EA019805B1 - Paracetamol-based combined analgetic - Google Patents

Abstract

A novel paracetamol-based pharmaceutically combined preparation is proposed having better therapeutic index than a comparison preparation.

Description

The invention relates to medicine and pharmacology, specifically to new combined analgesics based on paracetamol containing, as another basic component, a non-steroidal anti-inflammatory drug (NSAID). The invention can be used to treat a wide range of pathological conditions of various origins, accompanied by the development of pain.

Background of the Related Art

Paracetamol-based combined analgesics are a combination of over-the-counter combined medicines intended to relieve mild to moderate pain attacks.

Depending on the combination with which medicines paracetamol is used, it is customary to divide all combined preparations based on it into the following groups, which overlap to some extent:

1. In combination with psycholeptics (with barbiturates): Quintalgin, Pentalgin-1SY, Pentalgin-Nova, Pentalgin-FC, Santoperalgin, Sedal-M, Sedalgin-Neo, Pentalgin Plus, NeoTeofedrin, Teofedrin-N, etc.

2. In combination with other drugs, excluding psycholeptics:

2.1. In combination with opioids (most often with codeine): Prohodol Forte, Solpadein, Noshpalgin, Unispaz, Kaffetin, etc.

2.2. In combination with other non-narcotic analgesics and / or caffeine: Migrenol, Panadol Extra, Panoxen (containing paracetamol + diclofenac), Brustan, Ibuklin (containing paracetamol + ibuprofen), Citramon-MFF, Citramon P, Citramon-Acre (containing paracetamal acid + acetylsol + caffeine) - analogues of the proposed pharmaceutical composition (reference Vidal, 2010), etc.

2.3. In various combinations with decongestants, expectorants and ascorbic acid (combined drugs to eliminate the symptoms of acute respiratory infections and colds): Efferalgan with Vitamin C, Coldrex HotRem, Coldrex, TeraFlu, AntiFlu, Rinza, Antigrippin, Fervex and many others.

2.4. A small group in which paracetamol is used in combination with other drugs, consisting of Trigan-D and Femizol.

Among the noted groups of combined analgesics, we especially note preparations containing non-steroidal anti-inflammatory drugs (NSAIDs), which are one of the most popular non-narcotic painkillers designed to relieve moderate pain and febrile conditions of various etiologies.

NSAIDs have been widely used in medicine for over 40 years and are among the most effective symptomatic medicines (drugs) for the relief of pain, inflammation and fever [Nasonov E.L. Cardiovascular complications of COX-2 inhibitors: there are more questions than answers. Breast cancer. 2005, volume 13, No. 7, p. 383-392. Ananyeva L.P. Symptomatic pain therapy for rheumatic diseases. Soi811shsh shsFsish 2002. Volume 04 / No. 8]. Due to acceptable relatively low toxicity, many of them (ibuprofen, naproxen, ketoprofen, acetylsalicylic acid) in low doses are approved for use as over-the-counter drugs.

At the same time, many years of experience with NSAIDs have revealed a number of serious side effects of this group of drugs: headache, dizziness, impaired platelet aggregation, kidney function, a negative effect on the circulatory system and, finally, the most significant - the toxic effect of NSAIDs on gastrointestinal intestinal tract. It is well known that due to a violation of the synthesis of prostaglandins in the gastric mucosa and the irritant effect, non-steroidal agents cause its damage with the possible development of ulcerations and bleeding. With the systematic administration of NSAIDs, these phenomena occur in a significant percentage of cases [D.A. Kharkevich, Pharmacology, 2004].

The interpretation of the mechanisms underlying the anti-inflammatory activity and side effects of NSAIDs, and the development on this basis of new drugs of this class is rightfully considered one of the major achievements in pharmacology of the late XX century [Nasonov E.L. Cardiovascular complications of COX-2 inhibitors: there are more questions than answers. Breast cancer. 2005, volume 13, No. 7, p. 383-392. Kozachok N.N., Selyuk M.N., Bychkova S.A. The optimal choice of non-steroidal anti-inflammatory drug in modern clinical practice. Handbook of a specialist. 2007, 8 (212)].

The principle of creating new drugs based on NSAIDs is to preserve the severity of the effect characteristic of NSAIDs (triad - anti-inflammatory, analgesic, antipyretic effects) and the possible improvement of the safety profile.

The principle is carried out by selecting a combination of NSAIDs with other analgesics related to other types of analgesics. At the same time, the breadth of therapeutic use naturally expands with the use of analgesics with a mechanism of action different from that of NSAIDs and, as a result, having a pharmacological effect different from NSAIDs. Nevertheless, a characteristic feature of most of the created complex analgesics based on NSAIDs is the combination of NSAIDs with one or two (so that the total number of substances is no more than three) additional analgesics (see the composition of analogues).

This is due to the fact that otherwise significant difficulties arise in achieving the balance of the severity of activity activity (efficiency profile) and safety profile described above.

The most complex and closest in composition of the components to the proposed one, in which the specified balance was achieved, is the applicant's drug Pentalgin N (selected by the applicant as a prototype).

It contains analgin (often used as an alternative to paracetamol, belongs to NSAIDs, a group of pyrazolone derivatives) + phenobarbital + codeine + naproxen + caffeine (Vidal Handbook, 2010). As auxiliary substances, the dosage form contains potato starch, low molecular weight polyvinylpyrrolidone (povidone), sodium citrate, and magnesium stearate. The undoubted advantage of this drug is its simplicity of manufacture (in particular, separation of components according to their compatibility is not required), a small assortment of excipients.

However, metamizole sodium (analgin), codeine and phenobarbital that are part of the drug can cause such side effects as dyspeptic disorders (nausea, vomiting, constipation), epigastric pain, dizziness, drowsiness, palpitations, and in rare cases, inhibition of blood formation (leukopenia) granulocytopenia, agranulocytosis), with prolonged use in high doses - impaired liver and kidney function. The presence of two peripheral NSAIDs (analgin and naproxen) in the preparation increases the risk of gastrointestinal complications. Also, when using the drug, caution should be taken and refrain from activities requiring increased attention and speed of psychomotor reactions. In addition, the components of the drug - codeine and phenobarbital, have a risk of misuse.

Thus, at present, there is an urgent need for the creation of new broad-spectrum analgesics that do not have the restrictions on the use noted above.

An inventive task is to create a safer combination analgesic with a better therapeutic index (medium-to-average-dose ratio) and a large therapeutic range.

SUMMARY OF THE INVENTION

The inventive problem is solved by the fact that a pharmaceutical preparation for oral administration is proposed having analgesic activity, containing paracetamol, caffeine, naproxen, drotaverin and pheniramine (or their salts) in effective amounts and excipients.

According to the standard clinical and pharmacological article of the State Register of Medicines (TKFS), the generally accepted doses for the components are

Paracetamol: with monotherapy, a single dose according to TKFS is 500 mg, the maximum single dose is 1 g. As a rule, paracetamol is included in the composition of combination preparations at a dose of 300-750 mg.

Naproxen: with monotherapy, a single dose according to TKFS is 275-750 mg, the maximum single dose is 825 mg. As a rule, naproxen is included in a combination dose of 100 mg.

Anhydrous caffeine: both with monotherapy and as part of combination preparations is used at a dose of 30-50-100 mg per dose. The maximum single dose is 400 mg.

Drotaverine hydrochloride: both with monotherapy and in combination preparations is used at a dose of 40-80 mg per dose.

Pheniramine: the average single dose for oral administration for adults is 25 mg, in the composition of combined preparations - 10-25 mg.

These quantities can be used in the proposed composition, however, according to the invention, the effective amounts of the components of the composition can be somewhat expanded and in a single dose are, mg:

Paracetamol 50-1200 Naproxen 20-1000 Caffeine 5-500 Drotaverinum (as hydrochloride) 10-150 Pheniramine (as Maleate) 5-70

Preferably, the content of active substances in the preparation is 10-90% of the total weight.

The inventive task is also solved by the creation of a pharmaceutical preparation for oral administration with analgesic, anti-inflammatory and antipyretic activity,

- 2 019805 containing Paracetamol, Naproxen, Caffeine, Pheniramine maleate and Drotaverin hydrochloride and excipients, which are compressed granules, the first granules include Paracetamol, Naproxen, Caffeine, the second granules include Paracetamol and Pheniramine maleate and the third granules include Paracetamol D and and excipients are part of the granules, granulating solution and the ready-made mixture for tabletting, in the following preferred ratio of the components of the drug, mg per od dose:

Active components:

Paracetamol 325 Naproxen one hundred Caffeine fifty Drotaverine hydrochloride 40 Feniramine maleate 10

Excipients for granules:

Microcrystalline cellulose

Starch

Excipients for granules and for the finished mixture for tabletting:

Croscarmellose sodium

Magnesium stearate

Talc

130

Excipients for granulating solution:

Hydroxypropyl cellulose

Citric Acid Monohydrate

Butylhydroxytoluene

Dyes (for granules and for granulating solution:

Quinoline yellow dye

Indigo carmine dye

The preparation is preferably a film-coated tablet in the following ratio of shell components, mg per tablet:

0.3

0.5

0.02

Hydroxypropyl methyl cellulose 12.17 Medium molecular weight polyvinylpyrrolidone 3.87 Twin 80 1,1 Talc 4,218 Titanium dioxide 3.43 Quinoline yellow dye 0.2035 Indigo carmine dye 0.0085

The applicant unexpectedly found that the proposed composition of active and auxiliary substances allows not only to expand the therapeutic capabilities of the drug (to achieve pronounced effectiveness with a wider range of pain syndromes due to the effect on different mechanisms of pain formation), but also to obtain a more pronounced therapeutic effect with less toxicity of the drug , which will improve the safety of therapy for patients.

The composition and the proposed dosage form allows you to get the finished product with stable quality, free from harmful impurities (decomposition products / interaction of the original drug substances with potential reagents), the presence of which inevitably leads to additional toxicity of the combined drug.

So, in particular, it was experimentally established that when using the three granules described above in the manufacture of tablets, the greatest stability of the dosage form during storage is achieved.

Below are examples of obtaining solid finished forms, as well as a biological example, confirming the achievement of the technical result and industrial applicability of the invention.

Information confirming the possibility of carrying out the invention.

- 3 019805

Example 1. A drug and method for its preparation.

According to an example, the following drug formulations per dose (tablet) can be obtained.

Table 1

Name Content, g (Following the example; in parentheses are the ranges of values) Content% one 3 4 Core composition Paracetamol 0.32500 39.39000 Naproxen 0,10000 12,12,000 Caffeine 0.05000 6,10000 Drotaverine hydrochloride 0.04000 4,84850 Feniramine maleate 0.01000 1.21000 Microcrystalline cellulose RN-101 0.12800 (0.1-0.2) 15,550,000 Potato starch 0,05538 (0.01-0.1) 6,70000

- 4 019805

Croscarmellose sodium ο, υ ^ ζυο (0.01-0.1) 3.88000 Hydroxypropyl cellulose (Klucel EP) 0,03252 (0.01-0.1) 3.94000 Citric Acid Monohydrate 0.00300 (0.001-0.004) 0.36400 Butylhydroxytoluene 0,00030 (Up to 0.0001) 0,03640 Magnesium stearate 0,00720 (0.005-0.008) 0.87200 Talc 0.016120 (0.01-0.02) 1,954 Quinoline yellow dye 0,0004608 (0,0004-0,0005) 0,0558 Indigo carmine dye 0.0000192 (0.00001-0.00002) 0.0023 Core mass 0,800,000 - The composition of the film shell Hydroxypropyl methylcellulose (GPMC 15 SPZ) 0.01217 (0.01-0.02) 1.47000 Medical polyvinylpyrrolidone (PVP K-25) 0,00387 (0.003-0.004) 0.47000 Twin 80 0.00110 (0.001-0.002) 0.13000 Talc 0.004218 (0.004-0.005) 0.5113 Titanium dioxide 0,00343 (0.003-0.004) 0.42000 Quinoline yellow dye 0,0002035 (0,0001-0,0004) 0,0247 Indigo carmine dye 0.0000085 (0,000004- 0.000009) 0.001 Tablet weight 0.82500 100,0000

The content of the amount of active substances is approximately 64 wt.% Of the total weight of the drug, the remaining 36% are excipients. The content of active substances in example 1 is, mg:

Paracetamol 325 Naproxen one hundred Caffeine fifty Drotaverinum (as hydrochloride) 40 Pheniramine (as Maleate) 10

To obtain tablets of the above composition, the method uses the following calculated amounts of raw materials for loading on a pilot plant.

- 5 019805

table 2

name of raw materials Amount, g For the preparation of 3.0 kg of kernels Preparation of granulate No. 1: Paracetamol 399.75 Naproxen 375.00 Caffeine 187.50 Microcrystalline cellulose 139.20 Potato starch (humidity 17%) 71.40 (in terms of 100%) 59.26 Croscarmellose Sodium 17.80 Humidifier: 12.8% alcohol-water solution of HPC with citric acid, butylhydroxytoluene and dye Solution No. 1: 15.0% aqueous solution hydroxypropyl cellulose with dye total quantity in it: 440,000 -gpc 56,470 - purified water, including: - on the solution of the GOC 293,400 - for dye solution 25.8656

- dye quinoline yellow - dye indigo carmine 0.8000 0,03335 Solution No. 2: an aqueous solution of citric acid, including: citric acid purified water 5,210 28,850 Solution No. 3: alcohol solution of butylhydroxytoluene, including: butylhydroxytoluene, ethanol 0.521 28,850 Preparation of granulate No. 2: Paracetamol 375,000 Drotaverine hydrochloride (100%) 150,000 Microcrystalline cellulose 171,600 Potato starch (humidity 17%) (in terms of 100%) 85,200 70,720 Croscarmellose Sodium 21,300 Humidifier: 12.8% alcohol-water solution of HPC with citric acid, butylhydroxytoluene and dye

- 6 019805

Solution No. 1: 15.0% aqueous solution hydroxypropyl cellulose with dye total quantity in it: 250,000 -gpc 32,080 - purified water, including: - on the solution of the GOC 166,600 - for dye solution 14,890 - dye quinoline yellow 0.455 - dye indigo carmine 0.01895 Solution No. 2: an aqueous solution of citric acid, including

including: citric acid, purified water 2,960 16,350 Solution No. 3: alcohol solution of butylhydroxytoluene, in including: butylhydroxytoluene, 0.296 ethanol 16,350 Preparation of granulate No. 3: Paracetamol 444.0 Feniramine maleate 37,500 Microcrystalline cellulose RN-101 169,200 Potato starch (100%) 70.72 (ow. 17%) 85,200 Croscarmellose Sodium 20,900 Humidifier: 12.8% alcohol-water solution of HPC with citric acid, butylhydroxytoluene and dye Solution No. 1: 15.0% aqueous solution hydroxypropyl cellulose with dye total quantity in it: 260,000 -GPC, 33,400 - purified water, including: - on the solution of the GOC 173,400 - for dye solution 15,220 - dye quinoline yellow 0.473 - dye indigo carmine 0.0197 Solution No. 2: an aqueous solution of citric acid, including including: citric acid 3,080 purified water 17,050 Solution No. 3: alcohol solution of butylhydroxytoluene, in including: butylhydroxytoluene, 0,308 ethanol 17,050

- 7 019805

Dusting components:

Talc 60,450 Croscarmellose Sodium 60,000 Magnesium stearate 27,000

Preparation of a film coating for coating 3.0 kg of cores:

Hydroxypropyl methyl cellulose 59,330 Medium molecular weight polyvinylpyrrolidone medical 18,870 Twin 80 5,360 Talc 20,560 Titanium dioxide 16,720 Quinoline yellow dye 0,992 Indigo carmine dye 0.0414 Alcohol ethyl rectified 1039,100 Purified water: In stock solution for soaking talc and titanium dioxide to dissolve the dye for washing sieves 265,000 66,670 16,660 66,670

Process statement

Raw material preparation

Screening of raw materials

The sifting of raw materials is carried out on a vibrating sieve, having previously installed the necessary mesh. Table 3

name of raw materials

Paracetamol, naproxen Microcrystalline cellulose, pheniramine maleate, caffeine

Drotaverine hydrochloride

Croscarmellose sodium, talc, magnesium stearate, potato starch

The size of the mesh holes, mm

1,000 (1.0 ± 0.07)

0.500 (0.5 ± 0.05)

0.315

0.224

Humidifier preparation

1) Preparation of a 15% aqueous solution of hydroxypropyl cellulose with a dye Table 4

Preparation of dye solution

Table 5

Name Amount, g Quinoline yellow dye 1,728 Indigo carmine dye 0,072 Purified water 55.98

The purified water is weighed into a 1000 ml beaker, heated to a temperature of 60-70 ° C, and hydroxypropyl cellulose is added with constant stirring. Stirring is carried out for 40 minutes until a homogeneous, clear solution is obtained.

A dye solution is prepared in a separate beaker with a volume of 100.0 ml: the purified water is heated to 75 ± 5 ° C and dyes, quinoline yellow and indigo carmine, are added with stirring. The solution was cooled to room temperature. Then a dye solution is added to the HPC solution and mixed for 15-20 minutes until a uniformly colored solution is obtained.

The resulting solution was filtered through sieve No. 61 (0.09 ± 0.015) mm.

2) Preparation of citric acid solution

- 8 019805

Table 6

Name Amount, g Citric Acid 11.25 Purified water 62.25

The purified water is weighed into a 100 ml beaker and citric acid is added with stirring. Stirring is continued until the citric acid is completely dissolved.

3) Preparation of an alcoholic solution of butylhydroxytoluene

Table 7

Name Amount, g Butylhydroxytoluene 1,125 Ethanol 62,250

Ethyl alcohol was weighed into a 100 ml beaker and butylhydroxytoluene was added with stirring. Stirring is continued until the butylhydroxytoluene is completely dissolved.

An aqueous solution of citric acid and an alcoholic solution of butylhydroxytoluene are added to the resulting HPC solution with dyes. The solution is thoroughly mixed. The finished solution is used as a humidifier in the process of preparing granules.

Preparation of the mixture for tabletting.

Sifted raw materials are weighed into technological containers on the scales in the amount indicated in the table. 2.

Preparation of granulate No. 1.

Paracetamol, naproxen, caffeine, microcrystalline cellulose, potato starch, sodium croscarmellose are loaded into a vertical mixer and mixed for 20 minutes. The humidifier is administered in an amount of 440.0 g in 2 divided doses:

1) 300.0 g - stirred for 5 minutes;

2) 140.0 g - stirred for 5 minutes.

Wet granulation is carried out on a vertical granulator through a mesh with a hole diameter of 4.0 mm. The granulate is dried in a shelf dryer at a temperature of 50-60 ° C to a residual moisture content of 1.7-2.1%. Dry granulation is carried out on a vertical granulator through a mesh with a hole size of 1.5 mm, then manually through a sieve with a hole diameter of 1.0 mm.

Preparation of granulate No. 2.

Paracetamol, drotaverine hydrochloride, microcrystalline cellulose, potato starch, sodium croscarmellose are loaded into a vertical mixer and mixed for 20 minutes. The humidifier is introduced into the dry mixture in an amount of 250.0 g in two doses:

1) 150.0 g - stirred for 5 minutes;

2) 100.0 g - stirred for 5 minutes.

Wet granulation is carried out on a vertical granulator through a mesh with a hole diameter of 4.0 mm. The granulate is dried in a shelf dryer at a temperature of 50-60 ° C to a residual moisture content of 1.7-2.1%. Dry granulation is carried out on a vertical granulator through a mesh with a hole size of 1.5 mm, then manually through a sieve with a hole diameter of 1.0 mm.

Preparation of granulate No. 3.

Paracetamol, pheniramine maleate, microcrystalline cellulose, potato starch, sodium croscarmellose are weighed into a technological container and mixed manually for 10 minutes. The humidifier is introduced into the dry mixture in an amount of 260.0 g in two divided doses. Wet granulation is carried out manually through a sieve with a hole diameter of 2.0 mm. The granulate is dried in a shelf dryer at a temperature of 50-60 ° C to a residual moisture content of 1.7-2.1%. Dry granulation is carried out manually through a sieve with a hole diameter of 1.0 mm.

Association of granules.

Granules No. 1, 2 and 3 are mixed in a technological container in a ratio of 1.0 (100%): 0.664 (100%): 0.628 (100%):

1) mix granulate No. 1 with granulate No. 2 for 2 minutes;

2) weighed granulate No. 3 in the specified ratio and mix the whole mass for 3 minutes;

3) dusting of granules is carried out manually in a laboratory container for 3 minutes.

The composition of the dusting mixture: sodium croscarmellose, magnesium stearate, talc.

Tableting.

Tableting was performed on a tablet press using a biconvex press tool with a diameter of 13 mm. The average mass of the core is 0.80 g ± 5%. It is necessary to store the kernels in a dry, dark place at an air temperature of not more than 25 ° C, relative humidity (60 ± 5)% of not more than 10 days.

Preparation of film-forming suspension.

- 9 019805

1039.1 g of ethyl alcohol are loaded into a container with a stirrer and 59.33 g of HPMC are dissolved with constant stirring (at least 30 minutes). After complete dissolution of HPMC, add 18.87 g of PVP K25 and mix until a clear, homogeneous solution is obtained. Then 265.0 g of purified water is added to the solution.

In a 250 ml beaker, 20.56 g of talc, 16.72 g of titanium dioxide and 5.36 g of Tween-80 are soaked in 66.67 g of purified water. Dyes: quinoline yellow and indigo carmine are dissolved in purified water heated to 70-80 ° С. The dye solution is transferred to the stock solution. The suspension with titanium dioxide, talc and tween is transferred to the main solution. The film suspension is stirred for 60 minutes and filtered through sieve No. 61 (0.09 ± 0.015) mm, the sieve is washed with water in an amount of 66.66 g.

Coating.

The coating is carried out in an automatic installation in accordance with the mode specified in the table. 8.

Nozzle number 4.

The expiration time of the finished suspension is 31-37 s.

The mode of applying a film suspension on a tablet core.

Table 8

Cycle number 1-5 6 onwards Injection, min-s 3.00 3.00 Drying time, min-s 0.03 0.03 Cores temperature, ° С 39-40 39-40 Inlet air temperature, ° С 50-60 50-60 Boiler rotation speed, rpm 8-10 15-20 Pump capacity ml / min sixteen 16-20 Atomization pressure, bar 1,6 1,6 Air supply pressure, mm water 8 8 Depression, mm water column -0.5 -0.5

It is necessary to store coated tablets in a dry, dark place at an air temperature of not more than 25 ° C, relative humidity (60 ± 5)%.

Examples 2-3.

The preparation operations described in Example 1 were carried out, however, according to Example 2, the content of the sum of active substances is approximately 10 wt.% Of the total weight of the drug, the remaining 90% is accounted for by auxiliary substances. The content of active substances in the preparation (per dose) is, mg:

Paracetamol fifty Naproxen twenty Caffeine 5 Drotaverinum (as hydrochloride) 150 Pheniramine (as Maleate) 70

According to example 3, the content of the amount of active substances is approximately 90 wt.% Of the total weight of the drug, the remaining 10% are excipients. The content of active substances in the preparation (per dose) is, mg:

Paracetamol 1200 Naproxen 1000 Caffeine 500 Drotaverinum (as hydrochloride) 10 Pheniramine (as Maleate) 5

Example 4. Biological tests.

The composition was studied to study acute and subchronic toxicity (general toxic effect), analgesic, anti-inflammatory and antipyretic activity in comparison with the drug Pentalgin-N manufactured by Pharmstandard-Leksredstva OJSC.

1. The study of acute and subchronic toxicity of the composition.

In the study of acute toxicity to white mice of both sexes, enter intragastrically once

- 10 019805 were administered the preparations according to this invention and Pentalgin-N (prototype), intragastrically in doses of 0.5 tab / kg, 1 tab / kg, 1.5 tab / kg, 2 tab / kg, 2.5 tab / kg ( according to example 1) in an amount acceptable for intragastric administration to a given animal species. It was revealed that the studied drugs in the indicated doses at a single dose did not have a dose-dependent toxic effect, causing the death of animals during the first 3 days of observation. The value of L0 ₅₀ calculated by the Shtabsky method for the combinations according to the invention was 1.73 ± 0.12 tab / kg; for tablets Pentalgin-Hb ₅₀ - (1.50 ± 0.14) tab / kg. According to the classification of K.K. Sidorova, the proposed composition and the drug based on it can be attributed to low toxicity drugs.

When studying subchronic toxicity, for a long time - within 2 weeks - the rats received intragastric administration of the studied drug and the comparison drug Pentalgin-N in a double therapeutic dose (0.2 tab / kg), four times (0.4 tab / kg) and eight times therapeutic doses (0.8 tab / kg). It was revealed that the studied drug and the comparison drug in a dose that is 2 times higher than the therapeutic one, when administered intragastrically for 14 days, do not have a toxic effect on the cellular and biochemical composition of the blood and the state of internal organs. Prolonged intragastric administration (within 14 days) to rats of both drugs at a dose of 0.4 and 0.8 tab / kg caused the death of animals due to the development of peritonitis associated with the specificity of the action of non-steroidal anti-inflammatory drugs on the intestines of rats.

Based on the morphological study, we can conclude that in a low dose (0.2 tab / kg), both drugs do not have a noticeable toxic effect on the animal organism, while at doses of 0.4 tab / kg and 0.8 tab / kg the drugs have an equally pronounced toxic effect on the internal organs of experimental rats, due to the species specificity of the action of large doses of non-steroidal anti-inflammatory drugs with prolonged administration.

Thus, a study of the toxic effect of the preparations showed that the preparation according to the invention does not differ from the preparation Pentalgin®-N in acute and subchronic toxicity.

2. The study of analgesic, anti-inflammatory and antipyretic activity of the proposed drug in comparison with the drug Pentalgin-N.

The pharmacological activity of the proposed drug (composition according to example 1) was studied in rats and mice.

The analgesic, antipyretic and anti-inflammatory effects of the drug were studied in comparison with the drug Pentalgin-N. Both drugs were administered on an empty stomach intragastrically in the form of an aqueous suspension in doses from 0.025 to 0.5 tab / kg.

The analgesic activity of the drugs was studied on an experimental model of acetic acid cramps in rats (at doses of 0.025 and 0.175 tab / kg) and in the test a hot plate in mice (at doses of 0.05, 0.15 and 0.25 tab / kg). The anti-inflammatory effect was evaluated in conditions of acute aseptic inflammation of the foot of mice caused by formalin. The antipyrogenic effect of the preparations was studied on male Wistar rats, the pyrogenic reaction was modeled by intramuscular administration of pyrogenal at a dose of 100 μg / kg.

Based on the studies, it was found that the proposed drug has a pronounced dose-dependent analgesic, antipyretic (anti-pyrogenic) and anti-inflammatory effect.

During the experimental study of the analgesic effect in the test of acetic acid cramps when calculating the therapeutic index, the advantage of the proposed drug was found compared with Pentalgin-N: 10.8 and 8.8, respectively.

When evaluating the anti-inflammatory effects of the proposed drug and the well-known drug Pentalgin-N when calculating the therapeutic index, it was found that the proposed drug is characterized by a wider therapeutic range: 6.9 and 6.25, respectively.

When studying the antipyretic effect, which was estimated by reducing the temperature increase 2 hours after the introduction of pyrogenal, it was shown that the proposed drug is superior to Pentalgin-N tablets.

The results indicate a greater severity and breadth of the analgesic, anti-inflammatory and antipyretic effects of the proposed drug compared to Pentalgin-N while maintaining the level of toxicity, which is an unexpected effect for this combination.

Claims (4)

1. A pharmaceutical preparation for oral administration having analgesic activity, containing paracetamol, caffeine, naproxen, drotaverin and pheniramine (or their salts) in effective amounts and auxiliary substances, while the effective amounts of the components in a single dose are, mg: - 11 019805 Paracetamol 50-1200 Naproxen 20-1000 Caffeine 5-500 Drotaverinum (as hydrochloride) 10-150 Pheniramine (as Maleate) 5-70 2. The drug according to claim 1, characterized in that the content of active substances in it is 1090 wt.% Of the total weight of the drug. 3. The drug according to claim 1, characterized in that it is a compressed granules, the first granules include paracetamol, naproxen, caffeine, the second granules include paracetamol and pheniramine maleate and the third granules include paracetamol and drotaverine hydrochloride, and excipients are part of the granules and granulating solution in the following ratio of the components of the drug, g in one dose: Active Ingredients: Paracetamol Naproxen Caffeine Drotaverine hydrochloride Feniramine maleate 0.325 0.10 0.05 0.04 0.01 Excipients for granules: Fillers: Microcrystalline cellulose Starch Croscarmellose sodium 0.13 0.06 0,03 Magnesium stearate (glidant) Talc (dusting agent) 0.007 0.016 Excipients in the granulating solution: Hydroxypropyl cellulose Citric acid Monohydrate Butylhydroxytoluene Dyes: Quinoline yellow dye Indigo carmine dye 0,033 0.003 0,0003 0,0005 0.00002 4. The drug according to claim 3, characterized in that it has a film membrane in the following ratio of components, g per tablet: Hydroxypropylmethyl cellulose Polyvinylpyrrolidone molecular weight Tween-80 Talc Titanium dioxide Quinoline yellow dye Indigo carmine dye 0.01217 0,00387 0.00110 0,004218 0,00343 0,0002035 0.0000085 Eurasian Patent Organization, EAPO Russia, 109012, Moscow, Maly Cherkassky per., 2