UA80087C2 - Matrix tablet for prolonged release of trimetazidine and method for production thereof - Google Patents

Abstract

The invention concerns a matrix object for prolonged release of trimetazidine or one of its additive salts to a pharmaceutically acceptable acid after oral administration, characterized in that the prolonged release is controlled by the use of a polymer derived from cellulose.

Description

- the granulate obtained in this way is mixed with 16. The matrix tablet according to any of paragraphs 1 - 14, a cellulose derivative, which is used for preventive treatment - after that, a lubricating agent and angina pectoris are added, in cases of chorioretinal attacks, an agent that increases fluidity, and for the treatment of vertigo, vascular po- then the resulting mixture is pressed. jinn

The subject of the present invention is the plasma matrix after each administration and thus preserving the solvent, which when taken orally causes the effect of trimetazidine, as well as to support the prolonged release of trimetazidine or its energetic metabolism in a cell exposed to an additive salt with a pharmaceutically acceptable acid. hypoxia or ischemia, and avoid a decrease in intercellular volume. level of ATP.

Trimetazidine, or 1-(2,3,4- The drug also allows you to avoid peripheral trimethoxybenzyl)piperazine is a compound that has a vasodilating effect, while at the same time by maintaining energy metabolism, it stabilizes the intensity of blood circulation and pressure. wine in a cell exposed to hypoxia or ischemia, to- According to this invention, the new composition allows to avoid the destruction of the intercellular level preserves the positive characteristics of the composition, adenosine triphosphate (ATP). Thus, it heals (EC patent 2490963), at the same time ensuring the functioning of ion pumps and achieving a higher level of prolonged action during the evo-potassium transmembrane fluxes and the sub-day, which guarantees the satisfaction of the corresponding needs and maintains cellular homeostasis. continuous protection.

Trimetazidine hydrochloride is currently used. The subject of this invention is a matrix tablet therapeutically for the prophylactic treatment of letka, which when taken orally causes angina, in cases of chorioretinal attacks, the prolonged release of trimetazidine or its and for the treatment of vertigo of vascular poho-additive salt and which consists of a hydrophilic (Meniere's dizziness, ringing in the ears). matrix, which differs in that it is elongated

Trimetazidine hydrochloride until now, the release of the active substance is provided orally in doses from 40 to bomg per by using a polymer derived from ce- day in the form of tablets containing 20 mg of active cellulose. substance, or a drinking solution containing 20 mg of active substance per ml. These two forms of the drug are given twice a day, provide prolonged release forms with a rapid release of the active reactive substance, which is achieved with the preservation of guilt (EC patent 2 490 963 describes the form of a tablet - a large maximum plasma level after the skin). Trimetazidine hydrochloride is rapidly absorbed. At the same time, it is absorbed and destroyed by the body after each intake, since the period when the plasma level in the human body reaches above its plasma half-life lasts less than 67Ocg/l, and by the time of the next intake, it takes less than three hours. This means that a plasma level that exceeds or exceeds the plasma level of the active substance of its use of 40O0tsg/l is sufficient for maintenance, which was not observed during the three- should be divided into 2 or 3 times a day. The most frequent is the daily intake of tablets according to (the patent and the necessary therapeutic dose are three tablets of EB 24909631). for a day. The disadvantage of repeated administration is that, among the cellulose derivatives used in both patients who lead an active lifestyle and the matrix according to this invention, it is possible, especially for older people who simultaneously use and - to single out cellulose esters, such as hydroxypropyl - which is a lot other drugs, may forget the next dose. cellulose, methyl cellulose and hydroxypropyl me-

Because trimetazidine hydrochloride has ethylcellulose. juicy degree of digestibility and b-hour half- Among polymers derived from cellulose, disintegration, when using forms of the drug with rapid revaga during the preparation of the tablet is provided by hydro- release at the time of taking the next dose in xypropylmethyl of whole vine. The share of the polymer, blood-derived, already has a low level of actinic content from cellulose, is from 25 to 5095 of the substance. At the same time, the importance of the total mass of the tablet is known. maintenance of effective myocardial protection Hydroxypropyl me- can be used throughout the day, especially early in the morning, when tylcelluloses, which have a viscosity of 100 CsP to the consequences of ischemia, are most serious. Since 100000sP. In this case, the advantage is given to the viscosity when using the forms of the drug with a quick release of 4000 cP. the required level of action of the active substance The hydrophilic matrix contains various during the day is not reached. The applicant has developed excipients, for example, binders, diluents, a form with extended release, which additional lubricating agents and agents that increase the ability to provide an ideal level of action. Among the binding agents, povidone is given the advantage after 24 hours, a sufficient level of active content for the production of tablets. The substance in the blood in the period between doses, while povidone is from 3 to 1295 of the total weight, maintaining a large maximum level of the tablet. Among thinners, the advantage when using

the melting of tablets is given to calcium hydrogen - Step A: Mixing trimetazidine, polyvinyl phosphate dihydrate, which provides better plin- and calcium hydrogen phosphate dihydrate, then ness and better compressibility than other diluents, wetting the mixture with a sufficient amount of disti- such as lactose monohydrate. The share of calcium-hydrogen cast water, granulation and drying of granu-phosphate is from 25 to 7595 of the total cast mass. pills - Stage B: Mixing the obtained granulate

Although you should not narrow the range of lubricants at stage A, with hydroxypropylmethylcellulose. agents that can potentially be used - Stage C: Lubrication of the mixture obtained on magnesium stearate, stage B, magnesium stearate and colloidal dioxide stearic acid, glycerine behenate and silicon benzoate stand out among them. sodium Preference is given to stearate - Stage 0: Compression of the lubricated mixture obtained - magnesium. As for the agent that increases the liquid in stage C, on the rotary unit, in the resolution, in this case, preference is given to the cat, which produces tablets with approximately Tverloid silicon dioxide. from 40 to 160 M, measured at

According to this invention, in the manufacture of mat- refraction along the diameter. rix tablet, preference is given to trimethase- Example 1: Formulas of different matrix tabletin in the form of dihydrochloride. current with the content of different volumes of trimetazidine

The proportion of trimetazidine dihydrochloride is ЯХаблице /: General formulas of tablets from 15 to 3095 of the total weight of the tablet, mainly g p m Y - from 15 to 1895. Mr. V.S.M.

Specialists in this field of technology believe that rilmetazidine dihydrochlornd 5 (8

Y. Shpidroxyprovivmethincellulose. pe 74 174 the kinetics of the release of the active substance inherent in matrix tablets IPolyvilon 134 87 7 depends on the composition and IZHCalcium water phosphate dihydrate 2 855 doses and the volume of the main component of the matrix, which, in general, in this case is a derivative cellulose | semu ie i et

However, unexpectedly, it turns out that the kinetics of the release of the active substance, inherent in the matrix and Example 2 What is the triple tablet according to the present invention, does not depend Example 2 shows that the difference in the volume of hydrogen does not depend on the amount, nor does the degree of purity of oxypropylmethylcellulose affect the solubility of the used cellulose derivative. | general kinetics of the tablet.

Various preparations, in the manufacture of which Table 2; The mentioned forming gtminchi zbszhen podroxynproponiemetitneyaktsy were used, On the one hand, pdroxypropyl 0 ma methylcellulose of different viscosity and, on the other hand, and different volumes of hydroxypropyl methylcellulose of the same and high degree of purity, they found an equivalent p kloksnzrogylmetnscheyunovypa with the kinetics of the release of the active substance, which indicates the existence of a certain interaction between the derivative of cellu- NStgevrate magnesium B: M lozi and trimetazidine. Anhydrous colloidal dioxide aremniyu 40000 - : Hegolna Mora VEINS of the eye

This invention also relates to the process of manufacturing a matrix tablet. Matrix tablet Table C shows the percentage of the substance that can be produced by wet granulation with release during a certain period of time with subsequent compression, by dry granulation from the composition of FA and Fo. by further compression, as well as by direct Toblich. 3: Kinetics of the release of the active substance of compression. Preference is given to wet granulation with o Frequency) Percentage of substance released (953; by further compression. Fa Ф5 !

Wet granulation is performed by mixing trimetazidine, povidone and a solvent with Z 5 nkh! subsequent wetting of the obtained mixture. Such z ho: z and the first stage cause the creation of around and 97 z6 sh of the active ingredient of the hydrophilic medium, Example 3: what contributes to the tab; dissolution, and also allows Example C shows that different degrees of purity

We gave the most homogeneous doses. - of the used hydroxypropylmethylcellulose, and in the second stage, the pre-obtained gran- does not affect the dissolution kinetics of the tablet, is mixed with a cellulose derivative. After that, a lubricating agent and an agent are added to the mixture, tabu zi: sah / flaxen stnulen ikotyuyugu hidrovsttrem heka neoovy that increases fluidity. At the third stage, the forerunners of the NN see the compression of the obtained lubricated mixture. Mr. A

In this way, tablets are made, which, after a three-month period of 00000001350035 13, if necessary, are covered with a shell for Hydropropinmethiacetologist h000 ST in - and. ! . Hydroprotsylmetialtsslloga 300 s - - | 73 standard technology. y Hydrolropitmetyatepioga 300,000 ST - t 1- E

The examples below illustrate the process, but are not limiting it in any way. Mat- Haltsyvolnkyan phosphech ditylrich zpa peryx tablets, described in the Examples, were made Bezvatsnyi potoidnyi, diozhendcremino da shSHUSHY H 4 as follows:

Table 5 shows the percentage of the substance that Trimetazidine dihydrochloride 20 mg is released during a certain period of time, and the starch MG

Yeets: the weight of the evnoy o ace with K Z ohm 26 composition F3Z, Fb and F7. Mannitol З4ммг з облица Z Kinetics of release of active rehovin Polyvidon Am

Chasikod) Pyrocene of the released substance (5) Magnesium stearate 1 mg (Fu. Z2Z2K00ZZ 5 55-0- I Talc 5MG 1 43 and for the average plasma concentration is shown on 1 I6z isobo Figure 1 z |v Ivz 83 UR ! 4 1605 pos about Fig. 1 - plasma kinetics of trimetazidine;

Example 4: Study of plasma kinetics of the average plasma concentration of trimetazidine (v

Plasma kinetics were studied after oral intake by 12 healthy volunteers of a matrix tablet prepared according to the formula F3, which is described in the FZ, and SHV-form.

Examples 1 This diagram clearly shows that the form Ф3 is

Reception was carried out for 4 days under the scheme of extended-release trimetazidine, I take two tablets a day. The plasma kinetics of the tablet, while maintaining a large maximum of the tablet made according to the F3 formula, was equal to the plasma level after each intake. a woman with this indicator for a tablet with a fast After each administration, the level of the release of the active substance (SW) is observed, which pri- plasma, approaching Zotsg/l and little was cut off within 4 days according to the scheme of three tablets per day from the level that is reached when using a day SHV-form. At the end of the 24-hour period, the

The general formula of a tablet with a rapid plasma clearance exceeds 40 mg/l, while for the active substance (SHV) absorption, this indicator is only about the following: cy.

Plasma concentration (shg/ya) niji Tsiv (ve , ! 160 kaiy-k 3 y 80 KU zu b y wk t M y kh y ; Ya cha 2. y -y i S. v ya ha A ША 50 a Я cha " x U

Z S g g. x x .. 5 Her Shch y; - mch 2 t 8. U K GU u - 404 i) che o Time (year)

Oh 7577 7 I 85 87 90 5

Fig. 1

Computer typesetting by I. Skvortsov Signed Circulation 26 approx.

Ministry of Education and Science of Ukraine

State Department of Intellectual Property, str. Urytskogo, 45, Kyiv, MSP, 03680, Ukraine

SE "Ukrainian Institute of Industrial Property", str. Glazunova, 1, Kyiv - 42, 01601