Halenic compositions of organic compounds

FIELD: medicine.

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

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

18 cl, 2 ex

 

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, is 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.

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 of vysokogorskoje. 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 roller compaction 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, 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 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 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, 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 unit dosage forms without dormancy is ytia 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 are the best way to obtain 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 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)

Tablet balavage pressingDosage form 1Dosage form 2Dosage form 3
Component
Profumata of aliskiren165,750165,750165,750165,750
Microcrystalline cellulose220,65084,75072,250107,250
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
Microcrystalline cellulose45,9728,2524,0831,545
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)

Tabletcialis pressing Dosage form 1Dosage form 2Dosage form 3
Component
Internal phase
Profumata of aliskiren165,75165,75165,75165,75
Microcrystalline cellulose220,6584,7572,2590,25
Polyvinylpyrrolidone K 30--12,0012,00
Crosspovidone36,00--14,20
Product Aerosil 200----
Magnesium stearate2,40---
External phase
Crosspovidone48,0045,0044,0034,00
Microcrystalline cellulose---17,00
Product Aerosil 2004,801,501,51,80
Magnesium stearate2,403,004,505,00
The total mass480,00300,00300,00340,00

The composition of 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/concentration75 mg (free base)150 mg (free base)300 mg (free base)
Component
Profumata of aliskiren82,875165,750331,500
Microcrystalline cellulose 53,625107,250214,500
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 red0,0240,2381,8382
OPADRY premix black0,0300,0510,2002
The total mass of the film-pills180,000375,000 706,000

1. The composition is a solid oral dosage form comprising a therapeutically effective amount of aliskiren or its pharmaceutically acceptable salt in an amount of more than 46 wt.% calculated on the total weight of the dosage form and the dosage form is a form of pills or tablets are film-coated and not get wet granulation with excipients using water and/or aqueous solution of a binding agent.

2. The composition is a solid oral dosage form according to claim 1, obtained by wet granulation of organic compounds.

3. The composition is a solid oral dosage form according to claim 1 or 2, obtained by wet granulation using a mixture of organic solvents or organic binder solutions.

4. The composition is a solid oral dosage form according to claim 1, in which the active ingredient is contained in more than 48 wt.%.

5. The composition is a solid oral dosage form according to claim 1, in which the active ingredient is contained in an amount of from 46 to 60 wt.%.

6. The composition is a solid oral dosage form according to claim 5, in which the active ingredient consists entirely of aliskiren or its pharmaceutically acceptable salts and contains the I in the amount of from about 75 to about 600 mg of the free base in one standard dosage form.

7. The composition is a solid oral dosage form according to claim 6, 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.

8. The composition is a solid oral dosage form according to claim 7, 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.

9. The composition is a solid oral dosage form according to claim 1, which is represented in form, consisting of many particles, including pellets and minitablets, wax matrix systems, polymer matrix tablets or tablets with a polymer coating, oral osmotic systems, coated tablets, matrix tablets, compressed tablets with coating and multi-layer tablets.

10. The composition is a solid oral dosage form of claim 8, where the dosage form further comprises a filler.

11. The composition is a solid oral dosage form of claim 10, in which the filler is microcrystalline cellulose.

12. The composition is a solid oral dosage form of claim 10, and dosage form further includes disintegrity agent.

13. HDMI is of solid oral dosage form according to item 12, moreover, the dosage form further includes a lubricant.

14. The composition is a solid oral dosage form according to item 13, and dosage form further includes glidant.

15. The composition is a solid oral dosage form according to 14, and dosage form further includes a binder.

16. The composition is a solid oral dosage form according to claim 1 or 15, used for getting medicines 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.

17. The method of obtaining the composition is a solid oral dosage form according to item 15, 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 application of p is offset by the resulting core tablets to obtain a tablet with a film coating.

18. The method according to 17, in which the additive at the stage (1) selected from a filler, dezintegriruetsja agent and a binder agent and excipients external phase to phase (3) selected from a filler, dezintegriruetsja agent, sizing and glidant.



 

Same patents:
Antiishemic agent // 2384327

FIELD: medicine.

SUBSTANCE: there is offered to apply 4-(2-hydroxyethyl)phenol(n-thyrozol) as a medicinal agent with anti-ischemic properties.

EFFECT: intravenous introduction of n-thyrozol improves the survival rate of animals with old myocardial ischemia and reperfusion, reduces a region of myocardial ischemia, and enables higher integrity of myocardial tissue.

3 tbl, 3 ex

Triazole derivative // 2383536

FIELD: chemistry.

SUBSTANCE: described are novel triazole derivatives with general formula where values of radicals are given in the formula of invention, a pharmaceutical composition containing said derivatives, and a method of treating autoimmune diseases. Compounds with general formula (1) and their pharmaceutically acceptable salts have inhibition effect on S1P and its Edg-1 receptor (S1P1).

EFFECT: possibility of use as a pharmaceutical product.

43 cl, 10 ex, 1 tbl

FIELD: medicine.

SUBSTANCE: for treatment of left ventricle hypertrophy (HLV) in patients with coronary disease in combination with hypertension during 6 months standard drug therapy, consisting of IATA, beta-blocker, aspirin and stanin is realised. Additionally ivabradin in day dose 5 - 15 mg is introduced in two intakes daily.

EFFECT: method ensures transformation of HLV in concentric remodeling of left ventricle and in such way reduces degree of cardiovascular complications risk.

2 ex, 1 tbl

FIELD: medicine.

SUBSTANCE: pharmaceutical compositions include divalent, namely calcium, magnesium or zinc salt, of pravastatin or fluvastatin and omega-3 fat, for prevention, reduction or treatment of increased cholesterol levels, atherosclerosis, hyperlipidemia, cardio-vascular disorders and diseases, coronary heart disease and/or cerebrovascular disease.

EFFECT: improved bioavailability of compositions, easily obtained and introduced.

40 cl, 33 dwg, 2 tbl, 8 ex

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely to cardiology, and concerns treating of myocardial infarction (MI). That is ensured by primary transcutaneous transluminal coronary angioplasty with underlying standard conservative therapy is followed with myocardial unload with beta-blocker Carvedilol. Said myocardial unload is combined with introduction of Levosimendan at first administered as a bonus intravenously at 16 mcg/kg during 10 min, and then in stable AP it is infused intravenously within 20-38 hours in total dose 12.5 mg/kg at the rate 0.05 to 0.2 mcg/kg/minutes.

EFFECT: method provides higher survival rate and ensured clinical compensation in the MI patients of elderly and senile age with cardiac failure complications due to combination of endovascular revascularisation and myocardial unload with underlying introduction of inotropic stimulator Levosimendan in the developed doses and regimen.

2 tbl

FIELD: medicine.

SUBSTANCE: invention concerns medicine, neurology section and can find application in neurologic and neural rehabilitation clinic in treating the patients with aphasia. That is ensured by administration of acatinol memantin according to certain schedule with underlying logopedic lessons. Within the first week of therapy, the dose is 5 mg/day in the morning at mealtime. Within the second week, the dose is 10 mg/days, with 5 mg in the morning and in the evening. Within the third week, the dose is increased to 15 mg/days, with 10 mg in the morning and 5 mg in the evening. Within the fourth week, the dose is increased to 20 mg/days. And the maintenance dose makes 20 mg/days.

EFFECT: method provides effective treatment of apparent rough aphasia caused by disordered cerebral blood flow.

1 ex, 2 tbl

FIELD: chemistry.

SUBSTANCE: novel isoquinoline derivatives are described by general formula I, where q equals zero; p equals zero or one; Ra is -COOH or WR8; under the condition that, if Ra is -COOH, then p equals zero, and if Ra is -WR8, then p equals one; W is selected from an oxygen atom and -NR9-, where R9 is selected from a group consisting of a hydrogen atom, acyl and alkyl; and R8 is selected from a group consisting of a hydrogen atom and alkyl; R1 is selected from a group consisting of a hydrogen atom, alkyl, alkyl substituted with one group selected from alkoxy and dialkylamino, a halogen atom, heteroaryl containing up to six carbon atoms, one of which is nitrogen, aminoacyl, aryl, aryl substituted with alkyl, and -XR6, where X is an oxygen atom, -S(O)n- or -NR7, where n equals zero, one or two, R6 is selected from a group consisting of alkyl, aryl, aryl substituted with one group selected from a halogen atom, alkoxy, alkylcarbonylamino and alkylsulfonamide, heteroaryl, containing up to six carbon atoms, one of which is nitrogen, and R7 is a hydrogen atom or aryl; R2 and R3 are independently selected from a group consisting of a hydrogen atom, amino, amino substituted with alkoxy-substituted phenylsulfonyl, alkyl, alkyl substituted with up to three times by a halogen atom, aryl, halogen atom -NR6C(O)NR6R6, and -XR6, where X is an oxygen atom or -S(O)n-, where n equals zero, one or two, each of the substitutes R6 is independently selected from a group consisting of hydrogen, alkyl, alkyl substituted with aryl, aryl , aryl substituted with one or two groups selected from a halogen atom, alkyl, alkyl substituted with up to three times by a halogen, alkoxy, alkoxy substituted with up to three times by a halogen, aryloxy substituted with a halogen, nitro, alkylsulfonamide, arylsulfonamide and alkyl-substituted arylsulfonamide, cycloalkyl, heteroaryl, containing up to six carbon atoms, one of which is nitrogen, under the condition that if X is -SO2-, R6 cannot be a hydrogen atom; or R2 and R3 together with carbon atoms to which they are bonded, are bonded with formation of an aryl group; R4 and R5 are independently selected from a hydrogen atom or aryl; R is selected from a group which includes a hydrogen atom, deuterium and methyl; R' is selected from a group consisting of a hydrogen atom, deuterium, alkyl or alkyl substituted with one group selected from hydroxyl, amino, carboxyl, aryl, aryl substituted with one hydroxyl and heteroaryl, containing up to five carbon atoms, two of which can be nitrogen; on the other hand, R and R' and the carbon atom to which they are bonded can be bonded with formation of cycloalkyl; R" is formed from a hydrogen atom and alkyl, or R" together with R' and the nitrogen atom to which they are bonded can be bonded with formation of a heterocyclic group containing up to six carbon atoms, one of which is nitrogen; R'" is selected from a group consisting of hydroxyl, alkoxy, alkoxy substituted with aryl, acyloxy, aryl, -S(O)n-R10, where R10 is hydrogen, and n is zero; or its pharmaceutically acceptable salts, esters or amides; under the condition that restrictive conditions given in paragraph 1 of the formula of invention are met. The invention also relates to specific produced and described compounds, a pharmaceutical composition based on compounds with general formula I, a method of treating, preventing and pretreatment using said pharmaceutical composition, a method of inhibiting activity of hydrolase enzyme, based on taking an effective amount of a formula I compound, a composition for preventing and pretreatment, based on formula I compound and erythropoietin.

EFFECT: new isoquinoline derivatives have useful biological properties.

53 cl, 4 tbl, 253 ex

FIELD: medicine.

SUBSTANCE: claimed invention relates to chemical-pharmaceutical industry and concerns pharmaceutical composition for prevention and treatment of diseases and disease states connected with metabolic pathways of cycloxygenase-2 (CG-2) and 5-lipooxygenase (5-LO), which contains mixture of extract obtained from Scutellariae and enriched with flavonoids with free B-ring, which include baicalein, and extract obtained from Acacia and enriched with flavans, which include catechine and epicatechine. Claimed invention also relates to method of body weight loss and control over glucose level in blood. Methods by claimed invention include introduction to person, who needs it, of efficient amount of composition by claimed invention together with pharmaceutically acceptable carrier. Claimed invention mainly relates to prevention and treatment of diseases and states connected with metabolic pathways of cycloxygenase-2 (CG-2) and 5-lipooxygenase (5-LO), including, but not confining to it, stopping discomfort and pain in joints, induced by such states as osteoarthritis, rheumatoid arthritis and other injuries caused by overload.

EFFECT: composition possesses high efficiency.

35 cl, 22 ex, 15 tbl

FIELD: medicine.

SUBSTANCE: there is offered application of antagonist of angiotensin (II) (ATP) type 1 receptor or its pharmaceutically acceptable salt, particularly Candesartan, Candesartan cylexetyl, Losartan, Valsartan, Irbesartan, Ta-sosartan, Telmisartan and Eprosartan for making a medical product for prevention of stroke, or for making a medical product for prevention of diabetes, or for making a medical product for prevention of congestive heart failure (CHF) in the patient with high risk of cardiovascular attack in view of the previous history of coronary heart disease, stroke or peripheral arterial disease.

EFFECT: there is shown apparent reduction of number of patients with developed stroke, diabetes or CHF, thus in the beginning of study, the patients had normal or lowered blood pressure and no CHF signs.

9 cl, 1 ex

FIELD: medicine.

SUBSTANCE: invention refers to medicine and chemical-pharmaceutical industry. Trimetazidine preparation as a matrix tablet of prolonged action contains an active substance, montanic glycolic wax, polymer of methacrylic acid, hydrophilic polymer representing hydroxypropyl methylcellulose, microcrystalline cellulose, mannitol and adjuvants, in amounts specified in the patent claim. There is also disclosed method for making Trimetazidine preparation as a matrix tablet.

EFFECT: invention provides controlled prolonged release of Trimetazidine that leads to stable concentration level of the active substance.

10 cl, 2 tbl, 4 ex

Antiishemic agent // 2384327

FIELD: medicine.

SUBSTANCE: there is offered to apply 4-(2-hydroxyethyl)phenol(n-thyrozol) as a medicinal agent with anti-ischemic properties.

EFFECT: intravenous introduction of n-thyrozol improves the survival rate of animals with old myocardial ischemia and reperfusion, reduces a region of myocardial ischemia, and enables higher integrity of myocardial tissue.

3 tbl, 3 ex

FIELD: medicine.

SUBSTANCE: therapeutic course involves examination that implies photography of eye-ground vessels and measurement of diametre of retinal vessels on an empty stomach of the patient prior to and after administration of a medicine. Observed increase in diametre of supero-temporal branch of central retinal artery at a distance of one vertical diametre of disk of optic nerve from an edge of disk of optic nerve by 10% and more from the initial one ensures to diagnose efficiency of the administered medicine. The absence of increase in diametre of supero-temporal branch of central retinal artery by 10% and more in administration of the same dosage of the medicine enables to diagnose development of tolerance.

EFFECT: method extends range of means to determine antihypertensive drug tolerance.

3 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula

or

or to their pharmaceutically acceptable salts, where ring A, R2, R3, R4 and X are as defined in the description. The disclosed compounds are useful as 11βHSD1 inhibitor. The invention also relates to a pharmaceutical composition, an agent for treating or preventing pathology related to glucocorticoids, a 11βHSD1 inhibitor containing the disclosed compound or its pharmaceutically acceptable salt, and use of the disclosed compounds.

EFFECT: compounds are highly effective.

40 cl, 48 tbl, 191 ex

Triazole derivative // 2383536

FIELD: chemistry.

SUBSTANCE: described are novel triazole derivatives with general formula where values of radicals are given in the formula of invention, a pharmaceutical composition containing said derivatives, and a method of treating autoimmune diseases. Compounds with general formula (1) and their pharmaceutically acceptable salts have inhibition effect on S1P and its Edg-1 receptor (S1P1).

EFFECT: possibility of use as a pharmaceutical product.

43 cl, 10 ex, 1 tbl

FIELD: medicine.

SUBSTANCE: invention can be applied for treatment of patients with bronchial asthma of medium-severe or severe clinical course in phase of exacerbation with high risk of sinus tachycardia development. If high risk of sinus tachycardia development is determined, ivabradine is introduced in standard complex of treatment, which includes beta2-agonists. Medicine is used during all exacerbation period in daily doze 10-14 mg.

EFFECT: method allows to increase treatment safety and efficiency of correcting side effect of high doses of beta2-agonists.

2 cl, 10 tbl, 2 ex

FIELD: medicine.

SUBSTANCE: for prevention and treatment of diseases of cardiovascular and/or nervous system, arterial hypertension claimed is original composition of ethylmethylhydroxypyridine succinate, succinic acid and ethylenediaminetetraacetic acid disodium salt in form of solution for injections, which additionally contains pyridoxin or its pharmaceutically acceptable salt and povidon.

EFFECT: high stability, convenience in application and high therapeutic efficiency in prevention and treatment of diseases of cardiovascular and nervous system and arterial hypertension.

14 cl, 5 ex

FIELD: medicine.

SUBSTANCE: invention relates to medicine, namely to anesthesiology and can be used in carrying out regional anesthesia with application of clonidine. For this purpose in pre-operation period Kerdo's vegetative index is determined. In case Kerdo's vegetative index is higher than zero, hemodynamics correction is not necessary, if index is lower than -30, such correction is necessary.

EFFECT: method allows to ensure considerable reduction of anesthesia risk due to prediction of possible complications on the part of hemodynamics and therefore taking necessary measures aimed at their prevention.

3 tbl, 3 ex, 6 dwg

FIELD: medicine.

SUBSTANCE: for treatment of left ventricle hypertrophy (HLV) in patients with coronary disease in combination with hypertension during 6 months standard drug therapy, consisting of IATA, beta-blocker, aspirin and stanin is realised. Additionally ivabradin in day dose 5 - 15 mg is introduced in two intakes daily.

EFFECT: method ensures transformation of HLV in concentric remodeling of left ventricle and in such way reduces degree of cardiovascular complications risk.

2 ex, 1 tbl

FIELD: medicine.

SUBSTANCE: pharmaceutical compositions include divalent, namely calcium, magnesium or zinc salt, of pravastatin or fluvastatin and omega-3 fat, for prevention, reduction or treatment of increased cholesterol levels, atherosclerosis, hyperlipidemia, cardio-vascular disorders and diseases, coronary heart disease and/or cerebrovascular disease.

EFFECT: improved bioavailability of compositions, easily obtained and introduced.

40 cl, 33 dwg, 2 tbl, 8 ex

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely to cardiology, and concerns treating of myocardial infarction (MI). That is ensured by primary transcutaneous transluminal coronary angioplasty with underlying standard conservative therapy is followed with myocardial unload with beta-blocker Carvedilol. Said myocardial unload is combined with introduction of Levosimendan at first administered as a bonus intravenously at 16 mcg/kg during 10 min, and then in stable AP it is infused intravenously within 20-38 hours in total dose 12.5 mg/kg at the rate 0.05 to 0.2 mcg/kg/minutes.

EFFECT: method provides higher survival rate and ensured clinical compensation in the MI patients of elderly and senile age with cardiac failure complications due to combination of endovascular revascularisation and myocardial unload with underlying introduction of inotropic stimulator Levosimendan in the developed doses and regimen.

2 tbl

FIELD: food industry.

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

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

24 cl, 2 ex

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