Rivaroxaban tablet and preparation method thereof

Abstract

The invention relates to a rivaroxaban tablet and a preparation method thereof. The rivaroxaban tablet comprises the following components in parts by weight: 5-15 parts of rivaroxaban, 2-10 parts of a disintegrating agent, 0.1-1 part of an adhesive, 0.1-1 part of a surfactant, 55-80 parts of a filler and 0.2-1.2 parts of a lubricant. The cumulative dissolution rate of the rivaroxaban tablet under different pH values and different medium conditions within 15 minutes is greater than 85%, the dissolution behavior is rapid, and the batch-to-batch stability is realized. The preparation method is simple in process, the content of the obtained tablets is uniform, the dissolution speed of the tablets is high, impurities do not have an obvious growth trend, the content and the dissolution rate basically remain unchanged, and the preparation stability is good.

Description

Technical Field

[0001] The present invention relates to the technical field of pharmaceutical preparations, and in particular to a rivaroxaban tablet and a preparation method thereof. Background Art

[0002] Rivaroxaban is a low molecular weight oral anticoagulant with high selectivity and direct inhibitory effect on factor Xa. It was jointly developed by Bayer Pharmaceuticals and Johnson & Johnson for the prevention of deep vein thrombosis (DVT) and pulmonary embolism (PE) in patients after hip and knee replacement surgery. Rivaroxaban was launched in Canada on September 15, 2008 and was approved for marketing in the European Union on October 1 of the same year. Chemical name: 5-chloro-nitrogen-((5S)-2-oxo-3-[-4-(3-oxo-4-morphinyl)phenyl-1,3-oxazolidin-5-yl-2-thiophene-carboxamide, molecular formula: C 19 H 18 ClN3O5S, molecular weight: 435.89, structural formula is as follows:

[0003]

[0004] Rivaroxaban exists in the form of crystal form I, II, III, hydrate, NMP solvate and THF-containing inclusion compound. The preparation process of crystal form II is complicated and the production cost is high. Crystal form I is the most common form on the market. Rivaroxaban has poor water solubility. The solubility of crystal form I of rivaroxaban in room temperature water medium is 5-7 mg / L, which leads to slow dissolution of the active ingredient in the pharmaceutical composition in vitro and low bioavailability in vivo.

[0005] CN101128205A transforms the raw material drug from crystalline state to amorphous state through the process of melt extrusion. The amorphous state has a smaller lattice energy, which greatly improves the solubility of the drug and promotes the absorption of the drug in the body. However, the stability of amorphous rivaroxaban is poorer than that of crystalline state, and the control of drug impurities will produce certain risks.

[0006] CN104055743A adopts a preparation method of direct powder mixing and tableting, which solves some problems of tableting, such as roughness, sticking, loose tablet disintegration, etc. However, the patent does not mention whether the raw material drug is micronized, and the mixing and in vitro dissolution of rivaroxaban raw materials cannot be guaranteed.

[0007] CN104666262A combines solid dispersion technology, solubilizers and adsorbents, first prepares a solid dispersion, then adsorbs the drug dispersion solution on fumed colloidal silica, mixes evenly with pharmaceutically acceptable excipients and performs direct tableting. The invention process is cumbersome. In the preparation of solid dispersions, diethylene glycol ethyl ether is used, and organic solvents are introduced during the production process. It is necessary to conduct a risk assessment on the use of organic solvents and establish corresponding EHS measures. At the same time, solid dispersions are prone to aging, and it is not guaranteed whether the drug can be evenly adsorbed on fumed colloidal silica, and the operability of commercial production is not strong.

[0008] CN103705520A adopts colloid mill or high-speed stirring bead mill to wet pulverize rivaroxaban, and the particle size of rivaroxaban raw material can be crushed to less than 5 microns, and a suspension is prepared at the same time, and the suspension is sprayed into other auxiliary materials to make suitable particles, and then further prepared into the minimum pharmaceutical dosage unit. The invention adopts wet pulverization technology to crush the rivaroxaban raw material to less than 5 microns, but the density of rivaroxaban and other materials is quite different, and in the process of preparing particles, especially in the fluidized bed granulation process, the loss of raw materials may be increased. Therefore, in the whole preparation process, there is pulverization and granulation. Two steps will cause the risk of loss of raw materials, which may also be the reason why its dissolution endpoint does not reach 100%.

[0009] CN110893176A treats the active substance with a granulation liquid containing a solvent, a wetting agent, and a disintegrant, and uses a wet granulation process to granulate the liquid containing the active substance with pharmaceutically acceptable excipients to complete the preparation of the composition. Although the invention improves the solubility of the pharmaceutical composition, it still requires wet granulation, drying, granulation and other processes, which are complex, time-consuming, and have a long production cycle, and increase the risk points of personnel and equipment during the operation.

[0010] Therefore, how to improve the solubility of rivaroxaban has become an urgent problem to be solved. Summary of the invention

[0011] To solve the above technical problems, the present invention provides a rivaroxaban tablet and a preparation method thereof. The rivaroxaban tablet of the present invention has a stable content without a downward trend, no impurity growth trend, and controllable quality under high temperature, high humidity, and light conditions, which is superior to the same product on the market. From small batch production to large batch amplification, the mixing is uniform, the data is stable, the dissolution behavior is fast, and the batch-to-batch stability is achieved.

[0012] To achieve this object, the present invention adopts the following technical solutions:

[0013] In a first aspect, the present invention provides a rivaroxaban tablet, comprising 5-15 parts of rivaroxaban, 2-10 parts of a disintegrant, 0.1-1 parts of a binder, 0.1-1 parts of a surfactant, 55-80 parts of a filler and 0.2-1.2 parts of a lubricant;

[0014] The disintegrant comprises any one of sodium carboxymethyl starch, cross-linked sodium carboxymethyl cellulose, cross-linked polyvinylpyrrolidone or calcium carboxymethyl cellulose, or a combination of at least two thereof;

[0015] The binder comprises any one of hydroxypropyl cellulose, hydroxypropyl methyl cellulose, methyl cellulose or povidone, or a combination of at least two thereof;

[0016] The filler comprises any one of mannitol, lactose monohydrate, anhydrous lactose, spray-dried lactose, microcrystalline cellulose, powdered cellulose, microcrystalline cellulose with micropowdered silica gel, or a combination of at least two thereof;

[0017] The surfactant includes any one of lecithin, stearyl alcohol, poloxamer or sodium lauryl sulfate or a combination of at least two thereof;

[0018] The lubricant includes any one of stearic acid, magnesium stearate, sodium stearyl fumarate or colloidal silicon dioxide or a combination of at least two thereof.

[0019] The 5-15 parts may be, for example, 5 parts, 6 parts, 7 parts, 8 parts, 9 parts, 10 parts, 11 parts, 12 parts, 13 parts, 14 parts or 15 parts, etc. The 2-10 parts may be, for example, 2 parts, 3 parts, 4 parts, 5 parts, 6 parts, 7 parts, 8 parts, 9 parts or 10 parts, etc. The 0.1-1 part may be, for example, 0.1 part, 0.2 part, 0.3 part, 0.4 part, 0.5 part, 0.6 part, 0.7 part, 0.8 part, 0.9 part or 1 part, etc. The 55-80 parts may be, for example, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85. The 0.2-1.2 parts may be, for example, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1 or 1.2 parts, etc.

[0020] The rivaroxaban tablets of the present invention include the above-mentioned raw materials. Through the mutual coordination of the above-mentioned raw materials, the solubility of the rivaroxaban tablets is significantly improved. Within the above-mentioned weight parts range, while ensuring good mixing uniformity, the dissolution rate of rivaroxaban is significantly improved. The cumulative dissolution rate at 15 minutes is much higher than that of the currently commercially available products, which is more conducive to the absorption of rivaroxaban.

[0021] Preferably, the particle size D90 of rivaroxaban is 1-60 μm, for example, it can be 1 μm, 5 μm, 10 μm, 15 μm, 20 μm, 25 μm, 30 μm, 35 μm, 40 μm, 45 μm, 50 μm, 55 μm or 60 μm, etc.

[0022] Preferably, the particle size D90 of rivaroxaban is 1-20 μm, for example, it can be 1 μm, 2 μm, 3 μm, 4 μm, 5 μm, 6 μm, 7 μm, 8 μm, 9 μm, 10 μm, 11 μm, 12 μm, 13 μm, 14 μm, 15 μm, 16 μm, 17 μm, 18 μm, 19 μm or 20 μm, etc.

[0023] In the present invention, the average particle size of rivaroxaban becomes smaller, so that its surface area increases, solubility increases, and the dissolution rate of the drug can be improved to a certain extent. However, after a certain degree of reduction, the particle surface becomes smoother and smoother, the original medicinal material characteristics become less and less obvious, and the application of micronization technology does not change the main functional group structure of the original medicinal material. On the contrary, if the particle size is too small, it affects the dissolution effect of the ultrafine powder. Within the above range, good original medicinal material characteristics can be obtained, and good dissolution effect can be achieved.

[0024] Preferably, the filler is a combination of a first filler and a second filler.

[0025] Preferably, the first filler is spray-dried lactose and the second filler is microcrystalline cellulose.

[0026] The mass ratio of rivaroxaban to spray-dried lactose is 1:(3-5), and the (3-5) may be, for example, 3, 3.5, 4, 4.5 or 5.

[0027] Preferably, the shape of the spray-dried lactose comprises a spherical shape;

[0028] Preferably, the mass ratio of rivaroxaban to microcrystalline cellulose is 1:(2-4), more preferably 1:(2.5-3.5). The (2-4) may be, for example, 2, 2.5, 3, 3.5 or 4. The (2.5-3.5) may be, for example, 2.5, 3 or 3.5.

[0029] Preferably, the type of microcrystalline cellulose includes any one of PH101, PH102, PH301, PH302, UF-711 or UF-702, or a combination of at least two thereof;

[0030] Preferably, the model of the microcrystalline cellulose is UF-711.

[0031] Preferably, the particle size of the spray-dried lactose is 40-120 mesh, for example, it can be 40 mesh, 45 mesh, 50 mesh, 55 mesh, 60 mesh, 65 mesh, 70 mesh, 75 mesh, 80 mesh, 85 mesh, 90 mesh, 95 mesh, 100 mesh, 105 mesh, 110 mesh, 115 mesh or 120 mesh, etc.

[0032] Preferably, the particle size of the spray-dried lactose is 60-80 mesh, for example, it can be 60 mesh, 61 mesh, 62 mesh, 63 mesh, 64 mesh, 65 mesh, 66 mesh, 67 mesh, 68 mesh, 69 mesh, 70 mesh, 71 mesh, 72 mesh, 73 mesh, 74 mesh, 75 mesh, 76 mesh, 77 mesh, 78 mesh, 79 mesh or 80 mesh.

[0033] In the present invention, the particle size of the spray-dried lactose is getting closer to that of the raw material drug, the mixing uniformity RSD is gradually reduced, and the micronized raw material drug can be uniformly adsorbed on the surface of the spray-dried lactose. The good mixing uniformity of the particles can ensure the content uniformity of the tablets, thereby ensuring the efficacy.

[0034] Preferably, the disintegrant is cross-linked carboxymethyl cellulose sodium.

[0035] Preferably, the mass ratio of rivaroxaban to cross-linked sodium carboxymethyl cellulose is (1-3):1, and the (1-3) can be, for example, 1, 1.5, 2, 2.5 or 3.

[0036] Preferably, the binder is povidone.

[0037] Preferably, the mass ratio of rivaroxaban to povidone is (15-25):1, and the (15-25) can be, for example, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24 or 25, etc.

[0038] Preferably, the rivaroxaban tablet comprises, by weight, 10 parts of rivaroxaban, 40 parts of spray-dried lactose, 28.3 parts of microcrystalline cellulose UF-711, 5 parts of cross-linked sodium carboxymethyl cellulose, 0.5 parts of povidone K30, 0.5 parts of sodium lauryl sulfate and 0.7 parts of magnesium stearate.

[0039] In a second aspect, the present invention provides a method for preparing the rivaroxaban tablets according to the first aspect, the preparation method comprising the steps of: air flow grinding rivaroxaban, and then mixing with a disintegrant, a binder, a surfactant, a filler and a lubricant respectively to prepare the rivaroxaban tablets.

[0040] Preferably, the steps of the preparation method include:

[0041] (1) performing air flow pulverization on rivaroxaban;

[0042] (2) mixing rivaroxaban and the first filler for the first time;

[0043] (3) adding a binder, a disintegrant and a surfactant to the mixture obtained in step (2) for a second mixing;

[0044] (4) adding the mixture obtained in step (3) to the second filler for a third mixing;

[0045] (5) Adding a lubricant to the mixture obtained in step (4) for a fourth mixing, and directly tableting.

[0046] In the mixing direct compression process, mixing time also has a crucial influence on mixing uniformity. Generally speaking, the effect of mixing time on mixing uniformity is that it first increases and then decreases. However, if the mixing time is further extended, the mixing uniformity will decrease to a certain extent. This phenomenon is called "over-mixing". This phenomenon shows that the effect of increasing mixing time on mixing uniformity is not linear, but there is an optimal point. Beyond this point, continuing to increase the mixing time will lead to a decrease in mixing uniformity. In the present invention, within the above-mentioned time range, better mixing uniformity can be obtained, thereby promoting the dissolution of the raw materials.

[0047] Preferably, the stirring speed of the first mixing is 5-15 rpm, and the time is 5-15 min. The 5-15 rpm can be, for example, 5 rpm, 6 rpm, 7 rpm, 8 rpm, 9 rpm, 10 rpm, 11 rpm, 12 rpm, 13 rpm, 14 rpm or 15 rpm, etc. The 5-15 min can be, for example, 5 min, 6 min, 7 min, 8 min, 9 min, 10 min, 11 min, 12 min, 13 min, 14 min or 15 min, etc.

[0048] Preferably, the stirring speed of the second mixing is 5-15 rpm, and the time is 15-20 min. The 5-15 rpm can be, for example, 5 rpm, 6 rpm, 7 rpm, 8 rpm, 9 rpm, 10 rpm, 11 rpm, 12 rpm, 13 rpm, 14 rpm or 15 rpm, etc. The 15-20 min can be, for example, 15 min, 16 min, 17 min, 18 min, 19 min or 20 min, etc.

[0049] Preferably, the stirring speed of the third mixing is 5-15 rpm, and the time is 5-30 min. The 5-15 rpm can be, for example, 5 rpm, 6 rpm, 7 rpm, 8 rpm, 9 rpm, 10 rpm, 11 rpm, 12 rpm, 13 rpm, 14 rpm or 15 rpm, etc. The 5-30 min can be, for example, 5 min, 10 min, 15 min, 20 min, 25 min or 30 min, etc.

[0050] The stirring speed of the fourth mixing is 5-10 rpm, and the time is 5-10 min. The 5-10 rpm may be, for example, 5 rpm, 6 rpm, 7 rpm, 8 rpm, 9 rpm or 10 rpm, etc. The 5-10 min may be, for example, 5 min, 6 min, 7 min, 8 min, 9 min or 10 min, etc.

[0051] Preferably, the hardness of the rivaroxaban tablets after tableting is 40-80N, for example, 40N, 45N, 50N, 55N, 60N, 65N, 70N, 75N or 80N.

[0052] Preferably, the diameter of the hardness of the rivaroxaban tablet after tableting is 2-10 mm, for example, it can be 2 mm, 3 mm, 4 mm, 5 mm, 6 mm, 7 mm, 8 mm, 9 mm or 10 mm.

[0053] Compared with the prior art, the present invention has at least the following beneficial effects:

[0054] 1. The RSD (n=11) of 11 sampling points of the intermediate before tableting obtained by the combination and preparation method of rivaroxaban tablets used in the present invention is less than 5.0%; from small batch production to large batch amplification, the mixing is uniform and the data is stable. The cumulative dissolution of the rivaroxaban tablets used in the present invention is greater than 85% at 15 minutes under different pH and different media conditions, and the dissolution behavior is fast and stable between batches.

[0055] 2. The rivaroxaban tablets prepared by the present invention have a stable content with no decreasing trend and no increasing trend of impurities under high temperature, high humidity and light conditions; after being placed under accelerated conditions (40°C / 75%RH) for six months, the dissolution behavior has no obvious slowing down or accelerating trend, remains stable, and has controllable quality, which is superior to similar products on the market.

[0056] 3. The preparation method adopted by the present invention does not require dry granulation, wet granulation or fluidized bed granulation, and can be directly tableted, which is simple in process, high in efficiency in preparing the pharmaceutical composition, low in production cost, and easy for commercial production. The obtained intermediate before tableting has a small angle of repose, good fluidity, a small difference between the bulk density and the tap density, small pores inside the particles, good fluidity due to small compression, and small difference in tablet weight, and a tablet of good quality is obtained after tableting.

[0057] 4. The preparation method of the present invention only requires tableting after mixing, which reduces the procedures of granulation, granulation, drying, etc., is time-saving, saves energy, reduces production costs, effectively improves the economic benefits of the enterprise, and increases the competitiveness of the enterprise. BRIEF DESCRIPTION OF THE DRAWINGS

[0058] Figure 1 This is an electron micrograph of spray-dried lactose particles;

[0059] Figure 2 This is an electron micrograph of lactose monohydrate particles;

[0060] Figure 3 is the mixing uniformity sampling location map;

[0061] Figure 4 It is the average drug-time curve (PKCS) of the test preparation T and the reference preparation R under fasting conditions;

[0062] Figure 5 It is the semi-logarithmic plot (PKCS) of the mean drug-time curve of the test preparation T and the reference preparation R under fasting conditions;

[0063] Figure 6 It is the mean drug-time curve (PKCS) of the test preparation T and the reference preparation R under the postprandial condition;

[0064] Figure 7 It is the semi-logarithmic plot (PKCS) of the mean drug-time curve of the test preparation T and the reference preparation R under fed conditions. DETAILED DESCRIPTION

[0065] The technical solution of the present invention is further described below in conjunction with the accompanying drawings and through specific implementation methods. However, the following examples are only simplified examples of the present invention and do not represent or limit the scope of protection of the present invention. The scope of protection of the present invention shall be subject to the claims.

[0066] The sources of reagents used in the following examples are:

[0067] Spray dried lactose: Jiangsu Daoning Pharmaceutical Co., Ltd.

[0068] Povidone K30: BASF (China) Co., Ltd.

[0069] Microcrystalline cellulose PH101: Asahi Kasei Corporation

[0070] Microcrystalline cellulose PH102: Asahi Kasei Corporation

[0071] Microcrystalline cellulose PH301: Asahi Kasei Corporation

[0072] Microcrystalline cellulose PH302: Asahi Kasei Corporation

[0073] Microcrystalline cellulose UF-711: Asahi Kasei Corporation

[0074] Microcrystalline cellulose UF-702: Asahi Kasei Corporation

[0075] Example 1

[0076] This embodiment provides a rivaroxaban tablet.

[0077] 10 parts of rivaroxaban raw materials were air flow crushed to 20 μm, and mixed with 40 parts of 80 mesh spray-dried lactose at a speed of 10 rpm for 10 min for the first mixing. Then 0.5 parts of povidone K30, 5 parts of cross-linked carboxymethyl cellulose sodium and 0.5 parts of sodium lauryl sulfate were added at a speed of 10 rpm and mixed for 17 min for the second mixing. 28.3 parts of microcrystalline cellulose UF-711 were added at 10 rpm and mixed for 5 min for the third mixing. Finally, 0.7 parts of magnesium stearate were added at a speed of 10 rpm and mixed for 5 min. After mixing, tablets were directly compressed, and the tablets had a diameter of 6 mm and a hardness of 60 N.

[0078] Example 2

[0079] This embodiment provides a rivaroxaban tablet.

[0080] 15 parts of rivaroxaban were air flow crushed into 10 μm, and mixed with 50 parts of 60 mesh spray-dried lactose at a speed of 5 rpm for 15 minutes for the first mixing. Then 0.75 parts of povidone K30, 10 parts of cross-linked carboxymethyl cellulose sodium and 1 part of sodium lauryl sulfate were added at a speed of 15 rpm and mixed for 15 minutes for the second mixing. 30 parts of microcrystalline cellulose UF-711 were added at 15 rpm and mixed for 5 minutes for the third mixing. Finally, 0.2 parts of magnesium stearate were added at a speed of 5 rpm and mixed for 10 minutes. After mixing, the tablets were directly compressed, and the tablets had a diameter of 2 mm and a hardness of 80N.

[0081] Example 3

[0082] This embodiment provides a rivaroxaban tablet

[0083] 6 parts of rivaroxaban were air flow crushed to 1 μm, and mixed with 30 parts of 80 mesh spray-dried lactose at a speed of 15 rpm for 5 min for the first mixing. Then 0.3 parts of povidone K30, 2 parts of cross-linked carboxymethyl cellulose sodium and 0.1 parts of sodium lauryl sulfate were added at a speed of 5 rpm and mixed for 20 min for the second mixing. 25 parts of microcrystalline cellulose UF-711 were added at 5 rpm and mixed for 5 min for the third mixing. Finally, 1.2 parts of magnesium stearate were added at a speed of 7 rpm and mixed for 7 min. After mixing, tablets were directly compressed, and the tablets had a diameter of 10 mm and a hardness of 40 N.

[0084] Example 4

[0085] This embodiment provides a rivaroxaban tablet, which is different from Embodiment 1 only in that an equal amount of spray-dried lactose is replaced with lactose monohydrate, and the rest is the same as Embodiment 1.

[0086] Example 5

[0087] This embodiment provides a rivaroxaban tablet, which is different from Embodiment 1 only in that an equal amount of spray-dried lactose is replaced with anhydrous lactose, and the rest is the same as Embodiment 1.

[0088] Example 6

[0089] This embodiment provides a rivaroxaban tablet, which is different from Example 1 only in that an equal amount of spray-dried lactose is replaced with mannitol, and the rest is consistent with Example 1.

[0090] Example 7

[0091] This embodiment provides a rivaroxaban tablet, which is different from Embodiment 1 only in that the particle size of the spray-dried lactose is 40 mesh, and the rest is the same as Embodiment 1.

[0092] Example 8

[0093] This embodiment provides a rivaroxaban tablet, which is different from Example 1 only in that the particle size of the spray-dried lactose is 100 mesh, and the rest is the same as Example 1.

[0094] Example 9

[0095] This embodiment provides a rivaroxaban tablet, which is different from Embodiment 1 only in that the particle size of the spray-dried lactose is 120 mesh, and the rest is the same as Embodiment 1.

[0096] Example 10

[0097] This embodiment provides a rivaroxaban tablet, which is different from Example 1 only in that the amount of spray-dried lactose is 30 parts, that is, the ratio of rivaroxaban to spray-dried lactose is 1:3, and the rest is consistent with Example 1.

[0098] Embodiment 11

[0099] This embodiment provides a rivaroxaban tablet, which is different from Example 1 only in that the amount of spray-dried lactose is 50 parts, that is, the ratio of rivaroxaban to spray-dried lactose is 1:5, and the rest is consistent with Example 1.

[0100] Example 12

[0101] This embodiment provides a rivaroxaban tablet, which is different from the embodiment 1 only in that the particle size of rivaroxaban is 52.4 μm, and the rest is the same as the embodiment 1.

[0102] Example 13

[0103] This embodiment provides a rivaroxaban tablet, which is different from the embodiment 1 only in that the particle size of rivaroxaban is 31.8 μm, and the rest is the same as the embodiment 1.

[0104] Embodiment 14

[0105] This embodiment provides a rivaroxaban tablet, which is different from the embodiment 1 only in that the particle size of rivaroxaban is 7.65 μm, and the rest is the same as the embodiment 1.

[0106] Embodiment 15

[0107] This embodiment provides a rivaroxaban tablet, which is different from Example 1 only in that an equal amount of cross-linked sodium carboxymethyl cellulose is replaced by sodium carboxymethyl starch, and the rest is consistent with Example 1.

[0108] Example 16

[0109] This embodiment provides a rivaroxaban tablet, which is different from Example 1 only in that an equal amount of cross-linked carboxymethyl cellulose sodium is replaced by cross-linked polyvinylpyrrolidone, and the rest is consistent with Example 1.

[0110] Embodiment 17

[0111] This embodiment provides a rivaroxaban tablet, which is different from Example 1 only in that an equal amount of cross-linked sodium carboxymethyl cellulose is replaced by carboxymethyl cellulose calcium, and the rest is the same as Example 1.

[0112] Embodiment 18

[0113] This embodiment provides a rivaroxaban tablet, which is different from Example 1 only in that the amount of cross-linked carboxymethyl cellulose sodium is 10 parts, that is, the ratio of cross-linked carboxymethyl cellulose sodium to rivaroxaban is 1:1, and the rest is consistent with Example 1.

[0114] Embodiment 19

[0115] This embodiment provides a rivaroxaban tablet, which is different from Example 1 only in that the amount of cross-linked carboxymethyl cellulose sodium is 3 parts, that is, the ratio of cross-linked carboxymethyl cellulose sodium to rivaroxaban is 1:3, and the rest is consistent with Example 1.

[0116] Embodiment 20

[0117] This embodiment provides a rivaroxaban tablet, which is different from Example 1 only in that an equal amount of povidone K30 is replaced by hydroxypropyl cellulose, and the rest is consistent with Example 1.

[0118] Embodiment 21

[0119] This embodiment provides a rivaroxaban tablet, which is different from Example 1 only in that an equal amount of povidone K30 is replaced by hydroxypropyl methylcellulose, and the rest is consistent with Example 1.

[0120] Embodiment 22

[0121] This embodiment provides a rivaroxaban tablet, which is different from Example 1 only in that an equal amount of povidone K30 is replaced by methylcellulose, and the rest is consistent with Example 1.

[0122] Embodiment 23

[0123] This embodiment provides a rivaroxaban tablet, which is different from Example 1 only in that the amount of povidone K30 is 0.4 parts, that is, the ratio of povidone K30 to rivaroxaban is 1:25, and the rest is consistent with Example 1.

[0124] Embodiment 24

[0125] This embodiment provides a rivaroxaban tablet, which is different from Example 1 only in that the amount of povidone K30 is 0.7 parts, that is, the ratio of povidone K30 to rivaroxaban is 1:15, and the rest is consistent with Example 1.

[0126] Embodiment 25

[0127] This embodiment provides a rivaroxaban tablet, which is different from Embodiment 1 only in that an equal amount of sodium lauryl sulfate is replaced with lecithin, and the rest is the same as Embodiment 1.

[0128] Embodiment 26

[0129] This embodiment provides a rivaroxaban tablet, which is different from Example 1 only in that an equal amount of sodium lauryl sulfate is replaced by stearyl alcohol, and the rest is consistent with Example 1.

[0130] Embodiment 27

[0131] This embodiment provides a rivaroxaban tablet, which is different from Embodiment 1 only in that an equal amount of sodium dodecyl sulfate is replaced by poloxamer, and the rest is the same as Embodiment 1.

[0132] Embodiment 28

[0133] This embodiment provides a rivaroxaban tablet, which is different from Example 1 only in that an equal amount of magnesium stearate is replaced by stearic acid, and the rest is consistent with Example 1.

[0134] Embodiment 29

[0135] This embodiment provides a rivaroxaban tablet, which is different from Example 1 only in that an equal amount of magnesium stearate is replaced by sodium stearyl fumarate, and the rest is consistent with Example 1.

[0136] Embodiment 30

[0137] This embodiment provides a rivaroxaban tablet, which is different from Example 1 only in that an equal amount of magnesium stearate is replaced by colloidal silicon dioxide, and the rest is the same as Example 1.

[0138] Embodiment 31

[0139] This embodiment provides a rivaroxaban tablet, which is different from Example 1 only in that an equal amount of microcrystalline cellulose UF-71 1 is replaced by powdered cellulose, and the rest is consistent with Example 1.

[0140] Embodiment 32

[0141] This embodiment provides a rivaroxaban tablet, which is different from Example 1 only in that an equal amount of microcrystalline cellulose UF-711 is replaced with microcrystalline cellulose powdered silica gel, and the rest is consistent with Example 1.

[0142] Embodiment 33

[0143] This embodiment provides a rivaroxaban tablet, which is different from Example 1 only in that an equal amount of microcrystalline cellulose UF-711 is replaced by mannitol, and the rest is consistent with Example 1.

[0144] Embodiment 34

[0145] This embodiment provides a rivaroxaban tablet, which is different from Example 1 only in that an equal amount of microcrystalline cellulose UF-711 is replaced by microcrystalline cellulose PH101, and the rest is consistent with Example 1.

[0146] Embodiment 35

[0147] This embodiment provides a rivaroxaban tablet, which is different from Example 1 only in that an equal amount of microcrystalline cellulose UF-711 is replaced by microcrystalline cellulose PH102, and the rest is consistent with Example 1.

[0148] Embodiment 36

[0149] This embodiment provides a rivaroxaban tablet, which is different from Example 1 only in that an equal amount of microcrystalline cellulose UF-711 is replaced by microcrystalline cellulose PH301, and the rest is consistent with Example 1.

[0150] Embodiment 37

[0151] This embodiment provides a rivaroxaban tablet, which is different from Example 1 only in that an equal amount of microcrystalline cellulose UF-711 is replaced by microcrystalline cellulose PH302, and the rest is consistent with Example 1.

[0152] Embodiment 38

[0153] This embodiment provides a rivaroxaban tablet, which is different from Example 1 only in that an equal amount of microcrystalline cellulose UF-711 is replaced by microcrystalline cellulose UF-702, and the rest is consistent with Example 1.

[0154] Embodiment 39

[0155] This embodiment provides a rivaroxaban tablet, which is different from Embodiment 1 only in that the time of the third mixing speed is 10 minutes, and the rest is the same as Embodiment 1.

[0156] Embodiment 40

[0157] This embodiment provides a rivaroxaban tablet, which is different from Embodiment 1 only in that the time of the third mixing speed is 15 minutes, and the rest is the same as Embodiment 1.

[0158] Embodiment 41

[0159] This embodiment provides a rivaroxaban tablet, which is different from Embodiment 1 only in that the time of the third mixing speed is 25 min, and the rest is the same as Embodiment 1.

[0160] Embodiment 42

[0161] This embodiment provides a rivaroxaban tablet, which is different from Embodiment 1 only in that the time of the third mixing speed is 30 minutes, and the rest is the same as Embodiment 1.

[0162] Comparative Example 1

[0163] This comparative example provides a rivaroxaban tablet, which is different from Example 1 only in that the patent CN104055743A method is adopted, and the dry powder is mixed and directly compressed into tablets. The raw materials used include 10 parts of rivaroxaban, 70 parts of lactose, 5 parts of mannitol, 3 parts of cross-linked carboxymethyl cellulose sodium, 2 parts of citric acid, 1 part of sodium lauryl sulfate, 4 parts of carbomer, 4 parts of povidone K90, 4 parts of hydroxypropyl cellulose, 1 part of magnesium stearate and 1 part of silicon dioxide.

[0164] Comparative Example 2

[0165] The present comparative example provides a rivaroxaban tablet, which differs from Example 1 only in that the method of patent CN104666262A is adopted to combine solid dispersion technology with solubilization technology and adsorbent, firstly prepare solid dispersion solubilized drug, adsorb the drug dispersion solution with gas phase colloidal silica, then mix evenly with pharmaceutically acceptable excipients, and directly tablet. The raw materials used include 10 parts of rivaroxaban, 30 parts of diethylene glycol monoethyl ether, 20 parts of hydroxypropyl cellulose, 150 parts of gas phase silica, 200 parts of microcrystalline cellulose M102QD, 15 parts of cross-linked polyvinylpyrrolidone and 5 parts of magnesium stearate.

[0166] Comparative Example 3

[0167] This comparative example provides a rivaroxaban tablet, which is different from Example 1 only in that the method of patent CN103550165A is adopted, and pharmaceutically acceptable excipients are wet granulated to obtain blank particles without active ingredients, and then rivaroxaban is mixed with the above blank particles and additional pharmaceutically acceptable additives, and finally tableted. The raw materials used include 40 parts of lactose monohydrate, 26.5 parts of microcrystalline cellulose, 3.40 parts of cross-linked sodium carboxymethyl cellulose, 1.70 parts of sodium lauryl sulfate, 2.55 parts of povidone, 10 parts of rivaroxaban and 0.85 parts of magnesium stearate.

[0168] Comparative Example 4

[0169] This comparative example provides a rivaroxaban tablet, which differs from Example 1 only in the order of mixing materials. Spray-dried lactose, microcrystalline cellulose and rivaroxaban are mixed for the first time, then cross-linked sodium carboxymethyl cellulose and sodium lauryl sulfate are added for the second mixing, and finally magnesium stearate is added for the third mixing. A direct tableting process is used, and the rest is consistent with Example 1.

[0170] Comparative Example 5

[0171] The present comparative example provides a rivaroxaban tablet, which differs from Example 1 only in that the method of patent CN109419778A is adopted, rivaroxaban, a binder and a surfactant are mixed and sieved, and then air flow crushing is performed after sieving, and then mixed with part of the diluent and sieved, and then mixed with the remaining diluent and other materials in the prescription except the lubricant and sieved, and finally mixed evenly with the lubricant, and the powder is directly tableted. The raw materials used include 10 parts of rivaroxaban, 27.9 parts of lactose monohydrate, 40 parts of microcrystalline cellulose, 3 parts of cross-linked carboxymethyl cellulose sodium, 3 parts of hydroxypropyl methylcellulose (5cp), 0.5 parts of sodium lauryl sulfate and 0.6 parts of magnesium stearate.

[0172] Comparative Example 6

[0173] This comparative example provides a rivaroxaban tablet, which is different from Example 1 only in that the rivaroxaban tablet is a commercial product of Bayer Pharmaceuticals in Germany, Xarelto The batch number is BJ58093.

[0174] Comparative Example 7

[0175] This comparative example provides a rivaroxaban tablet, which is different from Example 1 only in that the rivaroxaban tablet is a commercial product of Bayer Pharmaceuticals in Germany, Xarelto The batch number is BJ54779.

[0176] Comparative Example 8

[0177] This comparative example provides a rivaroxaban tablet, which is different from Example 1 only in that the rivaroxaban tablet is a commercial product of Bayer Pharmaceuticals in Germany, Xarelto The batch number is BJ56486.

[0178] Comparative Example 9

[0179] This comparative example provides a rivaroxaban tablet, which is different from Example 1 only in that the rivaroxaban tablet is a commercial product of Bayer Pharmaceuticals in Germany, Xarelto The batch number is BJ57602.

[0180] Test Example 1

[0181] This test case tests the mixing uniformity.

[0182] Among the process steps of oral solid preparations, the powder mixing uniformity of the mixing process is a key step in the process inspection. The qualification of the mixing uniformity directly affects the quality of the preparation. How to make the mixing uniformity of the mixed materials meet the production requirements and ensure that each unit dose of the material contains equal active substances is the prerequisite for achieving uniform content of the finished product.

[0183] Refer to the Technical Guidelines for the Study of Mixing Uniformity and Unit Uniformity of Controlled Dosages of Chemical Oral Solid Preparations (Trial) to determine the sampling points and sampling methods, and select appropriate testing methods to test the samples. The mixing uniformity requirements are: select 3 sampling points at the top, middle and bottom positions of the entire batch and 10 sampling points at the discharge port, and take three samples at each sampling point. The specific sampling locations for mixing uniformity are as follows: Figure 3 One sample was tested at each sampling point, and the relative standard deviation of all samples was calculated. The sample RSD was <5.0%; and all single values ​​were within ±10.0% (absolute) of the mean, indicating good mixing uniformity.

[0184] Determination method: According to high performance liquid chromatography (Chinese Pharmacopoeia 2020 Edition Part IV General Rules 0512)

[0185] Solvent: acetonitrile-0.01 mol / L phosphoric acid solution (volume ratio of 3:2).

[0186] Test solution: Take an appropriate amount of the product, accurately weigh (equivalent to 20 mg of rivaroxaban), place in a 100 mL volumetric flask, add about 70 mL of solvent, and ultrasonically treat for 15 min to completely dissolve rivaroxaban. Cool, dilute to the scale with solvent, shake well, filter, and take the filtrate.

[0187] Reference substance solution: Take an appropriate amount of rivaroxaban reference substance, weigh accurately, dissolve in solvent and quantitatively dilute to make a solution containing 0.2 mg per 1 mL.

[0188] Chromatographic conditions: octadecylsilane bonded silica gel was used as filler (purospher star RP-18 endcapped, 55 mm×4.0 mm, 3 μm); 0.01 mol / L phosphoric acid solution was used as mobile phase A, and acetonitrile was used as mobile phase B; linear gradient elution was performed according to Table 1; the detection wavelength was 250 nm; the column temperature was 45°C, the flow rate was 1.0 mL per minute, and the injection volume was 5 μL.

[0189] Table 1

[0190]

[0191]

[0192] Determination method: Accurately measure the test solution and the reference solution, inject them into the liquid chromatograph respectively, record the chromatogram, and calculate the peak area according to the external standard method. The specific results are shown in Table 2:

[0193] Table 2

[0194]

[0195]

[0196] The results show that:

[0197] (1) From the above mixing uniformity test data, it can be seen that the mixing uniformity RSD value in Example 1 is the smallest, indicating that the mixing uniformity of the intermediate before rivaroxaban tablets is the best, and its prescription component combination and process parameters are the optimal combination.

[0198] (2) By comparing Example 1 with Examples 4-6, it can be seen that Figure 1 This is an electron microscope image of spray-dried lactose particles. Figure 2This is an electron microscope image of lactose monohydrate particles. After lactose monohydrate or anhydrous lactose was used instead of spray-dried lactose for preparation, the uniformity of the mixed particles was significantly deteriorated, indicating that the appearance of lactose has a great influence on the mixing of raw materials. Although mannitol is a general auxiliary material for mixed direct compression, the RSD of the mixing uniformity is significantly increased and exceeds all intermediates mixed with lactose, indicating that mannitol is not the first choice for mixing with rivaroxaban.

[0199] (3) Example 1 By comparing Example 7, it can be seen that the spray-dried lactose is spherical, and since the drug components can be adsorbed on the porous surface, it can be evenly distributed in low-dose formulations. The RSD value of the mixing uniformity of spray-dried lactose (40-60 mesh) is 3.8%, compared with the RSD value of the mixing uniformity of spray-dried lactose (60-80 mesh) of 1.2%. As the particle size of the spray-dried lactose becomes closer to that of the raw material drug, the mixing uniformity RSD gradually decreases and reaches a stable fluctuation below 60 mesh. At the same time, for the micronized raw material drug, it can be evenly adsorbed on the surface of the spray-dried lactose. The good mixing uniformity of the particles can ensure the content uniformity of the tablets, thereby ensuring the efficacy.

[0200] (4) By comparing Example 1 with Examples 10-11, it can be seen that when the ratio of spray-dried lactose is 1:(3-5), the mixing uniformity RSD does not exceed 2.5%. Among them, when the ratio of rivaroxaban to spray-dried lactose is 1:4, the mixing uniformity RSD is the best.

[0201] (5) By comparing Example 1 with Examples 12-13, it can be seen that the mixing uniformity data show that the raw material particle size of rivaroxaban is 40-60 μm, 20-40 μm, and less than 20 μm can be mixed evenly with materials such as spray-dried lactose. At the same time, the RSD value of the mixing uniformity of the raw material particle size within the range of less than 20 μm is 1.2%, not more than 2.0%. Considering the energy consumption of pulverization and the convenience of industrial production, it is more conducive to subsequent production to control the particle size of the raw material within the range of less than 20 μm.

[0202] (6) Comparing Example 1 with Examples 15-17, it can be seen that in terms of disintegrants, the RSD of the mixing uniformity of sodium carboxymethyl starch, cross-linked sodium carboxymethyl cellulose, cross-linked polyvinylpyrrolidone, and calcium carboxymethyl cellulose is between 1.2% and 2.3%, all of which do not exceed 2.5%. The data is relatively stable, and has good mixing uniformity. Comparing Example 1 with Examples 18-19, it can be seen that the ratio of cross-linked sodium carboxymethyl cellulose and rivaroxaban is between 1.2% and 2.7%, and the mixing uniformity RSD is between 1.2% and 2.7%, all of which do not exceed 3.0%. The data is not much different, and has good mixing uniformity. Disintegrants are mainly substances that quickly break tablets into fine particles, so that the functional ingredients are quickly dissolved and absorbed to play a role. They are mainly related to the dissolution rate, and the specific selection needs to be selected in combination with the dissolution curve data.

[0203] (7) By comparing Example 1 with Examples 20-22, it can be seen that the RSD of the mixing uniformity of hydroxypropyl cellulose, hydroxypropyl methylcellulose, methyl cellulose and povidone is 1.2% to 3.8%, all of which do not exceed 4.0%. Among them, the RSD of the mixing uniformity of povidone is 1.2%, which is significantly less than the RSD of the mixing uniformity of the other three adhesives. Based on the RSD of the mixing uniformity, povidone can be preferentially selected. By comparing Example 1 with Examples 23-24, it can be seen that the mixing uniformity RSD of rivaroxaban and povidone in the ratio of (15-25): 1 is between 1.2% and 2.2%, all of which do not exceed 2.5%. The data are relatively close, and have good mixing uniformity. The working principle of the adhesive mainly involves the adhesion and cohesion of the surface, which can allow different objects to be closely combined, and when the pharmaceutical preparation is formed, it plays a role in maintaining the stability, safety or homogeneity of the drug. The amount of the adhesive used will affect the dissolution rate, and the specific ratio selection needs to be selected in combination with the dissolution curve data.

[0204] (8) By comparing Example 1 with Examples 25-27, it can be seen that the surfactant may not have a significant effect due to the small amount added. The RSDs of lecithin, stearyl alcohol, poloxamer, and sodium lauryl sulfate are between 1.2% and 2.5%, all of which do not exceed 3.0%, and the data are not much different. At the same time, in tablet manufacturing, surfactants are used as auxiliary disintegrants. They can increase the wettability of the drug, promote the penetration of water, and thus accelerate the disintegration process of the tablet. This is because surfactants can reduce the surface tension of the liquid, making it easier for water to penetrate into the interior of the tablet, so that the tablet can be decomposed faster after taking it, which is beneficial for the human body to absorb the drug ingredients. The amount of surfactant used will affect the dissolution rate, and the specific ratio selection needs to be selected in combination with the dissolution curve data.

[0205] (9) In the present invention, the lubricant can reduce the friction between the powder and the mold, reduce the mutual adhesion between the powder particles, and thus improve the fluidity and compressibility of the tablet. The participation of the lubricant in the total mixing may not be a completely uniform mixing process. Therefore, this time, the mixing uniformity of the lubricant is not specifically investigated, and a comparative screening is performed in the powder fluidity evaluation.

[0206] (10) Comparing Example 1 with Examples 34-38, it can be seen that the RSD of the mixing uniformity of microcrystalline cellulose, powdered cellulose, microcrystalline cellulose with micropowdered silica gel and mannitol is between 1.2% and 2.5%, all of which do not exceed 3.0%, and the data are not much different. Comparing Example 1 with Examples 34-38, it can be seen that the RSD of the mixing uniformity of microcrystalline cellulose models PH101, PH301, and UF-711 is between 1.2% and 2.6%, all of which do not exceed 2.9%, and the data are not much different. The RSD of the mixing uniformity of microcrystalline cellulose models PH102, PH302, and UF-702 is between 2.9% and 3.5%, which is quite different from PH101, PH301, and UF-711. At the same time, since microcrystalline cellulose has certain bonding and disintegrating effects, it is necessary to combine the formability, disintegration and dissolution of each model for selection.

[0207] (11) By comparing Example 1 with Examples 39-42, it can be seen that the RSD of the mixing uniformity of the third mixing at the mixing time of 10min, 15min, 20min, 25min, and 30min are 2.0%, 1.9%, 1.2%, 1.8%, and 2.4%, respectively. The RSD of the mixing uniformity is between 1.2% and 2.4%, all of which do not exceed 2.5%. The data are not much different, and the mixing uniformity is good.

[0208] (12) Comparing Example 1 with Comparative Examples 1-5, it can be seen that the mixing uniformity RSD values ​​of Comparative Examples 1-5 are between 3.9% and 6.6%, the mixing uniformity RSD of Comparative Example 1 exceeds the specified limit, and the mixing uniformity RSD values ​​of Comparative Examples 2-5 are between 3.9% and 4.8%, which are closer to the limit of 5% and cannot reach the enterprise internal control standard (RSD < 4.0%). In Comparative Example 4, the mixing method was adjusted, and spray-dried lactose, microcrystalline cellulose and micronized rivaroxaban were mixed together. It was found that the mixing uniformity of rivaroxaban was poor. Therefore, rivaroxaban mixed with a single spray-dried lactose is more conducive to mixing. If other materials are added at the same time to interfere with the mixing of rivaroxaban and spray-dried lactose, other materials are added later.

[0209] Test Example 2

[0210] This test case evaluates the powder flowability

[0211] Powders with poor flowability, large differences in particle size, large differences in bulk density, and irregular shapes are not conducive to uniform mixing. For example, particles of powders with poor flowability adhere to each other, which is not conducive to the mutual insertion, movement and convection of powders, resulting in uneven mixing. And irregularly shaped particles are also not easy to mix evenly. The flowability of powders can be evaluated by a variety of physical and chemical properties, including particle size distribution, bulk density, angle of repose, etc.

[0212] Angle of repose: The angle of repose is the angle formed when the gravity and the friction between particles are balanced when the particles slide on the free slope of the powder accumulation layer. The smaller the angle of repose, the better the fluidity of the powder.

[0213] Bulk density: also known as bulk density, in powder science, refers to the mass per unit volume. The volume here refers to the total volume occupied by the particles and the gaps between the particles.

[0214] Tap density: refers to the mass per unit volume of powder in a container measured after being tapped under specified conditions.

[0215] One of the evaluation indicators is Haunser ratio. Haunser ratio = tap density / bulk density. When the Haunser ratio is between 1.00 and 1.11, the fluidity evaluation is very good; when it is between 1.12 and 1.18, the fluidity evaluation is good; when it is between 1.19 and 1.25, the fluidity evaluation is good or medium; when it is between 1.26 and 1.34, the fluidity evaluation is fair; when it is between 1.35 and 1.45, the fluidity evaluation is poor; when it is between 1.46 and 1.59, the fluidity evaluation is very poor; when it is greater than 1.60, the fluidity evaluation is very, very poor.

[0216] The specific results are shown in Table 3:

[0217] Table 3

[0218]

[0219]

[0220] (1) By comparing Example 1 with Examples 4-5, it can be seen that, considering the first filler type, the Haunser ratio of spray-dried lactose and anhydrous lactose is not greater than 1.34, and the fluidity is acceptable; the Haunser ratio of monohydrate lactose is not greater than 1.46, and the fluidity is poor.

[0221] (2) By comparing Example 1 with Examples 8-9, it can be seen that in the selection of the particle size of spray-dried lactose, the Haunser ratio of spray-dried lactose (60-80 mesh) is not greater than 1.34, and the fluidity is acceptable; the Haunser ratio of spray-dried lactose (80-100 mesh) and spray-dried lactose (100-120 mesh) is not greater than 1.46, and the fluidity is poor.

[0222] (3) By comparing Example 1 with Examples 10-11, it can be seen that in the selection of the spray-dried lactose ratio, in the ratio of 1:(3-5), the Haunser ratio of rivaroxaban to spray-dried lactose is 1:3 is not greater than 1.46, and the fluidity is poor; the Haunser ratio of rivaroxaban to spray-dried lactose is 1:5 and 1:4 is not greater than 1.34, and the fluidity is acceptable.

[0223] (4) By comparing Example 1 with Examples 12-14, it can be seen that the particle size of the rivaroxaban raw material is investigated. The Haunser ratio of the rivaroxaban raw material with a particle size of 20-40 μm, less than 20 μm, and less than 10 μm is between 1.25-1.31, and the fluidity is good or acceptable. The particle size of the raw material has little effect on the fluidity.

[0224] (5) By comparing Example 1 with Examples 15-17, it can be seen that the Haunser ratios of sodium carboxymethyl starch, cross-linked sodium carboxymethyl cellulose, cross-linked polyvinylpyrrolidone, and calcium carboxymethyl cellulose are between 1.28 and 1.34, and the fluidity is acceptable. The type of disintegrant has little effect on the fluidity.

[0225] (6) By comparing Example 1 with Examples 18-19, it can be seen that the amount of disintegrant used was investigated. The ratio of cross-linked sodium carboxymethyl cellulose to rivaroxaban was between 1:(1-3). The Haunser ratios of Experiment 1 (1:1) and Experiment 2 (1:3) of Example 7 and Example 1 (1:2) were between 1.28-1.34, and the fluidity was acceptable. The amount of disintegrant used had little effect on the fluidity.

[0226] (7) Comparison of Example 1 with Examples 20-22 shows that, in terms of the type of binder, the Haunser ratios of hydroxypropyl cellulose, methyl cellulose and povidone are between 1.28-1.34, and the fluidity is acceptable. The Haunser ratio of hydroxypropyl methyl cellulose is 1.35, and the fluidity is poor. Comparison of Example 1 with Examples 23-24 shows that, in terms of the selection of the amount of binder, the Haunser ratios of valsartan to povidone are between 1.28-1.34 when the ratios are 25:1, 20:1 and 15:1, and the fluidity is acceptable. The selection of the amount of binder has little effect on the fluidity.

[0227] (8) By comparing Example 1 with Examples 25-27, it can be seen that the Haunser ratios of stearyl alcohol, poloxamer, and sodium lauryl sulfate are between 1.28-1.34, and the fluidity is acceptable. The Haunser ratio of lecithin is 1.37, and the fluidity is poor.

[0228] (9) By comparing Example 1 with Examples 28-30, it can be seen that the Haunser ratios of stearic acid, magnesium stearate, sodium stearyl fumarate, and colloidal silicon dioxide are between 1.28 and 1.33, and the fluidity is acceptable. The type of lubricant has little effect on the fluidity.

[0229] (10) Comparing Example 1 with Examples 31-33, it can be seen that the Haunser ratios of microcrystalline cellulose, microcrystalline cellulose powder and mannitol are between 1.28-1.33, and the fluidity is acceptable; the Haunser ratio of powdered cellulose is 1.41, and the fluidity is poor. The fluidity of microcrystalline cellulose powder and mannitol is slightly worse than that of microcrystalline cellulose. Comparing Example 1 with Examples 34-38, it can be seen that the microcrystalline cellulose models are investigated. The Haunser ratios of microcrystalline cellulose models PH101 and PH102 are 1.37, and the fluidity is poor. The Haunser ratios of microcrystalline cellulose models PH301, PH302, UF-702, and UF-711 are between 1.28-1.33, not exceeding 1.34, and the fluidity is acceptable. Then, the selection is made based on the dissolution conditions of each model.

[0230] (11) By comparing Example 1 with Comparative Examples 1-5, it can be seen that the repose angle data are the same as that of Example 1, but the Haunser ratios of Comparative Examples 1-5 are between 1.38 and 1.46, indicating poor or very poor fluidity.

[0231] Test Example 3

[0232] This test case is used to test the dissolution

[0233] Dissolution: refers to the speed and degree of drug dissolution from solid preparations such as tablets in a specified solvent. Dissolution is an important indicator for tablet quality control, and poorly soluble drugs should generally be tested for dissolution. Since drug dissolution directly affects the absorption and utilization of drugs in the body, dissolution testing has become one of the indicators for evaluating preparation quality and production process.

[0234] The dissolution curve refers to the curve of the relationship between the amount of drug dissolved and time in the drug dissolution test. It is a curve fitted by multiple points. It is more intuitive than the dissolution rate in expressing the trend of drug dissolution behavior and reflecting the changes in raw materials, auxiliary materials, prescription ratios, and process parameters during the production process.

[0235] The type of dissolution medium is determined according to the solubility of the drug. A pH-solubility experiment is required to examine the saturated solubility of rivaroxaban raw materials in different pH media. Excess raw materials are added to 500 ml of the medium, stirred, and a saturated solution is formed in a 37°C water bath before sampling and testing. The saturated solubility of rivaroxaban raw materials in each pH is tested by referring to the content detection method. The specific results are shown in Table 4.

[0236] Table 4

[0237] Dissolution medium Saturated solubility concentration mg / ml pH 1.0 hydrochloric acid solution 0.01119 pH 2.0 hydrochloric acid solution 0.01076 pH 4.0 Acetate buffer 0.01108 pH 5.5 acetate buffer 0.01042 pH 6.0 phosphate buffer 0.01001 pH 7.0 phosphate buffer 0.00974 pH 8.0 phosphate buffer 0.00959

[0238] From the above results, it can be seen that the saturated solubility of rivaroxaban raw material in pH1.0-pH8.0 medium is 0.00959-0.01119 mg / mL, which is not pH-dependent. Therefore, in the selection of dissolution curve medium, pH4.5 medium is selected as the main investigation medium. The specific dissolution curve method is as follows:

[0239] Take this product and follow the dissolution and release determination method (Method 0931, Part 4, General Rules, 2020 Edition of the Chinese Pharmacopoeia), with a rotation speed of 75 rpm and 900 mL of the corresponding medium. Operate according to the law. After 5 min, 10 min, 15 min, 30 min, 45 min, and 60 min, take 10 mL of the dissolution solution respectively, and quickly replenish 10 mL of the solution, filter, and take the filtrate as the test solution.

[0240] Medium preparation method:

[0241] pH 4.5 acetate buffer containing 0.2% SDS: Take 2.99g sodium acetate, put it in 1000mL water, add 1.66mL glacial acetic acid and 20mL 10% SDS solution, adjust the pH value to 4.50±0.1 with sodium hydroxide or glacial acetic acid, mix well, and obtain. (2.99g sodium acetate + 1.66mL glacial acetic acid + 2g SDS → 1000mL degassed water, measure pH) The tablets of the above examples and comparative examples were subjected to dissolution experiments, and the results are shown in Table 5:

[0242] Table 5

[0243]

[0244]

[0245] From the results in Table 5, we can see that:

[0246] (1) By comparing Example 1 with Examples 4-6, it can be seen that, considering the first filler type, the samples prepared with mannitol, anhydrous lactose and monohydrate lactose did not reach 85% dissolution at 15 min, which was not similar to the original research. Considering the comprehensive mixing uniformity, spray-dried lactose was preferred.

[0247] (2) Comparing Example 1 with Examples 7-9, it can be seen that in the selection of the spray-dried lactose particle size, the samples with spray-dried lactose particle sizes of 40-60 mesh and 60-80 mesh have a cumulative dissolution rate greater than 85% at 15 minutes, which can be considered similar to the "Byritu" tablets, but the cumulative dissolution rates of 80-100 mesh and 100-120 mesh are lower, which may be because the smaller the lactose particle size, the larger the specific surface area. Under the same tablet hardness, the particles are more tightly bound, the internal stress is greater, and it is relatively difficult to disintegrate and disperse. Considering the comprehensive mixing uniformity, the spray-dried lactose particle size of 60-80 mesh is preferred.

[0248] (3) Comparing Example 1 with Examples 10-11, it can be seen that in the selection of the spray-dried lactose ratio, among the ratios of 1:(3-5), the samples with ratios of 1:3 and 1:4 had a cumulative dissolution rate greater than 85% at 15 minutes, which can be considered similar to the "Byritu" tablets. The cumulative dissolution rate of the sample with a ratio of 1:5 did not reach 85% at 15 minutes. It may be that in the prescription, as the ratio of spray-dried lactose increases, the ratio of microcrystalline cellulose decreases, and its disintegration effect decreases. Combined with the flowability data and the mixing uniformity data, the preferred ratio of rivaroxaban to dry lactose is 1:4.

[0249] (4) By comparing Example 1 with Example 12-13, it can be seen that the average particle size of the bulk drug is reduced by micropowder or fine powder treatment, so that its surface area is increased, solubility is increased, and the dissolution rate of the drug can be improved to a certain extent. However, after a certain degree of reduction, the particle surface becomes smoother and smoother, the original medicinal material characteristics become less and less obvious, and the application of micronization technology does not change the main functional group structure of the original medicinal material. On the contrary, if the particle size is too small, it affects the dissolution effect of the ultrafine powder. The rivaroxaban raw material particle size is investigated. The smaller the bulk drug particle size, the faster the dissolution rate. When the bulk drug particle size is less than 20 μm, there is no obvious difference in the dissolution rate. Considering the mixing uniformity and the bulk drug pulverization efficiency, it is more in line with the cost-effective requirements and the energy consumption maintenance requirements of the equipment and equipment.

[0250] (5) Comparing Example 1 with Examples 15-17, it can be seen that the samples with cross-linked carboxymethyl cellulose sodium and cross-linked polyvinylpyrrolidone as disintegrants have a cumulative dissolution rate greater than 85% at 15 minutes, which can be considered similar to "Byritu" tablets, while the samples with carboxymethyl starch sodium and carboxymethyl cellulose calcium as disintegrants have a cumulative dissolution rate less than 85% at 15 minutes. Under the same ratio of disintegrants, cross-linked carboxymethyl cellulose sodium has the best disintegration and dissolution effect, so cross-linked carboxymethyl cellulose sodium is preferably used as a disintegrant.

[0251] (6) By comparing Example 1 with Example 18, it can be seen that the amount of disintegrant is investigated. When the ratio of cross-linked sodium carboxymethyl cellulose to rivaroxaban is between 1: (1-2), the main difference is that the cumulative dissolution at 5 min and 10 min is slightly different. As the amount of disintegrant increases, the dissolution at 5 min and 10 min increases. However, when the ratio of cross-linked sodium carboxymethyl cellulose to rivaroxaban is 1: 1, it may be that the cross-linked sodium carboxymethyl cellulose swells to form a colloid, which hinders the late dissolution of the tablet, so that the cumulative dissolution at 60 min does not reach 100%.

[0252] (7) By comparing Example 1 with Examples 20-22, it can be seen that, after examining the type of binder, the cumulative dissolution rate of the samples using hydroxypropyl cellulose or hydroxypropyl methylcellulose as the binder did not reach 85% at 15 minutes, and the cumulative dissolution rate of the samples using methyl cellulose or povidone as the binder was greater than 85% at 15 minutes, which can be considered to be similar to the "Byritu" tablets. The cumulative dissolution rate of the samples using povidone as the binder at 5 minutes, 10 minutes, 15 minutes, and 30 minutes was slightly higher than that of the samples using methyl cellulose as the binder. Therefore, povidone is preferably used as the binder.

[0253] (8) Comparing Example 1 with Example 24, it can be seen that the cumulative dissolution rate at 15 minutes is greater than 85% for the selection of the amount of binder, which can be considered similar to the "Byritu" tablets. The dissolution of the binder decreases slightly with the increase of the amount of binder; at 1:20, the dissolution rate is higher, so the preferred ratio of povidone K30 to rivaroxaban is 1:20.

[0254] (9) Comparing Example 1 with Examples 25-27, it can be seen that the samples with stearyl alcohol, poloxamer, and lecithin as surfactants did not reach a cumulative dissolution of 85% at 15 minutes, while the samples with sodium dodecyl sulfate as surfactants had significantly higher cumulative dissolution at each time point than the samples with other surfactants. Sodium dodecyl sulfate, as an anionic surfactant, has a biodegradability of >90%, good emulsification, foaming, water solubility, biodegradability, alkali resistance, hard water resistance, stability in aqueous solutions with a wide pH value, easy synthesis, and low price, so sodium dodecyl sulfate is preferred.

[0255] (9) Comparing Example 1 with Examples 28-30, it can be seen that the types of lubricants are investigated. The samples with stearic acid, magnesium stearate, sodium stearyl fumarate, and colloidal silicon dioxide as lubricants have a cumulative dissolution rate greater than 85% at 15 minutes, which can be considered similar to the tablets. Magnesium stearate is used as a lubricant, anti-adherent agent, and glidant, and the mixing uniformity, flowability evaluation parameters, excipient accessibility, and economic benefits are comprehensively considered.

[0256] (10) Comparing Example 1 with Examples 31-32, it can be seen that the type of the second filler is investigated. The samples with powdered cellulose or mannitol as the second filler have a cumulative dissolution rate of less than 85% at 15 minutes, while the samples with microcrystalline cellulose or microcrystalline cellulose powdered silica gel as the second filler have a cumulative dissolution rate of more than 85% at 15 minutes, which can be considered similar to "Byritu" tablets. Microcrystalline cellulose is commonly used as an adsorbent, suspending agent, diluent, and disintegrant. Microcrystalline cellulose is widely used in pharmaceutical preparations, mainly as a diluent and binder in oral tablets and capsules. It can be used not only for wet granulation but also for dry direct tableting. It also has a certain lubrication and disintegration effect and has good compressibility.

[0257] (11) Comparing Example 1 with Examples 34-38, it can be seen that the cumulative dissolution of microcrystalline cellulose models PH101, PH102, PH301, and PH302 at 15 minutes did not reach 85%, while the cumulative dissolution of samples with UF-702 and UF-711 at 15 minutes was greater than 85%, which can be considered similar to "Byritu" tablets. At the same time, UF-711 is superior to UF-702 in terms of mixing uniformity and dissolution degree.

[0258] (12) Comparing Example 1 with Comparative Examples 1-5, it can be seen that in the dissolution curve in the pH 4.5 medium, the cumulative dissolution of the comparative example 5min does not exceed 50%, and the final dissolution of Comparative Example 3 and Comparative Example 5 does not exceed 95%, which means that the dissolution is not complete. Comparative Example 5 is a raw material, a binder, and sodium lauryl sulfate that are added according to the prescription amount, and there is a loss after micronization, resulting in dissolution loss; in Comparative Example 3, the blank particles and the raw materials are mixed, and the raw materials are not adsorbed on the particles or embedded in the particles, which will also cause the dissolution rate to be less than 100%, both of which may affect the bioavailability. The dissolution of Example 1 is faster than that of the original preparation, which is better than the original preparation. Therefore, the rivaroxaban tablets in this Example 1 are significantly better than other comparative examples in terms of dissolution behavior.

[0259] Test Example 4

[0260] This test case is used to test stability

[0261] The influencing factor test is conducted under severe conditions, with the purpose of understanding the factors affecting stability and possible degradation pathways and degradation products, and providing a basis for the screening of preparation processes, the selection of packaging materials and containers, and the determination of storage conditions. It also provides a basis for the temperature and humidity conditions that should be used in accelerated tests and long-term tests, and can also provide a basis for the selection of analytical methods.

[0262] The rivaroxaban tablets of Example 1 and the "Byritu" tablets of Comparative Example 6 were tested for drug quality at 0 days, 5 days, 10 days, and 30 days under high temperature (40°C, 60°C), high humidity (75%RH, 92.5%) and light conditions using the smallest dosage unit without the inner packaging. The specific dissolution is shown in Table 6, the content change is shown in Table 7, the impurities will change during the stability period, the impurity information is shown in Table 8, and the impurity change amount is shown in Table 9

[0263] Table 6

[0264]

[0265]

[0266] Table 7

[0267]

[0268] Table 8 Impurity information

[0269]

[0270]

[0271] Table 9

[0272]

[0273]

[0274]

[0275] Under high temperature (40°C, 60°C), high humidity (75%RH, 92.5%) and illumination conditions, the rivaroxaban tablets of Example 1 and the "Bai Rui Tuo" tablets (BJ58093) of Comparative Example 6, after 5 days, 10 days and 30 days, the sample dissolution and content did not decrease significantly, and the related substances in impurities B, impurity D, impurity E, impurity M, impurity L, impurity F, impurity I, impurity J, other largest single impurities and total impurities did not increase, the quality was stable, and the impurities B and D of Example 1-1 were not detected on day 0, which was lower than the 0-day data of "Bai Rui Tuo" tablets (BJ58093). In summary, under high temperature (40°C, 60°C), high humidity (75%RH, 92.5%) and illumination conditions, the quality of the rivaroxaban tablets of Example 1 is better than that of the "Bai Rui Tuo" (BJ58093) of Comparative Example 6, and the quality is stable and controllable.

[0276] Test Example 5

[0277] This test case performs stability testing under accelerated conditions

[0278] Accelerated testing is conducted under extraordinary conditions. Its purpose is to examine the stability of drugs by speeding up the rate of chemical or physical changes in drugs in commercial packaging, to simulate the stability of drugs under short-term extraordinary conditions that may be encountered during transportation and storage, and to preliminarily predict the long-term stability of samples under specified storage conditions.

[0279] The accelerated test is usually conducted with three batches of samples at a temperature at least 15°C higher than that of the long-term test. Generally, the test can be conducted for 6 months at 40°C±2°C and RH75%±5%. Samples are taken at the end of the 0th, 1st, 2nd, 3rd, and 6th month of the test to test the indicators.

[0280] Therefore, the rivaroxaban tablets prepared in Example 1-1 and the commercially available original preparation "Byritu" tablets (10 mg) were placed under accelerated conditions (40°C / 75% RH) for 1 month, 2 months, 3 months and 6 months, and the 4-medium dissolution curve test was performed. The test results are shown in Table 10:

[0281] Table 10

[0282]

[0283]

[0284]

[0285] The above results show that after the rivaroxaban coated tablets prepared in Example 1 of the present application were placed under 40°C / 75% conditions for 3 months and 6 months, the dissolution of the "Byritu" tablets of Comparative Example 9 was significantly reduced, while there was no significant change in Example 1. Therefore, the process samples using spray-dried lactose and direct compression tableting still have good stability, which is significantly better than the rivaroxaban tablets on the market.

[0286] Test Example 6

[0287] To verify the maturity of this application, ensure that the tablet combination and process production route of this application are mature and reasonable, the main technical indicators are close to the production requirements, and provide a production route with consistent and stable quality for commercial production. Further scale-up production is carried out in batches of 100,000 tablets, and three batches are produced in parallel, namely Example 1-1, Example 1-2, and Example 1-3, with the same process flow as above, to examine the uniformity and stability between batches and within batches.

[0288] The dissolution curves of the scaled-up examples 1-1 to 1-3 and the commercially available original preparation "Byrette" tablets (10 mg) of comparative example 9 were compared in different dissolution media to examine the inter-batch and intra-batch uniformity. The method is as follows:

[0289] Take this product and follow the dissolution and release determination method (Chinese Pharmacopoeia 2015 Edition Part 4 General Rules 0931 Method 2), with a rotation speed of 75 rpm and 900 mL of the corresponding medium. Operate according to the law. After 5 min, 10 min, 15 min, 30 min, 45 min, and 60 min, take 10 mL of the dissolution solution respectively, and quickly make up 10 mL of the solution, filter, and take the filtrate as the test solution.

[0290] Medium preparation method:

[0291] ① pH 4.5 acetate buffer containing 0.2% SDS: Take 2.99g sodium acetate, put it in 1000mL water, add 1.66mL glacial acetic acid and 20mL 10% SDS solution, adjust the pH value to 4.50±0.1 with sodium hydroxide or glacial acetic acid, mix well, and you have it. (2.99g sodium acetate + 1.66ml glacial acetic acid + 2g SDS → 1000mL degassed water, measure pH)

[0292] ② pH 6.8 phosphate buffer containing 0.2% SDS: Accurately weigh 6.0g of anhydrous sodium dihydrogen phosphate and 0.9g of sodium hydroxide, add to 1000mL of water, mix thoroughly, add 20mL of 10% SDS solution, mix well, and you have it. (6.0g of anhydrous sodium dihydrogen phosphate + 0.9g of sodium hydroxide + glacial acetic acid + 2g SDS → 1000mL of degassed water, measure pH)

[0293] ③ pH 1.0 hydrochloric acid solution containing 0.2% SDS (low temperature injection): Accurately measure 9mL of hydrochloric acid and dilute it to 1000mL with water, add 20mL of 10% SDS solution, mix well, and you have it. (9mL hydrochloric acid + 2g SDS → 1000mL degassed water, measure pH)

[0294] ④ Aqueous solution containing 0.2% SDS: Take 1000mL of water, add 20mL of 10% SDS solution, mix well, and you have it. (2g SDS → 1000mL degassed water)

[0295] The cumulative dissolution data of three batches of commercially available original preparation "Byritu" tablets (10 mg) in different dissolution media of Examples 1-1 to 1-3 and Comparative Example 9 are shown in Tables 11-14 below:

[0296] Table 11

[0297]

[0298]

[0299] The solubility of the commercially available original preparation "Baijueluo" tablets in Examples 1-1 to 1-3 and Comparative Example 9 in pH 4.5 acetate buffer (containing 0.2% SDS) was greater than 85% in 15 minutes, and the dissolution was better than that of "Baijueluo" tablets; the average dissolution RSD of Examples 1-1 to 1-3 was less than 5%, and the intra-batch uniformity was good.

[0300] Table 12

[0301]

[0302] The solubility of the commercially available original preparation "Baijueluo" tablets in Examples 1-1 to 1-3 and Comparative Example 9 in pH 6.8 phosphate buffer (containing 0.2% SDS) was greater than 85% in 15 minutes, and the dissolution was better than that of "Baijueluo" tablets; the average dissolution RSD of Examples 1-1 to 1-3 was less than 10%, and the intra-batch uniformity was good.

[0303] Table 13

[0304]

[0305]

[0306] The solubility of the commercially available original preparation "Baijueluo" tablets in aqueous solution (containing 0.2% SDS) of Examples 1-1 to 1-3 and Comparative Example 9 was greater than 85% in 15 min, and the dissolution was better than that of "Baijueluo" tablets; the average dissolution RSD of Examples 1-1 to 1-3 was less than 10%, and the intra-batch uniformity was good.

[0307] Table 14

[0308]

[0309] The similarity factors (f2) of the commercially available original preparation "Bai Rui Tuo" tablets of Examples 1-1 to 1-3 and Comparative Example 9 in 0.1 mol / L hydrochloric acid solution (containing 0.2% SDS) are all greater than 50, and the dissolution is better than that of "Bai Rui Tuo" tablets; the average dissolution RSD of Examples 1-1 to 1-3 at 5 min is less than 20%, and the average dissolution RSD of the other time points is less than 10%, and the intra-batch uniformity is good.

[0310] In summary: the similarity factors (f2) of Examples 1-1 to 1-3 and "Bai Rui Tu" tablets (BJ57602 batch) in 0.1 mol / L hydrochloric acid solution (containing 0.2% SDS) are all greater than 50, the 15 min solubility in other media is greater than 85%, and the dissolution curves are better than those of "Bai Rui Tu" tablets.

[0311] Test Example 7

[0312] This test case conducts human bioequivalence study

[0313] According to the "Technical Guidelines for Human Bioequivalence Studies of Generic Chemical Drugs Using Pharmacokinetic Parameters as Endpoint Evaluation Indicators", "Technical Guidelines for Bioequivalence Studies of Rivaroxaban Tablets", "Technical Guidelines for Bioequivalence Studies of Narrow Therapeutic Index Drugs", the General Rules of the Appendix of the 2020 Edition of the Chinese Pharmacopoeia "Guidelines for Human Bioavailability and Bioequivalence of Drug Preparations" and relevant requirements in GCP, a research plan was formulated with reference to existing research literature on the pharmacokinetics and relative bioavailability of rivaroxaban tablets in humans, and the rivaroxaban tablets (specification: 10 mg, test preparation T) of Experimental Example 1-1 were evaluated with the rivaroxaban tablets (trade name: Strength: 10 mg, reference formulation R) Bioequivalence and safety under fasting and fed conditions in healthy volunteers.

[0314] Design basis for test substances:

[0315] According to the Technical Guidelines for Human Bioequivalence Studies of Generic Chemical Drugs Using Pharmacokinetic Parameters as Endpoint Evaluation Indicators, it is generally recommended to only test the parent drug, because the drug-time curve of the parent drug can more sensitively reflect the differences between preparations than metabolites. This test detects the concentration of rivaroxaban in plasma.

[0316] The design basis of the cleaning period is:

[0317] According to the Technical Guidelines for Human Bioequivalence Studies of Generic Chemical Drugs Using Pharmacokinetic Parameters as Endpoint Evaluation Indicators: "There should be a sufficiently long washout period between test administrations (generally more than 7 times the half-life of the substance to be tested)". According to the instructions: The terminal elimination half-life of this product is t1 / 2 It is about 5 to 9 hours, and the cleaning period of this test is set at 7 days.

[0318] Pharmacokinetic indicators:

[0319] In this study, the non-compartmental model was used to analyze the pharmacokinetic parameters of the blood drug concentration data. The main pharmacokinetic index was the peak plasma drug concentration (C max ), area under the drug-time curve (AUC 0-t , AUC 0-∞ The secondary pharmacokinetic parameter was the peak time (T max ), apparent terminal elimination half-life (t 1 / 2 ) etc. The pharmacokinetic parameters evaluated include: Cmax: peak concentration, Tmax: time to peak, λz: apparent terminal elimination rate constant, t 1 / 2 : Apparent terminal elimination half-life, AUC 0-t:0 to the last concentration can accurately determine the area under the blood drug concentration-time curve at sample collection time t, AUC 0-∞ : Area under the plasma drug concentration-time curve from time 0 to infinite time (∞), AUC_%Extrap: Percentage of residual area, when it is greater than 20%, it means AUC 0-t / AUC0-∞ ratio is less than 80%; AUC_%Extrap = (AU C0-∞ -AUC 0-t ) / AUC 0-∞ ×100.

[0320] Bioequivalence evaluation analysis methods and standards:

[0321] After a single dose, blood concentration-time data were collected to analyze the main pharmacokinetic parameters (such as C max , AUC) were statistically analyzed to compare the C max The AUC of rivaroxaban in rivaroxaban tablets was calculated by WinNonlin version 8.3 software. max and T max , take the measured value. max and AUC compared with the C of the reference preparation R max After logarithmic transformation, C max The point estimates of the variance and AUC were analyzed by multi-factor analysis of variance (ANOVA) and then statistically analyzed by two-sided t-test.

[0322] Based on the Technical Guidelines for Bioequivalence Studies of Rivaroxaban Tablets and the Technical Guidelines for Bioequivalence Studies of Narrow Therapeutic Index Drugs, the bioequivalence criteria are as follows: the C level of rivaroxaban in plasma after the subjects took the test preparation of rivaroxaban tablets and the reference preparation. max , AUC 0-t , AUC 0-∞ If the 90% confidence interval of the geometric mean ratio (test preparation / reference preparation) falls between 80.00% and 125.00%, and the upper limit of the 90% confidence interval of the ratio of the individual standard deviations of the test preparation and the reference preparation is ≤2.5, the two preparations can be judged to be bioequivalent.

[0323] Fasting equivalence study

[0324] This study is a randomized, open, two-sequence, four-cycle completely repeated crossover, single-dose, fasting bioequivalence trial, and 28 healthy subjects were enrolled. The dosage was 10 mg. According to the subject randomization table, the subjects took the test preparation T or reference preparation R1 tablet with 240 mL of water on an empty stomach in each cycle. Blood samples were collected at set time points before and after taking the medicine, and the washout period was 7 days.

[0325] The block randomization method was used to randomly divide the selected subjects into two groups in a 1:1 ratio through the ProcPlan process of SAS (9.4) statistical software. The subjects took the medicine according to the order of medication in the random grouping table.

[0326] Planned number of subjects: 28 subjects; all subjects can be included in the full analysis set (FAS), safety data set (SS), pharmacokinetic concentration set (PKCS), pharmacokinetic parameter set (PKPS) and bioequivalence set (BES).

[0327] The average drug-time curves of the test preparation T and the reference preparation R when the subjects took a single oral dose of rivaroxaban tablets (10 mg) on ​​an empty stomach are shown in the figure below. Figure 4 As shown, Figure 5 The semi-logarithmic graph of the average drug-time curve of the test preparation T and the reference preparation R under fasting conditions is shown. The specific results are as follows: Table 15 is a summary of the plasma PK parameters (PKPS) of rivaroxaban after oral administration of the test preparation T or the reference preparation R on an empty stomach; Table 16 is the variance analysis results of the main PK parameters of rivaroxaban after oral administration on an empty stomach; Table 17 is the bioequivalence results (BES) of the main PK parameters of rivaroxaban after oral administration on an empty stomach; Table 18 is the intra-individual standard deviation ratio results (BES) of the main PK parameters of rivaroxaban after oral administration on an empty stomach; Table 19 is the non-parametric rank sum test for Tmax.

[0328] Table 15

[0329]

[0330] Note: N is the number of times, Tmax describes the median (minimum value, maximum value).

[0331] Table 16

[0332]

[0333]

[0334] Table 17

[0335]

[0336] Table 18

[0337]

[0338] Table 19

[0339] Secondary PK parameters Test statistic P-value <![CDATA[T max ]]> 79.5 0.0693

[0340] Results of bioequivalence evaluation of oral administration of rivaroxaban tablets by subjects on an empty stomach:

[0341] (1) Pharmacokinetic parameter Cmax

[0342] The average bioequivalence results of Cmax are as follows: the geometric mean of the test preparation T is 156.59 ng / mL, the geometric mean of the reference preparation R is 177.74 ng / mL, the geometric mean ratio of the test preparation T to the reference preparation R is 88.10%, and the 90% confidence interval is 82.25% to 94.37%, which is between 80% and 125% required by regulations. The individual standard deviation results of Cmax of the test preparation T and the reference preparation R are as follows: the individual standard deviation of the test preparation T is 0.1859, the individual standard deviation of the reference preparation R is 0.1906, the ratio of the individual standard deviation of the test preparation T to the reference preparation R is 0.9755, and the upper limit of the 90% confidence interval is 1.3549, which is less than 2.5, and meets the regulatory requirements.

[0343] (2) Pharmacokinetic parameters AUC0-t

[0344] The average bioequivalence results of AUC0-t are as follows: the geometric mean of the test preparation T is 1030.49 ng·h / mL, the geometric mean of the reference preparation R is 1111.03 ng·h / mL, the geometric mean ratio of the test preparation T to the reference preparation R is 92.75%, and the 90% confidence interval is 87.48% to 98.33%, which is between 80% and 125% required by regulations. The individual standard deviation results of AUC0-t of the test preparation T and the reference preparation R are as follows: the individual standard deviation of the test preparation T is 0.1508, the individual standard deviation of the reference preparation R is 0.1412, the ratio of the individual standard deviation of the test preparation T to the reference preparation R is 1.0681, and the upper limit of the 90% confidence interval is 1.4836, which is less than 2.5, meeting the regulatory requirements.

[0345] (3) Pharmacokinetic parameters AUC0-∞

[0346] The average bioequivalence results of AUC0-∞ are as follows: the geometric mean of the test preparation T is 1071.98 ng·h / mL, the geometric mean of the reference preparation R is 1146.32 ng·h / mL, the geometric mean ratio of the test preparation T to the reference preparation R is 93.51%, and the 90% confidence interval is 88.23% to 99.12%, which is between 80% and 125% required by regulations. The individual standard deviation results of AUC0-∞ of the test preparation T and the reference preparation R are as follows: the individual standard deviation of the test preparation T is 0.1635, the individual standard deviation of the reference preparation R is 0.1479, the ratio of the individual standard deviation of the test preparation T to the reference preparation R is 1.1059, and the upper limit of the 90% confidence interval is 1.5361, which is less than 2.5, meeting the regulatory requirements.

[0347] The analysis of the Tmax index in the fasting test showed that there was no statistically significant difference in the median of the overall distribution of Tmax between the two preparations (P=0.0693).

[0348] In summary, the fasting test results show that the rivaroxaban tablets test preparation of Example 1-1 and the rivaroxaban tablets produced by Bayer AG (trade name: ) Bioequivalence to the reference product.

[0349] Test Case 8

[0350] This test case conducts a postprandial bioequivalence test

[0351] This study is a randomized, open, two-sequence, four-cycle completely repeated crossover, single-dose, postprandial bioequivalence trial, and 28 healthy subjects were enrolled. The dosage was 10 mg. A high-fat, high-calorie meal was started 30 minutes before the morning administration of each cycle, and the meal was completed within 30 minutes. 30 minutes (±1 minute) after the start of the meal, the test preparation T or reference preparation R1 tablet was taken with 240 mL of water according to the subject randomization table, and blood samples were collected at the set time points before and after taking the medicine. Washout period: 7 days.

[0352] The subjects took a single oral dose of rivaroxaban tablets (10 mg) after meals. Figure 6 The average drug-time curves of the test preparation T and the reference preparation R under the postprandial condition are shown in the figure. Figure 7 The semi-logarithmic graph of the average drug-time curve of the test preparation T and the reference preparation R under the condition of postprandial administration is shown. The specific results are shown as follows. Table 20 is the summary of plasma PK parameters (PKPS) of rivaroxaban after oral administration of the test preparation T or the reference preparation R after a meal, Table 21 is the variance analysis results of the main PK parameters of rivaroxaban after oral administration after a meal, Table 22 is the bioequivalence results (BES) of the main PK parameters of rivaroxaban after oral administration after a meal, Table 23 is the results of the intra-individual standard deviation ratios of the main PK parameters of rivaroxaban after oral administration after a meal (BES), and Table 24 is the non-parametric rank sum test for Tmax

[0353] Table 20

[0354]

[0355] Note: N is the number of times, and Tmax describes the median (minimum value, maximum value). Both CH007 and CH021 subjects (dosing sequence: TRTR) dropped out before the fourth cycle of dosing, so the number of times for the test preparation is N=56, and the number of times for the reference preparation is N=56.

[0356] Table 21

[0357]

[0358] Table 22

[0359]

[0360] Table 23

[0361]

[0362]

[0363] Note: N is the number of times, and Tmax describes the median (minimum value, maximum value). Both CH007 and CH021 subjects (dosing sequence: TRTR) dropped out before the fourth cycle of dosing, so the number of times for the test preparation is N=56, and the number of times for the reference preparation is N=56.

[0364] Table 24

[0365] Secondary PK parameters Test statistic P-value <![CDATA[T max ]]> 51 0.2010

[0366] Results of bioequivalence evaluation of rivaroxaban tablets taken orally after meals:

[0367] (1) Pharmacokinetic parameter C max

[0368] C max The average bioequivalence results are as follows: the geometric mean of the test preparation T is 258.08 ng / mL, the geometric mean of the reference preparation R is 274.30 ng / mL, the geometric mean ratio of the test preparation T to the reference preparation R is 94.09%, and the 90% confidence interval is 88.81% to 99.68%, which is between 80% and 125% required by regulations. max The intra-individual standard deviation results of the test preparation T and the reference preparation R are as follows: the intra-individual standard deviation of the test preparation T is 0.1909, the intra-individual standard deviation of the reference preparation R is 0.1953, the ratio of the intra-individual standard deviation of the test preparation T to the reference preparation R is 0.9776, and the upper limit of the 90% confidence interval is 1.3640, which is less than 2.5, and meets regulatory requirements.

[0369] (2) Pharmacokinetic parameter AUC 0-t

[0370] AUC 0-t The average bioequivalence results are as follows: the geometric mean of the test preparation T is 1708.13 ng·h / mL, the geometric mean of the reference preparation R is 1746.42 ng·h / mL, the geometric mean ratio of the test preparation T to the reference preparation R is 97.81%, and the 90% confidence interval is 94.61% to 101.11%, which is between 80% and 125% required by regulations. AUC 0-tThe intra-individual standard deviation results of the test preparation T and the reference preparation R are as follows: the intra-individual standard deviation of the test preparation T is 0.1057, the intra-individual standard deviation of the reference preparation R is 0.1121, the ratio of the intra-individual standard deviation of the test preparation T to the reference preparation R is 0.9423, and the upper limit of the 90% confidence interval is 1.3146, which is less than 2.5, and meets regulatory requirements.

[0371] (3) Pharmacokinetic parameter AUC 0-∞

[0372] AUC 0-∞ The average bioequivalence results are as follows: the geometric mean of the test preparation T is 1720.75 ng·h / mL, the geometric mean of the reference preparation R is 1757.56 ng·h / mL, the geometric mean ratio of the test preparation T to the reference preparation R is 97.91%, and the 90% confidence interval is 94.75% to 101.16%, which is between 80% and 125% required by regulations. AUC 0-∞ The intra-individual standard deviation results of the test preparation T and the reference preparation R are as follows: the intra-individual standard deviation of the test preparation T is 0.1052, the intra-individual standard deviation of the reference preparation R is 0.1102, the ratio of the intra-individual standard deviation of the test preparation T to the reference preparation R is 0.9545, and the upper limit of the 90% confidence interval is 1.3317, which is less than 2.5, and meets regulatory requirements.

[0373] Postprandial test max The analysis of indicators showed that the two preparations T max There was no statistically significant difference in the overall distribution medians (P=0.2010).

[0374] In summary, the postprandial test results show that the rivaroxaban tablets test preparation of Example 1-1 and the rivaroxaban tablets produced by Bayer AG (trade name: ) Bioequivalence to the reference product.

[0375] In summary, the rivaroxaban tablets used in the present invention have a cumulative dissolution rate greater than 85% at 15 min under different pH and different media conditions, a fast dissolution behavior, and stable batch-to-batch. The preparation method is simple in process, obtains tablets with uniform content, fast tablet dissolution rate, no obvious growth trend of impurities, and the content and dissolution rate remain substantially unchanged, and the preparation has good stability.

[0376] The applicant declares that the above is only a specific implementation mode of the present invention, but the protection scope of the present invention is not limited thereto. Those skilled in the art should understand that any changes or substitutions that can be easily thought of by those skilled in the art within the technical scope disclosed by the present invention shall fall within the protection scope and disclosure scope of the present invention.

Claims

1. A rivaroxaban tablet, characterized in that: The rivaroxaban tablet comprises, by weight, 5-15 parts of rivaroxaban, 2-10 parts of a disintegrant, 0.1-1 parts of a binder, 0.1-1 parts of a surfactant, 55-80 parts of a filler and 0.2-1.2 parts of a lubricant; The disintegrant comprises any one of sodium carboxymethyl starch, cross-linked sodium carboxymethyl cellulose, cross-linked polyvinylpyrrolidone or calcium carboxymethyl cellulose, or a combination of at least two thereof; The binder comprises any one of hydroxypropyl cellulose, hydroxypropyl methyl cellulose, methyl cellulose or povidone, or a combination of at least two thereof; The filler comprises any one of mannitol, lactose monohydrate, anhydrous lactose, spray-dried lactose, microcrystalline cellulose, powdered cellulose, microcrystalline cellulose with micropowdered silica gel, or a combination of at least two thereof; The surfactant includes any one of lecithin, stearyl alcohol, poloxamer or sodium lauryl sulfate or a combination of at least two thereof; The lubricant includes any one of stearic acid, magnesium stearate, sodium stearyl fumarate or colloidal silicon dioxide or a combination of at least two thereof.

2. The rivaroxaban tablet according to claim 1, characterized in that The particle size D90 of the rivaroxaban is 1-60 μm; Preferably, the particle size D90 of rivaroxaban is 1-20 μm; Preferably, the filler is a combination of a first filler and a second filler; Preferably, the first filler is spray-dried lactose and the second filler is microcrystalline cellulose.

3. The rivaroxaban tablet according to claim 1 or 2, characterized in that: The mass ratio of rivaroxaban to spray-dried lactose is 1:(3-5); Preferably, the shape of the spray-dried lactose comprises a spherical shape; Preferably, the mass ratio of rivaroxaban to microcrystalline cellulose is 1:(2-4), more preferably 1:(2.5-3.5); Preferably, the type of microcrystalline cellulose includes any one of PH101, PH102, PH301, PH302, UF-711 or UF-702, or a combination of at least two thereof; Preferably, the model of the microcrystalline cellulose is UF-711.

4. The rivaroxaban tablet according to any one of claims 1 to 3, characterized in that The particle size of the spray-dried lactose is 40-120 mesh; Preferably, the particle size of the spray-dried lactose is 60-80 mesh.

5. The rivaroxaban tablet according to any one of claims 1 to 4, characterized in that The disintegrant is cross-linked carboxymethyl cellulose sodium; Preferably, the mass ratio of rivaroxaban to cross-linked sodium carboxymethyl cellulose is (1-3):1; Preferably, the binder is povidone; Preferably, the mass ratio of rivaroxaban to povidone is (15-25):

1.

6. The rivaroxaban tablet according to any one of claims 1 to 5, characterized in that The rivaroxaban tablet comprises, by weight, 10 parts of rivaroxaban, 40 parts of spray-dried lactose, 28.3 parts of microcrystalline cellulose UF-711, 5 parts of cross-linked sodium carboxymethyl cellulose, 0.5 parts of povidone K30, 0.5 parts of sodium lauryl sulfate and 0.7 parts of magnesium stearate.

7. A method for preparing a rivaroxaban tablet according to any one of claims 1 to 6, characterized in that: The preparation method comprises the following steps: air flow pulverizing rivaroxaban, and then mixing the rivaroxaban with a disintegrant, a binder, a surfactant, a filler and a lubricant respectively to obtain the product.

8. The preparation method according to claim 7, characterized in that: The steps of the preparation method include: (1) performing air flow pulverization on rivaroxaban; (2) mixing rivaroxaban and the first filler for the first time; (3) adding a binder, a disintegrant and a surfactant to the mixture obtained in step (2) for a second mixing; (4) adding the mixture obtained in step (3) to the second filler for a third mixing; (5) Adding a lubricant to the mixture obtained in step (4) for a fourth mixing, and directly tableting.

9. The preparation method according to claim 8, characterized in that: The stirring speed of the first mixing is 5-15 rpm, and the time is 5-15 min; Preferably, the stirring speed of the second mixing is 5-15 rpm and the time is 15-20 min; Preferably, the stirring speed of the third mixing is 5-15 rpm, and the time is 5-30 min.

10. The preparation method according to claim 8 or 9, characterized in that: The stirring speed of the fourth mixing is 5-10 rpm, and the time is 5-10 min; Preferably, the hardness of the rivaroxaban tablet after tableting is 40-80N; Preferably, the diameter of the hardness of the rivaroxaban tablet after tableting is 2-10 mm.

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