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Novel galneical form for oral administration with prolonged release of molsidomine

A technology of mesketamine and preparations, applied in the field of novel mesketamine oral sustained-release preparations, can solve the problems of reducing the maximum plasma concentration, delaying the range of the therapeutic dose, etc., and achieving the effect of high plasma concentration

Inactive Publication Date: 2008-06-25
THERABEL PHARMA LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0014] However, prolonged efficacy is known in the pharmaceutical art to significantly reduce maximum plasma concentrations and delay reaching the therapeutic range

Method used

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  • Novel galneical form for oral administration with prolonged release of molsidomine
  • Novel galneical form for oral administration with prolonged release of molsidomine
  • Novel galneical form for oral administration with prolonged release of molsidomine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0058] Preparation of multi-layered tablets of the invention with a dose of 16 mg

[0059] The present invention includes the preparation of tablets with one active layer sandwiched between two inactive layers, the dimensions of which are as follows:

[0060] - Diameter: 8.0mm

[0061] - Thickness of inserted active layer: about 2.1mm

[0062] - Thickness of each inactive layer: about 1.55 and 1.95mm

[0063] Each of these layers was made from substantially the same materials in Table I, the amounts in the table being for one sheet.

[0064] Table I

[0065]

[0066] The preparation method of the active layer is as follows:

[0067] Mosketamine, polymeric materials (METHOCEL K100M), lipophilic substances (COMPRITOL 888 ATO), hydrophilic filler (MANNITOL 60) and granulating agent (PLASDONE K29-32) mixed well in a suitable mixer.

[0068] Another 95% ethanol solution is prepared for wetting the powdery mixture obtained above.

[0069] The resulting homogeneo...

Embodiment 2

[0072] Determination of the in vitro dissolution curve of the preparation of the present invention

[0073] The preparation of the present invention as prepared in Example 1 in vitro The dissolution rate was determined by the method described in the European Pharmacopoeia, Third Edition (or USP XXIV).

[0074] The test conditions are as follows:

[0075] .Sotax AT7 mixer with paddle

[0076] .Rotation speed: 50rpm

[0077] .Dissolving medium temperature: 37℃

[0078] .Filter: Whatman GF-D filter

[0079] . Inspection: UV spectrophotometry at 286 or 311 nm

[0080] .Spectrometer: Hitachi U-3000 with 1cm quartz cell

[0081] .Dissolution medium: 500ml 0.1N HCl

[0082] Got the following result:

[0083] 18% of mesketamine released after 1 hour

[0084] 27% of mesketamine released after 2 hours

[0085] 57% of mesketamine released after 6 hours

[0086] 88% of mesketamine released after 12 hours

[0087] 96% of mesketamine released after 18 hours

[0088] 100% Mosk...

Embodiment 3

[0090] A comparative study on the main pharmacokinetic properties of mesketamine formulations

[0091] In order to demonstrate the advantages and value of the formulation of the present invention over the prior art mesketamine formulations, the main pharmacokinetic properties of the following three formulations were determined:

[0092] . A 4mg formulation of mesketamine equivalent to the trade name CORVATON now sold in Belgium 4mg of product

[0093] .The 8 mg formulation of mesketamine, now sold in Belgium under the trade name CORVATARD The product

[0094] . The dose of the present invention is 16 mg of the morphostonamine formulation (prepared from Example 1).

[0095] The following different parameters in the above formulations were determined using techniques known in the art:

[0096] -Cmax: maximum plasma concentration

[0097] -Tmax: time at which maximum plasma concentration is observed

[0098] -AUC 0-t: area under the curve from time 0 to time t

[0099]...

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Abstract

The present invention relates to a novel galenical form for oral administration with prolonged release of molsidomine for treating angina attack in its various forms (exertion angina, spastic angina, mixed angina). The present invention is characterised in that said novel galenical form contains a therapeutically efficient amount of molsidomine or one of its active metabolites and it has a dissolution rate in vitro (measured by spectrophotometry at 286 or 311 nm according to the European Pharmacopeia, 3rd edition (or U.S.P XXIV) at 50 rpm in 500 ml of a HCl 0.1N medium, at 37 DEG C) of: 15 to 25 % of molsidomine released after 1 hour, 20 to 35 % of molsidomine released after 2 hours, 50 to 65 % of molsidomine released after 6 hours, 75 to 95 % of molsidomine released after 12 hours, > 85 % of molsidomine released after 18 hours, > 90 % of molsidomine released after 24 hours, the plasma peak of molsidomine obtained in vivo occurring between 2.5 to 5 hours, preferably between 3 to 4 hours, depending on the administration of said form and exhibiting a value between 25 and 40 ng / ml of plasma. The invention has therapeutic uses.

Description

technical field [0001] The present invention relates to a novel oral sustained-release preparation of mesketamine, which is used for treating various types of angina pectoris (exertion type or supine position type, unstable type). Background technique [0002] It is known that morphostonamine (also known as N-(ethoxycarbonyl)-3-(4-morpholinyl) steketimines) is the first representative of the new antianginal drug family steketimines. Medicine, special medicine patent No.6734 has described it. [0003] The compound is used in particular for the prevention and treatment of various types of angina pectoris due to its vasodilation of vascular smooth muscle fibers and inhibition of early platelet activation. [0004] This activity of the compound derives from its ability to directly release nitroso groups during biotransformation. [0005] More precisely, mesketamine is a prodrug. [0006] After oral administration, mesketamine is completely absorbed and undergoes an enzymatic ...

Claims

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Application Information

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IPC IPC(8): A61K31/535A61K9/20A61K9/16A61K9/22A61K9/24A61K9/26A61K31/5377A61K47/38A61P9/10
CPCA61K9/2086A61P11/06A61P9/00A61P9/10A61K9/00
Inventor 约瑟夫-米歇尔·盖齐
Owner THERABEL PHARMA LTD