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Oral solid tablet comprising bruton's tyrosine kinase inhibitor and preparation method therefor

Pending Publication Date: 2022-08-11
BEIGENE SWITZERLAND GMBH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The present invention provides a solid tablet for oral administration of Zanubrutinib that overcomes its physicochemical properties, such as high viscosity, poor fluidity, and poor solubility, and ensures good dissolution of the drug. The inventors discovered that a certain amount of colloidal silica as a glidant and other excipients have a significant contribution to improve the sticking of the drug and ensure a good dissolution rate of the drug. The solid tablet for oral administration of Zanubrutinib has no special requirements for production equipment, has a simple preparation process, a stable product, and low production costs. It may also contain one or more agents selected from a sweetening agent, a corrective, a colouring agent, and a preservative to provide a pharmaceutically aesthetic and palatable preparation.

Problems solved by technology

The melting point of the active pharmaceutical ingredient is 145° C., which is lower than the ideal melting point of 150° C. for tablet development, and the material is relatively viscous, which poses a huge challenge to the development and large-scale industrial production of Zanubrutinib tablets.

Method used

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  • Oral solid tablet comprising bruton's tyrosine kinase inhibitor and preparation method therefor
  • Oral solid tablet comprising bruton's tyrosine kinase inhibitor and preparation method therefor
  • Oral solid tablet comprising bruton's tyrosine kinase inhibitor and preparation method therefor

Examples

Experimental program
Comparison scheme
Effect test

example 1

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

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

Zanubrutinib (Crystal form A)34.8gLactose53.2gCroscarmellose sodium2gColloidal silica4.5gSodium lauryl sulfate1gMicrocrystalline cellulose4gMagnesium stearate0.5gOpadry2.4g

[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]...

example 2

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

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

Zanubrutinib (Crystal form A)36.2gLactose55.6gCroscarmellose sodium2.2gColloidal silica4.3gSodium lauryl sulfate1.1gMagnesium stearate0.5g

[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):

Zanubrutinib (Crystal form A)33.3gLactose49.2gHypromellose2gCroscarmellose sodium2gColloidal silica4gSodium lauryl sulfate1gMicrocrystalline cellulose8gMagnesium stearate0.5g

[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.

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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.

Description

TECHNICAL FIELD[0001]The present invention relates to an solid tablet for oral administration containing a Bruton's Tyrosine Kinase (BTK) inhibitor, in particular (S)-7-[4-(1-acryloylpiperidine)]-2-(4-phenoxyphenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide and a preparation method thereof.BACKGROUND ART[0002]International application WO 2014173289 A disclosed a novel Bruton's Tyrosine Kinase (BTK), more particularly (S)-7-[4-(1-acryloylpiperidine)]-2-(4-phenoxyphenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a] pyrimidine-3-carboxamide (with a generic name of Zanubrutinib), which has a chemical structure as follows:[0003]Zanubrutinib belongs to the second-generation BTK inhibitor, which irreversibly inactivates the tyrosine kinase by covalently binding with the enzyme. It is used as a single agent or in combination with other drugs for the treatment of B lymphocyte tumors, including chronic lymphocytic leukemia / small lymphocytic lymphoma (CLL / SLL), mantle cell lymphoma (MCL),...

Claims

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Application Information

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IPC IPC(8): A61K31/519A61K9/20A61K9/28
CPCA61K31/519A61K9/2018A61K9/2866A61K9/2009A61K9/2013A61K9/2054A61K9/2806
Inventor QIU, GANGSHEN, YIWEIFAN, WENYUANXU, SHUOLV, HUIRUBIAN, JIALINDU, ZHENGMING
Owner BEIGENE SWITZERLAND GMBH
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