ORAL SOLID TABLET COMPRISING BRUTON'S TYROSINE KINASE INHIBITOR AND PREPARATION METHOD THEREFOR

Abstract

Provided are an oral solid tablet comprising (S)-7-[4-(1-acryloylpiperidine)]-2-(4-phenoxyphenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide and preparation method therefor. The oral solid tablet has good drug release characteristics, features easy administration, quick and high-efficient release, no particular requirements on equipment, and a simple formulation preparation process, can ensure formulation stability and facilitate transportation and storage, and is suitable for large-scale production.

Claims

1. An solid tablet for oral administration containing Zanubrutinib, comprising: (1) 20% to 70%, preferably 30% to 50% of Zanubrutinib, all in mass percentages; and (2) one or more pharmaceutically acceptable excipients.

2. The solid tablet for oral administration according to claim 1, wherein the Zanubrutinib is of a crystal form A, an amorphous form, or a mixture of a crystal form A and an amorphous form.

3. The solid tablet for oral administration according to claim 1 or 2, wherein the excipient is selected from a filler, a binder, a disintegrant, a wetting agent, a glidant, a lubricant, and any combination thereof.

4. The solid tablet for oral administration according to 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. The solid tablet for oral administration according to claim 4, wherein the filler is lactose, and the content of the lactose is 20% to 70%, preferably 40% to 60%, all in mass percentages.

6. The solid tablet for oral administration 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 in mass percentages.

7. The solid tablet for oral administration 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% to 70% and 0% to 50%, preferably 40% to 60% and 4% to 10%, respectively, all in mass percentages.

8. The solid tablet for oral administration according to claim 3, wherein the binder is selected from starch, hypromellose, polyvinylpyrrolidone, sodium carboxymethyl cellulose, hydroxypropyl cellulose, methyl cellulose, ethyl cellulose, gelatin, sucrose, and any combination thereof.

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

10. The solid tablet for oral administration according to claim 3, wherein the disintegrant is selected from sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, crospovidone, croscarmellose sodium, croscarmellose, methyl cellulose, pre gelatinized starch, sodium alginate, and any combination thereof.

11. The solid tablet for oral administration 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 in mass percentages.

12. The solid tablet for oral administration 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 in mass percentages.

13. The solid tablet for oral administration according to claim 3, wherein the glidant is selected from powdered cellulose, magnesium trisilicate, colloidal silica, talc powder, and any combination thereof.

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

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

16. The solid tablet for oral administration 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 in mass percentages.

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

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

19. A method for preparing the solid tablet for oral administration according to any one of claims 1 to 17, comprising the following steps: (1) mixing the zanubrutinib and one or more excipients; (2) subjecting the mixture of the zanubrutinib and one or more excipients to wet granulation with purified water, or an organic reagent, or an aqueous solution or an organic solution containing a binder, followed by drying and sizing; (3) optionally, mixing the sized granules with an additional excipient and compressing them into plain tablets; (4) optionally, coating the plain tablets, wherein, if step (3) is not performed, the sized granules obtained in step (2) are compressed into plain tablets.

20. The method according to claim 19, wherein the organic reagent in step (2) is selected from ethanol, acetone, and a combination thereof.

21. The method according to claim 19 or 20, wherein the additional excipient in step (3) is selected from a filler, a lubricant, a glidant, and any combination thereof.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0044] FIG. 1 is an X-ray powder diffraction pattern of the crystal form A of Zanubrutinib.

[0045] FIG. 2 is a schematic diagram of the cumulative drug dissolution (in vitro dissolution) of the solid tablet for oral administrations of Zanubrutinib in Example 1.

[0046] FIG. 3 is a schematic diagram of the cumulative drug dissolution (in vitro dissolution) of the solid tablet for oral administrations of Zanubrutinib in Example 8 and Example 9. It can be seen therefrom that the drug dissolution rate of Example 8 is significantly better than that of Example 9.

DETAILED DESCRIPTION OF EMBODIMENTS

[0047] The following examples can help those skilled in the art to understand the present invention more comprehensively, but do not limit the present invention in any way. In the following, unless otherwise specified, the temperature is in ° C. Reagents are purchased from commercial providers such as Sigma-Aldrich, Alfa Aesar or TCI, and can be used without further purification unless otherwise specified.

Example 1

[0048] Preparation of Solid Tablet for Oral Administrations of Zanubrutinib, Specification: 160 mg

[0049] Prescription (Per 100 g Plain Tablets):

TABLE-US-00001 Zanubrutinib (Crystal form A) 34.8 g Lactose 53.2 g Croscarmellose sodium 2 g Colloidal silica 4.5 g Sodium lauryl sulfate 1 g Microcrystalline cellulose 4 g Magnesium stearate 0.5 g Opadry 2.4 g

[0050] Preparation Process: 53.2 g of lactose, 2 g of croscarmellose sodium, 1 g of sodium lauryl sulfate and 34.8 g of Zanubrutinib are added into a high-shear granulator (MYCROMIX, manufactured by BOSCH) and mixed for 5 minutes, an appropriate amount of purified water is added for granulation, followed by dying and then sizing, 4.5 g of colloidal silica, 4 g of microcrystalline cellulose and 0.5 g of magnesium stearate are further added and mixed. After mixing, the above ingredients are pressed into tablets to obtain plain tablets. The above-mentioned plain tablets are coated with 2.4 g of Opadry to obtain solid tablet for oral administrations containing Zanubrutinib.

[0051] Drug Cumulative Dissolution (In Vitro Dissolution) Test: The in vitro dissolution experiment is determined by an automatic sampling dissolution tester (Model: 708+850DS, purchased from AGILENT), according to USP<711>, the “dissolution” is determined using the basket method, the automatic sampling dissolution tester is set at a water bath temperature of 37±0.5° C., at a rotating speed of 100 rpm, with a pH 1.2 (HCl)+0.5% SLS dissolution medium of a volume of 900 mL. Samples are taken at 10 min, 15 min, 30 min, 45 min, and 60 min, and all samples are passed through a 0.45 μm filter membrane, and the samples are determined and analyzed according to the sample dissolution test method. As shown in FIG. 2, when the Zanubrutinib solid tablet for oral administration of the present invention is in a pH 1.2 (HCl)+0.5% SLS medium, more than 90% of Zanubrutinib is dissolved at 30 minutes, which can meet the requirements of rapid release.

[0052] In the following Examples 2-12, the drug cumulative dissolution (in vitro dissolution) are all measured according to the method of Example 1.

Example 2

[0053] Preparation of Solid Tablet for Oral Administrations of Zanubrutinib, Specification: 160 mg

[0054] Prescription (Per 100 g Plain Tablets):

TABLE-US-00002 Zanubrutinib (Crystal form A) 36.2 g Lactose 55.6 g Croscarmellose sodium 2.2 g Colloidal silica 4.3 g Sodium lauryl sulfate 1.1 g Magnesium stearate 0.5 g

[0055] Preparation Process: 55.6 g of lactose, 2.2 g of croscarmellose sodium, 1.1 g of sodium lauryl sulfate, 4.3 g of colloidal silica and 36.2 g of Zanubrutinib are added into a high-shear granulator and mixed for 5 minutes, an appropriate amount of purified water is added for granulation, followed by dying and then sizing, and 0.5 g of magnesium stearate is further added and mixed. After mixing, the above ingredients are pressed into tablets to obtain plain tablets, that is, an solid tablet for oral administration containing Zanubrutinib.

[0056] Drug Cumulative Dissolution (In Vitro Dissolution) Test: About 90% of Zanubrutinib is dissolved at 30 minutes.

Example 3

[0057] Preparation of Solid Tablet for Oral Administrations of Zanubrutinib, Specification: 160 mg

[0058] Prescription (Per 100 g Plain Tablets):

TABLE-US-00003 Zanubrutinib (Crystal form A) 33.3 g Lactose 49.2 g Hypromellose 2 g Croscarmellose sodium 2 g Colloidal silica 4 g Sodium lauryl sulfate 1 g Microcrystalline cellulose 8 g Magnesium stearate 0.5 g

[0059] Preparation Process: 49.2 g of lactose, 2 g of croscarmellose sodium, 1 g of sodium lauryl sulfate and 33.3 g of Zanubrutinib are added into a high-shear granulator and mixed for 5 minutes, 2 g of hypromellose aqueous solution is added for granulation, followed by dying and then sizing, 4 g of colloidal silica, 8 g of microcrystalline cellulose and 0.5 g of magnesium stearate are further added and mixed. After mixing, the above ingredients are pressed into tablets to obtain plain tablets, that is, an solid tablet for oral administration containing Zanubrutinib.

Example 4

[0060] Preparation of Solid Tablet for Oral Administrations of Zanubrutinib, Specification: 320 mg

[0061] Prescription (Per 100 g Plain Tablets):

TABLE-US-00004 Zanubrutinib (Crystal form A) 50 g Croscarmellose sodium 4 g Colloidal silica 12.0 g Sodium lauryl sulfate 1 g Microcrystalline cellulose 32.5 g Magnesium stearate 0.5 g Opadry 1.5 g

[0062] Preparation Process: 50 g of Zanubrutinib, 4 g of croscarmellose sodium, 12.0 g of colloidal silica, 1 g of sodium lauryl sulfate, 32.5 g of microcrystalline cellulose are sieved and then mixed in a high-shear granulator, then 0.5 g of magnesium stearate is added and mixed uniformly. The mixed powder is pressed directly to obtain plain tablets. The above-mentioned plain tablets are coated with a coating liquid containing 2.4 g of Opadry to obtain solid tablet for oral administrations containing Zanubrutinib.

[0063] Drug Cumulative Dissolution (In Vitro Dissolution) Test: The dissolution rate (%) of the drug at 30 minutes is about 80%.

Example 5

[0064] Preparation of Solid Tablet for Oral Administrations of Zanubrutinib, Specification: 80 mg

[0065] Prescription (Per 100 g Plain Tablets):

TABLE-US-00005 Zanubrutinib (Crystal form A) 26.7 g Lactose 23.8 g Croscarmellose sodium 2 g Colloidal silica 4 g Sodium lauryl sulfate 1 g Microcrystalline cellulose 40 g Hypromellose 2 g Magnesium stearate 0.5 g Opadry 1.5 g

[0066] Preparation Process: 23.8 g of lactose, 40 g of microcrystalline cellulose, 2 g of croscarmellose sodium, 1 g of sodium lauryl sulfate, 4 g of colloidal silica, and 26.7 g of Zanubrutinib are added to a fluidized bed, then 2 g of a hypromellose aqueous solution is sprayed for granulation, followed by drying and then magnesium stearate is added and mixed. After mixing, the above ingredients are pressed into tablets to obtain plain tablets. The above-mentioned plain tablets are coated with a coating liquid containing 1.5 g of Opadry to obtain solid tablet for oral administrations containing Zanubrutinib.

Example 6

[0067] Preparation of Solid Tablet for Oral Administrations of Zanubrutinib, Specification: 80 mg

[0068] Prescription (Per 100 g Plain Tablets):

TABLE-US-00006 Zanubrutinib (Crystal form A) 26.7 g Lactose 35.8 g Croscarmellose sodium 2 g Colloidal silica 4 g Sodium lauryl sulfate 1 g Silicified microcrystalline cellulose 30 g Magnesium stearate 0.5 g

[0069] Preparation Process: 26.7 g of Zanubrutinib, 2 g of croscarmellose sodium, 4 g of colloidal silica, 1 g of sodium lauryl sulfate, 35.8 g of lactose and 30 g of silicified microcrystalline cellulose are sieved and then mixed in a high-shear granulator, then 0.5 g of magnesium stearate is added and mixed uniformly. The powder is pressed into tablets directly, coated with an Opadry coating liquid to obtain solid tablet for oral administrations containing Zanubrutinib.

Example 7

[0070] Preparation of Solid Tablet for Oral Administrations of Zanubrutinib, Specification: 320 mg

[0071] Prescription (Per 100 g Plain Tablets):

TABLE-US-00007 Zanubrutinib (Crystal form A) 50.0 g Lactose 36.5 g Croscarmellose sodium 4 g Colloidal silica 8 g Sodium lauryl sulfate 1 g Magnesium stearate 0.5 g

[0072] Preparation Process: 50.0 g of Zanubrutinib, 4 g of croscarmellose sodium, 8 g of colloidal silica, 1 g of sodium lauryl sulfate, 36.5 g of lactose are sieved and then mixed in a high-shear granulator, then 0.5 g of magnesium stearate is added and mixed uniformly. The powder is pressed directly into tablets to obtain plain tablets, that is, an solid tablet for oral administration containing Zanubrutinib.

[0073] Drug Cumulative Dissolution (In Vitro Dissolution) Test: The dissolution rate (%) of the drug at 30 minutes is about 40%.

Example 8

[0074] Preparation of Solid Tablet for Oral Administrations of Zanubrutinib, Specification: 320 mg

[0075] Prescription (Per 100 g Plain Tablets):

TABLE-US-00008 Zanubrutinib (Crystal form A) 50.0 g Croscarmellose sodium 4 g Colloidal silica 8 g Sodium lauryl sulfate 1 g Microcrystalline cellulose 36.5 g Magnesium stearate 0.5 g

[0076] Preparation Process: 50.0 g of Zanubrutinib, 36.5 g of microcrystalline cellulose, 4 g of croscarmellose sodium, 8 g of colloidal silica, 1 g of sodium lauryl sulfate are sieved and then mixed in a high-shear granulator, then 0.5 g of magnesium stearate is added and mixed uniformly. The powder is pressed directly into tablets to obtain plain tablets, that is, an solid tablet for oral administration containing Zanubrutinib.

[0077] Drug Cumulative Dissolution (In Vitro Dissolution) Test: The dissolution curve of the drug is shown in FIG. 3. It can be seen that the dissolution is greater than 80% at 30 minutes.

Example 9

[0078] Preparation of Solid Tablet for Oral Administrations of Zanubrutinib, Specification: 320 mg

[0079] Prescription (Per 100 g Plain Tablets):

TABLE-US-00009 Zanubrutinib (Crystal form A) 60.0 g Croscarmellose sodium 4 g Colloidal silica 0.8 g Sodium lauryl sulfate 1 g Microcrystalline cellulose 33.7 g Magnesium stearate 0.5 g

[0080] Preparation Process: 60 g of Zanubrutinib, 33.7 g of microcrystalline cellulose, 4 g of croscarmellose sodium, 0.8 g of colloidal silica, 1 g of sodium lauryl sulfate are sieved and then mixed in a high-shear granulator, then 0.5 g of magnesium stearate is added and mixed uniformly. The powder is pressed directly into tablets to obtain plain tablets, that is, an solid tablet for oral administration containing Zanubrutinib.

[0081] Drug Cumulative Dissolution (In Vitro Dissolution) Test: The dissolution curve of the drug is shown in FIG. 3. It can be seen that the dissolution is less than 60% at 30 minutes.

Example 10

[0082] Preparation of Solid Tablet for Oral Administrations of Zanubrutinib, Specification: 320 mg

[0083] Prescription (Per 100 g Plain Tablets):

TABLE-US-00010 Zanubrutinib (Crystal form A) 46.69 g Croscarmellose sodium 4.38 g Colloidal silica 0.88 g Sodium lauryl sulfate 0.88 g Microcrystalline cellulose 46.69 g Magnesium stearate 0.50 g

[0084] Preparation Process: 53.2 g of lactose, 2 g of croscarmellose sodium, 1 g of sodium lauryl sulfate and 34.8 g of Zanubrutinib are added into a high-shear granulator (MYCROMIX, manufactured by BOSCH) and mixed for 5 minutes, an appropriate amount of purified water is added for granulation, followed by dying and then sizing, 4.5 g of colloidal silica, 4 g of microcrystalline cellulose and 0.5 g of magnesium stearate are further added and mixed. After mixing, the above ingredients are pressed into tablets to obtain plain tablets, that is, an solid tablet for oral administration containing Zanubrutinib.

[0085] Drug Cumulative Dissolution (In Vitro Dissolution) Test: The dissolution rate (%) of the drug at 60 minutes is about 80%.

Example 11

[0086] Preparation of Solid Tablet for Oral Administrations of Zanubrutinib, Specification: 320 mg

[0087] Prescription (Per 100 g Plain Tablets):

TABLE-US-00011 Zanubrutinib (Crystal form A) 46.69 g Lactose 46.69 g Croscarmellose sodium 4.38 g Colloidal silica 0.88 g Sodium lauryl sulfate 0.88 g Magnesium stearate 0.50 g

[0088] Preparation Process: According to a method similar to Example 10, the solid tablet for oral administrations containing Zanubrutinib can be prepared.

[0089] Drug Cumulative Dissolution (In Vitro Dissolution) Test: The dissolution rate (%) of the drug at 60 minutes is less than 80%.

Example 12

[0090] Preparation of Solid Tablet for Oral Administrations of Zanubrutinib, Specification: 320 mg

[0091] Prescription (Per 100 g Plain Tablets):

TABLE-US-00012 Zanubrutinib (Crystal form A) 22.21 g Croscarmellose sodium 3.00 g Colloidal silica 0.50 g Sodium lauryl sulfate 0.50 g Microcrystalline cellulose 73.29 g Magnesium stearate 0.50 g

[0092] Preparation Process: According to a method similar to Example 10, the solid tablet for oral administrations containing Zanubrutinib can be prepared.

[0093] Although the foregoing description teaches the principles of the present invention and provides examples for the purpose of illustration, the practice of the present invention includes all common changes, adaptations and/or modifications within the scope of the following claims. The references involved in this disclosure are incorporated herein by reference.