RU2225724C1 - "panzym forte" enzymatic preparation - Google Patents

Abstract

FIELD: medicine, pharmacology. SUBSTANCE: a new medicinal preparation in tableted form has been suggested the center of which contains pancreatin as an active substance and additional substances microcrystalline cellulose, aerosil (silica powder), sodium starch glycolate, magnesium stearate, moreover, the center is covered with a membrane including Eudragit E-100, polyethylene glycol 6000, citric acid, propylene glycol, Vaseline oil, carmoisin, indigo carmine, hydroxypropylmethyl cellulose, suspension Opandry PINK. Enzymatic preparation is a low-toxicity one and, moreover, has no locally irritating action upon gastric mucosa. EFFECT: higher efficiency. 1 ex, 3 tbl

Description

The invention relates to medicine and relates to an enzyme preparation based on pancreatin.

Known drugs based on pancreatin from the pancreas of slaughter cattle. In these agents, pancreatin contains mainly trypsin and amylase. Means can be made in the form of a powder or tablets, soluble in the intestine (Mashkovsky MD Medicines. - M., 2001, v.2, p.115).

The closest in technical essence and the achieved result is the drug Mezim forte (Germany), made in the form of coated tablets and containing pancreatin with a minimum enzyme activity of amylase 4200 UNITS Ph.Eur., Lipase 3500 UNITS Ph.Eur. and proteases 250 PIECES of Ph.Eur. (Vidal Handbook “Medicinal Products in Russia”, 2002, p. B-366). In addition to the active component of pancreatin, tablets contain auxiliary ingredients: poly- (ortho-carboxymethyl) -starch, hydroxypropylmethyl cellulose, poly- (ethyl-acrylatemethylmeth) -acrylate, talc, Macrogol 600, polydimethylsiloxane, food colors E 122 and E 171.

The objective of the present invention is to provide a domestic enzyme preparation with low toxicity due to the qualitative and quantitative selection of ingredients.

To solve this problem, an enzyme preparation called “Panzim forte” was proposed.

The drug is made in the form of tablets, the core of which contains the active substance pancreatin and auxiliary substances - microcrystalline cellulose, aerosil, sodium starch glycolate, magnesium stearate - in the following ratio of ingredients, wt.%:

Pancreatin 75-95

Microcrystalline cellulose 1-4

Aerosil Not more than 10

Magnesium stearate Not more than 1

Sodium Starch Glycolate Else

The core is coated, including Eudragit E-100, polyethylene glycol 6000, citric acid, propylene glycol, liquid paraffin, carmuazine, indigo carmine, hydroxypropyl methylcellulose, Opadry PINK suspension in the following ratio of ingredients, wt.%:

Eudragit E-100 25-50

Polyethylene glycol 6000 3-9

Citric Acid 15-25

Propylene glycol 3-9

Vaseline oil 2-8

Karmuazin no more than 0,2

Indigo carmine no more than 0.05

Hydroxypropyl methylcellulose 1-2.5

Suspension Opadry PINK 15-35

Example. Getting pills "Panzim forte."

Composition per tablet, FIP UNIT:

Pancreatin corresponding to minimal activity

Amylases 4200

Lipase 3500

Proteases 250

Excipients, g:

Microcrystalline Cellulose 0.00625

Aerosil 0.01275

Magnesium Stearate 0,00075

Sodium starch glycolate 0.01025

The shell of the tablet includes, g:

Eudragit E-100 0.00565383

Polyethylene glycol 6000 0,00090437

Citric acid 0.00287694

Propylene glycol 0.00090436

Vaseline oil 0,00075050

Carmuazine 0.00001884

Indigo Carmine 0.00000104

Hydroxypropyl methylcellulose 0,00025017

Suspension Opadry PINK 0,00363995

Pancreatin is mixed with microcrystalline cellulose, aerosil and part of the sodium starch glycolate. The resulting mixture is granulated using ethyl alcohol as granulating liquid. The granulate is dried, dusted with magnesium stearate and the remaining sodium starch glycolate, and then tableted. The tablet cores are coated in a coating pan or in a fluidized bed installation.

The preparation “Panzim forte” is a round, biconvex tablet, coated with a pink shell. The core is a fracture of beige or brownish-beige color with weakly expressed dark and light inclusions, odorless or with a faint specific smell.

The main component of the drug is pancreatin, an extract of the pancreas that contains protease, lipase, and amylase in a highly concentrated form. These pancreatic enzymes facilitate the digestion of proteins, carbohydrates and fats, which contributes to their more complete absorption in the small intestine. Pancreatin increases the synthesis and excretion of the intestine and its own enzymes in the stomach, pancreas, intestines. The use of the drug helps to improve the functional state of the gastrointestinal tract, normalize the digestion process. The drug compensates for the insufficiency of exocrine pancreatic function.

The action of the drug is a cumulative manifestation of the effect of all its components, therefore, kinetic observations are not possible. All together and at the same time, the components cannot be traced using either a marker or bioassays. For the same reason, it is impossible to detect the metabolites of the drug.

Assessment of acute and subacute toxicity of the Panzim Forte preparation was carried out in comparison with the Mezim Forte drug of the Berlin-Chemie company, Germany.

White outbred mice weighing 18-22 g were used for experimental determination of acute toxicity. Preparations for administration were prepared as follows: the tablets were peeled off, the purified kernels were ground in a porcelain mortar, and after weighing on an analytical balance, a suspension was prepared using 3% starch as a liquid medium water solution.

The suspension was administered to animals per os through a probe in a volume of 0.5 ml. The highest content of the powder of the tablet cores in the finished suspension was 100 mg / ml, so the maximum achievable dose of the drug was 2500 mg / kg. After a single injection of the animals, the animals were kept on a normal vivar diet for two weeks. Laboratory animals were divided into three groups of six mice in each. The experimental and control preparations were administered at doses of 1500, 2000 and 2500 mg / kg.

It was found that the lethal dose of both the experimental and control drug was not achieved. The introduction of both drugs in doses exceeding 1000 mg / kg caused dyspeptic disorders, which were manifested in the appearance of vomiting, an increase in the number of bowel movements, and the appearance of loose stools. Dyspeptic disorders significantly reduced the amount of the drug involved in the metabolic processes of the animal’s body, which significantly complicated the quantitative determination of LD ₅₀ , however, this complication was entirely determined by the method of drug administration.

The LD ₅₀ value for both the experimental preparation and the comparison preparation exceeded 2500 mg / kg with per os administration.

Thus, the assessment of acute toxicity showed low toxicity of both experimental and control drugs, which allowed Panzim forte to be classified as a low-toxic drug.

The determination of subacute toxicity was carried out on white outbred rats weighing 180-220 g. Preparations for administration were prepared as follows: the tablet was cleaned from the shell, the purified kernels were ground in a porcelain mortar and an exact weight was taken, then a suspension was prepared using 3% starch solution as a liquid medium . The suspension was administered to rats per os through a probe in a volume of 0.5 ml. Based on a therapeutic dose of 25 mg / kg and a ten-fold therapeutic dose of 250 mg / kg, appropriate dilutions of the preparation were prepared (Table 1). Laboratory animals were divided into five groups:

group 1 - a dose of 250 mg / kg, the drug “Panzim forte”;

group 2 - dose of 25 mg / kg, the preparation “Panzim forte”;

group 3 - dose 250 mg / kg, Mezim Forte;

group 4 - a dose of 25 mg / kg, the drug Mezim Forte;

group 5 - intact animals, saline.

The duration of drug administration was 14 days. The degree of intoxication was assessed by the general condition of the animals, the condition of the coat, changes in uria, defecation, salivation, tremor, seizures, changes in the frequency and rhythm of respiration. After the introduction of drugs, animals were slaughtered and their autopsy was performed. For light optical analysis, samples were taken of the kidneys, liver, spleen, thymus, stomach, and brain. In addition, biochemical and hematological parameters such as total protein, glucose, urea, alanine transferase (ALT), aspartate transferase (ACT), alkaline phosphatase, hemoglobin concentration, platelet and white blood cell counts were determined in animal blood.

When the experimental drug and the comparison drug were administered to laboratory animals for 14 days in both doses, not a single fatal case was recorded. Both drugs did not cause signs of intoxication. When evaluating the general toxic effect, no differences were found between the Panzim forte and Mezim forte preparations.

In a comparative study of subacute toxicity of drugs, it was found that the biochemical and hematological parameters of blood do not statistically differ in all groups of animals, both experimental and control. The results of blood tests of animals are presented in tables 2 and 3.

During postmortem examination of laboratory animals, it was revealed that the macroscopic structure of the liver, kidneys, thymus, spleen and brain is normal and corresponds to the structure of these organs in healthy animals. The histological structure of the liver, kidneys, thymus, spleen, brain tissue - without visible signs of pathology.

To study the local irritating effect of the preparations, a visual examination of the gastric mucosa was performed in order to identify the possible appearance of petechiae (small focal hemorrhages) and ulcerative lesions. In all five groups of laboratory animals, the presence of 1-2 petechiae on the gastric mucosa was noted, regardless of which drug was administered (experimental, comparison drug or physiological saline) and at what dose. No ulcerative lesions of the mucosa were found at all.

Thus, during the experimental study of acute and subacute toxicity of Panzim forte tablets with the use of biochemical, hematological and histological research methods, it was established that this drug is a low-toxic drug.

Claims (1)

An enzyme preparation, characterized in that it is made in the form of tablets, the core of which contains the active substance pancreatin and auxiliary substances - microcrystalline cellulose, aerosil, sodium starch glycolate, magnesium stearate in the following ratio of ingredients, wt.%: Pancreatin 75-95 Microcrystalline cellulose 1-4 Aerosil Not more than 10 Magnesium stearate Not more than 1 Sodium Starch Glycolate Else wherein the core is coated, including Eudragit E-100, polyethylene glycol 6000, citric acid, propylene glycol, liquid paraffin, carmuazine, indigo carmine, hydroxypropyl methyl cellulose, Opadry PINK suspension in the following ratio of ingredients, wt.%: Eudragit E-100 25-50 Polyethylene glycol 6000 3-9 Citric Acid 15-25 Propylene glycol 3-9 Vaseline oil 2-8 Carmoisine Not more than 0.2 Indigo Carmine Not more than 0.05 Hydroxypropyl methylcellulose 1-2.5 Suspension Opadry PINK 15-35