Pharmaceutical composition in the form of effervescent tablets

 

(57) Abstract:

Usage: medicine and the medical industry, in particular to obtain effervescent quick-dissolving tablets containing paracetamol. The inventive pharmaceutical composition comprises, in wt.%: Na-carboxymethylcellulose 0.5 to 1, glycine 2-5, sodium bicarbonate 30-40, sodium digitaltruth 50-60 and para-acetaminophenol - the rest is up to 100. The new composition has a stability and allows you to get the quick-dissolving tablets that form a clear solution.

The present invention relates to pharmaceutical industry. More specifically, it relates to a new composition of the soluble gas-forming compositions containing para-acetaminophenol in the form of tablets, soluble in water.

Para-acetaminophenol, known worldwide as paracetamol, acetaminophen, Panadol, acetogen, alphadol, aramid, Dalaman, for many decades used as an antipyretic and analgesic agent, to enhance the effects of other analgesics. Anti-inflammatory activity expressed he is weaker than that of acetylsalicylic acid. For pain management activity corresponds to acetylsalicylic sour the Xia compatibility with a wide range of other drugs in combined dosage forms [1]

Para-acetaminophenol the safest analgesic agent, it is well absorbed from the gastrointestinal tract and is present in the blood at the highest concentration 40-60 minutes after ingestion; easily penetrates the blood-tissue interfaces barriers, including the placental barrier; inactivated in the liver by the formation of conjugates with glucuronic (up 63%), sulfuric (up 34%) and cysteine (up 3%) [1] has no irritant effect on the mucous membrane of the intestine, does not violate the circulation, respiration, liver function and blood formation, and acid-base condition of the stomach. Para-acetaminophenol unlike salicylates can be applied in cold blood clotting, bleeding from the lungs, stomach, uterus and other organs. When using pair-acetaminophenol unlike analgesics pirazolonovogo series (analgin, amidopyrine) does not develop agranulocytosis, which may fail with a fatal outcome. When using pair-acetaminophenol less likely the occurrence of methemoglobinemia, anemia, hematuria and phenacetine" jade, which can develop when using phenacetin.

The product is widely used for fevers, headaches and subcylinder and maltogenase drug for the treatment of various diseases puts it in range of one of the most frequently used and effective drugs. However, the low solubility of the drug in water (especially cold), its relatively low bioavailability, and the bitter taste was forced to limit its application in practice. It should also be noted that the pair-acetaminophenol gives fragile tablets, shows a strongly expressed elastic deformation during compaction, which leads to delamination when pelletizing [2] the Introduction of the tablets excipients improves the ability of the masses to tabletroute. So up to the present day and conducted a search of various new soluble forms of para-acetaminophenol, safe and easy to use and stable during storage. So some of the leading companies of Germany, France, USA, Japan, etc. were created by the famous preparations of soluble para-acetaminophenol containing, as a rule, gas-forming components and various additives, including ascorbic, citric and other acids derived from a number of sugars and others [3-5] Methods for their production, often including the use of food additives, binding agents, pharmaceutically acceptable substances for coverage based on individual General practices (granulation, drying, grinding, pelleting), contain a number of special features of the rata.

As a prototype chose US patent N 4687662 (MKI And 61 To 31/60) [5] 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 composition, and the other way it was received. According to the formula, the composition is a mixture of A (from 7 to 57.5% by weight) containing granular therapeutic agent (including para-acetaminophenol) with particle sizes from 100 to 600 microns in an amount of from 2 to 27% by weight and a water-soluble granular agent (0,3-2,5%), compatible with therapeutic drug and having a viscosity below 100 ops (10% solution in water at 25oC), and B - components of the gas system, consisting of a carbonate of an alkali metal and/or acid with a particle size of from 50 to 600 microns in an amount of 5 to 30% by weight. Effervescent drug also contains effervescent system (42,5-90%) consisting of carbonate and acid.

As carbonates used sodium carbonate, potassium carbonate, carbonate of ammonia, lithium carbonate, bicarbonate or a mixture thereof.

As the acid used mainly citric acid.

the program 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 mixing this solution with a therapeutic agent. The obtained granulate is dried, crushed and sieved to particle sizes from 100 to 600 microns, mix it with gas-forming system with a particle size of from 50 to 600 microns and get a homogeneous mixture of granules. Next (if necessary) tabletirujut.

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 mixture.

The use described in the patent as a moving agent sodium benzoate in an amount of from 1.7 to 10% can significantly affect the taste and appearance of tablets para-acetaminophenol.

In addition, most often used as a granulating means polyvinylpyrrolidone not suitable for obtaining effervescent tablets. He (and other frequently used granularly is good binding property cannot ensure the stability of therapeutic agent during storage.

Our goal was to create a stable, soluble gas-forming composition comprising para-acetaminophenol with improved processing characteristics.

This goal was not achieved previously described in the literature, composition, containing para-acetaminophenol, sodium carboxymethylcellulose in an amount of from 0.5 to 1.0% sodium bicarbonate (30-40%), sodium digitaltruth (50-60%) and glycine (2,0-5,0%).

A method of obtaining a composition is that consists of separate granulation acid and alkaline component, pre-crushed to a particle size not exceeding 50 microns. Granulation is carried out using solution of sodium carboxymethyl cellulose. Both granulate is forced through a sieve with a mesh size of 1.25 mm and dried at a temperature of 60oC. Received two granulate (particle size 1200 microns) is mixed in the ratio: acid component is from 50 to 60 weight.h and alkaline from 30 to 40 weight.h. This ratio is chosen so that when dissolving tablets the value of pH was 5.6 to 6.5. Next, the resulting mixture tabletirujut using a moving agent. In this case, it is best to take the glycine in the amount of 2-5%

The particle size of the basis is aeternae grinding para-acetaminophenol, 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 above powdered ingredients, dissolve for 1 min with the formation of a transparent solution.

As already mentioned, a significant role is played by the ratio of acid and alkaline component. It is chosen so that when dissolving tablets, the value of pH was 5.6 to 5.8. It is important for the rate of dissolution of tablets. In addition, weak acid solution improves the quality of consumer tablets para-acetaminophenol.

Significant for the proposed composition 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 polyvinylpyrrolidine stability of pair-acetaminophenol. 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 para-acetaminophenol during storage. Polyvinylpyrrolidone and polyethylene glycol is hygroscopic. Having known quite a good binding properties, they cannot ensure the stability of pair-acetaminophenol during storage.

Finally, the main significant feature is the use of glycine 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, leucine, etc.

It should be noted that glycine, in addition to function a moving agent in the proposed therapeutic composition, has a sedative effect. It is used in doses of 0.1 g at depressivnii usually accompanied by pain syndromes [6]

In addition, glycine has a detoxifying effect, it is involved in the neutralization in the body of a number of toxic substances (benzoic acid, bile acids) [7]

Equally important is the participation of glycine in a number of important body processes: synthesis of substances such as creatine (an integral part of striated muscle, and other organs); pyrrole, which is part of the coloring matter of the red blood cells; glutathione (activator of a number of proteolytic enzymes); the number of essential amino acids such as serine; porphyrin (a derivative of vitamin b 12); purine (derived nucleic acids) [7]

Finally, glycine, having a sweet taste, significantly improves the quality of consumer tablets soluble para-acetaminophenol.

So it shows the differences that allow it to achieve its goal to create a convenient and economical way stable, instant and safe form of steam-acetaminophenol 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.

Example 1.

Preparation Gras acid carboxymethylcellulose (165 ml of 5% solution) [0,00824 kg, (0,8%)] All the dry ingredients pre-shredded in a hammer mill to a particle size not exceeding 50 microns. The mixing occurs at a speed of 30 rpm for 10 minutes. Thereafter, the granulated mass is forced through a sieve of parties holes 1.25 mm and dried in a fluidized bed apparatus for 60 minutes at a temperature of 60oC. the Dried granulate is forced through a sieve with a size of the orifice of 1.25 mm. Receive 0,56624 kg acid granulate.

Preparation of alkaline resin:

In a mixer put sodium bicarbonate (0,41097 kg, (39,9%)] crushed in a hammer mill until the particle size is not more than 50 μm), and sodium carboxymethylcellulose (41 ml of 5% solution in distilled water) [0,00206 kg, (0,2%)] and stirred at a speed of 30 rpm for 10 minutes. After this mass forced through a sieve of parties holes 1.25 mm and dried in a fluidized bed apparatus for 60 minutes at a temperature of 60oC. the Dried granulate is forced through a sieve with a size of the orifice of 1.25 mm. Receive 0,41303 kg alkaline granulate.

Getting pills.

In the mixer mix of acid and alkaline granules with the addition of glycine in the number 0,05047 kg (4.9%) with the phenol. The mixture for tabletting press using a tablet machine. Receive tablets of white color face shape. Average weight of tablet 3,00,1,

The contents of para-acetaminophenol each tablet is 0,1250,01,

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

Shelf life 2 years.

Example 2.

Preparation of acid granulate:

In a mixer put the pair-acetaminophenol [0,06968 kg, (6,7%)] digitaltruth sodium [0,624 kg, (60,0%)] and sodium carboxymethylcellulose (62 ml of 5% solution) [0,00312 kg, (0,3%)] All the dry ingredients pre-shredded in a hammer mill to a particle size not exceeding 50 microns. The mixing occurs at a speed of 30 rpm for 10 minutes. Thereafter, the granulated mass is forced through a sieve of parties holes 1.25 mm and dried in a fluidized bed apparatus for 60 minutes at a temperature of 60oC. the Dried granulate is forced through a sieve with a size of the orifice of 1.25 mm. Receive 0,6968 kg acid granulate.

Preparation of alkaline granulate.

In a mixer put sodium bicarbonate [0,32032 kg, (30,8%)] crushed in a hammer mill to a size Cheremisina at a speed of 30 rpm for 10 minutes. After this mass forced through a sieve with a size of the orifice of 1.25 mm. Receive 0,3224 kg alkaline granulate.

Getting pills.

In the mixer mix of acid and alkaline granules with the addition of glycine in the number 0,0208 kg (2,0%) with a speed of 30 rpm for 20 minutes. Get 1,040 kg (100%) of sparkling water-soluble drug para-acetaminophenol. The mixture for tabletting press using a tablet machine. Receive tablets of white color face shape. Average weight of tablet 3,0 0,1 g

The contents of para-acetaminophenol in each tablet is 0,200 of 0.01,

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

Shelf life 2 years.

Example 3.

Preparation of acid granulate.

In a mixer put the pair-acetaminophenol [0,1009 kg, (10,0%)] digitaltruth sodium [0,5050 kg, (50,4%)] and sodium carboxymethylcellulose (105 ml of 5% solution) [0,00525 kg (0,5%)] All the dry ingredients pre-shredded in a hammer mill to a particle size not exceeding 50 microns. The mixing occurs at a speed of 30 rpm for 10 minutes. Thereafter, the granulated mass is forced through a sieve with the size of the military granulate is forced through a sieve with a size of the orifice of 1.25 mm. Get 0,6111 kg acid granulate.

Preparation of alkaline resin:

In a mixer put sodium bicarbonate [0,3464 kg, (34,6%)] crushed in a hammer mill until the particle size is not more than 50 μm) and sodium carboxymethylcellulose (35 ml of a 5% solution in distilled water) [0,00175 kg, (0,2%)] and stirred at a speed of 30 rpm for 10 minutes. After this mass forced through a sieve of parties holes 1.25 mm and dried in a fluidized bed apparatus for 60 minutes at a temperature of 60oC. the Dried granulate is forced through a sieve with a size of the orifice of 1.25 mm. Receive 0,3481 kg alkaline granulate.

Getting pills.

In the mixers mix the acid and alkaline granules with the addition of glycine in the number 0,0437 kg (4,3%) with a speed of 30 rpm for 20 minutes. Get 1,0003 kg (100%) of sparkling water-soluble drug para-acetaminophenol. The mixture for tabletting press using a tablet machine. Receive tablets of white color face shape. Average weight of tablet 2,0 0,1 g

The contents of para-acetaminophenol each tablet is 0,200 of 0.01,

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

In a mixer put the pair-acetaminophenol [0,13566 kg, (13,3%)] digitaltruth sodium [0,510 kg, (50,0%)] and sodium carboxymethylcellulose (120 ml 5% solution) [0,006 kg (0,6%)] All the dry ingredients pre-shredded in a hammer mill to a particle size not exceeding 50 microns. The mixing occurs at a speed of 30 rpm for 10 minutes. Thereafter, the granulated mass is forced through a sieve of parties holes 1.25 mm and dried in a fluidized bed apparatus for 60 minutes at a temperature of 60oC. the Dried granulate is forced through a sieve with a size of the orifice of 1.25 mm. Receive 0,65166 kg acid granulate.

Preparation of alkaline granulate.

In a mixer put sodium bicarbonate [0,32538 kg (31.9 per cent), crushed in a hammer mill until the particle size is not more than 50 μm] and sodium carboxymethylcellulose (48 ml of a 5% solution in distilled water) [0,0024 kg, (0,2%)] and stirred at a speed of 30 rpm for 10 minutes. After this mass forced through a sieve of parties holes 1.25 mm and dried in a fluidized bed apparatus for 60 minutes at a temperature of 60oC. the Dried granulate is forced through a sieve with a size of the orifice of 1.25 mm. Receive 0,32778 kg alkaline coast is by adding glycine in the number 0,0408 kg (4.0 per cent) with a speed of 30 rpm for 10 minutes. Get 1,020 kg (100%) of sparkling water-soluble drug para-acetaminophenol. The mixture for tabletting press using a tablet machine. Receive tablets of white color face shape. Average weight of tablet 3,0 0,1 g

The contents of para-acetaminophenol in each tablet is 0,400 of 0.02,

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

Shelf life 2 years.

Example 5 (control).

Example 5 differs from example 3 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, polyethylene glycol.

Receive tablets of white color face shape, average weight of tablets 2,0 0,1 g

The contents of para-acetaminophenol each tablet is 0,200 of 0.0125 g

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

Shelf life 2 years.

When using sodium benzoate on the surface of the punch film is formed, i.e., worsen the sliding properties of the drug, and the drugs are rough, matte on skopicki substance, leads to loss of stability of tablets para-acetaminophenol.

In addition, the use of sliding ingredients such widely used in the technology of gas-forming water-soluble tablets, as sodium benzoate, polyethylene glycol, etc. in the proposed technology is not advisable, due to its appreciation by adding to the formulation an additional component.

Example 6 (control).

Example 6 differs from example 3 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 than 5.5 to 6.5 significantly deteriorate the taste of the drug (it seems like sodium bicarbonate) and, most importantly, reduces the stability of the solution of the drug.

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 is less than 5.5 solubility of the tablets decreased significantly (up to 7 minutes). At the same time reduced palatability of the drug. AMI stomach, duodenal ulcer.

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, the sodium bicarbonate is completely neutralized. Tablets para-acetaminophenol dissolved in water, have good taste.

Example 7 (control).

Example 7 differs from example 3 that as the granulating agent instead of sodium carboxymethylcellulose use polyvinylpyrrolidone or polyethylene glycol.

The resulting tablets of white color face shape.

Average weight of tablet 2,0 0,1 g

The contents of para-acetaminophenol each tablet is 0,200 of 0.01,

Time dissolve 1 tablet in 100 ml not more than 1 minute.

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.

Na-carboxymethylcellulose 0.5 to 1

Glycine 2 5

Sodium bicarbonate 30 40

Sodium digitaltruth 50 60

Para-acetaminophenol Rest to 100

 

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