Pro-medication composition for struggle against hepapatitis c virus

FIELD: medicine, pharmaceutics.

SUBSTANCE: pharmaceutical composition, which has anti-viral activity against hepatitis C, includes solid suspension, obtained by extrusion of melt of hydrochloride (2R,3S,4R,5R)-5-(4-amino-2-oxo-2H-pyrimidine-1-yl)-2-azido-3,4-bis-isobutiryoxytetrahydrofuran-2-ylmethyl ether of isobutyric acid (I) and block-copolymer polyethyleneglycol (PEG)/polypropylenglycol (PPG). Preferably block-copolymer PEG/PPG represents poloxamer 188.

EFFECT: pharmaceutical composition has improved speed of dissolution and bio-availability.

14 cl, 2 ex

 

The present invention relates to new compositions containing as the active ingredient 4'-azidothymidine-2',3',5'-triisobutylene (I), and to a method for producing the composition. The composition is applicable to combat the hepatitis C virus (HCV).

Derivatives of nucleosides are often active antiviral agents (e.g., affect HIV (human immunodeficiency virus), HCV, Herpes simplex, CMV (cytomegalovirus)and anti-cancer chemotherapeutics. Unfortunately, their use is often limited by two factors. First, poor pharmacokinetic characteristics often limit the absorption of nucleoside in the intestine and the concentration of the nucleoside derivative in the cell, and, secondly, are not optimal physical characteristics impose restrictions on methods of preparation of compositions that could be used to improve the release of the active ingredient.

The use of prodrugs (P. Ettmayer et al, J. Med Chem: 2004 47(10):2393-2404; K. Beaumont et al, Curr. Drug Metab. 2003 4:461-485; H. Bundgaard, Design of Prodrugs: Bioreversible derivatives for various functional groups and chemical entities in Design of Prodrugs, H. Bundgaard (ed) Elsevier Science Publishers, Amersterdam 1985; G. M. Pauletti et al. Adv. Drug Deliv. Rev. 1997 27:235-256; R.J.Jones and N. Bischofberger, Antiviral Res. 1995 27; 1-15 and .R.Wagner et al, Med. Res. Rev. 2000 20:417-45) is a method of improving the absorption of the drug. Typical examples of prodrugs on the hunger for connection, which contain biologically labile protective group attached to the functional fragment of the active compounds. To obtain pronucleotides used alkylation, acylation and other lipophilic modification of the hydroxy-group (hydroxyl groups) of the sugar fragment. These pronucleotides can be either hydrolyzed or dezalkilirovania in vivo with the formation of active connections.

Unfortunately, many prodrugs suitable for other characteristics, sparingly soluble in water, which complicates the preparation of the compositions. To overcome the poor solubility in water is usually used grinding with obtaining particles of a smaller size or, when appropriate, the transformation of the parent compound in better water-soluble salt.

For preparation of compositions of the compounds poorly soluble in water, you can use solid dispersion. Published surveys on the use of solid dispersion systems for the preparation of pharmaceutical compositions: (W.L.Chiou and S.Riegelman, J.Pharm. Sci. 1971 60(9):1281-1302; C.Leuner and J.Dressman, Eur. J.Pharm. Biopharm. 2000 50:47-60; A. .M.Serajuddin, J.Pharm. Sci. 1999 88(10):1058-1066, A.Forster et al. Pharm. Technol. Eur. 2002 14(10):27; J.Breitenbach Eur. J.Pharm. and Biopharm. 2002:54:107-117; J.Breitenbach and M.Mägerlein Drugs and the Pharmaceutical Sciences 2003 133:245-260 and K.A.Coppens et al, Pharm. Technol. 2006 30(1):62-70). Solid dispersion systems include eutectic mixtures, solid solutions and suspensions, with cleopatria suspensions and solutions, amorphous precipitates in crystalline media. The use of solid dispersions is a convenient and efficient method for producing compositions of poorly soluble active ingredients. The disintegration and dispersion of solid solutions or suspensions leads to the formation of small colloidal particles of the active ingredient that promotes absorption of the active ingredient (AI) in the gastrointestinal (LCD) tract.

Solid dispersions can be obtained by melt extrusion of a mixture of AI with the carrier or by the rapid evaporation of solvent from a solution of AI and media. In the solid dispersion comprised a variety of media, including polyethylene glycol (PEG), polyethylene oxide (PEO), polyvinylpyrrolidone (PVP), polyvinyl alcohol (PVA), hypromellose (HPMC), hydroxypropylcellulose (GOC), carboximetilzellulozu (CMAC), the phthalate of hydroxypropylmethylcellulose (HPMCP), polyacrylates, polymethylacrylates, urea and sugars (e.g. mannitol) (Leuner, see above). Although there are different media, media selection, which is optimal for a particular active ingredient, remains a challenge.

The first and most thoroughly studied of solid dispersion systems include griseofulvin and PEG (W.L.Chiou and S.Riegelman, see above). Produced PEG with molecular masses found in a wide range the Ohe, and PEG having a molecular mass of approximately 2000 to 6000, possess physical characteristics that are optimal for the preparation of solid dispersions with griseofulvina. Griseofulvin sparingly soluble in water and it is known that it is poorly absorbed when administered orally. Solid dispersion grizeofulvina and PEG are sold under the trade name Gris-PEG®. PEG are not a good surface-active substances, and the dissolution is improved, if in solid dispersion include emulsifiers, such as Polysorbate 80, poliatilenzellofana simple ether (Brij® 35) or sodium dodecyl sulphate. The increase in the rate of release when using the compositions in the form of solid dispersions with PEG 4000 and found for other drugs, including oxazepam (J..Gines et al, Int.J.Pharm. 1996 143:247-253), piroxicam (M.Fernandez et al, Int.J.Pharm. 1993 98:29-35), zoldipem (G.Trapani et al, Int.J.Pharm. 1999 184:121-130), Ketoprofen (M.V.Margarit and I.C.Rodriguez, Int.J.Pharm. 1994 108:101-107), oxepa (R.Jachowicz et al, Int.J.Pharm. 1993 99:321-325), nifedipine (H.Suzuki et al, Chem. Pharm. Bull 1997-45:1688-1693), phenytoin (R.Jachowicz, Int.J.Pharm. 1987 35:7-12), fenofibrate (M.T.Sheu et al., Int.J.Pharm. 1994 103:137-146), prednisolone (R.Jachowicz, Int.J.Pharm. 1987 35:1-5) and gliburid (G.V.Betageri et al, Int.J.Pharm. 1995 126:155-160).

In WO 97/49384, published December 31, 1997, J.McGinity and F. Zhang described pharmaceutical composition, comprising excretiruyutza from a melt blend of therapeutic compounds and about daysago large molecular weight poly(ethylene oxide) (PEO), optionally containing polyethylene glycol as a plasticizer. PEO used in the present invention, has a molecular weight in the range of from 1000000 to 10000000. This application was later obtained US patent No. 6488963.

In the publication US No. 2004/0253314, published 16 December 2004, H.-U. Petereit et al. described obtained by extrusion from the melt composition comprising an active pharmaceutical ingredient and a copolymer of (meth)acrylate containing from 40 to 75 wt.% obtained by radical copolymerization With1-C4alilovic esters of acrylic acid or methacrylic acid.

In the publication US No. 2005/0048112, published March 3, 2005, J.Breitenbach et al. described solid pharmaceutical dosage form comprising a solid dispersion of at least one inhibitor of HIV protease, at least one pharmaceutically acceptable water-soluble polymer and at least one pharmaceutically acceptable surfactant, in which the water-soluble polymer has a value of Tg(glass transition temperature)is not lower than about 50°C.

In the publication US No. 2005/0044529 published on April 21, 2005, J.Rosenberg et al. described solid pharmaceutical dosage form comprising a solid dispersion of at least one inhibitor of HIV protease, at least one pharmaceutically who realimage the water-soluble polymer and at least one pharmaceutically acceptable surfactant.

The present invention relates to pharmaceutical compositions comprising obtained by extrusion from the melt of the solid dispersion hydrochloride (2R,3C,4R,5K)-5-(4-amino-2-oxo-2H-pyrimidine-1-yl)-2-azido-3,4-bis-isobutyrylacetate-2-Eletropaulo ether somaclonal acid (I; the present invention also uses the name 4'-azidothymidine-2',3',5'-triisobutylene) and a block copolymer of polyethylene glycol (PEG)/polypropylenglycol (BCPs).

The present invention relates to intended for oral administration the pharmaceutical composition 4'-azidothymidine-2',3',5'-triisobutylaluminum, which includes in terms of total weight of the composition, from about 250 mg to 500 mg of 4'-azidothymidine-2',3',5'-triisobutylaluminum (I). This compound is described and claimed in patent US 6846810, issued January 2, 2005 metodika get the source of nucleoside described So .Connolly et al. in the publication US 20050038240, published February 17, 2005

It is established that triallylamine nuke I decreases viral load for patients infected with hepatitis C virus (HCV). Hepatitis C virus is a major cause of liver disease worldwide (N. Boyer et al., J. Hepatol. 2000 32:98-112). For patients infected with hepatitis C virus, there is a risk of development of cirrhosis and subsequent hepato cellulare carcinoma, and, consequently, the presence of HCV is the major indication to liver transplantation. Although compound I is produced in crystalline form, it has a pH-dependent physico-chemical characteristics. In addition, when exposed to water, the compound easily forms a gel and it is difficult to handle in the form of aqueous solutions.

Although described a series of compounds with limited solubility in water, of which successfully obtained dispersion composition, each AI has specific characteristics, and optimization of the composition for a specific AI remains a difficult empirical task. For optimal release of the need for effective dispersion of the active ingredient. For use in melts and the active ingredient and the carrier should have sufficient thermal stability. Thermal stability of the organic azide, which is the AI is completely inadequate. In addition, the chemotherapy of viral diseases often require large doses to quickly reduce your viral load and to avoid mutations that lead to drug resistance. The amount of active ingredient contained in the dosage forms necessary to obtain large concentrations is large, which leads to difficulties associated with solubility, and limits the number to omnitele used inert fillers, which could be used in the absence of such difficulties.

One reason for the successful use of solutions and suspensions of amorphous substances is that the presence of hydrophilic carrier and drug promotes wetting of the active ingredient and potentially increases the solubility of AU in the diffuse layer surrounding the particle (Forster, see above). It is established that the incorporation of emulsifiers sometimes improves the wettability and solubility of compounds in solid solutions/suspensions. Surfactants such as sodium lauryl sulfate and Tween 80, increase the rate of release of naproxen from PEG 4000, 6000 and 20000 (.Leuner and J.Dressman, see above).

According to the invention it has been unexpectedly found that the block copolymers of polyethylene glycol (PEG)/polypropylenglycol (BCP) is a suitable matrix for solid suspensions I and improve bioavailability compared with other matrices. The composition proposed in the present invention are suspensions of amorphous substances, in which the block copolymer is an amorphous phase in which the suspended crystalline I. Composition is prepared from the block copolymer, melting point which is lower than I, and the temperature of the heating zones maintained within the range between the melting points of I and copolymer.

The term "block copolymer" p and used in the present invention means a copolymer, with 2 or more blocks (or segments) of different homopolymers. The term "copolymer" means a polymer consisting of a single monomer. There are various options block copolymers, including simple diblock copolymers with the structure a-b and triblock copolymers with the structure a-b-a or a-b-C. Poloxamer (or Lutrol®) are a-b-A block copolymers, in which segment a is a hydrophilic homopolymer of polyethylene glycol and a segment is a hydrophobic homopolymer of polypropylenglycol. Poloxamer sold by the BASF Corporation. Depending on the relative magnitudes of block copolymer can be solid, liquid or pasty. LUTROL® is a trading name of poloxamers. The terms poloxamer and Lutrol in the present invention are used interchangeably. Poloxamer 188 has an average molecular weight of approximately 8600, melting point equal 52-54°C, and indicator products HLB (hydrophilic-lipophilic balance)equal 18-29, and an average particle size in the range from 1 to 500 μm. Polyoxyethylene links represent approximately 81% of the molecular weight. Poloxamer 188 it is soluble in water. In the compositions of prodrugs for HCV block copolymer limits the moisture, which leads to undesirable gel formation AI. Other solid carriers which can be used for Prigat the effect of solid dispersions I, include vitamin E TPGS (Eastman Kodak), Gelucire 44/14, Gelucire 50/13 (Gattefosse, NJ), Solutol HS15, poloxamer 407, Lutrol F77, Cremophor RH40 (BASF, NJ), dipalmitate sucrose and distearate sucrose (Croda, NJ).

In one embodiment, the present invention relates to pharmaceutical compositions comprising a solid suspension, obtained by extrusion of the melt hydrochloride (2R,3S,4R,5R)-5-(4-amino-2-oxo-2H-pyrimidine-1-yl)-2-azido-3,4-bis-isobutyrylacetate-2-Eletropaulo ether somaclonal acid (I) and the block copolymer PEG/BCP. In another embodiment of the present invention the solid suspension is combined with at least one carrier, diluent and/or inert filler.

In yet another embodiment, the present invention relates to a pharmaceutical composition, which is solid suspension (I) and poloxamer. In yet another embodiment of the present invention the pharmaceutical composition is a solid suspension (I) and poloxamer, combined with at least one carrier, diluent and/or inert filler. In yet another embodiment, the present invention relates to solid suspension (I) and poloxamer contained in compressed tablet or capsule, which may also contain more carriers, diluents and/or inert fillers.

In another variationbetween the present invention relates to pharmaceutical compositions, includes solid suspension (I) and poloxamer 188. In yet another embodiment, the present invention relates to pharmaceutical compositions comprising a solid suspension (I) and poloxamer 188, in which the solid suspension contains 20 to 40 wt.% poloxamer 188.

In another embodiment, the present invention relates to a compressed tablet comprising a solid suspension (I) and poloxamer 188, containing microcrystalline cellulose, mannitol, crosspovidone, colloidal silicon dioxide, corn starch or talcum powder), magnesium stearate. Additionally pressed tablet may optionally contain sodium bicarbonate, arginine or maltodextrin and don't have to be surrounded by the coating material.

In yet another embodiment, the present invention relates to a compressed tablet comprising a solid suspension (I) and poloxamer 188, in which the solid suspension contains approximately 540 mg I and from about 175 to about 260 mg poloxamer 188, from about 125 mg to about 225 mg microcrystalline cellulose (Avicel® PH 101), from about 70 to about 125 mg of mannitol (Parteck™ 200), from about 90 mg to about 150 mg of crosspovidone (Polyplasdone® XL), from about 10 to about 40 mg of colloidal silicon dioxide (Aerosil® 380), from about 10 to about 40 mg of corn starch (or talc), from about 10 to about 25 the g of magnesium stearate. Tablet in this embodiment may optionally contain a coating of Opadry yellow C 12429.

In another embodiment, the present invention relates to a compressed tablet comprising a solid suspension (I) and poloxamer 188, in which the solid suspension contains approximately 537 mg I and about 230 mg poloxamer 188, about 175 mg microcrystalline cellulose, about 72 mg of mannitol, about 120 mg of crosspovidone, about 24 mg of colloidal silicon dioxide, about 24 mg of corn starch (or talc) and about 18 mg of magnesium stearate and pressed tablet contains optional coating of Opadry yellow C 12429.

In another embodiment, the present invention relates to a compressed tablet comprising a solid suspension (I) and poloxamer 188, in which the solid suspension contains approximately 537 mg I and about 179 mg poloxamer 188, about 175 mg microcrystalline cellulose, about 123 mg of mannitol, about 120 mg of crosspovidone, about 24 mg of colloidal silicon dioxide, about 24 mg of corn starch and about 18 mg of magnesium stearate and pressed tablet contains optional coating of Opadry yellow C 12429.

Another variant of implementation relates to pharmaceutical compositions comprising a solid suspension I, poloxamer and plasticizer. In this embodiment, domestic the plasticizer improves elasticity, the workability or distensibility of the extrudate. In addition, the plasticizer can reduce the melt viscosity and to reduce the modulus of elasticity of the product. Plasticizers are usually reduce the glass transition temperature or the softening temperature of the block copolymer to reduce the temperature of the processing, the torque of the extruder and the pressure in the extruder during the extrusion. Plasticizers are usually also reduce the viscosity of the molten extrudate. Examples of plasticizers that can be used in the context of the present invention, include triacetin, polypropylenglycol, polyethylene glycol having a molecular weight equal to from about 200 to about 1000 (e.g., PEG 4600), dibutyl phthalate, dibutylsebacate, triethylcitrate, vegetable and mineral oils, glycerides6-C18fatty acids, for example, Tween 80, etc.

In another embodiment, the present invention relates to a method for solid suspension I and the block copolymer PEG/BCP, which includes stages: (i)mixing of solids in the mixer; (ii) introducing the resulting mixture of solid substances in the heating zone of the extruder to melt as the temperature of the heating zone is in the range above the melting temperature of the specified block copolymer and below the melting point of I; (iii) extruding the obtained melt and (iv) refining TV is rdeu suspension to obtain a particle size of from about 20 to about 2000 microns. In another embodiment of the present invention the particles are milled to a size of about 100 to about 600 microns.

In another embodiment, the present invention relates to pharmaceutical compositions comprising a solid suspension and I poloxamer 188, in which the solid suspension contains from about 55 to about 70% I (wt./wt), from about 5 to about 12% mannitol, from about 13 to about 16% of microcrystalline cellulose, from about 8 to about 12% crosspovidone, from about 1 to about 3% colloidal silica, from about 1 to about 3% corn starch (or talc) and from about 1 to about 2% magnesium stearate.

In one embodiment of the present invention the solid suspension together with carriers, diluents and inert fillers include in the pressed tablet. Inert fillers include together with the solid suspension to give the required characteristics. Suitable inert fillers, which usually include the composition of CT include binders, surfactants, solvents, agents for improving the compressibility, agents, providing raspadaemost, agents, adhesion, stabilizers, antioxidants, dyes, wetting agents and lubricating agents. The media will dilute the Lee and inert fillers, the applicability of which is confirmed, well known in the pharmaceutical field and are described in the publication Remington: The Science and Practice of Pharmacy 1995, edited by E.W.Martin, Mack Publishing Company, 19th edition, Easton, Pennsylvania. Many ingredients can be used with different purposes, even in a single composition, and inert fillers and diluents included in the present invention, without deviating from the essence of the present invention can be replaced or modified.

Tablets containing solid suspension, optionally containing coating. Membrane coating can optionally contain other inert fillers, forming a coating, such as agents, which impart opacity, pigments, dyes, etc. the Choice of these substances and used the number of conducts is determined by the person skilled in the technical field.

The term "inert fillers" when used in the present invention means an inert substances that give the songs a satisfactory performance needed to handle and pressing, or give the necessary physical characteristics of the finished tablet.

Diluents and inert ingredients are added to increase the volume to ensure that the size, suitable for pressing. The usual diluents include dicalcium phosphate, calcium sulfate, lactose, cellulose, kaolin, mannitol, compound sodium chloride with the collapse of the al, and powdered sugar. Diluents such as mannitol, lactose, sorbitol, sucrose and Inositol, when used in sufficient quantities contribute to the disintegration of the tablet and are often used in chewable tablets. Microcrystalline cellulose (AVICEL®) used as an inert filler in compositions intended for direct compression.

A binder is added to the powders to give them the ability to stick together, which allows to preserve the integrity of the molded tablets. Substances commonly used as binders include starch, gelatin and sugars such as sucrose, glucose, dextrose, molasses, and lactose. Some of the compositions as a binder also use natural and synthetic gums, including gum acacia, sodium alginate, gum panwar gum, Ghatti, carboxymethylcellulose, methylcellulose, polyvinylpyrrolidone, ethylcellulose.

Lubricating agents are used to prevent adhesion of the material of the tablet to the surfaces of the dies and punches. Usually used lubricating agents include talc, magnesium stearate, calcium stearate, stearic acid, hydrogenated vegetable oil and PEG. Water-soluble lubricating agents include sodium benzoate, mixtures of sodium benzoate and sodium acetate, sodium chloride, leucine and Carbowax 4000.

Agents, imparting lubricity include is to improve the flowability of the powder, used for the manufacture of tablets. An ordinary agent, which imparts lubricity is colloidal silicon dioxide (AEROSIL®). Talc can simultaneously act as a lubricating agent/agent, which imparts lubricity.

Agent, providing raspadaemost is a substance or mixture of substances added to facilitate the destruction or disintegration after administration. Common agents that provide raspadaemost are dried and powdered corn starch and potato starch. They have high affinity to water and swell when wet, which leads to the destruction of the tablets. The group of substances known as a particularly effective agents providing raspadaemost includes croscarmelose, crosslinked cellulose, crosspovidone, cross-linked polymer and glycolate, sodium salt of starch, crosslinked starch. Crosspovidone (POLYPLASDONE®) is a synthetic insoluble, but quickly swelling crosslinked homopolymer N-vinylpyrrolidone.

The following examples illustrate how to retrieve and biological evaluation of the compounds included in the scope of the present invention. These examples and preparations below, refer to specialists in the art can understand and implement the present invention. They should not be considered as limiting the volume of the present invention, but just as his illustrations and examples. Specialist in the field of pharmaceutical chemistry should be familiar with inert fillers, diluents, and carriers that can be used interchangeably, and these changes do not deviate from the essence of the present invention.

Example 1

Below is a composition in wt.%.

IngredientContent (wt./wt.)
4'-azidothymidine-2',3',5'-triisobutyl Hcl (I)44,73%
poloxamer 188MT 19 : 18%
microcrystalline cellulose14,59%
mannitol6,00%
crosspovidone10,00%
colloidal silicon dioxide2,00%
corn starch2,00%
magnesium stearate1,50%

Specialist in the art should understand that the amount I can easily change to obtain tablets or capsules, containing the four different doses of AI, by replacing AI with additional quantity of diluent and that the change in the number I or solid dispersion I does not deviate from the essence of the present invention.

Active ingredient I, poloxamer 188 and optional plasticizer is mixed in the mixer. The mixed solids are served in a twin-screw Leistritz extruder. The temperature of the heating zones set equal 45, 65, 65, 65, 65, 70, 75 and 80°C. the temperatures of the heating zones are maintained equal to ±5°C. This ensures the melting poloxamer and inert fillers without melting I. twin-screw extruder operates at a speed of 100±30 rpm, and the flow rate of powder is from 5 to 20 g/min, preferably from 10 to 15 g/min. Under these conditions, the polymer melts and forms a uniform coating of the active ingredient. The extrudate is collected at room temperature (15 to 30°C) in containers with double PE coating. Extruded substance is passed through a Fitz mill Mill and milled substance is mixed with AVICEL RN, mannitol, POLYPLASDONE XL and corn starch (optional with talcum powder instead of cornstarch). In conclusion to the mixed substance was added magnesium stearate. Milled particles have a size of from 100 to 2000 μm. The resulting mixture was fed in tabletiruemuju machine and pressed into core tablets.

Suspension of glennette coating can be prepared by combining Opadry and purified water and stirring for 45 min until complete dispersion of Opadry. Cores are placed in a perforated drum for coating and heat up the incoming air, the temperature of which is equal to 45±5°C, with occasional stirring, until the temperature of the outgoing air will be equal to 40±5°C. Then the temperature of the incoming air is increased to 60±5°C and the cores are coated with continuously stir the slurry coating using an air spray system that is configured so that the pill can cause 25 mg film coating, calculated on the dry matter. The coated tablets are dried by shaking to a moisture content equivalent to less than 2%, and then the tablet is cooled to room temperature and store in an airtight container with double PE coating.

Example 2

Preparing a composition of the following composition.

IngredientContent
Example 2AExample 2b
4'-Azidothymidine-2',3',5'-triisobutyl Hcl536,80 mg536,80 mg
Poloxamer 188230,11 mg179,00 mg
AVICEL PH 101175,09 the g -
AVICEL PH 102-175,00 mg
PARTECK 20072,00 mg123,20 mg
POLYPLASDONE XL120,00 mg120,00 mg
AEROSIL 8024,00 mg24,00 mg
Corn starch24,00 mg24,00 mg
Magnesium stearate18,00 mg18,00 mg
Mass of nucleus1200,0 mg1200,0 mg
The composition of film coating
Opadry Yellow C 1242935,00 mg-
Purified water183,75 mg-
Weight of film coating35,00 mg-
The total weight of the tablet with a film on the freight 1235,0 mg-

The features disclosed in the above description, or the following claims, expressed in a concrete form or in the form of means for imparting disclosed function, or method, or technique to ensure disclosed results, depending on what is appropriate, may, separately or in any combination of such features apply to implement the present invention in its various forms.

Above the invention is described for illustration and as an example for its explanation and its understanding. To a person skilled in the art should understand that the scope of the attached claims you can make changes and modifications. Therefore, it should be understood that the above description is illustrative and not limiting. Therefore, the scope of the present invention should be determined not with reference to the above description, and to determine with reference to the attached claims together with all equivalents that the claims.

All patents, patent applications and publications cited in the present description, in their entirety are included in the present invention as a reference for all objects in the same degree, in which is included each individual mentioned patent, the application for the patent or publication.

1. Pharmaceutical composition having antiviral activity against hepatitis C, including solid suspension, obtained by extrusion of the melt hydrochloride (2R,3S,4R,5R)-5-(4-amino-2-oxo-2H-pyrimidine-1-yl)-2-azido-3,4-bis-isobutyrylacetate-2-Eletropaulo ether somaclonal acid (I) and a block copolymer of polyethylene glycol (PEG)/polypropylenglycol (BCPs).

2. The composition according to claim 1, additionally comprising at least one diluent, carrier and/or excipient.

3. The pharmaceutical composition according to claim 1, in which the specified block copolymer PEG/BCP represents poloxamer.

4. The pharmaceutical composition according to claim 3, additionally comprising at least one diluent, carrier and/or excipient.

5. The pharmaceutical composition according to claim 3, which is contained in a capsule or compressed tablet and this tablet or the specified optional capsule contains one or more carriers, diluents and/or inert fillers.

6. The pharmaceutical composition according to claim 5, in which the solid suspension includes connecting first and poloxamer 188.

7. The pharmaceutical composition according to claim 6, in which the solid suspension contains 20-40% (wt./wt.) poloxamer 188.

8. The pharmaceutical composition according to claim 7, in which the solid su is penzija contained in the molded tablet, this tablet is optionally contains one or more inert fillers selected from the group comprising microcrystalline cellulose, mannitol, crosspovidone, colloidal silicon dioxide, corn starch or talcum powder), magnesium stearate, sodium bicarbonate, arginine, maltodextrin and substance coverage.

9. The pharmaceutical composition of claim 8 where the specified molded tablet contains mg:

The connection Iapproximately 540
Poloxamer 188from 175 to 260
Microcrystalline cellulose (AVICEL PH 101)from 125 to 225
Mannitolfrom 70 to 125
POLYPLASDONE XLfrom 90 to 150
Colloidal silicon dioxide (AEROSIL 380)from 10 to 40
Corn starch or talcfrom 10 to 40
Magnesium stearatefrom 10 to 25

where indicated pressed tablet contains optional coating of Opadry yellow C 12429.

10. Pharmaceutical compositions the Oia according to claim 9, including, mg:

The connection I537
Poloxamer 188230
Microcrystalline cellulose175
Mannitol72
POLYPLASDONE XL120
Colloidal silicon dioxide24
Corn starch or talc24
Magnesium stearate18

where indicated pressed tablet contains optional coating of Opadry yellow C 12429.

11. The pharmaceutical composition according to claim 9, comprising, mg:

The connection I537
Poloxamer 188179
Microcrystalline cellulose175
Mannitol123
POLYPLASDONE XL120
Colloidal silicon dioxide24
Corn starch or talc24
Magnesium stearate18

where indicated pressed tablet contains optional coating of Opadry yellow C 12429.

12. Pharmaceutical composition having antiviral activity against hepatitis C, including solid suspension, obtained by extrusion of the melt hydrochloride (2R,3S,4R,5R)-5-(4-amino-2-oxo-2H-pyrimidine-1-yl)-2-azido-3,4-bis-isobutyryloxy-tetrahydrofuran-2-Eletropaulo ether somaclonal acid (I), poloxamer 188 and plasticizer.

13. A method of obtaining a solid suspension of the hydrochloride (2R,3S,4R,5R)-5-(4-amino-2-oxo-2H-pyrimidine-1-yl)-2-azido-3,4-bis-isobutyryloxy-tetrahydrofuran-2-Eletropaulo ether somaclonal acid (I) and the block copolymer PEG/BCP, which includes stages:
(i) mixing of solids in the mixer;
(ii) introducing the resulting mixture of solid substances in the heating zone of the extruder to melt as the temperature of the heating zone is in the range above the melting temperature of the specified block copolymer and below the melting temperature of the compound I;
(iii) extruding the obtained melt,
(iv) grinding the solid suspension to obtain a particle size of from about 20 to PR is about 2000 microns.

14. The method according to item 13, in which the solid, the suspension is milled to obtain a particle size of from about 100 to about 600 microns.



 

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FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to medicine, and concerns a method of preparing a influenza vaccine. Substance of the invention includes influenza virus infection of chicken embryos, incubation, sampling of a virus-containing fluid, purification of influenza virus, concentration and final virus purification by gel filtration HW-65C carrier column chromatography. Purified virions are destroyed by the detergent β-octylglucoside to be removed then. Three half-finished vaccines prepared with the use of received with use of H1N1, H3N2 and B serotypes are combined so that the hemagglutinin concentration in each serotype is about 30 mcg/ml.

EFFECT: reduction in price of the method of preparing the influenza vaccine and its improvement.

5 ex, 1 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to compounds of formula (I) where R1 is chosen from ethyl, n-propyl, isopropyl or isobutyl, and to its pharmaceutically acceptable salts. Besides, the invention refers to a pharmaceutical composition on the basis of said compounds used for treating a hepatitis C virus (HCV) mediated disease, and also to a method of treating the hepatitis C virus (HCV) mediated disease, and to the method of selective O-acylation nucleoside II for producing O-acyl nucleoside I in an alkaline reaction medium including the stages: (i) dissolution of II and DMAP in a heterogeneous mixture of water and a solvent and addition of a water base for pH control between approximately 7.5 to approximately 12; (ii) optional addition of a sufficient amount of saturated aqueous NaCl for preparing a diphase reaction mixture; (iii) addition of an acidating agent and an accessory base sufficient for pH preservation between approximately 7.5 to approximately 12; (iv) reaction monitoring and interruption of adding said acidating agent and said base after sufficient conversion provided; (v) optional contact of O-acylnucleoside with the pharmaceutically acceptable acid to produce a pharmaceutically acceptable salt.

EFFECT: production of the pharmaceutical composition for treating the hepatitis C virus (HCV) mediated disease.

9 cl, 2 tbl, 8 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of formula (I) where values of the substitutes are disclosed in the patent claim.

EFFECT: compounds can be applied for treating the infections caused by Pneumovirinae subfamily viruses (RSV, PCB).

53 cl, 502 ex, 11 tbl

FIELD: medicine.

SUBSTANCE: invention relates to field of medicine and deals with method of obtaining lice culture influenza vaccine. Essence of the invention includes method of obtaining virus-containing substance by cultivation of one of cold-adapted influenza virus reassortants with enoculation dose, with multiplicity of infection not lower than 0.0001 EID50/cell in MDCK cell culture on micro-carriers, which have concentration not less than 1 g/l, with application as micro-carrier material of porous polypropelene, in supporting serum-free nutritional medium, containing proteolytic enzyme in amount 0.25-50.0 mcg/ml, and stabilising additive, which includes sorbitol, or sucrose, or peptone from soya in concentration 0.5-4.0 wt%, collection of virus-containing liquid after cultivation is carried out at least 2 times when specific influenza virus activity before each collection of virus-containing liquid reaches at least 7.0 Ig EID50/ml, concentration and purification of virus substance from ballast admixtures, introduction into purified substance before drying of stabilising additives, with application as such of either proline, glycene, lactose, glutamine-acidic sodium, sucrose, gelatins in final concentration (1.5-5), (1.5-5), (1.5-10), (1.5-5), (5-30) and (1-10) wt % respectively, or sucrose, gelatose and soya peptone in final concentration (1-8), (1-8) and (1-8) wt % respectively, or sorbitol and gelatose in final concentration (3-8) and (3-8) wt % respectively.

EFFECT: obtaining more thermostable vaccine with high output.

2 cl, 6 ex, 1 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to field of chemical-pharmaceutical and food industry, namely to field of creating liquid forms of medications and biologically active food additives, with wide spectrum of pharmacological action, namely general health-improving, anti-inflammatory, antimicrobial, antiviral and immunomodelling and antioxidant action. Claimed medication for treatment and prevention of upper airways diseases is made in form of syrup of thallus of Island moss Cetraria islandica (L.) Ach., enriched with complex of biologically active substances, including polysaccharides and lichen acids. Also claimed is method of obtaining medicinal syrup of Island moss. Vegetable raw material before extraction is preliminarily crushed and extraction is carried out with syrup of various concentrations with its further filtering.

EFFECT: method ensures obtaining of final product - syrup of Island moss, maximal substance extraction, as well as preservation of biologically active substances (BAS) in syrup (polysaccharides, lichen acids) during long term in native state, thus, ensuring high medication efficiency.

8 cl, 9 ex, 3 tbl, 3 dwg

FIELD: medicine.

SUBSTANCE: invention relates to compounds of formula

and their pharmaceutically acceptable salts, inhibiting activity of serine protease, in particular, activity of protease of hepatitis C virus HC3-HC4A. Claimed invention also relates to pharmaceutical compositions, which contain said compounds, method of inhibiting serine protease activity.

EFFECT: elimination or reduction of infection with hepatitis C virus.

27 cl, 1 tbl, 5 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula [I-D1] or pharmaceutically acceptable salt thereof,

,

where each symbol is defined in the claim. The invention also relates to pharmaceutical compositions containing said compound and having HCV polymerase inhibiting activity.

EFFECT: disclosed compound exhibits anti-HCV activity, based on HCV polymerase inhibiting activity and is useful as an agent for preventing and treating hepatitis C.

32 cl, 497 tbl, 1129 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: declared formulation of the combined pharmaceutical chondroprotective drug presented in a solid dosage form contains as active substances sodium chondroitin sulphate and glucosamine sulphate sodium chloride, a binding agent, antifriction substances, an aerating agent, an excipient; the composition is film-coated. The ingredients are taken in proportions, wt %: sodium chondroitin sulphate - 10-35, glucosamine sulphate sodium chloride - 15-45, the binding agent (low-molecular povidone and potato starch) - 3.1-11, the antifriction substances (aerosil, calcium stearate and talc) - 2.7-5, the aerating agent (kollidon) - 1.7-10, the excipient (ludipress) - 10-44.2. The coating ingredients are taken in proportions, wt %: film-forming material (hypromellose) - 1-2, a plasticiser (macrogol and propylene glycol) - 1-1.8, a pigment (titanium dioxide) - 0.5-1.

EFFECT: auxiliary ingredients enables high release rate of a tabletted mass, complete drug absorption and shelf-life stability of all measures.

3 dwg, 3 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to medicine, and concerns a coformulated drug exhibiting antituberculous action and representing a solid dosage form which contains as an active principle a formulation of rifampicin, isoniazid, pyrazinamide, and a zinc-containing compound, and pharmaceutically acceptable excipients. The zinc-containing compound is zinc salt, preferentially zinc sulphate.

EFFECT: pharmaceutical composition under the invention is characterised by high efficacy and provides synergetic antimycobacterial activity when using the formulation of rifampicin, isoniasid, pyrazinamide and zinc sulphate as an antituberculous drug as compared with a formulation of standard antituberculous drugs.

9 cl, 3 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to field of medicine, namely to anti-tuberculosis composition. Claimed is pharmaceutical composition which includes sodium salt of para-aminosalicylic acid, zinc sulfate, sorbitol, polyvinylpyrrolodone, citric acid, stearic acid salt, sodium carboxymethyl starch, colloidal silicon dioxide and polyethylene glycol in amounts stated in invention formula.

EFFECT: pharmaceutical composition is characterised by high therapeutic activity, satisfactory technological characteristics and has storage term more than 2 years.

8 cl, 1 tbl, 1 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to field of chemical-pharmaceutical industry, namely to novel anti-tuberculosis medication. Claimed medication contains as active substance 4-thioureidoiminomethyperidinium perchlorate in effective and safe quantity and pharmaceutically acceptable auxiliary substances. Also claimed is method of its obtaining, which makes it possible to obtain target product with high yield. Novel medication, obtained by claimed method, possesses high tuberculostatic activity and low toxicity, preserves its stability in long-term storage.

EFFECT: invention can be used for treatment of all forms of pulmonary and extra-pulmonary tuberculosis, as well as in prophylaxis in composition of combined tuberculosis therapy.

12 cl, 8 tbl, 16 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to stable solid medication, containing olmesartan medoxomil and amlodipine or its pharmaceutically acceptable salt. Said solid medication is, in fact, free of reducing sugars. Stable solid medication optionally can additionally contain hydrochlortiazide or its pharmacologically acceptable salt. Medicinal form is intended for treatment or prevention of diseases caused by hypertension.

EFFECT: solid medicinal form in accordance with invention has improved solubility properties in comparison with lactose-containing composition.

42 cl, 2 dwg, 4 tbl, 2 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention claims per oral drug form of neramexam with modified release, which is applied for long therapy of patients with such diseases and states as dimentia in Alzheimer's disease and neuropathic pain. Neramexane is dispersed inside hard matrix, which contains release-regulating filler. Filler is selected from copolymer of polyvinylpyrrolidone and vinyl acetate, hydroxypropylmethylcellulose. Hydroxypropylmethylcellulose is present in mixture with microsrystalline cellulose. Content of said filler is selected in such a way as to obtain profile of neramexan release in vitro, characterised by dissolution time of, at least, 1 hour for amount of neramexane, constituting 50 wt %.

EFFECT: profile of release ensures concentrations of neramexane in plasma with fluctuation index 0,4 or lower with introduction of matrix tablet of neramexane one time per day at steady state.

23 cl, 4 tbl, 7 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to chemical-pharmaceutical industry, namely to creation of pharmaceutical composition in form of hard peroral drug form for treatment of gastrointestinal tract diseases. Pharmaceutical composition contains the following ingredients: trimebutin maleate, lactose, colloidal silicon dioxide, talc, corn starch, magnesium stearate.

EFFECT: obtained pharmaceutical composition ensures high clinical effect.

5 cl, 2 ex, 1 tbl

FIELD: medicine, pharmaceutics.

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

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

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to pharmaceutical industry and solid dosage form of calcium atorvastatin. Solid dosage form consists of core containing the following components, wt %: calcium atorvastatin - 1.5-25; microcrystalline cellulose - 2-30; calcium carbonate - 5-30; croscarmellose sodium - 0.5-5; stearic acid and/or its salt - 0.5-1.04; lactose "Lactopress Spraydry" - balance; and shell containing the following components, wt %: polyethylene glycol - 6-28; titanium dioxide - 10-35; talc - 5-25; silicon emulsion - 0.05-4; dye - 0-3; polyvinyl alcohol - balance.

EFFECT: invention provides for production of calcium atorvastatin pills satisfying requirements of National pharmacopeia XI.

4 cl, 5 tbl

FIELD: medicine.

SUBSTANCE: invention concerns a solid oral dosage form composition containing therapeutically effective amount of aliskiren or its pharmaceutically acceptable salt in amount exceeding 46 wt %. The oral dosage form represents a tablet or a film-coated tablet. Aliskiren tablet is made by wet granulation with using mixed organic solvents or organic binding solutions.

EFFECT: elimination of aqueous granulation provides high stability of the dosage form of aliskiren and prolonged shelf-life.

18 cl, 2 ex

FIELD: medicine.

SUBSTANCE: invention relates to composition for peroral introduction, which possesses properties of modified release. According to invention composition includes pharmaceutically acceptable excipients and complex medication-ion-exchanging resin with coating with modified release, which contains pharmaceutically active medication, combined with pharmaceutically acceptable ion-exchanging resin. Complex has solidified barrier coating with high rupture strength, water-permeable, water-insoluble, which contains polyvinyl acetate polymer, stabiliser and efficient amount of plastifier. Said coating is in fact non-sticky, when applied onto complex in absence of anti-adhesive preparation, if composition presents tablet, complex medication-ion-exchanging resin with coating additionally contains release-retarding substance in matrix together with complex medication-ion-exchanging resin. Invention also relates to product with modified release, including package which contains composition described above.

EFFECT: invention ensures regulated prolonged active agent release without breaking coating integrity, without application of water-soluble impregnating substances and without agglomeration of complex particles during application of coating.

27 cl, 22 ex

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