RU2519741C2 - Pharmaceutical composition possessing antithrombotic, thrombolytic, immunomodulatory, anti-inflammatory action, normalising lipid and carbohydrate metabolism - Google Patents

Abstract

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to medicine, more specifically to a pharmaceutical composition possessing antithrombotic, thrombolytic, immunomodulatory, anti-inflammatory action, normalising lipid and carbohydrate metabolism, more specifically to the pharmaceutical composition of the substance Pijavitum (hereinafter referred to Pijavitum) made from lyophilised medicinal leech. The above pharmaceutical composition is presented in the form of an enteric coated tablet.

EFFECT: coating prevents the active ingredients of Pijavitum from destruction under action of the enzymes and acid medium of the stomach.

Description

The invention relates to medicine, specifically to a pharmaceutical composition having antithrombotic, thrombolytic, immunomodulatory, anti-inflammatory, normalizing lipid and carbohydrate metabolism, specifically to a pharmaceutical composition based on the substance “leech” (hereinafter referred to as leech) made from a lyophilized medical leech and registered in as such, the FC of the Russian Federation (state registration number, regulatory document PIYAVIT SUBSTANCE P N00363 / 01 of 08/07/2007. Validity is not limited. FSP 42-0543-06).

The active principle of the drug leech is the secret of salivary cells of a medical leech (SSC), which represents a vast “leech pharmacy”, which includes a balanced complex of more than a hundred high molecular weight proteins and several hundred low molecular weight compounds.

It is important to keep in mind that CCK is able to maintain its many functions only in the state of immobilization of particles of muscle tissue of a medical leech, which takes place in the composition of lyophilized and ground medical leeches. In addition to SSC, an important role in the composition of leech is given to fragments of the intestinal canal of leeches, which are the main source of inhibitors of proteolytic enzymes, trypsin and chymotrypsin, which protect biologically active compounds of SSC from destruction in the gastrointestinal tract.

When studying piyavit, the main functions of piyavit were previously identified: protective (plasma hemostasis, platelet-vascular hemostasis); thrombolytic effect; bacteriolytic and bactericidal action; hypoglycemic effect; anti-inflammation; increased phagocytosis; immunomodulatory effect (activation of cellular immunity, suppression of humoral immunity; neuroregulation (neurotrophic effect, analgesia, preservation of a memorable trace); as anti-sclerosis (normalization of lipid metabolism) (IP Baskova and G. Isakhanyan, “Hirudotherapy. Science and Practice” 2004, Moscow: “Monolith”).

The antithrombotic and anti-inflammatory effect is characterized by antiproteolytic and anticoagulant activity, the latter is aimed at inhibiting platelet-vascular (Kalin, Saratin, apyrase, etc.) and plasma hemostasis (plasma kallikrein inhibitor, factor Xa inhibitor, thrombin inhibitor - hirudin). Antiproteolytic activity (antichymotryptic and antitryptic) is due to the presence in the salivary cell complex of leeches such substances as bdelins (trypsin, plasmin and acrosin inhibitors), aeglins (α-chymotrypsin, chymazine, subtilisin, elastase and cathepsin G inhibitors), girustazin , elastase and cathepsin G). Thrombolytic effect is associated with the presence of the enzyme destabilase - lysozyme, a bifunctional enzyme with isopeptidase (thrombolytic) and lysozyme (antibacterial) and non-enzymatic antimicrobial function. Additionally, this enzyme inhibits spontaneous and induced aggregation of human platelets. In this case, the thrombus lysis proceeds slowly, which allows the reparative processes of healing of the wound surface of the vascular wall to be connected and thus eliminates the re-formation of the thrombus in this section of the vessel. The thrombolytic effect of piyavit, in contrast to drugs known in medical practice, does not depend on the life of the thrombus.

Thus, the uniqueness of the active piyavit complex lies in the fact that the drug has both fibrinolytic and anticoagulant activities (resolves existing blood clots and prevents the formation of new ones). This process is accompanied by the removal of inflammatory phenomena caused by stagnation of blood in the vessels due to their thrombosis. The anti-inflammatory effect is also determined by the presence in the active complex of eglins and girustazin, which block the anti-inflammatory enzymes elastase and cathepsin G neutrophils, an analogue of prostacyclin, which prevents the release of inflammatory mediators, and the presence of a blood plasma kallikrein inhibitor that inhibits the formation of inflammatory mediators - kinins.

Collagenase and hyaluronidase contained in the active complex have a decongestant effect.

The antisclerotic and analgesic effect of the active complex is due to antithrombotic and decongestant activity, the ability to normalize lipid metabolism, and a number of other factors that are currently being studied.

Thus, pharmaceutical compositions based on the substance of leech, containing a balanced complex of highly effective substances produced by a medical leech, are an effective prophylactic and therapeutic antithrombotic agent for thrombophlebitis of saphenous veins.

Among the first to become famous piyavit capsules - the oral medicine “Piyavit-capsules” (state registration number, regulatory document P N000363 / 02 of 05.22.2008. The validity period is not limited. FSP 42-0544-06. Decision N11-22486 / 09 of November 2, 2009. CAPSULES PIYAVIT, 150 mg). The drug is a gastro-soluble gelatin capsule containing 0.15 g or 0.30 g of leech substance, recommended for the prevention and treatment of superficial vein thrombophlebitis, as well as for the prevention and treatment of diabetic micro- and macroangiopathies. They are able to inhibit the activation of platelet-vascular and plasma hemostasis, have anti-inflammatory, anti-atherosclerotic and thrombolytic properties, normalize lipid and carbohydrate metabolism and have a number of other properties.

A known method for the manufacture of tablets from lyophilized medical leeches powder (published application CN 101897727 A, abstract) has the disadvantages of using granulation in the manufacture of tablets and the absence of an effective preservative for leech enzymes, which can lead to the destruction of leech components.

There is a method of treating atonic dermatitis and cheilitis using piyavit ointment (RF Patent No. 2138276).

A medicinal film containing piyavit is proposed for the treatment of inflammatory periodontal diseases (RF Patent No. 2201194).

Known therapeutic gel piyavit with anticoagulant, anti-inflammatory and analgesic activities, and a method for producing a gel (RF Patent No. 2268739).

The closest in technical essence to the claimed object is the proposed method for the treatment of long-term non-healing wounds in patients with diabetes mellitus (RF Patent No. 2358757), which consists in applying ointment to the wound surface 2-3 times a day, performing skin grafting surgery and taking capsules to leech 300 mg 2 times a day for the entire course of treatment.

The disadvantage of the dosage form in the form of capsules is the absorption of pivavite active substances in the stomach, which leads to the partial decomposition of a number of biologically active components of pivavite under the action of gastric juice and a decrease in the effectiveness of the drug. In addition, the substance leech has a characteristic (unpleasant) smell, which penetrates the gelatin capsule.

The aim of the invention is a new pharmaceutical composition based on the substance of pewavite in the form of a tablet, enteric coated. The coating protects the active components of piyavite from destruction by enzymes and the acidic environment of the stomach, which is confirmed by special experimental studies. Enteric coated tablets were placed in artificial gastric juice (pH 1-3), while the tablet shell did not break down and no active piyavit enzymes were released. It has been shown that the film coating based on acrylis breaks down only in the intestinal environment (pH7.0-8.0). When released in the intestine, the components of piyavit act more efficiently, which reduces the dose of the drug. It was experimentally established that enteric-coated tablets more than double the time for thrombus formation (table 3, examples 3 and 4). This pharmaceutical composition must meet the requirements of the State Pharmacopoeia of the XI and XII editions, have a shelf life of at least 2 years.

This goal is achieved by creating a solid dosage pharmaceutical composition in the form of a tablet containing the active substance piyavit and targeted additives.

The specified composition is obtained by pre-mixing the target additives and pewavite, followed by direct compression of the resulting mixture and coating with an enteric coating.

The ratio of active substance and target additives is, wt.%:

active substance (piyavit powder) 5.0-40.0 targeted supplements 60.0-95.0

The choice of target additives, their ratios made it possible to develop a technology for direct compression of the mass with the substance of leech without granulation, which avoids the destruction of leech enzymes.

As target additives, the pharmaceutical composition optionally simultaneously contains starch, sodium croscar-mellose, polyvinylpyrrolidones, cellulose derivatives, aerosil, stearic acid salts, corrective substances in the following ratio, wt.%:

starch 1.0-15.0 sodium chloride 5.0-60.0 croscarmellose sodium 2.0-5.0 polyvinylpyrrolidones 0,0-5,0 cellulose derivatives 2.0-50.0 silicon dioxide colloidal (aerosil) 0.5-10.0 stearic acid salts 0.5-1.0 acrylization 5.0-10.0

Colorcon's acrylis contains the following ingredients: a copolymer of methacrylic acid, titanium dioxide, sodium bicarbonate, sodium lauryl sulfate, talc and silicon colloidal dioxide (aerosil)

The presence in the solid dosage forms of starch, primellose, polyvinylpyrrolidones, cellulose derivatives provides an increase in the release rate and completeness of absorption of the active substance, increases the disintegration and dissolution of the dosage form, and also creates conditions for the penetration of water and enzymes into the tablet.

Starch is preferably corn or potato.

The presence of stearic acid salts provides the sliding effect required at the stage of tablet compression. It is advisable to use magnesium or calcium stearate as salts.

Sodium chloride plays the role of a preservative, since the active components of pivavite contain organic compounds that are prone to oxidation and destruction. The addition of sodium chloride increases the shelf life of the dosage form.

Acrylization, as an enteric film coating, protects the tablet from degradation by gastric enzymes and masks the specific smell of piyavit.

The claimed ratios of components and the technology of direct compression are found experimentally, are optimal and allow you to get a technical result that matches the task: the resulting pharmaceutical composition meets the requirements of the State Pharmacopoeia of the 11th and 12th editions, has a shelf life of at least 2 years and provides a high pharmacotherapeutic effect of the active substance.

The composition and manufacturing methods of the claimed pharmaceutical compositions are given in the examples for the preparation of a solid pharmaceutical composition in the form of a tablet coated with an enteric coating.

Example 1. In the apparatus with a mixer load 2.14 kg of starch (10.24%), colloidal silicon dioxide 2.04 kg (9.76%), sodium chloride 1.06 kg (5.07%), croscarmellose sodium 0 52 kg (2.51%), microcrystalline cellulose 10.49 kg (50.23%); the mass is stirred for 10-15 minutes To the resulting homogeneous mass, 2.27 kg (10.86%) of pivavite substance was loaded, the remaining starch was 1.0 kg (4.78%), the mixture was stirred for 10 minutes, after which 0.21 kg (1.00%) of magnesium was loaded stearate. The mass is stirred until smooth for 15-20 minutes. Get 19.45 kg of mass for tabletting containing 2.16 kg of pewavite, which is tabletted by direct compression. Get 51184 pieces of tablet cores (mass of cores - 380 mg), which are coated with an enteric coating. Acrylis consumption is 1.02 kg (5.26%). Get 50360 pieces of pewat tablets weighing 400 mg, enteric-coated, containing 2.12 kg of pewavite. The yield is 93.4%, counting on the initial leech.

Tablets meet the requirements of the State Pharmacopoeia XI and XII editions (Table 1).

Example 2. Analogously to example 1, based on 0.4 kg (5.00%) of piyavite, 3.4 kg (42.50%) of sodium chloride, 1.16 kg (14.50%) of corn starch, 2.08 kg (26.00%) microcrystalline cellulose, 0.16 kg (2.00%) croscarmellose sodium, 0.32 kg (4.00%) colloidal silicon dioxide, 0.08 kg (1.00%) magnesium stearate and 0 , 4 kg (5.00%) of acrylis receive 18,000 pieces of pewavite tablets weighing 400 mg, enteric-coated, containing 0.38 kg of pewavite. The yield is 95.0%, counting on the initial leech.

The tablets comply with the requirements of the State Pharmacopoeia XI and XII editions (Table 1).

Example 3. Analogously to example 1, based on 160 g (40.00%) of piyavite, 158 g (39.50%) of sodium chloride, 4 g (1.00%) of corn starch, 22 g (5.50%) of microcrystalline cellulose , 20 g (5.00%) of croscarmellose sodium, 2 g (0.50%) of colloidal silicon dioxide, 4.0 g (1.00%) of magnesium stearate and 30.0 g (7.50%) of acrylis receive 948 , 0 pieces of leech tablets weighing 400 mg, enteric-coated, containing 152 g of leech. The yield is 95.0%, counting on the initial leech.

Tablets meet the requirements of the State Pharmacopoeia XI and XII editions (Table 1).

Example 4. Analogously to example 1, based on 2.00 kg (25.00%) piyavite, 3.60 kg (45.00%) sodium chloride, 0.12 kg (1.50%) corn starch, 0.44 kg (5.50%) microcrystalline cellulose, 0.28 kg (3.50%) croscarmellose sodium, 0.32 kg (4.00%) colloidal silicon dioxide, 0.04 kg (0.50%) magnesium stearate, 0 , 4 kg (5.00%) of polyvinylpyrrolidone and 0.8 kg (10.00%) of acrylate receive 18,000 pieces of 400 mg piyavit tablets, enteric coated, containing 1.52 kg of piyavit. The yield is 95.0%, counting on the initial leech.

Tablets meet the requirements of the State Pharmacopoeia XI and XII editions (Tables 1, 2).

Table 1 The compositions of the pewavite tablets Ingredients Example 1 Example 2 Example 3 Example 4 % mg % mg % mg % mg Leeches 10.86 43,44 5,0 twenty 40,0 160 25.0 one hundred Starch 15.02 60 14.5 58 1.00 four 1,50 6 Silicon Colloidal Dioxide 9.76 39 4.0 16 0.50 2 4.00 16 Sodium chloride 5.07 20.3 42.5 170 39.5 158 45.0 180 Croscarmellose Sodium 2,51 10.04 2.0 8 5.00 twenty 3,50 fourteen Microcrystalline cellulose 50.23 200.9 26.0 104 5.50 22 5.50 22 Magnesium stearate 1.00 four 1.00 four 1.00 four 0.50 2 Polyvinylpyrrolidone 5.00 twenty Acrilize 5.55 22.2 5,0 twenty 7.5 thirty 10.0 40 Total one hundred 400,0 one hundred 400 one hundred 400 one hundred 400

table 2 Quality indicators of the solid pharmaceutical composition of leech tablets coated with enteric coating Quality indicators Quality Standards Actual figures Example 1 Example 2 Example 3 Example 4 Description White or white with a creamy tint White White White Creamy white Stability in the gastric juice Must not collapse Compliant Compliant Compliant Compliant The quantitative content of piyavita No less than 98.5% 99.0 99.0 99,2 98.9 Foreign matter Not more than 1% (TLC) Less than 0.5 Less than 0.5 Less than 0.5 Less than 0.5 Stability 2 years at 20 ° C 2 years 2 years 2 years 2 years

Table 3 Thrombolytic (anticoagulant) activity, AKE Known piyavit capsules, 150 mg, gastro-soluble Enteric coated leech tablets Example 1 Example 2 Example 3 Example 4 43.44 mg 20 mg 160 mg 100 mg Not less than 154.0, AKE 140.5, ACE 63.2, ACE 390.5, AKE 308.0, AKE Note: Thrombolytic (anticoagulant) activity is expressed in arbitrary units (ACB) by lengthening the time of clot formation (thrombus).

Table 4 Tablet coating requirements Experiment Conditions Tablet coating requirements Actual figures Example 1 Example 2 Example 3 Example 4 pH1-2 (gastric conditions) Should not collapse Coating integrity maintained Coating integrity maintained Coating integrity maintained Coating integrity maintained pH7-8 (conditions of the small intestine) The tablet breaks down with the release of the enzyme gerudin The tablet breaks down with the release of the enzyme gerudin The tablet breaks down with the release of the enzyme gerudin The tablet breaks down with the release of the enzyme gerudin The tablet breaks down with the release of the enzyme gerudin

Claims (1)

A solid dosage pharmaceutical composition having antithrombotic, thrombolytic, immunomodulatory, anti-inflammatory effects, normalizes lipid and carbohydrate metabolism, characterized in that it is made in the form of a tablet by direct compression and contains as an active substance a substance made from lyophilized medical leech, and as target additives - sodium chloride, starch, croscarmellose sodium, microcrystalline cellulose, colloidal silicon dioxide, magnesium stearate, optionally polyvinylpyrrolidone in the following ratio, wt.%
Leeches 5.0-40.0 Starch 1.0-15.0 Sodium chloride 5.0-60.0 Croscamelose Sodium 2.0-5.0 Polyvinylpyrrolidones 0,0-5,0 Cellulose derivatives 2.0-50.0 Silicon Colloidal Dioxide (Aerosil) 0.5-10.0 Stearic acid salts 0.5-1.0
In this case, the tablet is coated with an enteric coating of the composition Acrylis in an amount of 5-10%.