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Solid preparation containing insoluble thienopyridine composition and preparation method thereof

A technology for solid preparations and compositions, which is applied in the field of solid preparations and preparations containing insoluble thienopyridine compositions, can solve the problems of slow dissolution rate and reduced bioavailability, and achieves low production cost, improved dissolution rate, suitable for effect on industrial production

Active Publication Date: 2020-12-15
CHENGDU SHIBEIKANG BIOLOGICAL MEDICINE TECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In the process of rapid disintegration and absorption of solid preparations, the rate-limiting step of drug absorption is often the dissolution rate of the drug, especially for poorly soluble drugs, the slow dissolution rate will lead to a decrease in bioavailability

Method used

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  • Solid preparation containing insoluble thienopyridine composition and preparation method thereof
  • Solid preparation containing insoluble thienopyridine composition and preparation method thereof
  • Solid preparation containing insoluble thienopyridine composition and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0040] This embodiment discloses the preparation method of the compound of formula II, specifically:

[0041] (S)-2-(2-chlorophenyl)-2-(7a-hydroxy-2-oxo-2,6,7,7a-tetrahydrothieno[3,2-c]pyridine-5(4H )-base) Synthesis of methyl acetate

[0042] Step 1. Synthesis of IM1:

[0043]

[0044] At room temperature, slowly drop 35 mL of anhydrous THF suspension with 7.1 g of sodium hydride into 586 mL of anhydrous THF dissolved with 58.6 g of SM1, stir for 30 min, then slowly drop into 70 mL of anhydrous THF with 69.2 g of SM2 dissolved therein and Stir at room temperature for 12 h, and monitor the reaction by TLC iodine display. After the reaction was completed, 650 mL of saturated brine was added and extracted with 1500 mL of DCM. Organic layer with Na 2 SO 4 After drying, the solvent was removed by evaporation under reduced pressure. The residue was purified on a silica gel column to obtain 52.3 g (62.3% yield) of IM1 as a colorless oily liquid (PE / EA=20 / 1 to 5 / 1). LC-MS(E...

Embodiment 2

[0057] Embodiment 2: the research of the different ratio of formula II compound and formula I compound

[0058] In this example, the pure products of the compound of formula I and compound of formula II in the thienopyridine composition with different proportions were added to conduct research to investigate their quality stability. Specifically: using the same amount of thienopyridine composition and auxiliary materials, only the ratio of the formula II compound to the formula I compound is different, and the same preparation method is used to make tablets. The content of the related substances was determined on the tablet at 0 days and accelerated at 6 months. Its prescription composition is calculated by 1000 tablets, as shown in Table 1:

[0059] Table 1 Prescription Composition Table 1

[0060]

[0061]

[0062] The preparation method is:

[0063] 1. Weigh the pure products of the compound of formula I and the compound of formula II respectively; after mixing eve...

Embodiment 3

[0075] Embodiment 3: control the ratio of II compound and formula I compound, refined preparation method

[0076] Prepare the crude compound shown in I according to the method disclosed in Example 2 of CN 104245707, take 1.0g of the crude compound shown in formula I and put it into a 50mL eggplant-shaped bottle, add 30mL tetrahydrofuran, heat up to 60°C and stir to dissolve, basically dissolve, and heat Filtrate, stir the filtrate in a 50mL beaker, and slowly cool down to room temperature, stir overnight to crystallize, and dry to obtain 0.38g of the finished compound. The mass ratio of the compound II to the compound of formula I in the finished product is less than or equal to 0.5:100, which can be refined repeatedly. Thereby further reducing the mass ratio of the II compound to the formula I compound.

[0077] The assay method of formula II compound and formula I compound is as follows:

[0078] Amylose-tris(3,5-xylylcarbamate) was used as filler, n-hexane-isopropanol-abso...

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Abstract

The invention discloses a solid preparation containing an insoluble thienopyridine composition and a preparation method thereof. The preparation is low in impurity content and can be rapidly dissolvedout. According to the solid preparation containing the insoluble thienopyridine composition, the composition comprises a compound with a structure shown in a formula I and a compound with a structureshown in a formula II, wherein the mass ratio of the compound shown in the formula II to the compound shown in the formula I is smaller than or equal to 1: 100.

Description

technical field [0001] The invention belongs to the technical field of pharmaceutical preparations, and in particular relates to a solid preparation containing an insoluble thienopyridine composition and a preparation method. Background technique [0002] The compound whose structure is shown in formula I, its chemical name is: (S)-2-(2-chlorophenyl)-2-((S)-2-oxo-2,6,7,7a-tetrahydro Thieno[3,2-c]pyridin-5(4H)yl)methyl acetate. [0003] [0004] The compound of formula I is the metabolite of clopidogrel in human body. Clopidogrel is the first-line drug for the prevention and treatment of heart, brain and other arterial circulation disorders caused by high platelet aggregation. However, there are significant individual differences in the efficacy of clopidogrel, especially in Asians, that is, clopidogrel resistance (CPGR). Recent studies have shown that the cause of CPGR is due to the differences in the activity of CYP enzymes in the liver of individuals. The specific ma...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/4365A61P7/02A61P9/10
CPCA61K31/4365A61P7/02A61P9/10Y02A50/30
Inventor 岑国栋杨茂廷谭少军谢龙
Owner CHENGDU SHIBEIKANG BIOLOGICAL MEDICINE TECH CO LTD
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