WO2018120777A1 - Rivaroxaban self-emulsifying preparation and preparation method therefor - Google Patents

Abstract

Provided are a rivaroxaban self-emulsifying preparation and a preparation method therefor, wherein the preparation comprises by mass percentage, 1 to 13% of rivaroxaban, 5 to 50% of oil phase, 20 to 70% of emulsifier, 0 - 50% of the coemulsifier; the preparation method therefor comprises mixing the oil phase, the emulsifier and the coemulsifier uniformly, and then mixing the mixture with rivaroxaban to obtain the rivaroxaban self-emulsifying preparation.

Description

Rivaroxaban self-emulsifying preparation and preparation method thereof

This application claims priority to Chinese Patent Application No. 201611220383.9, entitled "A rivaroxaban Self-Emulsifying Formulation and Its Preparation Method", filed on December 26, 2016, the entire contents of which are hereby incorporated by reference. The citations are incorporated herein by reference.

Technical field

The invention belongs to the field of medicine, and in particular relates to a rivaroxaban self-emulsification preparation and a preparation method thereof.

Background technique

Rivaroxaban is a drug for the prevention and treatment of venous thrombosis. It is also the world's first oral direct inhibitor of factor Xa. It was developed by Bayer/Johnson and is clinically used to prevent patients after hip and knee joint replacement. The formation of deep vein thrombosis (DVT) and pulmonary embolism (PE) can also be used to prevent stroke and non-central nervous system embolism in patients with non-valvular atrial fibrillation, and to reduce the risk of recurrence of coronary syndrome. At present, rivaroxaban has been registered and approved in Canada, the European Union, South America, China, Australia and other countries and regions. The trade name is Xarelto.

Rivaroxaban molecular formula: C ₁₉ H ₁₈ C _l N ₃ O ₅ S, chemical name 5-chloro-nitrogen-((5s)-2-oxo-3-[-4-(3-oxo-4-) Polinyl)phenyl]-1,3-oxazolidin-5-yl-2-thiophene-carboxamide, the structural formula is as follows:

Rivaroxaban belongs to class II (low solubility hypertonicity) in the classification of biopharmaceutics classification system (BCS). The low solubility of drugs leads to slow dissolution or incomplete dissolution in vitro, which greatly limits its in vitro Release and bioavailability in the body.

In summary, rivaroxaban greatly limits its application in the medical field due to its low solubility and low bioavailability. Therefore, finding a preparation which can improve the solubility and bioavailability of rivaroxaban is a technical problem to be solved by those skilled in the art.

Summary of the invention

In view of this, it is an object of the present invention to provide a formulation which improves the solubility and bioavailability of rivaroxaban against the prior art.

In order to achieve the object of the present invention, the present invention adopts the following technical solutions:

The invention discloses a rivaroxaban self-emulsification preparation, which comprises the following components in terms of mass percentage:

The rivaroxaban self-emulsified preparation of the invention is a thermodynamically stable uniform system composed of rivaroxaban, an oil phase, an emulsifier and a co-emulsifier, and can spontaneously form a particle size smaller than stirring at an ambient temperature and a small amount of water. The 100nm O/W microemulsion, due to the small microemulsion particles and large surface area, greatly increases the contact area of rivaroxaban with the medium and mucous membrane, and can promote the oral absorption of refractory rivaroxaban.

Preferably, the rivaroxaban self-emulsifying formulation comprises, by mass percent, the following components:

Preferably, the oil phase is oleic acid, soybean oil, ethyl oleate, isopropyl myristate, isopropyl palmitate, corn oil, castor oil, caprylic/capric triglyceride, glycerol monooleate At least one of ester, linoleic acid glyceride, oleic acid, olive oil, sesame oil, peanut oil, almond oil.

In some embodiments, the oil phase is oleic acid, soybean oil, ethyl oleate, nutmeg One of isopropyl citrate.

Preferably, the emulsifier is polyoxyethylene castor oil, polyoxyethylene hydrogenated castor oil, polyethylene glycol stearate-15, oleic acid polyethylene glycol glyceride, polyethylene glycol octyl phenyl ether , octanoic acid polyethylene glycol glyceride, poloxamer 188, Tween-80, phospholipids, liquid lecithin, sucrose laurate, sucrose palmitate, sucrose stearate, lauric acid polyethylene glycol At least one of a glyceride, glycerol polyethylene glycol-75-stearate.

In some embodiments, the emulsifier is one of polyoxyethylene castor oil, poloxamer 188, Tween-80.

Preferably, the co-emulsifier is glycerin, ethanol, propylene glycol, polyethylene glycol 200, polyethylene glycol 400, isopropanol, 1,2-propanediol, n-butanol, diethylene glycol monoethyl ether, and propylene carbonate. At least one of the diesters.

In some embodiments, the co-emulsifier is one of glycerin, ethanol.

The invention also provides a preparation method of the rivaroxaban self-emulsified preparation, comprising the steps of: uniformly mixing an oil phase, an emulsifier and a co-emulsifier, and then uniformly mixing with rivaroxaban to obtain rivaroxaban self-emulsification preparation.

The present invention also provides a pharmaceutical preparation comprising the rivaroxaban self-emulsifying preparation and a pharmaceutically acceptable excipient.

Preferably, it is an oral preparation or an injection preparation.

According to the present invention, the oral preparation may be a granule, a tablet, a dispersant, or a capsule.

In some embodiments, the rivaroxaban self-emulsifying formulation is filled orally in a soft capsule, and in some embodiments, the rivaroxaban self-emulsifying formulation is dispersed for use in physiological saline or 5% dextrose for injection.

In some embodiments, the rivaroxaban self-emulsifying formulation is a rivaroxaban self-emulsifying dispersible tablet.

Further, the auxiliary material is at least one of an adsorbent, a diluent, a disintegrant, a flavor, and a lubricant.

Preferably, the adsorbent is selected from the group consisting of anhydrous calcium hydrogen phosphate, calcium phosphate, calcium carbonate, magnesium carbonate, magnesium oxide micropowder silica gel, microcrystalline cellulose, lactose, aluminum hydroxide gel powder, and chlorination. Sodium, pregelatinized starch, sucrose powder, glucose powder, mannitol, sorbitol starch, cyclodextrin, sodium carbonate, sodium hydrogencarbonate, calcium sulfate, povidone, polyethylene glycol 4000, polyethylene glycol 6000 At least one of them.

In some embodiments, the adsorbent is one of lactose, anhydrous calcium hydrogen phosphate.

Preferably, the diluent is at least one selected from the group consisting of microcrystalline cellulose, calcium hydrogen phosphate, lactose, starch, dextrin, pregelatinized starch, mannitol, glucose powder, sucrose powder, and sorbitol.

In some embodiments, the diluent is microcrystalline cellulose.

Preferably, the disintegrant is selected from the group consisting of crospovidone, croscarmellose sodium, crosslinked polyvinylpyrrolidone, sodium carboxymethyl starch, low substituted hydroxypropyl cellulose, partially pregelatinized starch At least one of them.

In some embodiments, the disintegrant is one of crospovidone, croscarmellose sodium.

Preferably, the flavoring agent is selected from at least one of stevioside, aspartame, citric acid, food flavor, lactose, glucose, sucrose, and mannitol.

In some embodiments, the flavoring agent is citric acid.

Preferably, the lubricant is selected from at least one of micronized silica gel, magnesium stearate, talc, and sodium stearyl fumarate.

In some embodiments, the lubricant is one of micronized silica gel, magnesium stearate, sodium stearyl fumarate.

In some embodiments, the pharmaceutical formulation is a rivaroxaban self-emulsifying dispersible tablet, the mass of each component being:

The absorbent is anhydrous calcium hydrogen phosphate or lactose; the diluent is microcrystalline cellulose; The disintegrant is crospovidone or croscarmellose sodium; the flavoring agent is citric acid; the lubricant is micronized silica gel, magnesium stearate or sodium stearyl fumarate .

The invention also provides a preparation method of a rivaroxaban self-emulsifying dispersible tablet, which is mixed with a rivaroxaban self-emulsifying preparation, and then mixed with a diluent, a disintegrant, a flavoring agent and a lubricant, Tableting.

It can be seen from the above technical solutions that the present invention provides a rivaroxaban self-emulsifying preparation and a preparation method thereof. The rivaroxaban self-emulsified preparation of the present invention comprises 1-1% by weight of rivaroxaban, 5-50% of oil phase, 20-70% of emulsifier, and 0-50% of co-emulsifier. The rivaroxaban self-emulsified preparation of the invention has a particle size distribution of less than 1 μm, and can spontaneously emulsify in the body to form microemulsions having a particle diameter of 20 to 1000 nm, thereby improving the solubility and bioavailability of rivaroxaban. At the same time, the rivaroxaban self-emulsifiable preparation can be mixed with a suitable solid auxiliary material to achieve solidification, and the obtained rivaroxaban self-emulsifying dispersible tablet improves the low permeability problem of rivaroxaban and dissolves more rapidly. The preparation method of the rivaroxaban self-emulsified preparation of the invention has the advantages of simple process and low cost.

detailed description

The invention provides a rivaroxaban self-emulsifying preparation and a preparation method thereof for solving the technical defects in the prior art.

The technical solutions in the embodiments of the present invention are clearly and completely described below. It is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments. All other embodiments obtained by those skilled in the art based on the embodiments of the present invention without creative efforts are within the scope of the present invention.

Among them, the raw materials are all commercially available.

Example 1: Rivaroxaban self-emulsifying preparation

formula:

Preparation:

Weigh the above prescribed amount of oleic acid, polyoxyethylene castor oil and glycerin, mix, magnetically stir for 10min, form a uniform liquid, then add the prescribed amount of rivaroxaban, continue to stir for 30min, and then fully dissolve to obtain rivaroxaban Self-emulsifying preparation.

Example 2: Rifasanban self-emulsifying preparation

formula:

Preparation:

Weigh the above prescribed amount of oleic acid, polyoxyethylene castor oil and glycerin, mix, magnetically stir for 10min, form a uniform liquid, then add the prescribed amount of rivaroxaban, continue to stir for 30min, and then fully dissolve to obtain rivaroxaban Self-emulsifying preparation.

Example 3: Rifasanban self-emulsifying preparation

formula:

Preparation:

Weigh the above prescribed amount of oleic acid, poloxamer 188 and glycerin, mix, magnetically stir for 15min, then form a uniform liquid, then add the prescribed amount of rivaroxaban, continue to stir for 30min, and then fully dissolve to obtain rivaroxaban Self-emulsifying preparation.

Example 4: Rifasanban self-emulsifying preparation

Recipe:

Preparation:

Weigh the above prescribed amount of soybean oil, Tween-80 and glycerin, mix, magnetically stir for 10 min, form a uniform liquid, then add the prescribed amount of rivaroxaban, continue to stir for 30 min, and then fully dissolve to obtain rivaroxaban. Emulsified preparation.

Example 5: Rifasanban self-emulsifying preparation

formula:

Preparation:

Weigh the above prescribed amount of isopropyl myristate, ethyl oleate, poloxamer 188 and ethanol, mix, magnetically stir for 15 min, form a uniform liquid, then add the prescribed amount of rivaroxaban, stirring for 30 min, The rivaroxaban self-emulsified preparation is obtained after being sufficiently dissolved.

Comparative example 1:

formula:

Preparation:

Weigh the above prescribed amounts of isopropyl myristate, oleic acid polyethylene glycol glyceride and propylene Alcohol, mixing, magnetic stirring for 15 min, a uniform liquid was formed, and then a prescribed amount of rivaroxaban was added, and stirring was continued for 30 minutes, and the rivaroxaban self-emulsified preparation was obtained after being sufficiently dissolved.

Comparative example 2:

formula:

Preparation:

The prescribed amount of castor oil, glycerol monooleate, lauric acid polyethylene glycol glyceride and glycerin were weighed, mixed, and magnetically stirred for 20 min to form a uniform liquid, and then a prescribed amount of rivaroxaban was added, and stirring was continued for 30 minutes. The rivaroxaban self-emulsified preparation is obtained after being sufficiently dissolved.

Test Example 1:

The rivaroxaban self-emulsified formulations of Examples 1-5 were separately added to a Malvern laser particle size analyzer to measure the particle size distribution.

Table 1 Particle size distribution of rivaroxaban self-emulsified preparation (μm)

The results in Table 1 show that the rivaroxaban self-emulsified preparations of Examples 1-5 have a particle size distribution of 1 μm or less and the self-emulsification effect is superior to Comparative Example 1-2 as compared with Comparative Examples 1-2.

Example 6: Rivaroxaban self-emulsifying dispersible tablet

formula:

Preparation:

The anhydrous calcium hydrogen phosphate was weighed according to the above prescription, and the prescribed amount of rivaroxaban self-emulsified preparation was added to make the rivaroxaban self-emulsified preparation fully adsorbed, and the wet granules were prepared, transferred to a fluidized bed to be dried, and the moisture was controlled. Dry granules are obtained within 3%, and the dry granules are further granulated (the No. 1 sieve removes the large particles, and the No. 5 sieve removes the fine powder) to obtain rivaroxaban self-emulsified granules;

The rivaroxaban self-emulsified oral granules were added to the mixing hopper, microcrystalline cellulose, croscarmellose sodium, and citric acid were added, premixed for 10 min, then magnesium stearate and breeze silica gel were added and mixed for 4 min. Tableting, that is, rivaroxaban self-emulsifying dispersible tablets.

Example 7: Rivaroxaban self-emulsifying dispersible tablet

formula:

Preparation:

The anhydrous calcium hydrogen phosphate was weighed according to the above prescription, and the prescribed amount of rivaroxaban self-emulsified preparation was added to make the rivaroxaban self-emulsified preparation fully adsorbed, and the wet granules were prepared, transferred to a fluidized bed to be dried, and the moisture was controlled. Dry granules are obtained within 3%, and the dry granules are further granulated (the No. 1 sieve removes the large particles, and the No. 5 sieve removes the fine powder) to obtain rivaroxaban self-emulsified granules;

Adding rivaroxaban self-emulsified oral granules to the mixing hopper, adding microcrystalline cellulose, The croscarmellose sodium was premixed for 13 min, then magnesium stearate and breeze silica gel were added, mixed for 4 min, and compressed to obtain a rivaroxaban self-emulsifying dispersible tablet.

Example 8: Rivaroxaban self-emulsifying dispersible tablet

formula:

Preparation:

The anhydrous calcium hydrogen phosphate was weighed according to the above prescription, and the prescribed amount of rivaroxaban self-emulsified preparation was added to make the rivaroxaban self-emulsified preparation fully adsorbed, and the wet granules were prepared, transferred to a fluidized bed to be dried, and the moisture was controlled. Dry granules are obtained within 3%, and the dry granules are further granulated (the No. 1 sieve removes the large particles, and the No. 5 sieve removes the fine powder) to obtain rivaroxaban self-emulsified granules;

The rivaroxaban self-emulsified oral granules were added to the mixing hopper, microcrystalline cellulose, croscarmellose sodium, and citric acid were added, premixed for 10 min, then magnesium stearate and breeze silica gel were added and mixed for 4 min. Tableting, that is, rivaroxaban self-emulsifying dispersible tablets.

Example 9: Rivaroxaban self-emulsifying dispersible tablet

formula:

Preparation:

The anhydrous calcium hydrogen phosphate was weighed according to the above prescription, and the prescribed amount of rivaroxaban self-emulsified preparation was added to make the rivaroxaban self-emulsified preparation fully adsorbed, and the wet granules were prepared, transferred to a fluidized bed to be dried, and the moisture was controlled. Dry granules are obtained within 3%, and the dry granules are further granulated (the No. 1 sieve removes the large particles, and the No. 5 sieve removes the fine powder) to obtain rivaroxaban self-emulsified granules;

Add rivaroxaban self-emulsified oral granules to the mixing hopper, add microcrystalline cellulose, croscarmellose sodium, premix for 15 min, then add magnesium stearate and breeze silica gel, mix for 4 min, compress, ie Derivaroxaban self-emulsifying dispersible tablets.

Example 10: Rivaroxaban self-emulsifying dispersible tablet

formula:

Preparation:

The lactose is weighed according to the above prescription, and the prescribed amount of rivaroxaban self-emulsified preparation is added to make the rivaroxaban self-emulsified preparation fully adsorbed, and the wet granules are prepared, transferred to a fluidized bed for drying, and the controlled moisture is obtained within 3%. Dry granules, dry granules are further granulated (No. 1 sieve removes large granules, No. 5 sieve removes fine powder), and rivaroxaban self-emulsified granules are obtained;

The rivaroxaban self-emulsified oral granules were added to the mixing hopper, microcrystalline cellulose and crospovidone were added, premixed for 15 min, then sodium stearyl fumarate and breeze silica gel were added, mixed for 4 min, and compressed. Rivaroxaban self-emulsifying dispersible tablets.

Comparative example 3:

formula:

Preparation:

The microcrystalline cellulose was weighed according to the above prescription, and the prescribed amount of rivaroxaban self-emulsified preparation was added to make the rivaroxaban self-emulsified preparation fully adsorbed, and the wet granules were prepared, transferred to a fluidized bed to be dried, and the moisture was controlled at 3 Dry granules are obtained within %, and the dry granules are further granulated (the No. 1 sieve removes the large granules, and the No. 5 sieve removes the fine powder) to obtain rivaroxaban self-emulsified granules;

Add rivaroxaban self-emulsified oral granules to the mixing hopper, add lactose, croscarmellose sodium, premix for 15min, then add sodium stearyl fumarate and breeze silica gel, mix for 4min, and compress. Rivaroxaban self-emulsifying dispersible tablets.

Comparative example 4:

formula:

Preparation:

The anhydrous calcium hydrogen phosphate was weighed according to the above prescription, and the prescribed amount of rivaroxaban self-emulsified preparation was added to make the rivaroxaban self-emulsified preparation fully adsorbed, and the wet granules were prepared, transferred to a fluidized bed to be dried, and the moisture was controlled. Dry granules are obtained within 3%, and the dry granules are further granulated (the No. 1 sieve removes the large particles, and the No. 5 sieve removes the fine powder) to obtain rivaroxaban self-emulsified granules;

Add rivaroxaban self-emulsified oral granules to the mixing hopper, add lactose, croscarmellose sodium, premix for 15 minutes, then add magnesium stearate and breeze silica gel, mix 4 min, tableting, that is, rivaroxaban self-emulsifying dispersible tablets.

Test Example 2: Drug dissolution measurement

Take the sample, according to the dissolution and release determination (blue method), with 0.1mol / L hydrochloric acid solution 900ml dissolved medium, rotating at 50 rpm, according to the law, after 20 minutes, take 10ml of the solution filtered, precision filtrate Appropriate amount, according to high performance liquid chromatography, the absorbance was measured at 250 nm. Another rivaroxaban self-emulsifying dispersible tablet was accurately weighed, and 60% acetonitrile was added to make the rivaroxaban reference substance 0.2 mg/ml. The same method was used to determine the dissolution rate of each tablet.

Using octadecylsilane bond and silica gel as filler (such as Agilent, 50mm × 4.6mm, 2.7μm); water as mobile phase A, acetonitrile as mobile phase B, A: B = 70:30 as mobile phase, Isocratic elution. The detection wavelength was 250 nm, the column temperature was 45 ° C, and the injection amount was 5 μl.

Table 2 dissolution comparison (%)

The results in Table 2 show that the rivaroxaban self-emulsifying dispersible tablets of Examples 6-10 were more rapidly dissolved as compared with the comparative examples 3-4 rivaroxaban self-emulsifying dispersible tablets and commercially available ordinary tablets (Xarelto).

Test Example 3: Pharmacological experiment

A small-tailed Han sheep model was established, and 18 male small-tailed Han sheep were taken, weighing 45-55 kg, with an average of 47 kg. Captive for 7 to 10 days before surgery, parallel pest control, fasting 24 hours before surgery, banned drink for 8 hours, left chest and limbs skin preparation. Another 9 small-tailed Han sheep were taken, male or female, and the rats were sacrificed under sterile conditions for about 2000 ml of blood through the femoral artery. Fresh blood was used. 12 domestic double-leaf mechanical valves were sterilized by autoclaving at 121 °C for 20 minutes.

Ketamine 20 ~ 30mg / kg, diazepam 2 ~ 2.5mg / kg intramuscular injection induction, Ato 1mg intramuscular injection, endotracheal intubation, anesthesia machine; limb conduction ECG, continuous monitoring of percutaneous oxygen saturation; right venous puncture to establish venous access for venous pressure, transfusion and medication; right radial artery catheterization Continuous monitoring of arterial pressure, parallel blood gas, blood potassium and whole blood activated clotting time (ACT) detection; monitoring of rectal temperature, homemade urine bag to measure urine output.

Take 12 sheep in the right lateral position, the left intercostal space into the chest, cut the happy bag and suspend, lift the aorta double purse line, right atrium, right superior vena cava single charge envelope, respectively, aorta, upper and lower cavity Intravenous intubation, heparin 400 IU / kg heparinized, ACT > 800 seconds after the establishment of extracorporeal circulation. The superior and inferior vena cava were blocked, and the aorta was not blocked. The pulmonary artery was incised at 1 cm above the pulmonary valve. The heart was beaten with a double-leaf mechanical flap, and the 4-0 Prolene line was three. The annulus was sutured continuously. The flaps were normally opened and closed, and the 4-0 Prolene line was used to suture the pulmonary incision continuously. Adjust the flow rate, measure blood pressure, heart rate, blood gas, blood potassium and hemoglobin in the normal range, stop, give anticoagulant, withdraw from extracorporeal circulation. The left 6th intercostal space near the sternum was 2cm. The chest drainage tube was treated with a water-sealed bottle, and the chest was closed layer by layer. Preoperative and intraoperative injection of penicillin was 3.2 million units, so a good model was established.

Eighteen small-tailed Han sheep undergoing heart valve replacement were randomly divided into three groups. Six of the control group started taking rivaroxaban tablets (commercially available) on the first day after surgery for anticoagulant therapy. On the first day after surgery, the rivaroxaban self-emulsifying dispersible tablets prepared in Example 6 were used for bridging anticoagulation; the first two groups of the experimental group began to take rivaroxaban self-emulsifying dispersion on the first day after surgery. The tablets were bridged for anticoagulation, and the INR values of the three groups of small-tailed Han sheep were compared.

Table 3 Comparison of postoperative anticoagulation initiation status between the two groups

Table 2 shows that the INR of the experimental group was significantly different from the control group and the experimental group. The rivaroxaban self-emulsifying dispersible tablet prepared in Examples 7-10 and the benefit prepared in Example 1 The results of the venezuela self-emulsifying dispersible tablets are comparable. It is indicated that the rivaroxaban self-emulsifying dispersible tablet prepared by the invention can effectively exert a good anticoagulant effect on the small-tailed Han sheep undergoing heart valve replacement.

The above description is only a preferred embodiment of the present invention, and it should be noted that those skilled in the art can also make several improvements and retouchings without departing from the principles of the present invention. It should be considered as the scope of protection of the present invention.

Claims (10)

A rivaroxaban self-emulsifying preparation characterized by comprising the following components in terms of mass percentage:

The rivaroxaban self-emulsifying preparation according to claim 1, which comprises, by mass percentage, the following components:

The rivaroxaban self-emulsified preparation according to claim 1 or 2, wherein the oil phase is at least one of soybean oil, ethyl oleate, isopropyl myristate, and oleic acid; The emulsifier is at least one of polyoxyethylene castor oil, poloxamer 188, and Tween-80; and the co-emulsifier is at least one of glycerin and ethanol. The method for preparing a rivaroxaban self-emulsified preparation according to any one of claims 1 to 3, characterized in that the oil phase, the emulsifier and the co-emulsifier are uniformly mixed, and then mixed with rivaroxaban to obtain a rivar. Shaban self-emulsified preparation. A pharmaceutical preparation comprising the rivaroxaban self-emulsifying preparation according to any one of claims 1 to 3 and a pharmaceutically-acceptable adjuvant. The pharmaceutical preparation according to claim 5, which is a dispersible tablet. The pharmaceutical preparation according to claim 5, wherein the adjuvant is at least one of an adsorbent, a diluent, a disintegrant, a flavor, and a lubricant. The pharmaceutical preparation according to claim 6, wherein the adsorbent is selected from at least one of anhydrous calcium hydrogen phosphate and lactose; the diluent is microcrystalline cellulose; and the disintegrant is selected from the group consisting of At least one of crospovidone and croscarmellose sodium; the flavoring agent is citric acid; the lubricant is selected from the group consisting of micronized silica gel, magnesium stearate, and sodium stearyl fumarate At least one of them. A pharmaceutical preparation according to claim 5, which is a rivaroxaban self-emulsifying and dispersible tablet, and the content of each component is: by mass percentage:

The invention discloses a preparation method of rivaroxaban self-emulsifying dispersible tablet, characterized in that the adsorbent is mixed with rivaroxaban self-emulsifying preparation, and then mixed with a diluent, a disintegrating agent, a flavoring agent and a lubricant, and pressed. sheet.