Oral solid dosage form and method of treating

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to an oral solid dosage form containing a therapeutically effective amount of aliskiren or its pharmaceutically acceptable salt wherein an active ingredient makes more than 46 wt % of total weight of the oral dosage form. The oral dosage form is presented in the form of a tablet or a film-coated tablet, and contains an internal phase containting aliskiren or its pharmaceutically acceptable salt, an excipient, a binding agent and a disintegrant, and an external phase containing a disintegrant, an excipient, a glidant and a lubricant.

EFFECT: invention provides administration of the active ingredient aliskiren in the small oral dosage form; it is characterised by an acceptable disintegration time.

32 cl, 2 ex

 

The present invention relates to solid oral dosage forms comprising a renin inhibitor oral action aliskiren or its pharmaceutically acceptable salt as an active ingredient in an environment suitable media. In particular, the present invention provides glenavy compositions comprising aliskiren, preferably Poluboyarov salt, alone or in combination with another active agent. The present invention also relates to methods for their preparation and use as pharmaceuticals.

Used below, the term "aliskiren", if not specifically indicated, includes free base and a salt, especially a pharmaceutically acceptable salt of aliskiren, most preferably profumata.

Renin, secreted by the kidneys, split angiotensinogen in the bloodstream with the formation of Decapeptide angiotensin I. Angiotensin I in turn cleaved angiotenzinkonvertiruyuschego enzyme in the lungs, kidneys and other organs with the formation of oktapeptid of angiotensin II. Oktapeptid increases blood pressure and directly by narrowing of the arteries, and indirectly through the adrenal glands release the hormone aldosterone that hold sodium ions, and high blood pressure accompanied by an increase in the volume of extracellular fluid. Inga is itory the enzymatic activity of renin cause a decrease in the formation of angiotensin I. It results in fewer angiotensin II. Decreased concentration of this active peptide hormone is the direct cause, for example, the antihypertensive effect of inhibitors of renin. Therefore, inhibitors of renin or their salts can be used, for example, as antihypertensive agents or for the treatment of congestive heart failure.

It is known that the inhibitor of the renin aliskiren, especially his profumata, effective for the treatment of low blood pressure, regardless of age, gender or race of the patient, and well tolerated. Aliskiren in the form of a free base represented by the formula

and has the chemical name 2(S),4(S)5(S),7(S)-N-(3-amino-2,2-dimethyl-3-oxopropyl)-2,7-di(1-methylethyl)-4-hydroxy-5-amino-8-[4-methoxy-3-(3-methoxypropane)phenyl]octanamide. It was noted above that the most preferred form is a salt profumata of aliskiren, which is specifically described in EP 678503 AS in example 83.

Oral administration of such pharmaceutical agents in the form of tablets or capsules has certain advantages over, for example, intravenous or intramuscular. Diseases requiring treatment painful injectable compositions are regarded as more serious illnesses than those comprising the Oia, which can be treated with oral dosage forms. However, the big advantage of oral formulations is that they can be self-introduction patients, in contrast to parenteral formulations, which in most cases should be entered by the physician or a representative of mid-level medical personnel.

However, aliskiren difficult to process, and therefore were not able to receive oral compositions in the form of tablets reliable and clear way. In Galanova composition comprising aliskiren or its pharmaceutically acceptable salt, typically require a large number of medicinal substances (LV) with such properties that make it difficult for the preparation of tablets.

For example, aliskiren forms needle-like crystals, which have a negative effect on the bulk properties of medicinal substances, such as flow properties and bulk density. The medicinal substance is hard pressed, under pressure from weak links are formed between the particles and polymorphic changes. Aliskiren has a pronounced elasticity, and this property also leads to a weakening of ties inside of the particles. High dose (300 or 600 mg free base per tablet) requires a large load of medicinal substance in order to achieve an acceptable size tablets.

Quality lekarstvennogo variabelno, what influences the technological characteristics of the tablets, such as the distribution of particle size, bulk density, fluidity, ability to hydration, surface area, and a tendency to sintering. In addition, aliskiren highly hygroscopic. Upon contact with water polymorphic drug enters the amorphous phase, which shows a lower stability compared to the crystalline state. The combination of these problems is extremely difficult way to obtain standard tablets.

Direct pressing is impossible in the ordinary course of production, for example, due to the high hygroscopicity, the needle structure of particles, poor fluidity with relevant technological problems and problems of standardization of doses. The process balavage pressing reduces a large amount of medicinal substance. Still preliminary pressing of medicinal substance when welceom pressing makes further pressed into pellets with considerable rigidity and resistance to breakage without the high content of excipients, very difficult process due to the low compressibility of the medicinal substance. It was found that the tablet, in which the load medicinal compounds of aliskiren above about 35%, results in poor quality tablets (EmOC is emer, brittle, hard) and poor process (for example, pasting and manual sorting at welceom pressing and pelletizing).

Thus, it is necessary to develop appropriate and quality glenavy formulations to overcome the above problems associated with the properties of aliskiren.

The present invention solves the above problems by offering a quality composition that is free from all of the above deficiencies in the process suitable for large-scale production of solid oral dosage forms.

The present invention relates to a solid oral dosage form containing a therapeutically effective amount of aliskiren or its pharmaceutically acceptable salts, in which the active ingredient is present in more than 46 wt.% of the total weight of the oral dosage forms, dependent or not dependent on any covering or capsule material.

If there is no dependence on any of the coatings or capsule, the active ingredient is present in more than 48 wt.% of the total weight of the oral dosage form. If based on any of the coatings or capsule, the active ingredient is present in more than 46 wt.% of the total weight of the oral dosage form.

In preferably the m embodiment of the present invention the active agent is present in the amount of 46-60 wt.% of the total weight of the oral dosage form.

In another preferred embodiment of the present invention the active agent is present in more than 46% to 56 wt.% of the total weight of the oral dosage form.

In a solid oral dosage form according to the present invention, in which the active agent consists solely of aliskiren or its pharmaceutically acceptable salt, preferably, if the active agent is present in amounts ranging from about 75 mg to about 600 mg of the free base in one standard dosage form.

In a preferred embodiment of the present invention the active agent consists solely of aliskiren or its pharmaceutically acceptable salt and is present in amounts ranging from about 75 mg to about 300 mg of the free base in one standard dosage form.

In another preferred embodiment of the present invention, the dose of aliskiren applied in the form of profumata and is contained in an amount of about 83, about 166, approximately 332 or about 663 mg per single dosage form.

Solid oral dosage form according to the present invention provides for the introduction of the active ingredient to a lesser oral form than was previously possible for a given one dose AK the active agent. Furthermore, the oral dosage form is stable and when the receiving process and during storage, for example, within 2 years in traditional packaging, for example in sealed aluminium blister pack.

The concept of "effective amount" and "therapeutically effective amount" refers to the amount of active ingredient or agent that reduces the progression under treatment condition or which wholly or partially cure or palliative effect in this state.

Aliskiren or its pharmaceutically acceptable salt, for example, are prepared in known manner, primarily described in EP 678503 AS, for example, in example 83.

Solid oral dosage form is a capsule, or more preferably a tablet or tablet with a film coating (film-tablet).

Solid oral dosage form according to the present invention includes additives or excipients which are suitable for the preparation of solid oral dosage forms according to the present invention. Can be used AIDS for tabletting, commonly used in tablets, and it is known that on this issue there are many literary sources, for example Fiedler''s "Lexicon der Hilfstoffe", 1996, 4th ed., ECV Aulendorf, included in this is e to the invention in the form of links. These include, but are not limited to, fillers, binders, dezintegriruetsja agents, sizing, glidant, stabilizers, fillers or diluents, surfactants, film forming agents, softeners, pigments, etc.

In a preferred embodiment of the present invention is a solid oral dosage form according to the present invention includes as an additional agent filler.

In a preferred embodiment of the present invention is a solid oral dosage form according to the present invention includes as an additional agent in addition to the filler, disintegrity agent.

In a preferred embodiment of the present invention is a solid oral dosage form according to the present invention includes as an additional agent in addition to the filler and dezintegriruetsja agent, a sizing.

In a preferred embodiment of the present invention is a solid oral dosage form according to the present invention includes as an additional agent in addition to the filler, dezintegriruetsja agent and sizing, glidant.

In a preferred embodiment of the present invention the solid oral l the drug form according to the present invention includes as an additional agent, in addition to the filler, dezintegriruetsja agent, sizing and glidant linking agent.

Under the fillers mainly refers to starches such as potato starch, wheat starch, corn starch, hydroxypropylcellulose, hydroxyethylcellulose, hypromellose (HPMC) and preferably microcrystalline cellulose, for example commercial products registered under the trade marks AVICEL, FILTRAK, HEWETEN or PHARMACEL.

Under binding agents for wet granulation mainly refers to polyvinylpyrrolidone (PVP), for example, the product PVP K 30, HPMC, for example viscosity grades 3 or 6 SP, and polyethylene glycol (PEG)such as PEG 4000. The most preferred binder is a product of PVP K 30.

Under dezinfeciruyuhimi agents mainly refers to the calcium salt of carboxymethyl cellulose (CMC-CA), sodium salt of carboxymethyl cellulose (CMC-Na), PVP with crosslinking (for example, products CROSPOVIDONE, POLYPLASDONE or KOLLIDON XL), alginic acid, sodium alginate or guar gum, most preferably PVP with crosslinking (product CROSPOVIDONE), CMC with crosslinking (product Ac-Di-Sol), sodium salt of carboxymethyl amylum (products PIRIMOJEL and EXPLOTAB). The preferred baking powder is the product CROSPOVIDONE.

Under the agents with whom algenia mainly refers to colloidal silica, for example colloidal silicon dioxide, for example, the product AEROSIL, magnesium trisilicate, powdered cellulose, starch, talc and phosphate trehosnovnogo calcium or combinations thereof with fillers or binding agents, such as silicified microcrystalline cellulose (PROSOLV). The most preferred glidant is colloidal silicon dioxide (e.g., product AEROSIL 200).

Under fillers or diluents mainly refers to the icing, pressed sugar, dextrine, dextrin, dextrose, lactose, mannitol, microcrystalline cellulose, especially with a density of about 0.45 g/cm3for example, the product AVICEL, powdered cellulose, sorbitol, sucrose and talc. The most preferred filler is microcrystalline cellulose.

Under sizing mainly refers to magnesium stearate, stearate aluminum (Al) or calcium (CA), glycols from PEG PEG 4000 to 8000, talc, gidrirovannoe castor oil, stearic acid and its salts, esters of glycerin, sodium fumarate, gidrirovannoe cottonseed oil, and others. The most preferred lubricating agent is magnesium stearate.

To the auxiliary materials used for film coating include polymers, for example HPMC, PEG, PVP copolymer is of polivinilpirrolidona and vinyl acetate (PVP-VA), polyvinyl alcohol (PVA) and sugar as film-forming agents. The most preferred material for the coating is HPMC, especially HPMC 3 SP (preferably 5 to 6 mg/cm2), and its mixture with additional auxiliary means, for example that known under the registered trademark OPADRY. Additional additives include pigments, matrix, varnishes, most preferred Tio2and iron oxides, agents from gluing, for example talc, and softeners, such as PEG 3350, 4000, 6000, 8000, and others. The most preferred tools are talc and PEG 4000.

The present invention also relates to a solid oral dosage form comprising a therapeutically effective amount of aliskiren or its pharmaceutically acceptable salt as an active agent and a filler as an aid. Other utilities include, but are not limited to, binding agents, dezintegriruetsja agents, sizing, glidant, stabilizers, diluents, surfactants, film forming agents, pigments, softeners, preventing the bonding agents and the like, the Amount of the active ingredient and auxiliary means are preferably the same as opian the e above.

The present invention also relates to a solid oral dosage form comprising a therapeutically effective amount of aliskiren or its pharmaceutically acceptable salt as an active agent, and a filler and disintegrity agent as an auxiliary means. Other utilities include, but are not limited to, binders, sizing, glidant, stabilizers, diluents, surfactants, film forming agents, pigments, softeners, preventing the bonding agents and the like, the Amount of the active ingredient and auxiliary means are preferably the same as described above.

The present invention also relates to a solid oral dosage form comprising a therapeutically effective amount of aliskiren or its pharmaceutically acceptable salt as an active agent, and a filler, disintegrity agent and sizing as an auxiliary means. Other utilities include, but are not limited to, binding agents, glidant, stabilizers, diluents, surfactants, film forming agents, pigments, softeners, preventing the bonding agents and the like, the Amount of the active ingredient and more the positive auxiliary means preferably are the same as explained above.

The present invention also relates to a solid oral dosage form comprising a therapeutically effective amount of aliskiren or its pharmaceutically acceptable salt as an active agent, and a filler, disintegrity agent, sizing and glidant as an auxiliary means. Other utilities include, but are not limited to, binding agents, stabilizers, diluents, surfactants, film forming agents, pigments, softeners, preventing the bonding agents and the like, the Amount of the active ingredient and auxiliary means are preferably the same as described above.

The present invention also relates to a solid oral dosage form comprising a therapeutically effective amount of aliskiren or its pharmaceutically acceptable salt as an active agent, and a filler, disintegrity agent, lubricant, glidant and binding agent as an auxiliary means. Other utilities include, but are not limited to, stabilizers, diluents, surfactants, film forming agents, pigments, softeners, preventing the bonding agents and the like, the number of active and what gradient and additional supporting means preferably are the same as explained above.

One or more of these helpers can be selected and can be applied by a specialist in this field with specific desired properties of the solid oral dosage form using conventional experiments and without excessive strain.

The number of AIDS used each type, such as glidant, a bonding agent, dezintegriruetsja agent, filler or diluent and lubricant or film forming agent may be varied within the ranges commonly used in the art. For example, the number of sizing can vary in the range of 0.2-5 wt.%, for example, magnesium stearate 0.5 to 2 wt.%, for example 0.8 to 1.5 wt.%; the amount of coupling agent can vary in the range of 0-20 wt.%, for example 3-4 wt.%; the number dezintegriruetsja agent can vary in the range of 0-20 wt.%, for example 13,5-16 wt.%; the amount of filler or diluent can vary in the range of 0-80 wt.%, for example 20-32 wt.%; while the number of glidant can vary in the range of 0-5 wt.%, for example of 0.4-0.6 wt.%; and the amount of film coating can vary in the range of 0-20 mg/cm2for example 4-7 mg/cm2.

Distinctive property provided for in this invention is a solid oral dosage forms is that they contain only a relatively small number of AIDS and, accordingly, a high content of active agent. This allows you to get real small unit dosage form. The total amount of additives in this single dose form without coating may comprise about 60 wt.% or less of the total weight of the solid oral dosage form, more preferably about 54 wt.% or less. Preferably the content of additives in the range of about 35-55 wt.%, more preferably, the content of additives varies from about 50 to about 52 wt.%.

The preferred amount of filler, especially microcrystalline cellulose, varies from approximately 20 to 32 wt.% from the weight of the unit dosage form.

The preferred amount of binder agent, especially PVP K 30, varies from about 3 to 4 wt.% from the weight of the unit dosage form.

The preferred number dezintegriruetsja agent, especially of crosspovidone, varies from about 13.5 to 15 wt.% from the weight of the unit dosage form.

The preferred amount of glidant, especially colloidal silicon dioxide ranges from about 0.4 to 0.6 wt.% from the weight of the unit dosage form.

The preferred amount of sizing, especially stearate, varies from about 0.8 to 1.5 wt.% from the weight of the unit dosage form.

The preferred amount is in the film coating, especially HPMC 3 SP, varies from about 4 to 7 mg/cm2unit dosage forms.

The preferred number of aliskiren and AIDS are also shown in the illustrative examples.

The absolute amount of each supporting means and the quantity expressed relative to other AIDS, also depend on the desired properties of a solid oral dosage form and can also be selected by the person skilled in the art using conventional experiments and without excessive strain. For example, the solid oral dosage form can be selected to be accelerated and/or delayed release of the active agent with quantity control release of the active agent or without it.

Thus, if you want accelerated release dezintegriruetsja agent can be used, for example, PVP with crosslinking, for example those products that are registered under the trademarks POLYPLASDONE XL or KOLLIDON CL, in particular having a molecular weight in excess of 1,000,000, more preferably having a particle size of less than 400 μm, or preferably less than 74 microns or including reactive additive (powder mixture), which cause rapid erosion of the tablet in the presence of water, for example so-called effervescent tablets contain Amie acid in solid form, usually citric acid, which acts in the water at the base, containing chemically bound carbon dioxide, such as sodium bicarbonate or sodium carbonate, and releasing carbon dioxide.

If you want to release with a delay, you can use the technology coating for forms, consisting of many particles (e.g., pellets, mini-tablets), wax matrix systems, polymer matrix tablets, or polymer coatings, or other technologies, conventional in the art.

Quantitative control release of the active agent can be achieved by conventional methods known in the art. Such dosage forms are known as oral osmotic systems (e.g., OROS), coated tablets, matrix tablets, tablet coating, extrusion, multilayer tablets, etc.

In a solid oral dose form in which the active agent is only represented by aliskiren, or its pharmaceutically acceptable salt, or a combination of aliskiren with other active pharmaceutical ingredients, the preferred auxiliary means are microcrystalline cellulose, hydroxypropylcellulose, PVP with crosslinking, PVP, PEG, CMC-Na or CMC-Ca, magnesium stearate, CA stearate or stearate Al, svodnyy colloidal silica, talc, titanium dioxide and iron oxide pigments. The number of used assistive devices will depend on the number of used active agent. Stearate, such as magnesium stearate, are preferably used in amounts of 0.8 to 1.5 wt.%, silicon is preferably used in an amount of 0.4-0.6 wt.%.

The number of aliskiren in the form of profumata of the total weight of the unit dosage form without coating is preferably from about 83 to about 663 mg, most preferably the number of profumata of aliskiren is about 83, about 166 or about 332 mg per dosage form.

The amount of coupling agent in the composition of the total mass of the unit dosage form without coating is preferably 2-5 wt.%, most preferably 3-4 wt.% one dosage form.

The number dezintegriruetsja agent in the composition of the total mass of the unit dosage form without coating is preferably 0-20 wt.%, most preferably 13,5-16 wt.% one dosage form.

The number of glidant in the composition of the total mass of the unit dosage form without coating is preferably 0-5 wt.%, most preferably 0.4 to 0.6 wt.% one dosage form,

The amount of lubricant in the composition of the total mass of unit dosage forms without treatment the Oia is preferably 0.2 to 5 wt.%, most preferably 0.8 to 1.5 wt.% for stearate per dosage form.

The preferred amount of film coating, especially HPMC 3 SP, is from about 4 to about 7 mg/cm2one dosage form.

The mass ratio of aliskiren and a bonding agent preferably ranges from about 8:1 to about 25:1, more preferably from about 11:1 to about 15:1. Most preferably, the mass ratio is about 12.5:1.

The mass ratio of aliskiren and dezintegriruetsja agent preferably ranges from about 2:1 to about 4:1, more preferably about 2.5:1 to about 3.7:1. Most preferably, the mass ratio is about 3.1:1.

The mass ratio of aliskiren and glidant preferably ranges from about 75:1 to about 125:1, more preferably from about 80:1 to about 90:1. Most preferably, the mass ratio is approximately 83,3:1.

The mass ratio of aliskiren and sizing preferably ranges from about 25:1 to about 63:1, more preferably from about 30:1 to about 50:1. Most preferably, the mass ratio is approximately 30:1.

Solid oral dosage form according to the present invention can also be in the form of film-coated tablets (film-tablet is) or bean, moreover, in this case, the solid oral dosage form is provided with a coating typically polymeric nature, for example HPMC, PVP and so on, or consisting of sugar, shellac or other film coatings, are well known in the art. Attract the attention of numerous methods of coating known in the art, such as a sputtering method in a fluidized bed, for example, known methods using equipment that can be purchased on the firms Aeromatic, Glatt, Wurster or Hüttlin, using the installation for coating with a perforated cuvette, for example, known methods using devices firms Accela Cota, Glatt, Driam or others, or other methods known in the art. Tools typically used in the manufacture of confectionery, can be used in these ways.

Another embodiment of the present invention is a method of obtaining a solid oral dosage form according to the present invention.

Wet granulation of aliskiren with excipients in the presence of water and/or aqueous binder solution leads to a change of polymorphism of drug substances, which partially transforms into an amorphous state, and causes the deterioration of the chemical stability of the drug product (the P).

However, it was found that the wet granulation of aliskiren in the presence of a mixture of organic solvents or organic binder solutions is the best way of obtaining suitable solid oral dosage forms of aliskiren, especially tablets, having the following advantages:

- the specified wet granulation reduces the amount of aliskiren by granulation;

- impact on the change in the quality of medicinal substances are minimal;

- high load medicines in excess of 46 wt.% from the weight of the unit dosage form, can easily be reached;

- the composition of the tablets makes it possible to ensure sufficient strength, resistance to breakage, time splitting, dissolution rate, etc.;

- the tendency to sintering and slowly removing medicinal substance is reduced to a minimum;

the result is a quality way to obtain PL;

- achieved the scale composition and method of obtaining PL repeatable manner;

- achieved sufficient stability to ensure a reasonable shelf life.

Excipients may be distributed partially in the internal (granulated) phase and partly in the external phase, and this is the case described in the present invention. Microcrystalline, cellulo is a (filler) and crosspovidone (disintegrity agent) are partially internal and partially external phase, PVP K 30 (binder) is only partially in the internal phase, as a binding agent during granulation, and colloidal silicon dioxide (glidant) and magnesium stearate (lubricant) are only part of the external phase.

Excipients internal phase, such as filler, binder and disintegrity agent, and the medicinal substance are mixed and granularit with ethanol solution of a binding agent and additional ethanol. The granulate is dried and sieved. Internal phase containing, for example, disintegrity agent, a filler, a slip agent and a lubricating agent, sift together the dry granulate and mixed. The mixture is pressed into tablets. The core may not necessarily be applied film coating.

Phase granulate is defined as the internal phase and added to the granular excipients are defined as the external phase tableting the mixture.

The present invention also relates to a method for preparation of solid oral dosage forms as described above. Such solid oral dosage forms can be obtained by processing components described above in suitable quantities for the formation of unit dosage forms. Thus, the present invention provides a method obtained the I solid oral dosage forms of the present invention, including:

1) mixing the active ingredient and auxiliary means and granulation of these components in the presence of fluid granulating

2) drying the obtained granules

3) mixing the dried granulate with excipients external phase,

4) pressing the resulting mixture to obtain a solid oral dosage forms in the form of core tablets and

5) optional coating on the resulting core tablets to obtain a tablet with a film coating.

Preferably AIDS in stage (1) is selected from a filler, dezintegriruetsja agent and a binder agent and excipients external phase to phase (3) is selected from a filler, dezintegriruetsja agent, sizing and glidant.

Fluid granulation may be ethanol, a mixture of ethanol and water, a mixture of ethanol, water and isopropanol, or a solution of PVP in the above-described mixtures. The preferred mixture of ethanol and water varies from about 50/50 to about 99/1 ratio (wt.%), most preferably, the ratio of components in the mixture is about 94/6 ratio (wt.%). The preferred mixture of ethanol, water and isopropanol varies from about 45/45/5 to about 98/1/1 ratio (wt.%), most preferably from about 88,5/5,5/6,0 up to about 91,5/4,5/4.0 (with the ratio of the AC.%). The preferred concentration of PVP in the above mixtures varies from about 5 to 30 wt.%, preferably from about 15 to about 25 wt.%, more preferably from about 16 to about 22 wt.%.

Attract the attention of numerous known methods of granulating, drying and mixing used in the art, such as granulation by spraying in a fluidized bed, wet granulation in a mixer with a powerful scissors, melting granulation, drying in a fluidized bed dryer, mixing in mixer free falling or overturning, pressed into pellets oneproblem or rotary press for tablets.

Getting granulate can be performed on standard equipment suitable for the processes of granulation of organic compounds. The final mixture and compressing the tablets can also be performed on standard equipment.

For example, stage (1) can be performed on the pellet with strong scissors, for example demand include Collette Gral; stage (2) can be performed in the fluidized bed dryer; stage (3) can be performed in a free fall mixer (e.g., container mixer, the mixer curl); and stage (4) can be performed using the method of dry pressing, for example, on a rotary presses tablets.

As mentioned above, at the core of the tablets can then be applied film coating.

Due to the high hygroscopicity and sensitivity of aliskiren to water, which modify polymorphism, preferably should avoid using water in order to prevent polymorphic changes medicinal substance for the above reasons (amorphous state, reduced chemical stability). The solution of this problem is the application of the method of applying an organic film coating.

Unexpectedly it was found that the method of applying a water film coating using standard film coating composition can be applied to the core tablets aliskiren without changing polymorphism.

Film coating preferably consists of HPMC used as polymer, iron oxide pigments, titanium dioxide, used as a dye, PEG as a softener and talc as an agent to prevent sticking. The use of coloring agents or dyes may be useful for improving the appearance, as well as to identify compositions. Other dyes suitable for use, typically include carotenoids, chlorophyll and colorful nail polishes.

Conditions of the coating film must ensure that the heart is eveny tablets will not absorb significant amounts of moisture and that the medicinal substance in the tablets do not come into contact with water droplets. This is achieved by setting process parameters, which reduce the amount of moisture that enters the core tablets.

Solid oral dosage forms of the present invention is used for lowering blood pressure, systolic or diastolic, or both. The conditions for which treatment can be applied to the present invention, without limitation, include hypertension (regardless of whether it is malignant, idiopathic renal-vascular, diabetic, solitary systolic, or other secondary type), congestive heart failure, angina (stable and unstable), myocardial infarction, atherosclerosis, diabetic nephropathy, diabetic cardiomyopathy, renal failure, peripheral vascular disease, left ventricular hypertrophy, cognitive dysfunction (such as Alzheimer's disease), stroke, headache and chronic heart failure.

The present invention also relates to a method for treating hypertension (regardless of whether it is malignant, idiopathic renal-vascular, diabetic, solitary systolic, or other secondary type), congestive heart failure, angina (stable and unstable), myocardial infarction, atherosclerosis, di is piticescu nephropathy, diabetic cardiomyopathy, renal failure, peripheral vascular disease, left ventricle hypertrophy, cognitive dysfunction, such as Alzheimer's, stroke, headache and chronic heart failure, consisting in the introduction of animal and human in need of such treatment, a therapeutically effective solid oral dosage form according to the present invention.

The present invention also relates to the use of solid oral dosage forms according to the present invention for obtaining a medicinal product for the treatment of hypertension (regardless of whether it is malignant, idiopathic renal-vascular, diabetic, solitary systolic, or other secondary type), congestive heart failure, angina (stable and unstable), myocardial infarction, atherosclerosis, diabetic nephropathy, diabetic cardiomyopathy, renal failure, peripheral vascular disease, left ventricle hypertrophy, cognitive dysfunction, such as Alzheimer's, stroke, headache and chronic heart failure.

The present invention also relates to pharmaceutical compositions for the treatment of hypertension (whether of Lyon malignant, idiopathic renal-vascular, diabetic, solitary systolic, or other secondary type), congestive heart failure, angina (stable and unstable), myocardial infarction, atherosclerosis, diabetic nephropathy, diabetic cardiomyopathy, renal failure, peripheral vascular disease, left ventricle hypertrophy, cognitive dysfunction, such as Alzheimer's, stroke, headache and chronic heart failure, including solid oral dose form according to the present invention.

Thus, accurate dose of the active agent and the particular composition intended for administration will depend on a number of factors, such as being treated condition, the desired duration of treatment and rate of release of the active agent. For example, the required amount of the active agent and its rate of release can be determined by known methods in vitro and in vivo, by which establish the duration of maintaining the plasma concentration of the active agent, which is acceptable for therapeutic effect.

The above description fully discloses the present invention, including preferred options for its implementation. Modifications and enhancements to the options OS the implement of the present invention, in particular, in the present description, correspond to the following claims. The person skilled in the art using the present description, can fully apply the present invention without additional improvements. Therefore, given the examples should be considered only in the form of illustrations, which in no way limit the present invention.

Example 1

The composition of the tablets are uncoated (mg/unit), containing 150 mg of aliskiren (free base)

The composition of the tablets without coating (wt.%), containing 150 mg of aliskiren (free base)

The composition of the tablets are uncoated (mg/unit), containing 150 mg of aliskiren (free base) (the composition is divided into internal/external phase)

The composition of the tablets without coating (wt.%), containing 150 mg of aliskiren (free base) (the composition is divided into internal/external phase)

Example 2

The composition of the tablets aliskiren coated (dosage form 3) (mg/unit)

Dosage form 3/concentration75 mg (free base)150 mg (free base) 300 mg (free base)
Component
Profumata of aliskiren82,875165,750331,500
Microcrystalline cellulose53,625107,250214,500
Polyvinylpyrrolidone K 306,00012,00024,000
Crosspovidone24,10048,20096,400
Product Aerosil 200to 0.9001,8003,600
Magnesium stearate2,5005,00010,000
Total weight pills179,000349,000680,000
OPADRY premix white9,94616,71123,9616
OPADRY premix red is 0,0240,2381,8382
OPADRY premix black0,0300,0510,2002
The total mass of the film-pills180,000375,000706,000

1. Solid oral dosage form comprising a therapeutically effective amount of aliskiren or its pharmaceutically acceptable salts, in which the active ingredient is contained in more than 46 wt.% calculated on the total weight of the dosage form, and in which the oral dosage form is in the form of pills or tablets are film-coated, and contains (a) an internal phase comprising aliskiren or its pharmaceutically acceptable salt, a filler, a binder agent and disintegrity agent, and b) an external phase comprising disintegrity agent, filler, glidant and sizing.

2. Solid oral dosage form according to claim 1, in which the active ingredient is contained in more than 48 wt.%.

3. Solid oral dosage form according to claim 1, in which the active ingredient is contained in an amount of from 46 to 60 wt.%.

4. Solid oral drug formapi to claim 1, in which the active ingredient is contained in more than 46% to 56 wt.%.

5. Solid oral dosage form according to claim 1, in which the active ingredient consists entirely of aliskiren or its pharmaceutically acceptable salt and is contained in an amount of about 75 to about 600 mg of the free base in one standard dosage form.

6. Solid oral dosage form according to claim 1, in which the active ingredient consists entirely of aliskiren or its pharmaceutically acceptable salt and is contained in an amount of about 75 to about 300 mg of the free base in one standard dosage form.

7. Solid oral dosage form according to claim 5, in which aliskiren is present in the form of profumata and is contained in an amount of about 83, about 166 or about 332 mg in one dosage form.

8. Solid oral dosage form according to claim 1, in which the dosage form contains a filler selected from starches, hydroxypropylcellulose, hydroxyethyl cellulose, hydroxypropylmethylcellulose, microcrystalline cellulose, sugar glaze, cube sugar, dextrates, dextrins, dextrose, lactose, mannitol, powdered cellulose, sorbitol, sucrose and talc.

9. Solid oral dosage form of claim 8 in which the filler is one which SJ microcrystalline cellulose.

10. Solid oral dosage form according to claim 1, in which the dosage form contains disintegrity agent selected from the calcium salt of carboxymethyl cellulose, sodium salt of carboxymethylcellulose, polyvinylpyrrolidone with crosslinking, alginic acid, sodium alginate, guar resin, carboxymethyl cellulose with crosslinking and sodium salt of carboxymethyl amylum.

11. Solid oral dosage form of claim 8, in which the dosage form contains disintegrity agent selected from the calcium salt of carboxymethyl cellulose, sodium salt of carboxymethylcellulose, polyvinylpyrrolidone with crosslinking, alginic acid, sodium alginate, guar resin, carboxymethyl cellulose with crosslinking and sodium salt of carboxymethyl amylum.

12. Solid oral dosage form of claim 10 or 11, in which dezintegriraat agent is polyvinylpyrrolidone with crosslinking.

13. Solid oral dosage form according to claim 1, in which the dosage form contains a lubricant selected from magnesium stearate, aluminum stearate or calcium stearate, polyethylene glycol 4000 to 8000, talc, hydrogenated castor oil, stearic acid and its salts, esters of glycerol, fumarate, sodium and hydrogenated is locofoco oil.

14. Solid oral dosage form according to claim 11, in which the dosage form contains a lubricant selected from magnesium stearate, aluminum stearate or calcium stearate, polyethylene glycol 4000 to 8000, talc, hydrogenated castor oil, stearic acid and its salts, esters of glycerol, fumarate, sodium and hydrogenated cottonseed oil.

15. Solid oral dosage form according to item 13 or 14, in which the lubricant is magnesium stearate.

16. Solid oral dosage form according to claim 1, in which the dosage form contains glidant selected from colloidal silica, trisilikata magnesium, powdered cellulose, starch, talc, phosphate trehosnovnogo calcium and silicified microcrystalline cellulose.

17. Solid oral dosage form according to 14, in which the dosage form contains glidant selected from colloidal silica, trisilikata magnesium, powdered cellulose, starch, talc, phosphate trehosnovnogo calcium and silicified microcrystalline cellulose.

18. Solid oral dosage form according to item 16 or 17, in which glidant is colloidal silicon dioxide.

19. Solid oral dosage form according to claim 1, in which dosage form comprises a binding agent selected from polyvinylpyrrolidones,hydroxypropylmethylcellulose and glycols.

20. Solid oral dosage form according to 17, in which dosage form comprises a binding agent selected from polyvinylpyrrolidones, hydroxypropylmethylcellulose and glycols.

21. Solid oral dosage form according to claim 19 or 20, in which the binding agent is polyvinylpyrrolidone.

22. Solid oral dosage form according to claim 1, in which the dosage form further includes a film coating comprising a material film coating selected from hydroxypropylmethylcellulose, glycols, polyvinylpyrrolidone, copolymer of polyvinylpyrrolidone and vinyl acetate, polyvinyl alcohol and sugar.

23. Solid oral dosage form according to claim 20, in which the dosage form further includes a film coating comprising a material film coating selected from hydroxypropylmethylcellulose, glycols, polyvinylpyrrolidone, copolymer of polyvinylpyrrolidone and vinyl acetate, polyvinyl alcohol and sugar.

24. Solid oral dosage form according to item 22 or 23, in which the material film coating is hypromellose.

25. Solid oral dosage form according to item 22 or 23, in which the film coating further includes additives selected from pigments, matrices dioxide is Ethan, iron oxides, talc and polyethylene glycol 3350, 4000, 6000 and 8000.

26. Solid oral dosage form according to item 22 or 23, in which the film coating comprises hypromellose, iron oxide pigments, titanium dioxide, polyethylene glycol and talc.

27. Solid oral dosage form according to claim 1 or 4 for the treatment of hypertension, congestive heart failure, angina, myocardial infarction, atherosclerosis, diabetic nephropathy, diabetic cardiomyopathy, renal failure, peripheral vascular disease, left ventricle hypertrophy, cognitive dysfunction, stroke, headache and chronic heart failure.

28. Solid oral dosage form according to claim 20 or 23 for the treatment of hypertension, congestive heart failure, angina, myocardial infarction, atherosclerosis, diabetic nephropathy, diabetic cardiomyopathy, renal failure, peripheral vascular disease, left ventricle hypertrophy, cognitive dysfunction, stroke, headache and chronic heart failure.

29. A method of treating hypertension, congestive heart failure, angina, myocardial infarction, atherosclerosis, diabetic nephropathy, diabetic cardiomyopathy, renal failure, diseases of perifericheskie the vessels, of left ventricular hypertrophy, cognitive dysfunction, stroke, headache and chronic heart failure, which includes the introduction of a therapeutically effective amount of a solid oral dosage form according to claim 1 or 4 to a patient in need of such treatment.

30. A method of treating hypertension, congestive heart failure, angina, myocardial infarction, atherosclerosis, diabetic nephropathy, diabetic cardiomyopathy, renal failure, peripheral vascular disease, left ventricle hypertrophy, cognitive dysfunction, stroke, headache and chronic heart failure, which includes the introduction of a therapeutically effective amount of a solid oral dosage form according to claim 20 or 23 to a patient in need of such treatment.

31. The use of solid oral dosage form according to claim 1 or 4 to get medicines to treat hypertension, congestive heart failure, angina, myocardial infarction, atherosclerosis, diabetic nephropathy, diabetic cardiomyopathy, renal failure, peripheral vascular disease, left ventricle hypertrophy, cognitive dysfunction, stroke, headache and chronic heart failure.

32. The use of solid oral pharmaceutical the public forms claim 20 or 23 to obtain drugs for the treatment of hypertension, congestive heart failure, angina, myocardial infarction, atherosclerosis, diabetic nephropathy, diabetic cardiomyopathy, renal failure, peripheral vascular disease, left ventricle hypertrophy, cognitive dysfunction, stroke, headache and chronic heart failure.



 

Same patents:

FIELD: medicine.

SUBSTANCE: correction of ischemic disorders caused by reperfusion liver injury in experiment in white Wistar male rats involves modelling an ischemic and reperfusion liver injury. 30 Minutes before, L-norvalin arginase blocker 10 mg/kg is introduced intraperitoneally, and distant ischemic pre-conditioning is conducted. Then, another dose of L-norvalin arginase blocker is introduced immediately after liver ischemia.

EFFECT: effective correction of the hepatocellular damage ensured by minimising the oxidative stress effects.

1 tbl, 1 ex

FIELD: medicine.

SUBSTANCE: invention refers to medicine and concerns methods of treating acute cerebrovascular disease. A method of treating acute ischemic and hemorrhagic cerebrovascular disease consists in administering a pharmaceutical composition containing a protein-polypeptide complex taken as a biologically active substance and prepared of fast-frozen embryo brain of hoofed farm animals of a gestation term from the middle of the first one-third to the middle of the last one-third of pregnancy, in the amount of 0.05-0.8 mg/day subcutaneously, intramuscularly, intravenously, intranasally and intrathecally. Said protein-polypeptide complex contains negative weak acid neutral proteins and polypeptides referring to growth/differentiation factors, signal molecules, intercellular adhesion molecule, of molecular weights 5 to 200 kD with min. 80% of total weight of proteins having molecular weight 10 to 120 kDa, and characterised nu a peak at UV wave length 274-284 nm and bands at the pi values of 4.2 to 8.4 at isoelectric focusing in 5% polyacrylamide gel.

EFFECT: protein-peptide complex is safe and tolerable when in use; it is effective in treating the patients with acute cerebrovascular disease that ensures clinically significant effect of survivability, dynamics and recovery length of the lost functions in the patients when using the method.

4 cl, 9 tbl, 23 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to using a compound of formula (I):

wherein R represents a hydrogen atom or CH3, and X represents a physiologically acceptable counter ion for preparing a hepatoprotective agent for treating or preventing a liver injury. The invention also refers to a method for treating or preventing the liver injury which involves a therapeutically or preventive effective amount of said compound of formula (I).

EFFECT: declared group of inventions provides hepatoprotective activity ensured by an ability of the compounds of formula (I) to improve an endothelium function to release endogenic prostacyclin.

14 cl, 7 dwg, 3 tbl, 5 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to medicine, namely anaesthesiology, and concerns the early postoperative drug-induced correction of central hemodynamic disorders in oncological patients. That is ensured by measuring a cardiac index (CI), an impact index (II), a LV filling pressure (LVFP), a total peripheral vascular resistance (TPVR), a LV mechanical work index (LVMWI), a systolic blood pressure (SBP); the derived relations of these values in a patient are used to prescribe an individual drug-induced therapy.

EFFECT: method provides reducing a number of hemodynamic complication in this group of patients by taking account of the individual haemodynamic values of the particular patient.

5 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pharmaceutical industry, particularly a drug preparation for preventing the development of cardiovascular diseases in individuals of a high-risk group. A capsule for preventing the development of cardiovascular diseases in individuals of a high-risk group which contains acetylsalicylic acid tablets coated by partially hydrolised polyvinyl alcohol (PVA), tablets of simvastatin and pravastatin coated by hydroxypropyl methylcellulose (HPMC) and tablets of lisinopril, ramipril or perindopril coated by partially hydrolised polyvinyl chloride. Using the capsule in producing the drug preparation for preventing the development of cardiovascular diseases in individuals of a high-risk group.

EFFECT: capsule is stable at variable temperature and relative humidity, as well as resistant to decomposition of the active ingredients under exposure to light.

8 cl, 29 tbl, 9 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel tetrahydroisoquinoline derivatives of general formula (I) or pharmacologically acceptable salts thereof, where R1 is a phenyl aminocarbonyl group which can be substituted with 1-3 groups independently selected from a substituting group A, a heteroaryl aminocarbonyl group, where the heteroaryl is pyridine, pyrazine, thiazole, pyrazole or isoxazole, which can be substituted with 1 group selected from a substituting group A, benzoxazol-2-yl group, which can be substituted with 1 group selected from a substituting group A, benzothiazol-2-yl group, (C1-C6 alkyl which can be monosubstituted with a C3-C6 cycloalkyl group), aminocarbonyl group, (C3-C6 cycloalkyl)aminocarbonyl group or adamantyl aminocarbonyl group; R2 independently represents a C1-C6 alkyl group; R3 is a heterocyclic group, where the heterocycle is oxazole, oxadiazole, pyrazole, isoxazole or tetrazole, which can be substituted with 1 group selected from a substituting group A, a group of formula -C(=O)-O-R4, or a group of formula -C(=O)-N(R5)R6; R4 is a hydrogen atom, a C1-C6 alkyl group which can be substituted with 1-2 groups independently selected from a substituting group B; R5 is a hydrogen atom, a C1-C6 alkyl group which can be substituted with 1 group selected from a substituting group B, a C3-C6 cycloalkyl group which is monosubstituted with a carboxyl group, or a heterocyclic group, where the heterocycle is tetrazole, which can be substituted with 1 group selected from a substituting group A; R6 is a hydrogen atom or a C1-C6 alkyl group; in those cases when both R5 and R6 represent a C1-C6 alkyl group, which can be substituted with 1 group selected from a substituting group B, their carbon atoms can be bonded to each other to form a 5-member saturated ring; X is an oxygen atom, a methylene group, a group of formula -NH-, a methylene group which is monosubstituted with a C1-C6 alkyl group, or a group of formula -N(R7)-; R7 is a C1-C6 alkyl group; L is a single bond, a methylene group, a 1,1-dimethylmethylene group, an ethylene group, a group of formula - CH=, or a methylene group which is monosubstituted with a C1-C6 alkyl group; … denotes a single bond or a double bond (however, … denotes a single bond when L is a group of formula -CH=); m equals 1 or 2; n equals 0 or 1; substituting group A is a group of substitutes selected from a halogen atom, a C1-C6 alkyl group, a C1-C6 halogenated alkyl group, a C1-C6 alkoxy group, a C1-C6 halogenated alkoxy group, a C1-C6 alkylthio group, a carboxyl group, a di-(C1-C6 alkyl)amino group, a cyano group, a hydroxy group, a C1-C6 alkylthionyl group and an oxo group; and substituting group B is a group of substitutes selected from a carboxyl group and a hydroxy group. The invention also relates to a pharmaceutical composition based on the compound of formula (I), use of the compound of formula (I) and a method of treating and/or preventing a disease.

EFFECT: obtaining novel tetrahydroisoquinoline derivatives, having excellent inhibiting action on acyl-coenzyme A: diacylglycerol-acyltransferase and excellent food intake suppression.

31 cl, 113 ex

FIELD: chemistry.

SUBSTANCE: disclosed are novel 4-dimethyl aminobutyric acid derivatives of formula (I) (pharmaceutically acceptable salts thereof), where values of A1, A2, R1, m and n are given in the claim, which inhibit activity of carnitine palmitoyltransferase (CPT), and more specifically CPT2.

EFFECT: compounds are an agent of pharmaceutical compositions, having CPT2 inhibiting activity.

18 cl, 71 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (IX) wherein radicals and symbols have values given in the claim, and pharmaceutically acceptable salts or tautomers thereof. Said compounds are inhibitors of poly(ADP-ribose)polymerase (PARP) and can be used to treat cancer, inflammatory diseases, reperfusion injuries, ischaemic conditions, stroke, renal failure, cardiovascular diseases, vascular diseases other than cardiovascular diseases, diabetes mellitus, neurodegenerative diseases, retroviral infections, retinal damage, skin senescence and UV-induced skin damage, and as chemo- or radiosensitisers for cancer treatment. The invention also relates to a pharmaceutical composition containing said compounds, use of said compounds and a method of treating said diseases.

EFFECT: high efficiency of using the compounds.

10 cl, 18 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pharmaceutical industry and represents a biologically compatible polysaccharide gel composition possessing the properties of prolonged release and containing triamcinolone acetonide engrafted to hyaluronic acid by covalent binding of triamcinolone acetonide and hyaluronic acid.

EFFECT: invention provides controlled release of the active ingredient representing triamcinolone acetonide.

19 cl

FIELD: medicine.

SUBSTANCE: invention refers to a lyophilised DNA compound to be applied for treating an ischemic disease and to a method of treating an ischemic disease in an individual. The lyophilised DNA compound contains plasmid DNA, salt and carbohydrate wherein said plasmid DNA contains HGF gene, or its version, and wherein said HGF gene, or its version is specified in a group consisting of flHGF, dHGF, NK1, NK2, NK4 or their mixture. The method of treating an ischemic disease in a human or a mammal involves the introduction of a composition recovered from the lyophilised DNA compound by direct injection.

EFFECT: invention enables effective treatment of the ischemic disease in the human or the mammal.

14 cl, 5 dwg, 2 tbl, 5 ex

FIELD: medicine.

SUBSTANCE: endothelial dysfunction is experimentally simulated in male white Wistar rats by daily intraperitoneal introduction of the endothelial synthetase inhibitor L-nitro-L-arginine-methyl ester 25 mg/kg for 7 days A degree of dysfunction development is estimated by the relation of endothelium-dependent and endothelial-independent vasodilation. Endothelial dysfunction is corrected by daily inhalations of mixed helium and oxygen in the amount of 150 ml and 50 ml respectively, for 7 days.

EFFECT: method provides evident endothelial dysfunction correction.

1 ex, 2 tbl

FIELD: medicine.

SUBSTANCE: correction of ischemic disorders caused by reperfusion liver injury in experiment in white Wistar male rats involves modelling an ischemic and reperfusion liver injury. 30 Minutes before, L-norvalin arginase blocker 10 mg/kg is introduced intraperitoneally, and distant ischemic pre-conditioning is conducted. Then, another dose of L-norvalin arginase blocker is introduced immediately after liver ischemia.

EFFECT: effective correction of the hepatocellular damage ensured by minimising the oxidative stress effects.

1 tbl, 1 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to medicine, particularly to pharmacology in cardiology, particularly to a herbal tea for treating adolescents with labile arterial hypertension. The herbal tea for treating the adolescents suffering stable arterial hypertension containing dried grinded herbal raw material: quinquelobate motherwort herb, origanum herb, Baikal skullcap roots, thin-leaved milkwort roots taken in certain proportions.

EFFECT: herbal tea is effective in treating the adolescents with labile arterial hypertension.

2 cl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to medicine, more specifically to an agent to be used for treating arterial hypertension and congestive cardiac failure. A pharmaceutical composition contains ramipril, a combination of sodium bicarbonate and arginine as a stabiliser, lactose monohydrate, microcrystalline cellulose, hypromellose, sodium croscarmellose, glidant and a lubricant and optionally a dying agent. A method for preparing the pharmaceutical composition involves moisturising of a mixture of ramipril, lactose monohydrate, microcrystalline cellulose, sodium bicarbonate, and optionally the dying agent in a solution of hypromellose and arginine, granulation, drying, dry granulation, addition of sodium croscarmellose, glidant and the lubricant, and tableting of the prepared mixture. The pharmaceutical composition in the form of a solid dosage form is characterised by decreased formation of all impurities, including ramiprilate and diketopiperazine ramipril, fast release of the active substance, high strength and storage stability of the quality characteristics guaranteed within more than 2 years of shelf life.

EFFECT: preparing the agent for treating arterial hypertension and congestive cardiac failure.

11 cl, 2 tbl, 12 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of formula (I) possessing a property of DGAT inhibitor, its N-oxides, its pharmaceutically acceptable salts and solvates, as well as to a based pharmaceutical composition and their application. In general formula (I) , A represents CH or N; a dash line represents an optional bond provided A represents a carbon atom; X represents -O-C(=O)-; -NRx-C(=O)-; -Z-C(=O)-; -Z-NRx-C(=O)-; -NRX-C(=S)-; Z represents C1-6alkandiyl; Rx represents hydrogen; Y represents -C(=O)-NRx- or -NRx-C(=O)-; R1 represents aryl1 or Het1; R2 represents C3-6cycloalkyl, phenyl, 2,3-dihydro-1,4-benzodioxynyl, or a 6-member aromatic heterocycle containing 1 or 2 N atoms wherein said phenyl or the 6-member aromatic heterocycle containing 1 or 2 N atoms may be optionally substituted by one, two, three or four substitutes with each substitute independently specified in a group consisting of halogen; C1-6alkyl, C1-6alkyloxy, C1-6alkylthio; C1-6alkyloxycarbonyl, nitro; mono- or di(C1-4alkyl)amino; R4R3N-C1-6alkyl; Het-C(=O)-C1-4alkyl; R3 represents C1-4alkyl; R4 represents C1.4alkyl; R5 represents hydrogen; C1-4alkyl; C1-4alkylcarbonyl; R6 represents hydrogen or C1-4alkyl; or R5 and R6 may be taken together with a nitrogen atom whereto bound to form a saturated monocyclic 5, 6 or 7-member heterocycle which may additionally contain one or more heteroatoms each of which independently specified in O, S, S(=O)P or N; and such heterocycle may be optionally substituted by C1-4alkyl; R' represents hydrogen or halogen; aryl represents phenyl or phenyl substituted by halogen, C1-6alkyl, polyhalogen C1-6alkyl; C1-6alkylxoycarbonyl; aryl represents phenyl or fluorenyl; each of said phenyl or fluorenyl may be optionally substited by one or two substitutes with each substitute independently specified in a group involving oxo; carboxyl; halogen; C1-6alkyl optionally substituted by carboxyl or C1-4alkyloxycarbonyl; C1-6alkyloxy; C1-6alkyloxycarbonyl; amino; aryl; Het; Het represents a monocyclic nonaromatic or aromatic heterocycle containing at least one heteroatom each independently specified in O, S, S(=O)p or N; or a bicyclic nonaromatic or aromatic heterocycle containing at least one heteroatom each independently specified in N; said monocyclic heterocycle or said bicyclic heterocycle may be optionally substituted by at least one or two substitutes with each substitute independently specified in a group containing oxo; or C1-6alkyl; Het1 represetns a monocyclic nonaromatic or aromatic heterocycle containing at least one heteroatom each independently specified in S or N; said monocyclic heterocycle may be optionally substituted by one substitute, particularly by one or two substitutes with each substitute independently specified in a group consisting of hydroxyl, oxo, C1-6alkyl, C1-6alkyloxycarbonyl, aryl; Het; p has the value of 2.

EFFECT: there are presented new piperidine/piperazine derivatives.

17 cl, 10 tbl, 146 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to chemical-pharmaceutical industry, more specifically to (1-hydroxy-4,5-dimethyl-1H-imidazol-2-yl)(phenyl)methanonoxime of formula (1)

EFFECT: what is prepared is a new compound possessing antiarrhythmic activity and low toxicity.

2 ex, 1 tbl

FIELD: medicine.

SUBSTANCE: endothelial dysfunction is induced in experimental Wistar male rats for 28 days by daily intraperitoneal introduction of N-nitro-L-arginine methyl ester (L-NAME) 12.5 mg/kg a day. An agent for dysfunction correction is a mixture of solutions of homoeopathic dilutions of tumour necrosis factor-alpha (TNF-α) antibodies - C12, C30, C200. This mixture is introduced at the same time for 28 day intragastrically 2 times a day in a dose of 4.5 ml/kg.

EFFECT: effective endothelial dysfunction correction.

1 tbl

FIELD: chemistry.

SUBSTANCE: present invention relates to compounds of formula (I) or pharmaceutically acceptable salts of such a compound, where R1 is an unsubstituted phenyl; R2 is -CO-R21; R21 is C1-5alkyl; m equals 3; p equals 2 or 3; and R3 is hydrogen. The invention also relates to specific compounds of formula ,

a pharmaceutical composition based on the compound of formula (I) and use of the compound of formula (I).

EFFECT: novel compounds which are useful as T/L channel blockers are obtained.

6 cl, 1 tbl, 8 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pharmacology in cardiology, particularly to a herbal tea for treating the adolescents suffering stable arterial hypertension. The herbal tea for treating the adolescents suffering stable arterial hypertension containing dried grinded herbal raw material: creeping thyme herb, Baical woundwort herb, rose hips, Siberian patrinia roots in certain proportions.

EFFECT: herbal tea is effective for treating the adolescents suffering stable arterial hypertension.

2 cl

FIELD: medicine.

SUBSTANCE: invention refers to medicine, particularly clinical pharmacology and cardiology, and may be used for achieving target arterial pressure in the patients suffering degree 1-2 arterial hypertension (AH). A start antihypertensive preparation is individually selected by taking into account systolic arterial blood pressure (SABP) variations in passive orthostatic test. The measurements are taken in an initial horizontal position on the first, fifth, tenth and fifteenth minutes of the test. A response index (RI) is calculated by formula: If the RI is less than zero, a monotherapy with an angiotensin converting enzyme inhibitor is required. If the RI is equal to zero or more, a combined therapy with the angiotensin converting enzyme inhibitor Zofenopril and the beta-adrenoreceptor blocking agent Nebivolol is required.

EFFECT: method provides a differentiated approach to selection of the start therapy in this group of patients for achieving target pressure.

2 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: coated pharmaceutical product for nicotine delivery into an individual in any form contains at least one core, nicotine in any form and/or a nicotine-imitating agent, at least one coating layer, and optionally one or more additions wherein at least said coating layer contains a buffer agent containing at least one amino acid. Amino acid is specified in a group consisting of asparagine, glutamic acid, glutamine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, serine, threonine, valine, cysteic acid, N-glycylglycine and ornithine. There are also provided a method for nicotine delivery in any form, a method for reduction of craving to smoke or use tobacco, as well as a method for preparing said coated product and applying it for ensuring fast oral nicotine absorption.

EFFECT: invention provides fast oral nicotine absorption; pharmaceutical product under the invention is characterised by the satisfactory organoleptic properties.

49 cl, 3 tbl, 6 ex

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