Solid dosage form having hypolipidemic and hypocholesteremic activity, and method of its production
FIELD: medicine, pharmaceutics.
SUBSTANCE: invention relates to pharmaceutical industry and solid dosage form of calcium atorvastatin. Solid dosage form consists of core containing the following components, wt %: calcium atorvastatin - 1.5-25; microcrystalline cellulose - 2-30; calcium carbonate - 5-30; croscarmellose sodium - 0.5-5; stearic acid and/or its salt - 0.5-1.04; lactose "Lactopress Spraydry" - balance; and shell containing the following components, wt %: polyethylene glycol - 6-28; titanium dioxide - 10-35; talc - 5-25; silicon emulsion - 0.05-4; dye - 0-3; polyvinyl alcohol - balance.
EFFECT: invention provides for production of calcium atorvastatin pills satisfying requirements of National pharmacopeia XI.
4 cl, 5 tbl
The invention relates to the pharmaceutical industry, namely the solid dosage form of atorvastatin with hypolipidemic and hypocholesterolemic activity, and to the way it was received.
Atorvastatin [R(R*, R*)]-2-(4-forfinal)-beta,Delta-dihydroxy-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-pyrrol-1-heptane acid (as calcium salt) is a hypolipidemic agent from a group of statins. Statins (inhibitors of HMG-CoA reductase) are widely used for the treatment of hypercholesterolemia and hyperlipidemia. Their inhibitory action is based on agonism towards reductase HMG-CoA, which is a decrease of the concentration of low-density lipoprotein (LDL) to a greater extent than when using drugs other pharmacological groups, lower cholesterol. In addition, statins normalize the concentration of triglycerides in patients with hypertriglyceridemia.
Statins are well tolerated by patients and is characterized by reliable performance. Clinical studies in patients with coronary heart disease (CHD) and without it, as well as high and normal cholesterol levels consistently demonstrated that statins reduce the relative risk of serious complications from coronary heart disease by approximately 30%, with an absolute positive E. the effect is stronger pronounced in the group of patients with a high baseline risk. This result is explained by the positive effect of statins on plasma lipoproteins on endothelial function, structure and stability of plaques, as well as suppression of thrombosis and inflammation. Mechanisms that do not depend on reduction of LDL may play an important role in achieving positive clinical effect in the use of statins, so maybe the doctors consider them not only as medicines to reduce blood lipid levels, but also as antiatherogenic tools.
The appearance of inhibitors of the reductase 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA), or statins, have revolutionized the treatment of hypercholesterolemia. Statins have become the drugs most often prescribed for the treatment of this condition due to their effectiveness in reducing LDL, as well as good tolerance and safety.
Statins completely inhibit the reductase HMG-CoA enzyme that catalyzes the step that limits the rate of the biosynthesis of cholesterol (Blizzard VI Handbook on clinical pharmacology of cardiovascular drugs. - M.: Binom, 2002). This reduces the concentration of cholesterol in hepatocytes, which increases the expression of LDL receptors in the liver, which removes LDL and its precursors from the circulating blood.
Statins can inhibit the liver Sint is C apolipoprotein b-100, as well as the synthesis and secretion of lipoproteins triglyceride-rich (Oganov RG, Akhmedzhanov NM Atorvastatin is a new inhibitor of HMG-COA reductase inhibitor for the treatment of atherosclerosis and hyperlipidemia // Cardiology. - 2000. - So 40, No. 7).
Available for clinical use of statins atorvastatin is one of the most powerful manifestations lipidemias effect.
Atorvastatin is used for the treatment of primary hypercholesterolemia (heterozygous familial and non-family hypercholesterolemia, Fredrickson type IIA), combined (mixed) hyperlipidemia (Fredrickson type IIb and III), dysbetalipoproteinemia (Fredrickson type III) (as a Supplement to the diet), a family of endogenous hypertriglyceridemia (Fredrickson type IV)that are resistant to diet treatments; homozygous hereditary hypercholesterolemia (as an adjunct to lipid-lowering therapy, including autohemotransfusions purified LDL from the blood); diseases of the cardiovascular system (eg, patients without clinical manifestations of coronary artery disease but with increased risk factors for its occurrence - the age of 55 years, nicotine dependence, hypertension, genetic predisposition), including background dyslipidemia - secondary prevention to reduce total risk of death, infarction, stroke, re-hospitalization for angina and the need for revascularization.
The mechanism of action of atorvastatin is associated mainly with infringement of synthesis of cholesterol in the liver at the stage of avalonbay acid by selective competitive inhibition of HMG-COA reductase. Atorvastatin reduces levels of cholesterol and lipoproteins in the plasma due to disorders of cholesterol synthesis in the liver and increasing the number and activity of hepatic LDL receptors on the cell surface, which leads to increased capture and catabolism of LDL. At the same time increasing the level of high density lipoprotein (HDL) and apolipoprotein A. the Inhibitory effect of atorvastatin against HMG-COA reductase by about 70% determined by the activity of its circulating metabolites. Atorvastatin lowers cholesterol levels in patients with homozygous familial hypercholesterolemia, which is usually not amenable to therapy with lipid-lowering drugs.
Atorvastatin is rapidly absorbed after oral administration. The maximum concentration in plasma is reached after 1-2 hours, the bioavailability of the tablets of atorvastatin compared with the solution is 95-99%. The absolute bioavailability of atorvastatin equal to about 14%and systemic bioavailability inhibitory activity against HMG-COA reductase - OK is around 30%. Low systemic bioavailability due to presystemic metabolism in the mucosa of the gastrointestinal tract (GIT) and at the first passage through the liver. When atorvastatin in the evening the concentration in the plasma is lower than when taken in the morning. However, the degree of reduction of LDL cholesterol does not depend on time of taking the drug during the day. The relationship of plasma proteins 98%.
Atorvastatin is metabolized mainly in the liver under the action of cytochrome P450 4 with the formation of metabolites (ortho - and parahydroxylated derivatives, products of beta-oxidation). Atorvastatin and its metabolites are excreted mainly in the bile. However, atorvastatin is not subjected to severe intestinal-hepatic recirculation. The average half-life of atorvastatin is approximately 14 hours With a urine output of less than 2% of the administered dose of the medication.
The recommended starting dose of atorvastatin is 10 mg 1 time per day. Depending on the initial level of cholesterol dose picked individually and it can vary from 10 to 80 mg/day. Due to the high efficiency of atorvastatin calcium as a hypolipidemic and hypocholesterolemic means its content in solid dosage forms is quite low (less than 10% wt. of the total weight). To prevent segregation of the assets is the main and auxiliary substances in the manufacturing process of solid dosage forms often resort to the stage of granulation, which greatly complicates the process of obtaining and increases the cost of medicines (EN 2332211, 2008, US 6126971, 2000, EN 2325903, 2008). In this regard, the preparation of solid dosage forms of atorvastatin without the stage of granulation is preferred.
The closest analogue of the claimed invention is a solid dosage form, registered under the name "Liprimar", which contains, wt%:
|Lactose monohydrate||of 21.9|
Known dosage form contains a large number of auxiliary components, and the way of obtaining includes a step of granulation, which leads to complication of the process and increase the cost of medicines.
The present invention solves the problem of expansion of the means stated purpose - solid dosage forms containing atorvastatin, by creating solid dosage forms of atorvastatin calcium using available auxiliary substances economical and simple instrumental in the execution of the method. Solid dosage form stated purpose must meet the requirements of the State Pharmacopoeia XI, issue 2.
The problem is solved in that the solid dosage form having hypolipidemic and hypocholesterolemic activity, consists of a nucleus, containing as active substance atorvastatin in the form of its calcium salt and auxiliary components: lactose "Ektapress Spraydry", microcrystalline cellulose (MCC), calcium carbonate, CROs is carmellose sodium (Primerose), stearic acid and/or its salt in the following ratio, wt.%:
|Stearic acid and/or its salt||0,5-1,04|
|Lactose "Ektapress Spraydry"||the rest,|
as well as shell, which is composed of polyvinyl alcohol, titanium dioxide, talc, polyethylene glycol, silicone emulsion, and optionally the dye in the following ratio, wt.%:
|The polyethylene glycol||6-28|
|Polyvinyl alcohol :||rest|
As part of the claimed solid dosage forms such as lactose proposed to use a special brand of lactose: lactose "Ektapress Spraydry". Lactose "Ektapress Spraydry" is lactose obtained by the method of spray drying, is composed of not less than 98% of particles with a size of 250 μm, with a water content of 4.5-5.5 percent. Lactose "Ektapress Spraydry" has the ability to shrink and excellent flowability, which allows its use as a filler in compositions intended for direct compression (without stage granulation).
In the claimed solid dosage form is reduced in comparison with the prototype of the content of microcrystalline cellulose from 40 to 25 %wt. and less. MCC, once in the stomach, absorbs water and swells, creating in him a feeling of heaviness that can be frustrating for patients, especially the elderly. In this regard, the content decreases ICC in the composition of the dosage form is appropriate.
The task is also solved by a method for producing solid dosage forms of atorvastatin with hypolipidemic and hypocholesterolemic activity. The method includes the mixing of atorvastatin calcium and auxiliary substances - lactose "Ektapress Spraydry", mi is recrystallizes cellulose, calcium carbonate in the mixer for uniform distribution of the components in the total mass, dusting stearic acid and/or its salt in a mixture with sodium croscarmellose and tableting mainly progressive pressing on a rotary tablet press with simultaneous dust obtained tablets-cores. Next tablets-engine cover film-forming suspension comprising polyvinyl alcohol, titanium dioxide, talc, polyethylene glycol, silicone emulsion, and optionally a dye.
Atorvastatin calcium is practically insoluble in water which, of course, complicates the problem of choosing pharmaceutically acceptable and compatible auxiliary components in order to obtain such a dosage form from which it would release occurred at a rather high speed.
On the other hand, the solid dosage form of atorvastatin should have sufficient mechanical strength so as tableting, usually occurs on high-speed presses under pressure, and good stability during storage.
In addition, you must choose among acceptable such targeted supplements that will help get the pill by way of direct pressing (without stage granulation).
Thus, the choice of a pharmaceutically acceptable Zell who's additives to obtain the pharmaceutical composition of atorvastatin in solid dosage form due to the need not only compatibility auxiliary components atorvastatin calcium and opportunity forming a solid tablet by direct compaction, but also achieve high speed of its release to ensure availability for absorption.
Main forming excipients in the composition of the inventive solid dosage forms are lactose "Ektapress Spraydry" and microcrystalline cellulose, which largely determine the rate of release, speed, and completeness of absorption of drug substances, as well as the stability of the tablet during storage.
Molding materials possess good flowability and compressibility, so create the necessary mass and volume and contribute to the preservation of a certain form of pill.
As the alkalizing agent used calcium carbonate. The action of this substance due to its ability to affect the functioning of the digestive system, namely to adjust the pH of the acidic environment of the stomach, thereby increasing the bioavailability and dissolution rate of atorvastatin calcium, which is poorly soluble in water and in acidic environment. Also, many enzymes (pancreatic lipase, ATP-ASE, phosphodiesterase and others) are activated in the presence of calcium carbonate, which is a hydrophilic substance, and it is soluble in the acidic environment of the stomach with the formation of the ion of CA2+. The presence of IO is s Sa 2+in the gastric environment catalyzes the effect of atorvastatin and faster onset of therapeutic effect. In addition, the presence in the composition of the dosage form alkalizing agent (calcium carbonate) is favorable for patients with high acidity of the stomach.
The use of calcium carbonate in the amount specified improves the consistency of the tablet mass, which contributes to the increase of the forming properties of the tablets.
The presence of an alkalizing agent in larger proportions than stated, may cause increased secretions of hydrochloric acid and pepsin, which significantly reduces therapeutic effect of the drug, and in smaller impairs the stability and molding properties of the tablets.
As a substance that provides rapid mechanical destruction of the tablets in liquid environment, promote rapid release of atorvastatin and early beginning of its suction, and hence the provision of therapeutic effect, apply sodium croscarmellose (Primerose).
The action of sodium croscarmellose as disintegrant, due to the fact that due to its high absorption capacity, it increases the porosity of the tablets due to the formation of hydrophilic pores through which the fluid penetrates into the tablet and destroy it.
The presence of sodium croscarmellose in savlon the m number creates optimal conditions for penetration into the pores of the liquid and provides accelerated dissolution of atorvastatin calcium. When using a smaller amount of sodium croscarmellose than stated, decreasing the solubility of the tablet and, consequently, decreases the rate of release of the active substance. Introduction sodium croscarmellose the tablet on stage dusting ensures optimum profile disintegration of the tablets.
As outrivaled substances that protect the press tool from the aggressive actions of the ingredients of the tablet mass on the walls of punches and matrices and giving the tablet weight, the fluidity, the use of stearic acid and/or its salt, preferably magnesium stearate.
The use of stearic acid and/or its salt in the stated quantities ensures even after the tablet mass from the hopper into the matrix that ensures the accurate dosing of atorvastatin calcium, contributes to facilitating the ejection of the tablets from the die, prevents the formation of scratches on the faces of the matrix, prevents sticking of tablet mass on the walls of punches and matrices, as well as the adhesion of particles to each other. In addition, sliding substances remove electrostatic charge from the particles of substances that also improves their flowability.
As stearates (as stearic acid) are hydrophobic substances, they impede the penetration of liquid into the porous structure of the tablet which impairs its raspadaemost. Therefore, more than stated, the quantities of these components affects the raspadaemost pills, and less number impairs the flowability tablet mass.
The coatings are solid dosage forms of atorvastatin was carried out to achieve the following objectives: to give the tablets a beautiful appearance, increase their mechanical strength, to hide the unpleasant taste and smell, to protect from exposure to the environment (light, moisture, oxygen). In the private version of the invention when creating a water-soluble film coating is used as film-forming agent is a special component of Opadry. This is an artificial material that is different ecological plasticity and high strength combined with low weight, and resistance to ultraviolet radiation. This substance not only has all the necessary properties for the shell, but also allows you to get a thin coating. Such shell corrects taste better decays, providing quick and complete release in the body of the active substance from the tablets, increasing the bioavailability of the tablets. It consists of the following components: polyvinyl alcohol, titanium dioxide, talc, polyethylene glycol and sometimes dye.
To improve the quality of the coating as antifoam used the SJ silicone emulsion, which increases water-repellent properties of the coating and its resistance to UV irradiation. The use of silicone emulsions in the claimed amount does not affect the gloss of the coating and does not change color dyes.
The following are examples of compositions of the inventive solid dosage forms of atorvastatin calcium, in particular tablets, coated (for dosage of atorvastatin 10 mg table 1 for dosage 20 mg table 2).
|Name||wt.%.||The quantity mg|
|Lactose "Ektapress Spraydry"||66,72||93,41|
|Calcium carbonate||15,54||a 21.75|
|Sodium croscarmellose (Primerose)||2,07|
|Magnesium stearate||1,04 (1% by weight of the whole tablet)||1,45|
|Polyvinyl alcohol :||39,2||1,960|
|Polyethylene glycol (Macrogol)||19,8||0,99|
|Name||wt.%.||The quantity mg|
|Lactose "Ektapress Spraydry"||they accounted for 60,54||121,08|
|Microcrystalline cellulose||the 10.40||20,80|
|Sodium croscarmellose (Primerose)||2,08||4,16|
|Magnesium stearate||1,04 (1% by weight of the whole tablet)||2,08|
|Polyvinyl alcohol :||39,25||3,1400|
|Polyethylene glycol (Macrogol)||received 19.82||1,5857|
|Dye (blue aluminium painted)||0,33||0,0267|
Claimed in the invention the method is as follows. In the mixer download powders of atorvastatin calcium and auxiliary substances - lactose "Ektapress Spraydry", microcrystalline cellulose and calcium carbonate, are thoroughly mixed to a uniform distribution in the total mass and, as a consequence, the accuracy of dosing. Then in the mixer load sodium croscarmellose and stearic acid and/or its salt, optivault.
After mixing and dusting homogeneous pellet mass is sent to the stage tabletting, which is accomplished with the simultaneous dust obtained tablets-cores mainly progressive pressing on a rotary tablet press.
The coated surface of the tablet cores is carried out in a machine of the drum type. Film-forming suspension comprising polyvinyl alcohol, titanium dioxide, talc, polyethylene glycol, silicone emulsion, and optionally the dye is sprayed through a nozzle on the pill cores, which are simultaneously dried by the warm air stream with constant stirring in a rotating perforated drum.
When determining raspadaemosti tablets obtained according to the claimed invention, it was found that tablets were disintegrated for 4-10 min, while on the mesh the disk particles did not remain, that meets the requirements of the global Fund XI, issue 2.
According to the data obtained from studies of the rate of dissolution of tablets, it was found that all the subjects of a series of drug comply with FSA requirements, the solution was released more than 75% (Q) in 45 minutes at raspadaemosti tablets for a period of not more than 30 min). Experimental data on raspadaemosti and dissolution are presented in table 3.
|Series, No.||Raspadaemost, min||Dissolution, %|
|The dose of 10 mg||The 20 mg dose||The dose of 10 mg||The 20 mg dose|
To establish the purity of the preparation was determined by "impurities using HPLC method. All the tests for the determination of impurities in drug showed compliance with the requirements stated in the project Fund, namely: any unidentified impurities is not more than 0.5%. The amount of the impurities is not more than 1.5%.
For medicines dosage of atorvastatin 10 mg conducted the test for "Uniformity of dosing using a UV-spectrophotometry. Test results all the tablets comply with the requirements of the global Fund XI, issue 2, s and were homogeneous for the quantitative content.
Table 4 shows the composition of the tablets within the stated intervals, which have been subjected to research on indicators: raspadaemost, dissolution, hardness, resistance to abrasion, as well as stability during storage.
|The name of the substance||Formulation composition, %|
|Croscarmellose sodium (Primerose)||2,07||2,07||2,07||2,07||2,07||2,07||0,5||5,0|
|Lactose "Ektapress Spraydry"||72,6||54,1||71,96||48,96||77,25||52,25||63,78|
|Polyvinyl alcohol :||33,0||53,95||39,2||39,2||39,2||39,2||39,2||39,2|
All tablets of table 4 had high solubility of the active substance (the norm of the Fund - not less than 70% (Q) in 45 min) and raspadaemosti tablets (norm of the Fund not more than 30 min): recipe No. 1 - 95.6% of at raspadaemosti tablets for 4:45 min, recipe No. 2 - 95,1% at raspadaemosti tablets within 4:57 min, recipe No. 3 - 95,9% at raspadaemosti tablets for 4:51 min, recipe No. 4 - 95,5% at raspadaemosti tablets for 4:50 min, recipe No. 5 - 95.3 per cent in raspadaemosti tablets for 4:52 min; formulation No. 6 - 95,7% at raspadaemosti tablets for 4:47 min; formulation No. 7 - 95.2 per cent in raspadaemosti tablets for 4:48 min; formulation No. 8 is 95.8% at raspadaemosti tablets for 4:55 minutes
Tablets whose composition is shown in table 4, have high durability and resistance to abrasion:
recipe # 1 - strength - 75 N, strength abrasion - 99,1%;
recipe # 2 - strength - 77 N., strength is on the abrasion - 99,2%;
recipe # 3 - strength - 79 N., strength abrasion - 99,3%;
recipe # 4 - durability - 70 N, strength abrasion - 99,7%;
recipe # 5 - strength - 78 N., strength abrasion - 99,8%;
recipe No. 6 - durability - 70 N, strength abrasion - 99,5%;
recipe No. 7 - strength - 71 N., strength abrasion - 99,3%;
recipe No. 8 - strength - 73 N., strength abrasion - 99,5%.
All formulations listed in table 4, showed stability during storage for 3 years.
Table 5 shows the composition of the tablets dosage 20 mg within the stated intervals, which have been subjected to research on indicators: raspadaemost, dissolution, hardness, resistance to abrasion, as well as stability during storage.
|The name of the substance||Formulation composition, %|
|Microcrystalline cellulose||the 10.40||the 10.40||2,0||30,0||the 10.40||the 10.40||the 10.40||the 10.40|
|Croscarmellose sodium (Primerose)||2,08||2,08||2,08||2,08||2,08||2,08||0,5||5,0|
|Lactose "Ektapress Spraydry"||68,88||45,88||68,94||40,94||71,14||46,14||62,66||56,62|
|Polyvinyl alcohol :||33,95||49,95||39,25||39,25||39,25||39,25||39,25||39,25|
|Polyethylene glycol||28,0||6,0||received 19.82||received 19.82||received 19.82||received 19.82||received 19.82||received 19.82|
|Dye (blue aluminium painted)||3,0||0,05||0,33||0,33||0,33||0,33||0,33||0,33|
All tablets had high solubility of the active substance (the norm of the Fund - not less than 70% (Q) in 45 min) and raspadaemosti tablets (norm of the Fund not more than 30 min): recipe No. 1 - 94,7% at raspadaemosti tablets for 3:55 min, formulation No. 2 was 94.2% at raspadaemosti tablets for 3:59 min, recipe No. 3 - 94,8% at raspadaemosti tablets for 3:55 min, recipe No. 4 - 94,5% at raspadaemosti tablets for 3:52 min, recipe No. 5 - 94,4% at raspadaemosti tablets for 3:54 min; formulation No. 6 - 94,9% at raspadaemosti tablets for 4:02 min; formulation No. 7 - 94,3% at raspadaemosti tablets for 4:05 min; formulation No. 8 - a 94.6% at raspadaemosti tablets for 3:55 minutes
Pills, the compositions of which are given in table 5, have high durability and resistance to abrasion:
recipe # 1 - strength - 86 N., strength abrasion - 99,3%;
recipe No. 2 strength - 88 N., strength abrasion - 99,1%;
formulation No. 3 strength - 85 N., strength abrasion - 99,5%;
recipe # 4 strength - 83 N., strength abrasion - 99,6%;
recipe No. 5 strength - 87 N., strength abrasion is th - 99,1%;
recipe No. 6 strength - 82 N, strength friability was 99.4%;
recipe No. 7 strength - 81 N., strength abrasion - 99,5%;
recipe No. 8 strength - 84 N, strength abrasion - 99,7%.
All formulations listed in table 5, showed stability during storage for 3 years.
Carefully selected qualitative composition and quantitative ratios of the components responsible for the preparation of solid dosage forms of atorvastatin calcium, which meets all the requirements of the global Fund XI, high technology of its production method without the stage of granulation using available auxiliary substances at high speed raspadaemosti and rapid release tablets of the active substance.
The present method of producing solid dosage forms of atorvastatin provides complete mechanization of the process, its high performance, cleanliness and hygiene tablets, dosage accuracy and speed of release of the active substance, good stability of solid dosage forms during storage.
1. Solid dosage form having hypolipidemic and hypocholesterolemic activity, consisting of a nucleus containing atorvastatin in the form of its calcium salt and additives target - lactose, microcrystalline cellulose, ka is bonat calcium,
stearic acid and/or its salt, sodium croscarmellose, and shell, which is composed of polyvinyl alcohol, titanium dioxide, talc, polyethylene glycol, silicone emulsion, and optionally, a colorant, characterized in that as lactose contains lactose "Ektapress Spraydry" in the following ratio, wt.%:
|Stearic acid and/or its salt||0,5-1,04|
|Lactose "Ektapress Spraydry"||rest|
|The polyethylene glycol||6-28|
|Paint the ü||0-3|
|Polyvinyl alcohol :||the rest of it.|
2. Solid dosage form according to claim 1, characterized in that salts of stearic acid contains magnesium stearate.
3. Solid dosage form according to claim 1, characterized in that the dye contains blue aluminum lacquer.
4. A method of obtaining a solid dosage form according to claim 1, namely, that stirred atorvastatin calcium, lactose "Ektapress Spraydry", microcrystalline cellulose and calcium carbonate, optivault stearic acid and/or its salt in a mixture with croscarmellose sodium, tabletirujut with simultaneous dust tablets-cores and covered with a sheath consisting of polyvinyl alcohol, polyethylene glycol, titanium dioxide, talc, silicone emulsion, and optionally a colorant.
FIELD: medicine, pharmaceutics.
SUBSTANCE: invention relates to compounds of formula I: and their pharmaceutically acceptable salts, in which R1-R4 have values, given in item 1 of invention formula. Said compounds possess inhibiting activity with respect to 11-beta-hydroxysteroid-dehydrogenase and can be applied for production of medications, intended for treatment and prevention of diabetes, especially, diabetes of II type, obesity, malnutrition and hypertension.
EFFECT: development of efficient method of obtaining formula I compounds and based on them pharmaceutical composition.
25 cl, 1 tbl, 149 ex
SUBSTANCE: invention refers to medicine, namely to haematology, cardiology, endocrinology, and can be used for correction of the blood microvesicle level in the patients with arterial hypertension with dyslipidemia and type II diabetes mellitus. That is ensured by graduated physical exercises and the administration of Valsartan 80 mg once in the morning, Lovastatin 40 mg once a day in the evening at mealtimes and Metformin 500 mg twice a day. The length of treatment is at least 6 weeks.
EFFECT: method ensures reduced risk of thrombotic complications, higher clinical effectiveness and improved prognosis in the case patients due to the rating correction of the blood microvesicle level.
SUBSTANCE: invention relates to novel substituted 2-alkylamino-3-sulfonyl-pyrazolo[1,5-a]pyrimidines, their pharmaceutically acceptable salts and/or hydrates which have serotonin 5-HT6 receptor antagonist properties and can be used in treating or preventing development of various central nervous system diseases, whose pathogenesis is related to 5-HT6 receptors, particularly Alzheimer's disease, Parkinson's disease, Huntington disease, schizophrenia, other neurodegenerative diseases, cognitive and anxiety disorders and obesity. In general formula (I):
R1 and R3 independently denote optionally identical C1-C3alkyl, R2 is a -(CH2)nX group or R1 and R3 independently denote different substitutes selected from C1-C3 alkyl or a -(CH2)nX group, and R2 is a hydrogen atom or C1-C3alkyl; R4 is C1-C3alkyl; Ri 5 is a hydrogen atom, one or two identical or different halogen atoms, C1-C3alkyl; i is equal to 0, 1 or 2; n is equal to 0, 1, 2 or 3; X is a carboxyl CO2H, C1-C3alkyloxycarbonyl, aminocarbonyl CONR6R7 or a NR6R7 amino group; R6 and R7 denote optionally identical hydrogen atom, optionally substituted C1-C3 alkyl, C3-C7cycloalkyl or an optionally substituted 5-7-member azaheterocyclyl containing 1-2 nitrogen atoms in the ring, where the substitutes are selected from C1-C3alkyl; or R6 and R7 together with the nitrogen atom to which they are bonded form an optionally substituted 5-6-member azaheterocyclyl containing 1-2 nitrogen atoms in the ring, where the substitutes are selected from C1-C3alkyl.
EFFECT: obtaining new biologically active compounds.
26 cl, 12 dwg, 4 tbl, 14 ex
FIELD: medicine, pharmaceutics.
SUBSTANCE: invention refers to new compounds of formula I , where: R1, R2, R3 and R4 independently from each other mean hydrogen, F, CI, Br, I; R5 designates hydrogen, alkyl with 1, 2, 3, 4, 5 or 6 C atoms, or cycloalkyl with 3, 4, 5 or 6 C atoms; R6 designates hydrogen; R7 and R8 independently from each other mean hydrogen, W means CrH2r or CsH2S-2; and one or more CH2-groups in C2H2r and CsH2s-2 can be substituted with NR17, oxygen or S; R17 means hydrogen, alkyl with 1, 2, 3 or 4 C atoms; r means 1, 2, 3, 4, 5 or 6; s means 2, 3 or 4; X designates-with C(O)- or -S(O)2-; Z means -C(O)- or a bond; and also to their pharmaceutically acceptable salts and trifluoroacetates. The invention also concerns application of the compounds of formula I, and also to a pharmaceutical composition.
EFFECT: preparation of new biologically active compounds exhibiting NHE3 inhibiting activity.
16 cl, 64 ex, 1 tbl
FIELD: medicine, pharmaceutics.
SUBSTANCE: invention refers to medicine and pharmacology, namely to liquid compositions for treating hyperlipidemia, containing fenofibrate dissolved in an excipient which contains omega-3 fatty acid ether and ethanol, and optionally, a surface-active substance. Besides there is disclosed a method for improving fenofibrate solubility in omega-3 fatty acid ether that involves addition of ethanol to said omega-3 fatty acid ether, and also a methods of treating a patient suffering hyperlipidemia. Said improvement of fenofibrate solubility is ensured by the fact that the liquid compositions additionally contain ethanol in minimum amount 10 wt % of the composition weight. Besides a surface-active substance is optionally added to the liquid compositions specified above to ensure better digestion and reduced food intake effect.
EFFECT: improved bioavailability and higher effectiveness in small amount due to better fenofibrate solubility in omega-3 fatty acid ether.
27 cl, 32 tbl, 22 ex, 16 dwg
SUBSTANCE: claimed group of inventions relates to medicine, namely to endocrinology, and deals with regulation of fat in organism. For this purpose stabilisation of alpha subunit of hypoxia-induced factor protein (HIFα) is realised. In order to stabilise HIFα efficient amounts of compound inhibiting HIF hydroxylase activity, representing 2-oxoglutarate-dioxygenase mimetic are introduced.
EFFECT: inventions ensure reduction of fat formation and deposition due to regulation of its metabolism.
31 cl, 11 dwg, 13 ex
SUBSTANCE: invention relates to novel compounds of formula (I) , where X is C(R8R9), NR10, O, S; R1 is phenyl which is substituted with 1-3 substitutes selected from a group which includes halogen, hydroxy group, lower alkyl, hydroxy-lower alkyl and CN; R2 is hydrogenor lower alkyl; R3 and R4 are hydrogen; R5 and R6 are hydrogen; R7 is oxadiazolyl or triazolyl, where oxadiazolyl or triazolyl is substituted with R11; R8 and R9 denote hydrogen; R10 denotes hydrogen, lower alkyl, lower alkyl-carbonyl or lower alkyl-sulfonyl, R11 denotes aryl or hetearyl, selected from a group comprising pyridinyl, pyrazinyl, pyrimidinyl, pyridinyl-2-one, oxadiazolyl, indazolyl, 1,3-dihydrobenzimidazol-2-one, 1,3-dihydroindol-2-one, benzotriazolyl, imidazopyridinyl, triazolepyridinyl, tetrazolepyridinyl, benzimidazolyl, 2-oxo-2,3-dihydro-1H-indol-5-yl, pyrimidin-4-one, furanyl, thiadiazolyl, pyrazolyl, isoxazolyl, pyrimidin-2,4-one, benzoxazin-3-one, 1,4-dihydrobenzoxazin-2-one, indolyl, thiophenyl, oxazolyl, benzooxazin-2-one; 3,4-dihydroquinazolin-2-one, pyridazinyl, quinoxalinyl, benzothiazolyl, benzothiadiazolyl, naphthyridinyl, cinnolinyl, 1,4-dihydroquinoxalin-2,3-dione and 1,2-dihydroindazol-3-one, where the aryl or heteroaryl is optionally substituted with 1-3 substitutes selected from a group which includes lower alkyl, hydroxy group, B(OH)2, carboxy-lower alkoxy group, carbamoyl-lower alkoxy group, cyano group, hydroxy-lower alkyl, fluoro-lower alkyl, lower alkoxy group, halogen, S(O2)R13, C(O)R14, NO2, NR15R16, phenyl-lower alkoxy group, [1,3,4]oxadiazol-2-one, oxadiazolyl, triazolyl and isoxazolyl, imidazolyl, pyrazolyl, tetrazolyl, pyrrolyl, where imidazolyl is optionally substituted with lower alkyl, and where isoxazolyl is substituted with lower alkyl; R12 denotes hydrogen or lower alkyl; R13 denotes lower alkyl, NR17R18 or fluoro-lower alkyl; R14 denotes NR19 R20, lower alkoxy group, lower alkenyl-oxy group or lower alkyl; R15 and R16 independently denote hydrogen, lower alkyl, lower alkyl-carbonyl, lower alkyl-SO2, lower alkenyl-oxycarbonyl and lower alkyl-NH-carbonyl; or NR15R16 denotes heterocyclyl selected from a group which includes morpholinyl, thiomorpholinyl, 1,1-dioxothiomorpholinyl, piperidinyl, piperidin-2-one, piperazin-2-one, 8-oxa-3-aza-bicyclo[3.2.1]octyl, piperazinyl, pyrrolidinyl, 1,1-dioxoisothiazolidinyl, pyrrolidin-2-one, imidazolidine-1,4-dione, 2,4-dihydro[1.2.4]triazol-3-one, pyrrolidine-2,5-dione, azetidin-2-one and 1,3-dihydroimidazol-2-one, where the heterocycle is optionally substituted with hydroxy-lower alkyl or lower alkyl-carbonyl; R17 and R18 independently denote hydrogen, lower alkyl, hydroxy-lower alkyl, lower alkoxy group-lower alkyl; or NR17 R18 denotes morpholinyl; R19 and R20 independently denote hydrogen, lower alkyl, cycloalkyl, hydroxy-lower alkyl, lower alkoxy group-lower alkyl or cyano-lower alkyl; or NR19 R20 denotes heterocyclyl selected from a group which includes morpholinyl, pyrrolidinyl, 8-oxa-3-aza-bicyclo[3.2.1]octyl, piperidinyl, piperazinyl, piperazin-2-one, thiazolidinyl, thiomorpholinyl, 1,3,8-triaza-spiro[4.5]decane-2,4-dione and spiro(1- phthalan)piperidin-4-yl, where the heterocyclyl is optionally substituted with a hydroxy group, lower alkyl-(SO2), lower alkyl, lower alkyl-carbonyl or lower alkoxy group, carboxyl group, carbamoyl, cyano group and phenyl; and to their pharmaceutically acceptable salts. Invention also pertains to a pharmaceutical composition.
EFFECT: obtaining novel biologically active compounds which inhibit hepatic carnitine palmitoyltransferase 1 (L-CPT1).
35 cl, 565 ex, 10 tbl
SUBSTANCE: invention refers to chemical-pharmaceutical industry, and medicine, namely to a new hypolipidemic preparation representing a molecular complex of atorvastatin and β-glycyrrhizic acid at the mole ration of atorvastatin: β-glycyrrhizic acid 1: (1-4).
EFFECT: invention exhibits high efficiency with much smaller dosage than initial atorvastatin.
5 ex, 2 dwg, 3 tbl
SUBSTANCE: invention relates to use of existing and novel N-sulfamoyl- N'-arylpiperazines and their physiologically compatible acid-addition salts of formula I , where Ar denotes a monocyclic or bicyclic C6-C10aryl in which ring carbon atoms are optionally substituted with 1-3 nitrogen or oxygen atoms, and/or where the C6-C10aryl ring system optionally contains 3-5 double bonds, and/or where the C6-C10aryl ring system is optionally substituted with 1 or 2 substitutes which can be identical or different and which can be selected from a group containing halogen, trifluoromethyl, cyano group, nitro group, C1-C4alkyl, C1-C4alkoxy group, C1-C4alkylsulfonyl; and two oxygen atoms which are bonded to two neighbouring carbon atoms of the C6-C10aryl ring system and are bonded by a C1-C2alkylene bridge; or where the C6-C10aryl ring system is substituted with phenyl which can optionally be substituted in the phenyl ring by one substitute which can be selected from a group containing halogen; for preventing or treating obesity and related diseases.
EFFECT: design of a method of obtaining the said compounds and a pharmaceutical composition based on the said compounds.
25 cl, 9 tbl, 5 ex
SUBSTANCE: there are claimed pharmaceutical compositions of atorvastatin, which contain effective quantity of atorvastatin for reduction of low-density lipoprotein level and pharmaceutically acceptable carrier, and method of preparing such compositions. Composition contains atorvastatin with average particle size maximum 50 micron or micronised atorvastatin.
EFFECT: compositions by invention insure reduction of food impact on biological availability of atorvastatin.
48 cl, 1 tbl, 11 ex
SUBSTANCE: invention concerns a solid oral dosage form composition containing therapeutically effective amount of aliskiren or its pharmaceutically acceptable salt in amount exceeding 46 wt %. The oral dosage form represents a tablet or a film-coated tablet. Aliskiren tablet is made by wet granulation with using mixed organic solvents or organic binding solutions.
EFFECT: elimination of aqueous granulation provides high stability of the dosage form of aliskiren and prolonged shelf-life.
18 cl, 2 ex
FIELD: food industry.
SUBSTANCE: present invention relates to gastral retentive composition containing active agent granulated together with the mixture of the first and the second gelatinating agents and mentioned composition production method the first gelatinating agent is a mixture of microcrystalline cellulose and sodium-carboxymethyl cellulose the second gelatinating agent is a compound with viscosity of 1% water solution which makes at least 600 centipoise at 25°C active agent is chosen from antibacterial compounds such as fluoroquinolones, antidiabetic compounds and antihypertensive medicinal agents.
EFFECT: invention provides gastral retentive composition with sustained release effect, which stays in stomach; medical agent has maximal absorption with improved therapeutic action there.
24 cl, 2 ex
SUBSTANCE: invention relates to pharmaceutical dosed form, which contains pharmaceutically active substance, unstable in presence of acid, which includes central nucleus, containing active substance and loosening agent, swelling coating, surrounding central nucleus, and enterosoluble coating, surrounding swelling coating. Swelling coating includes prolamin, preferably, zein. Pharmaceutically active substance includes benzimidazole, selected from omeprazole, lansoprazole, rabeprazole and pantoprazole.
EFFECT: invention ensures fast release of pharmaceutically active substance in medium, which has pH value at least 5.
33 cl, 12 ex
SUBSTANCE: invention concerns a tablet containing fluvastatin with sodium carboxymethylcellulose of calcium in the form of raising agent. The fluvastatin tablet is characterised by time of disintegration from 10 to 30 minutes and good bioavailability equivalent to bioavailability of serially produced capsules, containing fluvastatin. Manufacturing of tablets does peroral application of fluvastatin economically more favourable and more convenient for patients.
EFFECT: rising of profitability and convenience of peroral fluvastatin application to patients.
12 cl, 7 dwg, 6 tbl, 2 ex
FIELD: medicine, pharmaceutics.
SUBSTANCE: invention concerns pharmaceutical chemistry, namely to the method of obtaining of a medical product with a covering from a Pioglitazone hydrochloride which can be used as a therapeutic agent for treatment of diabetes, lipidemias, and also can be an antihypertensive agent, an antiobesity agent, diuretic or an antithrombotic agent.
EFFECT: medical product covered with a hydrochloride pioglitazon, possesses larger stability of an agent at storage, and also improved properties, such as solubility of a Pioglitazone hydrochloride.
11 cl, 30 ex, 3 tbl
FIELD: medicine, pharmaceutics.
SUBSTANCE: invention describes solid dispersed measured drug including a core with pharmacological agent dispersed in the first matrix for controlled liberation at relatively low speed; and coating covering the core and including the agent dispersed in the second matrix for controlled liberation at relatively high speed. The first matrix can be represented by cross-linked starch with high amylose content, and the second matrix can be represented by polyvinylacetate and polyvinylpyrrolidone mix. Solid measured drug is preferably a pill.
EFFECT: reduced administration frequency, relatively stable medicine concentration in organism for a given time period and reduced undesired side effect frequency and intensity due to reduction of high concentrations in plasma.
19 cl, 5 dwg, 4 tbl, 4 ex
SUBSTANCE: claimed composition contains core including Rabeprasol or pharmaceutically acceptable salt thereof as acid secretion inhibitor in stomach and basic compound, intermediate coat coating the core, and overcoat applied on intermediate layer and containing water insoluble polymer and enterosoluble polymer. Also described is method for production of composition containing said preparation.
EFFECT: composition of prolonged storage time providing effective concentration of Rabeprasol in blood for long period of time.
16 cl, 5 dwg, 14 ex
FIELD: chemical-pharmaceutical industry, pharmacy.
SUBSTANCE: invention relates to solid medicinal formulations covered by enterosoluble envelope. Enterosoluble envelope represents a polymeric derivative as conglomerate of hydroxypropylcellulose and acetatephthalatecellulose in the presence of wax and Tween. Envelope has 1-10 layers and its mass is 0.1-10% of the solid pharmaceutical composition mass in the definite ratio of component in envelope. Also, invention represents methods for coating a pharmaceutical composition by such enterosoluble envelope. Invention provides the required disintegration of envelope for capsules as a whole and expanding assortment of active components among medicinal agents useful for applying the claimed cover and with inclusion to this enumeration of thermolabile medicinal immunobiological preparations.
EFFECT: improved and valuable properties of envelope, improved coating method.
9 cl, 7 ex
FIELD: medicine, pharmacy.
SUBSTANCE: invention proposes a composition comprising as active components pyridoxine hydrochloride and doxylamine succinate and a disintegrating agent that provide the following dissolving pattern: 20-90% of the total amount of each component among pyridoxine hydrochloride and doxylamine succinate are dissolved in 5-120 min. The composition is made preferably as a tablet with an enterosoluble envelope. The tablet has a core comprising pyridoxine hydrochloride and doxylamine succinate, and inactive excipients also. The composition is used in treatment of nausea, vomiting being especially in pregnancy. The composition provides rapid and simultaneous release of synergetic pair of indicated active components.
EFFECT: improved and valuable properties of composition.
24 cl, 2 dwg, 9 tbl, 3 ex
SUBSTANCE: invention relates to medicine, namely to pharmaceutical compositions for providing address delivery of medications, which includes water-soluble polysaccharides and medication(s) and can be applied in surgery, oncology and other fields. In method of obtaining medicinal composition for its application on textile material, which includes preparation of polymeric base by introduction of biopolymer with regular mixing in distillated water, seasoning during 12-24 hours at temperature 22-30°C, introduction of medications, mixing of mixture for 45-90 minutes on slow mixer, is proposed to prepare polymeric base with content in biopolymer of not less than 90% of particles with size 20-250 nm, after that to prepare control sample of composition, to measure its viscosity, to carrying out γ - sterilisation according to the standard scheme, after that to re-measure its viscosity, and if viscosity reduces at not more than 15%, in comparison with the initial, to apply said composition for its application on textile material. In case of composition application on textile material with cellulose fibres, content of the latter must constitute not less than 60%.
EFFECT: composition ensures treatment efficiency due to prolonged address delivery of medication to affected areas.
2 cl, 5 ex