Pharmaceutical compositions

FIELD: medicine, pharmacology, pharmaceutical technology, pharmacy.

SUBSTANCE: invention relates to a solid pharmaceutical composition used in treatment of cyclooxygenase-2-dependent disorder or state that comprises from 200 mg to 400 mg of 5-methyl-2-(2'-chloro-6'-fluoroaniline)-phenylacetic acid and excipients wherein level of residual moisture in composition is from 1.5% to 5%. Also, invention relates to a method for stabilization of 5-methyl-2-(2'-chloro-6'-fluoroaniline)-phenylacetic acid as a component of the solid pharmaceutical composition that involves preparing the solid pharmaceutical composition comprising 5-methyl-2-(2'-chloro-6'-fluoroaniline)-phenylacetic acid wherein the composition comprises the level of residual moisture from 1.5% to 5%. The dried granulated preparation comprises 5-methyl-2-(2'-chloro-6'-fluoroaniline)-phenylacetic acid, microcrystalline cellulose, lactose monohydrate, croscarmellosa sodium wherein the level of residual moisture in the granulated preparation is from 2.5% to 4.5%. Solid pharmaceutical compositions comprise indicated dried granulated preparation. Invention provides enhancing stability of 5-methyl-2-(2'-chloro-6'-fluoroaniline)-phenylacetic acid as component of compositions and preparations.

EFFECT: improved and valuable properties of pharmaceutical compositions.

31 cl, 3 tbl, 1 ex

 

The invention relates to compositions for treatment of cyclooxygenase-2-mediated diseases and methods of stabilizing pharmaceutical compositions suitable for treating a cyclooxygenase-2-mediated diseases.

In particular, the present invention relates to compositions that contain 5-methyl-2-(2'-chloro-6'-ftoranila)phenylacetic acid.

Unexpectedly, it was found that when the drug substance 5-methyl-2-(2'-chloro-6'-ftoranila)phenylacetic acid is prepared in solid form, for example in tablet form, the stability of the drug substance increases with increasing moisture content in the tablet in a relatively narrow range, outside of which there is a decrease stability. Thus, in contrast to the typical characteristics of drug substances certain breakdown products of 5-methyl-2-(2'-chloro-6'-ftoranila)phenylacetic acid are formed with a higher rate in more than dry tablets. Mainly moisture in the form of water harms the stability of the drug substance, so packaging for pharmaceutical substances often contains some form of absorbing the moisture of the material to minimize levels of moisture.

The present invention presents a composition for treating a cyclooxygenase-2-dependent disorders or conditions containing 5-methyl-2-(2'-chloro-6'-f is Oranien)phenylacetic acid. The compositions contain from about 200 to about 400 mg of 5-methyl-2-(2'-chloro-6'-ftoranila)phenylacetic acid and have a level of residual moisture ("LOD") from about 1.5% to about 5%. In some embodiments, the implementation of the composition containing approximately 200 mg of 5-methyl-2-(2'-chloro-6'-ftoranila)phenylacetic acid, will have a LOD of approximately 2 to 5% or from about 2.1% to about 4.5%. In other embodiments, the implementation of the composition containing approximately 400 mg of 5-methyl-2-(2'-chloro-6'-ftoranila)phenylacetic acid, will have a LOD from about 1.5% to about 4%, or from about 1.7% to about 3.5%. In some embodiments, the implementation of the compositions are tablets, and in other embodiments, implementation of the compositions are tablets, film-coated (film-tablet).

In another aspect the invention is a dry granular products, suitable for the preparation of pharmaceutical compositions. Dry granular products may contain 5-methyl-2-(2'-chloro-6'-ftoranila)phenylacetic acid, microcrystalline cellulose, lactose monohydrate and nitrocresols, the level of residual moisture granulated drug is from about 2.5% to about 4.5%. The level of residual moisture gr is nomirovanija drug may also be from approximately 3% to approximately 3,75%, for example, approximately 3.5%. In another aspect the invention relates to a dry granular preparations containing 5-methyl-2-(2'-chloro-6'-ftoranila)phenylacetic acid, nutritionnelles and povidone, and the level of residual moisture granulated drug is from about 1.5% to about 4%, for example from about 1.7% to about 3.5%, for example from about 2% to about 3%, for example about 2.5%. The above-mentioned granulated preparations used for the manufacture of tablets, which contain, for example, 100, 200 or 400 mg of 5-methyl-2-(2'-chloro-6'-ftoranila)phenylacetic acid, and these tablets will have the levels of residual moisture, appropriate to this level in a dry granular drug used for the manufacture of tablets.

In another aspect the invention is a stabilizing 5-methyl-2-(2'-chloro-6'-ftoranila)phenylacetic acid in the pharmaceutical composition. The method consists in the preparation of solid pharmaceutical compositions containing 5-methyl-2-(2'-chloro-6'-ftoranila)phenylacetic acid, and the preparation leads to the formation of the composition with the level of residual moisture ("LOD") from about 1.5% to about 5%. In some embodiments, the implementation of the method will lead to the formation of the composition, with the containing a series of approximately 200 mg 5-methyl-2-(2'-chloro-6'-ftoranila)phenylacetic acid, which will have a LOD of approximately 2 to 5% or from about 2.1% to about 4.5%. In other embodiments, implementation of the method will lead to the formation of a composition containing approximately 400 mg of 5-methyl-2-(2'-chloro-6'-ftoranila)phenylacetic acid, which will have a LOD from about 1.5% to about 4%, or from about 1.7% to about 3.5%. In some embodiments, the implementation of the obtained compositions are tablets, and in other embodiments, the implementation arrangements are film-tablet.

Pharmaceutical compositions suitable for the practical implementation of the invention, are intended for oral administration and presents dosage forms with "immediate-release". Thus, pharmaceutical compositions suitable for the practical implementation of the invention, no pharmacokinetic or physical characteristics of pharmaceutical dosage forms with delayed release. Then, the pharmaceutical composition is suitable for the practical implementation of the invention, if it presents solid form, will rapidly disintegrate or dissolve, preferably within one hour after administration, and use of pharmaceutical compositions suitable for the practical implementation of the invention, will drive the IC as a result of the rapid increase in the concentration of 5-methyl-2-(2'-chloro-6'-ftoranila)phenylacetic acid in blood plasma. Preferably, when the concentration in plasma 5-methyl-2-(2'-chloro-6'-ftoranila)phenylacetic acid will peak within two to six hours after oral administration, and then will quickly fall due to the relatively short (3 to 6 hours) half-life of 5-methyl-2-(2'-chloro-6'-ftoranila)phenylacetic acid.

Medicinal compositions with release, other than immediate, which is not included in the scope of the present invention or used in it include, among other compositions, characterized by the release of delayed and delayed release. Compositions with delayed release can further be divided into composition with slow release and controlled release. System, characterized by the release delay, are such systems that use repeated intermittent dosing of medicinal substances from one or more immediate-release entered in a single dosage form. Examples of compositions characterized by the release delay, include tablets and capsules with repeated action and tablets with intersolubility coating, which is computed at the time the release is achieved by using a barrier coating. The composition described is of iesa release delayed do not form or do not support constant concentration of drug in blood plasma, but rather give alternating peaks of maximum and minimum concentrations of the drug in the blood plasma, which in both cases, the optimal range of therapeutic action of a drug.

Pharmaceutical composition with delayed release include pharmaceutical compositions that achieves slow release of drug over an extended period of time. If the composition with delayed release can maintain a constant concentration of drug in plasma, it is in this context called the song "controlled release". If it does not support a constant concentration of drug in blood plasma, but supports the concentration of drug in the range of therapeutic effects over a longer period of time than was achieved using the composition with the immediate-release, it is in this context called the song "slow release". Thus, compositions with controlled release in contrast to the compositions of the present invention maintain a relatively constant peak is th concentration of drug in plasma for a long period of time, as a rule, within twelve to twenty-four hours.

As a rule, based oral dosage compositions with delayed release lie diffusion system, dissolving system and osmotic system or ion-exchange system.

In diffusive systems, the rate of release of a drug is determined by its diffusion through the water-insoluble polymer. There are two types of diffusion devices: reservoir devices in which a core of drug is surrounded by a polymer membrane, and matrix devices in which are dissolved or dispersed drug is evenly distributed throughout an inert polymer matrix. Typical methods used for manufacturing devices tank types include microencapsulation particles of the drug and the coating is produced by pressing whole tablets or particles. In General, particles, covered by microencapsulation, form a system in which the drug is contained in the covering film, as well as in the core of the microcapsules. Some of the materials that are typically used as water-insoluble coating in the form of monocomponent or in combination, presents hardened gelatin, methyl - or ethylcellulose, polyhydroxybutyrates, hydroxypropyl what ellulose, the polyvinyl acetate and wax.

For the manufacture of a matrix device, as a rule, mix the drug with the matrix material, and then the mixture is pressed to tablets. When using a wax matrix drug usually is dispersed in the molten wax, which is then allowed to harden, granularit and pressed him to the core. The matrix system, as a rule, contain the initial dose of the drug deposited in the form of a coating on the core of the drug and matrix. The main types of materials used for the manufacture of matrix devices are insoluble plastics, hydrophilic polymers, and fatty compounds. Plastic matrix include methyl acrylate-methyl methacrylate, polyvinyl chloride and polyethylene. Hydrophilic polymers include methylcellulose, hypromellose and sodium carboxymethyl cellulose. Fatty compounds include waxes, such as karnovsky wax and glycerylmonostearate.

Most drugs with a slow release soluble type are either encapsulated dissolving system, or matrix dissolving system. Encapsulated soluble drugs can be prepared either by coating particles or granules of a medicinal product by a shell of slow RA is taraudage polymer of different thickness, either by microencapsulation. The usual method of microencapsulation is coacervation, which includes adding a hydrophilic substance to the colloidal dispersion. Hydrophilic substance, which covers the suspended particles may be selected from a wide range of natural and synthetic polymers, including Shallaki, waxes, starches, cellulitecellulite (or butyrate) or polyvinylpyrrolidone. After covering material is dissolved, the whole drug in the microcapsule, immediately available for dissolution and absorption, which allows to control the release of drug by adjusting the thickness and dissolution rate of the coating. If the microcapsules, which contain the drug, use three or four variations of the coating thickness drug will be released at a different specified time, leading to pulse effect, characteristic for the release delay. When using a range of different thicknesses can be achieved more constant concentration of the drug in the blood. The encapsulated particles may be compressed into tablets or placed in capsules.

Matrix soluble drugs with a slow release obtained by preparing particles containing Leka is the only drug and slowly dissolving polymer particles. These particles can be prepared by hardening drug with the polymer or wax and spray solidification of the particles, or by cooling the mixture of the drug and coating and sieving it. An alternative may be used water dispersion method, according to which the mixture of drug and polymer is sprayed or placed in water and collect the resulting particles. Then of particles containing drug and polymer, pressed tablets.

Drugs, which are based on osmotic gradients were also used to obtain a drug with a slow release. Typically, these drugs include a membrane permeable to water but not to drug substance that surrounds the nucleus of this drug substance. The membrane has a small hole for delivery. The water passes through a semipermeable membrane, dissolves the drug substance, which is then pumped out of the drug through the opening for delivery. Materials that can be used as a semi-permeable membrane, presents polyvinyl alcohol, polyurethane, cellulose acetate, ethylcellulose and polyvinyl chloride.

Medicines immediate-release, used in practice the practical implementation of the invention, intended for oral administration and can be prepared by any known in the field of engineering by the method of the manufacture of pharmaceutical compositions immediate-release. These compositions can contain one or more components selected from the group consisting of sweeteners, flavouring substances, dyes and preservatives, to get committed from the pharmaceutical point of view and palatable preparations. Tablets contain the active ingredient in a mixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. Such excipients can be represented, for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate, components for granulation or leavening agents, such as corn starch or alginic acid, binders, such as starch, gelatin or gum Arabic, and lubricating agents such as magnesium stearate, stearic acid or talc. If water-soluble, water-insoluble or permeable polymer or wax is present in a quantity sufficient to impart a medicinal drug slow release properties, excipients cannot be represented water-soluble, not water soluble elevateprivilege polymers or waxes. In the most preferred embodiment, the pharmaceutical composition of the immediate-release formulation is a tablet.

Unexpectedly, it was found that 5-methyl-2-(2'-chloro-6'-ftoranila)phenylacetic acid when it is prepared in the form of solid dosage forms such as tablets, undergoes a series of processes of disintegration. Tablets containing approximately 200 mg of active agent, preferably have a LOD of 3.5% at the optimum range from about 2.1% to about 4.5%. Tablets with a load of drug 65%, containing about 400 mg of active agent, preferably have LOD approximately 2.5% at optimal range from about 1.7% to about 3.5%. It has been unexpectedly found that if the LOD tablets support within the above parameters, the active agent, 5-methyl-2-(2'-chloro-6'-ftoranila)phenylacetic acid, has a higher chemical stability.

It has been unexpectedly discovered that the above ranges are optimal LOD values between two different directions, which is the disintegration of 5-methyl-2-(2'-chloro-6'-ftoranila)phenylacetic acid, namely between oxidation and cyclic collapse. Compositions and methods corresponding to the invention, are solid pharmaceutical is e compositions for oral administration, containing 5-methyl-2-(2'-chloro-6'-ftoranila)phenylacetic acid with minimal levels of total degradation products.

Levels of oral doses of 5-methyl-2-(2'-chloro-6'-ftoranila)phenylacetic acid are of the order of from about 200 to about 1200 mg/patient/day. In a preferred embodiment, the effective amount is from about 200 mg to about 800 mg In a more preferred embodiment, the effective amount is from about 200 mg to about 600 mg In an even more preferred embodiment, the effective amount is from about 200 mg to about 400 mg, In a preferred embodiment, the effective amount is about 400 mg.

The amount of drug that can be combined with the materials of the media to produce a dosage form for a single admission, will vary depending on the size and weight of the recipient, the body of the recipient, and the particular method of administration. For example, a drug product intended for oral administration to the recipient is a person, can contain from about 50 mg to about 1200 mg of the agent, mixed with the appropriate and suitable amount of mA is Arial media which can vary from approximately 5% to approximately 95% of the total composition. Dosed unified form, as a rule, can contain the drug in quantities 50, 100, 200, 300, 400, 600 or 800 mg In one of the embodiments of the pharmaceutical composition with an immediate release contains from about 50 mg to about 1200 mg of 5-methyl-2-(2'-chloro-6'-ftoranila)phenylacetic acid. In a preferred embodiment, the pharmaceutical composition of immediate-release contains from about 50 mg to about 600 mg of 5-methyl-2-(2'-chloro-6'-ftoranila)phenylacetic acid. In an even more preferred embodiment, the pharmaceutical composition of immediate-release contains from about 50 mg to about 400 mg of 5-methyl-2-(2'-chloro-6'-ftoranila)phenylacetic acid. In the most preferred embodiment, the pharmaceutical composition of immediate-release contains approximately 400 mg of 5-methyl-2-(2'-chloro-6'-ftoranila)phenylacetic acid. In a specific embodiment, the composition of the immediate-release formulation is a capsule or tablet. In another embodiment, the pharmaceutical dosage form is a film-tablet.

Typically, the composition is sootvetstvuyushie the invention, contain 5-methyl-2-(2'-chloro-6'-ftoranila)phenylacetic acid on the load level drug from 50 to 90 wt.% in terms of the total mass of the composition.

In the private aspect of the present invention is a tablet with an immediate-release formulation containing approximately 400 mg of 5-methyl-2-(2'-chloro-6'-ftoranila)phenylacetic acid, while the tablet contains from about 60 wt.% to about 70 wt.% 5-methyl-2-(2'-chloro-6'-ftoranila)phenylacetic acid. Tablet immediate-release may contain about 65 wt.% 5-methyl-2-(2'-chloro-6'-ftoranila)phenylacetic acid. In another aspect the invention is a tablet with an immediate-release formulation containing approximately 200 mg of 5-methyl-2-(2'-chloro-6'-ftoranila)phenylacetic acid, while tablet contains approximately 50 wt.% 5-methyl-2-(2'-chloro-6'-ftoranila)phenylacetic acid.

It should be understood, however, that individual dose level for any particular patient will depend upon a number of factors, including age, body weight, General health, sex, diet, time of administration, rate of excretion, drug combination, and the type and severity of specific diseases, which take the treatment. For many patients is shown a single daily dose in diapazonom about 200 to about 1200 mg/day or from about 200 to about 400 mg/day.

In an additional aspect, the invention is a highly compressed tablet with a high burden of drug drug. The tablet may be small in size, for example, have a diameter of 10-20 mm, preferably 15 to 20 mm, most preferably 17-18 mm; width of 5-10 mm, preferably of 6.5-7.5 mm, the thickness of the tablet is from 4 to 8 mm, preferably 4.5-6.5 mm, most preferably about 5.8 mm For the manufacture of compressed tablets using a compression force of 10 to 20 kilonewton (kN). The advantages of this high-stress drug include improved bioavailability characteristics of the release and elastic deformation.

The following are examples of pharmaceutical compositions corresponding to the invention (table 1-3).

USP U.S. Pharmacopeia.
Table 1
IngredientAmount/batch of tablets 200 mg (kg)
Core
Pellet
Drug substance 5-methyl-2-(2'-chloro-6'-ftoranila)phenylacetic acid50**
Microcrystalline cellulose, NF (PH 101)12,85
The lactose monohydrate, NF11,65
Nitrocresols, NF1
On icon, USP4
Titanium dioxide, USP2
Purified water***, USP20,375
Extrarespiratory phase
Microcrystalline cellulose, NF (PH 102)13
Nitrocresols, NF3
Titanium dioxide, USP2
Magnesium stearate, NF0,5
Floor
Opadry ®white2,801****
Opadry® yellow2,0****
Opadry® red0,4****
Opadry® black0,0504****
Purified water***, USP29,758****
** The weight of the drug substance take calculated on dry substance (100%) based on the result of analysis (factorization). The difference in mass adjusted using the amount of microcrystalline cellulose.
*** Removed during processing.
**** Includes 50% excess losses in the coating process.
(NF - national (pharmaceutical) form (Supplement to the American Pharmacopoeia).

Table 1 presents the composition for a party of approximately 250,000 film-tablets-5-methyl-2-(2'-chloro-6'-ftoranila)phenylacetic acid immediate-release. For the preparation of tablets titanium dioxide is dispersed in water followed by the addition of povidone and stirred for 20 minutes to obtain a suspension of povidone/titanium dioxide. Drug substance, lactose, microcrystalline cellulose and croscarmellose stirred in the mixer intensive mixing with shear force (for example, demand include Collette Gral) for 5 minutes to obtain a medicinal mixture. The medicine mixture granularit in the intensive mixer mixing with shear force along with the suspension of povidone/titanium dioxide. The suspension is pumped with a speed of 3 kg/min drug mixture. The resulting mixture was additionally stirred for 90 seconds after adding the entire suspension. Wet the granulated product is dried in a fluidized bed dryer at a temperature of supplied air 50°to form a dry granular product. Given the residual amount of water in a dry granular product is 3.5% (with an acceptable range of 2.1 to 4.5%). Dry the granulated product is sifted with ispolzovaniem (vibration) and sieve with a mesh 30 mesh. The preceding stages repeat with the aim of obtaining a second dry granular product.

Titanium dioxide extraglomerular phase sift through the hand sieve with a mesh of 60 mesh. Dry granules are mixed with microcrystalline cellulose, nitrocresols and titanium dioxide extraglomerular phase in the mixer with a double hull at a power of 300 rpm for education penultimate mixture. Magnesium stearate is screened through a hand sieve with a mesh of 60 mesh and mixed with the penultimate mixture in the mixer with a double hull at 50 rpm for the formation of the mixture for tabletting. From the mixture for tabletting compressed tablets using a tablet press and oval dies.

Powders for coating (Opadry®) is mixed with purified water to prepare a 15 wt.% suspension for coating. The tablets covered with a film by covering the suspension in the pan to cover, using the temperature of the air 60-75°C. In table 2 lead composition film tablets containing 200 mg of 5-methyl-2-(2'-chloro-6'-ftoranila)phenylacetic acid.

Table 2
Ingredienttheoretical amount [mg]Function
Core
Drug substance 5-methyl-200The active substance
2-(2'-chloro-6'-ftoranila)phenylacetic acid
Microcrystalline cellulose (PH 101)51,4Filler
Lactose46,6Filler
Povidone16Binder
Titanium dioxide8Dye
Nitrocresols4Baking powder
Purified water*Q.S.Granulating liquid
Extrarespiratory phase
Microcrystalline cellulose (PH 102)52Filler
Croscarmellose12Baking powder
Titanium dioxide8Dye
Magnesium stearate2Grease
Mass of nucleus400
Floor
Opadry® white (00F18296) 7,4676Dye
Opadry® yellow (00F 12951)5,3312Dye
Opadry® red (00F 15613)1,0668Dye
Opadry® black (00F 17713)0,1344Dye
Purified water*Q.S.The solvent for
Cover
The total mass414
* removed during processing
(Q.S. - sufficient)

The table containing 400 mg of the drug substance may have the following composition (table 3).

Table 3
The composition of the dosage form having a weight of 400 mg
Wt.%IngredientMg/doseKg/batch
Pellet
65,04Drug substance400,0020,00
2,15Nitrocresols, NF (Ac-Di-Sol)13,220,661
6,60Povidone K, USP40,59to 2.29
18,12Purified water, USP*QsQs
Mixture
23,56Microcrystalline cellulose, NF(Avicel PH 102)144,906,066
2,15Nitrocresols, NF (Ac-Di-13,220,553
Sol)
0,50Magnesium stearate, NF (vegetable source)of 3.070,128
Film coating
84,46Opadry®Global White 00F1829615,20280,296637
14,03Opadry®Global Red 00F156132,52540,049275
1,51Opadry®Global 00F Black 177130,27180,005303
Purified water, USP*Qs1,990218
The weight of the film-pills633,00
* Not detected in the final product. The percentage of added water used for granulation, calculated on the dry weight of the drug substance and nitrocresols.

That is the tap hole is prepared by first mixing a binder polyvinylpyrrolidone with water followed by addition of the drug substance and nitrocresols to a solution of povidone. This mixture granularit in Gral mixer. Resulting from the granulated product is dried in a fluidized bed dryer, getting dry granular product with a LOD approximately 2.5%, with an acceptable range from 1.7 to 3.5% and sift through a vibrating sieve with a mesh 18 mesh. Microcrystalline cellulose (Avicel PH-102, NF) is mixed with nitrocresols and the resulting mixture is sieved through a sieve with a mesh 18 mesh. The sifted mixture is stirred with sifted dry granular drug, polyvinylpyrrolidone, drug substance and nitrocresols. Then the resulting mixture is stirred with magnesium stearate, sifted through a sieve with a mesh 18 mesh. Then the resulting mixture is pressed in a tablet press.

All patents, patent applications and other publications cited in this context, specifically incorporated by reference in their entirety. In the event of any conflict between this description and the material incorporated by reference, the present description is a reference.

1. Solid pharmaceutical composition for treating a cyclooxygenase-2 dependent disorders or conditions, comprising from 200 to 400 mg of 5-methyl-2-(2'-chloro-6'-ftoranila)phenylacetic acid and excipients, and the levels of residual moisture of the composition ranges from 1.5 to 5%.

2. TV is RDA pharmaceutical composition according to claim 1, includes 200 mg of 5-methyl-2-(2'-chloro-6'-ftoranila)phenylacetic acid, and the level of residual moisture of the composition is from 2 to 5%.

3. Solid pharmaceutical composition according to claim 2, the level of residual moisture which is from 2.1 to 4.5%.

4. Solid pharmaceutical composition according to claim 3, the level of residual moisture which is 3.5%.

5. Solid pharmaceutical composition according to claim 1, comprising 400 mg of 5-methyl-2-(2'-chloro-6'-ftoranila)phenylacetic acid, and the level of residual moisture of the composition ranges from 1.5 to 4%.

6. Solid pharmaceutical composition according to claim 5, comprising 400 mg of 5-methyl-2-(2'-chloro-6'-ftoranila)phenylacetic acid, and the level of residual moisture of the composition ranges from 1.7 to 3.5%.

7. Solid pharmaceutical composition according to claim 6, the level of residual moisture which is 2.5%.

8. Solid pharmaceutical composition according to claim 3, which is a tablet.

9. Solid pharmaceutical composition according to claim 4, which is a tablet.

10. Solid pharmaceutical composition according to claim 6, which is a tablet.

11. Solid pharmaceutical composition according to claim 7, which is a tablet.

12. The method of stabilization 5-methyl-2-(2'-chloro-6'-ftoranila)phenylacetic acid and the solid pharmaceutical composition, providing for the preparation of solid pharmaceutical to the position, includes 5-methyl-2-(2'-chloro-6'-ftoranila)phenylacetic acid and excipients, with the level of residual moisture from 1.5 to 5%.

13. The method according to item 12, in which solid pharmaceutical composition comprises 200 mg of 5-methyl-2-(2'-chloro-6'-ftoranila)phenylacetic acid, and the level of residual moisture of the composition is from 2 to 5%.

14. The method according to item 13, in which solid pharmaceutical composition contains 200 mg of 5-methyl-2-(2'-chloro-6'-ftoranila)phenylacetic acid, and the level of residual moisture of the composition is from 2.1 to 4.5%.

15. The method according to 14, in which solid pharmaceutical composition contains 200 mg of 5-methyl-2-(2'-chloro-6'-ftoranila)phenylacetic acid, and the level of residual moisture of the composition is from 3 to 4%.

16. The method according to item 15, in which solid pharmaceutical composition comprises 200 mg of 5-methyl-2-(2'-chloro-6'-ftoranila)phenylacetic acid, and the level of residual moisture of the composition is 3.5%.

17. The method according to item 12, in which solid pharmaceutical composition comprises 400 mg of 5-methyl-2-(2'-chloro-6'-ftoranila)phenylacetic acid, and the level of residual moisture of the composition ranges from 1.5 to 4%.

18. The method according to 17, in which solid pharmaceutical composition comprises 400 mg of 5-methyl-2-(2'-chloro-6'-ftoranila)phenylacetic acid, and the level of residual moisture of the composition ranges from 1.7 to 3.5%.

19. the manual on p, in which solid pharmaceutical composition comprises 400 mg of 5-methyl-2-(2'-chloro-6'-ftoranila)phenylacetic acid, and the level of residual moisture of the composition is from 2 to 3%.

20. The method according to claim 19, in which solid pharmaceutical composition comprises 400 mg of 5-methyl-2-(2'-chloro-6'-ftoranila)phenylacetic acid, and the level of residual moisture of the composition is 2.5%.

21. Dry granular product intended for the treatment of a cyclooxygenase-2 dependent disorders or state and including 100-400 mg 5-methyl-2-(2'-chloro-6'-ftoranila)phenylacetic acid, microcrystalline cellulose, lactose monohydrate, croscarmellose, and the level of residual moisture granulated drug is from 2.5 to 4.5%.

22. Dry the granulated product according to item 21, the level of residual moisture which is from 3 to 3.75%.

23. Dry the granulated product according to item 22, the level of residual moisture which is 3.5%.

24. Dry granular product intended for the treatment of a cyclooxygenase-2 dependent disorders or state and including 100-400 mg 5-methyl-2-(2'-chloro-6'-ftoranila)phenylacetic acid, croscarmellose, povidone, and the level of residual moisture granulated drug ranges from 1.5 to 4%.

25. Dry the granulated product according to paragraph 24, the level of residual moisture catalogservlet from 1.7 to 3.5%.

26. Dry the granulated product according A.25, the level of residual moisture which is 2 to 3%.

27. Dry the granulated product according p, the level of residual moisture which is 2.5%.

28. Solid pharmaceutical composition comprising the dry granular preparation according to item 21.

29. Solid pharmaceutical composition comprising the dry granular preparation according to item 22.

30. Solid pharmaceutical composition comprising a dry, granular drug A.25.

31. Solid pharmaceutical composition intended for the treatment of a cyclooxygenase-2 dependent disorders or condition and includes dry the granulated product according p.



 

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6 cl, 3 tbl, 6 ex

FIELD: medicine, veterinary science, agriculture, biotechnology.

SUBSTANCE: the present innovation refers to preparations of medicinal and veterinary indication and methods for their obtaining. The suggested complex preparation-probiotic includes a carrier being a porous aluminum oxide-based enterosorbent SUMS-1 and cells of bacteria-eubiotics with nutritive and protective media immobilized upon the mentioned carrier-enterosorbent. The cells of bacteria-eubiotics with nutritive medium are being a lyophilized concentrate of the consortium of either bifidobacteria or lactobacteria, or their mixture at titer being 108-1010 CFU/g, and as a porous carbon-modified enterosorbent SUMS-1 it contains enterosorbent SUMS-1 additionally treated with the solution of metal salt at the following ratio of the preparation components in lyophilized form, weight%: cells with nutritive medium of the consortium of bifido-, or lactobacteria-eubiotics, or their mixture with titer of 108-1010 CFU/g 1.0-10.0; protective medium 0.1-10.0; enterosorbent SUMS-1 additionally treated with the solution of metal salt - the rest up to 100%. Method for obtaining the suggested preparation deals with treating a porous enterosorbent SUMS-1 with the solution of metal salt at volumetric ratio being 1:1, not more and its washing against a reagent with 2-3-fold volumes of distilled water followed by mixing enetrosorbent and bacteria-eubiotics with nutritive and protective media at the ratio of 1:1, not more to keep the mixture till complete immobilization of bacterial cells onto enterosorbent with its subsequent freezing and freeze drying before sterilization. As bacteria one should apply the concentrate of the consortium of bifidobacteria, or lactobacteria, or their mixture at titer being 108-1010 CFU/g. The suggested complex preparation-probiotic provides higher efficiency of sorption and desorption of bacterial cells with enterosorbent SUMS-1 that shows its clinical efficiency and higher colonization activity of bacteria-eubiotics.

EFFECT: higher efficiency.

9 cl, 5 ex, 2 tbl

FIELD: medicine, surgery.

SUBSTANCE: the present innovation refers to treating osseous cavity in patients with chronic post-traumatic osteomyelitis, so, after necrsequestrectomy one should irrigate an osseous cavity with aqueous solution of sodium chloride, then it is necessary to treat the cavity with 3%-hydrogen peroxide solution with subsequent removal of foam with 0.02%-chlorohexidine bigluconate aqueous solution. Then twice during 1 min it is necessary to treat osseous cavity with 0.9%-ozonized sodium chloride solution at ozone concentration being 9000-10000 mgl/l. After that, one should introduce the mixture of anti-infectious chemotherapeutic preparations along with ultrasound cavitation for 3 min at frequency of 40 kHz followed by treating the cavity with the flow of nitrogen monoxide for 5 min at concentration being 5000 mg/cu. m. The innovation enables to increase penetrating capacity of medicinal preparations due to matching the desired mode of cavitary treatment.

EFFECT: higher efficiency of antiseptic treatment.

1 ex

FIELD: biotechnology, molecular biology.

SUBSTANCE: invention proposes a polynucleotide VEGI-192a encoding polypeptide that inhibits growth of human vascular endothelial cells. Invention describes expressing vector comprising polynucleotide and E. coli cell-host comprising vector. Invention discloses polypeptide encoded by polynucleotide and fused protein based on indicated polypeptide. Invention describes polynucleotide encoding fused protein and expressing vector based on indicated polynucleotide. Invention discloses a pharmaceutical composition used for inhibition of angiogenesis based on polypeptide-inhibitor of growth of human vascular endothelial cells and polynucleotide encoding its. Invention describes therapeutic methods for inhibition of angiogenesis and suppression of tumor growth based on this composition. Invention describes an antibody raised to polypeptide that inhibits growth of human vascular endothelial cells. Using this invention provides novel forms of inhibitor of human growth of vascular endothelial cells and can be used in medicine.

EFFECT: valuable biological and medicinal properties of inhibitor.

27 cl, 27 dwg, 13 tbl, 34 ex

FIELD: medicine.

SUBSTANCE: method involves opening pyo-inflammatory focus. Rexod is introduced in addition to basic therapy. Rexod is introduced during the operation or immediately after the operation and then every day once a day intravenously in bolus dose. The drug is introduced during 4-5 days in physiologic saline or in 5% glucose solution at a dose of 0.2 mcg/kg of patient body weight.

EFFECT: enhanced effectiveness of treatment; improved general health state within a short period; reduced oxidation stress; prevented secondary active oxygen forms production.

3 tbl

FIELD: medicine.

SUBSTANCE: disclosed is application of Ximedon (N-(β-oxyethyl)-4,6-dimethyl-1,2-dihydro-2-oxopyrimidine) for treatment and prophylaxis of various intoxication.

EFFECT: preparation of large spectrum of action and inducing effect comparable with Phenobarbital effect.

2 tbl, 13 ex

FIELD: medicine.

SUBSTANCE: method involves treating root canals with instruments and preparation containing calcium hydroxide is temporarily placed into the canals several times changing the portion every 2-5 weeks for fresh one. Before introducing fresh portion, the root canals are treated with antiseptic solution in combination with their ultrasonic treatment.

EFFECT: enhanced effectiveness of treatment; stopped inflammatory responses in periodontium tissues; prevented reinfection.

8 cl

FIELD: medicine, pulmonology.

SUBSTANCE: it is necessary to study initial values of functional reserve ability (FRA) of pulmonary-capillary circulation in %, average pressure value in pulmonary artery (AvPPA) in mm mercury column and daily variability of peak volumetric expiration rate (ΔPVRexp.) in % to calculate the following equation: D=+1.376·FRA-2.087·AvPPA-1.023·ΔPVRexp. At D value being above -25.71 one should predict instable flow of bronchial asthma. The innovation enables to carry out integral evaluation of functional state of pulmonary microcirculation, pressure in pulmonary artery and reactivity of respiratory tract.

EFFECT: higher efficiency and accuracy of prediction.

2 ex

FIELD: organic chemistry, biochemistry.

SUBSTANCE: invention describes novel substituted pyrazoles of the general formula (I): wherein values of radicals Ar, Ar2, W, G, R5-R8, RZ and n are given in the invention claim. Also, invention relates to a pharmaceutical composition based on these compounds, using this pharmaceutical composition for manufacturing agent designated for treatment of asthma, and a method for inhibition of activity of cathepsin S. Compounds indicated above can be used in medicine.

EFFECT: valuable medicinal and biochemical properties of compounds and pharmaceutical composition.

27 cl, 3 tbl, 352 ex

FIELD: medicine, dermatology, pharmaceutical industry, pharmacy.

SUBSTANCE: invention relates to a composition used in treatment and prophylaxis of allergic diseases and non-allergic inflammatory diseases in mammals and containing winter-hardy kiwi extract. Also, invention relates to a method for preparing the composition containing winter-hardy kiwi extract and involving diluting milled and dried winter-hardy kiwi with water or lower alcohols, heating a diluted winter-hardy kiwi and extraction of product to obtain winter-hardy kiwi extract. Also, invention relates to a method for treatment, relive or prophylaxis of allergic diseases and non-allergic inflammatory diseases in mammals involving administration in a mammal winter-hardy kiwi extract for treatment or prophylaxis of at least one symptom of allergic disease or non-allergic inflammatory disease. Also, invention elates to a method for treatment and prophylaxis of allergic diseases and non-allergic inflammatory diseases in mammals involving prescription or administration in mammal winter-hardy kiwi extract for treatment or prophylaxis of at least one symptom of allergic disease or non-allergic inflammatory diseases in mammal. Also, invention relates to using winter-hardy kiwi extract for treatment, relieve or prophylaxis of allergic diseases or non-allergic inflammatory diseases in mammals. Above described winter-hardy kiwi extract and a composition based on thereof show effectiveness in treatment, relieve or prophylaxis of allergic diseases or non-allergic inflammatory diseases in mammals.

EFFECT: valuable medicinal properties of composition.

58 cl, 5 dwg, 11 tbl, 11 ex

FIELD: organic chemistry, medicine.

SUBSTANCE: invention relates to a novel compound - ((1R,3S)-3-isopropyl-3-{[3-(trifluoromethyl)-7,8-dihydro-1,6-naphthyridine-6(5H)-yl]carbonyl}cyclopentyl)[(3S,4S)-3-methoxytetrahydro-2H-pyran-4-yl]amine succinate of the formula: that possesses property of CCR-2 antagonist. Also, invention relates to a method for modulation of activity of chemokine receptors and a method for treatment, improvement, control and reducing risk of inflammatory and immunoregulatory disorder or disease, and to a method for improvement, control and reducing risk of rheumatic arthritis.

EFFECT: valuable medicinal properties of compound.

4 cl, 3 tbl, 5 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to drugs and in particular provides a receptor ligand activated by peroxisome proliferator γ (PPAR γ), and a composition comprising the indicated ligand used for aim in improving insulin-resistance state or for prevention and/or improving the insulin-resistance syndrome state. Invention relates to a receptor ligand activated by peroxisome proliferator that comprises prenylflavonoid, chalcone derivative, flavonol derivative and their salt, glycoside and/or esterified form. Also, invention relates to composition comprising abovementioned ligand, a vegetable extract containing abovementioned ligand, and to a novel compound (dehydroglyasperin D) represented by the following formula: .

EFFECT: improved preparing method, valuable medicinal properties of ligand.

33 cl, 26 tbl, 13 ex

FIELD: organic chemistry, chemical technology, medicine.

SUBSTANCE: invention describes 6,6-dimethyl-8-oxo-5,6,8,9-tetrahydrobenzo[f]pyrrolo[2,1-α]isoquinoline-9-spiro-2-(3-aroyl-4-hydroxy-1-o-hydroxyphenyl-5-oxo-2,5-dihydro-7H-pyrroles) and 6,6-dimethyl-8-oxo-5,6,8,9-tetrahydrobenzo[f]pyrrolo[2,1-α]isoquinoline-9-spiro-2-(3-benzoyl-4-hydroxy-1-o-hydroxyphenyl-5-oxo-2,5-dihydro-1H-pyrrole) of the formula (I) (a, b, c) wherein Ar means C6H5 (a); p-C6H4OMe (b); p-C6H4Br (c) eliciting analgesic activity and related to substituted 13-aza-analogs of steroids, and to a method for their synthesis. Invention provides the development of a simple method of synthesis of 6,6-dimethyl-8-oxo-5,6,8,9-tetrahydrobenzo[f]pyrrolo[2,1-α]isoquinoline-9-spiro-2-(3-aroyl-4-hydroxy-1-o-hydroxyphenyl-5-oxo-2,5-dihydro-1H-pyrroles) related to 13-azagonanes - heterocyclic analogs of steroid comprising a spiro-heterocyclic substitute at position 16 of tetracyclic system among them compound 6,6-dimethyl-8-oxo-5,6,8,9-tetrahydrobenzo[f]pyrrolo[2,1-α]isoquinoline-9-spiro-2-(3-benzoyl-4-hydroxy-1-o-hydroxyphenyl-5-oxo-2,5-dihydro-1H-pyrrole) elicits analgesic activity and these compounds have not been described. The proposed reaction represents a novel approach to synthesis of heterocyclic analogs of steroids.

EFFECT: improved method of synthesis, valuable medicinal property of compound.

2 tbl, 3 ex

FIELD: organic chemistry, medicine, pharmacy, biochemistry.

SUBSTANCE: invention relates to a method for treatment of states caused by activity of p38 kinase. Method involves administration to a patient needed in this treatment of at least one compound of the formula (I): or its pharmaceutically acceptable salt or solvate wherein R3 means hydrogen atom, methyl, perfluoromethyl, methoxy-group, halogen atom, cyano-group or NH2-group; X is chosen from -O-, -OC(=O)-, -S-, -S-, -S(=O)-, -SO2-, -C(=O)-, -CO2-, -NR10-, -NR10C(=O)-, -NR10C(=O)NR11-, -NR10CO2-, -NR10SO2-, -NR10SO2NR11-, -SO2NR10-, -C(=O)NR10, halogen atom, nitro- and cyano-group, or X is absent; Z is chosen from oxygen (O), sulfur (S), nitrogen (N) atoms, and -CR20 being wherein Z means -CR20 optionally substituted bicyclic aryl or heteroaryl with R4 or R5; R1 means hydrogen atom, -CH3, -OH, -OCH3, -SH, -SCH3, -OC()=O)R21, -S(=O)R22, -SO2NR23R25, -CO2R21, -C(=O)NR24R25, -NH2, -NR24R25, -NR21SO2NR24R25, -NR21SO2R22, -NR24C(=O)R25, -NR24CO2R25, -NR21C(=O)NR24R25, halogen atom, nitro- or cyano-group; R2 is chosen from the following group: (a) hydrogen atom under condition that R2 doesn't mean hydrogen atom if X means -S(=O)-, -SO2-, -NR10CO2- or -NR10SO2-; (b) alkyl, alkenyl and alkynyl comprising up to four R26 groups or pentafluoroalkyl as substitutes; (c) aryl and heteroaryl comprising up to three groups R27 as substitutes, and (d) heterocyclo-group or heteroalkyl optionally comprising keto-group (=O), up to three groups R27 as substitutes, and/or comprising carbon-carbon bridge comprising 3-4 carbon atoms, or (e) R2 is absent if X means halogen atom, nitro- or cyano-group; R4 means substituted aryl, aryl comprising NOSE-alkyl, substituted heteroaryl or optionally substituted bicyclic 7-11-membered saturated or unsaturated carbocyclic or heterocyclic fragment as a substitute, and R5 means hydrogen atom, alkyl or substituted alkyl with exception of cases when Z means O or S and then R5 is absent, or R4 and R5 in common with Z form optionally substituted bicyclic 7-11-membered aryl or heteroaryl; R6 means hydrogen atom, alkyl, substituted alkyl, aryl, substituted aryl, heterocyclo-group, substituted heterocyclo-group, -NR7R8, -OR7 or halogen atom; R10 and R11 are chosen independently from the following group: hydrogen atom, alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heterocyclo-group and substituted heterocyclo-group; R7, R8, R21, R24 and R25 are chosen independently from the following group: hydrogen atom, alkyl, substituted alkyl, aryl, substituted aryl, heterocyclo-group and substituted heterocyclo-group; R20 means hydrogen, lower alkyl or substituted alkyl, or R20 can absent if carbon atom to which is bound and in common with R4 and R5 represents part of bicyclic aryl or heteroaryl; R22 means alkyl, substituted alkyl, aryl, substituted aryl, heterocyclo-group or substituted heterocyclo-group; R26 is chosen from the following group: halogen atom, trifluoromethyl, halogenalkoxy-group, keto (=O)-, nitro-, cyano-group, -SR28, -OR28, -NR28R29, -NR28SO2, -NR28SO2R29, -SO2R28, -SO2NR28R29, -CO2R28, -C(=O)R28, -C(=O)NR28R29, -OC(=O)R28, -C(=O)NR28R29, -NR28C(=O)R29, -NR28CO2R29,=N-OH, =N-O-alkyl; aryl optionally comprising as a substitute from one to three R27 groups; cycloalkyl optionally comprising a substituted keto-group (=O), from one to three R27 groups, or carbon-carbon-containing bridge comprising of 3-4 carbon atoms; and heterocyclo-group comprising optionally as a substitute keto-group (=O), from one to three R27 groups or comprising carbon-carbon bridge comprising 3-4 carbon atoms, and wherein each R28 and R29 is chosen independently from the following group: hydrogen atom, alkyl, alkenyl, aryl, aralkyl, (C3-C7)-cycloalkyl and (C3-C7)-heterocycle, or they can form in common (C3-C7)-heterocycle; and each R28 and R29, in turn, can comprise optionally up to two substitutes representing alkyl, alkenyl groups, halogen atoms, halogenalkyl groups, halogenalkoxy-, cyano-, nitro-, amino-, hydroxy-, alkoxy-, alkylthio-groups, phenyl, benzyl, phenyloxy- and benzyloxy-groups; and R27 is chosen from the following group: alkyl, R32 and (C1-C4)-alkyl comprising as substitutes from one to three R32groups and wherein each R32 group is chosen independently from the following group: halogen atom, halogenalkyl, halogenalkoxy-, nitro-, cyano-groups, -SR30, -OR30, -NR30R31, -NR30SO2, -NR30SO2R31, -SO2R30, -SO2NR30R31, -CO2R30, -C(=O)R30, -C(=O)NR30R31, --OC(=O)R30, -OC(=O)NR30R31, -NR30C(=O)R31, -NR30CO2R31 and from 3-7-membered carbocyclic or heterocyclic ring comprising optionally as a substitute alkyl, halogen atom, hydroxy-, alkoxy-group, halogenalkyl, halogenalkoxy-, nitro-, amino- or cyano-group, and wherein each R30 and R31 is chosen independently from the following group: hydrogen atom, alkyl, alkenyl, aryl, aralkyl, (C3-C7)-cycloalkyl, and heterocycle, or they in common can form (C3-C7)-heterocycle. Also, invention describes pyrrolotriazine compounds, a pharmaceutical composition based on thereof and a method for treatment of inflammatory diseases using above proposed compounds and pharmaceutical compositions.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

30 cl, 14 tbl, 152 ex

FIELD: organic chemistry, chemical technology, biochemistry, pharmacy.

SUBSTANCE: invention relates to compounds of the formula (I): wherein both X1 and X2 represent methylene; R3 represents -CR5=CHR6, and R5 and R6 in common with atoms to which R5 and R6 are bound form (C6-C12)-aryl wherein R3 is substituted optionally with 1-5 radicals of the formula: -X4OR9 wherein X4 represents a bond; R9 represents halogen-substituted (C1-C3)-alkyl, and R4 represents -C(O)X5R11 wherein X5 represents a bond, and R11 represents hetero-(C6-C6)-cycloalkyl-(C0-3)-alkyl; X3 represents group of formulae (a) , (b) or (c) wherein n = 0, 1 or 2; R20 represents hydrogen atom (H); R21 is chosen from group consisting of H, -C(O)R26, -S(O)2R26 wherein R23 is chosen from H and (C6-C12)-aryl-(C0-C6)-alkyl; R25 is chosen from H, (C6-C12)-aryl-(C0-C6)-alkyl or -X4S(O)2R26 wherein X4 has above given values; R26 is chosen from group consisting of H, (C6-C12)-aryl-(C0-C6)-alkyl; wherein X3 comprises optionally, except for, one substitute that being in alicyclic or in aromatic ring system represents a radical chosen independently from group consisting of -X6OR17 wherein R17 represents H, (C1-C6)-alkyl, and X represents a bond or (C1-C6)-alkylene; and its N-oxide derivatives, protected derivatives, individual isomers and mixtures of these isomers; and pharmaceutically acceptable salts and solvated of such compounds, its N- oxide derivatives, protected derivatives, individual isomers and mixtures of these isomers. Also, invention describes a pharmaceutical composition possessing inhibitory activity with respect to cathepsin S-proteases based on compounds of the formula (I), and compound of the formula (Ix) given in the invention description. Invention provides preparing novel compounds possessing useful biological properties.

EFFECT: improved preparing method, valuable medicinal and biological properties of compounds and pharmaceutical composition.

16 cl, 3 tbl, 17 ex

FIELD: medicine, pharmaceuticals.

SUBSTANCE: invention relates to composition for treatment of cyclooxygenase-5 related disorder or condition containing 5-methyl-2-(2'-chloro-6-fluoroaniline)-phenylacetic acid or pharmaceutically acceptable salt thereof. Said composition represents pharmaceutical composition of rapid release and has effective and safe anti-inflammation action for about 24 hours after single administering.

EFFECT: effective and safe pharmaceutical composition with anti-inflammation action.

20 cl, 11 tbl, 3 ex, 8 dwg

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to a novel compound of the general formula (I): wherein R means hydrogen atom (H), -OH, carbamoyl group; n = 1 or 2, or to its pharmaceutically acceptable salt. Compounds of the formula (I) are potential inhibitors of cellular adhesion mediated by integrins that allows its using as components of pharmaceutical composition used in treatment or prophylaxis of inflammatory, autoimmune or allergic state or rejection mediated by LFA-1.

EFFECT: valuable medicinal properties of compound and pharmaceutical composition.

19 cl, 2 sch, 3 dwg, 3 tbl, 7 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel substituted derivatives of 4-aminocyclohexanol of the general formula (I) being optionally as their physiologically acceptable salts and first of all physiologically compatible acids. In compound of the general formula (I) R1 and R2 mean independently of one another hydrogen atom (H) or (C1-C8)-alkyl that can be saturated or unsaturated but both R1 and R2 can't mean simultaneously H, or residues R1 and R form a ring in common and mean (CH2)3-6; R2 means unsubstituted phenyl or phenyl substituted with halogen atom that is added through saturated or unsaturated, branched or linear (C1-C4)-alkyl group; R4 means heteroaryl chosen from 5-membered heteroaryl wherein heteroatoms are chosen from nitrogen, oxygen or sulfur atoms and each of these atoms is condensed with benzene ring and means unsubstituted or monosubstituted (C1-C8)-alkyl; -CHR6R7, -CHR6-CH2R7, -CHR6-CH2-CH2R7, -CHR6-CH2-CH2-CH2R7 wherein R6 represents H; R7 represents phenyl that can be unsubstituted or mono- either multi-substituted with halogen atoms. Also, invention relates to a method for synthesis of compounds of the formula (I) and a medicinal agent based on thereof. Synthesized compounds can be sued for preparing a medicinal agent designated for treatment of pain being first of all acute, visceral, neuropathic or chronic pain, and to a medicinal agent designated for treatment of diseases mediated by function of ORL1-receptor, for example, such as fear state, epilepsy, cardiovascular diseases.

EFFECT: improved method of synthesis, valuable medicinal properties of compounds and drug.

10 cl, 1 tbl, 21 ex

FIELD: medicine, pharmacy.

SUBSTANCE: invention relates to a tablet composition with rapid releasing fludara (fludarabin) showing the purity degree >99.19% (ultra-pure fludara) and containing the definite composition of residual impurities in the amount from 1 to 100 mg in combination with lactose monohydrate, colloidal silicon dioxide, microcrystalline cellulose (Avicel), croscarmellose sodium salt (carboxymethylcellulose sodium) and magnesium stearate. Except for, invention relates to using this tablet composition for preparing a drug used in cancer treatment.

EFFECT: improved and valuable medicinal and pharmaceutical properties of composition.

12 cl, 1 tbl, 2 ex

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