Rivaroxaban orally disintegrating tablet and preparation method thereof

Abstract

The invention belongs to the field of pharmaceutical preparations, and particularly relates to a rivaroxaban orally disintegrating tablet and a preparation method thereof. The orally disintegrating tablet provided by the invention is rapidly disintegrated when being placed in the mouth or water, has enough hardness and excellent storage stability in general production, transportation and use, and is simple in preparation method and suitable for modern industrial mass production.

Description

Technical Field

[0001] The invention belongs to the field of pharmaceutical preparations, and particularly relates to a rivaroxaban orally disintegrating tablet and a preparation method thereof. Background Art

[0002] The incidence of venous thromboembolism in my country has increased year by year, from 0.28‰ in 2004 to 0.48‰ in 2016. It is worth noting that the incidence of venous thromboembolism increases exponentially with age. The annual incidence rate of people aged 50 is less than 1‰, while the annual incidence rate of people over 80 is as high as 6‰ to 8‰. In addition, the incidence rate of venous thrombosis in the elderly over 75 years old is 7 to 10 times that of adults under 50 years old. my country has entered an aging society with a large elderly population, including hospitalized elderly patients and ordinary elderly groups at home and in nursing homes. They are all high-risk groups for venous thromboembolism. Therefore, it needs to attract widespread attention and attention from the whole society.

[0003] Rivaroxaban is a new oral anticoagulant that is widely used in the following situations:

[0004] 1. Prevention and treatment of venous thromboembolism (VTE): such as deep vein thrombosis (DVT) and pulmonary embolism (PE).

[0005] 2. Prevent stroke and systemic embolism in patients with atrial fibrillation: Patients with atrial fibrillation are prone to blood clots, increasing the risk of stroke.

[0006] 3. Prevent thrombosis after major surgery: such as hip or knee replacement surgery, to help reduce the risk of postoperative thrombosis.

[0007] The chemical name of rivaroxaban is 5-chloro-nitrogen-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]-1,3-oxazolidin-5-yl}methyl)-2-thiophene-carboxamide, and the chemical structure is as follows:

[0008]

[0009] The molecular weight is 435.88, and it belongs to the low solubility, high permeability compound (Class II) in the biopharmaceutical classification system. Its solubility in aqueous media is limited and is not affected by pH (5-7 mg / L; pH 1-9). It exhibits moderate lipophilicity when the logP value (octanol / water partition) coefficient is 1.5, which is reflected in its low to moderate affinity for peripheral tissues. The slow dissolution rate and low bioavailability have a certain impact on the absorption of drugs in the body.

[0010] The rivaroxaban available on the market in China comes in the form of tablets, granules, and dry suspensions. Tablets are difficult to swallow, and granules and dry suspensions need to be taken after being rinsed with water. They are not suitable for bedridden patients after surgery and patients with swallowing difficulties.

[0011] The Chinese patent with publication number CN 114533899 B discloses a rivaroxaban preparation and a preparation method thereof, including rivaroxaban, cellulose, and pharmaceutically acceptable excipients. By preparing an inclusion compound intermediate and further preparing a preparation, the problem of rivaroxaban being poorly soluble is solved. However, the preparation process is cumbersome, and organic reagents are used in the process, and the process requirements are relatively high, which is not conducive to commercial production.

[0012] Patent document CN118001245B discloses a rivaroxaban orally disintegrating tablet and a preparation method thereof, which comprises internal granulation particles and external excipients; the internal granulation particles include rivaroxaban, fillers, binders, disintegrants, solubilizers, and the external excipients include disintegrants, fillers, glidants, and lubricants; and are further compressed into tablets. However, the prepared tablets have a low hardness, are easily worn, and are difficult to withstand physical impacts during production, transportation, and use.

[0013] As dosage forms of oral solid preparations in the fields of medicine and food, tablets, capsules, granules, powders, etc. are known, and it is desired to develop orally disintegrating tablets that quickly disintegrate and dissolve when placed in the mouth or in water as a dosage form that is easier to be taken by the elderly, bedridden patients after surgery, and patients with swallowing difficulties.

[0014] The orally disintegrating tablet is required to have the property of rapid disintegration in the oral cavity and to have sufficient hardness so that it can withstand physical impacts during production, transportation and use like a traditional tablet. Summary of the invention

[0015] The object of the present invention is to provide a rivaroxaban orally disintegrating tablet which rapidly disintegrates and dissolves when placed in the mouth or in water and has sufficient hardness for general production, transportation and use.

[0016] Another object of the present invention is to provide a method for preparing an orally disintegrating tablet having the above-mentioned excellent properties by conventional excipients, conventional processes and traditional compression without requiring special equipment and excipients, which is excellent in terms of industrial production.

[0017] The technical scheme of the present invention is as follows: a rivaroxaban orally disintegrating tablet, the orally disintegrating tablet comprising drug-containing particles, blank particles and external excipients; the drug-containing particles comprising rivaroxaban, mannitol, microcrystalline cellulose, cross-linked sodium carboxymethyl cellulose, hypromellose and sodium lauryl sulfate; the blank particles comprising mannitol, microcrystalline cellulose and pregelatinized starch; the external excipients comprising cross-linked polyvinylpyrrolidone, colloidal silicon dioxide and magnesium stearate.

[0018] In some embodiments, the rivaroxaban is in a micronized form with a particle size D90 ≤ 20 μm, preferably D90 ≤ 15 μm.

[0019] In some embodiments, the microcrystalline cellulose in the blank granules has a bulk density of 0.10 g / cm 3 to 0.23 g / cm 3 , preferably 0.10 g / cm 3 to 0.15 g / cm 3 .

[0020] In some embodiments, the mannitol in the blank particles is selected from any one of α-type, β-type, δ-type or amorphous type; the particle size is 10 microns to 250 microns, preferably 20 microns to 150 microns; the specific surface area is 0.1 square meters / gram to 4 square meters / gram, preferably 0.1 square meters / gram to 2 square meters / gram.

[0021] In some embodiments, the drug-containing particles contain 8-10%, preferably 8-9%, of rivaroxaban per 100% by weight of the orally disintegrating tablet; 35-45%, preferably 38-42% of mannitol and microcrystalline cellulose; 0.5-1.5%, preferably 0.8-1.2% of hypromellose; 1-3%, preferably 1.5-2.5% of cross-linked carboxymethyl cellulose sodium; 0.2-0.8%, preferably 0.3-0.6% of sodium lauryl sulfate; the content ratio of mannitol to microcrystalline cellulose in the prescription is (1-8):1, preferably (1-4):1;

[0022] The blank granules contain 10-20%, preferably 10-15%, of microcrystalline cellulose having a bulk density of 0.23 g / cm3 or less (preferably 0.10 g / cm3 to 0.15 g / cm3) per 100% by weight of the orally disintegrating tablet; 15-35%, preferably 20-30% of mannitol; and 1-8%, preferably 1-5% of pregelatinized starch;

[0023] The external auxiliary materials contain 6-8% of cross-linked polyvinylpyrrolidone, 1-2% of colloidal silicon dioxide and 1-3% of magnesium stearate per 100% by weight of the orally disintegrating tablet.

[0024] In some typical embodiments, the drug-containing particles contain 8-9% rivaroxaban per 100% by weight of the orally disintegrating tablet; 38-42% mannitol and microcrystalline cellulose; 0.8-1.2% hypromellose; 1.5-2.5% cross-linked carboxymethyl cellulose sodium; 0.3-0.6% sodium lauryl sulfate; the content ratio of mannitol to microcrystalline cellulose in the prescription is (1-4):1;

[0025] The blank granules contain 10-15% microcrystalline cellulose, 20-30% mannitol, and 1-5% pregelatinized starch per 100% by weight of the orally disintegrating tablet;

[0026] The external auxiliary materials contain 6-7% of cross-linked polyvinylpyrrolidone, 0.5-1% of colloidal silicon dioxide and 1-2% of magnesium stearate per 100% by weight of the orally disintegrating tablet.

[0027] In some typical embodiments, the formulation of rivaroxaban orally disintegrating tablets is as follows:

[0028]

[0029] On the other hand, the present invention provides a method for preparing the rivaroxaban orally disintegrating tablet, comprising the following steps:

[0030] 1) Preparation of granulation liquid: adding pregelatinized starch into stirred purified water, stirring and dispersing to form a pregelatinized starch suspension;

[0031] 2) Blank granulation: Step 1) prepares a liquid as a slurry, uses a portion of the blank granules in the prescribed amount of microcrystalline cellulose and mannitol as the inner granules for granulation, and performs fluidized bed granulation; sprays the slurry onto the inner granules, and continues to dry in the fluidized bed after the slurry is sprayed, to obtain blank granules;

[0032] 3) Preparation of granulation liquid: sodium lauryl sulfate is added to purified water and stirred until completely dissolved, hypromellose is added while stirring, and stirred until completely dissolved, and then the prescribed amount of rivaroxaban is added to prepare a rivaroxaban suspension, and homogenized to make it evenly dispersed;

[0033] 4) Granulation of drug-containing particles: In step 3), a liquid is prepared as a slurry, and a portion of the prescribed amount of microcrystalline cellulose, mannitol and cross-linked sodium carboxymethyl cellulose in the drug-containing particles is used as the inner particles for granulation, and the slurry is sprayed onto the inner particles. After the slurry is sprayed, the particles are dried in the fluidized bed to obtain drug-containing particles.

[0034] 5) Pretreatment of excipients: The prescribed amount of colloidal silicon dioxide is sieved together with part of the drug-containing particles.

[0035] 6) Total mixing: blank granules, drug-containing granules, the pre-treated additional excipients in step 5), and cross-linked polyvinylpyrrolidone are mixed together, and magnesium stearate is added and then mixed again.

[0036] 7) Tablet compression: Use a round punch die to compress orally disintegrating tablets.

[0037] In some embodiments, the fluidized bed granulation conditions of step 2) are: setting the air inlet temperature to 60±5°C, the material temperature to 40°C±5°C, the fan frequency to 25±5HZ, the atomization pressure to 2bar, and the spray speed to 170rpm.

[0038] In some embodiments, the fluidized bed granulation conditions of step 4) are: setting the inlet air temperature to 60±5°C, the material temperature to 40°C±5°C, the fan frequency to 30±5HZ, the atomization pressure to 2bar, and the spray speed to 150rpm.

[0039] In some embodiments, in step 7), an orally disintegrating tablet is pressed using a 8.5 mm round punch die with a theoretical tablet weight of 180 mg and a hardness of 70-80 N.

[0040] As microcrystalline cellulose with a bulk density of 0.23 g / cm3 or less, commercially available microcrystalline cellulose can be used. Examples may include microcrystalline cellulose KG-1000 (bulk density: 0.10 to 0.15 g / cm3) and microcrystalline cellulose KG-802 (bulk density: 0.13 to 0.23 g / cm3). Alternatively, microcrystalline cellulose obtained by merging two or more microcrystalline celluloses with different bulk densities to obtain a desired bulk density can also be used.

[0041] The amount of microcrystalline cellulose added is preferably 5% to 50% by weight per 100% by weight of the orally disintegrating tablet. When the amount added exceeds 50% by weight, fluidity may be impaired and ease of preparation may be reduced. A more preferred amount added is 10 to 40% by weight.

[0042] Advantageous Effects of the Invention: The orally disintegrating tablet of the present invention thus obtained is excellent in disintegration properties and solubility when placed in the oral cavity or in water, and is also excellent in physical and chemical stability.

[0043] The disintegrating property or solubility of the orally disintegrating tablet of the present invention is such that the time required for disintegration and dissolution is generally about 5 to 60 seconds, preferably about 5 to 45 seconds.

[0044] The orally disintegrating tablet of the present invention is gradually disintegrated or dissolved by saliva when the tablet is placed in the mouth, and disintegrates or dissolves in a shorter time when pressure is applied in the oral cavity, i.e., by the upper jaw and tongue, or when rubbed by the tongue, i.e., by a "licking" action, etc. For people with dry mouth or people with a small amount of saliva, the tablet can be disintegrated or dissolved in the oral cavity with water or hot water, or the tablet can be taken with water like a conventional tablet.

[0045] On the other hand, the orally disintegrating tablet of the present invention has such hardness that the tablet does not produce cracks during the production steps or distribution process, even after stability testing under temperature and humidity (e.g., temperature of 25° C., humidity of 75%, open system, 30 days).

[0046] The orally disintegrating tablet of the present invention can be used as a preparation that is easy to take by the elderly, bedridden patients after surgery or patients with inphagia, or as a preparation that is safe for general adults for the treatment, prevention or diagnosis of various diseases. DETAILED DESCRIPTION

[0047] The following embodiments can enable those skilled in the art to more fully understand the present invention, but the present invention is not limited to the scope of the embodiments.

[0048] Since the added drugs will not significantly affect the pharmaceutical properties of the orally disintegrating tablet, experiments were conducted without adding drugs in some of the following examples.

[0049] The hardness was measured by means of a tablet continuous measuring device (mean values ​​of 10 tablets are described).

[0050] The disintegration time was obtained by measuring the time required for the test tablet to completely disintegrate by placing the tablet in a disintegration apparatus (describing the average value of six samples).

[0051] A dissolution development target of greater than 80% at 30 min was established (describing the average of six samples).

[0052] The friability was measured according to the “0923 Tablet Friability Test Method” in the 2020 edition of the Chinese Pharmacopoeia.

[0053] 1. Investigation of API particle size

[0054] Comparative Examples 1-2 and Example 1 Prescription Composition:

[0055]

[0056]

[0057] The preparation methods of the prescriptions of Comparative Examples 1 to 2 and Example 1 are as follows:

[0058] 1) Preparation of granulation liquid: Add pregelatinized starch into stirred purified water, and stir to disperse into pregelatinized starch suspension.

[0059] 2) Blank granulation: Step 1) Prepare liquid as slurry, use part of the blank granule prescription amount of microcrystalline cellulose and mannitol as granulated inner granules, perform fluidized bed granulation, set the inlet air temperature to 60±5°C, material temperature to 40°C±5°C, fan frequency to 30±5HZ, atomization pressure to 2bar, spray speed to 150rpm, use a top atomization spray gun to spray the slurry onto the inner granules, and after the slurry is sprayed, continue to dry in the fluidized bed to obtain blank granules.

[0060] 3) Preparation of granulation liquid: Sodium lauryl sulfate was added to purified water and stirred until completely dissolved. Hydroxypropyl methylcellulose was added while stirring and stirred until completely dissolved. Then, the prescribed amount of rivaroxaban was added to prepare rivaroxaban suspension. The suspension was homogenized with a homogenizer for 10 minutes to make it evenly dispersed.

[0061] 4) Granulation of drug-containing granules: Step 3) prepares a liquid as a slurry, and uses a portion of the prescribed amount of microcrystalline cellulose, mannitol and cross-linked sodium carboxymethyl cellulose in the drug-containing granules as the inner granules for granulation, and performs fluidized bed granulation. The inlet air temperature is set to 60±5°C, the material temperature is set to 40°C±5°C, the fan frequency is set to 25±5HZ, the atomization pressure is set to 2bar, and the spray speed is set to 170rpm. The slurry is sprayed onto the inner granules using a top atomizing spray gun. After the slurry is sprayed, continue to dry in the fluidized bed to obtain drug-containing granules.

[0062] 5) Pretreatment of excipients: The prescribed amount of colloidal silicon dioxide and part of the drug-containing particles are sieved through a 40-mesh sieve.

[0063] 6) Total mixing: blank granules, drug-containing granules, pre-treated additional excipients in step 5) and cross-linked polyvinylpyrrolidone are mixed together in a mixer for 12 minutes, and magnesium stearate is added and mixed for another 3 minutes.

[0064] 7) Tablet compression: Use 8.5 mm round punch die, theoretical tablet weight 180 mg, hardness 70-80 N.

[0065] Conclusion: It is known from Comparative Examples 1-2 and Example 1 that, except for the particle size of the raw material drug, other conditions are the same. The particle size D90 of the rivaroxaban raw material drug used in Comparative Example 1 is about 32 μm, the particle size D90 of the rivaroxaban raw material drug used in Comparative Example 2 is about 21 μm, and the particle size D90 of the rivaroxaban raw material drug used in Example 1 is about 15 μm. The disintegration times of the obtained orally disintegrating tablets are 42S, 43S, and 40S, respectively, and there is no obvious difference in the disintegration time, indicating that within the range of D90 less than 32 μm, the particle size of the raw material drug has no effect on the disintegration time; the 30min dissolution rate is 62% for Comparative Example 1, 81% for Comparative Example 2, and 90% for Example 1. The dissolution rate increases as the raw material particle size decreases. Only when the particle size D90 of the raw material drug is less than 21 μm, the 30min dissolution rate meets the development target.

[0066] 2. Investigation of bulk density of microcrystalline cellulose

[0067] The prescription compositions of Comparative Examples 3-4 and Example 2, Comparative Examples 5-6 and Example 1 are as follows:

[0068] Prescription composition Comparative Example 3 Comparative Example 4 Example 2 Mannitol 858 600 556 Microcrystalline Cellulose / 267 251 Microcrystalline cellulose bulk density / 0.35-0.46 g / cm3 0.13-0.23 g / cm3 Pregelatinized starch 33 33 33 water 566 300 380 Magnesium Stearate 7.2 7.3 6.8 Tablet weight / mg 180 180 180 Tableting pressure / KN 10 10 10 Hardness / N 36 53 104 Disintegration time / S 38 59 33 Friability / % 3.7 1.8 0 Number of cracks after friability test 3 2 0

[0069] Comparative Example 3 Preparation method: 858 g of mannitol was placed in a fluidized bed granulator, and a liquid obtained by dispersing 33 g of pregelatinized starch in 566 g of purified water was sprayed thereon and dried to produce a granular product. The obtained granular product was mixed with 7.2 g of stearic acid, and the mixture was tableted in a rotary tablet press at a tableting pressure of 8 KN and 10 KN to produce an orally disintegrating tablet.

[0070] Comparative Example 4, Example 2 Preparation method: The prescribed amount of mannitol and microcrystalline cellulose are placed in a fluidized bed granulator, and a liquid obtained by dispersing pregelatinized starch in purified water is sprayed thereon and dried to produce a granular product. The obtained granular product is mixed with magnesium stearate, and the mixture is tableted in a rotary tablet press at a tableting pressure of 10 KN and 12 KN to produce an orally disintegrating tablet.

[0071] The prescription composition is as follows:

[0072]

[0073]

[0074] The preparation methods of Comparative Examples 5-6 are the same as those of Example 1.

[0075] Conclusion: In the case where microcrystalline cellulose is not added as in Comparative Example 3, the disintegration time is fast, but the friability is high (1% or more), and cracks are produced after the friability test, so it is difficult to prepare an orally disintegrating tablet with balanced hardness and disintegration properties. In addition, in the case where mannitol and microcrystalline cellulose with a high bulk density are added as in Comparative Examples 4 to 5, the friability and hardness are slightly improved, but the friability is still high and cracks are produced, and the disintegration time is prolonged, so it is difficult to prepare an orally disintegrating tablet with balanced hardness and disintegration properties. When mannitol and microcrystalline cellulose with a bulk density of 0.23 g / cm3 or less are added as in Examples 1-2 and Comparative Example 6, an orally disintegrating tablet that ensures rapid disintegration properties and has high hardness and low friability and does not produce cracks can be prepared, but Example 1 has a faster disintegration time limit than Comparative Example 6, and Example 1 is better.

[0076] 3. Investigation of preparation process

[0077] Comparative Examples 7-8 and Example 1 Prescription Composition:

[0078]

[0079]

[0080] The preparation method of Comparative Example 7 is as follows:

[0081] 1) Preparation of granulation liquid: Add pregelatinized starch into stirred purified water, and stir to disperse into pregelatinized starch suspension.

[0082] 2) Granulation of blank granules: Step 1) Prepare a liquid as a slurry, place a portion of the blank granule prescription amount of microcrystalline cellulose and mannitol as granules in the granulation in a high shear granulator, stir and premix for 5 minutes at gear 2, add the granulation slurry to the premixed material, shear at gear 2, stir at gear 2 to make a soft material for 2 minutes, pass the soft material through a 30-mesh rocking wet finishing, place the rocking product in a fluidized bed granulator and dry to produce a granular product, i.e., blank granules.

[0083] 3) Preparation of granulation liquid: Sodium lauryl sulfate was added to purified water and stirred until completely dissolved. Hydroxypropyl methylcellulose was added while stirring and stirred until completely dissolved. Then, the prescribed amount of rivaroxaban was added to prepare rivaroxaban suspension. The suspension was homogenized with a homogenizer for 10 minutes to make it evenly dispersed.

[0084] 4) Granulation of drug-containing granules: Step 3) prepare a liquid as a slurry, use a portion of the prescribed amount of microcrystalline cellulose, mannitol and cross-linked sodium carboxymethyl cellulose in the drug-containing granules as the inner granules for granulation, perform fluidized bed granulation, set the inlet air temperature to 60±5°C, the material temperature to 40°C±5°C, the fan frequency to 25±5HZ, the atomization pressure to 2bar, the spray speed to 170rpm, and use a top atomizing spray gun to spray the slurry onto the inner granules. After the slurry is sprayed, continue to dry in the fluidized bed to obtain drug-containing granules.

[0085] 5) Pretreatment of excipients: The prescribed amount of colloidal silicon dioxide and part of the drug-containing particles are sieved through a 40-mesh sieve.

[0086] 6) Total mixing: blank granules, drug-containing granules, pre-treated additional excipients in step 5) and cross-linked polyvinylpyrrolidone are mixed together in a mixer for 12 minutes, and magnesium stearate is added and mixed for another 3 minutes.

[0087] 7) Tablet compression: Use 8.5 mm round punch die, theoretical tablet weight 180 mg, hardness 70-80 N.

[0088] Conclusion: Comparative Example 7 adopts a common wet granulation process, and its disintegration time is significantly increased compared with the fluidized bed granulation process of Example 1.

[0089] Comparative Example 8 prescription composition:

[0090]

[0091]

[0092] The preparation method of Comparative Example 8 is as follows:

[0093] 1) Preparation of granulation liquid: Sodium lauryl sulfate was added to purified water and stirred until completely dissolved. Hydroxypropyl methylcellulose was added while stirring and stirred until completely dissolved. Then, the prescribed amount of rivaroxaban was added to prepare rivaroxaban suspension. The suspension was homogenized with a homogenizer for 10 minutes to make it evenly dispersed.

[0094] 2) Granulation of drug-containing particles: Step 3) Prepare a liquid as a slurry, use a portion of the prescribed amount of microcrystalline cellulose, mannitol and cross-linked sodium carboxymethyl cellulose in the drug-containing particles as the inner particles for granulation, perform fluidized bed granulation, set the inlet air temperature to 60±5°C, the material temperature to 40°C±5°C, the fan frequency to 25±5HZ, the atomization pressure to 2bar, the spray speed to 170rpm, and use a top atomization spray gun to spray the slurry onto the inner particles. After the slurry is sprayed, continue to dry in the fluidized bed to obtain drug-containing particles.

[0095] 3) Pretreatment of excipients: The prescribed amount of colloidal silicon dioxide and part of the drug-containing particles are sieved through a 40-mesh sieve.

[0096] 4) Total mixing: the drug-containing granules, the pre-treated additional excipients in step 5), mannitol, microcrystalline cellulose, pregelatinized starch, and cross-linked polyvinylpyrrolidone are mixed together in a mixer for 12 minutes, and then magnesium stearate is added and mixed for another 3 minutes.

[0097] 5) Tablet compression: Use 8.5mm round punch die, theoretical tablet weight 180mg, hardness 70~80N.

[0098] Conclusion: Comparative Example 8 adopts the process of direct powder compression, which absorbs water and swells after disintegration, blocking the screen, and cannot meet the requirements. The blank granule technology obtained by fluidized bed granulation by spraying or adding liquid obtained by dispersing pregelatinized starch in pure water has been proven to be a very useful technology for preparing orally disintegrating tablets. This technology greatly improves the disintegration time of tablets and improves flowability and compressibility.

[0099] Test Example 1

[0100] The orally disintegrating tablets obtained in Example 1 were placed in open weighing bottles and placed under high temperature 60°C, high humidity RH75% and light (illuminance 4500±500LX) conditions. Samples were taken on the 5th, 10th and 30th days to examine the changes in sample hardness, disintegration time and friability. The results are shown in the following table:

[0101]

[0102] After investigation of influencing factors, the results showed that the orally disintegrating tablets obtained in Example 1 were placed under high temperature (60°C) and light (illuminance 4500±500LX) conditions for 5 days, 10 days, and 30 days, and there was no significant change compared with 0 day; after being placed under high humidity RH75% conditions for 5 days, 10 days, and 30 days, the hardness decreased, and the friability weight loss increased, but there were no broken, cracked, or crushed tablets, and the weight loss did not exceed 1%, meeting the friability requirements, and the disintegration time was always within 60S.

Claims

1. A rivaroxaban orally disintegrating tablet, comprising drug-containing granules, blank granules and additional excipients; the drug-containing granules comprise rivaroxaban, mannitol, microcrystalline cellulose, cross-linked sodium carboxymethyl cellulose, hypromellose and sodium lauryl sulfate; the blank granules comprise mannitol, microcrystalline cellulose and pregelatinized starch; the additional excipients comprise cross-linked polyvinylpyrrolidone, colloidal silicon dioxide and magnesium stearate.

2. The orally disintegrating tablet according to claim 1, characterized in that The rivaroxaban is in a micronized form with a particle size D90≤20 μm, preferably D90≤15 μm.

3. The orally disintegrating tablet according to claim 1, characterized in that The microcrystalline cellulose in the blank granules has a bulk density of 0.10 g / cm3 to 0.23 g / cm3, preferably 0.10 g / cm3 to 0.15 g / cm3.

4. The orally disintegrating tablet according to claim 1, characterized in that The mannitol in the blank particles is selected from any one of α-type, β-type, δ-type or amorphous type; the particle size is 10 microns to 250 microns, preferably 20 microns to 150 microns; The specific surface area is 0.1 m2 / g to 4 m2 / g, preferably 0.1 m2 / g to 2 m2 / g.

5. The orally disintegrating tablet according to claim 1, characterized in that The orally disintegrating tablets containing the drug-containing particles contain 8-10%, preferably 8-9%, of rivaroxaban per 100% by weight; 35-45%, preferably 38-42%, of mannitol and microcrystalline cellulose; 0.5-1.5%, preferably 0.8-1.2% of hypromellose; 1-3%, preferably 1.5-2.5% of cross-linked sodium carboxymethyl cellulose; 0.2-0.8%, preferably 0.3-0.6% of sodium lauryl sulfate; the content ratio of mannitol to microcrystalline cellulose in the prescription is (1-8):1, preferably (1-4):1; The blank granules contain 10-20%, preferably 10-15%, of microcrystalline cellulose having a bulk density of 0.23 g / cm3 or less (preferably 0.10 g / cm3 to 0.15 g / cm3) per 100% by weight of the orally disintegrating tablet; 15-35%, preferably 20-30% of mannitol; and 1-8%, preferably 1-5% of pregelatinized starch; The external auxiliary materials contain 6-8% of cross-linked polyvinylpyrrolidone, 1-2% of colloidal silicon dioxide and 1-3% of magnesium stearate per 100% by weight of the orally disintegrating tablet.

6. The orally disintegrating tablet according to claim 1, characterized in that The orally disintegrating tablets containing the drug-containing particles contain 8-9% of rivaroxaban per 100% by weight; 38-42% of mannitol and microcrystalline cellulose; 0.8-1.2% of hypromellose; 1.5-2.5% of cross-linked sodium carboxymethyl cellulose; and 0.3-0.6% of sodium lauryl sulfate; the content ratio of mannitol to microcrystalline cellulose in the prescription is (1-4):1; The blank granules contain 10-15% microcrystalline cellulose, 20-30% mannitol, and 1-5% pregelatinized starch per 100% by weight of the orally disintegrating tablet; The external auxiliary materials contain 6-7% of cross-linked polyvinylpyrrolidone, 0.5-1% of colloidal silicon dioxide and 1-2% of magnesium stearate per 100% by weight of the orally disintegrating tablet.

7. The orally disintegrating tablet according to claim 1, characterized in that The formulation of rivaroxaban orally disintegrating tablets is as follows:

8. The method for preparing the rivaroxaban orally disintegrating tablet according to claim 1, comprising the following steps: 1) Preparation of granulation liquid: adding pregelatinized starch into stirred purified water, stirring and dispersing to form a pregelatinized starch suspension; 2) Blank granulation: Step 1) prepares a liquid as a slurry, uses a portion of the blank granules in the prescribed amount of microcrystalline cellulose and mannitol as the inner granules for granulation, and performs fluidized bed granulation; sprays the slurry onto the inner granules, and continues to dry in the fluidized bed after the slurry is sprayed, to obtain blank granules; 3) Preparation of granulation liquid: sodium lauryl sulfate is added to purified water and stirred until completely dissolved, hypromellose is added while stirring, and stirred until completely dissolved, and then the prescribed amount of rivaroxaban is added to prepare a rivaroxaban suspension, and homogenized to make it evenly dispersed; 4) Granulation of drug-containing particles: Step 3) prepares a liquid as a slurry, uses a portion of the prescribed amount of microcrystalline cellulose, mannitol and cross-linked sodium carboxymethyl cellulose as inner particles for granulation, performs fluidized bed granulation, sprays the slurry onto the inner particles, and continues to dry in the fluidized bed after the slurry is sprayed to obtain drug-containing particles; 5) Pretreatment of excipients: the prescribed amount of colloidal silicon dioxide is sieved together with part of the drug-containing particles; 6) Total mixing: blank granules, drug-containing granules, pre-treated additional excipients in step 5), and cross-linked polyvinylpyrrolidone are mixed together, and magnesium stearate is added and then mixed again; 7) Tablet compression: Use a round punch die to compress orally disintegrating tablets.

9. The method for preparing an orally disintegrating tablet according to claim 8, characterized in that: The fluidized bed granulation conditions of step 2) are: setting the inlet air temperature to 60±5°C, the material temperature to 40°C±5°C, the fan frequency to 25±5HZ, the atomization pressure to 2bar, and the spray speed to 170rpm; the fluidized bed granulation conditions of step 4) are: setting the inlet air temperature to 60±5°C, the material temperature to 40°C±5°C, the fan frequency to 30±5HZ, the atomization pressure to 2bar, and the spray speed to 150rpm.

10. The method for preparing an orally disintegrating tablet according to claim 8, characterized in that: In the step 7), an orally disintegrating tablet is pressed using a 8.5 mm round punch die with a theoretical tablet weight of 180 mg and a hardness of 70-80 N.

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