A rivaroxaban tablet and a method for preparing the same

Abstract

The present application relates to a kind of rivaroxaban tablets and its preparation method, the rivaroxaban tablet includes 5-15 parts rivaroxaban, 2-10 parts disintegrating agent, 0.1-1 part binder, 0.1-1 part surfactant, 55-80 parts filling agent and 0.2-1.2 parts lubricant by weight fraction.The rivaroxaban tablet used in the present application is greater than 85% at 15min under different pH and different medium conditions Cumulative dissolution, dissolution behavior is fast, batch stability.The preparation method is simple, and the content of the obtained tablet is uniform, the dissolution rate of the tablet is fast, the impurity has no obvious increasing trend, the content and dissolution degree are basically unchanged, and the preparation stability is good.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical formulation technology, and in particular to a rivaroxaban tablet and its preparation method. Background Technology

[0002] Rivaroxaban is a low-molecular-weight oral anticoagulant with highly selective direct inhibitory effector factor Xa. Developed jointly by Bayer Pharmaceuticals and Johnson & Johnson, it is used to prevent 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 approved for marketing in the European Union on October 1 of the same year. Chemical name: 5-chloro-nitro-((5S)-2-oxo-3-[-4-(3-oxo-4-morphoneyl)phenyl-1,3-azolidin-5-yl-2-thiophene-carboxamide, Molecular formula: C 19 H 18 ClN3O5S, molecular weight: 435.89, structural formula as follows:

[0003]

[0004] Rivaroxaban exists in crystal forms I, II, III, hydrates, NMP solvates, and THF-containing inclusion complexes. Crystal form II has a complex preparation process and high production costs, so crystal form I is more prevalent in the market. Rivaroxaban has poor water solubility; crystal form I has a solubility of 5-7 mg / L in aqueous medium at room temperature, resulting in slow in vitro dissolution of the active ingredient and low in vivo bioavailability.

[0005] CN101128205A describes a process that transforms a crystalline drug substance into an amorphous form through melt extrusion. The amorphous form has lower lattice energy, significantly improving drug solubility and promoting absorption in vivo. However, compared to its crystalline form, the amorphous rivaroxaban exhibits lower stability, posing certain risks to the control of drug impurities.

[0006] CN104055743A employs a method for preparing tablets by directly mixing powders and compressing them, which solves some problems associated with tablet compression, such as roughness, sticking, and tablet disintegration. However, this patent does not mention whether the active pharmaceutical ingredient (API) undergoes micronization, and the homogenization and in vitro dissolution of rivaroxaban API cannot be guaranteed.

[0007] CN104666262A combines solid dispersion technology with solubilizers and adsorbents. First, a solid dispersion is prepared, then the drug dispersion solution is adsorbed onto fumed colloidal silica, mixed uniformly with pharmaceutically acceptable excipients, and directly compressed into tablets. This invention has a cumbersome process. In preparing the solid dispersion, diethylene glycol ethyl ether is used, introducing organic solvents during production. Risk assessments of the use of organic solvents and the establishment of corresponding EHS (Environment, Health, and Safety) measures are necessary. Furthermore, solid dispersions are prone to aging, and the uniform adsorption of the drug onto fumed colloidal silica cannot be guaranteed, limiting its feasibility for commercial production.

[0008] CN103705520A employs a colloid mill or high-speed stirred bead mill to wet-mill rivaroxaban, reducing the particle size of the rivaroxaban raw material to below 5 micrometers. Simultaneously, a suspension is prepared, which is then sprayed into other excipients to form suitable granules, which are further prepared into the smallest pharmaceutical dosage units. While this invention utilizes wet milling technology to reduce rivaroxaban raw material to below 5 micrometers, the significant density difference between rivaroxaban and other materials may increase the loss of the active pharmaceutical ingredient during granulation, especially in fluidized bed granulation. Therefore, the entire preparation process involves both milling and granulation. These two steps carry the risk of active pharmaceutical ingredient loss, which may explain why the dissolution endpoint was not reached 100%.

[0009] CN110893176A describes a method for preparing a drug composition by treating an active substance with a granulating liquid containing a solvent, wetting agent, and disintegrant, and then using a wet granulation process to granulate the liquid containing the active substance with pharmaceutically acceptable excipients. While this invention improves the dissolution rate of the drug composition, it still requires processes such as wet granulation, drying, and sizing, which are complex, time-consuming, and have a long production cycle, increasing risks to personnel and equipment during operation.

[0010] Therefore, improving the solubility of rivaroxaban has become an urgent problem to be solved. Summary of the Invention

[0011] To address the aforementioned technical problems, this invention provides a rivaroxaban tablet and its preparation method. The rivaroxaban tablets of this invention exhibit stable content without decreasing trend and no increasing trend of impurities under high temperature, high humidity, and light conditions, demonstrating controllable quality and superior performance compared to similar products on the market. From small-batch production to large-scale production, the tablets demonstrate uniform mixing, stable data, rapid dissolution behavior, and batch-to-batch stability.

[0012] To achieve this objective, the present invention adopts the following technical solution:

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

[0014] The disintegrant includes any one or a combination of at least two of sodium carboxymethyl starch, croscarmellose sodium, croscarmellose or calcium carboxymethyl cellulose;

[0015] The adhesive comprises any one or a combination of at least two of hydroxypropyl cellulose, hydroxypropyl methylcellulose, methylcellulose, or povidone.

[0016] The filler includes any one or a combination of at least two of the following: mannitol, lactose monohydrate, anhydrous lactose, spray-dried lactose, microcrystalline cellulose, powdered cellulose, and microcrystalline cellulose made from silica gel.

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

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

[0019] The 5-15 portions can be, for example, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 portions. The 2-10 portions can be, for example, 2, 3, 4, 5, 6, 7, 8, 9, or 10 portions. The 0.1-1 portion can be, for example, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, or 1 portion. The 55-80 portions can 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, or 85 portions. The 0.2-1.2 portions can 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 portions, etc.

[0020] The rivaroxaban tablets of this invention include the above-mentioned raw materials. Through the synergistic effect of the above-mentioned raw materials, the solubility of rivaroxaban tablets is significantly improved. Within the above-mentioned weight ratio 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 currently commercially available products, which is more conducive to the absorption of rivaroxaban.

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

[0022] Preferably, the particle size D90 of the 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 this invention, the average particle size of rivaroxaban is reduced, thereby increasing its surface area and solubility, which can improve the drug's dissolution to a certain extent. However, when the particle size is reduced to a certain extent, the particle surface becomes increasingly smooth, the original medicinal material characteristics become 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 will affect the dissolution effect of the ultrafine powder. Within the above range, both good original medicinal material characteristics and good dissolution effect can be obtained.

[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), where (3-5) can be, for example, 3, 3.5, 4, 4.5, or 5.

[0027] Preferably, the spray-dried lactose is spherical in 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) can be, for example, 2, 2.5, 3, 3.5, or 4. The (2.5-3.5) can be, for example, 2.5, 3, or 3.5.

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

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

[0031] Preferably, the spray-dried lactose has a particle size of 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 spray-dried lactose has a particle size of 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, etc.

[0033] In this invention, the particle size of the spray-dried lactose becomes increasingly similar to that of the active pharmaceutical ingredient (API), resulting in a gradual decrease in the Relative Displacement (RSD) of the mixture. Simultaneously, this promotes the uniform adsorption of the micronized API onto the surface of the spray-dried lactose. The excellent mixing uniformity of the particles ensures the uniformity of the tablet content, thereby guaranteeing efficacy.

[0034] Preferably, the disintegrant is croscarmellose sodium.

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

[0036] Preferably, the adhesive is polyvinyl chloride.

[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.

[0038] Preferably, the rivaroxaban tablets comprise, by weight, 10 parts rivaroxaban, 40 parts spray-dried lactose, 28.3 parts microcrystalline cellulose UF-711, 5 parts croscarmellose sodium, 0.5 parts povidone K30, 0.5 parts sodium dodecyl sulfate, and 0.7 parts magnesium stearate.

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

[0040] Preferably, the preparation method includes the following steps:

[0041] (1) Rivaxaban was subjected to air jet milling;

[0042] (2) Mix rivaroxaban with the first filler for the first time;

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

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

[0045] (5) Add the mixture obtained in step (4) to the lubricant for a fourth mixing and directly compress into tablets.

[0046] In direct-pressure mixing processes, mixing time has a crucial impact on mixing uniformity. Generally, the effect of mixing time on mixing uniformity initially increases and then decreases. However, if the mixing time is further extended, the mixing uniformity may actually decrease to some extent; this phenomenon is called "overmixing." This phenomenon indicates that the effect of increasing mixing time on mixing uniformity is not linear, but rather there is an optimal point. Beyond this point, further increasing the mixing time leads to a decrease in mixing uniformity. In this invention, within the aforementioned defined time range, better mixing uniformity can be obtained, thereby promoting the dissolution of raw materials.

[0047] Preferably, the stirring speed for 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. 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.

[0048] Preferably, the stirring speed for 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. The 15-20 min can be, for example, 15 min, 16 min, 17 min, 18 min, 19 min, or 20 min.

[0049] Preferably, the stirring speed for 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. The 5-30 min can be, for example, 5 min, 10 min, 15 min, 20 min, 25 min, or 30 min.

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

[0051] Preferably, the hardness of the rivaroxaban tablets after compression molding is 40-80N, for example, it can be 40N, 45N, 50N, 55N, 60N, 65N, 70N, 75N or 80N, etc.

[0052] Preferably, the diameter of the rivaroxaban tablet after compression molding 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, etc.

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

[0054] 1. The rivaroxaban tablet combination and preparation method used in this invention resulted in an RSD (n=11) of less than 5.0% at 11 sampling points of the pre-compression intermediate; from small-batch production to large-scale production, the mixing was uniform and the data was stable. The rivaroxaban tablets used in this invention exhibited a cumulative dissolution rate greater than 85% at 15 minutes under different pH and media conditions, demonstrating rapid dissolution behavior and batch-to-batch stability.

[0055] 2. The rivaroxaban tablets prepared by this invention have a stable content without decreasing trend and no increasing trend of impurities under high temperature, high humidity and light conditions; under accelerated conditions (40℃ / 75%RH) for six months, the dissolution behavior does not show a significant slowing or accelerating trend, remains stable, and the quality is controllable, which is superior to similar products on the market.

[0056] 3. The preparation method used in this invention does not require dry granulation, wet granulation, or fluidized bed granulation; it allows for direct tableting. The process is simple, highly efficient in preparing pharmaceutical compositions, low in production cost, and easy for commercial production. The resulting intermediate before tableting has a small angle of repose, good flowability, a small difference between bulk density and tapped density, small internal pores in the particles, low compressibility leading to good flowability, and minimal tablet weight variation, resulting in high-quality tablets after compression.

[0057] 4. The preparation method in this invention only requires mixing and then tableting, which reduces the number of processes such as granulation, sizing, and drying. It is time-saving, energy-saving, reduces production costs, effectively improves the economic benefits of enterprises, and increases their competitiveness. Attached Figure Description

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

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

[0060] Figure 3 This is a sampling location diagram for mixing uniformity;

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

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

[0063] Figure 6 This is the mean pharmacokinetic-time curve (PKCS) of the test formulation T and the reference formulation R under postprandial conditions;

[0064] Figure 7 This is a semi-logarithmic plot (PKCS) of the mean drug-time curves of the test formulation T and the reference formulation R under postprandial conditions. Detailed Implementation

[0065] The technical solution of the present invention will be further described below with reference to the accompanying drawings and specific embodiments. However, the following examples are merely 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 is determined by the claims.

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

[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] Ten parts of rivaroxaban raw material were air-milled to 20 μm and mixed with 40 parts of 80-mesh spray-dried lactose at 10 rpm for 10 min for the first mixing. Then, 0.5 parts of povidone K30, 5 parts of croscarmellose sodium, and 0.5 parts of sodium dodecyl sulfate were added and mixed at 10 rpm for 17 min for the second mixing. Next, 28.3 parts of microcrystalline cellulose UF-711 were added and mixed at 10 rpm for 5 min for the third mixing. Finally, 0.7 parts of magnesium stearate were added and mixed at 10 rpm for 5 min. After mixing, the mixture was directly compressed into tablets with 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-milled to 10 μm and mixed with 50 parts of 60-mesh spray-dried lactose at 5 rpm for 15 min for the first mixing. Then, 0.75 parts of povidone K30, 10 parts of croscarmellose sodium, and 1 part of sodium dodecyl sulfate were added and mixed at 15 rpm for 15 min for the second mixing. Next, 30 parts of microcrystalline cellulose UF-711 were added and mixed at 15 rpm for 5 min for the third mixing. Finally, 0.2 parts of magnesium stearate were added and mixed at 5 rpm for 10 min. After mixing, the mixture was directly compressed into tablets with a diameter of 2 mm and a hardness of 80 N.

[0081] Example 3

[0082] This embodiment provides a rivaroxaban tablet.

[0083] Six parts of rivaroxaban were air-milled to 1 μm and mixed with 30 parts of 80-mesh spray-dried lactose at 15 rpm for 5 min for the first mixing. Then, 0.3 parts of povidone K30, 2 parts of croscarmellose sodium, and 0.1 parts of sodium dodecyl sulfate were added and mixed at 5 rpm for 20 min for the second mixing. Next, 25 parts of microcrystalline cellulose UF-711 were added and mixed at 5 rpm for 5 min for the third mixing. Finally, 1.2 parts of magnesium stearate were added and mixed at 7 rpm for 7 min. After mixing, the mixture was directly compressed into tablets with a diameter of 10 mm and a hardness of 40 N.

[0084] Example 4

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

[0086] Example 5

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

[0088] Example 6

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

[0090] Example 7

[0091] This embodiment provides a rivaroxaban tablet, which differs from Example 1 only in that the particle size of the spray-dried lactose is 40 mesh, otherwise it is the same as Example 1.

[0092] Example 8

[0093] This embodiment provides a rivaroxaban tablet, which differs 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 differs from Example 1 only in that the particle size of the spray-dried lactose is 120 mesh, and the rest is the same as Example 1.

[0096] Example 10

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

[0098] Example 11

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

[0100] Example 12

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

[0102] Example 13

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

[0104] Example 14

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

[0106] Example 15

[0107] This embodiment provides a rivaroxaban tablet, which differs from Example 1 only in that cross-linked carboxymethyl cellulose sodium is replaced with carboxymethyl starch sodium in an equal amount, while the rest is the same as Example 1.

[0108] Example 16

[0109] This embodiment provides a rivaroxaban tablet, which differs from Example 1 only in that cross-linked carboxymethyl cellulose sodium is replaced with cross-linked polyvinyl ketone in equal amounts, while the rest is the same as Example 1.

[0110] Example 17

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

[0112] Example 18

[0113] This embodiment provides a rivaroxaban tablet, which differs from Example 1 only in that the amount of croscarmellose sodium is 10 parts, that is, the ratio of croscarmellose sodium to rivaroxaban is 1:1, and the rest is the same as Example 1.

[0114] Example 19

[0115] This embodiment provides a rivaroxaban tablet, which differs from Example 1 only in that the amount of croscarmellose sodium is 3 parts, that is, the ratio of croscarmellose sodium to rivaroxaban is 1:3, and the rest is the same as Example 1.

[0116] Example 20

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

[0118] Example 21

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

[0120] Example 22

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

[0122] Example 23

[0123] This embodiment provides a rivaroxaban tablet, which differs 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 the same as Example 1.

[0124] Example 24

[0125] This embodiment provides a rivaroxaban tablet, which differs 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 the same as Example 1.

[0126] Example 25

[0127] This embodiment provides a rivaroxaban tablet, which differs from Example 1 only in that sodium dodecyl sulfate is replaced with an equal amount of lecithin, while the rest is the same as Example 1.

[0128] Example 26

[0129] This embodiment provides a rivaroxaban tablet, which differs from Example 1 only in that sodium dodecyl sulfate is replaced with stearyl alcohol in an equal amount, while the rest is the same as Example 1.

[0130] Example 27

[0131] This embodiment provides a rivaroxaban tablet, which differs from Example 1 only in that sodium dodecyl sulfate is replaced with poloxamer in equal amounts; otherwise, it is the same as Example 1.

[0132] Example 28

[0133] This embodiment provides a rivaroxaban tablet, which differs from Example 1 only in that magnesium stearate is replaced with stearic acid in equal amounts, while the rest is the same as Example 1.

[0134] Example 29

[0135] This embodiment provides a rivaroxaban tablet, which differs from Example 1 only in that magnesium stearate is replaced with sodium stearate fumarate in equal amounts; otherwise, it is the same as Example 1.

[0136] Example 30

[0137] This embodiment provides a rivaroxaban tablet, which differs from Example 1 only in that magnesium stearate is replaced with an equal amount of colloidal silica, while the rest is the same as Example 1.

[0138] Example 31

[0139] This embodiment provides a rivaroxaban tablet, which differs from Example 1 only in that microcrystalline cellulose UF-711 is replaced with an equal amount of powdered cellulose, and the rest is the same as Example 1.

[0140] Example 32

[0141] This embodiment provides a rivaroxaban tablet, which differs from Embodiment 1 only in that microcrystalline cellulose UF-711 is replaced with microcrystalline cellulose silica gel in equal amounts, while the rest is the same as Embodiment 1.

[0142] Example 33

[0143] This embodiment provides a rivaroxaban tablet, which differs from Example 1 only in that microcrystalline cellulose UF-711 is replaced with mannitol in equal amounts, while the rest is the same as Example 1.

[0144] Example 34

[0145] This embodiment provides a rivaroxaban tablet, which differs from Example 1 only in that microcrystalline cellulose UF-711 is replaced with microcrystalline cellulose PH101 in equal amounts, while the rest is the same as Example 1.

[0146] Example 35

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

[0148] Example 36

[0149] This embodiment provides a rivaroxaban tablet, which differs from Example 1 only in that microcrystalline cellulose UF-711 is replaced with microcrystalline cellulose PH301 in equal amounts, while the rest is the same as Example 1.

[0150] Example 37

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

[0152] Example 38

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

[0154] Example 39

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

[0156] Example 40

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

[0158] Example 41

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

[0160] Example 42

[0161] This embodiment provides a rivaroxaban tablet, which differs from Embodiment 1 only in that the time for 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 differs from Example 1 only in that it uses the patented method CN104055743A, where dry powder is mixed and directly compressed into tablets. The raw materials used include 10 parts rivaroxaban, 70 parts lactose, 5 parts mannitol, 3 parts croscarmellose sodium, 2 parts citric acid, 1 part sodium lauryl sulfate, 4 parts carbomer, 4 parts povidone K90, 4 parts hydroxypropyl cellulose, 1 part magnesium stearate, and 1 part silica.

[0164] Comparative Example 2

[0165] This comparative example provides a rivaroxaban tablet, which differs from Example 1 only in that it uses the patented method CN104666262A, combining solid dispersion technology with solubilization technology and adsorbents. First, a solid dispersion is prepared to solubilize the drug. The drug dispersion solution is then adsorbed with fumed colloidal silica. After that, it is mixed evenly with pharmaceutically acceptable excipients and directly compressed into tablets. The raw materials used include 10 parts rivaroxaban, 30 parts diethylene glycol monoethyl ether, 20 parts hydroxypropyl cellulose, 150 parts fumed silica, 200 parts microcrystalline cellulose M102QD, 15 parts crospovidone, and 5 parts magnesium stearate.

[0166] Comparative Example 3

[0167] This comparative example provides a rivaroxaban tablet, which differs from Example 1 only in that it uses the method of patent CN103550165A, in which pharmaceutically acceptable excipients are wet-granulated to obtain blank granules without active ingredients, and then rivaroxaban is mixed with the above blank granules and additional pharmaceutically acceptable additives, and finally compressed into tablets. The raw materials used include 40 parts of lactose monohydrate, 26.5 parts of microcrystalline cellulose, 3.40 parts of croscarmellose sodium, 1.70 parts of sodium dodecyl 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 material mixing. Spray-dried lactose, microcrystalline cellulose and rivaroxaban are mixed for the first time, then croscarmellose sodium and sodium dodecyl sulfate are added for the second mixing, and finally magnesium stearate is added for the third mixing. The direct compression process is used, and the rest is the same as in Example 1.

[0170] Comparative Example 5

[0171] This comparative example provides a rivaroxaban tablet, which differs from Example 1 only in that it uses the method of patent CN109419778A. The rivaroxaban, binder and surfactant are mixed and sieved, then air-jet pulverized, then mixed with a portion of the diluent and sieved, then mixed with the remaining diluent and other materials in the formulation except for the lubricant and sieved, and finally mixed evenly with the lubricant. The powder is then directly compressed into tablets. The raw materials used include 10 parts rivaroxaban, 27.9 parts lactose monohydrate, 40 parts microcrystalline cellulose, 3 parts croscarmellose sodium, 3 parts hydroxypropyl methylcellulose (5cp), 0.5 parts sodium dodecyl sulfate and 0.6 parts magnesium stearate.

[0172] Comparative Example 6

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

[0174] Comparative Example 7

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

[0176] Comparative Example 8

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

[0178] Comparative Example 9

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

[0180] Test Example 1

[0181] This test case is used to detect the uniformity of mixing.

[0182] In the process of oral solid dosage forms, the uniformity of powder mixing is a key step in the process evaluation. Whether the uniformity of mixing is qualified directly affects the quality of the preparation. Ensuring that the uniformity of the mixed materials meets the production requirements and that each unit dose contains an equal amount of active substances is a prerequisite for achieving uniform content in the finished product.

[0183] Referring to the "Technical Guidelines for the Study of Mixing Uniformity and Controlled Dosage Unit Uniformity of Oral Solid Dosage Forms of Chemical Drugs (Trial Implementation)," the sampling points and methods were determined, and appropriate testing methods were selected to test the samples. The mixing uniformity requirements were as follows: 10 sampling points were selected, including 3 sampling points each at the top, middle, and bottom of the entire batch, and the discharge port. Three samples were taken from each sampling point. Specific sampling locations for mixing uniformity are as follows... Figure 3 One sample was tested at each sampling point shown, and the relative standard deviation of all samples was calculated. The sample RSD was < 5.0%; and all individual values ​​were within ±10.0% (absolute) of the mean, indicating good mixing homogeneity.

[0184] Determination method: High performance liquid chromatography (Chinese Pharmacopoeia 2020 Edition, Part IV, General Chapter 0512)

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

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

[0187] Reference solution: Weigh an appropriate amount of rivaroxaban reference standard accurately, dissolve it in solvent and dilute quantitatively to prepare a solution containing 0.2 mg per 1 mL.

[0188] Chromatographic conditions: Octadecylsilane-bonded silica gel was used as the stationary phase (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 ℃, the flow rate was 1.0 mL per minute, and the injection volume was 5 μL.

[0189] Table 1

[0190]

[0191]

[0192] Assay: Accurately measure the test solution and reference solution, inject them separately into the liquid chromatograph, record the chromatograms, and calculate the results by peak area using the external standard method. The specific results are shown in Table 2.

[0193] Table 2

[0194]

[0195]

[0196] The results show that:

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

[0198] (2) Comparing Example 1 with Examples 4-6, it can be seen that... Figure 1 Electron micrographs of spray-dried lactose particles. Figure 2The images show electron micrographs of lactose monohydrate particles. Replacing spray-dried lactose with lactose monohydrate or anhydrous lactose significantly worsened the uniformity of the mixed particles, indicating that the appearance of lactose has a significant impact on the mixing of raw materials. Although mannitol is a commonly used excipient in direct compression mixing, its mixing uniformity RSD increased significantly, exceeding that of all intermediates mixed with lactose, suggesting that mannitol is not the first choice for mixing with rivaroxaban.

[0199] (3) Example 1: Comparing with Example 7, it can be seen that spray-dried lactose is spherical. Because the drug components can be adsorbed onto 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 to 1.2% for spray-dried lactose (60-80 mesh). As the particle size of spray-dried lactose becomes closer to that of the active pharmaceutical ingredient (API), the RSD of the mixing uniformity gradually decreases, reaching a stable fluctuation below 60 mesh. Simultaneously, the micronized API can be uniformly adsorbed onto the surface of the spray-dried lactose. Good particle mixing uniformity ensures the uniformity of tablet content, thereby guaranteeing efficacy.

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

[0201] (5) A comparison of Example 1 with Examples 12-13 shows that the mixing uniformity data indicates that rivaroxaban raw material with a particle size of 40-60 μm, 20-40 μm, and less than 20 μm can be mixed uniformly with spray-dried lactose and other materials. Meanwhile, the RSD value of the mixing uniformity for raw material particles smaller than 20 μm is 1.2%, not exceeding 2.0%. Considering the energy consumption of pulverization and the convenience of industrial production, controlling the particle size of the raw material within the range of less than 20 μm is more beneficial for subsequent production.

[0202] (6) Comparing Example 1 with Examples 15-17, it can be seen that the RSD of the mixing uniformity of sodium carboxymethyl starch, croscarmellose sodium, croscarmellose ketone, and calcium carboxymethyl cellulose as disintegrants is between 1.2% and 2.3%, all not exceeding 2.5%, indicating relatively stable data and good mixing uniformity. Comparing Example 1 with Examples 18-19, it can be seen that when the ratio of croscarmellose sodium to rivaroxaban is between [value missing], the RSD of the mixing uniformity is between 1.2% and 2.7%, all not exceeding 3.0%, with little difference in data, indicating good mixing uniformity. Disintegrants are substances that rapidly break down tablets into fine particles, thereby enabling the functional components to dissolve and be absorbed quickly and exert their effects. They are mainly related to the dissolution rate, and the specific selection needs to be based on dissolution curve data.

[0203] (7) Comparing Example 1 with Examples 20-22, the RSD of the mixing uniformity of hydroxypropyl cellulose, hydroxypropyl methylcellulose, methylcellulose, and povidone is between 1.2% and 3.8%, all not exceeding 4.0%. Among them, the RSD of the mixing uniformity of povidone is 1.2%, which is significantly lower than the RSD of the other three adhesives. Based on the mixing uniformity RSD, povidone can be preferred. Comparing Example 1 with Examples 23-24, the RSD of the mixing uniformity of rivaroxaban to povidone at a ratio of (15-25):1 is between 1.2% and 2.2%, all not exceeding 2.5%, and the data are relatively close, indicating good mixing uniformity. The working principle of adhesives mainly involves surface adhesion and cohesion, enabling different objects to be tightly bound together. In the molding of pharmaceutical formulations, they play a role in maintaining the stability, safety, or homogeneity of the drug. The amount of adhesive used will affect the dissolution rate, and the specific ratio should be selected in conjunction with dissolution curve data.

[0204] (8) A comparison of Example 1 with Examples 25-27 shows that the effect of surfactants may be insignificant due to the small amount added. The RSDs for lecithin, stearyl alcohol, poloxamer, and sodium lauryl sulfate are between 1.2% and 2.5%, all not exceeding 3.0%, and the data are not significantly different. Meanwhile, surfactants are used as co-disintegrants in tablet manufacturing. They can increase the wettability of the drug, promote water penetration, and thus accelerate the tablet disintegration process. This is because surfactants can reduce the surface tension of the liquid, making it easier for water to penetrate into the tablet, thereby allowing the tablet to decompose more quickly after ingestion, which is beneficial for the body to absorb the drug components. The amount of surfactant used will affect the dissolution rate; the specific ratio should be selected based on dissolution curve data.

[0205] (9) In this invention, the lubricant can reduce the friction between the powder and the mold and reduce the mutual adhesion between powder particles, thereby improving the fluidity and compressibility of the tablet. The lubricant's participation in the total mixing is not necessarily a completely uniform process. Therefore, the mixing uniformity of the lubricant is not specifically examined in this study. The comparison and screening are conducted in the evaluation of powder fluidity.

[0206] (10) A comparison of Example 1 with Examples 34-38 shows that, when examining the types of the second filler, the RSD of the mixing uniformity of microcrystalline cellulose, powdered cellulose, microcrystalline silica gel, and mannitol is between 1.2% and 2.5%, all not exceeding 3.0%, with little difference in data. A comparison of Examples 1 with Examples 34-38 shows that the RSD of the mixing uniformity of microcrystalline cellulose types PH101, PH301, and UF-711 is between 1.2% and 2.6%, all not exceeding 2.9%, with little difference in data. The RSD of the mixing uniformity of microcrystalline cellulose types PH102, PH302, and UF-702 is between 2.9% and 3.5%, which is significantly different from PH101, PH301, and UF-711. Furthermore, since microcrystalline cellulose has a certain adhesive and disintegrating effect, it is necessary to further consider the formability, disintegration, and dissolution properties of each type when selecting.

[0207] (11) Comparing Example 1 with Examples 39-42, it can be seen that the mixing uniformity RSD of the third mixing time of 10 min, 15 min, 20 min, 25 min and 30 min is 2.0%, 1.9%, 1.2%, 1.8% and 2.4% respectively. The mixing uniformity RSD is between 1.2% and 2.4%, and none of them exceed 2.5%. The data are not much different and have good mixing uniformity.

[0208] (12) Comparing Example 1 with Comparative Examples 1-5, the RSD values ​​of the mixing uniformity of Comparative Examples 1-5 ranged from 3.9% to 6.6%. The RSD value of Comparative Example 1 exceeded the specified limit, while the RSD values ​​of Comparative Examples 2-5 ranged from 3.9% to 4.8%, which was close to the limit of 5% and could not meet the company's internal control standard (RSD < 4.0%). In Comparative Example 4, the mixing method was adjusted by mixing spray-dried lactose, microcrystalline cellulose, and micronized rivaroxaban together. The results showed that the mixing uniformity of rivaroxaban was poor. Therefore, mixing rivaroxaban with spray-dried lactose alone is more conducive to uniform mixing. If other materials are added at the same time, it will interfere with the mixing of rivaroxaban and spray-dried lactose. Therefore, other materials should be added later.

[0209] Test Example 2

[0210] This test case evaluates the flowability of powder.

[0211] Powders with poor flowability, large particle size variations, large variations in bulk density, and irregular morphology are all detrimental to uniform mixing. For example, poor flowability causes powder particles to adhere to each other, hindering interpenetration, movement, and convection, resulting in uneven mixing. Irregularly shaped particles are also difficult to mix uniformly. The flowability of powders can be evaluated through various physical and chemical properties, including particle size distribution, bulk density, and angle of repose.

[0212] Angle of repose: The angle of repose is the angle formed when a particle slides on a free inclined plane of a powder accumulation layer, and the forces of gravity and friction between the particles reach equilibrium. The smaller the angle of repose, the better the flowability of the powder.

[0213] Bulk density, also known as mass density, refers to the mass per unit volume in micronization. Here, volume refers to the total volume occupied by the particles and the spaces between them.

[0214] Tapped density: refers to the mass per unit volume of powder in a container after it has been tapped under specified conditions.

[0215] One of the evaluation indicators is the Haunser ratio. The Haunser ratio = tapped density / loose density. A Haunser ratio between 1.00 and 1.11 indicates excellent liquidity; between 1.12 and 1.18 indicates good liquidity; between 1.19 and 1.25 indicates good or moderate liquidity; between 1.26 and 1.34 indicates fair liquidity; between 1.35 and 1.45 indicates poor liquidity; between 1.46 and 1.59 indicates very poor liquidity; and greater than 1.60 indicates extremely poor liquidity.

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

[0217] Table 3

[0218]

[0219]

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

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

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

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

[0224] (5) Comparing Example 1 with Examples 15-17, it can be seen that, when examining the types of disintegrants, the Haunser ratios of sodium carboxymethyl starch, croscarmellose sodium, croscarmellose polyvinylpyrrolidone, and calcium carboxymethyl cellulose are between 1.28 and 1.34, and the flowability is acceptable. The type of disintegrant has little effect on the flowability.

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

[0226] (7) Comparing Example 1 with Examples 20-22, it can be seen that, considering the type of adhesive, the Haunser ratio of hydroxypropyl cellulose, methylcellulose, and povidone is between 1.28 and 1.34, resulting in acceptable flowability, while the Haunser ratio of hydroxypropyl methylcellulose is 1.35, indicating poor flowability. Comparing Example 1 with Examples 23-24, it can be seen that, regarding the selection of adhesive dosage, the Haunser ratios of valxaban to povidone at ratios of 25:1, 20:1, and 15:1 are between 1.28 and 1.34, resulting in acceptable flowability, and the selection of adhesive dosage has little impact on flowability.

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

[0228] (9) Comparing Example 1 with Examples 28-30, it can be seen that, when examining the types of lubricants, the Haunser ratio of stearic acid, magnesium stearate, sodium stearate fumarate, and colloidal silica is 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, regarding the type of the second filler, the Haunser ratio of microcrystalline cellulose, microcrystalline silica powder, and mannitol is between 1.28 and 1.33, indicating acceptable flowability; the Haunser ratio of powdered cellulose is 1.41, indicating poor flowability. The flowability 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, regarding the type of microcrystalline cellulose, the Haunser ratio of microcrystalline cellulose types PH101 and PH102 is 1.37, indicating poor flowability. The Haunser ratio of microcrystalline cellulose types PH301, PH302, UF-702, and UF-711 is between 1.28 and 1.33, not exceeding 1.34, indicating acceptable flowability. The selection should be based on the dissolution characteristics of each type.

[0230] (11) Comparing Example 1 with Comparative Examples 1-5, it can be seen that the repose angle data is similar to that of Example 1, but the Haunser ratio of Comparative Examples 1-5 is between 1.38 and 1.46, indicating poor or very poor fluidity.

[0231] Test Example 3

[0232] This test case is used to detect dissolution.

[0233] Dissolution rate refers to the rate and extent to which a drug dissolves from a solid dosage form, such as a tablet, in a specified solvent. Dissolution rate is an important indicator for tablet quality control, and it should generally be tested for poorly soluble drugs. Because drug dissolution directly affects its absorption and utilization in the body, dissolution testing has become one of the indicators for evaluating the quality of pharmaceutical preparations and manufacturing processes.

[0234] Dissolution profile is a curve showing the relationship between the amount of drug dissolved and time in a drug dissolution test. It is a curve fitted from multiple points and is more intuitive than dissolution rate in expressing the trend of drug dissolution behavior and reflecting changes in raw materials, formulation ratios, and process parameters during the production process.

[0235] The type of dissolution medium is determined based on the drug's solubility. A pH-solubility test is required to examine the saturated solubility of rivaroxaban raw material in different pH media. An excess of raw material is added to 500 ml of the medium, stirred, and the solution is incubated in a 37°C water bath to form a saturated solution before sampling and testing. Following the content assay method, the saturated solubility of rivaroxaban raw material in each pH is determined. 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] The results above show that the saturated solubility of rivaroxaban in media with pH 1.0–8.0 ranges from 0.00959 to 0.01119 mg / mL, exhibiting no pH dependence. Therefore, pH 4.5 was chosen as the primary medium for dissolution curve analysis. The specific dissolution curve method is as follows:

[0239] Take this product and perform the dissolution and release determination method (Chinese Pharmacopoeia 2020 Edition, Part IV, General Chapter 0931, Method II) at 75 rpm with 900 mL of the corresponding medium. After 5 min, 10 min, 15 min, 30 min, 45 min, and 60 min, take 10 mL of the dissolution solution at each time and quickly add 10 mL of the solution. Filter the solution and use the filtrate as the test solution.

[0240] Medium preparation method:

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

[0242] Table 5

[0243]

[0244]

[0245] The results in Table 5 show that:

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

[0247] (2) Comparing Example 1 with Examples 7-9, it can be seen that in the selection of spray-dried lactose particle size, samples with spray-dried lactose particle sizes of 40-60 mesh and 60-80 mesh, having a cumulative dissolution rate greater than 85% at 15 min, can be considered similar to "Xarelto" tablets. However, the cumulative dissolution rate is lower for 80-100 mesh and 100-120 mesh samples. This 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, resulting in greater internal stress and making them relatively more difficult to disintegrate and disperse. Considering the overall mixing uniformity, a 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 have a cumulative dissolution rate greater than 85% at 15 minutes, which can be considered similar to "Xarelto" tablets. The sample with a ratio of 1:5 does not reach a cumulative dissolution rate of 85% at 15 minutes, possibly because in the formulation, as the proportion of spray-dried lactose increases, the proportion of microcrystalline cellulose decreases, thus reducing its disintegration effect. Combining the flowability data and mixing uniformity data, the preferred ratio of rivaroxaban to dried lactose is 1:4.

[0249] (4) Comparing Example 1 with Examples 12-13, it can be seen that micronization or fine powder treatment reduces the average particle size of the active pharmaceutical ingredient (API), thereby increasing its surface area and solubility, which can improve the drug's dissolution rate to a certain extent. However, when the particle size is reduced to a certain extent, the particle surface becomes increasingly smooth, and the characteristics of the original drug material become less and less obvious. Furthermore, the application of micronization technology does not change the main functional group structure of the original drug material. On the contrary, if the particle size is too small, it will affect the dissolution effect of the ultrafine powder. An investigation into the particle size of rivaroxaban API revealed that the smaller the particle size, the faster the dissolution rate. When the API particle size was less than 20 μm, there was no significant difference in dissolution rate. Considering both mixing uniformity and API pulverization efficiency, a particle size of less than 20 μm is more in line with economic requirements and the energy consumption and maintenance requirements of the equipment.

[0250] (5) Comparing Example 1 with Examples 15-17, it can be seen that, considering the type of disintegrant, the samples using croscarmellose sodium and croscarmellose as disintegrants had a cumulative dissolution rate greater than 85% at 15 minutes, which can be considered similar to "Xarelto" tablets. The samples using carboxymethyl starch sodium and carboxymethyl cellulose calcium as disintegrants did not reach a cumulative dissolution rate of 85% at 15 minutes. Under the same disintegrant ratio, croscarmellose sodium has the best disintegration and dissolution effect, therefore croscarmellose sodium is preferred as the disintegrant.

[0251] (6) Comparing Example 1 and Example 18, it can be seen that when examining the amount of disintegrant used, the main difference lies in the slight difference in the cumulative dissolution rate at 5 min and 10 min when the ratio of croscarmellose sodium to rivaroxaban is between 1:(1-2). The dissolution rate at 5 min and 10 min increases with the increase of disintegrant dosage. However, when the ratio of croscarmellose sodium to rivaroxaban is 1:1, the croscarmellose sodium may swell and form a colloid, hindering the later dissolution of the tablets, resulting in the cumulative dissolution rate not reaching 100% at 60 min.

[0252] (7) Comparing Example 1 with Examples 20-22, it can be seen that, in terms of the type of adhesive, the samples with hydroxypropyl cellulose or hydroxypropyl methylcellulose as adhesives did not reach a cumulative dissolution rate of 85% at 15 min, while the samples with methylcellulose or povidone as adhesives had a cumulative dissolution rate of more than 85% at 15 min, which can be considered similar to "Xarelto" tablets. The samples with povidone as adhesives had a slightly higher cumulative dissolution rate at 5 min, 10 min, 15 min, and 30 min than the samples with methylcellulose as adhesives. Therefore, povidone is preferred as the adhesive.

[0253] (8) Comparing Example 1 and Example 24, it can be seen that the selection of adhesive dosage, with a cumulative dissolution rate of more than 85% at 15 min, can be considered similar to that of "Xarelto" tablets. As the amount of adhesive increases, the dissolution rate decreases slightly; at a ratio of 1:20, the dissolution rate is relatively high. Therefore, 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, in terms of the type of surfactant, the samples using stearyl alcohol, poloxamer, and lecithin as surfactants did not reach a cumulative dissolution rate of 85% at 15 min, while the samples using sodium dodecyl sulfate as surfactant had a significantly higher cumulative dissolution rate at each time point than the samples using other surfactants. Sodium dodecyl sulfate, as an anionic surfactant, has a biodegradability >90%, good emulsifying, foaming, water solubility, biodegradability, alkali resistance, hard water resistance, and stability in aqueous solutions with a wide pH range. It is also easy to synthesize and inexpensive. Therefore, sodium dodecyl sulfate is preferred.

[0255] (9) Comparing Example 1 with Examples 28-30, it can be seen that, considering the types of lubricants, the samples using stearic acid, magnesium stearate, sodium stearate fumarate, and colloidal silica as lubricants all had a cumulative dissolution rate greater than 85% at 15 minutes, which can be considered similar to the tablets. Magnesium stearate, as a lubricant, anti-sticking agent, and flow aid, is considered comprehensively based on mixing uniformity, flowability evaluation parameters, accessibility of excipients, and economic benefits.

[0256] (10) Comparing Example 1 with Examples 31-32, it can be seen that, regarding the type of second filler, the samples using powdered cellulose or mannitol as the second filler did not reach a cumulative dissolution rate of 85% after 15 minutes, while the samples using microcrystalline cellulose or microcrystalline silica gel as the second filler all had a cumulative dissolution rate greater than 85% after 15 minutes, and can be considered similar to "Xarelto" 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 in wet granulation but also in dry direct compression. It also has certain lubricating and disintegrant properties and good compressibility.

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

[0258] (12) Comparing Example 1 with Comparative Examples 1-5, it can be seen that in the dissolution curves at pH 4.5, the cumulative dissolution rate of the comparative examples after 5 minutes does not exceed 50%, while the final dissolution rate of comparative examples 3 and 5 does not exceed 95%, indicating incomplete dissolution. In comparative example 5, the raw materials, binder, and sodium dodecyl sulfate were added according to the prescription, but there were losses after micronization, resulting in dissolution loss. In comparative example 3, the blank particles were mixed with the raw materials, and the raw materials were not adsorbed onto the particles or were embedded in the particles, which also resulted in a dissolution rate of less than 100%. Both of these factors may affect bioavailability. The dissolution of Example 1 was faster than that of the original formulation and was superior to that of the original formulation. Therefore, the rivaroxaban tablets in Example 1 were significantly better than the other comparative examples in terms of dissolution behavior.

[0259] Test Example 4

[0260] This test case performs stability testing.

[0261] Influencing factor tests are conducted under harsh conditions to understand the factors affecting stability, possible degradation pathways, and degradation products. This provides a basis for formulation process screening, selection of packaging materials and containers, and determination of storage conditions. It also provides a basis for the temperature and humidity conditions to be used in accelerated and long-term tests, and can also provide a basis for the selection of analytical methods.

[0262] The quality of rivaroxaban tablets (Example 1) and Xarelto tablets (Comparative Example 6) was examined using the smallest dosage unit excluding the inner packaging. The drugs were tested at 0, 5, 10, and 30 days under high temperature (40°C, 60°C), high humidity (75% RH, 92.5%), and light conditions. Specific dissolution rates are shown in Table 6, content changes are shown in Table 7, and impurity changes during the stability period are shown in Table 8 and 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℃, 60℃), high humidity (75%RH, 92.5%), and light conditions, the rivaroxaban tablets of Example 1 and the "Xarelto" tablets (BJ58093) of Comparative Example 6 showed no significant decrease in dissolution and content after 5, 10, and 30 days. Related substances showed no increase in impurities B, D, E, M, L, F, I, J, other maximum single impurities, and total impurities, indicating stable quality. Furthermore, impurities B and D from Example 1-1 were not detected on day 0, lower than the day 0 data for "Xarelto" tablets (BJ58093). In summary, under high temperature (40℃, 60℃), high humidity (75%RH, 92.5%), and light conditions, the rivaroxaban tablets of Example 1 exhibited superior quality compared to "Xarelto" (BJ58093) of Comparative Example 6, demonstrating stable and controllable quality.

[0276] Test Example 5

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

[0278] Accelerated testing is conducted under extreme conditions to examine drug stability by accelerating the rate of chemical or physical changes in commercially available packaging. It simulates the stability of drugs under transient extreme conditions that may be encountered during transportation and storage, and provides a preliminary prediction of the long-term stability of samples under specified storage conditions.

[0279] Accelerated testing typically involves three batches of samples, conducted at a temperature at least 15°C higher than that used for long-term testing. A typical 6-month test is performed at 40°C ± 2°C and RH 75% ± 5%. Samples are taken at the end of months 0, 1, 2, 3, and 6 of the test period to assess key performance indicators.

[0280] Therefore, the rivaroxaban tablets prepared in Example 1-1 and the commercially available original formulation "Xarelto" tablets (10mg) were subjected to four-medium dissolution curve detection under accelerated conditions (40℃ / 75%RH) for 1 month, 2 months, 3 months and 6 months. The test results are shown in Table 10:

[0281] Table 10

[0282]

[0283]

[0284]

[0285] The above results show that after 3 and 6 months of storage at 40°C / 75% humidity, the rivaroxaban-coated tablets prepared in Example 1 of this application showed a significant decrease in dissolution compared to the "Xarelto" tablets in Comparative Example 9, while no significant change was observed in Example 1. Therefore, the sample prepared using spray-dried lactose and direct compression tableting still exhibits good stability, which is significantly superior to commercially available rivaroxaban tablets.

[0286] Test Example 6

[0287] To verify the maturity of this application and ensure that the tablet composition and production process are mature and reasonable, with key technical indicators close to production requirements, and to provide a production route with consistent and stable quality for commercial production, further scale-up production was conducted with a batch size of 100,000 tablets. Three parallel batches were produced, namely Example 1-1, Example 1-2, and Example 1-3, with the same process flow as above, to examine the inter-batch and intra-batch uniformity and stability.

[0288] Dissolution profiles of Examples 1-1 to 1-3 (scaled-up production) and Comparative Example 9 (comparative example 9) of the commercially available original formulation "Xarelto" tablets (10 mg) were compared in different dissolution media to examine inter-batch and intra-batch homogeneity. The methods are as follows:

[0289] Take this product and perform the dissolution and release determination method (Chinese Pharmacopoeia 2015 Edition, Part IV, General Chapter 0931, Method II) at 75 rpm with 900 mL of the corresponding medium. After 5 min, 10 min, 15 min, 30 min, 45 min, and 60 min, take 10 mL of the dissolution solution at each time and quickly add 10 mL of the solution. Filter the solution and use 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, place it in 1000mL of water, add 1.66mL glacial acetic acid and 20mL of 10% SDS solution, adjust the pH to 4.50±0.1 with sodium hydroxide or glacial acetic acid, mix well, and the solution is ready. (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 6.0 g of anhydrous sodium dihydrogen phosphate and 0.9 g of sodium hydroxide into 1000 mL of water, mix thoroughly, add 20 mL of 10% SDS solution, mix well, and the solution is ready. (6.0 g anhydrous sodium dihydrogen phosphate + 0.9 g sodium hydroxide + glacial acetic acid + 2 g SDS → 1000 mL degassed water, measure pH)

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

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

[0295] The cumulative dissolution data of three batches of Xareltox tablets (10mg) from Examples 1-1 to 1-3 and Comparative Example 9, produced by different dissolution media, are shown in Tables 11-14 below:

[0296] Table 11

[0297]

[0298]

[0299] Examples 1-1 to 1-3 and Comparative Example 9 showed that the commercially available original formulation of "Xarelto" tablets had a dissolution rate of greater than 85% in pH 4.5 acetate buffer (containing 0.2% SDS) for 15 minutes, and the dissolution rate was better than that of "Xarelto" tablets. The average dissolution RSD of Examples 1-1 to 1-3 was less than 5%, and the intra-batch homogeneity was good.

[0300] Table 12

[0301]

[0302] Examples 1-1 to 1-3 and Comparative Example 9 showed that the commercially available original formulation of "Xarelto" tablets had a dissolution rate of greater than 85% in pH 6.8 phosphate buffer (containing 0.2% SDS) for 15 minutes, and the dissolution rate was better than that of "Xarelto" tablets. The average dissolution RSD of Examples 1-1 to 1-3 was less than 10%, and the intra-batch homogeneity was good.

[0303] Table 13

[0304]

[0305]

[0306] Examples 1-1 to 1-3 and Comparative Example 9 showed that the commercially available original formulation of "Xarelto" tablets had a dissolution rate of greater than 85% in aqueous solution (containing 0.2% SDS) for 15 minutes, and the dissolution rate was better than that of "Xarelto" tablets. The average dissolution RSD of Examples 1-1 to 1-3 was less than 10%, and the intra-batch homogeneity was good.

[0307] Table 14

[0308]

[0309] Examples 1-1 to 1-3 and Comparative Example 9 showed that the similarity factor (f2) of the commercially available original formulation "Xarelto" tablets in 0.1 mol / L hydrochloric acid solution (containing 0.2% SDS) was greater than 50, and the dissolution was superior to that of "Xarelto" tablets. The average dissolution RSD at 5 min in Examples 1-1 to 1-3 was less than 20%, and the average dissolution RSD at other time points was less than 10%, indicating good intra-batch homogeneity.

[0310] In summary: Examples 1-1 to 1-3 and "Xarelto" tablets (batch BJ57602) all had similarity factors (f2) greater than 50 in 0.1 mol / L hydrochloric acid solution (containing 0.2% SDS), and their dissolution rates in other media were all greater than 85% after 15 min. Moreover, their dissolution curves were all superior to those of "Xarelto" tablets.

[0311] Test Example 7

[0312] This test case is used for a human bioequivalence study.

[0313] Based on the "Technical Guidelines for Bioequivalence Studies of Generic Chemical Drugs Using Pharmacokinetic Parameters as Endpoints," "Technical Guidelines for Bioequivalence Studies of Rivaroxaban Tablets," "Technical Guidelines for Bioequivalence Studies of Narrow Therapeutic Index Drugs," Appendix General Rules of the 2020 Edition of the Chinese Pharmacopoeia "Guidelines for Human Bioavailability and Bioequivalence of Drug Formulations," and relevant requirements in GCP, and referring to existing research literature on the pharmacokinetics and relative bioavailability of rivaroxaban tablets in humans, a research plan was developed to evaluate the rivaroxaban tablets (specification: 10 mg, test formulation T) in Experimental Example 1-1 and the rivaroxaban tablets (trade name: Bayer AG) produced by Bayer AG. Specification: 10 mg, Reference formulation R) Bioequivalence and safety in healthy volunteers under fasting and postprandial conditions.

[0314] Design basis for the detection substance:

[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 measure only the parent drug, as the pharmacokinetic curve of the parent drug can more sensitively reflect the differences between formulations than that of metabolites. This study measured the concentration of rivaroxaban in plasma.

[0316] Design basis for the cleaning period:

[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 analyte)." According to the product information leaflet, the terminal elimination half-life of this product is... t1 / 2 The cleaning time is approximately 5 to 9 hours, and the cleaning period for this experiment is set at 7 days.

[0318] Pharmacokinetic parameters:

[0319] In this study, a non-compartmental model was used to analyze pharmacokinetic parameters of the blood drug concentration data. The main pharmacokinetic parameter was the peak plasma drug concentration (C60). max ), Area under the curve (AUC) 0-t AUC 0-∞ The secondary pharmacokinetic parameter is the time to peak concentration (T). max ), apparent terminal elimination half-life (t) 1 / 2 The pharmacokinetic parameters evaluated include: Cmax: peak concentration, Tmax: time to peak concentration, λz: apparent terminal elimination rate constant, t... 1 / 2 Epitaxial elimination half-life, AUC 0-tThe area under the blood drug concentration-time curve (AUC) can be accurately measured from 0 to the last concentration at sample collection time t. 0-∞ Area under the plasma concentration-time curve from 0 to infinity (∞), AUC_%Extrap: Percentage of residual area; when it is greater than 20%, it indicates AUC_%Extrap. 0-t The ratio of / AUC0-∞ is less than 80%; AUC_%Extrap = (AU C0-∞ -AUC 0-t ) / AUC 0-∞ ×100.

[0320] Bioequivalence evaluation analysis methods and standards:

[0321] Blood drug concentration-time data were collected after a single dose, and the main pharmacokinetic parameters (such as C) were analyzed. max Statistical analysis was performed on the CUC (Cost Per Count) of the test formulation and the reference formulation. max AUC comparison. The AUC of rivaroxaban in rivaroxaban tablets was calculated using WinNonlin 8.3 software. max and T max Take the measured value. The C of the test formulation T... max and AUC compared to reference formulation R C max After logarithmic transformation of AUC, C is calculated. max The point estimates of AUC were obtained, and significance was tested using multivariate analysis of variance (ANOVA), followed by two-tailed t-tests for statistical processing.

[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 determination criteria are as follows: The C0.05 of rivaroxaban in plasma after the subject takes the test formulation and the reference formulation of rivaroxaban tablets is used as the criterion. max AUC 0-t AUC 0-∞ The two formulations can be considered bioequivalent if the 90% confidence interval of the geometric mean ratio (test formulation / reference formulation) falls between 80.00% and 125.00%, and the upper limit of the 90% confidence interval of the ratio of the intra-individual standard deviations of the test formulation and the reference formulation is ≤2.5.

[0323] Fasting equivalence test

[0324] This study was a randomized, open-label, two-sequence, four-period fully replicate crossover, single-dose, fasting bioequivalence trial, enrolling 28 healthy subjects. The dosage was 10 mg. Subjects were randomly assigned to take either the test formulation T or the reference formulation R1 tablet with 240 mL of water on an empty stomach each period. Blood samples were collected before and after administration at predetermined time points. The washout period was 7 days.

[0325] The block randomization method was used, and the enrolled subjects were randomly divided into two groups in a 1:1 ratio using the ProcPlan procedure of SAS (9.4) statistical software. The subjects took the medication in the order specified in the randomization table.

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

[0327] The mean drug-time curves of the test formulation (T) and the reference formulation (R) under fasting conditions after a single oral administration of rivaroxaban tablets (10 mg) to the subjects are shown in the figure below. Figure 4 As shown, Figure 5 The figure shows the mean drug-time semi-logarithmic plots of the test formulation T and the reference formulation R under fasting conditions. Specific results are shown below: Table 15 summarizes the plasma rivaroxaban PK parameters (PKPS) after fasting oral administration of the test formulation T or the reference formulation R; Table 16 shows the results of the analysis of variance for the main PK parameters of fasting oral administration of rivaroxaban; Table 17 shows the results of the bioequivalence (BES) for the main PK parameters of fasting oral administration of rivaroxaban; Table 18 shows the results of the ratio of within-individual standard deviations (BES) for the main PK parameters of fasting oral administration of rivaroxaban; and Table 19 shows the Tmax nonparametric rank-sum test.

[0328] Table 15

[0329]

[0330] Note: N is the number of times, and Tmax describes the median (minimum and 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] Bioequivalence evaluation results of subjects taking rivaroxaban tablets orally on an empty stomach:

[0341] (1) Pharmacokinetic parameter Cmax

[0342] The Cmax mean bioequivalence results are as follows: the geometric mean of the test formulation T is 156.59 ng / mL, and the geometric mean of the reference formulation R is 177.74 ng / mL. The ratio of the geometric mean of the test formulation T to the reference formulation R is 88.10%, with a 90% confidence interval of 82.25%–94.37%, which falls within the regulatory range of 80%–125%. The Cmax intra-individual standard deviations of the test formulation T and the reference formulation R are as follows: the intra-individual standard deviation of the test formulation T is 0.1859, and the intra-individual standard deviation of the reference formulation R is 0.1906. The ratio of the intra-individual standard deviations of the test formulation T to the reference formulation R is 0.9755, with an upper limit of the 90% confidence interval of 1.3549, which is less than 2.5 and meets regulatory requirements.

[0343] (2) Pharmacokinetic parameter AUC0-t

[0344] The AUC0-t mean bioequivalence results are as follows: the geometric mean of the test formulation T is 1030.49 ng·h / mL, and the geometric mean of the reference formulation R is 1111.03 ng·h / mL. The ratio of the geometric mean of the test formulation T to that of the reference formulation R is 92.75%, with a 90% confidence interval of 87.48%–98.33%, which falls within the regulatory range of 80%–125%. The intra-individual standard deviations of the AUC0-t test formulation T and the reference formulation R are as follows: the intra-individual standard deviation of the test formulation T is 0.1508, and that of the reference formulation R is 0.1412. The ratio of the intra-individual standard deviations of the test formulation T to that of the reference formulation R is 1.0681, with an upper limit of the 90% confidence interval of 1.4836, which is less than 2.5 and meets the regulatory requirements.

[0345] (3) Pharmacokinetic parameters AUC0-∞

[0346] The mean bioequivalence results for AUC0-∞ are as follows: the geometric mean of the test formulation T is 1071.98 ng·h / mL, and the geometric mean of the reference formulation R is 1146.32 ng·h / mL. The ratio of the geometric mean of the test formulation T to the reference formulation R is 93.51%, with a 90% confidence interval of 88.23%–99.12%, which falls within the regulatory range of 80%–125%. The intra-individual standard deviations for the test formulation T and the reference formulation R for AUC0-∞ are as follows: the intra-individual standard deviation of the test formulation T is 0.1635, and the intra-individual standard deviation of the reference formulation R is 0.1479. The ratio of the intra-individual standard deviations of the test formulation T to the reference formulation R is 1.1059, with an upper limit of the 90% confidence interval of 1.5361, which is less than 2.5 and meets the regulatory requirements.

[0347] Analysis of the fasting test Tmax index showed that there was no statistically significant difference between the median distributions of the overall Tmax of the two formulations (P = 0.0693).

[0348] In summary, the fasting test results indicate that the rivaroxaban tablets tested in Example 1-1 and the rivaroxaban tablets manufactured by Bayer AG (trade name: The reference formulation is bioequivalent.

[0349] Test Example 8

[0350] This test case was used for a postprandial bioequivalence test.

[0351] This study was a randomized, open-label, two-sequence, four-period fully replicate crossover, single-dose, postprandial bioequivalence trial, enrolling 28 healthy subjects. The dosage was 10 mg. Each week, subjects ate a high-fat, high-calorie meal 30 minutes before administration in the morning, finishing the meal within 30 minutes. 30 minutes (±1 minute) after the start of the meal, subjects took either the test formulation T or the reference formulation R1 tablet with 240 mL of water according to a randomization table. Blood samples were collected before and after administration at the designated time points. The washout period was 7 days.

[0352] Subjects received a single oral dose of rivaroxaban tablets (10 mg) after a meal. Figure 6 The mean drug-time curves of the test formulation T and the reference formulation R under postprandial conditions are shown below. Figure 7 The figure shows the semi-logarithmic plots of the mean drug-time curves for the test formulation T and the reference formulation R under postprandial conditions. Specific results are shown below: Table 20 summarizes the plasma rivaroxaban PK parameters (PKPS) after oral administration of the test formulation T or the reference formulation R following a meal; Table 21 shows the ANOVA results for the main PK parameters of oral rivaroxaban following a meal; Table 22 shows the bioequivalence results (BES) for the main PK parameters of oral rivaroxaban following a meal; Table 23 shows the intra-individual standard deviation ratios (BES) for the main PK parameters of oral rivaroxaban following a meal; and Table 24 shows the Tmax nonparametric rank-sum test.

[0353] Table 20

[0354]

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

[0356] Table 21

[0357]

[0358] Table 22

[0359]

[0360] Table 23

[0361]

[0362]

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

[0364] Table 24

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

[0366] Bioequivalence evaluation results of oral administration of rivaroxaban tablets after meals in subjects:

[0367] (1) Pharmacokinetic parameter C max

[0368] C max The average bioequivalence results are as follows: the geometric mean of the test formulation T was 258.08 ng / mL, the geometric mean of the reference formulation R was 274.30 ng / mL, the geometric mean ratio of the test formulation T to the reference formulation R was 94.09%, and the 90% confidence interval was 88.81%–99.68%, which is within the regulatory range of 80%–125%. max The intra-individual standard deviations of the test formulation T and the reference formulation R are as follows: the intra-individual standard deviation of the test formulation T is 0.1909, the intra-individual standard deviation of the reference formulation R is 0.1953, the ratio of the intra-individual standard deviations of the test formulation T to the reference formulation R is 0.9776, the upper limit of the 90% confidence interval is 1.3640, which is less than 2.5, and meets the 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 formulation T was 1708.13 ng·h / mL, and the geometric mean of the reference formulation R was 1746.42 ng·h / mL. The geometric mean ratio of the test formulation T to the reference formulation R was 97.81%, with a 90% confidence interval of 94.61%–101.11%, which falls within the regulatory range of 80%–125%. 0-tThe intra-individual standard deviations of the test formulation T and the reference formulation R are as follows: the intra-individual standard deviation of the test formulation T is 0.1057, the intra-individual standard deviation of the reference formulation R is 0.1121, the ratio of the intra-individual standard deviations of the test formulation T to the reference formulation R is 0.9423, the upper limit of the 90% confidence interval is 1.3146, which is less than 2.5, and meets the regulatory requirements.

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

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

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

[0374] In summary, the postprandial test results indicate that the rivaroxaban tablets tested in Example 1-1 and the rivaroxaban tablets manufactured by Bayer AG (trade name: The reference formulation is bioequivalent.

[0375] In summary, the rivaroxaban tablets used in this invention exhibit a cumulative dissolution rate greater than 85% at 15 minutes under different pH and media conditions, demonstrating rapid dissolution behavior and batch-to-batch stability. The preparation method is simple, yields tablets with uniform content, rapid dissolution, no significant increase in impurities, and maintains essentially constant content and dissolution rate, resulting in good formulation stability.

[0376] The applicant declares that the above description is only a specific embodiment 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 conceived by those skilled in the art within the technical scope disclosed in the present invention fall within the protection and disclosure scope of the present invention.

Claims

1. A rivaroxaban tablet, characterized in that, The rivaroxaban tablets, by weight, consist of 10 parts rivaroxaban, 40 parts spray-dried lactose, 28.3 parts microcrystalline cellulose UF-711, 5 parts croscarmellose sodium, 0.5 parts povidone K30, 0.5 parts sodium dodecyl sulfate, and 0.7 parts magnesium stearate. The particle size D90 of the rivaroxaban is 20 μm; The spray-dried lactose includes spherical shapes; The spray-dried lactose has a particle size of 80 mesh; The rivaroxaban tablets are prepared by the following method: (1) Rivaxaban was subjected to air jet milling; (2) Mix rivaroxaban with spray-dried lactose for the first time; (3) Add the mixture obtained in step (2) to povidone K30, croscarmellose sodium cellulose and sodium dodecyl sulfate for a second mixing; (4) Add the mixture obtained in step (3) to microcrystalline cellulose UF-711 for a third mixing; (5) Add magnesium stearate to the mixture obtained in step (4) for a fourth mixing, and then directly compress into tablets; The stirring speed for the first mixing was 10 rpm, and the time was 10 min. The second mixing was performed at a stirring speed of 10 rpm for 17 minutes. The stirring speed for the third mixing was 10 rpm, and the time was 5 min. The stirring speed for the fourth mixing was 10 rpm, and the time was 5 min. The hardness of the rivaroxaban tablets after compression molding is 60 N; The diameter of the rivaroxaban tablet after compression molding is 6 mm.

2. A method for preparing rivaroxaban tablets according to claim 1, characterized in that, The preparation method includes the following steps: (1) Rivaxaban was subjected to air jet milling; (2) Mix rivaroxaban with spray-dried lactose for the first time; (3) Add the mixture obtained in step (2) to povidone K30, croscarmellose sodium cellulose and sodium dodecyl sulfate for a second mixing; (4) Add the mixture obtained in step (3) to microcrystalline cellulose UF-711 for a third mixing; (5) Add magnesium stearate to the mixture obtained in step (4) for a fourth mixing, and then directly compress into tablets; The stirring speed for the first mixing was 10 rpm, and the time was 10 min. The second mixing was performed at a stirring speed of 10 rpm for 17 minutes. The stirring speed for the third mixing was 10 rpm, and the time was 5 min. The stirring speed for the fourth mixing was 10 rpm, and the time was 5 min. The hardness of the rivaroxaban tablets after compression molding is 60 N; The diameter of the rivaroxaban tablet after compression molding is 6 mm.

Images