Oral tablets containing bruton's tyrosine kinase inhibitor and preparation methods thereof

Abstract

To provide oral tablets comprising (S)-7-[4-(1-acryloyl piperidine)]-2-(4-phenoxyphenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide and preparation methods thereof.SOLUTION: The oral tablets of the invention have good drug releasing properties, featured by easy administration, quick and highly efficient release, no specific requirements on equipment and simple formulation process, with ensured formulation stability, easy transportation and storage, and suitability for mass production.SELECTED DRAWING: None

Description

[Technical field]

[0001] The present invention relates to Bruton's tyrosine kinase (BTK) inhibitors, in particular, (S)-7-[4- (1-acryloylpiperidine)]-2-(4-phenoxyphenyl)-4,5,6,7 -Tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide-containing oral The present invention relates to solid tablets and methods for their preparation. [Background technology]

[0002] The international application WO 2014173289 A pamphlet describes a novel Breton-type Tyrosine kinase (BTK), more specifically, the chemical structure: [ka] (S)-7-[4-(1-acryloylpiperidine)]-2-(4-phenoxy Phenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxylate Ruboxamide (which has the generic name zanubrutinib) has been disclosed.

[0003] Zanubrutinib binds covalently to tyrosine kinases, irreversibly blocking the enzyme. Zanubrutinib is a second-generation BTK inhibitor that inactivates BTK in chronic lymphocytic leukemia. Chronic lymphoma / small lymphocytic lymphoma (CLL / SLL), mantle cell lymphoma (MCL), warts Denström's macroglobulinemia (WM), follicular lymphoma (FL), non-germinal center subtype B-lymphomas, including diffuse large B-cell lymphoma (non-GCB DLBCL) It is used as a single agent or in combination with other drugs to treat

[0004] The active pharmaceutical ingredient of zanubrutinib is slightly hygroscopic. DSC results show that The materials have a clear endothermic peak when melting, and the initial temperatures are 139°C and 144°C, respectively. The melting point of this active pharmaceutical ingredient is 145°C, and the peak temperature is This is below the ideal melting point of 150°C for tablet development, and the material is relatively viscous. This poses significant challenges for the development and large-scale industrial production of zanubrutinib tablets. In addition, zanubrutinib has pH-dependent solubility and is classified as Class I of the Biopharmaceutical Classification System. It belongs to the I (low solubility and high permeability) drug class. Therefore, it has good bioavailability. The active ingredient is extracted from the formulation to maintain rapid release of the drug throughout the small intestine. There is an urgent need to develop a rapidly dissolving zanubrutinib tablet. Summary of the Invention [Means for solving the problem]

[0005] The active pharmaceutical ingredient (AP) of zanubrutinib, such as high viscosity, poor flowability, and poor solubility, In order to overcome the deficiencies in the physicochemical properties of I) and ensure good dissolution of this drug, The present invention relates to an oral solid tablet containing the Bruton's tyrosine kinase inhibitor zanubrutinib and The present inventors provide a method for preparing the same. Ricin and other excipients improve the adhesion of the drug and ensure good dissolution rate of the drug. It has been unexpectedly discovered that the oral solid tablet of zanubrutinib of the present invention significantly contributes to the , and was released relatively rapidly into a medium containing sodium lauryl sulfate at pH 1.2 (HCl). For example, the dissolution rate can reach more than 80% within 30 to 60 minutes at a certain formulation excipient ratio. Preferably, the dissolution rate of zanubrutinib is 95% or greater within 30 minutes at a given formulation excipient ratio. Furthermore, the oral solid tablet of zanubrutinib of the present invention can reach a production facility of It has no special requirements, a simple preparation process, stable products, and low production costs.

[0006] In one embodiment of the present invention, there is provided an oral solid tablet containing zanubrutinib, comprising: (1) 2 0% to 70% (mass percentage), preferably 30% to 50% (mass percentage) of zanuburuci (1) a nib; and (2) one or more pharma- ceutically acceptable excipients. do.

[0007] In certain embodiments of the invention, zanubrutinib is administered in any solid form thereof, e.g. Crystal form (for example, the crystal form disclosed in International Publication No. 2018033853 A) It may be form A), an amorphous form or a mixture of crystalline and amorphous forms. The oral solid tablets are formulated to contain crystalline form A, amorphous form, or a mixture of crystalline form A and amorphous form. In certain embodiments of the invention, the particle size of zanubrutinib is less than 40 μm. Below.

[0008] In one embodiment, the X-ray powder diffraction pattern of crystalline form A is about 14.8±0.2°. , 15.6±0.2°, 16.4±0.2°, and 21.4±0.2°, independently selected from In one embodiment, the X-ray powder diffraction peaks of crystalline form A include diffraction peaks having 2θ angle values ​​corresponding to the 2θ angle values ​​of the diffraction peaks. The diffraction patterns are approximately 12.2±0.2°, 12.9±0.2°, 14.8±0.2°, Independently selected from 15.6±0.2°, 16.4±0.2° and 21.4±0.2° In one embodiment, the X-ray powder diffraction peaks of crystalline form A include diffraction peaks having 2θ angle values ​​of 0.01 to 0.01. The diffraction patterns are approximately 12.2±0.2°, 12.9±0.2°, 14.8±0.2°, and 1 5.6±0.2°, 16.4±0.2°, 17.7±0.2°, 18.5±0.2°, 2 A rotation having a 2θ angle value independently selected from 0.7±0.2° and 21.4±0.2° In one embodiment, the X-ray powder diffraction pattern of crystalline form A includes a peak similar to that of FIG. It is substantially identical.

[0009] In certain embodiments of the present invention, the excipients may optionally include fillers, binders, disintegrants, wetting agents, , glidants, lubricants, and any combination thereof.

[0010] In certain embodiments of the present invention, the filler is selected from starch, sucrose, microcrystalline cellulose, cellulose, mannitol, lactose, pregelatinized starch, glucose, maltodextrin phosphorus, cyclodextrin, cellulose, silicified microcrystalline cellulose, and any of the above. is selected from the combination of:

[0011] In certain embodiments of the present invention, the fillers are present in an amount of about 20% to about 70% by weight. %, preferably about 40% to 60% lactose.

[0012] In certain embodiments of the present invention, the filler is microcrystalline cellulose, The microcrystalline cellulose is an internal filler, and the contents of the microcrystalline cellulose filler are all in weight percent. The rate is about 10% to 50%, preferably about 30% to 50%.

[0013] In certain embodiments of the present invention, the filler is lactose and microcrystalline cellulose. The lactose and microcrystalline cellulose contents are all in mass percent. The ratio is about 0% to 70% and about 0% to 50%, preferably about 40% to 60% and about 4% to It is 10%.

[0014] In one embodiment of the present invention, the binder is starch, hypromellose, polyvinylpyrrolidone, rolidone, sodium carboxymethylcellulose, hydroxypropylcellulose, cellulose, ethyl cellulose, gelatin, sucrose, and any combination thereof is selected from.

[0015] In certain embodiments of the present invention, the binder is hypromellose. The content of the base is about 0% to 10%, preferably about 0% to 5%, all expressed as mass percentage.

[0016] In certain embodiments of the present invention, the binder is present in an amount of about 0% to about 10%, all by weight. Preferably, the content of the croscarmellose is about 0% to 5%.

[0017] In one embodiment of the present invention, the disintegrant is sodium carboxymethyl starch, low Substituted hydroxypropyl cellulose, crospovidone, croscarmellose sodium , croscarmellose, methylcellulose, pregelatinized starch, sodium alginate, and any combination thereof.

[0018] In certain embodiments of the present invention, the disintegrant is croscarmellose sodium. The content of croscarmellose sodium is about 0.5% to 5% by mass. Preferably, it is about 1% to 3%.

[0019] In one embodiment of the present invention, the wetting agent is sodium lauryl sulfate (SLS). The content of sodium lauryl sulfate is about 0% to 5%, preferably about It is 0.5% to 1.0%.

[0020] In one embodiment of the present invention, the glidant is powdered cellulose, magnesium trisilicate, The inorganic filler is selected from the group consisting of tallow, colloidal silica, talc, and any combination thereof.

[0021] In certain embodiments of the present invention, the glidant is colloidal silica. The content of colloidal silica is about 0.1% to 20% by mass. When less than 0.1% (by weight), colloidal silica is not able to effectively disperse the API. and, as a result, rapid disintegration of the tablet and dissolution of the API cannot be ensured; When the content of colloidal silica exceeds 20% (mass percentage), due to its large volume, It is not preferred for commercial production. More preferably, the content of colloidal silica is about 4 parts by mass. %~8%.

[0022] In one embodiment of the present invention, the lubricant is zinc stearate, glycerol monostearate. Ceryl, glyceryl stearate palmitate, magnesium stearate, stearin acid sodium fumarate, and any combination thereof.

[0023] In certain embodiments of the present invention, the lubricant is about 0.1% to 2% by weight. %, preferably about 0.3% to 1% magnesium stearate.

[0024] Furthermore, the zanubrutinib oral solid tablet provided by the present invention may be coated The composition further comprises an agent.

[0025] In one embodiment of the present invention, the coating is an Opadry film coating. Powdered sugar, polyvinyl alcohol, hydroxypropyl cellulose, polyethylene glycol Opadry film coating powders, is preferred.

[0026] In one aspect of the invention, the present invention provides a method for preparing a zanubrutinib oral solid formulation. The granulation process includes direct powder compression, dry granulation, and wet granulation, preferably , wet granulation.

[0027] In one aspect of the invention, the present invention provides a method for preparing zanubrutinib oral solid tablets. 1. A method for producing a pharmaceutical composition comprising the steps of: (1) Zanubrutinib active pharmaceutical ingredient and excipients (including but not limited to fillers, binders, , disintegrants, wetting agents, glidants, and lubricants; (2) The mixture of zanubrutinib active pharmaceutical ingredient and excipients is dissolved in purified water or organic reagents ( including but not limited to ethanol, acetone), or aqueous solutions containing binders or wet granulation with an organic solution followed by drying and sizing; (3) Optionally, the sized granules are mixed with additional excipients, including but not limited to fillers, lubricants, and compressing them into a core tablet; (4) optionally coating the plain tablets; Including, When step (3) is performed, the sized granules obtained in step (2) are compressed into a core tablet. The present invention provides a method for

[0028] In one embodiment of the present invention, the organic reagent in step (2) is ethanol, acetonitrile, and combinations thereof.

[0029] In one embodiment of the present invention, the further excipient described in step (3) is a bulking agent ( microcrystalline cellulose), lubricants (e.g., magnesium stearate), flow enhancers accelerators (eg, colloidal silica), and any combination thereof.

[0030] In the above preparation method, fillers, binders, disintegrants, wetting agents, glidants, lubricants and Specific examples of coatings and content are described above.

[0031] In the above preparation method, the "mixing" in the preparation step (1) is generally used. The mixing is carried out by a method that uses a hopper mixer, vertical granulator, etc. Mixing machines such as the FLO-5M, V-type mixer, and tumbler mixer are used for mixing. .

[0032] In the above preparation method, the granulation in the preparation step (2) is carried out according to a general granulation method. Granulation can be carried out by equipment such as a wet granulator. Compression can be carried out by equipment such as a ZP10 After the tablets are made, they can be optionally " Drying can be "dried" by any method used to dry a formulation, e.g. Drying, vacuum drying, fluidized bed drying, etc. can be generally used. The following terms are used in accordance with the definitions set forth below.

[0033] Unless otherwise stated, all ranges cited herein are inclusive of the endpoints; That is, a range includes the upper and lower values ​​of the range, as well as all values ​​therebetween. For example, The temperature ranges, percentages, equivalent ranges, etc. described herein are within the upper and lower limits of the ranges. This includes all values ​​in the range 0 to 100, as well as any value in the continuous interval therebetween.

[0034] As used herein, the term "mass percentage" refers to a zanubrutinib pharmaceutical It represents the content of active ingredient and various excipients, which is calculated with respect to the total mass of the oral solid tablet. can be.

[0035] As used herein, the term "formulation" refers to a pharmaceutical composition that contains an active pharmaceutical ingredient (API). A formulation refers to a mixture, aggregate, solution or other combination of substances suitable for a particular route of administration. and for oral administration, e.g., in the treatment, management, and prevention of a condition or disorder in a patient. The pharmaceutical composition is suitable for compression into tablet formulations designed for this purpose.

[0036] As used herein, "coating" refers to a coating (containing zanubrutinib) The coating is not limited to the coating of the entire surface of the tablet (uncoated tablet), but may be partial coating of the coating. The enteric coating components are absorbed or adsorbed into the coating, or the inner core is coated. The oral solid tablet prepared according to the present invention has a hardness of 60N to 220N. and the dissolution rate is greater than 85% within 30 minutes.

[0037] In one embodiment of the invention, the content of zanubrutinib in a solid oral tablet is typically About 70 mg to about 400 mg of zanubrutinib per formulation, preferably about 80 mg, 160 mg, mg or 320 mg of zanubrutinib.

[0038] In one embodiment of the present invention, the solid oral tablet is medicamentously aesthetic and palatable. To provide the formulation, one or more agents selected from sweeteners, correctives, colorants, and preservatives. It may also contain an agent.

[0039] In one embodiment of the present invention, the solid oral tablet is available in a variety of possible shapes (oval, capsule, etc. Double-sided convex round lamp It can be prepared by [Brief description of the drawings]

[0040] [Figure 1] FIG. 1 is an X-ray powder diffraction pattern of crystalline form A of zanubrutinib. [Diagram 2] FIG. 1 is a schematic diagram of cumulative drug dissolution (in vitro dissolution) of oral solid tablets of zanubrutinib in Example 1. [Diagram 3] FIG. 1 is a schematic diagram of cumulative drug dissolution (in vitro dissolution) of oral solid tablets of zanubrutinib in Example 8 and Example 9. It can be seen from this figure that the drug dissolution rate of Example 8 is significantly better than that of Example 9. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0041] The following examples may help those skilled in the art to understand the present invention more comprehensively, but by no means are intended to be limiting of the present invention. The present invention is not limited to the above. Unless otherwise specified, the temperature is in °C. , Sigma-Aldrich, Alfa Aesar, or TCI and may be used without further purification unless otherwise specified. EXAMPLES

[0042] Example 1 Preparation of oral solid tablets of zanubrutinib, size: 160mg Formulation (per 100g uncoated tablet): Zanubrutinib (crystal form A): 34.8g Lactose: 53.2g Croscarmellose sodium: 2g Colloidal silica: 4.5g Sodium lauryl sulfate: 1g Microcrystalline cellulose: 4g Magnesium stearate: 0.5g Opadry: 2.4g

[0043] Preparation process: 53.2g lactose, 2g croscarmellose sodium, 1g 1.0 g of sodium lauryl sulfate and 34.8 g of zanubrutinib were mixed in a high shear granulator (BOS Add the mixture to the CH-made MYCROMIX (mixture), mix for 5 minutes, and add an appropriate amount of purified water for granulation. After adding, drying and sizing, 4.5g of colloidal silica, 4g of microcrystalline cellulosic acid were added. Add 0.5 g of glycerin and magnesium stearate and mix. After mixing, add the above The ingredients are pressed into tablets to obtain uncoated tablets. The uncoated tablets are mixed with 2.4 g of Opadry. to obtain an oral solid tablet containing zanubrutinib.

[0044] Drug Cumulative Dissolution (In Vitro Dissolution) Testing: In vitro dissolution experiments are performed according to the USP <711> west Therefore, an automatic sampling dissolution test apparatus (model: 70 purchased from AGILENT) was used. 8+850DS) and "dissolution" is determined using the basket method and is The dynamic sampling dissolution test apparatus was equipped with a volume of 900 mL of pH 1.2 (HCl) + 0.5% Using SLS dissolution medium, set the water bath temperature to 37 ± 0.5 °C, with a rotation speed of 100 rpm. Samples were taken at 10, 15, 30, 45, and 60 minutes, all The sample was passed through a 0.45 μm filter membrane and the sample was subjected to the sample dissolution test method. Therefore, the zanubrutinib oral solids of the present invention are determined and analyzed as shown in FIG. When the tablet was placed in pH 1.2 (HCl) + 0.5% SLS medium, over 90% of the xanthate was detected. Brutinib was dissolved at 30 min, which could meet the requirement of rapid release. do.

[0045] In the following Examples 2 to 12, the cumulative drug dissolution (in vitro dissolution) was performed according to the method of Example 1. It is measured according to the method.

[0046] Example 2 Preparation of oral solid tablets of zanubrutinib, size: 160mg Formulation (per 100g uncoated tablet): Zanubrutinib (crystal form A): 36.2 g Lactose: 55.6g Croscarmellose sodium: 2.2g Colloidal silica: 4.3g Sodium lauryl sulfate: 1.1g Magnesium stearate: 0.5g

[0047] Preparation process: 55.6g lactose, 2.2g croscarmellose sodium, 1.1g sodium lauryl sulfate, 4.3g colloidal silica and 36.2g xanub Lutinib is added to the high shear granulator and mixed for 5 minutes, and an appropriate amount of purified water is added for granulation. After adding, it is dried, then sized, and 0.5 g of magnesium stearate is added. After mixing, the above ingredients are pressed into tablets to form uncoated tablets, i.e., Zanubu tablets. An oral solid tablet containing lutinib is obtained.

[0048] Cumulative drug dissolution (in vitro dissolution) test: Approximately 90% of zanubrutinib was dissolved at 30 minutes. It is dissolved.

[0049] Example 3 Preparation of oral solid tablets of zanubrutinib, size: 160mg Formulation (per 100g uncoated tablet): Zanubrutinib (crystal form A): 33.3 g Lactose: 49.2g Hypromellose: 2g Croscarmellose sodium: 2g Colloidal silica: 4g Sodium lauryl sulfate: 1g Microcrystalline cellulose: 8g Magnesium stearate: 0.5g

[0050] Preparation process: 49.2g lactose, 2g croscarmellose sodium, 1g of sodium lauryl sulfate and 33.3 g of zanubrutinib were added to a high shear granulator. The mixture was mixed for 5 minutes, and 2 g of hypromellose solution was added for granulation, followed by drying and granulation. Granules, 4 g colloidal silica, 8 g microcrystalline cellulose and 0.5 g stearin Magnesium acetate is then added and mixed. After mixing, the above ingredients are pressed into tablets. This results in an uncoated oral solid tablet containing zanubrutinib.

[0051] Example 4 Preparation of oral solid tablets of zanubrutinib, size: 320mg Formulation (per 100g uncoated tablet): Zanubrutinib (crystal form A): 50g Croscarmellose sodium: 4g Colloidal silica: 12.0g Sodium lauryl sulfate: 1g Microcrystalline cellulose: 32.5g Magnesium stearate: 0.5g Opadry: 1.5g

[0052] Preparation process: 50g zanubrutinib, 4g croscarmellose sodium, 12 .0g colloidal silica, 1g sodium lauryl sulfate, 32.5g microcrystalline cellulosic acid The mixture is sieved and then mixed in a high shear granulator, followed by addition of 0.5 g of mag- nesium stearate. Add nesium and mix evenly. The mixed powder is directly pressed to obtain plain tablets. The above uncoated tablets were coated with a coating solution containing 2.4 g of Opadry to obtain zanubruti. An oral solid tablet containing the nibs is obtained.

[0053] Cumulative drug dissolution (in vitro dissolution) test: The drug dissolution rate (%) at 30 minutes was approximately 8. The probability is 0%.

[0054] Example 5 Preparation of oral solid tablets of zanubrutinib, size: 80mg Formulation (per 100g uncoated tablet): Zanubrutinib (crystal form A): 26.7g Lactose: 23.8g Croscarmellose sodium: 2g Colloidal silica: 4g Sodium lauryl sulfate: 1g Microcrystalline cellulose: 40g Hypromellose: 2g Magnesium stearate: 0.5g Opadry: 1.5g

[0055] Preparation process: 23.8g lactose, 40g microcrystalline cellulose, 2g cross Carmellose sodium, 1 g sodium lauryl sulfate, 4 g colloidal silica, and 26.7 g of zanubrutinib was added to the fluidized bed, followed by 2 g of the aqueous hypromellose solution. After spraying for granulation, dry and then add magnesium stearate and mix. After mixing, the above ingredients are pressed into tablets to obtain uncoated tablets. The oral solid phase containing zanubrutinib is coated with a coating solution containing Opadry. Get body pills.

[0056] Example 6 Preparation of oral solid tablets of zanubrutinib, size: 80mg Formulation (per 100g uncoated tablet): Zanubrutinib (crystal form A): 26.7g Lactose: 35.8g Croscarmellose sodium: 2g Colloidal silica: 4g Sodium lauryl sulfate: 1g Silica-treated microcrystalline cellulose: 30g Magnesium stearate: 0.5g

[0057] Preparation process: 26.7g zanubrutinib, 2g croscarmellose sodium, 4 g colloidal silica, 1 g sodium lauryl sulfate, 35.8 g lactose and 3 0 g of silicified microcrystalline cellulose is sieved and then mixed in a high shear granulator, then Add 0.5g of magnesium stearate and mix evenly. Press the powder directly. An oral solid formulation containing zanubrutinib is formulated into a tablet and coated with Opadry coating fluid. Get the pills.

[0058] Example 7 Preparation of oral solid tablets of zanubrutinib, size: 320mg Formulation (per 100g uncoated tablet): Zanubrutinib (crystal form A): 50.0 g Lactose: 36.5g Croscarmellose sodium: 4g Colloidal silica: 8g Sodium lauryl sulfate: 1g Magnesium stearate: 0.5g

[0059] Preparation process: 50.0 g zanubrutinib, 4 g croscarmellose sodium, 8 g colloidal silica, 1 g sodium lauryl sulfate, 36.5 g lactose sieved Then mix in a high shear granulator, then add 0.5 g of magnesium stearate. The powder is directly pressed into tablets, i.e., uncoated tablets, i.e., zanuburu. An oral solid tablet containing tinib is obtained.

[0060] Cumulative drug dissolution (in vitro dissolution) test: The drug dissolution rate (%) at 30 minutes was approximately 4. The probability is 0%.

[0061] Example 8 Preparation of oral solid tablets of zanubrutinib, size: 320mg Formulation (per 100g uncoated tablet): Zanubrutinib (crystal form A): 50.0 g Croscarmellose sodium: 4g Colloidal silica: 8g Sodium lauryl sulfate: 1g Microcrystalline cellulose: 36.5g Magnesium stearate: 0.5g

[0062] Preparation process: 50.0 g zanubrutinib, 36.5 g microcrystalline cellulose, 4 g of croscarmellose sodium, 8g of colloidal silica, 1g of sodium lauryl sulfate The milk is sieved and then mixed in a high shear granulator, then 0.5 g of magnesium stearate is added. The powder is directly pressed into tablets, i.e., uncoated tablets. An oral solid tablet containing zanubrutinib is obtained.

[0063] Drug cumulative dissolution (in vitro dissolution) test: The dissolution curve of the drug is shown in Figure 3. It can be seen that at 30 minutes it exceeds 80%.

[0064] Example 9 Preparation of oral solid tablets of zanubrutinib, size: 320mg Formulation (per 100g uncoated tablet): Zanubrutinib (crystal form A): 60.0 g Croscarmellose sodium: 4g Colloidal silica: 0.8g Sodium lauryl sulfate: 1g Microcrystalline cellulose: 33.7g Magnesium stearate: 0.5g

[0065] Preparation process: 60 g zanubrutinib, 33.7 g microcrystalline cellulose, 4 g clotting agent. Loscarmelose sodium, 0.8g colloidal silica, 1g sodium lauryl sulfate The milk is sieved and then mixed in a high shear granulator, then 0.5 g of magnesium stearate is added. The powder is directly pressed into tablets, i.e., uncoated tablets. An oral solid tablet containing zanubrutinib is obtained.

[0066] Drug cumulative dissolution (in vitro dissolution) test: The dissolution curve of the drug is shown in Figure 3. It can be seen that at 30 minutes it is less than 60%.

[0067] Example 10 Preparation of oral solid tablets of zanubrutinib, size: 320mg Formulation (per 100g uncoated tablet): Zanubrutinib (crystal form A): 46.69g Croscarmellose sodium: 4.38g Colloidal silica: 0.88g Sodium lauryl sulfate: 0.88g Microcrystalline cellulose: 46.69g Magnesium stearate: 0.50g

[0068] Preparation process: 53.2g lactose, 2g croscarmellose sodium, 1g 1.0 g of sodium lauryl sulfate and 34.8 g of zanubrutinib were mixed in a high shear granulator (BOS Add the mixture to the CH-made MYCROMIX (mixture), mix for 5 minutes, and add an appropriate amount of purified water for granulation. After adding, drying and sizing, 4.5g of colloidal silica, 4g of microcrystalline cellulosic acid were added. Add 0.5 g of glycerin and magnesium stearate and mix. After mixing, add the above The components are pressed into tablets to prepare uncoated oral solid tablets containing zanubrutinib. Get the pills.

[0069] Cumulative drug dissolution (in vitro dissolution) test: The drug dissolution rate (%) at 60 minutes was approximately 8. The probability is 0%.

[0070] Example 11 Preparation of oral solid tablets of zanubrutinib, size: 320mg Formulation (per 100g uncoated tablet): Zanubrutinib (crystal form A): 46.69g Lactose: 46.69g Croscarmellose sodium: 4.38g Colloidal silica: 0.88g Sodium lauryl sulfate: 0.88g Magnesium stearate: 0.50g

[0071] Preparation process: According to the same method as in Example 10, oral administration of zanubrutinib was Solid tablets may be prepared.

[0072] Cumulative drug dissolution (in vitro dissolution) test: The drug dissolution rate (%) at 60 minutes was 80%. % or less.

[0073] Example 12 Preparation of oral solid tablets of zanubrutinib, size: 320mg Formulation (per 100g uncoated tablet): Zanubrutinib (crystal form A): 22.21 g Croscarmellose sodium: 3.00g Colloidal silica: 0.50g Sodium lauryl sulfate: 0.50g Microcrystalline cellulose: 73.29g Magnesium stearate: 0.50g

[0074] Preparation process: According to the same method as in Example 10, an oral solid tablet containing zanubrutinib can be prepared.

[0075] The above description teaches and provides illustrative examples of the principles of the present invention, but practice of the invention encompasses all generic variations, modifications and / or alterations that fall within the scope of the following claims. References contained in this disclosure are incorporated herein by reference. In an embodiment of the present invention, for example, the following items are provided: (Item 1) An oral solid tablet containing zanubrutinib, comprising: (1) zanubrutinib in an amount of 20% to 70%, preferably 30% to 50%, all by mass; and (2) one or more pharma- ceutically acceptable excipients. (Item 2) 2. The oral solid tablet according to item 1, wherein the zanubrutinib is in crystalline form A, an amorphous form, or a mixture of crystalline form A and an amorphous form. (Item 3) 3. The oral solid tablet according to item 1 or 2, wherein the excipients are selected from fillers, binders, disintegrants, wetting agents, glidants, lubricants, and any combination thereof. (Item 4) 4. The oral solid tablet according to item 3, wherein the filler is selected from starch, sucrose, microcrystalline cellulose, mannitol, lactose, pregelatinized starch, glucose, maltodextrin, cyclodextrin, cellulose, silicified microcrystalline cellulose, and any combination thereof. (Item 5) 5. The oral solid tablet according to item 4, wherein the filler is lactose and the content of the lactose is 20% to 70%, preferably 40% to 60%, all by mass percentage. (Item 6) 5. The oral solid tablet according to item 4, wherein the filler is microcrystalline cellulose, and the content of the microcrystalline cellulose is 10% to 50%, preferably 30% to 50%, all by mass percentage. (Item 7) 5. The oral solid tablet according to item 4, wherein the filler is a combination of lactose and microcrystalline cellulose, and the contents of the lactose and the microcrystalline cellulose are, respectively, 0% to 70% and 0% to 50%, preferably 40% to 60% and 4% to 10%, all by mass percentage. (Item 8) 4. The oral solid tablet according to item 3, wherein the binder is selected from starch, hypromellose, polyvinylpyrrolidone, sodium carboxymethylcellulose, hydroxypropylcellulose, methylcellulose, ethylcellulose, gelatin, sucrose, and any combination thereof. (Item 9) Item 9. The oral solid tablet according to Item 8, wherein the binder is hypromellose, and the content of the hypromellose is 0% to 10%, preferably 0% to 5%, all by mass percentage. (Item 10) 4. The oral solid tablet according to item 3, wherein the disintegrant is selected from sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, crospovidone, croscarmellose sodium, croscarmellose, methylcellulose, pregelatinized starch, sodium alginate, and any combination thereof. (Item 11) Item 11. The oral solid tablet according to item 10, wherein the disintegrant is croscarmellose sodium, and the content of the croscarmellose sodium is 0.5% to 5%, preferably 1% to 3%, all by mass percentage. (Item 12) 4. The oral solid tablet according to item 3, wherein the wetting agent is sodium lauryl sulfate, and the content of the sodium lauryl sulfate is 0% to 5%, preferably 0.5% to 1.0%, all by mass percentage. (Item 13) 4. The oral solid tablet according to item 3, wherein the glidant is selected from powdered cellulose, magnesium trisilicate, colloidal silica, talc, and any combination thereof. (Item 14) Item 14. The oral solid tablet according to item 13, wherein the glidant is colloidal silica, and the content of the colloidal silica is 0.1% to 20%, preferably 4% to 8%, all by mass percentage. (Item 15) 4. The oral solid tablet according to item 3, wherein the lubricant is selected from zinc stearate, glyceryl monostearate, glyceryl stearate palmitate, magnesium stearate, sodium stearate fumarate, and any combination thereof. (Item 16) Item 16. The oral solid tablet according to item 15, wherein the lubricant is magnesium stearate, and the content of the magnesium stearate is 0.1% to 2%, preferably 0.3% to 1%, all by mass percentage. (Item 17) 17. The oral solid tablet according to any one of items 1 to 16, wherein the oral solid tablet further comprises a coating agent selected from Opadry film coating powder, polyvinyl alcohol, hydroxypropyl cellulose, polyethylene glycol, and any combination thereof, preferably Opadry film coating powder. (Item 18) 18. The method for preparing an oral solid tablet according to any one of items 1 to 17, wherein a granulation method for the oral solid tablet is selected from direct powder compression, dry granulation, and wet granulation, preferably wet granulation. (Item 19) A method for preparing an oral solid tablet according to any one of items 1 to 17, comprising the following steps: (1) mixing the zanubrutinib and one or more excipients; (2) The mixture of zanubrutinib and one or more excipients is dissolved in purified water, or an organic reagent, or wet granulation with an aqueous or organic solution containing a binder, followed by drying and sizing; (3) optionally blending the sized granules with additional excipients and compressing them into core tablets; (4) optionally coating the plain tablets; Including, The method, wherein when step (3) is performed, the sized granules obtained in step (2) are compressed into a core tablet. (Item 20) The organic reagent in step (2) is selected from ethanol, acetone, and combinations thereof. 20. The method according to claim 19, wherein said (Item 21) The additional excipients in step (3) include fillers, lubricants, glidants, and the like. 21. The method according to item 19 or 20, wherein the method is selected from any combination of the following:

Claims

1. An oral solid tablet containing zanubrutinib, comprising: (1) 20% to 70%, preferably 30% to 50%, of zanubrutinib; and (2) one or more pharma- ceutically acceptable excipients, all by weight.

2. 2. The oral solid tablet of claim 1, wherein the zanubrutinib is of crystalline form A, an amorphous form, or a mixture of crystalline form A and the amorphous form.

3. 3. The oral solid tablet of claim 1 or 2, wherein the excipients are selected from fillers, binders, disintegrants, wetting agents, glidants, lubricants, and any combination thereof.

4. 4. The oral solid tablet of claim 3, wherein the filler is selected from starch, sucrose, microcrystalline cellulose, mannitol, lactose, pregelatinized starch, glucose, maltodextrin, cyclodextrin, cellulose, silicified microcrystalline cellulose, and any combination thereof.

5. 5. The oral solid tablet according to claim 4, wherein the filler is lactose and the content of the lactose is 20% to 70%, preferably 40% to 60%, all by mass percentage.

6. The oral solid tablet according to claim 4, wherein the filler is microcrystalline cellulose, and the content of the microcrystalline cellulose is 10% to 50%, preferably 30% to 50%, all by mass percentage.

7. 5. The oral solid tablet according to claim 4, wherein the filler is a combination of lactose and microcrystalline cellulose, and the contents of the lactose and the microcrystalline cellulose are 0%-70% and 0%-50%, preferably 40%-60% and 4%-10%, respectively, all by mass percentage.

8. 4. The oral solid tablet of claim 3, wherein the binder is selected from starch, hypromellose, polyvinylpyrrolidone, sodium carboxymethylcellulose, hydroxypropylcellulose, methylcellulose, ethylcellulose, gelatin, sucrose, and any combination thereof.

9. The oral solid tablet according to claim 8, wherein the binder is hypromellose and the content of the hypromellose is 0% to 10%, preferably 0% to 5%, all by mass percentage.

10. 4. The oral solid tablet of claim 3, wherein the disintegrant is selected from sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, crospovidone, croscarmellose sodium, croscarmellose, methylcellulose, pregelatinized starch, sodium alginate, and any combination thereof.

11. The oral solid tablet according to claim 10, wherein the disintegrant is croscarmellose sodium, and the content of the croscarmellose sodium is 0.5% to 5%, preferably 1% to 3%, all by mass percentage.

12. The oral solid tablet according to claim 3, wherein the wetting agent is sodium lauryl sulfate, and the content of the sodium lauryl sulfate is 0% to 5%, preferably 0.5% to 1.0%, all by mass percentage.

13. 4. The oral solid tablet of claim 3, wherein the glidant is selected from powdered cellulose, magnesium trisilicate, colloidal silica, talc, and any combination thereof.

14. The oral solid tablet according to claim 13, wherein the glidant is colloidal silica, and the content of the colloidal silica is from 0.1% to 20%, preferably from 4% to 8%, all by mass percentage.

15. 4. The oral solid tablet of claim 3, wherein the lubricant is selected from zinc stearate, glyceryl monostearate, glyceryl stearate palmitate, magnesium stearate, sodium stearate fumarate, and any combination thereof.

16. The oral solid tablet according to claim 15, wherein the lubricant is magnesium stearate, and the content of the magnesium stearate is 0.1% to 2%, preferably 0.3% to 1%, all by mass percentage.

17. 17. The oral solid tablet according to any one of claims 1 to 16, wherein said oral solid tablet further comprises a coating agent selected from Opadry film coating powder, polyvinyl alcohol, hydroxypropyl cellulose, polyethylene glycol, and any combination thereof, preferably Opadry film coating powder.

18. A method for preparing an oral solid tablet according to any one of claims 1 to 17, wherein the granulation method for said oral solid tablet is selected from direct powder compression, dry granulation, and wet granulation, preferably wet granulation.

19. A method for preparing an oral solid tablet according to any one of claims 1 to 17, comprising the steps of: (1) mixing said zanubrutinib and one or more excipients; (2) The mixture of zanubrutinib and one or more excipients is dissolved in purified water, or an organic reagent, or wet granulation with an aqueous or organic solution containing a binder, followed by drying and sizing; (3) optionally blending the sized granules with additional excipients and compressing them into core tablets; (4) optionally coating the plain tablets; Including, The method, wherein when step (3) is performed, the sized granules obtained in step (2) are compressed into a core tablet.

20. The organic reagent in step (2) is selected from ethanol, acetone, and combinations thereof. The method of claim 19, wherein

21. The additional excipients in step (3) include fillers, lubricants, glidants, and the like.

21. The method of claim 19 or 20, wherein the combination is selected from any combination of:

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