Galenic compositions of organic compounds

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to a method of treating hypertension, congestive cardiac failure, stenocardia, myocardial infarction, atherosclerosis, stroke. A method of treating involves introduction to a patient requiring such treatment of the solid oral dosage form containing a therapeutically effective amount of aliskiren or its pharmaceutically acceptable salt in which the 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 produced by methods other than wet granulation with excipients by means of water and/or a water solution of a binding agent.

EFFECT: realisation of the specified purpose.

12 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 is 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 status the I, 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.

The quality of the drug which substances 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 independent of any coating or material of the capsule.

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 capsules the active ingredient is present in more than 46 wt.% of the total weight of the oral dosage form.

In preferably the 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 for 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 the 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 a 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 the present is its 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 is calgene 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, soda is containing 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 polymeric 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 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, b is 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 the unit dosage form without the rite 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 cellulose is (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 press is for 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, dia is eticheskoi nephropathy, diabetic cardiomyopathy, renal failure, peripheral vascular disease, left ventricle hypertrophy, cognitive dysfunction, such as Alzheimer's, stroke, headache and chronic heart failure, which consists 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 (regardless of whether l is it 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)

Tablet balavage pressingDosage form 1Dosage form 2Dosage form 3
Component
Profumata of aliskiren165,750165,750165,750165,750
Microcrystallite-
Skye cellulose
220,65084,75072,250107,250
Polyvinylpyrrolidone K 30 --12,00012,000
Crosspovidone84,00045,00044,00048,200
Product Aerosil 2004,8001,5001,5001,800
Magnesium stearate4,8003,0004,5005,000
The total mass480,000300,000300,000340,000

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

Tablet balavage pressingDosage form 1Dosage form 2Dosage form 3
Component
Profumata of aliskiren34,53 55,2555,2548,75
Microcrystallite-
Skye cellulose
45,9728,2524,0831,545
Polyvinylpyrrolidone K 30--43,53
Crosspovidoneof 17.51514,6714,175
Product Aerosil 20010,50,50,53
Magnesium stearate111,51,47
Total %100,00100,00100,00100,00

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

Tablet balavage pressingDosage form 1Dosage form 2Dosage form 3
Component
Internal phase
Profumata of aliskiren165,75165,75165,75165,75
Microcrystallite-
Skye cellulose
220,6584,7572,2590,25

Tablet balavage pressingDosage form 1Dosage form 2Dosage form 3
Component
Polyvinylpyrrolidone K 30--12,0012,00
Crosspovidone36,00 --14,20
Product Aerosil 200----
Magnesium stearate2,40---
External phase
Crosspovidone48,0045,0044,0034,00
Microcrystallite-
Skye cellulose
---17,00
Product Aerosil 2004,801,501,51,80
Magnesium stearate2,403,004,505,00
The total mass480,00300,00300,00340,00

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

Tablet balavage pressingDosage form 1Dosage form 2Dosage form 3
Component
Internal phase
Profumata of aliskiren34,5355,2555,2548,75
Microcrystalline cellulose45,9728,2524,0826,545
Polyvinylpyrrolidone K 30--43,530
Crosspovidone7,5--4,175
Product Aerosil 200-- --
Magnesium stearate0,5---
External phase
Crosspovidone101514,6710
Microcrystalline cellulose---5
Product Aerosil 20010,50,50,53
Magnesium stearate0,511,51,47
The total mass100,00100,00100,00100,00

Example 2:

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

Dosage form 3/concentration 75 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 white9,946 16,71123,9616
OPADRY premix red0,0240,2381,8382
OPADRY premix black0,0300,0510,2002
The total mass of the film-pills180,000375,000706,000

1. 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, including the introduction in need of such treatment to the patient a therapeutically effective amount of a solid oral dosage form containing 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, where the oral dosage form is presented in the form of pills or tablets with planon the m coating and is not obtained by the method of wet granulation with excipients with water and/or aqueous solution of the binder.

2. The method according to claim 1, where the use of solid oral dosage form, in which the active ingredient is contained in more than 48 wt.%.

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

4. The method according to claim 3, where the use of solid oral pharmaceutical form whose 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.

5. The method according to claim 4, where the use of solid oral pharmaceutical form whose 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.

6. The method according to claim 5, where the use of solid oral dosage form, 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.

7. The method according to claim 6, where the use of solid oral dosage form, which also contains a filler.

8. The method according to claim 7, where the use of solid oral dosage form, in to the Torah, the filler is microcrystalline cellulose.

9. The method according to claim 7, where the use of solid oral dosage form, which additionally includes disintegrity agent.

10. The method according to claim 9, where the use of solid oral dosage form, which includes an additional sizing.

11. The method according to claim 10, where the use of solid oral dosage form, which additionally includes glidant.

12. The method according to claim 11, where the use of solid oral dosage form, which further includes a binder.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of general formula where R1 denotes CH3; R2 denotes halogen or CN; R3 denotes H or CH3; R4 denotes H or CH3; n equals 1; and pharmaceutically acceptable salts thereof. The invention also relates to a pharmaceutical composition and use of compounds of formula (I) in preparing a medicinal agent, having CX3CR1 receptor antagonist activity.

EFFECT: compounds can be used as CX3CR1 receptor antagonists.

13 cl, 1 tbl, 10 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to application of binuclear sulphur-nitrosyl complex of anion type iron of formula Na2[Fe2(S2O3)2(NO)4]·4H2O as vasodepressor means for obtaining medication for treatment of ischemic diseases.

EFFECT: invention ensures extension of arsenal of cardiotropic medications with improved activity spectrum based on said iron complex, which is non-toxic water-soluble NO donor.

2 cl, 4 dwg, 5 tbl

FIELD: medicine.

SUBSTANCE: modelling a myocardial infraction is followed by intravenous introduction of the immune corrector tamerite 3 mg/kg in an animal every days for seven days. The histological results of the myocardial tissue presented after the first, third and seventh days show the sufficiency and efficacy of the therapy.

EFFECT: effective therapy of the acute myocardial infraction ensured by reducing the intensity of an acute inflammatory reaction, providing faster granulation tissue formation.

2 tbl

FIELD: medicine.

SUBSTANCE: modelling a myocardial infraction is followed in a rat is followed by intravenous introduction of the immune corrector tamerite 3 mg/kg. The preparation is injected daily for seven days. The histological results of the myocardial tissue presented after the first, third and seventh days show the sufficiency and efficacy of the therapy.

EFFECT: effective therapy of the acute myocardial infraction with high possibility of cure ensured by reduced manifestations of systemic inflammation response syndrome, faster granulation tissue formation and necrotic zone replacement by cicatricial tissue.

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely to purulent surgery, and can be used for treating patients with critical ischemia of lower extremities. For this purpose, standard medical therapy is additionally combined with single-step wound layered infiltration of soft tissues by Perftoran at 3 cm from wound edges in dose 10-15 ml if the wound is localised on a feet, and 40-50 ml if the wound is localised on a leg or a hip every second day in amount 8-10 procedures.

EFFECT: method allows reducing length of treatment and managing pain syndrome, accelerating wound cleansing and healing in higher intensity of repair processes ensured by constant maximally effective active Perftoran concentration in the wound zone.

1 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to chemical-pharmaceutical industry, and concerns creation of a pharmaceutical composition with a wide spectrum of pharmacological activity, namely exhibiting antihypoxic, neuroprotective and antiamnestic activity, and also showing an ergogenic nature. The declared pharmaceutical composition contains semax and choline. The outcome of experiments proves that the offered pharmaceutical composition containing semax and choline, mutually intensifies an effect of each of them.

EFFECT: composition can find application in creation of the new drug preparations exhibiting neuroprotective activity in a combination with antihypoxic and antiamnestic activity and the ergogenic nature and used for treatment of various pathologies of the central nervous system.

12 tbl, 4 dwg

FIELD: medicine.

SUBSTANCE: invention refers to a therapeutic and diagnostic agent used in treatment or diagnostics of a cerebral disease caused by a mitochondrial dysfunction, or in a method for prevention within a surgical intervention and an intravascular surgery, and also to a diagnostic technique for cerebral diseases. The therapeutic agent contains an iron compound and δ-aminolevulinic acid or its salt by formula R2R1NCH2COCH2CH2COR3 (1) where each R1 and R2 independently represents hydrogen atom, and R3 represents a hydroxyl group or C1-24 alkoxy group. The diagnostic agent contains 8-aminolevulinic acid or its salt by formula specified above. The diagnostic technique for the cerebral disease caused by mitochondrial dysfunction, involves a stage of introduction of the specified diagnostic agent followed by a stage of exposure of a diagnosed brain region to light, capable to excite protoporphyrin IX, accompanied by emission of red light, and a stage of diagnostics of the involved brain by the detected emission of red light.

EFFECT: higher diagnostic efficiency.

7 cl, 4 dwg, 2 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to medicine, in particular, to pharmacy. As medical substance composition contains therapeutically effective quantity of trimetazidine dihydrochloride, as prolonging agent - interpolymer complex of polyacrylic acid and polyethylenglucol. As additional substances composition includes: bibasic calcium phosphate, monocrystalline cellulose, basic calcium carbonate, group of sliding substances - stearic acid and/or its salts. Composition can be made in form of pills, covered with coating, contains optimal quantity of additional substances, makes it possible to sufficiently release medical substance and ensures its high bio-availability.

EFFECT: obtaining prolonged pharmaceutical composition, which has antianginal action.

16 cl, 6 tbl, 6 ex, 2 dwg

FIELD: chemistry.

SUBSTANCE: pharmaceutical compositions containing at least one compound of formula (IIIa) or (IIIb) or (IVa) or (IVb), where -X- and Y are described in the claims, or pharmaceutically acceptable salts, esters or amides thereof and a pharmaceutically acceptable carrier, which can be used in processes with modulation or E- and P-selectin expression.

EFFECT: obtaining low-molecular non-glycoside and non-peptide compounds, capable of creating antagonism to selectin-mediated processes.

11 cl, 38 ex, 3 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed invention relates to field of pharmaceutics and medicine and pharmaceutical composition for treatment of reperfusion disorders, which contains inert auxiliary substances and as active component compounds of general formula I-Iva.

EFFECT: obtaining pharmaceutical composition for treatment of reperfusion disorders.

3 ex

FIELD: medicine.

SUBSTANCE: for the purpose of hypoestrogen-induced endothelial dysfunction correction in white female Wistar rats, hypoestrogen-induced endothelial dysfunction is simulated by bilateral ovariectomy. The dysfunction correction is ensured by introduction of mixed solutions of homoeopathic dilutions of polyclonal rabbit C12, C30, C200 antibodies to human endothelial nitrogen oxide synthase for 6 weeks following the ovariectomy. The specified mixture is added to drinking bowls once a day.

EFFECT: method provides effective correction with reducing an endothelial dysfunction coefficient in females to the level observed in intact animals ensured by the effect on various developmental mechanisms of this dysfunction in hypooestrogenic conditions.

2 tbl, 1 ex

FIELD: medicine.

SUBSTANCE: for the purpose of hypoestrogen-induced endothelial dysfunction correction in white female Wistar rats, hypoestrogen-induced endothelial dysfunction is simulated by bilateral ovariectomy. The dysfunction correction is ensured by daily intragastric introduction of enalapril 0.5 mg/kg for 6 weeks following the ovariectomy. The mixed solutions of homoeopathic dilutions of polyclonal rabbit C12, C30, C200 antibodies to human endothelial nitrogen oxide synthase are also introduced. The specified mixture is added to drinking bowls once a day.

EFFECT: method provides effective correction with reducing an endothelial dysfunction coefficient in females to the level observed in intact animals ensured by the effect on various developmental mechanisms of this dysfunction in hypooestrogenic conditions.

2 tbl, 1 ex

FIELD: medicine.

SUBSTANCE: endothelial dysfunction is ensured by intragastric introduction to a laboratory animal of the NO-synthase inhibitor - N-nitro-L-arginine of methyl ester (L-NAME) 25 mg/kg daily for 7 days. The endothelial dysfunction correction is ensured by intragastric introduction of atorvastatin 2.2 mg/kg and intragastric introduction of resveratrol 2 mg/kg once a day.

EFFECT: effective action of the combination of two specified preparations on vascular endothelium function.

1 ex, 2 tbl

FIELD: medicine.

SUBSTANCE: endothelial dysfunction is ensured by intragastric introduction to a laboratory animal of the NO-synthase inhibitor - N-nitro-L-arginine of methyl ester (L-NAME) 25 mg/kg daily for 7 days. The endothelial dysfunction correction is ensured by intragastric introduction of atorvastatin 2.2 mg/kg and intragastric introduction of resveratrol 2 mg/kg once a day.

EFFECT: effective action of the combination of two specified preparations on vascular endothelium function.

1 ex, 2 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of general formula where R1 denotes CH3; R2 denotes halogen or CN; R3 denotes H or CH3; R4 denotes H or CH3; n equals 1; and pharmaceutically acceptable salts thereof. The invention also relates to a pharmaceutical composition and use of compounds of formula (I) in preparing a medicinal agent, having CX3CR1 receptor antagonist activity.

EFFECT: compounds can be used as CX3CR1 receptor antagonists.

13 cl, 1 tbl, 10 ex

FIELD: chemistry.

SUBSTANCE: invention relates to indole and indazole compounds of formula in which n equals a whole number from 1 to 3, m equals 0 or 1, A denotes phenyl, X denotes C or N, R1 denotes hydrogen, alkyl, -(CH2)rNR7R8, where r equals a whole number from 1 to 5, and R7 and R8 independently denote hydrogen, alkyl or alkylcarbonyl, or can together form an optionally alkyl-substituted alkylene chain, where optionally one methylene is substituted with a N atom, R2 denotes hydrogen, halogen, cyano, nitro, hydroxy, alkyl, alkoxy or trialkylsilyl, denotes -(CH2)pCO2R7, -(CH2)pOR7, -(CH2)pNR7R8, -NHR10, -N(H)S(O)2R7, -NHC(O)R10, -(CH2)pS(O)2R7 or (CH2)p-heterocycle-R10, where p equals a whole number from 0 to 3, R7 and R8 are as defined above, R10 denotes hydrogen, oxo, alkylsulphonyl, alkylcarbonyl, alkyloxycarbonyl, alkoxy, alkyl or heterocycle, R3 denotes hydrogen, cyano, halogen, alkyl or phenyl, or denoes -(CH2)n-heterocycle or -(CH2)n-aryl, where n equals a whole number from 0 to 3, provided that R3 denotes phenyl when X denotes C and m=0, R4 denotes -YR11, where Y denotes a direct bond or -(CR7R8)pY′-, where p equals a whole number from 0 to 3, R7 and R8 are as defined above, Y′ is selected from a group consisting of -O-, -S-, -NR12-, -NR12C(O)-, -C(O)-, -C(O)O-, -C(O)NR12-, -S(O)q- and -S(O)qNR12-, where R12 denotes hydrogen, alkyl, aryl or heteroaryl, q equals a whole number from 0 to 2, R11 is selected from a group consisting of hydrogen, cyano, halogen, hydroxy, thiol, carboxy, alkyl and -(CH2)tB-R13, where t equals a whole number from 0 to 3, B denotes heterocycle, heteroaryl or aryl, R13 denotes hydrogen, cyano, halogen, hydroxy, oxo, thiol, carboxy, carboxyalkyl, alkylcarbonyloxy, alkyl, alkoxy, alkylthio, alkylcarbonyl or alkylsulphonyl, R5 denotes hydrogen, alkyl, cycloalkyl, heterocycle or heterocyclylalkyl, R6 denotes (CR7R8)p-Z-D-W-R14, where Z denotes a direct bond, or is selected from a group consisting of -C(O)-, -C(O)O, -C(O)NR12- and -S(O)y-, y equals a whole number from 1 or 2, D denotes a direct bond, or denotes cycloalkyl, heteroaryl or heterocycle, W denotes a direct bond, or denotes -NR -, -C(O)-, -C(O)O-, -C(O)NR12-, -S(O)y-, -S(O)yNR12- or -NR12S(O)y, wherein R14 denotes hydrogen, hydroxy, alkyl, alkoxy, heterocycle, heteroaryl, aryl or aralkyl, R5 and R6 together denote an alkylene chain, provided that R6 denotes cycloalkyl or heterocyclyl when X denotes N, where the heteroaryl is a 5-6-member aromatic ring containing 1-2 heteroatoms selected from N, O and S, the heterocycle is a 3-8-member ring containing 1-3 heteroatoms selected from N, O and S, where the alkyl, alkoxy, aryl, cycloalky, heterocycle and heteroaryl can be optionally substituted, and the substitutes, one or more, are selected from a group consisting of hydroxy, halogen, nitrile, amino, alkylamino, dialkylamino, carboxy, alkyl, alkoxy, carboxyalkyl, alkylcarbonyloxy, alkylthio, alkyloxycarbonyl, alkylaminocarbonyl, arylalkoxy and oxo, and pharmaceutically acceptable salts or stereoisomers thereof. The invention also relates to a composition, as well as a method of preparing said composition.

EFFECT: obtaining novel biologically active compounds for preventing or treating necrosis and necrosis-associated diseases.

40 cl, 162 ex, 2 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to application of binuclear sulphur-nitrosyl complex of anion type iron of formula Na2[Fe2(S2O3)2(NO)4]·4H2O as vasodepressor means for obtaining medication for treatment of ischemic diseases.

EFFECT: invention ensures extension of arsenal of cardiotropic medications with improved activity spectrum based on said iron complex, which is non-toxic water-soluble NO donor.

2 cl, 4 dwg, 5 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to application of binuclear sulphur-nitrosyl complex of anion type iron of formula Na2[Fe2(S2O3)2(NO)4]·4H2O as vasodepressor means for obtaining medication for treatment of ischemic diseases.

EFFECT: invention ensures extension of arsenal of cardiotropic medications with improved activity spectrum based on said iron complex, which is non-toxic water-soluble NO donor.

2 cl, 4 dwg, 5 tbl

FIELD: medicine.

SUBSTANCE: modelling a myocardial infraction is followed by intravenous introduction of the immune corrector tamerite 3 mg/kg in an animal every days for seven days. The histological results of the myocardial tissue presented after the first, third and seventh days show the sufficiency and efficacy of the therapy.

EFFECT: effective therapy of the acute myocardial infraction ensured by reducing the intensity of an acute inflammatory reaction, providing faster granulation tissue formation.

2 tbl

FIELD: medicine.

SUBSTANCE: modelling a myocardial infraction is followed in a rat is followed by intravenous introduction of the immune corrector tamerite 3 mg/kg. The preparation is injected daily for seven days. The histological results of the myocardial tissue presented after the first, third and seventh days show the sufficiency and efficacy of the therapy.

EFFECT: effective therapy of the acute myocardial infraction with high possibility of cure ensured by reduced manifestations of systemic inflammation response syndrome, faster granulation tissue formation and necrotic zone replacement by cicatricial tissue.

FIELD: medicine, pharmaceutics.

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

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

14 cl, 2 ex

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