Pharmaceutical composition for preventing and treating cardiovascular diseases

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a pharmaceutical composition for outpatient treatment and prevention of the cardiovascular diseases, containing therapeutic amounts of a vasodilator, a renin-angiotensin system inhibitor, a thrombocyte aggregation inhibitor, a cholesterol-lowering agent, and an antihypoxic agent. As a vasodilator, the declared composition contains an agent possessing α-adrenergic receptor antagonist action, and a thrombocyte aggregation inhibitor is presented by an ADP-dependent thrombocyte activation mechanism blocking agent.

EFFECT: invention provides the integrated therapeutic effect on the cardiovascular system after acute administration that improves the compliance with treatment regimen by the patient.

20 cl, 1 tbl, 15 ex

 

The technical field to which the invention relates.

The invention relates to medicine, namely to pharmaceutical compositions intended for the prevention and treatment of cardiovascular diseases.

The level of technology

Diseases of the circulatory system ranked first in the world among the causes of death. The main way to solve this problem is to combat risk factors. When pharmacologic treatment and prevention of cardiovascular disease (CVD) use a range of drugs of various kinds of actions. Primarily, these include vasoactive drugs, drugs, improves blood rheology, acting on the renin-angiotensin system, diuretics and β-blockers.

However, in case of the appointment of a large number of medicines at the same time especially acute problem of compliance sick of taking the drug (compliance). One of the most effective ways to increase the level of compliance is to develop a combined, multi-component preparations, suggesting a complex therapeutic effect when taking a tablet (preferably) once a day. One tablet instead of a handful of much more attractive for the doctor (easier to give greater assurance of compliance with recommendations), and for the patient to take technically and sychologically easier besides, no need to buy multiple drugs).

Thanks to advances in the field of protective coatings and polymeric materials has managed to overcome the serious limitations in the preparation of the combined formulations associated with the possibility of unwanted interaction between constituents of the drug during storage and in the process of releasing its individual components in vivo. Developed drugs, including up to five active pharmaceutical ingredients (APIs) in a single dosage form. To date, some companies have conducted large-scale clinical trials such combined preparations according to the register Clinical-Trials.gov [http://clinicaltrials.gov/ct2/results?term=polypill] - the largest database of clinical trials, which is administered by the National library of medicine (the United States National Library of Medicine NLM) at the National institutes of health (the National Institute of Health). The research results show that the combination of five remedies can have an effect comparable to the sum of effects of each drug separately.

So, the Indian manufacturer of generic drugs Cadila Pharmaceuticals proposed composition of the Polycap (Quintapill (R)), which consists of: the diuretic hydrochlorothiazide, beta-blocker atenolol, the angiotensin-converting enzyme inhibitor (ACE inhibitor) ramipril, holesterin lowering means of simvasta the ins and aspirin anti-platelet agent. Tests 2053 volunteers (14.02.07-22.09.10) showed that Polycap has all the effects included drug and well tolerated (The Indian Polycap Study (TIPS). NCT00443794).

Completed study of the "Polypill For Prevention of Cardiovascular Disease", Phase II (NCT00567307), which was held under the auspices of the world Health Organization (30.11.07-25.05.10). Studied "Polypill" of the following composition: aspirin anti-platelet agent, holesterin lowering agent simvastatin, the ACE inhibitor lisinopril and diuretic hydrochlorothiazide.

They conducted test (01.01.08-22.09.09) on the safety and effectiveness of the Polypill ingredients: aspirin anti-platelet agent, holesterin lowering agent atorvastatin, the ACE inhibitor enalapril and the diuretic hydrochlorothiazide (Phase II. Study of Heart Polypill Safety and Efficacy in Primary Prevention of Cardiovascular Disease. NCT00603590).

In November 2010, became aware of this research, the "Polypill and Nonalcoholic Steatohepatitis" (NCT01245608)held by Tehran University of Medical Sciences presumably in the period from 09.2011 on 03.2018. This composition includes holesterin lowering agent atorvastatin, aspirin anti-platelet agent, diuretic hydrochlorothiazide and ACE inhibitor enalapril.

Currently, the company "Dr. Reddy's Laboratories conducting large-scale clinical studies - UMPIRE - Use of a Multidrug Pill In Reducing Cardiovascular Events. Phase III. NCT01057537 offering 2 versions of the "polypill" (Red Heart Pill):

Version 1: aspirin, simvastatin, lisinopril and atenolol;

Version 2: aspirin, simvastatin, lisinopril and hydrochlorothiazide.

This version of the "polypill" described in EN 2380093, publ. 27.01.2010, and closest to the claimed pharmaceutical compositions.

In addition, US 6121249, publ. 19.09.2000, 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 aspirin, at least one antioxidant, cyanocobalamine connection (vitamin B12), compounds of folic acid, pyridoxine connection (vitamin B6and Niacin compounds.

In WO 01/76632, publ. 18.10.2001, describe a pharmaceutical composition, which contains at least two agents that lower blood pressure, having different mechanisms of action (diuretic, β-blocker, ACE inhibitor, blocker angiotensin II receptor and calcium channel blocker), plus two agents selected from three categories: lipid-lowering agents; agents that alter platelet function; and agents, lowering homocysteine in serum.

Article N.J. Wald et al. "A Strategy to Reduce Cardiovascular Disease by More Than 80%of the" British Medical Journal, Vol.26, p.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 diuretic teased, β-blocker and ACE inhibitor (each half of the standard dose), folic acid (0.8 mg) and aspirin (75 mg).

In WO 01/15674 proposed for the prevention of cardiovascular diseases to the use of a pharmaceutical combination of an inhibitor system the renin-angiotensin; optional, additional antihypertensive agent; agent, lowering cholesterol, diuretic and aspirin.

In WO 2009/118359, publ. 01.10.2009 offer for the prevention of cardiovascular diseases capsule, consisting of a protected polymeric shell aspirin, simvastatin, or pravastatin, lisinopril, ramipril or perindopril.

The closest option to the claimed solution, we offer Dr. Reddy's Laboratories described in EN 2380093, publ. 27.01.2010.

However, for outpatient practice, this solution has the following disadvantages:

1. the use of β-blockers, those who are more in combination with acetylsalicylic acid, has an adverse effect on lung respiration due to spasm of the bronchi, and in the predisposition of patients to asthma possible seizures, life-threatening. The effect of breathing difficulties compounded by the specific side effects of ACE inhibitors, causing unexplained cough. For β-blockers is typical in General a significant number of side effects that significantly reduces the quality of life of patients and their adherence to treatment. Among these effects are seen most often following:

- deterioration of the lipid profile.

- decrease insulin sensitivity;

- worsening of chronic obstructive pulmonary disease, heart failure, peripheral artery disease;

- potentiation of the hypoglycemic effects of antidiabetic agents, massaging hypoglycemia;

Central effects - insomnia, nightmares, depression, decreased intellectual-mnestic abilities, impotence;

- toxic effects on the thyroid gland;

- spasms of peripheral blood vessels, which can lead to serious complications (disruption and blockage of blood supply to the extremities with the subsequent development of gangrene);

2. the use of acetylsalicylic acid, which, even in small doses, is capable of is redit mucous membrane of the gastro-intestinal tract (GIT) with the development of life-threatening complications. In addition, acetylsalicylic acid under certain viral diseases (influenza and other acute respiratory infections) leads to the development of deadly hepato-cerebral toxicity syndrome Rhine; exhibits a pronounced antagonism to ACE inhibitors that require dose increase, and, consequently, increases the likelihood of side effects (antagonism to ACE inhibitors also exhibit most of the group of nonsteroidal anti-inflammatory drugs, which makes their use in these compositions is undesirable). Acetylsalicylic acid has lengthy and difficult to manage antiplatelet effect, which can be dangerous for injuries and surgical interventions;

3. the use of ACE inhibitors leads to a significant reduction in blood pressure at the beginning of treatment that in the presence of significant atherosclerotic changes in blood vessels can cause acute circulatory disturbance of the heart muscle (myocardial infarction) or brain tissue (ischemic stroke).

In addition to these undesirable therapeutic effects of acetylsalicylic acid creates a number of difficulties technological character:

- acetylsalicylic acid is a very strong acid and has allermuir action, as a result, it reacts with many substances and many excipients and pharmaceutical compositions;

- acetylsalicylic acid is very easily hydrolyzed, especially in the presence of organic bases, and the resulting salicylic acid capable of decarboxylation, leading to the formation of toxic phenol;

- acetylsalicylic acid in the form of pharmaceutical compositions tend to "cementing", this reduces the bioavailability of the components of the composition and increases the likelihood of damage to the mucosa of the gastrointestinal tract;

- acetylsalicylic acid has high corrosion activity to structural alloys based on iron, with brightly colored forms complexes;

- acetylsalicylic acid slows down or blocks the dissolution of the pH-sensitive film coating and swelling auxiliary agents, forming a matrix system in the intestinal contents with a pH from 6.0 to 7.5 due to the high acidity and ability to form soluble adducts of acrylic polymers and derivatives (phthalates) cellulose. This greatly complicates the development of systems with a given modified-release on a certain kinetically curve [Klaus Lehmann with colleagues. Practical course covering film-coated pharmaceutical dosage forms using Eudragit EUDRAGIT. - Darmstadt: Pharma polymers, 2002].

These drawbacks are eliminated in before agema version.

Disclosure of inventions

The subject of this invention is a pharmaceutical composition for outpatient treatment and prevention of cardiovascular diseases containing as the active ingredients of therapeutic amount of a vasodilator, an inhibitor of the renin-angiotensin system; inhibitor of platelet aggregation; agent that lowers cholesterol and antihypoxic drug. Additionally, the composition may contain a diuretic. The pharmaceutical composition is an oral dosage form with modified nature of the release of active substances (tablet or capsule)taken once a day, mostly in the evening.

In the proposed pharmaceutical composition mentioned disadvantages of the prototype [EN 2380093, publ. 27.01.2010] are eliminated as follows:

- as an inhibitor of platelet aggregation instead of acetylsalicylic acid use an agent that does not affect prostaglandin-thromboxane system and has no side effects typical of drugs NSAIDs group (the mucosa of the digestive tract, antagonism to ACE inhibitors, dangerous long-term manifestation of antiplatelet action after discontinuation of the drug, the possibility of induction of bronchial asthma attacks);

as vasodilator α-adrenergic receptor blocker, not having these side effects, characteristic for β-blockers, in particular not having spastic actions on the bronchi and peripheral vessels - on the contrary, improves blood flow to the extremities and providing a therapeutic effect in peripheral angiopathies;

- to prevent ischemic effects in critical organs pharmaceutical composition contains antihypoxic drug that protects tissue during hypoxia-induced decrease in blood pressure when using ACE inhibitors.

Implementation of the invention is made possible thanks to the previously developed modification of release of the active ingredient with a given kinetics [EN 2411035, publ. 10.02.2011]. This procedure allows to provide the desired therapeutic properties of the composition: a single dose during the day, reducing the side effects associated with a sharp increase in the concentration of active ingredient in the blood, etc. and at the same time eliminates unwanted chemical interaction between the ingredients.

Pharmaceutically active ingredients of the composition contained in the daily dose prescribed by primary evidence (can be found in the recipe books; British National Formulary (BNF 57), march, 2009). However, at least some desirable for use in smaller quantities than their usual those who piticescu dose given the synergy of the components of the composition. In many cases, long-term use of pharmaceutical drugs in lower doses, but as part of a synergistic compositions, allows to obtain the desired result with minimum risk of side effects. The term "therapeutic amount" means a minimal amount of ingredient taking into account the synergistic effects of the ingredients that have defined therapeutic effect.

In the proposed pharmaceutical composition as vasodilator can be used non-selective α-blocker, nicergoline or α1-blockers prazosin, terazosin, doxazosin, R(+)-5-[2-(3-tert-butylamino-2-hydroxypropoxy)phenoxymethyl]-3-methyl-1,2,4-oxadiazole hydrochloride (Butylaminomethylphosphonate metronidazol, practolol), or R(+)-1-(N-carbazole-4-yloxy)-3-[[2-(2-methoxyphenoxy)ethyl]amino]propanol (carvedilol). In addition, you can use the racemates of practolol and carvedilola as substances containing R(+)-isomer, but cheaper compared to the pure R(+)-isomers of practolol and carvedilola. It should be noted that the use of α-blockers allows you to have a therapeutic effect on the number of comorbidities in older patients with cardiovascular disease: spasms of peripheral blood vessels, migraine, Zabol the of the prostate gland, etc. For taken when developing compositions doses of α-blockers only possible side effect is excessive reduction of blood pressure at the beginning of treatment; this effect is eliminated with the use of ingredients with modified release, excluding the rapid growth of the α-blocker in the blood after administration of the pharmaceutical composition.

As an inhibitor of the renin-angiotensin system in the proposed pharmaceutical composition can be used any of the long-acting ACE inhibitors: enalapril, lisinopril, ramipril, perindopril, moexipril, fosinopril, cilazapril, spirapril, inapril or trandolapril. To enhance the effect can additionally be entered receptor blocker angiotensin II, such as candesartan. In addition, it can be used alone in the composition. Because all of these drugs are metabolic prolongation, providing uniform and prolonged effect during the day, they can be used without modification release. In some cases, the modification of the release has to have a goal - shift effect in the morning time and reduced antihypertensive effect at night, which reduces the likelihood of dangerous effects, such as cerebral ischemia.

As agents that reduce the level of cold and the Sterol, in the proposed pharmaceutical composition can be used in natural, semi-synthetic and synthetic inhibitors of HMG-COA reductase, mainly in the minimum therapeutically relevant doses. In some cases, muscle pathology, or when significant changes in the liver can be used inhibitor of cholesterol absorption, ezetimibe alone or in combination with reduced doses of an inhibitor of HMG-COA reductase.

As an inhibitor of platelet aggregation can be used blocker of ATP-dependent mechanism of activation of platelets clopidogrel or dipyridamole. This excludes unwanted effects, both therapeutic and technological characteristic of acetylsalicylic acid. Ticlopidine and pentoxifylline, showing similar effects on platelet aggregation, can also be used, but their high minimum significant therapeutic dose hamper technological character.

As antihypoxants protecting tissue in the first place, brain, and heart muscle from hypoxia caused by reduced blood pressure (the desired therapeutic effect) on the background of atherosclerotic changes in blood vessels, can be used piracetam, Trimetazidine, geksobendin, 2-ethyl-6-methyl-3-hydroxypyridine succinate. Natures who's antihypoxants ubiquinone and tocopherol, not having a high therapeutic activity, but at the same time and no toxicity even at high doses, can be applied independently in the composition or in combination with one of the proposed antihypoxants.

As part of the proposed pharmaceutical composition to enhance the antihypertensive actions can be applied one of diuretics: furosemide, clopamide, gipotiazid, cyclomethicone, indapamide or xipamide, mainly in the minimum therapeutic dose.

The proposed composition of a large part of the ingredients it contains in the form of providing modified release of active substances. Because it is designed for a single admission, modification of the metabolically unstable ingredients, quickly removed from the body, is designed to lengthen and make uniform their therapeutic effect within days. It is known that for many biologically active compounds elimination of the "peak" effects increases bioavailability by improving the absorption, reduce oxidation in the liver, reduction of renal excretion (Belousov SHE Moiseev, B.C., Lepakhin VK Clinical pharmacology and pharmacotherapy. Hands-on for physicians. - Ed. 2nd cor. and supplementary): Universe publishing, 1997). This helps to reduce therapeutically active doses. In the same lie is with this modification dramatically decreases the probability of the dangerous unwanted effects, for example, a sharp decrease in pressure vasodilators. For some ingredients of the composition (vasodilators, diuretics) a suitable shift of the onset of pronounced effect on morning and evening time, while for inhibitors of HMG-COA reductase during the night. These goals were achieved due to the procedure previously developed and described in the patent RU 2411035, publ. 10.02.2011 popular and proven for the claimed compositions and their ingredients.

Structurally, the inventive composition may be in the form of tablets, coated or not coated with a polymer sheath, or capsule.

When the composition is made in the form of tablets, tablet core made mostly of matrix type, because it contains components, the release of which should be detained; the most critical ingredients (such as vasodilators, antiplatelet agents, antihypoxants) in addition, prior to pelletizing microcapsular the patent RU 2411035, publ. 10.02.2011, to avoid chemical interaction between the ingredients and additional prolonged release. In addition, ingredients, uncomfortable with technology physico-chemical properties (oil, low-melting, hygroscopic) also lead to the composition in microencapsulated form. Ingredients, becausee slow metabolism (such as inhibitors of HMG-COA reductase, inhibitors of intestinal cholesterol absorption), but the release of which is more profitable in therapeutic plan to ensure at night, is injected into the outer layer tablets double pressing and not subjected to microencapsulation (recommended taking tablets in the evening).

Also, the pharmaceutical composition may be in the form of tablets with conventional excipients, not creating a matrix effect. In this case, the fast metabolizing ingredients included in the composition in microencapsulated form similar to EN 2411035, publ. 10.02.2011 than allows a single use and minimized side effects.

It is desirable for tablets to use enteric coated, because the contact with the acidic gastric contents for many of the ingredients can lead to their destruction, on the other hand, may be a manifestation of gastrotoxicity for some ingredients.

In addition, the composition may be in the form of capsules, which are filled with granulate, mini or microtablets.

In that case, when the capsule is filled with granulate, it must be a component that creates a matrix effect. These components can be esters of cellulose (hypromellose and others), as well as acrylic for emery, called Eudragit; their property is the formation in contact with the contents of the intestine mechanically dense gel, providing a slower diffusion of the ingredients. In this fast-metabolizing ingredients must be entered in the granulate in microencapsulated form.

Another option is to trim capsules mini and microtelecom.

Accessories capsule mini-pill (3-6 units) can be identical in composition and manufacturing techniques (example 10), and the total content of ingredients for all tablets kit should correspond to the required therapeutic.

In the case of pharmaceutical compositions, designed to be placed in picking microtelecom capsules, a convenient, technologically separate tabletting pharmaceutically active ingredients with providing modified release of each ingredient for optimal kinetic curve, which allows to achieve the maximum therapeutic effect and minimize side effects.

There is also a variant variable capsules, which are as follows:

In the basic mini-tablet comprises a vasodilator, inhibitor system the renin-angiotensin, inhibitor of platelet aggregation, the agent that reduces the level of cholesterol is Rina and antihypoxic drug in minimally significant therapeutic quantities. The capsule is equipped with only basic mini-pill can be used for preventive and curative outpatient use in cardiovascular disease in remission or with minor deviations from the norm.

However, for capsules, and complete mini tablets, it is possible to provide tocompletely to the "base" composition mini-tablets (with added ingredients in the framework of the foregoing) conditions in the pharmacy with a doctor's prescription for personal reasons.

The "mini-pill" for additional equipment are delivered to the pharmacy in packaging "Angro"and "basic" tablet is placed in the capsule on the manufacturer. Thus, the doctor can increase a therapeutic effect on certain manifestations of cardiovascular disease in the preservation of these advantages (ease of use, security). For example, for the treatment of hypertension II-III degree can be added the diuretic and the extension number of the ACE inhibitor. At high levels of cholesterol can be enhanced by interventions aimed at normalization of level of cholesterol, etc. are Some ways to manufacture, assemble and use "variable" capsules described in example 8. The total content of each of the ingredients in each of the potential VA is Ianto "variable capsules meet the criteria stated above.

The proposed pharmaceutical composition, in addition to the above benefits, can significantly reduce the cost of treatment compared with separated common purpose of individual components, and compared with the prototype. In example 15 shows a variant of the pharmaceutical composition with an extremely low cost. On the one hand, as a pharmaceutically active ingredients taken quite cheap but effective substance, on the other hand, the technology of the manufacture of pharmaceutical compositions selected the least costly, while providing the necessary modified-release. This pharmaceutical composition may be administered to patients with ischemic heart disease who have low income and do not fall in the dated state categories of the population.

The implementation of the invention

Examples of manufacturing, we offer pharmaceutical compositions described in the examples.

Example 1 (tablet dual extrusion coated)

Substance carvedilola, indapamide, dipyridamole and 2-ethyl-6-methyl-3-hydroxypyridine succinate subjected to microencapsulation in U.S. Pat. EN 2411035 C2 (example 6). The content of substances of drugs in the resulting spheroids 50%; during the first two hours after administration of the drug is released less than 3% of the action is found substances full release in standard conditions simulating the intestinal content is 12 hours.

From the resulting spheroids substances simvastatin and ramipril and auxiliary substances form a two-layer (double pressing) tablet, enteric-coated shell.

The composition of the inner core:

1. R(+)-1-(N-carbazole-4-yloxy)-3-[[2-(2-methoxyphenoxy)ethyl]amino]propyl alcohol microencapsulated 10 mg, including active substance 5 mg;

2. Indapamide microencapsulated 2 mg, including active substance 1 mg;

3. Dipyridamole microencapsulated 100 mg, including active substance 50 mg;

4. 2-Ethyl-6-methyl-3-hydroxypyridine succinate microencapsulated 100 mg, including active substance 50 mg;

5. Tocopherol acetate (1 mg;

6. Lecithin in an amount of 5 mg;

7. Magnesium stearate (1 mg;

8. Microcrystalline cellulose 50 mg;

9. Lactose 50 mg;

10. Polyvinylpyrrolidone weight in the amount of 6 mg;

11. Croscarmelose sodium salt in an amount of 10 mg

The composition of the outer layer:

1. Substance simvastatin 5 mg;

2. Substance ramipril 5 mg;

3. Lactose in the number 66,75 mg;

4. Microcrystalline cellulose in the amount of 69,75 mg;

5. Crosscarmellose sodium Sol is in the amount of 10 mg.

6. Magnesium stearate 2 mg

The tablet has an enteric shell, consisting of Eudragit L30D-55, triethylcitrate and talc. The coated tablets are carried out with 30% aqueous dispersion. The weight of the film coating 10 mg and the total weight of the tablets 500 mg

For the preparation of tablets the components are mixed, subjected to dry granulation, and then using the dual pressing form a two-layer tablet, then the tablet is applied film coating.

For maintenance treatment in outpatients prescribed taking two tablets in the evening. According to indications, the dose can be reduced to one tablet or increased to four or five tablets, in any case, take medication in the evening at one time.

Example 2 (tablet direct compression coated)

Analogously to example 1 substance carvedilola, furosemide, Trimetazidine dihydrochloride and dipyridamole is subjected to microencapsulation. From the resulting spheroids and substances form the tablet.

The composition of tablets:

1. R(+)-1-(N-carbazole-4-yloxy)-3-[[2-(2-methoxyphenoxy)ethyl]amino]propyl alcohol microencapsulated 20 mg, including active substance 10 mg;

2. Furosemide microencapsulated 40 mg, including the active ingredient 20 mg;

3. Dipyridamole microencapsulated 100 mg, including current prophetic is TBA 50 mg;

4. Trimetazidine a dihydrochloride microencapsulated 100 mg, including active substance 50 mg;

5. Fluvastatin (20 mg;

6. Enalaprilat 5 mg;

7. Tocopherol acetate in an amount of 10 mg;

8. Lecithin in the amount of 12 mg;

9. Magnesium stearate in an amount of 3 mg;

10. The weight polyvinylpyrrolidone in an amount of 10 mg;

11. Croscarmelose sodium salt (20 mg;

12. Lactose in the amount of 75 mg;

13. Milanesiana microcrystalline cellulose (Prosolv SMCC) in the amount of 75 mg;

The components are mixed, subjected to dry granulation, the resulting granules tabletirujut. Tablet cover 30%alcohol suspension Eudragit L 100-55, as a plasticizer use triethylcitrate as pigments - titanium dioxide and Indigo Carmine. The weight of the film coating is 10 mg, the total weight of the tablets 500 mg

For maintenance treatment in outpatients appoint one pill in the evening. The dose may be increased to four tablets as a single dose, while controlling the biochemical parameters (cholesterol, liver enzymes etc). If the detected change, then reduce the dose.

Example 3 (tablet dual extrusion, without shell)

Substance of doxazosin, klopamida, ezetimibe, clopidogrel and Trimetazidine expose microcapsule is to Finance the procedure, described in example 4 of U.S. Pat. EN 2411035. The full release of the active substance is provided within 12 hours, within the first two hours is released 8-10% of the active substance. From the resulting spheroids, unmodified substances and auxiliary substances form a double tablet by double pressing.

The composition of the granulate kernel:

1. Clopamide microencapsulated 20 mg, including active substance 10 mg;

2. Clopidogrel microencapsulated 140 mg, including active substance 70 mg;

3. Trimetazidine microencapsulated 100 mg, including active substance 50 mg;

4. Fosinopril in the amount of 10 mg;

5. Tocopherol acetate 50 mg;

6. Milanesiana microcrystalline cellulose (Prosolv SMCC) in an amount of 40 mg;

7. Hydrogenated vegetable oil (Lubritab) 40 mg;

The mixture is subjected to dry granulation and used to form the core of the tablet.

The composition of the granulate of the outer layer tablets:

1. Doxazosin microencapsulated 2 mg, including active substance 1 mg;

2. Ezetimib microencapsulated 20 mg, including active substance 10 mg;

3. Pravastatin in the amount of 10 mg;

4. Milanesiana microcrystalline cellulose (Prosolv SMCC) in the amount of 85 mg;

5. Hydrogenated vegetable oil (Lubritab) in which Alceste 30 mg;

6. Riboflavin in the amount of 0, 01 mg;

7. Croscarmelose sodium salt of 4 mg;

The mixture is subjected to dry granulation, the granules used to form the outer layer of the tablet.

Weight tablets 500 mg

The pill is administered in the amount of 1-2 pieces in the evening mostly male elderly with pathology of the cardiovascular system, in the presence of concomitant pulmonary disease, Smoking, prostate adenoma. In addition to target therapeutic effects of this pharmaceutical composition facilitates the passage of urine in the morning.

Example 4 (tablet direct compression, without shell)

The substance 2-ethyl-6-methyl-3-hydroxypyridine succinate microcapsules according to example 3 of U.S. Pat. EN 2411035, substance carvedilola and dipyridamole - example 5 Pat. EN 2411035. In both cases, the full release of the active substance is provided for 12 hours for the first two hours is released about 35 to 40% of the substance 2-ethyl-6-methyl-3-hydroxypyridine succinate and from 15 to 20% carvedilola and dipyridamole.

The composition of the granules for tablets:

1. R(+)-1-(N-carbazole-4-yloxy)-3-[[2-(2-methoxyphenoxy)ethyl]amino]propyl alcohol microencapsulated 20 mg, including active substance 10 mg

2. Dipyridamole microencapsulated 100 mg, including active substance 50 mg

3. 2-This is-6-methyl-3-hydroxypyridine succinate microencapsulated 100 mg, including the active substance 50 mg

4. Cyclomatic 0, 5 mg

5. Pravastatin 5 mg

6. Ezetimib 5 mg

7. Moexipril 15 mg

8. Ubiquinone 10 mg

9. Tocopherol acetate 10 mg

10. Lecithin 25 mg

11. Milanesiana microcrystalline cellulose 53 mg

12. Libritab 50 mg

13. Titanium dioxide pigment 5 mg

14. Riboflavin 1,49 mg

15. The Indigo Carmine 0.01 mg

The components are mixed, subjected to dry granulation, the granulate tabletirujut obtained tablets are polished. One tablet has a weight of 400 mg

Assign 1-2 tablets in the evening, once in cardiovascular diseases, mainly in the presence of symptoms of osteoporosis and other disorders of calcium metabolism.

Example 5 (tablet direct compression, without shell)

The substance 2-ethyl-6-methyl-3-hydroxypyridine succinate microcapsules according to the procedure of example 5 of U.S. Pat. EN 2411035.

The composition of the granules for tablets:

1. R(+)-5-[2-(3-tert-butylamino-2-hydroxy-propoxy)phenoxymethyl]-3-methyl-1,2,4-oxadiazole hydrochloride 25 mg;

2. Gipotiazid 5 mg;

3. Atorvastatin 5 mg;

4. Spirapril in an amount of 5 mg;

5. Clopidogrel in the amount of 35 mg;

6. 2-Ethyl-6-methyl-3-hydroxypyridine succinate microencapsulated 100 mg, including active substance 50 mg;

7. Microcrystalline cellulose 80 mg;

8. Lubritb 33 mg;

9. Aerosil 2 mg;

10. Titanium dioxide pigment 10 mg

The mixture is subjected to dry granulation, tabletirujut, tablets polished. The weight of one tablet 300 mg Prescribed 1-2 tablets, once in the evening.

The pharmaceutical composition reduces the tolerance to nitrates, therefore, indicated for unstable versions of angina, involving frequent and irregular taking nitrates (nitroglycerin).

Example 6 (tablet direct compression, without shell)

The substance 2-ethyl-6-methyl-3-hydroxypyridine succinate pre hydrophobizing to eliminate its unwanted interaction with other components of the pharmaceutical composition; that is, 5 parts of substance 2-ethyl-6-methyl-3-hydroxypyridine succinate, 10 parts of microcrystalline cellulose, 1 part of tocopherol acetate and 1 part of lecithin pound for half an hour in a ball mill. Tocopherol acetate is a stabilizer that protects against oxidation during storage.

For tablets direct compression prepare the following mixture:

1. Terazosin 2 mg;

2. Cyclomatic in the amount of 0.2 mg;

3. Fluvastatin in the amount of 10 mg;

4. Ezetimibe 5 mg;

5. Perindopril erbumine in the amount of 2 mg;

6. Clopidogrel 30 mg;

7. Gidrofobizirovannym substance 2-ethyl-6-methyl-3-hydroxypyridine succinate is USD 170.1 mg, including:

- 2-Ethyl-6-methyl-3-hydroxypyridine succinate 50 mg;

- Tocopherol acetate in an amount of 10 mg;

Lecithin in an amount of 10 mg;

- Microcrystalline cellulose in the amount 100,1 mg.

8. Aerosil 5 mg;

9. Magnesium stearate 2 mg;

10. Polyvinylpyrrolidone in an amount of 10 mg;

11. Hydroxypropylcellulose 63.5 mg;

12. Riboflavin 0,2 mg

The technology of reception of tablets described in example 10 of U.S. Pat. EN 2411035. The weight of the tablet 300 mg For supporting outpatient treatment shall 1-2 tablets, once in the evening. By order of the attending physician, the dose can be increased to 4-5 tablets once a day under the control of biochemical parameters.

In model conditions of the pharmaceutical composition is released from 15 to 20% of each of the active substances in the first hour, (50±10) % for 5 hours, and the full release is after 16-20 hours after administration.

Example 7 (capsule contains a mixture of microcapsulating substances, not modified substances and excipients)

To obtain pharmaceutical compositions used gidrofobizirovannogo substance 2-ethyl-6-methyl-3-hydroxypyridine succinate, prepared similarly to the experience of 6.

The mixture for filling capsules contains the following components:

1. Doxazosin 1 mg;

2. And dopamin in the amount of 1 mg;

3. Atorvastatin at 10 mg;

4. Cilazapril in the amount of 1 mg;

5. Candesartan (1 mg;

6. Clopidogrel in quantity of 25 mg;

7. Gidrofobizirovannym substance 2-ethyl-6-methyl-3-hydroxypyridine succinate USD 170.1 mg, including:

- 2-Ethyl-6-methyl-3-hydroxypyridine succinate 50 mg;

- Tocopherol acetate in an amount of 10 mg;

Lecithin in an amount of 10 mg;

- Microcrystalline cellulose in the amount 100,1 mg.

8. Aerosil in the amount of 2 mg;

9. Magnesium stearate in the amount of 1.9 mg;

10. The hypromellose in the amount of 38 mg.

Mix all ingredients (except Aerosil and magnesium stearate) mix, then into the mixer, not stopping stirring, add Aerosil and magnesium stearate. The finished powder filled hard gelatin capsules (weight content of 250 mg). Appoint 1-2 capsules in the evening to support outpatient treatment of coronary heart disease.

Example 8 (as a variant variable capsules).

Basic mini-tablet And placed in the capsule on the manufacturer, contains a vasodilator; ACE inhibitor; an inhibitor of HMG-COA reductase in the minimum therapeutic dose; inhibitor of platelet aggregation and antihypoxic drug. Additional mini-tablets that are placed in the same capsule pharmacy in conditions with a doctor's prescription may be DIUR the tick, inhibitor of cholesterol absorption blocker angiotensin II receptor, an additional dose of an inhibitor of HMG-COA reductase.

Substance ezetimibe, carvedilola, dipyridamole, 2-ethyl-6-methyl-3-hydroxypyridine succinate, Trimetazidine, indapamide subjected to microencapsulation with modified release according to example 6 of U.S. Pat. EN 2411035.

The content of active substance in the obtained microspheres of 50%, the release in bicarbonate buffer after 1 hour, about 2%after 4 hours, approximately 70%of the full release after 12 hours.

For the preparation of basic mini-pill required a mixture of the following composition:

1. RS(±)-1-(N-carbazole-4-yloxy)-3-[[2-(2-methoxyphenoxy)ethyl]amino]propanol (carvedilol) microencapsulated in an amount of 10 mg, including active substance 5 mg;

2. Fluvastatin in the amount of 10 mg;

3. Ramipril 2 mg;

4. Dipyridamole microencapsulated in a quantity of 50 mg, including active ingredient 25 mg;

5. 2-Ethyl-6-methyl-3-hydroxypyridine succinate microencapsulated 100 mg, including active substance 50 mg;

6. Aerosil in the amount of 2 mg;

7. Magnesium stearate 2 mg;

8. Polyvinylpyrrolidone in an amount of 5 mg;

9. The hypromellose in the number of 26 mg;

The components are thoroughly mixed, subjected to dry granulation and tablets is mirouet. Tablet cover enteric shell (suspension Eudragit L30D-55, pigment titanium dioxide). The weight of the shell tablets 3 mg and the total weight of the base mini tablet 210 mg Color of pill is white.

For the preparation of additional tablets №1 use the following mixture:

1. RS(±)-1-(N-carbazole-4-yloxy)-3-[[2-(2-methoxyphenoxy)ethyl]amino]propanol (carvedilol) microencapsulated 10 mg, including active substance 5 mg;

2. Fluvastatin in the amount of 10 mg;

3. Ramipril 2 mg;

4. Dipyridamole microencapsulated 50 mg, including active ingredient 25 mg;

5. Trimetazidine microencapsulated 100 mg, including active substance 50 mg;

6. Aerosil in the amount of 2 mg;

7. Magnesium stearate (1 mg;

8. Polyvinylpyrrolidone in the amount of 6 mg;

9. The hypromellose in the number of 26 mg;

The tabletting procedure similar to that described for the base of the tablet, except that a suspension for coating add the Indigo Carmine. The weight of the tablet 210 mg Color blue.

For the preparation of additional tablet No. 2 use the following structure:

1. RS(±)-1-(N-carbazole-4-yloxy)-3-[[2-(2-methoxyphenoxy)ethyl]amino]propanol (carvedilol) microencapsulated 10 mg, including active substance 5 mg;

2. Indapamide microencapsulated 3 mg, including the current ve is esta 1.5 mg;

3. Ramipril in the amount of 2.5 mg;

4. Candesartan 4 mg;

5. Aerosil in the amount of 2 mg;

6. Magnesium stearate (1 mg;

7. Polyvinylpyrrolidone in the amount of 6.5 mg;

8. The hypromellose in the amount of 30 mg;

9. Microcrystalline cellulose in the amount of 48 mg.

Procedure tabletting and coating shell is identical to the procedure for a basic tablet. In the slurry for coating add yellow dye, tropeolin Acting Weight pills 110 mg Color yellow.

For the preparation of additional tablets №3 use the following structure:

1. Fluvastatin 50 mg;

2. Ezetimib microencapsulated 20 mg, including active substance 10 mg;

3. Aerosil in the amount of 1 mg;

4. Magnesium stearate (1 mg;

5. Polyvinylpyrrolidone in the amount of 8 mg;

6. Microcrystalline cellulose in the amount of 28 mg

Procedure tabletting and coating shell is identical to the procedure for a basic tablet. In the slurry for coating add green dye green S. the weight of the tablet 110 mg Color green.

For the preparation of additional tablets no 4 use the following structure:

1. Clopidogrel in the amount of 35 mg;

2. 2-Ethyl-6-methyl-3-hydroxypyridine succinate microencapsulated 60 mg, including active substance 30 mg;

3. Aerosil in the number 1 is g;

4. Magnesium stearate (1 mg;

5. Polyvinylpyrrolidone in an amount of 7 mg;

6. Microcrystalline cellulose in the amount of 6 mg

Procedure tabletting and coating shell is identical to the procedure for a basic tablet. In the slurry for coating add red dye acid red 2C. Weight pills 110 mg Color red.

Examples of configuration variable capsules for the prevention and treatment of various cardiovascular diseases are shown in Table 1.

Example 9 (tablet direct compression coated)

Substance of nicergoline, pyracetam, ezetimibe, dipyridamole, 2-ethyl-6-methyl-3-hydroxypyridine succinate subjected to microencapsulation technology Pat. EN 2411035 (example 6). The content of the active ingredients in the microencapsulated product of (50±5) %, the release after an hour of not more than 2.5%, after 4 hours - 70%. The full release is achieved after 12 hours. The coating is a water dispersion of Eudragit L30D-55.

To obtain an elliptical tablet (oblonga) preparing granules of the following composition;

1. Nicergoline microencapsulated 60 mg, including active substance 30 mg;

2. Lisinopril 5 mg;

3. Piracetam microencapsulated in the amount of 500 mg, including active substance 250 mg;

4. Piracetam substance in quantities is 100 mg;

5. Fluvastatin in the amount of 10 mg;

6. Ezetimib microencapsulated in the amount of 20 mg, including active substance 10 mg;

7. Dipyridamole microencapsulated in the amount of 100 mg, including active substance 50 mg;

8. 2-Ethyl-6-methyl-3-hydroxypyridine succinate microencapsulated 100 mg, including active substance 50 mg;

9. Aerosil 5 mg;

10. Magnesium stearate in an amount of 10 mg;

11. Polyvinylpyrrolidone in an amount of 30 mg;

12. The hypromellose 200 mg

The components are mixed, subjected to dry granulation, pressed into elliptical tablets. Tablet cover film cover of the pH-sensitive polymer with aqueous dispersions of Eudragit L30D-55, as a plasticizer use triethylcitrate with the addition of titanium dioxide pigment and dye E110. The total weight of the elliptical tablets 1200 mg

This pharmaceutical composition is mainly used for the treatment of stable angina and hypertension II-III degree, complicated cerebral pathology (senile and presenilny dementia, atherosclerotic circulatory disorders of the brain, Alzheimer's disease). Take one tablet in the afternoon, on the testimony may receive up to two tablets.

Example 10 (capsule with the same minitablets)

The composition of the granulate for one mini-pill;

1. Prazosin microencapsulated in the amount of 1.4 mg, including active substance 1 mg;

2. Perindopril erbumine in the amount of 1 mg;

3. Pravastatin 5 mg;

4. Dipyridamole microencapsulated in the amount of 28.6 mg, including the active ingredient 20 mg;

5. Geksobendin microencapsulated in the number of 42.9 mg, including active substance 30 mg;

6. Aerosil in the amount of 2 mg;

7. Magnesium stearate 2 mg;

8. Polyvinylpyrrolidone in an amount of 19.3 mg;

9. The hypromellose in the number 119,1 mg.

The components are thoroughly mixed, subjected to dry granulation and tabletirujut. Mini tablet cover enteric shell (Eudragit L30D-55 pigment titanium dioxide). The weight of the shell 3 mg Total weight of mini-tablets 210 mg.

In a capsule Packed with 3 mini-pill. Appoint one capsule in the evening with ischemic heart disease, accompanied by hypertension I-II degree, the increased level of cholesterol and the Church is brovascular failure.

Example 11 (capsule microtablet)

From each is taken for the manufacture of pharmaceutical compositions pharmaceutically active ingredient form microtablets.

The composition of the granulate for the production of microtablets of alfuzosin:

1. Alfuzosin microencapsulated (example 6 Pat. EN 2411035) in an amount of 10 mg, including active substance 5 mg;

2. Microcrystalline cellulose (20 mg;

3. The hypromellose of 15 mg;

4. Aerosil in the amount of 1 mg;

5. Magnesium stearate (1 mg;

6. Polyvinylpyrrolidone in an amount of 3 mg

The components are thoroughly mixed, subjected to dry granulation and pressed microtablets. The weight of one microtablets 50 mg

The composition of the granulate for the production of microtablets with ramipril:

1. Ramipril 5 mg;

2. Microcrystalline cellulose (20 mg;

3. The hypromellose of 20 mg;

4. Aerosil in the amount of 1 mg;

5. Magnesium stearate (1 mg;

6. Polyvinylpyrrolidone in an amount of 3 mg

The components are thoroughly mixed, subjected to dry granulation and pressed microtablets. The weight of one microtablets 50 mg

The composition of the granulate for the production of microtablets with fluvastatin:

1. Fluvastatin (20 mg;

2. Microcrystalline the cellulite, tighten the for in the amount of 9 mg;

3. Magnesium stearate (1 mg;

4. The hypromellose in the amount of 2 mg;

5. Lactose anhydrous in the amount of 18 mg

The components are thoroughly mixed and pressed microtablets (direct pressing method). The weight of one microtablets 50 mg

The composition of the granulate for the production of microtablets with xipamide:

1. Xipamide in the amount of 10 mg;

2. Microcrystalline cellulose in the amount of 14 mg;

3. The hypromellose of 20 mg;

4. Aerosil in the amount of 1 mg;

5. Magnesium stearate (1 mg;

6. Polyvinylpyrrolidone in an amount of 3 mg

The components of the mixture are thoroughly mixed and pressed, microtablets cover the shell of the pH-sensitive polymer with the use of aqueous dispersions of Eudragit L30D-55. The weight of one microtablets 50 mg

The active substance is released not more than 3% after 2 hours after administration, the full release is achieved after 12 hours.

The composition of the granulate for the production of microtablets dipyridamole:

1. Dipyridamole in quantity of 25 mg;

2. Microcrystalline cellulose 4 mg;

3. The hypromellose of 15 mg;

4. Aerosil in the amount of 1 mg;

5. Magnesium stearate (1 mg;

6. Polyvinylpyrrolidone in an amount of 3 mg

The components of the mixture are thoroughly mixed and pressed is microtablets, which cover similar to the previous shell. The weight of one microtablets 50 mg Complete release of the active substance is achieved after 12 hours after administration.

The composition of the granulate for the production of microtablets with 2-ethyl-6-methyl-3-hydroxypyridine succinate:

1. 2-Ethyl-6-methyl-3-hydroxypyridine succinate in the amount of 25 mg;

2. Microcrystalline cellulose in the amount of 11.5 mg;

3. The hypromellose of 10 mg;

4. Polyvinylpyrrolidone in an amount of 1.5 mg

5. Aerosil in the amount of 1 mg;

6. Magnesium stearate in the amount of 0.5 mg;

7. Succinic acid is 0.5 mg

Manufacturing technology and the release profile shown in example 10 of U.S. Pat. EN 24111035.

Received microtablets Packed in hard gelatin capsule, which is completed as follows:

- Tablet # 1, alfuzosin 5 mg - 1 piece

- Tablet # 2, ramipril 5 mg - 1 piece

- Tablet # 3, fluvastatin 20 mg - 1 piece

- Tablet # 4, xipamide 10 mg - 1 piece

- Tablet # 5, dipyridamole 25 mg - 2 pieces

- Tablet # 6, 2-ethyl-6-methyl-3-hydroxypyridine succinate 25 mg - 2 pieces

The pharmaceutical composition is prescribed mainly to patients with ischemic heart disease with hypertension II-IV degree, complicated by renal failure (of vascular origin or due to glomerulonephritis). Intake : 1-2 capsules in the evening.

Example 12 (pill double pressing without shell)

For the manufacture of pharmaceutical compositions used available on the market microencapsulated tocopherol acetate. Substance of practolol (racemate) and dipyridamole is subjected to microencapsulation in U.S. Pat. EN 2411035, example 5. The content of active substance in the microcapsules 65%. After 1 hour is released (10±1)% of active substance, the full release is after 12 hours.

Received and prepared ingredients form a tablet double pressing.

The kernel tablet:

1. RS(±)-5-[2-(3-tert-butylamino-2-hydroxypropoxy)phenoxymethyl]-3-methyl-1,2,4-oxadiazole hydrochloride (Butylmethacrylate-phenoxymethyl metronidazol, practolol) microencapsulated in the number of 46.2 mg, including active substance 30 mg;

2. Candesartan 4 mg;

3. Ezetimib in the amount of 10 mg;

4. Tocopherol microencapsulated in an amount of 200 mg, including active ingredient 100 mg;

5. Dipyridamole microencapsulated in the number 115,4 mg, including active substance, 75 mg;

6. Microcrystalline cellulose in the amount of 61.4 mg;

7. The hypromellose 100 mg;

8. Polyvinylpyrrolidone in 20 mg;

9. Aerosil in the amount of 1 mg;

10. Fumarate sodium in quantities is 2 mg;

The composition of the granulate outer layer:

1. Lactose in the amount of 87 mg;

2. Microcrystalline cellulose 50 mg;

3. Croscarmellose sodium salt (8 mg;

4. Aerosil in the amount of 2 mg;

5. Fumarate sodium 2 mg;

6. The Indigo Carmine in the amount of 1 mg;

Components of the core and the outer layer is subjected to dry granulation and the method of double pressing get a tablet. Weight tablets 700 mg Prescribed one tablet in the evening with ischemic heart disease I-II degree, hypertension I-II degree in related liver pathology.

Example 13 (tablet dual extrusion without shell)

For the manufacture of tablets using microencapsulated tocopherol acetate available in the market. Substance of nicergoline, 2-ethyl-6-methyl-3-hydroxypyridine succinate and dipyridamole is subjected to microencapsulation in U.S. Pat. EN 2411035 (example 5). Of microencapsulated substances form a tablet dual extrusion.

The composition of the granulate core tablets:

1. Nicergoline microencapsulated in the number of 46.2 mg, including active substance 30 mg;

2. Trandolapril in the amount of 0.5 mg;

3. Tocopherol acetate microencapsulated in the amount of 100 mg, including active substance 50 mg;

4. 2-Ethyl-6-methyl-3-hydroxypyridine succinate microencapsulated in Koli is este 115,4 mg, including the active substance 75 mg;

5. Dipyridamole microencapsulated in the number 115,4 mg, including active substance, 75 mg;

6. Lecithin in the amount of 22.5 mg;

7. Microcrystalline cellulose in the amount of 48 mg;

8. The hypromellose in the amount of 80 mg;

9. Polyvinylpyrrolidone in 20 mg;

10. Aerosil in the amount of 1 mg;

11. Magnesium stearate (1 mg

The components are mixed, subjected to dry granulation and pressed the elliptical core tablets

The composition of the granulate outer layer:

1. Ezetimib in the amount of 10 mg;

2. Lactose anhydrous in the amount of 77 mg;

3. Microcrystalline cellulose in the amount of 46 mg;

4. Croscarmellose sodium salt (8 mg;

5. Aerosil in the amount of 2 mg;

6. Fumarate sodium 2 mg;

7. Riboflavin 5 mg

The components are thoroughly mixed, subjected to dry granulation to form the outer layer of the tablet. Weight tablets 700 mg.

The pharmaceutical composition is administered one tablet before dinner with ischemic heart disease, hypertension I-II degree and severe liver pathology, including viral hepatitis. Included in the antihypoxants have proven hepatoprotective action, and other pharmaceutically active ingredients in these doses does not render the tender the undesirable side effects on the hepatobiliary system.

Example 14 (tablet matrix type, the method of double pressing, without shell)

The pharmaceutical composition is made in the form of a two-layer matrix tablets produced by double pressing. For making use of available on the market microencapsulated ubiquinone.

The composition of core tablet (matrix tablet);

1. Ubiquinone microencapsulated in the amount of 180 mg, including active substance 90 mg;

2. Doxazosin 1 mg;

3. Inapril in the amount of 3 mg;

4. Clopidogrel in the amount of 75 mg;

5. Oksodolin in the amount of 25 mg;

6. Microcrystalline cellulose in the amount of 103 mg;

7. The hypromellose in the amount of 80 mg;

8. Polyvinylpyrrolidone (crospovidone) in an amount of 20 mg;

9. Aerosil in the amount of 2 mg;

10. Fumarate sodium in quantities of 1 mg.

The components are thoroughly mixed, subjected to dry granulation and pressed tablet core.

The composition of the granulate outer layer:

1. Pravastatin in the amount of 10 mg;

2. Lactose anhydrous 41 mg;

3. Microcrystalline cellulose 30 mg;

4. Croscarmellose sodium salt in an amount of 10 mg;

5. Aerosil in the amount of 2 mg;

6. Fumarate sodium 2 mg;

7. β-carotene in an amount of 5 mg (as dye);

The components are thoroughly mixed, under the will eraut dry granulation, and using the dual extrusion form the tablet. The weight of the tablet 600 mg Appoint 1-2 tablets in the evening with ischemic heart disease II-III degree, complicated by severe hypertension if there is swelling.

Example 15 (pill matrix type, the method of direct compression, without shell)

Substance 2-ethyl-6-methyl-3-hydroxypyridine succinate and dipyridamole is subjected to a hydrophobization. For that 5 parts (by weight) of a substance, 10 parts of microcrystalline cellulose, 1 part of tocopherol acetate and 1 part of lecithin grind for hours in a ball mill. This procedure allows to avoid chemical interaction of ingredients with other components of the pharmaceutical composition.

The tablet matrix type form by the method of direct compression of a mixture of the following composition (per tablet):

1. RS(±)-1-(N-carbazole-4-yloxy)-3-[[2-(2-methoxyphenoxy)ethyl]amino]propanol (carvedilol) in an amount of 5 mg;

2. Amlodipine 5 mg;

3. Indapamide in quantities of 1 mg;

4. Lovastatin 20 mg;

5. Gidrofobizirovannym substance 2-ethyl-6-methyl-3-hydroxypyridine succinate in the amount of USD 170.1 mg, including active substance 50 mg, tocopherol 10 mg, lecithin 10 mg, microcrystalline cellulose 100,1 mg;

6. Gidrofobizirovannym substance of dipyridamole in the amount of USD 170.1 m is, including dipyridamole 50 mg, tocopherol 10 mg, lecithin 10 mg, microcrystalline cellulose 100,1 mg;

7. Succinic acid 5 mg;

8. Magnesium stearate 2 mg;

9. Aerosil in the amount of 2 mg;

10. Polyvinylpyrrolidone in an amount of 12.5 mg;

11. The hypromellose in the amount of 107 mg;

12. The Indigo Carmine in the amount of 0.3 mg.

In the tank carefully mix the hypromellose, hydrophobizated substance, polyvinylpyrrolidone, Aerosil, succinic acid and magnesium stearate. Then add the remaining substance and Indigo Carmine, mix until smooth coloring and compressed matrix tablets. The weight of the tablets of 500 mg. Full release of ingredients is 11 hours. Appoint 1-2 tablets in the evening in patients with ischemic heart disease, complicated by hypertension II-III degree. This variant of the pharmaceutical composition has a minimum cost of manufacture while maintaining the claimed therapeutic effects.

Table 1
Variants "variable" capsules
No.The nosologyAdditional the pill
1 (210 mg)2 (110 mg)3 (110 mg)4 (110 mg)The base (210 mg)
1Old age without clinical manifestations of cardiovascular disease1
2Advanced age, hypertension first degree under normal cholesterol level1÷2
11
3Coronary heart disease, hypertension I-II degree in malaysiana the cholesterol level11
4Hypertension II-III degree in malaysiana the cholesterol level 1÷21
5Hypertension II-III degree with high cholesterol and atherosclerosis1÷21÷21
6Post condition, hypertension, high cholesterol embolism, blood clots1÷21÷21
7Post or pre-heart attack condition, hypertension II-III degree, the phenomenon of the development of pulmonary edema211
8Stable angina, hypertension first degree without progression, reasonable cholesterolemia1 1
9Atherosclerotic cardiosclerosis12
10Unstable progressive angina, pre-heart attack state121

1. Pharmaceutical composition for outpatient treatment and prevention of cardiovascular disease containing as an active ingredient of a therapeutic amount of a vasodilator, an inhibitor of the renin-angiotensin system inhibitor of platelet aggregation agent that reduces the level of cholesterol, characterized in that as a vasodilator use the agent that has an antagonistic effect against α-adrenergic receptors, as an inhibitor of platelet aggregation - blocker of ATP-dependent mechanism of activation of platelets, and further comprises antihypoxic drug.

2. The pharmaceutical composition according to claim 1, characterized in that it further contains a diuretic.

3. The pharmaceutical composition according to claim 2, characterized in that DIU is etika use furosemide, or clopamide, or gipotiazid, or cyclomethicone, or indapamide, or xipamide.

4. The pharmaceutical composition according to claim 1, characterized in that as a vasodilator use nicergoline, or prazosin, or terazosin, or doxazosin, or R(+) - 5-[2-(3-tert-butylamino-2-hydroxypropoxy)phenoxymethyl]-3-methyl-1,2,4-oxadiazole hydrochloride, or RS(±) - 5-[2-(3-tert-butylamino-2-hydroxypropoxy)phenoxymethyl]-3-methyl-1,2,4-oxadiazole hydrochloride (Butylaminomethylphosphonate metronidazol, practolol), or R(+) - 1-(N-carbazole-4-yloxy)-3-[[2-(2-methoxyphenoxy)ethyl]amino]propyl alcohol, or RS(±)- 1-(N-carbazole-4-yloxy)-3-[[2-(2-methoxyphenoxy)ethyl]amino]propanol (carvedilol).

5. The pharmaceutical composition according to claim 1, characterized in that as an inhibitor of the renin-angiotensin system use angiotensin-converting enzyme inhibitor or receptor blocker angiotensin II blocker AT1receptors).

6. The pharmaceutical composition according to claim 1, characterized in that as angiotensin-converting enzyme inhibitor use enalapril, or lisinopril or ramipril or perindopril, or moexipril, or fosinopril, or cilazapril, or spirapril, or inapril, or trandolapril.

7. The pharmaceutical composition according to claim 1, characterized in that as a blocker angiotensin II receptor (block the ora AT 1receptors) use candesartan.

8. The pharmaceutical composition according to claim 1, characterized in that as an inhibitor of platelet aggregation using clopidogrel or dipyridamole.

9. The pharmaceutical composition according to claim 1, wherein the agent that reduces the level of cholesterol, use of inhibitors of HMG-COA reductase and / or inhibitor of cholesterol absorption.

10. The pharmaceutical composition according to claim 1, characterized in that as an inhibitor of HMG-COA reductase inhibitor use simvastatin, or pravastatin, or fluvastatin or atorvastatin.

11. The pharmaceutical composition according to claim 1, characterized in that as an inhibitor of cholesterol absorption use ezetimib.

12. The pharmaceutical composition according to claim 1, characterized in that as antihypoxic drug use piracetam, or Trimetazidine, or geksobendin, or 2-ethyl-6-methyl-3-hydroxypyridine succinate, and (or) ubiquinone and / or tocopherol acetate.

13. The pharmaceutical composition according to claim 1, characterized in that it is an oral dosage form with modified nature of the release of active substances.

14. The pharmaceutical composition according to item 13, characterized in that it is made in the form of tablets, coated or uncoated polymer shell.

15. The pharmaceutical composition according to claim 3, characterized in that the capsule type.

16. The pharmaceutical composition according to item 15, wherein the capsule contains a mixture of microencapsulated substances, unmodified substances and auxiliary substances.

17. The pharmaceutical composition according to item 15, wherein the capsule contains a mini-tablet with modified nature of the release of active substances, while the base of the mini-pill contains ingredients according to claim 1 in minimum therapeutic doses, and additional mini-pills contain ingredients according to claim 2 to 12 within therapeutic amounts.

18. The pharmaceutical composition according to 17, characterized in that the capsule is equipped with an additional mini-tablets in the pharmacy environment in accordance with a medical prescription for an individual readings.

19. The pharmaceutical composition according to item 15, wherein the capsule contains the same set of mini-tablets with modified nature of the release of active substances, with the mini-pill contains ingredients according to claim 1 in minimum therapeutic doses.

20. The pharmaceutical composition according to item 15, wherein the capsule contains microtablets with modified nature of the release of active substances, with each microtablet has given the individual the kinetics of the release which contains one of the ingredients according to claim 2 to 12 in the minimum therapeutic doses.



 

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EFFECT: present invention can find further use in therapy and diagnosis of α5β1-mediated diseases.

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2 tbl

FIELD: medicine.

SUBSTANCE: invention refers to pharmaceutical industry and represents a pharmaceutical composition for reducing triglycerides in an individual in need thereof, wherein the pharmaceutical composition contains at least 95 wt % of EPA of total fatty acids present in the composition and HMG-CoA reductase inhibitor.

EFFECT: invention provides reducing triglycerides in the individual in need thereof.

28 cl, 1 ex, 4 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: group of inventions refers to a liquid oral solution for treating angiotensin II mediated disorders and conditions, and to a method for preparing it. The liquid oral solution contains valsartan in the concentration of 5 mg/ml or less, a wetting agent, a preserving agent, a flavouring agent, a buffer system and water with pH of the solution making 4.5-5.9. The wetting agent is poloxamer 188 described by the structure HO(CH2CH2O)a(CH(CH3)CH2OH)b(CH2CH2O)cH, wherein a is equal to 75, b is equal to 30, and c is equal to 75, with average molecular weight 8350. The buffer system contains alkali citrates and citric acid, alkali acetates and acetic acid, alkali succinates and succinic acid, or any mixtures thereof. The method for preparing the above solution involves mixing the ingredients added then with valsartan when heated.

EFFECT: group of inventions provides preparing the liquid solution of valsartan with an extended storage period.

8 cl, 12 tbl, 1 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to cyclic azaindole-3-carboxamides of formula (I) in any of its stereoisomeric forms or in the form of a mixture of stereoisomeric forms in any ratio, or a physiologically acceptable salt thereof or a physiologically acceptable solvate of any of them: wherein A is specified in O, S and C(Ra)2; Ra is specified in hydrogen and (C1-C4)-alkyl wherein the two groups Ra are independent from each other and may be identical or different; R is specified from hydrogen, (C1-C4)-alkyl, hydroxy-(C1-C4)-alkyl-, (C1-C4)-alkyl-O-(C1-C4)-alkyl-, phenyl-(C1-C4)-alkyl-, (C1-C4)-alkyl-O-CO-CuH2u- and R1-NH-CO-CuH2u-, wherein all the groups R are independent from each other and may be identical or different; R1 is specified from hydrogen, (C1-C4)-alkyl and H2N-CO-(C1-C4)-alkyl-; R10 is specified from hydrogen, (C1-C6)-alkyl-O-CO-; R20 is specified from phenyl which is optionally substituted by one or more identical or different substitutes specified in halogen, (C1-C4)-alkyl and (C1-C4)-alkyl-O-; R30 is specified from (C3-C7)-cycloalkyl and phenyl, wherein phenyl is optionaly substituted by one or more identical or different substitutes specified in halogen and (C1-C6)-alkyl; R40 is specified in halogen, (C1-C4)-alkyl, phenyl-(C1-C4)-alkyl-, hydroxy, (C1-C4)-alkyl-O-, HO-CO-(C1-C4)-alkyl-O- and (C1-C4)-alkyl-O-CO-(C1-C4)-alkyl-O-, wherein all the substitutes R40 are independent from each other and may be identical or different; one of the groups Y1, Y2, Y3 and Y4 represents N, while the others are identical or different groups CH or CR40; n is specified in 0, 1, 2 and 3; p and q which are independent from each other and may be identical or different being specified in 2 and 3; n is specified in 0, 1 and 2, wherein all the values are independent from each other and may be identical or different; wherein all the alkyl groups are independently from each other optionally substituted by one or more fluorine atoms; wherein all the phenyl groups found in R and R40 are independently from each other optionally substituted by one or more identical or different substitutes specified in halogen and (C1-C4)-alkyl. Besides, the invention describes a method for preparing a compound of formula I, a pharmaceutical compositions having renin inhibitory activity and containing the compound of formula I and to using the compound of formula I for making a therapeutic preparation.

EFFECT: described and prepared are the new compounds that inhibit the enzyme renin, and modulate activity of the renin-angiotensin system, and are effective for treating the diseases such as, eg hypertension.

7 cl, 141 ex, 8 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to compounds of formula (I) or pharmaceutically acceptable salts thereof wherein A, R1, R2, R3 and m are specified in the patent claim. The present invention also refers to the number of specific compounds, and to a pharmaceutical composition containing the above compounds effective for inhibition of kinases, such as glycogen synthase kinase 3 (GSK-3), Rho kinase (ROCK), Janus kinase (JAK), AKT, PAK4, PLK, CK2, KDR, MK2, JNK1, aurora, pim 1 and nek 2.

EFFECT: preparing the specific compounds and pharmaceutical composition containing the above compounds effective for kinase inhibition.

18 cl, 393 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: microparticle contains an agglomerate of particles containing a hydrophilic active substance, wherein the particle contains an amphiphilic polymer composed of a hydrophobic segment of polyhydroxy acid and a hydrophilic segment of polysaccharide or polyethylene glycol, and a hydrophilic active substance. What is also disclosed is a method of producing the agglomerated microparticles, which involves (a) a stage of preparing a reverse phase emulsion, (b) a stage of preparing a solid residue containing the hydrophilic active substance, and (c) a stage of introducing the solid residue into a liquid phase containing a surface modifier.

EFFECT: agglomerated microparticles provide the effective encapsulation of the hydrophilic active substance and the release of the hydrophilic active substance at an appropriate speed.

14 cl, 22 dwg, 4 tbl, 31 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to medicine and represents gel-forming mixed dextran esters containing phosphate and carbamate groups of general formula: {C6H7O2(OH)3-x-y{[(OP(O)ONa)mONa)]xl[(O2P(O)ONa)k]x2}x(OCONH2)y}n, wherein x=x1+x2 is a degree of substitution in phosphate groups (mono- and diesters), x=0.47-1.09; X1 is a degree of substitution in monoesters, X1=0.01-0.48; m is a number of phosphates in monoesters, m=1-2; x2 is a degree of substitution in diesters, x2=0.01-1.09; k is a number of phosphates in diesters, k=1-2; y is a degree of substitution in carbamate groups, y=0.39-1.23; n is a degree of polymerisation, 20≥n≤1000.

EFFECT: invention provides producing low-toxic low- and high-substituted dextran phosphates in the form of hydrogels containing additionally carbamate groups and possessing antiproliferative activity with respect to cancer cells.

2 cl, 3 dwg, 14 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to field of pharmacy and represents microsphere with controlled release, which has covering layer and contains core, which contains exendin as active ingredient and biodegradable polymer, and covering layer, which covers core with covering material, exendin being exendin-4 (SEQ ID NO:2), biodegradable polymer represents polymer, selected from group, consisting of polylactide (PLA), polyglycolide (PGA), lactide and glycolide copolymer (PLGA), polyorthoester, polyanhydride, polyhydroxybutyric acid, polycaprolactone and polyalkylcarbonate; copolymer or simple mixture of two or more polymers, selected from said group of polymers; copolymer of said polymer and polyethylene glycol (PEG); or polymer-sugar complex, in which sugar is bound with said polymer or said copolymer, covering material is selected from group, consisting of essential amino acids, polypeptides and organic nitrogenous compounds, essential amino acid being one or more, selected from group, consisting of arginine, lysine and histidine; polypeptide represents L-Lys-L-Thr-L-Thr-L-Lys-L-Ser; and organic nitrogenous compound is selected from group, consisting of creatine, creatinine and urea, content of covering layer constitutes from 0.01 to 5 wt fractions in terms per 100 wt fractions of microsphere.

EFFECT: invention ensures increase of bioaccessability and reduction of initial peak of exendin for prevention of such side effects as vomiting, nausea, headache.

10 cl, 7 ex, 5 tbl, 7 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: dosage form contains oxycodone hydrochloride as a physiologically active substance (A), optionally one or more physiologically combined excipients (B), a synthetic or natural polymer (C) and optionally natural, semisynthetic or synthetic wax (D).

EFFECT: dosage form of oxycodone hydrochloride possess degradation resistance of at least 400 N to less than 500 N, and releases max 99% of oxycodone hydrochloride in the physiological conditions after 5 h.

14 cl, 7 dwg, 17 ex

FIELD: medicine.

SUBSTANCE: declared invention refers to medicine. What is declared is a delayed release complex pharmaceutical composition containing a delayed release part and an immediate release part. The delayed release part contains AII-receptor blocker as an 'active ingredient'. The immediate release part contains HMG-CoA reductase inhibitor as an active ingredient.

EFFECT: declared composition is effective for treating hypertension and preventing complications in the patients suffering metabolic syndromes, such as diabetes, obesity, hyperlipidemia, coronary vessel disease, etc.

10 dwg, 13 bl, 8 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pharmaceutical industry and represents a pharmaceutical preparation for controlled release of a contained active ingredient, differing by the fact that said pharmaceutical preparation contains medically acceptable yeast able for alcoholic fermentation.

EFFECT: invention provides release of the active ingredient from the pharmaceutical preparation regardless of the environmental conditions.

13 cl, 4 ex, 3 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to medicine and may be used for treating patients with hypertension and lipid storage disease. There is applied a combined drug containing dihydropyridine, calcium canal blockers, and statin, a hypolipidemic agent. The drug is prepared in such a manner that release rate of said ingredients can be controlled with respect to each other.

EFFECT: method allows higher clinical effectiveness and compliance, prevented antagonist and side effects of the combined therapy.

27 cl, 12 tbl, 10 dwg, 7 ex

FIELD: medicine.

SUBSTANCE: there are offered an oral pharmaceutical composition containing a) a testosterone ester and a fatty acid ester of a medium chain size; and b) two or more lipid ingredients, at least first of which contains a hydrophilic surfactant and at least second of which contains a lipophilic surfactant; said lipid ingredients together provide solubilisation of said testosterone ester in amount 10-20 % of weight of a pharmaceutical composition; a method for prevention or release of testosterone deficiency symptoms in mammal subjects and a method for maintenance of prolonged oral testosterone release.

EFFECT: invention provides medium-size testosterone and fatty acid ester delivery of intensified and prolonged adsorption, desired testosterone levels which are detected in people who do not suffer testosterone deficiency.

30 cl, 15 dwg, 4 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to field of medicine, namely to chemical-pharmaceutical industry, in particular to drug form, such as capsule, ordinary or orally disintegrating tablet, able to deliver nitrogen-(N)-containing therapeutic medications, which have pKa in range from approximately 5 to 14 in organism in form with delayed release in order to be suitable for two-time or one-time day regimen of dosage, includes, at least, one organic acid, which solubilises medication before its release into unfavourable intestine environment, in which said medication is practically insoluble.

EFFECT: single drug form, composed of multitude of multi-layered particles, is manufactured in such a way, that said weak-base medication and said organic acid do not come into close contact with formation in situ of acidic adducts, guaranteeing that acid will not run out before release of medication finishes.

39 cl, 1 tbl, 10 ex, 9 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to field of pharmaceutical and food industry, in particular to production of vitamin-mineral complexes (VMC) and food additives, used for prevention and treatment of vitamin-mineral deficiency. Simultaneously, taken into account are all antagonistic and synergic interactions between active VMC components, arising in production, storage and application of medication. Delivery of micronutrients by time and place of their digestion is realised within one preparative form, which is made in form of tablet or capsule, containing several independent elements - pellets. Pellets have their time of dissolution, depending on acidity of surrounding medium. During movement of ready form along GIT time of beginning of substances release from one pellet follows time of end of substances release from other pellet in such a way that simultaneously in solution there were no active substances that have antagonistic interaction.

EFFECT: invention is aimed at increase of VMC efficiency and improvement of user's comfort during its application.

23 cl, 10 ex, 2 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a pharmaceutical multiparticulate-type dosage form. The declared dosage form contains one or more sets of synchronised pulse release (SPR) granules of a weakly alkaline drug wherein the weakly alkaline drug contains a nitrogen (N) containing selective 5-HT3 serotonin antagonist or a pharmaceutically acceptable salt thereof, having a pKa within the range from approximately 5 to approximately 14 and a solubility of no more than approximately 200 mg/ml at pH 6.8. The above SPR granules comprise the particles with organic acid nuclei coated with a film providing a release time delay. Also, the invention refers to a method for preparing a pharmaceutical dosage forms.

EFFECT: invention provides achieving the adequate plasma drug concentration 24 hours after the dose intake that makes it applicable for the OD regimen.

39 cl, 10 dwg, 2 tbl, 7 ex

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