RU2232018C2 - Spasmolytic medicinal agent - Google Patents

Abstract

FIELD: medicinal industry, pharmacy.

SUBSTANCE: invention relates to a spasmolytic medicinal agent comprising drotaverine hydrochloride used for arresting smooth muscle spasm. Agent comprises the following components, wt.-%: drotaverine hydrochloride, 15.0-62.5; inert pharmaceutical vehicle, 28.1-84.696; binding agent, 0.1-7.0; stearic acid and/or stearate, 0.2-1.0; inorganic acid, 0.004-1.4. Agent comprises phosphoric or hydrochloric acid as an inorganic acid. Agent is made as a tablet, its mass is from 0.065 to 0.26 g. Drotaverine hydrochloride tablets are stable in the making process and in storing for 2 years. Quality of tablets satisfies Pharmacopoeia requirements.

EFFECT: improved and valuable pharmaceutical and medicinal properties of agent.

6 cl, 1 dwg, 5 tbl, 4 ex

Description

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

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 a medicinal product [9] (prototype), containing paracetamol, drotaverine hydrochloride, codeine phosphate, excipients, characterized in that it additionally contains one or a mixture of organic kisadag or sodium sorbate as a stabilizer as a stabilizer.

The specified drug is a tablet containing 500 mg of paracetamol, 40 mg of drotaverine and 8 mg of codeine phosphate, disintegrating in water in 15 minutes.

The disadvantage of this antispasmodic is the lack of stability of drotaverine during storage. The process of inactivation of drotaverine hydrochloride begins with the removal of a molecule of hydrochloric acid from a molecule of the active substance. As a result, a drotaverin base is formed, which is easily oxidized by atmospheric oxygen to form colored decomposition products. Therefore, during storage, the tablets change color, the appearance of yellow-brown spots is observed.

The aim of the present invention is to develop the composition of drotaverine tablets in the task of increasing the stability of the drug during 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> 253, G> 246, 175 <B <185),

- 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 an antispasmodic drug is developed in the form of tablets weighing 0.065-0.26 g, containing drotaverine hydrochloride, an inert pharmaceutical excipient, a binder, stearic acid and / or its salts, characterized in that it additionally contains (0.004-1, 4) wt.% Inorganic acid, in the following ratio, wt.%: Drotaverine hydrochloride 15.0-62.5, inert pharmaceutical excipient 28.1-84.696, binder 0.1-7.0, stearic acid and / or its salt is 0.2-1.0.

In this case, the claimed drug contains as:

- inorganic acid phosphoric or hydrochloric acid,

an inert pharmaceutical excipient of a food grade or medical grade carbohydrate class compound, in particular glucose, lactose, sucrose, fructose, starch or / and mixtures thereof.

- a binder - polyvinylpyrrolidone, polyethylene glycol, starch and / or a mixture thereof. Thus, the essence of the invention is that:

- in the composition of the claimed medicinal product, in comparison with the known one, an inorganic acid is contained, which prevents the transformation of drotaverine from a salt form into a base during wet granulation and drying and during storage during the shelf life, including at temperatures above 20 ° C. The claimed change in the composition of the tablet allows to exclude the cleavage reaction occurring in a neutral and alkaline medium from a molecule of drotaverine hydrochloride hydrochloride with the formation of a free base drotaverine.

- used a new ratio of ingredients that allows you to change the dissolution rate of the tablets from 40 seconds to 15 minutes 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 and at elevated temperature.

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.

Drotaverine hydrochloride, an inert pharmaceutical filler of the carbohydrate class of food and medical value, in particular a mixture of starch and lactose, calcium stearate, is preferably loaded in a mixer, preferably in a ratio of 1: 1.4: 1.12: 0.05. This ratio is necessary to ensure the disintegration of the tablets, not more than 15 minutes, at their nominal strength (see example 4).

The mass in the mixer is mixed, then a 3-25% PVP solution containing acid is added in an amount calculated to obtain its concentration in the dried tablet mass from 0.004 to 1.4%.

The concentration limit of 0.004-1.4% of the acid in the tablet mass is necessary to stably prevent the transition of drotaverine hydrochloride from the salt form to the base. In the experiments, a stable transition of the color of the tablets to light yellow-green was established (the “B” color coordinates are more than 175-185 Units) at a concentration of hydrochloric acid in the composition of the tablets more than 0.004% (see example 1, table 1, op. No. 2). An increase in the concentration of phosphoric acid of more than 1.4% is impractical because leads to a discoloration of the tablets (see example 1, table. 2, op. No. 5).

The mixture is stirred until evenly moistened, and then dried to a moisture content of 1.9-5.0%. The choice of this interval is based on data (see example 2), according to which it was found that when the moisture content for tabletting is less than 1.9%, decolorization of the obtained granulate is observed. Pressing granulate with a moisture content of more than 5.0% is hindered by the sticking of the tablet mass on the surface of the press tool during the tabletting process.

The dried mass is subjected to dry granulation through a mesh with 1.0 mm holes. An increase in granule size of more than 1.0 mm leads to a heterogeneous color of the tablets (see example 3). It is preferable to use a granulate passing through a sieve with openings of 0.4 mm.

The granulate obtained is tabletted with punches with a diameter of 6-10 mm tablet press RTM-41. The weight of the tablets is from 0.065 to 0.26 g. Tablets weighing more than 0.26 g do not meet the requirements of the Pharmacopoeia in terms of “strength”. The lower limit is selected from the calculation of the minimum diameter of punches produced by industry.

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 are stable during storage.

Example 1

10 g of drotaverine hydrochloride, 14 g of potato starch, 11.25 g of lactose, 0.5 g of calcium stearate were loaded into a mortar, the components were thoroughly ground. The mixture was moistened with a solution of 0.75 g of PVP in 12 g of water. In the experiments, the amount of hydrochloric or phosphoric acid, which was introduced in a humidifier solution, was varied. Moistened masses were granulated through a grid with 0.8 mm holes and dried to a moisture content of 2.2-2.8%.

The control in the experiments was the options obtained in full accordance with the method adopted in the prototype (see tab. 1 and 2 op. No. 1). 10 g of drotaverine hydrochloride was mixed with 13 g of lactose, 8.75 g of starch, 0.35 g of a 1: 1 mixture of magnesium stearate and stearic acid, moistened with a solution of 0.24 g of citric acid and 1.5 g of PVP in 5.64 g of water . Dried at 60 ° C to a moisture content of 2.2%, granulated through a sieve with holes of 1.0 mm [2].

The experimental and control masses were tableted with punches with a diameter of 7 mm. The weight of the tablets is 0.15 g.

The obtained experimental and control samples of tablets were placed in an HP scanjet-4470c scanner. Color analysis was performed when processing the received graphic files with Corel 7 Photo-Paint software in “RGB” color coordinates.

The result of measuring the color characteristics of drotaverine tablets is presented in tables 1-2.

The optimality criterion was to obtain tablets of light yellow-green color with color coordinates R> 253, G> 246.175 <B <185.

From tables 1 and 2 it is seen that the introduction of 0.004-0.10 hydrochloric acid or 0.35-1.4% phosphoric acid into the tablet mass stabilizes the quality of the tablets during wet granulation, drying and tabletting (in the experiment without acid, the color coordinate was 170.5 IU, compared with the value of 176-181 IU in experiments with 0.35-1.4% acid). An increase in acid of more than 1.4% leads to a change in the color of the tablets to the bright side (“B” the color coordinate increases by 10-15 units in comparison with other experiments). A study of the dynamics of color changes confirmed the hypothesis about the beneficial effect of acid on the stability of drotaverine hydrochloride (see drawing) during processing. The color coordinates of the experimental options and the prototype are at the level of 180-185 units, in comparison with the color of tablets without acid 170 units. (see values for a storage duration of 0 days).

Studying the dynamics of the color change of the tablets during storage at elevated temperatures, all variants have a color change (see drawing), as evidenced by a change in the “B” color coordinate from 180 to 160-150 units. However, when inorganic acid is introduced into tablets, the hydrolysis of drotaverine hydrochloride slows down. The rate of color change of the drug with the introduction of inorganic acids (see the drawing curves for hydrochloric and phosphoric acids) is at the prototype level (with the introduction of 0.7% citric acid) and the process is much slower than in experiments without acid (see the drawing curve “Without acid”).

Thus, the optimality condition (R> 254, G> 246, 175 <B> 185) corresponds to variants containing from 0.004% hydrochloric acid to 1.4% phosphoric acid.

A further increase in the concentration of acid is impractical because does not improve the color characteristics of the tablets.

Example 2

To determine the optimum moisture content of the tablet mass, 10 g of drotaverine hydrochloride, 14 g of potato starch, 11.25 g of lactose, 0.5 g of calcium stearate were loaded into a mortar, the components were thoroughly ground. The mixture was moistened with a solution of 0.75 g of PVP, 0.26 g of phosphoric acid in 12 g of water. The moistened mass was granulated through a grid with 0.8 mm holes and dried at a temperature of 60 ° C. In the drying process, samples with different humidity were taken, which were tabletted with 7 mm punches. The color coordinates of the tablets are presented in table 4.

In experiments with granulate moisture of 22 and 17%, high-quality tablets could not be obtained due to the adherence of t / mass to the surface of the punches. Satisfactory tabletting results were obtained in experiments 5% and 1.8%. However, in the experiment, 1.8% was observed discoloration of the tablets. As a result, an optimal moisture range of t / mass of 1.9-5.0% was proposed.

Example 3

To determine the optimal phase-dispersed composition of the granulate, 10 g of drotaverine hydrochloride, 14 g of potato starch, 11.25 g of lactose, 0.5 g of calcium stearate were loaded into a mortar, the components were thoroughly ground. The mixture was moistened with a solution of 0.75 g of PVP, 0.26 g of phosphoric acid in 12 g of water. The moistened mass was granulated through a mesh with 1.0 mm holes and dried at a temperature of 60 ° C to a moisture content of 2.5%. The obtained t / mass was sieved through sieves with holes, taking fractions with granules of more than 1 mm, from 1.0 to 0.6 mm, less than 0.6 mm. Fractions were pelletized with 7 mm punches. In the image obtained as a result of scanning, the color coordinates of the tablets and the size of the dark and light spots on the surface of the tablets were measured with an increase of 100 · 1 (programmatically).

The data presented make it possible to determine the optimal granule size of the tablet mass of less than 1.0 mm, at which uniform coloring of the tablets is observed.

Example 4

Received 140 g of a mixture of drotaverine hydrochloride, filler (a mixture of starch and lactose 1/1), magnesium stearate was mixed and moistened with 20 ml of a solution of a binder (PVP). The wetted mass was dried at a temperature of 50 ° C to a moisture content of 2.0%. Granulated through a mesh with 1.0 mm holes. Tablets were punched with 6-10 mm punches. The weight of the tablets was 0.065-0.26 g. The disintegration and color of the tablets were determined.

From table 5 it is seen that the conduct of the process beyond the stated limits does not allow you to get tablets that match the specified parameters.

Literature

1. Mashkovsky M.D. Medicines: - Мn .: Belarus, 1987, part 1. p.393.

2. Grabowski, et al., Slow-release torus, matrix pellets and the production thereof United States Patent 6290990, 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 6245350, June 12,2001.

4. Van Lengerich, Embedding and encapsulation of controlled release particles. United States Patent 6190591, 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 6080426, June 27, 2000.

6. Goertz, et al., Preparation of solid pharmaceutical forms. United States Patent 4801460, January 31, 1989.

7. Breitenbach, et al., Storage-stable drug form. United States Patent 5945127, August 31, 1999.

8. Klimesch, et al., Continuous preparation of solid pharmaceutical forms. United States Patent 5073379, December 17, 1991.

9. International application WO 01/07024 PHAKMACEUTICAL COMPOSITION AND PREPARATION THEREOF KALMANNE MATHE IRMA; VITANYINE MORVAI MAGDOLNA; JAKAB BOGLARKA; KOVACS PETERNE, VEGELI ERZSEBET. 2001-02-01. MKI A 61 K 31/00. Prototype.

10. State Pharmacopoeia of the USSR, vol. 2. General methods of analysis. Medicinal and vegetable raw materials / Ministry of Health of the USSR. - 11th ed., Ext. - M .: Medicine, 1989. - V.2. - S. 154-159.

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

Claims (5)

1. An antispasmodic drug containing drotaverine hydrochloride, an inert pharmaceutical excipient, a binder, stearic acid and / or its salt, characterized in that it additionally contains 0.004-1.4 wt.% Inorganic acid in the following ratio, wt.%: Drotaverinum hydrochloride 15.0-62.5 Inert pharmaceutical filler 28.1-84.696 Binder 0.1-7.0 Stearic acid and / or its salt is 0.2-1.0 2. An antispasmodic drug according to claim 1, characterized in that it contains phosphoric or hydrochloric acid as an inorganic acid. 3. The antispasmodic drug according to claim 1, characterized in that as an inert pharmaceutical excipient, it contains compounds of the carbohydrate class of food or medical value, in particular glucose, lactose, sucrose, fructose, starch or / and mixtures thereof. 4. The antispasmodic drug according to claim 1, characterized in that it contains polyvinylpyrrolidone, polyethylene glycol, starch and / or a mixture thereof as a binder. 5. An antispasmodic drug according to claim 1, characterized in that it is a tablet weighing from 0.065 to 0.26 g.