RU2252024C2 - Method for obtaining spasmolytic medicinal preparation - Google Patents

Abstract

FIELD: medicinal industry.

SUBSTANCE: the present innovation deals with manufacturing medicinal preparation containing drotaverin hydrochloride to be applied for interrupting spasms of smooth musculature. Mass for tableting should be prepared due to mixing the powder of drotaverin hydrochloride with that of dyed granulate at the ratio of 1:3 to 2:1. One should obtain the dyed granulate by moisturizing inert pharmaceutical filler with binder's solution dyed with quinoline yellow dyestuff. Then comes drying up to 0.1-2.5% followed by granulation and tableting. The innovation enables to obtain tablets of drotaverin hydrochloride upon industrial equipment at its degradability being below 15 min, being stable during manufacturing and at storage. Quality of tablets meets all the requirements of pharmacopoeic article.

EFFECT: higher efficiency of manufacturing.

2 cl, 4 ex, 3 tbl

Description

The present invention relates to the medical industry, namely the production of medicines containing drotaverine hydrochloride used to relieve smooth muscle spasm.

Antispasmodic effect, i.e. decrease in tone and the removal of spasms of smooth muscles of internal organs and blood vessels can be achieved using various substances, in particular derivatives of purine (theobromine, theophylline), benzylbenzimidazole (dibazole), isoquinoline (papaverine, drotaverine) [1].

It is known that drotaverine hydrochloride is easily oxidized in an aqueous medium with the formation of colored decomposition products. To prevent the destruction of drotaverine, a number of compositions and methods have been proposed, characterized in that the stage of hydration of drotaverine hydrochloride is excluded from the composition of drugs and production technology. The process is implemented by encapsulating a drug in a system of water-insoluble polymers [2-5], vinylpyrrolidone copolymers [6], modified starch [7] or melt extrusion [8].

The listed compositions and production methods allow to obtain drotaverin dosage forms (tablets, granules) that are stable during storage, but require the use of expensive equipment and a complex technological scheme.

The closest in composition and sequence of technological operations is an antispasmodic drug [9] (prototype), antispasmodic drug [Nesterchuk V.V., Syrov K.K. A pharmaceutical composition having antispasmodic activity, and a method for its preparation. RF patent No. 2183119, 06/10/2002] containing drotaverin hydrochloride, milk sugar, starch, crospovidone, talc, calcium stearate and a preparation method consisting in the fact that the mixture of drotaverin hydrochloride, starch, lactose is moistened with 3% starch paste, granulated, dried , re-passed through a granulator, the obtained dry granulate is mixed with crospovidone, calcium stearate, talc, and tabletted.

The implementation of this method allows to obtain tablets weighing 0.14-0.16 g, containing 0.04 g of drotaverine hydrochloride, disintegrating in water in 15 minutes, containing, wt.%: 29.8 drotaverine hydrochloride, 38.7 lactose, 26, 0 starch, 1.0 mixture of magnesium stearate and stearic acid, 4.5 polyvinylpyrrolidone (hereinafter referred to as PVP) and a method for producing it, according to which the mixture of ingredients is moistened with a 21% PVP solution, dried at 60 ° C to a moisture content of 2-3 %, granulated through a sieve with holes of 1.0-2.0 mm, tableted with punches with a diameter of 7 mm

The implementation of this method allows to obtain tablets weighing 0.12-0.16 g, containing 0.04 g of drotaverine hydrochloride, disintegrating in water in 15 minutes.

The disadvantage of this antispasmodic is the lack of stability of drotaverine hydrochloride when processed into tablets, namely during wet granulation and drying. As a result of the removal of the hydrochloride molecule of hydrochloride from the drotaverin molecule, the drotaverin base is formed, which is easily oxidized by atmospheric oxygen to form colored decomposition products. Therefore, during processing and storage, the tablets change color, the appearance of yellow-brown spots is observed.

The aim of the present invention is to develop a method for producing drotaverin tablets in the task of increasing the stability of the drug during processing and storage, subject to full compliance with the requirements of the pharmacopeia [10] and pharmacopeia article on drotaverine tablets 0.04 g [11]:

- appearance (tablets are round in shape with flat surfaces, solid edges of a uniform light yellow-green color with color coordinates R> 254, G> 253, 150 <B> 175),

- abrasion resistance (not less than 97%),

- deviation in the mass of individual tablets (not more than ± 5%),

- disintegration not more than 15 minutes,

- storage stability for two years.

This goal is achieved in that a method for producing an antispasmodic drug based on drotaverin hydrochloride is developed, which includes preparing the tablet mass, tableting, characterized in that the tablet mass is prepared by mixing drotaverin hydrochloride powder with colored granulate powder in a ratio of 1: 3 to 2: 1, and the preparation of colored granulate is carried out by wetting an inert pharmaceutical excipient with a colored quinoline yellow solution with knitting, drying to a moisture content of 0.1-2.5%, dry granulation, while the components are taken in the following ratio,% by weight of the granulate: inert pharmaceutical excipient 93.90-99.77, a binder of 0.1-5.0, quinoline yellow dye 0.03-0.1, stearic acid or its salts 0.1 = 1.0.

In accordance with the invention proposed as:

- inert pharmaceutical excipient to use substances approved for use in the pharmaceutical industry, preferably lactose and starch, and mixtures thereof in a ratio of 4: 1-3: 2.

- binder - use substances approved for use in the medical industry, preferably polyvinylpyrrolidone.

Thus, the essence of the invention is that:

- the claimed method for producing an antispasmodic drug eliminates the stage of moisturizing and drying at high temperature, drotaverine hydrochloride. The proposed sequence of operations involves mixing the initial drotaverine powder with dried granulate powder and pressing under normal conditions. As a result, the effect of high temperatures and humidity on the drotaverin molecule is excluded, which favorably affects its stability during processing and during the shelf life.

- the composition, in comparison with the known, additionally contains a dye - quinoline yellow, which is necessary to obtain a granulate color identical to the yellow-green color of drotaverine hydrochloride powder. As a result, it becomes possible to obtain uniformly colored tablets.

- used a new ratio of ingredients, allowing you to change the dosage of the active substance from 40 and 80 mg per tablet and, therefore, pharmacokinetic parameters of the effectiveness of the tablets.

The proposed ratios of active and excipients are optimal and make it possible to obtain tablets disintegrating within 15 minutes, meeting the requirements of the Pharmacopoeia in all respects, stable during production and storage for two years.

Reducing or increasing the parameters of the process away from the stated limits leads to a decrease in the quality of the resulting tablets or makes tabletting difficult.

An antispasmodic drug is prepared as follows.

An inert pharmaceutical excipient of 93.90-99.77%, preferably lactose and starch in a ratio of 4: 1-3: 2, stearic acid or its salts 0.1-1.0% is loaded into the mixer, mixed and a colored binder solution is added in the calculation a binder of 0.1-5.0%, a dye of 0.03-0.1% by weight of the obtained granulate is mixed. This ratio is necessary to ensure the disintegration of the tablets, not more than 15 minutes, at their nominal strength (see example No. 1).

The dye concentration of 0.03-0.1% is selected based on the calculation of the color of the granules identical to the color of the powder drotaverine hydrochloride (see example No. 2).

The colored mass from the mixer is transferred to the dryer and dried to a moisture content of 0.1-2.5%.

The choice of this limit is based on experimental data on the effect of granulate moisture on pressing stability. At a moisture content of more than 2.5%, sticking of the tablet mass to the surface of the punches is observed. A decrease in humidity of less than 0.1% leads to irrational waste of heat.

The dried mass is granulated through a sieve with openings of less than 1.0 mm. Preferably 0.4 mm. This indicator is necessary to exclude the possibility of the formation of tablets of a heterogeneous (spotty) surface.

Drotaverin hydrochloride powder is mixed with colored granulate powder in a ratio of 1: 3 to 2: 1, respectively. This ratio is necessary and sufficient to obtain tablets weighing 0.12-0.16 g, containing 0.08 or 0.04 g of drotaverine hydrochloride, respectively (see examples 3 and 4).

The tablet mass is pressed with punches with a diameter of 7.0 mm of the RTM 41 tablet press with a rotor speed of 14 revolutions per minute. The weight of the tablets is 0.14 ± 0.02 g. The height of the tablets is 2.2-3.2 mm.

As can be seen from the foregoing, only the proposed intervals of the ratios of the ratios of the ingredients are optimal and allow you to get a more effective drug in the form of tablets that meet the requirements of scientific and technical documentation [10, 11] for all indicators and stable during storage.

Example 1

100 g of lactose and starch were mixed in a mortar in the ratios 5: 1, 4: 1, 3: 2, 3: 1. To the resulting masses were added 0.05, 0.1, 1.0, 1.2 calcium stearate and moistened with 20 g of a solution containing 0.05 g of PVP and 0.01 g of quinoline yellow, 0.1 and 0.03 g 5.0 and 0.1 g, 7.0 and 0.15 g, respectively. The masses were granulated through a sieve with 8 mm openings. Dried to a moisture content of less than 2.0%. Granulated through a sieve with 0.4 mm holes.

Drotaverine hydrochloride was mixed with the obtained colored granules in a ratio of 1: 4, 1: 3, 2: 1, 3: 1, pressing tablets with punches with a diameter of 7.0 mm hydraulic press at a pressure of 50 kg / cm ² , weighing 0.11, 0, 12, 0.16, 0.18 g, respectively.

At the same time, drotaverine hydrochloride tablets were prepared according to the method adopted in the prototype. 29.8 drotaverine hydrochloride, 38.7 lactose, 26.0 starch, 1.0 1: 1 mixture of magnesium stearate and stearic acid were mixed in a mortar and moistened with a solution of 4.5 g of polyvinylpyrrolidone in 16.93 g of water. The resulting mass was dried at 60 ° C to a moisture content of 2-3%, granulated through a sieve with holes of 1.0-2.0 mm and tableted with punches with a diameter of 7 mm of a hydraulic press with a pressure of 50 kg / cm ² . The average weight of the tablets is 0.15 g.

The data on the disintegration and color of the tablets of the experimental options in comparison with the prototype (see table. 1 experiment No. 5) are presented in table 1.

Table 1 The effect of the concentration of ingredients on the properties of drotaverine hydrochloride tablets No. Drotaverine hydrochloride / colored granulate ratio Colored granulate Tablet weight, g Decay capacity, minutes “B” color coordinate of tablets filler magnesium stearate,% binder,% crane,% lactose / starch ratio % 1 1: 4 5: 1 99.94 0,0 0.05 0.01 0.11 0.8 182 2 1: 3 4: 1 99.77 0.1 0.10 0,03 0.12 1,2 172 3 2: 1 3: 2 93.90 1,0 5.00 0.10 0.16 7.5 152 4 3: 1 4: 2 91.65 1,2 7.00 0.15 0.18 fifteen 134 5 29.8 1: 1,453 70,2 1,0 4,50 - 0.15 7.0 170

The data in the table show that in the experiments obtained with the ratio of drotaverine hydrochloride: colored granulate 1: 3-3: 1, with the ratio in the colored granulate lactose: starch 4: 1-4: 2 and the concentration of magnesium stearate 0.1-1.0 %, a binder of 0.1-7.0 and a dye of 0.03-0.10% obtained tablets containing 0.04-0.08 g of drotaverine, meeting the requirements of the Pharmacopoeia in appearance, disintegrating in 5-7 minutes and corresponding to color tablets obtained by the method of the prototype. Leading the process beyond the stated limits does not allow you to get tablets that match the specified parameters.

Example 2

To determine the effect of the quinoline yellow concentration on the color properties of the tablets, 30 g of starch were mixed with 67 g of lactose and 1 g of calcium stearate. The mixture was moistened with a solution of 2 g of PVP in 30 ml of water containing various amounts of quinoline yellow. Dried to a moisture content of less than 2.0%. Granulated through a sieve with 0.4 mm holes. The substance of drotaverine hydrochloride was ground in a rotary mill and the powder was sieved through a nylon sieve No. 23. 7 g of the obtained colored granules were mixed with 3.0 g of sifted drotaverine. Tableted with 7 mm punches. Samples were scanned. Drotaverin hydrochloride tablets, 0.04 g obtained in full accordance with the prototype method, were used as the color optimality criterion (see Table 2, experiment No. 8).

table 2 The effect of the concentration of quinoline yellow on the color properties of drotaverine tablets The concentration of quinoline yellow,% Color coordinates R G IN 0.01 253.16 ± 0.16 252.83 ± 0.16 204.50 ± 0.22 0,03 253.83 ± 0.16 252.66 ± 0.21 174.83 ± 0.40 0.05 253.16 ± 0.16 252.83 ± 0.16 164.50 ± 0.22 0,07 253.83 ± 0.16 252.66 ± 0.16 154.50 ± 0.22 0.10 253.83 ± 0.16 252.66 ± 0.16 150.50 ± 0.22 0.11 253.83 ± 0.16 252.66 ± 0.16 142.83 ± 0.40 Prototype 253.83 ± 0.16 252.66 ± 0.16 170.50 ± 0.22

The data presented in table 2 allow us to determine the optimal concentration of quinoline yellow 0.03-0.10%, which allows to obtain tablets corresponding in color in the range of 175-150 units “B” color coordinates of the tablets of the prototype.

Example 3

0.25 g of quinoline yellow was dissolved in 25 g of water. 6.6 g of PVP was dissolved in 93.4 g of water. 8 g of PVP solution was mixed with 2.15 g of dye solution. The resulting colored PVP solution was moistened with a mixture of 22.3 lactose, 10 g of starch, 0.33 g of calcium stearate. The tablet mass was dried to a moisture content of less than 2.0%. The tablet mass was granulated through a nylon sieve No. 23. Grinded drotaverine hydrochloride, sieved through a nylon sieve No. 23. To obtain tablets containing 0.04 g of drotaverine hydrochloride, 7 g of colored granulate was mixed with 3 g powder of ground drotaverine hydrochloride.

To obtain tablets containing 0.08 g of drotaverine hydrochloride, 4.3 g of colored granulate were mixed with 5.7 g of drotaverine hydrochloride, respectively.

The obtained tablet masses were pressed with punches of 7 mm hydraulic tablet press with a force of 50 kg / cm ² . The weight of the tablets is 0.14-0.15 g.

The stability of the drug was determined in vivo by measuring the color of the tablets after two years. As control used tablets obtained by the method of the prototype. The results are presented in table 3 and 4.

Table 3 Coloristic properties of tablets before storage Name Color coordinates R G IN Drotaverine tablets 0.04 g 253.83 ± 0.16 252.66 ± 0.16 175.50 ± 0.22 Drotaverine tablets 0.08 g 253.83 ± 0.16 252.66 ± 0.21 172.83 ± 0.40 Prototype 253.16 ± 0.16 252.83 ± 0.16 174.50 ± 0.22

Table 4 Coloristic properties of tablets after storage for two years Name Color coordinates R G IN Drotaverine tablets 0.04 g 247.50 ± 0.22 217.66 ± 5.11 172.22 ± 7.72 Drotaverine tablets 0.08 g 254.73 ± 0.54 239.33 ± 2.61 169.53 ± 0.80 Prototype 248.00 ± 0.24 220.13 ± 1.26 155.50 ± 3.82

From tables 3 and 4 it is seen that the tablets obtained by dry pressing, are more stable in comparison with samples obtained by wet granulation. The change in color coordinate of the tablets obtained by the claimed method is 10.2-10.7%, while in the prototype 18.7%.

Example 4

22.3 kg of lactose, 10 kg of starch, 0.33 kg of calcium stearate were successively loaded into the mixer, mixed and moistened with a solution of 0.528 kg of PVP and 0.0215 kg of quinoline yellow in 9.83 kg of water. The mixture was transferred to a SP-60 fluidized-bed dryer basket and dried to a moisture content of less than 2.0%, wiped through a nylon sieve No. 23 to obtain 31 kg of colored granulate.

41 kg of drotaverin hydrochloride sieved through a No. 23 sieve and 31 kg of colored granulate were loaded into the mixer, mixed.

The obtained tablet mass was tabletted with punches with a diameter of 7 mm of the RTM-41 tablet press at a speed of 14 revolutions per minute. The weight of the tablets is 0.14 g. The height of the tablets is 2.8-3.2 mm. Disintegration 3 minutes. Abrasion 99.6%. Dissolution of 84.85% by weight of the active substance within 30 minutes. Tablets are characterized by a smooth smooth surface, uniform color.

Literature:

1. Mashkovsky M.D. Medicines: -Mn .: Belarus, 1987.- 4.1. from. 393.

2. Grabowski, et al. Slow-release torus, matrix pellets and the production thereof United States Patent 6,290,990 September 18,2001.

3. Amey, et al .. Process for encapsulation of caplets in a capsule and solid dosage forms obtainable by such process. United States Patent 6,245,350 June 12,2001.

4. Van Lengerich, Embedding and encapsulation of controlled release particles. United States Patent 6,190,591 February 20,2001

5. Amey, et al. Process for encapsulation of caplets in a capsule and solid dosage forms obtainable by such process. United States Patent 6,080,426 June 27,2000.

6. Goertz, et al. Preparation of solid pharmaceutical forms. United States Patent 4,801,460 January 31,1899.

7. Breitenbach, et al. Storage-stable drug form. United States Patent 5,945,127 August 31, 1999.

8. Klimesch, et al .. Continuous preparation of solid pharmaceutical forms. United States Patent 5,073,379 December 17,1991.

9. Starting schedule for the production of tablets of drotaverine hydrochloride 0.04 g, Moscow, TSHLS VNIHFI, 06/16/2000. Prototype.

10. State Pharmacopoeia of the USSR: Issue. 2 General methods of analysis. Medicinal

and vegetable raw materials / Ministry of Health of the USSR. 11th ed. - M .: Medicine, 1989. - T. 2. - S.154-159.

11. VFS 42-3107-98. Drotaverine hydrochloride tablets 0.04 g.

Claims (3)

1. A method of producing an antispasmodic drug based on drotaverine hydrochloride, comprising preparing a tablet mass, tableting, characterized in that the tablet mass is prepared by mixing drotaverin hydrochloride powder with colored granulate powder in a ratio of 1: 3 to 2: 1, and obtaining colored granulate is carried out by moistening an inert pharmaceutical excipient with a colored quinoline yellow binder solution, drying to a moisture content of 0.1-2.5%, dry granules the components are taken in the following ratio,% by weight of the granulate: inert pharmaceutical excipient 93.90-99.77, binder 0.1-5.0, quinoline yellow dye 0.03-0.1, stearic acid or its salts of 0.1-1.0. 2. The method according to claim 1, characterized in that as an inert pharmaceutical excipient use substances approved for use in the pharmaceutical industry, preferably lactose and starch and mixtures thereof in a ratio of 4: 1-3: 2. 3. The method according to claim 1, characterized in that as a binder use substances approved for use in the medical industry, preferably polyvinylpyrrolidone.