Method for preparing pure monosialoganglioside gm1 for medical applications

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pharmaceutics, namely a method for preparing and purifying monosialoganglioside GM1. The method for preparing pure monosialoganglioside GM1 in the form of its sodium salt involves (a) GM1 separation from Fucosyl GM1 in a lipid mixture containing monosialoganglioside GM1 as a main ganglioside component by a column ion-exchange chromatography using an eluent comprising potassium or cesium ions, (b) recovery of the dissolved substance from the eluted solution, (c) diafiltration of the aqueous solution of the recovered dissolved substance of the stage (b), (d) addition of sodium salt, and diafiltration of the prepared aqueous solution (d) recovery of GM1 in the form of its sodium salt. The method for purifying monosialoganglioside GM1 from Fucosyl GM1 in the lipid mixture, the column ion-exchange chromatography using the eluent comprising potassium or cesium ions. The preparation of monosialoganglioside GM1 has a purity of 99.0% or more, and contains less than 0.1% of Fucosyl GM1. The method of treating disorders and diseases of the central nervous system and the peripheral nervous system, comprising administering the preparation of monosialoganglioside GM1 to the patient in its effective amount. The use of the preparation of monosialoganglioside GM1 in preparing a pharmaceutical composition.

EFFECT: use the above preparation of monosialoganglioside GM1 in treating has the considerable advantages due to reducing side effects.

17 cl, 1 ex

 

The technical field to which the invention relates.

The present invention relates to monosialoganglioside GM1, more specifically, to methods for obtaining and purifying monosialoganglioside GM1.

The level of technology

Gangliosides are a class of glycosphingolipids containing one or more sialic acid residues, and are found in large amounts in brain and nervous tissue of humans and animals. There are many pharmaceutical applications monosialoganglioside GM1, especially in the recovery and treatment of disorders of the Central and peripheral nervous systems.

According to US 4,849,413, gangliosides conveniently be extracted from the brain tissue of bulls or pigs. In order to be suitable for pharmaceutical applications, monosialoganglioside GM1 must then be isolated and purified.

It is known that to increase the output of monosialoganglioside GM1 extracted lipid mixture is treated with a chemical or enzymatic methods for the conversion of other ganglioside components in monosialoganglioside GM1. Such methods include acid hydrolysis dilute acid, such as described in CN 1353112, or enzymatic hydrolysis using sialidase, for example as described in US 5,296,360.

Further purification of this GM1-enriched lipid mixture pressure chromatography using ale the NTA chloroform: methanol: water 60:30:4,5 described in EP 0150712. EP 0489352 describes the purification of GM1-enriched lipid mixture by ultrafiltration of a solution of the lipid mixture of alpha-cyclodextrin, followed by extraction GM1 selective extraction with ethanol. Reported that GM1 may be obtained with a purity of 95%.

Previously it was shown that when used on an industrial scale, these processes have disadvantages in terms of cleanliness and exit GM1, and in terms of cost, efficiency and economy.

For pharmaceutical applications required to produce ganglioside GM1 high purity. Accordingly, the constant need for methods for producing ganglioside GM1 high purity.

Disclosure of inventions

The authors of this application has unexpectedly found that ganglioside GM1 can be effectively separated from other gangliosides method, based on ion-exchange chromatography.

According to the present invention, it was found that ganglioside GM1 can be obtained with high purity by the way, where GM1 is separated from lipid mixtures containing monosialoganglioside GM1 as the main ganglioside component, ion-exchange column chromatography using the eluent containing ions of potassium or cesium.

According to the present invention is the isolation and purification of ganglioside GM1 according to claim 1.

Preferably according the implementation variant of the present invention provides a method, includes General stages:

(a) the allocation of GM1 lipid mixtures containing monosialoganglioside GM1 as the main ganglioside component, ion-exchange column chromatography using the eluent containing ions of potassium or cesium,

(b) removing dissolved solids from lirovannomu solution

(C) diafiltrate aqueous solution extracted solute,

(g) adding a sodium salt and diafiltrate the obtained solution, and

(d) removing the GM1.

Mainly the method of the present invention provides the preparation of meagangood GM1 high degree of purification. According to the present invention, the preparation of monosialoganglioside GM1 may have a purity higher than 98%, even higher than 99,0% and even to 99.9%.

The method of the present invention also uses mostly simple stage, economical and suitable for use on an industrial scale.

Other objectives and advantages of the present invention will be apparent from the formula and from the following detailed description and examples.

The implementation of the invention

The present invention relates to a method of cleaning meagangood GM1, in which GM1 separated from lipid mixtures containing monosialoganglioside GM1 as the main ganglioside component, chromatography on ion-exchange column using ale the NTA, containing ions of potassium or cesium.

In a preferred embodiment, the implement is provided a method of producing monosialoganglioside GM1 high purity, which includes stages:

(a) the allocation of GM1 lipid mixtures containing monosialoganglioside GM1 as the main ganglioside component by chromatography on ion-exchange column using elution solvent containing ions of cesium or potassium.

(b) removing dissolved solids from lirovannomu solution of stage (b)

(C) diafiltrate aqueous solution extracted solute phase (g) to remove residual salts, potassium or cesium,

(d) adding sodium ions, preferably in the form of a suitable sodium salt, to displace ions of potassium or cesium associated with GM1, and diafiltrate aqueous solution to remove residual sodium salt,

(d) removing the GM1 in the form of its sodium salt.

The lipid mixture can be obtained from a crude lipid extract of brain tissue of a bull, sheep, horses or pigs.

Mainly lipid mixture containing monovariate GM1 as the prevailing ganglioside component, can be obtained from the lipid extract containing at least 30%, preferably at least 50% and more preferably at least 70% of a mixture of gangliosides. The remainder of the lipid extract may in General the case to consist of sulfatides, the cerebrosides, fatty acids and proteins.

For desalting of the solution of the lipid extract can first be diafiltration through a membrane having a pore size of from 10000 to 100000 daltons, preferably about 50000 daltons. For diafiltration can be used with any conventional dialysis membrane. Mainly you can use the filter cassettes, for example the type polysulfonic cassettes SARTOCON® (Sartorius), for example, border transmission 50,000 daltons.

Preferably the lipid extract was processed by hydrolysis to convert other major ganglioside components, such as GT1b, GD1a and GD1b, GM1 to increase the GM1 content.

The hydrolysis can be accomplished using conventional methods. Mainly hydrolysis can be accomplished using either of two General ways hydrolysis of gangliosides, known in the literature, namely, acid hydrolysis or enzymatic hydrolysis.

Acid hydrolysis can be performed, for example, using a dilute inorganic acid, such as dilute hydrochloric acid, sulphuric acid and nitric acid. Hydrolysis in the acidic environment can be controlled changing the pH of an aqueous solution of the lipid extract to a pH of between 3.5 and 5, preferably a pH of around 4.0, and heating the solution to a temperature preferably between 90°and 100°is in a period of time required to complete the conversion of other major ganglioside components in GM1. The time required for hydrolysis of the major gangliosides in GM1, depends on the pH and the temperature selected. In General, the higher the pH, the longer the time required for complete hydrolysis, and the higher the reaction temperature, the shorter the time required for complete hydrolysis. The hydrolysis reaction can in General spend more than 2-5 hours. For example, if the hydrolysis is carried out at pH 4.0 and 95°C, the time required for complete hydrolysis is about 3 hours.

Enzymatic hydrolysis can be carried out using any suitable sialidase. Preferably, you can use sialidase Arthrobacter ureafaciens strain S or sialidase Vibrio cholerae. Sialidase Arthrobacter ureafaciens strain S and sialidase Vibrio cholerae active mainly against GT1a, GD1a, GD1b, but not GM1. Enzymatic hydrolysis can be accomplished, for example, by changing the pH of an aqueous solution of the lipid extract to a pH at which the used enzyme has its optimum activity, for example between pH 4 and pH 6, for example, approximately pH 5 by the addition of a suitable buffer such as acetate buffer, addition of ions of CA2+if sialidase is sialidases Vibrio cholerae, and heating the solution at a temperature at which the used enzyme immemorially activity for example, about 37°C. for the time required to complete the transformation. The hydrolysis can generally make more than 12-24 hours, depending on the added units of enzyme activity.

Acid hydrolysis is less preferred because it is a nonspecific way of hydrolysis and in General provides a lower output GM1 due to conversion to other gangliosides. The method of acid hydrolysis leads to the formation of impurities asialo-GM1.

Methods of enzymatic hydrolysis are preferred, since they in General provide higher output of GM1 due to the high specificity of chemical transformations. For enzymatic hydrolysis is preferred sialidase Arthrobacter ureafaciens, since its activity is not required adding ions of CA2+. Also due to the molecular weight of 52000 Dalton (compared with 82000 daltons to sialidase Vibrio cholerae) it can mainly wash diafiltrate.

To extract thus obtained lipid mixture having a high content of monosialoganglioside GM1, from the reaction solution, the reaction solution can preferably be diafiltrate, for example, through a membrane having a pore size 10000-100000 daltons, preferably about 50000 daltons. For diafiltration can use the ü any conventional dialysis membrane. Mainly you can use filter cartridges, such as the type polysulfonic cassettes SARTOCON® (Sartorius), preferably abroad bandwidth 50000 daltons. The permeate can then be dried to obtain a powder of lipid mixtures containing monosialoganglioside GM1 as the main ganglioside component. Drying can be done in the usual ways. Mainly drying can be accomplished by spray drying or vacuum drying.

The lipid mixture may generally have a concentration of GM1 from 10 to 200 g/l and preferably at least 100 g/l

According to the method of the present invention ganglioside GM1 is separated from the other gangliosides in lipid mixtures using ion-exchange chromatography.

Unexpectedly, it was found that when using an eluent containing ions of potassium or cesium, can be successfully separated GM1 from other monosialoganglioside.

In most cases, it was found that the traditionally used methods of ion exchange are not effectively separate the GM1 from other monosialoganglioside. Especially known monosialoganglioside Fucosyl-GM1 is present as the main ganglioside impurities in the pig lipid mixture made known treatments by hydrolysis.

Two molecules GM1 and Fucosyl-GM1 have very similar physical SV is istwa. Both have a single negative charge provided by the carboxyl group of sialic acid, and have similar molecular weight: 1558 and 1704, respectively. Accordingly, when loaded into a pre-equilibrated ion exchange column strength of binding of these two gangliosides resin is the same.

To date it has been observed that if eluent to increase ionic strength eluent add sodium acetate and provide conditions for replacement of gangliosides, as GM1 and Fucosyl-GM1 suiryudan at the same ionic strength at the same time. The separation of these two monosialoganglioside cannot be achieved.

While the authors of the present invention unexpectedly discovered that by using ions of cesium or potassium, for example, by adding a methanolic solution of potassium acetate or cesium, GM1 and Fucosyl-GM1 suiryudan separately, with the first eluted Fucosyl-GM1. The separation is complete, and can be allocated to each of the gangliosides GM1 and Fucosyl-GM1.

Not wishing to be bound by any theory, the authors present invention believe that the observed splitting can be due to the fact that, contrary to conventional theory of ion exchange of dissolved substances, GM1 and Fucosyl-GM1, not only are released from the column in order of their strength of binding resin,but also in the order of their affinity to the counterion, they must be linked to be derived from a gel. Accordingly, from this theory it follows that if one of these two solutes have different affinity to the counterion, then the solute will be released at two different ionic strength and can be cleaned.

The authors of the present invention unexpectedly found that monosialoganglioside GM1 and Fuc-GM1 have the same affinity for sodium, but not the same affinity for potassium or cesium, despite the fact that all three metals belong to the same group. The authors of the present invention unexpectedly found that Fuc-GM1 has a higher affinity for potassium and cesium than GM1, and eluted first.

The method of ion-exchange chromatography of the present invention mainly provides the ability to effectively separate GM1 from Fucosyl-GM1. Next, the method of the present invention also provides mainly the Department of GM1 from the corresponding fatty acids. Fatty acids have the same charge as ganglioside, but a higher affinity for ions of cesium or potassium.

For ion-exchange chromatography can be any suitable resin. Mainly, you can use the resin having the Quaternary amino group, for example, FRACTOGEL® EMD TMAE (S) or Sepharose resin, for example, resin, Q-Sepharose HP.

In the first stage resin equal to eshivot with a suitable solvent. Suitable solvents include ethanol, methanol or a mixture of methanol and chloroform. Preferably the solvent is methanol, because it is a solvent in which soluble gangliosides and salts of potassium and cesium.

Then in a column, you can download the solution of the lipid mixture in a suitable elution solvent. The solvent for elution should contain the same components of the solvent as the solvent used for equilibration of the resin. Preferably, the selected solvent is methanol. Pre-elution with the solvent for elution allows eluted available substances, such as cerebrosides.

Then, the solvent for elution add ions of potassium or cesium. Ions of potassium or cesium, preferably provided in the form of a methanol solution of potassium acetate or cesium formate, propionate or in the form of salts of other organic acids. The preferred methanol solution of sodium acetate or potassium. Mainly acetates of potassium or cesium may be present in eluent in a quantity sufficient to provide conductivity eluent 1100-1400 µs/cm, the preferred conductivity 1200-1300 µs/see This eluent solution containing a salt of sodium or potassium, can pass through the column isocratically in any suitable IC is grow thread for example, at a flow rate of 100 ml/h to 140 ml/hour.

If the separation is carried out using the method of ion exchange chromatography according to the present invention, fatty acids and Fuc-GM1 suiryudan before GM1, while sulfatide remaining associated with the column, can buyouts during washing of the column.

The eluate containing GM1, collect, and, mainly, an eluting solvent, suirvey from the column can be removed by distillation.

The solution containing GM1, can be removed by drying of the eluate solution with the formation of a powder containing GM1. Drying can be accomplished using conventional methods, for example, spray drying or vacuum drying.

The solution containing GM1, can then be purified by diafiltration its aqueous solution through a membrane having a pore size 10000-100000 daltons, preferably about 50000 daltons, to remove residual salts, potassium or cesium. Optionally, inorganic acid, such as aqueous sulfuric acid, nitric acid or preferably hydrochloric acid, may be added to the solution to bring the pH between pH 6-8, preferably about pH 7 to diafiltration.

Sodium ions, respectively, in the form of an aqueous solution of sodium salt, preferably NaCl, can then be added to the solution to displace ions of potassium or cesium, is knitted with GM1, and receive GM1 in the form of a physiological sodium salt. The solution can then be subjected to a second diafiltration to remove residual salts (such as NaCl), using a membrane having a pore size of from 10000 to 100000 daltons, preferably about 50000 daltons. Mainly you can use the filter cassette, such as cassette polysulfonamide type SARTOCON® (Sartorius), preferably abroad bandwidth 50000 daltons.

The solution can then be dried to extract GM1 in powder form. Drying can be done in the usual ways. Mainly drying can be accomplished by spray drying or vacuum drying.

GM1 obtained according to the present invention has a purity of 98% or more, generally from about a 99.0 to 99.9%. GM1 obtained according to the process of the present invention contains less than 0.1% impurities Fucosyl-GM1.

The method of the present invention mainly allows to effectively separate the GM1 from other monosialoganglioside. In particular, the method of the present invention allows to separate GM1 from impurities Fucosyl-GM1.

Mainly the method of the present invention provides the preparation of monosialoganglioside GM1 with high purity in good yield.

GM1, purified according to the method of the present invention may be used in the treatment of human subject or animal. In h is particularly GM1, purified according to the present invention, is considered for the treatment of humans or mammals, especially for the recovery and treatment of disorders and diseases of the Central and peripheral nervous system, including stroke, Parkinson's disease, spinal cord injury, Alzheimer's disease, late dyskinesia, amyotrophic lateral sclerosis, peripheral neuropathy and autonomic neuropathy.

The present invention is further illustrated by the following examples.

EXAMPLES

Example 1

Receiving lipid mixtures containing monosialoganglioside GM1 as the main ganglioside

The lipid extract containing a mixture of gangliosides having a purity of 70%, is dissolved in purified water at a concentration of about 25 g/L. Then the solution diafiltrate through polysulfone filter cassettes SARTOCON® (Sartorius)with a boundary bandwidth 50000 daltons.

Then 200 l of a solution balance to pH 5.5 by the addition of 50 mm acetate buffer and 4 mm calcium chloride. Add 30000 units sialidase Vibrio cholerae and heat the solution to 37°C for 12 hours to complete the conversion of other major gangliosides (GT1b, GD1a, GD1b) in GM1. The concentration of GM1 in the resulting solution is equal to 14-15 g/l

After enzymatic hydrolysis solution diafiltrate through the filter cartridge with a boundary bandwidth 50000 gave the tone. Then retentate add 1 M NaCl and subjected to the solution of the second diafiltration. After the second diafiltration retentate concentrated to a concentration of GM1 100 g/l, leaving the permeate stream without any replacement water. Then the solution is dried under vacuum to obtain about 3200 g of powder having a concentration of GM1 85%, measured by HPLC.

Purification of GM1 lipid mixtures containing monosialoganglioside GM1 as the main ganglioside

Prepare a methanol solution at a concentration of 10 g/l using the powder obtained in the previous phase, and filter the solution through a 0.22 μm filter cartridge Sartopore (Sartorius AG).

Then for each cycle of the load 7 l filtered solution into HPLC column containing 20 l of resin Fractogel ® EMD TMAE (S), equilibrated in methanol. Then the column elute with methanol: methanol potassium acetate solution having a conductivity 1200-1300 µs/cm, at a flow rate of 120 l/h Cycles were repeated until the exhaustion of the solution GM1.

Then the eluate (approximately 60-70 l) concentrate by distillation, and then dried to obtain a powder, and the methanol recovered. Thus obtained powder is a mixture of pure GM1 and potassium acetate.

Thus obtained powder is dissolved in purified water at a concentration of 25 g/l and balance to pH 7 by the addition of 18% HCl. The solution diafiltrate across the cassette filter, bordering bandwidth 50 000 daltons. Then add 1M NaCl and the solution again diafiltrate through cassette filter with border transmission 50 000 daltons. After this second diafiltration retentate concentrate to 100-120 g/l, leaving the permeate stream without any replacement water.

Then the concentrated solution is filtered through 0.22 μm filter and dried by spray drying to obtain approximately 2700 g from white to a white-beige powder GM1 identified by TLC, with this powder GM1 has a purity 99.8%measured by HPLC. The resulting powder GM1 has a content Fuc-GM1 less than 0.1%, measured by HPLC.

Comparative example

Was carried out by way of obtaining and purification GM1, as in the above Example 1, except that in column chromatography methanol: methanol solution of potassium acetate was replaced with methanol: methanol solution of sodium acetate.

Got 3100 g powder GM1 containing 91% GM1 and 8% Fuc-GM1, as measured by HPLC.

From the above examples you can see that is much lower purity GM1, if for elution GM1 using sodium acetate. This result may be due to the fact that the sodium counterion does not distinguish between GM1 and Fuc-GM1 in the process of elution, compared with counterions potassium or cesium, which, on the contrary, I fully share both peaks.

1. the manual isolation and purification of monosialoganglioside GM1, incorporating the following stages:
(a) Department of GM1 from Fucosyl GM1 in lipid mixtures containing monosialoganglioside GM1 as the main ganglioside component, using ion-exchange column chromatography using the eluent containing ions of potassium or cesium,
(b) extracting a solute from lirovannomu solution,
(C) diafiltration aqueous solution extracted solute phase (b),
(g) adding a sodium salt and diafiltration obtained aqueous solution,
(d) removing the GM1 in the form of its sodium salt.

2. The method according to claim 1, in which the eluent contains acetate cesium or potassium.

3. The method according to claim 2, in which the eluent is methanol solution of cesium acetate or potassium.

4. The method according to claim 1, in which the ion exchange column contains a resin having a Quaternary amino group.

5. The method according to claim 1, in which the ion-exchange column first, balance methanol.

6. The method according to claim 1, in which NaCl added at stage (g).

7. The method according to claim 1, in which diafiltration carried out using a membrane having a pore size 10000-100000 Yes.

8. The method according to claim 1, in which the extraction of GM1 on stage (d) comprises drying the solution permeate spray drying or vacuum drying to form a powder.

9. The method according to claim 1, comprising a stage of pre-treatment GM1 before separating inoome the Noah chromatography, with specified cleaning stage includes:
(a) diafiltration aqueous solution of lipid mixtures containing monosialoganglioside GM1 as the main ganglioside component through a membrane having a pore size 10000-100000 Yes,
(b) the concentration of the permeate and removing permeate lipid mixtures containing GM1.

10. The method according to claim 1, wherein the lipid mixture containing monosialoganglioside GM1 as the main ganglioside component, obtained by hydrolysis of the lipid extract containing a mixture of gangliosides having a purity of at least 50%.

11. The method according to claim 10, in which the hydrolysis is carried out by treatment of the lipid extract by sialidases Arthrobacter ureafaciens strain S or validate Vibrio cholerae.

12. The way to clean monosialoganglioside GM1, including the Department of monosialoganglioside GM1 from Fucosyl-GM1 in lipid mixtures containing monosialoganglioside GM1 as the main ganglioside component, ion-exchange column chromatography using the eluent containing ions of cesium or potassium.

13. Drug monosialoganglioside GM1 from pigs, obtained by the method according to item 12, having a purity of 99.0% or more and containing less than 0.1% Fucosyl GM1.

14. Drug monosialoganglioside GM1 on 13 for use as a drug.

15. A method of treatment of disorders and diseases of the Central and accessories the integrity of the nervous system, includes introduction to the needy in this patient a pharmaceutical composition comprising a therapeutically effective amount of the drug monosialoganglioside GM1 on item 13.

16. The method according to item 15, in which the disturbance or disease of the Central or peripheral nervous system selected from the group consisting of stroke, Parkinson's disease, spinal cord injury, Alzheimer's disease, tardive dyskinesia, amyotrophic lateral sclerosis, peripheral neuropathy and autonomic neuropathy.

17. The drug of meagangood GM1 on 13 for the manufacture of pharmaceutical compositions for treating disorders and diseases of the Central and peripheral nervous system.



 

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5 ex

FIELD: medicine.

SUBSTANCE: invention refers to medicine and veterinary medicine, namely to neurosurgery, and may be used for targeted drug delivery into the central nervous system of a living body. That is ensured by making a surgical approach to a segment of the central nervous system specified for local administration of the drug. Further, a drug source is placed therein. The drug source is a block of carbon composite - nanodiamond graphite-like carbon of the diamond content of 50-95 wt % and the porosity of 40-75 vol % pores of which are filled with the drug. The ratio of the block volume to its outer surface is 10-1000 mcm.

EFFECT: method provides a simplified and accurate targeted drug delivery to the specified region of the central nervous system.

2 cl, 2 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to producing new 5,8,9,10-tetrahydropyrimido[4,5-d]azocine derivatives having triflate, secondary and tertiary amino groups in the 4th position of general formula specified below. In general structural formula: 2-12 2 X=OTf (Tf means triflate), X means NR1R22 related to the groups 3-12

.

The method consists in the fact that 6-isopropyl-2-phenyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4(3H)-one reacts with methyl propyolate in methanol at room temperature to produce methyl 8-isopropyl-4-oxo-2-phenyl-5,8,9,10-tetrahydropyrimido[4,5-d]azocine-6-carboxylate (1). Thereafter, the prepared compound reacts with triftalane hydride in dichloromethane in the presence of pyridine at t°=-10°C; it is recovered and purified with by means of column chromatography to prepare methyl 8-isopropyl-2-phenyl-4-{[(trifluoromethyl)sulphonyl]oxy}-5,8,9,10-tetrahydropyrimido[4,5-d]azocine-6-carboxylate (2); then the solution I mmole of the prepared product (2) in absolute dioxide is added with 2 mmole of K2CO3 and 1.5 mmole of appropriate amine. After being boiled for two hours and removing the solvent, respective 4-amino substituted 5,8,9,10-tetrahydropyrimido[4,5-d]azocine of formula 3-12 is prepared. The method is directed to prepare the products in the form of white or yellow powder, or in the form of drying oil.

EFFECT: after the primary screening, the compounds appeared to be acetyl- and butyrylcholin esterase inhibitors and can find application as scaffolds in searching the preparations for treating neurodegenerative diseases.

10 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to solid fast-disintegrating dosage form of medication with antiparkinsonian action, which contains as active pharmaceutical ingredient memantine and/or memantine hydrochloride and cellulose II with the following ingredient ratio, wt %: memantine and/or memantine hydrochloride - 5-10, cellulose II - 90-95. Dosage form can represent pellet, created by method of direct pelletting.

EFFECT: obtaining fast-disintegrating in oral cavity dosage form, its distribution throughout oral cavity and delay of its transport to stomach, in order to provide medication delivery, not entering gastrointestinal tract and eliminating metabolism of medication in liver.

2 cl, 2 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds - substituted 1,3-diethyl-8-vinyl-7-methyl-3,7-dihydropurine-2,6-diones of general formula 1, which exhibit antagonist activity on adenosine A2A receptors. The compounds can be used as an active source of a medicinal agent or adjuvant for pharmaceutical compositions and medicinal agents. The invention also relates to a method of inhibiting and a method of treating diseases of the central nervous system, oncological, viral and bacterial diseases which are mediated by adenosine A2a receptor activity. In general formula 1 , where: Ar is 2,5-dimethoxyphenyl, 4-isobutoxy-3-methoxyphenyl, 3-phenoxyphenyl substituted with pyrrolidinyl, morpholinyl, piperidinyl, piperazinyl, C1-C5alkoxy group, amino group, optionally substituted with a mono- or di-C1-C5alkyl; 3-methylthiophen-2-yl, pyrazol-4-yl, substituted with C1-C5alkyl; 2,3-dihydro-benzo[1,4]dioxin-6-yl, optionally substituted with C1-C5alkoxycarbonyl, carbamoyl, which is optionally substituted with mono- or di-C1-C5alkyl, or carbonyl-piperazine, optionally substituted with C1-C5alkyl.

EFFECT: improved properties.

13 cl

FIELD: medicine, pharmaceutics.

SUBSTANCE: group of inventions relates to medicine and deals with application of composition, which includes rotigotine in concentration, sufficient for providing flow of rotigotine, necessary for obtaining therapeutic effect, and, at least one chloride salt in concentration from 1 to 140 mmol/l, where said composition has pH from 4 to 6.5, for charging device for ionophoresis for treatment of Parkinson disease.

EFFECT: group of inventions provides flow of rotigotine through stratum comeum of humans, which is higher than flow, earlier obtained with application of conventional systems of passive diffusion.

9 cl, 3 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to new substituted phenoxyacetic acids of general formula 1 possessing the properties of a selective antagonist inhibiting A2a adenosine receptor activity. The compounds may be used in preventing and treating central nervous system diseases, such as cognitive disorders, Parkinson's disease, or depression, tumour diseases, inflammatory processes. The invention also refers to an agent for intensification of immune response or action of drug preparations in the combination treatment of the diseases. In general formula

, R1, R2 and R3, optionally simultaneously represent hydrogen. C1-C5alkyl, C3-C5alkenyl or C3-C5-alkynyl; R4 represents hydrogen, a halogen atom, hydroxyl, C1-C3alkyl, C1-C3alkyloxy; R5 represents hydrogen, C1-C3alkyl, the group -C(O)R6;R6 represents hydroxyl, C1-C5alkyloxy, C3-C5alkenyloxy, C3-C5alkynyloxy optionally substituted by an amino group wherein the substitutes optionally identical are specified in hydrogen, C1-C3alkyl optionally substituted by a mono- or dialkylaminogroup, an alkyloxygroup, 5-6-member saturated heterocyclyl containing 1-2 heteroatoms specified in nitrogen and oxygen: pyridyl, phenyl optionally substituted by 1-3 methoxygroups; or optionally substituted 6-member, optionally annulated with 5-member unsaturated heterocyclyl, saturated heterocyclyl containing 2 nitrogen atoms wherein the substitutes are specified in C1-C3alkyl optionally substituted by 5- member heteroaryl containing 1-3 heteroatoms specified in nitrogen and oxygen; or 6- member optionally saturated heterocyclyl containing 1-2 nitrogen atom optionally substituted by C1-C3alkyl, oxo, optionally substituted by phenyl; a dashed line with an accompanying continuous line represents a single, double or triple bond.

EFFECT: preparing new substituted phenoxyacetic acids of general formula 1 possessing the properties of the selective agonist inhibiting A2a adenosine receptor activity.

15 cl, 3 tbl, 7 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new indole compounds of formula:

wherein A means 5-member heteroaryl or heterocyclyl each of which has 1 to 3 heteroatoms specified in N, O and S, R1 means R5 -X-B-X'-, R2 means -(CR8 R9 )p-Y-R7, R3 means hydrogen, C1-C6-alkyl or -(CH2)q-C3-C6-cycloalkyl, R4 means C3-C6-cycloalkyl (the other radical values are presented in cl.1 of the patent claim), their pharmaceutically acceptable salts or isomers which may be used for preventing or treating cell necrosis and necrosis-related diseases.

EFFECT: preparing the compounds to be used for preventing or treating cell necrosis and necrosis-related diseases.

34 cl, 2 tbl, 263 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to organic chemistry and medicine, and concerns salts of (2S,3R-)-N-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)benzofurane-2-carboxamide, substantially free from (2S,3S)-N-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)benzofurane-2-carboxamide, (2R,3S)-N-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)benzofurane-2-carboxamide and (2R,3R)-N-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)benzofurane-2-carboxamide.

EFFECT: preparing the compositions applicable for treating the conditions and disorders associated with central and vegetative nervous system dysfunction.

5 cl, 19 dwg, 7 tbl, 18 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: declared group of inventions refers to a pharmacological composition for intranasal introduction for cerebral delivery, and a method for preparing said composition. The declared composition comprises a container base formed by porous particles of calcium carbonate and titanium dioxide of particle size 100-5000 nm and a pharmacologically active component - loperamide. The container surface is modified by surfactants specified in polysorbates, or by polymers specified in a group containing glycosaminoglycanes and polypeptides, or their combination. A method for preparing the pharmacological composition consists in preparing the container base by porous particle synthesis, sorption of loperamide in its pore spaces and modification of the container surface by polymers and surfactants by container incubation in their solutions.

EFFECT: invention provides preparing the pharmacological composition which is applicable for cerebral loperamide delivery after the intranasal introduction.

5 cl, 5 dwg, 1 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a compound of formula possessing action on a BH4 sensitive condition.

EFFECT: invention refers to a pharmaceutical composition containing said compound to applying the compound for preparing a drug for treating the BH4 sensitive condition, such as a vascular disease, a psychoneurological disease, hyperphenylalaninemia.

12 cl, 31 dwg, 20 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to novel derivatives of cycloalkylamines, possessing inhibiting activity with respect to, at least, one monoamine transporter, selected from group, consisting of serotonin transporter, dopamine transporter and norepinephrine transporter. In formula (IV): n equals 1; s equals 1; Y and Z each independently represents halogen; X represents OR5; where R5 stands for H or non-substituted C1-C10alkyl; A represents H, non-substituted C1-C10alkyl or halogen; R1 and R2 each independently represents H; R3 and R4 each independently represents H or on-substituted C1-C10alkyl.

EFFECT: invention relates to pharmaceutical composition, containing said compounds and to method of treatment or prevention of neurological disorder or eating disorder, mediated by activity of monoamine transporter, selected from group, consisting of serotonin transporter, dopamine transporter and norepinephrine transporter, such as depression, neurodegenerative disease, abuse with psychoactive substances, fibromyalgia, pain, sleep disorder, syndrome of attention-deficit disorder, syndrome of attention-deficit disorder with hyperactivity, restless legs syndrome, schizophrenia, anxiety, obsessive-compulsive disorder, panic disorder, post-traumatic stress, premenstrual dysphoria.

35 cl, 6 dwg, 8 ex

FIELD: medicine.

SUBSTANCE: invention relates to medicine and deals with application of erythropoietic molecule for obtaining medication for treatment of neurodegenerative disorders of brain and spinal cord by introduction of efficient amount of medication into the bloodstream of patient requiring such treatment, in which erythropoietic molecule includes part of erythropoietin molecule, which has at least one free amino group, selected from group, including human erythropoietin and its analogues, which have human erythropoietin sequence, modified by addition of 1-6 sites of glycosylation or rearrangement of at least one site of glycosylation; said part of erythropoietin molecule is covalently bound with "n" groups of polyethylene glycol of formula -CO-(CH2)x-(OCH2CH2)m-OR with -CO of each polyethylene group, forming amide bond with one of said amino groups.

EFFECT: invention ensures penetration of erythropoietic molecule through the barrier between blood and brain, good period of half-life, which makes it possible to introduce molecule in lower initial dose.

19 cl, 3 ex, 3 dwg, 1 tbl

FIELD: medicine.

SUBSTANCE: invention relates to medicine, namely to pediatric neurology, and can be used for rehabilitation of neurological disorders in children in case of neuroinfections. For this purpose, at the background of adequate complex and pathogenetic therapy, parenteral introduction of actovegin in acute period of disease additionally from the first days of disease cytoflavin is introduced intravenously by drop infusion in dose 0.6 ml/kg or 10 ml per day for 3-5 days, elcar perorally in dose 70-100 mg/kg of weight per day for 3-4 weeks. In the period of early reconvalescence pantogam is additionally introduced perorally in dose 50-70 mg/kg of weight per day for 4 weeks. In case if multifocal affection of brain substance is present, gliatilin is introduced intravenously by drop infusion in dose 1 ml per 5 kg of body weight per day in combination with intramuscular introduction of ipidacrine in dose 5-15 mg per day for 7-10 days, after that gliatilin perorally in dose 50 mg/kg of weight per day together with ipidacrine inside in dose 1 mg/kg per day for 4 weeks.

EFFECT: method makes it possible to improve disease outcome due to reduction of frequency of residual neurological deficiency formation with reduction of term of hospital treatment.

3 ex

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