RU2286150C1 - Pharmaceutical formulation of prolonged action with diuretic, vasodilatation and hypotensive activity, and method for production thereof - Google Patents

Abstract

FIELD: pharmaceutical industry, in particular, in particular solid pharmaceutical formulations useful in treatment of arterial hypertension and chronic heart failure.

SUBSTANCE: claimed formulation comprises core containing (mass %): inapamide 0.3-2.0; colloidal silica 0.1-2.5; hydroxypropyl cellulose 8-35; vinyl pyrrolidone-vinyl acetate copolymer 1.8-4.5; magnesium stearate 0.1-1.0; lactose 15.0-55.0; and balance: microcrystalline cellulose; and sell dissolvable in stomach and containing (mass %) polyethylene glycol 10.0-17.0; titanium dioxide 11.5-20.5; talk 1.8-6.3; and balance hydroxypropylmethyl cellulose. Method for production of said formulation also is provided.

EFFECT: Agent with gradual releasing of active ingredient; tablets with increased mechanical strength; preparation of improved quality in storage process.

3 cl, 1 tbl, 2 ex

Description

The invention relates to medicine, in particular to pharmacy, can be used in the manufacture of solid dosage forms of drugs used in the treatment of arterial hypertension and chronic heart failure.

The closest dosage form to the proposed one is the dosage form disclosed in published application No. 2003103482/15 of 08/20/2004.

This dosage form consists of a core containing, wt.%:

Indapamide 0.8-5.0 Milk sugar 50-70 Polyvinylpyrrolidone 1-3 Microcrystalline cellulose 20-30 Starch Glycolate 3-10 Magnesium stearate 0.1-1.0

and shell containing wt.%:

Hydroxypropyl cellulose 25-40 Vinylpyrrolidone copolymer and vinyl acetate 25-40 Titanium dioxide 20-30 Talc 10-20.

The same source discloses a method of manufacturing this dosage form, according to which milk powders, indapamide, microcrystalline cellulose are mixed with a portion of starch glycolate, moistened with an aqueous solution of polyvinylpyrrolidone, re-mixed, wet granulation, subsequent drying, dry granulation, added to the granulate magnesium stearate and starch glycolate residue. Then, the resulting mass is tabletted and coated from a suspension containing a copolymer of vinylpyrrolidone and vinyl acetate, hydroxypropyl cellulose, titanium dioxide and talc.

The disadvantages of the described dosage form, as well as the method of its manufacture, include the fact that the drug does not have a prolonged effect, the maximum therapeutic effect is achieved within two hours after taking the drug. The extension of the time of release of the active component provided by the proposed composition allows to stabilize the concentration of the antihypertensive drug in the human body during the day. This allows you to reduce the dose of the drug in the human body during the day. This allows you to reduce the dose of the drug to achieve the desired therapeutic effect, to reduce the likelihood of side effects.

The objective of the invention is to obtain a drug with vasodilating, diuretic and antihypertensive activity, as well as a prolonged duration of the drug.

The problem is solved in that the dosage form having diuretic, vasodilating and antihypertensive activity consists of a core containing indapamide, milk sugar, microcrystalline cellulose and magnesium stearate, and a shell dissolving in the stomach containing talc and titanium dioxide, while the core additionally contains silicon colloidal dioxide, a copolymer of vinylpyrrolidone and vinyl acetate and hydroxypropyl methylcellulose, in the following ratio, wt.%:

Indapamide 0.3-2.0 Silicon Colloidal Dioxide 0.1-2.5 Hydroxypropyl methylcellulose 18-35 Vinylpyrrolidone Vinyl Acetate Copolymer 1.8-4.5 Magnesium stearate 0.1-1.0 Milk sugar 15.0-55.0 Microcrystalline cellulose rest

and the shell additionally contains hydroxypropylmethyl cellulose and polyethylene glycol in the following ratio of components, wt.%:

Polyethylene glycol 10.0-17.0 Titanium dioxide 11.5-20.5 Talc 1.8-6.3 Hydroxypropyl methylcellulose rest

In private embodiments of the invention, the problem is solved in that the core as a copolymer of vinylpyrrolidone and vinyl acetate contains VA 64 collidone.

The problem is also solved by a method of manufacturing a dosage form, including mixing powders of milk sugar, indapamide and microcrystalline cellulose, subsequent wetting, re-mixing until even distribution of moisture, subsequent wet granulation, drying, dry granulation, dusting the granulate with a mixture containing magnesium stearate, tableting and application a coating of a suspension containing titanium dioxide and talc, in accordance with which hydration is carried out with an aqueous solution of a vinyl copolymer irrolidona and vinyl acetate, a mixture of powdering is performed, further comprising hydroxypropylcellulose and colloidal silicon dioxide, and the coating is carried out from the suspension, further comprising polyethylene glycol and hydroxypropyl methylcellulose.

The invention consists in the following.

As an active principle, the drug contains indapamide (Indapamide) with the chemical name 3- (Aminosulfonyl) -4-chloro-N- (2,3-dihydro-2-methyl-1H-indol-1-yl) benzamide (and hemihydrate form).

In the invention, in comparison with the known technical solution, the content of auxiliary substances in both the core and the shell is selected in such a way as to achieve a gradual release of the active substance, which determines its prolonged action. To achieve a stable effect, its content in the core in the amount of 0.8-5.0% by weight is optimal.

The technical result of the invention lies in the fact that the components included in the composition create a hydrophilic matrix when exposed to moisture in the human gastrointestinal tract, which ensures the gradual release of the active component in normalized amounts over certain periods of time, increase the mechanical strength of the tablets, and ensure the stability of the quality indicators of the drug during storage.

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 combination and sequence of operations in the method and their modes provide ease of manufacture of dosage forms and the lowest cost.

The invention is as follows.

Sifted powders of indapamide, milk sugar and microcrystalline cellulose are loaded into the mixer, thoroughly mixed for 200-300 seconds. For optimal mixing, indapamide is first triturated with milk sugar, followed by the addition of the remaining milk sugar and microcrystalline cellulose. Other mixing options for the dry components are also possible.

The dry mixture is moistened with VA 64 collidone solution, mixed until the moisture is evenly distributed and granulated.

The granules are dried, ground, dusted with a mixture of hydroxypropyl methylcellulose, magnesium stearate and silicon dioxide colloidal, which is used as aerosil, and mixed until a homogeneous mass. The resulting mixture was tabletted.

The tablets are film-coated, for which a suspension of talc and titanium dioxide is prepared in an aqueous solution of hydroxypropyl methylcellulose 15 cf with the addition of polyethylene glycol 4000.

Example 1

Received tablets "Ionic Retard" prolonged action, coated, 1.5 mg.

Sifted powders of milk sugar (7.18 g) and indapamide (0.52 g) were loaded into the mixer and mixed for 90 s. Then another 13 g of sifted milk sugar were loaded and mixed for 60 s. To the resulting mixture was added 20.14 g of microcrystalline sieved cellulose and thoroughly mixed for 90 seconds.

Then, 31.2 g of a 5% solution of VA 64 collidone was added in several doses, mixed until the moisture was evenly distributed and granulated on a granulator with a hole diameter of 1.5-2 mm.

The granules were dried, ground and granulated on a granulator with a hole diameter of 1 mm. Then the dry granules were dusted with a mixture of 18.76 g of Benecel 824 hydroxypropyl methylcellulose, magnesium stearate 0.614 g and aerosil 0.307 g, mixed until a homogeneous mass was obtained.

The resulting mixture was tableted.

The core tablets were film-coated, for which a suspension of 0.74 g of talc and 0.259 g of titanium dioxide in an aqueous solution of 1.28 kg of hydroxypropyl methylcellulose 15 sr was added with 0.222 g of polyethylene glycol 4000 added.

Example 2

Sifted powders of milk sugar (12.272 g) and indapamide (0.52 g) were loaded into the mixer and mixed for 90 s. Then loaded another 13 g of milk sifted sugar and mixed again. To the resulting mixture was added 14.317 g of microcrystalline sieved cellulose and mixed thoroughly for 90 seconds.

Then, 37.44 g of a 5% solution of VA 64 collidone was added in several doses, mixed until the moisture was evenly distributed and granulated on a granulator with a hole diameter of 1.5-2 mm.

The granules were dried, ground and granulated on a granulator with a hole diameter of 1 mm. Then the dry granules were dusted with a mixture of 19.22 g of Benecel 824 hydroxypropyl methylcellulose, 0.437 g of magnesium stearate and 0.62 g of aerosil, and mixed until a homogeneous mass was obtained.

The resulting mixture was tableted.

The core tablets were film-coated, for which a suspension of 0.74 g of talc and 0.259 g of titanium dioxide in an aqueous solution of 1.28 g of hydroxypropyl methylcellulose 15 sr was added with the addition of 0.222 g of polyethylene glycol 4000.

Table 1 shows the tablet formulations of the proposed composition.

Tablet composition one 2 3 four The composition of the core, wt.%: 1. Indapamide. 0.83 0.83 0.3 2.0 2. Aerosil 0.5 1,0 2,5 0.1 3. Hydroxypropyl methyl cellulose (Benecel MP 824) 30.56 31 35 eighteen 4. Kollidon VA 64 2,5 3.0 4,5 1.8 5. Magnesium stearate 1,0 0.7 0.1 1,0 6. Milk sugar 32.33 40.50 15.0 55.0 7. Microcrystalline cellulose The rest is up to 100% The composition of the shell, wt.%: 1. Polyethylene glycol 4000 12 12 10 17 2. Talc four four 1.8 6.3 3. Titanium Dioxide fourteen fourteen 20.5 11.5 4. Hydroxypropylmethylcellulose vine 15 Wed The rest is up to 100%.

In the manufacture of the drug in accordance with the above example, tablets were obtained that meet the requirements of the FSP.

For tablets with an average weight of 0.192 g:

dissolution: after 4 hours - 21.15%

after 8 hours - 46.21%

after 16 hours - 75.12%;

- foreign impurities: two impurities less than 0.5% each, in total - 0.67%;

- dosage uniformity: from - 7.8% to 9.5%;

- indapamide content: 0.00159 g.

Claims (3)

1. A dosage form having diuretic, vasodilating and hypotensive activity, consisting of a core containing indapamide, milk sugar, microcrystalline cellulose and magnesium stearate, and a shell dissolving in the stomach containing talc and titanium dioxide, characterized in that the core additionally contains silicon dioxide colloidal, a copolymer of vinyl pyrrolidone and vinyl acetate and hydroxypropyl methyl cellulose, with the following components, wt.%: Indapamide 0.3-2.0 Silicon Colloidal Dioxide 0.1-2.5 Hydroxypropyl methylcellulose 18-35 Vinylpyrrolidone copolymer and vinyl acetate 1.8-4.5 Magnesium stearate 0.1-1.0 Milk sugar 15.0-55.0 Microcrystalline cellulose Rest and the shell further comprises hydroxypropylmethyl cellulose and polyethylene glycol, with the following components, wt.%: Polyethylene glycol 10.0-17.0 Titanium dioxide 11.5-20.5 Talc 1.8-6.3 Hydroxypropyl methylcellulose Rest 2. The dosage form according to claim 1, characterized in that the core as a copolymer of vinyl pyrrolidone and vinyl acetate contains VA 64 collidone. 3. A method of manufacturing a dosage form having diuretic, vasodilating and antihypertensive activity, comprising mixing powders of milk sugar, indapamide and microcrystalline cellulose, subsequent wetting, re-mixing until even distribution of moisture, subsequent wet granulation, drying, dry granulation, dusting the granulate with a mixture containing magnesium stearate, tabletting and coating from a suspension containing titanium dioxide and talc, characterized in that the hydration is carried out odnym solution of the copolymer of vinylpyrrolidone and vinyl acetate, a mixture of powdering is performed, further comprising hydroxypropylcellulose and colloidal silicon dioxide, and the coating is carried out from the suspension, further comprising polyethylene glycol and hydroxypropyl methylcellulose.