Pharmaceutical composition in form of tablet and method of obtaining thereof

FIELD: medicine.

SUBSTANCE: composition includes glutaryl histamine in an amount of 18.0-75.0 wt % as an active substance, and as auxiliary substances: microcrystalline cellulose in an amount of 18.0-71.0 wt %, sodium croscarmellose in an amount of 0.25-1.0 wt %, colloidal silicon dioxide in an amount of 0.5-2.0 wt %, calcium stearate in an amount of 0.5-2.0 wt % and lactose monohydrate. The invention also relates to a method of obtaining the said composition.

EFFECT: invention is characterised by the high bioavailability of the active component and high pharmacological activity.

4 cl, 6 tbl, 3 ex

 

The invention relates to the field of medicine, chemical-pharmaceutical industry and relates to funds with VirusTotal and immunogenic activity. Relates to new compositions of glutamylcysteine and methods for their production. In particular, glutamylcysteine formula mixed with various excipients with obtaining solid forms of glutamylcysteine.

In some embodiments, the solid form is a tablet form, in other embodiments, is a capsule.

An additional aspect of the present invention includes a method of producing formulations of glutamylcysteine. Other aspects of the present invention include the use of these compositions for the treatment of viral diseases in a mammal in need which includes the introduction of a given mammal a therapeutically effective amount of the compositions of the present invention.

Among viral diseases one of the most serious problems is the flu.

Influenza is one of the most dangerous in the epidemic, infections. For example, every year, in the Russian Federation and holds about 7 million cases of influenza infection on the 142 million population. That is about 20% in the structure of infectious and parasitic diseases, and this is a significant figure. One of the evolutionary person�values of influenza virus - high ability to rapidly mutate through antigenic variation. Influenza viruses are common both in humans and in some animal species, including mammals and birds. So influenza viruses of some animals, for example birds and pigs are the most pathogenic.

The most common form of exposure to the influenza virus is vaccination. Vaccine therapy has a good performance of preventing morbidity and/or reduce the intensity of the disease. And even such activities are not able to stop the massive outbreak of the disease, especially in the cold season.

Mortality from some forms of the flu, even with high-tech methods of treatment, more than 50%. The disease, however, like other forms of influenza etiology characterized by acute onset and severe course: high (40°C or more) temperature and prolonged fever with symptoms of intoxication - headache, insomnia, pain in muscles and joints, meningeal symptoms. One of the adverse currents is a fulminant form, i.e. the rapid development of hemorrhagic toxic pulmonary edema and death from respiratory and cardiovascular failure [Int. J. Tuberc. Lung Dis. // 2007 - V. 11. - N7. - Pp. 710-721].

In the treatment of influenza was widely used and still ispolzuetsyaprintsip Amantadine and Rimantadine, which are antiviral against influenza virus strains. [Am. J. Med. - 1997. - V. 102(FOR) - N17. - P. 55-60], [J. Watts "Asian nations step up action to curb spread of avian influenza" // Lancet. - 2004. - V. 363 - N9406. - P. 373]. In the Russian Federation became widespread antiviral drug Rimantadine. It is used to treat or prevent infection caused by influenza virus type A. a Pronounced therapeutic effect of the drug showed against influenza virus subtype H3N2. The mechanism of action linked to the virus by blocking the function of viral protein inside the membrane. Inhibition of viral activity occurs at the stages of receptor-mediated endocytosis, decapetala in phagolysosome, and Assembly and budding of viral particles [Bulletin of the Russian Academy of medical Sciences // 1993. - N 3. - R. 10-15]. However, Rimantadine, as the representative of the group of adamantane, there are restrictions in use. At high doses experience side effects of the Central nervous system, in particular, can cause convulsive phenomena. He also has an adverse influence on the liver, kidney, makes it unlikely that its use in people with diseases of these organs.

It is now widely used inhibitors of neuraminidase of influenza A and B oseltamivir phosphate (seltamivir) and zanamivir (zanamivir), which is bonded to the hydrophobic phase of the active site of the neuraminidase of influenza virus, blocking capability.�there last to cleave sialic acid residues from the surface of infected cells, thereby suppressing the release of her new Mature virions.

Oseltamivir trade name Tamiflu®, zanamivir, trade name relenza® are considered as one of effective antiviral drugs [Cheung C. L., Rayner J. M., Smith G. J. et al. Distribution 20 of amantadine-resistant H5N1 avian influenza variants in Asia // J. Infect. Dis. - 2006. - Vol.193. - P. 1626-1629]. Currently there are cases of emergence of resistance to oseltamivir and zanamivir [Menno D. de Jong, Tran Tan Thanh, Truong Huu Khanh et al. Oseltamivir Resistance during Treatment of Influenza A (H5N1) Infection // N. Engi. J. Med. - 2005. - N353. - P. 2667-2572], [Smee D. F., Wong M. H., Bailey, K. W., et al. Activities of oseltamivir and ribavirin used alone and in combination against infections in mice with recent isolates of influenza A (H1N1) and In viruses // Antivir Chem Chemother. - 2006. - V. 17, N4. - P. 185-192]. It is due to mutations in the gene encoding for protein Mg that make the virus resistant to this class of compounds [Li K. S., Guan Y., Wang J., et al. Genesis of a highly pathogenic and potentially pandemic H5N1 influenza virus in eastern Asia // Nature. - 2004. - V. 430, N6996. - P. 209-213], [Hui-Ling Y., Ilyshina N. A., Salomon, R. et al. Neuraminidase ingibitor-resistant recombinant A/Vietnam/1203/04 (H5N1) influenza viruses retain their replication efficiency and pathogenicity in vitro and vivo // J. Virol. - 2007. - Vol.81. - P. 12418-12426; Q. M. Le, M. Kiso, K. Someya et al. Avian flu: isolation of drug-resistant H5N1 virus // 30 Nature. - 2005. - Vol. 437. - P. 1108]. Mutation, according to some, occur in approximately 30% of cases. Neuraminidase inhibitors have severe side effects on CNS. So the experts of the British Agency for the protection of health made recommendations to the British�from the government the oseltamivir or Tamiflu should not be prescribed to children for the prevention of influenza A/H1N1 from the large number of unwanted side effects.

In Russia one of the most common drugs for treatment and prophylaxis of viral infections, including influenza, is Arbidol®. However, when administered orally in relation to highly pathogenic strain of influenza A (H5N1) in vivo according to the schemes of emergency prevention and treatment (135 mg/kg of body weight of mice) his defensive efficiency is only 25% and 10% respectively. This level of protection is not consistent with existing national regulations to control the effectiveness of anti-viral drugs (30%) [Manual on experimental (preclinical) study of new pharmacological substances. - M., 2005. - P. 541].

Among the highly pathogenic viral diseases also includes severe acute respiratory syndrome (SARS) is a new coronavirus acute disease caused by the pathogen genotype IV and 5 characterized by a mortality rate of up to 10% [Revised U.S. Surveillance case definition for severe acute respiratory syndrome (SARS) and update on SARS cases - United States and worldwide, December 2003 // MMWR Wkly Rep. - 2003. - Vol.52, N. 49. - P. 1202 - 1206].

In one embodiment, the present invention proposes the manufacture of a composition of glutamylcysteine containing no magnesium salt of silicic acid and/or talc. Other in�the implementation options include compositions of glutamylcysteine with one or more diluents, the disintegrating agents, binders and lubricants. In a practical embodiment of the proposed composition, which consists of glutamylcysteine with one or more diluents, disintegrating agents, binders and lubricants. In other preferred, but not exclusively, embodiments, the composition comprises glutamylcysteine, one or more diluents, where the diluents are selected from starch, lactose monohydrate or microcrystalline cellulose, one or more dezintegriruetsja substances, each independently selected from a pre-gelatinizing starch or crosslinked carboxymethylcellulose sodium, a binder and lubricant. In other preferred, but not exclusively, embodiments, the binder is selected from polyvinylpyrrolidone, and a lubricant selected from magnesium salt of silicic acid. In other preferred embodiments, the diluent is selected from lactose monohydrate, dezintegriruetsja substance selected from the group and represents croscarmellose sodium, and the binder is povidone. Excipients chosen to deliver the proper amount of glutamylcysteine in industrially manufactured medicinal �Ormes. All excipients are selected are inert and acceptable organoleptic and compatible with glutamylcysteine. Excipients used in solid formulations for oral administration, as a rule, include fillers or diluents, binders, dezintegriruetsja substances, lubricants, anti-adhesive substances, sliding, moisturizers and surfactants, colorants, flavorings, sweeteners, adsorbents and substances that improve the organoleptic properties.

Fillers or diluents are added to the active substance to increase the volume pills. These include lactose and may be either crystalline or amorphous. Different types of lactose include lactose monohydrate, alpha-lactose monohydrate, such as anhydrous forms of lactose (α-, β-) and agglomerated lactose. Other diluents include sugars such as derivatives of Sugars. One of the most used filler is lactose monohydrate. Also using microcrystalline cellulose in the form of microparticles.

Also to diluents and excipients include starch and starch derivatives.

Other starches include pre-jellied starch and starch modified with glycolate sodium. Brahma�s and derivatives of starches may act as dezintegriruetsja substances. Other reducing agents include inorganic salts such as dibasic calcium phosphate, tribasic calcium phosphate and calcium sulfate. Diluents can also serve as polyols such as mannitol, sorbitol and xylitol. Many also act as diluents dezintegriruetsja substance and a binder, and these additional properties should be taken into account in the formulation development. Dezintegriruetsja substances include in tablet formulations for falling of tablets on the particles of the active pharmaceutical component and excipients, which will facilitate dissolution of the active ingredient and increase the bioavailability of the active component. Disintegrating jellied substance is starch. Other disintegrating substance is crosslinked carboxymethylcellulose sodium, also dezintegriruetsja materials include cross-linked polyvinylpyrrolidone (e.g. Copovidone), microcrystalline cellulose.

Binders used in wet granulation. The binder performs the function of fluidity of the powder and is used for pressing. Binder is cellulose derivatives such as microcrystalline cellulose, methylcellulose, carboxymethylcellulose sodium, methylcellulose, hydroxyethylcellulose� and hydroxypropyl cellulose. Other binders are polyvidon, polyvinylpyrrolidone, gelatin, natural gums, such as acacia, tragacanth, guar and pectin resin, starch paste, pre-jellied starch, sucrose, corn syrup, polyethylene glycols and sodium alginate, ammonium calcium alginate, magnesium aluminosilicate, polyethylene glycols. Preferred, but not exclusive, the binder is polyvinylpyrrolidone, in particular povidone.

Lubricants used in tablet formulations to prevent adhesion of the tablet with the drum surface and to reduce friction during the stages of pressing. Lubricants typically include vegetable oils, such as corn oil, mineral oil, polyethylene glycols PEG, salts of stearic acid such as calcium stearate, magnesium stearate, and sodium fumarate, mineral salts, such as talc, inorganic salts, such as sodium chloride, organic salt, such as sodium benzoate, sodium acetate and sodium oleate, and polyvinyl alcohols. Preferred in the industrial use of lubricating substance is magnesium stearate.

Sliding substances used in solid dosage forms to improve the fluidity of the tablet mass. This usually ispolzuyteskryty cellulose, the alkali metal stearates, such as magnesium stearate or calcium stearate; a silicate salt, such as magnesium silicate, calcium silicate; starches and varieties of starches and/or derivatives; talc; colloidal silica, for example, the known Aerosil®.

In some embodiments, glutamylcysteine is from about 30-50% by weight of the composition. The song in this version contains a diluent, which is a lactose monohydrate, also a diluent selected from microcrystalline cellulose, dezintegriruetsja a substance selected from a pre-jellied starch, the second dezintegriruetsja substance selected from carboxymethylcellulose, cross-linked, the binder selected from polyvinylpyrrolidone, and a lubricant is a substance selected from magnesium stearate.

In another embodiment, the lactose monohydrate is about 25-40%, microcrystalline cellulose is about 5-15%, pre-jellied starch is about 5-15%, cross-linked carboxymethylcellulose sodium is about 1-10%, polyvinylpyrrolidone is about 1-10% magnesium stearate is about 0,2-2,0%.

In an additional embodiment, the technological applicability of glutamylcysteine is about to 40.0% by weight of the composition, lactose monohydrate �leaves about 30%, microcrystalline cellulose is about 10.5%, pre-gelatinizing starch is about 11%, croscamellose is about 4.0%, povidone is about 5.5% and magnesium stearate is about 0.5%. In other embodiments, glutamylcysteine is up to 80% (70-80%) by weight of the composition. The composition may additionally contain lactose in an amount of 2.5-20% by weight of the composition; dezintegriruetsja substance, namely, crosslinked carboxymethylcellulose in an amount of from 1-10% by weight of the composition; a binding agent selected for example polyvinylpyrrolidone, in an amount of from 2-10% by weight of the composition; and a lubricant selected from the group of stearates, such as magnesium stearate (potassium), in the amount of 0.2-2.0% by weight of the composition.

In the different ways of implementing the present invention as a diluent selected lactose monohydrate, as dezintegriruetsja substances selected croscarmellose sodium, the binder is povidone, and as the lubricant is magnesium stearate.

In other embodiments, implementation of the content of glutamylcysteine is up to 80% by weight of the composition, as a diluent selected lactose monohydrate, the content of which ranges from 8-15% by weight of the composition; a disintegrating substance selected crosslinked, carboximetilzellulozu�and sodium in amounts of 1-10% by weight of the composition; the binder is polyvinylpyrrolidone with a content of 1-10% by weight of the composition; a binder agent is a stearate content of 0.2-2.0% by weight of the composition. In a more preferred embodiment of the invention, the diluent is selected from lactose monohydrate content of 9.5% by weight of the composition, dezintegriruetsja substance selected from croscarmellose sodium and 5% by weight of the composition, the binder is povidone, containing 5% by weight of the composition, the lubricating substance is magnesium stearate in an amount of 0.5% by weight of the composition. In additional embodiments, the implementation of glutamylcysteine is about 90% by weight of the composition. Preferably, but not exclusively, the composition also contains a diluent, such as lactose monohydrate, in a preferred amounts of 3-10% by weight of the composition; dezintegriruetsja substance, such as crosslinked carboxymethylcellulose in the amount of 2-5% by weight of the composition; a binder such as polyvinylpyrrolidone, in an amount of 2-5% by weight of the composition; a lubricant such as magnesium stearate, in an amount of 0.2-2.0% by weight of the composition. In other preferred embodiments, the implementation of a diluent selected from lactose monohydrate in the amount of 3.5% by weight of the composition, dezintegriruetsja substance selected from croscarmellose sodium, it is about 3% by weight �oppozitsii, the binder is povidone containing about 3% by weight of the composition, and a lubricant selected from magnesium stearate containing about 1% by weight of the composition.

In an additional embodiment of the present invention, it is proposed that the composition of glutamylcysteine in the amount of 90 mg where glutamylcysteine is contained in the amount of 40-90% by weight of the composition. In another embodiment, glutamylcysteine in the composition is contained in an amount of 60-90%, or may be in the amount of 70-80%. In an embodiment, the implementation of these compositions can contain one and/or more of starches, such as corn starch, pre-jellied starch, cross-linked sodium salt of carboxymethyl ether of starch, lactose monohydrate, microcrystalline cellulose, cross-linked carboxymethylcellulose sodium; methylcellulose; polyvinylpyrrolidone, a silicate salt, such as magnesium silicate; salt of stearic acid, such as potassium stearate; and mineral compounds, such as talc.

In the variants of implementation data of the composition, preferably, but not exclusively, include one standard dose of glutamylcysteine. Preferably, the standard dose is in the form of a solid dosage form such as tablet or capsule, and more preferably represents the�tapped. In particular, this tablet may include 30, 60, 100, and preferably 90 mg glutamylcysteine in solid dosage form 250 mg.

In process embodiment of the present invention provides a method of obtaining a pharmaceutical composition in tablet form as follows: the sifted powder of microcrystalline cellulose are thoroughly mixed for 1÷2 minutes, add the sifted powder of glutamylcysteine and sieved lactose monohydrate, the mixture was thoroughly stirred for 5÷7 minutes, then add the sifted powder croscarmellose of sodium and stirred for 3÷5 minutes, add the sifted powders of silicon dioxide and colloidal calcium stearate and again stirred for 2÷4 min, the resulting mixture was tableted by direct compression method of the solid dosage forms of glutamylcysteine by wet mixing of glutamylcysteine and excipients with water, granulation, drying and grinding of the granulated mixture. Perhaps the final mixture is pressed into tablet. Perhaps the final mixture to encapsulate. The process includes the stage of dry mixing of glutamylcysteine and one or more auxiliary substances for the formation of a dry mix; wetting a pre-prepared dry mixture with water to obtain wet gr�noational mixture; drying to obtain a dry granulation mixture; pulverizing to obtain the ground granulation mixture; blending with a lubricant milled granulation mixture to a nal mixture; obtaining of ready mix solid dosage forms for oral use. In some preferred embodiments, the final mixed the mixture is compressed into tablets. In other preferred embodiments, the final mixed mixture into capsules.

Example 1.

Preparation of tablets of Glutamylcysteine 100 mg.

Getting dry granulate.

Table 1.
Spent on stage (total)
Name the intermediates and raw materialsSpent
weight, kg
Minimum seriesMaximum series
123
A. the Intermediates:
Glutamylcysteine sifted, 100%, to the series 3,00023,252
on party-7,751
Potato starch, dry sieved on a series1,41410,956
on party-3,652
Lactose (milk sugar), sieved on a series4,19332,495
on party-10,832
5%=s ' starch paste to the series2,02815,720
on party-5,240
Total:10,63582,423

Obtained at the stage (total)

Table 2.
Name the intermediates and raw materialsReceived
weight, kg

Minimum seriesMaximum series
123
A. the Intermediates:
The dry granulate, including*8,53466,139
Glutamylcysteine2,70022,787
B. Waste:
Nous with equipment, incl.0,0870,675
Glutamylcysteine0,1500,233
Losses:
In sewers and drains, including0,058is 0.450
Glutamylcysteine0,1000,155
In the atmosphere, including0,0290,225
Glutamylcysteine0,0500,077
Ash moisture1,927 14,934
Total:10,63582,423

Obtaining wet granulate.

Glutamylcysteine sifted, 100% - 3,000 (7,751) kg, potato starch sifted dry - 1,414 (3,652) kg, lactose (milk sugar), sifted - 4,193 (10,832) kg 5%=s ' starched paste - 2,028 (5,240) kg weighed on the scales in production capacity.

In a high-speed mixer-granulator, for example GHL-250 GF-335 (for minimum series: production capacity GF-201), load glutamylcysteine sifted the dry sifted potato starch, lactose (milk sugar), sifted and stirred for 3-5 min, Then add 5%=s ' starch paste and stir for 20-30 s, (for minimum series: 2-3 min) until evenly moistened mass. When compressed in the hand weight easily lumps and splits in mild shock.

The wetted mass is passed to a drying operation.

Drying and dry granulation.

The wetted mixture is dried in the granulator, fluidized FL-60 SS-337 at a temperature (45±5)°C for 20-45 min until the residual moisture content of 2.0 to 3.0% (Sartorius moisture analyzer at 100°C) or minimum series: the wetted mixture is air dried on trays, 10-12 h. the dried Sample mass, before the definition therein of moisture content on the moisture analyzer Sartorius, should be� progranulin with the aim of obtaining more accurate results.

The dried mixture is discharged in a production capacity and passed through a granulator universal G-1 GF-332 with hole diameter of the drum is 1.0-1.5 mm (minimum series: through a sieve manual GF-210 with a hole diameter of 1000 μm in a fume hood HS-208 (1)) and collect in a production capacity (KT-3; TP-3.2).

The output of glutamylcysteine on stage: 90,00 (for 98.00) %.

The deviation from routine exit(98,00±0,50)%: (65,808-66,470) kg or(90,00±0,50)%: (8,491-8,577) kg of dry granulate.

The reception of tablets glutamylcysteine 100 mg.

Preparation of tablet mass.

The dry granulate - 8,534 (22,046) kg, stearic acid milled sifted - 0,081 (0,228) kg, magnesium stearate sifted - 0,081 (0,228) kg, calcined talc sieved - 0,081 (0,228) kg colloidal silicon dioxide (Aerosil) sifted - 0,020 (0,057) kg, grinding substandard tablets and screenings - 0,025 (0,107) kg weighed on the scales in production capacity GF-201 GF-302, (KT-1, TP-4.1).

In a coating boiler DR-5 GF-340 (for minimum series: production capacity GF-201) load dry granules, colloidal silicon dioxide (Aerosil) sifted, grinding substandard tablets and screenings, stirred for 1-2 minutes Then add the magnesium stearate is sieved, calcined talc sieved stearic acid milled, sifted, stirred for 2-3 min (CT-2; TP-4.1).

Tablet weight averaged in drag�adjusting the boiler DR-5 GF-340 for 3-5 min, a sample of the tablet mass to analyze the content of glutamylcysteine, and upon receipt of positive results of the tablet mass is passed to the stage of tableting. (CT-3, TP-4.1).

Tabletting and screening.

Tabletting is carried out at a rotary machine line MRC-30N GF-230 with a diameter of 9 mm punches the Pills must be white or white with a cream tint valium with chamfered and mark, with solid edges, smooth and uniform surface, free of cracks and chips.

Before starting on a rotary tableting machine line MRC-30N GF-230 gets a label stating the name of the drug, batch numbers, weight pills. In the bunker press download tablet mass and proceed to tableting. The filling of the tablet mass and dedusting of tablets automatically. During tableting check the average mass of tablets, the deviation from the average mass of tablets, description, strength.

Cull substandard tablets, collected in a container GF-201 and guide them on a grinding granulator universal G-1 GF-332. Certified tablet incubated for 6-8 h for tension relaxation within the tablet, the resulting high pressure during compaction.

Example 2.

Getting dry granulate.

Table 3
Spent on stage (total)
Name the intermediates and raw materialsSpent
weight, kg
Dosage 30 mgDosage 90 mg
Minimum seriesMaximum seriesMinimum seriesMaximum series
12345
A. the Intermediates:
Glutamylcysteine sifted, 100%, to the series4,06616,2649,78539,140
on party-4,066-9,785
Lactose, sieved on a series13,59454,3769,83939,357
on party-13,594-9,839
Potato starch, dry sieved on a series5,97023,8803,56114,245

on party-5,970-3,561
5%=s ' starch paste to the series4,48017,9005,10020,400
on party-4,480-5,100
Total:28,110112,42028,285113,142
Obtained at the stage (total)
Name the intermediates and raw materialsReceived
weight, kg
Dosage 30 mgDosage 90 mg
Minimum seriesMaximum seriesMinimum seriesMaximum series
12345
A. the Intermediates:
The dry granulate, including*23,34193,36422,93791,746
Glutamylcysteine3,97915,9159,57438,297
B. Waste:
Nous with equipment, incl.0,2571,0260,2521,008
Glutamylcysteine0,0440,1750,1060,422
Losses:
In sewers and drains, including 0,1710,6840,1680,672
Glutamylcysteine0,0290,1160,0700,281
In the atmosphere, including0,0850,3410,0830,336
Glutamylcysteine0,0140,0580,0350,140
Ash moisture4,25617,0054,84519,380
Total:28,110112,42028,285113,142

Obtaining wet granulate.

Glutamylcysteine sifted, a 100% 4,066 (9,785) kg, potato starch sifted dry - 5,970 (3,561) kg sieved lactose - 13,594 (9,839) kg, 5% starch paste - 4,480 (5,100) kg weighed on the scales in production capacity GF-201, 302. (KT-1, TP-3.1)

In a high-speed mixer-granulator GHL-250 GF-222 (2), GF-335 download sieved lactose, starch. * �flax dry sieved, glutamylcysteine sifted and stirred for 3-5 min, Then add 5%=s ' starch paste and stir for 20-30 C to obtain a uniformly wetted mass. When compressed in the hand weight easily lumps and splits in mild shock. (CT-2, TP-3.1).

The moistened mass is collected in a production capacity GF-201, 302 and passed to the drying operation TP-3.2.

Drying and dry granulation.

The wet mixture is dried in the dryer-granulator SG-30m SS-219 (1,2), granulator, fluidized FL-60 GF-337 at a temperature of (55±5)°C for 40-60 min until the residual moisture content of 2.0 to 3.0%. The dried sample mass, before the definition therein of moisture content on the moisture analyzer Sartorius, should be progranulin with the aim of obtaining more accurate results.

The dried mixture is discharged in a production capacity GF-201 GF-302 and passed through a granulator universal G-1 GF-218 (2), GF-332 (2) with hole diameter of the drum is 1.0-1.5 mm and collected in production capacity GF-201 GF-302 (CT-3; TP-3.2). The dry granulate is passed to the stage of obtaining a mixture for encapsulation TP-4.1.

Encapsulation.

Encapsulation is carried out on the production line for filling capsules MG Compact GF-237, auto machine for filling capsules NJP-800C GF-338, auto machine for filling capsules SF-100N GF-.

The hopper 1 capsule CME machinery load�ü to encapsulate, in the hopper 2 download hard gelatin capsules and begin the encapsulation process. Filling mixture for encapsulation is performed automatically as the liberation of bunkers.

The object of the invention is to expand the Arsenal of tools with VirusTotal and immunogenic activity.

The problem is solved by creating a new pharmaceutical composition in solid dosage form with VirusTotal and immunogenic activity, characterized in that it comprises as active principle glutamylcysteine in mass to 94 wt.% and auxiliary substances to 100%. In the most preferred embodiment, the content of glutamylcysteine can range from 80 to 94 wt.%. As excipients pharmaceutical form may contain lactose monohydrate, microcrystalline cellulose, croscarmellose sodium, colloidal silicon dioxide (Aerosil 300) and calcium stearate. Such high content of active principle as disclosed in the prior art.

A special case of the new pharmaceutical compositions in the form of tablets having VirusTotal and immunogenic activity, is a dosage form, characterized in that it comprises as active principle glutamylcysteine, as excipients lactose monohydrate, cellulose microcrystalline, Crocker�elloso sodium, colloidal silicon dioxide (Aerosil 300) and calcium stearate with the following content of ingredients, wt.%:

glutamylcysteine18,0-75
microcrystalline cellulose18,0-71
croscarmellose sodium0.25 to 1
colloidal silicon dioxide (Aerosil 300)0,5-2
calcium stearate0,5-2
lactose monohydrateelse

To further increase the stability of the composition the active substance is pre-dried to a moisture content of not more than 1.5%.

Examples of the invention.

Example A. The Composition.

Active substance:

glutamylcysteine30,00 mg

Auxiliary substances:

lactose monohydrate

(BP/Eur.Ph. or USP-NF)34,00 mg

microcrystalline cellulose

tr>
(BP/Eur.Ph. or USP-NF)47,62 mg
croscarmellose sodium0,68 mg

(BP/Eur.Ph. or USP-NF)

Aerosil 300

(GOST 14922-77 or BP/Eur.Ph. or USP-NF)1,35 mg
calcium stearate (BP/Eur.Ph. or USP-NF)1,35 mg
Weight pills135,00 mg

Example B. Composition.

Active substance:

glutamylcysteine100,00 mg

Auxiliary substances:

lactose monohydrate

(BP/Eur.Ph. or USP-NF)68,00 mg

microcrystalline cellulose

(BP/Eur.Ph. or USP-NF)95,25 mg

croscarmellose sodium

(BP/Eur.Ph. or USP-NF)1,3 5 mg

colloidal silicon dioxide (Aerosil)

(GOST 14922-77 or BP/Eur.Ph. or USP-NF)2,70 mg
calcium stearate (BP/Eur.Ph. or USP-NF)2,70 mg
Weight pills270,00 mg

The values of pharmacokinetic parameters showed no significant deviations in the study.

Constant elimination rate of 0.22±0,004.

The rate constant of absorption 1,695±0.028.

The time to reach maximum concentration, Tmax. h 1,3±0,1.

The maximum concentration, Cmax greater, µg/ml 70,3±2,0

Example 3. Research dosage form.

3.1. Toxicological studies.

Table 5.
Type of researchSpeciesMethods of administrationDoseDur. OBS.

Acute toxicity substanceMouse ratorally, intraperitoneallyTo 3000 mg/kg14 days
Chronic toxicity substanceRats orally, intraperitoneally2.5 and 25 mg/kg6 months.
dogsoral2.5 mg/kg3 mo.
Acute toxicity to SFFmouseoral150, 300, 450, 600 and 750 mg14 days
Subacute toxicity of the SFFrabbitsoral12 and 36 mg/kg1 mo.

Table 6.
Type of researchSpeciesStudied dosesType of studies.
AllergenicityGuinea pigs,500, 5000 mg/kgin vivo
nonlinear mice (n=12)11.5 mg/kgin vivo
Reproductive toxicityrats of either �Ola 2.5 and 25 mg/kgin vivo
Mutagenicitymouse12.5 mg/kgin vivo
Ames test1,0, 10,0 100, 1000 and 10000 μg/mlin vitro
Carcinogenicityrats and miceof 0.05, 0.5 and 5.0 mg/kgin vivo

The results of Toxicological studies

1. According to acute and chronic toxicity of the composition of glutamylcysteine can be attributed to relatively harmless drugs.

2. If there are no songs allergenic, mutagenic properties.

3. The composition of glutamylcysteine has no reproductive toxicity.

4. Composition in all studied doses (0.05, 0.5 and 5.0 mg/kg on glutamylcysteine) does not have carcinogenic activity, which was shown at a 24-month experiment.

3.2. A study of the effectiveness of the composition of glutamylcysteine against the pathogen of influenza A and adenovirus in vitro and in vivo.

Materials and methods:

For in vitro studies were used:

strains A/Aichi/2/68 (H3N2) and A/chicken/Kurgan/Russia/2/05 (H5N1);

permanent cell cultures of the kidneys Zele�'s monkeys GMK-AH-1, the dog kidney MDCK;

- life-sized semi-synthetic medium PS-4.

For in vivo studies were used

white outbred mice weighing 15 g, obtained from the vivarium of the CC niim MO.

Infection of laboratory animals was performed intranasally.

In vitro studies with infectious dose of 0.1 CPD/cell composition of glutamylcysteine at a concentration of 100-200 μg/ml effectively inhibits the reproduction of influenza A virus (strain A/Aichi/2/68 (H3N2) and A/chicken/Kurgan/Russia/2/05 (H5N1)) if you make 2 h after infection of the monolayer.

In vivo studies, the composition of glutamylcysteine at a dose of 5 mg/kg effective as a prophylactic against influenza A (H3N2 and H5N1).

Prophylactic efficacy of the composition of glutamylcysteine slightly inferior to Tamiflu.

When using the emergency scheme for the prevention and treatment composition of glutamylcysteine inferior to Tamiflu. The optimal dose when using compositions of glutamylcysteine under this scheme is 15 mg/kg.

3.3. Study of interferon and immunomodulatory activity of the composition of glutamylcysteine:

- preparation and dose: the composition of glutamylcysteine, oral administration

- samples: blood samples of 15 healthy rats before and after administration of the drug.

Materials and methods:

monitoring indicators IFN-status held� 2, 4, 6, 8, 12, 24, 48 h after taking the drug.

3.3.1. The results of the study of interferon and immunomodulatory activity of the composition of glutamylcysteine:

single oral administration causes in 73.3% of donors, the increase in the content of IFN in the blood within the upper limits of physiological norm 24-48 h.

stimulates and normalizes the reduced alpha-IFN-producing ability of white blood cells after 24 h in healthy animals.

a single dose of the composition of glutamylcysteine stimulates the production of gamma-IFN.

Thus, the new composition showed good results of pharmacological activity and can be recommended for implementation in clinical practice.

1. Pharmaceutical composition in solid dosage form with VirusTotal and immunogenic activity, which comprises as active substance glutamylcysteine, as excipients - lactose monohydrate, cellulose microcrystalline, croscarmellose sodium, colloidal silicon dioxide and calcium stearate with the following content of ingredients, wt.%:
glutamylcysteine 18,0-75,0
microcrystalline cellulose 18,0-71,0
croscarmellose sodium 0,25-1,0
colloidal silicon dioxide of 0.5-2.0
calcium stearate from 0.5-2.0
lactose monohydrate the rest.

2. Headlights�aseptically composition according to claim 1, characterized in that the active substance is pre-dried to a moisture content of not more than 1.5%.

3. Pharmaceutical composition according to claim 1, characterized in that the composition of glutamylcysteine used in the form of capsules.

4. A method of obtaining a pharmaceutical composition according to any one of claims. 1-2, characterized by the fact that the sifted microcrystalline cellulose powder mix thoroughly for 1-2 minutes, add the sifted powder of glutamylcysteine and sieved lactose monohydrate, the mixture was thoroughly stirred for 5-7 minutes, then add the sifted powder croscarmellose sodium and stir for 3-5 minutes, add the sifted powders of silicon dioxide and colloidal calcium stearate and again stirred for 2-4 min, the resulting mixture was tableted by direct compression method.



 

Same patents:

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to immunoeffectors of formula:

,

where n equals 1 (C6alkyl) or 5 (C10 alkyl), and R1 represents CO2H.

EFFECT: claimed novel compounds and pharmaceutical compositions based on them enhance immune response, increase production of antibodies in immunised animals, stimulate production of cytokines and activate macrophages.

7 cl, 5 ex

FIELD: biotechnologies.

SUBSTANCE: group of inventions relates to the method for production of a preparation suitable for use in nutrition, including the following stages a) incubation of an aqueous substrate with Bifidobacteria, b) inactivation of Bifidobacteria by heating of the incubation mix and/or removal of Bifidobacteria cells from the incubation mix with the help of whirling and/or filtering, c) combination of a composition comprising a mixture produced at the stage a) directly before the stage b) and produced at the stage b), with at least two different non-digestible carbohydrates selected from the group that includes the following: fructooligosaccharides and galactooligosaccharides, where Bifidobacteria is of B. breve type; a preparation suitable for use in nutrition; a food composition including the specified preparation.

EFFECT: synergetic effect of an incubation mix and non-digestible carbons at an immune system.

20 cl, 7 ex, 3 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to medicine, more specifically to a composition for treating dermatologic diseases, preferentially skin itching. The composition causes antiallergic action and is used in treating allergic reactions (rash, urticaria), insect bites, ultraviolet erythema and skin burns. The pharmaceutical composition contains azelastine hydrochloride and benzocaine as active substances, and a hydrophobic ingredient, a hydrophilic ingredient, an emulsifying agent and a pH corrective agent as additive agents. As the pH corrective agent, the composition contains preferentially succinic acid. The pharmaceutical composition is presented as a soft dosage form, preferentially in the form of a cream.

EFFECT: composition according to the invention is characterised by high pharmacologic activity, good package extrusion, and storage-stability.

9 cl, 1 tbl, 14 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to biotechnology. Presented are versions of an antigen-binding polypeptide specific to LIGHT polypeptide characterised by a variable domain of heavy and light chains, as well as versions of based conjugates for treating a disease or a condition. What is described is a pharmaceutical composition for inhibiting apoptosis induced by human LIGHT based on a therapeutically effective amount of the polypeptide. There are disclosed: a method of treating or a diagnosing the disease or condition on the basis of the composition. There are described versions of the recovered polynucleotide or a cell transformed by the polynucleotide for preparing the antigen-binding polypeptide, as well as a method for producing the antigen-binding polypeptide on the basis of the cell.

EFFECT: using the invention provides the antibodies, which block the human or macaque LIGHT interaction to LIGHT receptors that can find application in treating various diseases related to high T-cell activity.

23 cl, 11 dwg, 8 tbl, 3 ex

FIELD: pharmacology.

SUBSTANCE: invention represents methods for treatment of an autoimmune disease, including introduction of a pharmaceutical composition to a subject, containing a pharmaceutically acceptable carrier and a humanised anti-CD4-antibody, capable of activating regulatory T-cells CD4+CD25+, where the specified antibody contains a V-domain of an H-chain, containing sequences DCRMY, VISVKSENYGANYAESVRG and SYYRYDVGAWFAY, and a V-domain of an L-chain, containing sequences RASKSVSTSGYSYIY, LASILES and QHSRELPWT. The specified composition is introduced to a subject with frequency from daily intake to introduction every 31st day and with a dose of a humanised anti-CD4-antibody from 20 to 200 mg, or from 8 to 60 mg/m2 of the subject body surface area, or from 0.2 to 2 mg/kg. This invention also discloses a set for treatment of an autoimmune disease, which contains multiple doses of the above pharmaceutical composition.

EFFECT: invention makes it possible to introduce a pharmaceutical composition containing a humanised anti-CD4-antibody, with more lengthy intervals of dosing and in higher doses, not losing the therapeutical effect and not causing side effects.

59 cl, 41 dwg, 27 tbl, 9 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to biotechnology and represents methods of treating an autoimmune disease involving administering into an individual a pharmaceutical composition containing a pharmaceutically acceptable carrier and a humanised anti-CD4-antibody, able to activate the regulatory C-cells CD4+CD25+, wherein the above antibody contains V-domain of H-chain containing the sequences DCRMY, VISVKSENYGANYAESVRG and SYYRYDVGAWFAY, and V-domain of L-chain containing the sequences RASKSVSTSGYSYIY, LASILES and QHSRELPWT; the above composition is administered subcutaneously into the individual in a dose of the humanized anti-CD4-antibody 20 to 200 mg or 8 to 60 mg/m2 of the individual's body surface, or 0.2 to 2 mg/kg. The present invention also discloses the pharmaceutical compositions applicable in the above methods of treating the autoimmune disease.

EFFECT: invention enables administering the pharmaceutical composition containing the humanised anti-CD4-antibody in higher doses losing no therapeutic effect and causing no intensification of any side effects.

46 cl, 20 dwg, 21 tbl, 8 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to field of biochemistry, in particular to single variable domain, aimed against IL-6R, to polypeptide and construction, directed against IL-6R, containing said single variable domain, as well as to methods of obtaining them. Disclosed are nucleic acids, coding said single variable domain, polypeptide and construction, as well as genetic constructions, containing said nucleic acids. Described are host cells and host organisms, containing said nucleic acids. Invention also deals with composition for blocking interaction of IL-6/IL-6R, containing effective quantity of described single variable domain, polypeptide, construction, nucleic acid or genetic construction. Also disclosed is method of prevention and/or treatment of at least one of diseases or disorders, associated with IL-6, IL-6R, complex IL-6/IL-6R and/or signal pathways, in which IL-6, IL-6R or complex IL-6/IL-6R is involved and/or biological functions and reactions, win which IL-6, IL-6R or complex IL-6/IL-6R takes part with application of described single variable domain, polypeptide, construction or composition.

EFFECT: invention makes it possible to block interaction of IL-6/IL-6R effectively with increased affinity and biological activity.

25 cl, 70 dwg, 56 tbl, 61 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: group of inventions refers to organic chemistry, namely to a compound of formula I and to their pharmaceutically acceptable salt or their ester, wherein W means C(H)2, C(H)2-C(H)2 or C(H)(CH3); X is specified in a group consisting of: (1) O, (2) N(H), (4) S, (5) S(O) and (6) S(O)2; Y means carbon or nitrogen; R1 is specified in a group consisting of: (1) hydrogen, (2) halogen, (3) methyl optionally substituted by fluorine, (4) C1-7alkoxygroup optionally substituted by fluorine, (5) cyano group and (6) C1-7alkylsulphonyl; R2 means hydrogen, fluorine, chlorine or C1-7alkoxygroup; R3 means hydrogen, fluorine, chlorine, bromine or methyl; R4 is specified in a group consisting of: (1) hydrogen, (2) halogen, (3) C1-7alkyl optionally substituted by fluorine, (4) C3-7cycloalkyl, and (5) ethenyl; R5 and R6 are independently from each other specified in a group consisting of: (1) hydrogen, (2) halogen, (3) C1-7alkyl, (4) cyanogroup and (5) C3-7cycloalkyl; R7 means cyano group or S(O)2-R8, wherein R8 is specified in a group consisting of: (1) C1-7alkyl, (2) C3-7cycloalkyl, (4) C1-7alkylamino group, (5) C1-7dialkylamino group, (6) lower heterocycloalkyl optionally substituted by halogen, C1-7alkyl, or C1-7alkoxycarbonyl and (7) 2-oxa-6-azaspiro[3.3]hept-6-yl, wherein lower heterocycloalkyl means a saturated or partially unsaturated non-aromatic ring fragment containing 3 to 7 atoms bound together to form a ring structure, wherein one, two or three ring atoms are heteroatoms, whereas the rest ring atoms are carbon atoms; and pharmaceutically acceptable esters represent methyl and ethyl acid esters of formula I acceptable as prodrugs. The invention also refers to a pharmaceutical composition based on the compound of formula .

EFFECT: prepared are new compounds possessing the CRTH2 receptor antagonist or partial agonist activity.

23 cl, 90 ex

FIELD: medicine.

SUBSTANCE: invention refers to molecular biotechnology and medicine. There are described methods of treating an autoimmune disease. The methods provide administering a pharmaceutical composition containing CD4 humanised antibody. The antibody is able to activate CD4+ CB25+ regulatory T-cells.

EFFECT: presented group of inventions can be used in medicine.

33 cl, 41 dwg, 20 tbl, 5 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to immunology. There are presented: an antibody binding to interleukin-17 (IL-17) characterised by 6 CDR of a light and heavy chain, as well as a coding nucleic acid and a vector for expression of the above antibody. What is described is a pharmaceutical composition for treating a patient with multiple sclerosis, rheumatoid arthritis, psoriasis, Crohn's disease, chronic obstructive pulmonary disease, asthma, graft rejection on the basis of the above antibody. What is disclosed is a method for preparing the antibody by means of expressing the respective nucleic acid and recovering the antibody from a cell culture or a cell culture supernatant.

EFFECT: using this invention provides the antibody with IC50 twice as much as shown by in vitro IL-6 and IL-8 neutralisation as compared to the known NVP-AIN-497 antibody, which binds human IL-17A and IL-17F that can find application in medicine in therapy of various inflammatory diseases.

9 cl, 6 tbl, 11 ex

FIELD: medicine.

SUBSTANCE: therapeutic agent contains recombinant interferon specified in a group of: recombinant interferon alpha, recombinant interferon beta, recombinant interferon gamma, metronidazole, fluconazole and/or voriconazole, and a pharmaceutically acceptable base in the following proportions, g per 1 ml of the mixture: recombinant interferon, international units 100-10,000,000; metronidazole 0.00001-0.5; fluconazole and/or voriconazole 0.00001-0.5; pharmaceutically acceptable base - the rest. Besides, the therapeutic agent contains boric acid in an amount of 0.00001-0.5 g and hypromellose in an amount of 0.00001-0.5 g. As a pharmaceutically acceptable base, it contains macrogol 400 or macrogol 1500, or macrogol 4000.

EFFECT: higher efficacy of the compound.

2 cl, 5 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a compound of formula:

,

wherein: each D and Z is independently absent or represents an optionally substituted linear aliphatic group containing zero to eight carbons, wherein 'aliphatic' refers to an alkyl, alkenyl or alkynyl group, and 'optionally substituted' refers to substituting by replacing independently one, two or more hydrogen atoms by substitutes specified in -F, -Cl, -Br, -I, -OH, -NO2, -N3, -CN, -NH2, -NH-C1-C12-alkyl, -NH-C2-C8-alkenyl, -NH-C2-C8-alkynyl, -NH-C3-C12-cycloalkyl, -dialkylamino, -O-C1-C12-alkyl, -NHC(O)-C1-C12-alkyl, -NHC(O)-C2-C8-alkenyl, -NHC(O)-C2-C8-alkynyl, -NHC(O)-C3-C12-cycloalkyl; each A and E is independently absent or represents a cyclic group with the above cyclic group is independently specified in a group consisting of aryl or heteroaryl, each of which is optionally substituted; 'aryl' refers to phenyl, naphthyl, tetrahydronaphthyl, indanyl or idenyl; 'heteroaryl' refers to pyridinyl, pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isoxazolyl, thiadiazolyl, oxadiazolyl, thiophenyl, furanyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzoxazolyl or quinoxalinyl; 'optionally substituted' refers to substituting by replacing independently one, two, three or more hydrogen atoms by substitutes specified by -F, -Cl, -Br, -I, -OH, -NO2, -N3, -CN, -NH2, -NH-C1-C12-alkyl, -NH-C2-C8-alkenyl, -NH-C2-C8-alkynyl, -NH-C3-C12-cycloalkyl, -dialkylamino, -O-C1-C12-alkyl, -NHC(O)-C1-C12-alkyl, -NHC(O)-C2-C8-alkenyl, -NHC(O)-C2-C8-alkynyl, -NHC(O)-C3-C12-cycloalkyl; T is absent or represents an optionally substituted aliphatic group containing 1 to 24 carbons; 'aliphatic' refers to an alkyl, alkenyl or alkynyl group; 'optionally substituted' refers to substituting substituting by replacing independently one, two, three or more hydrogen atoms by substitutes specified in -F, -Cl, -Br, -I, -OH, -NO2, -N3, -CN, -NH2, -NH-C1-C12-alkyl, -NH-C2-C8-alkenyl, -NH-C2-C8-alkynyl, -NH-C3-C12-cycloalkyl, -dialkylamino, -O-C1-C12-alkyl, -NHC(O)-C1-C12-alkyl, -NHC(O)-C2-C8-alkenyl, -NHC(O)-C2-C8-alkynyl, -NHC(O)-C3-C12-cycloalkyl; one to four of A, D, E, T and Z are absent; the ring B is specified in imidazolyl, pyrazolyl, 1,3,4-thiazolyl, and 1,3,4-oxadiazolyl, and the ring B is bound to J through atom C and bound to Z, E, T, A and D through atom C; in each specific case, R1 is independently specified in a group consisting of hydrogen, halogen, cyano optionally substituted by C1-C4alkyl, -O-R11, -NRaRb, -C(O)R11, -CO2R11 and -C(O)NRaRb; in each specific case, R11 independently represents hydrogen or optionally substituted C1-C8alkyl; in each specific case, each Ra and Rb are independently specified in hydrogen, C1-C8alkyl and C2-C8alkenyl; u is independently equal to 1, 2 or 3; Q and J represent R6 is specified in a group consisting of -C(O)-R12, -C(O)-C(O)-R12, -S(O)2-R12, and -C(S)-R12; in each specific case, R12 is independently specified in a group consisting of -O-R11, -NRaRb, and -R13; and in each specific case, R13 is independently specified in a group consisting of: hydrogen, C1-C8alkyl, C2-C8alkenyl, C2-C8alkynyl, C3-C8cycloalkyl and C3-C8cycloalkenyl, each of which is optionally substituted; 'optionally substituted' refers to substituting independently by replacing one, two, three or more hydrogen atoms by substitutes specified in -F, -Cl, -Br, -I, -OH, -NO2, -N3, -CN, -NH2, -NH-C1-C12-alkyl, -NH-C2-C8-alkenyl, -NH-C2-C8-alkynyl, -NH-C3-C12-cycloalkyl, -dialkylamino, -O-C1-C12-alkyl, -NHC(O)-C1-C12-alkyl, -NHC(O)-C2-C8-alkenyl, -NHC(O)-C2-C8-alkynyl, -NHC(O)-C3-C12-cycloalkyl, which inhibit an RNA-containing virus, particularly hepatitis C virus (HCV).

EFFECT: preparing hepatitis C inhibitors.

38 cl, 22 tbl, 516 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of structural formula (I), which possess the properties of HCV polymerase inhibitors. In formula , is specified in a group consisting of a single carbon-carbon bond and a double carbon-carbon bond; R1 and R3 are specified in hydrogen and methyl; R2 represents hydrogen; R5 is specified in a group consisting of hydrogen, hydroxy, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, C2-C6alkenyloxy, C3-C6alkynyloxy and halo; L represents a bond, and R6 represents a condensed 2-ring carbocyclyl, wherein each substitute is optionally substituted by one or more substitutes independently specified in a group consisting of RE, RF, RG, RH, RI, RJ and RK; or L is specified in a group consisting of a bond, C≡C, C(O)N(RC), N(RD)C(O), C1-C2-alkylene, C(H)2O, OC(H)2, cyclopropyl-1,2-ene, C(H)2N(RL), N(RM)C(H)2, C(O)CH2 and CH2C(O), and R6 is specified in a group consisting of C5-C6-carbocyclyk and 5-6-merous heterocyclyl, wherein each substitute is optionally substituted by one or more substitutes independently specified in a group consisting of RE, RF, RG, RH, RI, RJ, RK, RL and RM; the R4, RE, RF, RG, RH, RI, RJ, RK, RL and RM values are presented in the patent claim.

EFFECT: invention refers to a pharmaceutical composition containing the above compounds, to using the compounds for producing a drug preparation for HCV RNA polymerase inhibition and hepatitis C treatment, and to a method for preparing the above compounds.

21 cl, 46 dwg, 42 tbl, 140 ex

FIELD: medicine.

SUBSTANCE: invention refers to a medicated product based on a chemical compound of 7-[N'-(4-trifluoromethylbenzoyl)-hydrazinocarbonyl]-tricyclo[3.2.2.02,4]non-8-ene-6-carboxylic acid (NIOH-14, N.N. Vorozhtsov Novosibirsk Institute Of Organic Chemistry) in a dose of 4 to 60 mg/kg of body weight, possessing the anti-smallpox virus activity, as well as a method for producing and using for the smallpox virus for preventing and treating mammals involving oral administration once a day in a dose range from 4 to 60 mg/kg of the mammalian body weight. A method for producing the medicated product possessing the anti-smallpox virus activity involves diluting and performing a reaction of 4-trifluorobenzoic acid hydrazide and 3,3a,4,4a,5,5a,6.6a-octahydro-1,3-dioxo-4,6-etheno-cycloprop[f]-furane in a molar ratio of 1:1 in a solvent and mixing the produced suspension until producing sediments which are removed from the solution, filtered and dried to produce an end product that is a chemical compound of 7-[N'-(4-trifluoromethylbenzoyl)-hydrazinocarbonyl]-tricyclo[3.2.2.02,4]non-8-ene-6-carboxylic acid (NIOH-14, N.N. Vorozhtsov Novosibirsk Institute Of Organic Chemistry). The solvent is ethyl or isopropyl alcohol; preparing the suspensions, separating and filtering the sediments are performed at a temperature of +2-10°C, while a dry product yield makes 96.0%.

EFFECT: invention provides the less toxic preparation of the medicated product, possessing the high anti-smallpox virus activity.

4 cl, 4 tbl, 4 ex

FIELD: chemistry.

SUBSTANCE: invention provides an agent for arresting undesirable vaccinal reactions and complications during primary vaccination with variolar vaccines, characterised by that it contains 7-[N'-(4-trifluoromethylbenzoyl)-hydrazine-carbonyl]-tricyclo[3.2.2.02,4]non-8-ene-6-carboxylic acid, and a method of using said agent in doses of 3.3-50 mg/kg body mass once a day on the day of vaccination and two days after vaccination, which does not reduce potency of the vaccine.

EFFECT: arrests undesirable vaccinal reactions and complications during primary vaccination with variolar vaccines.

2 cl, 5 ex, 4 tbl

Antiviral agent // 2542488

FIELD: medicine, pharmaceutics.

SUBSTANCE: group of inventions refers to an antiviral agent and aims at inactivating a wide range of viruses. The antiviral agent contains an active agent presented by particles of at least one type of iodide formed by iodine and an element formed in 4-6th periods of the 8-10th or 12-15th groups of the periodic table, Cu or Au. The above element found in the 4-6th periods of the 8-10th or 12-15th groups of the periodic table represents Sb, Ir, Ge, Sn, Tl, Pt, Pd, Bi, Fe, Co, Ni, Zn, In or Hg. What is also presented is the antiviral agent containing particles of at least one type of a cuprous compound as an active ingredient. The above cuprous compound represents chloride, acetate, sulphide, iodide, bromide, peroxide, oxide or thiocyanide.

EFFECT: using the group of inventions provides the agent having the high antiviral activity; the above agent is able to exhibit and maintain its antiviral activity easily since it requires no preparation or special washing.

5 cl, 4 tbl, 27 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of structural formula I, their pharmaceutically acceptable salts and crystalline forms, which possess the properties of HCV polymerase inhibitor. In formula I is specified in a group consisting of a single carbon-carbon bond and a double carbon-carbon bond; R1 represents hydrogen; R2 is specified in a group consisting of hydrogen and halo; R3 represents hydrogen; R4 is specified in a group consisting of halo, C1-C6alkyl, C1-C6alkylsulphonyl and 5-6-merous heteroaryl containing heteroatom specified in N, O and S, wherein alkyl is optionally substituted by one or more hydroxy; R5 is specified in a group consisting of hygrogen, hydroxy, C1-C6alkyloxy and halo; L is specified in a group consisting of C(RA)=C(RB), ethylene and cyclopropyl-1,2-ene; RA and RB are independently specified in a group consisting of hydrogen, C1-C6alkyl, C1-C6alkyloxy and halo; R6 represents C6aryl optionally substituted by one or more substitutes independently specified in a group consisting of RE, RF, RG, RH, RI and RJ; the substitutes RE, RF, RG, RH, RI and RJ are presented in the patent claim.

EFFECT: invention refers to the pharmaceutical composition containing the above compounds, to using the compounds for inhibiting HCV RNA-polymerase and treating hepatitis C and to a method of preparing the above compounds.

40 cl, 23 dwg, 7 tbl, 40 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: presented inventions refer to a lyophilised composition for inducing an immune response to flavivirus, compositions for preparing the above lyophilised composition, and a method for preparing the lyophilised composition. The characterised lyophilised composition contains an effective amount of live attenuated flavivirus, one or more stabilising agents, one or more buffer components, lactose and amorphous mannitol, which is prepared by lyophilising mixture containing an effective amount of live attenuated flavivirus, one or more stabilising agents, one or more buffer components, lactose and mannitol; flavivirus can be chimeric flavivirus. Preparing the above lyophilised composition involves freezing the components and drying them thereafter.

EFFECT: inventions enable preparing the transportation and storage stable compositions containing flavivirus.

31 cl, 13 dwg, 10 tbl, 2 ex

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely to gastroenterology, and can be applied as a method of treating hormone-dependent/hormone-resistant ulcerative colitis complicated by opportunistic infections. That is ensured by measuring herpes simplex virus type 1 IgG, herpes virus type 6 IgG, cytomegalovirus IgG, mycoplasm IgG, Chlamydia IgG. If herpes simplex virus type 1 IgG is 185 units/ml and more, and IgM is 0.4 units/ml and more, herpes virus type 6 IgG is 1.5 units/ml and more, cytomegalovirus IgG k is 185 units/ml and more, IgM is 3.4 units/ml and more, mycoplasm IgG is 119 units/ml and more, IgM is 0.4 units/ml and more, Chlamydia IgG is 105 units/ml and more, IgM is 0.8 units/ml and more, a systemic transplantation of allogenic mesenchymal stem cells in a dose of 150-250 million cells.

EFFECT: using the given method enables providing the more effective therapeutic treatment of hormone-dependent/hormone-resistant ulcerative colitis, promotes CMV elimination with no anti-viral therapy required and overcoming of hormone-dependency/hormone-resistance.

3 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pyrimidine derivatives of structural formula (I-L0) and their crystalline forms possessing the inhibitory activity on the hepatitis C virus (HCV) polymerase. In formula is specified in a single or double carbon-carbon bond; R1, R2 and R3 represent hydrogen; R4 is specified in halo, C1-C6alkyl, C2-C6alkinyl, amino, C1-C6alkylsulphonyl, C3-C10carbocyclyl and 5-6-merous heterocyclyl having a heteroatom specified in a group consisting of O and S, wherein amino is optionally substituted by one or two C1-C6alkylsulphonyls, and C1-C6alkyl and C2-C6alkynyl are optionally substituted by one or more substitutes optionally specified in a group consisting of halo, oxo, hydroxy, C1-C6alkyloxy and trimethylsilyl, and C3-C10carbocyclyl and 5-6-merous heterocyclyl are optionally substituted by substitutes specified in C1-C6alkyl, halo and amino, wherein amino is optionally substituted by one or two C1-C6alkylsulphonyls; R5 is specified in a group consisting of hydrogen, hydroxy, C1-C6alkyloxy and halo; R6 represents a condensed 2-ring C3-C10carbocyclyl optionally substituted by substitutes specified in RE, RF, RG, RH, RI, RJ and RK, the values of which are specified in the patent claim.

EFFECT: invention refers to a pharmaceutical composition containing the above compounds, to using the compounds for producing a therapeutic agent for hepatitis C, to an intermediate compound for producing the compound of structural formula (I-L0) and to a method for preparing the above compounds and their crystalline forms.

70 cl, 23 dwg, 9 tbl, 83 ex

FIELD: medicine.

SUBSTANCE: method for preparing a gel for wound and burn healing involving diluting chitosan in an organic acid, combining it with a biologically active substance and water; chitosan is diluted in citric or lactic acid; mussel hydrolysate is used as the biologically active substance; the hydrolysate is added to the chitosan solution before PEG 600 and calcium alhylose are added in the certain environment.

EFFECT: method enables preparing the new effective wound-healing agent.

2 dwg, 1 tbl, 2 ex

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