Modified release 6-methyl-2-ethyl-hydroxypyridine succinate dosage form

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to medicine, and consists in development of a new dosage of the preparation 6-methyl-2-ethyl-3-hydroxypyridine succinate providing modified release of an active substance. A unit dosage form contains 6-methyl-2-ethyl-3-hydroxypyridine succinate in amount 30.0-70.0 wt %, as a release modifier - cellulose derivatives and/or polyacrylic resins in amount 1.0-20.0 wt %, as an excipient - microcrystalline cellulose in amount 20.0-50.0 wt % and lubricants. The unit dosage form represents a tablet or a capsule consisting of a variety of small dense spheroids containing 6-methyl-2-ethyl-3-hydroxypyridine succinate as a major component. A combination of matrix and instant, coated and uncoated spheroids enables preparation of a drug in the various dosage forms with controlled release rate.

EFFECT: invention allows to produce the unit dosage forms of the preparation 6-methyl-2-ethyl-3-hydroxypyridine succinate for certain treatment regimens of various diseases.

 

The invention relates to medicine and is the creation of a new dosage form of an existing drug 6-methyl-2-ethyl-3-hydroxypyridine succinate, providing modified release of the active substance (immediate, immediately after admission to the extended, for at least 12 hours).

The drug 6-methyl-2-ethyl-3-hydroxypyridine succinate (AMHPS) found effective application in various areas of clinical medicine: neurology, psychiatry, cardiology, ophthalmology, surgery, dentistry, endocrinology and other

Use AMPS in neurology and psychiatry is due to the original spectrum neurotropic action of the drug on neuronal level (anxiolytic, anticonvulsant, anti-stress, cerebroprotective, ANTIPARKINSONISM, antiamnesic and protivooskolochnye properties). At the vascular level AMPS improves cerebral circulation, inhibits platelet aggregation, increases potential anti-platelet blood, reduces total cholesterol, has cardioprotective and anti-atherosclerotic action.

Effective AMHPS and acute disorders of cerebral circulation, discirculatory encephalopathy, vascular dystonia, atherosclerotic disorders of the brain and in each the x States, accompanied by tissue hypoxia. Action AMHPS shown both prevention and treatment of these diseases.

In addition, AMPS can be used in the treatment of various forms of coronary heart disease (CHD). It is noted that AMHPS accelerates the stabilization of angina, improves the clinical course of myocardial infarction, reduces blood levels of LDL, increases the antianginal efficacy of nitrates, but does not affect the efficacy of calcium antagonists and β-blockers. Positive impact AMPS on the parameters of diastolic function of left ventricle in patients with coronary artery disease.

High therapeutic activity AMHPS, his ability to have a positive impact on key stages of pathogenesis of various diseases, the absence of significant side effects, a wide therapeutic range and low toxicity, and the ability to potentiate the action of neurotropic drugs was the basis for drug design on the basis of this substance in different forms such as injectable solutions, tablets, capsules).

But, unfortunately, each dosage form is not without drawbacks.

Injectable forms of the drug on the basis of AMHPS intramuscularly or intravenously 1-3 times a day in a daily dose of 50-800 mg, which is sotoco the dose of 2.5-40 mg of active principle. Known injectable form AMHPS in the form of a 5% aqueous solution AMHPS [PPM Mashkovsky. "Medicinal product", 1993, ch. II, s] and in the form of a solution containing 5-6% AMPS, 0.5-5.0% of succinic acid and up to 0.2% of the trylon B [EN 2205640].

The disadvantage of this method of treatment is that the injectable form AMHPS does not provide long-term neuroprotective effect, traumatic for the patient. In addition, when using AMPS in the form of injections during the course of treatment (more than 30 days), we observed the change in the spectrum of pharmacological activity of the drug, resulting in increased aggressiveness, emotional reactivity, reducing anti-stress action [see description EN 2065299].

Tableted drugs AMPS include ~ 60-80% by weight of the tablet excipients, such as starch and white clay [EN 2065299]. However, the presence of these additives do not prevent the flow of the processes of degradation of the active principle - even at the stage of manufacturing the core tablets yellow [see description EN 2205640].

Capsule form of of medicines on the basis of AMHPS have a slightly lower content of excipients [EN 2145855, EN 2144822]. However, the stability of the finished dosage form is also rather low also observed yellowing of the capsule mass [see description EN 2205640]. To improve the stability of the finished pharmaceutical the public funds, containing AMPS, it was proposed to enter into their composition stabilizer - succinic acid [EN 2205640]. The drug in powder form for capsules contains 50-60% AMPS, 20-35% cellulose, 15-20% starch, 4% to 6% polyvinylpyrrolidone, 0.5-5.0% of succinic acid, 0.8-1.0% stearinovokisly magnesium, 0.6-1.1% talc and up to 0.2% of the trylon B. Solid dosage form produced by this recipe is the closest analogue to the claimed invention, but as others discussed earlier has a fast rate of elimination and through 4,7-5,0 h AMHPS almost not logged in the body, which is the reason for the repeated use of the drug.

Granular application AMPS requires a wide range of the speed of release of drug from dosage forms (as fast as possible when an emergency to the longest prolonged hospitalization), which directly raises the question of the need for SFF with pre-programmed release of drugs. Finished dosage forms containing AMHPS known up to the present time, cannot satisfy this request. Maintaining active plasma concentration for a relatively long period of time is by taking large doses of dosage forms or introducing them several times a day. This approach is not the right, as such doses can create toxic and undesirable high content of drug in the body of the patient. The administration of a medicinal product with some time intervals leads to the formation of the fluctuating level of the medicinal product, the so-called peak-to-failure actions, which in turn leads to inefficiency or failure of treatment, increase the risk of toxic side effects. So sick it is desirable to have a constant concentration of the introduced medicines in the blood.

It is known that to achieve and maintain levels of active ingredients in the plasma used retarding compositions in which the active ingredient is gradually stands out in a biological system.

The release rate from tablets or powders is determined by the solubility characteristics of the active ingredient, which, in turn, depend on the particle size, specific surface area and interaction between the binder. Dissolution can be slowed using a diffusion barriers in the core tablets or film coating. The slow dissolution using diffusion barriers in the core is used quite often because of its technical simplicity. It is possible to use different fillers, such as agents nab the Hania, lipophilic substances or punctuating the plastic substance as diffusion barriers. The base may be such that the release of active ingredient occurs by diffusion of the dissolved active ingredient mainly through the pores of the core tablet and, if required in special cases, by diffusion through the retardation substance that needs to have the appropriate structure. The Foundation may also have the property of slow erosion, leading to the slow excretion of the active ingredient.

The use of hydrophilic and hydrophobic polymers, as a slowing down of the base material, it is well known and tested on a large number of active ingredients (for example, US 4389393; EN 2138253; EN 2212885; EN 2205007), but still was not described any compound that would be suitable for achieving the desired goals with 6-methyl-2-ethyl-3-hydroxypyridine succinate.

The behavior of specific medical substance in combination with retarding filler is impossible to calculate or predict in General. Although the main factors influencing the selection of system basics, well researched, the interaction between slow-wave material, on the one hand, and the active ingredient and other excipients, can have varying effects on slowing down the action.

From all the above-mentioned is about what you can see what cannot be expected a priori selection of various substances with linear kinetics in the previously described systems. The kinetics of allocation should be considered as a case that can take place only under certain forms of dosage of active substances and excipients. Need of a large number of well-known pharmaceutical excipients to choose those that are appropriate for the selected destination, and use them in the right proportions, which also should be selected to get the base system. Such dosage forms specifically for 6-methyl-2-ethyl-3-hydroxypyridine succinate and described in the present invention.

Thus, the object of this invention to provide pharmaceutical compositions containing 6-methyl-2-ethyl-3-hydroxypyridine succinate as the active ingredient and which is characterized by a controlled rate of release. Dosage form is a tablet or capsule, composed of plural small dense spheroids (covered and uncovered a polymeric shell), including 6-methyl-2-ethyl-3-hydroxypyridine succinate as a main component and an excipient.

Each spheroid 6-methyl-2-ethyl-3-hydroxypyridine succinate in accordance with this invention forms a separate element that visuo ordet drug with a predetermined speed.

Matrix and soluble coated and uncoated spheroids enable the manufacture of the drug in different dosage forms with controlled rate of release. They can be enclosed, for example, hard gelatin capsules or tablets, this will provide the desired dissolution profile and, accordingly, the desired profile in plasma concentrations, and duration. In those cases, when the spheroids containing 6-methyl-2-ethyl-3-hydroxypyridine succinate tabletirujut, they are mixed with additives, for example, microcrystalline cellulose (MCC), starch, povidone, or mixtures thereof in the form of a powder or spheroids.

Dense spheroids containing 6-methyl-2-ethyl-3-hydroxypyridine succinate, have a size of 0.25 - 2 mm, preferably 0.35 to 1 mm.

The first group of spheroids (instant) contains 3-hydroxy-6-methyl-2-ethylpyridine succinate and excipients, such as MCC, Aerosil, magnesium stearate, GOC. The composition of the spheroids is chosen so that 6-methyl-2-ethyl-3-hydroxypyridine succinate fully released within 0.5-2 hours

The second group includes a first group of spheroids coated with a polymer shell, consisting of a pH-sensitive polymer (copolymer of methacrylic acid and a complex of methacrylic acid - Eudragit L and Eudragit S) and/or pH-independent polymers (Eudragit NF-ester of methacrylic acid, ethylcellulose). The polymer shell may contain plasticizers, fillers, pigments. Polymeric materials membranes regulate the release of 6-methyl-2-ethyl-3-hydroxypyridine succinate within 2-8 hours

The third group of spheroids is a matrix spheroid, which contains 6-methyl-2-ethyl-3-hydroxypyridine succinate polymer matrix and auxiliary substances. As patriciabrasel polymers can be used hydrophobic pH-independent polymers Eudragit RL, Eudragit NE, Eudragit RS, ethylcellulose mixed with hydrophilic polymers (GOC, HPMC, PVP). For the claimed dosage forms preferred hydrophobic polymer is Eudragit NE in the amount of 10.0 to 20.0 wt.% mixed with hydrophilic GOC in the amount of 2.0 to 6.0 wt.%. The release of 6-methyl-2-ethyl-3-hydroxypyridine succinate from the third group of spheroids is uniform for 5-8 hours as excipients may be any pharmaceutically acceptable excipients, diluents, binding, slip agents and lubricants.

The fourth group includes the spheroids of the third group, covered with a polymer shell, consisting of a pH-sensitive polymer (copolymer of methacrylic acid and a complex of methacrylic acid - Eudragit L and Eudragit S) and/or pH-independent polymers (Eudragit NF - ester of methacrylic acid, etilzelluloza). The polymer shell may contain plasticizers, fillers, pigments. The release of 6-methyl-2-ethyl-3-hydroxypyridine succinate of the fourth group of spheroids is evenly 5-14 hours

Spheroids prepared as follows: 6-methyl-2-ethyl-3-hydroxypyridine succinate, microcrystalline cellulose and other additives, for example, Aerosil, magnesium stearate, are thoroughly mixed in the mixer. Then add the binder solution, for example an aqueous solution of the GOC, and stirred until a homogeneous plastic mass. The mass is passed through an extruder to obtain the extrudate with a diameter of 0.75 mm

The wet extrudate is loaded into spheronization" with a rotary disk with a diameter of 15 cm and a speed of 1500 Rev/min Duration of spheronization is 10 minutes Then the spheroids are dried at a temperature of 50-60°C, passed through a sieve selected spheroids with a diameter of 0,5-0,8 mm

Then part of the spheroids (or all) cover the mixture in the form of a solution in an organic solvent or aqueous dispersion of the polymer.

For each group obtained spheroids determine the dissolution profile and based on the data, calculate the required ratio of the spheroids in the nal dosage form to achieve the desired dissolution profile.

The dissolution profile receive, using apparatus 2 farmacopea the United States (USP apparatus 2): volume environment dissolution 900 ml; the rotation speed of the stirrer at 50 rpm; temperature 37±0.5°C. Environment dissolution in 0.1 N Hcl0-within 2 h, the rest of the time - phosphate buffer, pH 6.8.

In addition, in order to obtain pharmaceutical compositions containing 6-methyl-2-ethyl-3-hydroxypyridine succinate as the active ingredient and is characterized by a modified rate of release of the active substance, the proposed receiving tablets 6-methyl-2-ethyl-3-hydroxypyridine succinate by direct pressing in certain selected ratios of components:

6-methyl-2-ethyl-3-hydroxypyridine succinate in the amount of 30.0-70,0 wt.%, the release modifier in the amount of 1.0 to 20.0 wt.%, the filler is microcrystalline cellulose in an amount of 20.0-to 50.0 wt.%, sliding substances. In this case, as a retarding agent (modifier release) using the cellulose ethers, such as methylcellulose, hydroxypropylcellulose, hypromellose.

Cited specific examples of carrying out the invention.

Example 1. Cooking instant spheroids.

The composition of the spheroids, wt.%:

6-Methyl-2-ethyl-3-hydroxypyridine succinate - 60,0%

ICC - 32,0%

GOC - 4,0%

Aerosil - 2,0%

Magnesium stearate - 1,0%

Succinic acid is 1.0%

In the tank mix microcrystalline cellulose (MCC), hydroxypropy the pulp (GOC) or hypromellose (HPMC), Aerosil, magnesium stearic and succinic acid (mixture A). Then add 6-methyl-2-ethyl-3-hydroxypyridine succinate and mixed (mixture B). Mixture B is loaded into the mixer, add water and mix for 5 minutes Ready extrudate is loaded into spheronization. Time spheronization is 2-5 minutes. Ready spherical granules are dried in air for 24 h, then placed for 24 h in an oven (40°C).

Dissolve instant spheroids:

Time min01530456075
Number, %070,12101,0101,0101,0102,0

The dissolution profile instant spheroids is shown in figure 1.

Example 2. Preparation of spheroids on a matrix basis.

The composition of the spheroids, wt.%:

6-Methyl-2-ethyl-3-hydroxypyridine succinate - 50,0%

ICC-27,0%

GOC-4,0%

Aerosil - 2,0%

Magnesium stearate - 1,0%

Succinic acid is 1.0%

Eudragit NE 30D - 15,0%

Technology of production of spheroids on a matrix basis analogion the example 1, use the dispersion of Eudragit NE 30D.

Dissolution of spheroids:

Time, h0124812
Number, %050,2170,1185,10101,0101,0

The dissolution profile of the spheroids is shown in figure 2.

Example 3. Application of a membrane of a pH-independent polymer soluble spheroids.

For spheroids, prepared according to example 1, is applied membrane that regulate the release of active substance. The coating is carried out in an apparatus for spheronization. The coating solution contains Eudragit NE 30D (pH-independent polymer) as plenkoobrazovatelja.

Dissolution of spheroids coated governing the release of active ingredient:

tr>
Time, h0124812
Number, %020,1135,1355,2185,14100,0

Technology of application of membranes, regulating the release: spheroids fall asleep in spheronization include the supply of warm air (the temperature of the incoming air should be 41-43°C), then through the jet spray of the coating solution. To avoid clumping of the spheroids in the process of applying membrane on the spheroids during add talc.

The dissolution profile of the spheroids is shown in figure 3.

Example 4. Application of a membrane of a pH-sensitive polymer on instant spheroids.

The obtained dried spheroids according to example 1 are covered with a shell of pH-sensitive polymer that regulates the release of the drug. The coated spheroids are performed with use of spheronization 30%aqueous dispersion of Eudragit L30D-55 or alcohol Eudragit L 100-55. As the plasticizer used triethylcitrate. To prevent clumping of spheroids using talcum powder.

Dissolution of spheroids, covered with a protective shell:

Time, h01 24812
Number, %03,128,20101,0102,0103,0

Technology of application of membranes, regulating the release: spheroids fall asleep in spheronization include the supply of warm air (the temperature of the incoming air should be 41-43°C), then through the jet spray of the coating solution. If during the process of applying shell spheroids stick together among themselves, then add talc.

The dissolution profile of spheroids coated, shown in figure 4.

Example 5. Application of a membrane of a pH-independent polymer spheroids prepared on a matrix basis.

For spheroids, prepared according to example 2, is applied membrane regulating the release of the active substance. The coating is carried out in an apparatus for spheronization. The coating solution contains Eudragit NE 30D (pH-independent polymer) as plenkoobrazovatelja.

Dissolution of coated spheroids prepared on a matrix basis:

Time, h01 24812
Number, %09,1218,1935,1165,2195,33

Technology of application of membranes, regulating the release: spheroids fall asleep in a rotary machine. Include the flow of warm air (the temperature of the incoming air should be 41-43°C). Then through the jet spray of the coating solution. If during the process of applying shell spheroids stick together among themselves, then add talc.

The dissolution profile of spheroids coated, shown in figure 5.

Example 6. Application of a membrane of a pH-sensitive polymer spheroids prepared on a matrix basis.

The obtained dried spheroids according to example 2 is covered with a shell of pH-sensitive polymer that regulates the release of the drug. The coated spheroids are performed with use of spheronization 30%aqueous dispersion of Eudragit L30D-55 or alcohol Eudragit L 100-55. As the plasticizer used triethylcitrate. To prevent clumping of spheroids using talcum powder.

Dissolution of coated spheroids prepared on a matrix basis:

Time, h0124812
Number, %02,333,1470,2185,1895,11

The technology of applying a protective shell: the spheroids fall asleep in a rotary apparatus, include the flow of warm air (the temperature of the incoming air should be 41-43°C), then through the jet spray of the coating solution. If during the process of applying shell spheroids stick together among themselves, then add talc.

The dissolution profile of spheroids coated, shown in Fig.6.

Example 7. Preparation of tablets (uncoated) of spheroids. You need to make a tablet with the average theoretical dissolution profile:

Time, h0124812
Number, %0 50,00PHP 64.00at 76.0092,00100,00

The required number of spheroids mg tablet:

Spheroids on a matrix basisSpheroids on a matrix basis, coatedInstant spheroids
279,82121,5982,16

The resulting spheroids according to examples 1, 2, 5 pressed into tablets by a method known per se.

The dissolution profile obtained tablets:

Time, h0124812
Number, %050,2363,5876,0892,3099,62

The dissolution profile obtained tablets are shown in Fig.7 and 8.

Example 8. Preparation of tablets of the spheroids and the application shell, regulatory wysw the leave, the obtained tablets.

You need to make a tablet with the average theoretical dissolution profile:

Time, h0124812
Number, %018,0033,0056,0084,00100,00

The required number of spheroids mg tablet:

Spheroids on a matrix basisSpheroids on a matrix basis, coatedInstant spheroids
132,39367,610,00

The resulting spheroids according to examples 2, 5 pressed into tablets by a method known per se. The obtained tablets are covered with a membrane that regulates the release, 6-methyl-2-ethyl-3-hydroxypyridine succinate containing the GOC. Technology coating on tablets similar technologies cover shell spheroids. The solution is of coated tablets:

Time, h0124812
Number, %020,0031,9448,3574,6996,83

The dissolution profile of the coated tablets that regulate the release of active substance, shown in figures 9 and 10.

Example 9. Preparation of gelatin capsules containing spheroids. You need to make a capsule with an average theoretical dissolution profile:

Time, h0124812
Number, %033,3348,0061,3384,00100,00

The required number of spheroids mg per capsule:

Spheroids on a matrix basisSpheroids on a matrix basis, coatedInstant spheroids
350,31356,8635.70 barm

The resulting spheroids according to examples 1, 2, 5 Packed in capsules by a method known per se.

Dissolving capsules:

Time, h0124812
Number, %033,5647,1762,2283,9798,30

The dissolution profile obtained capsules shown at 11 and 12.

Example 10. Preparation of tablets with modified nature of the release of the active substance by the method of direct compression.

The composition of the tablets, wt.%:

6-Methyl-2-ethyl-3-hydroxypyridine succinate - 60,0%

ICC-13,5%

GPMC-20,0%

PVP-2,5%

Aerosil - 2,0%

Magnesium stearate - 1,0%

Succinic acid is 1.0%

Cooking technology: the capacity mix thoroughly MCC, HPMC, PVP, Aerosil, magnesium stearate and succinic acid. Then add 6-methyl-2-ethyl-3-hydroxypyridine succinate, mix until smooth and pressed tablets.

Dissolution of tablets obtained by direct compression:

Time min012481216
Number, %018,230,1240,8662,379,696,4

The dissolution profile of the tablets shown on Fig.

1. Pharmaceutical composition containing as the active ingredient 6-methyl-2-ethyl-3-hydroxypyridine succinate, characterized in that it is an oral dosage form with modified nature of the release of 6-methyl-2-ethyl-3-hydroxypyridine succinate, taken in an amount of 30.0-70,0 wt.%, at the same time as the release modifier it contains derivatives of cellulose and/or polyacrylate resin in the amount of 1.0 to 20.0 wt.%, as filler - microcr stallions cellulose in the amount of 20.0-50.0, wt.% and sliding substances.

2. The pharmaceutical composition according to claim 1, characterized in that the at least one group of spheroids having a diameter of 0.25 to 2.0 mm

3. The pharmaceutical composition according to claim 2, characterized in that as release modifier use hypromellose, methylcellulose and/or ethers of cellulose.

4. The pharmaceutical composition according to claim 2, characterized in that as a modifier release using Eudragit NE 30D, or Eudragit RS or Eudragit RL, or mixtures thereof.

5. The pharmaceutical composition according to claim 2, wherein the spheroids are covered or uncovered by the protective membrane that regulate the release of active substance consisting of Eudragit L, and/or Eudragit RS, and/or Eudragit RL, and/or Eudragit NE 30D, talc and triethylcitrate.

6. The pharmaceutical composition according to claim 2, characterized in that the spheroids in a desired ratio is Packed into tablets.

7. The pharmaceutical composition according to claim 2, characterized in that the spheroids in a desired ratio is Packed into capsules.

8. The pharmaceutical composition according to claim 6, characterized in that the obtained tablets applied polymer membrane that regulate the release of active substance consisting of Eudragit L, and/or Eudragit RS, and/or Eudragit RL, and/or Eudragit NE 30D, talc and triethylcitrate.

9. The pharmaceutical composition according to claim 1, characterized in that it is the floor of the ene in the form of tablets by direct pressing.

10. The pharmaceutical composition according to claim 9, characterized in that as release modifier use methylcellulose, hydroxypropylcellulose, hypromellose.



 

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20 cl, 33 dwg, 23 tbl, 18 ex

FIELD: medicine.

SUBSTANCE: invention concerns administering an urokinase inhibitor representing 4-chlorobenzylsulphonyl-(D)-Seg-Gly-(4-guanidinobenzyl)amide or its pharmaceutically acceptable salt for prevention and/or treatment of amyotrophic lateral sclerosis, a pharmaceutical composition for prevention and/or treatment of amyotrophic lateral sclerosis, administration thereof for treatment and/or prevention of neuropathological and/or neurodegenerative diseases, as well as a method for urokinase activity inhibition.

EFFECT: improved clinical effectiveness.

7 cl, 8 dwg, 6 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to compounds of formula (Ia) or their pharmaceutically acceptable salts, tautomers, or N-oxides, for use in prevention or treatment of unhealthy conditions or diseases, mediated with cyclin-dependent kinase and glycogen synthase-kinase-3, such as cancerous diseases. In formula (Ia) X stands for group R1-A-NR4; A stands for link, C=O, or NRg(C=O, where R8 stands for hydrogen or C1-3 alkyl; Y stands for link or alkylene chain, made of 1, 2 or 3 atoms of carbon; R1 stands for carbocyclic or heterocyclic group, containing from 3 to 12 circular units; or saturated C1-8hydrocarbyl group, optionally substituted with one or more substituents selected from halogen (for instance, fluorine), hydroxygroups, C1.4alkoxygroups, and carbocyclic or heterocyclic groups, and where 1 or 2 atoms of hydrocarbyl group carbon may be optionally substituted with atom or group selected from O, S, NH, SO, SO2; R2 stands for hydrogen or methyl; R3 is selected from hydrogen and carbocyclic or heterocyclic groups, containing from 3 to 6 circular units; and R4 stands for hydrogen or methyl. Specified carbocyclic and heterocyclic groups are determined in formula of invention and may be optionally substituted with groups specified in invention formula. Objects of invention are also a pharmaceutical composition based on proposed compounds, their application to produce medicinal agents and methods of their application.

EFFECT: production of pharmaceutical composition based on proposed compounds for use in prevention or treatment of unhealthy conditions or diseases, mediated with cyclin-dependent kinase and glycogen synthase-kinase-3, such as cancerous diseases.

48 cl, 6 tbl, 254 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: medicinal composition for treating cerebral ischemia and senile dementia contains 1-10 weight parts of ginseng root, 1-10 weight parts of ginkgo leaves, 0.05-0.5 weight parts of saffron snouts and 5-10 weight parts of soya bean; said ginseng root, ginkgo leaves, saffron snouts and soya bean can be presented in the form of raw vegetable materials or extracts prepared by extraction of the raw vegetable material in the same amounts. At least double amount of 60-80 % ethanol is added to ginkgo leaves, and immersing extraction is carried out at 50-70°C at least once to produce liquid extracts; the liquid extracts are mixed and concentrated to enable relative density of the produce liquid concentrate to reach approximately 1.05; water is added to the liquid concentrate, and the prepared mixture is filtered to produce a filtrate; the filtrate is chromatographed on polar macroporous adsorption styrene resin in a protonation form; resin and drug substances are eluted with water and 60% ethanol; an aqueous eluent is discharged, while an ethanol containing eluent is collected and concentrated to eliminate alcohol odour and to produce a concentrated eluent; water is added to the concentrated eluent, and said mixture is filtered to prepare another filtrate; the filtrate is chromatographed on weakly polar macroporous adsorption styrene resin; resin and drug substances are eluted with water, 15% ethanol and 60% ethanol, respectively; the aqueous eluent and 15% ethanol eluent are discharged, while 60% ethanol eluent is collected. The inventions allow implementing specified object matters.

EFFECT: preparation of the composition for treating cerebral ischemia and senile dementia.

12 cl, 5 ex, 12 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to novel ligands, including novel compounds of general formula 1, a wide range of biological activity which simultaneously includes alpha-adrenoceptors, dopamine receptors, histamine receptors, imidazoline receptors and serotonin receptors, including serotonin 5-HT7 receptors, in form of free bases, geometric isomers, racemic mixtures or separate optical isomers, as well as in form of pharmaceutically acceptable salts and/or hydrates. In formula 1

R1 denotes hydrogen; C1-C4alkyl optionally substituted with C1-C4alkoxycarbonyl, aromatic or saturated optionally annelated or optionally substituted with a five- or six-member heterocycle containing 1-2 N heteroatoms; C1-C3acyl; saturated optionally substituted six-member N-heterocycle; C1-C4alkoxycarbonyl; optionally substituted arylsulphonyl, R2 denotes a substitute of a cyclic system, including hydrogen; halogen; optionally substituted C1-C4alkyl;CF3, CN, C1-C4alkoxy; C1-C4alkoxycarbonyl; carboxyl; unsaturated six-member N-containing heterocyclyl or optionally substituted arylsulphonyl, Ar denotes phenyl, optionally substituted with C1-C4alkyl, dimethylamino group, one or more C1-C4alkoxy groups, one or more halides, CF3 group, nitro group, carboxyl, C1-C4alkoxycarbonyl, C1-C4acylamino group, CN, optionally annelated with a saturated heterocycle; optionally annelated and optionally substituted unsaturated five- or six-member heterocycle containing one or two heteroatoms selected from nitrogen, oxygen or sulphur; W denotes an optionally substituted (CH2)m group, optionally substituted CH=CH group, optionally substituted CH2-CH=CH group, C≡C group, SO2 group; n = 1 or 2; m=1, 2 or 3, the solid line accompanied by a dotted line (---) denotes a single or double bond.

EFFECT: compounds can be used to treat and/or prevent diseases or pathological conditions of the central nervous system, whose pathogenesis is associated with hyper- or hypo-activation of said receptors, for example anxiety or cognitive disorders, neurodegenerative and psychotic diseases.

42 cl, 26 dwg, 12 tbl, 20 ex

Sugar-coated drug // 2407515

FIELD: medicine, pharmaceutics.

SUBSTANCE: declared invention refers to chemical-pharmaceutical industry and concerns a drug which contains a portion containing an oxygen-intolerant active ingredient wherein the oxygen-intolerant active ingredient is (R)-5,6-dimethoxy-2-[2,2,4,6,7-pentamethyl-3-(4-methylphenyl)-2,3-dihydro-1-benzofuran-5-yl]isoindoline and a sugar coating containing (1) sugar alcohol as a base material of the sugar coating where sugar alcohol is erythrite and (2) a binding agent where the binding agent is gum arabic wherein a portion is sugar-coated. Also, the invention concerns a method for preparing the declared drug.

EFFECT: agent exhibits high storage stability and oxygen tolerance.

8 cl, 18 ex, 15 tbl, 1 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to chemical-pharmaceutical industry, more specifically to a pharmaceutical composition of choline alphoscerate in the form of a solution for injections exhibiting nootropic activity and cholinomimetic action. The pharmaceutical composition contains choline alphoscerate in the therapeutically effective amount as an active ingredient and povidone (plasdone or collidone) in the amount 0.2-0.8 wt % at 100% of the whole composition as a pharmaceutically acceptable carrier. The pharmaceutical composition under the invention is used for treatment or prevention of CNS diseases and effects of craniocereberal injures.

EFFECT: pharmaceutical composition under the invention keeps prolonged storage stability, exhibits minimum by-effects and improved bioavailability.

5 cl, 1 tbl

FIELD: chemistry.

SUBSTANCE: present invention relates to heterocyclic compounds of formula I or their stereo isomer, tautomer or pharmaceutically acceptable salt or solvate, where W denotes -C(=S)- or -C(=O); X denotes -N(R5)-; U denotes a bond or -(C(R6)(R7))b- where b equals 1; R1, R2 and R5 are independently selected from a group comprising H, alkyl with 1-6 carbon atoms, alkenyl with 2-6 carbon atoms, cycloalkyl with 3-7 carbon atoms and other radicals given in claim 1 of the formula of invention; R3, R4, R6 and R7 are independently selected from a group comprising H, alkyl with 1-6 carbon atoms, cycloalkyl with 3-7 carbon atoms, cycloalkylalkyl with 3-7 carbon atoms in the cycloalkyl part and 1-6 carbon atoms in the alkyl part and other radicals given in claim 1 of the formula of invention; R15, R16 and R17 indicated below are independently selected from a group comprising H, alkyl with 1-6 carbon atoms, alkenyl with 2-6 carbon atoms, alkynyl with 2-4 carbon atoms, cycloalkyl with 3-7 carbon atoms, cycloalkylalkyl with 3-7 carbon atoms in the cycloalkyl part and 1-6 carbon atoms in the alkyl part and other radicals given in claim 1 of the formula of invention; or R15, R16 and R17 denote ; , where R23 denotes 0-2 substitutes, m equals 0 and n equals 1 or 2, and where all alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroaryl alkyl, alkenyl and alkynyl groups in R1, R2, R3, R4, R5, R6, R7 can be independently substituted with 1-3 R21 groups independently selected from alkyl with 1-6 carbon atoms, cycloalkyl with 3-7 carbon atoms, halogen, aryl with 6-10 carbon atoms; -CN, -OR15, -C(O)R15, -C(O)OR15, - C(O)N(R15)(R16), -S(O)2N(R15)(R16), -N(R15)(R16), -N(R15)C(O)R16, -CH2-N(R15)C(O)R16, - CH2-R15; -N(R15)S(O)R16, -N(R15)S(O)2R16, -N(R15)C(O)N(R16)(R17), -CH2-N(R15)C(O)N(R16)(R17), -N(R15)C(O)OR16, -CH2-N(R15)C(O)OR16, -N3, -NO2 and -S(O)2R15; and where alkyl with 1-6 carbon atoms and cycloalkyl with 3-7 carbon atoms are independently substituted or contain substitutes in form of 1-5 R22 groups, independently selected from a group comprising halogen, -CN or -OR15; R23 denotes alkyl with 1-6 carbon atoms; provided that if W denotes -C(O)- and U denotes a bond, then R1 does not denote, if needed, a substituted phenyl, provided that neither R1 nor R5 denotes alkyl disubstituted with -CO(O)R15 or -C(O)N(R15)(R16)) and (-N(R15)(R16), -N(R15)C(O)R16, -N(R15)S(O)R16, -N(R15)S(O)2R16, -N(R15)C(O)N(R16)(R17) or -N(R15)C(O)OR16) groups; provided that if R1 denotes methyl, R2 denotes H, W denotes C(O)- and U denotes a bond, then (R3, R4) does not denote (H, H), (phenyl, phenyl), (H, phenyl), (benzl, H), (benzyl, phenyl), (isobutyl, H), (isobutyl, phenyl), (OH-phenyl, phenyl), (halogenphenyl, phenyl) or (CH3O-phenyl, NO2-phenyl);provided that if R1 and R5 both denote H, W denotes -C(O)- and U denotes a bond, then (R3, R4) does not denote (substituted phenyl if needed, substituted benzyl if needed), (substituted phenyl if needed, heteroarylalkyl) or (heteroaryl, heteroarylalkyl); provided that if R1 denotes R21-aryl or R21 arylalkyl, where R21 denotes -OCF3, -S(O)2CF3, -S(O)2alkyl, -S(O)2CHF2, -S(O)2CF2CF3, -OCF2CHF2, -OCHF2, -OCH2CF3 or -S(O)2NR15R16; where R15 and R16 are independently selected from a group comprising H, said alkyl, alkenyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, R18-alkyl, R18-cycloalkyl, R18-heterocycloalkyl and R18 -aryl, and U denotes a bond; then R5 denotes H, where R18 is as defined in claim 1 of the formula of invention. The present invention also relates to a pharmaceutical composition based on the compound of formula , use of the formula I compound in preparing a medicinal agent.

EFFECT: novel heterocyclic derivatives of formula I, having aspartyl protease inhibiting properties, are obtained.

16 cl, 1 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to compounds of formula Ia and their pharmaceutically acceptable salts, hydrates, solvates, esters and amides. In formula Ia , A is specified from -C(O)OR5 where R5 represents hydrogen; W represents C1-3alkylene; Y is specified from phenyl and 5-6-member heteroaryl containing one heteroatom specified from N, S, O; where any phenyl or heteroaryl Y can be optionally substituted with 1 to 3 radicals specified from halogen, C1-6alkyl, C1-6alkoxygroup, halogen-substituted C1-6alkyl and halogen-substituted C1-6alkoxygroup; Z is specified from: where left and right asterisks Z specify an attachment point between -C(R3)(R4)- and A of formula la; R6 is specified from hydrogen and C1-6alkyl; or R6 can be attached to carbon atom in Y to form a 5-7-member ring; R1 is specified from phenyl and 5-member heteroaryl containing one heteroatom specified from S, O; where any phenyl or heteroaryl R1 is substituted with a radical specified from phenylC0-4alkyl, heteroarylC0-4alkyl where heteroaryl represents 5-6-member heteroary containing one heteroatom specified from N, S, O, C3-8cycloalkylC0-4alkyl, C3-8heterocycloalkylC0-4alkyl which contains nitrogen atom as heteroatom, or C1-6alkyl; where any phenyl, heteroaryl, cycloalkyl or heterocycloalkyl group R1 can be optionally substituted with 1 to 3 radicals specified from halogen, C1-6alkyl, C1-6alkoxygroup, halogen-substituted C1-6alkyl group and halogen-substituted C1-6alkoxygroup; R2 represents C1-6alkyl group; R3 and R4 represent hydrogen.

EFFECT: preparation of the pharmaceutical composition exhibiting EDG/S1P receptor modulating properties, containing therapeutically effective amount of the compound under the invention, development of a method of treating the disease mediated by EDG/S1P receptor activity, application of the compounds for preparing a drug for prevention or treatment of the disease mediated by EDG/S1P receptor activity.

16 cl, 1 tbl, 86 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compound of general formula (I): , where Ar1 is a phenyl group substituted with 1-3 halogen atoms; Ar2 is a phenyl group which can be substituted with a halogen, alkoxyalkyl, alkoxyhalogenalkyl, or pyridyl group which can be substituted with halogenalkyl; X is -S-, -SO- or -SO2-; Y is a hydrogen atom, -NR1R2 (where R1 is a hydrogen atom, lower alkyl group or hydroxy group; and R2 is a hydrogen atom, lower alkyl group which can be substituted, lower alkanoyl group, alkoxycarbonyl group which can be substituted, lower alkoxy group which can be substituted, amino group which can be substituted; or R1 and R2 together with a nitrogen atom with which they are bonded form a piperidine, morpholine, azetidine or piperazine ring, which can be substituted wiht a hydroxy group) or -OR1', where R1 is a hydrogen atom); Z is an oxygen atom or sulphur atom; and R is a hydrogen atom or a lower alkyl group; or to salts thereof. The invention also relates to a medicinal agent and a pharmaceutical composition which inhibit production/secretion of β- amyloid protein, to use of said compounds to prepare a medicinal agent and to a method of treating diseases caused by abnormal production or secretion of β- amyloid protein.

EFFECT: novel compounds which can inhibit production/secretion of β- amyloid protein and which can be used in treating Alzheimer disease or Down syndrome are obtained and described.

30 cl, 136 ex, 1 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to the field of medicine, namely, to chemical-pharmaceutical industry, in particular, to block-copolymer pharmaceutical compositions, containing 3,3'-diindolylmethane (DIM). Invention also relates to methods for treatment of various diseases with the help of specified compositions.

EFFECT: compositions improve absorption of active compound into blood flow in case of its peroral delivery.

6 cl, 4 dwg, 2 tbl, 10 ex

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