An apixaban orally disintegrating tablet composition and its preparation method

Abstract

The present invention discloses a new formulation composition of apixaban with obvious clinical advantages and a preparation method thereof, belonging to the field of pharmaceutical preparations. The new formulation composition of apixaban comprises the following components: apixaban, a filler, a binder, a disintegrant, a solubilizer, a glidant, a lubricant and a flavoring agent; wherein, the binder is hydroxypropyl cellulose, and calculated by weight percentage, the proportion of the binder is 1.0-3.0%. The new formulation composition of apixaban provided by the present invention has a short disintegration time in the oral cavity and does not need to be swallowed with water, thereby improving the convenience and compliance of administration, improving the medication safety of special populations, and providing a better choice for patients with dysphagia and / or those who need to crush tablets and then take them orally or by nasogastric feeding after surgery.

Description

Technical Field

[0001] The present invention belongs to the field of pharmaceutical preparations, and particularly relates to a novel apixaban preparation composition with obvious clinical advantages and a preparation method thereof. Background Art

[0002] Apixaban is a factor Xa inhibitor and is clinically used in adult patients undergoing elective hip or knee replacement surgery to prevent venous thromboembolism events (VTE). Its commonly used clinical dosage form is an ordinary tablet (for oral administration). However, ordinary tablets are not suitable for patients with difficulty swallowing or those who need to crush the tablets and then take them orally or by nasogastric feeding after surgery. Therefore, it is very meaningful to develop an apixaban orally disintegrating tablet composition, which does not require swallowing with water, improves the convenience and compliance of patient administration, and improves the medication safety of special populations to avoid potential risks such as asphyxia caused by inhalation into the lungs during taking.

[0003] Apixaban was first disclosed in US Patent US6967208B2, with the chemical name of 1-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxopiperidin-1-yl)phenyl]-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide. The structural formula of apixaban is as follows:

[0004]

[0005] Apixaban is insoluble in water and has the disadvantages of slow dissolution rate, low dissolution degree, and low bioavailability, which has a certain impact on the absorption of the drug in the body.

[0006] Chinese Patent CN104095823 discloses a preparation method of apixaban tablets, which is prepared from apixaban, lactose, microcrystalline cellulose, croscarmellose sodium, sodium dodecyl sulfate, and magnesium stearate. The specific steps are as follows: mixing apixaban with a water-soluble material and then crushing it; mixing the crushed mixture with one or more auxiliaries and then directly tabletting to obtain apixaban tablets. The dissolution degree of the apixaban tablets prepared by this method can only reach an average of more than 80% after 15 minutes of dissolution, and the dissolution degree can only reach an average of more than 90% after 30 minutes of dissolution. The dissolution rate is slow and the impurity content is high.

[0007] Chinese Patent Application CN102770126A discloses an apixaban composition, which adopts a dry granulation process. There are problems such as high consumption, low production efficiency, poor reproducibility, and low finished product yield in industrial production when preparing granules by dry granulation.

[0008] Chinese Patent Application CN102908324A discloses an apixaban tablet prepared by a solid dispersion technology. The apixaban raw material is added to hot polyethylene glycol for dispersion, and after curing and cooling, it is pulverized to obtain an apixaban solid dispersion. It has relatively high requirements for the workshop in large-scale production, with cumbersome steps, is not easy to realize industrial production, and has poor practicability.

[0009] In view of the problems existing in the prior art, it is still necessary to find an apixaban preparation and its preparation method that are simple to prepare, have a fast onset of action, good dissolution effect, and are suitable for modern industrial large-scale production. Summary of the Invention

[0010] In view of this, the object of the present invention is to provide a new apixaban preparation composition with obvious clinical advantages and its preparation method. Compared with the prior art, the new apixaban preparation composition provided by the present invention has the characteristics of convenient administration, simple preparation, fast onset of action, and good dissolution effect, and is suitable for modern industrial large-scale production.

[0011] To achieve the above-mentioned invention object, the technical solution of the present invention is as follows:

[0012] On the one hand, the present invention provides a new apixaban preparation composition with clinical advantages, including the following components:

[0013] Apixaban, filler, binder, disintegrant, solubilizer, glidant, lubricant, and flavoring agent. Among them, the binder is hydroxypropyl cellulose, and calculated by weight percentage, the proportion of the binder is 1.0 - 3.0%.

[0014] Preferably, the hydroxypropyl cellulose includes at least one of hydroxypropyl cellulose ELF PHARM, hydroxypropyl cellulose EF PHARM, hydroxypropyl cellulose LF PHARM, hydroxypropyl cellulose JF PHARM, and hydroxypropyl cellulose GF PHARM.

[0015] More preferably, the hydroxypropyl cellulose includes at least one of hydroxypropyl cellulose ELF PHARM and hydroxypropyl cellulose EF PHARM.

[0016] Most preferably, it is hydroxypropyl cellulose EF PHARM.

[0017] Preferably, the new apixaban preparation composition, by weight percentage, contains 2 - 3% of apixaban, 75 - 85% of filler, 1 - 3% of hydroxypropyl cellulose, 1 - 15% of disintegrant, 0.5 - 3.5% of glidant, 0.1 - 2% of flavoring agent, 0.1 - 1% of lubricant, and 0.1 - 2% of solubilizer.

[0018] Further preferably, the novel apixaban preparation composition, by weight percentage, comprises 2.5% of apixaban, 78% of filler, 2% of hydroxypropyl cellulose, 12% of disintegrant, 3% of glidant, 1% of flavoring agent, 0.5% of lubricant, and 1% of solubilizer.

[0019] Preferably, the apixaban is in micronized form, D90 ≤ 40 μm; the filler is selected from at least one of mannitol, microcrystalline cellulose, lactose, and anhydrous calcium hydrogen phosphate; the disintegrant is selected from at least one of crospovidone, croscarmellose sodium, sodium carboxymethyl starch, and corn starch; the solubilizer is selected from at least one of sodium dodecyl sulfate, poloxamer 188, and tween 80; the glidant is selected from at least one of silica and colloidal silica; the lubricant is selected from at least one of magnesium stearate, stearic acid, sodium stearyl fumarate, and talc powder; the flavoring agent is selected from at least one of fruit flavor essence, sucralose, aspartame, and sorbitol.

[0020] Further preferably, the particle size of the apixaban is 5 - 20 μm; the filler is selected from at least one of mannitol and microcrystalline cellulose; the disintegrant is crospovidone; the solubilizer is sodium dodecyl sulfate; the glidant is colloidal silica; the lubricant is magnesium stearate; the flavoring agent is selected from at least one of fruit flavor essence and sucralose.

[0021] Among them, the novel preparation includes but is not limited to tablets, granules, powders, pills, etc.

[0022] Preferably, the novel preparation is at least one of tablets, granules, powders, and pills.

[0023] More preferably, the novel preparation is a tablet.

[0024] Even more preferably, and as an example of the present invention, the novel preparation is an orally disintegrating tablet.

[0025] On the other hand, the present invention provides a preparation method of the above-mentioned novel apixaban preparation composition, comprising the following steps:

[0026] (1) Mix apixaban, a filler accounting for ≥ 70% of the total filler dosage, a disintegrant accounting for ≥ 30% of the total disintegrant dosage, and a flavoring agent accounting for ≥ 50% of the total flavoring agent dosage as internal granulation excipients evenly, spray into a pre-prepared aqueous binder solution, and wet-size to obtain a soft mass.

[0027] (2) Dry the soft mass obtained in step (1), dry-size, add the remaining fillers, disintegrants, solubilizers, glidants, lubricants, and flavoring agents in the prescription, mix evenly, and press into tablets to obtain the product.

[0028] Preferably, in step (1), the filler, disintegrant, and flavoring agent can be added according to different types, and a glidant accounting for ≥30% of the total glidant dosage can also be added.

[0029] Preferably, in step (1), the specific steps of the mixing are as follows: Weigh the internal granulation excipients according to the formula and add them to a wet granulator. Start the equipment for premixing, with a stirring speed of 400 rpm, a shearing speed of 1000 rpm, and a mixing time of 5 min.

[0030] Preferably, in step (1), the concentration of the aqueous binder solution is 1.5 - 10%.

[0031] More preferably, in step (1), the concentration of the aqueous binder solution is 3 - 10%.

[0032] Most preferably, in step (1), the viscosity of the aqueous binder solution is 300 - 600 mPa·s.

[0033] Preferably, in step (1), the wet screening is carried out using a screening machine with a screen aperture of 3*3 mm and a rotation speed of 500 rpm.

[0034] Preferably, in step (2), the drying is to put the material after wet screening into a fluidized bed dryer, set the inlet air volume to 40 - 80 m 3 / h, set the inlet air temperature to 60°C, and discharge the material when the loss on drying is ≤2.0%.

[0035] Preferably, in step (2), the dry screening is to screen the dried material using a screening machine with a screen aperture of 1.0 mm and a rotation speed of 500 rpm.

[0036] Preferably, in step (2), the specific steps of the mixing are as follows:

[0037] The externally added excipients (except the lubricant) are first mixed with the granules after dry screening at a rotation speed of 10 rpm for 15 min; after completion, the lubricant is added for mixing at a rotation speed of 10 rpm for 5 min.

[0038] Preferably, in step (2), the tableting is to press the self-developed preparation using a circular 6 mm punch die, with a theoretical tablet weight of 100 mg per tablet and a hardness of 3 - 4 kgf.

[0039] The beneficial effects of the present invention are as follows:

[0040] (1) The present invention uses micronized APIs, reduces the particle size of the APIs to improve the dissolution rate. It avoids the hindrance of the particle size of the APIs to drug release. Compared with the reference drug, the release of the product of the present invention is significantly accelerated, the dissolution curve is more reasonable, and the onset is rapid.

[0041] (2) The present invention examines the types of binders, selects hydroxypropyl cellulose as the binder and uses it in combination with other components, which can effectively improve the yield of the apixaban orally disintegrating tablet composition. The yield is increased by about 15%. Among them, there is also good synergistic cooperation among apixaban, filler and binder.

[0042] (3) The present invention examines the dosage of the binder, making the granules more uniform, reducing the difference in dissolution curves among tablets, improving the uniformity of product quality and making it safer to take.

[0043] (4) The present invention adopts the wet granulation process, and the process steps are simple. A large production scale can improve production efficiency and save costs.

[0044] (5) The orally disintegrating tablets prepared by the present invention are convenient to carry, do not need to be chewed, nor need to be taken with water. Saliva can make them disintegrate or dissolve quickly, which is easy to swallow, improving the drug administration convenience and compliance of people with dysphagia or postoperative patients. Detailed implementation mode

[0045] In order to make the technical means, creative features, achieved purposes and effects of the present invention easy to understand, the following combines specific embodiments to further clarify the present invention. However, the following embodiments are only the preferred embodiments of the present invention, not all of them. Based on the embodiments in the implementation mode, other embodiments obtained by those skilled in the art without creative work belong to the protection scope of the present invention. In the following embodiments, unless otherwise specified, the used operation methods are all conventional operation methods, the used equipment is all conventional equipment, and the equipment materials used in each embodiment are the same.

[0046] When the embodiment gives a numerical range, it should be understood that unless otherwise specified by the present invention, both endpoints of each numerical range and any value between the two endpoints can be selected. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those of ordinary skill in the technical field to which the present invention belongs.

[0047] It is worth noting that the raw and auxiliary materials used in the present invention are all obtained commercially unless otherwise specified.

[0048] Example 1

[0049] For each of the apixaban orally disintegrating tablet compositions, by weight percentage, its formula composition is: apixaban 2.5%, mannitol 60.5%, crospovidone 12%, hydroxypropyl cellulose EF PHARM 2%, colloidal silicon dioxide 3%, sucralose 0.5%, sodium lauryl sulfate 1%, microcrystalline cellulose 102 17.5%, magnesium stearate 0.5%, powdered orange essence 0.5%. Among them, the micronized apixaban raw material drug is used, and the particle size of the raw material drug D90 = 12 μm.

[0050] Preparation method:

[0051] 1. Wet granulation:

[0052] Binder preparation: Prepare a 4.5% concentration binder slurry using hydroxypropyl cellulose EF PHARM and purified water.

[0053] Premixing: Weigh the internal granulation excipients according to the formula and add them to the wet granulator. Start the equipment for premixing with a stirring speed of 400 rpm, a shearing speed of 1000 rpm, and a mixing time of 5 min.

[0054] Liquid addition and granulation: After premixing, set the stirring speed to 600 rpm, the shearing speed to 1500 rpm, atomize and spray the binder slurry, set the peristaltic pump speed to 60 rpm, the liquid addition time not exceeding 180 s, and the granulation time to 90 s.

[0055] Wet screening: After granulation, screen the granules using a screening machine with a screen aperture of 3*3 mm and a speed of 500 rpm.

[0056] 2. Drying:

[0057] Put the material after wet screening into a fluidized bed dryer, set the inlet air volume to 40 - 80 m 3 / h, set the inlet air temperature to 60 °C, and discharge the material when the loss on drying is ≤ 2.0%.

[0058] 3. Dry screening

[0059] Screen the dried material using a screening machine with a screen aperture of 1.0 mm and a speed of 500 rpm.

[0060] 4. Mixing:

[0061] Mix the external excipients (except magnesium stearate) with the granules after dry screening (Mixing 1) at a speed of 10 rpm for 15 min. After Mixing 1 is completed, add magnesium stearate and mix (Mixing 2) at a speed of 10 rpm for 5 min.

[0062] 5. Tableting:

[0063] Press the self-developed preparation using a circular 6 mm punch die, with a theoretical tablet weight of 100 mg per tablet and a hardness of 3 - 4 kgf.

[0064] Examples 2 - 5

[0065] Compared with Comparative Example 1, only change hydroxypropyl cellulose EF PHARM to an equal amount of hydroxypropyl cellulose ELFPHARM, hydroxypropyl cellulose LF PHARM, hydroxypropyl cellulose JF PHARM, and hydroxypropyl cellulose GF PHARM in sequence, and keep other conditions the same; they are respectively used as Example 2, Example 3, Example 4, and Example 5.

[0066] Examples 6 - 9

[0067] Comparative Example 1, only the content of hypromellose EF PHARM was changed to 0.5%, 1%, 1.5%, and 3% respectively in sequence, and the corresponding mannitol content was adjusted to 62.0%, 61.5%, 61.0%, and 59.5% respectively, with other conditions being the same; they were used as Example 6, Example 7, Example 8, and Example 9 respectively.

[0068] Examples 10 - 13

[0069] Comparative Example 8, only the concentration of hypromellose EF PHARM aqueous solution was changed to 3%, 5%, 7%, and 10% respectively in sequence, with other conditions being the same; they were used as Example 10, Example 11, Example 12, and Example 13 respectively.

[0070] Control Example 1

[0071] Comparative Example 1, no binder was added; during wet granulation, purified water was atomized and sprayed in the liquid addition and granulation steps, and the rest were the same.

[0072] Control Example 2

[0073] Comparative Example 1, apixaban raw material drug that was not micronized was used, D90 = 117 μm; no binder was added; during wet granulation, purified water was atomized and sprayed in the liquid addition and granulation steps, and the rest were the same.

[0074] Control Example 3

[0075] Comparative Example 1, only the binder was changed to povidone K30, with other conditions being the same.

[0076] Control Example 4

[0077] Comparative Example 1, only the binder was changed to hypromellose E5, with other conditions being the same.

[0078] Control Example 5

[0079] Comparative Example 1, only the content of the binder hypromellose EF PHARM was changed to 8%, and the corresponding mannitol content was adjusted to 54.5%, with other conditions being the same.

[0080] Control Example 6

[0081] Apixaban tablets prepared according to Example 1 of Patent CN113041227A.

[0082] Result Detection

[0083] 1. Investigation of Binder Types

[0084]

[0085]

[0086] Example 1, Comparative Example 1, Comparative Example 3, and Comparative Example 4 used micronized apixaban API, with the particle size D90 = 12 μm. Comparative Example 2 used non-micronized apixaban API, D90 = 117 μm. In Comparative Example 1 and Comparative Example 2, no binder was added, and the content of the total mixed granules was relatively low, with content loss occurring during the granulation and drying steps. In Example 1, Comparative Example 3, and Comparative Example 4, different types of binders were added. After adding the binder, the content of the total mixed granules increased significantly, but the disintegration time limit was significantly prolonged. Comparative Example 3 and Comparative Example 4 did not meet the requirements of ChP2020 (not exceeding 60 s). Example 1 achieved the unity of two properties: a high content of total mixed granules and an appropriate tablet disintegration time.

[0087] 2. Investigation of different types of hydroxypropyl cellulose

[0088]

[0089]

[0090] The results showed that adding different types of hydroxypropyl cellulose to the formulation could increase the content of the granules, meeting the requirement of the content being between 95.0 - 105.0%. Different types of hydroxypropyl cellulose corresponded to different molecular weights and viscosities. As the viscosity of hydroxypropyl cellulose increased, the disintegration time of tablets with the same hardness prolonged. The disintegration time limit and content of the EF PHARM and ELF PHARM types of hydroxypropyl cellulose could both meet the requirements.

[0091] 3. Investigation of the dosage of hydroxypropyl cellulose

[0092]

[0093]

[0094]

[0095] The results showed that as the dosage increased, the disintegration time of the preparation with the same hardness prolonged. When the dosage of EF PHARM type of hydroxypropyl cellulose was in the range of 0.5 - 3.0%, the disintegration time limit all met the requirements of ChP2020. In Example 6, the dosage of EF PHARM type of hydroxypropyl cellulose was 0.5%, and the yield of the total mixed granules was lower than 95%, not meeting the requirements of 95 - 105%. Therefore, when the dosage of EF PHARM type of hydroxypropyl cellulose was within 1.0 - 3.0%, it could not only improve the process yield, but also enable the product to disintegrate and release quickly.

[0096] 4. Investigation of the binder concentration

[0097]

[0098]

[0099] The results showed that for the hydroxypropyl cellulose EF PHARM at a concentration of 3-10% (w / w), the content and disintegration time limit of its tablets both met the requirements of ChP2020. The viscosity corresponding to the hydroxypropyl cellulose EF PHARM at a concentration of 3-10% (w / w) was 300-600 mPa·s.

[0100] 5. Determination of content uniformity

[0101] Respectively take the samples of each example and comparative example and commercially available ordinary tablet preparations According to the content determination method (General Chapter 0941 of the Fourth Part of Chinese Pharmacopoeia 2020), the content uniformity of the preparations was detected. The determination results are as follows:

[0102] Sample Content Uniformity (%) A+2.2 Example 1 97 5.7 Example 2 97 6.4 Example 3 99 4.4 Example 4 96 7.2 Example 5 96 7.4 Example 6 94 8.7 Example 7 97 5.7 Example 8 97 6.2 Example 9 99 3.7 Example 10 99 4.2 Example 11 97 6.2 Example 12 98 5.4 Example 13 97 5.7 Comparative Example 1 85 18.2 Comparative Example 2 84 19.4 Comparative Example 3 97 5.7 Comparative Example 4 98 5.2 Comparative Example 5 99 4.1 Comparative Example 6 / 3.6 Alectinib 99 6.3

[0103] The results showed that: the content uniformity of the tablet compositions of the present invention all met the requirements of Chinese Pharmacopoeia 2020 edition, and the product quality was uniform.

[0104] 6. Determination of dissolution

[0105] Respectively take the samples of each example and comparative example and commercially available ordinary tablet preparations According to the dissolution determination method (the second method of General Chapter 0931 of the Fourth Part of Chinese Pharmacopoeia 2020), using pH 6.8 phosphate buffer solution + 0.05% SDS, 900 ml as the solvent, the rotation speed was 75 revolutions per minute. At 60 minutes, samples were taken at 5, 10, 15, 20, 30 and 45 min, 10 ml of the solution was taken each time, filtered through a filter membrane with a pore size of 0.45 μm, and 3 ml of the initial filtrate was discarded. The subsequent filtrate was used as the test solution; an appropriate amount of apixaban reference substance dried under reduced pressure at 105 °C for 4 hours was accurately weighed, dissolved in water and quantitatively diluted to prepare a solution containing 10 μg per 1 ml. Take the above two solutions, according to the ultraviolet-visible spectrophotometry (General Chapter 0401 of the Fourth Part of Chinese Pharmacopoeia 2020), the absorbance was measured at a wavelength of 280 nm, and the percentage of each tablet was calculated. The determination results are as follows:

[0106] Time 5 min 10 min 15 min 20 min 30 min 45 min Example 1 85 89 91 91 92 97 Example 2 84 90 90 93 94 94 Example 3 67 76 82 85 89 92 Example 4 61 71 83 87 95 96 Example 5 50 64 78 86 90 93 Example 6 86 96 98 100 101 101 Example 7 85 89 91 91 92 97 Example 8 85 92 94 95 96 97 Example 9 85 89 90 91 92 96 Example 10 90 96 97 98 99 99 Example 11 85 92 94 95 96 97 Example 12 84 92 94 95 96 97 Example 13 83 91 94 95 95 96 Comparative Example 1 73 82 83 83 84 84 Comparative Example 2 12 37 58 71 81 86 Comparative Example 3 36 62 72 77 82 88 Comparative Example 4 56 67 78 85 89 92 Comparative Example 5 42 61 74 81 87 93 Comparative Example 6 77.6 96.3 99.5 / 99.3 / Alectinib 36 62 72 77 82 91

[0107] The results showed that the tablet compositions of the present invention could rapidly disintegrate or dissolve relative to the commercially available products. Among them, for Examples 1, 2, 6-13, the cumulative dissolution at 15 min could reach the dissolution plateau ≥ 85%, with faster release, which was more conducive to drug absorption, and thus the efficacy could be rapidly exerted.

[0108] In summary, the present invention provides a new formulation composition of apixaban. By using micronized active pharmaceutical ingredient, the particle size of the active pharmaceutical ingredient is reduced to improve the dissolution rate. Selecting hydroxypropyl cellulose as the binder and using it in combination with other components can effectively improve the yield of the apixaban orally disintegrating tablet composition. Selecting a specific dosage of the binder makes the particles more uniform and improves the uniformity of the product quality. The wet granulation process is adopted, with simple process steps and large production scale, which can improve production efficiency and save costs.

[0109] The above are only the preferred embodiments of the present invention and are not intended to limit the present invention. Any modifications, equivalent substitutions, improvements, etc. made within the spirit and principle of the present invention shall be included within the protection scope of the present invention.

Claims

1. An apixaban orally disintegrating tablet composition, characterized in that, By weight percentage, it contains 2.5% apixaban, 60.5% filler mannitol, 12.0% disintegrant crospovidone, 2.0% binder hypromellose EF PHARM, 3.0% glidant colloidal silicon dioxide, 0.5% flavoring agent sucralose, 1.0% solubilizer sodium lauryl sulfate, 17.5% filler microcrystalline cellulose 102, 0.5% lubricant magnesium stearate, 0.5% flavoring agent powdered orange essence; The hypromellose EF PHARM is formulated into an aqueous solution with a concentration of 4.5% before preparation for use; The apixaban is in micronized form, D90 = 12 μm.

2. An apixaban orally disintegrating tablet composition, characterized in that, By weight percentage, it contains 2.5% apixaban, 60.5% filler mannitol, 12.0% disintegrant crospovidone, 2.0% binder hypromellose ELF PHARM, 3.0% glidant colloidal silicon dioxide, 0.5% flavoring agent sucralose, 1.0% solubilizer sodium lauryl sulfate, 17.5% filler microcrystalline cellulose 102, 0.5% lubricant magnesium stearate, 0.5% flavoring agent powdered orange essence; The hypromellose ELF PHARM is formulated into an aqueous solution with a concentration of 4.5% before preparation for use; The apixaban is in micronized form, D90 = 12 μm.

3. An apixaban orally disintegrating tablet composition, characterized in that, By weight percentage, it contains 2.5% apixaban, 61.5% filler mannitol, 12.0% disintegrant crospovidone, 1.0% binder hypromellose EF PHARM, 3.0% glidant colloidal silicon dioxide, 0.5% flavoring agent sucralose, 1.0% solubilizer sodium lauryl sulfate, 17.5% filler microcrystalline cellulose 102, 0.5% lubricant magnesium stearate, 0.5% flavoring agent powdered orange essence; The hypromellose EF PHARM is formulated into an aqueous solution with a concentration of 4.5% before preparation for use; The apixaban is in micronized form, D90 = 12 μm.

4. An apixaban orally disintegrating tablet composition, characterized in that, By weight percentage, it contains 2.5% apixaban, 61.0% filler mannitol, 12.0% disintegrant crospovidone, 1.5% binder hypromellose EF PHARM, 3.0% glidant colloidal silicon dioxide, 0.5% flavoring agent sucralose, 1.0% solubilizer sodium lauryl sulfate, 17.5% filler microcrystalline cellulose 102, 0.5% lubricant magnesium stearate, 0.5% flavoring agent powdered orange essence; The hypromellose EF PHARM is formulated into an aqueous solution with a concentration of 4.5% before preparation for use; The apixaban is in micronized form, D90 = 12 μm.

5. An apixaban orally disintegrating tablet composition, characterized in that, By weight percentage, it contains 2.5% apixaban, 59.5% filler mannitol, 12.0% disintegrant crospovidone, 3.0% binder hypromellose EF PHARM, 3.0% glidant colloidal silicon dioxide, 0.5% flavoring agent sucralose, 1.0% solubilizer sodium lauryl sulfate, 17.5% filler microcrystalline cellulose 102, 0.5% lubricant magnesium stearate, 0.5% flavoring agent powdered orange essence; The hydroxypropyl cellulose EF PHARM is formulated into an aqueous solution with a concentration of 4.5% before preparation for use; The apixaban is in a micronized form, with D90 = 12 μm.

6. An apixaban orally disintegrating tablet composition, characterized in that, By weight percentage, it contains 2.5% of apixaban, 61.0% of the filler mannitol, 12.0% of the disintegrant crospovidone, 1.5% of the binder hydroxypropyl cellulose EF PHARM, 3.0% of the glidant colloidal silicon dioxide, 0.5% of the flavoring agent sucralose, 1.0% of the solubilizer sodium lauryl sulfate, 17.5% of the filler microcrystalline cellulose 102, 0.5% of the lubricant magnesium stearate, and 0.5% of the flavoring agent powdered orange essence; The hydroxypropyl cellulose EF PHARM is formulated into an aqueous solution with a concentration of 3% before preparation for use; The apixaban is in a micronized form, with D90 = 12 μm.

7. An apixaban orally disintegrating tablet composition, characterized in that, By weight percentage, it contains 2.5% of apixaban, 61.0% of the filler mannitol, 12.0% of the disintegrant crospovidone, 1.5% of the binder hydroxypropyl cellulose EF PHARM, 3.0% of the glidant colloidal silicon dioxide, 0.5% of the flavoring agent sucralose, 1.0% of the solubilizer sodium lauryl sulfate, 17.5% of the filler microcrystalline cellulose 102, 0.5% of the lubricant magnesium stearate, and 0.5% of the flavoring agent powdered orange essence; The hydroxypropyl cellulose EF PHARM is formulated into an aqueous solution with a concentration of 5% before preparation for use; The apixaban is in a micronized form, with D90 = 12 μm.

8. An apixaban orally disintegrating tablet composition, characterized in that, By weight percentage, it contains 2.5% of apixaban, 61.0% of the filler mannitol, 12.0% of the disintegrant crospovidone, 1.5% of the binder hydroxypropyl cellulose EF PHARM, 3.0% of the glidant colloidal silicon dioxide, 0.5% of the flavoring agent sucralose, 1.0% of the solubilizer sodium lauryl sulfate, 17.5% of the filler microcrystalline cellulose 102, 0.5% of the lubricant magnesium stearate, and 0.5% of the flavoring agent powdered orange essence; The hydroxypropyl cellulose EF PHARM is formulated into an aqueous solution with a concentration of 7% before preparation for use; The apixaban is in a micronized form, with D90 = 12 μm.

9. The apixaban orally disintegrating tablet composition according to any one of claims 1-8, characterized in that, The viscosity of the aqueous solution of the hydroxypropyl cellulose is 300 - 600 mPa•s.

10. A method for preparing the apixaban orally disintegrating tablet composition according to any one of claims 1-8, characterized in that, It includes the following steps: (1) Mix the apixaban, the filler accounting for ≥70% of the total filler dosage, the disintegrant accounting for ≥30% of the total disintegrant dosage, and the flavoring agent accounting for ≥50% of the total flavoring agent dosage as the internal granulation excipients, spray the aqueous solution of the binder, and perform wet granulation to obtain a soft material; (2) Dry the soft material obtained in step (1), perform granulation, add the remaining amount of the filler, disintegrant, solubilizer, glidant, lubricant, and flavoring agent in the prescription, mix well, and press into tablets to obtain the product.

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