RU2235544C1 - Preparation eliciting analgetic, antripyretic and spasmolytic effect - Google Patents

Abstract

FIELD: medicine, pharmacy.

SUBSTANCE: invention relates to the development of the combined preparation based on sodium metamizole and tempidon eliciting analgetic, antipyretic and spasmolytic activity. Preparation is made as an envelope-covered tablet. Tablet core comprises active substances sodium metamizole and tempidon and accessory substances - maize starch, microcrystalline cellulose, polyvinylpyrrolidone, sodium starch, glycolate, talk and magnesium stearate. Envelope comprises Opadory Green, titanium dioxide, talk, polyethylene glycol-6000, dye blue, quinoline yellow. The combined preparation shows low toxicity, it doesn't induce disturbances of biochemical and hematological indices of blood owing to qualitative and quantitative ratio of components.

EFFECT: improved and valuable medicinal properties of preparation.

2 dwg, 8 tbl

Description

The invention relates to medicine and relates to a combined preparation based on metamizole sodium and tempidone.

The combined drug, which includes the analgesic-antipyretic metamizole sodium and the tempidone tranquilizer, has an analgesic, antipyretic, weak anti-inflammatory and sedative effect.

The closest in technical essence and the achieved result is a drug with analgesic, antipyretic and antispasmodic activity, made in the form of a coated tablet (Bulgarian patent No. 63147, 05/31/2001). The drug includes active substances - metamizole sodium and tempidone, and as auxiliary substances - wheat starch, microcrystalline cellulose, polyvidone, talc, magnesium stearate.

The objective of the present invention is to create, based on metamizole sodium and tempidone, a domestic combined preparation that has low toxicity and does not cause a violation of biochemical and hematological blood parameters due to the qualitative and quantitative selection of ingredients.

To solve this problem, a drug is made in the form of a coated tablet. The tablet core contains active substances - metamizole sodium and tempidone, as well as excipients - corn starch, microcrystalline cellulose, polyvinylpyrrolidone, sodium starch glycolate, talc, magnesium stearate. These ingredients are taken in the following proportions, wt.%:

Metamizole Sodium 59.0-72.0

Tempidone 2.4-2.9

Microcrystalline cellulose 8.5-11.0

Polyvinylpyrrolidone 7.0-9.0

Sodium starch glycolate 1.0-1.5

Talc 1.5-2.5

Magnesium stearate 0.9-1.5

Corn Starch Else

The tablet shell includes Opadry Green, titanium dioxide, talc, polyethylene glycol 6000, dye blue, quinoline yellow in the following ratio of ingredients, wt.%:

Titanium dioxide 10-16

Talcum 15-25

Blue dye 0.05-0.1

Quinoline yellow 0.1-0.2

Polyethylene glycol 6000 6-8

Opadry Green Else

An example of obtaining the proposed tablets

The composition of the core per 1 tablet, g:

Metamizole Sodium 0.5

Tempidone 0.02

Microcrystalline Cellulose 0.075

Polyvinylpyrrolidone 0.06

Sodium Starch Glycolate 0.01

Talcum powder 0.015

Magnesium Stearate 0.01

Corn Starch Else

Metamizole sodium, tempidone, part of corn starch, microcrystalline cellulose and part of sodium starch glycolate are mixed. Granulation is carried out in a fluidized bed installation using a mixture of 1.5% corn starch paste and a 25% aqueous solution of polyvinylpyrrolidone as a granulating liquid. The dried granulate is sieved through a sieve and dusted with corn starch, sodium starch with glycolate, talc, magnesium stearate. After dusting, the granulate is tabletted on a tablet press using punches with a diameter of 13 mm. The obtained tablet cores have an average weight of 0.76 g.

The cores are coated, the composition of which per tablet is as follows, g:

Opadry Green 0.00572668

Titanium dioxide 0.00143167

Talc 0.00214751

Blue dye E-133 0.00000859

Quinoline yellow E-104 0.00001747

Polyethylene glycol 6000 0,00066808.

The coated tablets have a mass of 0.77 g (0.73 to 0.81 g). They have a round biconvex shape, a smooth, smooth, shiny surface of light green color. Two layers are visible in the cross section.

Comparative studies of the proposed drug on the basis of metamizole sodium and tempidone and the drug Tempalgin manufactured by Farmahim (Bulgaria) - coated tablets, series 596500, shelf life - until 09.2004 were carried out.

We determined the absorption spectrum of the preparations.

The UV spectrum was recorded using a U1-trospec-II spectrophotometer manufactured by LKB Biochrom. When registering the absorption spectra, the tablet of the proposed drug was dissolved in 10 ml of distilled water, the solution was filtered through a Millipor filter with a pore size of 0.45 μm. The filtrate was diluted with water to a final ratio of 1: 10000. Comparison with a tablet of a preparation was similar.

Figure 1 shows the absorption spectrum of the solution of the comparison drug in the wavelength range from 200 to 400 nm: there are two absorption peaks at 225 and 260 nm, respectively 0.76 and 0.61 units. optical density.

Figure 2 shows the absorption spectrum of a solution of the proposed drug, shot in the same wavelength range. At 225 nm, the optical density was 0.69 units, and at 260 nm, 0.56 units.

The obtained absorption spectra are almost identical: for the reference drug and the proposed drug, both peaks of optical density coincide both in wavelength and in optical density.

The determination of the disintegration of the compared dosage forms was carried out in accordance with the requirements of the Global Fund XI (article “Tablets” and Appendix 3 thereto, v.2, p.154, 158). The data obtained are shown in table 1. The values of the disintegration time for both drugs are very close and in all cases significantly lower than the requirements of GF (for coated tablets, no more than 30 minutes).

The test of drugs according to the “Dissolution” test was carried out in accordance with the requirements of the Global Fund XI (article “Tablets” and Appendix 4 thereto, v.2, p. 154, 159). The results obtained for both drugs differed little and met the requirements of the Global Fund (at least 75%).

Acute toxicity was experimentally determined on white mice of the C-57 black-6 line weighing 16-20 g.

Preparations for administration were prepared as follows: the tablet was ground in a porcelain mortar, the necessary amount of powder was weighed, and a suspension was prepared on the basis of a 3% starch paste. Suspension in a volume of 1.0 ml was administered to animals per os through a probe.

Laboratory animals were divided into six groups of six mice each. The proposed and control preparations were administered to animals at doses of 6.0; 5.5; 5.0; 4,5; 4.0 and 3.0 g / kg.

It was found that the introduction of both drugs caused an increase in respiratory rate, the number of uria and defecation, and the activation of salivation. With an increase in dose to 4.0 g / kg, the appearance of tonic convulsions was observed, with a further increase in the dose, generalized clonic-tonic convulsions were observed. The death of animals occurred during the first days after the administration of the drug. Observation of the surviving mice was carried out for 14 days. On the second and subsequent days of observation, the state of these animals returned to normal. The results of the acute toxicity study are presented in tables 2 and 3. As the studies showed, the LD ₅₀ value was 4.08 ± 0.49 g / kg for the proposed drug, and 4.37 ± 0.51 g / kg for the comparison drug.

The study of subacute drug toxicity was performed on outbred white rats weighing 180-220 g. The drugs were administered intragastrically in the volumes and dilutions indicated in Table 4. Based on the fact that the therapeutic dose of the drugs is 37.5 mg / kg, and the ten-fold therapeutic dose is 375 mg / kg, laboratory animals were divided into five groups:

group 1 - 10-fold dose of the proposed drug;

group 2 - therapeutic dose of the proposed drug;

group 3 - 10-fold dose of the comparison drug;

group 4 - therapeutic dose of the comparison drug;

group 5 - intact animals (saline).

The drugs were administered to rats for 14 days. The degree of intoxication was assessed by the general condition of the animals, the condition of the coat, the change in the number of uria, defecation, salivation, the onset of tremor, seizures, changes in the frequency and rhythm of respiration.

After the end of the administration of drugs, they performed slaughter and pathological anatomical dissection of animals. Samples of tissue of the kidneys, liver, spleen, thymus, brain were taken for light-optical analysis and blood samples for determining biochemical and hematological parameters.

For the entire time of the introduction of drugs not a single fatal case was recorded. Both drugs in both therapeutic and 10-fold therapeutic doses did not cause statistically significant deviations in the mass of the internal organs of animals. No other visible signs of intoxication were observed.

In hematological studies, the calculation of blood cells was carried out in samples of whole blood using a Goryaev’s camera. When determining the number of red blood cells, an aliquot of whole blood was diluted with saline in a ratio of 1: 200, the study was carried out no later than 2-3 hours after dilution. When determining the number of leukocytes, the blood was diluted in a ratio of 1:20 with a 4% solution of acetic acid with methylene blue (for staining cell nuclei). When determining the number of platelets, a blood sample was diluted with a 1% solution of ammonium oxalate in a ratio of 1:20. To count the platelet count, a phase contrast device for the microscope was used.

For biochemical studies, blood in polyethylene tubes was incubated for 4 hours at 37 ° C to form a clot and then centrifuged for 10 minutes at 1500 g. The resulting blood serum was stored at a temperature of -20 ° C until the time of the study. Quality control of measurements and standardization of biochemical methods was carried out using control lyophilized sera Serodos Lyophilized Human Serum company “Human”. Biochemical analysis was performed on a Specol-221 spectrophotometer using the reagent kits listed in Table 5.

Laboratory animals were divided into five groups:

group 1 - 10-fold dose of the proposed drug;

group 2 - therapeutic dose of the proposed drug;

group 3 - 10-fold dose of the comparison drug;

group 4 - therapeutic dose of the comparison drug;

group 5 - intact animals (saline).

From the results of a biochemical analysis of blood serum (table 6), it is seen that statistically significant differences are noted only for transaminases, and an increase in the activity of liver enzymes is registered only in groups of animals that received drugs at a 10-fold therapeutic dose. However, there was no significant difference between the proposed drug and the comparison drug. An increase in the activity of “hepatotropic” enzymes most likely can be a reflection of the hepatotoxic effect and is mediated, apparently, by an increase in the permeability of the cell membrane of hepatocytes, which leads to an increased release of enzymes from the cytoplasm of liver cells.

Table 7 shows the results of hematological analysis. In the blood of animals treated with the preparations in a 10-fold therapeutic dose, severe thrombocytopenia is observed. The remaining integral hematological parameters of the comparison drug and the proposed drug are not significantly different.

The leukocyte blood count in laboratory animals in response to the administration of drugs in both studied doses practically did not change (table 8).

In the study of subacute toxicity, histological studies were carried out, which showed that with the introduction of the comparison drug and the proposed drug in a therapeutic dose, pronounced pathological changes in the organs and gastric mucosa were not observed. The determining characteristics of the microscopic structure of the liver, kidneys, thymus, spleen, brain tissue without pathology and correspond to those in the control group of animals. A similar pattern was observed with the introduction of the comparison drug in a ten-fold therapeutic dose. When introduced in the same dose of the proposed drug, a macroscopic examination revealed no changes either from the studied organs or from the gastric mucosa.

Microscopic studies showed the following:

Liver. Without visible changes, the lobation of the structure is clearly expressed. There are single small-cell infiltrates along the portal tracts in the parenchyma. Separate central and sublobular veins are dilated and filled with blood, there are areas with enhanced capillary pattern, endotheliocytes are clearly visible.

The kidneys. In general, the histoarchitectonics of the organ is the same as in the control group of laboratory animals. The cortical substance is represented by vascular glomeruli and tubules of the nephron. The capsule fits snugly to the organ parenchyma. Large vascular arteries preserved, vascular walls without features. The brain substance is represented by the rays of the collecting tubes, longitudinal and transverse sections of the nephron loops. Epithelial lining of the tubules without pathological changes. There are areas with focal small cell infiltrates.

Thymus. Without visible pathological changes detected by histological examination. The cortical substance is covered with a thin capsule and prevails over the medulla. Mostly small thymocytes are found in the medulla, and the periphery of the cortex is abundantly infiltrated by large and medium thymocytes. Capillaries dilated in places and blood-filled.

Spleen. Of usual structure, the capsule is well developed and contains fibrous components. White pulp is detected in the form of periarterial couplings and primary lymphatic follicles. The border between the red and white pulps is unsharp. Red pulp is enhanced by dilatation of sinusoidal structures and pronounced filling of the red blood cell mass.

Brain. As in the control group of animals, the cortex has five distinct layers with cells characteristic in shape and size. The width, cell density of the layers, cytoarchitectonics, and the state of the basophilic substance do not significantly differ from similar characteristics of brain tissue in rats from the control group.

Assessment of the locally irritating effect of the preparations was carried out according to the state of the gastric mucosa. In all groups of animals treated with drugs, ulcerative lesions of the mucosa were noted. Single petechiae were observed in all groups, and their number did not depend on the dose of the drug administered.

Microscopic examination of the histological picture of the mucosa in rats of the control group was typical. Krista is well defined, smooth muscles of the submucosa are stained and clearly structured. The vessels are moderately dilated. In groups of animals that were injected with drugs, the picture was similar.

Claims (1)

The drug has an analgesic, antipyretic and antispasmodic effect, characterized in that it is made in the form of a tablet, the core of which contains the active substances metamizole sodium and tempidone, as well as excipients - corn starch, microcrystalline cellulose, polyvinylpyrrolidone, sodium starch glycolate magnesium, talcium magnesium stearate in the following ratio of ingredients, wt.%: Metamizole Sodium 59.0 - 72.0 Tempidone 2.4 - 2.9 Microcrystalline cellulose 8.5 - 11.0 Polyvinylpyrrolidone 7.0 - 9.0 Sodium Starch Glycolate 1.0 - 1.5 Talc 1.5 - 2.5 Magnesium stearate 0.9 - 1.5 Corn Starch Else while the core is coated, including Opadry Green, titanium dioxide, talc, polyethylene glycol 6000, dye blue, quinoline yellow in the following ratio of ingredients, wt.%: Titanium dioxide 10 - 16 Talc 15 - 25 Blue dye 0.05 - 0.1 Quinoline yellow 0.1 - 0.2 Polyethylene glycol 6000 6 - 8 Opadry Green Else

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