RU2445958C2 - Matrix tablet with trimetazidine prolonged-release base and method for preparing it - Google Patents

Abstract

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to medicine, particularly to pharmaceutical industry. A matrix tablet with a trimetazidine prolonged-release base contains a core comprising 8-12% trimetazidine or its pharmaceutically acceptable salt as an active ingredient and excipients being hypromellose, microcrystalline cellulose, magnesium stearate, colloidal silicon dioxide with a dissolving coating. A trimetazidine tablet is prepared by direct compression technique with film coating.

EFFECT: according to the invention, the matrix tablet formulation enables improved homogeneity and dose accuracy, provides sustained release of trimetazidine for a long period of time and maintains the required blood plasma trimetazidine concentration.

5 cl, 6 tbl

Description

The invention relates to medicine, in particular to the pharmaceutical industry, and can be used in the manufacture of solid dosage forms of drugs for the sustained release of trimetazidine or its pharmaceutically acceptable salt, used as a cytoprotector, antihypoxant and antioxidant.

The prior art dosage form of prolonged action (RU 2362548, publ. 07/27/2009, A61K 9/22, A61K 31/495, A61P 9/10), which is a tablet consisting of a core and a shell and containing as the active substance of the core of trimetazidine or its pharmaceutically acceptable salts, as well as excipients:

hydroxypropyl cellulose, microcrystalline cellulose, capovidone, calcium phosphate dihydrate, stearic acid salt, colloidal silicon dioxide. The drug is coated in accordance with generally accepted coating methods.

Also known are matrix tablets with prolonged release of trimetazidine or its pharmaceutically acceptable salt (EA 8223, publ. 04/27/2007, A61K 9/22, A61K 31/495, A61K 47/38, A61P 9/10), selected as the closest analogue of the claimed invention, consisting of a core and shell covering it and having 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%

silicon dioxide 0.2%

Matrix tablets prepared in accordance with the indicated composition are coated according to generally accepted methods.

The use of trimetazidine as an active substance normalizes the energy metabolism of cells subjected to hypoxia or ischemia, and prevents a decrease in the intracellular content of ATP. Thus, the drug ensures the normal functioning of membrane ion channels, transmembrane transfer of potassium and sodium ions and preservation of cellular homeostasis.

Trimetazidine slows down the oxidation of fatty acids due to the selective inhibition of long-chain 3-ketoacetyl-CoA thiolase, which leads to an increase in glucose oxidation and to restoration of conjugation between glycolysis and oxidative decarboxylation and determines the protection of the myocardium from ischemia. Switching fatty acid oxidation to glucose oxidation underlies the antianginal action of trimetazidine.

Therefore, it is relevant to create a drug with prolonged and uniform release of the active substance.

In the above dosage forms, the content of trimetazidine or its pharmaceutically acceptable salt is from 15% and above. When studying the compositions of matrix tablets of trimetazidine or its pharmaceutically acceptable salt of prolonged action on dosage uniformity, it was unexpectedly found that with a decrease in the content by weight of trimetazidine or its pharmaceutically acceptable salt, less than 15% per tablet, the dosage uniformity is significantly improved.

The technical task of the invention is the creation of new matrix bases for the manufacture of tablet dosage forms of trimetazidine or its pharmaceutically acceptable salt, providing a modified release of the active substance from tablets with high uniformity of substance content.

The technical result of the use of the invention is to improve the indicators of uniformity and accuracy of dosage, and therefore, this will allow to maintain the necessary concentration of trimetazidine in blood plasma stably and at the same level over a long period of time. The specified technical result is achieved due to the fact that the matrix tablet with the basis for the sustained release of trimetazidine consists of a core containing trimethadisidine or its pharmaceutically acceptable salts and excipients, as well as a dissolving shell, with the core containing 8-12% trimetazidine or its pharmaceutically acceptable salt, and as auxiliary substances, hypromellose is used as a matrix-forming component of the core, as a core filler - miculose a crystalline or other filler that facilitates the production of a core by direct compression, as an antifriction substance — magnesium stearate, and as a substance that promotes fluidity — colloidal silicon dioxide. Most preferred is the following content of components, wt.%:

Table 1 Components % Core: Trimetazidine Dihydrochloride 8-12 Hypromellose 20.0-50.0 Microcrystalline cellulose 33.38-68.18 Magnesium stearate 0.5-1.0 Silicon Colloidal Dioxide 0.2-0.5 Total core: 96.88 Shell: Hypromellose 1.25-2.50 Macrogol 4000 (PEG) 0.16-0.63 Titanium dioxide 0.63-0.94 Total tablet: 100.0

To confirm the technical result in accordance with the requirements of the Global Fund XI, studies were conducted on the quantitative content and uniformity of dosage. Tests were carried out for tablets without a shell with a content of 0.05 g or less of a drug substance and for coated tablets with a content of a drug substance of 0.01 g or less. From the series to be tested, a sample of tablets in the amount of 30 pieces was taken. In each of 10 tablets, the drug content was determined. The content of the drug substance in one tablet can deviate by no more than +/- 15% from the average content and in no tablet should exceed +/- 25%. If out of 10 tested tablets, 2 tablets have deviations of the drug content by more than +/- 15% from the average, the drug content in each of the remaining 20 tablets is determined. The deviation in the content of the drug substance in none of the 20 tablets should exceed more than +/- 15% of the average.

The results of the study of the deviation of the content of trimetazidine dihydrochloride are shown in table 2. Based on the data on the study of the quantitative content and uniformity of dosage of the active substance, we can conclude that the result could not be predicted on the basis of the existing level of technology.

table 2 Tablets containing trimetazidine 15-30 wt.% Tablets containing trimetazidine 8-12 wt.% Recipes Options one 2 3 Deviation of the drug content in each tablet from the average content,% +8.7; -4.2; -5.2; -3.8; -1.5; +0.4; -0.8; +2.1; +1.7; +1.4; -2.2; -1.6; +2.8; +2.1; +9.4; -7.6; -1.8; +3.1; -0.9; +1.1; -2.5; -1.7; +1.8; -1.0; +1.4; +3.2; +6.0; -4.7 -2.4; -1.9; +0.7; -3.1; -0.3; -2.0; -2.5; -0.2; +1.3; +1.8 +2.9 -1.5 Average value, % -0.11 -0.11 +0.03 -0.03 Dispersion 34.65 2.93 4.37 3.87 Standard deviation, % 5.89 1.71 2.09 1.97

Table 3 shows the results of a study of the solubility of the drug, confirming the prolonged release of trimetazidine and the stability of the indicator over the shelf life.

Table 3 A study of the stability of a drug containing trimetazidine, prolonged action. Shelf life Dissolution After 1 h, from 25 to 45%. After 2 hours - from 43 to 63%. After 5 hours - at least 70%. 41.2% 01/13/10 52.8% 0 days 78.8% 29.7% 02/05/10 55.2% 23 days 78.6% 35.2% 02/28/10 50.8% 46 days 85.2% 30.8% 03/23/10 54.5% 69 days 98.7% 39.2% 04/15/10 52.8% 92 days 92.4% 28.7% 05/08/10 53.7% 115 days 76.9% 38.4% 05/31/10 61.0% 138 days 75.9%

Table 4 shows the results of a study of individual values of the concentration of trimetazidine (ng / ml) in the blood plasma of the subjects after the use of the drug. The study was conducted on the basis of the State Health Institution Clinical Hospital No. 23 named after Medsantrud (Moscow). A total of 18 volunteers were included in the study. The concentration of trimetazidine was determined by high performance liquid chromatography with mass spectrometric detection. The substance used is trimetazidine dihydrochloride. The analysis was performed on an Agilent 1100 liquid chromatograph (USA) with a mass spectrometric detector (electrospray). Quantitative determination was carried out by the absolute calibration method using Agilent software.

Table 4 The values of the maximum concentrations (C _max ) of trimetazidine in the blood and the time to reach them (T _max ) No. C _max , ng / ml T _max , h p / p one 54.10 3.00 2 71.14 5.00 3 68.09 3.00 four 57.70 3.00 5 61.88 5.00 6 99.02 3.00 7 61.70 3.00 8 52.51 5.00 9 87.66 3.00 10 65.82 3.00 eleven 102.67 5.00 12 67.65 8.00 13 55.39 3.00 fourteen 91.96 5.00 fifteen 50.17 5.00 16 70,42 3.00 17 34.87 3.00 eighteen 75.76 3.00 Mean ± 68.25 3.94 Geometrical mean values 66.05 3.76 Standard deviation 17.82 1.39 The coefficient of variation 25.37 34.30 Standard error 4.20 0.33 Interval values 59.64 ÷
76.86 3.27 ÷
4.62

Table 5 shows the maximum concentrations (C _max ) of trimetazidine in the blood and the time to reach them (T _max ).

Table 5 Individual values of the concentration of trimetazidine (ng / ml) in the blood plasma of the subjects after the use of the drug No. Time after drug administration, h p / p 0.00 1.00 2.00 3.00 4.00 5.00 6.00 8.00 10.00 12.00 24.00 one 0.00 29.69 52.01 54.10 51.00 47.91 44.19 35.47 19.85 12.07 2.11 2 0.00 22,99 48.78 58.90 65.02 71.14 47.18 23,23 23.44 15.04 3.26 3 0.00 25.78 55.72 68.09 54.77 41.44 40.50 39.56 36.18 21.56 3.41 four 0.00 23.09 48.27 57.70 53.00 48.30 35.13 21.97 18.67 11.38 2.01 5 0.00 14.81 38.66 52.40 57.14 61.88 46.09 30.31 17.69 10.99 2.11 6 0.00 38.63 82.00 99.02 79.48 59.94 55.02 50.09 41.10 24.57 3.95 7 0.00 23.44 50.56 61.70 58.64 55.58 48.75 41.92 26.48 16.18 2.89 8 0.00 23.63 42.64 45.54 49.03 52.51 39.06 25.61 18.52 12.47 3.15 9 0.00 40.54 77.92 87.66 70.90 54.15 45.04 35.93 21.64 13.65 2.79 10 0.00 33,50 61.08 65.82 65.25 64.69 59.60 44.51 25.37 14.60 1.88 eleven 0.00 28.43 58.77 69.72 86.19 102.67 73.91 45.15 31,43 19.09 3.32 12 0.00 11.48 30.45 41.58 52,57 63.56 65.61 67.65 54.51 32.69 5.34 13 0.00 20.63 45.04 55.39 47.85 40.31 31.46 22.61 16.75 11.33 2.90 fourteen 0.00 23.14 57.78 76.65 84.31 91.96 70.02 48.07 25.09 14.38 1.80 fifteen 0.00 26.35 46.82 49.33 49.75 50.17 44.47 38.77 23.55 13.85 2.03 16 0.00 25.27 56.46 70,42 50.80 31.18 30.53 29.87 22.35 13.46 2.25 17 0.00 15.88 30.79 34.87 31.03 27,20 23.11 19.03 12.27 8.61 2.44 eighteen 0.00 27.16 60.72 75.76 72.23 68.70 56.80 44.90 28.28 17.03 2.84 Averages 0.00 25.25 52,47 62.48 59.94 57.41 47.58 36.93 25.73 15.72 2.80 Standard deviation 0.00 7.45 13.55 16.13 14.34 18.92 13.86 12,43 10.04 5.77 0.88 The coefficient of variation - 28.68 25.09 25.09 23.25 32.03 28.31 32.71 37.93 35.64 30.56 Standard error - 1.76 3.19 3.80 3.38 4.46 3.27 2.93 2,37 1.36 0.21 Interval values 21.65 ÷ 45.92 ÷ 54.69 ÷ 53.01 ÷ 48.26 ÷ 40.88 ÷ 30.92 ÷ 20.88 ÷ 12.93 ÷ 2.38 ÷ - 28.85 59.02 70.27 66.87 66.55 54.28 42.93 30.59 18.51 3.23

Table 6 shows the formulation options of the claimed composition.

Table 6 Components Recipes one 2 3 mg % mg % mg % Core Trimetazidine Dihydrochloride 35.0 8.0 35.0 10.0 35.0 12.0 Hypromellose 90.0 20.6 120.0 34.3 140.0 47.94 Microcrystalline cellulose 295.85 67.6 180.3 51.5 103.5 35.45 Magnesium stearate 2.1 0.48 2.6 0.74 2.9 0.99 Silicon Colloidal Dioxide 0.9 0.21 1,2 0.34 1,5 0.51 Kernel mass: 423.85 96.88 339.1 96.88 282.9 96.88 Shell: Hypromellose 10.19 2,33 6.0 1.71 4,52 1.55 Macrogol 4000 (PEG) 0.70 0.16 1,5 0.43 1.84 0.63 Titanium dioxide 2.76 0.63 3.4 0.97 2.74 0.94 Tablet weight: 437.5 one hundred 350,0 one hundred 292.0 one hundred

The present invention also claims a method of manufacturing a matrix tablet.

In the above prototype, a tablet preparation method is used in which wet granulation is carried out by mixing trimetazidine, polyvidone and a diluent and moisturizing the mixture. Then, the obtained granulate is mixed with hydroxypropyl methylcellulose, a sizing agent and a flow promoting agent are added, and then the resulting mixture is pressed and dried.

When implementing this method, the starting materials used for the manufacture of tablets are exposed to increased humidity and temperature, which may affect the chemical properties of the components, which is undesirable in the manufacture of medicines.

The technical task of the proposed method for the manufacture of matrix tablets is to provide optimal conditions for maintaining the chemical properties of the starting materials used for the manufacture of tablets.

The technical result of the application of the proposed method is the ability to avoid exposure to the mixture of increased humidity and temperature and ensuring high performance by simplifying the manufacturing process.

The specified technical result is achieved due to the fact that the method of manufacturing a matrix tablet with a base of the above substances contains the following steps: mix trimetazidine hydrochloride and colloidal silicon dioxide in a paddle mixer and calibrate. Next, the resulting mixture is mixed with hypromellose and microcrystalline cellulose and powdered with magnesium stearate. The powdered mixture is pressed, followed by film coating of the tablet cores from an aqueous suspension containing hypromellose, macrogol, titanium dioxide.

A method of manufacturing a matrix tablet with a basis for the sustained release of trimetazidine or its pharmaceutically acceptable salt is as follows.

The mixture of powders consisting of trimetazidine hydrochloride or its pharmaceutically acceptable salt and colloidal silicon dioxide is stirred for 30-60 seconds in a paddle mixer at a blade rotation speed of 600 rpm. The resulting mixture was calibrated on a vertical granulator through a mesh with a hole size of 0.45 mm. The calibrated concentrate is mixed for 10 minutes at a speed of 10-15 rpm in a drum type mixer with microcrystalline cellulose and hypromellose. Then the mixture was dusted with magnesium stearate by stirring in the same mixer for 5 minutes.

The powdered mixture is tableted on a rotary press with a cylindrical biconvex press tool installed with a diameter of 10.0 mm.

Using a reactor and a colloid mill from hypromellose, macrogol, titanium dioxide and purified water, a suspension solution is prepared for applying a film coating. The resulting solution is sprayed through the nozzles onto the tablet cores moving in the perforated drum while drying with heated air until the required tablet weight is reached.

The invention, thus, provides the optimal quantitative and qualitative composition of the components for the manufacture of matrix tablets with a basis for the sustained release of trimetazidine or its pharmaceutically acceptable salt, providing high precision dosing and gradual release of the active substance over a long period of time and with sufficient mechanical strength of the tablet.

Claims (5)

1. A matrix tablet with a base for sustained release of trimetazidine, consisting of a core containing trimethadisidine or its pharmaceutically acceptable salts and excipients as an active ingredient, as well as a dissolving shell, characterized in that the core contains 8-12% trimetazidine or its pharmaceutically acceptable salts in the following components, wt.%:
Trimetazidine Dihydrochloride 8-12 Hypromellose 20.0-50.0 Microcrystalline cellulose 33.38-68.18 Magnesium stearate 0.5-1.0 Silicon Colloidal Dioxide 0.2-0.5 2. The matrix tablet according to claim 1, characterized in that the shell contains 1.25-2.50% hypromellose. 3. The matrix tablet according to claim 1, characterized in that the shell contains 0.16-0.63% Macrogol 4000 (PEG). 4. The matrix tablet according to claim 1, characterized in that the shell contains 0.63-0.94% titanium dioxide. 5. A matrix tablet according to any one of claims 1 to 4, characterized in that in the manufacture of a matrix tablet with the basis for the sustained release of trimetazidine, trimetazidine dihydrochloride and colloidal silicon dioxide are mixed and calibrated, then the resulting mixture is mixed with micromellose and microcrystalline cellulose and dusted with magnesium stearate then the powdered mixture is pressed followed by film coating of the tablet cores from an aqueous suspension containing hypromellose, macrogol, titanium dioxide.