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Pharmaceutical composition containing dabigatran etexilate and preparation method thereof

A technology of dabigatran etexilate and dabigatran etexilate mesylate, which is applied in the field of pharmaceutical compositions containing dabigatran etexilate and its preparation, and can solve the problems of side effects and low therapeutic index

Pending Publication Date: 2019-10-22
SHANGHAI WD PHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Due to the low therapeutic index of DEM, the C max More likely to cause harmful side effects such as heavy bleeding

Method used

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  • Pharmaceutical composition containing dabigatran etexilate and preparation method thereof
  • Pharmaceutical composition containing dabigatran etexilate and preparation method thereof
  • Pharmaceutical composition containing dabigatran etexilate and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0093] The screening experiment carried out in Example 1 aims at finding a polymer capable of inhibiting the precipitation of DEM at neutral pH, and the following polymers are intended to be used in the screening experiment.

[0094] Eudragit L100Klucel EF Kollicoat IR Kollidon VA64KolliphorP188Kolliphor P407HPMC E5HPMC VLV HPMCP HP55HPMCAS MG PVP K12PVP K30Soluplus

[0095] Screening experiments include the following steps:

[0096] 1. Prepare DEM stock solution at 50 mg / mL drug concentration in 0.1 N HCl.

[0097] 2. Put 40 mg of the above polymer into a 5 mL vial, add 3.6 mL of sodium phosphate buffer solution with pH 6.8 to dissolve the polymer, and obtain a polymer solution.

[0098] 3. Add 0.4 mL of the stock solution from step 1 to the polymer solution from step 2, while adding 0.4 mL of the stock solution to pH 6.8 phosphate buffer without polymer as a control.

[0099] 4. Shake the vial at 250 rpm under ambient room temperature conditions.

[0100] 5. Take 0.4 mL a...

Embodiment 2

[0109] Embodiment 2 is a micro-dissolution experiment, the purpose is to evaluate the dissolution behavior of DEM solid dispersion film (SDF), the following table is the composition of the SDF to be evaluated in this micro-dissolution experiment, and each percentage refers to the mass percentage.

[0110]

[0111] In this example, DEM SDF containing 3mg of DEM was prepared in a 20mL glass bottle by solvent evaporation method, and then the dissolution medium was added to carry out the dissolution test at 37°C. The specific experimental steps are as follows:

[0112] 1. Prepare a DEM stock solution with a drug concentration of 100 mg / mL in an ethanol solution with a volume fraction of 95%.

[0113] 2. Prepare a polymer stock solution at a polymer concentration of 100 mg / mL in 95% ethanol by volume.

[0114] 3. According to the volume shown in the table below, add the stock solution in step 1 and step 2 into a 20mL vial and mix thoroughly to obtain a mixed solution;

[0115] ...

Embodiment 3

[0130] Example 3 is a micro-dissolution experiment, the purpose of which is to evaluate the dissolution behavior of DEM solid dispersion film (SDF) in pH4.5 sodium acetate buffer and pH6.8 sodium phosphate buffer, and the specific experimental steps are the same as in Example 2. The specific experimental steps are as follows:

[0131] 1. Prepare DEM stock solution at 100 mg / mL drug concentration in 95% ethanol solution.

[0132]2. Prepare a polymer stock solution at a polymer concentration of 100 mg / mL in 95% ethanol solution.

[0133] 3. According to the volume shown in the table below, add the stock solution in step 1 and step 2 into a 20mL vial and mix thoroughly to obtain a mixed solution;

[0134] Among them, DEM F is that the solution in step 1 is added to the ethanol solution with a volume fraction of 95% and fully mixed to obtain a mixed solution; DEM P does not do any treatment in this step; the numbered DEM F and DEM P are controls Group.

[0135]

[0136] 4. A...

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Abstract

The invention discloses a pharmaceutical composition containing dabigatran etexilate and a preparation method thereof. The pharmaceutical composition comprises a pharmaceutical active component and anamphoteric polymer, wherein the pharmaceutical active component is dabigatran etexilate and / or dabigatran etexilate mesylate; the amphoteric polymer is a polyethylene caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer; the pharmaceutical composition is prepared by hot melt granulation. The pharmaceutical composition not only can improve the bioavailability of the pharmaceutical active component, but also can reduce the absorption variability, and provides a more stable concentration of dabigatran in plasma, thereby alleviating the adverse side effects and reducing the possibility of GIT bleeding. In addition, due to absorption enhancement, unabsorbed DEM in gastrointestinal tracts is significantly reduced, and thus the massive bleeding of GIT can be further alleviated.

Description

technical field [0001] The invention relates to a pharmaceutical composition containing dabigatran etexilate and a preparation method thereof. Background technique [0002] The chemical name of dabigatran etexilate mesylate (DEM) is β-alanine, N-[[2-[[[4-[[(hexyloxy)carbonyl]amino]iminomethyl]benzene Base]amino]methyl]-1-methyl-1H-benzimidazol-5-yl]carbonyl]-N-2-pyridyl-ethyl ester methanesulfonate, the empirical formula is C 34 h 41 N 7 o 5 ·CH 4 o 3 S, molecular weight is 723.86, CAS# is 872728-81-9. The structural formula of DEM is: [0003] [0004] DEM is the active pharmaceutical ingredient (API) of commercial Pradaxa capsules. DEM, a prodrug of dabigatran, is a direct inhibitor of thrombin. Pradaxa capsules are marketed by Boehringer Ingelheim to reduce the risk of stroke and blood clots in patients with atrial fibrillation not caused by heart valve problems, and are also used to treat deep vein thrombosis and pulmonary embolism. [0005] DEM is a white t...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/4439A61K47/34A61P7/02
CPCA61K31/4439A61K47/34Y02A50/30
Inventor 董良昶张世忠焦艳张丹勇赵文芳石劲敏
Owner SHANGHAI WD PHARM CO LTD
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