Solid medication of olmesartan medoxomil and amlodipine

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

 

The technical field to which the invention relates

The present invention relates to a solid dosage form containing olmesartan medoxomil and amlodipine and additionally optionally containing hydrochlorothiazide.

Background of invention

Olmesartan medoxomil is a receptor antagonist of angiotensin II, developed for the treatment of hypertension and other medical symptoms described in U.S. patent 5616599. Its chemical name is 2,3-dihydroxy-2-butenyl 4-(1-hydroxy-1-methylethyl)-2-propyl-1-[p-(about-1H-tetrazol-5-ylphenyl)benzyl]imidazole-5-carboxylate, cyclic 2,3-carbonate or (5-methyl-2-oxo-1,3-dioxolan-4-yl)methyl 4-(1-hydroxy-1-methylethyl)-2-propyl-1-{4-[2-(tetrazol-5-yl)phenyl]phenyl}Mei-5-carboxylate, having the following structure:

Olmesartan medoxomil markets Sankyo company under the trade name Olmetec® or Benicar®. It is presented in the form of oral tablets with a drug content of the substance in the tablet 5 mg, 10 mg, 20 mg and 40 mg Inactive ingredients in the tablets Olmetec® include hydroxypropylcellulose with a low degree of substitution, microcrystalline cellulose, lactose monohydrate, hydroxypropylcellulose and magnesium stearate.

Olmesartan medoxomil is a prodrug that p is following ingestion releases only active metabolite, 4-(1-hydroxy-1-methylethyl)-2-propyl-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]-1H-imidazole-5-carboxylic acid (RNH-6270). The chemical structure of RNH-6270 is a

In acidic or alkaline conditions and in the presence of water RNH-6270 is formed through hydrolysis of the ester bonds of olmesartan of medoxomil.

Amlodipine is a calcium channel blocker developed for the treatment of hypertension and other medical symptoms described in U.S. patent 4572909 and U.S. patent 4879303. Its chemical name is 3-ethyl-5-methyl-(±)-2-[(2-aminoethoxy)methyl]-4-(2-chlorophenyl)-1,4-dihydro-6-methylpyridine-3,5-in primary forms, having the following structure:

Amlodipine supplies company Pfizer in the form of monopersulfate salt of amlodipine besylate under the trade name By® (norvasc). It is available as oral tablets with a content of drug substance in a tablet 2.5 mg, 5 mg and 10 mg Inactive ingredients in tablets By® include microcrystalline cellulose, anhydrous secondary acidic calcium phosphate, matrikamantra and magnesium stearate.

In WO 2006/059217 revealed that amlodipine of vysokogorskoje and absorbs moisture, which leads to degradation. One of the main ways degradation is a catalytic oxidation process to the th pH dependent. One of the main degradation products is 3-ethyl-5-methyl-2-[(2-aminoethoxy)methyl]-4-(2-chlorophenyl)-6-methylpyridine-3,5-in primary forms (impurity D). The chemical structure of impurity D is a

In "Pharmaceutical Development and Technology, vol. 9, No. 1, pp.15-24, 2004" it is shown that a mixture of lactose, alkaline fillers and water stimulate the instability of amlodipine besylate, due to the Maillard reaction between the primary amino group and lactose.

As amlodipine is an unstable compound, it is necessary Technomarine methods, to form a pharmaceutical composition having good stability.

Despite the fact that WO 04/067003 and in EP 1604664 describe the drug containing olmesartan medoxomil and amlodipine, a stable solid dosage form containing olmesartan medoxomil and amlodipine, is unknown.

The purpose of the invention

I believe that the mechanisms of action of olmesartan of medoxomil and amlodipine interact favorably in the treatment or prevention of hypertension or diseases caused by hypertension. As an increasing number of clinical data confirms this assumption, there is a growing need in the medicinal product containing the active ingredients of olmesartan of medoxomil and amlodipine, with constant doses in combination. However, as olmesartan medoxomil and amlodipine are chemical compounds of which it is difficult to make a mixture, due to stability problems with these active ingredients. Therefore, although there is an obvious need in the remedy, which is a combination of ingredients with fixed doses, which combines the properties of pharmacological efficacy with acceptable stability and solubility, it is necessary to overcome a number of technical problems to achieve this. The aim of the present invention to provide such drug which is a combination of ingredients with fixed doses.

There are various types of solid dosage forms, which could be considered, but it is impossible to predict which of these dosage forms best way to combine pharmacological efficacy, product stability and solubility. Generally, drugs that are combination of ingredients with fixed doses of ingredients, their instant release, receive, forming a powder blend of the co-granulate of two active ingredients with appropriate fillers, preserving the basic structure of one of the respective nanolekarstvo drugs and simply d is bawley second medicinal component.

For the combination of olmesartan of medoxomil and amlodipine such an approach does not seem feasible due to the incompatibility of amlodipine with components of conventional drugs olmesartan of medoxomil. When the drug on the basis of Olmetec® is used in medicine, which is a combination of fixed doses of ingredients in the dosage form occurs degradation products due to the Maillard reaction occurring inside the drug between amlodipine and lactose. On the other hand, when drug use based By®, solubility and bioavailability of olmesartan of medoxomil reduced. Moreover, drugs olmesartan of medoxomil and amlodipine shipped currently on the market, have several disadvantages. Mass known tablets Olmetec® and tablets By® are relatively high (218 mg, and 432 mg tablets Olmetec®; 200 mg and 400 mg tablets By®, respectively). Due to the large quantities of fillers present in the preparations, the size of the tablets drug Olmetec®By® is relatively large; such large tablets difficult to swallow, especially in elderly patients. The present invention concerns a preparation, which is a stable solid dosage form containing olmesartan medoxomil and amlodipine, which overcome the above problems is s.

The invention

The aim of the present invention to provide a solid dosage form containing olmesartan medoxomil and amlodipine or a pharmacologically acceptable salt, which has an improved stability of the active ingredients and a reduced weight. According to the present invention, the problems associated with obtaining a solid dosage form containing olmesartan medoxomil and amlodipine or a pharmacologically acceptable salt, can be solved by taking drugs, which essentially does not contain the drug of reducing sugars.

The present invention offers a solid dosage form containing olmesartan medoxomil and amlodipine or a pharmacologically acceptable salt, which have a concentration of RNH-6270 less than 2.5% (wt./wt.), the concentration of impurity D is less than 0.4% (wt./wt.) and the concentration of total impurities less of 5.1% (wt./wt.) and, in fact, do not contain reducing sugars (in particular, dosage form for the prevention or treatment of hypertension; offer the use of olmesartan of medoxomil and amlodipine or a pharmacologically acceptable salt for the manufacture of the above-mentioned solid pharmaceutical forms (in particular, the dosage form for the prevention or treatment gipe is the tensions); offer a way to prevent or treat a disease (particularly hypertension), in which the above-mentioned solid dosage form containing a pharmacologically effective amount of olmesartan of medoxomil and amlodipine or a pharmacologically acceptable salt, is administered warm-blooded animals (particularly humans); and offer the use of solid dosage forms containing olmesartan medoxomil and amlodipine or a pharmacologically acceptable salt in the manufacture of a medicine for the prevention or treatment of disease (particularly hypertension). In a preferred embodiment of the invention, the solid dosage form according to the invention additionally contains hydrochlorothiazide, a thiazide diuretic structure, which has the following structural formula:

Hydrochlorothiazide

Specifically, in the present invention offer:

(1) a solid dosage form containing olmesartan medoxomil and amlodipine or a pharmacologically acceptable salt, and having a concentration of 4-(1-hydroxy-1-methylethyl)-2-propyl-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]-1H-imidazole-5-carboxylic acid (RNH-6270), comprising less than 2.5% (wt./wt.);

(2) a solid dosage form containing olmesartan medoxomil and amlodipine or his farm is ecologicheski acceptable salt, and with the concentration of 3-ethyl-5-methyl-2-[(2-aminoethoxy)methyl]-4-(2-chlorophenyl)-6-methylpyridine-3,5-in primary forms (impurity D)component is less than 0.4% (wt./wt.);

(3) a solid dosage form containing olmesartan medoxomil and amlodipine or a pharmacologically acceptable salt, and having a concentration of total amounts of impurities, comprising a minimum of 5.1% (wt./wt.);

(4) a solid dosage form containing olmesartan medoxomil and amlodipine or a pharmacologically acceptable salt, and having a concentration of RNH-6270, comprising less than 2.5% (wt./wt.), and the concentration of total amounts of impurities, comprising a minimum of 5.1% (wt./wt.);

(5) a solid dosage form under item (1) or (2), optionally containing hydrochlorothiazide or its pharmacologically acceptable salt;

(6) a solid dosage form under item (5)having a concentration of total impurities constituting less than 7.3 percent (wt./wt.);

(7) a solid dosage form containing olmesartan medoxomil and amlodipine or a pharmacologically acceptable salt, where this solid dosage form, in essence, does not contain reducing sugars;

(8) a solid dosage form under item (1)where the specified solid dosage form, in essence, does not contain reducing sugars;

(9) a solid dosage form according to p. (2)where the specified solid the dosage form, essentially, does not contain reducing sugars;

(10) a solid dosage form under item (3)where the specified solid dosage form, in essence, does not contain reducing sugars;

(11) a solid dosage form under item (4)where the specified solid dosage form, in essence, does not contain reducing sugars;

(12) a solid dosage form under item (5) or (6)where the specified solid dosage form, in essence, does not contain reducing sugars;

(13) a solid dosage form according to any one of paragraphs. (7)-(12)where the specified solid dosage form contains less than 2.0% (wt./wt.) reducing sugars.

(14) a solid dosage form according to any one of paragraphs. (7)-(12)where the specified solid dosage form contains less than 0.3% (wt./wt.) reducing sugars;

(15) a solid dosage form according to any one of paragraphs. (7)-(12)where the specified solid dosage form contains less than 0.05% (wt./wt.) reducing sugars;

(16) a solid dosage form according to any one of paragraphs. (1), (5) and (7)-(15) having a concentration of RNH-6270 constituting less than 0.5% (wt./wt.);

(17) a solid dosage form according to any one of paragraphs. (1), (5) and (7)-(15)having a concentration of RNH-6270 constituting less than 0.4% (wt./wt.);

(18) a solid dosage form according to any one of paragraphs. (2), (5) and (7)-(15)having a concentration of impurity D, component Myung is e of 0.3% (wt./wt.);

(19) a solid dosage form according to any one of paragraphs. (2), (5) and (7)-(15)having a concentration of impurity D, which is less than 0.05% (wt./wt.);

(20) a solid dosage form according to any one of paragraphs. (3) and (5)-(15)having a concentration of total amounts of impurities, comprising less than 1.5% (wt./wt.);

(21) a solid dosage form according to any one of paragraphs. (4)-(15)having a concentration of RNH-6270 constituting less than 0.5% (wt./wt.), and the concentration of total amounts of impurities, comprising less than 1.5% (wt./wt.);

(22) a solid dosage form according to any one of paragraphs. (4)-(15)having a concentration of RNH-6270 constituting less than 0.4% (wt./wt.) and the concentration of total amounts of impurities, comprising less than 1.5% (wt./wt.);

(23) a solid dosage form according to any one of paragraphs. (1)to(6) and (16)to(22), in which the concentration of the specified impurity or impurities was measured after accelerated tests specified solid dosage forms for three months at 40°C and a relative humidity of 75%;

(24) a solid dosage form according to any one of paragraphs. (1)to(23), where amlodipine is present in the form besylate salt;

(25) a solid dosage form according to any one of paragraphs. (1)to(24), optionally containing one or more pharmacologically acceptable additives;

(26) a solid dosage form under item (25), in which one or more pharmaceutically acceptable additives selected from fillers, blur the surrounding substances, binders, dezintegriruetsja agents, emulsifiers, stabilizers, corrective agents, and diluents;

(27) a solid dosage form under item (26), in which the filler is selectonemenu microcrystalline cellulose and/or mannitol;

(28) a solid dosage form under item (26), in which the lubricating substance is magnesium stearate;

(29) a solid dosage form under item (26), in which disintegrity agent is a pre-gelatinising starch and/or nitrocresols;

(30) a solid dosage form according to any one of paragraphs. (1)to(29), where the solid dosage form comprises a tablet;

(31) a solid dosage form under item (30), where the tablet will be received, using direct pressing;

(32) a solid dosage form under item (30) or (31), where the tablet cover, at least one thin elastic layer;

(33) a solid dosage form under item (32), where the elastic film contains at least one hydrophilic polymer;

(34) a solid dosage form under item (33), in which the hydrophilic polymer is a polyvinyl alcohol and/or macrogol;

(35) a solid dosage form according to any one of paragraphs. (1)to(34), which contains 20-40 mg olmesartan of medoxomil;

(36) a solid dosage form according to any one of paragraphs. (1)to(35), which contains -10 mg of amlodipine or a pharmacologically acceptable salt of amlodipine, equivalent to 5-10 mg of amlodipine;

(37) a solid dosage form according to any one of paragraphs. (1)to(36), which contains 12.5 to 25 mg of hydrochlorothiazide or pharmacologically acceptable salt of hydrochlorothiazide, equivalent to 12.5-25 mg of hydrochlorothiazide;

(38) a method of treating or preventing hypertension in a warm-blooded animal in need of treatment, including the introduction of a specified animal an effective amount of a solid dosage form according to any one of paragraphs. (1)-(37);

(39) the use of a solid dosage form according to any one of paragraphs. (1)to(37) for the manufacture of a medicinal product for the treatment or prevention of hypertension;

(40) a solid dosage form according to any one of paragraphs. (1)to(37) for use in the treatment or prevention of hypertension.

Brief description of figures

Figure 1 shows the results obtained for the concentrations of the impurities D and RNH-6270, measured in the sample test 1 for Olmetec®, By®, preparation example 1 and preparation of comparative example 1.

Figure 2 shows the results obtained for the degree of dissolution of the preparation example 1 and preparation of comparative example 1, measured in the sample test 2.

Detailed description of the invention

Solid dosage form of the present invention as active ingredients contains olmesartan medoxomil and amlodipine or its farmacologicas is acceptable acid salt, and optionally additionally contains hydrochlorothiazide, or its pharmacologically acceptable acid salt.

Olmesartan medoxomil can be easily obtained according to the procedures described in the art; suitable examples include the techniques described in U.S. patent No. 5616599.

Amlodipine can be easily obtained according to the procedures described in the art; suitable examples include the techniques described in U.S. patent No. 4572909. Amlodipine may be used in the form of its pharmacologically acceptable acid salts, such as besylate, maleate, fumarate, Kamelot, hydrochloride, hydrobromide, lactate, tartrate, citrate, mesilate, nicotinate, gluconate and the like, as well as in free base form. Of them, the use of amlodipine besylate is preferred.

Hydrochlorothiazide can be easily obtained according to the procedures described in the art; suitable examples include the techniques described in U.S. patent No. 3025292. The connection of hydrochlorothiazide is called 1,1-dioxide, 6-chloro-3,4-dihydro-2H-1,2,4,-benzothiadiazin-7-sulfonamida. Hydrochlorothiazide according to the invention includes its pharmacologically acceptable salt, such as salt halogen acids, such as hydroptere, hydrochloride, hydrobromide or hydroiodide; nitrate; perchlorate; sulfate; phosphate; salt C1-C4Alka is sulfonic acid, which may be optionally substituted atom(s) halogen, such as methanesulfonate, triftorbyenzola or econsultant; salt C6-C10arylsulfonic acid, which optionally may be substituted C1-C4alkyl(reference) group(s), such as bansilalpet or p-toluensulfonate; salt C1-C6aliphatic acids, such as acetate, malate, fumarate, succinate, citrate, tartrate, oxalate or maleate; or a salt of the amino acids, such as salt of glycine, lysine salt, salt arginine, salt, ornithine salt of glutamic acid or a salt asparginase acid. The preferred salts are the hydrochloride, nitrate, sulfate or phosphate; and especially preferred salt is the hydrochloride.

According to one aspect of the invention, the solid dosage form has a concentration of RNH-6270, comprising less than 2.5% (wt./wt.), preferably, less than 0.5% (wt./wt.) and, more preferably, less than 0.4% (wt./wt.). According to another aspect of the invention, the solid dosage form has a concentration impurity D, which is less than 0.4% (wt./wt.), preferably, the concentration constituting less than that of 0.3% (wt./wt.), and, more preferably, the concentration, comprising less than 0.05% (wt./wt.). According to another aspect of the invention, the solid dosage form has also the concentration of total number is the number of impurities, component minimum of 5.1% (wt./wt.), and, preferably, concentration, comprising less than 1.5% (wt./wt.).

According to one preferred aspect izobreteniya, solid dosage form further comprises hydrochlorothiazide or its pharmacologically acceptable salt. According to a preferred aspect of this triple combination solid dosage form containing olmesartan medoxomil, amlodipine or its pharmacologically acceptable salt and hydrochlorothiazide or its pharmacologically acceptable salt), solid dosage form has a concentration of RNH-6270 less than 2.5% (wt./wt.), preferably, the concentration constituting less than 0.5% (wt./wt.), and, more preferably, the concentration of that component is less than 0.4% (wt./wt.). According to another preferred aspect of the triple combination solid dosage form according to the invention, the solid dosage form has a concentration impurity D, which is less than 0.4% (wt./wt.), preferably, the concentration is less than 0.3% (wt./wt.) and, more preferably, a concentration of less than 0.05% (wt./wt.). According to another aspect, the triple combination solid dosage form has a concentration of total impurities constituting less than 7.3 percent (wt./wt.), and, preferably comprising less than 1.5% (wt./wt.).

The term “stable”, as used in the description, the seat is t chemical stability of olmesartan of medoxomil and/or amlodipine or a pharmacologically acceptable acid salt in solid dosage forms and means the presence of RNH-6270 concentration, component of less than 2.5% (wt./wt.), and/or the presence of impurity D in concentrations of less than 0,4% (wt./wt.), and/or concentrations of total impurities constituting a minimum of 5.1% (wt./wt.). For solid dosage forms according to the invention, optionally containing hydrochlorothiazide or its pharmacologically acceptable salt, the term “stable”, as used here, refers to the chemical stability of solid dosage forms olmesartan of medoxomil and/or amlodipine or a pharmacologically acceptable acid salt and indicates the presence of RNH-6270 concentration that constitutes less than 2.5% (wt./wt.), and/or impurity D in concentrations of less than 0,4% (wt./wt.), and/or concentrations of total impurities less than 7.3 percent (wt./wt.). Preferably, the stability is measured using the HPLC method, so that after the accelerated testing conducted for three months at 40°C and a relative humidity of 75%, to assess the presence of related substances, based on the percent concentration of impurities relative to the active substances from which they derive; for example, a 2.5% concentration (wt./wt.) RNH-6270 means that at the time of measuring the number of RNH-6270 is 2.5% of the number of olmesartan of medoxomil, measured at the same time. These stability data are shown below in table 1, in the form of interest to the of ncentrate (wt./wt.) concerning active substances, derivatives which they are.

The term "total amount of impurities" refers to the total degradation products olmesartan of medoxomil and amlodipine or a pharmacologically acceptable salt. When the solid dosage form further comprises hydrochlorothiazide or its pharmacologically acceptable salt, the term "total amount of impurities also includes the degradation products specified hydrochlorothiazide or its pharmacologically acceptable salt.

Revitalizing sugar are a type of sugar, having aldehyde group, which allows the sugar to act as a reducing agent, for example, in the Maillard reaction or reactions Benedict. Examples of "reducing sugars" include, among others, lactose, glucose, fructose, glyceraldehyde, arabinose, mannose, galactose, maltose, xylose, cellobiose, melibiose, maltotriose and the like, as well as their hydrates.

The term "essentially free" refers to the use of a reducing sugar concentration lower than the concentration needed to use it as a filler. Solid dosage form preferably contains less than 2.0% (wt./wt.) reducing Sugars, more preferably, less than 0.3% (wt./wt.) reducing Sugars and, most preferably, less than 0.05% (wt./wt.) the barrel is ivalsa sugars.

Solid dosage form of the present invention may optionally further comprise at least one additional additive, such as a suitable pharmacologically acceptable excipient, a lubricating substance, binder, dezintegriruetsja agents, emulsifier, stabilizer, corrective agent or diluent.

Suitable “fillers” includes, among others, organic fillers, input or in combination, or separately, including sugar derivatives, not having reducing properties, such as sucrose, trehalose, mannitol, or sorbitol; starch derivatives such as corn starch, potato starch, α-starch or dextrin; cellulose derivatives such as microcrystalline cellulose or selectiona microcrystalline cellulose; gum Arabic; dextran; & pullulan; and inorganic excipients including derivatives, silicates, such as light anhydrous silicic acid, synthetic aluminum silicate, calcium silicate, metasilicate magnesium; phosphates, such as secondary acidic calcium phosphate or the dihydrate of the calcium hydrogen phosphate; carbonates such as calcium carbonate; and sulfates such as calcium sulfate. Of them, selectiona microcrystalline cellulose and mannitol are preferred the La use.

Suitable “lubricants” include, among others, stearic acid; metal salts and stearic acid such as calcium stearate or magnesium stearate; talc; colloidal silica; waxes such as beeswax or spermaceti; boric acid; adipic acid; sulfates such as sodium sulfate; glycol; fumaric acid; sodium benzoate; D,L-leucine; laurilsulfate, such as sodium lauryl sulfate or lauryl sulfate, magnesium; silicates such as silicic anhydride or hydrosilicate; and input in combination or separately, the above derivatives of starch. Of them, the use of magnesium stearate is preferred.

Suitable “binders” include, but are not entered in combination or separately, hydroxypropylcellulose, hypromellose, polyvinylpyrrolidone, macrogol and connections, like the above fillings.

Suitable “dezintegriruetsja agents” include, but are not entered in combination or separately, derivatives of cellulose, such as hydroxypropylcellulose with a low degree of substitution, carboxymethylcellulose, calcium carboxymethylcellulose or stitched sodium carboxymethyl cellulose; crosslinked polyvinylpyrrolidone; and chemically modified starch/cellulose, such as carboximetilkrahmal, three is carboximetilkrahmal, matrikamantra, pre gelatinising starch, nitrocresols. Of them, pre-gelatinising starch and nitrocresols are preferred for use.

Suitable “emulsifying agents” include, but are introduced individually or in combination, colloidal clay, such as bentonite or beeswax; metal hydroxides such as magnesium hydroxide or aluminum hydroxide; anionic surfactants such as sodium lauryl sulfate or calcium stearate; cationogenic surfactants, such as benzylaniline; and nonionic surfactants such as polyoxyethylene ether Olkiluoto alcohol, polyoxyethylene ether of sorbitol and fatty acids or ether of sucrose and fatty acids.

Suitable “stabilizers” include, but are introduced individually or in combination esters of para-oksibenzoynoy acid, such as methylparaben or propylparaben; alcohols such as chlorobutanol, benzyl alcohol or phenethyl alcohol; benzylaniline; phenols, such as phenol or cresol; thimerosal; dehydroacetic acid; and sorbic acid.

Suitable corrective agents, among others, include sugar substitutes, administered in combination or separately, such as nutria the traveler salt of saccharin or aspartame; sour flavoring agents such as citric acid, malic acid or tartaric acid; and flavors such as menthol, lemon or orange flavoring.

Suitable “thinners”, among others, include introduced separately or in combination mannitol, sucrose, calcium sulfate, calcium phosphate, hydroxypropylcellulose, microcrystalline cellulose, water, ethanol, polyethylene glycol, propylene glycol, glycerol, starch, polyvinylpyrrolidone, metasilicates magnesium and mixtures thereof.

The term “solid dosage form according to the present invention includes any pharmaceutical form used by the specialist in the art for administration to the patient of one or more pharmacologically active ingredients in solid form. Suitable solid dosage forms well known to the person skilled in the art. Examples of solid dosage forms of the present invention include, but are tablets (including sublingual tablets and tablets that disintegrate in the mouth), capsules (including soft capsules and microcapsules), granules, pills and pellets. Of these the most preferred are tablets.

Solid dosage form according to the present invention can be obtained using any of the commonly used methods well known is the shaft specialist in the field of engineering, dealing with the technology of preparation of medicines; and there are no special restrictions. Examples of suitable methods include methods described in publications such as Powder Technology and Pharmaceutical Processes [D. Chulia et al., Elsevier Science Pub. Co. (December 1, 1993)].

The tablet of the present invention can be obtained by direct pressing. In the method of directly pressing the active ingredients are mixed in a suitable mixer, along with one or more pharmaceutically acceptable additives, then move directly into the compressor for crushing the tablet. Can also be used other conventional methods such as wet granulation or dry granulation.

In addition, the tablet of the present invention can also be obtained, at least one layer of film coating. If you want a film coating, there can be used any type of apparatus for applying film coatings, are well known in the art. And as bases for film coating suitable examples include sugar bases for coatings, hydrophilic base for film coating, intersolubility the basis for the film coating and the basis for film coating with a continuous release.

Suitable examples of sugar bases for coatings in luchot sucrose; they can be used in combination with one or more additives, such as talc, precipitated calcium carbonate, calcium phosphate, calcium sulfate, gelatin, gum Arabic, polyvinylpyrrolidone & pullulan.

Suitable examples of hydrophilic bases for film coatings include cellulose derivatives such as hydroxypropylcellulose, hypromellose (e.g., drug Opadry® OY S 38956 (white), commercially available from use, Inc.), hydroxyethylcellulose, methylhydroxyethylcellulose and sodium carboxymethyl cellulose; synthetic polymers, such as diethylaminoacetate polyvinylacetal, a copolymer of aminoalkylsilane, polyvinylpyrrolidone, polyvinyl alcohol (e.g., drug Opadry® II, commercially available from use, Inc.), graft copolymers of polyvinyl alcohol/polyethylene glycol (for example, the drug Kollicoat® IR, commercially available from BASF) and macrogol; and polysaccharides, such as pullulan. Of them, preferred are polyvinyl alcohol and macrogol.

Suitable examples intersolubility fundamentals for film coatings include cellulose derivatives, such as hypromellose, acetylsalicylic hydroxypropylmethylcellulose, karboksimetiltselljuloza and acetochlor cellulose; derivatives of acrylic acid such as L-copolymer met krylovii acid, LD-methacrylic acid copolymer and S-methacrylic acid copolymer; and natural substances such as shellac.

Suitable examples of bases for film coating c continuous release include derivatives of cellulose, as ethylcellulose; derivatives of acrylic acid, such as RS-copolymer aminoalkylsilane, emulsion copolymer, the acrylate/methacrylate.

Can also be used in the appropriate ratio mixture of two or more different bases for coatings, from those listed above. Additionally, the covering film may also contain suitable pharmaceutically acceptable additives, such as plasticizers, fillers, lubricants, agents lightproof, dyes or preservatives, if necessary.

The dose and dosing ratio olmesartan of medoxomil or amlodipine or its pharmacologically acceptable salt and, where applicable, hydrochlorothiazide or its pharmacologically acceptable salts which are active ingredients of solid dosage forms of the present invention, it is possible to change, depending on various factors, such as the activity of each of the active ingredients, symptoms, age and body weight of the patient. Although the dosage vary depending on symptoms, age of patients the NTA and the like, in oral introduction adult dosage of olmesartan of medoximil typically ranges from 5 mg to 80 mg per day, preferably from 10 to 40 mg per day. Dosage of amlodipine or a pharmacologically acceptable salt is usually the equivalent of 2.5-20 mg per day, preferably 5-10 mg of amlodipine per day; and the dosage of hydrochlorothiazide or its pharmacologically acceptable salt is generally equivalent to 5-50 mg, preferably 12.5 to 25 mg of hydrochlorothiazide per day. Depending on the symptoms of patients, the dose can enter from one to six times a day, preferably once a day.

Additionally, the dosing ratio olmesartan of medoxomil or amlodipine or its pharmacologically acceptable salts which are active ingredients of solid dosage forms of the present invention, it is also possible to vary in a wide interval. For example, the dosing ratio by weight of olmesartan of medoxomil and amlodipine or a pharmacologically acceptable salt can usually be within the range 1:50-50:1, preferably within the range of 1:5-5:1. Currently, the preferred forms are tablets containing 40/10 mg, 40/5 mg, 20/10 mg, 20/5 mg, 10/10 mg and 10/5 mg olmesartan of medoxomil and amlodipine or a pharmacologically acceptable salt, respectively, equivalent to a specified number amlodi the ina. For a triple combination, optionally containing hydrochlorothiazide or its pharmacologically acceptable salt, dosing weight ratio of olmesartan of medoxomil, amlodipine or its pharmacologically acceptable salt, or hydrochlorothiazide or its pharmacologically acceptable salt can usually be within the range 1:50:1-50-50:1:1-50, preferably, within the range of 1:5:1-5 and 5:1:1-5. Currently, the preferred forms are tablets containing 40/10/12 .5 mg, 40/5/12,5 mg, 40/10/25 mg, 40/5/25 mg, 20/10/12,5 mg and 20/5/12 .5 mg of olmesartan of medoxomil, amlodipine or its pharmacologically acceptable salt, equivalent to a specified number of amlodipine, and hydrochlorothiazide or its pharmacologically acceptable salt, equivalent to a specified number of hydrochlorothiazide, respectively.

The total mass of solid dosage forms containing olmesartan medoxomil and amlodipine or a pharmacologically acceptable salt as the sole active agents containing 40 mg of olmesartan of medoxomil, reaches the value of 100 mg to 300 mg, preferably about 200 mg of the Total mass of solid dosage forms containing olmesartan medoxomil and amlodipine or a pharmacologically acceptable salt as the sole active agent, which contains 20 mg of olmesartan of medoxomil, reaches the value of 50 mg to 150 mg, preferably, approximately 100 mg of Total weight of the triple combination of solid dosage forms containing olmesartan medoxomil, amlodipine or its pharmacologically acceptable salt and hydrochlorothiazide or its pharmacologically acceptable salt, which contains 40 mg of olmesartan of medoxomil, reaches the value of 100 mg to 400 mg, preferably about 300 mg

Solid dosage form of the present invention is effective for prevention or treatment, for example, hypertension or diseases caused by hypertension [more precisely, hypertension, heart disease (angina, myocardial infarction, arrhythmia, heart failure or hypertrophy of the heart), renal diseases (diabetic nephropathy, glomerular nephritis or nephrosclerosis) or cerebrovascular disease (ischemic stroke or intracerebral hemorrhage)] and the like.

Examples

The present invention will be described in more detail using the following examples, which is not a limitation of the scope of the present invention.

Example 1

The COMPOSITION of TABLETS:

Olmesartan medoxomil40,00 mg
Amlodipine besylate13,89 mg
Pre gelatinising starch70,00 mg
Selectiona microcrystalline cellulose65,31 mg
Nitrocresols10,00 mg
Magnesium stearate0,80 mg
Opadry® II8,00 mg
The total mass208,00 mg

Tablets were received in accordance with the composition described above, using the following steps.

The powder mixture was obtained in a drum mixer, mixing the active ingredients (crushed olmesartan medoxomil and amlodipine besylate) with pre-gelatinising starch, silication microcrystalline cellulose and nitrocresols.

The powder mixture was then screened using a mill with a screening of the crushed material and a sieve with mesh size of 1.9 mm Sieved powder mixture was stirred again in a drum mixer.

Magnesium stearate was added to the powder mixture and mixed in a drum mixer to obtain the final mixture. The final mixture was compressed in a slightly convex tablets using a rotary press; RA the measures and shape consistent with the content of the drug substance in a tablet.

Slurry for coating was obtained, dispersive Opadry® II in purified water. The core tablets were subjected to procedure a film coating using standard equipment for coating.

Example 2

The COMPOSITION of TABLETS:

Olmesartan medoxomil40,00 mg
Amlodipine besylate13,89 mg
Hydrochlorothiazide12,50 mg
Pre gelatinising starch105,00 mg
Selectiona microcrystalline cellulose112,41 mg
Nitrocresols15,00 mg
Magnesium stearate1,20 mg
Opadry® II10,00 mg
The total mass310,00 mg

Tablets were prepared in accordance with the composition described above, by applying the following stage.

The powder mixture was obtained in a drum mixer, mixing the active ingredients (crushed olmesartan medoxomil and amlodi the ina besylate and hydrochlorothiazide) with pre-gelatinising starch, selectonemenu microcrystalline cellulose and nitrocresols.

The powder mixture was then screened using a mill with a screening of the crushed material and a sieve with mesh size of 1.9 mm Sieved powder mixture was stirred again in a drum mixer.

Magnesium stearate was added to the powder mixture and stirred drum mixer to obtain the final mixture. The final mixture was compressed in a slightly convex tablets using a rotary press; the size and shape consistent with the content of the drug substance in a tablet.

Slurry for coating was obtained, dispersive Opadry® II in purified water. The core tablets were subjected to procedure a film coating using standard equipment for coating.

Comparative example 1 (preparation based Olmetec®)

The COMPOSITION of TABLETS:

Olmesartan medoxomil40,00 mg
Amlodipine besylate13,89 mg
Hydroxypropylcellulose with a low degree of substitution80,00 mg
Microcrystalline cellulose40,00 mg
Mo is agitat lactose 232,51 mg
Hydroxypropylcellulose10,00 mg
Magnesium stearateof 3.60 mg
Opadry® OY S 3895612,00 mg
The total mass432,00 mg

Tablets were received in accordance with the composition described above, using the following stage.

The powder mixture was obtained in the granulator wet machining with high cutting force, mixing the active ingredients (crushed olmesartan medoxomil, amlodipine besylate) with nitrosamines hydroxypropylcellulose, microcrystalline cellulose, lactose monohydrate and hydroxypropylcellulose, and then kneaded with purified water.

The wet granules were sieved using a mill with a screening of the crushed material and a sieve with mesh size of 9.5 mm, and then dried in the dryer fluidized bed.

The dried granules were sieved using a mill with a screening of the crushed material and a sieve with mesh size of 1.9 mm

Magnesium stearate was added to the sifted granules and mixed in a drum mixer to obtain the final mixture.

The final mixture was compressed in a slightly convex tablets, ispolzuemyi press; the size and shape of tablets consistent with the content of the drug substance in a tablet.

Slurry for coating was obtained, dispersive Opadry® OY S 38956 (white) in purified water. The core tablets were subjected to procedure a film coating using standard equipment for coating.

Example test 1

The TEST FOR STORAGE STABILITY

Tablets of example 1 were placed for testing vials of high-density polyethylene (HDPE) with desiccant, and the vial was tightly closed with a screw from high density polyethylene (HDPE). Tablets in bottles kept for 3 months at 40°C and at a relative humidity of 75% (R.H.) (accelerated testing).

Impurities resulting from the degradation of olmesartan of medoxomil and amlodipine in tablets was determined using HPLC (Agilent 1100, Agilent Technologies Co., Ltd.). The results were as follows:

Table 1
Olmetec® + By®Example 1Comparative example 1
RNH-62700,570,380,46
Impurity D 0,310,040,04
Total impurities-0,871,55

As can be seen from table 1 and figure 1, the product of example 1, the preparation of the present invention, shows the best stability, in comparison with drugs olmesartan of medoxomil and amlodipine commercially available as Olmetec® By®, respectively.

Based on the results presented in table 1 and figure 1, you can see the relationship between the formation of impurities and the presence or absence of the drug reducing sugars. In comparative example 1, in which the drug contains lactose, three months later find a relatively high level of total impurities. In contrast, the product of example 1, essentially free of reducing sugars in the product, and as a result, in comparison with comparative example 1 had a significantly lower level of total impurities.

Thus, the data in table 1 and figure 1 indicate that the stability of the dosage forms containing olmesartan medoxomil and amlodipine, can be improved, depending on the presence or absence of the drug reducing sugars.

An example is sterowania 2

TEST the SOLUBILITY

To test the tablets of example 1, the solubility of the used tester solubility EP/USP, equipped spectrophotometer with diode array suitable for multicomponent analysis (MCA).

Key parameters are the following:

Medium: phosphate buffer solution with a pH of 6.8 +/- 0,5 (Jap. Pharm)

Volume: 900 +/- 9 ml

Temperature: 37,0 +/- 0.5°C

The type of the cell: unit 2 United States Pharmacopeia (USP)

Stirrer: 50 rpm +/- 2 rpm

The amount of dissolved olmesartan of medoxomil and amlodipine is the besylate determined by multicomponent analysis (MCA) of filtered portions of the test solution and compared with the corresponding reference solutions.

Table 2
Example 1 solubility(%)Comparative example 1 solubility (%)
Olmesartan medoxomil84,074,0
Amlodipine besylate91,789,4

As can be seen from table 2 and figure 2, the product of example 1 showed the best characteristics of solubility and olmesartan Medo is Camila, and of amlodipine besylate, when comparing with the preparation of comparative example 1.

Example test 3

The TEST FOR STORAGE STABILITY

Test tablets of example 2 were placed in vials of high-density polyethylene (HDPE) with desiccant, and the vial was tightly closed with a screw from high density polyethylene (HDPE). Tablets in bottles kept for 3 months at 40°C and at a relative humidity of 75% (R.H.) (accelerated testing).

The admixture obtained in tablets, as a result of degradation of olmesartan of medoxomil, amlodipine and hydrochlorothiazide, was determined at the end of tremellaceae period using HPLC (Agilent 1100, Agilent Technologies Co., Ltd.). The results were as follows:

Table 3
Olmetec® + By®Example 1Example 2
RNH-62700,570,380,34
Impurity D0,310,04<0,04
Total impurities0,57

As can be seen from table 3, the product of example 2, which is a triple drug combination of the present invention, shows the best stability when compared with drugs olmesartan of medoxomil and amlodipine, commercially available as Olmetec® By®, respectively. Even after the accelerated test within 3 months of RNH-6270 and impurity D have significantly lower levels. The drug, which is the triple combination of the present invention, have found excellent stability. Indeed, as can be seen from the above comparison, the stability was even slightly higher than that of the product, which is the dual combination of the present invention tested in example test 1.

Example test 4

TEST the SOLUBILITY

To test the tablets of example 2 on the solubility of the used tester solubility EP/USP, equipped spectrophotometer with diode array suitable for multicomponent analysis (MCA).

Key parameters are:

Medium: phosphate buffer solution with a pH of 6.8 +/- 0,5 (Jap. Pharm)

Volume: 900 +/- 9 ml

Temperature: 37,0 +/- 0.5°C

The type of the cell: unit 2 United States Pharmacopeia (USP)

Stirrer: 50 rpm +/- 2 rpm

The amount of dissolved olmesartan of medoxomil, amlodipine drive is ATA and hydrochlorothiazide was determined by multicomponent analysis (MCA) of filtered portions of the test solution and compared with the corresponding reference solutions. For comparison included the results of the sample test 2.

Table 4
The reference standardsExample 1Example 2
Olmesartan medoxomil74,084,082,0
Amlodipine besylate89,491,790,0
Hydrochlorothiazide99,0

As can be seen from table 4, the product of example 2 demonstrates excellent solubility for olmesartan of medoxomil, amlodipine is the besylate and hydrochlorothiazide.

Based on the above experiments, we can easily establish that both the quality and stability of the tablets of examples 1 and 2 obtained by the present invention, are entirely satisfactory.

Industrial applicability

The present invention gives a stable solid dosage form containing olmesartan medoxomil and amlodipine or FA is mikologicheskie acceptable salt, optional contains hydrochlorothiazide.

1. Solid dosage form for the treatment or prophylaxis of hypertension or diseases caused by hypertension, containing olmesartan medoxomil and amlodipine or a pharmacologically acceptable salt, where this solid dosage form, essentially free of reducing sugars.

2. Solid dosage form according to claim 1, having less than 2.5% (wt./mass.) the concentration of 4-(1-hydroxy-1-methylethyl)-2-propyl-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]-1H-imidazole-5-carboxylic acid (RNH-6270).

3. Solid dosage form according to claim 1, having a concentration of 3-ethyl-5-methyl-2-[(2-aminoethoxy)methyl]-4-(2-chlorophenyl)-6-methylpyridine-3,5-in primary forms (impurity D) less than 0.4% (wt./mass.).

4. Solid dosage form according to claim 1, having a concentration of total impurities less of 5.1% (wt./mass.).

5. Solid dosage form according to claim 1, having a concentration of RNH-6270 less than 2.5% (wt./mass.), and the concentration of total impurities less of 5.1% (wt./mass.).

6. Solid dosage form according to claim 2, which additionally contains hydrochlorothiazide, or its pharmacologically acceptable salt.

7. Solid dosage form according to claim 3, which additionally contains hydrochlorothiazide, or its pharmacologically acceptable salt.

8. Solid dosage form according to claim 6, having a concentration is a function of total impurities less than 7.3 percent (wt./mass.).

9. Solid dosage form according to claim 7, having a concentration of total impurities less than 7.3 percent (wt./mass.).

10. Solid dosage form according to any one of claims 1 to 9, where this solid dosage form contains less than 2.0% (wt./mass.) reducing sugars.

11. Solid dosage form according to any one of claims 1 to 9, where this solid dosage form contains less than 0.3% (wt./mass.) reducing sugars.

12. Solid dosage form according to any one of claims 1 to 9, where this solid dosage form contains less than 0.05% (wt./mass.) reducing sugars.

13. Solid dosage form according to any one of claims 1 to 9, having a concentration of RNH-6270 less than 0.5% (wt./mass.).

14. Solid dosage form according to any one of claims 1 to 9, having a concentration of RNH-6270 less than 0.4% (wt./mass.).

15. Solid dosage form according to any one of claims 1 to 9, having a concentration of impurity D less than 0.3% (wt./mass.).

16. Solid dosage form according to any one of claims 1 to 9, having a concentration of impurity D less than 0.05% (wt./mass.).

17. Solid dosage form according to any one of claims 1 to 9, having a concentration of total impurities less than 1.5% (wt./mass.).

18. Solid dosage form according to any one of claims 1 to 9, having a concentration of RNH-6270 less than 0.5% (wt./mass.) and the concentration of total impurities less than 1.5% (wt./mass.).

19. Solid dosage f the PMA according to any one of claims 1 to 9, with the concentration of RNH-6270 less than 0.4% (wt./mass.) and the concentration of total impurities less than 1.5% (wt./mass.).

20. Solid dosage form according to any one of claims 1 to 9, where the concentration of the specified impurity or impurities was measured after accelerated testing specified solid dosage forms for three months at 40°C and relative humidity of 75%.

21. Solid dosage form according to any one of claims 1 to 9, where amlodipine is present in the form of free salt.

22. Solid dosage form according to any one of claims 1 to 9, which further comprises one or more pharmaceutically acceptable additives.

23. Solid dosage form according to item 22, where one or more pharmaceutically acceptable additives selected from fillers, lubricants, binders, dezintegriruetsja agents, emulsifiers, stabilizers, corrective agents and diluents.

24. Solid dosage form according to item 23, where the filler is selectonemenu microcrystalline cellulose and/or mannitol.

25. Solid dosage form according to item 23, where the lubricating substance is magnesium stearate.

26. Solid dosage form according to item 23, where disintegrity agent is a pre-gelatinising starch and/or nitrocresols.

27. Solid dosage form according to any and what claims 1 to 9, where the solid dosage form comprises a tablet.

28. Solid dosage form according to item 27, where the tablet will receive by direct compression.

29. Solid dosage form according to item 27, where the tablet cover, at least one elastic layer.

30. Solid dosage form according p, where the tablet cover, at least one elastic layer.

31. Solid dosage form according to clause 29, where the elastic layer contains at least one hydrophilic polymer.

32. Solid dosage form according to item 30, where the elastic layer contains at least one hydrophilic polymer.

33. Solid dosage form according p, where the hydrophilic polymer is a polyvinyl alcohol and/or macrogol.

34. Solid dosage form according p, where the hydrophilic polymer is a polyvinyl alcohol and/or macrogol.

35. Solid dosage form according to any one of claims 1 to 9, which contains 20-40 mg olmesartan of medoxomil.

36. Solid dosage form according to any one of claims 1 to 9, containing 5-10 mg of amlodipine or a pharmacologically acceptable salt of amlodipine equivalent to 5-10 mg of amlodipine.

37. Solid dosage form according to any one of claims 1 to 9, containing 5-10 mg of amlodipine or a pharmacologically acceptable salt of amlodipine equivalent to 5-10 mg of amlodipine and 20-40 mg olmesartan of medoxomil.

3. Solid dosage form according to any one of claims 1 to 9, which contains 12.5 to 25 mg of hydrochlorothiazide or pharmacologically acceptable salt of hydrochlorothiazide, equivalent to 12.5-25 mg of hydrochlorothiazide.

39. Solid dosage form according to any one of claims 1 to 9, containing 5-10 mg of amlodipine or a pharmacologically acceptable salt of amlodipine equivalent to 5-10 mg of amlodipine, 20-40 mg olmesartan of medoxomil and 12.5-25 mg of hydrochlorothiazide or pharmacologically acceptable salt of hydrochlorothiazide, equivalent to 12.5-25 mg of hydrochlorothiazide.

40. A method of treating or preventing hypertension in a warm-blooded animal in need of treatment, including the introduction of a specified animal an effective amount of a solid dosage form according to any one of claims 1 to 39.

41. The use of a solid dosage form according to any one of claims 1 to 39, for the manufacture of a medicinal product for the treatment or prevention of hypertension.

42. Solid dosage form according to any one of claims 1 to 39 for use in the treatment or prevention of hypertension.



 

Same patents:

FIELD: medicine.

SUBSTANCE: invention relates to medicine, namely to cardiology and angiology, and deals with correction of functions of vascular walls in patients with arterial hypertension of I-II degree with metabolic syndrome, after thrombosis of eye vessels. For this purpose indices of anti-aggregate, anti-coagulant and fibrinolytic activity of vascular wall are determined. On the basis of said indices calculated is total anti-thrombotic potential of vessels and if its value is 0.069 and lower, complex treatment, including application of individually selected hypocaloric diet, dosed physical load, pioglitazone 30 mg 1 time per day and valsartan 160 mg 1 time per day in the morning during 4 months, is administered.

EFFECT: complex of drug and non-drug therapy in combination with empirically selected duration of treatment ensures correction of functions of vascular wall and, thus, reduction, of risk of thrombotic complications in said group of patients due to potentiation of therapeutic effect of separate components of therapeutic complex.

1 ex, 1 dwg

FIELD: medicine.

SUBSTANCE: invention relates to medicine, namely to cardiology and angiology, and deals with correction of functions of vascular walls in patients with arterial hypertension of III degree with metabolic syndrome, after thrombosis of eye vessels. For this purpose indices of anti-aggregate, anti-coagulant and fibrinolytic activity of vascular wall are determined. On the basis of said indices calculated is total anti-thrombotic potential of vessels and if its value is 0.069 and lower, complex treatment, including application of individually selected hypocaloric diet, dosed physical load, pioglitazone 30 mg 1 time per day and valsartan 80 mg 1 time per day in the morning and amlodipine 10 mg 1 time per day during 4 months, is administered.

EFFECT: complex of drug and non-drug therapy in combination with empirically selected duration of treatment ensures correction of functions of vascular wall and, thus, reduction, of risk of thrombotic complications in said group of patients due to potentiation of therapeutic effect of separate components of therapeutic complex.

1 ex, 1 dwg

FIELD: medicine.

SUBSTANCE: invention relates to medicine, namely to cardiology and angiology, and deals with normalisation of functional activity of vessel wall in patients with arterial hypertension of I-II degree with metabolic syndrome, after thrombosis of eye vessels. For this purpose, indices of anti-aggregation, anti-coagulation and fibrinolytic activity of vascular wall are determined. On the basis of said indices general anti-thrombotic potential of vessels is calculated and if its value is 0.069 and lower, administered is complex treatment, including application of individually selected hupocaloric diet, dosed physical load, introduction of pioglitazone in dose 30 mg 1 time per day and lisinopril in dose 20 mg 1 time per day for 4 months.

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2 ex, 1 dwg

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely to cardiology and endocrinology, and concerns treating the patients with chronic cardiac failure compromised by type 2 diabetes. That is ensured by the additional introduction of the selective β1 adrenoceptor antagonist nebivolol in a single dose 5-7.5 mg/day within 12 months with underlying ACE inhibitor and diuretic therapy in the patients with a higher level of basal glycemia by more than 4.5 mmol/l and preserved LVEF by more than 52 %.

EFFECT: method provides effective treatment in the given group of patients due to ability of nebivolol to improve nitrogen oxide synthesis by a vascular endothelium and to provide normalising haemodynamic, metabolic, anti-ischemic and immune-correcting action.

1 ex, 3 tbl

FIELD: chemistry.

SUBSTANCE: present invention relates to novel 3,4-substituted pyrrolidine derivatives of general formula or pharmaceutically acceptable salts thereof, where R1 is an acyl selected from values given paragraph 1 of the formula of invention; R2 is unsubstituted C1-C4-alkyl or C3-C7-cycloalkyl; R3 is a fragment selected from a group of fragments of formulae: (a), (b),

(c) and (f), where any of the fragments of formulae given above (a), (b) and (f), the star (*) indicates a bond of the corresponding fragment R3 with the molecule residue in formula I; Ra denotes N-C1-C4-alkylaminocarbonyl, N-phenylaminocarbonyl, N-(phenyl-C1-C4-alkyl)aminocarbonyl, N-(C1-C4-alkyl)-N-(phenyl-C1-C4-alkyl)aminocarbonyl, N-(C3-C7-cycloalkyl- C1-C4-alkyl)-N-(phenyl-C1-C4-alkyl)aminocarbonyl, N-(C1-C4-alkyl)-N-(C3-C7-cycloalkyl-C1-C4-alkyl)aminocarbonyl, N,N-di-(C1-C4-alkyl)aminocarbonyl, N-(C3-C7-cycloalkyl)-N-(phenyl-C1-C4-alkyl)aminocarbonyl, N-(C3-C7-cycloalkyl)-N-(tetrahydropyranyl-C1-C4-alkyl)aminocarbonyl, N-(C3-C7-cycloalkyl)-N-(tetrahydropyranyl)aminocarbonyl or hydrogen; Rb and Rc are independently selected from a group comprising unsubstituted C1-C4-alkyl, unsubstituted monocyclic aryl, unsubstituted monocyclic heterocyclyl, unsubstituted or substituted monocyclic C3-C7-cycloalkyl, unsubstituted aryl- C1-C4-alkyl, usubstituted monocyclic C3-C7-cycloalkyl- C1-C4-alkyl, hydrogen or acyl, where the acyl is selected from values given in paragraph 1 of the formula of invention; or Rb and Rc together may form a 6-member nitrogen-containing ring which may be unsubstituted or disubstituted with =O; Rd in the fragment of formula (c) denotes a phenyl or phenyl-C1-C4-alkyl; Re denotes hydrogen or C1-C4-alkyl; and m equals 2; each of R4 and R5 denotes hydrogen; and T denotes methylene. The invention also relates to the pharmaceutical composition based on the compound of formula I and a method of treating hypertension using the compound of formula I.

EFFECT: novel pyrrolidine derivatives having renin inhibiting activity are obtained.

7 cl, 19 tbl, 37 ex

FIELD: medicine.

SUBSTANCE: invention relates to field of medicine, namely, to therapy and cardiology, and deals with treatment of arterial hypertension. For this purpose into complex of conventional therapy additionally introduced is prostaglandin E2 in form of 0.0008% solution. Prostaglandin is introduced intravenously, starting with rate 50-100 ng/kg/min, increasing rate of introduction each 10 minutes on 20-40 ng/kg/min, bringing rate to 150-300 ng/kg/min during 40-60, minutes. Altogether there are three introductions per a course with 1-2 day intervals between them.

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6 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (I): where: A is a monocyclic or polycyclic aryl or heteroaryl group, where the heteroaryl radical denotes a 5-10-member cyclic system containing at least one heteroaromatic ring and containing at least one heteroatom selected from O, S and N; optionally substituted with one or more substitutes independently selected from a group comprising halogen atoms, C1-4alkyl, C3-8cycloalkyl, C3-8cycloalkyl-C1-4alkyl, C1-4alkoxy and a hydroxyl group; B is a monocyclic nitrogen-containing heteroaryl group, where the heteroaryl radical denotes a 5-6-member heteroaromatic ring containing at least one heteroatom selected from S and N; optionally substituted with one or more substitutes selected from a group consisting of halogen atoms, C1-4alkyl, C3-8cycloalkyl, C3-8cycloalkyl-C1-4alkyl, aryl and C1-8alkylthio; either a) R1 is a group of formula: -L-(CR'R")n-G, where L is a binding group selected from a group consisting of a direct bond, -(CO)-, -(CO)NR'- and -SO2-; R' and R" is independently selected from hydrogen atoms; n assumes values from 0 to 1; and G is selected from a group consisting of a hydrogen atom and C1-4alkyl, aryl, heteroaryl, where the heteroaryl radical denotes a 5-6-member heteroaromatic ring containing at least one heteroatom selected from O, S and N; C3-8cycloalkyl and saturated heterocyclic groups, where heterocyclic group denotes a non-aromatic saturated 6-member carbocyclic ring in which one or two carbon atoms are substituted with a N heteroatom; where alkyl, C3-8cycloalkyl, aryl or heteroaryl groups are unsubstituted or substituted with one or more substitutes selected from halogen atoms; and R2 is a group selected from hydrogen atoms, halogen atoms and C1-4alkyl, C2-5alkynyl, C1-4alkoxy, -NH2 and cyano groups, where alkyl and alkynyl groups may be unsubstituted or substituted with one aryl group; or b) R2, R1 and -NH- group to which R1 is bonded form a group selected from groups of formulae and , where: Ra is selected from a hydrogen atom or groups selected from C1-4alkyl, C3-8cycloalkyl, aryl, aryl-C1-4alkyl, heteroaryl, where the heteroaryl radical denotes a 5-6-member heteroaromatic ring containing at least one heteroatom selected from O and N; saturated heterocyclic rings, where the heterocyclic group denotes a non-aromatic saturated 6-member carbocyclic ring in which one carbon atom is substituted with a heteroatom selected from O and N; and C1-4alkylthio; where the aryl or heteroaryl groups are unsubstituted or substituted with one or more groups selected from halogen atoms, cyano group, trifluoromethoxy and carbamoyl; Rb denotes hydrogen; and pharmaceutically acceptable salts thereof and N-oxides; provided that the compound is not selected from N-[6-(1-methyl-1H-indol-3-yl)-5-pyridin-2-ylpyrazin-2-yl]benzamide, N-[3-ethoxycarbonyl-6-(1-methyl-1H-indol-3-yl)-5-pyridin-2-ylpyrazin-2-yl]benzamide, and N-[3-ethoxycarbonyl-6-(1-methyl-1H-indol-3-yl)-5-pyridin-2-ylpyrazin-2-yl]formamide. The invention also relates to a pharmaceutical composition, use of compounds in any of claims 1-20, a method of treating a subject, as well as a composite product.

EFFECT: obtaining novel biologically active compounds having adenosine A2B receptor antagonist activity.

27 cl, 160 ex, 2 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula (I) or pharmaceutically acceptable salts thereof where R1 and R2 together denote a group selected form groups of formula (III-1): , where R9 denotes 1) a lower alkyl group, optionally substituted with a halogen atom or lower alkoxy group, 2) an aryl group, 3) an aralkyl group, 4) a heteroarylalkyl group, 5) a heteroaryl group, where the aryl, aralkyl, heteroarylalkyl and heteroaryl groups can be substituted with a halogen atom, lower alkyl group, optionally substituted with a lower alkoxy group or 1-3 halogen atoms, lower alkoxy group, optionally substituted with 1-3 halogen atoms, cyano group, hydroxy group, alkylsulphonyl group, cycloalkylsulphonyl group, aryl group, heteroaryl group, alkylaminocarbonyl group, alkanoyl amino group, alkyl amino group or dialkylamino group; R10 denotes a lower alkyl group, optionally substituted with 1-3 halogen atoms, or a lower alkylsulphonyl group; X9-X12 denotes a carbon atom or a nitrogen atom, where the carbon atom can be independently substituted with a lower alkyl group, optionally substituted with a halogen atom or a lower alkoxy group, lower alkoxy group, optionally substituted with a halogen atom, or a cyano group or a halogen atom; R3 denotes a) a group of formula (II-1): (ii-U where R4 and R5, taken together with a nitrogen atom, form a 5- or 6-member monocyclic ring, where the monocyclic ring may contain a substitute in form of a lower alkyl group, m1 equals 3; or b) a group of formula (II-2): , where R6 denotes a lower alkyl group or cycloalkyl group; m2 equals 1 or 2; X1-X4 all denote carbon atoms, or one of X1-X4 denotes a nitrogen atom and the rest denote carbon atoms; and where "heteroaryl" in each case relates to a 5- or 6-member aromatic ring containing 1-3 heteroatoms selected from a nitrogen atom, oxygen atom and a sulphur atom. The invention also relates to a histamine H3 receptor antagonist or inverse agonist, as well as a preventive or medicinal agent.

EFFECT: obtaining novel biologically active compounds, having histamine H3 receptor antagonist or inverse agonist activity.

11 cl, 8 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: compounds are suitable for use as kinase 1β-adrenergic receptor (βARK-1) inhibitors. The invention also relates to compositions containing such compounds and to use of compounds of formula to treat and prevent chronic heart failure, hypertension myocardial ischemia and hepatitis C viral infections (HCV) and for preventing opiate addiction. The invention also pertains to methods of producing formula (I) compounds.

EFFECT: more effective use of the compounds.

11 cl, 2 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: there are described 3,4-substituted piperidines applicable in diagnostics and drug therapy of a warm-blooded animal, preferentially for therapy of a disease which depends on renin activity; application of a compound of such kind for preparing a pharmaceutical composition for therapy of the disease which depends on renin activity; application of the compound of such kind for therapy of the disease which depends on renin activity; the pharmaceutical compositions containing 3,4-substituted piperidine, and/or a therapeutic mode involving administration of 3,4-substituted piperidine, a method for producing 3,4-substituted piperidine. The preferential compound (which also can be presented in the form of salts) are described by formula I' wherein R1, R2, T, R3 and R4 are such as described by the patent claim.

EFFECT: production of the compounds for therapy of the disease which depends on renin activity.

28 cl, 1 tbl, 375 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: food industry.

SUBSTANCE: present invention relates to gastral retentive composition containing active agent granulated together with the mixture of the first and the second gelatinating agents and mentioned composition production method the first gelatinating agent is a mixture of microcrystalline cellulose and sodium-carboxymethyl cellulose the second gelatinating agent is a compound with viscosity of 1% water solution which makes at least 600 centipoise at 25°C active agent is chosen from antibacterial compounds such as fluoroquinolones, antidiabetic compounds and antihypertensive medicinal agents.

EFFECT: invention provides gastral retentive composition with sustained release effect, which stays in stomach; medical agent has maximal absorption with improved therapeutic action there.

24 cl, 2 ex

FIELD: medicine.

SUBSTANCE: invention relates to pharmaceutical dosed form, which contains pharmaceutically active substance, unstable in presence of acid, which includes central nucleus, containing active substance and loosening agent, swelling coating, surrounding central nucleus, and enterosoluble coating, surrounding swelling coating. Swelling coating includes prolamin, preferably, zein. Pharmaceutically active substance includes benzimidazole, selected from omeprazole, lansoprazole, rabeprazole and pantoprazole.

EFFECT: invention ensures fast release of pharmaceutically active substance in medium, which has pH value at least 5.

33 cl, 12 ex

FIELD: medicine.

SUBSTANCE: invention concerns a tablet containing fluvastatin with sodium carboxymethylcellulose of calcium in the form of raising agent. The fluvastatin tablet is characterised by time of disintegration from 10 to 30 minutes and good bioavailability equivalent to bioavailability of serially produced capsules, containing fluvastatin. Manufacturing of tablets does peroral application of fluvastatin economically more favourable and more convenient for patients.

EFFECT: rising of profitability and convenience of peroral fluvastatin application to patients.

12 cl, 7 dwg, 6 tbl, 2 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention concerns pharmaceutical chemistry, namely to the method of obtaining of a medical product with a covering from a Pioglitazone hydrochloride which can be used as a therapeutic agent for treatment of diabetes, lipidemias, and also can be an antihypertensive agent, an antiobesity agent, diuretic or an antithrombotic agent.

EFFECT: medical product covered with a hydrochloride pioglitazon, possesses larger stability of an agent at storage, and also improved properties, such as solubility of a Pioglitazone hydrochloride.

11 cl, 30 ex, 3 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention describes solid dispersed measured drug including a core with pharmacological agent dispersed in the first matrix for controlled liberation at relatively low speed; and coating covering the core and including the agent dispersed in the second matrix for controlled liberation at relatively high speed. The first matrix can be represented by cross-linked starch with high amylose content, and the second matrix can be represented by polyvinylacetate and polyvinylpyrrolidone mix. Solid measured drug is preferably a pill.

EFFECT: reduced administration frequency, relatively stable medicine concentration in organism for a given time period and reduced undesired side effect frequency and intensity due to reduction of high concentrations in plasma.

19 cl, 5 dwg, 4 tbl, 4 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

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