Tranexamic acid oral dissolving system for improving bioavailability

Abstract

The invention relates to a tranexamic acid oral dissolving system for improving bioavailability, which relates to the technical field of medicines and comprises a tranexamic acid oral dissolving film and a tranexamic acid oral dissolving tablet. The design of the oral dissolving tablet and the oral dissolving film fully considers the requirements of different patient groups and the characteristics of medicine absorption, the characteristic that the oral dissolving tablet can be taken without water improves the compliance of patients, the problem that traditional tablets are difficult to swallow is solved, and the oral dissolving tablet and the oral dissolving film have very good application prospects for patients who often travel or need to take medicine under the anhydrous condition. An orally disintegrating system has good convenience; the tranexamic acid oral dissolution system can be rapidly disintegrated in the oral cavity, so that the medicine is rapidly dispersed, the contact area with the oral mucosa is increased, the medicine is promoted to be absorbed through the oral mucosa tissue and other pregastric regions, the bioavailability is improved, and the medicine absorption speed is increased.

Description

Technical Field

[0001] The present application relates to the field of medical technology, and in particular to a tranexamic acid oral dissolution system for improving bioavailability. Background Art

[0002] Tranexamic acid is a BCS class I molecule with high solubility and permeability in water. However, in women aged 18-49 years, tranexamic acid The absolute bioavailability of The label shows that the absorption rate of tranexamic acid after oral administration is 30% to 50% of the ingested dose, and the bioavailability is not affected by food intake. This means that due to the first-pass effect in the stomach, nearly 50-55% of the drug is metabolized and cannot play a therapeutic role.

[0003] Orally disintegrating systems, such as tablets or films, are becoming increasingly popular due to their high bioavailability, rapid pregastric absorption, and high patient compliance. One of the key factors affecting compliance is that patients can ingest orally disintegrating tablets without the need for water. For many patients, especially geriatric patients, pediatric patients, and those with dysphagia, orally disintegrating systems are more convenient than swallowing tablets. Orally disintegrating tablets are extremely valuable for patients who travel frequently or need to take medications when water is not always available. Once the drug is absorbed through the oral mucosal tissue and other pregastric areas, the bioavailability of the drug will increase, the absorption rate of the drug will also be accelerated, and the drug absorbed in the mouth can enter the blood faster.

[0004] Therefore, simply by changing the formulation ingredients, the bioavailability can be greatly improved, patient compliance can be enhanced, patients of all ages can take it, and it is convenient to take when traveling.

[0005] CN106265581A solves the problem of low solubility of tranexamic acid tablets prepared by wet process, which comprises dissolving sodium dodecyl sulfate into a binder slurry, spray granulating to obtain micro-powder tranexamic acid, and then mixing the micro-powder with magnesium stearate tablets. It also solves the problem of large weight difference of tablets and excessive brittleness of tablets.

[0006] CN106265581B solves the problem of low solubility of tranexamic acid tablets prepared by wet granulation by dissolving sodium dodecyl sulfate into a binder slurry, spraying granulation to obtain tranexamic acid micropowder, and then mixing the micropowder with magnesium stearate tablets, while also improving the problems of large tablet weight difference and excessive tablet brittleness.

[0007] CN110721169A discloses a method for preparing tranexamic acid tablets, which specifically relates to the technical field of drug production. The method effectively improves the stability of tranexamic acid drugs, increases the dissolution rate of the drugs, achieves hemostasis and treatment effects more quickly, and enhances the efficacy.

[0008] CN117180212A discloses a stable tranexamic acid tablet solid composition and a simple preparation method and use thereof.

[0009] However, the existing technology does not solve the main problem of low bioavailability of tranexamic acid, because a large amount of the drug is metabolized due to the first-pass effect and cannot play a therapeutic role. Therefore, it is necessary to improve the bioavailability of tranexamic acid through oral route and improve patient compliance. Summary of the invention

[0010] In order to improve the bioavailability and patient compliance of tranexamic acid, the present application provides a tranexamic acid oral dissolution system with improved bioavailability.

[0011] The present application provides a tranexamic acid oral dissolving system for improving bioavailability, which adopts the following technical scheme: a tranexamic acid oral dissolving system for improving bioavailability, comprising a tranexamic acid oral dissolving film and a tranexamic acid oral dissolving tablet.

[0012] Preferably, the raw materials for preparing the tranexamic acid orally dissolving film include tranexamic acid, xylitol, polyethylene glycol, hydroxypropyl methylcellulose, aspartame, sucralose, flavor, propylene glycol and water.

[0013] Preferably, the tranexamic acid oral dissolving film is prepared by the following steps: Dissolve xylitol and polyethylene glycol in water under stirring, add aspartame, sucralose and flavors and mix thoroughly, then add tranexamic acid and mix evenly to obtain a main phase; disperse hydroxypropyl methylcellulose in propylene glycol to obtain a dispersion; add the dispersion to the main phase, mix the two phases under stirring to hydrate them, remove entrained air, apply the mixture on a cast film, cut the film after drying, and obtain a tranexamic acid orally dissolving film.

[0014] Preferably, the hydroxypropyl methylcellulose includes hydroxypropyl methylcellulose having a dynamic viscosity of 6 centipoise and hydroxypropyl methylcellulose having a dynamic viscosity of 15 centipoise.

[0015] Preferably, the raw materials for preparing the tranexamic acid orally dissolving tablets include tranexamic acid, mannitol, xylitol, carboxymethyl cellulose, crystalline cellulose, cross-linked polyvidone, sucralose, aspartame, colloidal silicon dioxide and magnesium stearate.

[0016] Preferably, the tranexamic acid orally dissolving tablets are prepared by the following steps: Add tranexamic acid, mannitol, xylitol, carboxymethyl cellulose and crystalline cellulose to a fluidized bed granulator, spray water into the material, add cross-linked polyvinylpyrrolidone to the material, spray water into the material to obtain granules, dry the obtained granules to obtain dried granules, add sucralose, aspartame and colloidal silicon dioxide to the dried granules and mix them evenly, add magnesium stearate and mix them evenly, and compress them into tablets to obtain tranexamic acid orally dissolving tablets.

[0017] The design of orally disintegrating tablets and orally disintegrating films fully considers the needs of different patient groups and the characteristics of drug absorption. For elderly patients, pediatric patients and patients with dysphagia, the feature of taking the medicine without water greatly improves patient compliance and solves the problem of difficulty in swallowing traditional tablets. For patients who travel frequently or need to take medicine under water-free conditions, the orally disintegrating system has good convenience; orally disintegrating tablets can disintegrate rapidly in the mouth, allowing the drug to disperse quickly, increasing the contact area with the oral mucosa, and promoting the absorption of the drug through the oral mucosal tissue and other pregastric areas, thereby improving bioavailability and accelerating the absorption rate of the drug, allowing the drug to enter the blood faster and reducing the metabolic loss of the drug in the stomach; the orally disintegrating film, with its unique structure and composition, can better fit the oral mucosa, prolong the residence time of the drug on the mucosal surface, and further improve the absorption efficiency of the drug.

[0018] Xylitol can provide a certain sweetness to the tranexamic acid orally dissolving film, improve the taste, and can also work synergistically with polyethylene glycol to enhance the flexibility and stability of the film, so that the tranexamic acid orally dissolving film can maintain a good physical state in the oral environment; aspartame and sucralose further optimize the taste, and the addition of spices gives the film a pleasant smell, improving patient acceptance and compliance; hydroxypropyl methylcellulose can form a structure with viscosity and strength, allowing the film to better adhere to the oral mucosa, increasing the contact time and area between the drug and the mucosa, promoting the absorption of tranexamic acid, and thus improving the bioavailability of the drug.

[0019] Mannitol has good solubility and water absorption, can dissolve quickly in the mouth, provide a good dispersion environment for drugs, and help to improve the dissolution rate of tranexamic acid orally dissolving tablets; xylitol can not only improve the taste, but also interact with other ingredients to enhance the stability and compressibility of tablets; carboxymethyl cellulose and crystalline cellulose, as fillers and binders, can better combine drug particles together, and can also promote disintegration in the mouth and promote drug release; cross-linked polyvinylpyrrolidone has strong water absorption and swelling properties and can be used as a disintegrant. After contacting the saliva in the mouth, it quickly absorbs water and swells, making the tablets quickly disintegrate. The invention discloses a novel orally disintegrating orally soluble tranexamic acid tablet, which can disintegrate rapidly and increase the contact area between the drug and the oral mucosa, thereby improving the bioavailability of the drug; sucralose and aspartame as sweeteners can further optimize the taste and improve patient compliance; colloidal silicon dioxide can improve the fluidity of the material and make the material mixed more evenly; magnesium stearate is used as a lubricant to reduce the friction during tableting and ensure the smooth tableting, and also helps to improve the surface finish and quality of the tablets; the prepared orally disintegrating tranexamic acid tablets can disintegrate and dissolve rapidly in the oral cavity, so that the drug is quickly released and absorbed, and the bioavailability of the drug is effectively improved.

[0020] In a preferred embodiment, the mannitol and xylitol are in a eutectic state, and the mannitol and xylitol eutectic is prepared by the following steps: Mannitol and xylitol are mixed and dispersed in an ethanol aqueous solution, and the mixture is stirred in a water bath to obtain a eutectic suspension, and the eutectic suspension is filtered under reduced pressure to obtain a solid product, and the solid product is dried to obtain mannitol and xylitol eutectics.

[0021] Mannitol and xylitol cocrystals have a special molecular arrangement and lattice energy, which can provide more dissolution sites and channels for tranexamic acid. In the aqueous environment of the oral cavity, water molecules can more easily penetrate into the lattice gaps of the cocrystal and interact with tranexamic acid molecules, thereby promoting the dissociation and dissolution of tranexamic acid and increasing its solubility in the oral cavity, which in turn facilitates faster absorption of the drug into the body and improves its bioavailability.

[0022] In a preferred embodiment, the carboxymethyl cellulose and crystalline cellulose are cross-linked and modified by genipin.

[0023] Genipin can change the molecular chain structure and spatial arrangement of carboxymethyl cellulose and crystalline cellulose, forming a network with a certain pore structure. During the oral dissolution process, this network structure can better adsorb and retain saliva, providing a more favorable environment for the dissolution of tranexamic acid. At the same time, it can also enhance the mechanical properties of the tablets and prevent them from breaking during storage.

[0024] In a preferred embodiment, the cross-linked polyvinylpyrrolidone is modified to obtain a modified cross-linked polyvinylpyrrolidone, and the modified cross-linked polyvinylpyrrolidone is prepared by the following steps: The poloxamer is dissolved in ethanol, and the solution is stirred until the solution is clear and transparent to obtain a poloxamer solution; the cross-linked polyvinylpyrrolidone is dispersed in water, and the cross-linked polyvinylpyrrolidone dispersion is obtained after stirring and dispersion; the poloxamer solution is added to the cross-linked polyvinylpyrrolidone dispersion under stirring, and after the addition is completed, the mixture is stirred in a water bath for reaction to obtain a mixed solution, the mixed solution is centrifuged, the precipitate is collected, and the mixture is washed with water until the supernatant is clear, the washed precipitate is dispersed in water, and ultrasonic treatment is performed to obtain a nano-dispersion liquid after ultrasonic treatment, and the nano-dispersion liquid is homogenized to obtain a nano-particle suspension, the precipitate is collected after centrifugation, and the modified cross-linked polyvinylpyrrolidone is obtained after freeze-drying.

[0025] Poloxamer has good solubility and surface activity. Poloxamer molecules can interact with the molecular chains of cross-linked polyvinylpyrrolidone to change the surface properties and structure of cross-linked polyvinylpyrrolidone. The hydrophilicity of poloxamer helps to guide water into the tablet faster, shorten the disintegration time of orally dissolving tablets, and further promote the release and absorption of the drug, thereby improving bioavailability; nano-treatment helps to increase the specific surface area of ​​cross-linked polyvinylpyrrolidone, improve its compatibility with other ingredients and the stability of the tablet; this nano-structure also increases the contact area between the tablet and the oral mucosa, which is beneficial to the absorption of the drug in the mouth, thereby improving the bioavailability of tranexamic acid.

[0026] In summary, the present application includes at least one of the following beneficial technical effects: 1. The design of orally disintegrating tablets and orally disintegrating films fully considers the needs of different patient groups and the characteristics of drug absorption. For elderly patients, pediatric patients and patients with dysphagia, the feature of taking the medicine without water greatly improves patient compliance and solves the problem of difficulty in swallowing traditional tablets. For patients who travel frequently or need to take medicine under water-free conditions, the orally disintegrating system has good convenience; the orally disintegrating tablets can disintegrate rapidly in the mouth, allowing the drug to disperse quickly, increasing the contact area with the oral mucosa, and promoting the absorption of the drug through the oral mucosal tissue and other pregastric areas, thereby improving bioavailability and accelerating the absorption rate of the drug, allowing the drug to enter the blood faster and reducing the metabolic loss of the drug in the stomach; the orally disintegrating film, with its unique structure and composition, can better fit the oral mucosa, prolong the residence time of the drug on the mucosal surface, and further improve the absorption efficiency of the drug.

[0027] 2. Mannitol and xylitol cocrystals have special molecular arrangements and lattice energy, which can provide more dissolution sites and channels for tranexamic acid. In the aqueous environment of the oral cavity, water molecules can more easily penetrate into the lattice gaps of the cocrystals and interact with tranexamic acid molecules, thereby promoting the dissociation and dissolution of tranexamic acid and increasing its solubility in the oral cavity, which in turn facilitates faster absorption of the drug into the body and improves its bioavailability.

[0028] 3. Genipin can change the molecular chain structure and spatial arrangement of carboxymethyl cellulose and crystalline cellulose, so that they form a network with a certain pore structure. During the oral dissolution process, this network structure can better adsorb and retain saliva, providing a more favorable environment for the dissolution of tranexamic acid. At the same time, it can also enhance the mechanical properties of the tablets and prevent them from breaking during storage.

[0029] 4. Poloxamer has good solubility and surface activity. Poloxamer molecules can interact with the molecular chains of cross-linked polyvinylpyrrolidone, changing the surface properties and structure of cross-linked polyvinylpyrrolidone. The hydrophilicity of poloxamer helps to guide water into the tablet faster, shorten the disintegration time of orally dissolving tablets, and further promote the release and absorption of drugs, thereby improving bioavailability; nano-treatment helps to increase the specific surface area of ​​cross-linked polyvinylpyrrolidone, improve compatibility with other ingredients and tablet stability; this nanostructure also increases the contact area between the tablet and the oral mucosa, which is beneficial to the absorption of the drug in the oral cavity, thereby improving the bioavailability of tranexamic acid. DETAILED DESCRIPTION

[0030] The present application example discloses a tranexamic acid oral dissolution system for improving bioavailability. The raw materials used in the present application can be obtained from commercially available raw materials unless otherwise specified. The present application is further described in detail in conjunction with the examples below: Ingredients: Tranexamic acid (CAS No.: 1197-18-8), xylitol (CAS No.: 87-99-0), PEG 6000 (CAS No.: 25322-68-3), Hydroxypropyl Methylcellulose (CAS No.: 9004-64-2), Aspartame (CAS No.: 22839-47-0), Sucralose (CAS No.: 56038-13-2), Mannitol (CAS No.: 643-01-6), Carboxymethyl Cellulose (CAS No.: 9000-11-7), Crystalline Cellulose (CAS No.: 9004-34-6), Cross-linked Polyvinylpyrrolidone (CAS No.: 25249-54-1), Colloidal Silicon Dioxide (CAS No.: 10279-57-9), Magnesium Stearate (CAS No.: 557-04-0), Genipin (CAS No.: 6902-77-8), Poloxamer (CAS No.: 9003-11-6).

[0031] Example 1 Preparation of tranexamic acid oral dissolving film Xylitol and polyethylene glycol 6000 (PEG 6000) were dissolved in water under stirring, aspartame, sucralose and flavors were added and fully mixed, and then tranexamic acid was added and mixed evenly to obtain a main phase; hydroxypropyl methylcellulose 6 centipoise (HPMC 6 cps) and hydroxypropyl methylcellulose 15 centipoise (HPMC 15 cps) were dispersed in propylene glycol to obtain a dispersion; the dispersion was added to the main phase, the two phases were mixed under stirring to hydrate them, and after removing the entrained air, the mixture was coated on a cast film with a thickness of 600 μm, and the film was cut after drying to obtain a tranexamic acid oral dissolving film. The specific component amounts are shown in Table 1.

[0032] Table 1 Composition and dosage of tranexamic acid oral dissolving film Example 2 Preparation of tranexamic acid orally dissolving tablets Add tranexamic acid, mannitol, xylitol, carboxymethyl cellulose and crystalline cellulose to a fluidized bed granulator, spray 260-300 g of water into the material at a speed of 20-30 g / min, add cross-linked polyvinylpyrrolidone into the material, spray about 280-320 g of water into the material at a speed of 10-20 g / min per minute to obtain granules, dry the obtained granules at a temperature of 50-55° C. to a water content of less than 2% to obtain dried granules, add sucralose, aspartame and colloidal silicon dioxide to the dried granules and mix them evenly, add magnesium stearate and mix them evenly, and use a tablet press to obtain tranexamic acid orally dissolving tablets. The specific amounts of the ingredients are shown in Table 2.

[0033] Table 2 Composition and dosage of tranexamic acid orally dissolving tablets Serial number Ingredient name Dosage (mg / tablet) 1 Tranexamic acid 500.00 2 Mannitol 280.00 3 Xylitol 100.00 4 Carboxymethyl cellulose 71.00 5 Crystalline cellulose 100.00 6 Crospovidone 40.00 7 Sucralose 4.50 8 Aspartame 2.00 9 Colloidal Silica 2.00 10 Magnesium Stearate 0.50 Example 3 Example 3 is based on Example 2. The only difference between Example 3 and Example 2 is that in Example 3, mannitol and xylitol are in a eutectic state.

[0034] Preparation of mannitol and xylitol cocrystals Mannitol and xylitol in a mass ratio of 2.8:1 were dispersed in an ethanol aqueous solution with a volume fraction of 50% so that the mass ratio of the solute to the solvent was 1:10, and the mixture was stirred at 200 rpm at 30°C for 3 hours to obtain a eutectic suspension, and the eutectic suspension was filtered under reduced pressure to obtain a solid product, and the solid product was placed in an oven and dried at 40°C to obtain mannitol and xylitol eutectics.

[0035] Add tranexamic acid, mannitol and xylitol eutectics, carboxymethyl cellulose and crystalline cellulose into a fluidized bed granulator, spray 260-300 g of water into the material at a speed of 20-30 g / min, add cross-linked polyvinylpyrrolidone into the material, spray about 280-320 g of water into the material at a speed of 10-20 g / min per minute to obtain granules, dry the obtained granules at a temperature of 50-55° C. to a water content of less than 2% to obtain dried granules, add sucralose, aspartame and colloidal silicon dioxide into the dried granules and mix them evenly, add magnesium stearate and mix them evenly, and use a tablet press to compress the granules to obtain tranexamic acid orally dissolving tablets.

[0036] Example 4 Example 4 is based on Example 3. The only difference between Example 4 and Example 3 is that in Example 4, carboxymethyl cellulose and crystalline cellulose are cross-linked and modified by genipin.

[0037] Preparation of modified carboxymethyl cellulose The carboxymethyl cellulose was dissolved in an ethanol aqueous solution with a volume fraction of 50% to obtain a carboxymethyl cellulose solution with a mass fraction of 5%. The pH of the carboxymethyl cellulose solution was adjusted to 8 using a phosphate buffer. Genipin was added to the carboxymethyl cellulose solution after the pH adjustment at 50°C. The mass ratio of carboxymethyl cellulose to genipin was 15:1. The reaction was stirred at a speed of 400 rpm for 4 hours. The solvent was removed by rotary evaporation and the mixture was dried in a vacuum drying oven at 60°C to constant weight to obtain modified carboxymethyl cellulose.

[0038] Preparation of modified crystalline cellulose: The crystalline cellulose was crushed into a particle size of 100 μm, and the crushed crystalline cellulose was dispersed in an ethanol aqueous solution with a volume fraction of 50%, and stirred at a speed of 500 rpm for 30 minutes to obtain a suspension. The pH of the suspension was adjusted to 8 using a phosphate buffer solution, and genipin was added to the suspension after the pH adjustment at 60°C. The mass ratio of microcrystalline cellulose to genipin was 20:1. The reaction was stirred at a speed of 500 rpm for 5 hours, and the solid product was filtered to obtain a solid product. After washing with purified water, it was dried in a vacuum drying oven at 70°C to constant weight to obtain modified crystalline cellulose.

[0039] Add tranexamic acid, mannitol, xylitol, modified carboxymethyl cellulose and modified crystalline cellulose into a fluidized bed granulator, spray 260-300 g of water into the material at a speed of 20-30 g / min, add cross-linked polyvinylpyrrolidone into the material, spray about 280-320 g of water into the material at a speed of 10-20 g / min per minute to obtain granules, dry the obtained granules at a temperature of 50-55° C. until the water content is less than 2% to obtain dried granules, add sucralose, aspartame and colloidal silicon dioxide into the dried granules and mix them evenly, add magnesium stearate and mix them evenly, and use a tablet press to compress the granules to obtain tranexamic acid orally dissolving tablets.

[0040] Example 5 Example 5 is based on Example 3, and the only difference between Example 5 and Example 3 is that in Example 5, the cross-linked polyvinylpyrrolidone is modified to obtain modified cross-linked polyvinylpyrrolidone.

[0041] Preparation of modified cross-linked polyvinylpyrrolidone The poloxamer is dissolved in anhydrous ethanol, and the mixture is stirred at a speed of 400 rpm until the solution is clear and transparent to obtain a poloxamer solution, wherein the mass percentage of the poloxamer solution is 1%; the cross-linked polyvinylpyrrolidone is dispersed in purified water, and the mixture is stirred at a speed of 500 rpm for 4 hours to obtain a cross-linked polyvinylpyrrolidone dispersion liquid, wherein the mass percentage of the cross-linked polyvinylpyrrolidone dispersion liquid is 2%; the poloxamer solution is added to the cross-linked polyvinylpyrrolidone dispersion liquid at a stirring speed of 400 rpm, and the addition is completed within 1 hour. After the addition is completed, the mixture is stirred at a speed of 500 rpm for 5 hours at 40° C. to obtain a mixed solution, the mixed solution is centrifuged, the precipitate is collected, and the mixture is washed with ultrapure water until the supernatant is clear. The washed precipitate is dispersed in ultrapure water, and an ultrasonic cell crusher is used for ultrasonic treatment. After ultrasonic treatment for 30 minutes, a nano-dispersion liquid is obtained, and the nano-dispersion liquid is subjected to high-pressure homogenization treatment to obtain a nano-particle suspension liquid. The precipitate is collected after centrifugation, and freeze-dried at -40° C. to obtain a modified cross-linked polyvinylpyrrolidone.

[0042] Add tranexamic acid, mannitol, xylitol, carboxymethyl cellulose and crystalline cellulose into a fluidized bed granulator, spray 260-300 g of water into the material at a speed of 20-30 g / min, add modified cross-linked polyvinylpyrrolidone into the material, spray about 280-320 g of water into the material at a speed of 10-20 g / min per minute to obtain granules, dry the obtained granules at a temperature of 50-55° C. until the water content is less than 2% to obtain dried granules, add sucralose, aspartame and colloidal silicon dioxide into the dried granules and mix them evenly, add magnesium stearate and mix them evenly, and use a tablet press to compress the granules to obtain tranexamic acid orally dissolving tablets.

[0043] Performance testing (1) Dissolution test: The dissolution test was performed on the samples prepared in the example and randomly selected commercially available tranexamic acid tablets by the paddle method in simulated oral saliva at 37° C. using a dissolution tester. Each sample was tested three times, and the average value was taken after measurement. The results are recorded in Table 3.

[0044] (2) Disintegration performance test: The samples prepared in the examples and randomly selected commercially available tranexamic acid tablets were placed in a disintegrator and their disintegration time was tested in a simulated oral saliva at 37° C. Each sample was tested three times, and the average value was taken after measurement. The results are recorded in Table 3.

[0045] Table 3 Dissolution and disintegration test results As shown in Table 3, the tranexamic acid orally dissolving tablets and tranexamic acid orally dissolving films of Examples 1-5 have high solubility and good disintegration properties, and can be rapidly absorbed through the oral mucosa and pregastric area, thereby improving bioavailability.

[0046] As can be seen from Table 3, the only difference between Example 3 and Example 2 is that in Example 3, mannitol and xylitol are in a eutectic state, and compared with Example 2, Example 3 has increased solubility and disintegration rate; this is because mannitol and xylitol in the eutectic state can promote the dissolution of tranexamic acid, thereby promoting its absorption, and improving solubility and disintegration rate.

[0047] As can be seen from Table 3, the only difference between Example 4 and Example 2 is that in Example 4, carboxymethyl cellulose and crystalline cellulose are cross-linked and modified by genipin. Compared with Example 2, Example 4 has an increased solubility and a decreased disintegration rate. This is because the increase in the degree of cross-linking will affect the disintegration rate, but cross-linking can promote the formation of a network structure, better retain and adsorb saliva, so that tranexamic acid can be better dissolved and thus absorbed and utilized.

[0048] As can be seen from Table 3, the only difference between Example 5 and Example 2 is that the cross-linked polyvinylpyrrolidone in Example 5 is modified. Compared with Example 2, the disintegration rate and solubility of Example 5 are increased. This is because the modified cross-linked polyvinylpyrrolidone has better hydrophilicity and high specific surface area, which can allow water to quickly enter the interior of the tablet, shorten the drug disintegration time, and promote the absorption and utilization of tranexamic acid.

[0049] The commercially available tranexamic acid tablets have low dissolution within 20 minutes and slow disintegration rate. Compared with the commercially available tranexamic acid tablets, the films and tablets prepared in Examples 1-5 have good dissolution and disintegration rate, which is beneficial for the absorption of tranexamic acid in the oral mucosa and the pregastric area, thereby achieving the effect of improving its bioavailability.

[0050] Stability studies: The developed examples were subjected to stability studies under initial and accelerated stability storage conditions, particularly the degradation of tranexamic acid. The samples were analyzed using pharmacopoeia and effective impurity analysis methods. The results showed that the developed examples were stable for 6 months under accelerated storage conditions and met the impurity standards of the British Pharmacopoeia and the United States Pharmacopoeia, and the test results are recorded in Table 4.

[0051] Table 4 Stability test results of tranexamic acid oral dissolution system This specific embodiment is only an explanation of the present application, and it is not a limitation of the present application. Through the above description, relevant staff can make various changes and modifications without deviating from the technical idea of ​​the present application. The technical scope of the present application is not limited to the content in the specification, and its technical scope must be determined according to the scope of the claims.

Claims

1. A tranexamic acid oral dissolution system for improving bioavailability, characterized in that: Includes tranexamic acid orodissolving film and tranexamic acid orodissolving tablets.

2. A tranexamic acid oral dissolving system for improving bioavailability according to claim 1, characterized in that: The raw materials for preparing the tranexamic acid oral dissolving film include tranexamic acid, xylitol, polyethylene glycol, hydroxypropyl methylcellulose, aspartame, sucralose, essence, propylene glycol and water.

3. A tranexamic acid oral dissolving system for improving bioavailability according to claim 2, characterized in that: The tranexamic acid oral dissolving film is prepared by the following steps: Dissolve xylitol and polyethylene glycol in water under stirring, add aspartame, sucralose and flavors and mix thoroughly, then add tranexamic acid and mix evenly to obtain a main phase; disperse hydroxypropyl methylcellulose in propylene glycol to obtain a dispersion; add the dispersion to the main phase, mix the two phases under stirring to hydrate them, remove entrained air, apply the mixture on a cast film, cut the film after drying, and obtain a tranexamic acid orally dissolving film.

4. A tranexamic acid oral dissolving system for improving bioavailability according to claim 3, characterized in that: The molecular weight of the polyethylene glycol is 6000.

5. A tranexamic acid oral dissolving system for improving bioavailability according to claim 3, characterized in that: The hydroxypropyl methylcellulose includes hydroxypropyl methylcellulose with a dynamic viscosity of 6 centipoise and hydroxypropyl methylcellulose with a dynamic viscosity of 15 centipoise.

6. A tranexamic acid oral dissolution system for improving bioavailability according to claim 1, characterized in that: The raw materials for preparing the tranexamic acid orally dissolving tablets include tranexamic acid, mannitol, xylitol, carboxymethyl cellulose, crystalline cellulose, cross-linked polyvidone, sucralose, aspartame, colloidal silicon dioxide and magnesium stearate.

7. A tranexamic acid oral dissolving system for improving bioavailability according to claim 6, characterized in that: The tranexamic acid orally dissolving tablets are prepared by the following steps: Add tranexamic acid, mannitol, xylitol, carboxymethyl cellulose and crystalline cellulose to a fluidized bed granulator, spray water into the material, add cross-linked polyvinylpyrrolidone to the material, spray water into the material to obtain granules, dry the obtained granules to obtain dried granules, add sucralose, aspartame and colloidal silicon dioxide to the dried granules and mix them evenly, add magnesium stearate and mix them evenly, and compress them into tablets to obtain tranexamic acid orally dissolving tablets.

8. A tranexamic acid oral dissolving system for improving bioavailability according to claim 7, characterized in that: The mannitol and xylitol are in a eutectic state, and the mannitol and xylitol eutectic is prepared by the following steps: Mannitol and xylitol are mixed and dispersed in an ethanol aqueous solution, and stirred and mixed in a water bath to obtain a eutectic suspension. The eutectic suspension is filtered under reduced pressure to obtain a solid product, and the solid product is dried to obtain mannitol and xylitol eutectics.

9. A tranexamic acid oral dissolving system for improving bioavailability according to claim 7, characterized in that: The carboxymethyl cellulose and crystalline cellulose are cross-linked and modified by genipin.

10. The tranexamic acid oral dissolving system for improving bioavailability according to claim 7, characterized in that: The cross-linked polyvinylpyrrolidone is modified to obtain a modified cross-linked polyvinylpyrrolidone, and the modified cross-linked polyvinylpyrrolidone is prepared by the following steps: Dissolving poloxamer in ethanol and stirring until the solution is clear and transparent to obtain a poloxamer solution; dispersing cross-linked polyvinylpyrrolidone in water and stirring to obtain a cross-linked polyvinylpyrrolidone dispersion; The poloxamer solution is added to the cross-linked polyvinylpyrrolidone dispersion under stirring, and after the addition is completed, the mixture is stirred in a water bath to react to obtain a mixed solution, the mixed solution is centrifuged, the precipitate is collected, and the mixture is washed with water until the supernatant is clear, the washed precipitate is dispersed in water, and ultrasonic treatment is performed to obtain a nano-dispersion liquid after ultrasonic treatment, the nano-dispersion liquid is homogenized to obtain a nano-particle suspension, the precipitate is collected after centrifugation, and the modified cross-linked polyvinylpyrrolidone is obtained after freeze-drying.

Images