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Controlled release peroral compositions of levosimendan

A technology of levosimendan and composition, applied in the field of oral composition, capable of solving problems such as adverse side effects and increased heart rate

Inactive Publication Date: 2001-06-27
ORION CORPORATION
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Adverse side effects such as severe headache, palpitations, and increased heart rate are often observed when levosimendan is administered in long-acting formulations commonly used in the art to obtain therapeutic effects over a prolonged period of time

Method used

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  • Controlled release peroral compositions of levosimendan
  • Controlled release peroral compositions of levosimendan
  • Controlled release peroral compositions of levosimendan

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 3

[0029] Example 3 describes a method for determining the in vitro dissolution profile of compositions of the invention.

[0030] Compositions of the invention may be in the form of, for example, tablets, capsules, granules or powders.

[0031] A particularly preferred embodiment of the present invention is obtained by combining an immediate release portion comprising levosimendan and optionally excipients with a controlled release portion comprising levosimendan and a pharmaceutically controlled release component. Drug release control components can be selected as described above, but it is preferred to use hydrophilic gel-forming polymers. A controlled release portion comprising (a) an immediate release portion in powder form comprising levosimendan and at least one excipient, and (b) granular form comprising levosimendan and a controlled release hydrophilic gel-forming polymer Partial compositions are preferred. The immediate release portion in powder form and the controlle...

Embodiment 1

[0042] Example 1. Formulation Examples Formulation 1. Particles: Levosimendan 1.0mg

[0043] Alginic acid 18.0mg

[0044] Methocel K100LV 37.0mg

[0045] Stearic acid 0.6mg Powder part: Levosimendan 1.0mg

[0046] Avicel PH101 84.0mg

[0047] Stearic acid 1.5mg preparation 2. Particles: Levosimendan 1.0mg

[0048] Alginic acid 23.0mg

[0049] Methocel K100LV 46.0mg

[0050] Stearic acid - powder part: levosimendan 1.0mg

[0051] Avicel PH101 69.5mg

[0052] Stearic acid 1.5mg preparation 3. Particles: Levosimendan 1.0mg

[0053] Alginic acid 28.0mg

[0054] Methocel K100LV 56.0mg

[0055] Stearic acid 0.9mg Powder part: Levosimendan 1.0mg

[0056] Avicel PH101 56.0mg

[0057] Stearic acid 1.5mg preparation 4. Particles: Levosimendan 1.0mg

[0058] Alginic acid 33.0mg

[0059] Methocel K100LV 66.0mg

[0060] Stearic acid 0.6mg Powder part: Levosimendan 1.0mg

[0061] Avicel PH101 43.0mg

[0062] Stearic acid 1.5mg

[0063] In the above examples, the granula...

Embodiment 2

[0065] Example 2. Determination of active metabolites (II) in human plasma by liquid chromatography-tandem mass spectrometry

[0066] Preparation of Calibration Samples

[0067]The active metabolite (II) in 20 µl of phosphate buffer pH 7.2 was added to 0.5 ml of analyte-free plasma. Analytes were added in amounts of 0.100, 0.250, 0.500, 1.00, 2.50, 3.75, 5.00, 7.50 and 12.5 ng. After vortexing for 20 seconds, let stand for 10 minutes, add 2500pg internal standard (R)-N-[4-(1,4,5,6-tetrahydro- 4-Ethyl-6-oxo-3-pyridazinyl)phenyl]acetamide. The mixture was vortexed for 1 minute and allowed to stand for 15 minutes. The calibration sample was basified with 50 μl of 0.1 M NaOH and vortexed for 20 seconds. The calibration sample was extracted with 5 ml ethyl acetate:hexane (8:2) by vortexing for 3 minutes. After centrifugation for 7 minutes, the organic layer was separated and concentrated with a Turbo Vap evaporator at 40°C. When the calibration sample was dry, 200 μl of ethyl...

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Abstract

The invention relates to peroral pharmaceutical compositions which release levosimendan in a controlled fashion with reduced occurrence of undesired effects. Levosimendan, or (-)-[[4-(1,4,5,6-tetrahydro-4-methyl-6-oxo-3-pyridazinyl)phenyl]-hydrazono]propanedinitrile, is useful in the treatment of congestive heart failure.

Description

technical field [0001] The present invention relates to oral compositions that release levosimendan in a controlled manner with reduced side effects. Levosimendan, or (-)-[[4-(1,4,5,6-tetrahydro-4-methyl-6-oxo-3-pyridazinyl)phenyl]hydrazino]propane Dinitriles are used in the treatment of congestive heart failure. Background technique [0002] Levosimendan-[[4-(1,4,5,6-tetrahydro-4-methyl-6-oxo-3-pyridazinyl)phenyl]hydrazino]propanediene is described in EP565546B1 (-) Enantiomer of Nitrile and Process for its Preparation. Levosimendan is effective in the treatment of heart failure and has significant calcium-dependent binding to troponin. Levosimendan is represented by Formula I: [0003] The hemodynamic effects of levosimendan are described by Sundberg, S. et al. in Am. J. Cardiol., 1995;75:1061-1066. Sandell, E.-P et al. describe the intravenous administration of levosimendan and oral Pharmacokinetics in humans. The use of levosimendan in the ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K9/00A61K9/20A61K9/22A61K31/50A61K47/38A61P9/10
CPCA61K31/50A61K9/205A61K9/2054A61P9/00A61P9/04A61P9/10
Inventor I·拉尔玛M·哈朱拉S·安迪拉L·莱图南
Owner ORION CORPORATION
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