Method for obtaining spasmolytic medicinal preparation

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

 

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

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

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

These compositions and methods of production allow to obtain stable during storage of the dosage form (tablets, granules) of drotaverine, but require expensive equipment and complex technological scheme.

Most is similar in structure and sequence of technological operations is antispasmodic medicine [9] (prototype), antispasmodic medicine [Nesterchuk CENTURIES, Cheese K.K. Pharmaceutical composition having spasmolytic activity, and how you can get it. RF patent № 2183119, 10.06.2002], containing drotaverine hydrochloride, milk sugar, starch, crosspovidone, talc, calcium stearate and method of production, namely, that the mixture of drotaverine hydrochloride, starch, lactose hydrate 3% starch paste, granularit, dried, re-passed through the granulator, dry granulate is mixed with crosspovidone, calcium stearate, talc, tabletirujut.

The implementation of this method allows to get a tablet weight of 0.14 to 0.16 g, containing 0.04 g of drotaverine hydrochloride, disintegrating in water for 15 minutes, containing, wt.%: 29.8 drotaverine hydrochloride, 38,7 lactose, 26,0 starch, 1,0 mixture of stearate and stearic acid, 4,5 polyvinylpyrrolidone (PVP) and a method thereof, whereby the mixture of ingredients moisturize 21% PVP solution, dried at 60°to a moisture content of 2-3%, granularit through a sieve with apertures of 1.0-2.0 mm, tabletirujut the punches with a diameter of 7 mm

The implementation of this method allows to get a tablet weight of 0.12-0.16 g, containing 0.04 g of drotaverine hydrochloride, disintegrating in water for 15 minutes.

The disadvantage of this antispasmodic is n the sufficient stability of drotaverine hydrochloride in the processing into tablets, namely, in the process of wet granulation and drying. The result of detachment from the molecules of drotaverine hydrochloride molecule of hydrochloric acid formed the basis of drotaverine, which is easily oxidized by atmospheric oxygen with the formation of colored products of decay. Therefore, during processing and storage of tablets are changing color, there is the appearance of a yellow-brown spots.

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

- appearance (pill round shape with flat surfaces, solid edges homogeneous light yellow-green color with color coordinates R>254, G>253, 150<>175),

- strength friability (not less than 97%),

the deviation in the weight of individual tablets (no more than ±5%),

- raspadaemost no more than 15 minutes,

stability during storage for two years.

This objective is achieved in that a method of obtaining antispasmodic medicines on the basis of drotaverine hydrochloride, including the preparation of the masses for tabletting, tableting, characterized in that the prep for tabletting done is make by mixing powder of drotaverine hydrochloride powder colored granules in a ratio of from 1:3 to 2:1, and getting painted granulate is carried out by wetting inert pharmaceutical filler painted quinoline yellow solution of a binder, drying to a moisture content of 0.1 to 2.5%, by dry granulation, and the components are taken in the following ratio, % by weight of the granulate: inert pharmaceutical filler 93,90-99,77, a binder is 0.1 to 5.0, dye quinoline yellow 0,03-0,1, stearic acid or its salts 0,1=1,0.

In accordance with the invention proposed as:

- inert pharmaceutical filler to use substances authorized for use in the pharmaceutical industry, preferably lactose and starch and their mixtures in the ratio of 4:1-3:2.

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

Thus, the essence of the invention is that:

- the claimed method of obtaining antispasmodic drugs eliminates the stage of wetting and drying at a high temperature of drotaverine hydrochloride. The proposed sequence of operations involves the initial powder mixture of drotaverine with dried powder granulate and pressing at normal conditions. This action prevents the high temperatures and humidity molecule of drotaverine that benefits the pleasant effect on its stability during processing and during storage period.

in the composition, compared with the known, additionally contains a dye quinoline yellow, necessary to obtain the color of the granules identical to yellow-green powder of drotaverine hydrochloride. In result, it becomes possible to obtain a uniformly colored tablets.

- used new balance of ingredients that allow you to change the dosage from 40 and 80 mg tablets, and, therefore, pharmaco-kinetic parameters for the effectiveness of the tablets.

The proposed ratio of active substances and excipients are the best and allow you to get a tablet, disintegrating within 15 minutes, corresponding to the requirements of the Pharmacopoeia by all indicators, stable during production and storage for two years.

The increase or decrease of parameters of the process aside from the stated limits leads to lower quality pills or difficult tableting.

Antispasmodic drug obtained as follows.

In the mixer download inert pharmaceutical filler 93,90-99,77%, preferably lactose and starch ratio 4:1-3:2, stearic acid or its salts of 0.1 to 1.0%, mix and add colored binder solution is based binder is 0.1 to 5.0%, the dye 0,03-0,1% by weight of the obtained pellets of the same mix. This ratio is necessary to ensure raspadaemosti tablets, no more than 15 minutes at rated their strength (see example No. 1).

The concentration of dye 0,03-0,1% selected from a calculation of obtaining the color of the granules identical to the color of the powder of drotaverine hydrochloride (see example 2).

Painted a lot of the mixer is transferred to a dryer and dried to a moisture content of 0.1 to 2.5%.

The choice of this limit is based on the data of experiments the influence of the moisture content of the granulate on the stability of pressing. When humidity is more than 2.5% of the observed adhesion tablet mass to the surface of the punches. Reducing the moisture content is less than 0.1% leads to irrational waste of thermal resources.

The dried mass granularit through a sieve with apertures of less than 1.0 mm, Preferably of 0.4 mm This value is needed to exclude the possibility of formation of tablets heterogeneous (patchy) surface.

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

Tablet mass is pressed by the punches diameter 7.0 mm tablet press RTM 41 with the speed of rotation of the rotor 14 revolutions per minute. The weight table is current 0,14± 0,02, the Height of the tablets 2,2-3,2 mm

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

Example 1

In a mortar were mixed 100 g of lactose and starch in the ratio 5:1, 4:1, 3:2, 3:1. To the resulting mass was added of 0.05, 0.1, 1,0, 1,2 calcium stearate and watered 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. Mass was granulated through a sieve with holes of 8 mm were Dried to a moisture content of less than 2.0%. Was granulated through a sieve with holes of 0.4 mm

Of drotaverine hydrochloride was mixed with the obtained colored granules in the ratio 1:4, 1:3, 2:1, 3:1, extruding tablets punches diameter 7.0 mm hydraulic press at a pressure of 50 kg/cm2, weight of 0.11, 0.12 and, of 0.16, 0.18 g, respectively.

At the same time received the tablets of drotaverine hydrochloride adopted in the prototype method. 29.8 drotaverine hydrochloride, 38,7 lactose, 26,0 starch, 1,0 mixture of stearate and stearic acid 1:1 were mixed in a mortar and was moistened with a solution of 4.5 g of polyvinylpyrrolidone in 16,93 g of water. Dried the resulting mass at 60°to a moisture content of 2-3%, grained is through a sieve with apertures of 1.0-2.0 mm and alloy preformed the punches with a diameter of 7 mm hydraulic press pressure of 50 kg/cm 2. The average weight of the tablets of 0.15,

Measurement data raspadaemosti and color tablets experienced options in comparison with the prototype (see table. 1 experience No. 5) are presented in table 1.

Table 1
The effect of the concentration of ingredients on the properties of tablets of drotaverine hydrochloride
No.The ratio of drotaverine hydrochloride/ colored granulesColored granulesThe weight of the tablet, gDecay resistant, minutes“To coordinate the color of pill
fillermagnesium stearate,%swasey total,%Crain tel, %
the ratio of lactose/ starch%
11:45:199,940,00,050,010,110,8182
21:34:199,770,10,100,030,121,2172
32:13:293,901,05,00 0,100,167,5152
43:14:291,651,27,000,150,1815134
529,81:1,453to 70.21,04,50-0,157,0170

These tables show that in the experiments, obtained with a ratio of drotaverine hydrochloride: colored granulate 1:3-3:1, with a ratio in stained granules of lactose: starch 4:1-4:2 and the concentration of magnesium stearate 0.1 to 1.0%, the binder is 0.1 to 7.0 and dye 0,03-0,10% received tablets containing 0.04 to 0.08 g of drotaverine, meet the requirements of the Pharmacopoeia in appearance decaying in 5-7 minutes and the corresponding color of the tablets obtained according to the method of the prototype. The process beyond the stated limits is not possible to obtain tablets that match the specified parameters.

Example 2

To determine the effect of the concentration of quinoline yellow 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 quinoline yellow. Dried to a moisture content of less than 2.0%. Was granulated through when the holes of 0.4 mm The substance of drotaverine hydrochloride grinded on a rotary mill and proseware powder through a nylon sieve No. 23. 7 g of the obtained colored granules were mixed with 3.0 g of sifted drotaverine. Alloy preformed the punches 7 mm Samples scanned. The optimality criterion colors were the tablets of drotaverine hydrochloride, 0.04 g obtained in full accordance with the method of the prototype (see table 2, experience No. 8).

Table 2
The effect of the concentration of quinoline yellow on the color properties of the tablets of drotaverine
The concentration of quinoline yellow,%Color coordinates
RGIn
0,01253,16±0,16252,83±0,16204,50±0,22
0,03253,83±0,16252,66±0,21174,83±0,40
0,05253,16±0,16252,83±0,16164,50±0,22
0,07253,83±0,16252,66±0,16154,50±0,22
0,10253,83±0,16252,66±0,16150,50±0,22
0,11253,83±0,16142,83±0,40
The placeholder253,83±0,16252,66±0,16170,50±0,22

Presented in table 2, the data allow to determine the optimal concentration of quinoline yellow 0,03-0,10%, allowing to obtain tablets, the corresponding color in the interval 175-150 units “In” color coordinates tablets prototype.

Example 3

0.25 g quinoline yellow was dissolved in 25 g of water. 6.6 g of PVP was dissolved in 93,4 g of water. Mixed 8 grams of PVP solution with 2.15 g of the dye solution. The obtained dyed with a solution of PVP was moistened mixture of 22.3 lactose, 10 g starch, 0.33 g of calcium stearate. Dried pellet mass to a moisture content of less than 2.0%Granulirovanie tablet weight through a nylon sieve No. 23. Grinded of drotaverine hydrochloride, sieved through a nylon sieve No. 23. To obtain tablets containing 0.04 g of drotaverine hydrochloride, mixed 7 g of the colored granules with 3 g of the milled powder of drotaverine hydrochloride.

To obtain tablets containing 0.08 g of drotaverine hydrochloride, respectively, was mixed with 4.3 g of the colored granules with 5.7 g of drotaverine hydrochloride.

The obtained pellet mass is extruded by the punch 7 mm hydraulic tablet press with a force of 50 kg/cm2. The weight of the tablets 0,14-0,15,

Determination of the stability of p is eparate conducted in natural conditions, measuring the color of the tablets in two years. As control was used tablets obtained according to the method of the prototype. The results are presented in table 3 and 4.

Table 3
The coloristic properties of the tablets to bookmark storage
NameColor coordinates
RGIn
Tablets of drotaverine 0.04 g253,83±0,16252,66±0,16175,50±0,22
Tablets of drotaverine 0.08 g253,83±0,16252,66±0,21172,83±0,40
The placeholder253,16±0,16252,83±0,16174,50±0,22

254,73±0,54
Table 4
The coloristic properties of the tablets after storage for two years
NameColor coordinates
RGIn
Tablets of drotaverine 0.04 g247,50±0,22217,66±5,11172,22±7,72
Tablets of drotaverine 0.08 g239,33±2,61169,53±0,80
The placeholder248,00±0,24220,13±1,26155,50±3,82

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

Example 4

In the mixer sequentially loaded 22.3 kg of lactose, 10 kg of starch, 0.33 kg of calcium stearate were mixed and moistened with a solution 0,528 kg PVP and 0,0215 kg quinoline yellow in 9,83 kg of water. The mixture was transferred into the basket of the dryer fluidized bed SP-60 and dried to a moisture content of less than 2.0%, rubbed through a nylon sieve No. 23, receiving 31 kg colored granules.

In the mixer was downloaded 41 kg of drotaverine hydrochloride, sifted through sieve No. 23 and 31 kg stained granules were mixed.

The obtained tablets weight alloy preformed the punches with a diameter of 7 mm tablet press RTM-41 with a speed of 14 rpm. The weight of the tablets of 0.14, the Height of the tablets 2,8-3,2 mm Raspadaemost 3 minutes. Abrasion 99,6%. Dissolution 84,85% by weight of the active substance within 30 minutes. Tablets are characterized by a flat, smooth surface, uniform color.

Literature:

1. Mashkovsky PPM Medicines: -Mn.:”Belarus”, 1987.- 4.1. S. 393.

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

3. Ashoka has cut, 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. Ashoka has cut, 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 31,1989.

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. The starting order for the production of tablets of drotaverine hydrochloride and 0.04 g, Moscow, CHLS UNIFI, 16.06.2000. The prototype.

10. State Pharmacopoeia of the USSR: Vol. 2 General methods of analysis. Pharmaceutical

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

11. VFS 42-3107-98. Tablets of drotaverine hydrochloride and 0.04,

1. The method of obtaining antispasmodic medicines on the basis of drotaverine hydrochloride, including the preparation of the masses for tabletting, tableting, characterized in that the preparation of the masses for tabletting is carried out by mixing powder of drotaverine hydrochloride powder colored granules in a ratio of from 1:3 to 2:1, and the doctrine of the colored granules is carried out by wetting inert pharmaceutical filler painted quinoline yellow solution of the binder, drying to a moisture content of 0.1 to 2.5%, by dry granulation, and the components are taken in the following ratio, % by weight of the granulate: inert pharmaceutical filler 93,90-99,77, a binder is 0.1 to 5.0, dye quinoline yellow 0,03-0,1, stearic acid or its salts of 0.1 to 1.0.

2. The method according to claim 1, characterized in that an inert pharmaceutical filler is the use of substances authorized for use in the pharmaceutical industry, preferably lactose and starch and their mixtures in the ratio of 4:1-3:2.

3. The method according to claim 1, characterized in that the binder is the use of substances authorized for use in the medical industry, preferably polyvinylpyrrolidone.



 

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