BG65538B1 - Medicamentous form of silimarin and method for its preparation - Google Patents

Abstract

The invention relates to a medicamentous form of silimarin and to a method for its preparation, by means of which higher stability is ensured under storage conditions at high humidity- and heat-resistance characteristics. The medicamentous form is decomposed within 30 min and solubility degree no less than 80% for 45 min during its entire storage period.

Description

Technical field

The invention relates to a dosage form of an active substance, a collection of flavolignans derived from Silybum marianum, commonly known by the name Silymarin and a widely used hepatoprotector.

BACKGROUND OF THE INVENTION

The BG 43202 dosage formulation contains a dragee containing 0.035 g silymarin in the form of total extract of Silybum marianum and excipients - starch, microcrystalline cellulose, lactose, sorbitol, glucose, talc, magnesium stearate, polyvinylpyrrolidone K25, polyvinylpyrrolidone K25, polyvinylpyrrolidone K25, polyvinylpyrrolidone / 50 and sodium bicarbonate forming a tablet core coated with a layer of highly dispersed silica and a coating cellulose acetate phthalate, arabic gum, gelatin, sugar, titanium dioxide, talc and colorant. According to the example dragee formulation, the tablet core contains 0.048 g of starch, 0.057 g of microcrystalline cellulose, 0.060 g of lactose, polyvinylpyrrolidone 25/25 - 0.010 g and 0.007 g of polyvinylpyrrolidone CE 50/50.

The dragee formulation process involves mixing silymarin in dry succession with microcrystalline cellulose and starch, mixing the resulting concentrate with other excipients, and wetting. The granulation, drying and tableting are followed. The resulting tablet cores are coated with a cellulose film and a coating coating containing highly dispersed silica (in powder form) and the other excipients mentioned above.

This composition of the tablet core and the method of preparation do not provide stability of the dragees (shelf life) and sufficient mechanical strength of the tablet core. Moreover, the implementation of the production method encounters difficulties mainly related to the low mechanical strength of the tablet core, which impedes the subsequent technological phases. Requires solvents whose use is not desirable from a pharmacotherapeutic point of view.

The technical problem is that the satisfactory mechanical strength of the tablet core, using known methods and substances, results in the degradation of the core degradation and the degree of dissolution of the active substance.

Thus, the problem to be solved is the achievement of improvement simultaneously of all technological and analytical parameters, on the one hand, mechanical strength and stability under storage conditions, and on the other - disintegration of the tablet core and the required degree of dissolution of the active substance. to meet current pharmacopoeial requirements.

SUMMARY OF THE INVENTION

The problem of balanced stability of the drug based on Silymarin is solved by a solid dosage form made up of a tablet core comprising the active substance and excipients-polyvinylpyrrolidone K25, wheat starch, lactose, glucose, sorbitol, microcrystalline cellulose, thalassol, magnesium cellulose, thalassin sodium bicarbonate, the amounts of excipients in the tablet core being: polyvinylpyrrolidone K25 from 0.0010 to 0.009 g, starch 0.050-0.060 g, lactose 0.050-0.060, glucose 0.0150-0.0208 g, sorbitol 0.0040-0 , 00415 g and microcrystalline cellulose 0.0567-0.070 Mr Rücker

The method of preparing the dosage form according to the invention includes:

1) blending wheat starch, lactose, glucose and sorbitol and granulation with starch glue, followed by drying and regranulation;

2) homogenization of the granule obtained in item 1 on dry basis with the other excipients and the active substance;

3) after tabletting, treatment of the obtained tablets with acetophthalate cellulose mixed with diethyl phthalate, isopropyl alcohol and acetone;

4) glossing of the resulting dragees with a mixture of PEG 6000 and glycerol mixed with isopropyl alcohol and acetone.

The dosage form of the invention is stable under storage conditions and throughout, with high rates of

65538 Bl moisture and heat resistance. It has a breakdown of up to 30 min, a dissolution rate of at least 80% over a period of 45 min. The proposed ratios between the binder - polyvidone K25, the sixth and the microcrystalline cellulose, simultaneously lead to an increase in the mechanical strength of the tablet core, good degradability and a degree of dissolution of the active substance, which meets modern pharmacopoeial requirements. Removing one binder and reducing the amount of polyvinylpyrrolidone results in a decrease in production. The method is easily feasible on an industrial scale. In addition, the product does not contain highly dispersed silica, which, as recommended by the WHO, should be avoided whenever possible because of the risk of causing injury to production personnel.

Embodiments of the invention

Composition of one tablet in g:

Silymarin 100%

Colidon 25

Wheat starch

Lactose

Glucose

Sorbitol

Avicel

Talc

Magnesium stearate

Sodium bicarbonate Acetophthalate cellulose Diethyl phthalate

Sucrose

Arabic rubber

Gelatin

T ethane dioxide

Talc

Paint pigment brown

PEG 6000

Glycerin

The tablet mass is prepared by mixing wheat starch, lactose, glucose and sorbitol, the mixture is granulated with starch glue and then dried and regranulated. The resulting granulate is homogenized dry with silymarin, Colidone 25, Avicel (microcrystalline-

Example 1 Example 2 0,03500 0,03500 0,00165 0,00900 0,05538 0,05236 0,05538 0,05920 0,02060 0,01800 0,00413 0,00400 0,06700 0,05700 0,00700 0,00700 0,00250 0,00250 0,00136 0,00130 0,00084 0,00084 0,00060 0,00060 0,16219 0,1988 0,00219 0,00215 0,00086 0,00024 0,00482 0,01334 0,04583 0,06625 0,00313 0,00613 0,00013 0,00014 0,00003 0,000024

cellulose), talc, magnesium stearate and sodium bicarbonate. Tableting follows. The resulting tablets were treated with acetophthalate cellulose mixed with isopropyl alcohol and diethyl phthalate. The insulated tablets are coated with a coating film consisting of: sucrose,

65538 Bl arabic gum, gelatin, titanium dioxide, talc and pigment paint. The final treatment - glossing - is carried out with a mixture of PEG 6000, acetone, isopropyl alcohol and glycerin.

The achievement of high mechanical strength combined with good tablet disintegration and the required solubility of the active substance are illustrated by the following examples of tablet core and dragee formulation tests.

Three batches of tablets according to Example 1 were studied as follows:

Unwrapped tablets - for breakdown, mechanical strength, degree of dissolution of silymarin. 5 Coated tablets - disintegration.

1. Examination of uncoated tablets. The statistically processed survey results are given in the following table:

1. Decomposition of uncoated tablet

Norm: no more than 15 min

Lot # X X min X max 81001 5 3 5 21101 4 2 4 31101 3 2 3

2. Mechanical strength

Norm: 40-70 N

By № Batch No. 81001 Batch No. 21101 Batch № 31101 1. 44.0 50.0 51.0 2. 50.0 50.0 50.0 3. 46.0 48.0 51.0 4. 44.0 43.0 54.0 5. 44.0 54.0 56.0 6. 48.0 43.0 55.0 7. 41.0 48.0 55.0 8. 49.0 47.0 51.0 9. 50.0 39.0 54.0 10. 57.0 43.0 50.0 Xmin = 41.0 Xmin = 39.0 Xmin = 50.0 Xmax = 57.0 Xmax = 54.0 Xmax = 56.0 Range = 16.0 Range = 15.0 Range = 6.00 X = 47.3 X = 46.5 X = 52.7 S = 4.55 S = 4.45 S = 2.31 V = 9.61% V = 9.58% V = 4.39%

65538 Bl

3. The degree of dissolution of silymarin> of the declared content after 45 min • less than

Norm: 80%

Lot 81001 103.47%

Batch 21101 101.3%

Lot 31101 97.7% Study of coated tablets Degradation of coated tablet 5 Norm: not more than 30 min

Lot Ns X X min X max 81001 12 10 12 21101 12 8 12 31101 10 8 10

Claims

Claims (2)

Claims 1. A dosage form of Silymarin made up of a tablet core comprising silymarin, polyvinylpyrrolidone K25, wheat starch, lactose, glucose, sorbitol, microcrystalline cellulose, talc, magnesium stearate and sodium bicarbonate, coated with a layer of acetavetophthalate, with the tablet core comprising polyvinylpyrrolidone K25 from 0.0010 to 0.009 g, starch 0.050-0.060 g, lactose 0.050-0.060 g, glucose 0.0150-0.0208 g, sorbitol 0.00400-0.00415 g and microcrystalline cellulose 0.0567-0.070 g. A method for preparing a dosage form according to claim 1, comprising the preparation of a tablet core, tabletting, coating and glossing, characterized in that: - mixing of wheat starch, lactose, glucose and sorbitol and granulation with starch glue, subsequent drying and regranulation; - homogenization of the granulate obtained, dry with the other excipients and the active substance; - treatment of the obtained tablets with acetophthalate cellulose mixed with isopropyl alcohol, acetone and diethyl phthalate, and - glossing of the resulting dyes with PEG and glycerol mixed with acetone and isopropyl alcohol.