Stable combined pharmaceutical composition

FIELD: medicine, pharmaceutics.

SUBSTANCE: amlodipine base or its pharmaceutically acceptable salt, preferentially amlodipine besylate, bisoprolol fumarate, a disintegrating agent, a wetting agent, and if necessary additional excipients are homogenised; an antiadhesion agent is added, and the homogenisation procedure is continued; the homogenate is then tabletted by direct compression, or solid gelatine capsule is filled in; the prepared tablets or capsules are packed in moisture-proof protective packaging. The prepared tablets or capsules contain less than 0.5 wt % of active ingredients of compounds of formula

.

EFFECT: what is described is a method for preparing the stable solid pack dosage form containing the amlodipine base or its pharmaceutically acceptable salt and bisoprolol fumarate.

3 cl, 6 tbl, 2 ex

 

Field of the invention

The present invention relates to a stable solid pharmaceutical composition containing amlodipine of formula

and bisoprolol as active ingredients.

More specifically, the present invention relates to compositions, packaged in moisture-proof packaging that contains the basis of amlodipine or its pharmaceutically acceptable salt, preferably amlodipine besylate and bisoprolol fumarate formula

,

as well as a filler, a disintegrant, a lubricant and release agent used in the pharmaceutical industry, moreover, in which the number of connections N-(2-{[4-(2-chlorophenyl)-3-(ethoxycarbonyl)-5-(methoxycarbonyl)-6-methyl-1,4-dihydro-2-pyridinyl]-methoxy}-ethyl)-aspartic acid formula

does not exceed 0.5% during the preparation and storage of the composition.

Prior art

The desired value of the blood pressure to reduce the risk of cardiovascular disease and mortality can be achieved with the help of medications, consisting of a single connection or optimal combination of the two compounds in accordance with the practice of "evidence-based" therapy.

Combination therapy more effective; how the rights�lo, requires a smaller amount of each compound as compared with monotherapy, thus, reduced side effects and improved patient compliance with the treatment regimen.

Owing to these advantages, the role of combination therapy pharmaceutical drugs in the treatment of hypertension and its complications is increasing. Typically use a combination of beta-blockers, diuretic agents, ACE inhibitors (acetylcholinesterase), a receptor blocker angiotensin (ARB) calcium channel blockers.

Recently best for a patient's compliance with treatment and reduce the cost of therapy these combinations are often sold in the form of so-called fixed combination drugs containing both the active ingredient in a single dosage form.

The use of fixed combinations definitely recommended international guidelines.

Recently, the market offers several fixed combinations containing calcium channel blockers (calcium antagonists) and beta-blockers, used preferably for the treatment of hypertension and angina, such as tablets containing felodipine and metoprolol or nifedipine and atenolol.

The fixed combination of amlodipine and bisoprolol is still not on the market, but few articles�rd and patent applications relate to this combination. In the International patent application WO No. 2005/099699 disclosed a combination of S-amlodipine and beta-blockers, including combination with bisoprolol.

In the specified application mentioned several pharmaceutical solutions for the joint preparation of these ingredients, but they are also silent about the basic problem of practical applicability, namely the chemical incompatibility of both active ingredients.

In the so-called nanocomposite containing only one active ingredient, amlodipine is in a salt form bezilata and bisoprolol is used in the form of a fumarate salt.

The composition of amlodipine bezilata and bisoprolol fumarate in a single dosage form, apparently, is favorable, as bisoprolol fumarate and amlodipine besylate are suitable for the manufacture of stable pharmaceutical dosage forms.

As indicated in the patent application India No. 845/MUM/2004 of amlodipine besylate and bisoprolol fumarate interact. As a result, the authors of the present invention experiments it was found that the product is a compound of N-(2-{[4-(2-chlorophenyl)-3-(ethoxycarbonyl)-5-(methoxycarbonyl)-6-methyl-1,4-dihydro-2-pyridinyl]-methoxy}-ethyl)-aspartic acid of the formula (3). This compound is formed by chemical reaction of amlodipine base and fumaric acid. About�adowanie this product unexpectedly, because in the application for U.S. patent No. 6518288 indicated that the salt of amlodipine, which is formed with fumaric acid, is stable and is not converted into the compound of the formula (3).

The current requirements of the international pharmaceutical regulators permit only very low - a few tenths of a weight percent of the - limits of the content of degradation products of pharmaceutical compositions.

Absorbent properties and pharmacokinetic effects of the above-mentioned salts are well known. Patients accustomed to using compositions containing these salts, and they are accustomed to their effects.

There is a need for a stable solid dosage form, which contains amlodipine or its pharmaceutically acceptable salt, preferably amlodipine besylate and bisoprolol fumarate. The composition should be a tablet or capsule, in which the amount of impurities resulting from the incompatibility of both active ingredients is maintained at a low level and also during storage.

In accordance with the patent application India No. 845/MUM/2004 a combined composition of amlodipine bezilata and bisoprolol fumarate can be obtained only if the active ingredients are separated in different granules. The granules are mixed with additional excipients and fill in to�paly or sachets or compressed into so-called two-layer tablets. The essence of the decision in the Indian invention lies in the separation of the two ingredients from each other. While physical contact between the active ingredients, which may contribute to the formation of the reaction product of the formula (3) during mixing of the granules and, in particular, during the tabletting vigorous contact of large surfaces, essentially prevented.

Method in accordance with patent application in India has several drawbacks. Individual granulation and homogenization of the active ingredients increase the number of required process steps. The manufacture of bilayer tablets requires special medical equipment.

There is a need for a stable solid dosage form, which contains amlodipine or its pharmaceutically acceptable salt, preferably amlodipine besylate and bisoprolol fumarate. The composition should be a tablet or capsule, in which the amount of impurities resulting from the incompatibility of both active ingredients is maintained at a low level even during storage and which does not require separate processing of the active ingredients during the manufacturing process or in the composition.

A brief summary of the invention

The inventors unexpectedly found�or, in case of a correct choice of packaging and conditions can be prepared a stable pharmaceutical composition, which, when satisfactorily Packed, meets the requirements of stringent safety standards relating to medicines, and where the number N-(2-{[4-(2-chlorophenyl)-3-(ethoxycarbonyl)-5-(methoxycarbonyl)-6-methyl-1,4-dihydro-2-pyridinyl]-methoxy}-ethyl)-aspartic acid of the formula (3) in the composition during preparation or during storage prior to the expiry date of the composition, at least for two years, does not exceed 0.5%.

The present invention relates to a stable solid pharmaceutical composition containing amlodipine or its pharmaceutically acceptable salt, preferably amlodipine besylate, bisoprolol fumarate, and, in addition, pharmaceutically acceptable organic or inorganic filler, a disintegrant, a lubricant, anti-adhesive agents and Packed in moisture-proof packaging.

Detailed description of the invention

During the experiments, the inventors found that both active ingredients interact in a simple powder mixture and the reaction product is formed in considerable quantity. The incompatibility is more obvious in that case put both ingredients in a dosage form with low porosity,�reamer in a pill in which their crystals are in contact with each other at high pressure over a large area.

The interaction strongly depends on temperature: the content of amlodipine and bisoprolol in a mixture of amlodipine bezilata and bisoprolol fumarate varies after storage for one month at different temperatures as follows.

Table 1
25°C/1 month40°C/1 month70°C/1 month
Amlodipine-100%59%25%
Bisoprolol-100%85%71%

For the specialist in the field of pharmaceutical technology it is obvious that in the case of formation of a composition containing two incompatible ingredients, these ingredients must be separated using a suitable method. To solve this problem, coating one of the active ingredient polymer excipients may be sufficient. The polymer layer can form a suitable insulating layer between the crystal surfaces of both active ingred�coefficients.

Experiments with the development of compositions conducted by the authors of the present invention, was unsuccessful. The active ingredients were heat-sensitive. On the one hand, thermally-sensitive active ingredients causes problems not only in the case of water methods of application of the membrane, but also in the case of methods of coating with the use of organic solvents, since the removal of the solvent causes the temperature stress. On the other hand, during the drying process of the composition remain traces of moisture, which also contribute to the interaction of active ingredients.

The inventors unexpectedly discovered that the prevention of incompatibilities between both active ingredients and thermal degradation of active ingredients sufficient to exclude methods using water or organic solvents, accompanied with heat stress.

To prevent the adverse effects of temperature stress, the inventors have produced a combined tablets using direct compression method. If the tablet is kept in a glass vessel, closed with a plastic lid, at 30°C at 65% relative humidity for three months, the degradation products remained below the level of detection.

In the case where the W� the tablets were stored in thermoformed blister foil type PVC/PVdC (type polyvinyl chloride/ polyvinylidenechloride), closed with aluminum foil, at 30°C and 65% relative humidity for three months, the inventors unexpectedly found that the minimum humidity, which penetrates through the blister foil type PVC/PVdC (which is known as a more water resistant compared to PVC), is sufficient for the formation of unacceptably high degree of contamination.

It turned out that it is not enough to protect the product from moisture during the manufacturing process, but also during the storage environment should also be maintained dry.

These experiments suggest that the interaction between the ingredients in the solid phase rather the presence of extremely small amounts of water absorbed on the surfaces of the crystals. In the composition according to the present invention the reactions that lead to formation of impurities does not occur or happen only in a very limited range.

In accordance with the present invention proposed a stable solid packaged pharmaceutical composition, where the active pharmaceutical ingredients are amlodipine and bisoprolol, which contains less than 0.5%, preferably less than 0.3%, more preferably less than 0.2% of a compound of formula (3), Packed in moisture-proof packaging and contains the basis of Amla�ipina or its pharmaceutically acceptable salt, preferably amlodipine besylate, bisoprolol fumarate and pharmaceutically acceptable filler, a disintegrant, a lubricant, anti-adhesive agents, possibly binding agents.

In accordance with the discovery by the inventors amlodipine is reacted with fumaric acid. During the reactions leading to the formation of impurities, other salt-forming component (for example, the anion of a mixture of Benzenesulfonic acid) does not play any role. Thus, in accordance with the present invention amlodipine can be used in the form of a base or salt (such as amlodipine besilate).

The composition according to the present invention has a fundamental importance from the point of view of stability of the pharmaceutical composition.

For the manufacture of tablets using a dry method should be used such excipienti that possess suitable properties of pressuremost and free fluidity in addition to their primary function.

In accordance with the present invention all compounds of the composition excluding the active ingredients are excipienti.

Terms that refer to excipient, such as a filler, a disintegrant, a lubricant, anti-adhesive and binding agents, indicate category of excipients. Thus, they targetnode to mixtures of the corresponding excipients and their compositions in addition, to the normal use of excipients the same category in the same composition; This occurs, for example, if the filler composition used in two different filler used in the pharmaceutical industry, such as lactose and microcrystalline cellulose, in the form of a composite.

Terms related to the above excipients also apply to cases in which the composition contains several excipients different categories. In that case, if, for example, affinity is used in addition to the filler, for example lactose in the form of compositions with povidone and copovidone, or if lubricant or release agent is typically used with a filler, for example as a composition of microcrystalline cellulose with colloidal silicon dioxide.

In accordance with the present invention the use of such compositions equivalent to the conventional use of different components, therefore, these solutions also form part of the present invention.

As agents-fillers, the composition according to the present invention may contain excipients used in the pharmaceutical industry, or mixtures thereof, preferably microcrystalline cellulose, anhydrous hidratos�at calcium with spray-dried lactose or mannitol or a mixture thereof, most preferably grades of microcrystalline cellulose with low moisture content.

In the case conducted by the inventors of the tableting experiments found that the lowest degradation rate found in the case of microcrystalline cellulose (preferably used grades of microcrystalline cellulose with low moisture content; see Table 2).

Table 2

The effects of fillers in relation to degradation and speed of interaction after one month storage at 50°C (mixture of amlodipine besylate/bisoprolol fumarate/agent of filler and respect 0,1:0,1:5) are as follows.

Fillers
Microcrystalline cellulose (Vivapur)Anhydrous potassium hydrogen phosphate (Emcompress)Lactose DC 11 (Tablettose)DC mannitol (Perlitol)
The compound of formula (3)0,06%0,46%0,24%0,09%
All impurities0,29% 0,77%0,56%0,31%

Levels bulking agents suitable for direct compression into tablets in accordance with the present invention, comprise 60%-90%, preferably 70%-90%, more preferably 80% -90%.

The use of a filler in the case of products-caps is not necessary. To ensure uniform distribution of active ingredients in the same manufacturing batch and ensure that in each capsule is in the process of encapsulation was always filled with the required amount of both active ingredients, it is preferable to use a suitable amount of a filler having a high specific surface area, which prevents separation of ingredients in the method.

Such fillers having a high specific surface area, represent, for example, powdered cellulose or microcrystalline cellulose. Microcrystalline cellulose is preferred from the viewpoint that filling the capsule composition is held together with a relatively low pressure thickener due to mechanical blocking of the binding, which consequently prevents the dispersion of substances of the composition during the process of encapsulation.

Because of these reasons, the optimum amount of filler in �capsulerebel product is 10% -75%, preferably 45% -75%, more preferably 55%-65%, based on the mass of a substance filler in the composition.

The use of fillers with low moisture content in accordance with the present invention is more preferable.

In addition to the basic functional characteristics of excipient used for the preparation of tablet compositions using the dry method, must also possess acceptable properties of pressuremost and properties free yield.

Baking powder should be used as in the case of tableting, and in the case of encapsulated compositions, which allows for quick loosening of the tablet or capsule under the action of gastric juice, thus, the dissolution and absorption of active ingredients occur rapidly and completely. Suitable leavening agent, usually used in the pharmaceutical industry, can be used as a disintegrant. Large selection of baking powder, particularly suitable for tableting by direct compression, is at the disposal of the person skilled in the technical field.

Thus, the composition according to the present invention may include any of baking powder leavening agents, commonly used in the pharmaceutical industry, or a mixture thereof, preferably copovidone, sodium starch g�icost, croscarmellose, hydroxypropyl cellulose with a low degree of substitution or a mixture thereof, most preferably sodium starch glycolate. In accordance with the present invention the optimum amount of leavening agents in the compositions is 1% -10%, preferably 4%-6%, based on the weight of the tablets or filling capsules of the substance.

The use of release agents and lubricating agents need to be tableted and encapsulated compositions in which the release agents prevent moisture bulking agents that are prone to water absorption, and adhesion of the particles with each other due to intense hygroscopic properties.

Thus, as anti-adhesive agent composition according to the present invention can contain any type of anti-adhesive agents commonly used in the pharmaceutical industry, or a mixture thereof. Preferably it contains selody or colloidal silica or a mixture thereof. Most preferably it contains colloidal silicon dioxide. The optimal number of anti-adhesive agents in the compositions of the present invention is 0.3% -2%, preferably of 0.5% -1%.

The use of so-called lubricating agents, properties that reduce adhesion and friction, it is necessary in the case of tableting preparation and encapsulate�x compositions to facilitate the extrusion of tablets or filling substances in capsules form (devices) and prevent bonding of the components for forming or filling devices.

As the lubricant compositions according to the present invention can contain any types of lubricants used in the pharmaceutical industry, or a mixture thereof. Preferably, they contain magnesium stearate, sodium fumarate, glycerinated or a mixture thereof. Most preferably, they contain magnesium stearate. In accordance with the present invention, the optimum amount of lubricants in the compositions is 0.5% -3%, preferably 1%-2%.

Solid dosage form according to the present invention preferably is a tablet or capsule.

Unexpectedly, in the preferred case, for the manufacture of tablets do not require any of the binding agents used in the pharmaceutical industry. If, due to changes in the properties of tablets such as the increase of its hardness, it is necessary to use binding agents, any binding agent, for example polyvinylpyrrolidone, starch, etc., can be used as a binding agent.

In the case when the solid dosage form of the present invention is a tablet, in accordance with a preferred embodiment of the present invention the tablets are Packed in moisture-proof protective packaging, soda�RATM 2%-20%, preferably 2%-10%, most preferably 2%-6% of the base of amlodipine or its pharmaceutically acceptable salt, preferably amlodipine bezilata, 2%-20%, preferably 2%-10%, most preferably 2%-6% of bisoprolol fumarate, additionally 60%-90%, preferably 70%-90%, more preferably 80% -90% filler, 1%-10%, preferably 4%-6% disintegrant, and 0.5% -3%, preferably 1%-2% of the lubricant, of 0.3% -2%, preferably of 0.5% -1% anti-adhesive agent, and if necessary, with 0.1% -10%, preferably of 0.1% -5% of a binding agent based on the weight of the tablets.

In the case where the solid dosage form of the present invention is a capsule, in accordance with a preferred embodiment of the present invention capsules, Packed in moisture-proof protective packaging contain 5%-80%, preferably 5%-18%, most preferably 10%-15% of the base of amlodipine or its pharmaceutically acceptable salt, preferably amlodipine bezilata, 5%-80%, preferably 5% -15%, most preferably 1%-10% of bisoprolol fumarate, an additional 1% -10%, preferably 4%-6% disintegrant, and 0.5% -3%, preferably 1%-2% the lubricant, of 0.3% -2%, preferably of 0.5% -1% anti-adhesive agent and, if necessary, 10%-75%, preferably 45% -75%, more preferably 55%-65% of a filler based on the weight of the substance on�of omnitele capsules.

In a packaged dosage forms in accordance with the present invention a pharmaceutical composition comprising an active ingredient, such as tablets or capsules, in a package that separates the dosage form from the environment, thus protecting the dosage form from the environment prior to the introduction.

As examples of these different forms of packaging materials, for which the following abbreviations are used:

CFF - foil for cold forming

foil, OPA/AL/PVC foil from oriented polyamide/aluminium/polyvinyl chloride)

foil PVC/PE/PVdC (foil of polyvinyl chloride/ polyethylene/polyvinylidenechloride)

foil PVC/PCTFE (foil PVC/polychlorotrifluoroethylene)

layer/PVdC foil (polyvinylidenechloride)

foil PVC (polyvinyl chloride)

Moisture-proof packaging of solid dosage forms of the present invention is a hermetically closed vessel or so-called moisture-proof blister packs for cold forming (CFF) or termoformiruemy the blister.

In accordance with one embodiments of the present invention moisture-proof packaging may be a vessel having a closing component (e.g., bottle, plastic container, glass jar with airtight �polietileno or polypropylene cap, polypropylene jar, etc.), which put one or more than one tablet or capsule.

Vessels containing tablets or capsules, optionally, can contain in addition to the capsules and tablets auxiliary agents, which are able to bind moisture from the inner atmosphere of the vessel, such compounds for binding moisture to represent, for example, zeolites or silica gel. Auxiliary agents for water binding can be placed directly among capsules or tablets, but they can also be placed in a separate vessel or container, permeable to air and located among dosage forms. Such vessels are also suitable for the packaging of solid dosage forms in accordance with the present invention, in which a dosage form and a compound that binds the moisture, are located in two separate parts, and thus provides breathability.

In an atmosphere packaging can be air, inert gases or, if suitable, vacuum.

In accordance with an embodiment of the present invention, the moisture-proof protective packaging is a so-called blister packs for cold forming. Blister packaging cold forming is a form of packaging in which the blister package is subjected to cold forming of components�itoi foil and membrane is covered with the aluminum foil. Such a composite foil can be a OPA/AL/PVC foil from oriented polyamide/aluminium/polyvinyl chloride). In accordance with an embodiment of the present invention dosage forms containing the active ingredient, such as tablets or capsules, Packed in so-called blister packs for cold forming.

In accordance with another embodiment of the present invention, the moisture-proof packing represents, for example, blister packaging made from thermoformed, water resistant composite foil, which is coated aluminium membrane foil.

In accordance with another embodiment of the present invention, the dosage form containing the active ingredient, such as tablets or capsules, Packed in blister packaging made from water resistant thermoformed foil, which is coated aluminium membrane foil. This water resistant composite foil may be, for example PVC/PE/PVdC, the so-called triple foil or foil PVC/PCTFE.

In accordance with the preferred embodiment of the present invention a dosage form is a tablet, packaged in blister packs for cold forming of composite foil, OPA/AL/PVC membrane and coated aluminum� foil (so-called blister packaging cold forming/CFF/), or Packed in blister packs from thermoformed water-proof composite foil (for example, triple foil PVC/PE/PVdC or foil PVC/PCTFE), membrane coated aluminum foil, or in a glass or polypropylene vessel having a sealed lid for the container of polyethylene or polypropylene, where the tablet contains 2%-6% of amlodipine bezilata, 2%-6% of bisoprolol fumarate, 80% -90% of microcrystalline cellulose, 4%-6% of sodium chromalveolata, 1%-2% magnesium stearate and 0.5% -1% colloidal silicon dioxide relative to the total mass of the tablet.

In accordance with another preferred embodiment of the present invention proposed a capsule, packaged in blister packs for cold forming of composite foil, OPA/AL/PVC membrane and coated aluminum foil (so-called blister packaging cold forming/CFF/), or Packed in blister packs from thermoformed water-proof composite foil (e.g. triple foil PVC/PE/PVdC or foil PVC/PCTFE), membrane coated aluminum foil, or in a glass or polypropylene vessel having a sealed lid made of polyethylene or polypropylene, where the capsule contains 10%-15% amlodipine bezilata, 10%-15% of bisoprolol fumarate, 55%-65% of microcrystallinecellulose, 4%-6% of sodium chromalveolata, 1%-2% magnesium stearate,0,5% -1% colloidal silicon dioxide, the total mass filling the capsule substance.

The composition according to the present invention contains less than 0.5%, preferably from 0.01% to 0.5% N-(2-{[4-(2-chlorophenyl)-3-(ethoxycarbonyl)-5-(methoxycarbonyl)-6-methyl-1,4-dihydro-2-pyridinyl]-methoxy}-ethyl)-aspartic acid. In accordance with a preferred embodiment of the present invention, the amount of a derivative of aspartic acid is less than 0.3%, more preferably, the amount is 0.01% to 0.3%. In accordance with a preferred embodiment of the present invention, the amount of a derivative of aspartic acid is less than 0.2%, more preferably of 0.01% to -0.2%. Specialist in the art can prepare a product containing a compound of the formula (3) in redetection the amount using the essential characteristics of the present invention. Thus, the scope of protection of the present invention includes products that use essential characteristics of the present invention, and the product contains netdetective amount of a compound of formula (3).

In the process of preparation of compositions in accordance with the present invention the basis of amlodipine or its pharmaceutically acceptable salt, preferably amlodipine besylate, bisoprolol fumarate, additional organic or not�organicheski filler baking powder, lubricant and possibly linking agent used in the pharmaceutical industry, homogenized in a known manner, then add the adhesive agent and homogenized, then:

A) obtained homogenizate compressed into tablets in a known manner or

B) fill in hard gelatin capsules in a known manner, then the resulting tablets or capsules are packaged in moisture-proof packaging in a known manner.

If necessary, homogenization may be preceded by sieving to achieve a uniform grain-size components. For sifting preferably can be used a sieve of 250 μm. Homogenization can be carried out in any equipment suitable for the homogenization, preferably in the mixer drum. Tablets can be extruded using any type of equipment for the manufacture of tablets by direct compression in a known manner. Capsules can be manufactured in a known manner using any suitable process for encapsulating equipment.

Tablets or capsules are Packed in suitable blister packaging or receptacles in a known manner.

Tablets prepared using 2% -20%, preferably 2%-10%, most preferably 2%-6% of amlodipine base or a pharmaceutical� acceptable salt, preferably amlodipine bezilata, 2%-20%, preferably 2%-10%, most preferably 2%-6% of bisoprolol fumarate, in addition, 60%-90%, preferably 70%-90%, most preferably 80% -90% filler, 1%-10%, preferably 4%-6% disintegrant, about 0.5-3%, preferably 1%-2% of the lubricant, 0.3 to 2%, preferably of 0.5% -1% anti-adhesive agent, and optionally about 0.1% -10%, preferably 0.1-5% of a binding agent.

Capsules are prepared using 5%-80%, preferably 5%-18%, most preferably 10%-15% of the base of amlodipine or its pharmaceutically acceptable salt, preferably amlodipine bezilata, 5%-80%, preferably 5% -15%, most preferably 10%-15% of bisoprolol fumarate, in addition, 1%-10%, preferably 4%-6% disintegrant, about 0.5-3%, preferably 1%-2% of the lubricant, 0.3 to 2%, preferably of 0.5% -1% anti-adhesive agent, and optionally, 10%-90%, preferably 45%-75%, most preferably 55%-65% of a filler based on the weight of the filling substance of the capsule.

Microcrystalline cellulose, anhydrous calcium hydrogen phosphate, spray dried lactose or mannitol, preferably microcrystalline cellulose or a mixture thereof, more preferably microcrystalline cellulose having a low moisture content, can be used as a filler, copovidone, sodium chromalveolata, kroska�mellosa, viscosimetry hydroxypropyl cellulose or a mixture thereof, preferably sodium chromalveolata, can be used as disintegrant, magnesium stearate, sodium fumarate, glycerinated or a mixture thereof, preferably magnesium stearate, can be used as a lubricating substance for the manufacture of tablets or capsules in accordance with the present invention. Selody or colloidal silica or a mixture thereof, preferably colloidal silicon dioxide, used as anti-adhesive agents, and optionally polyvinylpyrrolidone or starch used as a binding agent.

Tablets or capsules are preferably packaged in blister packs for cold forming of composite foil, OPA/AL/PVC thickness 130 µm membrane coated aluminum foil with a thickness of 20 μm (so-called blister packaging cold forming/CFF/), or in blister packs obtained from thermoformed water-proof composite foil, membrane coated aluminum foil of thickness 20 μm, or in vessels equipped with leak-proof lid for a container made of polyethylene or polypropylene. Most preferably the composition is packaged in so-called blister packs for cold forming (CFF).

Another embodiment of the water resistant�th packaging, as mentioned above, consists in packing of tablets or capsules, together with desiccant, which bind moisture. These forms of packaging and auxiliary agents described above.

In accordance with a preferred method for preparing solid pharmaceutical dosage forms tablets, 2%-6% of amlodipine bezilata, 2%-6% of bisoprolol fumarate, 80% -90% of microcrystalline cellulose, 4%-6% of sodium chromalveolata, 1%-2% magnesium stearate, homogenize, then add 0.5% -1% of colloidal silicon dioxide and homogenized, and then the homogenate is compressed into tablets using direct compression method in a known manner, received tablets packaged in blister packs for cold forming of composite foil, OPA/AL/PVC and aluminum cover membrane foil (so-called blister packaging cold forming/CFF/), or in blister packs from thermoformed water-proof composite foil, such as triple-foil PVC/PE/PVdC or foil PVC/PCTFE, membrane coated aluminum foil, or packaged in glass or polypropylene vessel having a sealed lid made from polyethylene or polypropylene, preferably the tablets are packaged in blister packs for cold forming of composite foil, OPA/AL/PVC, covered aluminum membrane foil (so �so-called blister packaging cold forming/CFF/).

In accordance with the preferred method of preparation of a solid pharmaceutically acceptable dosage forms capsules, 10%-15% of amlodipine bezilata, 10%-15% of bisoprolol fumarate, 55%-65% of microcrystalline cellulose, 4%-6% of sodium chromalveolata, 1%-2% magnesium stearate based on the total weight of the filling substance homogenize, then add 0.5% -1% of colloidal silicon dioxide and homogenized, then homogenate encapsulate into hard gelatin capsules in a known manner and packaged in blister packaging cold forming of composite foil, OPA/AL/PVC and aluminum cover membrane foil (so-called blister packaging cold forming/CFF/), or in blister packs from thermoformed water-proof composite foil, such as triple-foil PVC/PE/PVdC or foil PVC/PCTFE, membrane coated aluminum foil, or in a glass or polypropylene vessel having a sealed container made of polyethylene or polypropylene, preferably the tablets are Packed in blisters of cold forming of composite foil, OPA/AL/PVC membrane coated aluminum foil (so-called blister pack for cold forming/CFF/).

An advantage of the present invention is that it makes possible the use of simple and Deshevo� of a direct tableting, even in the case of compositions in accordance with the present invention containing incompatible active ingredients. The content of compound (3) in the composition according to the present invention does not exceed 0.5% for at least 2 years.

In the case of combination of the composition with better patient adhered to the treatment regimen, thus, these compositions are more favourable than the composition used as monotherapy.

The present invention is demonstrated by the examples below without limiting examples of the scope of protection.

Example 1

Composition for 1000 tablets:

Amlodipine besylate13,9 g
Bisoprolol fumarate10.0 g
Microcrystalline cellulose265,1 g
Sodium chromalveolata10.0 g
Magnesium stearate4.0 g
Colloidal silicon dioxide2.0 g

Method:

Both the active ingredient was sieved with a sieve of 250 µm mesh, then homogenized with microcrystalline cellulose, n�of tri chromalveolata and colloidal silicon dioxide in a drum type mixer for ten minutes. Then magnesium stearate is added to the mixture and the resulting mixture was homogenized for two more minutes.

Homogenate compressed into tablets having a weight of 305 mg, by using the apparatus for compression of tablets.

The tablets are packaged in blister packs for cold forming of composite foil, OPA/AL/PVC thickness 130 μm membrane and coated aluminum foil with a thickness of 20 microns.

The results verify the content of impurities in tablets prepared in accordance with Example 1, on the date of manufacture and after storage for 3 months at 40°C/75% RH is shown below.

The impurityAt the date of manufactureAfter 3 months (40°C/75% relative humidity)After 6 months (40°C/75% relative humidity)
N-(2-{[4-(2-chlorophenyl)-3-(ethoxycarbonyl)-5-(methoxycarbonyl)-6-methyl-1,4-dihydro-2-pyridinyl]-methoxy}-ethyl)-aspartic acid<0,02%0,15%0,26%

Additional data on the quality of the product of example 1 by using the machinery discovered is shown below.

To date� manufacturing After 3 months (40°C/75% relative humidity)
Disintegration time1'1'
Dissolution of active ingredient (15 minutes)
Amlodipine besylate103,1%97,9%
Bisoprolol fumarate102,6%98,9%
Fracture resistance104 N113 N
Loss by friction0%0%
Moisture (Karl Fischer)3,3%3,5%

Example 2

Composition for 1000 capsules:

Amlodipine besylate6,95 g
Bisoprolol fumarate5.0 g
Microcrystalline cellulose30,05 g
Sodium chromalveolata20 g
Magnesium stearate2.0 g
Colloidal silicon dioxide1.0 g

Method:

Both the active ingredient was sieved with a sieve of 250 µm mesh, then homogenized with microcrystalline cellulose, sodium chromalveolata and colloidal silicon dioxide in a drum type mixer for ten minutes. Then magnesium stearate is added to the mixture, and the resulting mixture was homogenized for two more minutes.

The small particles filled in capsules containing 47 mg of the filling substance, with use of the device for compression of tablets.

The capsules are packaged in blister packs for cold forming of composite foil, OPA/AL/PVC thickness of 130 μm and coated aluminium membrane foil with a thickness of 20 microns.

The results verify the content of impurities in capsules, prepared and Packed in accordance with Example 2, on the date of manufacture and after storage for 3 months at 40°C/75% RH is shown below.

The impurityAt the date of manufactureAfter 3 months (40°C/75% relative humidity)After 6 months (40°C/75% �tosichella humidity)
N-(2-{[4-(2-chlorophenyl)-3-(ethoxycarbonyl)-5-(methoxycarbonyl)-6-methyl-1,4-dihydro-2-pyridinyl]-methoxy}-ethyl)-aspartic acid<0,02%0,11%0,23%

Reference example:

Composition for 1000 tablets:

Amlodipine besylate13,9 g
Bisoprolol fumarate10.0 g
The potassium hydrogen phosphate × 2H2O (Emcompress)189,0 g
Corn starch (STA-RX-1500)40,1 g
Povidone K-2514.0 g
Polyplasdone10.0 g
Magnesium stearate2.0 g
Colloidal silicon dioxide1.0 g

Method:

Both the active ingredient was sieved with a sieve of 250 µm mesh, then homogenized with Emcompres, corn starch, povidone, polyplasdone and colloidal silicon dioxide in a drum type mixer for ten minutes. Then magnesium stearate is added to�t to the mixture and the resulting mixture was homogenized for two more minutes.

Homogenate compressed into tablets having a weight of 280 mg, by using the apparatus for compression of tablets.

The tablets are Packed in blister packaging for thermoforming of PVC foil with a thickness of 250 μm and a layer of coating 60 g/m2PVdC, blister aluminum cover membrane foil with a thickness of 20 microns.

The results verify the content of impurities in tablets prepared in accordance with the Reference example, at the date of manufacture and after storage for 3 months at 40°C/75% RH is shown below.

The impurityAt the date of manufactureAfter 3 months (40°C/75% relative humidity)
N-(2-{[4-(2-chlorophenyl)-3-(ethoxycarbonyl)-6-(methoxycarbonyl)-6-methyl-1,4-dihydro-2-pyridinyl]-methoxy}-ethyl)-aspartic acid<0,02%0,47%

Impurities in tablets in accordance with the Reference example is significantly higher after storage for 3 months, which is partly a consequence of the chemical properties of the used excipients (humidity and chemical incompatibility), partly a consequence of the lack of moisture resistance properties of the packaging system.

1. A method of manufacturing a stable�Oh Packed solid dosage forms, contains the basis of amlodipine or its pharmaceutically acceptable salt and bisoprolol fumarate, characterized in that the base of amlodipine or its pharmaceutically acceptable salt and bisoprolol fumarate, a disintegrant, a lubricant and optionally additional excipient used in the pharmaceutical industry, homogenize, then add anti-adhesive agent and continue homogenization, then
(a) homogenate compressed into tablets using direct compression method or
b) fill in hard gelatin capsules in a known manner,
then, the resulting tablets or capsules are packaged in moisture-proof protective packaging in a known manner.

2. The method of manufacture of tablets according to claim 1, wherein using 2%-20%, preferably 2%-10%, more preferably 2-6% of the base of amlodipine or its pharmaceutically acceptable salt accession acid, preferably amlodipine bezilata, 2%-20%, preferably 2%-10%, more preferably 2%-6% of bisoprolol fumarate, additionally 60%-90%, preferably 70%-90%, more preferably 80% -90% filler, 1%-10%, preferably 4%-6% disintegrant, and 0.5% -3%, preferably 1%-2% the lubricant, and 0.1% -10%, preferably 0.1-5% of a binding agent relative to the weight of the tablets.

3. A method of manufacturing a capsule according to claim 1, in which approx�tween 5%-80%, preferably 5%-18%, more preferably 10-15% of the base of amlodipine or its pharmaceutically acceptable salt accession acid, preferably amlodipine bezilata, 5%-80%, preferably 5% -15%, more preferably 10%-15% of bisoprolol fumarate, an additional 1% -10%, preferably 4%-6% disintegrant, and 0.5% -3%, preferably 1%-2% of the lubricant, of 0.3% -2%, preferably of 0.5% -1% anti-adhesive agent, and optionally, 10%-75%, preferably 45% -75%, more preferably 55%-65% of the filler relative to the weight of filling the capsule substance.



 

Same patents:

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to the chemical-pharmaceutical industry and represents a composition in the form of a gelatine capsule possessing the antihypertensive action, containing lisinopril dihydrate granules and verapamil hydrochloride tablets in a ratio of 1:5 to 1:20.

EFFECT: invention refers to a method for preparing this composition, consisting in encasing the lisinopril granules and verapamil tablets into the gelatine capsule that provides the ease of preparing the dosage form, and an acceptable profile of the therapeutic substance release.

2 cl, 2 ex, 4 tbl, 2 dwg

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely to therapy and endocrinology, and concerns the correction of the crisis course of hypertensive disease and abdominal obesity. To this effect, Moxogamma 200-400 mcg/day and Reduxin 18-30 mg/day are administered with underlying a therapy of the angiotensin converting enzyme inhibitor lisinopril. The preparations are administered in two stages - in the morning and 6 or 7 hours later; Moxogamma is first to be administered, and Reduxin is administered 40-60 min later.

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12 tbl, 2 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new cyclic indolysincarboxamides and azaindolysincarboxamides of formulas Ia and Ib:

presented below, wherein the values of R, Ra, R10, R20, R30, R40, Y, n, p and q are specified in cl. 1 of formula. What is described is a method for preparing them.

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11 cl, 4 tbl, 17 ex

FIELD: pharmacology.

SUBSTANCE: invention relates to a therapeutical or preventive agent for treatment of hypertension or high blood pressure and to the appropriate method of treatment with its usage. The proposed agent contains (a) and (b) as active ingredients: (a) 2-(3-cyano-4-isobutyloxyphenyl)-4-methyl-5-thiazolcarbonic acid (febuxostat) or its pharmaceutically acceptable salt; (b) a compound selected from a group made of blockers of calcium channels, blockers of a receptor of angiotensin II, and inhibitors of an angiotensin-converting ferment and their salts applicable from the point of view of medicine.

EFFECT: synergism of lower blood pressure on a model of spontaneous hypertension.

9 cl, 4 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to organic chemistry, namely to mixture of E- and Z-isomers of (4-bromophenyl)ethylidene hydrazide of 2-[6-methyl-1-(thiethan-3-yl)uracyl-3-yl]acetic acid in molar ratio 3.5:1 of general formula: .

EFFECT: obtained is novel mixture of isomers, demonstrating hypotensive activity.

2 cl, 4 tbl, 4 ex

FIELD: chemistry.

SUBSTANCE: invention relates to heterocyclic compound of formula or to its pharmaceutically acceptable salt, where Alk represents linear C1-6 alkylene group, branched C1-6 alkylene group or C1-6 alkylene group, which has ring structure, where part of carbon atoms, constituting ring structure can be optionally substituted with oxygen atom, in ring X, X1 represents N or CRX1, X2 represents N or CRX2, X3 represents CRX3, X4 represents N or CRX4, where RX1, RX2, RX3 and RX4 each independently represents hydrogen atom; linear or branched C1-6alkyl group; linear or branched C1-6alcoxygroup; or halogen atom, in ring Y, Y1 represents CRY1, Y2 represents N or CRY2, Y3 represents N or CRY3, Y4 represents N or CRY4, RY1, RY2, RY3 and RY4 each independently represents hydrogen atom; linear or branched C1-6alkyl group, which can be substituted with halogen atom(s); C3-7alkyl group, which has ring structure; linear or branched C1-6alkoxygroup; halogen atom or cyanogroup, in ring Z, RZ represents linear or branched C1-6alkyl group, which can be substituted with halogen atom(s), or C3-7alkyl group, which has ring structure, which can be substituted with halogen atom(s). Invention also relates to particular compounds, DGAT1 inhibitor based on formula (I) compound, application of formula (I) compound, method of prevention or treatment of diseases, mediated by DGAT1 inhibition.

EFFECT: obtained are novel compounds, possessing useful biological activity.

19 cl, 19 tbl, 149 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to substituted isoquinolines and isoquinolinones of formula (I) and to their stereoisomer and/or tautomer forms and/or pharmaceutically acceptable salts, wherein R1 is H, OH or NH2; R3 is H; R4 is H, halogen or (C1-C6)alkylene-R'; R5 is H, halogen, (C1-C6)alkyl; R7 is H, halogen, (C1-C6)alkyl, O-(C1-C6)alkyl; R8 is H; R6 is absent; or is one of (C1-C4)alkylene related to a cycloalkyl ring related to a cycloalkyl ring, wherein (C1-C4)alkylene forms a second bond to another carbon atom of the cycloalkyl ring to form a bicyclic ring system, R10 is H, phenyl, or pyridine, wherein phenyl is unsubstituted or substituted; R11 is H, (C1-C6)alkyl; or R11 and R12 together with the carbon atom to which they are attached form (C3)cycloalkyl; R12 is (C1-C6)alkyl, (C3-C8)cycloalkyl or phenyl; or R12 is H, provided r=2 and another R12 is other than H; or R11 and R12 together with the carbon atom to which they are attached form (C3)cycloalkyl; R13 and R14 are independently H, (C1-C6)alkyl, (C1-C6)alkylene-R', C(O)O-(C1-C6)alkyl, n is equal to 0; m is equal to 1 or 2; s is equal to 1 or 2; r is equal to 1 or 2; L is O, NH; R' is (C3-C8)cycloalkyl, (C6-C10)aryl; wherein in R11 and R12 residues, alkyl is unsubstituted or optionally substituted by one OCH3; wherein in R11 and R12 residues, alkyl is unsubstituted or optionally substituted by one or more halogens; wherein in R10 and R12 residues, (C6-C10)aryl is unsubstituted or optionally substituted by one or two groups optionally specified in halogen, CN, (C1-C6)alkyl, O-(C1-C6)alkyl, SO2-(C1-C6)alkyl, CF3 and OCF3. Also, the invention refers to using a compound of formula (I).

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38 cl, 132 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to phenol derivatives of formula (1), wherein R1 represents C1-C6 alkyl group, C1-C6 alkynyl group, C1-C6 halogen alkyl group, C1-C6 alkyl sulphanyl group or a halogen atom, R2 represents a cyano group or a halogen atom, R3 represents a hydrogen atom, and X represents -S(=O)2. Besides, the invention refers to a drug preparation containing a compound of formula (I) as an active ingredient.

EFFECT: phenol derivatives of formula (1) characterised by the high urine concentration of the permanent compound, and possess the uricosuric action.

11 cl, 1 dwg, 2 tbl, 42 ex

FIELD: medicine.

SUBSTANCE: with the underlying conventional drug therapy, the patient is exposed to millimetre-wave electromagnetic emission at the molecular spectrum frequencies of oxygen emission and absorption spectra with the exposure localised within the xiphoid appendix. The exposure time is 3 minutes continuously within one session. The output emissive power is 500 mcW at the power density on the skin surface of 17.4 mcW/cm2. A distance of the exposure point and an object is specified to be equal to 4 cm. The therapeutic course makes 7-10 sessions, one session a day.

EFFECT: higher therapeutic effectiveness in patients with angina or arterial hypertension ensured by the antihypertensive and antianginal effect resulted from the specified mode of the terahertz exposure.

2 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: claim describes a standard solid dosage form for oral administration which represents a mini-tablet having a core and an outer coating, wherein the core contains a therapeutically effective amount of aliskiren or its pharmaceutically acceptable salt, while the outer coating represents a film coating containing a taste masking material specified in polyacrylates, and/or a release modifying ingredient of the coating specified in cellulose derivatives and acryl copolymers, and a mixture thereof. The above mini-tablet has a size of 1 mm to 4 mm and contains aliskiren in an amount making 2 mg/tablet to 4 mg/tablet. The oral solid dosage form is preferentially applied in paediatrics.

EFFECT: according to the invention, the dosage form of aliskiren can be dosed and possesses a taste that makes it applicable for children, and maintains a biological availability at a level comparable to that of the available medicinal product for adults.

19 cl, 13 dwg, 5 tbl, 3 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed invention relates to the pharmaceutical industry and provides a multilayered tablet, containing an effervescent layer, containing hydrochlorothiazide or amlodipine or its salt as an active ingredient, carbonate salt and organic acid, and a telmisartan-containing layer.

EFFECT: obtaining the multilayered tablet, containing the effervescent layer.

1 dwg, 9 tbl, 9 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention concerns a hot-melt extruded pharmaceutical dosage form with controlled-release pharmaceutically active ingredient (A) enclosed in a matrix containing polymer (C). A core of the pharmaceutical dosage form is morphologically oriented according to the holt-melt extrusion, which is substantially orthogonal to a long direction of the dosage form; and/or a release per a unit area of the pharmacologically active ingredient (A) through a front side and an opposite back side is faster than that through an annular ring.

EFFECT: dosage form shows min breaking strength 300 H; it has an oblong shape with the long direction and the cross direction orthogonal to the long one, with the front side opposite to the back side, and the annular rim between the above front and back sides.

11 cl, 20 tbl, 3 ex, 13 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: group of inventions refers to medicine. What is described is a pharmaceutical composition containing licarbazepine acetate, preferentially eslicarbazepine acetate, in a combination with acceptable excipients, particularly a binding agent and a disintegrating agent. What is also described is a method for wet granulation for preparing the pharmaceutical composition.

EFFECT: composition is compacted as a tablet, which has reduced size and volume density.

79 cl, 10 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to a method for producing a tablet by (i) compressing a powder mixture in a mould plate of one device for producing a tabletted form with the powder mixture comprising a pharmaceutically active substance and a fusible binding agent, and (ii) exposing the above tabletted form to radio-frequency radiation generated by the above device over a period of time adequate to soften or melt the binding agent inside the above tabletted form to produce a tablet. Oral absorption of the produced tablet placed on the tongue takes less than approximately 30 s.

EFFECT: more effective method for producing the tablet by (i) compression.

18 cl, 14 dwg, 7 tbl, 9 ex

FIELD: chemistry.

SUBSTANCE: invention provides a composition having antioxidant properties in the form of a tablet, comprising an active agent based on nicotinamide adenine dinucleotide in reduced form (NADH) and inert filling agents, characterised by that the active ingredient is a complex which is a mixture of 10 wt % NADH with 63 wt % vegetable fats, 17 wt % beeswax and 10 wt % chlorophyll, and the inert filling agents are in the form of microcrystalline cellulose, Macrogol 6000, intense sweetener and a food flavourant.

EFFECT: invention provides a new tablet form of NADH.

1 ex

FIELD: chemistry.

SUBSTANCE: as active component pharmaceutical composition contains dihydrochloride of 9-(2-morpholine ethyl)-2-(4-fluorophenyl)imidazo[1,2-α]benzimidasol, and as additional substances - fillers, binding, sliding and film coatings, in quantities, given in the invention formula. Composition can be made in form of solid medication form, mainly in form of tablets and capsules.

EFFECT: obtained solid medication forms satisfy the requirements of the State Pharmacopoeia.

7 cl, 2 dwg, 3 tbl, 14 ex

FIELD: medicine.

SUBSTANCE: invention refers to a pharmaceutical composition with anti-ischemic and antioxidant activity in the form of tablets or capsules, and a method for preparing it. The composition contains 4-((3-oxo-3-ethoxypropanoyl)amino)benzoic acid in an amount of 40 to 80 wt %, an amino-containing compound and pharmaceutically acceptable excipients. The amino-containing compound is specified in a group of trometamol, methyl glucamine and L-lysine; 1 mole of 4-((3-oxo-3-ethoxypropanoyl)amino)benzoic acid is accounted for 0.05 to 0.25 mole of the above amino-containing compound. The composition also contains lactose, microcrystalline cellulose, calcium stearate and other pharmaceutically acceptable excipients. According to the method for preparing the composition, taking 4-((3-oxo-3-ethoxypropanoyl)amino)benzoic acid and amino-containing compound in molar ratio 1:0.05 to 1:0.25, pre-mixing, moisturising with a aqueous or alcohol solution of a binding agent, adding pharmaceutically acceptable excipients in such an amount to provide the content of 4-((3-oxo-3-ethoxypropanoyl)amino)benzoic acid from 40 to 80 wt %, granulating the mixture, drying and producing tablets or capsules according to the known technique.

EFFECT: implementing the above application.

6 cl, 7 tbl, 4 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to pharmaceutics, in particular a pharmaceutical composition in the form of a peroral drug form is described. The composition includes rebamipide as an active ingredient and a pharmaceutically acceptable carrier. Rebamipide is contained in an amount from 0.5 to 50 mg/kg, preferably from 0.6 to 6 mg/kg.

EFFECT: application of the rebamipide-based pharmaceutical composition for the prevention and treatment of arthrosoarthritis.

5 cl, 3 dwg, 1 tbl, 1 ex

FIELD: medicine.

SUBSTANCE: agent is presented in the form of a tablet, contains isoniazid and a substance which reduces its toxicity; as the substance which reduces the isoniazid toxicity, it contains thiotriazolin. The isoniazid/thiotriazolin ratio makes 4:1.

EFFECT: combined antituberculous drug ensures reducing toxicity as compared to the known ones and increasing its pharmacological activity.

2 cl, 1 ex, 1 tbl

FIELD: medicine.

SUBSTANCE: invention represents a pharmaceutical composition for treating the HIV infection in the form of a solid dosage form, containing at least one HIV protease inhibitor in a therapeutically effective amount specified in a group of nelfinavir, sacvinavir, tipranavir, darunavir, indinavir, ritonavir, lopinavir, palinavir or fosamprenavir, and pharmaceutically acceptable additives differing by the fact that as the pharmaceutically acceptable additives it contains at least one water-insoluble polymer from 0.39 to 28 wt % of the total dosage form, surfactants, excipients up to 100% of the total dosage form, as well as a method of treating the HIV infection.

EFFECT: pharmaceutical composition according to the invention possesses the improved technological properties and improved bioavailability as compared to a prototype therapeutic agent.

10 cl, 4 ex, 1 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed invention relates to the pharmaceutical industry and provides a multilayered tablet, containing an effervescent layer, containing hydrochlorothiazide or amlodipine or its salt as an active ingredient, carbonate salt and organic acid, and a telmisartan-containing layer.

EFFECT: obtaining the multilayered tablet, containing the effervescent layer.

1 dwg, 9 tbl, 9 ex

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