RU2189810C1 - Method of medicinal preparation cholesan preparing - Google Patents

Abstract

FIELD: medicine, gastroenterology, pharmacy. SUBSTANCE: invention relates to a method of preparing a gastroenterological preparation into gelatin capsule showing proteolytic, hepatoprotective and cholelytic effects. Method of preparing the preparation involves the following stages. Dried mucosa and covering epithelium tissue of an avian muscle region of stomach are milled to preparing a homogeneous powder, mixed with dried milled chicken bile in the ratio 4:1, respectively, screened through a sieve with a hole diameter 0.75 mm and dosed into solid gelatin capsules by 0.3 g. Method provides preparing the preparation of high bioavailability, stability at storage and no showing the damage effect on stomach mucosa. EFFECT: improved method of preparing, valuable medicinal properties. 1 tbl, 3 ex

Description

 The invention relates to medicine and the medical industry, in particular to a gastroenterological agent - a drug having an organ-specific action and intended for the treatment of diseases of the gastrointestinal tract, liver and biliary tract and a method for its preparation.

 In recent years, diseases of the gastrointestinal tract have become widespread, the share of which is 40-50%.

 The relevance of the problem is confirmed by a large number of studies conducted in this area. As a rule, the solution to this problem comes down either to the creation of whole compositions, including extracts of plant origin (RU 2034849, RU 2045956, RU 2087154, RU 2106876), or to the search for technologies for their purification and preparation (SU 1343597, SU 1343592, RU 2034849) , or the allocation of biologically active agents from animal raw materials (US 3956483, RU 2019172, RU 2054947).

 Currently, a number of drugs are known that have choleretic, cholekinetic, cholelitolytic action. These are drugs such as: olimetin, capsules (Nizhpharm OJSC, Russia), 450 mg pumpkin capsules (Evropat Biofaarm CJSC, Russia), hepaten capsules (Merkle GmbH, Austria), hepatofalk plant capsules (Dr. Falk Pharma "GmbH", Germany) - herbal preparations; 250 mg capsules are grown ("Pro. Med. CS Pharma", Czech Republic), Odeston tablets 200 mg ("Polfa", Poland), henofalk capsules 250 mg ("Dr Falk Pharma "GmbH", Germany) - preparations obtained from chemical raw materials. The existing need of domestic health care for affordable gastroenterological agents stimulated work on obtaining domestic preparations from raw materials of animal origin, including through the development of new dosage forms.

 As pharmaceuticals for substitution therapy for digestive disorders, the domestic pharmaceutical industry produces lyobil (FS 42-2523-88), tablets with lyophilized bovine bile, pancreatin (FS 42-1397-83), multi-enzyme tablets containing trypsin and amylase (" Medicines Register 2000 "). The disadvantage of these drugs is that the patient is forced to take them at the same time.

 Known choleretic agent allochol (FS 42-3229-95), available in the form of coated tablets. One tablet contains animal bile 80 mg, dry garlic extract 40 mg, nettle extract 5 mg, activated charcoal 25 mg. The disadvantage of this drug is its low therapeutic activity.

 Known agent having a choleretic effect, including dry bear bile 0.00003-0.0045 g and sugar 0.015-1.5 g (RU 2003338). The disadvantage of this tool is the inconvenience of its use. Known drug cholenzyme (FS-42-2964-93), manufactured by the domestic industry, which is a tablet coated with an acid-labile shell.

Composition per tablet, g:
Dry bile - 0.1
Dried pancreas - 0.1
Dried mucous small intestines - 0.1
The weight of the tablet without shell 0.3 g

 The disadvantage of this drug is the low content of proteolytic and other enzymes.

 Known drug for the treatment of children with gastroduodenal pathology, representing granules of pepsin K (chicken) (RU 2054948).

The drug includes the following components, wt. hours:
Chicken pepsin (10%) - 7.0
Powdered Sugar - 88.0-78.0
Sugar in syrup - 5.0-15.0
The disadvantage of this drug is a narrow range of action, the active substance that is part of the drug is exposed to moisture, heat during drying of the granulate and pressure during compaction of the mass.

 In recent years, the pharmaceutical industry abroad has produced a significant number of oral preparations in the form of capsules, which have advantages over other dosage forms: the drugs are distributed more quickly and evenly over the gastric mucosa, are absorbed faster and more easily without any mechanical (irritating) effect, do not contain auxiliary and ballast substances.

 A known method of obtaining a dried substance obtained from the mucous membranes and integumentary epithelium of the muscular section of the stomach of a clinically healthy bird is a prototype (application 98101436, patent RU 2144826).

 The present invention has posed and solved the task of developing a method for producing the drug cholesan in hard gelatin capsules, which has a spectrum of pharmacological action characteristic of gastroenterology and a wide range of therapeutic action - the treatment of diseases of the gastrointestinal tract, liver and biliary tract, as well as for dissolving soft cholesterol stones.

 The essence of the invention lies in the fact that they mix dried and chopped to a homogeneous powder cuticle (mucous membranes and integumentary epithelium of the muscular part of the stomach of a clinically healthy bird) and dry bird bile in a ratio of 4: 1, sieved through a sieve with a hole diameter of 0.75 mm and dosed in hard gelatin capsules of 0.3 g.

 Upon receipt of the drug cholesan in capsules, the standard equipment used in chemical-pharmaceutical plants (shredders, vibrating screens, capsule filling machines, packaging machines) is used.

 The composition and quantitative content of cholesan in hard gelatin capsules were established as a result of research.

 The use of the dried substance obtained from the mucous membranes and integumentary epithelium of the muscular section of the stomach of a clinically healthy bird (patent RU 2144826) and the substance of dry bird bile during the preparation of the dosage form of the cholesan preparation, contributed to the preparation with multifunctional properties and a wide spectrum of action. The introduction of dry bird bile into the preparation made it possible to obtain a drug with a combined effect that enhances the secretion of bile and facilitates its entry into the intestine, also has a “hepatoprotective” character. Facilitating the outflow of bile and thereby reducing the burden on the liver parenchyma, facilitating blood flow, reducing inflammation, the drug cholesan improves the overall functional state of the liver. The drug cholesan also refers to cholelitic drugs and helps to dissolve soft cholesterol stones.

 The ratio of the mixed substances 4: 1 is established in a practical way. At this ratio, the powder has good technological properties - sufficient bulk density, good flowability of the product during dosing.

 The exclusion from the composition of the dosage form of all auxiliary substances makes it possible to obtain a drug that does not have a damaging effect on the gastric mucosa.

 The proposed method for producing the drug in the form of a powdered dosage form, which excludes contact of the composite mixture with moisture, temperature, and there is no pressure effect during mass compaction, makes it possible to obtain a drug that is stable during storage and with higher bioavailability.

 This dosage form of cholesan in hard gelatin capsules and the method for its preparation are not described in the literature and this dosage form has not been previously released.

 A method of obtaining a dosage form of cholesan in hard gelatin capsules is as follows.

 1. The dried mucous membranes and integumentary epithelium of the muscular section of the stomach of a clinically healthy bird are crushed to obtain a homogeneous powder.

 2. Spend the grinding of the substance of dry chicken bile.

 3. The crushed substances of the mucous membranes and integumentary epithelium of the muscular section of the stomach of a clinically healthy bird (cuticle) and dry chicken bile are mixed.

 The substances of the dried cuticle and dry chicken bile are mixed in a 4: 1 ratio in a universal mixer for powders with a V-shaped container. Get the substance of the drug cholesan.

 4. Sift the obtained substance of the drug cholesan.

 The cholesan powder is sieved through a sieve with a hole diameter of 0.75 mm.

 5. Fill gelatin capsules with powder.

 The substance of the drug cholesan is Packed in hard gelatin capsules of 0.3 g.

 Gelatin capsules with the drug are packaged in plastic containers with a lid, or glass jars of the BDS-30 type, or in a contour (blister) cell or other packaging.

 The inventive step of the invention lies in the fact that the proposed method and dosage form of the drug cholesan containing a mixture of powders is a powder obtained from the mucous membrane and integumentary epithelium of the muscular part of the stomach of a clinically healthy bird and powder of bird bile, taken in a ratio of 4: 1, without any auxiliary substances, which is dosed in hard gelatin capsules of 0.3 g, which makes it possible to obtain a drug with a wide range of therapeutic effects, with good biological properties - sufficient bulk density, good flowability of the product when dosing.

 The preparation cholesan obtained in accordance with the invention in hard gelatin capsules does not have a damaging effect on the gastric mucosa, contains keratin-like substances of protein nature, chondroitin sulfates, glycoamine glycans, mucin and bile acids.

 Pharmacological and toxicological studies of the dosage form of the drug cholesan in capsules were carried out.

 The specific pharmacological activity of the contents of the capsules of the drug cholesan was studied using standard methods for assessing multifunctional and side effects in comparison with other drugs of this group used in gastroenterology.

 Due to the fact that the preparation contains sulfated and carboxylated glycosaminoglycans, glucoproteins, bile acids, sialomucins and proteolytic enzymes, the following properties were investigated.

 The presence of bile acids (cholic acid) - 21.6%.

 Proteolytic activity was determined by the Ansen method and it was 40 u / g.

Adsorption properties were determined with respect to methylene orange - 16.1 mg / g, methylene blue - 15.4 mg / g and CuS0 ₄ - 7.5 mg / g.

 The bacteriostatic effect of the drug on gram-positive microorganisms was studied by the method of holes. Bac microorganism strains were used. subtilis, Staph.aureus, Salmonella enteritidis. It was found that the growth inhibition zones of gram-positive bacteria were 17–20 mm.

 Toxicological studies of the drug cholesan were carried out in two stages: first, acute and then subchronic toxicity was studied in order to identify their possible inhibitory effect on the body of experimental animals, as well as assess their safety.

 To study the toxicity of cholesan, a wide range of doses (concentrations) of the drug, various experimental animals, and criteria for assessing the safety of the drug used (dynamics of clinical status indicators taking into account blood biochemical parameters and pathological and morphological changes in organs and tissues) were selected.

 The drug cholesan had no toxic effect on experimental animals at doses exceeding the maximum therapeutic by 100 times. Significant deviations from the norm in the experimental groups of animals were not detected.

 Thus, obtained by the proposed method, the dosage form of the drug cholesan in capsules is an effective safe tool with a high relative degree of bioavailability, does not have a damaging effect on the gastric mucosa. The dosage form of the drug cholesan in capsules is stable during storage (does not change color, humidity, biological activity).

The invention is illustrated by the following examples:
Example 1
The substance of the drug from the mucous membranes and integumentary epithelium and the substance from dry chicken bile are crushed to obtain a homogeneous powder.

 The crushed substances are mixed in a ratio of 2: 1.

 The powder is sieved through a sieve with a hole diameter of 0.75 mm.

 The mixture is Packed in hard gelatin capsules 1 to 0.3 g.

Example 2
The substance of the drug from the mucous membranes and integumentary epithelium and the substance from dry chicken bile are crushed to obtain a homogeneous powder.

 The crushed substances are mixed in a ratio of 3: 1.

 The powder is sieved through a sieve with a hole diameter of 0.75 mm.

 The mixture is Packed in hard gelatin capsules 1 to 0.3 g.

Example 3
The substance of the drug from the mucous membranes and integumentary epithelium and the substance from dry chicken bile are crushed to obtain a homogeneous powder.

 The crushed substances are mixed in a ratio of 4: 1.

 The powder is sieved through a sieve with a hole diameter of 0.75 mm.

 The mixture is Packed in hard gelatin capsules 1 to 0.3 g.

 Studies have shown that the therapeutic efficacy of cholesan is achieved by mixing the substance in a ratio of 2: 1, 3: 1, 4: 1, however, when evaluating the technological properties of the powder mixture, the 4: 1 ratio is most optimal, since it does not require the introduction of auxiliary substances, which makes it possible to obtain a natural biological product without chemical additives.

 Information confirming the proteolytic, cholelitolic and hepatoprotective effect.

 1. The proteolytic effect of the drug cholesan is due to the presence of its own proteolytic enzymes, as well as the stimulation of exocrine pancreatic activity by the bile acids that make up the drug.

 A group of patients (8 patients) was diagnosed with biliary-dependent chronic pancreatitis. Patients had characteristic pancreatic pains, dyspeptic symptoms, diarrhea, weight loss, an increase in the head of the pancreas, obstructive jaundice due to compression of the common bile duct, impaired exocrine function, an abundance of undigested food in the stool. A course of treatment with the drug cholesan was prescribed and carried out 2 capsules 3 times a day for 20 days.

 Against the background of this therapy, the pain intensity decreased significantly, rumbling and bloating disappeared, the frequency of stools from the 14th day of treatment 1-2 times a day of a mushy or formed consistency, the carbene test time was 18 hours, during bacteriological examination, the number of lactobacilli and bifidobacteria increased, decreased sharply (before the extinction of certain species) the number of conditionally pathogenic aerobic and anaerobic flora.

 In the general analysis of blood and urine, in the biochemical analysis of blood, there were no changes after treatment with cholesan.

 The drug also has a lipolytic effect.

 Clinical observations were performed on 42 patients. Disruption of lipid absorption in the intestine was accompanied by mixed type steatorrhea in most patients with celiac disease (a group of 11 people: 7 women, 4 men) and a third of patients with chronic enteritis (a group of 17 people: 12 women and 5 men). The loss of total lipids (fat) with feces per day in patients with celiac disease was 25.3 ± 3.6 g (P <0.05), in patients with chronic enteritis - 15.5 ± 1.8 g (P <0.05 ) In some seriously ill patients, steatorrhea reached 68.5 ± 6.4 g per day. Most patients with celiac disease (83%) and chronic enteritis (77%) showed a decrease in total serum lipids - 3.9 ± 0.8 g / l (P <0.05) and 5.3 ± 1.1 g / l (P <0.05), respectively, with a norm of 7.65 ± 1.8 g / l. Low lipids and cholesterol (up to 3.11 ± 0.32 mmol (P <0.05) for celiac disease and up to 3.89 ± 0.54 mmol (P <0.05) for enteritis at a rate of 4.73 ± 0 , 56 mmol), in addition to the absorption disorder in the small intestine, is explained by the accelerated passage of fat through the intestine and entails an increased consumption of total lipids in the body as an energy material.

 A statistically significant decrease in the level of α-lipoproteins in patients with celiac disease to 21.14 ± 2.54%, chronic enteritis to 23.60 ± 2.25% with a norm of 29.13 ± 1.15%, β-lipoproteins was detected in the lipoprotein blood spectrum - up to 47.40 ± 3.2% and 41.32 ± 2.46%, respectively, with a norm of 52.65 ± 1.11%, with a simultaneous increase in the level of pre-β-lipoproteins with celiac disease to 39.65 ± 3.43 %, chronic enteritis up to 34.35 ± 2.35% with a norm of 26.43 ± 1.5%.

The fatty acid spectrum of total blood lipids in all patients who underwent treatment with the drug cholesan varied ambiguously, but had a clear tendency to form a spectrum corresponding to severity I and II severity of malabsorption syndrome. So, in 22 out of 28 patients, K _{t was} determined in the range of 0.67-0.88, in 5 patients - in the range of 0.9-1.0, in one patient - 0.49, that is, did not change. The effectiveness of cholesan can be attributed to the effectiveness of drugs that have proven themselves in the clinic for the treatment of gastroenterological diseases associated with impaired lipid metabolism.

 2. The cholelitolic effect of the drug was evaluated in patients under ultrasound examination (ultrasound) by the change in the volume of the gallbladder. In 15 patients, fasting gall bladder volume with ultrasound was 18.2-45.2 ml, and 15 minutes after taking cholesan, there was an increase in bladder volume by 12.0%, which after 1 hour was 7.3-32.7% .

 3. The hepatoprotective properties of the drug cholesan were studied in the treatment of chronic hepatitis, cirrhosis.

 Clinical observations were performed on 17 patients with cirrhosis and exacerbation of chronic hepatitis. 9 people were hospitalized in the clinic due to bleeding from varicose veins of the esophagus and cardiac section of the stomach. The severity of the clinical course of the disease in all patients was due to endogenous entoxication due to liver failure. Violations of the central nervous system were manifested by inhibition (8 patients), inappropriate behavior (4), stupor (5). The skin was icteric, sclera icteric. There was an expanded venous network on the anterior abdominal wall. The dense liver protruded from the costal arch by 8-15 cm. Patients had severe ascites, and patients with bleeding experienced melena. Bleeding was stopped by placing a Black Mohr probe and hematostatic therapy.

 In all patients, hyperbilirubinemia and hyperfermentemia were noted in blood tests (table 1). The total bilirubin concentration was 126 ± 14.7 μmol / L, in two patients it reached 424.8 μmol / L and 589.1 μmol / L (bond 318.6 μmol / L and 428.5 μmol / L). Against the background of jaundice, the ALT level was 132.8 ± 14 ME, ACT 120.97 ± 10.9 ME.

 Comprehensive treatment included: repeated procedures of plasmapheresis and plasmosorption, hemosorption, dialysis using a suspension of hepatocytes. In 6 patients, laparocentesis was performed to remove ascites fluid from the abdominal cavity. The amount of liquid withdrawn was 6-10 liters, and in 3 patients - 16-22 liters.

 Patients took cholesan according to the scheme: 2 capsules 3 times a day for 3 weeks. In patients with bleeding from varicose veins of the esophagus and stomach, drug treatment was started 2 days after the bleeding stopped.

 As studies have shown, against the background of stabilization of the condition of patients and relief of symptoms of liver failure, no side symptoms or complications were observed. Taking the drug did not provoke a repeated episode of bleeding. None of the patients complained of abdominal pain or discomfort when taking the drug. In the process of complex treatment, the clinical condition of patients improved, appetite was restored, the function of the gastrointestinal tract was gradually normalized. Positive dynamics of laboratory data and instrumental indicators were noted (table 1).

 Thus, the treatment of patients with cirrhosis of the liver and exacerbation of chronic hepatitis with the drug cholesan contributed to the exit of patients from a serious and extremely serious condition. Based on the data of experimental studies, the administration of cholesan as part of a complex treatment helped restore the function of the gastrointestinal tract, improve digestion, stop dyspeptic manifestations, reduce the toxic load on the altered liver of blood decay products after bleeding from varicose veins of the esophagus and stomach.

Claims (1)

 A method of obtaining a medicinal product with proteolytic, hepatoprotective and cholelitolic action, characterized in that the dried mucous membranes and integumentary epithelium of the muscle of the stomach of the bird are crushed to obtain a homogeneous powder, mixed with dry crushed chicken bile at a ratio of 4: 1, respectively, the mixture is sieved through a sieve with a hole diameter of 0.75 mm and dosed in hard gelatin capsules of 0.3 g.

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