Pharmaceutical composition in the form of effervescent tablets and how you can get

 

(57) Abstract:

The invention relates to pharmaceutical industry. The inventive composition contains acetylsalicylic acid, sodium carboxymethylcellulose as a granulating agent, the gas mixture comprising sodium bicarbonate, sodium digitaltruth, sodium phosphate dihydrate in the following ratio of components, acetylsalicylic acid of 0.05-0.5; sodium carboxymethylcellulose 0.1 to 1.5; sodium bicarbonate 0.5 to 1.5; sodium digitaltruth 0,8-1,5; sodium phosphate dihydrate of 0.01-0.1. The composition is produced by a separate granulation mixture of acetylsalicylic acid, sodium phosphate dihydrate, sodium dehydroacetate, sodium carboxymethylcellulose and mixtures of sodium bicarbonate and sodium carboxymethylcellulose, and components are pre-crushed to 50 μm, the obtained granules are dried and sieved to particle size of 1200 μm, followed by mixing the granules with a ratio of 1 granulate to the 2nd century 60-70 hours: 30-40 century, including a dusting sliding agent and pelletizing. 2 S. and 1 C.p. f-crystals.

The present invention relates to chemical-pharmaceutical industry, the new composition of the soluble gas-forming kompozitnykh.

Acetylsalicylic acid (ASA), known worldwide as aspirin, for many decades, it is used as anti-inflammatory, antipyretic and analgesic agent. Along with this, as you know, it has anticoagulant activity.

A wide range of ASA for the treatment of various diseases puts it in range of one of the most frequently used and effective drugs. However, low solubility in water (especially cold) and associated, typically, with its ulcerogenic action, leading to serious gastro-intestinal tract, was forced to limit its application in practice. So up to the present day and conducted a search of various new soluble forms of the ASC safe and easy to use and stable during storage. So some of the leading companies of Germany, USA, Japan, etc. were created by the famous preparations of soluble aspirin containing, as a rule, gas-forming components and various additives, including ascorbic, citric and other acids derived from a number of sugars and other Methods for their production, often including the use of food additives, binding agents, pharmaceutically acceptable substances which contain a number of features and variations in the process, significantly affect the quality and availability of this valuable drug. Here it is worth Recalling that this is particularly true of technology for domestic ASC, which is known to date comes in the form of, almost dangerous to use.

As a prototype we chose the U.S. patent N 4687662 class. And 61 To 31/60, which seems to be the most similar set of features and progressive on the achieved result. The claims of the patent protects two objects, one of which is soluble blowing therapeutic compensation, and the other way it was received. According to the formula, the composition is a mixture containing from 7 to 57.5% by weight:

a) granular therapeutic agent (including ASC) with particle sizes from 100 to 600 microns in an amount of from 2 to 27% by weight;

b) gas-forming components of the system, a mixture of carbonate of alkaline metal and acid with a particle size of from 50 to 600 microns in an amount of 5 to 30% by weight.

The cooking process in General is that first granulating agent is dissolved in a solvent to form a solution containing from 1 to 50% by weight of the agent, and then smeshivayte from 100 to 600 microns, mix it with gas-forming system with a particle size of from 60 to 600 microns and get a homogeneous mixture of granules. Next (if necessary) tabletirujut.

As a granulating agent used pharmaceutically acceptable substance with a viscosity below 100 ops in the amount of 10% by weight (t 25aboutWith water). Most often for these purposes, the preferred polyvinylpyrrolidone.

Described in the instant patent blowing therapeutic composition requires (at a given percentage) the need to have small granules, the particle size of which is in the range from 100 to 600 microns, mixed with a therapeutic agent. The same requirements apply to gas-forming MESI. This condition (and some others) complicate the creation of gas-forming composition with ASA as a therapeutic agent. May be that is why in the patent do not contain specific examples of the method using the ASC.

In addition, most often used as a granulating means polyvinylpyrrolidone unsuitable to work with ASA. He (and other frequently used granulating agent polyethylene glycol) can provide stability ASC during storage.

Our goal was to create a stable, soluble gas-forming composition comprising the ASC, with improved processing characteristics, and to develop a new way of its receipt.

This goal was not achieved previously described in the literature, composition, containing ASA, sodium carboxymethylcellulose in an amount of from 0.5 to 5% sodium bicarbonate (30-40%), sodium digitaltruth (50-60%), sodium orthophosphate dehydrate (0.5 to 5%) of the average weight of the tablets.

The objective is also achieved by a new method of obtaining this composition.

The method consists in the fact that carry out separate granulation acid and alkaline component, pre-crushed to a particle size not exceeding 50 microns. It is very important point is that the acid component containing ASC, (before granulation) administered sodium dihydroorotase in an amount of from 0.01 to 0.1 g by weight of the tablet. Granulation is carried out using solution of sodium carboxymethyl cellulose. Both granulate is forced through a sieve with a mesh size of 1.2 mm and dried at a temperature of 60aboutC. Received two granulate (particle size 1200 microns) is mixed in the ratio: acid component is from 60 to 70 national Department of standardization of the solution was 5.8. Next, the resulting mixture tabletirujut using a moving agent. In this case, it is best to take itself acetylsalicylic acid in an amount of 5% of its content in the tablet.

These differences are significant.

So, with the exception of the composition of sodium dihydrophosphate leads to the formation of colored (mostly in pink shades) tablets, for salts of phosphoric acid to form complex compounds with heavy metals, which form a colored compound with ASA and its attendant salicylic acid.

The particle size of the main ingredients in the tablets has a decisive influence on the speed and completeness of its dissolution. Pre-grinding acetylsalicylic acid, sodium dehydroacetate and sodium bicarbonate (see above) allows you to standardize the conditions for further processing ingredients and significantly reduce the time of dissolution of the tablets.

Tablets made from unground raw materials that dissolve slowly and unevenly. But after the dissolution of the main mass of the tablets in solution illustrates the different size of the agglomerates, hardly soluble after quite a long time. Tablets containing the decree is x2">

As already mentioned, a significant role is played by the ratio of acid and alkaline component. It is chosen so that, when dissolved tablets pH value of the solution was 5, 8. This is important because the solution with the same pH value stable during the day. Furthermore, the pH value ensures complete neutralization of sodium bicarbonate. Weak acid solution improves the quality of consumer tablets ASC.

Another significant difference is used as a granulating agent is sodium carboxymethylcellulose (CMC), which has several advantages over commonly used for the manufacture of water-soluble, gas-forming tablets polyvinylpyrrolidone and polyethylene glycol. CMC contains carboxyl groups, which in some degree ensures the stability of the ASC. In addition, when the granulating acid components is the neutralization of the sodium salt of cellulose. Resulting from the neutralization insoluble carboxymethylcellulose. Thus, the moisture diffusion inside the tablet slows down, leading to increased stability of tablets ASC during storage. Polyvinylpyrrolidone and polyethylene glycol is hygroscopic. Obladi.

Finally, another significant characteristic is the use of acetylsalicylic acid as a moving agent in the tabletting process. It allows you to achieve uniform filling of the matrix a press tool moldable material and to prevent significant build-up on his punches. This allowed to simplify and cheapen the process of obtaining the drug, excluding such widely used in the technology of gas-forming water-soluble tablets, as sodium benzoate, glycine, etc.

Thus summarizes the differences (not resulting from prior art) help you to achieve your goals to create a convenient and economical way stable, instant and safe form ASC with improved processing characteristics suitable for oral administration, including children.

For illustration of the present invention are the following examples which do not limit it.

P R I m e R 1. Preparation of acid granulate.

In a mixer put acetylsalicylic acid (95 g), sodium dihydroorotase (20 g), digitaltruth sodium (535,5 g) and sodium carboxymethylcellulose (100 ml of 2.5% solution). All the dry ingredients prior is of 10 min at a speed of 30 rpm Then granulated mass is forced through a sieve of sides of the orifice 1.20 mm and dried in a fluidized bed apparatus for 45 min at a temperature of 60aboutC. the Dried granulate is forced through a sieve with a size of the orifice of 1.20 mm Receive 653 g of acid granulate.

Preparation of alkaline granulate.

In a mixer put sodium bicarbonate (341,2 g, crushed in a hammer mill until the particle size is not more than 50 μm) and sodium carboxymethylcellulose (32 ml of 2.5% solution in distilled water) and stirred for 10 min at a speed of 30 rpm After that mass forced through a sieve of sides of the orifice 1.20 mm and dried in a fluidized bed apparatus for 45 min at a temperature of 60aboutC. the Dried granulate is forced through a sieve with a size of the orifice of 1.20 mm Receive 342 g of alkaline granulate.

Getting pills.

In the mixer mix of acid and alkaline granulators with the addition of acetylsalicylic acid in an amount of 5 g for 10 min at a speed of 30 rpm Receive 1 kg of sparkling water-soluble acetylsalicylic acid. The mixture for tabletting press using a tablet machine. Floor The content of acetylsalicylic acid in each tablet is 0,250 of 0.0125 g

Time dissolve 1 tablet in 100 ml of water no more than 1 min.

Shelf life 2 years.

The strength of the tablets by crushing 60-80 N.

P R I m m e R 2. Preparation of acid granulate.

In a mixer put acetylsalicylic acid (475 g), sodium dihydroorotase (50 g), digitaltruth sodium (1150 g) and sodium carboxymethylcellulose (300 ml, 5.0 percent solution). All the dry ingredients pre-shredded in a hammer mill to a particle size not exceeding 50 microns. The mixing occurs within 10 min with a speed of 80 Rev/min then the granulated mass is forced through a sieve of sides of the orifice 1.20 mm and dried in a fluidized bed apparatus for 45 min at a temperature of 60aboutC. the Dried granulate is forced through a sieve with a size of the orifice of 1.20 mm Get 1690 acid granulate.

Preparation of alkaline granulate.

In a mixer put sodium bicarbonate (1280 g, crushed in a hammer mill until the particle size is not more than 50 μm) and sodium carboxymethylcellulose (100 ml of a 5.0% solution in distilled water) and stirred for 10 min at a speed of 30 rpm After that mass forced through a sieve with a size of the granulate is forced through a sieve with a size of the orifice of 1.20 mm Get 1290 alkaline granulate.

Getting pills.

In the mixer mix of acid and alkaline granules with the addition of 25 g of acetylsalicylic acid for 10 min at a speed of 30 rpm Receive 3 kg of sparkling water-soluble acetylsalicylic acid (ASA). The mixture for tabletting press using a tablet machine. Receive tablets of white color face shape. The tablet diameter 25 mm, average weight of 3.0 g

The content of acetylsalicylic acid in each tablet is 0.500 of 0.0125 C.

Time dissolve 1 tablet in 100 ml of water no more than 1 min.

Shelf life 2 years.

The strength of the tablets by crushing not below 60-80 N.

P R I m e R 3. Preparation of acid granulate.

In a mixer put acetylsalicylic acid (95 g), digitaltruth sodium (555,5 g) and sodium carboxymethylcellulose (100 ml of 2.5% solution). All the dry ingredients pre-shredded in a hammer mill to a particle size not exceeding 50 microns. The mixing occurs within 10 min at a speed of 30 rpm then the granulated mass is forced through a sieve of the parties will otterstraat through a sieve with a size of the orifice of 1.20 mm Receive 653 g of acid granulate.

Preparation of alkaline granulate.

In a mixer put sodium bicarbonate (341,2 g, crushed in a hammer mill until the particle size is not more than 50 μm) and sodium carboxymethylcellulose (32 ml of 2.5% solution in distilled water) and stirred for 10 min at a speed of 30 rpm After that mass forced through a sieve of sides of the orifice 1.20 mm and dried in a fluidized bed apparatus for 45 min at a temperature of 60aboutC. the Dried granulate is forced through a sieve with a size of the orifice of 1.20 mm Receive 342 g of alkaline granulate.

Getting pills.

In the mixer mix of acid and alkaline granules with the addition of 5 g of acetylsalicylic acid for 10 min at a speed of 30 Rev/min the mixture for tabletting press using a tablet machine. Get tablets face shape. The tablet diameter 25 mm, average weight of 2.5 g

The content of acetylsalicylic acid in each tablet is 0,250 of 0.0125 g

Time dissolve 1 tablet in 100 ml of water no more than 3 minutes the Tablet during storage become pink. Shelf life not more than 2 months.

Receive tablets of white color face shape.

The tablet diameter 25 mm, average weight of 2.5 g

Time dissolve 1 tablet in 100 ml of water over 5 minutes the Solution is not transparent contains agglomerates of various sizes, which subsequently dissolve.

P R I m e R 5. Example 5 differs from example 1 in that as the sliding ingredient to ensure uniform filling of the matrix a press tool moldable material and to avoid large build-up on his punches, use sodium benzoate (glycine, and so on).

Receive tablets of white color face shape, the tablet diameter 25 mm, average weight of 2.5 g

The content of acetylsalicylic acid in each tablet is 0,250 of 0.0125 g

Time dissolve 1 tablet in 100 ml of water no more than 1 min.

Shelf life 2 years.

Use as sliding ingredients such widely used in the technology of gas-forming water-soluble tablets, as sodium benzoate, glycine, etc. in the proposed technology is not advisable, due to its appreciation by adding to the formulation an additional component. Acetylsalicylic the example 1, however, that changed the ratio of acid and alkaline components.

The increase in the ratio towards the alkaline component significantly increases gas-forming properties of the tablets, this increases the pH of the solution. At pH greater 7,0 significantly deteriorate the taste of the drug (it seems like sodium bicarbonate) and, most importantly, reduces the stability of the solution due to the rapid hydrolysis of acetylsalicylic acid.

The increase in the ratio of acid and alkaline components in the acid side, shifting the pH of the solution acidic side, greatly increases the stability of the solution. When the solution pH below 5.0 solubility of acetylsalicylic acid decreases. At the same time reduced palatability of the drug. In addition, this drug is unsuitable for use by patients suffering from hyperacidity and ulcers of the stomach, the duodenum.

The ratio of acid and alkaline components, shown in example 1 by dissolving tablets pH value of 5.8, the solution is stable for days. When the pH value of the sodium bicarbonate is completely neutralized. Acetylsalicylic acid tablets dissolved in the as granulating agent instead of sodium carboxymethylcellulose use polyvinylpyrrolidone or polyethylene glycol.

The resulting tablets of white color face shape. The tablet diameter 25 mm, average weight of 2.5 g

The content of ASA in each tablet is 0,250 of 0.0125 g

Time dissolve 1 tablet in 100 ml of water no more than 1 min.

Storage time less than 6 months.

Used as a granulating agent is sodium carboxymethylcellulose allows you to get pills at values of relative humidity, reaching 60-70% of These production conditions are not suitable for the production of effervescent tablets, if as granulating agents used polyvinylpyrrolidone and polyethylene glycol.

1. Pharmaceutical composition in the form of effervescent tablets containing acetylsalicylic acid, granulating agent, the gas mixture consisting of acid and alkaline components, characterized in that it additionally contains sodium phosphate dihydrate in an amount of 1 to 5% by weight of the tablet, as the granulating agent is sodium carboxymethylcellulose in an amount of 0.5 to 5% as the alkaline component is sodium bicarbonate in the amount of 30 to 40% and as the acidic component is sodium digitaltruth in the amount of 50 to 60% in the following ratio component is NAT 0,5 1,5

Sodium digitaltruth 0,8 1,5

Sodium phosphate dihydrate 0,01 0,1

2. A method of obtaining a pharmaceutical composition in the form of effervescent tablets by granulation, drying, sieving, tabletting, wherein the pre-milled components to 50 μm, and then separately granularit mixture of acetylsalicylic acid, sodium dehydroacetate, sodium phosphate dihydrate solution, sodium carboxymethylcellulose, and a mixture of sodium bicarbonate with a solution of sodium carboxymethylcellulose obtained pellets separately dried, sieved to obtain particles with a size of 1200 μm and mixed 60 to 70 wt. including the first granulate and 30 to 40 wt.h. the second granulate with subsequent dusting sliding agent prior to pelletizing.

3. The method according to p. 2, characterized in that the moving agent use of acetylsalicylic acid in an amount of 5% of its content in the tablet.

 

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