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Ibrutinib amorphous substance and medicinal composition thereof

A technology of ibrutinib and amorphous substances, which is applied in the amorphous field of pharmaceutical compounds, can solve the problems of affecting the bioavailability, solubility and stability of drugs, affecting the dissolution and release of pharmaceutical compositions, etc.

Pending Publication Date: 2021-07-20
北京赛思源生物医药技术有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] 1-[3(R)-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]piperidin-1-yl]- Different crystal forms of 2-propen-1-one may have differences in solubility and stability, which will affect the dissolution and release of its pharmaceutical composition in vitro, and then affect the bioavailability of the drug in vivo

Method used

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  • Ibrutinib amorphous substance and medicinal composition thereof
  • Ibrutinib amorphous substance and medicinal composition thereof
  • Ibrutinib amorphous substance and medicinal composition thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0061] Take 10g 1-[3(R)-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]piperidin-1-yl ]-2-propen-1-one was dissolved in 60ml of tetrahydrofuran, and the above solution was added to 120ml of isopropanol, and the above mixed solution was added to 600ml of n-heptane cooled to -20°C, and a white viscous substance was precipitated under stirring, poured The liquid is discharged, dried under reduced pressure, and the amorphous substance of ibrutinib can be collected, and the X-ray diffraction pattern of the product obtained is as follows: figure 1 shown.

Embodiment 2

[0063] Take 30g 1-[3(R)-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]piperidin-1-yl ]-2-propen-1-one was dissolved in 300ml of dichloromethane, stirred and dissolved at room temperature; concentrated and dried under reduced pressure to obtain the amorphous substance of ibrutinib, and the X-ray diffraction spectrum of the product obtained was the same as in Example 1 Basically the same.

Embodiment 3

[0064] The prescription and preparation technology of embodiment 3 capsules:

[0065] The above 1-[3(R)-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidine- 1-yl]piperidin-1-yl]-2-propen-1-one amorphous was formulated into capsules containing 140 mg per tablet, and the results are shown in Table 6.

[0066] Table 6 Prescription situation

[0067]

[0068] Preparation process: containing 1-[3(R)-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1 -base]-2-propen-1-one amorphous capsules are manufactured by combining the above-mentioned excipients with 1-[3(R)-[4-amino-3-(4-phenoxyphenyl)- The amorphous 1H-pyrazolo[3,4-d]pyrimidin-1-yl]piperidin-1-yl]-2-propen-1-one is mixed uniformly by the method of increasing the equal amount, and filled into capsules. The reference crystals were mixed and filled into capsules in the same manner. Table 7 shows the comparison of dissolution test results of capsule formulations

[0069] Table 7 Comparison of...

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PUM

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Abstract

The invention discloses an ibrutinib amorphous substance , which is radiated by Cu-Ka, no sharp diffraction peak exists in an X-ray powder diffraction spectrum expressed by degree 2 theta, and the X-ray powder diffraction is shown in figure 1. Compared with the existing ibrutinib crystal form, the ibrutinib amorphous substance disclosed by the invention has the advantages that the solubility is obviously increased, the flowability is better, the bioavailability of a medicinal preparation is more favorably improved, and the amorphous substance shows good stability under an accelerated test condition. In addition, the invention also provides a preparation method and a medicinal composition of the amorphous substance.

Description

technical field [0001] The present invention relates to the amorphous form of pharmaceutical compounds, in particular to 1-[3(R)-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidine-1 -yl]piperidin-1-yl]-2-propen-1-one amorphous and its preparation method and pharmaceutical composition. Background technique [0002] Ibrutinib (chemical name is 1-[3(R)-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl] Piperidin-1-yl]-2-propen-1-one), was approved by the US Food and Drug Administration (FDA) on November 13, 2013 as a single treatment drug for mantle cell lymphoma, also known as Ibrutinib. Ibrutinib is a targeted agent that selectively inhibits Bruton's tyrosine kinase (BTK) for the treatment of chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL). Both MCL and CLL belong to B-cell non-Hodgkin's lymphoma, which are refractory and easy to relapse. The commonly used chemoimmunotherapy is not targeted, and serious adverse reactions often occur. Ib...

Claims

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Application Information

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IPC IPC(8): C07D487/04A61K31/519A61P35/00A61P35/02
CPCC07D487/04A61K31/519A61P35/00A61P35/02
Inventor 赵紫岭王守亮
Owner 北京赛思源生物医药技术有限公司