Treatment and prevention of cardiovascular diseases

FIELD: medicine.

SUBSTANCE: pharmaceutical unit dosage form for treatment or prevention of cardiovascular episodes contains therapeutic amount of: antagonist of β-adrenergic receptor, diuretic or both; an agent lowering cholesterol level; an inhibitor of renin-angiotensin system; and aspirin. The pharmaceutical unit dosage form can be made in a two-layered tableted form. The first layer thereof contains simvastatin and aspirin, the second layer contains athenolol and lisinopril, or the second layer contains hydrichlorothiazide and lisinopril.

EFFECT: according to the invention pharmaceutical unit dosage form combines a number of drugs for oral intake once a day that improves compliance by the patient with prescribed regimen due to elimination of inconveniences related to intake of several doses of drugs during the day, and reduces probability of missing the dose.

24 cl, 5 ex

 

Introduction to the invention of

The present invention relates to the treatment of patients with increased risk of cardiovascular episodes, and more particularly to pharmaceutical compositions for such treatment, combining the blocking agent β-adrenergic receptor with the agent in order to decrease the cholesterol level, the inhibitor system of the renin-angiotensin and aspirin in a dosage form for a single reception, and to the method of preparation of pharmaceutical compositions.

Cardiovascular diseases are the major cause of morbidity and mortality in the world, contributing 16.6 million deaths in 2001, the Majority (80 percent) of all deaths attributed to cardiovascular diseases (CVDs), occur in low-and middle-income countries. It is expected that by 2010 CVDs will be the leading cause of death in developing countries. At the present time for developing and other countries there is an urgent need for the development and implementation of interventions with CVDs.

A significant portion of the world's population suffers from a serious and threatening the lives of cardiovascular episodes such as myocardial infarction (heart attack), cardiac arrest, congestive heart failure, stroke, peripheral vascular disease and intermittent claudication. the actors risk associated with such life-threatening episodes, including tobacco Smoking, diabetes, elevated serum cholesterol, hypertension, systemic lupus erythematosus, previous heart attacks or strokes, hemodialysis, elevated homocysteine levels, obesity, sedentary lifestyle, transplant organs, and others.

The risk of cardiovascular episode is not limited to patients with hypertension or hypercholesterolemia, and applies to all people with blood pressure above 115/75 mm Hg, and total cholesterol above 4.0 mmol/l (about 155 mg/DL). However, only in the last few years, clinical trials have confirmed the benefit of lower blood pressure and cholesterol in patients with high risk of not having a clinical diagnosis of hypertension or hypercholesterolemia. Thus, for the vast majority of the adult population and almost all people with established vascular disease would benefit from treatment to reduce blood pressure and cholesterol, requiring simultaneous administration of agents that lower blood pressure and cholesterol levels.

In the report on the recent meeting of the world health organization and the organization Wellcome Trust authors pointed to a huge unmet need in cardiovascular therapy and perekaman is ovali the development of combination products for her. The number of people at high risk, which would be useful affordable combined cardiovascular therapy in India and many other countries is significant. In the combined product of each component causes a proportional reduction in risk, independent of the presence or absence of other drugs. Long-term beneficial effects would be even greater, perhaps providing more than 75 percent reduction in overall risk, because the risk is only partially eliminated in the first one or two years of treatment to reduce blood pressure and cholesterol.

With the above unmet needs would be beneficial, effective and convenient treatment and compositions, including several drugs that prevent cardiovascular disease, which effectively reduced the risk of cardiovascular episodes. When conventional therapy patients with increased risk of cardiovascular episodes often receive drug therapy using several means, taking two or more different products at the same time. The inclusion of multiple drugs in a single composition improves patient compliance with the prescribed regime by eliminating the inconvenience with receiving multiple doses of drug medium is in for the day, and reduces the likelihood of missed dose.

U.S. patent No. 6235311, in the name of Ullah et al., discloses a pharmaceutical composition suitable for reducing cholesterol and reduce the risk of myocardial infarction, which includes statins, such as pravastatin, lovastatin, simvastatin, atorvastatin, tseriwastatina or fluvastatin in combination with aspirin, prepared in a way to minimize chemical interaction between aspirin and a statin, and to minimize the side effects of aspirin.

Weissman et al., in U.S. patent No. 6121249 and 6323188, disclose a method of reducing the frequency and severity of arteriosclerosis, atherosclerotic disease of the Central nervous system, intermittent claudication, coronary heart disease, homocysteine-associated disorders, hypertension, peripheral vascular disease, presenilny dementia and restenosis in humans by daily injection of an effective amount of a combination of acetylsalicylic acid (ASA)at least one antioxidant, cyanocobalamine connection (vitamin B12), compounds of folic acid, pyridoxine connection (vitamin B6and Niacin compounds.

U.S. patent No. 5622985, in the name Olukotun et al., reveals that inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme a (HMG COA) reductase inhibitor, also known as "statins," especially pravastatin when used separately or together with an inhibitor of angiotensin converting enzyme (ACE), reduce the risk of a second heart attack in patients with essentially normal cholesterol levels.

U.S. patent No. 6576256, in the name of Liang et al., discloses methods and compositions for reducing the risk of cardiovascular episodes in people in the group increased cardiovascular risk, including patients with systemic lupus erythematosus.

The methods include the introduction of combination: agent, lowering cholesterol, such as an inhibitor of HMG COA-reductase; of the inhibitor system of the renin-angiotensin, such as an ACE inhibitor, aspirin, and, optionally, one or more of vitamin B6vitamin B12and folic acid. There are also pharmaceutical compositions, comprising all the active agents in a single dosage form for admission once a day.

International patent publication WO 01/15674, in the name of Aventis Pharma Deutschland GmbH, refers to the combination of the inhibitor system of the renin-angiotensin optional, additional antihypertensive agent, agent, lowering cholesterol, diuretic and aspirin, which can be entered for the prevention of cardiovascular episodes.

International patent publication WO 01/76632, in the name of the Wald and Law, discloses a pharmaceutical composition, which contains at least two agents that lower blood pressure, having different mechanisms of action plus the active agent from at least two of: a lipid-regulating agents; agents that alter platelet function; and agents that lower homocysteine serum. In the specified document at least some of the drugs are preferably used in smaller quantities than their usual therapeutic doses.

Article N.J. Wald et al. "A Strategy to Reduce Cardiovascular Disease by More Than 80% (Strategy to reduce cardiovascular disease by more than 80%), British Medical Journal, Vol.326, pp.1419-1423, 2003, promotes daily prophylactic treatment of all people over the age of 55 years and all patients with cardiovascular disease with the use of the drug "Polypill"containing the following six drugs: a tool for lowering cholesterol such as atorvastatin (10 mg) or simvastatin (40 mg), a combination of three tools that lower blood pressure, belonging to different classes, such as teased, β-blocker and ACE inhibitor (each half of the standard dose), folic acid (0.8 mg) and aspirin (75 mg).

Finally, in accordance with the recommendations of the world health organization on the development of combined products for cardiovascular therapy and testing their effectiveness on people from high-risk groups would be very desirable to develop a composite product using various cardiovascular drugs, including β-adrenoceptor blocking agent, diuretic, and the UNT, lowering the cholesterol level, the inhibitor system of the renin-angiotensin, aspirin and, optionally, antidiabetic agent.

The essence of the present invention

For patients with increased risk of cardiovascular diseases to the present invention did not exist convenient drug therapy. In accordance with the invention provides for the combination of active agents in different categories, which can conveniently be administered once a day to reduce the risk of cardiovascular episodes.

The present invention provides a stable dosage form for oral administration once a day, containing a combination of therapeutically effective doses: blocker β-adrenergic receptor, diuretic, or both; a therapeutically effective dose of the agent, lowering cholesterol; therapeutically effective dose of the inhibitor system of the renin-angiotensin; a therapeutically effective dose of aspirin and, optionally, at least one of vitamin B6vitamin B12and folic acid; and a method for the treatment of patients with increased cardiovascular risk by introducing dosage forms daily.

In one aspect the present invention provides a pharmaceutical dosage form that includes therapeutic the ski quantity: antagonist of β-adrenergic receptor, the diuretic or both; agent, lowering cholesterol; inhibitor system the renin-angiotensin and aspirin.

In another aspect the present invention provides a pharmaceutical dosage form comprising a therapeutic amount: antagonist of β-adrenergic receptor, diuretic, or both; agent, lowering cholesterol; inhibitor system the renin-angiotensin and aspirin; in which the acid components are separated from the main component.

In another aspect the present invention provides a tablet comprising two layers where the first layer includes simvastatin and aspirin and the second layer includes atenolol and lisinopril.

In another aspect the present invention provides a tablet comprising two layers where the first layer includes simvastatin and aspirin and the second layer includes hydrochlorothiazide and lisinopril.

A detailed description of the present invention

In accordance with the present invention provides a pharmaceutical composition comprising a blocker β-adrenergic receptor, an agent that lowers the level of cholesterol, the inhibitor system of the renin-angiotensin and aspirin, diuretics or without it, which reduces the risk of cardiovascular episode with little or no physical and chemical incompatibilities, and have the utter reduced side effects, usually associated with use of these drugs.

When using the terms "active agent", "pharmacologically active agent" and "drug" is to be understood that they include active molecule, as well as pharmaceutically acceptable, pharmacologically active salts, esters, amides, prodrugs, metabolites, analogs, etc. of the Composition of many medicines are prepared using such other forms, but it will be identified only the active part.

The term "therapeutic amount" in relation to a medicinal product indicates the amount of drug contained in a daily dose, which is usually written on primary evidence and included in the scope of the present invention. These quantities are conveniently summarized for many medicines in the column of "BNF Recommended Dose (the Dose recommended by the British pharmacological reference) tables on pages 11-17 WO 01/76632 (the data in the tables conform to British pharmacological Handbook (British National Formulary), ed. March 2000) and can also be found in other standard prescription handbooks and other guidance on prescribing. For some drugs commonly prescribed dose for readings can vary as different from the wounds.

Antagonists of β-adrenergic receptor blocking action of the sympathetic nervous system and parts of the autonomic nervous system. By blocking the action of these nerves, they lower the heart rate and is suitable for treating abnormally rapid heart rhythms. These drugs also reduce the force of contraction of the cardiac muscle and lower blood pressure. By reducing the heart rate and force of contraction of the muscles of β-blockers reduce the need of the heart muscle of oxygen.

Suitable β-adrenoblockers agents are selected from the group including atenolol, betaxolol, acebutolol, bisoprolol, carteolol, labetalol, metoprolol, nadolol, oxprenolol, penbutolol, pindolol, propanolol, sotalol, and timolol. Atenolol is currently the preferred β-adrenoceptor blocking agent.

The present invention uses any effective agent that lowers cholesterol, or combination of such agents. Suitable agents, cholesterol-lowering, include inhibitors of HMG COA reductase, airing on the basis of bile acids, probucol and agents based on fibrin acid.

Also suitable is a selective inhibitor of intestinal absorption of cholesterol, have adopted the name "ezetimib" and the chemical name 1-(4-forfinal)-3(R)-[3(4-forfinal)-3(S)-hydroxypropyl]-4(S)-(4-hydroxyphenyl)-2-azetidinone. Ezetimib particularly effective when introduced together with a statin.

Preferred are inhibitors of HMG COA reductase. These agents are competitive inhibitors of HMG COA reductase, limiting the speed stages of the biosynthesis of cholesterol. They occupy part of the site of binding of the HMG COA, blocking access of this substrate to the active center of the enzyme. Inhibitors of HMG COA reductase include atorvastatin, cerivastatin, plugindomain, fluvastatin, lovastatin, mevastatin, pravastatin, simvastatin and melastatin; the most preferred agents are lovastatin and pravastatin, particularly lovastatin.

The system renin-angiotensin plays an important role in regulating blood pressure. Renin, representing the enzyme operates by action on angiotensinogen education Decapeptide angiotensin I. Angiotensin I is rapidly converted to oktapeptid angiotensin II angiotensinamidum enzyme (ACE). Angiotensin II acts through multiple mechanisms, increase blood pressure, including increased total peripheral resistance vessels. The system inhibitors of the renin-angiotensin divided into angiotensin converting enzyme inhibitors (ACE) and receptor antagonists angiotensin II (ARBs).

Examples of angiotensin converting enzyme (ACE) are the cap is April, cilazapril, delapril, enalapril, pentopril, fosinopril, indrapuri, lisinopril, perindopril, pivotal, quinapril, ramipril, spirapril, trandolapril and zofenopril; preferred for use in the present invention are captopril, enalapril, fosinopril, lisinopril, quinapril, ramipril and trandolapril, and most preferred is enalapril. Suitable antagonists of receptors of angiotensin II include losartan, irbesartan, eprosartan, candesartan, valsartan, telmisartan, Salamatin and tasosartan. Preferred is losartan. In the present invention, the angiotensin converting enzyme (ACE) are preferable receptor antagonists angiotensin II.

Inhibitors of cyclooxygenase suitable for use in the present invention due to its ability to affect platelets; the most widely used and studied inhibitor of cyclooxygenase is aspirin, which has been shown to prevent myocardial infarction and stroke caused by thrombosis, when taken daily in small doses over a long period of time to patients with risk of cardiovascular episodes. When present in the circulatory system of sufficient quantities of aspirin, resulting platelets have broken the ability to aggregation throughout his life - 7-10 days.

Diuretics increase urine secretion and excretion of sodium and is used to adjust the volume and/or composition of body fluids in various clinical situations, including hypertension, congestive heart failure, renal failure, nephritic syndrome, and cirrhosis. Can be selected from diuretics, belonging to different classes, such as carbonic anhydrase inhibitors, loop diuretics, thiazides and casinomodule diuretics, K+-sparing diuretics and antagonists mineralocorticoid receptors.

In the embodiment of the present invention thiazides and casinomodule derivatives are the preferred diuretics, including bendroflumethazide, chlorothiazide, hydrochlorothiazide, hydroflumethiazide, methyclothiazide, polythiazide, trichlormethiazide, chlorthalidone, indapamide, metolazone and quinethazone.

Currently, the most preferred diuretic is hydrochlorothiazide, which acts by blocking the reabsorption of salt and fluid in the kidneys, causing increased rochevilaine (diuresis). It is also widely used in the treatment of weak hypertension.

Next, the composite product can include at least one antidiabetic agent, such as hypoglycemic agents for oral administration, such as Metformin, a drug with which estva on the basis of sulfonylurea, for example glibenclamide, tolbutamide, tolazamide, gliburid, glipizide and glimepiride, and thiazolidinedione medicinal troglitazone, rosiglitazone and pioglitazone. They usually improve the disposal cells and (in some cases) stimulate the production of insulin by the pancreas or reduce the production of glucose by the liver. Antidiabetic agent may be included in a product designed for use by individuals with non-insulin-dependent diabetes mellitus.

Elevated levels of serum homocysteine is strongly associated with atherosclerosis, heart disease, stroke and peripheral vascular disease. Vitamin B6vitamin B12and folic acid cause a decrease in homocysteine levels and reduce the incidence of such illnesses. Vitamin B6used in amounts of between about 2 mg and 2 grams. Vitamin B12used in an amount of from about 3 μg to 2 mg of Folic acid is usually used in an amount up to about 5 mg, such as about 400 to 800 μg, from about 500 μg to 2 mg, or from about 1 mg to 5 mg

It should be understood that the above listing of medicines, specific classes, is not exclusive and that other drugs will also be suitable for use in the present izopet the Institute. In General, it is desirable to use drugs, doses that can be administered once a day due to its pharmacokinetic characteristics or due to the presence of possible use in the form of dosage forms with delayed release, in order to facilitate patient compliance with the regimen.

In accordance with an embodiment of the present invention in various dosage forms, allowing to effectively enter the combined drug, include tablets, capsules and tablets in capsule form (caplets) and may also include many granules, spherical granules, powders or pills, which can be encapsulated or not.

Various pharmaceutical compositions and methods for their preparation are described later in the description, where the terms "specified combination" or "combination" refers to a combination comprising a therapeutically effective single dose of a blocking agent β-adrenergic receptor, agent, lowering cholesterol, the inhibitor system of the renin-angiotensin, aspirin and, optionally, one or more vitamins, such as vitamin B6vitamin B12folic acid, or a combination of diuretic and/or hypoglycemic medication.

Combining two or more active ingredient is in the dosage form with a single dose is critical moments, because of the possibility of chemical interaction between drug substances. Acid active ingredients, such as aspirin, can react with essential medicines, and acidic ingredients, such as aspirin, can contribute to the degradation of unstable to acid medicines, including lovastatin, and pravastatin. In the present invention such drug interactions have been taken into account interactive active ingredients were physically separated by using different described below.

1. Multi-layered tablet or a tablet with an extruded coating. In combination, where drugs such as aspirin and enalaprilat are acidic drugs, and drugs such as atenolol and lovastatin are the main drugs, acidic and basic substances can be physically divided into two separate or isolated layer compressed tablet or core and shell of the tablet with the extruded coating. Hydrochlorothiazide, being compatible with both acidic and basic drugs can be placed in any of the layers.

In another embodiment, the multilayered composition of at least one active ingredient may have intersolubility floor. In the following embodiment, the multilayered composition of at least one active ingredient may be in the form controlled release.

Another suitable method is the use of a combination of three or more physically isolated segments of compressed tablets. Multilayer tablet may have a film coating.

2. Tablets or capsules containing many of spherical pellets, granules or pellets. All the active ingredients of the combination, including vitamins include granules or spherical granules or pellets, which are then covered with a protective layer, intersolubility coated or film coated to avoid possible chemical interactions. Granulation and coating of granules or spherical granules made using techniques well known to specialists in this field of technology. At least one active ingredient may be in the form of controlled-release. Finally, these granules or spherical granules coated are placed in hard gelatin capsules or pressed into tablets.

3. Capsules, including microtablets or mini-tablets of all active ingredients. Microtablets prepared from the individual components of this combination, using well-known Pharma is efticiency procedures for the preparation of tablets, such as direct compression, dry granulation or wet granulation. All these individual microtablets placed in hard gelatin capsules. The finished dosage form may include one or more than one microtablets each individual component. Further, these microtablets can have a film coating or intersolubility floor.

4. Capsule comprising one or more microtablets and powder, or one or more microtablets and granules or spherical granules. In order to avoid interaction between the drugs some of the active ingredients of this combination can be prepared in the form of microtablets, and others may be placed in a capsule in the form of powder, granules or spherical granules.

Microtablets may have a film coating or intersolubility floor. At least one active component may be in the form controlled release.

5. The active ingredient distributed in the inner and outer phases tablets. In an attempt to separate chemically incompatible components of the proposed combination of several interacting components into granules or spherical granules using pharmaceutical procedures well known in the art. Prepared g is annuli or spherical granules (internal phase) is then mixed with the external phase, including other active ingredients and at least one pharmaceutically acceptable excipients. Mixture comprising, thus, the internal and external phase, pressed into tablets or formed into tablets.

In the next version, included in this approach, granules or spherical granules may represent a spherical granules or pellets with a controlled release or immediate-release and may further, if necessary, to have the coating applied using Intercollege polymer in an aqueous or non-aqueous system, using methods and materials known to specialists.

6. Single dosage form, comprising a suitable buffering agent. All powdered ingredients of this combination is mixed and added to a mixture of suitable amounts of one or more buffer agents to minimize possible interactions.

In the above-described approaches for finished dosage forms coated, especially tablets, are film coating of 1-8%, preferably 2-6 wt.% polymer, such as cellulose ether, acrylic polymer, such as methacrylate and methylmethacrylate copolymer, or a vinyl polymer such as polyvinyl alcohol. Intersolubility coverage mentioned above, usually is about give a weight gain of 5-15 wt.% compared to tablets or granules without coverage due polymers Intercollege coverage, such as shellac, polymethacrylate, phthalate of hydroxypropylmethylcellulose, polyvinylacetate and acetate-phthalate cellulose. Many other film-forming substances and methods that are suitable for coating on the particles, known in the art and can be used in the practice of the present invention.

The following examples are typical variants of the present invention and should not be construed as limiting the scope of the present invention defined by the attached claims, and serve only as illustrations of how implemented in practice different approaches to the development of a combined product.

Example 1

Two-layer tablets weighing 360 mg prepared using the following ingredients:

Ingredientsmg tablet
First layer:
Aspirin with intersolubility coating (granulated)75
Enalaprilat5
Lactose64,5
Microcrystalline celluloseCroscarmelose sodium salt8
Colloidal silicon dioxide3
The zinc stearate3
Second layer:
Atenolol25
Lovastatin20
Bottled hydroxyanisol1,75
Hydrochlorothiazide6,25
Lactose46
Microcrystalline cellulose50
Iron oxide red1
Povidone K5
Croscarmelose sodium salt6
The zinc stearate4
Colloidal silicon dioxide5
Film coating:
P is encompassi material 10

For the preparation of tablets components of the first layer are combined and mixed to achieve homogeneity. Separately, the components of the second layer atenolol, lovastatin, hydrochlorothiazide, lactose, microcrystalline cellulose (AVICEL™ PH101 produced by FMC Corporation, Philadelphia, Pennsylvania U.S.A.) and iron oxide red sift through a sieve and mix until smooth, and then use an aqueous solution of isopropanol containing povidone and bottled hydroxyanisol, for granulating a powder mixture, which is then dried and pulverized, added croscarmellose sodium salt, silicon dioxide and zinc stearate and mix.

The mixture of the first layer and the second mixture layer is then pressed into the mold to obtain a two-layer tablets, which are then applied film coating.

Example 2

Hard gelatin capsules containing microtablets, mini-pill, powder, prepared using the following ingredients:

Ingredientsmg/dosage form
Microtablets
Enalaprilat5
Lacto is and anhydrous 40
Microcrystalline cellulose9
Maleic acid0,5
The zinc stearate0,5
The hypromellose1,1
Mini tablet
Aspirin with intersolubility coating (granulated)75
Croscarmelose sodium salt5
Stearic acid1
Intersolubility floor3,2
Powder
Atenolol25
Lovastatin20
Hydrochlorothiazide6,25
Microcrystalline cellulose25
Dibasic calcium phosphate, anhydrous25
Calcium carbonate10
Talc2
Magnesium stearate1,5
Colloidal silicon dioxide1,5

Microtablets of enalaprilat with film coating is prepared by mixing the first five listed ingredients, pressing in the tablet coating with a solution of hydroxypropylmethylcellulose and drying. Mini aspirin with intersolubility coating is prepared by mixing the first three ingredients, pressing in the tablet coating solution Intercollege polymer and drying. The powder is prepared by mixing atenolol, lovastatin, hydrochlorothiazide and mentioned excipients. Then microtablets, mini pill and powder is placed in hard gelatin capsules of size 0.

Example 3

Capsules containing a combination of cardiovascular drugs, prepared using the following ingredients:

Ingredientsmg/capsule
Enalaprilat5
Aspirin with intersol is stable coating (granulated) 75
Atenolol25
Lovastatin20
Hydrochlorothiazide6,25
Folic acid5
Lactose anhydrous30
Calcium carbonate30
Magnesium oxide25
Magnesium stearate2
Colloidal silicon dioxide1

Lovastatin, atenolol, enalaprilat, hydrochlorothiazide, aspirin, folic acid and lactose are mixed to a homogeneous state and to this mixture was added calcium carbonate and magnesium oxide, and then continue mixing. To the dry mixture, add magnesium stearate and silicon dioxide and stirred until smooth, and finished with powder filled hard gelatin capsules.

Example 4

Tablets containing combination drug, is prepared using the following ingredients:

Ingredientmg tablet
The first layer
Simvastatin20
Lactose monohydrate157
Bottled hydroxyanisol0,08
Ascorbic acid10
Citric acid anhydrous5
Reptitiously starch20
Microcrystalline cellulose20
The zinc stearate2,5
Aspirin75
The second layer
Atenolol50
Lisinopril10
Dibasic calcium phosphate89,94
Microcrystalline cellulose40
Mannitol 25
Dye ponso red 4R0,5
Povidone4
The zinc stearate1
Sodium salt of starch glycolate8
Film coating
Film-forming material10

For the preparation of tablets mix the first seven ingredients, then moisturize and granularit, dried, add the following two ingredients and mix, receiving the mixture of the first layer. The mixture of the second layer is prepared by dry granulation of the first five ingredients of the second layer, povidone, and half of the dye and zinc stearate; after the formation of the granules is added the remainder of the dye and zinc stearate plus all the sodium salt glycolate, starch and mix.

In conclusion, the mixture of the first layer is pressed into the mold, then add the mixture of the second layer and pressed with the formation of two-layer tablets, then put on the tablet film coating and dried.

Alternatively, the mixture of the second layer is prepared by wet granulating the first five ingredients of the second layer plus povidone; after you is the suturing and grinding add the entire quantity of zinc stearate, dye and sodium glycolate, starch and mix.

Example 5

Tablets containing a combination of drugs, is prepared using the following ingredients:

Name of ingredientmg tablet
The first layer
Simvastatin40
Lactose monohydrate157
Bottled hydroxyanisol0,08
Ascorbic acid10
Citric acid anhydrous5
Reptitiously starch20
Microcrystalline cellulose20
The zinc stearate2,5
Aspirin75
The second layer
Hydrochlorothiazide12,5
Whether the inopril 10
Dibasic calcium phosphate89,94
Microcrystalline cellulose40
Mannitol25
Povidone4
Dye ponso red 4R1
Sodium salt of starch glycolate8
The zinc stearate1
Film coating
Film-forming material10

For the preparation of tablets the ingredients of the first layer is prepared as in the previous Example 4. The first six ingredients in the second layer plus half of the zinc stearate and the dye is subjected to dry granulation, then add the second half of the zinc stearate and coloring plus all the sodium salt glycolate, starch and mix. Tabletirujut as described in Example 5, then applied film coating and dried.

As in Example 5, the first six ingredients alternative second layer may be subjected to wet granulares the tion, drying, grinding, and then add the last three ingredients and mix.

1. Pharmaceutical dosage form for the treatment and prevention of cardiovascular episodes, including therapeutic quantity: antagonist of β-adrenergic receptor, diuretic, or both; agent, lowering cholesterol; inhibitor system the renin-angiotensin; and aspirin.

2. The pharmaceutical dosage form according to claim 1, comprising the antagonist of β-adrenergic receptor.

3. The pharmaceutical dosage form according to claim 1, including a diuretic.

4. The pharmaceutical dosage form according to claim 1, in which the antagonist of β-adrenergic receptor includes atenolol.

5. The pharmaceutical dosage form according to claim 1, in which the agent that lowers cholesterol, includes an inhibitor of HMG COA reductase.

6. The pharmaceutical dosage form according to claim 1, in which the agent that lowers cholesterol, includes lovastatin.

7. The pharmaceutical dosage form according to claim 1, in which the agent that lowers cholesterol, includes simvastatin.

8. The pharmaceutical dosage form according to claim 1, in which the inhibitor system of the renin-angiotensin includes the ACE inhibitor.

9. Pharmaceutical dosage medicine is Naya form according to claim 1, in which the inhibitor system of the renin-angiotensin includes enalapril.

10. The pharmaceutical dosage form according to claim 1, in which the inhibitor system of the renin-angiotensin includes lisinopril.

11. The pharmaceutical dosage form according to claim 1, further comprising an agent for lowering homocysteine levels.

12. The pharmaceutical dosage form according to claim 1, further comprising folic acid.

13. The pharmaceutical dosage form according to claim 1, further comprising a hypoglycemic agent.

14. The pharmaceutical dosage form according to claim 1, including atenolol, lovastatin, enalapril, aspirin and hydrochlorothiazide.

15. Pharmaceutical dosage form for the treatment and prevention of cardiovascular episodes, including therapeutic quantity: antagonist of β-adrenergic receptor, diuretic, or both; agent, lowering cholesterol;
the inhibitor system of the renin-angiotensin; and aspirin; in which the acid components are separated from the main component.

16. The pharmaceutical dosage form according to item 15, further comprising a diuretic.

17. The pharmaceutical dosage form according to item 15, in which the acid components are in the same layer megaloi the second tablet, and the main components are in the other layer.

18. The pharmaceutical dosage form according to item 15, in which the acid components are located in one of the core and the shell multilayer molded tablets, and the main components are located in the other of the core and the shell.

19. The pharmaceutical dosage form according to item 15, comprising a mixture of acidic components, molded part.

20. The pharmaceutical dosage form according to item 15, comprising a mixture of the basic components that are molded part.

21. The pharmaceutical dosage form according to item 15, comprising a mixture of acidic components that are molded into the particle, and the mixture of the basic components that are molded into another particle.

22. The pharmaceutical dosage form according to item 15, in which at least one of a mixture of an acid component and a mixture of the main components is formed in the particle and the applied polymeric coating.

23. Tablet comprising two layers where the first layer includes simvastatin and aspirin, and the second layer includes atenolol and lisinopril.

24. Tablet comprising two layers where the first layer includes simvastatin and aspirin, and the second layer includes hydrochlorothiazide and lisinopril.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention relate to oxabispidinic compounds of formula I, ,where R1 is C1-12alkyl (where the given alky group is substituted with a group selected from phenyl, Het1, N(R5a)R6, -OR5c, -S(O)2N(R9b)R9c and -N(R9b)S(O)2R9d); R5a is H; R5c is C1-6alkyl (which is substituted with phenol) or phenyl; R6 is H or -C(O)OR10b; R10b is C1-6alkyl; R9b in each case where it is used in the given description of the invention represents H or C1-6alkyl; R9c and R9d in each case it is used in the given description of the invention independently presents C1-6alkyl (possibly substituted with one or more substitutes, selected from halogen or phenyl), phenyl or Het7, or R9c is H; R2 is H or OR13; R3 is H; R13 is H; Het1 and Het7 independently represent 5-12-member heterocyclic groups containing one or more heteroatoms, selected from oxygen and nitrogen, where these groups are possibly substituted with one or more substitutes selected from halogen and C1-6alkyl; A is a direct bond, -J-, J-S(O)2N(R19b)- or -J-N(R19c)S(O)2- (where in the last two groups -J is bonded to the nitrogen of an oxabispidinic ring); B is Z-{[C(O)]aC(H)(R20a)}b-, -Z-[C(O)]cN(R20b)-, -Z-N(R20c)S(O)2-, -Z-S(O)2N(R20d)-, -Z-S(O)n-, -Z-O- (where in the last six groups Z is bonded to a carbon atom, carrying R2 and R3), -N(R20e)-Z-, -N(R20f)S(O)2-Z-, -S(O)2N(R20g)-Z- or -N(R20h)C(O)O-Z- (where in the last four groups Z is bonded to a phenyl group which is possibly substituted with a R4 group); J is C1-6alkylene, possibly broken by a -S(O)2N(R19d)- or -N(R19e)S(O)2- group and/or possibly substituted with a substitute selected form -OH; Z is a direct bond or C1-4alkylene, possibly broken by a -N(R20i)S(O)2- or -S(O)2N(R20j)- group; a, b and c possibly represent 0 or 1; n is 0, 1 or 2; R19b-R19e in each case where used in the given description of the invention independently represents H or C1-6alkyl; R20a is H or together with the only substitute R4 on the position of the phenyl group, which is an ortho-position relative the position where group B is bonded, represents C2-4alkylene, possibly broken or ending with O, N(H) or N(C1-6alkyl) group; R20b is H or C1-6alkyl; R20c-R20j in each case when used in the given description of the invention independently represents H or C1-6alkyl; or R20g and R20i independently represent C1-6alkyl, substituted with 3,5-dimethylisoxazolyl; G is CH; R4 is one or more possible substitutes selected from cyano, halogen, C1-4alkyl and C1-6alkoxy, possibly substituted with one or more hanogen and a R4 substitute on the position of the phenyl group, which is an ortho-position relative the position where group B is bonded, together with R20a can represent C2-4alkylene; broken or ending with O or N(H) or a N(C1-6alkyl) group; R41-R46 independently represent H; where each phenyl group is possibly substituted with one or more substitutes selected from halogen, cyano, C1-6alkyl and C1-6alkoxy (where the last two groups are possibly substituted with one or more halogen atoms); or to their pharmaceutically acceptable salts. The invention also relates to methods of producing said compounds, as well as to a pharmaceutical composition based on said compounds, with HERG-channel blocking activity.

EFFECT: obtaining novel compounds and a pharmaceutical composition based on said compounds, which can be used in medicine for preventing and treating arrhythmia, particularly cardiac and ventricular arrhythmia.

32 cl, 1 tbl, 15 ex

FIELD: medicine.

SUBSTANCE: invention refers to compounds of formula I or formula II, to their pharmaceutically acceptable salts, enantiomers and diastereoisomers as metalloprotease inhibitors, and also to a pharmaceutical composition based thereon and to versions of application thereof. Said compounds can find application in treatment of the diseases mediated by activity of metalloproteases, Her-2 SHEDDASE, ADAM-10 and ADAM-17, such as arthritis, cancer, cardiovascular disorders, skin diseases, inflammatory and allergic conditions, etc. In general formula I or II: A represents CWNHOH; B represents CH2; G represents CH2; D represents oxygen; X represents CH2NRb; Y represents CH2; M represents C; U is absent or represents NRb; V is absent or represents phenyl, or 4-10-members heterocyclyl containing 1-2 heteroatoms chosen from N and S, substituted with 0-5 groups Re; U' is absent or represents C1-10alkylene, O or combinations thereof; V' represents H, C1-8alkyl, NRbRc, C6-10carbocyclyl substituted with 0-3 groups Re, or 5-14-members heterocyclyl containing 1-3 heteroatoms chosen from N, O and C substituted with 0-4 groups Re; Ra and Re, independently represents H, T, C1-8alkylene-T, C(O)NRa'(CRb'Rc')r-T, (CRb'Rc')r-O-(CRb'Rc')r-T, OH, Cl, F, CN, NO2, NRIRII, COORIV, ORIV, CONRIRII, C1-8halogenalkyl, C3-13carbocyclyl; Rb and Rc independently represents H, T, C1-6alkylene-T, C(O)O(CRb'Rc')r-T, C(O)(CRb'Rc')r-T, S(O)p(CRb'Rc')r-T; T represents H, C1-10alkyl substituted with 0-1 groups Rb'; C3-6carbocyclyl, 5-6-members heterocyclyl containing one oxygen atom; Ra' Rb' and Rc' independently represents H, ORIV or phenyl; R1 represents hydrogen; R2 represents hydrogen; R3 represents: (i) C1-10alkyl; (ii) 4-14-members heterocyclyl containing 1-3 nitrogen atoms optionally substituted with one or two substitutes chosen from C1-6alkyl, OR13, 5-10-members heterocyclyl containing 1-3 heteroatoms chosen from N O and C, or phenyl; (iii) NR16R17; R4 represents H; R4' represents H; R5' represents H; W represents oxygen; R13 represents C1-C6alkyl; R16 and R17 independently represents C1-C10alkyl or phenyl where each is optionally substituted with one C1-4alkyl; RI and RIIindependently represents H or C1-6alkyl; RIV represents C1-6alkyl; i is equal to 0; p is equal to 1 or 2 and r is equal to 0, 1 or 2; provided that a) a spiro ring represents a stable chemical base unit and b) NR8 and NRb do not contain neither N-N, nor N-O bonds.

EFFECT: higher efficiency of the composition and method of treatment.

54 cl, 1 tbl, 9 dwg, 284 ex

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: chemistry.

SUBSTANCE: invention relates to a class of sulphur-containing compounds of general formula R1-S(O)n-CH2-CH2-SR2, where n = 1 or 2, when n = 1 R2 = (X=Cl, Br, H2PO4), R1= lower alkyl, substituted or unsubstituted aryl; when n = 2 R2=H, C(O)CH3, SO3Na, (X=Cl, Br, H2PO4) R1=straight or branched C1-C8 alkyl, substituted alkyl; aryl, substituted aryl, with antiarhythmic activity, as well as medicinal agents and pharmaceutical compositions based on said compounds.

EFFECT: proposed compounds in low doses have antiarhythmic activity, have low toxicity and can be used as active substances in medicinal agents for treating and preventing heart rhythm disorder.

11 dwg, 4 cl, 45 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: 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: chemistry.

SUBSTANCE: invention relates to an improved method of producing 2H-1-benzopyran-2-methanol-α,α'-[iminobis(methylene)]bis[6-fluoro-3,4-dihydro-[2R*[R*[R*(S*)]]]], i.e. a nebivolol base of formula (IX), or its hydrochloride salt

as well as to a method of producing an intermediate compound - benzylated nebivolol of formula (VIII),

EFFECT: invention also relates to a pharmaceutical composition with antihypertensive action without using a wetting agent, and to a tablet containing this pharmaceutical composition.

21 cl, 20 tbl, 21 ex

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

FIELD: pharmacology.

SUBSTANCE: present invention concerns compounds of formula I where R1 represents group R5S(O)2O wherein R5 represents group C1-10alkyl optionally substituted with one or more fluoro; R2a and R2b represent H or chloro; R3 represents group CONHNR7R8 wherein NR7R8 represents pyperidine-1-yl; and R4 represents group C1-3alkyl, and its pharmaceutically acceptable salts. Besides the invention concerns a pharmaceutical composition based on the compound of formula I and to application thereof in manufacturing of medicines possessing activity to CB1 receptor.

EFFECT: new imidazole derivatives expressing effective biological properties.

16 cl, 14 ex

FIELD: medicine.

SUBSTANCE: invention refers to medical products and concerns method for making solid oral pharmaceutical composition containing a hydrophilised form of 5-chlor-N-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]-1,3-oxazolidine-5-yl}-methyl)-2-thiophencarboxaime (I), differing that at first by spraying granulation, a granulated material is prepared. It contains a hydrophilised form of active substance (I). Then said granulated material if necessary is transformed into a pharmaceutical composition with pharmaceutically acceptable additives added.

EFFECT: method allows improving biological availability of the active substance.

6 cl, 2 tbl, 5 ex

Solid dosage form // 2377987

FIELD: medicine.

SUBSTANCE: present invention refers to medical products, particularly to a solid dosage form, containing an active substance from the group of inhibitor monoamine neurotransmitter uptake inhibitors with 2 3-two-substituted tropane skeleton of formula (1) which is produced by spaying a solution of the active substance over the carrier and containing the following components: 0.01-5.00 wt % of the active substance, 80.00-95.00 wt % of one or more carriers chosen from the group including carbohydrates and binding agents, providing binding of the components in a dry state, 1.00-10.00 wt % of one or more adjuvants chosen from the group, including cellulose derivative and salts of fatty acids, 0-10.00 wt % of a film coating mainly containing one or more filming agents, one or more elasticity improving substances, one or more pigments and optionally one or more dyes. Besides the inventions concern the method for making said dosage form and application thereof.

EFFECT: said dosage form expresses improved uniformity of the active substance, stability and biocompatibility.

17 cl, 2 dwg, 6 tbl, 4 ex

FIELD: medicine.

SUBSTANCE: there is offered application of L-tryptophan and L-tryptophan peripheral decomposition inhibitor (preferentially, carbidopa or Benserazide) for making a medicinal agent for prevention or treatment of pain, depression, somnipathy and other serotonin-dependent diseases of central nervous system (CNS) with L-tryptophan being presented by a slow-release drug, and L-tryptophan peripheral decomposition inhibitor - by a fast-release drug.

EFFECT: there is assured constant high concentration of tryptophan in the patient's blood plasma with the real absence of by-effects following administration of the declared combination.

5 cl, 2 dwg, 2 ex

FIELD: food industry.

SUBSTANCE: invention refers to confectionary industry. Chewing confectionary composition contains from 0.1 to 3 % of weight of enzyme, solid material of base, sweetener not provoking caries, substance stabilising enzymes and water below 5% of weight. Enzyme is chosen from proteases extracted from fruit products and is introduced into solid material of composition base at temperature 80°C, also enzyme activity of proteases is maintained in the composition at least for 4 weeks at 23°C.

EFFECT: introduction of enzyme into composition facilitates destructing of dental deposit, prevents its formation and adhesion on teeth surface at product consumption.

13 cl, 7 tbl, 1 ex

FIELD: medicine.

SUBSTANCE: present invention concerns medical products, particularly a tableted solid veterinary-medical compound containing a pharmaceutical active raw material (particularly enrofloxacin, pradofloxacin) 0.001 to 90 wt %, a flavouring and/or aromatic substance representing Bayopal and Artificial Beef Flavor, in amount 5% to 15% in terms of total mass of ready compound and at least 1.5 wt %, and no more than 15 wt % of fine-grained silicon dioxide in terms of total mass of ready compound, and one or more adjuvants.

EFFECT: such qualitative and quantitative composition of tablets provides comprehensible flavouring properties thereof with preserving pharmaceutical properties (particularly solidity).

3 cl, 10 dwg, 9 tbl, 5 ex

FIELD: medicine.

SUBSTANCE: invention relates to field of medicine, in particular to pharmaceutics, and concerns pharmaceutical compositions, which contain as active substance therapeutically effective quantity of ladasten, and as target additives - starch, stearic acid and/or its salt or ludipress and stearic acid and/or its salt with definite ratio of said components. Composition is made in form of pills, contains optimal quantity of target additives, which allows to obtain easy swallowed pills. Pills meet all requirements of State Pharmacopoeia XI edition.

EFFECT: medication form easily releases active substance, which provides its high bioaccessibility.

13 cl, 1 tbl, 5 ex

Sweetening agent // 2376886

FIELD: food industry.

SUBSTANCE: invention relates to chemical and pharmaceutical industry and concerns production of sweeteners containing stevioside. Stevioside is mixed with lactose, sodium carboxy-methylcellulose and leucine and produced in form of tabs by direct pressing on rotary tablet press.

EFFECT: obtained tabs of food sweetener have improved stability while storaging.

4 ex, 7 tbl

FIELD: medicine.

SUBSTANCE: invention is related to chemical-pharmaceutical industry, namely to agents on vegetal basis, intended for intake together with food or drinks to facilitate consequences and reduce period of alcoholic intoxication of human body (withdrawal syndrome). Agent for reduction of alcoholic intoxication period contains active and auxiliary substances, besides active substances used are dry extracts of ginger, eleutherococcus, ginseng, paullinia and holly at the following ratio of components, wt %: dry extract of ginger 40-60; dry extract of eleutherococcus 14-28; dry extract of ginseng 2.0-6.0; dry extract of paullinia 5.0-9.0; dry extract of holly 0.5-2.5; auxiliary substances - the rest. Auxiliary substances used are mainly represented by citric acid, succinic acid, dry extract of licorice.

EFFECT: intake of agent is registered with significant reduction or complete absence of thirst, nausea, dizziness, fatigue, coordination disorder, headache.

3 cl

FIELD: medicine.

SUBSTANCE: invention refers to medical products and concerns a pharmaceutical tablet, contains a therapeutically effective dose of crystalline telmisartan sodium salt of fusion temperature 245±5°C and diuretic hydrochlorothiaside, as well as one or more adjuvants used to prepare medical products. There is also disclosed method for making thereof. According to the invention, the pharmaceutical tablets are storage-stable.

EFFECT: intended for prevention or treatment of diseases wherein application of angiotensin II antagonists ensures the therapeutic effect.

23 cl, 7 tbl, 8 ex

FIELD: medicine.

SUBSTANCE: invention concerns medicine, particularly novel solid pharmaceutical composition of thelithromycin. Composition includes thelithromycin or one of its addition salts with pharmaceutically acceptable acid as active agent, and microcrystalline cellulose as inert filler with plastic properties.

EFFECT: reduced size of thelithromycin tablet at the same thelithromycin content, increased rupture strength of tablet.

12 cl, 1 dwg, 1 tbl, 1 ex

FIELD: medicine.

SUBSTANCE: invention refers to inhibitors of enzymes cleaving protein after proline, such as depeptidyl peptidase IV inhibitors, as well as to their pharmaceutical compositions, and methods of application of such inhibitors. Particularly, inhibitors under this invention are improved in comparison with those currently in use in the present art by selecting special classes of side chains in P1 and/or P2 positions of inhibitor which contains carboxylic acid grouping.

EFFECT: compounds of specified formulas I, II and III can have the improved therapeutic index, partially owing to reduced toxicity and improved specificity in relation to target protease.

15 cl, 2 dwg, 6 ex

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