Biguanide-containing medications which facilitate dissolution for peptide delivery

FIELD: medicine, pharmaceutics.

SUBSTANCE: group of inventions relates to pharmacy and medicine. Pharmaceutical composition includes mixture of: (a) active macromolecular substance; (b) aromatic alcohol, absoption amplifier, selected from propylgallate, butylated hydroxytotuol (BHT), butylated hydroxyanisole (BHA) and their analogues and derivatives, or their mixtures; and (c) biguanide or its pharmaceutically acceptable salt, capable of increasing solubility of aromatic alcohol, absorption amplifier, in water medium, where aromatic alcohol, absorption amplifier, is present in amount (by weight) greater or equal to amount of active substance. Application in pharmaceutical composition of aromatic alcohol, selected from propylgallate, BHT, BHA and their analogues and derivatives, together with biguanide or its pharmaceutically acceptable salt, capable of increasing solubility of aromatic alcohol in water medium, as amplifier of macromolecule absorption through intestine wall. Method of increasing absorption of active macromolecular substance and method of patient treatment include introduction of claimed composition to patient. Application of active macromolecular substance, selected from insulin, C-peptide, GLP-1 or their mixture; aromatic alcohol, absorption amplifier, selected from propylgallate, butylated hydroxytotuol (BHT), butylated hydroxyanisole (BHA) and their analogues and derivatives, or their mixtures; and biguanide or its pharmaceutically acceptable salt, capable of increasing solubility of aromatic alcohol, absorption amplifier, in water medium, in manufacturing medications for treatment of diabetes, osteoporosis, obesity, cancer, osteoarthritis.

EFFECT: group of inventions ensures facilitation of passage of peptides, proteins and other macromolecular substances through intestinal wall for improvements of their bioavailability.

27 cl, 3 tbl, 11 ex

 

This invention relates to the use of some aromatic alcohols as amplifiers of absorption to facilitate the passage of peptides, proteins and other macromolecules across the intestinal wall and, in particular, to the use of new agents to ensure dissolution of these aromatic alcohols in order to improve the accessibility of such agents in biological fluids, which under normal conditions they are extremely poorly soluble.

Previously, in WO 2004/091584 described that aromatic alcohols, such as propylgallate, bottled hydroxyanisol and bottled hydroxytrol can act as enhancers of absorption of peptides and proteins through the mucosal surface, for example, intestines, and the effect of these agents becomes maximum when the manufacturer in combination with other agents that enhance their dissolution in aqueous media. Examples of such agents that promote dissolution, are cited previously bile salts, such as deoxycholate sodium and chenodeoxycholic sodium.

On the basis of information from prior art specialist in the field of technology will come to the conclusion that in order to achieve satisfactory results, a means of facilitating the dissolution, must possess surface activity, preferably, micelles is education, what have bile salts, and, in fact, one of the biological functions of bile salts in vivo is to ensure dissolution of dietary components, especially lipids in the intestine.

Now unexpectedly discovered that a new and unrelated class of small molecules (molecules with low molecular weight) can also act as a means of facilitating dissolution for poorly soluble aromatic alcohols, despite the fact that these molecules do not exhibit surface-active properties and have little tendency to the formation of micelles. This class of small molecules include substituted biguanides, typical examples of which include Metformin and phenformin.

It turns out that the action of biguanides as a means of promoting the dissolution is specific for aromatic alcohols and does not apply to other classes of molecules, such as cholesterol or fatty acids, for which bile salts are well known as solubilizing agents. Therefore, we can conclude that there is no information about the salts of bile acids, either structural or functional point of view that will lead specialist in the field of engineering to the assumption that the biguanides also have such properties that promote dissolution.

<> Biguanides can produce technologically with poorly soluble aromatic alcohols as excipients with obtaining input through the mucous membrane of pharmaceutical preparations containing one or more active molecular substances, the passage of which through the mucosal barrier increases as a result of the introduction in combination with a mixture of biguanid/ aromatic alcohol.

The invention provides a pharmaceutical composition, comprising a mixture of:

(a) an active macromolecular substances; and

(b) an aromatic alcohol, an amplifier absorption selected from propylgallate, bottled hydroxytoluene, bottled hydroxyanisole and their analogues and derivatives, and

(C) biguanide capable of increasing the solubility of the aromatic alcohol, amplifier absorption in aqueous environments

in which the aromatic alcohol, power absorption is present in quantity (by weight)of greater than or equal to the number of active macromolecular substances.

The invention also provides the use of pharmaceutical compositions of an aromatic alcohol selected from propylgallate, bottled hydroxytoluene, bottled hydroxyanisole and their analogues and derivatives, together with biguanide or its pharmaceutically acceptable salt, capable of increasing R is stoimosti aromatic alcohol in an aqueous medium, as the amplifier absorption of macromolecules in the body.

In the following embodiment, the invention provides the use of an aromatic alcohol selected from propylgallate, bottled hydroxytoluene, bottled hydroxyanisole and their analogues and derivatives, together with biguanide or its pharmaceutically acceptable salt, capable of increasing the solubility of the aromatic alcohol in the aquatic environment for the manufacture of the drug containing the active macromolecular substance, in order to increase the absorption of the active macromolecular substances in the human body or animal.

A common feature of groups of molecules, acting as a means of facilitating dissolution described in this invention is biguanidine the core, and molecules with a variety of substituents in biguanide core exhibit the desired activity. In order to assess the suitability of biguanide for use as a means of facilitating dissolution, you can apply the following procedure. Usually, the solution biguanide prepared in water with a concentration of 100 mg/ml, if necessary, under heating, and install the appropriate pH, if the solution does not get immediately. To 1 ml of the solution add 25 mg of propylgallate and the mixture is heated with shaking up to half an hour. If it turns transparent races is a thief, the substituted biguanide can be considered suitable for use as a means of facilitating dissolution.

For use in the present invention biguanides will respectively have the following formula

where R1, R2, R3and R4each independently selected from hydrogen, optionally substituted alkyl, optionally substituted phenyl, ethylene glycol, diethylene glycol, triethylene glycol and tetraethyleneglycol, or one of R1, R2, R3and R4can have the formula

where R5, R6and R7each independently selected from hydrogen, optionally substituted alkyl, optionally substituted phenyl, ethylene glycol, diethylene glycol, triethylene glycol and tetraethyleneglycol.

The substituents alkyl and phenyl groups include halogen, for example chlorine, bromine, fluorine or iodine, hydroxy and amino. The alkyl groups preferably have from 1 to 6 carbon atoms and can be saturated or unsaturated, with a normal chain or branched structure. Biguanide can be included in the composition according to the invention as a pharmaceutically acceptable salt.

Preferred biguanides for use in the present invention include Metformin, phenformin and chlorhexidine or pharmaceuticas is acceptable salt. Suitable pharmaceutically acceptable salts are the chloride, bromide, iodide or organic acid salts such as acetate, propionate, mesilate (methylsulfonate) or glucuronate.

Biguanide may be present in the composition in amounts of at least 50 wt.%, preferably, from 60 to 95% and, more preferably, from 80 to 90%.

Aromatic alcohol - power absorption can be propylgallate or its analogue or derivative and preferably represents propylgallate. Suitable analogs and derivatives of propylgallate include esters of Gallic acid. Esters may be esters having From1-12alkyl, C1-12alkyloxy,1-12akitio or2-12alkenyl with a normal chain or branched structure. Connections are optionally substituted with halogen, esters having From1-12alkyl, C1-12alkyloxy,1-12alkylthio or2-12alkenyl with a normal chain or branched structure. Aromatic alcohol, power absorption, you can also choose from BHT, BHA and their analogues and derivatives. Suitable analogs and derivatives of BHT or BHA include analogues and derivatives of hydroxytoluene or hydroxyanisole, where a methyl group or a methoxy group, associated with the aromatic ring, and/or the hydrogen atom in Portopalo the attachment to the hydroxyl group is replaced With 1-12the alkyl, C1-12alkyloxy,1-12alkylthio or2-12alkenyl with a normal chain or branched structure, or unsubstituted or substituted in any position, in particular by halogen atoms. Preferably, an aromatic alcohol, power absorption, selected from propylgallate, BHT and BHA.

Aromatic alcohols described above, which are used in pharmaceutical practice as antioxidants, are included in concentrations up to 0.1 wt.%/about. all of the drug (see item listings for individual compounds in Handbook of Parmaceutical Excipients, Eds Wade & Weller, The Pharmaceutical Press, London UK, 2thedition 1994). It is usually assumed that higher concentrations of the compounds do not provide additional benefits as antioxidants, and therefore there is a standard pharmaceutical practice to limit the concentration of antioxidants in the drugs to a value of not more than 0.1%. However, according to the present invention when applied as enhancers of absorption, the efficiency of such compounds depends on the concentration up to a much higher level, and their content in pharmaceutical drug significantly higher than previously described in the prior art.

For example, in WO-A-0222158 proposed compositions comprising cyclosporine (non-macromolecule) and contains BHA, BHT and PG usually as the antioxidants. Although specific antioxidant concentrations not given to the use of compounds as antioxidants assumes a level not higher than 0.1 wt.%.

The alcohol may be present in the composition in an amount of 5 to 30 wt.%, preferably, from 10 to 20%.

Active macromolecular substances included in the scope of the invention include any molecule having a useful effect when absorbed in the body of a human or animal, in particular through the intestinal wall. A useful action can be, for example, therapeutic, cosmetic or preventive, such as a prophylactic or contraceptive. Active macromolecular substances can be of natural (biological), synthetic or semi-synthetic origin.

Macromolecules, preferably represent molecules having a molecular weight above 1000 Da, preferably above 2000 Da, and most preferably above 3000 Da. Examples of macromolecules, including macromolecular active substances include:

1. Polypeptides and proteins, such as insulin; calcitonin; human serum albumin; growth hormone; factors that stimulates growth hormone; Galanin; parathyroid hormone; peptide YY; oxyntomodulin; blood coagulation proteins, such as cinogen, prothrombin, fibrinogen, factor VII, factor VIII or factor IX; erythropoetin the s and imitators EPO; colony-stimulating factors such as GCSF and GMCSF; platelet-derived growth factors; epidermal growth factor; fibroblast growth factors; transforming growth factors; GLP-1; attendin; leptin; GAG; cytokines; insulin-like growth factors; bone and cartilage inducing factors; neurotrophic factors; interleukins, including IL-1, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-11, IL-12; interferons, including interferon gamma, interferon-1A, interferon alpha; TNF-alpha; TNF-beta; TGF-beta; fragments a and b of cholera toxin, fragments a and b enterotoxin E. coli; secretin; enzymes, including the histone deacetylase, superoxide dismutase, catalase, adenosine deaminase, thymidine kinase, cytosine deaminase, protease, lipase, carbohydrase, nucleotides, polymerases, kinases and phosphatases, protein transport and binding, especially those that bind and/or transported vitamin, metal ion, amino acid or lipid or lipoprotein such as protein transfer of ester cholesterol, protein, phospholipid transfer protein binding of HDL; connective tissue proteins such as collagen, elastin or fibronectin; muscle proteins such as actin, myosin, dystrophin or minidystrophin; neuronal protein, protein liver, heart or adipocyte; cytotoxic protein; cytochrome; a protein that can cause replication, growth or differentiation of cells is to; molecule signal transmission, such as protein intracellular signal transduction or protein extracellular signal (e.g. a hormone); trophic factors such as BDNF, CNTF, NGF, IGF, GMF, aFGF, bFGF, VEGF, NT3, T3 and HARP; apolipoprotein; molecules-antibodies; soluble receptors in form, such as the receptors of T cells and receptors cytokines, interferons or chemokines; proteins or peptides containing antigenic epitopes and fragments; and derivatives, conjugates and variants of the sequence of any of the aforementioned proteins. These and other proteins can be obtained from the human body, plants, animals, bacteria and fungi as sources and either extracted from natural sources, obtained as a recombinant fermentation, or chemically synthesized.

2. Polynucleotide, such as having a long chain normal or cyclic structure of DNA with single, double or triple chain RNA with single, double or triple chain, oligonucleotides such as antisense DNA or RNA, and analogues, including RNA and phosphothioate derivatives. In one embodiment, it is preferable that polynucleotide used in the invention contain a CpG motif. The coding sequence of polynucleotide can encode a therapeutic product, in particular, the coding sequence can encode extracellular b the lock (for example, the secretory protein); intracellular protein (e.g., cytosolic, nuclear or membrane protein); protein present in the cell membrane, a blood protein, such as protein folding (e.g., cinogen, prothrombin, factor VII, factor VIII or factor IX, fibrinogen); an enzyme, such as catabolic, anabolic gastrointestinal, metabolic (e.g., glycolysis or the Krebs cycle), or the enzyme signal transmission cells, the enzyme that destroys or modifies lipids, fatty acids, glycogen, amino acids, proteins, nucleotides, polynucleotide (for example, DNA or RNA) or carbohydrate (e.g., protease, lipase or carbohydrate), or enzyme-modifying protein, such as an enzyme, which attaches or takes chemical motifs of the protein (e.g., kinase or phosphatase); protein transport or binding (e.g., one that binds and/or transports vitamin, metal ion, amino acid or lipid, such as a protein migration of ester cholesterol, protein, phospholipid transfer or binding protein (HDL); protein of connective tissue (e.g. collagen, elastin or fibronectin); muscle protein (e.g.actin, myosin, dystrophin or minidystrophin); neuronal protein, protein liver, heart or adipocyte; cytotoxic protein; cytochrome; a protein that can cause replication, growth or di is ferentinou cells; a protein that promotes the transcription or translation of the gene or regulates the transcription or translation (e.g., a transcription factor or protein which binds to a transcription factor or polymerase); molecule signal, such as a molecule intracellular or extracellular signal (e.g. a hormone); protein of the immune system, such as an antibody, receptor T cells, MHC molecule, a cytokine (such as IL-1, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, TNF-, TNF-, TGF-a), interferon (e.g., IFN-, IFN-, IFN-), chemokine (e.g., MIP-1, MIP-1, RANTES), immune receptor (e.g., the receptor for the cytokine, interferon or a chemokine, such as the receptor for any of the above cytokines, interferons or chemokines) or a cell surface marker (e.g., macrophage, T-cell, b-cell, NK-cell or token the surface of dendritic cells) (for example, CD 1, 2, 3, 4, 5, 6, 7, 8, 16, 18, 19, 28, 40 or 45; or its natural ligand), trophic factors (such as BDNF, CNTF, NGF, IGF, GMF, aFGF, bFGF, VEGF, NT3, T5, HARP) or apolipoprotein; a tumor suppressor (e.g., p53, Rb, Rap1A, DCC, or k-rev); suicidal protein (thymidine kinase or citizenguinea); or gene-repressor. Proteins and peptides encoded by polynucleotide used in the invention may be immunogenic, i.e. contain the antigen-specific activity of the protein against which the immune system generates antibodies.

Pauline is leatid may have a regulatory sequence, operable associated with the coding sequence. The regulatory sequence can usually be sequences of any eukaryotic or virus that infects these eukaryotes. Polynucleotide may include a replication source.

Polynucleotide can be chemically modified. This can enhance their resistance to nucleases or may enhance their ability to introduction into cells. For example, you can use phosphorothioate oligonucleotides. Other analogues of deoxynucleotide include methylphosphonate, phosphoramidate, phosphorodithioate, N3'P5'-phosphoramidate and oligoribonucleotide phosphorothioates and their 2'-O-alkyl analogs of 2'-O-methylribonucleotide methylphosphonate. Alternatively you can apply oligonucleotides with mixed main circuits (MBO). MBO contain segments phosphothioate oligonucleotides and respectively installed the modified segments of oligotex or oligoribonucleotides. MBO have segments phosphorothioate links and other segments of the other modified oligonucleotides, such as methylphosphonate, which is not ion and largely resistant to nucleases or 2'-O-alkylpolyglucosides.

Polynucleotide, suitable for use in the invention preferably is in the form in which it is essentially the free or associated with cells or cell, prokaryotic, eukaryotic, nuclear, chromatin, histone, or a protein substance. It can be, essentially, in an isolated form, or it can be, essentially, in purified form, in each case, typically, it will include more than 90%, for example more than or at least 95%, 98% or 99% of polynucleotide or dry matter in the product. Thus polynucleotide may be in the form of 'unprotected DNA'.

3. Polysaccharides, such as heparin, low molecular weight heparin, polymannose, cyclodextrins and lipopolysaccharide.

4. Any of the above substances either in isolation or in combination with each other (for example, in the form heteroconjugate) or with additional agents.

In preferred variants of the invention, the active macromolecular substance which is absorbed selected from calcitonin, insulin, low molecular weight heparin, erythropoietin, colony stimulating factors including granulocyte colony-stimulating factor (GCSF) and granulocyte macrophage-colony stimulating factor (GMCSF), interferon, C-peptide, like protein 1 (GLP-1), human growth hormone and parathyroid hormone and analogues and fragments.

In the compositions according to the invention an aromatic alcohol, power absorption is present in quantity (by weight)of greater than or equal share of the Wu active macromolecular substances. This provides an effective concentration of aromatic alcohol, amplifier, absorption, cellular barrier layer of the intestine (gut) such to cause increased absorption in the joint presence of a suitable amount of the active macromolecular substances, which after absorption will be normal useful effect. The amount of aromatic alcohol, amplifier, absorption, and active macromolecular substances easily (quickly) is chosen on the basis of the number (for example, the level of concentration in the blood) of interest active macromolecular substance which is necessary for therapeutic efficacy. The mass ratio of the aromatic alcohol, amplifier, absorption, active macromolecular substance in the mixture contained in the capsule, respectively, is at least 1:1, preferably at least 5:1, e.g. from 1:1 to 100:1, preferably from 3:1 to 50:1, most preferably from 5:1 to 20:1.

The ratio of biguanide to aromatic alcohol, an amplifier absorption, respectively, at least, is 2:1 (by weight), preferably from 2:1 to 10:1 and most preferably from 2:1 to 5:1.

The absolute number of active macromolecular substances can be selected on the basis dosing of substances required for the manifestation of normal is the volumetric efficiency with respect to the applicable dosage regimen and the patient. The determination of these quantities is within the scope of a specialist engaged in the practice of the invention.

In the composition for oral administration is preferred that the contents of the capsule includes a suitable amount of the active macromolecular substances to achieve its normal therapeutic action. For example, the composition may contain from 0.05 to 50%, preferably from 0.1 to 25%, more preferably from 0.1 to 10 wt.% active macromolecular substances, considering the weight of the contents of the capsules (not including the capsule).

The composition according to the invention may optionally include one or more others, enhancing the absorption of compounds such as fatty acids with medium chain length and monoglycerides with medium chain length.

The composition according to the invention may additionally include any conventional additive technology used in the manufacture of pharmaceutical products, including, for example, antioxidants, antimicrobial agents, suspendresume agents, fillers, diluents, dezintegriruetsja agents, agents for swelling, viscosity regulators, plasticizers and acidity regulators (in particular, additives, establishing the pH of the intestinal environment from 7 to 7.5), and protease inhibitors such as Aprotinin, soybean trypsin inhibitor Il is mesilate of gabexate.

In addition, the composition according to the invention may optionally include additional active substances which may synergistic manner to enhance the desired effect of the composition. For example, when the active macromolecular substance is insulin, the composition may also include an insulin sensitizer that is capable of strengthening the response to the absorbed insulin. Examples of sensitizers that can be used in this way are troglitazone, pioglitazone, rosiglitazone and other members of the class of molecules glitazones.

In the composition according to the invention, when the mixture is contained in a capsule or tablet, which includes an aromatic alcohol, power absorption, and active macromolecular substance, preferably, the drug is essentially anhydrous. In more preferred versions of the invention, the full composition is essentially anhydrous. Essentially anhydrous mixture in the context of this invention means a content of less than 5%, preferably less than 1% and, more preferably, less than 0.5 wt.% water.

Compositions according to the invention, depending on the active macromolecular substances can be used in the treatment of a number of illnesses and diseases of the human body or animal body by therapy or, in the Alt ERN case, you can apply for the introduction of macromolecules that are important for diagnosis of diseases and disease conditions in the human or animal. Compositions according to the invention, preferably, are pharmaceutical or cosmetic compositions.

The pharmaceutical compositions according to the invention is particularly used in the treatment of diabetes, when the composition may include insulin, C-peptide or GLP-1 or a mixture thereof as active substances for the treatment of osteoporosis, when the composition may include the PTH or PTH or their mixture; the treatment of osteoarthritis, when the composition may include calcitonin; in the treatment of obesity, when the composition may include peptide YY or oxyntomodulin or their mixture, or in the treatment of cancer, when the composition may include erythropoietin, GCSF, GMCSF, or their mixture.

In the compositions according to the invention the mixture contained in the capsule can be liquid, semi-solid substance or gel, which is either in the form of a solution or dispersion of microparticles. That is, the active macromolecular substance(a) for absorption means is introduced into the drug either in the form of a solution or as a dispersion of microparticles. Alternatively the composition may be in the form of solids.

Compositions according to the invention, respectively, is made by cooking essentially anhydrous mixture of the active macromolecular substances and aromatic alcohol, amplifier, absorption, and then optionally filled with a mixture of uncoated capsules and, optionally, coating them with a suitable polymer mixture to achieve the properties desired permeability.

Depending on the nature of the applied additional excipients, the pharmaceutical composition according to the invention can be in liquid, solid, semi-solid or gel-like form. The pharmaceutical composition according to the invention is suitable for insertion through any path that provides access to various tissues of the mucous membranes, such as the buccal or sublingual mucosa, the mucous membrane of the nose, palate, lung, colorectal, gastrointestinal tract (including the large and small intestines and the vagina. In the case of a liquid, semi-solid or gel-like drugs, they can be either anhydrous or aqueous.

When the intended scope of the composition according to the invention is the intestine, it is required that the composition was placed inside Intercollege coating that can withstand the stomach so that the components of the drug remained together, and undissolved directly merged until then, until they reach the tissues of the small intestine or colon. These drugs are, in essence, will be waterless. Compositions in liquid form will be on the walking for administration in the form of capsules with intersolubility coating, while hard drugs you can either enter the inside of the pod with intersolubility coating, or in tablet form.

Intersolubility coating chose to resist the natural condition of the stomach and to become permeable to the desired location in the intestine. Preferably, this is determined by the terms of pH, which modulate throughout the length of the intestine. When the scene of action is the small intestine, it is preferable that intersolubility coating becomes permeable and releases its contents at pH 3 to 7, preferably 5.5 to 7, more preferably from 5.5 to 6.5. When the intended site of action is the colon, it is preferable that intersolubility coating becomes permeable and releases its contents at pH 6.8 or higher.

Suitable intersolubility coatings are well known in the field of engineering and include polymethacrylates, such as coating selected from L and S groups Eudragits especially Eudragits, L12.5P, L12.5, L100, L100-55, L30 D-55, S12.5P, S12,5, and S100. The selection of the appropriate coating for the capsule, which, preferably, is a gelatin capsule, can easily make a specialist in the field of technology on the basis of their knowledge and available literature supporting the Eudragit products.

When designed the place the action is nasal mucosa, the drug may be in the form of an aqueous solution or as a dry powder, which can be introduced as a spray.

When the intended site of action is the rectum, the appropriate method of administration is, for example, anhydrous liquid or solid substance inside a shell capsules or entered into the matrix erodirovannogo of the suppository.

For vaginal application also has a drug in gel form.

The following examples serve to illustrate the present according to the invention and should not be construed as limiting.

Examples

Example 1

The manufacturer of the drug containing Metformin and propylgallate

To 1 g of Metformin add to 1.83 g of distilled water. The mixture is then heated to approximately 60°C With vigorous shaking until then, until you dissolve all solid. To the clear solution add 250 mg of propylgallate. The mixture is then heated at approximately 60°C With vigorous shaking until then, until you dissolve all solid. Set pH 5.5 by adding approximately 25 μl of sodium hydroxide. Get a homogeneous solution, which is transparent at room temperature.

Example 2

The manufacturer of the drug containing phenformin and propylgallate

The drug penfor is in/propylgallate made, as described in example 1, except that Metformin substitute fentermina. Get a homogeneous solution, which is transparent at room temperature.

Example 3

The manufacturer of the drug containing digluconate chlorhexidine and propylgallate

The solution digluconate chlorhexidine 200 mg/ml diluted 2× with distilled water to form a solution of 100 mg/ml To 10 ml of this solution add 250 mg of propylgallate. The mixture is then heated at approximately 60°C With vigorous shaking until then, until all the solid has dissolved. Set pH 5.5 by adding approximately 25 μl of 1M sodium hydroxide. Get a homogeneous solution, which is transparent at room temperature.

Example 4

The manufacturer of the drug containing Metformin and bottled hydroxytoluene (EIT)

To 400 mg of Metformin add 4.0 g of distilled water. The mixture is then heated at about 70°C With vigorous shaking until then, until all the solid has dissolved. To the clear solution add 40 mg of BHT. The mixture is then heated at about 70°C With vigorous shaking until then, until all the solid has dissolved. Get a homogeneous solution, which is transparent at room temperature.

Example 5

And the cooking, preparation, containing phenformin and bottled hydroxytoluene (EIT)

To 400 mg of phentermine add 4.0 g of distilled water. The mixture is then heated at about 70°C With vigorous shaking until then, until all the solid has dissolved. To the clear solution add 100 mg of BHT. The mixture is then heated at about 70°C With vigorous shaking until then, until all the solid has dissolved. Get a homogeneous solution, which is transparent at room temperature.

Example 6

The manufacturer of the drug containing phenformin and bottled hydroxyanisol (BHA)

The method of manufacture of the drug such as described in example 5 for the preparation of Metformin/EIT, except that EIT replace the VNA. Get a homogeneous solution, which is transparent at room temperature.

Example 7

The manufacturer of the drug containing Metformin, propylgallate and insulin

The solution Metformin/propylgallate made as described in example 1. Then the resulting solution was cooled to 37°C and add to 28.1 mg of insulin. The mixture is then incubated at 37°C With stirring until until the insulin is completely dissolved. Then the solution is rapidly frozen at -20°C, then incubated at -20°C for 1 hour, and then dried by freezing in accordance with the s night, subjecting to a vacuum of 1 mbar. Then dry powdery mass is passed through a sieve to obtain fine powder.

Example 8

Dissolution of the drug containing Metformin, propylgallate and insulin

In 8-ml beaker weigh 244 mg powder Metformin/PG/insulin, which is then transferred to a water bath at 37°C. In the sample make 1 ml of simulated intestinal fluid from pH 5.5, preheated to 37°C, then incubated at 37°C. the Powder is dissolved within 10 minutes. 100 μl of the solution is transferred into a microplate well and measure the absorption at 620 nm and 492 nm. The optical density of the solutions is similar to the density of the simulated intestinal fluid, taken separately, demonstrating that the solution is transparent and contains no particles, and the scattering is not observed.

SampleThe absorption at 492 nmThe absorption at 620 nm
Powder0,0640,038
Intestinal fluid0,0380,043

Example 9

The efficiency of in vivo mixture hydrochloride Metformin/propylgallate/insulin juvenile SV is it

The preparations made in the same way as in example 7, is mixed with the swelling agent and the agent for slide, and dry powder filled capsules, each of which has components in the proportions shown below. For comparison, made preparations containing chenodeoxycholic instead of Metformin and calcitonin salmon instead of insulin. All drugs have the same number of propylgallate the capsule.

41C90AE
Insulin3.75 mg3.75 mg
Calcitonin1.00 mg
Metformin133,4 mg133,4 mg
Chenodeoxycholic70,60 mg
Propylgallate33,35 mg33,35 mg33,35 mg
Soda is the Wake salt starch glycolate RS 9.69 mgbr15.15 mgbr15.15 mg
Fine silicon oxide1.08 mg1.67 mg1.67 mg
Trypsin inhibitor soybean10,00 mg

The drugs were injected into the capsule through the opening into the small intestine eight juvenile pigs (each mass of ~40 kg). Glucose levels in the blood were measured at intervals during the six-hour period and the average change in AUC of glucose in plasma was calculated in cammal/L. As can be seen from the summary data below, the product containing a combination of Metformin/propylgallate, demonstrates the effectiveness of equal or greater value for chenodeoxycholic/propylgallate.

Calcitonin/Metformin/PG + SBTI (random effects (-ve), control)
AUC changes of plasma glucose after 6 hours (cammel/l)
41CInsulin/Heno/PG-2,25
90AInsulin/Metformin/PG-4,02
E-0,21

Example 10

The efficiency of in vivo mixture hydrochloride Metformin/propylgallate/calcitonin in the body of juvenile pigs

Drugs, such as produced in example 9 (containing 6000 IU of calcitonin salmon, 133 mg of Metformin hydrochloride and 33 mg of propylgallate or 6000 IU of calcitonin salmon and Metformin hydrochloride), was introduced in the form of dry powder inside the capsules through the hole in the small intestine eight juvenile pigs (each mass of ~40 kg). The composition of the contents of each capsule are presented in the table below. Drugs, containing chenodeoxycholic included for comparison.

The levels of calcium in the blood was measured at intervals during the six-hour period and average AUC of calcium in the plasma was calculated in cammal/L. As can be seen from the summary data below, the levels of calcium decrease, become below the baseline as a result of the introduction of calcitonin into the blood stream from the intestine. The combination of Metformin/PG is the most effective, more also than Metformin in the absence of PG, indicating that the effect of increased absorption caused not by Metformin, but is the result of the actions of propylgallate, the dissolution of which in the aquatic environment in kick which is due to the presence of Metformin. Further, the increased activity can be achieved by inclusion of protease inhibitors in the preparations.

AUC changes of calcium in plasma after 6 hours (cammel/l)
90AInsulin/Metformin/PG (random effects(-ve), control)-0,51
ACalcitonin/chenodeoxycholic/PG-0,89
WCalcitonin/chenodeoxycholic/PG + SBTI-1,43
ACalcitonin/Metformin/PG-1,12
82VCalcitonin/Metformin/PG + Aprotinin-2,04
ACalcitonin/Metformin - no PG-0,65
WCalcitonin/Metformin + Aprotinin - no PG-0,68

Example 11

The efficiency of in vivo mixture hydrochloride Metformin/propylgallate/calcitonin in the body Yu is analnyj pigs

The drug, such as produced in example 9 (each capsule contains 4 mg of parathyroid hormone, 133,4 mg of Metformin hydrochloride, 33,35 mg of propylgallate, br15.15 mg sodium starch glycolate, 1,65 mg of finely ground silica and 10.00 mg of trypsin inhibitor soybean) was injected through the opening into the small intestine eight juvenile pigs (each mass of ~40 kg). The levels of calcium in the blood was measured at intervals during the six-hour period. As you can see from the data below, the levels of calcium differ from the baseline as a result of the introduction of PTH in the blood stream from the intestine.

The difference between the maximum and minimum level of calcium in plasma (mmol/l)
A solution of PTH in bateriafina saline, subcutaneously (0.4 mg)0,31
WPTH in the drug Metformin/PG, inside of the small intestine (4.0 mg)0,27

1. Pharmaceutical composition, facilitating the passage of the active macromolecular substances through the intestinal wall, comprising a mixture of:
(a) an active macromolecular substances;
(b) an aromatic alcohol amplifier absorption, selected from propylgallate, bottled hydroxytoluene (BHT), butylated of hydroxyanisole (BHA) and their analogues and derivatives, or mixtures thereof; and
(c) biguanide or its pharmaceutically acceptable salt, capable of increasing the solubility of the aromatic alcohol, amplifier absorption in the aquatic environment,
where aromatic alcohol, power absorption is present (by weight) greater or equal to the number of active macromolecular substances.

2. The composition according to claim 1, which comprises less than 5 wt.% water.

3. The composition according to claim 1, where the composition is coated intersolubility coating, which is permeable at pH from 3 to 7.

4. The composition according to claim 1, where the mixture comprises from 5 to 30 wt.%, aromatic alcohol, amplifier absorption.

5. The composition according to claim 1, where biguanide selected from Metformin, phenformin and chlorhexidine and their pharmaceutically acceptable salts.

6. The composition according to claim 1, in which the mixture is in the form of a solution or dispersion of microparticles.

7. The composition according to claim 1, in which the mixture is in solid form.

8. The composition according to claim 1, where the active macromolecular substance is a polypeptide or protein, polynucleotide, polysaccharide or a mixture.

9. The composition of claim 8, where the active makromolekulare substance selected from calcitonin, insulin, heparin, low molecular weight, the hands of Eritrean is poatina, granulocyte colony-stimulating factor, interferon, C-peptide, GLP-1, human growth hormone and parathyroid hormone or its analogues or fragments.

10. The composition of claim 8, where the active macromolecular substance is insulin, calcitonin or parathyroid hormone or its analogue or derivative.

11. The composition of claim 10, where the active macromolecular substance is insulin or an analogue or derivative.

12. Composition according to any one of the preceding paragraphs for use in therapeutic or diagnostic treatment of a human or animal.

13. Used in the pharmaceutical compositions of an aromatic alcohol selected from propylgallate, BHT, BHA, and their analogues and derivatives, together with biguanide or its pharmaceutically acceptable salt, capable of increasing the solubility of the aromatic alcohol in the aquatic environment, as the amplifier absorption of macromolecules across the intestinal wall.

14. The use of an aromatic alcohol selected from propylgallate, BHT, BHA, and their analogues and derivatives, together with biguanide or its pharmaceutically acceptable salt, capable of increasing the solubility of the aromatic alcohol in an aqueous medium, in the manufacture of the drug containing the active macromolecular substance, in order to increase the absorption and the tive macromolecular substances in the human body or animal.

15. Use item 13 or 14, where the active macromolecular substance which is absorbed, is a polypeptide or protein, polynucleotide, polysaccharide or a mixture.

16. The application indicated in paragraph 15, where the active macromolecular substance which is absorbed, is selected from calcitonin, insulin, heparin, low molecular weight, erythropoietin, granulocyte colony-stimulating factor, interferon, C-peptide, GLP-1, human growth hormone and parathyroid hormone or its analogues or fragments.

17. The application of article 16, where the active macromolecular substance which is absorbed, is an insulin, calcitonin or parathyroid hormone or its analogs or fragments.

18. The application 17, where the active macromolecular substance which is absorbed, is an insulin or analogue or fragment.

19. The use according to any one of p-18, where the composition includes less than 5 wt.% water.

20. Use PP-18, which includes the introduction of the active macromolecular substance (s), which is absorbed in the aromatic alcohol in the form of a solution, in the form of a dispersion of particles or in the form of solids.

21. The way to increase absorption of the active macromolecular substances in the body of the patient, which includes the introduction of a specified patient compo is icii according to any one of claims 1 to 12.

22. A method of treating a patient suffering from a disease state or disease treatable by the introduction of a composition according to any one of claims 1 to 12.

23. The use of active macromolecular substance selected from insulin, C-peptide, GLP-1 or mixtures thereof; aromatic alcohol, amplifier, absorption selected from propylgallate, bottled hydroxytoluene (BHT), butylated of hydroxyanisole (BHA) and their analogues and derivatives, or mixtures thereof; and biguanide or its pharmaceutically acceptable salt, capable of increasing the solubility of the aromatic alcohol, amplifier absorption in an aqueous environment, in the manufacture of a drug for treatment of diabetes.

24. The use of active macromolecular substance selected from calcitonin and PTH; aromatic alcohol, amplifier, absorption selected from propylgallate, bottled hydroxytoluene (BHT), butylated of hydroxyanisole (BHA) and their analogues and derivatives, or mixtures thereof; and biguanide or its pharmaceutically acceptable salt, capable of increasing the solubility of the aromatic alcohol, amplifier absorption in an aqueous environment, in the manufacture of the drug for the treatment of osteoporosis.

25. The use of calcitonin, an aromatic alcohol, an amplifier absorption selected from propylgallate, bottled hydroxytoluene (BHT), butylated of hydroxyanisole (is ON) and their analogues and derivatives, or mixtures thereof; and biguanide or its pharmaceutically acceptable salt, capable of increasing the solubility of the aromatic alcohol, amplifier absorption in an aqueous environment, in the manufacture of the drug for the treatment of osteoarthritis.

26. The use of active macromolecular substance selected from a peptide YY, oxyntomodulin and mixtures thereof; aromatic alcohol, amplifier, absorption selected from propylgallate, bottled hydroxytoluene (BHT), butylated of hydroxyanisole (BHA) and their analogues and derivatives, or mixtures thereof; and biguanide or its pharmaceutically acceptable salt, capable of increasing the solubility of the aromatic alcohol, amplifier absorption in an aqueous environment, in the manufacture of the drug for the treatment of obesity.

27. The use of active macromolecular substance selected from erythropoietin, GCST, GMCSF, and mixtures thereof; aromatic alcohol, amplifier, absorption selected from propylgallate, bottled hydroxytoluene (BHT), butylated of hydroxyanisole (BHA) and their analogues and derivatives, or mixtures thereof; and biguanide or its pharmaceutically acceptable salt, capable of increasing the solubility of the aromatic alcohol, amplifier absorption in an aqueous environment, in the manufacture of the drug for the treatment of cancer.



 

Same patents:

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to compositions of quinolinone derivatives, methods of obtaining and application of such compositions. Pharmaceutical composition contains lactate of compound 4-amino-5-fluorine-3-[6-(4-methylliperazine-1-yl)-1H-benzimidazole-2-yl]-1H-quinoline-2-one, or its tautomer or their mixture, in quantity from 10 to 80 wt % and at least one ingredient, selected from group, which includes (I) cellulose; (II) silicon dioxide; (III) magnesium stearate and (IV) ingredient, selected from crospovidone, starch and lactose. Composition is included in composition of capsule or pill.

EFFECT: compositions according to invention demonstrate satisfactory properties relating to rates of solution and stability.

49 cl, 2 dwg, 21 tbl, 12 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to field of medicine and pharmaceutics and deals with composition for cancer treatment, which includes compound, presented by structure formula (I), and pharmaceutically acceptable crystalline volume filler, where molar ratio of compound (1) to claimed filler constitutes from 1:20 to 1:1, as well as method of its obtaining.

EFFECT: composition has increased activity.

50 cl, 3 tbl, 3 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to field of pharmaceutics and deals with pharmaceutical compositions, which contain a) nanoparticles, containing poorly soluble in water pharmaceutical substance, for example taxane, and albumen; b) edetate and c) sucrose, where significant growth of microbes in composition is suppressed. Invention describes vial and set, which contain claimed compositions. In addition, claimed is application of composition for obtaining medications for treatment of cancer diseases, as well as method of treating cancer diseases. Invention also deals with method of conservating composition, which contains a) nanoparticles, containing poorly soluble in water pharmaceutical substance and albumen and b) sucrose, including addition of edetate into composition. Invention ensures reduction of undesirable oligomerisation of albumen, improved ability of slowing down microbial growth and faster restoration of lyophilised composition. In addition, in case, when as poorly soluble pharmaceutical substance applied is taxane, compositions demonstrate improved profile of.

EFFECT: invention ensures reduction of undesirable albumen oligomerisation, improved ability of slowing down microbial growth and faster restoration of lyophilised composition, in addition, in case, when as poorly soluble pharmaceutical substance applied is taxane, compositions demonstrate improved profile of absence of admixtures in taxane.

61 cl, 1 tbl, 5 ex

FIELD: medicine.

SUBSTANCE: invention relates to medicine and can be used for photpdynamic therapy and surgical ablation of intraocular neoplasm. For this purpose, photosensitiser of chlorine series is introduced to patient intravenously in dose 0.8-1.1 mg/kg × 0.7 2 hours before irradiation. 10 minutes before irradiation the same photosensitiser is introduced to patient intravenously in bolus manner in dose 0.8-1.1 mg/kg × 0.3. Before second introduction of photosensitiser above tumour formed is superficial scleral flap with base from limb and thickness equal to 2/3 of sclera thickness. 10 minutes after second introduction of photosensitiser scleral bed is irradiated by means of lightconductor nozzle by laser irradiation with energy density 300 J/cm2 covering neighbouring fields on 5% of area. After finishing irradiation tumour is ablated transsclerally. After that gas SF6 is introduced intravitreally until normal tonus is achieved. After that by means of lightconductor nozzle laser irradiation around scleral flap is performed with energy density 100 J/cm2 covering covering neighbouring fields on 5% of area.

EFFECT: method makes it possible to ensure photoinduced thrombosis of neoplasm-feeding vessels, death of tumour cells, complete ablation of tumour, achieve absence of recurrences and metastases in remote postoperative period.

2 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed invention relates to novel derivatives of pyridine, of general formula I, where R represents hydroxyalkyl group with normal non-branched chain, which has 5-10 carbon atoms or its pharmaceutically acceptable salt. Also, invention relates to method of obtaining compound of formula I, pharmaceutical composition based on formula I compound, as well as preventive and therapeutic anti-Helicobacter pylori medicine based on formula I compound.

EFFECT: obtained is novel pyridine derivative, which has anti-Helicobacter pylori activity.

24 cl, 4 tbl, 9 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to pharmaceutical industry, in particular to medication, possessing antioxidant, cardioprotective, antidiabetic, anti-inflammatory, hepatoprotective, antitumoral and antiviral action. Medication, which has antioxidant, cardioprotective, antidiabetic, anti-inflammatory, hepatoprotective, antitumoral and antiviral action, representing luteolin 7,3'-disulphate, is obtained from water-ethanol extract of sea grass of family Zosteraceae.

EFFECT: medication has efficient antioxidant, cardioprotective, antidiabetic, anti-inflammatory, hepatoprotective, antitumoral and antiviral action.

4 tbl, 8 ex

FIELD: medicine.

SUBSTANCE: invention relates to field of medicine, pharmaceutics, namely to medicinal form, which possesses prolonged action, which can be used for treatment of oropharyngeal zone. Composition for preparation of medicinal form includes medication which represents active substance or mixture of substance, sodium alginate, chitosan succinate, water-insoluble salt of Ca and Ba from series of stearates, palmitates, ozalates, tartrates, citrates, sulfates and carbonates, and water, in given in the invention formula quantities.

EFFECT: medications on invention have recommended themselves as convenient in application, which allow to increase efficiency of therapeutic process, reduce probability of development of allergic reactions.

4 ex

FIELD: medicine.

SUBSTANCE: what is described is a method for malignant cell elimination with the use of an effective amount of an immunotoxin with a common structure, containing a core unit of gelonin toxin and a one-chained antibody specifically targeted on a malignant cell. According to the invention, the immunotoxin can be an ingredient of a pharmaceutically acceptable composition. The immunotoxin can be delivered to the malignant cell by introduction into a cell of an immunotoxin-expressing construct which is a viral vector.

EFFECT: immunotoxins according to the invention exhibit lower antigenic specificity with preserved biological activity, therefore the method and the composition used in the method have substantial positive properties for a subject requiring such method.

12 cl, 11 dwg, 9 tbl, 6 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pharmaceutics, and concerns applications of amphiphilic block copolymers for treating and preventing cancer, particularly by reduced cancer cell growth and proliferation rate. Besides, the amphiphilic block copolymers can be used for blocking of platelet and fibroblast growth factor linking with related receptors on a membrane. Preferential block copolymers contain a basic hydrophobic chain, preferentially a polypropylene oxide chain whereto there are attached at least two hydrophilic side chains, preferentially a polyethylene oxide chain with mean ethylene oxide making less than 80 % of said amphiphilic block copolymer and molecular weight of the basic hydrophobic polymeric chain making at least 2000 g/mol.

EFFECT: invention provides new chemotherapeutic polymer drug for various types of cancer, having an effect of reduced cancer cell proliferation rate.

18 cl, 13 dwg, 11 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pharmaceutical industry. An aqueous solution of a medical composition containing 20(R)-ginsenoside Rg3, with the certain ginsenoside Rg3 content in the solution (versions). A method of preparing the aqueous solution of the medical composition containing 20(R)-ginsenoside Rg3 (versions). A method of preparing a lyophilised powder for injection of the medical composition containing 20(R)-ginsenoside Rg3 (versions). The aqueous solution stated above contains total dissolved 20(R)-ginsenoside Rg3 and exhibits higher bioavailability. The solution and based compositions can be used for preparing an injection solution for oral administration and external application.

EFFECT: medical composition containing 20(R)-ginsenoside Rg3 is applicable for preparing the drug for anticancer, potentiating and toxicity-attenuating effects of the combined chemotherapy or radiation therapy for intensifying human immune functions, human memory improvement, stability to fatigue and reduced swelling, pain management and wound healing effects.

7 cl, 11 dwg, 20 tbl, 50 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: pharmaceutical composition of prolonged release in form of pill includes metformin or its pharmaceutically acceptable salt; agent, which generates gas, selected from carbonates or bicarbonates; hydrophilic or hydrophobic polymer as release moderator; disintegration-causing agent; hydrophilic polymer for ensuring system stability; additional hydrophilic polymer or gum as release moderator, binding substance and other pharmaceutical additional substances.

EFFECT: composition by invention ensures increased term of device holding in stomach and release of metformin by regulated method, in addition, it is simple and cheap in production.

19 cl, 1 dwg, 11 tbl, 8 ex

FIELD: medicine.

SUBSTANCE: invention relates to medicine, namely to hematology and cardiology, and can be used for reduction of spontaneous aggregation of erythrocytes in case of arterial hypertension with dyslipidemia and disturbance of tolerance to glucose. For this purpose at the background of hypolipidemic diet, dosed static and dynamic physical exercise and daily swimming for not less than 30 minutes per day in the middle of the day introduced are lisinopril and metformin. Physical exercise includes morning hygienic gymnastics, therapeutic-preventive gymnastics, fractional physical exercise throughout the day. Lisinipril is introduced in dose 10 mg 1 time per day in the morning. Metformin is introduced in dose 500 mg 2 times per day. Treatment is carried out for 2 months.

EFFECT: method makes it possible to normalise spontaneous aggregation of erythrocytes during 2 months, bringing it to the level close to the level of healthy people, which in its turn contributes to reduction of risk of thrombotic complications.

1 tbl, 2 ex

FIELD: medicine.

SUBSTANCE: invention relates to medicine, namely to hematology and cardiology, and can be used for reduction of spontaneous aggregation of erythrocytes in case of arterial hypertension with abdominal obesity and disturbance of tolerance to glucose. For this purpose at the background of hypocalory diet, dosed static and dynamic physical exercise and daily swimming for not less than 30 minutes per day in the middle of the day introduced are lisinopril and metformin. Physical exercise includes morning hygienic gymnastics, therapeutic-preventive gymnastics, fractional physical exercise throughout the day. Lisinipril is introduced in dose 10 mg 1 time per day in the morning. Metformin is introduced in dose 500 mg 2 times per day. Treatment is carried out for 2 months.

EFFECT: method makes it possible to normalise spontaneous aggregation of erythrocytes during 2 months, bringing it to the level close to the level of healthy people, thus contributing to prevention of vascular complications in patients with arterial hypertension with abdominal obesity and with disturbance of tolerance to glucose.

2 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed invention relates to novel pyrimidine derivatives or their pharmaceutically acceptable salts, possessing inhibiting activity with respect to glycogensintase kinase-3 (GSK3). In compound of formula I: R1 is selected from hydrogen, cyano, C1-3alogenoalkinyl, SO2NRbRc, C0-2alkyl(O)NRbRc, C1-4alkylNBbRc, SO2Ri, C(O)ORa, CH(OH)Rj and C(O)Rj; R2 and R4 are independently selected from hydrogen, halogeno, cyano, NO2, C1-4alkyl, C1-3ahalogenoalkyl, ORa, C(O)NRbRc, SO2Ri, and C(O)ORa; or R1 and R2 together with atoms, to which they are bound, are bound with formation of 5- or 6-member heterocyclic ring, which contains one S, any of the hydrogen atoms of group CH2 in said heterocyclic ring can be substituted by oxo, hydroxy, and sulphur atom in said heterocyclic ring is probably oxydised to -SO2-; R3 and R5 represent hydrogen; R6 represents tetrahydropyran; R7 is selected from hydrogen, C1-3alkyl, cyano and C1-3halogenoalkyl; R8 represents hydrogen; Ra is selected from C1-3alkyl and C1-3halogenoakryl. Other radicals are given in formula of invention.

EFFECT: compounds can be applied in manufacturing medication for prevention and/or treatment of predemential states, moderate cognitive failure and type II diabetes, Alzheimer's disease and Parkinson disease, as well as bone-associated malfunctions.

40 cl, 3 dwg, 1 tbl, 122 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to pharmaceutical industry, in particular to medication, possessing antioxidant, cardioprotective, antidiabetic, anti-inflammatory, hepatoprotective, antitumoral and antiviral action. Medication, which has antioxidant, cardioprotective, antidiabetic, anti-inflammatory, hepatoprotective, antitumoral and antiviral action, representing luteolin 7,3'-disulphate, is obtained from water-ethanol extract of sea grass of family Zosteraceae.

EFFECT: medication has efficient antioxidant, cardioprotective, antidiabetic, anti-inflammatory, hepatoprotective, antitumoral and antiviral action.

4 tbl, 8 ex

FIELD: medicine.

SUBSTANCE: invention relates to medicine, namely to hematology and cardiology, and can be used for reduction of spontaneous erythrocyte aggregation in case of arterial hypertension with abdominal obesity. For this purpose at the background of hypocaloric diet, dosed static and dynamic physical exercise and daily swimming for not less than 30 minutes per day in the middle of the day lisinopril and metformin are introduced. Physical exercise includes morning hygienic gymnastics, therapeutic and preventive gymnastics, dosed physical exercised throughout the day. Lisinopril is introduced in dose 10 mg 1 time per day in the morning. Metformin is introduced in dose 500 mg 2 times per day. Treatment is carried out for 2 months.

EFFECT: method makes it possible to normalise spontaneous erythrocyte aggregation during 2 months, bringing it to the level close to that of healthy people, thus favouring prevention of vascular complications in patients with arterial hypertension with abdominal obesity.

2 ex

FIELD: chemistry.

SUBSTANCE: invention relates to bis[3-(4-chlorophenyl)-1-(4-methylphenyl)carboxamido-1,3-propanedionato]oxovanadium of formula: . The compound has hypoglycemic and antihypoxic activity.

EFFECT: obtaining a compound having high hypoglycaemic and antihypoxic activity and low toxicity.

1 ex, 2 tbl

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely to haematology and endocrinology, and can be used for decreasing spontaneous erythrocyte aggregation in impaired glucose tolerance. That is ensured by introduction of metformin with underlying graduated static and dynamic physical exercises and daily swimming for at least 40 minutes a day in the middle of day. Physical exercises include morning hygienic gymnastics, therapeutic exercises, graduated physical exercises during the day. Metformin 500 mg is introduced 2 times a day. The therapy is carries out for 1.5 months.

EFFECT: method allows normalising spontaneous erythrocyte aggregation for 1,5 months, approaching a level close to such in healthy people, thereby promoting prevention of vascular complications in patients with impaired glucose tolerance.

2 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to an ester presented by formula [2] where R1' represents 1) C1-C6 alkyl which is optionally substituted by one or more identical or different halogens, or 2) -CO-C1-C6 alkoxy; R2' represents 1) hydrogen or 2) C1-C6 alkyl, R3', R4' and R5' are identical or different, and each represents 1) hydrogen, 2) halogen, 3) C1-C6 alkyl which is optionally substituted by one or more identical or different halogens, 4) C1-C6 alkoxy, 5) -COR13' where R13' represents (a) hydroxy, (b) C1-C6 alkyl, (c) C1-C6 alkoxy which is optionally substituted by one or more identical or different substitutes selected from (1) hydroxy, (2) C1-C6 alkoxy which is optionally substituted by phenyl, (3) -NR11'CO-C1-C6 alkyl where R11' represents hydrogen, (4) -CONR8'R9' where R8' and R9' are identical or different, and each represents C1-C6 alkyl, (5) -CO- C1-C6 alkoxy optionally substituted by phenyl, (6) phenyl optionally substituted by one or more identical or different substitutes selected from halogen, C1-C6 alkoxy and -CO-C1-C6 alkoxy, and (7) a heterocycle selected from pyridyl, thienyl and which all can be substituted by one or more identical or different C1-C6 alkyl groups, or (d) -OR19' where R19' represents a group or a group or piperidyl which is optionally substituted by -CO-C1-C6alkyl, 6) a heterocycle selected from oxadiazolyl and tetrazolyl, and said heterocycle is optionally substituted by C1-C6 alkyl optionally substituted by one or more identical or different substitutes selected from -CONR8'R9' (R8' and R9' have the same values as defined above) and -CO-aralkyloxy, or 7) nitrile; R6' and R7' are identical or different, and each represents 1) C1-C6 alkyl or 2) a nitrogen-containing 5 or 6-members saturated heterocycle containing a monocycle formed when R6', R7' and a neighbouring nitrogen atom are taken together, and optionally including oxygen as a heteroatom; Y1, Y2, Y3 are identical or different, and represent, 1) all carbon atoms, or 2) one of Y1, Y2, Y3 represent a nitrogen atom, and the others are carbon atoms; Y4 represent a carbon or nitrogen atom ;-X- represents 1) -(CH2)1 where 1 represents an integer 1 to 3, 2) -CH2-NR18'-CH2- where R18' represents C1-C6 alkyl, or 3) or to its pharmaceutically acceptable salt.

EFFECT: compounds presented by formula are effective as agents for treatment or prevention hyperlipidemia, arteriosclerosis, coronary artery disease, obesity, diabetes and hypertension or similar diseases since they are withdrawn very quickly and exhibit excellent MTP inhibitory activity.

23 cl, 32 tbl, 137 ex

FIELD: medicine.

SUBSTANCE: present invention refers to medicine, namely to therapy and endocrinology, and can be used for glucose level correction by gluconeogenesis optimisation in a body. That is ensured by introduction of a daily dietary intake with a carbohydrate quota reduced to 150-100 g and the content of glucogenic amino acids increased to 20000-40000 mg 2-3 times a week. Said dietary intake is prescribed after intensive physical exercises allowing to lose 2000-3000 kcal/day. Such loads are carried out in the form accessible to a specific person as jogging, swimming, football, volleyball or work in the garden.

EFFECT: method provides a protein-glucogenic diet stimulating gluconeogenesis enzyme development by a liver.

3 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: group of inventions relates to medicine, namely to infection diseases, hepatology, and can be applied for prevention or treatment of viral disease, caused by virus of hepatitis C. For this purpose therapeutic medication, as active ingredients in it are combined 22β-methoxyolean-12-en-3β,24(4β)-diol and interferon, is introduced to patient. High therapeutic effect of claimed medication is associated with synergetic effect of 22β-methoxyolean-12-en-3β,24(4β)-diol and interferon, manifested in inhibition of hepatitis C virus.

EFFECT: insuring high therapeutic effect.

6 cl, 1 ex

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