Oral capsule and preparation method therefor

Abstract

To provide an oral capsule and a method for filling the capsule by directly mixing powders, wherein the oral capsule comprises a composition for an oral capsule and a capsule shell, and the composition for the oral capsule comprises zanubrutinib, a filler, a disintegrant, a wetting agent, a glidant, a lubricant, and an optional binder.SOLUTION: The capsule composition can achieve satisfactory product stability, dissolution properties meeting bioavailability standards, a preparation process consistent with production equipment, and reasonable production costs. Furthermore, the method of the present invention is a non-granulating process, which can simplify the overall process and reduce the impact of the preparation process on product bioavailability.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to the field of pharmaceutical preparations. ton's tyrosine kinase (BTK) inhibitors, especially (S)-7-[4 -(1-acryloylpiperidine)]-2-(4-phenoxyphenyl)-4,5,6, Oral capsules containing 7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide The present invention relates to capsules and methods for preparing the same. [Background technology]

[0002] International patent application WO2014173289A describes a novel Bruton's tyrosine kinase (B ruton's Tyrosine Kinase,BTK), specifically (S)-7-[ 4-(1-acryloylpiperidine)]-2-(4-phenoxyphenyl)-4,5,6 ,7-Tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide (generic name: Zanubrutinib, whose chemical structure is as follows: It is.

[0003] JPEG2025123534000001.jpg4953

[0004] Zanubrutinib is a second-generation BTK inhibitor that binds covalently to tyrosine kinases. Zanubrutinib is used as a single agent to irreversibly inactivate the enzyme. or in combination with other drugs, chronic lymphocytic leukemia / small lymphocytic lymphoma (CLL) / SLL), mantle cell lymphoma (MCL), Waldenstrom's macroglobulinemia WM, follicular lymphoma (FL), non-germinal center subtype diffuse large B-cell lymphoma It is used to treat B lymphocyte tumors, including non-GCB DLBCL.

[0005] The active pharmaceutical ingredient (API) of zanubrutinib is slightly hygroscopic. DSC results show that The compound has a clear endothermic peak when melting, and the onset temperature and peak temperature are 139°C and 144°C, sticky punch phenomenon In addition, the solubility of zanubrutinib is pH-dependent and is classified as a biopharmaceutical. It belongs to the Class II drug of the stem. Therefore, it is important to maintain a good dissolution rate of the drug in the formulation. It is necessary to

[0006] Zanubrutinib, the active pharmaceutical ingredient used in the present invention, has a small particle size after pulverization, making it easy to flow. Furthermore, zanubrutinib, the active ingredient used in the present invention, has poor physical and and poor chemical properties (high viscosity, low fluidity). The above problems can be solved and the manufacturing cost is reasonable. Summary of the Invention

[0007] In order to overcome the above-mentioned problems of the active pharmaceutical ingredient zanubrutinib, the present invention provides a capsule formulation and a method for directly mixing the powders and then filling the capsules.

[0008] Specifically, the technical solution of the present invention is as follows: In one aspect, the present invention provides an oral capsule comprising an oral capsule composition and a capsule shell. A cell, wherein the composition for an oral capsule comprises zanubrutinib, a filler, a disintegrant, a wetting agent, An oral capsule is provided that includes a glidant and a lubricant.

[0009] In some embodiments, the oral capsule composition further optionally contains an adhesive. include.

[0010] Preferably, the zanubrutinib is in a crystalline form (e.g., as disclosed in WO2018033853A). The crystalline form shown is A), amorphous, or a mixture of crystalline and amorphous forms. It may be in any solid form, preferably the zanubrutinib is in crystalline form A, amorphous or a mixture of crystalline form A and amorphous form. 40 μm, and the zanubrutinib relative to the total mass of the oral capsule composition The mass percentage of is 20% to 70%, preferably 20% to 50%.

[0011] In some embodiments, 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° 2θ In some embodiments, the crystalline form comprises a diffraction peak independently selected from the angular values. The X-ray powder diffraction pattern of A is approximately 12.2±0.2°, 12.9±0.2°, 14.8± 0.2°, 15.6±0.2°, 16.4±0.2° and 21.4±0.2° In some embodiments, the resultant diffraction peaks are independently selected from 2θ angle values. The X-ray powder diffraction pattern of Form A is approximately 12.2±0.2°, 12.9±0.2°, and 14. 8±0.2°, 15.6±0.2°, 16.4±0.2°, 17.7±0.2°, 18. The 2θ angle values ​​of 5±0.2°, 20.7±0.2° and 21.4±0.2° were independently In some embodiments, the X-ray powder diffraction peaks of crystalline form A are selected from the group consisting of: The diffraction pattern is essentially identical to that shown in FIG.

[0012] Preferably, the filler is starch, sucrose, microcrystalline cellulose, anhydrous aqueous phosphoric acid. Calcium carbonate, mannitol, lactose, pregelatinized starch, glucose, maltodextrin Dextrin, cyclodextrin, cellulose, silicified microcrystalline cellulose, and and the total quality of the composition for oral capsules is selected from any combination of the above. The mass percentage of the filler relative to the amount is 20% to 90%, preferably 30% to 80% Preferably, the average particle size of the filler is 100 μm to 200 μm. Preferably, the average particle size of the filler matches the average particle size of the drug substance, thereby reducing product mixing. This ensures uniformity and is advantageous for process expansion.

[0013] More preferably, the filler is microcrystalline cellulose or a mixture of microcrystalline cellulose and colloidal silica. A mixture of silicon dioxide and anhydrous calcium hydrogen phosphate. More preferably, the filler is microcrystalline cellulose, and the oral capsule The mass percentage of the microcrystalline cellulose relative to the total mass of the composition for cells is 30% to 80%. do.

[0014] Preferably, the disintegrant is sodium carboxymethyl starch, low substituted hydroxybenzoate. Dipropylcellulose, crospovidone, croscarmellose sodium, croscarmellose Roasted syrup, methylcellulose, pregelatinized starch, sodium alginate and their Any combination of the above is selected, and the total mass of the composition for oral capsules is The mass percentage of the disintegrant is 0.5% to 5%, and preferably 1% to 3%. More preferably, the disintegrant is croscarmellose sodium.

[0015] Preferably, the wetting agent is sodium dodecyl sulfate, and The mass percentage of the sodium dodecyl sulfate relative to the total mass of the composition is 0% to 5%; The preferred range is 0.5% to 1.0%.

[0016] Preferably, the glidant is powdered cellulose, magnesium trisilicate, colloidal dimethicone, or the like. selected from silicon oxide, talc, and any combination thereof; and The mass percentage of the flow enhancer relative to the total mass of the composition for oral capsules is 0.1% to 2. 0%, preferably 0.1% to 0.5%. More preferably, the glidant It is colloidal silicon dioxide.

[0017] Preferably, the lubricant is zinc stearate, glyceryl monostearate, stearyl Glyceryl Palmitate, Magnesium Stearate, Sodium Stearate Fumarate and any combination thereof, and the oral capsule The mass percentage of the lubricant relative to the total mass of the lubricant composition is 0.1% to 2%, and preferably The content of the lubricant is 0.3% to 1%. More preferably, the lubricant is magnesium stearate. do.

[0018] Preferably, the adhesive is starch, hydroxypropyl methylcellulose, polyvinyl alcohol, or the like. Dimethylpyrrolidone, Sodium Carboxymethylcellulose, Hydroxypropylcellulose cellulose, methylcellulose, ethylcellulose, gelatin, sucrose and any of these and a combination of the above, and The mass percentage of the pressure-sensitive adhesive is 0 to 10%, preferably 0 to 5%. In the above, the adhesive is hydroxypropyl methylcellulose.

[0019] Preferably, the capsule shell is a gelatin capsule shell.

[0020] The capsules of the present invention have good fluidity of the intermediate, and can be filled directly after mixing without granulation. This simplifies the entire process and improves the formulation for product bioavailability. The impact of the process is reduced. In addition, the capsule composition has satisfactory product stability, biodegradability, and Dissolution rate characteristics that meet the standards for availability, preparation technology that matches the manufacturing equipment, and rational manufacturing Manufacturing costs can be obtained.

[0021] In another aspect, the present invention provides a method for producing a pharmaceutical composition comprising: zanubrutinib, a disintegrant, a wetting agent, and a portion of a filler are premixed to obtain a premix; and (1) sieving the mixture to obtain a first mixture. The glidant and remaining filler are sieved into the first mixture obtained in step (1). Step (2) of adding and mixing to obtain a second mixture; The lubricant is sieved and added to the second mixture obtained in step (2) and mixed to form the final mixture. Step (3) of obtaining a compound; and The final mixture obtained in step (3) is filled into a capsule shell to form the oral capsule. Step (4) to obtain The present invention provides a method for preparing a zanubrutinib oral capsule, comprising:

[0022] Preferably, the sieving is carried out using a conical granulator.

[0023] Preferably, the pre-mixing in step (1) is carried out at a rotation speed of 10 rpm to 25 rpm for 2 minutes. The sieving is carried out for 10 minutes, and the pore size of the screen used for sieving is 1.0 mm. ~2.5mm.

[0024] Preferably, the first mixture in step (1) is prepared by rotating the premix at 10 rpm. Mix at a rotation speed of 25 rpm for 40 minutes to 15 minutes.

[0025] Preferably, the mixing in step (2) is performed at a rotation speed of 10 rpm to 20 rpm. Do this for 3 to 5 minutes.

[0026] Preferably, the sieving in step (2) is performed at a speed of 550 rpm to 650 rpm. The sieving is carried out at a rotation speed of 1.0 mp, and the aperture diameter of the screen used for sieving is 1.0 mm to It is 2.5mm.

[0027] Preferably, the mixing in step (3) is carried out at a rotation speed of 10 rpm to 15 rpm for 3 minutes. The sieving is carried out for 10-6 minutes, and the aperture diameter of the screen used for sieving is 35mm-45mm. mm.

[0028] In the method for preparing oral capsules, the mixing in steps (1) to (3) is insufficient. If this occurs, the drug substance will be unevenly distributed in the mixed powder, resulting in excessive mixing in steps (1) to (3). This can cause stratification and segregation of the active ingredients and auxiliary ingredients, affecting product quality.

[0029] Preferably, the method for preparing zanubrutinib oral capsules comprises the following steps:

[0030] Zanubrutinib, disintegrant, wetting agent, and some fillers were mixed at 20 rpm for 3 minutes. The mixture is mixed to obtain a premix, which is then sieved, the aperture size of the screen used being 1.5 mm. The rotation speed of the granulator is 600 rpm, and the mixture is mixed at 20 rpm for 20 minutes, or 1 Step (1) mixing at a speed of 2 rpm for 35 minutes to obtain a first mixture; The glidant and remaining filler are sieved, the aperture size of the screen used is 1.5 mm. The rotation speed of the granulator was 600 rpm, and the sieved material was obtained in step (1). The mixture is added to the first mixture and mixed at 20 rpm for 5 minutes to obtain a second mixture. P (2), Passing the hard lubricant through a 40 mesh sieve and adding it to the second mixture obtained in step (2); and mixing at 20 rpm for 5 minutes to obtain the final mixture (3); , The final mixture obtained in step (3) is filled into a capsule shell to form the oral capsule ( Step (4) to obtain 4).

[0031] Preferably, the method for preparing zanubrutinib oral capsules comprises the following steps:

[0032] Zanubrutinib, disintegrant, wetting agent, and some fillers were mixed at 12 rpm for 5 minutes. The mixture is mixed to obtain a premix, which is then sieved. The pore size of the screen used is 1.9 mm or 2. The granulator rotation speed was 600 rpm, and the granulator rotation speed was 20 rpm for 20 minutes. Step (1) of mixing or mixing at a speed of 12 rpm for 35 minutes to obtain a first mixture. , The glidant and remaining filler are sieved, the aperture size of the screen used is 1.9 mm. The granulator rotation speed is 600 rpm, and the sieved material is sieved into a granulator. Add the first mixture obtained to the cup (1) and mix at 12 rpm for 5 minutes to form the second mixture. Step (2) of getting things; Passing the hard lubricant through a 40 mesh sieve and adding it to the second mixture obtained in step (2); and mixing at a speed of 12 rpm for 5 minutes to obtain the final mixture (3); and The final mixture obtained in step (3) is filled into a capsule shell to form the oral capsule. Step (4) to obtain

[0033] Preferably, the loading amount of the mixing hopper is 30 to 70% of the volume of the mixing hopper. do.

[0034] The aforementioned method of the present invention involves directly mixing powders to fill capsules, and therefore the method involves: There is no granulation step, which simplifies the entire process and improves the bioavailability of the product. The effect of the formulation process on the drug substance's crystalline form is reduced, and the drug substance's crystalline form is not altered during the process. do not have.

[0035] The aforementioned method of the present invention first premixes the drug substance with auxiliary ingredients to improve the flowability of the drug substance. It solves the problems of poor sieving properties, tendency to clump during storage, and difficulty in sieving the active pharmaceutical ingredient independently. In addition, sieving after pre-mixing breaks down agglomerates of the drug substance and reduces the final In addition, the uniformity of the drug content can be ensured. By mixing them together, the content and uniformity of the product can be improved. Reasonable formulation process parameters, such as not excessive lubricant mixing conditions, may result in product The dissolution rate cannot be guaranteed. [Brief explanation of the drawings]

[0036] [Figure 1] FIG. 1 is an XRPD diagram of zanubrutinib drug substance. DETAILED DESCRIPTION OF THE INVENTION

[0037] technical terms Unless otherwise specified, the technical and scientific terms used herein are understood by those skilled in the art. has the same meaning as is commonly understood by

[0038] As used herein, the terms "comprise," "contain," and grammatical variations thereof refer to a composition. Indicates that products and methods include the listed elements and do not exclude other elements.

[0039] Unless expressly indicated to the contrary, all ranges cited herein are inclusive. That is, the range includes the upper and lower limits of the range and any values ​​therebetween. All values ​​are included, e.g., temperature ranges, percentages, and equivalent weight ranges set forth herein. etc., including the upper and lower limits of said ranges and any value in the continuous interval therebetween. .

[0040] The compositions of the present invention comprise a mixture of the active ingredient and other chemical ingredients.

[0041] "Optionally" as used herein means to choose or not choose. For example, the optional adhesive may contain an adhesive or may not contain an adhesive. Indicates that. [Example]

[0042] The following examples may help those skilled in the art to more fully understand the present invention. All of the supplements listed below are commercially available and are not intended to limit the invention in any way.

[0043] Example 1 Preparation of zanubrutinib oral capsules The composition of one capsule is as follows: JPEG2025123534000002.jpg38122 preparation method: (1) Zanubrutinib, sodium dodecyl sulfate, croscarmellose sodium and and 60.28% microcrystalline cellulose were placed in the mixing hopper and stirred at 20 rpm for 3 minutes. Mix and premix the materials using a conical sieve and sift the used scraps. The pore size of the granulator is 1.5 mm, and the rotation speed of the granulator is 600 rpm. The materials were transferred to a mixing hopper and mixed at 20 rpm for 20 minutes. (2) The remaining microcrystalline cellulose was sieved with colloidal silicon dioxide and used The aperture of the screen was 1.5 mm, and the rotation speed of the granulator was 600 rpm. The materials were transferred to a mixing hopper and mixed at 20 rpm for 5 minutes. (3) Sieve magnesium stearate into a 40 mesh sieve and add it to the mixing hopper. The mixture was mixed at 20 rpm for 5 minutes. (4) The obtained mixed powder was filled into a gelatin hollow capsule shell, and the filling amount was 360 mg. Oral capsules were obtained.

[0044] The final mixed powder of Example 1 has good fluidity and uniform dispersion, and is suitable for filling capsules. It is possible. In addition, in the research on the mixing process, XRPD measurement of the mixed powder was carried out and it was found that The crystalline form of tinib was not altered in the process. Cumulative drug dissolution rate (in vitro dissolution) measurement: In vitro dissolution tests are performed using an automated sampling system. The measurement was carried out using a detector and conformed to the Chinese Pharmacopoeia 0931. Select "Dissolution Rate" to use the basket method, and the automatic sampling dissolution device is set to the water bath temperature The temperature was set at 37±0.5℃, the rotation speed at 100 rpm, and the container contained 0.5% sodium dodecyl sulfate. 0.1N hydrochloric acid was selected as the elution medium and the volume was 900 mL. Samples were taken at 0 min, 15 min, 30 min, 45 min, and 60 min. All samples were filtered through a 0.45 μm membrane and measured and analyzed according to the sample dissolution rate measurement method. The zanubrutinib oral capsules of Example 1 were prepared in the above solvent medium for 30 min. The dissolution rate (%) of n is over 85%, which meets the requirement of rapid release.

[0045] Example 2 Preparation of zanubrutinib oral capsules The composition of one capsule was as follows: JPEG2025123534000003.jpg38122 The target oral capsules were prepared in a similar manner to that of Example 1. The cumulative drug dissolution rate (in vitro dissolution) was measured. The capsules showed a dissolution rate (%) of more than 85% in 30 minutes in the dissolution medium.

[0046] Example 3 Preparation of zanubrutinib oral capsules The composition of one capsule was as follows: JPEG2025123534000004.jpg38122 The target oral capsules were prepared in a similar manner to that of Example 1. The cumulative drug dissolution rate (in vitro dissolution) was measured. The capsules showed a dissolution rate (%) of more than 85% in 30 minutes in the dissolution medium.

[0047] Example 4 Preparation of zanubrutinib oral capsules The composition of one capsule was as follows: JPEG2025123534000005.jpg38122 The target oral capsules were prepared in a similar manner to that of Example 1. The cumulative drug dissolution rate (in vitro dissolution) was measured. The capsules showed a dissolution rate (%) of more than 85% in 30 minutes in the dissolution medium.

[0048] Example 5 Preparation of zanubrutinib oral capsules The composition of one capsule was as follows: JPEG2025123534000006.jpg38122 The target oral capsules were prepared in a similar manner to that of Example 1. The cumulative drug dissolution rate (in vitro dissolution) was measured. The capsules showed a dissolution rate (%) of more than 85% in 30 minutes in the dissolution medium.

[0049] Example 6 Zanubrutinib oral capsule preparation The composition of one capsule was as follows: JPEG2025123534000007.jpg38122 The target oral capsules were prepared in a similar manner to that of Example 1. The cumulative drug dissolution rate (in vitro dissolution) was measured. The capsules showed a dissolution rate (%) of more than 85% in 30 minutes in the dissolution medium. As mentioned above, the present invention has been described in detail through general descriptions, specific embodiments and tests. Any modifications or improvements made without departing from the spirit of the invention are included in the scope of the invention. It falls within the scope of the claims of the present invention. In an embodiment of the present invention, for example, the following items are provided: (Item 1) An oral capsule containing zanubrutinib, the oral capsule comprising an oral capsule composition and a capsule shell, the oral capsule composition comprising zanubrutinib, a filler, a disintegrant, a wetting agent, a glidant and a lubricant. (Item 2) An oral capsule comprising zanubrutinib, wherein the oral capsule composition further optionally comprises an adhesive. (Item 3) 3. The oral capsule according to item 1 or 2, wherein the zanubrutinib is in crystalline form A or amorphous, or a mixture of crystalline form A and amorphous, the particle size of the zanubrutinib is ≦40 μm, and the mass percentage of the zanubrutinib relative to the total mass of the oral capsule composition is 20% to 70%, preferably 20% to 50%. (Item 4) 4. The oral capsule according to any one of items 1 to 3, wherein the filler is selected from starch, sucrose, microcrystalline cellulose, anhydrous calcium hydrogen phosphate, mannitol, lactose, pregelatinized starch, glucose, maltodextrin, cyclodextrin, cellulose, silicified microcrystalline cellulose, and any combination thereof, and the mass percentage of the filler relative to the total mass of the oral capsule composition is 20% to 90%, preferably 30% to 80%. (Item 5) 5. The oral capsule according to item 4, wherein the filler is microcrystalline cellulose, and the mass percentage of the microcrystalline cellulose relative to the total mass of the oral capsule composition is 30% to 80%. (Item 6) 4. The oral capsule according to any one of items 1 to 3, wherein the disintegrant is selected from the group consisting of sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, crospovidone, croscarmellose sodium, croscarmellose, methylcellulose, pregelatinized starch, sodium alginate, and any combination thereof, and is preferably croscarmellose sodium, and the mass percentage of the disintegrant relative to the total mass of the oral capsule composition is 0.5% to 5%, and preferably 1% to 3%. (Item 7) 4. The oral capsule according to any one of items 1 to 3, wherein the wetting agent is sodium dodecyl sulfate, and the mass percentage of the sodium dodecyl sulfate relative to the total mass of the composition for oral capsules is 0% to 5%, preferably 0.5% to 1.0%. (Item 8) 4. The oral capsule according to any one of items 1 to 3, wherein the glidant is selected from powdered cellulose, magnesium trisilicate, colloidal silicon dioxide, talc, and any combination thereof, preferably colloidal silicon dioxide, and the mass percentage of the glidant relative to the total mass of the oral capsule composition is 0.1% to 20%, preferably 0.1% to 0.5%. (Item 9) The oral capsule according to any one of items 1 to 3, wherein the lubricant is selected from zinc stearate, glyceryl monostearate, glyceryl stearate palmitate, magnesium stearate, sodium stearate fumarate, and any combination thereof, and is preferably magnesium stearate, and the mass percentage of the lubricant relative to the total mass of the composition for oral capsules is 0.1% to 2%, and preferably 0.3% to 1%. (Item 10) 4. The oral capsule according to any one of items 1 to 3, wherein the capsule shell is a gelatin capsule shell. (Item 11) (1) pre-blending zanubrutinib, a disintegrant, a wetting agent, and a portion of a filler to obtain a pre-blend, and then sieving the pre-blended mixture to obtain a first mixture; Step (2) sieving the glidant and remaining filler and adding and mixing the resulting first mixture from step (1) to obtain a second mixture; Step (3) of sieving the lubricant into the second mixture obtained in step (2) and mixing to obtain a final mixture; and Step (4) of filling the final mixture obtained in step (3) into capsule shells to obtain said oral capsules; 11. A method for preparing an oral capsule according to any one of items 1 to 10, comprising: (Item 12) Item 12. The method according to Item 11, wherein in step (1), the premixing is performed at a rotation speed of 10 rpm to 25 rpm for 2 minutes to 10 minutes, and the aperture size of the screen used for sieving is 1.0 mm to 2.5 mm. (Item 13) Item 13. The method according to item 12, wherein in step (1), the first mixture is obtained by mixing the premixed material at a rotation speed of 10 rpm to 25 rpm for 40 minutes to 15 minutes. (Item 14) 14. The method according to any one of items 11 to 13, wherein in step (2), the mixing is carried out at a rotation speed of 10 rpm to 20 rpm for 3 minutes to 5 minutes. (Item 15) 15. The method according to any one of items 11 to 14, wherein in step (2), the sieving is carried out at a rotation speed of 550 rpm to 650 rpm, and the aperture size of the screen used for the sieving is 1.0 mm to 2.5 mm. (Item 16) 16. The method according to any one of items 11 to 15, wherein in step (3), mixing is carried out at a rotation speed of 10 rpm to 15 rpm for 3 minutes to 6 minutes, and the aperture size of the screen used for sieving is 35 mm to 45 mm. (Item 17) 17. The method according to any one of items 11 to 16, wherein the loading amount of the mixing hopper is 30 to 70% of the volume of the mixing hopper.

Claims

1. An oral capsule comprising zanubrutinib, the oral capsule comprising a composition for the oral capsule and a capsule shell, the composition for the oral capsule comprising zanubrutinib, at least one filler, at least one disintegrant, at least one wetting agent, at least one glidant and at least one lubricant; the zanubrutinib is present in the composition for oral capsules in an amount of 20% to 50% by weight, based on the total weight of the composition for oral capsules; the at least one filler is starch, sucrose, microcrystalline cellulose, anhydrous calcium hydrogen phosphate, mannitol, lactose, pregelatinized starch, glucose, maltodextrin, cyclodextrin, cellulose, or silicified microcrystalline cellulose, and is present in the composition for oral capsules in an amount of 30% to 80% by weight, based on the total weight of the composition for oral capsules; the at least one disintegrant is sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, crospovidone, croscarmellose sodium, croscarmellose, methylcellulose, pregelatinized starch, or sodium alginate, and is present in the composition for oral capsules in an amount of 0.5% to 5% by weight, based on the total weight of the composition for oral capsules; the at least one humectant is sodium dodecyl sulfate and is present in the composition for oral capsules in an amount of 0.3% to 1% by weight, based on the total weight of the composition for oral capsules; the at least one glidant is colloidal silicon dioxide and is present in the composition for oral capsules in an amount of 0.1% to 0.5% by weight, based on the total weight of the composition for oral capsules; the at least one lubricant is zinc stearate, glyceryl monostearate, glyceryl stearate palmitate, magnesium stearate, or sodium stearate fumarate, and is present in the composition for oral capsules in an amount of 0.1% to 2% by weight, based on the total weight of the composition for oral capsules; An oral capsule, wherein at least about 85% of zanubrutinib dissolves in a solution having 0.1 N hydrochloric acid and sodium dodecyl sulfate in an amount of about 0.5% by weight of the solution at a temperature of 37±0.5°C and a rotation speed of 100 rpm within 30 minutes.

2. An oral capsule as described in claim 1, wherein the composition for the oral capsule further comprises at least one adhesive.

3. An oral capsule as described in claim 1 or 2, wherein the zanubrutinib is in crystalline form A or amorphous form, or a mixture of crystalline form A and amorphous form.

4. An oral capsule described in any one of claims 1 to 3, wherein the filler is microcrystalline cellulose.

5. An oral capsule described in any one of claims 1 to 3, wherein the disintegrant is croscarmellose sodium.

6. An oral capsule described in any one of claims 1 to 3, wherein the lubricant is magnesium stearate.

7. An oral capsule described in any one of claims 1 to 3, wherein the capsule shell is a gelatin capsule shell.

8. The steps of: (1) pre-blending zanubrutinib, a disintegrant, a wetting agent, and a portion of a filler to obtain a pre-blended material, and then sieving the pre-blended material to obtain a first mixture; (2) sieving the glidant and the remaining filler, and adding the sieved materials to the first mixture obtained in step (1) and mixing to obtain a second mixture; (3) sieving the lubricant and adding the sieved lubricant to the second mixture obtained in step (2), followed by mixing to obtain a final mixture; and (4) filling the final mixture obtained in step (3) into capsule shells to obtain the oral capsules; A method for preparing the oral capsule of any one of claims 1 to 7, comprising:

9. The method described in claim 8, wherein the premixing in step (1) is carried out for 2 to 10 minutes at a rotation speed of 10 to 25 rpm, and the aperture diameter of the screen used for sieving is 1.0 to 2.5 mm.

10. The method described in claim 9, wherein the first mixture in step (1) is obtained by mixing the pre-mixed material at a rotation speed of 10 rpm to 25 rpm for 40 minutes to 15 minutes.

11. A method described in any one of claims 8 to 10, wherein the mixing in step (2) is carried out at a rotation speed of 10 rpm to 20 rpm for 3 minutes to 5 minutes.

12. A method described in any one of claims 8 to 11, wherein the sieving in step (2) is carried out at a rotation speed of 550 rpm to 650 rpm, and the hole diameter of the screen used in the sieving is 1.0 mm to 2.5 mm.

13. A method described in any one of claims 8 to 12, wherein the mixing in step (3) is carried out at a rotation speed of 10 rpm to 15 rpm for 3 to 6 minutes, and the aperture diameter of the screen used for sieving is 35 mm to 45 mm.

14. A method according to any one of claims 8 to 13, wherein the loading of the mixing hopper is between 30% and 70% of the volume of the mixing hopper.

15. a) the filler is present in the composition for the oral capsule in an amount of 30% by weight to 80% by weight, based on the total weight of the composition for the oral capsule; b) the disintegrant is present in the composition for the oral capsule in an amount of 1% to 3% by weight, based on the total weight of the composition for the oral capsule; c) the wetting agent is sodium dodecyl sulfate present in the composition for oral capsules in an amount of 0.5% to 1.0% by weight, based on the total weight of the composition for oral capsules; d) the glidant is present in the composition for the oral capsule in an amount of 0.1% to 0.5% by weight, based on the total weight of the composition for the oral capsule; or e) the lubricant is present in the composition for the oral capsule in an amount of 0.3% to 1% by weight, based on the total weight of the composition for the oral capsule; The oral capsule of claim 1.

16. The disintegrant is croscarmellose sodium; the glidant is colloidal silicon dioxide; or The lubricant is magnesium stearate. The oral capsule of claim 1.

17. An oral capsule comprising zanubrutinib, the oral capsule comprising a composition for the oral capsule and a capsule shell, the composition for the oral capsule comprising approximately 80 mg of zanubrutinib, approximately 263.8 mg of microcrystalline cellulose, approximately 10.8 mg of croscarmellose sodium, approximately 1.8 mg of colloidal silicon dioxide, approximately 1.8 mg of sodium dodecyl sulfate, and approximately 1.8 mg of magnesium stearate, and the zanubrutinib is in the form of powder particles having a particle size of 40 μm or less.

18. An oral capsule as described in claim 1, wherein the at least one disintegrant is present in the composition for the oral capsule in an amount of 1% by weight to 3% by weight relative to the total weight of the composition for the oral capsule.

19. The oral capsule of claim 1, containing approximately 80 mg of zanubrutinib.

20. The oral capsule of claim 1, wherein the oral capsule comprises a composition for the oral capsule and a capsule shell, the composition for the oral capsule comprising approximately 80 mg of zanubrutinib, approximately 263.8 mg of microcrystalline cellulose, approximately 10.8 mg of croscarmellose sodium, approximately 1.8 mg of colloidal silicon dioxide, approximately 1.8 mg of sodium dodecyl sulfate, and approximately 1.8 mg of magnesium stearate, and the zanubrutinib is in powder particles.

21. The oral capsule of claim 1, wherein the zanubrutinib is powder particles having a particle size of 40 μm or less.

Images