EA009810B1 - Matrix for manufacturing tableted dosage form and method of treatment - Google Patents

Abstract

The invention relates to a pharmaceutical technology, more specifically to a matrix for manufacturing tableted dosage form for prolonged release of trimethazine or a pharmaceutically acceptable salt thereof (preferably dihydrochloride trimethazine) exhibiting membranostabilizing, cytoprotective, antihypoxant and antioxidant activities, comprising hydroxypropylcellulose and hydroxypropylmethylcellulose as accessory components in definite qualitative ratios defined in the invention claims, the matrix is chracterized in that further comprises 1-2.9% of copovidone, to a method for manufacting thereof and to a method of treatment and prevention of states when administration of membranostabilizers, cytoprotectors, antihypoxants and antioxidants is required, comprising administering a matrix for prolonged release of trimethazine or a pharmaceutically acceptable salt thereof according to the invention. The proposed invention provides optimum quantitative and qualitative composition of components for manufacturing solid oral dosage forms of trimethazine or a pharmaceutically acceptable salt thereof of prolonged action with no allergenic and toxic effects, providing gradual and prolonged release of the active substance for a long span of time thus to stably maintain the effective concentration of trimethazine in the blood plasmaduring long period of time.

Description

The present invention relates to the pharmaceutical industry, in particular to a matrix for the manufacture of a tablet dosage form for the sustained release of trimetazidine or a pharmaceutically acceptable salt thereof, used as a cytoprotective agent, antihypoxant and antioxidant, as well as a method for producing such a tablet dosage form.

BACKGROUND OF THE INVENTION

Trimetazidine dihydrochloride (1 - [(2,3,4-trimethoxyphenyl) methyl] piperazine dihydrochloride) has antianginal, antioxidant, antihypoxic, membrane-stabilizing, cytoprotective and metabolic pharmacological effects (Russian Medicines Register. Encyclopedia of Medicines S.-M. ”, Issue 14, 2006, p. 816), directly affects cardiomyocytes and brain neurons, optimizing their metabolism and functions. Cytoprotection is due to the provision of the necessary energy potential, activation of oxidative decarboxylation and rationalization of oxygen consumption (increased aerobic glycolysis and blockade of fatty acid oxidation). Trimetazidine maintains myocardial contractility, prevents intracellular depletion of ATP and creatinine phosphate, in conditions of acidosis normalizes the functioning of the ion channels of the membranes, prevents the accumulation of calcium and sodium in cardiomyocytes, normalizes the intracellular potassium content, reduces intracellular acidosis and phosphate levels caused by ischemia of myocardium free radicals, preserves the integrity of cell membranes, prevents the activation of neutrophils in zones e ischemia, increases the duration of the electric potential, reduces the yield of creatine phosphokinase from the cells and the severity of ischemic damage to the myocardium.

Trimetazidine reduces the frequency of angina attacks (the patient reduces nitrate intake), after 2 weeks of treatment, exercise tolerance increases, blood pressure drops decrease. Improves hearing and results of vestibular tests in patients with pathology of ENT organs, reduces dizziness and tinnitus. With vascular pathology, the eye restores the functional activity of the retina.

Acting as an antihypoxant, trimetazidine dihydrochloride improves the body's utilization of oxygen and reduces the need for it (increases hypoxia resistance) of organs and tissues. Trimetazidine dihydrochloride as an antioxidant plays an important role in the fight against hypoxia. Activation of free radical processes and peroxidation, as shown at present, accompanies many diseases, including coronary heart disease, myocardial infarction and vascular diseases of the retina, and antioxidants are essential components of their complex therapy. Free radical processes are normalized by the reduction of free radicals into a stable molecular form (not capable of participating in the autooxidation chain). Antioxidants either directly bind free radicals (direct antioxidants) or stimulate the body's antioxidant system (indirect antioxidants).

With the oral administration of trimetazidine, the dihydrochloride is rapidly and almost completely absorbed from the gastrointestinal tract. Bioavailability of 90%. The time to reach maximum plasma concentration T _max 2 hours (maximum concentration C _max after a single oral administration of 20 mg of trimetazidine is 55 ng / ml). It easily passes through histohematological barriers. Plasma Protein Binding 16%. Distribution volume 4.8 l / kg. Almost half of the amount administered is biotransformed. The half-life of trimetazidine (T1 / 2) is approximately 5-6 hours. Trimetazidine is excreted from the body by the kidneys (51% unchanged).

The recommended dose of trimetazidine dihydrochloride is 40-60 mg / day.

Preparations containing trimetazidine and its pharmaceutically acceptable salts (preferably trimetazidine dihydrochloride) are used in medical practice for Meniere's disease, syndromes characterized by vascular disorders, dizziness and impaired stability, impaired vestibular function, tinnitus, noise effects of the inner ear, hearing loss; cochleo-vestibular disorders of ischemic nature (tinnitus, hearing impairment), with dizziness of central origin, benign paroxysmal dizziness, with coronary heart disease: prevention of angina attacks (as part of complex therapy), with pain in the heart, chorioretinal vascular disorders, degeneration of the choroid, occlusion of the vessels of the retina.

A number of solid oral compositions of trimetazidine dihydrochloride are known from the prior art, providing both accelerated (8I 1318161, publ. 06/15/1987, KP 2260431, publ. September 20, 2005), and prolonged release of the active principle (EP 1195160, publ. 10.04.2002; XVO 03043610, published on May 30, 2003, IA 12297, published on January 15, 2006, EP 0673649, published on September 27, 1995, EP 1108424, published on June 20, 2001, νθ 02051417, published on July 4, 2002, KP 2281772, published. 08/20/2006).

The development of new prolonged forms of trimetazidine and its pharmaceutically acceptable salts (preferably trimetazidine dihydrochloride) is especially relevant due to the fact that the half-life of trimetazidine from the body is only 6 hours, i.e. by the time of the next administration of the usual (fast-acting) drug, the level of trimetazidine in the blood falls below the effective

- 1 009810 values. This leads to a weakening of the anti-ischemic and antihypoxic protection of the myocardium, which can have fatal clinical consequences, especially in the early morning hours, when the risk of developing ischemia and ischemic myocardial infarction is highest.

At the same time, a number of dosage forms of trimetazidine or its pharmaceutically acceptable salts with prolonged release, disclosed in known sources (IL 12297, XVO 02051417), contain polymers of acrylic acid, the use of which in pharmaceutical compositions is undesirable, due to their potential ability to provoke the development of allergic reactions.

The prior art known composition is a prolonged action containing trimetazidine (or its pharmaceutically acceptable salts), as well as a polymer insoluble in water, and a plasticizer that allows you to control the release of the active substance (EP 0673649). It was shown that the use of a number of plasticizers in this technical solution, such as triacetin, triethyl citrate, acetyl triethyl citrate, leads to an undesirable appearance of a 4-hour latent period, during which the release of the active principle is practically absent, and at the end of which a very rapid release of the active principle occurs.

European patent application EP 1195160 discloses sustained release dosage forms containing 60 mg of trimetazidine dihydrochloride, as well as hydrocolloid formative material and / or hydrophobic polymers and other hydrophobic materials as a retardant (retarding agent), releasing trimetazidine in a prodrug dihydrochloride course 24 hours after oral administration. However, obtaining a prolonged dosage form of trimetazidine dihydrochloride in accordance with EP 1195160 is a complex multi-stage process that increases labor costs and cost of the drug.

Disclosed in the publication of international PCT application νθ 03043610, the pharmaceutical composition of the trimetazidine dihydrochloride with a sustained release of the active principle, providing the release of the active principle within 24 hours after administration, is a polymer-coated beads containing 60 mg / dose of trimetazidine or its salt. This also increases the complexity of manufacturing and the cost of production of the drug.

Currently, there is a prolonged preparation of trimetazidine dihydrochloride Preductal® MV of Servier company in the domestic market, which makes it necessary to expand the arsenal of drugs of long-acting trimetazidine to provide reliable anti-ischemic and antihypoxic protection of the myocardium, and to obtain prolonged preparations of trimetazidine with improved pharmacokinetic characteristics.

European patent application EP 1108424 (published on June 20, 2001, priority dated December 17, 1999, in accordance with application 9915960 filed in France) discloses a servier trimetazidine dihydrochloride preparation (commercially available under the trade name Preductal® MV). This drug, proposed as the closest analogue (prototype) of the claimed invention, 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 hydroxypropyl 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 having a hardness of 40 to 160 N, which is evaluated by breaking the tablets in diameter;

e) if necessary, coating the tablet with a shell in accordance with generally accepted methods.

SUMMARY OF THE INVENTION

The aim of the present invention is to provide new matrix bases for the manufacture of tablet dosage forms of trimetazidine or its pharmaceutically acceptable salt, providing

- 2 009810 modified modified release of the active principle over a longer period of time compared with the prototype.

The problem is achieved by using a combination of several derivatives of cellulose selected from hydroxypropyl methylcellulose and hydroxypropyl cellulose, in combination with copovidone, at a specific quantitative ratio, namely 20.0-24.7 wt.% Hydroxypropyl methylcellulose: 2.0-3.0 wt. % hydroxypropyl cellulose: 1.3-8.0 wt.% copovidone.

The invention provides an optimal quantitative and qualitative composition of the components for the manufacture of solid oral dosage forms of trimetazidine or its pharmaceutically acceptable salt with a modified release that do not have an allergenic and toxic effect and provide a gradual and prolonged release of the active principle over a long period of time, and allows you to stably maintain an effective concentration plasma trimethazidine over a long period in belt.

Brief Description of the Drawing

The drawing shows the comparative kinetics of dissolution ίη νίίτο of a modified-release trimetazidine dihydrochloride preparation made from the matrix claimed in accordance with the present invention and Preductal® MV from Servier (prototype of the invention).

DETAILED DESCRIPTION OF THE INVENTION

In accordance with the present invention, there is provided a matrix for the manufacture of a sustained release tablet form of trimetazidine or a pharmaceutically acceptable salt thereof, prepared by the method according to any one of claims 1 to 5, characterized in that it contains a combination of several cellulose derivatives selected from hydroxypropyl methylcellulose and hydroxypropyl cellulose, in combination with copovidone in their quantitative ratio (wt.%): 20.024.0% hydroxypropyl methylcellulose: 2.0-3.0% hydroxypropyl cellulose: 1-2.9% copovid she.

Copovidone is a copolymer of vinyl pyrrolidone and vinyl acetate, described in foreign Pharmacopoeias as Soroyltopyopp Ry Eig; ί’οροίννίάοη ILV; Soroyltyops 18ΡΙ, BP, forms a barrier layer on the surface and in the pores of the claimed matrix; after oral administration of a prolonged-release trimetazidine preparation made on the basis of the inventive matrix containing copovidone, this component dissolves more slowly than povidone, which is used to control the rate of release of trimetazidine or its pharmaceutically acceptable salt from the matrix.

As copovidone, Plasdon 8-630 is preferably used.

The components that are additionally part of the inventive matrix are polyethylene glycol, talc, titanium dioxide and a dye - iron oxide (111) red or ponce.

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

Nucleus: Trimetazidine Dihydrochloride 15-25% Hydroxypropyl cellulose 2-3% ι Microcrystalline cellulose 25-30% Copovidone 1.3-8.0% Calcium Phosphate Dihydrate 15-20% Stearic acid salt 0.5-0.8% Hydroxypropyl methylcellulose 20.0-24.7% Silicon Colloidal Dioxide 2-2.5% Shell: Selecout 3.0-3.5%

As the salt of stearic acid, the matrix preferably contains magnesium stearate.

Selecote is a commercially available mixture for the manufacture of coatings for solid oral dosage forms, consisting of hydroxypropyl methylcellulose, copolymers of vinylpyrrolidone and vinyl acetate, polyethylene glycol, titanium dioxide and iron oxide, with a mass ratio of components: 0.4: 0.07: 0.09: 0, 07: 0.06.

Also in accordance with the present invention, a method for the manufacture of a tablet dosage form of trimetazidine or its pharmaceutically acceptable salt of prolonged action, comprising the following stages:

a) stirring under pressure of 0.2-0.5 MPa of a powder mixture consisting of trimetazidine or its pharmaceutically acceptable salt, lactose, hydroxypropyl methylcellulose, calcium phosphate

- 3 009810 dihydrate, silicon dioxide, colloidal, microcrystalline cellulose and copovidone;

b) moistening this mixture with a pre-prepared 5.5% hydroxypropyl cellulose solution with stirring until the moisture is evenly distributed and at the same time wet granulating the mass and, if necessary, adding water;

c) drying wet granules in a fluidized bed at a temperature of 40-50 ° C to a residual moisture content of not more than 2.5% with a compressed air pressure of at least 0.4 MPa;

b) dry granulation;

f) dusting with a homogeneous mixture of stearic acid salt and talc;

ί) tableting to obtain cores,

e) their simultaneous dedusting,

11) applying in a fluidized bed a prepared film-forming suspension containing hydroxypropyl methylcellulose, copovidone, polyethylene glycol, titanium dioxide and iron oxide, on dust-free cores, to obtain a film membrane 90-100 microns thick;

ί) cooling and holding until completely dry, characterized in that the film-forming suspension is applied at a spray pressure of 0.2-0.25 MPa, a suspension feed rate of 200-600 g / min and a temperature in the layer of tablets of 3050 ° C.

The third object of the invention is a method of treating or preventing a condition of a mammal in which it is necessary to administer antioxidants, antihypoxants, cytoprotectors and membrane stabilizing agents, including administering a sustained release tablet form of trimetazidine or its pharmaceutically acceptable salt obtained by the inventive method, characterized in that the administration of the tablet dosage form trimetazidine or a pharmaceutically acceptable salt thereof They are twice daily, with a total daily dose of 70 mg / day of trimetazidine.

The applicant conducted comparative studies of the ίη νίΐΓΟ kinetics of dissolution of the claimed drug of sustained release trimetazidine dihydrochloride and the prior art prolonged preparation of trimetazidine dihydrochloride Preductal® MV (Servier). The results are presented in the table and in the drawing.

Table

The amount of released active principle,% hours Time, Deprenorm MV Preductal MV one 35 40.6 2 53 59.8 3 70 81.8 4 76 one hundred 5 not prov. n / a 6 not prov. n / a 7 n / a n / a 8 80 n / a nine n / a n / a 10 n / a n / a eleven n / a n / a 12 n / a n / a

Thus, unexpectedly, it was found that Servier's Preductal® MV preparation, despite the declared prolonged action, in the ίη νίίτο trials releases most of the active principle within a rather limited period of time (about 4 hours). Thus, there are reasonable doubts that this drug, when taken 2 times (in accordance with the instructions for use), can provide reliable anti-ischemic protection (and, first of all, anti-ischemic protection of the myocardium) for 24 hours.

The obtained result, in our opinion, could not be foreseen on the basis of the existing level of technology.

The present invention, therefore, provides the optimal quantitative and qualitative composition of the components for the manufacture of solid oral dosage forms of trimetazidine or its pharmaceutically acceptable salt of prolonged action, without allergenic and toxic effects, providing a gradual and prolonged release of the active principle over a long period of time, which allows stably maintain an effective concentration of trimetazidine in blood plasma throughout length of time.

All of the above is the technical result of the claimed group of inventions.

Claims (18)

CLAIM 1. The matrix for the manufacture of a tablet dosage form with prolonged release of trimetazidine or its pharmaceutically acceptable salt, characterized in that it contains 20.0-24.7 wt.% Hydroxypropylmethyl cellulose, 2.0-3.0 wt.% Hydroxypropyl cellulose, 1, 38.0 wt.% Copovidone. 2. The matrix according to claim 1, characterized in that it contains 15-25% of trimetazidine or its pharmaceutically acceptable salt. 3. The matrix according to claim 1, characterized in that it contains 25.0-30.0% of microcrystalline cellulose. 4. The matrix according to claim 1, characterized in that it is coated with a shell containing hydroxypropyl methylcellulose, copovidone, polyethylene glycol, titanium dioxide and iron oxide in a mass ratio of 0.4: 0.07: 0.09: 0.07: 0, 06. 5. The matrix according to claim 1, characterized in that it additionally contains calcium phosphate dihydrate in an amount of 15-20%. 6. The matrix according to claim 1, characterized in that copovidone is Plasdon 8-630. 7. The matrix according to claim 1, characterized in that it further comprises a stearic acid salt in an amount of 0.5-0.8%. 8. The matrix of claim 8, wherein the stearic acid salt is selected from the group consisting of magnesium stearate, calcium stearate and zinc stearate. 9. The matrix according to claim 1, characterized in that it further comprises colloidal silicon dioxide in an amount of 2.0-2.5%. 10. The matrix according to claim 1, characterized in that, as hydroxypropyl cellulose, it contains KieCEE bE. 11. The matrix according to claim 1, characterized in that the pharmaceutically acceptable salt of trimetazidine is trimetazidine dihydrochloride. 12. A method of treating or preventing a condition of a mammal in which administration of antioxidants, antihypoxants, cytoprotectors and membrane stabilizing agents is necessary, comprising administering a tablet dosage form with a sustained release of trimetazidine or a pharmaceutically acceptable salt thereof made from a matrix according to any one of claims 1 to 12, this taking a tablet dosage form with a sustained release of trimetazidine or its pharmaceutically acceptable salt is carried out twice a day b, ensuring total daily dose of trimetazidine 70 mg / day. 13. The method of treatment or prevention according to item 13, wherein the mammal is a human. 14. The method of treatment or prevention of claim 14, wherein the condition in which administration of antioxidants, antihypoxants, cytoprotectors and membrane stabilizing agents is necessary is coronary heart disease. 15. The method of treatment or prevention according to claim 14, characterized in that the condition in which administration of antioxidants, antihypoxants, cytoprotectors and membrane-stabilizing agents is necessary is ischemic myocardial infarction. 16. The method of treatment or prophylaxis of claim 14, wherein the conditions in which administration of antioxidants, antihypoxants, cytoprotectors and membrane stabilizing agents is necessary are chorioretinal vascular disorders. 17. The method of treatment or prevention according to claim 14, characterized in that the condition in which administration of antioxidants, antihypoxants, cytoprotectors and membrane-stabilizing agents is necessary is the degeneration of the choroid. 18. The method of treatment or prevention according to claim 14, characterized in that a condition in which administration of antioxidants, antihypoxants, cytoprotectors and membrane stabilizing agents is necessary is retinal vascular occlusion.