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Pharmaceutical composition containing cyclin kinase inhibitor, and preparation method thereof

A composition and drug technology, applied in the field of pharmaceutical preparations, can solve problems such as affecting absorption and bioavailability, and achieve the effects of excellent dissolution behavior, low impurity content, and simple preparation process

Active Publication Date: 2022-02-11
CHANGZHOU LE SUN PHARMACEUTICALS CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] However, the solubility in water of the compound of formula I and its salt is about 40 μg / mL, insoluble or almost insoluble, which directly affects the absorption and bioavailability of the compound in the body, so it is necessary to carry out layer-by-layer research on the prescription, dosage form and prescription process Screening and optimization to obtain pharmaceutical compositions with excellent dissolution and bioavailability

Method used

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  • Pharmaceutical composition containing cyclin kinase inhibitor, and preparation method thereof
  • Pharmaceutical composition containing cyclin kinase inhibitor, and preparation method thereof
  • Pharmaceutical composition containing cyclin kinase inhibitor, and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0048] Embodiment 1: Screening of benchmark prescription

[0049] Poorly soluble drugs are developed into oral solid preparations. Due to the low solubility of drugs, it is particularly critical to improve their bioavailability in animals. In the animal in vivo test for formulation screening, design a true solution group and a suspension group, and compare them with the reference prescription group of the formulation. The composition and preparation method of each prescription are shown in the table below.

[0050]

[0051] The formulations prepared above were orally administered to cynomolgus monkeys to test their bioavailability and pre-evaluate the formulations. The results are shown in the table below. The plasma drug exposure of cynomolgus monkeys after oral administration of the capsule preparation was higher, and the average bioavailability was 50%, which was 1 times higher than that of the true solution group and suspension group, and unexpected results were obtain...

Embodiment 2

[0053] Embodiment 2: the screening optimization of prescription

[0054] (1) Unit prescription composition (unit: mg)

[0055]

[0056]Note: " / " means not added

[0057] (2) Preparation

[0058] Put the above 1000 tablets of succinate and other excipients into the hopper mixer and mix evenly, control the content and uniformity in the middle, and fill the capsules.

[0059] (3) Quality assessment

[0060]

[0061]

[0062] After mixing according to the ratio in the prescription table, the bulk density of the obtained preparation granules is 0.29-0.30g / cm 3 , the angle of repose is between 46.67° and 48.18°, and the formulation process still needs to be optimized.

[0063] The results of the dissolution test showed that for the 100mg capsules, the dissolution rate of each of the above formulations in 30 minutes could meet the expected requirements.

Embodiment 3

[0064] Embodiment 3: the optimization of prescription technology

[0065] (1) Composition of the unit prescription (unit: mg)

[0066]

[0067] (2) Preparation

[0068] Put the above 1000 tablets of succinate of the compound of formula I and other excipients into a wet granulator and mix evenly, wet granulate, granulate, granulate after fluidized bed drying, and mix to obtain the total blend Granules, controlled content, uniformity, filling capsules.

[0069] (3) Quality assessment

[0070]

[0071] Influencing factor test investigation, according to the Chinese Pharmacopoeia 2020 edition, the stability of the above-mentioned prescriptions was investigated, and samples were taken and tested on the 5th and 10th days under high temperature, high humidity and light conditions respectively. The test results are as follows:

[0072]

[0073]

[0074] The fluidity of the capsules obtained by the above different prescription processes is better, the bulk density meets ...

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Abstract

The invention relates to a pharmaceutical composition containing a cyclin inhibitor, and a preparation method thereof. The pharmaceutical composition takes N-cyclopentyl-5-(2-((5-((4-ethylpiperazine-1-yl)methyl)pyridin-2-yl)amino)-5-fluoropyrimidin-4-yl)-4-methylthiazol-2-amine or a salt thereof as an active ingredient. A prepared oral solid preparation has excellent dissolution behavior and good bioavailability, meets clinical application requirements, is extremely low in impurity content and good in stability, and can ensure controllable quality of the medicine; and meanwhile, the preparation process of wet / dry granulation is simple and easy to operate, and industrial production of the medicine is facilitated.

Description

technical field [0001] The invention belongs to the field of pharmaceutical preparations, and in particular relates to a pharmaceutical composition containing a cell cycle protein kinase inhibitor and a preparation method thereof. Background technique [0002] Cyclin-dependent kinases (CDKs) are a set of Ser / Thr kinase systems corresponding to cell cycle progression. They are associated with various cyclin subunits and play key roles in various important regulatory pathways in cells, including cell cycle control, apoptosis, neuronal physiology, differentiation and transcription. At present, there are more than 20 kinds of CDKs, which are mainly divided into two categories: cell cycle regulator CDK and transcription regulator CDK according to their functions. Cell cycle regulator CDKs include CDK1, CDK2, CDK3, CDK4 and CDK6, which cooperate with cyclin ligands (eg, cyclins A, B, D1, D2, D3, E and F) to regulate cell cycle progression. Transcriptional regulator CDKs include ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/506A61K9/48A61K9/30A61P35/00A61P35/02
CPCA61K31/506A61K9/1652A61K9/2054A61K9/282A61P35/00A61P35/02
Inventor 王辉江立群刘军
Owner CHANGZHOU LE SUN PHARMACEUTICALS CO LTD