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Dihydropyridine calcium antagonist salt composition as well as preparation method and application thereof

A technology of calcium antagonist and dihydropyridine, which is applied in the field of levamlodipine composition and its preparation, and dihydropyridine calcium antagonist drug, which can solve the problems of low melting temperature, poor solubility, and easy bonding, etc. Achieve the effects of high process temperature, high dissolution rate and good thermal stability

Inactive Publication Date: 2021-07-30
NEOFORM BIOPHARMACEUTICAL LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Levoamlodipine commercially available products are commonly used as benzenesulfonate; levamlodipine besylate 2.5 hydrate is unstable to humidity, light and heat, has a low melting temperature, and is easy to lose crystallization during the preparation process (such as granulation and drying) Water, prone to sticking during processing, and has poor solubility in the intestinal environment (Pharmaceutical Development and Technology, 2014, 19(8):930-941)

Method used

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  • Dihydropyridine calcium antagonist salt composition as well as preparation method and application thereof
  • Dihydropyridine calcium antagonist salt composition as well as preparation method and application thereof
  • Dihydropyridine calcium antagonist salt composition as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0036] Levoamlodipine: HPMCP salt composition preparation:

[0037] Under magnetic stirring, add 0.4g levamlodipine and 1.6g HPMCP into ethanol / dichloromethane 25mL (1:1 volume ratio) mixed solvent, make it dissolve to form a solution, basic levamlodipine and acidic polymer Ionic bonds are formed between HPMCPs. Then use the miniature spray drier B290 of inert cycle B295 ( Labortechnik AG, Switzerland) spray drying, a high-performance cyclone separator was used for separation, and a 50 mL blue cap flask could be directly mounted to the cyclone separator for product collection. The parameter settings of the spray drying process are shown in Table 1.

[0038] Table 1

[0039] parameter Settings Suction 40kg / h Inlet temperature 80℃ output temperature 60℃ Injection rate 5mL / min Atomizing airflow 0.5kg / h Inert loop cooling temperature -20℃

[0040] The levamlodipine that contains 20% levamlodipine (mass ratio) obtained aft...

Embodiment 2

[0042] Levoamlodipine: HPMCAS salt composition preparation:

[0043] Under magnetic stirring, add 0.4g levamlodipine and 1.6g HPMCAS into ethanol / dichloromethane 25mL (1:1 volume ratio) mixed solvent, make it dissolve to form a solution, basic levamlodipine and acidic polymer Ionic bonds are formed between HPMCAS. Then use the miniature spray drier B290 of inert cycle B295 ( Labortechnik AG, Switzerland) spray drying, a high-performance cyclone separator was used for separation, and a 50 mL blue cap flask could be directly mounted to the cyclone separator for product collection. The parameter settings of the spray drying process are shown in Table 2.

[0044] Table 2

[0045] parameter Settings Suction 40kg / h Inlet temperature 70℃ output temperature 54℃ Injection rate 5mL / min Atomizing airflow 0.5kg / h Inert loop cooling temperature -20℃

[0046]The levamlodipine containing 20% ​​levamlodipine (mass ratio) obtained aft...

Embodiment 3

[0047] Embodiment 3: preparation of levamlodipine besylate

[0048] Take 1.3g of levoamlodipine, add 10mL of methanol to dissolve completely, add 1.5mL of 40% mass fraction of benzenesulfonic acid aqueous solution and stir for 5min, add 50mL of water and continue stirring for 20min to form a large amount of precipitate, filter, wash with 30mL of water, and then transfer to vacuum drying Vacuum drying in oven at 40°C for 16h. The obtained solid powder is levamlodipine besylate 2.5 hydrate. Detecting the PXRD pattern is consistent with CN11689894A, such as image 3 .

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Abstract

The invention discloses a dihydropyridine calcium antagonist salt composition as well as a preparation method and an application thereof. The pharmaceutical composition comprises a salt formed by levamlodipine and an acidic polymer. The dihydropyridine calcium antagonist salt composition is in a stable amorphous state, and the amorphous state is kept for at least three months under accelerated stability conditions (40 DEG C, 75% relative humidity). The dihydropyridine calcium antagonist salt composition has higher instantaneous solubility and dissolution rate than a control substance in the pH environment of saliva, stomach funguses and intestinal tracts. The dihydropyridine calcium antagonist salt composition has better thermal stability, and can bear higher process temperature in a preparation process according to the glass transition temperature of the dihydropyridine calcium antagonist salt composition.

Description

Technical field: [0001] The invention belongs to the technical field of medicines, and in particular relates to a dihydropyridine calcium antagonist drug-levoamlodipine composition and its preparation method and application. Background technique: [0002] Levoamlodipine, the chemical name is (4S)-2-[(2-aminoethoxy)methyl]-4-(2-chlorophenyl)-1,4-dihydro-6-methyl-3 , 5-pyridinedicarboxylic acid-3-ethyl-5-methyl ester, which has the following molecular formula: [0003] [0004] Levoamlodipine is a long-acting dihydropyridine calcium antagonist used in the treatment of hypertension and coronary artery disease. Amlodipine has two isomers, left-handed and right-handed, and the calcium ion antagonistic activity of the left-handed isomer is 1000 times that of the right-handed isomer and twice that of the racemic form. Levoamlodipine commercially available products are commonly used as benzenesulfonate; levamlodipine besylate 2.5 hydrate is unstable to humidity, light and heat,...

Claims

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Application Information

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IPC IPC(8): A61K31/4422A61K31/717A61P9/12A61P9/10
CPCA61K31/4422A61K31/717A61P9/10A61P9/12A61K2300/00
Inventor 田芳高明
Owner NEOFORM BIOPHARMACEUTICAL LTD
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