;

[0083] The core layer particles are mixed with other raw materials and pressed to obtain the core layer;

[0084] Mixing the outer coating layer particles with other raw materials to obtain an outer coating layer mixed powder;

[0085] Filling the first portion of the outer coating layer mixed powder into a mold, placing the core layer in the middle of the first portion of the outer coating layer mixed powder, filling the second portion of the outer coating layer mixed powder, and performing tableting to obtain the tranexamic acid compressed coated sustained-release tablets;

[0086] The tranexamic acid is made into granules to improve its fluidity, wherein the tranexamic acid granules do not contain auxiliary materials and skeleton materials other than tranexamic acid;

[0087] The core layer should be placed in the middle of the first part of the outer coating layer mixed powder, with a deviation distance of less than 0.5 mm in the short diameter direction and less than 1 mm in the long diameter direction;

[0088] The mass ratio of the first part of the outer coating layer mixed powder to the second part of the outer coating layer mixed powder is 1:1.

[0089] In some embodiments, the preparation method of the granules is selected from dry granulation, wet granulation, fluidized bed granulation, and manual wet granulation, preferably dry granulation.

[0090] The compressed and coated sustained-release tablets of tranexamic acid and the preparation method thereof provided by the present disclosure are described in detail below with reference to the examples, but they should not be construed as limiting the scope of protection of the present disclosure.

[0091] Unless otherwise specified, the reagents and equipment used in this disclosure are conventional and commercially available. For example:

[0092] Table 1: Sources of raw materials and auxiliary materials

[0093] Table 2: Main instruments and equipment for the experiment

[0094] Example

[0095] A further understanding of the present disclosure may be obtained by reference to the specific examples provided herein. These examples are intended to illustrate the present disclosure only and are not intended to limit the scope of the present disclosure in any way. Obviously, various modifications and variations may be made to the present disclosure without departing from the essence of the present disclosure and, therefore, such modifications and variations are also within the scope of the present application. The percentages of the various raw materials in Examples 1-16 and Comparative Examples 8-12 are calculated based on the weight of the raw material in the core layer or outer coating layer.

[0096] Example 1-2

[0097] The prescription of the tranexamic acid compressed coated sustained-release tablets of the present embodiment is shown in Table 3.

[0098] Table 3: Prescription of Example 1-2 Tranexamic Acid Compressed Coated Sustained Release Tablets

[0099] The preparation process of the tranexamic acid compressed coated sustained-release tablets of Example 1 adopts dry granulation tableting, which comprises the following steps:

[0100] Granulation and screening;

[0101] The tranexamic acid raw material is placed in a dry granulator for granulation, and then sieved using 40-mesh and 60-mesh sieves to obtain tranexamic acid granules of 40-60 mesh size.

[0102] Mixing and pressing the core layer;

[0103] Weigh the prescribed amount of tranexamic acid granules, povidone, hydroxypropyl cellulose, and lactose for the core layer, mix well, add the prescribed amount of magnesium stearate for the core layer, and use 8mm round shallow concave punches to press the tablet cores with a hardness of 20-30N.

[0104] Mixing and pressing the outer coating layer;

[0105] Weigh the outer coating layer prescription amount of tranexamic acid granules, povidone, hydroxypropyl cellulose, and lactose, mix well, add the outer coating layer prescription amount of magnesium stearate and mix, take 1 / 2 weight of the outer coating layer powder, fill it into a 12mm circular deep concave die, add the tablet core and place it in the middle, take another 1 / 2 weight of the outer coating layer powder, fill it around the tablet core, and press it into tranexamic acid compressed coated sustained-release tablets with a hardness of 30-40N.

[0106] The tranexamic acid compressed coated sustained-release tablets of Example 2 were prepared by dry granulation and tableting, and the preparation method was the same as that of Example 1. The compression hardness of the whole tablets was 50N-60N.

[0107] Examples 3-4

[0108] The core layer formulation of the tranexamic acid compressed-coated sustained-release tablets of this embodiment is shown in Table 4.

[0109] Table 4: Formulation of the core layer of tranexamic acid compressed-coated sustained-release tablets of Example 3-4

[0110] The preparation process of the tranexamic acid compressed coated sustained-release tablets of Example 3 adopts dry granulation tableting, which comprises the following steps:

[0111] Granulation and screening;

[0112] The tranexamic acid raw material is placed in a dry granulator for granulation, and then sieved using 40-mesh and 60-mesh sieves to obtain tranexamic acid granules of 40-60 mesh size.

[0113] Mixing and pressing the core layer;

[0114] Weigh the prescribed amount of tranexamic acid granules, povidone, hydroxypropyl cellulose, microcrystalline cellulose, and micro-powdered silica gel in the core layer, mix well, add the prescribed amount of magnesium stearate in the core layer, and use a 9mm round shallow concave punch to press the tablet core with a hardness of 40-50N.

[0115] Mixing and pressing the outer coating layer;

[0116] Weigh the outer coating layer prescription amount of tranexamic acid granules, povidone, hydroxypropyl cellulose, microcrystalline cellulose, and micropowdered silica gel, mix well, add the outer coating layer prescription amount of magnesium stearate and mix, take 1 / 2 weight of the outer coating layer powder, fill it into a 12mm circular deep concave die, add the tablet core and place it in the middle, take another 1 / 2 weight of the outer coating layer powder, fill it around the tablet core, and press it into tranexamic acid compressed coated sustained-release tablets with a hardness of 75-85N.

[0117] The preparation process of the tranexamic acid compressed coated sustained-release tablets of Example 4 adopts dry granulation tableting, which comprises the following steps:

[0118] Granulation and screening;

[0119] The tranexamic acid raw material is placed in a dry granulator for granulation, and then sieved using 40-mesh and 60-mesh sieves to obtain tranexamic acid granules of 40-60 mesh size.

[0120] Mixing and pressing the core layer;

[0121] Weigh the prescribed amount of tranexamic acid granules, povidone, hydroxypropyl cellulose, microcrystalline cellulose, and micro-powdered silica gel in the core layer, mix well, add the prescribed amount of magnesium stearate in the core layer, and use a 9mm round shallow concave punch to press the tablet core with a hardness of 40-50N.

[0122] Mixing and pressing the outer coating layer;

[0123] Weigh the outer coating layer prescription amount of tranexamic acid granules, povidone, hydroxypropyl methylcellulose, microcrystalline cellulose, and micropowdered silica gel, mix well, add the outer coating layer prescription amount of magnesium stearate and mix, take 1 / 2 weight of the outer coating layer powder, fill it into a 12mm circular deep concave die, add the tablet core and place it in the middle, take another 1 / 2 weight of the outer coating layer powder, fill it around the tablet core, and press it into tranexamic acid compressed coated sustained-release tablets with a hardness of 85-95N.

[0124] Examples 5-7

[0125] The prescription of the tranexamic acid compressed coated sustained-release tablets of the present embodiment is shown in Table 5.

[0126] Table 5: Prescription of Example 5-7 Tranexamic Acid Pressed Coated Sustained Release Tablets

[0127] The tranexamic acid compressed coated sustained-release tablets of Example 5 were prepared using a dry granulation tableting process. The preparation method was the same as that of Example 4. The tablet core layer had a compression hardness of 30-40N, the whole tablet had a compression hardness of 105N-115N, the tablet core layer had a thickness of approximately 4.30mm, and the whole tablet had a thickness of approximately 8.62mm.

[0128] The compressed coated sustained-release tablets of tranexamic acid in Example 6 were prepared by dry granulation and tableting. The preparation method was the same as that in Example 4. The compression hardness of the whole tablet was 115N-125N, the thickness of the core layer was about 4.30mm, and the thickness of the whole tablet was about 8.44mm.

[0129] The compressed coated sustained-release tablets of tranexamic acid in this Example 7 were prepared by dry granulation and tableting. The preparation method was the same as that in Example 4. The compression hardness of the whole tablet was 95N-105N, the thickness of the core layer was about 4.30mm, and the thickness of the whole tablet was about 8.53mm.

[0130] Examples 8-10

[0131] The prescription of the tranexamic acid compressed coated sustained-release tablets of the present embodiment is shown in Table 6.

[0132] Table 6: Prescription of Examples 8-10 Tranexamic Acid Pressed Coated Sustained Release Tablets

[0133] The preparation process of the tranexamic acid compressed coated sustained-release tablets of Example 8 adopts dry granulation tableting, which comprises the following steps:

[0134] Granulation and screening

[0135] The tranexamic acid raw material is placed in a dry granulator for granulation, and then sieved using 40-mesh and 60-mesh sieves to obtain tranexamic acid granules of 40-60 mesh size.

[0136] Mixing and pressing core layer

[0137] Weigh the prescribed amount of tranexamic acid granules, povidone, hydroxypropyl cellulose, microcrystalline cellulose, and micropowdered silica gel in the core layer and mix them evenly. Add the prescribed amount of magnesium stearate and stearic acid in the core layer and mix. Use 6*13mm special-shaped punches to press the tablet core with a hardness of 40-60N and a thickness of approximately 3.87mm.

[0138] Mixing and pressing outer coating layer

[0139] Weigh the outer coating layer prescription amount of tranexamic acid granules, povidone, hydroxypropyl methylcellulose, microcrystalline cellulose, and micropowdered silica gel, mix evenly, add the outer coating layer prescription amount of magnesium stearate and stearic acid, mix, take 1 / 2 weight of the outer coating layer powder, fill it into a 9*19mm special-shaped die, add the tablet core and place it in the middle, take another 1 / 2 weight of the outer coating layer powder, fill it around the tablet core, and press into tranexamic acid compressed coated sustained-release tablets with a hardness of 115-125N and a thickness of about 5.95mm.

[0140] The compressed coated sustained-release tablets of tranexamic acid in Example 9 were prepared using a dry granulation tableting process. The preparation method was the same as in Example 8. The tablet core layer had a compression hardness of 60-70N, the whole tablet had a compression hardness of 95N-105N, the tablet core layer had a thickness of approximately 3.87mm, and the whole tablet had a thickness of approximately 5.87mm.

[0141] The compressed, coated sustained-release tablets of tranexamic acid in Example 10 were prepared using a dry granulation and tableting process. The preparation method was the same as in Example 8. The tablet core layer had a compression hardness of 60-70 N, and the entire tablet had a compression hardness of 125 N-135 N. The tablet core layer had a thickness of approximately 3.87 mm, and the entire tablet had a thickness of approximately 5.93 mm.

[0142] Example 11

[0143] The prescription of the tranexamic acid compressed coated sustained-release tablets of the present embodiment is shown in Table 7.

[0144] Table 7: Prescription of Example 11 Tranexamic Acid Pressed Coated Sustained Release Tablets

[0145] The preparation process of the tranexamic acid compressed coated sustained-release tablets of Example 11 adopts a full powder direct compression process, comprising the following steps:

[0146] Mixing and pressing core layer

[0147] Weigh the prescribed amount of tranexamic acid, povidone, hydroxypropyl cellulose, microcrystalline cellulose, and micro-powdered silica gel in the core layer and mix them evenly. Add the prescribed amount of magnesium stearate and stearic acid in the core layer and mix them. Use a 6*13mm special-shaped punch to press the core tablets at the same pressure to a hardness of 20-70N.

[0148] Mixing and pressing outer coating layer

[0149] Weigh the outer coating layer prescription amount of tranexamic acid, povidone, hydroxypropyl methylcellulose, microcrystalline cellulose, and micropowdered silica gel, mix evenly, add the outer coating layer prescription amount of magnesium stearate and stearic acid, mix, take 1 / 2 weight of the outer coating layer powder, fill it into a 9*19mm special-shaped die, add the tablet core and place it in the middle, take another 1 / 2 weight of the outer coating layer powder, fill it around the tablet core, and press it into tranexamic acid compressed coated sustained-release tablets.

[0150] Example 12

[0151] The prescription of the tranexamic acid compressed coated sustained-release tablets of the present embodiment is shown in Table 8.

[0152] Table 8: Prescription of Example 12 Tranexamic Acid Pressed Coated Sustained Release Tablets

[0153] The tranexamic acid compressed coated sustained-release tablets of this Example 12 are prepared by dry granulation and tableting. The preparation method is as follows: different batches of tranexamic acid compressed coated sustained-release tablets are compressed as in Example 8, and the compression hardness of the whole tablet is controlled between 115N and 125N, the thickness of the tablet core layer is 3.87-3.89 mm, and the thickness of the whole tablet is 5.95-5.99 mm.

[0154] Examples 13-15

[0155] Add the prescription and preparation method of Examples 13-15

[0156] The prescription of the tranexamic acid compressed coated sustained-release tablets of the present embodiment is shown in Table 9.

[0157] Table 9: Prescription of Examples 13, 14, and 15 Tranexamic Acid Compressed Coated Sustained-Release Tablets

[0158] The compressed coated sustained-release tablets of tranexamic acid in Example 13 were prepared by dry granulation and tableting. The preparation method was the same as that in Example 8, and the compression hardness of the whole tablets was 125N-135N.

[0159] The tranexamic acid compressed coated sustained-release tablets of Example 14 were prepared using a dry granulation tableting process. The preparation method was the same as that of Example 8, and the compression hardness of the entire tablet was 135N-145N.

[0160] The compressed coated sustained-release tablets of tranexamic acid in Example 15 were prepared by dry granulation and tableting. The preparation method was the same as that in Example 8, and the compression hardness of the whole tablet was 145N-155N.

[0161] Example 16

[0162] The prescription of the tranexamic acid compressed coated sustained-release tablets of the present embodiment is shown in Table 10.

[0163] Table 10: Prescription of Example 16 Tranexamic Acid Pressed Coated Sustained Release Tablets

[0164] The tranexamic acid compressed coated sustained-release tablets of Example 16 were prepared using a dry granulation tableting process. The preparation method was the same as in Example 8. The tablets were compressed to a hardness of 130N-140N, the core layer thickness was approximately 3.87mm, and the overall tablet thickness was approximately 5.96mm. Different batches of tranexamic acid compressed coated sustained-release tablets were compressed.

[0165] Comparative Example 1

[0166] The prescription of the tranexamic acid solid composition of this comparative example is shown in Table 11.

[0167] Table 11: Prescription of Comparative Example 1 Tranexamic Acid Solid Composition

[0168] In Comparative Example 1, a tranexamic acid solid composition was prepared using a wet granulation tableting process. The preparation method was as follows: tranexamic acid was weighed according to the prescribed amount and crushed through a 120-mesh sieve. Mannitol and hypromellose (K15M) were weighed and mixed uniformly using a stepwise method. Purified water was added as a binder to prepare a soft material, and granulated through a 16-mesh sieve. The mixture was dried and the moisture content was measured. The granules were sieved through a 24-mesh sieve, mixed with the prescribed amount of magnesium stearate, and then mixed with the granules. Tablets were punched into 10 mm shallow concave tablets.

[0169] Comparative Example 2

[0170] The prescription of the tranexamic acid solid composition of this comparative example is shown in Table 12.

[0171] Table 12: Prescription of Comparative Example 2 Tranexamic Acid Solid Composition

[0172] The solid composition of tranexamic acid in this comparative example 2 adopts a preparation process of direct powder tableting, and the preparation method is as follows: tranexamic acid is weighed according to the prescription amount, crushed through a 120-mesh sieve, and the prescription amount of micro-cellulose, pregelatinized starch, hypromellose (K4M), and povidone (K30) are weighed, mixed evenly by an equal amount addition method, and then mixed with the prescription amount of micro-powder silica gel and magnesium stearate, and 12 mm shallow concave punching tablets.

[0173] Comparative Example 3

[0174] The prescription of the tranexamic acid solid composition of this comparative example is shown in Table 13.

[0175] Table 13: Prescription of Comparative Example 3 Tranexamic Acid Solid Composition

[0176] Comparative Example 3: A tranexamic acid solid composition was prepared using a wet granulation process. The preparation method was as follows: tranexamic acid was weighed according to the prescribed amount and pulverized through a 120-mesh sieve. Lactose, starch, and hypromellose (K15M) were weighed and mixed uniformly using a stepwise addition method. An appropriate amount of 10% slurry was added to prepare a soft material, and granulated through a 16-mesh sieve. The composition was dried and the moisture content was measured. The granules were sieved through a 24-mesh sieve and mixed with the prescribed amount of talc to obtain granules, which were then filled into No. 2 capsule shells.

[0177] Comparative Example 4

[0178] The prescription of the tranexamic acid solid composition of this comparative example is shown in Table 14.

[0179] Table 14 Prescription of Comparative Example 4 Tranexamic Acid Solid Composition

[0180] The tranexamic acid solid composition of Comparative Example 4 adopts a wet granulation preparation process, and the preparation method is as follows: weigh tranexamic acid according to the prescription amount, crush it through a 120-mesh sieve, weigh the prescription amount of mannitol and hydroxypropyl cellulose, mix them uniformly by equal amount addition method, add 70% (W / W) alcohol aqueous solution to prepare a soft material, granulate it through a 14-mesh sieve, dry it, and measure the moisture content; sieve the granules through an 18-mesh sieve, mix them uniformly with the prescription amount of magnesium stearate, and package them to obtain granules.

[0181] Comparative Example 5

[0182] The prescription of tranexamic acid sustained-release tablets of this comparative example is shown in Table 15.

[0183] Table 15: Prescription of Comparative Example 5 Tranexamic Acid Sustained-Release Tablets

[0184] The comparative example 5 tranexamic acid sustained-release tablets adopt a solid dispersion tableting preparation process, the preparation method is as follows: pulverize tranexamic acid, pass through a 120-mesh sieve, and set aside; melt octadecyl alcohol at 70-80 ° C into a liquid; under a heat preservation condition of 70-80 ° C, add the pulverized tranexamic acid thereto while stirring, and mix thoroughly and evenly, quickly pour the mixture into a tray, cool to room temperature, and solidify the sample; pulverize the solidified solid with a grinder to less than 30 mesh, and finally add magnesium stearate, mix evenly, and tablet to obtain.

[0185] Comparative Example 6

[0186] The prescription of tranexamic acid sustained-release tablets of this comparative example is shown in Table 16.

[0187] Table 16: Prescription of Comparative Example 6 Tranexamic Acid Sustained-Release Tablets

[0188] The comparative example 6 tranexamic acid sustained-release tablets adopt a wet granulation tableting process, the preparation method is as follows: pulverize tranexamic acid, pass through a 120-mesh sieve, and set aside; pass carnauba wax through an 80-mesh sieve, and set aside; prepare a 10% concentration solution of polyvidone with water as a binder; mix tranexamic acid and carnauba wax evenly, add the binder to prepare a soft material, pass through a 30-mesh sieve to granulate, dry the wet granules at 50-60°C until the moisture content is less than 4%; discharge the material, pass through a 30-mesh sieve to form the whole granules, finally add magnesium stearate, mix evenly, and tablet.

[0189] Comparative Example 7

[0190] The prescription of tranexamic acid sustained-release tablets of this comparative example is shown in Table 17.

[0191] Table 17: Prescription of Comparative Example 7 Tranexamic Acid Sustained-Release Tablets

[0192] The comparative example 7 tranexamic acid sustained-release tablets adopt a wet granulation and tableting process, and the preparation method is as follows: pulverize tranexamic acid, pass through a 120-mesh sieve, and set aside; pass ethyl cellulose through an 80-mesh sieve, and set aside; take 5% of the prescribed amount of ethyl cellulose, and prepare a 10% concentration solution with 95% ethanol as a binder; mix the tranexamic acid and the remaining 95% of the prescribed amount of ethyl cellulose uniformly, add the binder to prepare a soft material, pass through a 30-mesh sieve to granulate, and dry the wet granules at 50-60° C. until the moisture content is less than 4%; discharge the material, pass through a 30-mesh sieve to granulate, and finally add magnesium stearate, mix uniformly, and tablet.

[0193] Comparative Example 8

[0194] The formulation of the glipizide compressed coated controlled-release tablets of this comparative example is shown in Table 18.

[0195] Table 18: Prescription of Comparative Example 8 Glipizide Compressed Coated Controlled Release Tablets

[0196] The preparation process of the glipizide compressed coated controlled-release tablets of this comparative example 8 adopts wet granulation tabletting, preparation method: the raw materials of the core layer (except magnesium stearate) are mixed evenly, 60 DEG C of dryings are dried after granulation using an appropriate amount of 8% HPC-SSL90% ethanol, and sieved whole grains, and then magnesium stearate is added to mix evenly. Under 30N pressure, a single punch tablet press is used to form a core tablet (diameter = 7mm) weighing 94.5mg per tablet. The raw materials of the outer coating layer (except magnesium stearate) are mixed evenly, 60 DEG C of dryings are dried after granulation, and sieved whole grains, and then magnesium stearate is added to mix evenly, and a dry coating machine (Kikusui Cleanpress Corret18DC) is used to compress the shell layer and the pre-prepared core to form a compressed coated tablet (diameter = 9mm) containing glipizide 5mg weighing 401mg per tablet. The drug loading capacity of the glipizide-β-cyclodextrin inclusion compound is 42.4%, and the drug loading capacity of the glipizide is 1.25%.

[0197] Comparative Example 9

[0198] The prescription of ofloxacin compressed coated controlled-release tablets of this comparative example is shown in Table 19.

[0199] Table 19: Prescription of Comparative Example 9 Ofloxacin Pressed Coated Controlled Release Tablets

[0200] The preparation process of the ofloxacin compressed coated controlled-release tablets of this comparative example 9 adopts wet granulation tableting, preparation method: the core layer raw materials (except magnesium stearate) are mixed evenly, dried at 60°C after granulation using an appropriate amount of 8% HPC-SSL90% ethanol, and sieved granules, and then magnesium stearate is added to mix evenly. Under 40N pressure, a single punch tablet press is used to form a core tablet (diameter = 7mm) weighing 90.5mg per tablet. The outer coating layer raw materials (except magnesium stearate) are mixed evenly, dried at 60°C after granulation using anhydrous ethanol, and sieved granules, and then magnesium stearate is added to mix evenly, and tableted under 70N pressure, the shell layer and the pre-prepared core are combined to form a compressed coated tablet (diameter = 11mm) weighing 472mg per tablet. Its drug loading for ofloxacin is 42.4%.

[0201] Comparative Example 10

[0202] The prescription of the acetaminophen compressed coated controlled-release tablets of this comparative example is shown in Table 20.

[0203] Table 20: Prescription of Comparative Example 10 Glipizide Pressed Coated Controlled Release Tablets

[0204] The preparation process of the paracetamol compressed coated controlled-release tablets of Comparative Example 10 is as follows: paracetamol and each auxiliary material are respectively passed through an 80-mesh sieve, paracetamol and auxiliary materials are weighed according to the prescription amount, and are fully mixed according to the equal amount increment method, sieved and mixed, an appropriate amount of magnesium stearate is added by the external addition method, and after fully mixing, the paracetamol tablet core is prepared by the powder direct tableting method. The prescription amount of paracetamol, chitosan, and sodium alginate are respectively passed through an 80-mesh sieve and are fully mixed according to the equal amount increment method, sieved and mixed, half of the coating material is evenly filled in the bottom of the die, and the tablet core is placed at its center and then filled with the other half of the coating material, and the secondary direct tableting is obtained. The drug loading of the paracetamol is 13.7%.

[0205] Comparative Example 11

[0206] The formulation of the tofacitinib citrate compressed coated sustained-release tablets of this comparative example is shown in Table 21.

[0207] Table 21: Prescription of Comparative Example 11 Tofacitinib Citrate Compressed Coated Sustained-Release Tablets

[0208] Comparative Example 11: The tofacitinib citrate compressed coated sustained-release tablets are prepared by direct powder compression. The preparation method is as follows: weigh the prescribed amount of tofacitinib citrate (passed through an 80-mesh sieve), microcrystalline cellulose, lactose, citric acid, and hypromellose, and mix them evenly according to the equal-increment method; add the prescribed amount of magnesium stearate and mix for 5 minutes; use a 6mm flat die to compress the tablets to obtain the tablet core, which has a hardness of about 25N. Weigh the prescribed amount of tofacitinib citrate (passed through an 80-mesh sieve), microcrystalline cellulose, lactose, citric acid, and hypromellose, and mix them evenly according to the equal-increment method; add the prescribed amount of magnesium stearate and mix for 5 minutes to obtain the outer coating layer material. Half the weight of the outer coating powder was filled into a 9mm shallow concave die, the tablet core was added, and another half of the outer coating powder was filled around the core. The tablets were then compressed under a set pressure and time to produce tofacitinib citrate compressed-coated sustained-release tablets with a hardness of approximately 100 N. The drug loading of tofacitinib citrate was 4.94%.

[0209] Comparative Example 12

[0210] The formulation of the nifedipine compressed coated controlled-release tablets of this comparative example is shown in Table 22.

[0211] Table 22: Prescription of Comparative Example 12 Nifedipine Compressed Coated Controlled Release Tablets

[0212] Comparative Example 12, nifedipine compressed coated controlled-release tablets, were prepared using a direct powder compression process. The preparation method was as follows: a prescribed amount of nifedipine was prepared using an ultrafine airflow milling method at a Venturi pressure of 4.5 bar, an annular pressure of 3.5 bar, and a feed rate of 10 Hz to obtain a fine nifedipine powder having a particle size D50 of 1.474 μm and a span of 1.80. The resulting nifedipine fine powder was then pre-mixed and coated with a prescribed amount of hydrophilic nanosilica to obtain a pre-mixed tablet core layer. The pre-mixing was performed using a high-speed shear mixer granulator with a paddle speed of 400 rpm, a shear blade speed of 2000 rpm, and a mixing time of 30 minutes. The coating was performed using an ultrafine airflow mill at a Venturi pressure of 2 bar, an annular pressure of 1 bar, and a feed rate of 20 Hz. The tablet core premix, along with the prescribed amount of lactose T80, HPC-L, and red iron oxide, was passed through a 0.4 mm sieve and then mixed using high-speed shear granulation at a paddle speed of 300 rpm for 7 minutes to obtain the tablet core premix. The prescribed amount of magnesium stearate was added to the tablet core premix and mixed for 10 minutes. The resulting tablet core premix had an angle of repose of 32.5°. Tablets were then pressed using a 4.98 mm oblique flat punch die with a pressing pressure of 12 kN, a pressing rate of 2600 tablets / hour, an actual pressing time of 42 minutes, and a holding time of 5 minutes. The tablet core hardness was measured to be 26 N.

[0213] The prescribed amount of nifedipine was weighed and the ultrafine airflow grinding method was used. The Venturi pressure was 4.5 bar, the annular pressure was 3.5 bar, and the feeding speed was 10 Hz to obtain nifedipine fine powder. The particle size of the obtained nifedipine fine powder was D 50 The particle size is 1.474 μm and the span is 1.80. The obtained nifedipine fine powder and the prescribed amount of hydrophilic nano-silicon are sequentially pre-mixed and coated to obtain the pre-mixed material for the compression coating layer: the pre-mixing is carried out by a high-speed shear mixing granulator, the stirring blade speed is 400 rpm, the shear blade speed is 2000 rpm, and the mixing time is 30 min. The coating treatment adopts an ultra-fine air flow mill, the venturi pressure is 2 har, the annular pressure is 1 bar, and the feeding speed is 20 Hz. The pre-mixed material for the compression coating layer, the prescribed amount of HPC-L, IIPC-M, and Eudragit RSPO are passed through a sieve with a pore size of 0.25 mm, and then mixed by high-speed shear granulation, the stirring blade speed is 300 rpm, and the mixing time is 7 min to obtain the compression coating layer premix.

[0214] Add the prescribed amount of magnesium stearate to the press-coat premix and mix for 10 minutes to obtain a press-coat mixture with an angle of repose of 28.8°. Add 1 / 2 the weight of the press-coat premix and fill an 8mm shallow concave die. Add the core layer and pre-press. Then add another 1 / 2 the weight of the press-coat premix. Set the pressing pressure to 11-15 kN, the pressing speed to 1500 tablets / hour, the actual pressing time to 90 minutes, and the dwell time to 6 minutes to produce press-coated nifedipine sustained-release tablets. The hardness of the press-coated tablets was measured at 75 Newtons. Prepare the Opadry film coating solution, adjust the coating pan temperature to 40°C and the pan speed to 120 rpm, and preheat the tablets for approximately 15 minutes. After testing, control the coating weight gain to 3%, stop the coating, and dry and solidify to obtain the final product. The drug loading of nifedipine is 17.3%.

[0215] Comparative Example 13

[0216] The prescription of the tranexamic acid compressed coated sustained-release tablets of this comparative example is shown in Table 23.

[0217] Table 23: Prescription of tranexamic acid compressed coated sustained-release tablets of Comparative Example 13

[0218] The preparation method of the tranexamic acid compressed coated sustained-release tablets of Comparative Example 13 is as follows:

[0219] Core layer:

[0220] a. Sieve tranexamic acid, microcrystalline cellulose and hypromellose through a suitable sieve;

[0221] b. dry mixing the material obtained in step (a) in a high shear mixer;

[0222] c. dissolving povidone in purified water and using it as a binder solution;

[0223] d. granulating the dry mixture of step (b) together with the binder solution;

[0224] e. The obtained wet mass was dried in a fluidized bed dryer until the desired LOD was reached;

[0225] f. The dried granules are sieved and ground through an appropriate sieve;

[0226] g. The sieved particles were mixed with colloidal silicon dioxide in a blender;

[0227] h. The obtained mixture was lubricated with magnesium stearate in the same blender;

[0228] i. The lubricated mixture is compressed using a rotary tablet press using appropriate tooling to obtain compressed tablets.

[0229] Drug-containing coating layer:

[0230] a. Disperse tranexamic acid and hypromellose in purified water under stirring;

[0231] b. Dissolve the polyethylene glycol under stirring;

[0232] c. Disperse the talc powder under stirring and keep it dispersed throughout the process;

[0233] d. Spray coat the core tablets with the above dispersion until the desired weight gain is achieved.

[0234] Film coating layer:

[0235] a. Disperse Opadry in purified water and stir until a uniform dispersion is formed;

[0236] b. Stir the dispersion continuously throughout the process;

[0237] c. Apply film coating over drug coated tablets until desired weight gain is achieved.

[0238] Test Example 1

[0239] The hardness of the core layer of the tranexamic acid compressed and coated sustained-release tablets prepared in Example 8 and Example 11 was measured:

[0240] Hardness test: Place the sample to be tested between the two pressure plates of the hardness tester. Press along the long diameter of the tablet and measure the pressure required to break it. The results are shown in Table 24.

[0241] Comparison was performed by RSD values;

[0242] The results of the core layer hardness of the tranexamic acid compressed-coated sustained-release tablets obtained in Example 8 and Example 11 are shown in Table 24:

[0243] Table 24: Hardness of the core layer of tranexamic acid compressed coated sustained-release tablets obtained in Example 8 and Example 11

[0244] The results in Table 24 show that the RSD value of the hardness of the core layer of the tranexamic acid compressed coated sustained-release tablets of Example 8 is less than 10%, indicating that the tranexamic acid compressed coated sustained-release tablets prepared by the dry granulation tableting preparation process of Example 8 have better reproducibility than the full powder tableting preparation process of Example 11.

[0245] Test Example 2: Determination of the in vitro cumulative release of tranexamic acid preparations

[0246] The release rate experiment was determined using Tianda Tianfa dissolution apparatus and Hitachi high performance liquid chromatography.

[0247] Release determination:

[0248] With reference to the release test method of tranexamic acid tablets in the Chinese Pharmacopoeia, a sample release determination method was established: rotation speed 50 rpm, water bath temperature (37.0±0.5)°C, dissolution medium was water, and the medium volume was 900 mL.

[0249] The chromatographic conditions refer to the inspection method of tranexamic acid in the "Chinese Pharmacopoeia": an octadecylsilane bonded silica gel chromatographic column is used; 0.23% sodium dodecyl sulfate solution (take 18.3 g of sodium dihydrogen phosphate, add 800 ml of water to dissolve, add 8.3 ml of triethylamine to mix, then add 2.3 g of sodium dodecyl sulfate, shake to dissolve, adjust the pH value to 2.5 with phosphoric acid, add water to 1000 ml, and shake well)-methanol (60:40) is used as the mobile phase; the detection wavelength is 220 nm; the injection volume is 20 μl.

[0250] 3 mL of samples were taken at 0.5 h, 1 h, 2 h, 4 h, 6 h, 8 h, 10 h and 12 h, respectively, filtered through a 0.22 μm microporous filter membrane, and the filtrate was used to determine the peak area by high performance liquid chromatography.

[0251] The dissolution curves of each preparation and their fitting values ​​R2 of the zero-order release equation were compared;

[0252] FIG3 is a dissolution curve of the tranexamic acid compressed coated sustained-release tablets of Examples 1-4.

[0253] The release results of the tranexamic acid compressed coated sustained-release tablets obtained in Examples 1-4 are shown in Table 25.

[0254] Table 25: Release of tranexamic acid compressed coated sustained-release tablets obtained in Examples 1-4

[0255] FIG4 is a dissolution curve of the tranexamic acid compressed coated sustained-release tablets of Examples 5-7.

[0256] The release results of the tranexamic acid compressed coated sustained-release tablets obtained in Examples 5-7 are shown in Table 26.

[0257] Table 26: Release rate of tranexamic acid compressed coated sustained-release tablets obtained in Examples 5-7

[0258] The results in Tables 25-26 and Figures 3-4 show that the dissolution curve of the preparation of Example 7 is close to zero-order release, and the drug is completely released at 12 hours, with a good drug sustained-release effect.

[0259] FIG5 is a dissolution curve of the tranexamic acid compressed coated sustained-release tablets of Examples 8-10.

[0260] The release results of the tranexamic acid compressed coated sustained-release tablets obtained in Examples 8-10 are shown in Table 27.

[0261] Table 27 Release rate of tranexamic acid compressed coated sustained-release tablets obtained in Examples 8-10

[0262] The results in Table 27 and Figure 5 show that the dissolution curve of the Example 8 preparation is close to zero-order release, with no burst release. At the same time, the drug is completely released after 12 hours, demonstrating a good sustained-release effect. Compared with the Example 7 preparation, the structure and size of the Example 8 preparation are more easily swallowed by the human body.

[0263] FIG6 is a dissolution curve of different batches of tranexamic acid compressed coated sustained-release tablets of Example 12.

[0264] The release results of the tranexamic acid compressed coated sustained-release tablets obtained in Example 12 are shown in Table 28.

[0265] Table 28: Release of tranexamic acid compressed coated sustained-release tablets obtained in Example 12

[0266] FIG7 is a dissolution curve of the tranexamic acid compressed coated sustained-release tablets of Examples 13-15.

[0267] The release results of the tranexamic acid compressed coated sustained-release tablets obtained in Examples 13-15 are shown in Table 29.

[0268] Table 29: Release rate of tranexamic acid compressed coated sustained-release tablets obtained in Examples 13-15

[0269] As shown in Table 29 and Figure 7, the dissolution profiles of Examples 13-15 were all good, approaching zero-order release with no burst release. Furthermore, complete drug release was achieved at 12 hours, demonstrating optimal sustained-release effects. Furthermore, the dissolution profiles of the tranexamic acid compressed-coated sustained-release tablets with a tablet hardness of 125-155 N exhibited minimal differences.

[0270] FIG8 is a dissolution curve of different batches of tranexamic acid compressed coated sustained-release tablets of Example 16.

[0271] The release results of the tranexamic acid compressed coated sustained-release tablets obtained in Example 16 are shown in Table 30:

[0272] Table 30: Release of tranexamic acid compressed coated sustained-release tablets obtained in Example 16

[0273] The results in Table 30 and Figure 8 indicate that the dissolution profiles of the different batches of the preparation in Example 16 were all favorable, approaching zero-order release. Complete drug release was achieved at 12 hours, demonstrating a good sustained-release effect. Furthermore, the differences in the dissolution profiles of the different batches of preparations were minimal, and the release behavior was stable between batches, indicating that the preparation in Example 16 exhibited good batch-to-batch uniformity and good process reproducibility.

[0274] The release results of the tranexamic acid solid compositions obtained in Comparative Examples 1-4 are shown in Table 31.

[0275] Table 31: Release of the tranexamic acid solid composition obtained in Comparative Examples 1-4

[0276] The results in Table 31 show that the in vitro release of tranexamic acid in the tranexamic acid solid composition obtained in Comparative Examples 1-4 is more than 20% at 0.5 h, and the cumulative release reaches more than 90% at about 3 h. The release rate is too fast, which easily produces a higher blood drug concentration, thereby leading to greater gastrointestinal side effects.

[0277] The release results of the tranexamic acid sustained-release tablets obtained in Comparative Examples 5-7 are shown in Table 32.

[0278] Table 32: Release of tranexamic acid sustained-release tablets obtained in Comparative Examples 5-7

[0279] The results in Table 32 show that the in vitro release of tranexamic acid in the tranexamic acid sustained-release tablets obtained in Comparative Examples 5-7 is about 30% at 0.5 h, and the cumulative release reaches more than 90% at about 3 h. The release rate is too fast, which easily produces a high blood drug concentration, thereby leading to greater gastrointestinal side effects. In addition, the dose of tranexamic acid per tablet is small, and it needs to be taken multiple times a day to meet the treatment needs of chloasma.

[0280] Test Example 3: Determination of the in vitro cumulative release of the tranexamic acid preparation of Comparative Example 13

[0281] The in vitro release of Comparative Example 13 was tested using the same method as in Test Example 2. The results are shown in Table 33 and Figure 9.

[0282] As can be seen from the above test results, the core layer medicine in the tranexamic acid dry granulation compressed coating tablets provided by the present disclosure mainly maintains the release in the later stage. The core layer sustained-release material uses a low-viscosity gel skeleton material, or reduces the ratio of the sustained-release material, to achieve the purpose of compensatory release in the later stage. In order to achieve zero-order release, the early stage release of the medicine then seems particularly important. Because tranexamic acid is a water-soluble drug, if wet granulation technology is used, when granulation is dried, the medicine will gradually migrate to the surface along with the evaporated moisture, causing the internal concentration difference on the surface to be large, and then causing the release rate to be too fast in the initial stage of release. The tranexamic acid tablets prepared by the present disclosure are compared to the release results of each comparative example. Through fitting, it is found that the tablet release situation obtained by wet granulation is more inclined to first-order release, while the release mechanism of dry granulation is more inclined to zero-order release.

[0283] In summary, the present invention adopts dry granulation tableting without wet granulation, and uses hydroxypropyl cellulose, hydroxypropyl methylcellulose and the like as sustained-release materials to make skeleton-type sustained-release tablets. Compared with the currently available tranexamic acid sustained-release tablets, the present invention's preparation is an asymmetric double-reservoir type compressed coated tablet, both of which contain tranexamic acid and sustained-release materials. The drug release is controlled by the compressed coating structure and the sustained-release material. By maximizing the drug content of the tablet core layer and the outer coating layer reservoir, increasing the powder ratio of the inner and outer layer reservoirs, and adjusting the type and amount of the sustained-release materials in each reservoir, the skeleton sustained-release of highly water-soluble drugs with high drug loading is achieved, so that the drug is slowly and constantly released into the dissolution medium, achieving a zero-order release of nearly 12 hours, and the 0.5-hour release amount is below 10%, with better sustained-release effect, longer sustained-release time, less prone to sudden release, reduced toxic and side effects, better safety, and higher reliability. The present invention's preparation contains tranexamic acid in both the inner and outer layers, and improves the release rate of each drug in the form of a double reservoir. The dosage and content of tranexamic acid tablets reduce the frequency and number of medications for patients, and the preparation structure is easy for human body to swallow, thereby improving the medication compliance of patients. Compared with the currently available double-reservoir gel skeleton sustained-release tablets, the drug loading of the present invention can reach 58.8%, achieving the sustained-release effect of drugs requiring high drug loading and low tablet weight without reducing the sustained-release effect, greatly reducing the amount of excipients used and reducing production costs. The equipment required for the present invention is a commonly used core-coating tablet press, which compresses and coats the tablet cores by compressing granules and powders. The production process is reasonable, the operation is simple, the cost is low, the environment is friendly, and it is suitable for industrial production. The present invention also provides another use of the tranexamic acid compressed and coated sustained-release tablets, namely, treating chloasma. The uses are diversified and suitable for a wide range of patients.

[0284] The above description is only an embodiment of the present disclosure and does not limit the present disclosure in any form or substance. It should be pointed out that ordinary technicians in this technical field can make several improvements and supplements without departing from the method of the present disclosure, and these improvements and supplements should also be regarded as the scope of protection of the present disclosure. Any equivalent changes, modifications and evolutions made by technicians familiar with this profession without departing from the spirit and scope of the present invention by using the technical content disclosed above are all equivalent embodiments of the present disclosure; at the same time, any equivalent changes, modifications and evolutions made to the above embodiments based on the essential technology of the present disclosure are still within the scope of the technical solution of the present disclosure.

Claims

1. A compressed, coated sustained-release tablet of tranexamic acid, comprising a core layer and an outer coating layer, wherein the core layer comprises the following raw materials in percentage by weight: 70%-85% tranexamic acid, 17%-19% sustained-release material, 0.5%-2% binder, 0.5%-8% filler, and 0.5%-2.5% lubricant; The outer coating layer comprises the following raw materials in percentage by weight: 52%-54% tranexamic acid, 20%-30% sustained-release material, 4%-6% binder, 9%-21% filler, and 1%-2.5% lubricant; wherein, The raw materials for tranexamic acid compressed and coated sustained-release tablets do not contain water; The sustained-release material accounts for 19%-28% of the total mass percentage of the tranexamic acid compressed coated sustained-release tablets. Preferably, the sustained-release material is selected from cellulose derivatives, and preferably the sustained-release material is selected from methylcellulose, sodium carboxymethylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxyethyl cellulose or a mixture thereof; preferably, the sustained-release material is selected from hydroxypropyl cellulose, hydroxypropyl methylcellulose or a mixture thereof, preferably, the sustained-release material of the core layer is selected from hydroxypropyl cellulose-L, hydroxypropyl cellulose-M or a mixture thereof, and preferably, the sustained-release material of the outer coating layer is selected from hydroxypropyl cellulose-M, hydroxypropyl methylcellulose K4M, hydroxypropyl methylcellulose K15M or a mixture thereof.

2. The tranexamic acid compressed coated sustained-release tablet of claim 1, wherein the mass of the core layer in the tranexamic acid compressed coated sustained-release tablet accounts for 23%-30% of the total tablet weight, and the mass of the outer coating layer accounts for 70%-77% of the total tablet weight.

3. tranexamic acid compressed coating sustained-release tablets as claimed in claim 1, wherein the drug loading of the tranexamic acid compressed coating sustained-release tablets is not less than 58.8%, the mass of each tranexamic acid compressed coating sustained-release tablet is not higher than 850mg, and the total dose of tranexamic acid in each tranexamic acid compressed coating sustained-release tablet is not less than 500mg.

4. The tranexamic acid compressed coated sustained-release tablet of claim 1, wherein the mass of tranexamic acid in the core layer of the tranexamic acid compressed coated sustained-release tablet accounts for 32%-36% of the total amount of tranexamic acid, and the mass of tranexamic acid in the outer coating layer accounts for 64%-68% of the total amount of tranexamic acid.

5. The compressed and coated sustained-release tablet of tranexamic acid according to claim 1, wherein the content of tranexamic acid in the core layer is 72-80%, more preferably 72% or 80%.

6. tranexamic acid compressed coating sustained-release tablets as claimed in claim 1, wherein the hardness of the core layer is 20N-70N, and the hardness of the tranexamic acid compressed coating sustained-release tablets is 30N-155N.

7. The tranexamic acid compressed coated sustained-release tablet according to claim 1, wherein the minor diameter of the core layer is not greater than 10 mm and the thickness is not greater than 5 mm; the minor diameter of the outer coating layer is not greater than 13 mm and the thickness is not greater than 9 mm.

8. The tranexamic acid compressed coated sustained-release tablets according to any one of claims 1 to 7, wherein the binder accounts for 3% to 5% of the total mass percentage of the tranexamic acid compressed coated sustained-release tablets, and preferably the binder is selected from povidone K30, povidone VA or a mixture thereof.

9. The tranexamic acid compressed coated sustained-release tablets according to any one of claims 1 to 8, wherein the filler accounts for 8% to 17% of the total mass percentage of the tranexamic acid compressed coated sustained-release tablets, and preferably the filler is selected from lactose, microcrystalline cellulose, and mixtures thereof; and the lubricant accounts for 0.5% to 2.5% of the total mass percentage of the tranexamic acid compressed coated sustained-release tablets, and preferably the lubricant is selected from micropowdered silica gel, magnesium stearate, stearic acid, and mixtures thereof.

10. A method for preparing the compressed, coated sustained-release tablets of tranexamic acid according to any one of claims 1 to 9, comprising: Tranexamic acid granules were prepared using a dry granulation method; The tranexamic acid particles of the tablet core layer are mixed with other raw materials and compressed to obtain the tablet core layer; mixing the tranexamic acid particles of the outer coating layer with other raw materials to obtain an outer coating layer mixed powder; Filling the first portion of the outer coating layer mixed powder into a mold, placing the core layer in the middle of the first portion of the outer coating layer mixed powder, filling the second portion of the outer coating layer mixed powder, and performing tableting to obtain the tranexamic acid compressed coated sustained-release tablets; The tranexamic acid granules do not contain any raw materials other than tranexamic acid; The core layer is placed in the middle of the first portion of the outer coating layer mixed powder; preferably, the distance between the core layer and the outer coating layer mixed powder is less than 0.5 mm in the short diameter direction and less than 1 mm in the long diameter direction; Preferably, the mass ratio of the first portion of the outer coating layer mixed powder to the second portion of the outer coating layer mixed powder is 1:

1.

11. Use of the tranexamic acid compressed coated sustained-release tablets according to any one of claims 1 to 9 or the tranexamic acid compressed coated sustained-release tablets prepared according to the preparation method according to claim 10 in the preparation of a medicament for treating bleeding and chloasma caused by hyperfibrinolysis.

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