RU2281772C1 - Medicinal formulation possessing anti-anginal effect and method for its preparing - Google Patents

Abstract

FIELD: medicine, pharmacy.

SUBSTANCE: invention relates to a medicinal formulation consisting of a core comprising the following components, wt.-%: trimetazidine dihydrochloride, 9.0-32.0; hydroxypropylcellulose, 3.0-10.5; hydroxyethylcellulose, 18.5-67.2; sodium alginate, 0.1-0.6; calcium phosphate dihydrate, 19.0-28.5; magnesium stearate, 0.5-2.0; talc, 0.5-2.0, and envelope comprising the following components, wt.-%: one component chosen from the group including hydroxypropylcellulose, water-soluble methylcellulose or hydroxypropylcellulose, 0.6-2.7; Tween-80, 0.3-1.2; pigment titanium dioxide, 0.1-1.0 and red iron oxide, 0.1-0.8. Method for preparing the medicinal formulation is carried out by wet granulation, tabletting prepared granules and applying the envelope from an aqueous suspension by spraying preferably. Release of trimetazidine dihydrochloride in the body from the new proposed formulation is carried out for 8 h that provides the constant level of the preparation in blood.

EFFECT: improved preparing method, valuable pharmaceutical properties of formulation.

3 cl, 2 tbl, 1 ex

Description

The invention relates to medicine, in particular to pharmacy, can be used in the production of solid dosage forms of drugs that have an antianginal effect, and can be used to treat coronary heart disease, prevent angina attacks, treat cochleovestibular disorders of an ischemic nature, such as dizziness, noise in the ears, hearing impairment. A known dosage form having antianginal action, which is a tablet consisting of a core and a shell and containing piperazine derivative as an active substance of the core, as well as excipients: starch, lactose, calcium stearate.

A method of obtaining this form involves mixing the active active principle with auxiliary means, subsequent moistening of the resulting mixture and granulation of the resulting moistened mixture. Then the granulate is dried, dusted with calcium stearate and tabletted (US patent No. 4370329, publ. 01.25.1983).

The disadvantages of the described dosage form, as well as the method of its manufacture, are that the described preparation has a short action and requires administration three times a day to achieve a satisfactory therapeutic effect.

The objective of the invention is the creation of domestic affordable drug with high bioavailability, prolonged duration and containing less technologically complex components.

The problem is solved in that in a dosage form having an antianginal effect, consisting of a core and a shell, the core contains trimetazidine dihydrochloride as an active substance and calcium phosphate dihydrate, magnesium stearic acid and additionally hydroxypropyl cellulose, hydroxyethyl cellulose, sodium alginate and and the shell contains titanium dioxide pigment, iron oxide red and additionally contains tween-80 and one component selected from the group including hydroxypropyl methyl cellulose, water-soluble methyl cellulose or hydroxypropyl cellulose, with the following content

Trimetazidine Dihydrochloride 9.0-32.0 Hydroxypropyl cellulose 3.0-10.5 Hydroxyethyl cellulose 18.5-67.2 Sodium Alginate 0.1-0.6 Calcium Phosphate Dihydrate 19.0-28.5 Magnesium stearic acid 0.5-2.0 Talc 0.5-2.0 Hydroxypropyl methylcellulose, or water soluble methyl cellulose, or hydroxypropyl cellulose 0.6-2.7 Twin 80 0.3-1.2 Titanium dioxide pigment 0.1-1.0 Iron oxide red 0.1-0.8

The problem is also solved by the method of manufacturing this dosage form, in accordance with which trimetazidine dihydrochloride and hydroxypropyl cellulose are mixed, this mixture is moistened with an aqueous solution of sodium alginate, mixed, wet granulation is carried out, followed by drying, dry granulation, dusting with a mixture of hydroxyethyl cellulose, calcium phosphate dihydrate, magnesium dihydrate and talc, followed by tabletting and coating from an aqueous suspension containing tween-80, titanium dioxide and iron oxide red and one component from the group comprising hydroxypropyl methyl cellulose, methyl cellulose, water-soluble and hydroxypropyl cellulose, hydroxypropyl methyl cellulose.

The invention consists in the following.

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, as shown, determines the myocardial protection from ischemia. Switching fatty acid oxidation to glucose oxidation underlies the antianginal action of trimetazidine.

The composition of the auxiliary components of the nucleus, which are used as calcium phosphate dihydrate, magnesium stearic acid, hydroxypropyl cellulose, hydroxyethyl cellulose, sodium alginate and talc in the stated proportions, is selected in such a way as to provide a gradual release of trimetazidine in the body, causing its prolonged action, and also provide high mechanical tablet strength with a small pressing force in the manufacturing process of the dosage form and the stability of the active substance storage.

The use of such materials in the aggregate as titanium dioxide pigment, iron oxide red, tween-80, and one component selected from the group including hydroxypropyl methylcellulose, water-soluble methyl cellulose or hydroxypropyl cellulose in the stated ratio allows to obtain a strong protective shell that is resistant to external influences, protecting tablets over their shelf life with a slight increase in tablet weight.

The invention is as follows.

Pre-sieved sodium alginate is dissolved in purified water, heated to a temperature of 45-50 ° C.

Then sifted trimetazidine dihydrochloride, hydroxypropyl cellulose are mixed and 7% sodium alginate solution is added, mixed again. The wet mass is granulated and dried at a temperature of 60-70 ° C to a residual moisture content of 2.0-3.0%.

The dried granules are cooled to room temperature and dry granulation is carried out. Dry granulate is dusted by the addition of sieved hydroxyethyl cellulose, disubstituted calcium, magnesium stearic acid and talc. The mixture is stirred until a homogeneous tablet mass is formed.

Then the mass is tableted.

For coating the tablet cores, an aqueous suspension containing tween-80, titanium dioxide pigment, iron oxide red and hydroxypropyl methylcellulose, or water-soluble methyl cellulose, or hydroxypropyl cellulose are used.

The coating is stopped when the required tablet weight is reached. The weight of the tablet in the shell is 0.205 g, diameter (8.0 ± 0.03) mm.

Example.

To obtain a 7% solution of sodium alginate, pre-sieved sodium alginate (0.22 kg) was thoroughly mixed with purified water (2.9 kg), heated to a temperature of 45-50 ° C.

Then the sieved trimetazidine dihydrochloride (15 kg), hydroxypropyl cellulose (5.15 kg) are mixed and 3.1 kg of a 7% sodium alginate solution are added, mixed again. The wet mass is granulated and dried at a temperature of 60-70 ° C to a residual moisture content of 2.0 -3.0%.

The dried granules are cooled to room temperature and dry granulation is carried out. Dry granulate is dusted by the addition of sieved hydroxyethyl cellulose (41.2 kg), disubstituted calcium (21.1 kg), stearic acid magnesium (0.845 kg) and talc (1.27 kg). The mixture is stirred until a homogeneous tablet mass is formed.

Then the mass in the amount of 84 kg tableted.

For coating the tablet core, an aqueous suspension containing tween-80 (0.628 kg), titanium dioxide pigment (0.347 kg), red iron oxide (0.135 kg) and hydroxypropyl cellulose (1.304 kg) per 17.0 l of water are used. The number of components taken taking into account 15%

The coating by spraying the resulting suspension is stopped when the required tablet weight is reached. Received round tablets biconvex form of a reddish-brown color. The weight of the tablet in the shell is 0.205 g, diameter (8.0 ± 0.03 mm) in an amount of 82.4 kg.

Table 1 shows the composition obtained in accordance with this example, the dosage form, as well as other compounds included in the claimed invention.

Table 1. Components Composition 1 Composition 2 Composition 3 g wt.% g wt.% g wt.% Core Trimetazidine dihydrochloride 0.035 08/17 0.018 8.78 0,065 31.7 Hydroxypropyl cellulose 0.012 5.85 0.006 2.93 0,021 10.24 Hydroxyethyl cellulose 0.975 47.56 0.1342 65.47 0.0468 22.83 Sodium Alginate Medical 0.0005 0.24 0,0002 0.1 0.0012 0.59 Calcium Phosphate Dihydrate 0.05 24.39 0,039 19.0 0.058 28.3 Magnesium stearic acid 0.002 0.98 0.001 0.5 0.004 1.95 Talc Medical 0.003 1.46 0.0016 0.8 0.004 1.95 Core mass 0.200 97.56 0.2 97.56 0.2 97.56 Shell Hydroxypropyl methylcellulose 0.0027 1.32 - - - - Water Soluble Methyl Cellulose - - 0.0013 0.63 - - Hydroxypropyl cellulose - - - - 0.0035 1.7 Twin 80 0.0013 0.63 0.0024 1.17 0,0006 0.3 Titanium dioxide pigment 0.00072 0.35 0,0009 0.47 0,0002 0.1 Red iron oxide 0.00028 0.14 0,0004 0.2 0,0007 0.34 Shell mass 0.005 2.44 0.005 2.44 0.005 2.44 Tablet weight 0.205 one hundred 0.205 one hundred 0.205 one hundred

The form obtained in accordance with the above examples meets all the necessary quality indicators included in the normative documentation. Table 2 shows the percentage of dissolution of the tablets according to the proposed invention for the compositions shown in table 1.

Table 2. Dissolution% After 1 hour In 2 hours After 8 hours Composition 1 35.7 58.5 95.4 Composition 2 34.9 56.3 94.1 Composition 3 36.0 59.8 95.9 Normative from 25 to 45 from 43 to 63 not less than 80

From table 2 it is seen that the proposed ratio of the components allows to obtain tablets with improved modified release of the active substance, as a result of which a constant level of the drug in the blood is achieved. An increase in solubility, and hence the bioavailability of the drug, has been achieved.

Claims (3)

1. A dosage form having an antianginal effect, consisting of a core containing trimetazidine dihydrochloride as an active substance and calcium phosphate dihydrate, magnesium stearic acid, hydroxypropyl cellulose, hydroxyethyl cellulose, sodium alginate and talc, and a coating containing tween on the core -80, one component selected from the group consisting of hydroxypropyl methyl cellulose, water-soluble methyl cellulose and hydroxypropyl cellulose, as well as titanium dioxide pigment Lesa oxide red, in the following ratio, wt.%: Trimetazidine Dihydrochloride 9.0-32.0 Hydroxypropyl cellulose 3.0-10.5 Hydroxyethyl cellulose 18.5-67.2 Sodium Alginate 0.1-0.6 Calcium Phosphate Dihydrate 19.0-28.5 Magnesium stearic acid 0.5-2.0 Talc 0.5-2.0 Hydroxypropyl methylcellulose, or water soluble methyl cellulose, or hydroxypropyl cellulose 0.6-2.7 Twin 80 0.3-1.2 Titanium dioxide pigment 0.1-1.0 Iron oxide red 0.1-0.8 2. A method of manufacturing a dosage form having the antianginal action described in claim 1, which consists in mixing the active substance trimetazidine dihydrochloride and hydroxypropyl cellulose, moisten the mixture with an aqueous solution of sodium alginate, granulate it, dry the granulate, dry granulate, granulate dusted with a mixture of hydroxyethyl cellulose, calcium phosphate dihydrate, magnesium stearic acid and talc and tableted, after which a coating is applied from an aqueous suspension containing tv n-80, titanium dioxide pigment, iron oxide red and one component from the group consisting of hydroxypropylmethylcellulose, methylcellulose and water-soluble hydroxypropyl cellulose. 3. The method according to claim 2, characterized in that the coating of the aqueous suspension is carried out by spraying it.