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Pharmaceutical preparation composition of pyrrolopyrimidine derivatives as alk/fak/igf1r multi-kinase inhibitors and preparation method thereof

A technology of pharmaceutical preparations and compositions, which is applied in the field of pharmaceutical preparations of pyrrolopyrimidine derivatives, and can solve problems such as degradation impurities, easy oxidation, low bioavailability, easy oxidation instability, etc.

Active Publication Date: 2022-02-01
SHOUYAO HLDG BEIJING CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

For example, in the environment of the stomach (pH about 1-2), the compound of formula (I) has a saturated solubility of about 30 mg / ml, and as the pH increases, the solubility of the compound of formula (I) decreases sharply to pH6. At 8 o'clock, the solubility is only about 4 μg / ml, which means that when the compound of formula (I) dissolved in gastric juice is transferred to the intestinal tract, a significant amount of compound of formula (I) may be precipitated, and the absorption is reduced, thereby reducing its bioavailability
In addition, the structure of the compound contains a large number of secondary and tertiary amines, which makes it easily oxidized during production and storage, resulting in degradation impurities
Lower bioavailability and oxidative instability are the challenges faced by formula (I) compound formulations

Method used

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  • Pharmaceutical preparation composition of pyrrolopyrimidine derivatives as alk/fak/igf1r multi-kinase inhibitors and preparation method thereof
  • Pharmaceutical preparation composition of pyrrolopyrimidine derivatives as alk/fak/igf1r multi-kinase inhibitors and preparation method thereof
  • Pharmaceutical preparation composition of pyrrolopyrimidine derivatives as alk/fak/igf1r multi-kinase inhibitors and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0020] Formula (I) compound sheet prescription is as follows:

[0021] Name of raw material Dosage (%, w / w) Compound of formula (I) 10 silica 5 Microcrystalline Cellulose PH102 75 Croscarmellose Sodium 3 Sodium dodecyl sulfate 6 Magnesium stearate 1 Coating powder 3

[0022] Formula (I) compound sheet preparation process is as follows:

[0023] 1) Mix 80g of the compound of formula (I) and 40g of silicon dioxide and pass through a 40-mesh sieve. The particle size of the compound of formula (I) is about 7.892 μm in D50 and about 19.172 μm in D90.

[0024] 2) Put the mixture of the sieved formula (I) compound and silicon dioxide with 600g microcrystalline cellulose PH102, 24g croscarmellose sodium, 48g sodium lauryl sulfate, 4g magnesium stearate In the HSD30 hopper mixer (Zhejiang Canaan Pharmaceutical Equipment Co., Ltd.), set the rotation speed at 12 rpm, and mix for 10 minutes.

[0025] 3) Put the material into the...

Embodiment 2

[0030] Formula (I) compound sheet prescription is as follows:

[0031] Name of raw material Dosage (%, w / w) Compound of formula (I) 28.5 silica 5 Microcrystalline Cellulose PH102 60.5 Croscarmellose Sodium 5 Magnesium stearate 1 Coating powder 3

[0032] Formula (I) compound sheet preparation process is as follows:

[0033] 1) Mix 228g of the compound of formula (I) and 40g of silicon dioxide and pass through a 40-mesh sieve. Wherein the particle size of the compound of formula (I) is the same as that of Example 1.

[0034] 2) Place the mixture of the sieved formula (I) compound and silicon dioxide with 484g microcrystalline cellulose PH102, 40g croscarmellose sodium, and 4g magnesium stearate in the HSD30 hopper mixer, set Mix at 12 rpm for 10 minutes.

[0035] 3) Put the material into the hopper of the GL2-25 dry granulator for dry granulation, set the feeding frequency to 6-30Hz, the tableting frequency to 10-30Hz, and ...

Embodiment 3

[0040] Formula (I) compound sheet prescription is as follows:

[0041]

[0042]

[0043] Formula (I) compound sheet preparation process is as follows:

[0044] 1) Weigh 24g of povidone K30 and 24g of poloxamer 188, dissolve in an appropriate amount of purified water to form a binder solution;

[0045] 2) 222.4g of the compound of formula (I), 24g of silicon dioxide, 297.6g of microcrystalline cellulose PH101 and 24g of croscarmellose sodium were placed in a G6 wet mixing granulator (Shenzhen Xinyite Technology Co., Ltd. Company), set the stirring paddle rotating speed 2r / sec, shear velocity 15r / sec, mix 10 minutes;

[0046] 3) Spray into the binder solution for wet granulation, the atomization pressure is about 0.4MPa, and granulate through a 20-mesh sieve;

[0047] 4) Dry the wet granules at 60°C until the water content is less than 2%, and sieve the granules with a 30-mesh sieve;

[0048] 5) Put the granules, 144g of microcrystalline cellulose PH102, and 32g of cros...

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Abstract

The present invention provides the preparation composition of the ALK / FAK / IGF1R multi-kinase inhibitor compound of formula (I) or a pharmaceutically acceptable salt thereof. It specifically relates to tablets, capsules or granules, especially tablet formulations and preparation methods thereof, novel compositions of medicines and hypromellose or hypromellose-derivative polymers and preparation methods.

Description

technical field [0001] The invention relates to a pharmaceutical preparation of pyrrolopyrimidine derivatives. Specifically, the present invention relates to the ALK / FAK / IGF1R multikinase inhibitor N-isopropyl-2-((2-((2-methoxy-4-(4-(4-methylpiperazine-1- Base) piperidin-1-yl) phenyl) amino)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)benzenesulfonamide or its pharmaceutically acceptable The salts are used in clinical stable preparations such as tablets, capsules or granules. Background technique [0002] Formula (I) compound N-isopropyl-2-((2-((2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)benzene yl)amino)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)benzenesulfonamide is an ALK, FAK, IGF1R multi-kinase inhibitor that targets The occurrence and development of tumors are closely related. The patents with application numbers 201110002776.3 and 201280004821.1 have both described the good prospect of this compound in the treatment of tumor growth and can...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D487/04
CPCA61K47/10A61K47/20A61K47/38A61K9/1652A61K9/2013A61K9/2031A61K9/2054A61K9/2866A61K31/519
Inventor 王再全马秋平杨利民张传玉孔凡胜张德富刘玲
Owner SHOUYAO HLDG BEIJING CO LTD
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