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Spherical particles of clopidogrel bisulfate, pharmaceutical composition including same, and method for manufacturing same

A technology of clopidogrel bisulfate and spherical particles, which is applied in the field of clopidogrel bisulfate spherical particles and its manufacture, to achieve the effects of improving compressibility, reducing weight deviation, and improving physical and chemical stability

Inactive Publication Date: 2014-04-09
SAMJIN PHARMA +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

But so far, there is no information about the particle shape, size and manufacturing method of this clopidogrel

Method used

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  • Spherical particles of clopidogrel bisulfate, pharmaceutical composition including same, and method for manufacturing same
  • Spherical particles of clopidogrel bisulfate, pharmaceutical composition including same, and method for manufacturing same
  • Spherical particles of clopidogrel bisulfate, pharmaceutical composition including same, and method for manufacturing same

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0064] Example 1: Production of Clopidogrel Bisulfate Spherical Particles (Crystal Form I)

[0065] Production of clopidogrel free base

[0066] After adding 554 g (1.0 mol) of clopidogrel (1R)-(-)-camphor-10-sulfonate to 300 mL of dichloromethane, 138.3 g of potassium carbonate was dissolved in 300 mL of water and added. After stirring the mixture for 30 minutes, the layers were separated, dehydrated by anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 318.6 g of oily clopidogrel free base (99% yield).

[0067] Production of Clopidogrel Bisulfate Spherical Particles (Form I)

[0068] Dissolve 200g of clopidogrel free base into 2000mL of 2-butanol, maintain the temperature at 26 to 28°C, and put the crystal form I as the seed crystal (relative to the amount of clopidogrel free base, 5-20%). Here, 62.3 g of 98% sulfuric acid was diluted with 400 mL of cyclohexane, the temperature was lowered by 0.5 to 2° C., and slowly added dropwise over 8 to ...

Embodiment 2 to 4

[0086] Examples 2 to 4: Manufacture of Tablets Utilizing Spherical Particles of Clopidogrel Bisulfate

[0087] Tablet 4 was used to produce tablets using the spherical particles of clopidogrel hydrogensulfate type I produced in Example 1.

[0088] In addition to the clopidogrel bisulfate described above, lactose hydrate was used as an excipient for direct compression D-Mannitol Silicified Microcrystalline Cellulose Use of low-displacement hydroxypropylmethylcellulase as a disintegrant Colloidal silica used as flow agent Sodium stearyl fumarate used as slip agent They were sieved with a No. 30 sieve and mixed, and the bare tablets were produced by a rotary tablet press by direct powder compression method. Opadry pink and ethanol are used as the coating material, mixed evenly with purified water, sprayed evenly on the surface of the bare chip, and dried to form a thin film coating.

[0089] Table 4

[0090]

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Abstract

The present invention relates to spherical particles of clopidogrel bisulfate having a 10% volume particle diameter (d0.1) of 30 [mu]m or more and a 50% volume particle diameter (d0.5) in the range of 50 to 200 [mu]m, and to a pharmaceutical composition including same. The spherical particles of the present invention not only significantly improve unfavorable properties in a conventional pharmaceutical preparation of clopidogrel bisulfate, i.e. defective compression and flow and a strong surface electrostatic force, but can also significantly reduce tableting impediments such as weight deviations and sticking during preparation by means of a direct powder compression technique, and the danger of crystalline conversion. Thus, the composition has improved physiochemical stability and, due to anti-clotting effects of the composition, can be effectively used as a therapeutic agent for arteriosclerosis, stroke, myocardial infarction, and atherosclerosis.

Description

technical field [0001] The present invention relates to spherical particles of clopidogrel bisulfate and a manufacturing method thereof, in particular to a 10% volume particle diameter (d0.1) above 30 μm and a 50% volume particle diameter (d0.5) within the range of 50 to 200 μm Spherical particles of clopidogrel bisulfate, a pharmaceutical composition containing the substance, a tablet using the same and a manufacturing method thereof. Background technique [0002] Clopidogrel (clopidogrel) is the chemical name methyl (+)-(S)-α-(o-chlorophenyl)-6,7-dihydrothiophenone[3,2-c]pyridine-5(4H )-acetate (methyl(+)-(S)-α-(o-chlorophenyl)-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-acetate) Thienopyridines ) class of typical antiplatelet coagulation drugs. Clopidogrel acts on the receptor of adenosine diphosphate (adenosine diphosphate) on platelets, reduces the activity of platelets, inhibits platelet aggregation, has antithrombotic effect, and is effective for arteriosclerosis, stroke...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K9/16A61K9/20C07D495/04A61K31/4365
CPCC07D495/04A61K9/14A61K31/4365A61K9/2018A61K9/2077A61K9/2054A61K9/20A61K9/146A61K9/2095Y10T428/2982A61P7/02A61P9/00A61P9/10A61K9/16
Inventor 曹义焕申熙钟李顺焕宋祐宪
Owner SAMJIN PHARMA
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