RU2412706C1 - Modified release dosage form of trimetazidine dihydrochloride - Google Patents

Abstract

FIELD: medicine, pharmaceutics.

SUBSTANCE: offered is a new modified release dosage form of trimetazidine dihydrochloride in the form of an oral tablet which contains an active substance in amount 3.5 - 70.0 wt %, mixed povidone and polyvinyl acetate as a release modifier in amount 20.0 - 70.0 wt % and pharmaceutically acceptable pharmaceutical aids. Preferentially, the dosage form of trimetazidine dihydrochloride as mixed povidone and polyvinyl acetate contains Collidon SR.

EFFECT: invention shall allow to enlarge the range of high quality, available domestic modified release drugs.

18 cl, 2 tbl

Description

The invention relates to the pharmaceutical industry, and in particular to a dosage form of a trimetazidine dihydrochloride modified release tablet for oral administration.

1 - [(2,3,4-Trimethoxyphenyl) methyl] piperazine (trimetazidine) in the form of dihydrochloride is used in modern medicine for chorioretinal vascular disorders, dizziness of vascular origin, dizziness in Meniere's disease, tinnitus, in the treatment of angina pectoris and coronary artery disease hearts.

Various types of tablet forms of trimetazidine dihydrochloride are known: conventional tablets provide rapid single release, modified release tablets (this term is synonymous with other terms that determine the nature of the release of the active substance from the tablet: slow, controlled, controlled, prolonged) provide a sustained dosage release of the active substance . Compared with conventional tablets, tablets with a modified release for patients have several advantages: the frequency of administration is reduced, it becomes possible to reduce the course dose and, as a result, the irritating effect on the gastrointestinal tract and the possibility of side effects are reduced. For each form, certain auxiliary components are selected that provide various technological properties to the tablets, a specific mode and rate of release of trimetazidine dihydrochloride.

Known pharmaceutical compositions of trimetazidine for sustained release.

A known dosage form having antianginal action, 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 applied to the core, containing tween, 80, one component selected from the group consisting of hydroxypropyl methylcellulose, water-soluble methyl cellulose and hydroxypropyl cellulose, as well as titanium dioxide pigment iron and red oxide (RF 2281772 C1, 08.20.2006).

The presence in the composition of the core of hydroxypropyl cellulose and hydroxyethyl cellulose, having a low bulk density, significantly reduces the flowability and compressibility of the tablets, which complicates the process.

Currently, PREDUCTAL MB from Servier, France is considered one of the best medicines for the treatment of angina pectoris, coronary heart disease. According to the information from the website of the Federal State Institution “Scientific Center for Expert Advice of Medical Applications” of the Federal Service for Supervision in the Field of Healthcare and Social Development (FGU NTsESMP), the page with the address from the Register of Registered Medicines is http://www.rlsnet.ru/prep_index_id_70434. htm, coated tablets and contain 35 mg of trimetazidine dihydrochloride and excipients: calcium hydrogen phosphate dihydrate, povidone, magnesium stearate, anhydrous colloidal silicon dioxide, titanium dioxide (E171), iron red oxide (E172), glycerol, macrogol, hypromellose (hydroxypropyl methylcellulose).

This drug corresponds to the technical solution protected by patent EA008223 B1, publ. 04/27/2007, patent holder - LE LABORATOIR SERVIE, France. The patent describes a tablet for the sustained release of trimetazidine, where the sustained release is controlled using the hydroxypropyl methylcellulose contained in the matrix. Hydroxypropyl methyl cellulose, a cellulose derivative, is a water soluble polymer.

But the regulatory documentation (ND 42-1623-05) for the drug PREDUCTAL MB of the applicant Servier Lab, France, is also known. According to ND, sustained release is controlled using hydroxyethyl cellulose, which is a water-insoluble polymer. When submitting documents for examination to the Federal State Institution “Scientific Center for Expert Advice of Medical Applications” of the Federal Service for Supervision of Health and Social Development (FGU NTsESMP) for the subsequent registration of the drug Trimetazidine dihydrochloride with a modified release, the drug PREDUCTAL MB was chosen by VERTEX CJSC as a comparison drug. Examination of the Federal State Institution NTsESMP compares the compositions and properties of the medicinal product submitted for registration according to the indicators given in the ND of the already registered drug. Therefore, and as the closest analogue of the claimed invention - the prototype, the composition of the drug PREDUCTAL MB, described in ND 42-1623-05, was selected.

The presence of both hydroxypropyl methylcellulose and hydroxyethyl cellulose with a low bulk density (0.3 and 0.35 g / cm ^3, respectively) in the core reduces the flowability and compressibility of the tablets, which somewhat complicates the manufacturing process for preparing the tablet form.

The problem to which the invention is directed, is to expand the range of high-quality affordable domestic drugs with modified release.

The task is achieved by developing a new dosage form based on trimetazidine dihydrochloride with a modified release in the form of tablets for oral administration. The tablet contains an effective amount of the active substance, a mixture of povidone and polyvinyl acetate as a release modifier, and pharmaceutically acceptable excipients.

An effective amount of trimetazidine dihydrochloride in modified-release tablets is known to be 35 mg (see, for example, the Register of Registered Medicines on the FSI NCESMP website, page at http://www.regmed.ru/InstrShow2.asp?InstrLinkNx=a59ba59ba54ba59b59 )

It is obvious that the kinetics of the release of the active substance from the tablets depends on the release modifier. It turned out that a mixture of povidone and polyvinyl acetate is a suitable release modifier for trimetazidine dihydrochloride. Povidone is a water-soluble polymer, and polyvinyl acetate is water-insoluble. Previously, this mixture was not used in modified release tablets of trimetazidine dihydrochloride. As a mixture of povidone and polyvinyl acetate, you can use Collidone SR, the properties of which are described in V. Buhler, Kollidon ^® , Polyvinylpyrrolidone for the pharmaceutical industry (Polyvinylpyrrolidone for the pharmaceutical industry), 233-249, BASF, Ludwigshafen, 2001. Collidone SR is 80% composed from polyvinyl acetate and 19% from povidone.

When the tablet is immersed in water, the water-soluble polymer dissolves, channels are formed that contribute to the release of the active ingredient. The water-insoluble polymer swells, forming a gel-forming layer through which the active substance gradually leaves. Thereby, the rate of release of the active substance from the tablet is controlled. The bulk density of the mixture of povidone and polyvinyl acetate, as well as Collidone SR, is 0.5 g / cm ³ , which turned out to be sufficient for high compressibility of trimetazidine dihydrochloride tablets.

The advantages of using a mixture of povidone and polyvinyl acetate, in particular Collidone SR, in the dosage form of the trimetazidine dihydrochloride according to the invention are that such a dosage form has a high sustained release effect, the release profile of the active component is pH independent and is easily adjusted from 8 to 24 hours. Tablets are obtained by dry mixing of the components and direct pressing them, which greatly simplifies the process. The tablets have high hardness combined with excellent ductility (low fragility of the tablets) and storage stability.

As excipients, the dosage form may contain fillers, lubricants, lubricants, disintegrants, disintegrants - the main groups of substances commonly used in the manufacture of tablets.

The preferred qualitative and quantitative composition of the dosage form, wt.%: 3,5-70,0 trimetazidine dihydrochloride, 20.0-70.0 a mixture of povidone and polyvinyl acetate, 0.2-1.0 sliding-lubricating, 7.0-40 , 5 filler, 1.0-5.0 disintegrant baking powder.

An effective amount of trimetazidine dihydrochloride in the dosage form of the invention is 35 mg. The amount of it in a percentage ratio depends on the weight of the tablet. With a tablet weight of 1.0 g, the percentage of trimetazidine dihydrochloride will be 3.5% by weight. With a tablet weight of 0.05 g, the percentage of trimetazidine dihydrochloride will be 70.0 wt.%.

As a filler, the dosage form contains one or more of the following substances: sugars and their derivatives (lactose, modified lactose, sucrose, glucose, mannitol, modified mannitol, sorbitol, fructose), polysaccharides (cellulose and its derivatives, starch, modified starch, dextrin , dextrose, dextrate, maltodextrin, calcium and its salts (phosphates, carbonates, chlorides), magnesium and its derivatives (oxide, carbonate), crospovidone, copovidones, cyclodextrins, alginic acid and its salts, saccharin and its salts, sodium and its salt (Chloride, citrate, fumarate, carbonate), aspartame, lactic acid and salts thereof, succinic acid, ascorbic acid, tartaric acid, colloidal silica, cyclamate, benzoic acid and its salt, parabens and their salts.

As a sliding lubricant, the dosage form contains a substance selected from the following: starch, talc, polyethylene oxides, colloidal silicon dioxide, stearic acid and its salts, fumaric acid and its salts, sodium stearyl fumarate.

As a disintegrant-disintegrant, the dosage form contains a substance selected from the following: starch and its derivatives (starch glycolate sodium, pregelatinized starch, amylopectin), croscarmellose sodium, crospovidones, polysorbates, sodium lauryl sulfate, colloidal sulfide, colloid.

To improve strength, the dosage form may contain 1.0-5.0 wt.% A binder, which is selected from the following substances: water, alcohol, sugar syrup, starch paste, solutions of cellulose ethers, povidones, gelatin, alginic acid or its salts, citric acid, shellac, polyvinyl alcohol, solutions of methacrylic acid and its copolymers.

The dosage form according to the invention can be made with a coating, which will ensure greater stability of the drug during storage.

The optimal mass fraction of the coating is from 3.0 to 6.0% by weight of the tablet core. The coating is made of a film-forming substance, a plasticizer and a pigment - traditional component coatings for tablets.

The preferred qualitative and quantitative composition of the coating contains, wt.%; 55.0-65.0 film-forming substances, 9.0-11.0 plasticizer and 25.0-45.0 pigment.

The film-forming coating agent is selected from the following: cellulose and its esters, sodium carboxymethyl cellulose and its derivatives, povidones, copovidones, methacrylic acid and its copolymers, sucrose, shellac, gelatin, xanthan gum, gum arabic, alginic acid and its salts.

The plasticizer for coating is selected from the following: polysorbates, glycerin and its esters, polyethylene glycol, propylene glycol, dibutyl phthalate, triethyl citrate, triacetin, povidone, mineral oils, vegetable oils.

The pigment for coating is selected from one or more of the following: talc, titanium dioxide, iron salts, dyes, kaolin.

The coating can also be made from ready-made coating mixtures containing cellulose and its esters, povidones, copolymers of vinyl pyrrolidone and vinyl acetate.

Preferred ready-mixed coatings are Advantia Prime and OpadryII. Advantia Prime is a mixture of hypromellose (hydroxypropyl methylcellulose), macrogol (polyethylene glycol), titanium dioxide and talc. By order of VERTEX CJSC, the mixture is manufactured by International Specialty Products, USA, the company's website http: // www.ispcorp.com/. Opadry II is a ready-made coating for tablets, which is a mixture of polyvinyl alcohol, macrogol, titanium dioxide and talc. This mixture is commissioned by VERTEX CJSC by Colorcon Limited, UK, company website http://www.colorcon.com/.

Excipients, their ratio in the proposed dosage form is selected experimentally and provides the necessary strength and disintegration in water.

In addition, all excipients that form the core and shell, as well as their content, are selected in such a way as to ensure easy granulation to the desired size and non-toxic to the body.

The advantages of using a tablet coating coating on the basis of ready-made mixtures is not only the simplification of the process (the coating solution is ready after 45 minutes, while it takes 1-2 hours to prepare the coating solution from the individual components).

The system of interaction with suppliers of auxiliary components is simplified: one mixture is ordered, not several components, respectively, incoming control must be carried out for only one component.

The proposed dosage form of trimetazidine dihydrochloride was prepared as follows.

Trimetazidine dihydrochloride and Collidone SR are loaded into a V-blender. The mixture is stirred for 5-6 minutes at a blender rotation speed of 18-20 rpm. Then, filler, baking powder, disintegrant, binder (if present) are loaded in layers. Mix the mixture for 10-15 minutes at a blender rotation speed of 18-20 rpm. Then stop the blender and load the sliding-lubricating. Mix the mixture for 1 min at a blender rotation speed of 18-20 rpm.

After mixing, the mixture is unloaded in a container, weighed. The finished tabletting mass is analyzed to quantify the content of trimetazidine dihydrochloride. Specific mass compositions are shown in Table 1.

Tableting is carried out on a high-speed rotary tablet press ECI-SH-31D in accordance with the SOP "Operation of a high-speed rotary tablet press ECI-SH-31D".

Tablets - the nucleus of trimetazidine dihydrochloride are white or almost white, with a splash. The shape of the tablets is biconvex, with a diameter of 9 mm, a radius of curvature of 0.9 D, an average weight of 0.25 g, the deviation in the mass of individual tablet cores from the average weight is ± 7.5% (0.231-0.269 g), the height of the tablets is 4, 2-4.3 mm, strength - 7-8 kg / cm ² .

To apply a film coating in a conventional manner, a mixture is prepared.

The process of applying a shell of Advantia Prime and OpadryII prepared at the factory or ready-mixed mixtures on Trimectal tablet cores should be carried out on a film coating machine type BG-80 (coater).

The process of coating the tablet cores with a film shell is carried out at the following parameters: incoming air temperature - 60 ° C, drum rotation speed at the beginning of the process - 8 rpm with a gradual increase to 9-12 rpm, compressed air pressure on the nozzle needle - 0 4 MPa, the pressure of compressed air to spray - 0.2 MPa, the feed rate of the film-forming suspension in water at the beginning of 9 ml / min with a gradual increase to 25-30 ml / min.

The process is carried out until the film-forming suspension is fully used, after which the tablets are finally dried for 9-10 minutes at an inlet air temperature of 50 ° C and a drum rotation speed of 5-6 rpm.

Then turn off the heat and cool the tablets to a temperature of 20-25 ° C.

The average weight of the coated tablets is 0.258 g. The deviation in the weight of the individual coated tablets from the average weight is ± 7.5% (0.238-0.277 g). The strength of the core tablets was 7-8 kgf / cm ² .

In the obtained tablet cores, dissolution is checked. Given that for most drugs there is a correlation of dissolution rate and absorption rate, the Dissolution test is a criterion for evaluating the prolonged action of tablets. The Dissolution test was carried out on a paddle mixer. As a dissolution medium, a 0.05 M phosphate buffer solution with a pH of 6.8 was used. The volume of the medium was 500 ml; the rotation speed of the stirrer was 50 rpm. The amount of trimetazidine dihydrochloride released from the tablets of the invention was determined on a spectrophotometer at a maximum absorption at a wavelength of 270 nm in a cuvette with a layer thickness of 10 mm.

In the manufacture of the drug in accordance with the above example, tablets were obtained that meet the requirements of the pharmaceutical article of the enterprise (FSP ZAO VERTEX). According to the FSP, the dissolution should be: after 1 hour - 25-45%, after 2 hours - 43-63%, after 8 hours - at least 80%, which will ensure high bioavailability of the active substance. Data on the dissolution of each of the compositions shown in Table 1 are summarized in Table 2. From Table 2 it follows that the tablets according to the invention meets the requirements of the FSP.

The drawing shows a graph reflecting the dissolution profile at the time of manufacture of the tablets (solid line) and after three years of storage. From the graph presented, it is seen that the dissolution profile of the tablets according to the invention during storage does not change.

Thus, the studies showed that the dosage form according to the invention has a prolonged effect and in its pharmacokinetic parameters is not inferior to the comparison drug Preductal MB tablets, as evidenced by the conclusion on the results of the test of the “Dissolution Kinetics” test conducted by the Scientific Research Institute of Vitamins.

table 2 TIME / Example Number In vitro release profile,% one 2 3 four 5 6 7 8 9 10 eleven 12 13 fourteen fifteen 16 17 eighteen 19 twenty After 1 hour 25 35 45 35 35 25 35 35 35 35 35 25 35 35 45 27 45 thirty 29th 25 In 2 hours 43 fifty 60 fifty fifty 43 fifty 45 55 45 55 43 55 55 63 fifty 60 52 48 43 After 8 hours ≥80 ≥80 ≥90 ≥80 ≥80 ≥80 ≥80 ≥80 ≥80 ≥80 ≥80 ≥80 ≥80 ≥80 ≥90 ≥80 ≥90 ≥80 ≥80 ≥80

The active substance in the new dosage form of trimetazidine dihydrochloride with modified release is evenly distributed in the volume of the hydrophilic matrix, which ensures its delayed controlled release. This allows you to increase the plateau of the concentration of trimetazidine in the blood during the day and makes it possible to maintain a constant antianginal efficacy of trimetazidine dihydrochloride for 24 hours. Since the new form allows you to increase the value of the minimum concentration by 31% while maintaining the maximum, trimetazidine dihydrochloride provides better protection of the myocardium from ischemia in the early morning hours. The dosage form of the trimetazidine dihydrochloride according to the invention is taken 2 times a day, which provides a more convenient dosage regimen and increases patient adherence to treatment.

Claims (18)

1. Dosage form of trimetazidine dihydrochloride with a modified release in the form of an oral tablet containing the active substance in an amount of 3.5-70.0 wt.%, A mixture of povidone and polyvinyl acetate as a release modifier in an amount of 20.0-70.0 wt. .% and pharmaceutically acceptable excipients. 2. The dosage form according to claim 1, characterized in that as auxiliary substances it contains fillers, lubricants, lubricants, disintegrants, disintegrants. 3. The dosage form according to claim 2, characterized in that it contains, wt.%: 3.5-70.0 trimetazidine dihydrochloride, 20.0-70.0 mixtures of povidone and polyvinyl acetate, 0.2-1.0 sliding -lubricating, 7.0-40.5 filler, 1.0-5.0 disintegrant disintegrant. 4. The dosage form according to claim 1, characterized in that as a mixture of povidone and polyvinyl acetate it contains Collidone SR. 5. The dosage form according to claim 2, characterized in that it contains one or more of the following substances as filler: sugars and their derivatives (lactose, modified lactose, sucrose, glucose, mannitol, modified mannitol, sorbitol, fructose), polysaccharides (cellulose and its derivatives, starch, modified starch, dextrin, dextrose, dextrate, maltodextrin, calcium and its salts (phosphates, carbonates, chlorides), magnesium and its derivatives (oxide, carbonate), crospovidone, copovidones, cyclodextrins, alginic acid and its salt, sa harin and its salts, sodium and its salts (chloride, citrate, fumarate, carbonate), aspartame, lactic acid and its salts, succinic acid, ascorbic acid, tartaric acid, colloidal silicon dioxide, cyclamate, benzoic acid and its salts, parabens and their salts. 6. The dosage form according to claim 2, characterized in that, as a sliding lubricant, it contains a substance selected from the following: starch, talc, polyethylene oxides, colloidal silicon dioxide, stearic acid and its salts, fumaric acid and its salts, sodium stearyl fumarate . 7. The dosage form according to claim 2, characterized in that it contains a substance selected from the following as a disintegrant, disintegrant: starch and its derivatives (sodium starch glycolate, pregelatinized starch, amylopectin), croscarmellose sodium, crospovidones, polysorbates sodium lauryl sulfate, colloidal silicon dioxide, polyethylene oxides, cellulose derivatives. 8. The dosage form according to claim 2, characterized in that it further comprises 1.0-5.0 wt.% A binder. 9. The dosage form of claim 8, characterized in that it contains a substance selected from the following as a binder: water, alcohol, sugar syrup, starch paste, solutions of cellulose ethers, povidones, gelatin, alginic acid or its salts, citric acid , shellac, polyvinyl alcohol, solutions of methacrylic acid and its copolymers. 10. The dosage form according to claim 1, characterized in that it is made with a coating. 11. The dosage form according to claim 10, characterized in that the mass fraction of the coating is from 3.0 to 6.0% by weight of the tablet core. 12. The dosage form according to claim 10, characterized in that the coating is made of a film-forming substance, a plasticizer and a pigment. 13. The dosage form according to claim 12, characterized in that the coating contains, wt.%: 55.0-65.0 film-forming substances, 9.0-11.0 plasticizer and 25.0-45.0 pigment. 14. The dosage form according to claim 12, characterized in that, as a film-forming substance, the coating contains a substance selected from the following: cellulose and its esters, sodium carboxymethyl cellulose and its derivatives, povidones, copovidones, methacrylic acid and its copolymers, sucrose, shellac, gelatin, xanthan gum, gum arabic, alginic acid and its salts. 15. The dosage form of claim 12, wherein the coating comprises a substance selected from the following as a plasticizer: polysorbates, glycerin and its esters, polyethylene glycol, propylene glycol, dibutyl phthalate, triethyl citrate, triacetin, povidone, mineral oils, vegetable oils. 16. The dosage form according to claim 12, characterized in that the coating contains one or more of the following substances as a pigment: talc, titanium dioxide, iron salts, dyes, kaolin. 17. The dosage form according to claim 10, characterized in that the coating is made from ready-to-use coating mixtures containing cellulose and its esters, povidones, copolymers of vinyl pyrrolidone and vinyl acetate. 18. The dosage form according to claim 17, characterized in that the coating is made from ready-to-use Advantia Prime coating mixtures based on hypromellose and macrogol or OpadryII based on polyvinyl alcohol and macrogol.

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