Dipropionate betulin composition
SUBSTANCE: anti-tumour composition of a betulin derivative with a biocompatible carrier, wherein the betulin derivative is presented by betulin dipropionate, while the biocompatible carrier is arabinogalactane in certain proportions; the composition is prepared by a mechanic activation of betulin dipropionate with arabinogalactane.
EFFECT: composition possesses the pronounced anti-tumour activity and the improved solubility.
2 cl, 2 dwg, 4 tbl, 4 ex
The invention relates to chemical-pharmaceutical industry, in particular the production of compositions of pharmacologically active substances.
Dipropionate betulin (DPB) - 3β, 28-dipropoxy loop 20 (29)-ene is a complex ester of propionic acid and betulin.
Betulin and its derivatives have unique pharmacological properties such as anticancer, antioxidant, antiviral and other [Tolstikov, A., Flechter O. B., Schultz, E. E., Baltina L. A., A. Tolstikov, Betulin and its derivatives. Chemistry and biological activity // Chemistry for sustainable development. 2005. No. 13. C. 1-30]. Propionic acid is found in some medicines (ibuprofen, fenobolin, naproxen and other non-narcotic analgesics and non-steroidal anti-inflammatory drugs), aromatic substances [Zefirov N. S., Kulov N. N. and other Chemical encyclopedia. So 4. - M.: Scientific publishing house "Great Russian encyclopedia", 1995. S. 107-108]. Targeted chemical modification of biologically active compounds leads to the production of substances that have a lower toxicity and a wide spectrum of pharmacological activity.
It is known that utility Betulinol antineoplastic action [Flechter O. B., Boreco E. I., Nigmatulin, R. L., Pavlova N. And., Medvedev N. And., Nikolaev, S. N., Tre is yakowa E. C., Savinova O. C., Baltina L. A., Karachurina L. T., Galin, F. H., Saudi F. C., Tolstikov, A. Synthesis and pharmacological activity of acylated Asimov betulone acid and 28-oxo-allobetulin // pharmaceutical journal. So 38. No. 3. 2004. S. 31-34]. Among allatom Betulinol revealed a highly active substances, such as dinicotinate, bichemistry, UseMyWallet Betulinol and other manifesting hepatoprotective and anti-HIV activity. Dinicotinate Betulinol helps to restore the level of marker enzymes in the serum, Alp and bilirubin and has antioxidant properties. The betulin diacetate [3β,28-diacetoxy loop-20(29)-ene(1)] hypolipidemic, choleretic, anti-oxidant properties [Vasilenko Y. K., Semenchenko C. F., Frolova L. M. and other Pharmacological properties of triterpenoids of birch bark. The experimental. and the wedge. Pharmacol. 1993. So 56. No. 4. S. 53-55].
It is established that a dose of Betulinol dose of 4000 mg/kg toxic (toxicity tests were conducted in an accredited test centre, Krasnoyarsk), but its pharmacological activity have not been studied. The main obstacle to use dipropionate betulin as a remedy for internal and external use is the low bioavailability is associated with poor solubility.
Known for the different ways to increase solubility and to increase the biological availability of drugs and biologically active substances, one of which is to create compositions with a water-soluble media.
Known antifungal agent, comprising as an active ingredient tebuconazole and natural or synthetic water-soluble polymers in the mass ratio of tebuconazole : water-soluble polymers 1:(1-5), respectively, obtained by mechanochemical interaction of tebuconazole with water-soluble polymers [RF Patent №2469536, publ. 20.12.2012,].
Known drug, which is a complex of nifedipine with arabinogalactan when the weight ratio of components nifedipine : arabinogalactan, equal to 1:(10-40) obtained by mechanical treatment in a planetary mill with the acceleration of 60 g having the best compared to the original antigipertenzivnoe activity [RF Patent №2391980, publ. 20.06.2010]. Using mechanical processing of the obtained compositions with arabinogalactan (AG) insoluble drugs (LV): sibazona mezapama, azaleptinum, indomethacin in the ratio of AB:AG=1:(5-20), which has anti-inflammatory and anxiolytic effect [RF Patent №2337710, publ.20.06.2008], the composition on the basis of dihydroquercetin and arabinogalactan with cardio properties, characterized in that it additionally contains basic magnesium carbonate [Patent P is No. 2451517, publ. 27.05.2012], and the fact that part of dihydroquercetin replaced glycoprotein from acacia Japanese [RF Patent №2421215, publ. 20.06.2011]. In the latter case, to obtain a used roller mill to reduce the mechanical impact. The disadvantage of these inventions is their narrow focus on a particular drug and the use of certain of the grinding apparatus. These drugs are not in possession of both capillary properties, anti-ulcer and anti-tumor activity as betulin and its derivatives.
Closest to the present invention is a composition of betulin with biocompatible carriers - polyethylene glycol and polyvinylpyrrolidone, in the following ratio of components: betulin (active substance) - 10-25%, of the polymeric carrier - 75-90%, obtained by mechanical activation in the mill-activator for 10-30 min with a load on the grinding body is not more than 20 g, and the ratio of the mixture to the mass of milling bodies 1:30 [RF Patent №2401118. Publ. 10.10.2010].
The disadvantage of this composition is the use as carriers of synthetic polymers.
The present invention consists in expanding the range of pharmacologically active compositions based on derivatives of betulin and natural polymeric carriers.
The technical result of the bretania - created antitumor composition based dipropionate betulin and soluble natural polymer carrier of arabinogalactan.
The technical result is achieved in that the composition of the derivative of betulin with a biocompatible carrier, according to the invention, has antitumor properties, and as a derivative of betulin includes dipropionate betulin, as a biocompatible carrier - arabinogalactan, when the ratio of components, wt. %: dose betulin - 10%, arabinogalactan - else, while it is received by mechanochemical activation of the source components. Composition based dipropionate betulin is a white powder with a yellowish tinge.
Arabinogalactan (AG) is a water - soluble natural cheap, available and non-toxic polysaccharide extracted from larch wood, with unique properties. Arabinogalactan harmless and approved for use as additives to food and biologically active additives. It has a low srednekamennogo molecular weight, guaranteeing increased solubility created compositions. Macromolecule AG has a branched structure that promotes strong retention solutes.
This composition was prepared as follows.
the similar components dipropionate betulin and arabinogalactan - get original techniques [RF Patent №2469043 "way to get the dose of Betulinol" RF patent No. 2280040 "Method of production of arabinogalactan"] with a purity of at least 95%. The song is produced by joint machining of the components does not lead to their destruction, in the mill-activator for 10-30 minutes when the load on the grinding body is not more than 10 g, and the ratio of the mixture to the mass of milling bodies 1:30. To prevent degradation of the starting components can be used vysokoenergeticheskie mill-activators with a cooled reactors, and the density of the material of the reactor and particles should not exceed the density of steel, or other apparatus with reduced load on the grinding body. One such apparatus is the mill SPEX 8000 (CertiPrep Corp., USA).
The dissolution of AG and mixtures thereof, with DPB in the water held in the tester solubility Varian 705 DS. In a vessel with water was placed 200 mg of AG or 180 mg of AG and 20 mg DUB and kept under stirring at 37°C for 2-48 hours. Then the solution was filtered using a filter with a pore diameter of 0.2 μm. The filtrate was subjected to evaporation under reduced pressure and a temperature of 35-40°C (rotary evaporator IL-1M, Russia). To receive the remainder in the form of a thin transparent film which, when the secondary Rast is orenji in the water completely in the solution. To determine the content DPB a portion of the balance weight 9-10 mg were subjected to triple extraction with 1 ml of chloroform. The obtained extract was evaporated and were dissolved in 1 ml ethanol. Content DPB was determined chromatographically using chromatograph MiLiChrome a-02 (CJSC "EcoNova", Russia) (N2301 2.0*75 mm ProntoSIL 120-S AQ, 35°C, H2O (A) - CH3CN (C), 80-100-100% In, 100 µl/min). Content DPB was determined at a wavelength of 200 and 210 nm. Obtained values of the concentrations were calculated on the weight of the sample taken for dilution.
X-ray phase analysis (XRD) of the mechanically activated powders was performed using a diffractometer D8 DISCOVER with a two-coordinate detector (Bruker), CuKαradiation, 2θ=5÷40. IR spectra were obtained by the method of frustrated total internal reflection (ATR) in the frequency range 4000-500 cm-1on Fourier transform infrared spectrometer (Digilab Excalibur 3100 (Varian) without pressing the samples. Molecular mass distribution (MMD) of the samples was investigated by gel-permeation chromatography on the chromatograph Agilent 1200 with a refractometric detector 1260 Infinity (PL aquagel-OH 40 300*7.5 mm, 30°C, 0.1 M LiNO31 ml/min). Calibration was carried out using standard samples of dextrans (SIGMA-ALDRICH) with molecular masses 10600, 20000, 41272, 70000.
The invention is illustrated with specific examples.
Example 1. Physical mixture consisting of 0.02 g of dipro is ionata betulin and 0.18 g of AG, without conducting mechanical activation was dissolved in 250 ml of distilled water at 37°C for 24 hours. The resulting solution was centrifuged and filtered. From the filtrate, water was removed using a rotary evaporator, after which the dry residue was investigated by HPLC method.
Example 2. A mixture consisting of 0.2 g dipropionate betulin and 1.8 g of AG, activated in the mill SPEX 8000 (CertiPrep Corp., USA) in a steel drum with a volume of 40 ml with grinding bodies in the form of steel balls with a diameter of 6 mm and the acceleration of milling bodies 8-10 g, download balls - 60, machining was carried out for 15 minutes, after which the mixture was subjected to dissolution in distilled water according to example 1 (see tab.1).
Example 3. A mixture consisting of 0.2 g of dipropionate betulin and 1.8 g of AG, activated in the mill SPEX 8000 (CertiPrep Corp., USA) in a steel drum with a volume of 40 ml with grinding bodies in the form of steel balls with a diameter of 6 mm and the acceleration of milling bodies 8-10 g, download balls - 60, machining was carried out for 30 minutes, after which the mixture was subjected to dissolution in distilled water according to example 1 (see tab.1).
Example 4. Arabinogalactan by weight of 2 g activated in the mill SPEX 8000 (CertiPrep Corp., USA) in a steel drum with a volume of 40 ml with grinding bodies in the form of steel balls with a diameter of 6 mm and the acceleration of milling bodies 8-10 g, download balls - 60, Under mechanical activation were selected probabability and defined molecular weight (see table.2). 0.02 g of the sample source and mechanically activated arabinogalactan was dissolved in 250 ml of distilled water at 37°C for 24 hours. Then there was the centrifuging and filtering the resulting solution. The filtrate was subjected to evaporation using a rotary evaporator, and after removal of water was obtained dry residue, when the secondary dissolution in water which was determined by the molecular weight.
Table 1 presents data on the solubility in water of the mechanically activated mixtures DPB-AG.
|№ p/p||The mixture (composition) DPB-AG (1:9, mass.)||Appearance||The duration of mechanical activation, min||The transition DPB in solution, %|
|1||Mechanically activated mixture (15 min)||Powder||10||20-25|
|2||Mechanically activated mixture (30 min)||Powder||30||20-25|
From table 1 it is evident that the increase in time of the mechanical act is activate your product does not increase the solubility of DPB and can be limited to the time of machining - 15 minutes.
Table 2 presents comparative data on the content DPB in water when dissolved mechanically activated within 15 minutes mixtures DPB with hypertension and their physical mixture.
|The mixture (composition) DPB-AG (1:9, mass.)||The duration of the dissolution, h||Concentration DPB, ug/ml|
|Mechanically activated mixture||1||2,9|
From table 2 it follows that after mechanical activation DPB with AG content DPB in aqueous solution increases almost 4 times compared to the physical mixture, and 10.8 mg/ml
Table 3 shows the molecular weight of the source of arabinogalactan and after mechanical activation (m/a).
|№ p/p||Srednevekovaja Mw||Brednikova Mn|
|1||AG source||1.716 E+4||1.069 F+4|
|2||AG after dissolution and evaporation of the solvent||1.721 E+4||1.189 E+4|
|3||AG m/10 min||1.288 E+4||0.726 E+4|
|4||AG m/30 min||1.095 has E+4||0.629 F+4|
|5||AG m/and 10 min after dissolution and evaporation of the solvent||1.465 E+4||1.027 F+4|
|6||AG m/and 30 min after dissolution and evaporation of the solvent||1.526 E+4||1.071 E+4|
From table 3 it follows that the mechanical treatment leads to mechanosensing chains of the polymer, as it was observed in [Medvedev, E. N., Neverova N. A., Fedorov I.e., Babkin C. A., M is televa E. C., A. Dushkin Century, Tolstikova, So, Tails, M. C., Long, M. P. Structural transformations of arabinogalactan from larch Siberian by mechanochemical treatment and biological properties of foods // Chemistry of plant raw materials. 2009. No. 3. S. 49-56] when machining AG other grinding machines (different type and other energonapryazhennosti). However, after dissolution in water molecular weight of AG is partially restored, and we can expect that this will not have much impact on the result.
It can be expected that when machining is formed intermolecular complex DPB with hypertension. In Fig.1 shows the diffraction patterns of mechanically activated compositions DPB AT 1:9 (by weight): 1 - after 5 min of mechanical activation, 2 - after 15 min of mechanical activation, 3 - after 30 min of mechanical activation. Curve 1 (activated within 5 min) are still visible reflexes inherent DPB, however, after activation for 15 min (curve 2) they are very Wirayuda, and after 30 min of machining almost disappear. The disappearance of the reflexes DPB may indicate the distribution of the dipropionate of betulin in the matrix of arabinogalactan with the formation of the amorphous composite. This is also shown by the data of differential scanning calorimetry. On the DSC mechanically activated mixture DPB with hypertension visible only "traces" of the peak PLA is of DPB. The presence of this peak suggests that perhaps not all the stuff moved in amorphous state, or a part of the substance secretaryshall when heated. However, the absence of the DSC true melting peak DPB indicates the formation when machining is quite durable composite DPB - AG. This may or dispersion DPB to nanoscale status with the formation of a homogeneous mechanical mixture with hypertension, or distribution of molecules (or ensembles of molecules) DPB in the polymer, as it was intended for some other low-molecular-weight drug substances in [A. Dushkin Century, Tolstikova, So, Tolstikov, A., Meteleva E. C. water-Soluble drug composition and method of reception // Patent RF №2337710. 2008. Bull. 31]. The stability of such composite when heated, apparently caused by the interaction of the components during mechanical activation.
In the IR spectra of the mixtures DPB with hypertension as a result of mechanical activation is observed broadening and decrease in intensity of the bands in the region of stretching vibrations ν(O-H) (3200-3500 cm-1), ν(C=O (1720 cm-1), ν(C-O) (1150 cm-1), which may be caused by amorphization DPB. Not there was a significant shift of the bands DPB and AG in mechanically activated mixture in comparison with individuals that you to definitely judge the formation of hydrogen tie the th between the components. It can be assumed that the relations between DPB and AG in mechanically activated mixtures are due to van der Waals interactions, and the formation of the complex facilitates the branched structure of arabinogalactan.
Conducted Toxicological study showed that the obtained mechanocomposites dipropionate betulin with arabinogalactan, as well as individual substances, the dose of 2000 mg/kg are not poisonous and, according to the international Toxicological classification, they can be attributed to the 4th class of low-toxic substances. The study of pharmacological activity of the resulting complexes in further experiments may be of interest for use in medicine.
The study of antitumor activity of complex dipropionate betulin with arabinogalactan on the cells of ascitic Ehrlich adenocarcinoma (EAC) in vitro experiments.
Antitumor activity of MA composites DPB with hypertension in comparison with pure DPB and AG were determined according to ion homeostasis and the fraction of apoptotic and necrotic ascitic cells of ascitic Ehrlich adenocarcinoma (EAC) at 24 h after exposure to the drugs.
Evaluation of ion homeostasis were given the concentration of sodium ions, potassium, calcium after 3 h after addition of the drugs. To determine the influence of the deposits of the studied substances on the parameters of ion homeostasis washed ascitic cells were incubated in the medium for cultivation with the concentration of the investigated substances 0.5 mg/ml for 3 h at 37°C, 5% CO2and humidity of 6%. To determine the level of intracellular calcium used fluorescent probe GreenCa2+, sodium - SBFI-AM, potassium - PBFI-AM. Washed colorless Hanks solution, the cells were incubated with the probe at a final concentration of 0.05 mg/ml for 30 min at 37°C, after which they were washed from excess dye. The fluorescence intensity was measured on a flow cytometer Beckman Coulter FC500. Native fluorescence of cells without dye was taken as zero.
To determine the percentage of apoptotic and necrotic cells washed ascitic cells were incubated in Hanks solution containing fluorescent dyes Hoechst 33342 (1 mg/ml) and Propidium iodide (1 mg/ml) for 10-15 min at room temperature. The number of apoptotic (bright blue), necrotic (red and red-blue) and weakly luminous blue of living cells was counted in the fluorescence mode, the total number of cells in the lighting mode in the same field of view. Expected percentage of all the three fractions of the cells.
Antitumor activity of the investigated substances was evaluated by their ability to induce apoptosis and necrosis in cells AKE.
|The survival rates of cells AKE *||Sample|
|AG||DPB||MA composite DPB+AG||Control|
|The total share of similarmusical cells||23,3±2,6||28,9±3,4||46,4±6,1||10,4±1,3|
|Note: * - significance of differences from control, P<0,05.|
From table 4 it is seen that the composites in Fe-GA DPB with hypertension most effectively inhibited the growth of cancer cells in culture, causing apoptosis compared with control cells, cells with DPB and AG. Thus, the share of ascitic cells in apoptosis in the control sample was 3.1±2.8% in the state of necrosis was 7.3±0.5% of the total share similarmusical cells AKE was 10.4±1.3 percent. The share similarmusical cells AKE able apoptosis increased under the influence of all of the substances under study: in the presence of AG is more than 5 times, in the presence of DPP - more than 8 times, and in the presence of composites in Fe-GA DPB with AG - more than 13 times (46,4±6,1%).
To identify possible mechanisms of action of the compounds under investigation was determined by the change in the content of calcium, sodium and potassium in the cells of the EAC. The population of ascitic cells in the control samples were divided into 2 fractions: high and low concentration of calcium cations. Analyte - composites in Fe-GA DPB with hypertension, DPB and AG reduced the proportion of cells with a high concentration of calcium, indicating that the suppression of the proliferation rate of ascitic cells (Fig. 2 (a).
All tested compounds reduced the concentration of intracellular potassium and sodium, confirming the apoptosis of cells, and in most cases, the content of potassium cations in the cell was reduced under the influence of composites in Fe-GA DPB with AG (Fig. 2 b).
Thus, through the creation of antitumor composition dipropionate betulin with arabinogalactan expanded range of pharmacologically active compositions based on derivatives of betulin and natural polymeric carriers.
1. Antitumor composition derivative of betulin with a biocompatible carrier, characterized in that as a derivative of betulin includes dipropionate betulin, and as a biocompatible carrier - arabinogalactan when the next zootoxin and components mass. %: dose betulin - 10%, arabinogalactan - rest, with her receive mechanical activation dipropionate betulin with arabinogalactan.
2. The composition according to p. 1, characterized in that it is a white powder with a yellowish tinge.
SUBSTANCE: invention represents an anti-tumour agent containing glucocorticoid hormone in an amount of 0.3 mcg%-40 mcg%, very low-density lipoproteins in an amount to provide the apolipoprotein E content in a formulation of not less than 1 mg%, and additionally a physiologically acceptable solvent, which can be used to inhibit the tumour growth by initiating the tumour cell apoptosis.
EFFECT: higher effectiveness of the antitumour agent and extended indications for use.
2 cl, 3 ex, 6 tbl, 5 dwg
FIELD: medicine, pharmaceutics.
SUBSTANCE: group of invention refers to medicine, namely to oncology, and can be used in treating cancer in a patient. The method involves administering at least one encapsulated chemotherapeutic agent, and at least one amphiphilic block copolymer in this patient. What is also presented is a composition, a kit for treating cancer in the patient and using the amphiphilic block copolymer.
EFFECT: group of inventions provides potentiating the encapsulated chemotherapeutic agent by stimulating the active chemotherapeutic agent release from liposomes by the use of the amphiphilic block copolymer, which is poly(ethylene oxide)-poly(propylene oxide)-poly(ethylene oxide) triblock copolymer, in the composition.
10 cl, 11 dwg, 3 tbl, 4 ex
SUBSTANCE: invention represents a method for preparing a substance with anti-tumour activity in hepatocellular carcinoma consisting in the fact that individual's enteric mucosa is homogenised with water in ratio 1:3-5 at +3-+5°C; the homogenate is centrifuged; the supernatant is heated for 7-10 min at temperature 20° to 38°C increased to 100°C and heated to 15-20 min at this temperature, centrifuged again; the cooled supernatant cooled to +4-+6°C is added with ethanol cooled (-15)-(-20)°C to the concentration of 65-70%; 15-17 h later it is centrifuged again; the alcohol is removed from the supernatant; the prepared end product is frozen and stored at (-65)-(-70)°C until used.
EFFECT: extended range of products possessing the anti-tumour activity.
1 tbl, 1 ex
SUBSTANCE: invention refers to medicine, namely to oncology and immunology, and can be used in treating an individual with a stable pathogenic infection or a tumour. That is ensured by administering a therapeutically effective amount of a programmed death (PD-1) peptide antagonist and a therapeutically effective amount of a pathogen or tumour antigen molecule (vaccine).
EFFECT: invention provides the synergetic action of the antigen and PD-1 antagonist (anti-PD-L1 antibody) combination by intensifying the T-cell immune response to the pathogen or tumour.
14 cl, 29 dwg, 5 tbl, 25 ex
FIELD: medicine, pharmaceutics.
SUBSTANCE: invention refers to biotechnology, more specifically to MUC1 cytoplasmic domain peptides, and can be used in the anticancer therapy. A method for inhibiting MUC1-positive cancer cell in an individual involves administering into an individual the MUC1-peptide of the length of at least 6 sequential MUC1 residues and no more than 20 sequential MUC1residues and containing the sequence CQCRRK, wherein the amino terminal cysteine from CQCRRK is closed at its NH2 terminal by at least one amino acid residue, which shall not conform with the native transmembrane sequence MUC-1. Alternatively, there can be used MUC-1 peptide of the length of at least sequential MUC1 residues and no more than 20 sequential MUC1 residues, which contains the sequence CQCRRK with all amino acid residues of the above peptide being D-amino acids.
EFFECT: invention enables inhibiting MUC1oligomerisation effectively and inducing the tumour cell apoptosis and the tumour tissue necrosis in vivo.
80 cl, 16 dwg, 1 tbl, 3 ex
FIELD: medicine, pharmaceutics.
SUBSTANCE: invention relates to field of biochemistry, in particular to single variable domain, aimed against IL-6R, to polypeptide and construction, directed against IL-6R, containing said single variable domain, as well as to methods of obtaining them. Disclosed are nucleic acids, coding said single variable domain, polypeptide and construction, as well as genetic constructions, containing said nucleic acids. Described are host cells and host organisms, containing said nucleic acids. Invention also deals with composition for blocking interaction of IL-6/IL-6R, containing effective quantity of described single variable domain, polypeptide, construction, nucleic acid or genetic construction. Also disclosed is method of prevention and/or treatment of at least one of diseases or disorders, associated with IL-6, IL-6R, complex IL-6/IL-6R and/or signal pathways, in which IL-6, IL-6R or complex IL-6/IL-6R is involved and/or biological functions and reactions, win which IL-6, IL-6R or complex IL-6/IL-6R takes part with application of described single variable domain, polypeptide, construction or composition.
EFFECT: invention makes it possible to block interaction of IL-6/IL-6R effectively with increased affinity and biological activity.
25 cl, 70 dwg, 56 tbl, 61 ex
SUBSTANCE: invention refers to biotechnology, in particular to tumour-specific promoters, and can be used in the anti-cancer therapy. There are constructed the broad-spectrum tumour-specific promoters providing the therapeutic gene expression inside a cancer cell. The invention also involves expression cassettes, expression vectors, pharmaceutical compositions, methods of treating cancer and using the expression cassettes and vectors.
EFFECT: promoters of the present invention provide a high expression level of the operatively linked therapeutic gene in the cancer cells of different origin, wherein the normal cell expression is absent or low.
29 cl, 19 dwg, 4 tbl, 20 ex
FIELD: medicine, pharmaceutics.
SUBSTANCE: invention refers to specific compounds or their therapeutically acceptable salts presented in the patent claim and representing sulphonyl benzamide derivatives. Besides, the invention refers to a pharmaceutical composition and a method of treating bladder cancer, brain cancer, breast cancer, bone marrow cancer, cervical cancer, chronic lymphocytic leukemia, colorectal cancer, stomach cancer, hepatocellular carcinoma, lymphoblastic leukemia, follicular lymphoma, T-cell or B-cell lymphoid process, melanoma, myelogenic leukaemia, myeloma, oral cancer, ovarian cancer, non-small-cell lung cancer, prostate cancer, small-cell lung cancer, spleen cancer with the above composition containing an excipient and a therapeutically effective amount of the sulphonyl benzamide derivative or its therapeutically acceptable salt.
EFFECT: preparing the new pharmaceutical composition.
5 cl, 45 ex
FIELD: medicine, pharmaceutics.
SUBSTANCE: invention relates to novel compounds of formula Ia, their stereoisomers or pharmaceutically acceptable salts, inhibiting JAK kinase activity. Compounds can be applied in treatment of inflammatory diseases, such as rheumatoid arthritis, psoriasis, contact dermatitis, in treatment of autoimmune diseases, such as lupus, multiple sclerosis, neurodegenerative diseases, such as Alzheimer's disease, etc. In formula Ia R1 represents H; R2 represents -OR4, -NR3R4- or -NR3S(O)2R4; R3 represents H or C1-C6alkyl, where said alkyl is optionally substituted with ORa; R4 represents H, C1-C6alkyl, -(C0-C5alkyl)(C3-C6cycloalkyl), -(C0-C5alkyl)(C4-C5heteroaryl), where heteroaryl contains 1-2 nitrogen atoms as heteroatoms, or -(C0-C5alkyl)(C6aryl), where said alkyl is optionally substituted with group R8 and said aryl, cycloalkyl and heteroaryl are optionally substituted with group R9; or R3 and R4, taken together with nitrogen atom, which they are bound to, form C3heterocyclyl, containing 1 nitrogen atom as heteroatom, optionally substituted with group R13; Z represents -NR5R6; R5 represents H; R6 represents H, C1-C10alkyl, -(C0-C5alkyl)(C4-C5heterocyclyl), where heterocyclyl contains oxygen atom as heteroatom, -(C0-C5alkyl)(C3-C8cycloalkyl), -(C0-C5alkyl)(C3-C5heteroaryl), where heteroaryl contains 1 nitrogen atom or 1 oxygen atom or contains 2 atoms, selected fromoxygen, nitrogen and sulphur, as heteroatoms, -(C0-C5alkyl)(C6aryl), where said alkyl is optionally substituted with group R10, and said aryl, cycloalkyl, heteroaryl and heterocyclyl are optionally substituted with group R11; R7 represents H; R8 and R10 each independently represents halogen or ORa; R9 independently represents -CN, -CF3, halogen, -C(O)ORa, -C(O)NRaRb, -(C0-C5alkyl)NRaRb, -(C0-C5alkyl)ORa, -(C0-C5alkyl)SRa, -O[C(Ra)2]1-3O-, C1-C3alkyl, optionally substituted with F, -(C0-C5alkyl)(C3-C6cycloalkyl), optionally substituted with group oxo or F, -(C0-C5alkyl)C3-C6heterocyclyl, where heterocyclyl contains 1-2 heteroatoms, selected from atoms of oxygen and nitrogen, and where heterocyclyl is optionally substituted with halogen or C1-C3alkyl, -(C0-C5alkyl)C6aryl, optionally substituted with halogen, or -(C0-C5alkyl)C4-C5heteroaryl, where heteroaryl contains 1 nitrogen atom or 1 oxygen atom or contains 2 atoms, selected from atom of oxygen, nitrogen and sulphur as heteroatoms, and where heteroaryl is optionally substituted with or C1-C3alkyl; R10 independently represents halogen or ORa. Other values of radicals are given in the invention formula.
EFFECT: obtaining pharmaceutically acceptable salts, inhibiting JAK kinase activity.
15 cl, 4 tbl, 452 ex
FIELD: medicine, pharmaceutics.
SUBSTANCE: invention refers to compounds of formula I , II or IV , wherein the radical values W, V, Ra, Rb, X, L, Rt, A are presented in the patent claim.
EFFECT: declared compounds identify and bind the CA-IX protein; they can contain a radioactive element for radionuclide imaging or therapeutic application.
27 cl, 1 tbl, 5 dwg, 25 ex
SUBSTANCE: invention relates to radiation and experimental biology, biotechnology and medicine, namely to means of radiological protection and to stimulators of colony formation of stem cells. Invention can be used in research and clinical practice for protection of living organisms in case of exposure to ionising radiation, in emergency and military medicine, in case of emergency situations as means for protection against radiation injury. Claimed is application of preparation gamma-plant as radioprotector with colony-stimulating properties for increasing survival and improving state of organisms, subjected to irradiation. Gamma-plant is non-toxic polysaccharide of vegetable origin, registered by Ministry of Health of the Russian Federation and allowed for medical application; Gamma-plant is included into Russian Pharmacopoeia in section FG-9 "non-narcotic analgesics".
EFFECT: invention makes it possible to increase efficiency of colony formation of stem cells in spleen 2,0-2,3 times, increases survival of experimental animals to 95% with coefficient of dose reduction factor DRF, equal 2-2,2.
SUBSTANCE: invention is a composition having antibacterial, immunostimulating, anti-allergic and anti-inflammatory action, containing bacterial waste products useful for human body, in the form of exometabolites and fermentolysis products, characterised in that it is a culture medium of lactic acid bacteria, containing laxarane in an amount of 5-10 g/ml, caseicyne, isracydine or their mixture and lectins in an amount of 0.05-2.5 mol/l, histamine in an amount of 0.8-2.0 mmol/l and monocarboxylic fatty acid with an unbranched chain, namely, acetic acid, propionic acid, butyric acid and valeric acid - in an amount of 10-20 mg/ml.
EFFECT: expanding the range of agents having complementary antibacterial, immunomodulating, anti-allergic and anti-inflammatory action.
4 cl, 5 ex
SUBSTANCE: supramolecular complex, possessing an anti-inflammatory and angioprotective activity, which includes dihydroquercetin, arabinogalactan and water with a specified content of components. The method of obtaining the supramolecular complex includes mixing arabinoglactan with water to complete dissolution, then the addition of dihydroquercetin, heating the solution, mixing, with the following drying of the obtained solution by a method of spraying, under specified conditions.
EFFECT: increase of dihydroquercetin water solubility.
2 cl, 1 dwg, 5 tbl, 8 ex
FIELD: medicine, pharmaceutics.
SUBSTANCE: group of inventions refers to biotechnology. What is presented is an in vitro method for controlling a biofilm containing gram-negative bacteria, gram-positive bacteria or yeast, involving the contact of the above biofilm and an alginate oligomer. The alginate oligomer has an average molecular weight of less than 20000 Da and at least 80% of G residues, particularly α-L-guluronic acid. For the purpose of controlling the biofilm, including a biofilm infection, the above alginate oligomer can be also used as a part of a kit or a cleaning composition combined with other ingredients, as well as an abiotic surface coating.
EFFECT: above alginate oligomer can be used for preparing a therapeutic agent for using in treating or preventing the biofilm infection in an individual.
88 cl, 10 dwg, 7 tbl, 15 ex
FIELD: medicine, pharmaceutics.
SUBSTANCE: invention relates to the pharmaceutical industry, in particular to a peroral pharmaceutical composition, which contains polysaccharides from platyclades of Opuntia Ficus Indica, an extract of Olea Europeae leaves, alginate and sodium bicarbonate in a specified ratio. Components of the composition described above act with respect to reduction of gastroesophageal reflux.
EFFECT: peroral pharmaceutical composition is intended for the prevention and treatment of gastroesophageal reflux and GERD.
4 cl, 9 tbl, 6 dwg
SUBSTANCE: group of inventions relates to biotechnology and medicine. Disclosed is a polysaccharide which is isolated from the Bifidobacterium infantis NCIMB 41003 strain and has the structure [-β(1,3)-D-GalpNAc-β(1,4)-D-Glcp-]n, where said disaccharide unit repeats n times, which yields a polysaccharide with molecular weight greater than 100000 Da. The polysaccharide exhibits immunomodulating activity and is used in preparing medicinal agents for treating or preventing undesirable inflammatory activity, undesirable gastrointestinal inflammatory activity, rheumatoid arthritis and autoimmune disorders.
EFFECT: pharmaceutical composition for treating and preventing inflammatory disorders and a food product containing the isolated polysaccharide are disclosed.
9 cl, 6 dwg, 3 ex
FIELD: medicine, pharmaceutics.
SUBSTANCE: invention refers to pharmaceutical industry, namely to a method for preparing water-soluble fractions of mannoproteins and β-glucan. A method for preparing the water-soluble fractions of mannoproteins and β-glucan consisting in the fact that yeast biomass is prepared by mechanical activation in activators and mills; the prepared mechanical complex is added with a solution of enzymic complex showing β-glucanase or protease activity; that is followed by hydrolysis; the prepared hydrolysate is divided into mannoprotein and β-glucan fractions to be subject to purification under certain conditions.
EFFECT: method provides the more effective hydrolysis and higher yield of the end product.
2 cl, 4 dwg, 10 ex
FIELD: medicine, pharmaceutics.
SUBSTANCE: invention refers to pharmaceutical industry and represents pharmaceutical composition for treating gastroesophageal reflux disease, containing at least one proton pump inhibitor and at least one probiotic, wherein the proton pump inhibitor is taken in the amount of 0.05-25 wt % in the composition; and the probiotic is taken in the amount of 10-95 wt %; additive agents up to 100 wt %.
EFFECT: provided preventing Hpylori translocation, avoiding the necessity of Hpylori detection and antibacterial course of eradication, higher safety of the prolonged therapy with the proton pump inhibitors and avoided gastric mucosa atrophy, and a risk of gastric cancer.
5 cl, 10 tbl
SUBSTANCE: invention refers to medicine. What is described is using the material for the purpose of neural dysfunction recovery with the above material containing a polysaccharide derivative hydrogel wherein 0.5 wt % of the aqueous solution contains a complex module in the amount of 1 to 1000 N/m2, while a loss factor makes 0.01 to 2.0 that is measured at angular velocity 10 rad/sec with using a dynamic viscoelasticity meter. The above material for neural dysfunction recovery may represent hydrogel injected with using a syringe and has an excellent body residence, and has a restorative effect on the damaged or degenerated nerve function.
EFFECT: preparing the material for neural dysfunction recovery.
19 cl, 6 dwg, 6 ex
FIELD: medicine, pharmaceutics.
SUBSTANCE: group of inventions relates to medicine, particularly to ophthalmology. An ophthalmic composition for treating keratoconjunctival damages and inflammations consists of an aqueous solution containing arabinogalactan 1 to 10 wt %, one or more preserving agents specified in a group consisting of sodium merthiolate, thimerosal, phenylmercuric nitrate or phenylmercuric acetate, phenylethyl alcohol, methyl-, ethyl-, propyl parabene, chlorhexidine acetate or gluconate or chlorobutanol, and containing no benzalkonium chloride. The ophthalmic composition is applied as a lacrimal substitute recommended for people wearing contact lenses.
EFFECT: group of inventions provides treating corneal erosions caused by wearing contact lenses.
16 cl, 5 tbl, 7 dwg
SUBSTANCE: pharmaceutical composition possessing antiviral and antibacterial activity and containing L-N-2,6-diamino-hexanoyl-D-glucosamine, L-y-glutamyl-cysteinyl-glycyl-proline, lysine glycyrisinate, desoxyribonuclease, palmitoyl hydroxypropyl trimmonium amylopectin/glycerin cross polymer, hydroxypropyl-beta-cyclodextrin, D,L-pyrrolidone carboxylate N-cocoyl ethylarginate, escin, an emulsifying agent, a preserving agent, a pH control agent, demineralised water in certain amounts. The pharmaceutical composition possessing antiviral and antibacterial activity and containing L-N-2,6-diamino-hexanoyl-ascorbyl phosphate, N-pyrrolidine-carbamoyl-D-glucosamine, lysine ursolate, ribonuclease, a modified acrylic thickening agent, hydroxypropyl-beta-cyclodextrin, D,L-pyrrolidone carboxylate N-cocoyl ethylarginate, glycyrrhizic acid, an emulsifying agent, a preserving agent, a pH control agent, demineralised water in certain amounts. The pharmaceutical composition possessing antiviral and antibacterial activity and containing L-N-2,6-diamino-hexanoyl-hinokitiol, N-pyrrolidine-carbamoyl-D-glucosamine, lysine betulinate, collagenase, palmitoyl hydroxypropyl trimmonium amylopectin/glycerin cross polymer, hydroxypropyl-beta-cyclodextrin, chlorhexidine bigluconate, D-panthenol, an emulsifying agent, a preserving agent, a pH control agent, demineralised water in certain amounts. The pharmaceutical composition possessing antiviral and antibacterial activity and containing fusidoyl lysine, lysyl-valyl-proline pomolate, proline escinate, lysozyme, hydroxypropyl trimmunium maltodextrin, cross polymer, hydroxypropyl-beta-cyclodextrin, D,L-pyrrolidone carboxylate N-cocoyl ethylarginate, cedar extract, an emulsifying agent, a preserving agent, a pH control agent, demineralised water in certain amounts.
EFFECT: compositions possess expressed antiviral and antibacterial activity and are stable.
4 cl, 2 tbl, 11 ex