Using phospholipid-containing composition for removing subcutaneous fat by subcutaneous lypolysis

FIELD: medicine.

SUBSTANCE: invention refers to medicine and can be used for making a drug for removing subcutaneous fat. That is ensured by using a composition containing: at least one phospholipid, at least one glycyrrhizic acid or a glycyrrhizic acid salt, and wherein total content of phospholipids and glycyrrhizic acid or its salts makes 2-80 wt % and a weight ratio of phospholipids and glycyrrhizic acid or its salts makes from 30:1 to 0.5:1. The composition can additionally contain additives. As phospholipid, the composition contains animal or herbal phosphatidylcholine. The composition can also contain glycyrrhizic acid or potassium, sodium, ammonium or magnesium salt of glycyrrhizic acid. As an additive, the composition contains sugar, particularly glucose, or maltose, and/or their derivatives, mannitol, sorbitol or lactose. The composition contains phosphatidylcholine in a total amount of 15 to 98 wt %, preferentially 30 to 98 wt %, more preferentially 50 to 98 wt %, especially preferentially 75 to 98 wt %, and most preferentially 75 to 90 wt % of total content of phospholipids. The composition is used in the dry form, preferentially in the form of lyophilisate prepared by freezing and drying, or in the form of a solution. The composition can contain physiologically acceptable solvents, including water, normal saline, glucose solution, such monohydric alcohols, as ethanol, 2-propanol, n-propanol, such polyatomic alcohols, as glycerol and/or propane diol, such polyglycols, as polyethylene glycol and/or Miglyol, glycerol, formal, dimethylisosorbitol, natural and synthetic oils and/or esters. Diseases of subcutaneous fatty tissue can be particularly related to local fat maldistribution. Fatty tissue tumour decomposition and reduction can be also solved. The drug can be presented in the form of cream, ointment, gel, hydrogel, lotion, paste, powder or solution. Undesired unaesthetic and pathological local fat maldistribution involve lipoedema, adipose growth, abdominal adiposis, cellulites, pseudogynecomasty, "buffalo hump" in HIV-infected patients, panniculitis or nonspecific subcutaneous fat deposition. The preparation is administered by subcutaneous, intra-abdominal, intramuscular or intravenous injection. The administration is implemented by a method specified in a group consisting of ioophoresis, electroporetion and phonophoresis.

EFFECT: described invention is successfully used for the above purposes.

17 cl, 11 ex, 7 tbl, 11 dwg

 

The technical field to which the invention relates

The invention relates to the use of compositions based on phospholipids and at least one glycyrrhizic acid or salts of glycyrrhizic acid and its used in medical forms for treatment of subcutaneous fat at various phenotypes, such as violations of subcutaneous fat distribution, and to reduce resistant to the diet fat deposits.

The level of technology

Still in this area was applied surgical methods for the treatment of subcutaneous fat deposits or abnormal growth of fat cells type lipomas or fatty edema. Such treatment leads to the well-known complications or risks in connection with anesthesia, local reactions and possible infections. Often in such cases, patients have to stay in the hospital. To avoid such operations, you need to look for non-surgical alternatives for removing subcutaneous accumulations of fat.

Already developed various phospholipid compounds, which are introduced to patients by injection. Aqueous preparations containing at least one phospholipid, known for various applications. These systems are used, for example, in cosmetics or in pharmaceuticals. Often such systems form micelles or liposomes containing the aqueous phase.

In US 005/143347 A1 and its associated priority document DE 10361067 A1 disclosed aqueous composition, containing at least one phospholipid and/or at least one bile acid and a component that supports the decomposition of fat type of Riboflavin and water suitable for the manufacture of drugs for removing subcutaneous accumulations of fat and reduce fat phone at the same time as commercially available preparations listed Essentiale®N i.v. (Red List, March 2003)HLipostabil®Ni.v.

Essentiale®N i.v. described in EP 0615746 A1 water preparation containing phospholipids from soybeans, bile acid, Riboflavin, α-tocopherol, ethanol and water. The composition is processed in a micellar system, wherein the micelles have a diameter of from 30 nm to 100 nm. In EP 0615746 A1 does not describe the use of glycyrrhizic acid. This drug is administered intravenously, in particular, for the treatment of fatty degeneration of the liver, which is an excessive fat content in the parenchyma of the liver (fatty deposits in the form of droplets).

In DE 10361067 A1 disclosed a water form of the drug Essentiale®N i.v., containing at least one phospholipid and/or at least one bile acid and a component that supports the decomposition of fat and water for the manufacture of drugs for removing subcutaneous accumulations of fat. Also the drug is not added glycyrrhizic acid.

Lipostabil®N i.v. contains phospholipids from soybeans, DL-α-�acopera, 7-deoxycholic acid, alcohols, other auxiliary substances and water. However, the active substance of the composition of this compound does not contain glycyrrhizic acid. With subcutaneous injection Lipostabil®N i.v. removes fat deposits that appear under the eyes, on the abdomen or hips the overweight people.

There are other drugs on the basis of phospholipids, which are used in subcutaneous introduction the purpose of lipolysis fat deposits, which are described in WO 2008/113421, DE 102007015701, US 2005/143347 A1 and US 2005/0089555 A1.

The above disadvantages of the preparations of the prior art for subcutaneous lipolysis include, among others, swelling, bruising, pain in the treatment area and discomfort type of burning and itching at the injection site after treatment, but in particular cell death if the damage to the cell structure and integrity of membranes (cell death).

Disclosure of the invention

When you search for active compounds for non-surgical removal of accumulations of subcutaneous fat, devoid of the above disadvantages, unexpectedly, the composition disclosed in RU 2133122 C1 for intravenous and oral treatment of acute and chronic liver diseases and disorders of lipid metabolism in atherosclerosis and related diseases, suitable for subcutaneous lipolysis, also called adipocytokines.

P�and application in accordance with the present invention this composition, containing at least one phospholipid, preferably phosphatidylcholine, and glycyrrhizinic acid or its salt, the previously described drawbacks of prior drugs used for subcutaneous lipolysis, reduced and/or eliminated.

A particular advantage of the use of the claimed composition for subcutaneous lipolysis fat accumulation of the present invention is the significant reduction up to prevent damage to the cell structure and integrity of cell membranes of adipose tissue (adipocytes). In the treatment according to the invention is subcutaneous disorders of adipose tissue by using the claimed composition is significantly reduced or completely prevented the occurrence of necrosis.

When applied according to the invention the deposition of fat in the bulk of fatty tissue in the treatment of decomposed through lipolysis, without causing destruction of the cell membrane.

Tend to have significantly fewer side effects until the complete absence of complaints of swelling, redness, burning, itching and pain in General, and hypersensitivity.

The composition used according to the invention, includes as one of the main components of the phospholipid, glycyrrhizic acid or its salt, and optionally at least one auxiliary substance.

Glycyrrhizic acid, which received�Ute from extracts of plants of the genus Glycyrrhiza - licorice (e.g., Glycyrrhiza glabra), or its salts, in particular DGL sodium or ammonium, described at the previous level of technology as amplifiers suction for transport, e.g., peptide hormones through the mucous membranes, in EP 0327756 A. Also in US 5238917 described A strengthening of the absorption of polypeptides of glycyrrhizic acid in transvaginal preparations.

In addition, glycyrrhizic acid is known as an antibacterial and anti-inflammatory agent and as an emulsifier in the prior art from US 2004-076652 A, US 2009-169588 A, US 2007-053852 A, WO 08/046791 A, WO 08/046795 A, WO 05/037239 A, EP 1676561 A and JP 2006/137 670.

The specific function of glycyrrhizic acid in the transport of molecules across the cell membrane confirms the special advantage of a rapid mode of action for use according to the invention of the claimed composition. Thanks glycyrrhizic acid phospholipid can penetrate into the cells of adipose tissue of the subcutaneous layer particularly well and quickly, while the above-mentioned disadvantages of the type of necrosis is reduced or not occur. Described swelling, bruising, pain and discomfort after the use of drugs prior art, in particular those that involve bile acids or their salts, are mitigated or are not found in combination with glycyrrhizic acid. This improvement portability is supported by protiva�specialname and antibacterial properties of glycyrrhizic acid.

Therefore, the present invention is characterized in that the inventive combination of at least one phospholipid, preferably phosphatidylcholine, and one of glycyrrhizic acid or its salts, shows less or do not exhibit cytotoxic effects and is better tolerated in comparison with compositions of drugs Essentiale®and Lipostabil®in the prior art.

The invention relates to the use of the composition, including:

a) at least one phospholipid;

(b) at least one glycyrrhizic acid or

c) the salt of glycyrrhizic acid; and

(d) optionally auxiliary substances; thus:

- the total content of phospholipids and glycyrrhizic acid or its salts is 2-80 wt.% and

- the ratio between phospholipids and glycyrrhizic acid or its salts by weight is from 30:1 to 0.5:1,

for the manufacture of a medicine for removing subcutaneous accumulations of fat.

The invention also relates to the use of drugs containing the above composition, which contains phosphatidylcholine as the phospholipid.

The invention also relates to the use of drugs containing the above composition, which contain phosphatidylcholine of animal or vegetable origin.

The invention also cases� use of drugs, containing the above composition, which contain sodium, potassium, ammonium or magnesium salt, or other suitable salt of glycyrrhizic acid.

The invention also relates to the use of drugs containing the above composition, which contains as a potential filler sugar, particularly maltose and/or its derivatives, sorbitol or lactose.

The invention also relates to the use of drugs containing the above composition containing phosphatidylcholine in the total number of from 15 to 98 wt.%, preferably from 30 to 98 wt.%, more preferably from 50 to 98 wt.%, particularly preferably 75 to 90 wt.% and most preferably from 75 to 98 wt.%

The invention also relates to the use of drugs containing the above composition, which is dissolved in dry form in a suitable solvent.

The invention also relates to the use of drugs containing the above composition, which is applied in dry form, preferably in the form of a lyophilizate obtained by freeze-drying.

The invention also relates to the use of drugs containing the above composition is applied in the form of a solution.

The invention also relates to the use of drugs containing the above composition, which contain physiological�ski suitable solvent, including water, physiological saline, glucose solution, such Monohydric alcohols, such as ethanol, 2-propanol, n-propanol, polyhydric alcohols such as glycerol and/or PROPANEDIOL, polyglycols such as polyethylene glycol and/or Miglyol, glycerol, formal, dimethylisoxazol, natural and synthetic oils and/or esters.

The invention also relates to the use of drugs containing the above composition, which are used for the manufacture of drugs for the treatment of subcutaneous accumulations of fat, diseases of the subcutaneous adipose tissue, in particular related to violation of local distribution of fat.

The invention also relates to the use of drugs containing the above composition, which are used for the manufacture of drugs for the decomposition and reduction (regression) tumors of adipose tissue.

The preparations according to the invention are applied in the form of creams, ointments, gels, hydrogels, lotions, pastes, freeze-dried products and solutions. The preferred dosage form is water in the form of various solutions.

The invention also relates to the use of drugs containing the above composition, with unwanted violations of distribution of fat having aesthetic character or pathological nature, are fat edema, lipoma, lipomatosis belly, cellulite (cellulite, warp podkin�th fiber), pseudogynecomastia, Buffalo humps in HIV-patients, panniculitis (cellulitis, purulent inflammation of subcutaneous tissue) or non-specific fat deposits under the skin.

The invention also relates to the use of drugs containing the above composition, which is characterized in that the drug is administered by subcutaneous, intraperitoneal, intramuscular or intravenous injection.

The invention also relates to the use of drugs containing the above composition, which is characterized in that for the introduction of a method selected from the group consisting of iontophoresis, electroporation, microporosity and phonophoresis.

A further object of the invention is the use of a composition for the manufacture of drugs for the treatment of adipose tissue in the subcutaneous layer (the lower layer of the dermis), in particular, violation of the local distribution of fat.

A further object of the invention is the use of a composition for the manufacture of drugs for regression and involution of tumors of adipose tissue.

A further object of the invention is the use of a composition for the manufacture of drugs for the treatment of unwanted disturbances of the distribution of fat for aesthetic or pathological nature, for example, fat edema, lipoma, lipomatosis belly, cellulite (cellulite, the subcutaneous tissue deformation), pseudogynecomastia, "b�whose hump" in HIV-patients paniculata (cellulitis, purulent inflammation of subcutaneous tissue) or nonspecific subcutaneous fat.

When applying the composition of the invention can avoid the above risks and side effects of surgical treatment or subcutaneous treatment with drugs of the prior art, in particular containing deoxycholic acid and its salts. In addition, outpatient treatment is more convenient for patients and less expensive than surgical treatment.

The above-described high therapeutic efficacy, as exemplified by the rapid decomposition of fatty tissue under the action of the composition, is associated with a synergistic effect of the interaction of the combinations according to the invention from one phospholipid and/or one glizirethinic acid or its salts. The use of the present invention the claimed composition differs in a significant reduction of side effects or in part by the absence of some of the previously described side effects.

The implementation of the invention

Disorders of subcutaneous fat distribution is the changes that occur in adipose tissue of humans and mammals as fat reserves are genetic or dietary nature in the form of localized fat deposits, which can be viewed as aesthetically annoying the critical zone, � particular belly, buttocks, thighs, knees, shins, thighs, arms, chin, cheeks. It is possible to deal with benign growth of fat cells type of lipoma (dyslipidemia proliferation).

Diseases of adipose tissue in the context of the present invention include, for example, the following diseases: lipoma (tumor of fatty tissue), which is a benign, slow-growing, usually spherical, possibly Stebenkova (=L. pendulum), or even branched (=L. arborescens, such as synovial) mesenchymal tumors of enlarged cells of adipose tissue, preferably in the subcutaneous tissue may ossification in the center (=L. ossificans), founded by sputum (=L. myxomatodes) or calcified (=L. petrificans), and with increased formation of connective tissue and capsules (=L. fibrosum), the formation of blood vessels (=L. telangiectodes), rarely with malignant degeneration (=L. sarcomatodes, liposarcoma). They can be classified as pathological, because they grow and their connective tissue membrane itself may be painful, and clamping them to the blood vessels can cause nerve pain. This includes multiple lipomatosis, which causes accumulation of lipomas in patients.

Illness Derkuma, which is called painful lipomatosis, is a special form of hypertrophic proliferation of LM�type of fabric which is located between the fascia of sebum (fat fascia Kampa) and the lower part of the dermis. The action of hormones leads to increased water binding capacity in these fat cells, which, in turn, under the action of pressure causes blockage of lymphatic tract in the region of the discharge dendrilopis lymphatic vessels, thereby providing additional compression and irritating effect on peripheral sensory nerves, so in these patients occurs extremely painful sensitivity to touch. For several years or decades formed fatty nodules of irregular shape, which sometimes go under the skin, which becomes thinner due to aging, while in places there is soreness and a strong disesthesias.

Diffuse lipomatosis of the neck of the Madelung syndrome Lanois-Bensaude) is a proliferative inflammation of adipose tissue, which, along with the formation of dystrophic tumor of adipose tissue also causes cicatricial contraction of the connective tissue in the subcutaneous space. In such cases, surgical procedures are only partially successful, since this process involves important anatomical structures and disease is manifested mainly in the area of the head, neck and shoulders.

Fat edema is a painful op�the Chania adipose tissue which occurs especially in the lower legs in women and progresses with age.

Regression lipolysis means of hydrolytic cleavage of fatty tissue and involution through the mobilization of accumulated fat.

Xanthelasma is a yellowish accumulation of fat under the eyes.

In HIV-patients often have disturbances of fat deposits in the tissues, which arise due to existing drugs, such as Buffalo humps" or "bull neck" in this group of patients. Patients with weakened immune systems should not have to go through the surgery, so they remain fat accumulation that becomes the mark.

Under the above diseases adipose tissue, unlike the related power of lipohypertrophy (which also leads to the deposition of fat in the sense of a violation of the distribution of fat), manifest distinct pathological changes in tissues or education, which are characterized histological parameters of scarring and inflammation, as well as the encapsulating connective tissue and histological changes in the morphology of adipose tissue.

A further object of the invention is the use of a composition for the manufacture of drugs for the treatment of cellulite. Cellulite is a specific form of hypertrophic proliferation of adipose tissue located between the fascia to�l fat (adipose fascia Kampa) and the lower part of the dermis. The action of hormones leads to increased water binding capacity in these fat cells, which, in turn, under the action of pressure causes blockage of lymphatic tract in the region of the discharge dendrilopis lymphatic vessels. For several years, or decades, are formed adipose nodules of irregular shape, which sometimes go under the skin, which becomes thinner due to aging, while in places there is soreness and a strong disesthesias.

A further object of the invention is the use of a composition for the manufacture of drugs for the treatment of pseudogynecomastia and lipomastia. Pseudogynecomastia represents the accumulation of fat in men around the nipples on the breast, which leads to an increase of the chest and is primarily manifested aesthetically. Lipomastia is a form of pseudogynecomastia without increasing the body of the mammary glands.

Phospholipids, which are described here are contained in the pharmaceutical composition, can be obtained from any animal or plant products, in particular from chicken eggs, oil seeds and fruits, such as dried coconut, palm seeds, peanuts, rape seeds, sunflower seeds, linseed, palm and/or olive oil. Most suitable phospholipids derived from soybeans according to the procedures described in EP 005477 B1 and EP 0054769 B1.

This phospholipid is exposed to good cleaning and contains from 15 to 98 wt.%, preferably from 30 to 98%, more preferably from 50 to 98%, especially preferably from 75 to 98% and most preferably 75 to 90 wt.% of phosphatidylcholine. Such highly purified phospholipids and may contain other components of phospholipids, in particular up to 15 wt.%, more preferably up to 12% phosphatidylethanolamine, to 8% phosphatidic acid, to 10% phosphatidylinositol, up to 6% of lysophosphatidylcholine or lysophosphatidylethanolamine, trace amounts of phosphatidylserine and other lipids in small amounts.

The invention also relates to the use of one of glycyrrhizic acid or more glycyrrhizic acid, glycyrrhizic acid is in the form of physiologically acceptable salts. As salts of glycyrrhizic acid are used physiologically acceptable salts, in particular mono-, di - or trinatrium salts or potassium salts, magnesium salts, or ammonium. Preferred mono-, di - or trinatrium salts or potassium salts and ammonium salts, more preferred are mono-, di - or trinatrium salt or potassium salt.

The mass ratio of phospholipid and glycyrrhizic acid is from 30:1 to 0.5:1, preferably 15:1 to 0.5:1, more preferably from 4:1 to 1:1, most preferably from 3:1 to 2:1.

Con�radio phospholipids in the composition is from 0.5% to 30 wt.%, preferably from 5% to 25 wt.%

It is recommended that the total content of phospholipids and glycyrrhizinate acid or its salt was 2-80 wt.% The weight ratio between the phospholipid and glycyrrhizinate acid or its salt is preferably 3:1 or 4:1. When the weight ratio between the phospholipid and glycyrrhizinate acid or its salt is from 2:1 to 3:1 preferably, the content of phospholipids and glycyrrhizinate acid or its salt is from 2 to 45 wt.%

The pH value of medicines is in the range from pH 6.0 to pH of 9.0, preferably from pH 7.5 to pH 8.5, more preferably from pH 6.5 to pH 7.5 and in particular from pH 6.5 to pH 7.0.

If necessary, are added suitable auxiliary substances. As pharmacologically acceptable excipients are sugars, particularly maltose, glucose, lactose, sorbitol and mannitol and their derivatives, colloidal silicic acid and its derivatives, silica gel, talc, lactose, starch, gelatin, water, alcohols with one or more hydroxyl groups, in particular ethanol, glycerin and propylene glycol, natural or synthetic oils, in particular mineral oil, vaseline oil, peanut oil, soybean oil, sesame oil and esters. In addition, suitable excipients are cellulose, sucrose, malt, R�with, fluoride, calcium, magnesium stearate, sodium stearate, glycerol monostearate, sodium chloride and dried skim milk. Preferred auxiliary substances, especially for subcutaneous lipolysis, are water, alcohols, in particular ethanol, saline, maltose dextrose and water.

Described herein pharmaceutical composition can be used in dry or liquid form.

Liquid forms include drops, solutions, suspensions, emulsions, suspensions for injection emulsion for injection and liposome-micellar systems, as well as liposome-micellar-water systems.

Preferred are liquid preparations in the form of solutions, suspensions, emulsions, suspensions for injection, or of emulsions for injection. Particularly preferred are suspension for injection emulsion for injection.

In particular, for injection is convenient to apply such liquid preparations such as solutions, suspensions, emulsions, suspensions for injection emulsion for injection of the above ingredients, auxiliary substances or solids which immediately become liquid after adding water, another solvent or a suitable buffer type Tris-buffer. Preferably as the basis for the production of liquid drug used lyophilization.

In the application described herein pharmaceutically� drugs for injection is recommended to use a suitable solvent, not possessing unwanted side effects, e.g., water, saline, glucose, monohydroxy alcohols such as ethanol, 2-propanol, n-propanol, polyhydric alcohols such as glycerol and/or PROPANEDIOL, polyglycols such as polyethylene glycol and/or Miglyol, glycerol, formal, dimethylisoxazol, natural and synthetic oils and/or esters, alone or in combination, whereas in the case of injections, it is recommended to apply liposome-micellar system.

Remaining after concentrating the volume of alcohol should be from 0% to 20 vol.%, preferably from 0% to 10 vol.%.

Most appropriate form of application of the drug described here is a mixture of active substances, containing one phospholipid and glycyrrhizic acid or its salt in the form liposome-micellar-water system. This liposome-micellar-water system designed for injection, preferably has a pH value of 6.0 to 7.5.

Dry forms described herein a pharmaceutical preparation include lyophilization, tablets, in particular film coated tablets and pills, powders, capsules, granules and pills. Are preferred lyophilization.

If the song is available in the form of lyophilized powder, add water or Tris-buffer leads to the formation of aqueous liposome system, which can be used for the introduction.

Aqueous liposome system also subjected to sterilization by filtration, and contain liposomes and micelles at high concentrations with a relatively small particle size of from 30 nm to 180 nm, preferably from 30 to 130 nm, particularly preferably from 30 to 90 nm. These liposomes can be subjected to sterilization by filtration through a filter with pore diameter of 0.2 µm.

The drug described here, which is obtained in the form of an aqueous solution, preferably in the form liposome-micellar system, which has high transparency, has a very long shelf life and can be sterilized by filtration. The system can be dried, for example, by lyophilization, this gives a stable lyophilized mixture.

If described herein, the pharmaceutical preparation is in the form of solution for injection, we especially recommend the use of such combinations of active substances, which contain phospholipids and trisodium salt of glycyrrhizic acid in a weight ratio between phosphatidylcholine and trinatrium salt of glycyrrhizic acid from 1:1 to 4:1, preferably from 2:1 to 3:1.

The production of the preparations of the invention is carried out, for example, dissolving or dispersing at least one phospholipid and at least one glycyrrhizic acid in the above rela�Oseni to each other in a suitable solvent. After this, the solution or dispersion of the concentrate and then add water.

Methods of making formulations are also described in European patent applications EP 0470437 A and EP 0615746 A.

If necessary, the preparations used according to the invention, it is possible to add appropriate antioxidants such as ascorbic acid, acidic sodium sulfite or sodium pyrosulfite, alpha-tocopherol, preservatives such as benzyl alcohol or n-hydroxybenzoate or suspendida funds type of sodium carboxymethyl cellulose.

Drugs may also optionally contain colloidal structures like micelles or mixed micelles. These structures have a particle diameter of 10 to 500 A. They consist of glycyrrhizic acid and phospholipid. The ratio of the masses between glycyrrhizic acid and phospholipid in the range of 0.1:2 to 2:1, preferably 1:2. The concentration of phospholipid in colloidal structures in drug ranges from 5% to 15%, preferably 10 wt.% Obtaining colloidal structures is carried out, for example, dissolution of glycyrrhizic acid in water, and the solution becomes slightly alkaline. It then dispersed phospholipid. A in the end it was filtered.

The drug is used according to the invention, and associated dose forms is carried out subcutaneously, intraperitoneally, inside�iseqno or intravenously. Preferred is subcutaneous administration.

In addition, the claimed and the percutaneous introduction of various media-media and with the help of various devices such as iontophoresis.

Uniform administration of drugs and dose forms used according to the invention, in some cases, may be exercised and the method of excitation (tumescence), in which, in order to ensure uniform distribution, hydrostatic pressure is used.

In addition, it becomes possible percutaneous introduction, which can be implemented in various environments-media such as creams, ointments, gels, hydrogels, lotions or pastes, and through a variety of devices, such as iontophoresis, microporosity, electroporation or phonophoresis.

Appropriate drugs and dose forms are, e.g., suspensions, emulsions or injectable solutions and also preparations with prolonged release of the active substance, manufactured using conventional tools. Drugs may also be in the form of concentrate dry matter or lyophilized powder, for example, to improve stability.

Preferably, the pharmaceutical preparations are produced and administered in dose units, with each unit as an active beginning contains a certain dose of the drug. For solutions for injections in ampoules this d�for can amount of 1 ml from 10 mg to 2000 mg, preferably from 50 mg to 2000 mg, more preferably from 250 mg to 500 mg in terms of the phospholipid.

For the treatment of adult patients, depending on the size of the subject to treatment of adipose tissue, with the introduction of solutions for injections are needed daily doses in terms of phospholipid from 5 mg to 2500 mg, preferably from 250 mg to 2500 mg a course of injections of 200 max. injection. Solutions for injection can be further diluted before administration, preferably with the help of saline. In some cases, however, may require a greater or smaller daily doses. The dose also depends on the size of clusters of fat, for small enough lip from 125 mg to 500 mg, preferably from 250 mg to 500 mg per lipoma in terms of the phospholipid.

The introduction of the daily dose can be carried out either as a single injection or in the form of several smaller dose units and also by multiple administration of fractional doses at certain intervals of time.

The invention is disclosed in detail in the examples.

Examples

Example 1. Preparation of solution for subcutaneous injection

A solution of 0.2 g (8%) trinatrium salt of glycyrrhizic acid, 1.8 g (72%) maltose and 4.5 ml of water is thoroughly mixed with the dispersion of 0.5 g (20%) of phospholipid from soy and 0.5 ml (20%) 96% ethanol in the atmosphere of inert gas.

The total content of f�of spolied and salts of glycyrrhizic acid was 28%. The ratio between the phospholipid and salt of glycyrrhizic acid was 2.5:1.

Emulsion was dispersively by processing ultrasound (disintegrator MSE Soniprep 150, England) at 4°C for 30 s with an interval of one minute. After about 10 min formed a suspension of liposomes.

The suspension of liposomes was filtered through a filter of 0.2 μm, and then subjected to lyophilization.

A suspension of liposomes (5.0 ml) was subjected to freeze-drying for 5 hours (liofilizirovanny). Received about 2.5 g loose, slightly yellowish powder.

To obtain a solution for subcutaneous injection of 2.5 g of the drug in the vials was dissolved at 9.0 ml of solvent (water or Tris-buffer).

Example 2. Getting liposome-water system for subcutaneous use only

Solution was prepared from 50 g of purified phospholipid from soybean (82.5% phospholipid+3,5% phosphatidylcholine, 10% of phosphatidylethanolamine, 0,6% of lysophosphatidylcholine and a maximum of 10% of other lipids) and 0.25 g of sodium salt of phosphatidyl 250 ml of ethanol. The resulting solution was evaporated under vacuum.

The resulting mixture of phospholipids (CA. 20%) were dispersible in the inert gas stream by mixing with 500 ml of water, which contained 20.0 g (7,99%) trinatrium salts of glycyrrhizic acid and of 180.0 g (71,92%) isomaltase.

The total content of phospholipid and salts of glycyrrhizic acid was 28,07%. With�the ratio between the phospholipid and salt of glycyrrhizic acid was 2.5:1.

This is five times the variance was subjected to homogenization at high pressure 600 bar. The obtained liposome system was filtered through a 0.2 μm filter and filled into vials 10.0 ml of inert gas. The product had the following characteristics:

appearance: transparent, slightly opalescent liquid,

pH: 6,5,

transparency (660 nm): 85%,

the average particle size (laser light scattering): 75 nm,

sterility: in accordance with the requirements

microscopic properties (criticize): mainly single-layered liposomes the size of 30-90 nm, single bilayer liposomes.

The transparency of the drug, filled into ampoules, tested after 2, 6, 9 and 12 months of storage. There was no difference from the original transparency of the drug 1.

Example 3. The study of membrane damaging action of phosphatidylcholine in cells 3T3-L1

In order to test in vitro the effects of phosphatidylcholine on the integrity and stability of the membranes, the differentiated cells 3T3-L1 were incubated with different concentrations of phosphatidylcholine for 4 and 24 hours and then analyzed by light microscopy.

As a model system for the study used a cell line preadipocytes 3T3-L1 mouse. Cells 3T3-L1 stimulated with hormone cocktail for adipogenesis (corticosteron, isobutylmethylxanthine,indomethacin, insulin) and were subjected to differentiation for 8 days in Mature adipocytes.

Mature adipocytes from cells 3T3-L1 treated with different concentrations of phosphatidylcholine.

First, the prepared stock solution of phosphatidylcholine: 500 mg/ml of phosphatidylcholine was dissolved in 70% ethanol.

Working concentrations of phosphatidylcholine: 1 mg/ml, 5 mg/ml, 10 mg/ml, 15 mg/ml, 20 mg/ml.

Fig.1A presents images by light microscopy of cells 3T3-L1 after 24 hours of treatment 1 mg/ml, 5 mg/ml, 10 mg/ml, 15 mg/ml and 20 mg/ml phosphatidylcholine, and Fig.1b presents detailed images by confocal laser scanning microscopy (CLSM) at 63 × magnification cells 3T3-L1 treated with phosphatidylcholine. Fig.1C presents stained by propidium iodide (PI) cells 3T3-L1 after treatment with phosphatidylcholine.

Figure 1A. Phase-contrast images of the treated differentiated cells 3T3-L1 in 2D cell culture. Treatment:

(a) control=untreated cells in differentiation medium

(b) 1 mg/ml of phosphatidylcholine in 24 hours

(c) 5 mg/ml of phosphatidylcholine in 24 hours

(d) 10 mg/ml of phosphatidylcholine in 24 hours

(e) 15 mg/ml of phosphatidylcholine in 24 hours

(f) 20 mg/ml of phosphatidylcholine in 24 hours.

Mark scale=100 µm.

Figure 1b. Phase-contrast images of CLSM method at 63 times magnification processing�nnyh differentiated cells 3T3-L1 in 2D cell culture. Treatment:

(a) control=untreated cells in differentiation medium after 4 hours

(b) 1 mg/ml of phosphatidylcholine in 4 hours

(c) 5 mg/ml of phosphatidylcholine in 4 hours

(d) 10 mg/ml of phosphatidylcholine in 4 hours.

Mark scale=20 µm.

Figure 1c. Phase-contrast (PC) images of CLSM method at 63 times magnification treated differentiated cells 3T3-L1 in 2D cell culture after PI staining. Treatment:

(a) control=untreated cells in ethanol

(b) positive control=untreated cells in differentiation medium+1% Triton

(c) 5 mg/ml of phosphatidylcholine in 4 hours

(d) 10 mg/ml of phosphatidylcholine in 4 hours

(e) 15 mg/ml of phosphatidylcholine in 4 hours.

After incubation (4 hours) adipocytes were stained with 5 μg/ml PI and analyzed by CLSM method. In the top row PI presents (a-e) fluorescence images of stained PI cells. In the bottom row PC are presented (a-e) corresponding phase-contrast images by overlaying them with fluorescent images. Mark scale=20 µm.

The treated phosphatidylcholine cells (Fig.1A and 1b) shows no morphological differences from the untreated control. Therefore, phosphatidylcholine does not have a cytotoxic effect. Comparable concentrations (20 mg/ml) Na-desoxycholate caused the apparent destruction of cell membranes, which wasn't there when used concentrations of phosphatidylcholine.

That phosphatidylcholine has no cytotoxic effect was confirmed by PI staining of the treated cells.

To do this, the differentiated cells 3T3-L1 treated with 5 mg/ml, 10 mg/ml and 15 mg/ml of phosphatidylcholine for 4 hours. Then on Wednesday at 5 minutes was added 5 mg/ml PI and analyzed the cells by the method of CLSM (Fig.1C).

In the control (Fig.1c, (a)) was added ethanol so that its concentration was the same as in solutions for cell processing. From figure 1c (a) shows that the cells are not colored PI. Therefore, when used concentrations of ethanol do not have a cytotoxic effect.

In positive control with 1% Triton in Fig.1c (b), there are multiple cells, stained with PI in red. This indicates damage to the cell membrane. When this stability is compromised membranes and cell integrity.

On the contrary, among the treated cells are not visible colored red (Fig.1c from (c) to (e)). Therefore, these cells no violations of the stability and the integrity of the membranes. Therefore, phosphatidylcholine has no destructive action on the differentiated cells 3T3-L1.

This result is in good agreement with the data of the method of light microscopy (see Fig.1A and 1b), which also was not observed damaging effect of phosphatidylcholine on the cells.

Example 4. Selection originating from fat�howl tissue stem cells (ADSC) from the subcutaneous adipose tissue of man

In order to get closer to clinical use, in the following experiments used a different model system with stem cells from the mesenchyme.

Subcutaneous adipose tissue may serve as a potential source of adult stem cells. These so-called "originating from adipose tissue-derived stem cells (ADSC) are multipotent and under appropriate stimuli may undergo differentiation into various cell types, e.g., osteoblasts, chondrocytes, adipocytes. The allocation of ADSCs from adipose tissue, which is removed during plastic reconstructive surgery, presented schematically in Fig.2.

First grease was washed with buffer to remove hematopoietic cells, and then crushed. These pieces of adipose tissue were digested with collagenase. When centrifuging the digested tissue was separated from the stromal-vascular fraction and discard the floating Mature adipocytes. The stromal-vascular fraction in the sediment consists of a heterogeneous population of cells: blood cells, fibroblasts, pericytes, endothelial cells and preadipocytes.

This population of cells was transferred into a culture vessel with the medium, wherein the cells are attached. When you add a suitable cocktail consisting of insulin, dexamethasone, indomethacin and isobutylene�xanthine or consisting of insulin, cortisol, troglitazone, triiodothyronine and isobutylmethylxanthine, the cells were subjected to stimulation of adipogenesis and improved adipogenic differentiation.

Example 5. The study of membrane damaging action of phosphatidylcholine and desoxycholate sodium on ADSCs

Na-deoxycholate (Na-DC)

Cells ADSCs from example 4, stimulated with hormone cocktail for adipogenesis (insulin, cortisol, troglitazone, triiodothyronine and isobutylmethylxanthine), and then subjected to differentiation for 21 days in Mature adipocytes.

This was followed by treatment with deoxycholate sodium. This used the following concentrations: 0.01 mg/ml, 0.05 mg/ml, 0.075 mg/ml, 0.1 mg/ml and 0.5 mg/ml In the control group consisted of untreated ADSCs. The incubation period was 4 hours.

This concentration range had been effective on 3T3-L1. After incubation for 4 hours treated differentiated cells were examined under the light microscope (Fig.3a).

In addition, treated desoxycholate sodium ADSCs were studied by CLSM. Differentiated, Mature adipocytes were treated with 0.01 mg/ml, 0.05 mg/ml and 0.1 mg/ml desoxycholate sodium for 4 hours. As a control, the untreated ADSCs. Then analyzed by microscopy CLSM with 63-fold increase (Fi�.3b).

Further analysis of the damaging effects desoxycholate sodium into cells ADSCs was performed by staining the treated cells PI and subsequent analysis by CLSM. Differentiated, Mature adipocytes were treated with 0.05 mg/ml, 0.1 mg/ml and 0.5 mg/ml desoxycholate sodium for 4 hours. As a control, the untreated ADSCs.

Then the cells were incubated for 5 minutes in a medium containing 5 g/ml of propidium iodide. Then analyzed by microscopy CLSM at 63 × magnification (Fig.3c).

Figure 3a. Images by light microscopy ADSC differentiated cells after treatment with different concentrations of desoxycholate sodium (Na-DC) in 2D cell culture. Treatment:

(a) control=untreated cells in differentiation medium after 4 hours

(b) 0.01 mg/ml Na-DC after 4 hours

(c) 0.05 mg/ml Na-DC after 4 hours

(d) 0.075 mg/ml Na-DC after 4 hours

(e) 0.1 mg/ml Na-DC after 4 hours

(f) 0.5 mg/ml Na-DC after 4 hours.

Black arrows indicate cells with damaged membrane or cell fragments. White arrows indicate the droplets of free lipids. Mark scale=100 µm.

Figure 3b. Images by CLSM method ADSC differentiated cells after treatment with different concentrations of desoxycholate sodium (Na-DC) in 2D cell culture. Treatment:

(a) control=untreated cells in medium differen�of zerouki in 4 hours

(b) 0.01 mg/ml Na-DC after 4 hours

(c) 0.05 mg/ml Na-DC after 4 hours

(d) 0.1 mg/ml Na-DC after 4 hours.

Black arrows indicate cells with damaged membrane or cell fragments. White arrows indicate the droplets of free lipids. Mark scale=20 µm.

Figure 3c. Images by confocal laser scanning microscopy ADSC differentiated cells after treatment with different concentrations of desoxycholate sodium (Na-DC) in 2D cell culture. Treatment:

(a) control=untreated cells in differentiation medium after 4 hours

(b) positive control=untreated cells in differentiation medium+1% Triton

(c) 0.05 mg/ml Na-DC after 4 hours

(d) 0.1 mg/ml Na-DC after 4 hours

(e) 0.5 mg/ml Na-DC after 4 hours.

After incubation (4 hours) adipocytes were stained with 5 μg/ml PI and analyzed by CLSM method. In the top row PI presents (a-e) fluorescence images of stained PI cells. In the bottom row PC are presented (a-e) corresponding phase-contrast images by overlaying them with fluorescent images. Mark scale=20 µm.

Very low concentrations of desoxycholate sodium 0.01 mg/ml had no effect on the cells (Fig.3a(b)). There were no differences from control group (Fig.3a(a)). Adipocytes were alive and had integral cell membrane. The increase in the concentration from 0.05 mg/ml caused no�allsome damage to the cell membrane (Fig.3a(c)). It amplified the next higher concentration (Fig.3a(d, e)). The highest dose of 0.5 mg/ml had a significant toxic effect on the cells (Fig.3a(f)). Adipocytes were killed, the cell membrane is completely destroyed so that mostly only present droplets of free lipids and cell fragments. Desoxycholate sodium on ADSCs did not differ from its effect on cells 3T3-L1. Manifested identical dose-effect. In both model systems at 0.05 mg/ml desoxycholate sodium Deplete any membrane effects, and the concentration of 0.5 mg/ml was highly toxic.

When a more detailed examination of the treated cells by confocal microscopy confirmed the earlier observation. At the time, as a low concentration of 0.01 mg/ml desoxycholate sodium (Fig.3b(b)) had no cytotoxic effect on the cells, the concentration of 0.1 mg/ml (Fig.3b(d)) caused severe damage to the membrane. This demonstrates the clear membrane damaging action of the Na-desoxycholate.

This effect was again confirmed by staining cells ADSCs with propidium iodide after treatment with deoxycholate sodium.

In positive control with 1% Triton clearly visible cells, stained with PI in red, indicating that cells with a damaged membrane (Fig.3c(b)).

After treatment with 0.05 �g/ml desoxycholate sodium dyed red cells was not so that was not the cells with the violation of the stability and the integrity of membranes (Fig.3c(c)). After treatment with 0.1 mg/ml desoxycholate sodium some appear coloured red cells, so that a small number of cells with impaired integrity and stability of the membranes (Fig.3d(d)). After treatment with 0.5 mg/ml desoxycholate sodium was detected much clearly painted red cells, so revealed many cells with impaired integrity and stability of the membranes (Fig.3c(e)).

This clearly indicates a membrane damaging action of desoxycholate sodium at a concentration of 0.5 mg/ml in ADSCs. Phosphatidylcholine (PC)

Similarly to the experiments with Na-desoxycholate also investigated the phosphatidylcholine on the subject of damaging the membranes of the action.

For this purpose, similar to the experiments with Na-desoxycholate, used ADSC cells of example 4 and subjected to differentiation using hormone cocktail (insulin, cortisol, troglitazone, triiodothyronine and isobutylmethylxanthine) in Mature adipocytes.

Then carried out the treatment with phosphatidylcholine. This used the following concentrations: 1 mg/ml, 5 mg/ml, 10 mg/ml, 15 mg/ml and 20 mg/ml In the control group consisted of untreated ADSCs. The incubation period was 4 hours.

This concentration range had been effektivnye 3T3-L1. After incubation for 4 hours treated differentiated cells were examined under the light microscope (Fig.4A).

In addition, treated with phosphatidylcholine cells ADSCs were studied by CLSM. Differentiated, Mature adipocytes were treated with 1 mg/ml, 5 mg/ml and 15 mg/ml of phosphatidylcholine for 4 hours. As a control, the untreated ADSCs. Then analyzed by microscopy CLSM at 63 × magnification (Fig.4b).

Further analysis of the damaging effects of phosphatidylcholine on the cells ADSCs was performed by staining the treated cells PI and subsequent analysis by CLSM. Differentiated, Mature adipocytes were treated with 5 mg/ml, 10 mg/ml and 15 mg/ml of phosphatidylcholine for 4 hours. As a control, the untreated ADSCs. Then the cells were incubated for 5 minutes in a medium containing 5 g/ml of propidium iodide. Then analyzed by microscopy CLSM at 63 × magnification (Fig.4C).

Figure 4A. Images by light microscopy ADSC differentiated cells after treatment with different concentrations of phosphatidylcholine (PC) in 2D cell culture. Treatment:

(a) control=untreated cells in differentiation medium after 4 hours

(b) 1 mg/ml PC after 4 hours

(c) 5 mg/ml PC after 4 hours

(d) 10 mg/ml PC after 4 hours

(e) 15 mg/ml PC after hours

(f) 20 mg/ml PC after 4 hours.

Mark scale=100 µm.

Figure 4b. Images by CLSM method ADSC differentiated cells after treatment with different concentrations of phosphatidylcholine (PC) in 2D cell culture. Treatment:

(a) control=untreated cells in differentiation medium after 4 hours

(b) 1 mg/ml PC after 4 hours

(c) 5 mg/ml PC after 4 hours

(d) 15 mg/ml PC after 4 hours.

Mark scale=20 µm.

Figure 4. Images by confocal laser scanning microscopy ADSC differentiated cells after treatment with different concentrations of phosphatidylcholine (PC) in 2D cell culture. Treatment:

(a) control=untreated cells in differentiation medium after 4 hours

(b) positive control=untreated cells in differentiation medium+1% Triton

(c) 5 mg/ml PC after 4 hours

(d) 10 mg/ml PC after 4 hours

(e) 15 mg/ml PC after 4 hours.

After incubation (4 hours) adipocytes were stained with 5 μg/ml PI and analyzed by CLSM method. In the top row PI presents (a-e) fluorescence images of stained PI cells. In the bottom row PC are presented (a-e) corresponding phase-contrast images by overlaying them with fluorescent images. Mark scale=20 µm.

In accordance with observations on cells 3T3-L1 (example 3), in cellular models of ADSC did not have any cytotoxic effect �of fosfatidilkholina (Fig.4A). Concentration-independent PC cells were alive and did not show morphological changes.

For comparison, when the concentration of Na-DC-in 0.05 mg/ml was observed damaged and at a concentration of 0.5 mg/ml ADSC cells were dead (Fig.3c).

The study of ADSC cells after treatment with phosphatidylcholine method CLSM confirmed that in cells no damage (4b). In the untreated control, as well as in ADSCs treated with 15 mg/ml, was shown holistic morphology. Therefore, phosphatidylcholine does not have a cytotoxic effect.

The PI staining of cells ADSCs treated with phosphatidylcholine, confirmed that phosphatidylcholine has no cytotoxic effect in vitro.

In positive control with 1% Triton clearly manifested red cells, stained with PI, indicating that cells with damaged membranes (Fig.4c(b)).

After treatment at 5, 10 and 15 mg/ml of phosphatidylcholine and after each PI staining was not observed painted red cells, so that cells with impaired integrity and stability of the membranes was not detected (Fig.4c from (c) to (e)).

This clearly shows that treatment with phosphatidylcholine has no damaging of the membrane action in ADSCs.

On the contrary, the integrity of membranes and stability of ADSCs significantly disrupted Na-desoxycholate (Fig.3c(d, e)).

Experiments with Na-desoxycholate�m and phosphatidylcholine showed what a cytotoxic effect has only Na-desoxycholate, but not phosphatidylcholine. Phosphatidylcholine does not cause damage to cell membranes or cells. These observations podtverdil using several methods such as light microscopy, staining with propidium iodide and subsequent fluorescence microscopy.

The action of substances is not changed in time during the study period: 2-hour incubation showed the same effects, and 24-hour incubation. Experiments with Na-desoxycholate showed that the bile salt destabilizes the membrane and causes necrosis. After evaluating the required doses in vitro, it became clear that used in vivo in the number of Na-desoxycholate can be cytotoxic.

In respect of phosphatidylcholine, there were no cytotoxic effects in vitro, which should be true and in vivo. This phospholipid is not cytotoxic.

Example 6. A study of a combination of phosphatidylcholine, DGL and maltose

Investigated the effect of a new combination of substances. This combination consists of 50 mg/ml of phosphatidylcholine (PC), 20 mg/ml trinatrium of DGL and 180 mg/ml of maltose.

First, we determined the dose-effect against the damage of membranes and cytotoxic effects, as well as conducted tests on lipolytic activity.

As mo�system for individual studies used a cell line preadipocytes mouse 3T3-L1. Cells 3T3-L1 stimulated with hormone cocktail for adipogenesis (corticosteron, isobutylmethylxanthine, indomethacin, insulin) and were subjected to differentiation for 8 days in Mature adipocytes.

Mature cells of adipocytes 3T3-L1 were incubated with different concentrations of phosphatidylcholine from 0.1 mg/ml to 50 mg/ml Phosphatidylcholine combined with 2-20 mg/ml of DGL and 18-180 mg/ml maltose.

Incubation of Mature 3T3-L1 cells with a combination of substances was performed for 4 hours.

Then the treated cells were examined by light microscopy at 63 × magnification on the subject of destabilizing the membrane and cytotoxic effects.

The results are presented in Fig.5 and 6.

Figure 5. Phase-contrast images of CLSM method treated differentiated cells 3T3-L1 in 2D cell culture. Treatment:

(a) control=untreated cells in differentiation medium

(b) 5 mg/ml PC+2 mg/ml of DGL+18 mg/ml maltose

(c) 10 mg/ml PC+4 mg/ml of DGL+36 mg/ml maltose

(d) 20 mg/ml PC+8 mg/ml of DGL+72 mg/ml of maltose

(e) 30 mg/ml PC+12 mg/ml of DGL+108 mg/ml maltose

(f) 50 mg/ml PC+20 mg/ml of DGL+180 mg/ml of maltose.

Mark scale=20 µm.

Figure 6. Images by CLSM method treated differentiated cells 3T3-L1 in 2D cell culture. Treatment:

(a) a denier�th control=untreated cells in differentiation medium

(b) positive control=untreated cells in differentiation medium+1% Triton X

(c) 20 mg/ml PC+8 mg/ml of DGL+72 mg/ml of maltose

(d) 30 mg/ml PC+12 mg/ml of DGL+108 mg/ml maltose

(e) 50 mg/ml PC+20 mg/ml of DGL+180 mg/ml of maltose.

After incubation (4 hours) adipocytes were stained with 5 μg/ml PI and analyzed by CLSM method. In the left lane PI presents (a-e) fluorescence images of stained PI cells. In the right lane PC presents (a-e) corresponding phase-contrast images by overlaying them with fluorescent images. Mark scale=20 µm.

During the processing of adipocytes combination of substances they did not differ from control cells (control, Fig.5A). Under a light microscope, they showed the same morphology as the cells in the control: they were alive and had integral cell membrane. The combination of substances has not been a noticeable damaging the membrane effects on the cells regardless of the concentration (Fig.5).

In order to verify the integrity of the membranes, PI staining was performed cells 3T3-L1 and control. For this purpose we used a combination of substances at the following concentrations:

20 mg/ml, 30 mg/ml and 50 mg/ml of phosphatidylcholine;

8 mg/ml, 12 mg/ml and 20 mg/ml of DGL; and

72 mg/ml, 108 mg/ml and 180 mg/ml of maltose.

The incubation period was 4 hours. Then processed�s cells and two controls were incubated with 5 μg/ml PI for 5 minutes. Analysis was performed by the method of CLSM (Fig.6).

Treatment of cells with Triton X led to the violation of the integrity of membranes. Therefore, the propidium iodide into the cells and stained the cells with destabilized membrane. In positive control (Fig.6b), as expected, shows cell staining, permeabilization Triton X. Untreated cells in the negative control (Fig.6A) were not stained PL. This means that the membranes of these cells remained intact.

The cells treated with 20 mg/ml PC (Fig.6c) and 30 mg/ml PC (Fig.6d), were stained PL Therefore, in these cells there is no damage to membranes and used a combination of substances does not have a cytotoxic effect (Fig.6c, d).

The cells treated with 50 mg/ml PC (Fig.6E), showed a weak red color (Fig.6F). These cells were treated with high doses of combinations of substances. In this environment waterpipes from the cells and there was a shortage of nutrients, causing damage to the cells during prolonged incubation. Therefore, slight staining treated with 50 mg/ml PC cells may be due to lack of nutrients and not damage cells phosphatidylcholine.

The combination of substances from phosphatidylcholine, DGL and maltose conducted in in vitro experiments did not show membrane damaging action. It should be noted that d�I identify the possible damage to the membranes used very high concentrations of the combination of substances according to the invention, which were significantly higher than those used therapeutically concentrations in vivo.

The ratio between the effects in vivo and in vitro is known as the correlation of in vivo/in vitro. Determination of correlation of in vivo/in vitro is a challenging task and is manifested in different ways in different conditions. In many cases you can accept that the correlation between in vivo/in vitro is approx. 100. This means that to achieve a close effect used in vitro concentrations are about two orders of magnitude smaller than the doses used in vivo. On this basis we should expect, for example, for Lipostabil®N when the lipolysis those concentrations in vitro, which are shown in table 1.

Table 1
Used in vivo concentration of compound [mg/ml]The expected concentrations in vitro (×100) [mg/ml]The concentration causing cell damage in vitro
Na-desoxycholate12,65 mg/ml0,12650.05 mg/ml
Phosphatidylcholine25 mg/ml0,25no
Na-DC, PC of Lipostabil12,65 mg/ml Na-DC0,12650.05 mg/ml Na-DC
25 mg/ml PC0,25from 0.1 mg/ml PC

In the case of the Na-desoxycholate as individual substances and substances in Lipostabil®expected concentration in vitro according to the calculations is consistent with the concentrations that were set in the experiments (table 1). Hence we can conclude that this substance is likely has a cell-damaging effect at the concentration used in the lipolysis.

Therefore, it is highly unlikely that the concentration of the combination of substances according to the invention is used in vivo for therapy, will cause the same damage to the cell membranes (and subsequent necrosis), as the concentration in the prior art. Therefore, you can take the same conversion factors and for a combination of phosphatidylcholine and glycyrrhizic acid.

Example 7. The study of the inflammatory response in the treated cells of mice

Since inflammation is a trigger for migration originating from the adipose tissue-derived stem cells (ADSC), mice BALB/c right in subcutaneous adipose tissue was injected with either mixture (Fig.8d-f) containing phosphatidylcholine (PC), glitzy�rezinovoy acid (GR) and maltose (MAL) (25 mg/ml PC, 10 mg/ml GR, 90 mg/ml MAL), or PBS buffer (Fig.8g-i), or E. coli cells (Fig.8a-c). Incubation continued for 5 days.

After this staining was performed on CD4, CD8, CD19 and CD20 to study the inflammatory response of cells.

In addition, originating from adipose tissue-derived stem cells (ADSC) was labeled with a lentiviral vector expressing eGFP/luciferase and injected 48 hours after the initial injection in the opposite adipose tissue of mice BALB/c.

Migration of cells ADSC was observed by bioluminescence. The results of example 7 shown in Fig.8.

Figure 8. Bioluminescent images tagged luciferase cells after subcutaneous injection of ADSC right in adipose tissue of mice Balb/c with: (a-c) E. coli cells(d-f) a mixture of phosphatidylcholine+maltose+DGL (PMC) (g-i) PBS buffer.

After 48 hours tagged luciferase cells ADSC were injected intraperitoneally in each case and watched the migration of ADSC cells by bioluminescence. In mice (d-i) ADSC cells migrated to the liver and spleen. In mice (a-c) ADSC cells migrated to the area that is infected with the introduction of E. coli and accumulated here.

In mice with PBS (Fig.8g-1) and mice with a mixture containing PC (Fig.8d-f), was not observed differences in cell migration ADSC. In contrast, in mice which were injected with E. coli, was observed migration and accumulation of cells ADSC in the zone infected with the introduction of E. coli.

Thus, when porosimetry luciferase stem cells originating from adipose tissue (ADSC), it was shown that the introduction of in vivo mixture containing phosphatidylcholine (PC), trinatrium DGL and maltose, does not cause inflammatory reactions. This is evidenced by the fact that labeled luciferase ADSC cells had not migrated and accumulated in the subcutaneous adipose tissue that was injected to the mixture.

These results demonstrate that phosphatidylcholine can be used as lipolytic active substance, not causing severe inflammatory reactions in combination with glycyrrhizic acid.

Example 8. The study of lipolytic action of the combination of substances in vitro

Cells 3T3-L1 stimulated with hormone cocktail for adipogenesis and were subjected to differentiation for 8 days in Mature adipocytes. This was followed by 4-hour incubation of cells with 10 mg/ml, 25 mg/ml and 50 mg/ml of phosphatidylcholine and 4 mg/ml, 10 mg/ml and 20 mg/ml of DGL and 36 mg/ml, 90 mg/ml and 180 mg/ml of maltose. Lipolytic activity was measured by the method of determination of lipolysis, as described below.

Method for determination of lipolysis

The breakdown of triglycerides to glycerol and three fatty acids known as lipolysis. This process is catalyzed mainly hormone-sensitive lipase and triglyceridemia adipose tissue. Method of determination of lipolysis can be used to detect �andpolitical activity of the cells. This method is based on measurement of glycerol formed during lipolysis, which is secreted by cells in the environment. Glycerin is metabolized in enzymatic reactions in glycerol-1-phosphate and then to dihydroxyacetonephosphate. This produces hydrogen peroxide, which is quantified photometrically by the reaction of the peroxidase staining. In order to judge the lipolytic action of substances, they are compared with the baseline activity of lipolysis in the cells and lipolysis by stimulation of the beta-adrenergic receptors. Such stimulation is caused by isoproterenol. The results from example 8 is shown in Fig.7.

Figure 7. A graphical representation of the method of lipolysis (µg glycerol/µg DNA) treated differentiated cells 3T3-L1. Cells ST-L1 stimulated with hormone cocktail for adipogenesis, and then subjected to differentiation for 8 days. Treatment of Mature adipocytes was performed for 4 hours, respectively, in 3% BSA/PBS with:

10 μm of isoproterenol (positive control for stimulation of lipolysis)

10 mg/ml of phosphatidylcholine+4 mg/ml of DGL+36 mg/ml maltose

25 mg/ml of phosphatidylcholine+10 mg/ml of DGL+90 mg/ml maltose

50 mg/ml of phosphatidylcholine+20 mg/ml of DGL+180 mg/ml of maltose.

As a control for baseline activity �ipolita used untreated cells in 3% BSA/PBS. Bars indicate standard deviation for n=3. The experiment was conducted twice. PC=phosphatidylcholine.

From the first column in Fig.7 shows that the basic activity of the lipolysis untreated cells in 3% BSA/PBS is 8 µg of glycerol/µg DNA. Based on this basic level we determined the activity of lipolysis in the other samples. In positive control (Fig.7) induced stimulation of lipolysis with 10 μm agonist R-adrenoretseptorov isoproterenol. In positive control is manifested lipolytic activity, which increased eight-fold from baseline. All cells treated with a combination of substances (10 mg/ml, 25 mg/ml and 50 mg/ml PC), showed an increase in lipolytic activity compared with baseline (Fig.7). Treatment of cells with combination of substances that contains 10 or 25 mg/ml PC, led to 5-fold increase in lipolytic activity compared with baseline. Treatment of cells with combination of substances containing 50 mg/ml PC, led to 3-fold increase in lipolytic activity compared with baseline (Fig.7). The decrease in lipolytic activity at the highest concentration, probably as already mentioned, is due to the fact that the cells lack nutrients due to the exhaustion of the environment that is needed for survival or to maintain the normal function�th, such as lipolytic activity.

The combination of substances according to the invention shows a marked lipolytic activity in vitro.

Comparative example 1. The drug Lipostabil®containing phosphatidylcholine and desoxycholate sodium

Used Na-deoxycholate at a concentration of 0.005-0.5 mg/ml (acts as a separate substance, starting with 0.05 mg/ml) and phosphatidylcholine at a concentration of 0.01-1 mg/ml (not applicable as a separate matter).

The procedure was analogous to example 8.

The results of the comparative example shown in Fig.9.

Figure 9. Phase-contrast images of the treated differentiated cells 3T3-L1. Cells 3T3-L1 stimulated with hormone cocktail for adipogenesis, and then subjected to differentiation for 8 days. Mature adipocytes were treated for 24 hours with phosphatidylcholine and desoxycholate sodium from Lipostabil at the following concentrations:

(a) untreated cells in differentiation medium,

(b) 0.01 mg/ml of phosphatidylcholine+0.005 mg/ml Na-desoxycholate,

(c) 0.1 mg/ml of phosphatidylcholine+0.05 mg/ml Na-desoxycholate,

(d) 0.25 mg/ml of phosphatidylcholine+0.125 mg/ml Na-desoxycholate,

(e) 0.5 mg/ml of phosphatidylcholine+0.25 mg/ml Na-desoxycholate,

(f) 1 mg/ml of phosphatidylcholine+0.5 mg/ml Na-desoxycholate.

Analyzed under a light microscope. Cells with a damaged membrane rickleton fragments observed typical black arrows, and droplets of free lipids are indicated by white arrows.

At the time, as the lowest concentration of phosphatidylcholine and desoxycholate sodium still showed no effect (Fig.9b), the next higher concentration was noted minor damage cells (Fig.5c), which increased with increasing concentration. Fig.5e cell membranes very impressed, pointing out that Lipostabil®at a concentration of 0.5 mg/ml of phosphatidylcholine together with 0.25 mg/ml desoxycholate sodium severely damages the cells and causes cell death by necrosis. The nature of the effect of Lipostabil®was most comparable to the detergent action of the Na-desoxycholate (typical damage of the cell membrane), which clearly dominates. Such a typical damaging the membrane action is not detected in phosphatidylcholine as a separate matter, indicating that the cytotoxic effect of Lipostabil®mainly comes from the Na-desoxycholate. Comparison of effective concentration range Lipostabil®to the one of the individual substances confirms this conclusion about the predominant action of desoxycholate. At the time, as phosphatidylcholin in the form of individual substances was not effective, Lipostabil®already at the concentration of 0.1 mg/ml of phosphatidylcholine has little effect (at this concentration no effect of PC in the form of individual�CSOs substances). However, Na-desoxycholate after a single dose at concentrations of 0.05 mg/ml already caused the initial damage to the membranes, which also happened to Lipostabil®at this concentration.

Example 9. Introduction Phosphogliv®and Lipostabil®subjects women and determine the effectiveness of subcutaneous lipolysis

The drug Phosphogliv®i.v., hitherto employed in diseases of the liver, instead of DC (as in Lipostabil®N i.v.) contains glycyrrhizic acid. First experimental results and studies on two subjects showed the same efficacy of the drug as Lipostabil®Ni.v., with much better portability.

In the experiments described here demonstrated comparable Lipostabil®the effect of Phosphogliv®when you have better tolerance Phosphogliv®.

In a prospective controlled study of six subjects women were introduced Phosphogliv®in the left shoulder and Lipostabil®in the right shoulder.

Used vials, which contained 0.5 g RRS, 0.2 g of DGL and 1.8 g of maltose in the form of a lyophilized powder, which was dissolved in 10 ml of water for injection. Depending on the size of the treated area was doing up to 60 subcutaneous injections in each arm, 0.5 ml at a distance of 1.5 cm, respectively.

Study the duration of drug action

Treatment continued for 16 weeks. Ops�adowanie was carried out for 1 day before treatment (t=-1), in the first treatment day (t=0), 8 weeks after start of treatment (t=8) and 16 weeks after the start of treatment (t=16).

The definition of effect

To identify the effect of the subjects was measured arm circumference. Arm circumference [cm] was measured using calipers (caliper) and roulette (myo-tape) before treatment and after 8 and 16 weeks.

In addition, blood was determined lipids, total cholesterol, LDL-cholesterol and HDL-cholesterol in mg/DL and atherogenic index - the ratio of EOE-cholesterol/NOAH-cholesterol.

Presentation of results

At measured values determined their changes as the difference from baseline and percentage change from baseline, mean values and standard deviations.

Table 2
The source data
DrugPLPL
The test personTime [t] Calli [cm]Cal re [cm]Myo li [cm]Myo re [cm]Total cholesterol [mg/DL]LDL-cholesterol [mg/DL]HDL-cholesterol [mg/DL]Clinical improvementNotes
No.the initi.
6I. B.-13,13,135,035,0269,0169,053,8
I. B.03,13,135,035,0
I. B.82,62,732,5 33,0159,0To 112.058,9DeI/DelPProbable acceptance of ezetrol
I. B.162,52,532,032,0172,0127,058,3DeI/DelP
2Ch.K.-12,92,9Of 30.5Of 30.5237,0136,075,4
Ch.K.02,92,9Of 30.5Of 30.5
Ch.K.82,22,2 28,229,0222,0129,078,0DrI/DrIP
Ch.K.162,02,028,028,5218,0128,079,0DrI/DrIP
7S. A.-13,23,331,032,0212,0104,088,4
S. A.03,23,331,032,0
S. A.82,82,9 27,028,5214,0103,089,1DrI/DrIP
S. A.162,72,826,027,0DrI/DrIP
1G. E.-13,83,833,033,0143,053,067,0
G. E.03,83,833,033,0
G. E.83,2 3,231.8 mm31.8 mm141,051,068,0DeI/DelP
G. E.162,82,8Of 30.5Of 30.5142,049,054,0DeI/DelP
M. St.-12,93,035,036,0198,0120,262,8
M. St.02,93,035,036,0
M. St.82,6 2,733,032,5182,0110,060,3DeI/DelP
M. St.162,52,632,032,0182,0110,960,8DeI/DelP
4E. K.-12,22,328,529,0187,099,068,7
E. K.02,22,328,529,0
E. K.8 1,41,526,027,0177,092,069,3DrI/DrIP
E. K.16
Cal li=a compass, left; Cal re=improvement in efficiency improvement and efficiency =a compass, right; Myo li=roulette, left; Myo re=roulette, right; P=Phosphogliv®; L=Lipostabil®; DeI=explicit and compatibility (the doctor); DeIP=clear improvement in efficiency and compatibility (patient); DrI=strong compatibility (the doctor); DrIP=strong improvement in the effectiveness and compatibility (the patient).

The circumference of the shoulder in subjects persons differed depending on the chosen method of measurement: calipers or a tape measure. Regardless of the method in each case was a decrease in the circumference of the shoulder. There was no difference between the action Phosphogliv and Lipostabil®. Both drugs caused a decrease in the circumference of the shoulder to the same extent (see table 3-1 � 3-2).

Table 3-1
Arm circumference when measured with calipers [cm]
The test personTime after the start of drug treatment (weeks)
No.initialsPhosphogliv®(left)Lipostabil®(right)
-10816-10816
6I. B.3,13,12,62,53,13,12,72,5
2Ch.K.2,92,92,22,02,9 2,92,22,0
7S. A.3,23,22,82,73,33,32,92,8
1G. E.3,83,83,22,83,83,83,22,8
3M. St.2,92,92,62,53,03,02,72,6
4E. K.2,22,21,42,32,31,5
Average 3,023,022,472,50Of 3.07Of 3.072,532,54
STD. deviation0,520,520,620,310,490,490,600,33
N66656665

Table 3-2
Changes the circumference of the shoulder when measured with calipers in cm in the form of absolute and relative difference compared to week 0
The test personTime after the start of drug treatment (weeks)
No.initials Phosphogliv®®(left)Lipostabil®(right)
816816
cm%cm%cm%cm%
6I. B.-0,5-16,1Of -0.6-19,4-0,4A decrease of 12.9 perOf -0.6-19,4
2Ch.K.-0,7-24,1-0,9-31,0-0,7-24,1-0,9-31,0
7S. A.-0,4-12,5-0,5-15,6-0,4 -12,1-0,5-15,2
1G. E.Of -0.6-15,8Of -1.0-26,3Of -0.6-15,8Of -1.0-26,3
3M. St.-0,3-10,3-0,4And 13.8-0,3-10,0-0,4-13,3
4E. K.-0,8-36,4-0,8-34,8
AverageBe 0,55-19,21-0,68-21,22-0,53-18,29-0,68-21,04
STD. deviation0,199,630,26To 7.280,209,470,267,49
N66556655

Table 3-2 shows that when measuring calipers drugs Lipostabil®and Phosphogliv®8 weeks caused reduction of the circumference of the shoulder 19,21% 18,29%. After 16 weeks, the arm circumference was reduced by 21,22% 21,04% when measured with calipers. Consequently, both of the drug Phosphogliv®and Lipostabil®has equal efficiency.

33,0
Table 4-1
Arm circumference when measured with a tape measure [cm]
The test personTime after the start of drug treatment (weeks)
No.initials Phosphogliv®(left)Lipostabil®(right)
-10816-10816
6I. B.35,035,032,532,035,035,033,032,0
2Ch.K.Of 30.5Of 30.528,228,0Of 30.5Of 30.529,028,5
7S. A.31,031,027,026,032,032,028,527,0
1G. E.33,031.8 mmOf 30.533,033,031.8 mmOf 30.5
3M. St.35,035,033,032,036,036,032,532,0
4E. K.28,528,526,029,029,027,0
Average32,1732,1729,7529,7032,5832,5830,3030,00
STD. deviation2,622,62Of 3.042,642,652,6 2,462,21
N66656665

Table 4-2
Changes the circumference of the shoulder with the tape measure in cm in the form of absolute and relative difference compared to week 0
The test personTime after the start of drug treatment (weeks)
No.initialsPhosphogliv®(left)Lipostabil®(right)
816816
cm%cm%cm %cm%
6I. B.Of -2.5-7,1-3,0-8,6Of -2.0-5,7-3,0-8,6
2Ch.K.-2,3-7,5Of -2.5-8,2Of -1.5-4,9Of -2.0-6,6
7S. A.-4,0A decrease of 12.9 per-5,0-16,1Is -3.5-10,9-5,0-15,6
1G. E.-1,2-3,6Of -2.5-7,6-1,2-3,6Of -2.5-7,6
3Of -2.0-5,7-3,0-8,6Is -3.5-9,7-4,0-11,1
4E. K.Of -2.5-8,8Of -2.0Down 6.9
Average-2,42-7,62-3,20-9,81-2,28-6,97-3,30-9,89
STD. deviation0,923,131,043,560,992,841,203,63
N6655 6655

From table 4-2 it is evident that drugs Lipostabil and Phosphogliv 8 weeks caused reduction of the circumference of the shoulder 7,62% 6,97% when measured with a tape measure. After 16 weeks arm circumference decreased by 9.81% and of 9.89 percent when measured with a tape measure. Consequently, both of the drug Phosphogliv®and Lipostabil®has equal efficiency.

Despite the fact that two methods - the calipers and tape measure - a decrease under the influence of drugs, the effectiveness of drugs Lipostabil®and Phosphogliv®the same.

Example 10. Evaluation of side effects when using Lipostabil®and Phosphogliv®

For this was the treatment of the subjects of women, as described in example 9, and determine the effectiveness. In order to document side effects, took pictures of the shoulder in subjects of women before and after treatment Phosphogliv®and Lipostabil®(Fig.10 and 11).

After 3 minutes has been a marked redness and swelling of the right at the shoulder of the test No. 1, which received Lipostabil®. By comparison, on the left shoulder which was treated Phosphogliv®noted only slight redness and swelling. This observation confirms the results of the experiments with phosphatidylcholine in vitro, which has corrupted�posing membrane effects on the cells (example 5, Fig.4a-c). The shots in test No. 02 in Fig.11 appear similar differences between the left (Phosphogliv®) and right (Lipostabil®) shoulder.

Figure 10. Photographs after treatment of the left (Phosphogliv®) and right (Lipostabil®) of the shoulder in test No. 01. Photoes were taken 3 minutes after the introduction of drugs Lipostabil®and Phosphogliv®.

Figure 11. Photographs after treatment of the left (Phosphogliv®) and right (Lipostabil®) of the shoulder in test No. 02. Photoes were taken 3 minutes after the introduction of drugs Lipostabil®and Phosphogliv®.

In addition, in table 5 below summarizes the side effects.

Table 5
Side effects when using Phosphogliv and Lipostabil
Tested well. facet=0t=8t=16
PLPLPL
No. 1only kratkofil. pain, pectine swelling therefore, swelling and pain almost 3 daysalmost no painswelling, redness up to 4 days
No. 2less strong swelling and rednessstronger redness and swellingalmost no painthe pain in tech. 1 week
No. 3absolutely nothingburning and itching 5 min, mild pain 2 weeksnonsense, there is no pain quiteslight pain during the first 2 weeksUNEX. reactions or complaints, lessUNEX. reactions or complaints, more
No. 4pain in the area of injections only 3 minutes, the swelling and Pokrass. in tech. 3 days, after that, no pain and swellingmore severe pain, swelling in the first 3 days is almost the same as when Phosphogliv, swelling and Pokrass. 12 days. The sensitivity remained almost all 8 weeks
No. 6almost no paincomplaints noPokrass. and swelling almost 3 days
No. 7almost no painpain and swelling on both shoulders easily transferred
P=Phosphogliv®; L=Lipostabil®

And the doctor, and the subjects face after first and second treatment in all cases equally noted clear or strong improvement - reduction of fat accumulation in the shoulders with both drugs, and significantly better tolerability Phosphogliv. In all cases, the skin elasticity was good after treatment.

From the data in table 5 shows that the complaints of the subjects after treatment with Lipostabil®include swelling, redness and pain at the injection sites. Such side effects rarely occur or not occur in the processing of Phosphogliv®. Thus, Phosphogliv®much better tolerated by the subjects than the drug Lipostabil®. As stated above, better portability due to a reduction or absence of cell damage. As shown in PR�least 5, phosphatidylcholine does not damage the cell membrane, whereas Lipostabil®damages the cells.

Example 11. Determination of cholesterol before and after subcutaneous lipolysis

For this tracked lipids in the blood of subjects over the course of treatment. Determined total cholesterol, LDL-cholesterol (low density lipoprotein) and HDL-cholesterol (high density lipoprotein). Table 6 shows the values at time moments t=-1, t=8 weeks t=16 weeks.

On average, blood lipids during treatment were changed in the same direction. Only two subjects persons (I. B. and Ch.K.) with a greatly increased total cholesterol and LDL-cholesterol, these values decreased, whereas HDL-cholesterol increased (table 6). Summary in this study are presented in table 7.

Other biochemical parameters: AST, ALT, γ-GT, bilirubin, creatinine and glucose remained within normal limits, except for a small increase in the level of γ-GT in the test person S. A. before processing.

Table 6
Cholesterol [mg/DL]
The test personTime after the start of treatment (weeks)
No.initialsTotal cholesterolLDL-cholesterolHDL-cholesterol
-1816-1816-1816
6I. B.269,0159,0172,0169,0To 112.0127,053,858,958,3
2Ch.K.237,0222,0218,0136,0129,0128,075,478,079,0
7 S. A.212,0214,0104,0103,088,489,1
1G. E.143,0141,0142,053,051,049,067,068,054,0
3M. St.198,0182,0182,0120,2110,0110,962,860,360,8
4E. K.187,0177,099,092,068,7 69,3
Average207,67182,50178,50113,5399,50103,7369,3570,6063,03
STD. deviation43,2331,1731,3438,9726,6737,3211,75Is 11.3911,01
N664664664
LDL/HDL-cholesterol:1 weekOf 1.64
(the value is<3) 8 weeks1,41
16 weeksThe 1.65
LDL-cholesterol=cholesterol low density lipoprotein
HDL-cholesterol=cholesterol high density lipoprotein

36,0
Table 7
Summary of the results of the study for subjects
The test personTimeClinical improvementNotes
leftrightleftright
No.the initi.PhosphoglivLipostabilPhosphoglivLipostabil
6I. B.selection3,13,135,035,0*Probable acceptance of ezetrol
03,13,135,035,0
82,62,732,533,0DeI/DeIPtotal cholesterol with 269,0 mg/DL to 159,0 mg/DL LDL-cholesterol with 169,0 mg/DL up to 112.0 mg/DL HDL-cholesterol from 53.8 mg/DL to 58.9 mg/DL
162,52,532,032,0DeI/DeIPtotal cholesterol with 159,0 mg/DL to 172,0 mg/DL LDL-cholesterol with to 112.0 mg/DL to 127,0 mg/DL HDL-cholesterol 58.9 mg/DL to 58.3 mg/DL; left - no complaints, right pain for about 3 days; skin elasticity improve. from average to very good
2Ch.K. selection2,92,9Of 30.5Of 30.5
02,92,9Of 30.5Of 30.5
82,22,228,229,0DrI/DrIPtotal cholesterol with 237,0 mg/DL to 222,0 mg/DL LDL-cholesterol 136.0 mg/DL to 129,0 mg/DL HDL-cholesterol with 75,4 mg/DL to 78,0 mg/DL
162,02,028,028,5DrI/DrIPtotal cholesterol with 222,0 mg/DL to 218,0 mg/DL LDL-cholesterol with 129,0 mg/DL to 128,0 mg/DL HDL-cholesterol with 78,0 mg/DL to 79.0 mg/DL; left - almost no pain, right is about 1 week.; the skin elasticity is good from the start
3M. St.selection2,93,035,0
02,93,035,036,0
82,62,733,032,5DeI/DeIPtotal cholesterol with 198,0 mg/DL to 182,0 mg/DL LDL-cholesterol with is 120.2 mg/DL to 110.0 mg/DL HDL-cholesterol from 62.8 mg/DL to 60.3 mg/DL
162,52,632,032,0DeI/DeIPtotal cholesterol with 182,0 mg/DL to 182,0 mg/DL LDL-cholesterol with 110,0 mg/DL before 110,9 mg/DL HDL-cholesterol with 60.3 mg/DL to 60.8 mg/DL; improve skin elasticity. from average to very good
4E. K.selection2,22,328,529,0
02,2 2,328,529,0
81,41,526,027,0DrI/DrIPtotal cholesterol with 187,0 mg/DL to 177,0 mg/DL LDL-cholesterol with 99,0 mg/DL to 92,0 mg/DL HDL-cholesterol with 68.7 mg/DL to 69.3 mg/DL; the skin elasticity is good from the start
7S. A.selection3,23,331,032,0
03,23,331,032,0
82,82,927,028,5DrI/DrIPtotal cholesterol with 212,0 mg/DL to 214,0 mg/DL LDL-cholesterol with 104,0 mg/DL to 103,0 mg/DL HDL-cholesterol with to 88.4 mg/DL to 89.1 mg/DL
162,72,826,027,0DrI/DrIPthe level of γ-GT is normalized the skin elasticity is good from the start
1G. E.selection3,83,833,033,0
03,83,833,033,0
83,23,231.8 mm31.8 mmtotal cholesterol with 143,0 mg/DL to 141,0 mg/DL LDL-cholesterol with 53,0 mg/DL up to 51,0 mg/DL HDL-cholesterol with 67,0 mg/DL to 68.0 mg/DL
162,82,8Of 30.5Of 30.5total cholesterol with 141,0 mg/DL to 142,0 mg/DL LDL-cholesterol � of 51.0 mg/DL 49.0 mg/DL HDL-cholesterol with 68,0 mg/DL to 54.0 mg/DL; the skin elasticity is good from the start
Del=clear improvement in efficiency and compatibility (the doctor); DeIP=clear improvement in efficiency and compatibility (patient); DrI=strong improvement in the effectiveness and compatibility (the doctor); DrIP=strong improvement in the effectiveness and compatibility (the patient).

1. The use of a composition comprising:
a) at least one phospholipid;
(b) at least one glycyrrhizic acid or
c) the salt of glycyrrhizic acid; and
in which:
- the total content of phospholipids and glycyrrhizic acid or its salts is 2-80 wt.% and
- the ratio between phospholipids and glycyrrhizic acid or its salts by weight is from 30:1 to 0.5:1,
for the manufacture of a medicine for removing subcutaneous accumulations of fat.

2. The use according to claim 1, wherein the composition further comprises excipients.

3. The use according to claim 1, wherein in the phospholipid composition comprises a phosphatidylcholine.

4. The use according to claims.1-3, wherein the composition comprises a phosphatidylcholine of animal or vegetable origin.

5. The use according to claim 1-3, wherein the composition contains glycyrrhizinic acid or a potassium, sodium, ammonium or magnesium salt of glycyrrhizic acid.

6. Approx�kit according to claims.1-3, where as excipients, the composition comprises a sugar, in particular glucose or maltose and/or their derivatives, mannitol, sorbitol or lactose.

7. The use according to claims.1-3, wherein the composition comprises a phosphatidylcholine in a total amount of from 15 to 98 wt.%, preferably from 30 to 98 wt.%, more preferably from 50 to 98 wt.%, particularly preferably from 75 to 98 wt.% and most preferably 75 to 90 wt.% the total content of phospholipids.

8. The use according to claims.1-3, wherein the composition is in dry form is dissolved in a suitable solvent.

9. The use according to claims.1-3, wherein the composition is used in dry form, preferably in the form of a lyophilizate obtained by freeze-drying.

10. The use according to claims.1-3, wherein the composition is used in the form of a solution.

11. The use according to claims.1-3, wherein the composition comprises a physiologically suitable solvents, including water, saline, glucose solution, such Monohydric alcohols, such as ethanol, 2-propanol, n-propanol, polyhydric alcohols such as glycerol and/or PROPANEDIOL, polyglycols such as polyethylene glycol and/or Miglyol, glycerol, formal, dimethylisoxazol, natural and synthetic oils and/or esters.

12. Use of the composition according to claims.1-3 for the manufacture of drugs for the treatment of subcutaneous accumulations of fat�, diseases of the subcutaneous adipose tissue, in particular related to violation of local distribution of fat.

13. Use of the composition according to claims.1-3 for the manufacture of drugs for the decomposition and reduction of tumors of adipose tissue.

14. Use of the composition according to claims.1-3 for the manufacture of medicines, characterized in that it has the form of a cream, ointment, gel, hydrogel, lotion, paste, powder or solution.

15. Use of the composition according to claims.1-3, in which unwanted disorders of fat distribution that have an aesthetic nature or pathological nature, are fat edema, lipoma, lipomatosis belly, cellulite (cellulite, the subcutaneous tissue deformation), pseudogynecomastia, Buffalo humps in HIV-patients, panniculitis (cellulitis, purulent inflammation of subcutaneous tissue) or non-specific fat deposits under the skin.

16. The use according to any one of claims.1-3, in which the drug is carried out by subcutaneous, intraperitoneal, intramuscular or intravenous injection.

17. The use according to any one of claims.1-3, in which for the introduction of a method selected from the group consisting of iontophoresis, electroporation and phonophoresis.



 

Same patents:

FIELD: medicine.

SUBSTANCE: what is presented is using meso-tetra(3-pyridyl)bacteriochlorin of structural formula (I) as a near-infrared photosensitiser for a photodynamic therapy. Doses 1.0-2.5 mg/kg of the declared photosensitiser have provided 70-100% tumour growth inhibition, 80-131% increase in life expectancy and 25-100% animals' recovery by selective tumour collection and fast clearance.

EFFECT: high photoinduced activity on human tumour cells of various epithelial origin and high dose-dependent anti-tumour effectiveness in the animal with tumours of various origins.

5 dwg, 8 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: presented invention refers to immunology. There are disclosed versions of a dimer compound for forming a multimer capable to reproduce the effector function of aggregated IgG with identical monomers. Each monomer of the dimer comprises: a monomer of IgG2 link region or a monomer of isoleucine zipper, dimerising each of which forms a multimerising region, and at least Fc-domain monomer containing a link region, CH2 domain and CH3 domain of IgG1. What is described is a multimer compound capable to reproduce the effector function of aggregated IgG and containing two or more dimers. There are disclosed a method for changing the immune response using the dimer or multimer, as well as a multimer-based method of treating an inflammatory disease.

EFFECT: using the invention provides the new compounds capable to bind at least one FcR specified in a group consisting of: FcγRI, FcγRII, FcγRIII, FcγRIV, or their non-human version that can find application in medicine for IVIG substitution for treating a wide range of diseases, including the inflammatory and autoimmune diseases.

7 cl, 25 dwg, 5 tbl, 25 ex

FIELD: veterinary medicine.

SUBSTANCE: product comprises Lycopodium clavatum, Acidum arsenicosum, Phosphorus, Podophyllum peltatum, Thuja occidentalis, Echinacea purpurea, Silybum marianum, Selenocysteine, and the components are taken in the dilutions described below in the following ratio, in parts: Lycopodium clavatum ⌀=D1 0.004, Podophyllum peltatum ⌀ 0.003, Acidum arsenicosum ⌀=D2 0.0001, Phosphorus ⌀=D3 0.001, Thuja occidentalis ⌀ 30, Echinacea purpurea ⌀ 30, Silybum marianum ⌀ 60, Selenocysteine 0.2.

EFFECT: product has an effective stress-protective and growth-stimulating effect, it regulates the metabolism in young farm animals.

3 cl, 10 tbl, 1 ex

FIELD: medicine.

SUBSTANCE: method for producing an agent for stimulating body cells involving preparing a mixture of aqueous solution of selenious acid and PEG 400; that is followed by preparing a mixture of hydrazine hydrochloride and PEG 400; the prepared mixtures are combined; the solution is put to dialyse against distilled water; surplus of water is driven off; the produced solution is added with hexamethylene tetramine; pH is reduced to 7.2-7.4; the method is implemented in certain circumstances.

EFFECT: producing high-effective, ecologically safe agent by the synergism of colloidal selenium and hexamethylene tetramine on body cell stimulation.

1 dwg, 2 tbl, 4 ex

FIELD: medicine.

SUBSTANCE: invention relates to medicine and can be used for the treatment of radiation-thermal injury of an organism. For this purpose a single subcutaneous introduction of bifidumbacterin, irradiated by gamma-rays in a dose of 14.0 Gy, is carried out. Bifidumbacterin is introduced in a dose of 1.43·106 CFU/kg. After that, 10% hypericum oil is applied on the burnt region. Then a 10% hypericum cream is applied after 3-4 days.

EFFECT: method makes it possible to carry out the treatment of combined radiation-thermal injuries in an effective way with the application of available and cheap pharmacotherapeutic means.

1 tbl, 4 ex

FIELD: medicine.

SUBSTANCE: erythrocyte cell medium is added with an aqueous solution of sodium and potassium salts of humic acids prepared on brown coal of leonardite in a dose of 10.0 mg/kg. That is incubated at a temperature of 37°C for 40 minutes before treatment with acidic haemolytic.

EFFECT: invention enables normalising the cell membrane permeability and reducing the damaged cell count under acidic haemolytic.

1 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a new intensifier of the antitumour effect, which is a uracil derivative of the general formula (I) or its pharmaceutically acceptable salt. In the general formula (I) X represents a C1-5-alkylene group, and wherein one of methylene groups making an alkylene group is optionally substituted by an oxygen atom; R1 represents a hydrogen atom or a C1-6-alkyl group; R2 represents a hydrogen atom or a halogen atom; and R3 represents a C1-6-alkyl group, C2-6-alkenyl group, C3-6-cycloalkyl group, (C3-6-cycloalkyl)-C1-6-alkyl group, halogen-C1-6-alkyl group or a 5-6-merous saturated heterocyclic group with an oxygen atom as a heteroatom, a uracil derivative presented by the following formula (I). The invention also refers to a method for potentiating the antitumour action or a method of treating tumours, involving administering an effective amount of a combination of the above uracil derivative or its pharmaceutically acceptable salt and an antimetabolite in an effective amount. The antimetabolite represents an agent specified in 5-fluoruracil (5-FU), potassium tegafur/gimeracil/oteracil (TS-1), tegafur/uracil (UFT), capecitabin, 5-fluor-2'-deoxyuridine (FdUrd) and Pemetrexed.

EFFECT: preparing the intensifier of the antitumour effect.

18 cl, 10 dwg, 10 tbl, 67 ex

FIELD: medicine.

SUBSTANCE: invention relates to medicine, namely to methods of purification and health improvement of an organism. For this purpose therapeutic starvation for not fewer than 5 days in case of a 7-day programme and for not fewer than 7 days in case of a 9-day programme is carried out. The duration of a recovery period constitutes two days. Food intake is realised nine times per day each day both in the process of therapeutic starvation and in the recovery period. In the period of therapeutic starvation the first food intake includes bee products "APIGRANULES 2" in a dose of one teaspoon, "KHINAZI balm" in a dose of one teaspoon, "A-P-V" in a dose of one teaspoon, "APITOK" in a dose of one teaspoon, "Antihelm phyto" - one capsule and still mineral water - one glass. The second food intake includes a drink with ginger, lemon juice, garlic and mint, honey - one teaspoon and one glass of apple-carrot juice. The third food intake supposes an intake of bee products "APIGRANULES 2" in a dose of one teaspoon, "KHINAZI balm" in a dose of one teaspoon, "A-P-V" in a dose of one teaspoon, "Antihelm phyto" - one capsule and still mineral water - one glass. The fourth food intake includes a drink with ginger, lemon juice, garlic and mint, honey - one teaspoon and one glass of apple-carrot juice. The fifth food intake consists of tea black or green with ginger, one teaspoon of honey and one glass of apple-carrot juice. The sixth food intake consists of bee products "APIGRANULES 2" in a dose of one teaspoon, "A-P-V" in a dose of one teaspoon, "Antihelm phyto" - one capsule and one glass of still mineral water. The seventh food intake includes tea black or green with ginger, one teaspoon of honey and one glass of apple-carrot juice. The eighth food intake supposes an intake of tea black or green with ginger, one teaspoon of honey and one glass of apple-carrot juice. The ninth intake of food includes depressant tea, including mint grass, valerian root, fennel seeds, cumin seeds, epilobium or strawberry leaves and one glass of apple-carrot juice. In the recovery period in 1-st, 2-nd, 3-rd, 4-th and 6-th intakes of food the composition of products remains the same as in the process of starvation. For the fifth intake of food the patients take tea black or green with ginger, one teaspoon of honey and vegetable soup. For the seventh intake of food the patients take tea black or green with ginger, "MILK COCKTAIL WITH CHITOSAN". The eighth intake of food includes tea black or green with ginger, one teaspoon of honey, "APICAMPA" cereal. The ninth intake of food for the recovery period includes a baked apple, depressant tea. In addition, a number of procedures are carried out after each food intake during the period of therapeutic starvation and the recovery period. After the first food intake gymnastics "5 Tibetan pearls" is realised. After the second food intake exercises on training apparatuses, procedures of press-therapy, electrolypolysis and myostimulation are realised. After the third food intake exercises of therapeutic physical training or aerobics are performed. After the fourth food intake a rest in form of a walk, a halotherapy session, combined with a session of relaxation therapy are realised. After the fifth food intake a course of strip-plastic is carried out. After the sixth food intake massage by manual application with a peloid-based mixture or manual massage with honey is carried out. After the seventh food intake an infra-red sauna, shower, phytobath with medicinal herbs, honey, ginger, lemon juice is taken. After the eighth food intake a shower is taken.

EFFECT: method ensures effective health improvement of the organism with the preservation of the full value life style and a sense of a comfortable state in the starvation period, reduction of recovery period term after starvation, purification of the organism without loading on the gastrointestinal tract, weight loss, and improvement of the general state and workability of the patients.

3 tbl, 7 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to biotechnology, specifically to a fused protein containing a variant of rodostomin, and can be used in medicine. An ανβ3 integrin selective polypeptide consisting of an amino acid sequence SEQ ID NO:1 conjugated on the N terminal by a linker amino acid sequence containing a combination of the amino acids glycine and serine with a variant of a human serum albumin (HSA) with SEQ ID NO:4.

EFFECT: invention enables the higher therapeutic effectiveness in the diseases related to ανβ3 integrin.

12 cl, 14 dwg, 2 tbl, 7 ex

FIELD: medicine.

SUBSTANCE: invention refers to medicine and can be used for the correction of the individual's functional state and performance. That is ensured by administering Semax neuroactive peptide in a dose of two drops in each nasal passage. That is followed by the electric current exposure covering a frontal-mastoid region at pulse length 0.2ms, current intensity 0.8mA and pulse train 800Hz for 40 min. The exposure is combined with at least 10 sessions of hyperbaric oxygenation at pressure 1.6 atm.

EFFECT: method provides the rapid and effective increase of performance in sportsmen, military men and individuals involved in the other professions related to significant physical and mental stress by improving the functions of various regions of brain cortex as a result of the selected complex exposure enabling the substantial vasodilatation and maximum tissue oxygenation.

1 tbl

FIELD: medicine.

SUBSTANCE: what is presented is a group of inventions; it involves a method for activating the health recovery of an involved respiratory epithelial cell an injury of which is related to cough, post-viral or -bacterial infection, acute/chronic bronchitis or chronic obstructive pulmonary disease (COPD) by administering a compound of formula and/or formula , a composition for the same application on the basis of the above compound, a respective method of treating an inflammatory respiratory condition, a pharmaceutical composition for treating the inflammatory respiratory condition, and using the compound of formula (1) and/or formula (2) for preparing the therapeutic agent for treating cough, post-viral or -bacterial, acute/chronic bronchitis or COPD.

EFFECT: health recovery of the respiratory cell for 48 hours as shown by sialylated glycoconjugates on its surface after treatment with influenza virus or bacterium neuraminidase, as well as reducing a rate of cough in guinea pigs sensitised with citric acid solution.

10 cl, 37 ex

FIELD: chemistry.

SUBSTANCE: claimed invention relates to novel crystals of type I of 1-(2'-cyano-2'-desoxy-β-D-arabinofuranosyl)cytosine monohydrochloride, which have characteristic peaks at 13.7°, 15.7°, 16.0°, 18.6°, 20.3° and 22.7° in form of diffraction angles (2θ±0.1°), measured in powder X-ray crystallography, and melting temperature 192-197°C, as well as to novel crystals of type II of 1-(2'-cyano-2'-desoxy-β-D-arabinofuranosyl)cytosine monohydrochloride, which have characteristic peaks at 6.4°; 12.6°; 17.3° and 21.7° in form of diffraction angles (2θ±0.1°), measured in powder X-ray crystallography, and melting temperature 192-196°C, possessing anti-tumour properties.

EFFECT: invention relates to anti-tumour medication, containing claimed crystals, and to methods of obtaining crystals of type I and crystals of type II of 1-(2'-cyano-2'-desoxy-β-D-arabinofuranosyl)cytosine monohydrochloride.

7 cl, 3 dwg, 1 tbl, 5 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new compounds of general formula 1 or their stereoisomers or pharmaceutically acceptable salts possessing the properties of inhibitors of RNA polymerase HCV NS5B, and to methods for producing them. In general formula 1 R1 represents C1-C4alkyl; R2 and R3 represents fluorine, or R2 represents fluorine, while R3 represents methyl; one of R4 and R5 represents hydrogen, and the other of R4 and R5 represents C1-C6acyl optionally substituted by α-aminoacyl specified in a group containing (dimethylamino)acetyl, 1-tert-butoxycarbonylamino-2-methyl-propylcarbonyl, 1-methylpyrrolidine-2-carbonyl, 1-methylpiperidine-3-carbonyl and 1-methylpiperidine-4-carbonyl, R6 represents hydrogen, methyl, methoxy and halogen.

EFFECT: compounds can be used for treating and preventing viral infections, including hepatitis C, optionally with additional agents specified in an inhibitor of inosin-5-monophosphate dehydrogenase, eg Ribamidine, an inhibitor of hepatitis C protease C NS3, eg Asunaprevir (BMS-650032), an inhibitor of hepatitis C protease C NS3/4A, eg Sofosbuvir (TMC435), an inhibitor of RNA-polymerase NS5A, eg Daclatasvir (BMS-790052) or Ledipasvir (GS-5885).

18 cl, 1 tbl, 14 ex

FIELD: medicine.

SUBSTANCE: hydrophilic therapeutic agent is specified in a group consisting of albuterol, bendamustine, captopril, carboplatin, ciprofloxacin, gemcitabine, ibandronate, lamivudine, metformin, niacin, oxycodone, ranitidine and sumatriptan. The composition also contains a solvent, a surfactant and a hydrophilic carrier. The above hydrophilic carrier is compatible to the therapeutic agent solution and the surfactant.

EFFECT: good stability and bioavailability compatible to that of injection formulations when administered orally.

21 cl, 2 dwg, 13 tbl, 4 ex

FIELD: medicine.

SUBSTANCE: effective amount of a chemotherapeutic agent and anti-VEGF antibodies (bevacizumab), wherein the agent represents either (a) capecitabine, (b) docetaxel or Abraxane, (c) or antracycline, and wherein the anti-VEGF antibody is administered at 15 mg/kg. No other chemotherapeutic agent has been administered into the individual for treating local recurrent or metastatic breast cancer, and/or the above individual has not undergone adjuvant pre-chemotherapy accompanying a recurrence for 12 months or less after the last dose administered. There are also presented the anti-VEGF antibody, using the anti-VEGF antibody and kits containing the anti-VEGF antibody in a combination with the chemotherapeutic agent for treating metastatic breast cancer.

EFFECT: prolonged individual's lifespan with no disease progression.

40 cl, 6 dwg, 5 tbl, 1 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: group of inventions refers to a pharmaceutical composition for treating diseases including cell proliferation, using it, and a kit containing the combined administration of a compound 1_ of formula wherein groups L, R1, R2, R3, R4 and R5 have the values presented in the patent claim and description, optionally in the form of tautomers, racemates, enanthiomers, diastereomers, and mixtures thereof, and optionally in the form of its pharmacologically acceptable acid addition salts, solvates, hydrates, polymorphic forms, physiologically functional derivatives or prodrugs, and an effective amount of an active compound 2_ and/or the integrated treatment with radiation therapy, in ratio to provide an additive and synergetic effect.

EFFECT: preparing the pharmaceutical composition for treating diseases including cell proliferation.

5 cl, 8 dwg, 2 tbl, 24 ex

FIELD: medicine.

SUBSTANCE: preparation citicoline is administered for the purpose of preventing cerebral ischemia in precerebral vasculoplasty prior to and after a carotid occlusion. Prior to the occlusion, citicoline is administered in a dose of 2000 mg in 0.9% sodium chloride 400 ml for a period of time sufficient for approaching the operated vessels, and terminated 5-7 minutes prior to the occlusion. After the occlusion, citicoline is administered starting from the second postoperative day for 5-8 days daily once a day, in a dose of 1000 mg in 0.9% sodium chloride 200 ml.

EFFECT: more effective prevention of cerebral ischemia in precerebral vasculoplasty by the empirically selected regimen of the staged administration of citicoline.

4 ex

FIELD: biotechnologies.

SUBSTANCE: invention refers to a method for obtaining a compound of formula 682, which is in a crystalline form, where the above method involves the following: (i) treatment of the compound of formula 682-9 with palmitic anhydride mixed with H2O/dioxane so that the compound of formula 682 is formed; (ii) treatment of the product obtained at stage (i) with methanol so that the compound of formula 682 is obtained in the form of solvate with methanol (Form K); (iii) extraction of the compound of formula 682, which has been obtained at stage (ii) in the form of solvate with methanol (Form K); (iv) optional cleaning of the product of stage (iii) by recrystallisation. Besides, the invention proposes a method for obtaining the compound of formula 682-4, where the above method involves the following: (i) conversion of the compound of formula 682-1 to the compound of formula 682-2' by treatment of the above compound of formula 682-1 with 1,3-dichloro-1,1,4,4-tetraisopropyldisiloxane (CIPS) in pyridine; (ii) conversion of the above compound of formula 682-2' to the compound of formula 682-3 by treatment of the above compound of formula 682-2' with acetic anhydride to EtOH; and (iii) conversion of the above compound of formula 682-3 to the compound of formula 682-4 by treatment of the above compound of formula 682-3 with an oxidiser, preferably with free radical 2,2,6,6-tetramethylpiperidinyloxy (TEMPO) and NaOCl. Further aspects of the invention refer to use of the above methods for obtaining 2'-cyano-2'-deoxy-N4-palmitoyl-1-β-D-arabinofuranosylcytosine, pyrimidine nucleoside, and are suitable for treatment and/or prevention of cancer.

EFFECT: improvement of compounds.

22 cl, 1 tbl, 1 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: group of inventions refers to medicine, more specifically to oncology and concerns using neranitib and capecitabine in a combination for treating a new growth (breast cancer); wherein neranitib is administered in the approximate amount of 240 mg a day, and capecitabine is administered in the approximate amount of 1500 mg a day. There are also presented: a pharmaceutical composition, a kit and a method of treating breast cancer which involves administering neranitib and capecitabine.

EFFECT: group of inventions provides a synergetic effect of administering neranitib in the approximate amount of 240 mg a day and capecitabine in the approximate amount of 1500 mg a day in a combination for treating new growths.

19 cl, 2 tbl, 4 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: application describes new pharmaceutical compositions of (2R,3R,4R,5R)-5-(4-amino-2-oxo-2H-pyrimidin-1-yl)-4-fluor-2-isobutylryloxymethyl-4-methyl-tetrahydrofurane-3-yl ester of isooleic acid and hydroxypropyl cellulose. The composition contains 50 to 95 wt % of the above active agent, 1 to 4 wt % of hydroxypropyl cellulose and at least one excipient in the amount up to 49 wt %.

EFFECT: compositions according to the invention provide high bulk density, low granule size, more applicable for better compactibility, flowability and improved solubility profiles.

21 cl, 8 dwg, 11 tbl, 20 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to the field of biotechnology, namely to obtaining oligopeptide compounds, containing a motive, interacting with a proliferating cell nuclear antigen (PCNA) and can be used in medicine. The oligopeptide compound consists of 14-70 amino acids and contains. a PCNA-interacting motive, representing [K/R]-[F/Y/W]-[L/I/V/A]-[L/I/V/A]-[K/R], at least one signal sequence of nuclear localisation and at least one signal sequence of penetration into a cell, with the PCNA-interacting motive being located towards an N-end relative to the signal sequence.

EFFECT: invention makes it possible to carry out the efficient treatment of hyperproliferative disorders by the application of the oligopeptide compound in cyctostatic therapy or in radiotherapy as a sensitising substance.

34 cl, 6 dwg, 4 tbl, 8 ex

Up!