RU2410097C2 - Modified release dosage form of trimethazidin and method for preparing thereof (versions) - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: modified release pharmaceutical composition of antianginal actions characterised by the fact that it contains a therapeutically effective amount of trimethazidin, polymers and pharmaceutical aids, differing by the fact that polymers are Methocel K 100 MCR, Methocel K 15 MCR and microcrystalline cellulose in the following ratio, wt %: trimethazidin - 15.9; Methocel K 100 MCR - 15.0; Methocel K 15 MCR - 15.0; microcrystalline cellulose - 53.1; aerosyl - 0.5; stearate - 0.5.

EFFECT: simplified process of preparing modified drugs.

3 cl, 2 ex

Description

The invention relates to the pharmaceutical industry, in particular to the production of drugs that have an antianginal effect, and can be used in modern therapy for the prophylactic treatment of angina pectoris, chorioretinal disorders and for the treatment of vertigo of vascular origin (Meniere's disease, sensation of noise in one or both ears )

Trimetazidine dihydrochloride has antianginal, antioxidant, antihypoxic, membrane stabilizing, cytoprotective and metabolic pharmacological effects (Russian Drug Register. M., “RLS-2006”, issue 14, 2006, p.816), directly affects cardiomyocytes and neurons of the head brain, optimizing their metabolism and function.

A number of solid compositions of trimetazidine hydrochloride are known from the prior art, providing both accelerated (SU 1318161, publ. 06/15/1987, RU 2260431, publ. 09/20/2005), and prolonged release of the active principle (EP 1195160, publ. 10.04.2002, WO 03043610, published May 30, 2003, UA 12297, published January 15, 2006, EP 0673649, published September 27, 1995, EP 1108424, published June 20, 2001, WO 02051417, published July 4, 2002, RU 2281772, published August 20, 2008 .2006).

The development of new prolonged forms of trimetazidine (preferably Trimetazidine dihydrochloride) is particularly relevant.

In the application for European patent EP 1108424 (published on 06/20/01, priority dated 12/17/1999) the drug Servier Trimetazidine dihydrochloride prolonged action is disclosed (commercially available under the trade name Preductal MB). This drug has the following composition:

Trimetazidine Dihydrochloride 15-30% Calcium Phosphate Dihydrate 25-75% Polyvidone 3-12% Hydroxypropyl methylcellulose 25-50% Magnesium stearate 0.1-0.5% Silica 0.2%

The finished dosage form is coated in accordance with conventional coating methods.

EP 1108424 also discloses a method for producing a prolonged composition of trimetazidine dihydrochloride, comprising the steps of:

a) mixing in the required quantities of trimetazidine, polyvidone and calcium phosphate dihydrate, moistening the mixture with water, granulating and drying;

b) mixing the granulate obtained in stage (a) with hydropropyl methylcellulose;

c) mixing the mixture obtained in stage (b) with magnesium stearate and colloidal silicon dioxide;

d) compressing the mixture obtained in step (c) on a rotary tabletting machine to obtain sustained release trimetazidine dihydrochloride tablets;

d) if necessary, coating the tablet with a shell.

In the application for Eurasian patent EA 200701503 from 08.13.2007 (Canonfarm Production CJSC), (commercially available under the trade name Deprenorm MB), “Solid oral dosage form of trimetazidine dihydrochloride with prolonged release, its preparation and method of treatment” is disclosed.

Patented matrix for the manufacture of tableted lek. sustained release forms of trimetazidine containing a combination of several cellulose derivatives selected from hydroxypropyl methylcellulose and hydroxypropyl cellulose, in combination with copovidone, in a quantitative ratio (wt.%): 20.0-24.0% hydroxypropyl methyl cellulose; 2.0-3.0% hydroxypropyl cellulose, 1-2.9 copovidone. As copovidone, Plasdon S-630 is preferably used.

Most preferred, but not limiting the scope of the invention is the following ratio of components, wt.%:

Core:

Trimetazidine 15-25% Hydroxypropyl cellulose 2-3% MCC 25-30% Copovidone 1.3-8.0% Calcium Phosphate Dihydrate 15-20% Stearic acid salt 0.5-0.8% GPMC 20.0-24.7% Silicon dioxide 2-2.5%

Shell:

Selecout 3.0-3.5%

Manufacturing method: mixing a mixture of powders consisting of trimetazidine, lactose, HPMC, calcium phosphate dihydrate, silicon dioxide, MCC and copovidone; moistening this mixture with 5.5% solution of HPC and wet granulation. Drying of wet granules, dry granulation, dusting with a mixture of a salt of stearic acid and talc, tabletting and applying a film-forming suspension in a fluidized bed, cooling and holding until completely dry.

The disadvantages of these inventions are quite complex compositions and methods for producing and, especially, the high temperatures to which mixtures of ingredients are subjected to obtain these compositions.

Thus, the dosage forms of sustained release trimetazidine dihydrochloride known from the literature are characterized by complex, multi-stage methods for their preparation.

A number of dosage forms of trimetazidine or its pharmaceutically acceptable sustained release salts disclosed in known sources (UA 12297, WO 02051717) contain acrylic acid polymers, the use of which in pharmaceutical compositions is undesirable due to their potential ability to provoke the development of allergic reactions.

Closest to the claimed composition and method is a pharmaceutical composition with a sustained release of the active substance, which is used as a therapeutically effective amount of glycazide containing targeted additives according to patent No. 2273482 dated 2006.04.10 (Akrikhin OJSC) "Pharmaceutical composition with a sustained release of glycazide" .

As the target additives, hydroxypropylmethyl cellulose (HPMC), microcrystalline cellulose (MCC), aerosil and stearic acid salt are used in the following ratio of components, parts by weight per 1 part by weight active substance:

GPMC 2,50-3,50 MCC 2.12-3.00 Aerosil 0.01-0.05 Stearic acid salt 0.02-0.15

The HPMC and MCC tablets included in the composition create a hydrophilic matrix that provides a modified, controlled release of glycazide and its prolonged action.

As a salt of stearic acid, it contains magnesium and / or calcium salts.

The new pharmaceutical composition is in the form of a solid dosage form, preferably in the form of a tablet.

Manufacturing method: mix gliclazide, Aerosil, MCC and HPMC thoroughly, then add calcium stearate, mix thoroughly again and tablet.

The prototype developed a composition and method for producing a prolonged form of gliclazide.

SUMMARY OF THE INVENTION

The aim of the present invention is the creation of new matrix bases for the manufacture of tablet dosage forms of trimetazidine, providing a modified release of the active principle in a simpler way with less time and labor.

The goal is achieved by using trimetazidine as the active substance and by developing the optimal composition and method for preparing the dosage form.

The technical result of the proposed invention is expressed in the composition and method of obtaining a dosage form of trimetazidine with modified release by using Methocel K 100 MCR, Methocel K 15 MCR, MCC, aerosil and stearic acid salts at a certain quantitative ratio, namely: 15.9% trimetazidine; 15.0 wt.% Methocel K 100 MCR; 15.0 wt.% Methocel K 15 MCR; 53.1 wt.% MCC; 0.5 wt.% Aerosil and 0.5 wt.% Salt of stearic acid.

Composition per 1 tablet, mg:

Trimetazidine 35 Methocel K 100 MCR 33 Methocel K 15 MCR 33 MCC 116.8 Aerosil 1,1 Stearic acid salt 1,1 Total: 220.0

The proposed ratio of active substance and target additives is found experimentally and is optimal, providing a prolonged preparation of trimetazidine compliance with all the requirements of the Gosfarmakopei XI ed. and high bioavailability. The prolonged release of trimetazidine from the dosage form is confirmed by the quality indicator of the Dissolution tablets. The amount of trimetazidine transferred to the dissolution medium after 2 hours is from 25 to 45%, after 4 hours - from 45 to 63%, and after 8 hours - not less than 80%.

The Methocel K 100 MCR, Methocel K 15 MCR, and MCC tablets included in the composition create a hydrophilic matrix that provides a modified, controlled release of trimetazidine and its prolonged action.

As a salt of stearic acid, it contains magnesium and / or calcium salts.

The new pharmaceutical composition is in the form of a solid dosage form, preferably in the form of a tablet.

Also, in accordance with the present invention, methods for manufacturing a modified release trimetazidine tablet dosage form are provided, comprising the following steps:

Option 1:

a) in the container, trimetazidine is thoroughly mixed manually with Methocel K 100 MCR and Methocel K 15 MCR for 30 minutes;

b) in another container, the MCC is thoroughly mixed with Aerosil and passed through a sieve ⌀ 0.125 mm;

c) two mixtures are mixed in another container for 15-20 minutes and only then magnesium stearate is added and mixed for 15-20 minutes;

g) the finished mixture is passed through a sieve ⌀ 0.5 mm;

d) tableting is carried out on a tablet machine with a weight of 1 tablet 220 mg, a diameter of a tablet core 8 mm, tablet strength 7-9 kgf / cm ² ;

f) white Opadry II coating.

Option 2:

a) in one container, 50% of the total amount of trimetazidine with Methocel K 100 MCR is thoroughly mixed for 10 minutes, in the other the rest of trimetazidine with Methocel K 15 MCR for 10 minutes; then both mixtures are combined and stirred for 10-15 minutes.

The remaining stages are similar to option 1.

Claims (3)

1. A pharmaceutical composition of antianginal action with a modified release of trimetazidine, characterized in that it is made in the form of a tablet containing a core coated with a white Opadry II membrane, the core containing a therapeutically effective amount of trimetazidine, polymers and excipients, characterized in that in the quality of the polymers used Methocel K 100 MCR, Methocel K 15 MCR and MCC in the following ratio of components, wt.%:
trimetazidine 15.9 Methocel K 100 MCR 15.0 Methocel K 15 MCR 15.0 MCC 53.1 aerosil 0.5 stearic acid salt 0.5 2. A method of obtaining a pharmaceutical composition of antianginal action according to claim 1, characterized in that it includes the following stages:
mixing trimetazidine with Methocel K 100 MCR and Methocel K 15 MCR for 30 min;
mixing MCC with aerosil and granulation through a sieve ⌀ 0.125 mm;
mixing the two mixtures in another container for 15-20 minutes and dusting with magnesium stearate;
the finished mixture is passed through a sieve ⌀ 0.5 mm;
tableting is carried out on a tablet machine with a weight of 1 tablet 220 mg, a diameter of a core tablet of 8 mm, tablet strength 7-9 kgf / cm ² ;
white Opadry II coating. 3. A method of obtaining a pharmaceutical composition of antianginal action according to claim 1, characterized in that it includes the following stages:
in one container, 50% of the total amount of trimetazidine with Methocel K 100 MCR is thoroughly mixed for 10 minutes, in the other, the rest of trimetazidine with Methocel K 15 MCR for 10 min; then both mixtures are combined and stirred for 10-15 minutes;
MCC is mixed with Aerosil and granulated through a sieve ⌀ 0.125 mm;
mix the two mixtures in another container for 15-20 minutes and dust with magnesium stearate;
the finished mixture is passed through a sieve ⌀ 0.5 mm;
tableting is carried out on a tablet machine with a weight of 1 tablet 220 mg, a diameter of a core tablet of 8 mm, tablet strength 7-9 kgf / cm ² ;
white Opadry II coating.