BG1345U1 - Modified-release pharmaceutical formulation - Google Patents

Abstract

The pharmaceutical formulation can be applied in long-term therapy of coronary vessels disease, attacks of stenocardia and ischaemic heart disease, angina pectoris, ischaemic cardiomyopathia, chorioretinal vascular lesions, tinnitus, dizziness (vascular lesions, MeniereÆs disease). As specified in the utility model, the pharmaceutical formulation has the following composition in mg: trimetazidinedihydrochloride û 35, Ca hydrogen phosphate anhydrous û from 25.0 to 80, hypromellose Ki5 M û from 35.0 to 80, carbopol - from 5.0 to 25.0, povidon or copovidon from 4.0 to 15.0, anhydrous colloidal silicon dioxide û from 0.25 to 2.0, magnesium stearate or calcium stearate û from 0.25 to 2.5, sodium stearyl fumarate - from 0.1 to 2.5,

Description

(54) AMENDED PHARMACEUTICAL FORM

Technique $

The utility model relates to a modified-release formulation containing 1 - [(2,3,4-trimethoxyphenyl) methyl] piperazine hydrochloride (trimethazidine) and a method for its preparation. The dosage form will find application for long-term treatment in coronary artery disease angina attacks and ischemic heart disease, angina, ischemic cardiomyopathy, choreoretinal vascular disorders, tinnitus, dizziness (vascular disorders, menstrual disease).

which leads to a lengthening in time and an increase in final output. Despite the good stability of the trimethazidine substance, wetting during so-called wet granulation and drying are dangerous in this direction. Confirmation of this is the need for additional wrap / film / tablets with waterproof film.

The technical nature of the utility model

The object of the utility model is to provide a modified-release formulation containing trimethazidine or a salt thereof, in which a higher release rate of the active substance is achieved over a period of 1 to 4 hours of administration. This guarantees a pronounced antihypoxic effect and a successful prior art

There is a known delayed release formulation based on trimethazidine for use in the management of severe angina attacks.

A formulation containing trimethazidine or a salt thereof has been devised, and the combination is a reservoir system obtained by a controlled-thickness polymer film that covers the tablet or granule to obtain a controlled release of the following excipients in mg:

(EP 0673649). In this dosage form it is necessary to pre-wrap the trimethazidine particles, after which they are incorporated into the matrix tablet, i. there is another microencapsulation process.

Delayed formulations known Trimetazidine dihydrochloride Ca anhydrous phosphate anhydrous Hypromellose K _and M Carbopol

Povidone or copovidonog

Anhydrous colloidal silica Magnesium stearate or calcium stearate

Sodium stearyl fumarate 25.0 to 80.0 35.0 to 80.0 5.0 to 25.0

4.0 to 15.0 from 0.25 to 2.0 from 0.25 to 2.5 from 0.1 to 2.5 divination containing trimethazidine using combinations of cellulose ether and methoxyethylene copolymer / maleic anhydride (EP 0207638). In this dosage form, an additional microencapsulation process is required.

An orally applicable tablet is a delayed release matrix of trimethidine or a salt thereof, consisting of a hydrophilic matrix, in which the delayed release is controlled solely by the use of a cellulose derivative polymer (BG 106927 A1). The orally administrable tablet matrix is obtained by wet granulation, tabletting and filming of the resulting tablet. Getting this tablet-matrix is relatively technologically complicated,

The dosage form is a stable hydrophilic-hydrophobic complex in which, by interference with the linear chains of hypromellose and carbopol, they form a cohesive network resistant to erosion of the tablet during dissolution. This is due to the better compressibility of carbopol, which is preferably carbopol 71G.

The combination of the two polymers allows for better programming of the degree of dissolution of trimethazidine.

The selected hydroxypropylmethylcellulose Hypromellose K _in M has a viscosity of 17 to 21,000 scp, which provides better controlled release of trimethazidine.

The carbopol selected according to the utility model also controls the diffusion of ak2 better

1345 A suture through a formed hydrogel having a structure different from that of the linear polymers used in other commercial products.

The combination used results in a change in the order of dissolution of the active ingredient. By diffusion of the active ingredient, an increased release is achieved in the first hours of 1-4 hours, after which the release is uniform and sustained during the remaining hours from the 8th to the 10th hour.

According to a useful model, the method for preparing a modified-release dosage form containing trimethazidine or a salt thereof involves the following sequence of technological operations. Screening of the components trimethazidine dihydrochloride, anhydrous colloidal silica, magnesium stearate or calcium stearate, sodium stearyl fumarate (SSF), anhydrous phosphate anhydrous, hypromellose K _i5 M, carbopol, povidone or copovidone. Homogenization of trimethazidine dihydrochloride, Ca anhydrogen phosphate anhydrous, carbopol, hypromellose K _i5 M, anhydrous colloidal silica and povidone or copovidone. Addition of magnesium stearate or calcium stearate and additionally sodium stearyl fumarate / SSF / 3 min before the end of homogenization and tablet directly.

According to a useful dry mix method, the incorporation into the SSF composition results in better rheological and physico-mechanical performance of the direct tabletting mixture and some physico-mechanical performance of the tablet cores. As a salt of stearyl (fatty) acid, SSF has much better lubricating properties for tabletting, which prevents during tableting: sticking it on the pans; retention of the tablet in the matrix; the need for a higher value of the ejection force of the tablet, which impedes the operation of the tablet press. Combining it with magnesium stearate results in better rheological parameters (flowing properties) ensuring uniformity of dosage units and uniformity of drug substance in dosage units.

The method is a simplified process for direct tabletting using an additional 0.25-3% sodium stearyl fumarate (SSF) (Pruf) lubricant in the final blending step to improve the rheological and physico-mechanical properties of the direct blend tableting.

Due to the utility model, which is a direct tableting method, the particle size of trimethazidine substance is in the range of 45 to 80 micrometer, which provides suitable rheological parameters - flowability, uniformity and uniformity of dosage, which leads to standardized serum concentrations after oral administration.

Examples of implementation of the utility model

Example 1. Composition of the dosage form in mg

Trimetazidine dihydrochloride 35.0

Hydrogen phosphate is anhydrous 25.0

Hypromellose K _i5 M35.0

Carbopol 71 G5.0

Povidone K 254.0

Anhydrous colloidal silica 0.25

Magnesium stearate 0.25

Sodium stearyl fumarate 0.1

Example 2.

The process for preparing a modified release formulation containing trimethazidine or a salt thereof includes: sieving through a 0.63 sieve aperture of trimethazidine dihydrochloride, anhydrous colloidal silica, magnesium stearate and sodium stearyl fumarate (SSF). The components Ca anhydrous phosphate anhydrous, hypromellose K _a M, povidone K25 and carbopol 71G were weighed and sieved through a 1.0 mm bright hole sieve.

1. Homogenization natrimetazidin dihydrochloride, Ca hydrogen phosphate anhydrous, carbopol, povidone K25, hypromellose K _and M and anhydrous colloidal silica in a V-blender in a dry time 40 min.

4. Addition of sodium stearyl fumarate (SSF) and magnesium stearate 3 min before the end of homogenization.

5. Direct tableting of a rotary tablet machine at the following parameters: revolutions 30 gr; pre-pressure - 8 KN; pressure - 25 KN.

Example 3. Composition of the dosage form in mg:

1345 Ul

Trimetazidine dihydrochloride 35.0 Hydrogen phosphate is anhydrous 35.0 Hypromellose K _{| 5} M 45.0 Carbopol 71 G 12.0 Povidone K25 7.0 5 Anhydrous colloidal silicon dioxide 0.85 Magnesium stearate 6.0 Sodium stearyl fumarate 0.75 Example 4. Composition of the dosage form 10 Trimetazidine dihydrochloride 35.0 Hydrogen phosphate is anhydrous 80.0 Hypromellose K _b M 80.0 Carbopol 71G 25.0 15 Povidone K25 15.0 Anhydrous colloidal silicon dioxide 2.0 Magnesium stearate 2.5 Sodium stearyl fumarate / SSF / 2.5 20

EXAMPLE 5 The formulation of Example 5 is an embodiment of the utility model and is prepared by the method described in Example 2, but copovidone and calcium stearate are included in the composition.

Composition of the dosage form in mg:

Trimetazidine dihydrochloride 35.0

Hydrogen phosphate is anhydrous80.0

Hypromellose Κ _ΰ M80.0

Carbopol 71G25.0

Kopovidone15.0

Anhydrous colloidal silica 2.0

Calcium stearate 2.5

Sodium stearyl fumarate / SSF / 2.5 Example 6.

In the study of strengths it is found with about 14% increase in their values and a decrease in the value of abrasion by about 30%, which is essential in the phase of coating the matrix tablets

Table 1

COMPARISON DETAILS OF DILUTION PROFILES in vitro

TRIMETASIDINE COMMERCIAL PRODUCT

Useful model

1h 33.07% 38.5% 2h 51,54% 57.3% 4h 72.68% 78.2% 8h 97.15% 93,8%

From the dissolution results it can be concluded that in the dosage form according to the utility model, the release of the substance from 1 to 4 hours inclusive is 11.58% higher than that of a known commercial product.

Example 7.

Pharmacokinetic studies have shown that with trimethazidine 35 mg, the release of substance over the 1- to 4-hour period is greater than the known trimethazidine preparation (Table 2).

Based on the in vitro pharmacokinetic data of the substance, after oral administration, the maximum concentration after 24 hours for 11 hours will be above 90% of the maximum, compared to 75% of a known commercial product, which is essential for antihypoxic effest.

Similarity factor f ₂ = 65

Pharmacokinetic studies have been performed.

Claims (2)

Claims A modified release formulation comprising trimethazidine or a salt thereof, anhydrous colloidal silica, Trimetazidine dihydrochloride 35 Are hydrogen phosphate anhydrous from 25.0 to 80 Hypromellose Κ _ΰ M from 35.0 to 80 Carbopol 5.0 to 25.0 Povidone or copovidone 4.0 to 15.0 Anhydrous colloidal silica from 0.25 to 2.0 Magnesium stearate or calcium stearate from 0.25 to 2.5 Sodium stearyl fumarate from 0.1 to 2.5 Modified-release dosage form according to claim 1, characterized in that it contains Carbopol 71G. magnesium stearate, Ca-hydrogen phosphate, hypromellose Κ _ι5 M and povidone, characterized in that Ca-hydrogen phosphate is anhydrous and homogeneous in the following quantitative ratios in mg: