Cyclodextrene-based polymers for therapeutics delivery

FIELD: chemistry.

SUBSTANCE: invention relates to cyclodextrin-containing polymeric compounds, which are carriers for delivery of therapeutics, and pharmaceutical preparations based on them. Invention also relates to method of treating subjects with therapeutically effective quantity of said cyclodextrin-containing polymeric compound. Claimed cyclodextrin-containing polymers improve medication stability, increase its solubility and reduce toxicity of therapeutics when used in vivo. Furthermore, by selecting from a variety of linker groups and targeting ligands of said polymers it is possible to realise controlled delivery of therapeutic agents.

EFFECT: obtaining cyclodextrin-containing polymer compounds, improving medication stability, increasing its solubility and reducing toxicity of therapeutics when used in vivo.

56 cl, 13 dwg, 7 tbl, 46 ex

 

The text descriptions are given in facsimile form.

1. Containing cyclodextrin polymer connection for delivery of therapeutic agents having the structure represented by formula I

where P denotes a linear or branched polymer chain;

CD denotes the units of the cyclodextrin;

L1and L3independently in each case may be absent or denote a group of the linker and L1represents a group of the linker with biohydrology or biodegradable communication with D;

D is independently in each case refers to a therapeutic agent or prodrug;

T is independently in each case denotes a target ligand or its predecessor;

a, m and v are independently in each case denote an integer in the range from 1 to 10;

n and w independently in each case denote an integer in the interval from 0 to about 30000;

b represents an integer in the range of from 1 to about 30000,

and or R contains links cyclodextrin, or n is at least 1.

2. The compound according to claim 1, in which the polymer chain contains n units U, and n' denotes an integer in the range of from 1 to about 30000 and U represented by the following formula

where CD is the hereafter which includes cyclodextrins molecule or its derivative; L4, L5and L7independently in each case may be absent or denote a group of the linker and L6represents a group of the linker with biohydrology or biodegradable communication with D;

D and D' independently in each case denote the same or different therapeutic agents or their prodrugs;

T and T' independently in each case denote the same or different target ligands or their predecessors;

f and independently in each case denote an integer in the range from 1 to 10; and

g and z is independently in each case denote an integer in the interval from 0 to 10.

3. The compound according to claims 1 and 2, in which the linker group is hidrocarburos group in which one or more methylene groups, possibly substituted by a group Y (provided that none of the groups Y is not adjacent to another group Y), where each Y is independently in each instance selected from substituted or unsubstituted aryl, heteroaryl, cycloalkyl, geterotsiklicheskie or-O-, C(=X) (where X is NR1, O or S), -OC(O)-, -C(=O)O, -NR1-, -NR1CO-, -C(O)NR1-, -S(On)- (where n is 0, 1 or 2), -OC(O)-NR1, -NR1-C(O)-NR1-, -NR1-C(NR1)-NR1- a and-B(OR1)-; and R1independently in each case represents H or lower alkyl.

4. The compound according to claims 1 and 2, in which l is ncrna group represents an amino acid, or peptide, or a subclass thereof.

5. The compound according to claims 1 and 2, in which therapeutic agent is a small molecule, peptide, protein or polymer having therapeutic activity.

6. The compound according to claims 1 and 2, in which therapeutic agent is hydrophobic (log P > 0,4, 0,6, 0,8, 1).

7. The compound according to claims 1 and 2, in which therapeutic agent has a low solubility in water.

8. The compound according to claims 1 and 2, in which the target ligand is covalently bonded to the linker group via biohydrology connection.

9. The compound according to claims 1 and 2, which biohydrology communication chosen from ester, amide, carbonate or urethane linkages.

10. The compound according to claims 1 and 2, in which therapeutic agent is covalently bonded to the linker group containing ester, amide, carbonate or urethane link.

11. The compound according to claims 1 and 2, in which therapeutic agent is selected from anticancer, antifungal, antibacterial, antifungal or antiviral agent.

12. The compound according to claims 1 and 2, in which therapeutic agent is an agonist of the receptor.

13. The compound according to claims 1 and 2, in which therapeutic agent is an antagonist of the receptor.

14. The compound according to claims 1 and 2, which is biodegradable or biorazlagaemykh.

15. The compound according to claims 1 and 2, which has srednesemennyh molecular weight (M nin the range from 10000 to 500000 srole

16. The compound according to claims 1 and 2, which has srednesemennyh molecular weight (Mnin the range from 5000 to 200000 srole

17. The compound according to claims 1 and 2, which has srednesemennyh molecular weight (Mnin the range from 10000 to 100000 srole

18. The compound according to claims 1 and 2, characterized in that therapeutic agent is selected from anorexia, anti-arthritis means, Antiasthmatic agents, anticonvulsants, antidepressants, antihistamine agents, anti-inflammatory agents, decongestants funds antineoplastics agents, antipsychotic agents, antipyretic, antispasmodic funds, cardiovascular drugs, antihypertensive drugs, diuretics, vasodilators funds, stimulants of the Central nervous system, nutrients, antiemetics, antipruritic drugs, cough and colds, neuroleptic agents, antidepressants, antagonists, diagnostic drugs, hormones, bone growth stimulants and inhibitors of bone resorption, immunosuppressants, muscle relaxants, psychostimulants, sedatives, tranquilizers, anti-inflammatory agents, anti-epileptics, anesthetics, hypnotic, antipsychotic agents, anxiolytics, protivostala the different agents, agents that block the action on neurons, anticholinergic and cholinomimetic agents, antimuskarinovoe act occurs and muscarinic agents, antiadrenergic, antiarrhythmic drugs, and antihypertensive agents.

19. Containing cyclodextrin polymer connection for delivery of therapeutic agents having the structure represented by formula II

where R denotes a Monomeric unit of the polymer;

T is independently in each case denotes a target ligand or its predecessor;

L6, L7, L8and L10independently in each case may be absent or denote a group of the linker and L9represents a group of the linker with biohydrology or biodegradable communication with D;

CD independently in each case denotes cyclodextrines fragment or derivative;

D is independently in each case refers to a therapeutic agent or prodrug;

m is independently in each case denotes an integer in the range from 1 to 10;

p, n and q independently in each case denote an integer in the interval from 0 to 10,

moreover, CD and D, each, is present in the connection at least once.

20. The connection according to claim 19, in which the linker group is hidrocarburos group, in which one is more methylene groups, possibly substituted by a group Y (provided that none of the groups Y is not adjacent to another group Y), where each Y is independently in each instance selected from substituted or unsubstituted aryl, heteroaryl, cycloalkyl, geterotsiklicheskie or-O-, C(=X) (where X is NR1, O or S), -OC(O)-, -C(=O)O, -NR1-, -NR1CO-, -C(O)NR1-, -S(On)- (where n is 0,1 or 2), -OC(O)-NR1, -NR1-C(O)-NR1-, -NR1-C(NR1)-NR1- a and-B(OR1)-; and R1independently in each case represents H or lower alkyl.

21. The connection according to claim 19, in which the linker group is an amino acid or peptide, or a subclass thereof.

22. The connection according to claim 19, in which therapeutic agent is a small molecule, peptide, protein or polymer having therapeutic activity.

23. The connection according to claim 19, in which therapeutic agent is hydrophobic (log P > 0,4, 0,6, 0,8, 1).

24. The connection according to claim 19, in which therapeutic agent has a low solubility in water.

25. The connection according to claim 19, in which the target ligand is covalently bonded to the linker group via biohydrology connection.

26. Connection A.25, which biohydrology communication chosen from ester, amide, carbonate or urethane linkages.

27. The connection according to claim 19, in which therapeutic agent is covalently related the to the linker group, which contains ester, amide, carbonate or urethane link.

28. The connection according to claim 19, in which therapeutic agent is selected from anticancer, antifungal, antibacterial, antifungal or antiviral agent.

29. The connection according to claim 19, in which therapeutic agent is an agonist of the receptor.

30. The connection according to claim 19, in which therapeutic agent is an antagonist of the receptor.

31. The connection according to claim 19, which is biodegradable or biorazlagaemykh.

32. The connection according to claim 19, which has srednesemennyh molecular weight (Mnin the range from 10000 to 500000 srole

33. The connection according to claim 19, which has srednesemennyh molecular weight (Mnin the range from 5000 to 200000 srole

34. The connection according to claim 19, which has srednesemennyh molecular weight (Mnin the range from 10000 to 100000 srole

35. The connection according to claim 19, characterized in that therapeutic agent is selected from anorexia, anti-arthritis means, Antiasthmatic agents, anticonvulsants, antidepressants, antihistamine agents, anti-inflammatory agents, decongestants funds antineoplastics agents, antipsychotic agents, antipyretic, antispasmodic funds, cardiovascular drugs, antihypertensive drugs, DIU is Mikov, vasodilatory funds, stimulants of the Central nervous system, nutrients, antiemetics, antipruritic drugs, cough and colds, neuroleptic agents, antidepressants, antagonists, diagnostic drugs, hormones, bone growth stimulants and inhibitors of bone resorption, immunosuppressants, muscle relaxants, psychostimulants, sedatives, tranquilizers, anti-inflammatory agents, anti-epileptics, anesthetics, hypnotic, antipsychotic agents, anxiolytics, anticonvulsant agents, agents that block the action on neurons, anticholinergic and cholinomimetic agents, antimuskarinovoe act occurs and muscarinic agents, antiadrenergic, antiarrhythmic drugs, and antihypertensive agents.

36. Containing cyclodextrin polymer connection for delivery of therapeutic agents having the structure represented by formula III

where CD denotes cyclodextrines molecule or its derivative;

L4, L5and L7independently in each case may be absent or denote a group of the linker, and L6represents a group of the linker with biohydrology or biodegradable communication with D;

D and D' independently in each case denote the same or different therapeutic agents or their prodrugs;

T and T' independently in each case denote the same or different ligands or their predecessors;

f and independently in each case denote an integer in the range from 1 to 10;

g and z is independently in each case denote an integer in the interval from 0 to 10,

moreover, at least one value of g and at least one value z denotes an integer greater than 0.

37. Connection p, which the linker group is hidrocarburos group in which one or more methylene groups, possibly substituted by a group Y (provided that none of the groups Y is not adjacent to another group Y), where each Y is independently in each instance selected from substituted or unsubstituted aryl, heteroaryl, cycloalkyl, geterotsiklicheskie or-O-, C(=X) (where X is NR1, O or S), -OC(O)-, -C(=O)O, -NR1-, -NR1CO-, -C(O)NR1-, -S(On)- (where n is 0, 1 or 2), -OC(O)-NR1, -NR1-C(O)-NR1-, -NR1-C(NR1)-NR1- a and-B(OR1)-; and R1independently in each case represents H or lower alkyl.

38. Connection p, which the linker group is an amino acid or peptide, or a subclass thereof.

39. Connection p, in which therapeutic agent is a small molecule, peptide, protein or polymer, with t rapeutically activity.

40. Connection p, in which therapeutic agent is hydrophobic (log P > 0,4, 0,6, 0,8, 1).

41. Connection p, in which therapeutic agent has a low solubility in water.

42. Connection p, whose target ligand is covalently bonded to the linker group via biohydrology connection.

43. Connection 42, which biohydrology communication chosen from ester, amide, carbonate or urethane linkages.

44. Connection p, in which therapeutic agent is covalently bonded to the linker group containing ester, amide, carbonate or urethane link.

45. Connection p, in which therapeutic agent is selected from anticancer, antifungal, antibacterial, antifungal or antiviral agent.

46. Connection p, in which therapeutic agent is an agonist of the receptor.

47. Connection p, in which therapeutic agent is an antagonist of the receptor.

48. Connection p, which is biodegradable or biorazlagaemykh.

49. Connection p, which has srednesemennyh molecular weight (Mnin the range from 10000 to 500000 srole

50. Connection p, which has srednesemennyh molecular weight (Mnin the range from 5000 to 200000 srole

51. Connection p, which is OE has srednesemennyh molecular weight (M nin the range from 10000 to 100000 srole

52. Connection p, wherein therapeutic agent is selected from anorexia, anti-arthritis means, Antiasthmatic agents, anticonvulsants, antidepressants, antihistamine agents, anti-inflammatory agents, decongestants funds antineoplastics agents, antipsychotic agents, antipyretic, antispasmodic funds, cardiovascular drugs, antihypertensive drugs, diuretics, vasodilators funds, stimulants of the Central nervous system, nutrients, antiemetics, antipruritic drugs, cough and colds, neuroleptic agents, antidepressants, antagonists, diagnostic drugs, hormones, bone growth stimulants and inhibitors of bone resorption, immunosuppressants, relaxants muscle, psychostimulants, sedatives, tranquilizers, anti-inflammatory agents, anti-epileptics, anesthetics, hypnotic, antipsychotic agents, anxiolytics, anticonvulsant agents, agents that block the action on neurons, anticholinergic and cholinomimetic agents, antimuskarinovoe act occurs and muscarinic agents, antiadrenergic, antiarrhythmic drugs, and antihypertensive agents.

53. The pharmacist is mental preparation with antitumor activity containing pharmaceutical excipient and from 0.01 to 2000 mg of the compound according to any one of claims 1, 2, 19, 36, or its pharmaceutically acceptable complex ester, salt or hydrate.

54. Pharmaceutical dosage form having antitumor activity, containing pharmaceutical excipient and from 0.01 to 2000 mg of the compound according to any one of claims 1, 2, 19, 36, or its pharmaceutically acceptable complex ester, salt or hydrate.

55. The use of compounds according to any one of claims 1, 2, 19, 36 for the manufacture of a medicinal product for the treatment of cancer.

56. Linear water-soluble cyclodextrines polymer designed for delivery of therapeutic agents to which covalently attached many fragments of therapeutic agent through the group split in the biological environment with the release of therapeutic agent, and the introduction of the polymer to the patient leads to their release.



 

Same patents:

FIELD: chemical technology.

SUBSTANCE: invention relates to the inclusion complex of cyclodextrins with elemental sulfur. Complex can be prepared using different homologues of cyclodextrins, for example, beta- and gamma-cyclodextrins and hydroxypropylated forms of gamma- and beta-cyclodextrins. Proposed complex can be used as a biologically active compound for medicinal, veterinary and agricultural designation. Invention provides the possibility for further preparing true solutions of elemental sulfur in water in the concentration up to 250-300 mg/l.

EFFECT: improved preparing method, valuable properties of complex.

7 cl, 7 ex

FIELD: chemical technology.

SUBSTANCE: invention describes a method for preparing immobilized β-cyclodextrin. Method involves pretreatment of organic and inorganic sorbents - polyvinyl alcohol and sorbitol based on silica with glutaraldehyde for incorporation of aldehyde group molecules into sorbents, washing out with water and dimethylsulfoxide on glass porous filter, drying on glass porous filter followed by addition of prepared sorbents to dimethylsulfoxide solution containing dissolved β-cyclodextrin in the ratio sorbent : β-cyclodextrin : dimethylsulfoxide = 1.0:(0.4- 2.0);10, respectively, stirring the prepared suspension at temperature 25-70°C for 30-180 min, washing out and drying. Method provides preparing an insoluble sorbent with immobilized β-cyclodextrin used for removing cholesterol or its derivatives.

EFFECT: improved preparing method.

5 ex

FIELD: organic chemistry, medicine.

SUBSTANCE: invention describes a derivative of 6-mercaptocyclodextrin of the general formula (I):

wherein n = 0-7; n = 1-8 and m + n = 7 or 8; R represents (C1-C6)-alkylene substituted optionally with 1-3 OH-groups, or (CH2)o-phenylene-(CH2)p wherein o and p = 0-4 independently; X represents COOH, CONHR1, NHCOR2, SO2OH, PO(OH)2, O(CH2-CH2-O)q-H, OH or tetrazole-5-yl; R1 represents hydrogen atom (H) or (C1-C3)-alkyl; R2 represents carboxyphenyl; q = 1-3; or its pharmaceutically acceptable salt in mixture with pharmaceutically acceptable accessory substances. Also, invention describes a set and pharmaceutical composition for reversing drug-induced neuromuscular blocking comprising derivative of 6-mercaptocyclodextrin of the general formula (I), and a method for reversing drug-induced neuromuscular blockade in patient that involves parenteral administration to indicated patient the effective dose of 6-mercaptocyclodextrine derivative of the general formula (I) by cl. 1.

EFFECT: valuable medicinal properties of agents.

11 cl, 1 tbl, 20 ex

The invention relates to a linear cyclodextrin copolymers and oxidized cyclodextrin, which can be used as a carrier for the delivery of various therapeutic agents

The invention relates to a new complex platinum compound, which is useful in medical practice for the treatment of cancer

- cyclodextrin and method of suppressing tumor growth" target="_blank">

The invention relates to organic chemistry, and medicine, and it applies to substances used in combination with ascorbic acid for the treatment of malignant neoplasms (binary catalytic "dark" therapy of malignant tumors) and method of suppressing tumor growth

The invention relates to new crystalline complex compound of-,and/or-cyclodextrin hydrochloride ranitidine when the molar ratio of these components is from 1:1 to 2:1

FIELD: chemistry.

SUBSTANCE: invention relates to the new pyrazole derivatives of formula (IIa) or their pharmaceutically acceptable salts, where: Rx and Ry banded with intervening atoms while deriving benzol or cyclohexylene rings, optionally substituted by R3; R1 represents T-(ring D); ring D represents phenyl, optionally substituted by 1-2 groups R5, or naphtyl or imidazolyl or benzymidazolyl, optionally substituted by C1-C6alkyl group; T represents the linking; R2 represents hydrogen, C1-C6alkyl or C3-C6cycloalkyl; R2' represents hydrogen, or R2 and R2' is banded with their intervening atoms while deriving phenyl ring; R3 is selected from C1-C6alkyl, hydrogen, halogen, -OH, -NH2, -NHOH, -NO2, C1-C6alkoxy, optionally substituted -N(R4)2; each R4 independently selected from C1-C6alkyl, -CO2C1-C6alkyl or two R4 at the same nitrogen atom joined with nitrogen atom while deriving morpholine ring; each R5 represents one or two substitutes, independently selected from C1-C6alkyl, halogen, OH, -NH2, -CF3, C1-C6alkoxy, -COOH, -CO2C1-C6alkyl, -NHCO-C1-C6aliphatic group, NHCO(C1-C6alkyl)N(R4)2, -CONHC1-C6alkyl, -CONH(C1-C6alkyl)N(R4)2, and -NHSO2C1-C6alkyl. The compounds are useful as inhibitors of protein kinase, in particular as inhibitors Aurora-2 and GSK-3 for the treatment of cancer, diabetes and Alzheimer's disease. The subjects matter is also pharmaceutical composition on basis of their compounds and methods of the treatment of diseases mediated by the protein kinase.

EFFECT: production of new pyrazole derivatives - inhibitors of protein kinase.

25 cl, 12 tbl, 292 ex

FIELD: medicine; oncology.

SUBSTANCE: invention can be applied in treatment of squamous cell carcinoma of oral mucosa. Chemioradiation therapy is used for that purpose, with simultaneous intramuscular injection of 2 ml of 12.5% cyclopheron solution on the pattern of 1st, 3rd, 6th, 9th and 12th day. Additionally, since the first day of chemioradiation therapy cyclopheron applications are applied to the oral mucosa for 20 days twice per day.

EFFECT: reduction of radiation stomatitis and increased total efficiency of treatment.

1 ex

FIELD: medicine; oncology.

SUBSTANCE: before lymphatic nodes and vessels selection Klein's solution in the dose of 2-2.5 ml per 1 cm2 of wound is injected into cellular space of regional metastasis areas. The invention enables cancer metastasis prevention due to anatomical vasospasm and prevention of tumour emboli entering larger lymphatic vessels and venules.

EFFECT: improved prevention efficiency.

FIELD: chemistry, pharmaceutics.

SUBSTANCE: invention proposes a lipid compound with formula (I): , where PHG is a polar head group, obtained from one of the following: phospholipid, lysophospholipid, ceramides, monoacylglycerine, diacylglycerine and triacylglycerine, or -W-Linker-HG, p is a number from 1 to 3, X is independently chosen from C6-24alkenyl, containing one or more double bonds and, possibly, one or more triple bonds, or C6-24alkyl, which are can be substituted with at least one of the following: F, hydroxy, C1-C4alkoxy, C1-C4alkylthio, C2-C5acyloxy and C1-C4alkyl; Y chosen from at least one of S, Se, SO2, SO, O and CH2; and Z is a C1-C10alkyl residue, where each of the X, Y and Z groups is chosen independently, when p is 2 or 3, under the condition that, at least one Y does not represent CH2. Description is also given of the use of formula (I) compound or its pharmaceutical salt in the production of medicinal preparations for curing and/prevention of different conditions, pharmaceutical composition, containing formula (I) compound and the method of obtaining a lipid compound with formula (I).

EFFECT: obtaining sulphur containing phospholipid compounds, with useful biological properties.

58 cl, 8 tbl

FIELD: chemistry, pharmaceuticals.

SUBSTANCE: invention pertains to new compounds with formula I, their pharmaceutical salts and to complex esters. The invented compounds have inhibiting propertied towards catepsin K and can be used for making medicinal preparations for curing diseases and conditions, in which catepsin K is involved, for example, inflammation, rheumatoid arthritis, osteoarthritis, osteoporosis and tumorous diseases. In general formula I R represents H, R13 represents (inferior)alkyl, C3-C10cylcloalkyl or C3-C10cycloalkyl(inferior)alkyl, each of which is independently optionally substituted with a halogen atom, hydroxyl, CN, NO2 or optionally mono- or di(inferior)alkyl substituted amino group; and R14 represents H or optionally substituted phenyl, phenyl-W-, phenyl(inferior)alkyl-W-, C3-C10cycloalkyl, C3-C10cycloalkyl-W-, N-heterocyclyl, N-heterocyclyl -W-. Substitutes of the indicated values of radicals are shown in the formula of invention. The invention also relates to methods of obtaining the compounds.

EFFECT: obtaining pyrrolopyrimidines with inhibiting properties towards catepsin K, which can be used for making medicinal preparations for curing diseases and conditions, in which catepsin K is involved.

4 cl, 59 tbl, 10 ex

FIELD: medicine.

SUBSTANCE: invention relates to medicine, particularly oncology. Method of treatment for liver metastases includes radio-frequency thermoablation. After this the collagen haemostatic sponge, impregnated with cytostatic solution, is attached to liver capsule. In postoperative period the preparation diffusion occurs from the sponge directly to liver tissue, surrounding the necrotic focus, and that can prevent residual tumour cells multiplication.

EFFECT: producing the method of liver metastases local chemotherapy along with prevention of residual tumour cells multiplication.

1 ex

FIELD: chemistry.

SUBSTANCE: invention concerns pyrido[2,3-b]pyrazine derivatives of the general formula I where R1 and R2 are hydrogen, unsubstituted C1-C8 alkyl or substituted with hydroxy-, alkoxy-, nitro- or CO2-alkyl, aryl, heteroaryl selected out of the group of pyrinidile or benzodioxalyl, independently from each other; R4 is hydrogen, R3 is a NR9R10 group where R9 is hydrogen and R10 is a -C(Y)NR11R12 group where Y is O or S and R11 is hydrogen, R12 is an alkyl, alkenyl, alkinyl, cycloalkyl, aryl, possibly substituted by a haloid nitro-, trifluormethyl, alkyl, substituted aryl or heterocyclyl selected out of the group of furanyl or morpholinyl, alkyl or their salts endurable physiologically, their solvates, hydrates and polymorphous forms, where the mentioned compounds can be in the forms of theirs racemates, pure enantiomers and/or diastereomers, or anatiomer and/or diastereomer mixes, or tautomers. The invention also describes a medicine based on the compounds, a method of the medicine obtaining, and application of the medicine in treatment of diseases or abnormalities caused by misdirected cellular signal transduction processes.

EFFECT: possible application in cancer treatment.

12 cl, 2 tbl, 38 ex

FIELD: medicine; pharmacology.

SUBSTANCE: invention concerns composition for treatment, inhibition and prevention of breast cancer containing: one of the processed products and extracts Morinda Citrifolia, in amount five percent by mass; and methylsulphonylmethane in amount five percent by mass. Also application of processed Morinda Citrifolia in manufacturing of composition for treatment, inhibition and prevention of breast cancer and application of processed Morinda Citrifolia in manufacturing of medicinal composition chemically preventing and inhibiting carcinogenesis at initiative stage of carcinogen chemical blocking, free radicals isolation, lipid peroxides suppression and COX-2 inhibition are discovered.

EFFECT: offered composition has synergetic effect.

18 cl, 5 dwg, 5 ex

FIELD: medicine; pharmacology.

SUBSTANCE: wood of Siberian or Daurian larch is debarked, cleaved and dried at 40-50°C to residual moisture 23-27%. Dried wood is chopped, and soluble substances are extracted with 75-85% ethyl alcohol aqueous solution at temperature 45-50°C in ratio raw material:extracting agent 1:(7-10). Further extracting agent is distilled off, and sawdust is supplied to press for additional alcohol return. Then extract aqueous part is cooled to 20-25°C within 20-30 minutes for isolation of resinous impurity accompanying dihydroquercetin (DHQ). Deresined extract aqueous part is added with methyltertbutyl ether (MTBE) in ratio 1: (0.3-0.45), and DHQ is reextracted within 2-3 hours. Extract ether part is isolated separate from aqueous part through sedimentation within 2-2.5 hours and supplied to MTBE evaporation, while target product is crystallised of hot water. Invention enables to produce DHQ with yield 2.2-2.5% of bone-dry wood mass with grade 90-96%.

EFFECT: simplification of process and production of high-quality product.

4 cl, 2 ex

FIELD: medicine; pharmacology.

SUBSTANCE: invention concerns a combination for proliferative disease treatment which contains antidiarrheal agent and epothylon derivative of formula (1) or epothylon derivative, method of diarrhoeia management, associated with epothylon introduction of formula (1), pharmaceutical composition, trade packing and medical product, including antidiarrheal agent and epothylon derivative.

EFFECT: compositions have improved efficiency.

9 cl, 6 ex

FIELD: agriculture; veterinary science.

SUBSTANCE: application of cysteamine, its salt or composition, containing cysteamine or its salt, stabilizer and/or coated carrier to improve lactation of the milking animals, particularly cows.

EFFECT: increases milk yield, its fat and protein content.

42 cl, 24 tbl, 1 dwg

Up!