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Levosimendan sodium pharmaceutical composition for acute decompensated heart failure symptoms and preparation method

A composition and compound technology, applied in drug combination, drug delivery, pharmaceutical formulation, etc., can solve the problems of tumor formation, tumor-like reaction, insoluble particles and particles increase, etc.

Active Publication Date: 2021-09-17
CHENGDU XINJIE HIGH TECH DEV CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Therefore, in the specific implementation examples of patents CN108261398A and CN1082898832A, in order to achieve the stability of levosimendan inclusion compound, after reconstitution into a solution, levosimendan is prevented from being separated out, which will lead to an increase in insoluble particles and particles, which will affect the efficacy of clinical medication. Safety, the amount of sulfobutyl ether beta cyclodextrin is very large, although sulfobutyl ether beta cyclodextrin has excellent characteristics such as low hemolysis and low nephrotoxicity, but excessive dosage may affect renal metabolism pose a certain security risk
Patents CN108261398A and CN1082898832A adopt the cyclodextrin inclusion process, such as sulfobutyl ether beta-cyclodextrin sodium, hydroxypropyl beta-cyclodextrin, etc., in order to maintain the stability of the drug, not only the dosage is particularly large, but also such excipients are high Molecular compounds, if the particles themselves are not strictly controlled, will seriously affect the production and clinical administration of drugs, and levosimendan is packaged with sulfobutyl ether beta cyclodextrin or hydroxypropyl beta cyclodextrin At the right time, if the inclusion process parameters and its ratio are unreasonable, or even the levosimendan inclusion compound is unstable, after clinical administration and redissolution, the precipitation of levosimendan will lead to an increase in particulate matter and affect clinical administration.
Particulate matter presents many safety hazards in clinical practice, such as causing drug allergic reactions, phlebitis, granuloma, local tissue embolism and necrosis, tumor formation and tumor-like reactions, etc. These major clinical adverse reactions lead to environmental Dextrin inclusion process is not the best solution

Method used

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  • Levosimendan sodium pharmaceutical composition for acute decompensated heart failure symptoms and preparation method
  • Levosimendan sodium pharmaceutical composition for acute decompensated heart failure symptoms and preparation method
  • Levosimendan sodium pharmaceutical composition for acute decompensated heart failure symptoms and preparation method

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0076] The preparation of embodiment 1 levosimendan sodium

[0077] Add 2.9g of sodium hydroxide and 120ml of purified water into a 250ml flask, stir to dissolve. Add 20 g of levosimendan and stir to dissolve levosimendan. Stir and crystallize at 5-10°C for 2 hours. Filter and wash the filter cake with 30ml ethanol. Dry under reduced pressure at 60°C to obtain 17.8 g of thermally stable form A levosimendan sodium, with a weight yield of 89.0%.

[0078] The 2θ angles of diffraction peaks of the thermally stable crystalline form of levosimendan sodium: 12.1°±0.2°, 15.1°±0.2°, 18.3°±0.2°, 19.4°±0.2°, 22.9°±0.2°, 24.3° ±0.2°, 27.4°±0.2°, 29.4°±0.2°, 32.3°±0.2°, 33.9°±0.2°.

Embodiment 2

[0081] (1) Take 270mg of levosimendan sodium and dissolve it in water for injection with stirring, then add 2.0g of mannitol and stir to dissolve, then add water for injection, adjust the pH to pH 7.8-8.2 with sodium hydroxide or hydrochloric acid to form solution A;

[0082] (2) Use a 0.22 μm polyethersulfone material filter membrane to filter solution A to sterilize, divide into bottles (bottles are vials, each vial contains 5ml of solution A), and use conventional freeze-drying production process to dry after bottling to control the moisture content in the bottle. 2% or less;

[0083] (3) Each vial is filled with nitrogen and sealed with a gland to obtain a sterile freeze-dried powder.

[0084] In this embodiment, the total amount of water for injection is 100ml.

[0085] The sterile freeze-dried powder of this example was tested for appearance, reconstitution time, solution particles, pH value and OR-1420 impurities, and the results are shown in Table 1 below.

Embodiment 3

[0087] (1) Stir and dissolve 270mg of levosimendan sodium in water for injection, then add 3.0g of lactose and 100mg of anhydrous sodium acetate, stir and dissolve, add injection water, adjust the pH to pH 7.8-8.2 with acetic acid, and form solution B;

[0088] (2) Use a 0.22 μm polyethersulfone material filter membrane to filter solution B to sterilize, divide into bottles (bottles are vials, each vial contains 5ml of solution B), and use conventional freeze-drying production process to dry after bottling to control the moisture content in the bottle. 2% or less;

[0089] (3) Each vial is filled with nitrogen and sealed with a gland to obtain a sterile freeze-dried powder.

[0090] In this embodiment, the total amount of water for injection is 100ml.

[0091] The sterile freeze-dried powder of this example was tested for appearance, reconstitution time, solution particles, pH value and OR-1420 impurities, and the results are shown in Table 1 below.

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Abstract

The invention discloses a pharmaceutical composition of levosimendan sodium for acute decompensated heart failure symptoms and a preparation method. The preparation of the invention can be an injection or a dry powder, and the dry powder is reconstituted to form an original solution. Mainly used for administration by injection route, the pharmaceutical composition of the present invention comprises: levosimendan sodium as an active ingredient, and excipients. The invention solves the problems of insolubility of levosimendan free base in water and instability of impurities degraded by hydrolysis during marketing and storage, so that levosimendan sodium can be prepared into a stable injection with water as a solvent.

Description

technical field [0001] The invention belongs to the field of pharmaceutical preparations, and in particular relates to a levosimendan sodium pharmaceutical composition and a preparation method. Background technique [0002] Levosimendan is the first listed variety among the new generation of cardiotonic drugs-calcium sensitizers, and it is mainly used clinically to treat various acute heart failure diseases. The drug was developed by the Finnish company Orion and was first listed in Sweden in October 2000. At present, Zuosimendan has been listed and used in dozens of countries including Europe and the United States. [0003] Levosimendan is insoluble in water, but soluble in ethanol, and the stability of levosimendan compound is poor, especially in long-term storage (more than 24 hours), the moisture in ethanol easily causes the hydrolysis of levosimendan side chain to form The hydrolyzed products OR-1855, OR-1896, OR-1420 and OR-1746, therefore, must be prepared into comm...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): A61K31/50A61K9/19A61K9/08A61K47/40A61K47/02A61P9/04
CPCA61K9/0019A61K9/08A61K9/19A61K31/50A61K47/02A61K47/40A61P9/04
Inventor 黄汉伟刘晓琳蒲洪朱鹏王旭
Owner CHENGDU XINJIE HIGH TECH DEV CO LTD
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