Two-layered tablet for preventing cardiovascular disturbances, drug and method for preventing cardiovascular disturbances, including apoplexy and paralysis by using said tablet

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to two-layer tablet containing a compartment comprising a pharmaceutically acceptable compound of simvastatin; and a simultaneously separate compartment containing a compound of lisinopril and a pharmaceutically acceptable compound of folic acid as active ingredients. Preferentially, the tablet is prepared by using either direct compression technique, or wet granulation technique. The two-layer tablet under the invention is applied for purposes of preventing cardiovascular disturbances, including apoplexy and paralysis accompanying diseases and complications including those related with the age of 55 and older, stenocardia, fits, atherosclerosis, Charcot syndrome, diabetes, coronary disease, peripheral vessel disease, abnormal thrombocyte function, hemodialysis, hypercholesterolemia, hypertension, myocardial infarction, congestive cardiac failure, ischemia, nephropathy, high blood plasma homocysteine level, cardiac arrest or restenosis, diseases and complications associated with smoking, obesity and sedentary life-style causing a high risk of cardiovascular diseases in individuals, including apoplexy and paralysis.

EFFECT: preparing an effective drug for treating cardiovascular diseases.

28 cl, 3 dwg, 2 tbl, 5 ex

 

The technical field to which the invention relates.

The invention relates to pharmaceutical compositions for the prevention of apoplexy or paralysis in patients with an increased risk of their occurrence. More specifically, the invention relates to a two-layer tablets comprising a combination of compounds of simvastatin, the compounds of lisinopril and connection of folic acid.

The level of technology

Cardiovascular diseases are a major cause of morbidity and mortality in developed countries and is now coming to the first place on morbidity and mortality worldwide. Although the risk factors for cardiovascular disease are well known, control is below optimal, even in the most developed countries. Without a doubt, changes in the habitual diet and lifestyle to reduce the risk of developing cardiovascular disease. However, is insufficient work to determine the most effective and efficient ways to implement these changes in life. On the other hand, the treatment and prevention of cardiovascular diseases is expensive, and its cost increases.

It is known that there are significant differences between the treatment prescribed by the physician, and self-treatment, which is a serious problem in the treatment of chronic the ski diseases, such as disorders of the cardiovascular system. The under treatment of chronic diseases physician's orders is achieved in 50% of the developed countries. The consequences of the low level of compliance is important both for the individual and for society as a whole. The patient has reduced the effectiveness of the treatment, which leads to an increase in its duration, and makes it more difficult to assess the effectiveness and determining the best dose for such treatment by a doctor. For society in General low compliance leads to increased chemical pollution, increased spending on health and self-treatment.

The complexity of dosing and side effects are factors that relate to those drugs, the use of which leads to the greatest controversy. These two factors quickly increase when you use numerous ways to treat the disease or in the treatment of more than one disease in the same patient, which further increases the disparity of treatment.

In this context, Wald and Law (Br. Med. J. 326, No. 7404, 1419-23, 2003) proposed the term polypill (polypill)related to a hypothetical combination of drugs, such as statins, protivogipertonicheskoe drugs, aspirin and vitamins, such as folic acid which is taken once a day as tabled is. The authors recommend the use of polypill to prevent complications in cardiovascular diseases with minimal side reactions, based on the interim analysis, performed using the short-term clinical trials. Thus, prevention of cardiovascular disease, based on the reception of polypill containing several components, effective to eliminate risk factors for cardiovascular disease, prevent high levels of ischemic heart diseases and heart disease. The authors concluded that the strategy of poliphilo will be safe, and their conventional technique will make a significant contribution to the prevention of cardiovascular diseases in Western countries compared with other methods. Also, the authors found that the reception of poliphilo may reduce the incidence of coronary heart disease and frequency of heart attacks up to 88% and 80%, respectively.

The authors reviewed the most suitable patients for the reception of poliphilo. Candidates for treatment may be patients suffering from acute coronary syndrome or ischemic stroke, patients with chronic stable angina, transient ischemic attacks and diabetes. Among the population who do not have cardiovascular disease, history of disease, the most su is the natural enemy factor is age. Because 96% of deaths from acute coronary syndrome or stroke occur in people over 55 years of age, preventive therapy for people over 55 years of age will help prevent almost all of these deaths. Thus, it is the best strategy for the treatment of all patients with coronary artery disease and all people over 55 years of age.

Regarding the use of poliphilo for the prevention of cardiovascular diseases was published several patents.

Patent US 6576256 considers the combination of the hypocholesterolemic agent, inhibitor system the renin-angiotensin, aspirin and at least one vitamin selected from vitamin B6, vitamin B12 and folic acid.

Patent application WO 0115674 discloses the use of a substance that inhibits the system renin-angiotensin, substance, lowering lipid levels, diuretic agent and aspirin.

Patent application WO 0176632 discloses the combination of hydrochlorothiazide, atenolol and enalapril, the antihypertensive agents, atorvastatin, substances that regulate lipid levels, aspirin, substances that prevent platelet aggregation, and folic acid to lower homocysteine levels in the serum.

Patent application WO 03020243 discloses a combination of substances, lowering lipid levels, the inhibitor system of the renin-angiotensin and aspirin.

Stated the ka patent WO 2004080488 discloses a combination of aspirin, inhibitor reductase HMG COA and antihypertensive agent.

Patent application WO 2005011586 discloses a combination of an antagonist of β-adrenergicheskoj receptor or diuretic agent, or both, hypocholesterolemic agent, inhibitor system the renin-angiotensin and aspirin.

Patent application WO 2005025673 discloses a combination of hypoglycemic agent from the family of biguanidine, substances, lowering lipid levels, and hypertensive agent.

On the other hand, simvastatin is one of the most often prescribed by a physician inhibitor of HMG COA reductase in the treatment of hypercholesterolemia. In addition, there are advantages in comparison to other compounds of the same family, they are an admixture of both quantitative and qualitative.

Similarly, lisinopril is one of the most frequently prescribed inhibitors of the enzyme that interacts with the angiotensin in the treatment of hypertension. With pharmacotechnical perspective, this connection has the following advantages over other connections of his family, receive it with fewer impurities, and its solubility in water is maximum, which causes it to easier absorption.

In turn, have provided evidence that high levels of homocysteine are associated with an increased risk of ischemic coronarias and cardiovascular disease. From this point of view is that folic acid regulates and normalizes high level of homocysteine. This connection mechanism is unknown, but it is established that folic acid reduces the level of homocysteine in plasma by strengthening its catabolism.

Currently not found publications related to the combination of the three above-mentioned active ingredients, as in pharmacological and clinical levels, under the combination refers to the introduction of all three components in a single dose or one-time introduction of components in different forms. Clinical trials of this combination was not carried out, also there is no technology of the preparation of drugs in a single dosage form or simultaneously introducing each of the three compounds individually.

Thus, it was appropriate to offer a combination of simvastatin, lisinopril and folic acid, including the optimal dose of the three active ingredients are presented as separate dosage forms to prevent apoplexy or paralysis in people with high risk of their occurrence. In particular, for people at high risk include people over 55 years of age, patients with a history of the disease is marked angina, stroke, atherosclerosis, syndrome Charcot, diabetes, ish the economic heart disease, the peripheral vascular disease, altered platelet function, hemodialysis, hypercholesterolemia, hypertension, myocardial infarction, congestive heart failure, ischemia, nephropathy, elevated levels of homocysteine in the serum, heart, or restenosis, are also at risk are smokers, obese people and people who lead a sedentary lifestyle.

Disclosure of inventions

The present invention satisfies the aforementioned need in the combination of simvastatin, lisinopril and folic acid, are presented in the form of a single dosage form at optimal doses, offering a two-layer tablet comprising the following two compartment:

- the compartment (i), comprising as an active ingredient, the pharmaceutically acceptable compound of simvastatin, and

- compartment (ii), comprising as active ingredients and pharmaceutically acceptable compound of lisinopril and pharmaceutically acceptable compound of folic acid;

characterized by the fact that both compartments isolated from each other.

In accordance with a preferred aspect of the present invention, pharmaceutically acceptable connection simvastatin is a free simvastatin, pharmaceutically acceptable connection lisinopril optional selected from free lisinop the sludge and dihydrate lisinopril, and pharmaceutically acceptable compound folic acid optionally selected from free folic acid and folic acid dihydrate. The connection of folic acid preferably is a free folic acid.

The amount of simvastatin used in each pill varies from 2.5 to 20 mg, inclusive, preferably from 5 to 10 mg; the connection lisinopril is present in an amount of from 1 to 10 mg, inclusive, preferably from 2.5 to 5 mg and free folic acid is present in an amount of from 0.1 to 1 mg inclusive, preferably from 0.2 to 0.5 mg, inclusive.

Simvastatin is very sensitive to light and moisture. For this reason, in tablets, in the present invention, the above compound is isolated in a separate compartment from compartment that contain lisinopril and folic acid.

In accordance with a preferred aspect of the present invention, the tablet obtained by direct compression.

In accordance with a preferred aspect of the present invention, a tablet is produced by wet granulation.

In accordance with a preferred aspect of the present invention, if the tablet obtained by direct compression, it includes the following suitable fillers:

for compartment (i): baking powder, a substance that help the it slip, thinner, moving the substance and the substance that helps to release; and

for compartment (ii): thinner, baking powder, a substance that promotes sliding, and the substance that helps to release.

Baking powder from compartment (i) selected from the group comprising croscarmellose sodium, glycolate, starch sodium, crosspovidone, sodium lauryl sulfate, several forms of microcrystalline cellulose, such as microcrystalline cellulose PH 101 and microcrystalline cellulose PH 102 and the like, and mixtures thereof, the total weight of baking powder is from 2 to 10%, inclusive, by weight of compartment.

A substance that promotes sliding of compartment (i) selected from the group comprising colloidal anhydrous silica, maize starch, talc, magnesium trisilicate, and the like, and mixtures thereof, the total weight of facilitating the sliding of substances ranging from 0.1 to 10%, inclusive, by weight of compartment.

The diluent from compartment (i) selected from the group comprising selectonemenu microcrystalline cellulose, several forms of microcrystalline cellulose, such as microcrystalline cellulose PH 101 and microcrystalline cellulose PH 102, lactose anhydride, gidratirovannuyu lactose, calcium phosphate, dicalcium phosphate, tricalcium phosphate, mannitol, sorbitol, sucrose, Inositol, Tex the RAM, xylitol, corn starch, kaolin, bentonite and the like, and mixtures thereof, the total weight of the solvent is from 20 to 90%, inclusive, by weight of compartment.

Moving the substance from compartment (i) selected from the group comprising talc, sodium benzoate, poloxamer and similar agents and mixtures thereof, the total weight of the above-mentioned moving substances ranges from 1 to 10%, inclusive, by weight of compartment.

A substance that helps to release from compartment (i)selected from the group comprising sodium stearate, sodium fumarate, calcium stearate, zinc stearate, stearic acid, polyethylene glycols with a molecular weight ≥ 6000 and the like, and mixtures thereof, the total weight of the substances that promote the release is from 0.25 to 5%, inclusive, of the total weight of compartment.

The diluent from compartment (ii) selected from the group comprising selectonemenu microcrystalline cellulose, several forms of microcrystalline cellulose, such as microcrystalline cellulose PH 101 and microcrystalline cellulose PH 102, lactose anhydride, gidratirovannuyu lactose, calcium phosphate, dicalcium phosphate, tricalcium phosphate, mannitol, sorbitol, sucrose, Inositol, trehalose, xylitol, corn starch, kaolin, bentonite and the like, and mixtures thereof, the total weight of the solvent is from 20 to 95%, inclusive is about, the weight of compartment.

A substance that promotes sliding of compartment (ii) selected from the group comprising colloidal anhydrous silica, maize starch, talc, magnesium trisilicate, and the like, and mixtures thereof, the total weight of facilitating the sliding of substances ranging from 0.1 to 10%, inclusive, by weight of compartment.

Baking powder from compartment (ii) selected from the group comprising croscarmellose sodium, glycolate, starch sodium, crosspovidone, sodium lauryl sulphate, several forms of microcrystalline cellulose, such as microcrystalline cellulose PH 101 and microcrystalline cellulose PH 102 and the like, and mixtures thereof, the total weight of baking powder is from 2 to 5%, inclusive, by weight of compartment.

A substance that helps to release from compartment (ii) selected from the group comprising magnesium stearate, sodium fumarate, calcium stearate, zinc stearate, stearic acid, polyethylene glycols with a molecular weight ≥6000 and the like, and mixtures thereof.

In accordance with a preferred aspect of the present invention, if the tablet is produced by wet granulation, it includes the following suitable fillers:

for compartment (i) baking powder, a substance that promotes sliding, thinner, binding agent, a solvent, a moving substance in the society, helps to release; and

for compartment (ii) baking powder, a substance that promotes sliding, solvent, binder and a substance that helps to release.

Baking powder from compartment (i) selected from the group comprising crosspovidone, crosscarmellose sodium, glycolate, starch sodium, sodium lauryl sulphate, several forms of microcrystalline cellulose, such as microcrystalline cellulose PH 101 and microcrystalline cellulose PH 102 and the like, and mixtures thereof, the total weight of baking powder is from 2 to 10%, inclusive, by weight of compartment.

A substance that promotes sliding of compartment (i) selected from the group comprising colloidal anhydrous silica, maize starch, talc, magnesium trisilicate, and the like, and mixtures thereof, the total weight of facilitating the sliding of substances ranging from 0.1 to 10%, inclusive, by weight of compartment.

The diluent from compartment (i) selected from the group comprising selectonemenu microcrystalline cellulose, several forms of microcrystalline cellulose, such as microcrystalline cellulose PH 101 and microcrystalline cellulose PH 102, lactose anhydride, gidratirovannuyu lactose, calcium phosphate, dicalcium phosphate, tricalcium phosphate, mannitol, sorbitol, sucrose, Inositol, trehalose, xylitol, starch ku is Uruz, kaolin, bentonite and the like, and mixtures thereof, the total weight of the solvent is from 20 to 90%, inclusive, by weight of compartment.

Binder from compartment (i) selected from the group comprising povidone k-30, hypromellose, carboxymethyl cellulose, pre-gelatinizing starch, paste, corn starch and the like, and mixtures thereof, the total weight of the binding substances is from 0.5 to 20%, inclusive, by weight of compartment.

The solvent from compartment (i) selected from the group comprising sodium lauryl sulfate, Polysorbate 80, lauroyl macrogol-32 glycerides and the like, and mixtures thereof, the total weight of the solvent is from 0.1 to 3%, inclusive, by weight of compartment.

Moving the substance from compartment (i) selected from the group comprising talc, sodium benzoate, poloxamer and the like, and mixtures thereof, the total weight of the sliding substances ranges from 1 to 10%, inclusive, by weight of compartment.

A substance that helps to release from compartment (i) selected from the group comprising magnesium stearate, sodium fumarate, calcium stearate, zinc stearate, stearic acid, polyethylene glycols with a molecular weight ≥6000 and the like, and mixtures thereof, the total weight of the substances that promote the release is from 0.25 to 5%, inclusive, by weight to the of mpartment.

Baking powder from compartment (ii) selected from the group comprising crosspovidone, crosscarmellose sodium, glycolate, starch sodium, sodium lauryl sulphate, several forms of microcrystalline cellulose, such as microcrystalline cellulose PH 101 and microcrystalline cellulose PH 102 and the like, and mixtures thereof, the total weight of baking powder is from 2 to 5%, inclusive, by weight of compartment.

A substance that promotes sliding of compartment (ii) selected from the group comprising colloidal anhydrous silica, wheat starch, talc, trisilikata magnesium and the like, and mixtures thereof, so that the overall weight easy slip agents ranged from 0.1 to 10%, inclusive, by weight of compartment.

The diluent from compartment (ii) selected from the group comprising microcrystalline cellulose PH 101, microcrystalline cellulose PH 102 and the like, and mixtures thereof, the total weight of the diluent ranges from 20 to 50%, inclusive, by weight of compartment.

Binder from compartment (ii) selected from the group comprising povidone k-30, hypromellose, carboxymethyl cellulose, pre-gelatinizing starch, paste, corn starch and the like, and mixtures thereof, the total weight of the connecting link is from 0.5 to 20%, inclusive, by weight to the of mpartment.

A substance that helps to release from compartment (ii) selected from the group comprising magnesium stearate, sodium fumarate, calcium stearate, zinc stearate, stearic acid, polyethylene glycols with a molecular weight ≥6000 and the like, and mixtures thereof, the total weight of the substances that promote the release is from 0.25 to 5%, inclusive, of the total weight of compartment.

The above-mentioned substances, contributing to the slide selected in such a way that colloidal anhydrous silica may be from 0.1 to 1.0%, maize starch from 1.0 to 10%, talc is from 1.0 to 10%, and magnesium trisilicate from 0.1 to 1.0%, while the total weight of the substances contributing to the slide, is from 0.1 to 10%, inclusive.

The above-mentioned sliding substances selected from the group comprising talc, the content of which can vary from 1.0 to 10%, sodium benzoate, the content of which may vary from 2.0 to 5.0%, and poloxamer, the total weight of the sliding substances ranges from 1 to 10%, inclusive.

The above-mentioned substances, helps to release selected so that the content of magnesium stearate may vary from 0.25 to 5.0%, the content of sodium fumarate can vary from 0.5 to 2%, the content of calcium stearate may vary from 0.5 to 1.0%, the content of zinc stearate can various is from 0.5 to 1.5%, the stearic acid may vary from 1.0 to 3.0% and the content of polyethylene glycols with a molecular weight ≥6000 may vary from 0.25 to 5.0%, while the total weight of the substances that promote the release is from 0.25 to 5%, inclusive.

The above-mentioned binder is selected so that the content of povidone may vary from 0.5 to 5.0%, the content of hydroxypropylmethylcellulose can vary from 2.0 to 5.0%, the content of sodium carboxymethyl cellulose can vary from 1.0 to 6.0%, the content of pre-gelatinizing maize starch can vary from 5.0 to 10.0% and the content of the paste of maize starch may vary from 10.0 to 20.0%, while the total weight of the binding substances ranged from 0.5 to 20%, inclusive.

The above solvents are selected so that the content of lauryl sodium sulfate can vary from 1.0 to 2.0%, the content of Polysorbate 80 (tween®80, Quimica Masso, Barcelona, Spain) may vary from 0.1 to 3.0%, and the content of lauroyl macrogol-32 glycerides (Gelucire (Helser)®44/14, Gattefosse S.A., Saint Priest, France) can vary from 0.5 to 1.0%, while the total weight of the solvent is from 0.1 to 3%, inclusive.

In accordance with a preferred aspect, the tablet of the present invention may optionally include a protective is bolocco (floor), protect it from light and moisture. The shell specified in the get with the use of film-forming polymers selected from acrylic polymers and cellulose derivatives. If you use acrylic polymer, it can represent the main bottled methacrylate copolymer. If you use a derivative of cellulose, it can be selected from the group comprising hypromellose, hydroxypropylcellulose, methyl cellulose, hydroxyethyl cellulose and mixtures thereof. Optional above, the shell may contain one or more moving substances and one or more cloud emulsions.

Floor, protect from light and moisture, is obtained by using a film-forming polymers. Film-forming polymers suitable for tablets according to the present invention are acrylic polymers of the Eudragit type®preferably, the film-forming polymer immediate release, such as Eudragit®EPO (main bottled methacrylate copolymer), cellulose derivatives, which can be selected from the group comprising hypromellose, hydroxypropylcellulose, methylcellulose, hydroxyethyl cellulose and mixtures thereof, mixtures of these film-forming polymers based on cellulose, sliding substances and cloud emulsions or mixtures of the above polymers with emollients and optional with cloud emulsions, ready and prepared for dispersion and application, such as Opadry®II (use, West Point, USA), Sepifilm®LP (Seppic, Paris, France), and similar substances and their mixtures.

In accordance with a preferred aspect of the present invention, the finished tablet has a total weight of from 150 to 400 mg, inclusive, preferably from 180 to 380 mg.

In accordance with another preferred aspect of the present invention, the tablet is used for obtaining a medicinal product intended for the prevention of apoplexy or paralysis, diseases or complications associated with an increased risk of their occurrence.

In accordance with the preferred aspect of the present invention, the tablet is used for diseases or complications associated with an increased risk, such as diseases or complications associated with age older than 55 years of age or diseases and conditions, such as angina, stroke, atherosclerosis, syndrome Charcot, diabetes, ischemic heart disease, peripheral vascular disease, altered platelet function, hemodialysis, hypercholesterolemia, hypertension, myocardial infarction, congestive heart failure, ischemia, nephropathy, elevated levels of homocysteine in plasma, cardiac arrest or restenosis, disease or complication, wired the e Smoking, obesity and a sedentary lifestyle.

In accordance with a preferred aspect of the present invention, a method of preventing apoplexy or paralysis, diseases or complications associated with an increased risk of their occurrence, may include the introduction of the above tablets of the present invention.

In accordance with the preferred aspect of the present invention is aimed at preventing apoplexy or paralysis, diseases or complications associated with an increased risk of their occurrence, such as, for example, diseases or complications associated with age older than 55 years, angina, stroke, atherosclerosis, syndrome Charcot, diabetes, ischemic heart disease, peripheral vascular disease, altered platelet function, hemodialysis, hypercholesterolemia, hypertension, myocardial infarction, congestive heart failure, ischemia, nephropathy, elevated levels of homocysteine in plasma, cardiac arrest or restenosis, disease or complication associated with Smoking, obesity and sedentary lifestyle, which is achieved by introduction of the above tablets of the present invention.

Brief description of drawings

The figure 1 shows the standard form and dimensions of the two-layer tablets weighing 360 mg, proposed in this invention.

In the figure 2 SSV is Zan profile release in vitro for each of the active ingredients of two-layer tablets, obtained by direct compression, as well as for the active ingredients separately in accordance with each compartment.

The figure 3 shows the release profile in vitro for each of the active ingredients of two-layer tablets, obtained by wet granulation, as well as for the active ingredients separately in accordance with each compartment.

The implementation of the invention

The present invention is additionally illustrated by the following examples which do not limit the scope of the claims of the claimed invention.

Example 1: Preparation of two-layer tablets

For the preparation of medicinal compositions were used the following fillers:

Microcrystalline cellulose PH 101, Avicel®- FMC, Barcelona, Spain;

Microcrystalline cellulose PH 102, Avicel®- FMC, Barcelona, Spain;

Selectiona microcrystalline cellulose, Prosolv®HD 90 - JRS Pharma, Riegate, Surrey, UK;

Croscarmellose sodium, Ac-Di-Sol®- FMC, Philadelphia, USA;

Crosspovidone, Polyplasdone®- ISP Technologies Inc., Calvert City, KY, USA;

Lauroyl macrogol-32 glycerides, Gelucire (Helser)®44/14 - Gattefosse SA - Saint Priest, France;

Povidone k-30, Platton®k29-32 - ISP Technologies Inc., Texas City, TX, USA; and

Colloidal anhydrous silica, Aerosil®200 - Degussa Corporation, Persippany, USA.

a) a Composition prepared by the method of direct comp is ASCII both compartments

The composition of the first compartment (A)
Number (%)Amount (mg)Function
Simvastatin5,5510,0The active ingredient
Ac-Di-Sol®(croscarmellose sodium)5,09,0Baking powder
Aerosil®200 (colloidal anhydrous silica)0,551,0Substance promoting slide

Number (%)Amount (mg)Function
Prosolv®HD 90 (selectiona microcrystalline cellulose)84,9152,8Thinner
Talc3,0of 5.4 Moving substance
Magnesium stearate1,01,8A substance that helps to release
Total100,0180,0-

Preparation of the first compartment (A)

All the components of the pharmaceutical composition were individually weighed and sifted through a sieve with a cell diameter of 0.5 mm, except magnesium stearate. They were mixed in the shaker and the mixture was postponed. Magnesium stearate was then screened through a sieve with cell diameter of 0.5 mm and added to the previous mixture in a shaker and mixed for another 5 minutes to get the mixture for extrusion.

The mixture, thus obtained, was ready for pressing using a press to tablets Manesty F3, punch with a hole diameter of 9 mm, with a nominal weight of the tablet 180 mg However, to obtain a two-layer tablets this mixture was stored before cooking the second compartment ().

The composition of the second compartment (In)
Number (%)Amount (mg) Function
Lisinopril dihydrate2,775,0The active Ingredient
Folic acid0,220,4The active Ingredient

Number (%)Amount (mg)Function
Avicel®PH 101 (microcrystalline cellulose PH 101)45,6882,2Solvent
Avicel®PH 102 (microcrystalline cellulose PH 101)45,6882,2Thinner
Aerosil®200 (colloidal anhydrous silica)0.551.0Substance promoting slide
Ac-Di-Sol®(croscarmellose sodium)of 4.448,0Baking powder
Magnesium stearate0,661.2A substance that helps to release
Total100,0180,0-

Preparation of the second compartment (In)

Weighted folic acid was ground in a mortar with a gradual dilution of the fraction of 5%of the total microcrystalline cellulose, pre-weighted, according to the formula. The remaining components of the formula were weighed with the exception of magnesium stearate was added to the mixture. The resulting mixture was sieved through sieves with mesh size of 0.5 mm and was stirred for 15 minutes.

Finally, magnesium stearate was weighed and sieved through sieves with mesh size of 0.5 mm, was added to the previously obtained mixture was stirred for 5 minutes.

The mixture, thus obtained, was ready for pressing using a press to tablets Manesty F3, punch with a hole diameter of 9 mm, with a nominal weight of the tablet 180 mg However, to obtain a two-layer tablets this mixture was stored for use with the previously prepared mixture, which corresponds to the first compartment (A).

Preparation of two-layer tablets

For preparation of the two is leunig tablets quantity of powder, required for each compartment (180 mg of the mixture, which corresponds to the first compartment (a) and 180 mg of the mixture, which corresponds to the second compartment (B)), were weighed separately. Used press for tablets Manesty F3 with concave shapes with a diameter of 9 mm. Composition dihydrate lisinopril and folic acid (In) extruded manually placing the mixture in the matrix of the press for tablets, and then, without removing the tablet from the die press and returning to the tightening cycle, fills the remaining space in the matrix mixture, which corresponds to the composition of compartment (A) with simvastatin, the cycle was completed by obtaining a two-layer tablet. Thus obtained tablets weighing 360 mg strength 180-220 N and certainty of less than 0.1 % without delamination or separation from each other of the two layers.

b) Composition prepared by the method of wet granulation both compartments

The composition of the first compartment (C)
Number (%)Amount (mg)Function
Fine simvastatin (1)5,5510,0The active ingredient
Polyplasdone®XL (crosspovidone)5,09,0Baking powder

Number (%)Amount (mg)Function
Aerosil®200 (colloidal anhydrous silica)0,551,0Substance promoting slide
Avicel®PH 101 (microcrystalline cellulose PH 101)78,9142,0Thinner
Platton®k29-32 (povidone K-30)(2)5,09,0Binder
Gelser®44/14(3)(Lauroyl macrogol-32 glycerides)1,01,8Solvent
Talc3,0of 5.4Moving substance
Magnesium stearate 1,01,8A substance that helps to release
Total100,0180,0-
(1)Fine original material in Rina-Jet. Grinding is done with the aim of improving the solubility of the active ingredient.
(2)Component included in the composition as a binding solution at a concentration of 10.0% in 96° ethanol.
(3)Component included in the binder.

Preparation of the first compartment (C)

Forming part of the inner component is the active ingredient (simvastatin), baking powder (crosspovidone), binder (povidone k-30), solvent (Gelucire®44/14) and 95% diluent (microcrystalline cellulose PH 101). Uncrystallizable filler is a substance that promotes sliding (Kolodny anhydrous silicon dioxide), moving the substance and the substance that helps to release (talc and magnesium stearate), and the remaining 5% of diluent (microcrystalline cellulose).

Intracrystalline components in addition to the binder and solvent were weighed. They were sieved through sieves with mesh size of 0.5 mm and was stirred those who tell 10 minutes. The mixture was placed in a mortar for further mixing.

Binder required for mixing, prepared in a separate container, also to this solution was added a solvent (gelucire®44/14).

It was mixed and subjected to wet granulation with a mesh size of 1.2 mm at 100 rpm Obtained pellets were left to dry for 20-24 hours in a thermostat at 40°C. after this time they were removed from thermostat and was passed through an oscillating granulator with a cell size of 0.8 mm

Approximately 2 grams were taken for moisture determination using thermobalance for 60 minutes at 90°C.

The remaining pellets were weighed to calculate how many uncrystallised components required for the finished part. After calculating the amount of each uncrystallizable component, all of them weighed and sieved through sieves with mesh size of 0.5 mm with the exception of magnesium stearate.

Crystal granules and uncrystallizable fillers was stirred for 15 minutes.

Magnesium stearate was weighed and sieved through sieves with mesh size of 0.5 mm and added to the previously obtained mixture was stirred tubulara mixer for 5 minutes.

The resulting mixture was ready for compression using the press to tablets Manesty F3 with forms with a diameter of 9 mm, rated in the with tablets was 180 mg However, in order to obtain a two-layer tablets of the mixture was maintained until the moment of preparation of the second compartment (D).

The composition of the second compartment (D)
Number (%)Amount (mg)Function
Lisinopril dihydrate2,775,0The active ingredient
Folic acid(1)0,220,4The active ingredient
Polyplasdone®XL (crosspovidone)4,07,2Baking powder
Aerosil®200 (colloidal anhydrous silica)0,551,0Substance promoting slide
Avicel®PH 101 (microcrystalline cellulose PH 101)43,478,1Thinner
Avicel®PH 102 (microcrystalline cellulose PH 102)43,478,1Thinner
Plasdon®k29-32(2)(povidone K-30)5,09,0Binder
Magnesium stearate0,661,2A substance that helps to release
Total100,0180,0-
(1)Component is included in the structure by binding solution to increase the homogeneity of the prepared tablets due to the low dose.
(2)Component included in the composition as a binding solution at a concentration of 5.0% (96° ethanol:purified water 50:50).

Preparation of the second compartment (D)

Forming part of the inside of the crystalline component is lisinopril dihydrate, baking powder (crosspovidone), binder (povidone k-30) and 95% diluent (microcrystalline cellulose PH 101 PH 102). Folic acid was added to the binder, to obtain a good distribution in the mixture and fo is the formation of vnutrikitayskoy part. Uncrystallizable fillers was the substance promoting sliding (colloidal anhydrous silicon dioxide), a substance that helps to release (magnesium stearate), and the remaining 5% of diluent (microcrystalline cellulose PH 101 PH 102).

Inner components are weighed, sieved through sieves with mesh size of 0.5 mm and was stirred for 10 minutes. The mixture was placed in a mortar for further mixing.

Binder required for mixing (with povidone k-30), was prepared in a separate container. Folic acid was dispersible in binding solution and successively added to a given solution with constant stirring on a magnetic stirrer.

The mixture was passed through a granulator with a cell diameter of 1.2 mm at 100 rpm Obtained pellets were left to dry for 20-24 hours in a thermostat at 40°C. after this time they were removed from thermostat and was passed through an oscillating granulator with a cell size of 0.8 mm

Approximately 2 grams were taken for moisture determination using thermobalance for 60 minutes at 90°C.

The remaining pellets were weighed to calculate how many uncrystallised components required for the finished part. After calculating the amount of each uncrystallizable component, all of them weighed and prosey the Ali through sieves with mesh size of 0.5 mm with the exception of magnesium stearate.

Crystal granules and uncrystallizable fillers mixed in tubulara mixer for 15 minutes.

Magnesium stearate was weighed and sieved through sieves with mesh size of 0.5 mm and added to the previously obtained mixture was stirred for 5 minutes.

The resulting mixture was ready for compression using the press to tablets Manesty F3 with forms with a diameter of 9 mm, nominal weight of tablets was 180 mg. However, in order to obtain a two-layer tablets of the specified mix continued to work with the mixture, which corresponds to the first compartment (C)prepared previously.

Preparation of two-layer tablets

For preparation of two-layer tablets, the amount of powder required for each compartment (180 mg of the mixture, which corresponds to the first compartment (C) and 180 mg of the mixture, which corresponds to the second compartment (D)), were weighed separately. Used press for tablets Manesty F3 with concave shapes with a diameter of 9 mm. Composition dihydrate lisinopril and folic acid (D) extruded manually placing the mixture in the matrix of the press to tablets and then, without removing the tablet from the die press and returning to the tightening cycle, fills the remaining space in the matrix mixture, which corresponds to the composition of compartment (C) with simvastatin, the cycle ended with getting the far East the layer tablets. Thus obtained tablets weighing 360 mg strength 180-220 N and certainty of less than 0.1 % without delamination or separation from each other of the two layers.

Were obtained deviations less than 5% for both compounds, compared with theoretical values of the weights and sizes of tablets, defined in accordance with the methods described in examples 3.1 and 3.6, respectively.

Destroyed both the composition is less than 5 minutes later, the value was determined in accordance with the method described in example 3.4. The value of the looseness was 0%, it has been determined in accordance with the method described in example 3.3. Two composition of matter release in excess of 95% after 30 minutes. Analysis of the content uniformity of each of the active ingredients has shown that it is 90-110%, which was determined in accordance with the method described in example 4.

The angles of repose were determined for both mixtures in accordance with the method described in example 3.7. It was found that the angles of repose at 25-30° provide excellent properties yield strength, while at 31-35° - good properties, at 36-40° - acceptable properties and at 41° - unacceptable. The results are presented in Table 1.

Table 1
Compartment Sliding speed (s)Angle of repose (°)
(A)13,5of 34.40

CompartmentSliding speed (s)Angle of repose (°)
(B)20,238,03
(In)9,1131,85
(G)8,731,60

The level of compressibility and the index Hausner was also determined in accordance with the method described in example 3.9. Index Hausner, is 1.26 to 1.34, and the level of compressibility equal to 21 -25%was considered acceptable, the values 1.00-1.11 and 1-10% respectively was considered excellent. The results are presented in Table 2.

Table 2
CompartmentBulk density (g/ml)Partitioned density (g/ml)Index HausnerLevel timemost the
(A)0,510,611,2016,39%
(B)0,400,521,29results were 23.08%
(In)0,340,411,1717,07%
(G)0,400,451,14is 11.11%

Example 2: two-layer coated tablets

For the preparation of compounds were used the following fillers:

Stearin, L2SM®- Cognis Iberia, Castellbisbal, Spain; and

The main bottled methacrylate copolymer, Eudragit®EPO - Rohm & Haas GmbH, Darmstadt, Germany.

Two-layer tablets obtained as described in example 1 was coated in such a way as to protect them from moisture and light and to improve their organoleptic characteristics (taste masking).

Composition composition used to prepare coating
Polymer suspension
Audrey®EPO22,62 g
Sodium lauryl sulfateof 2.26 g
Stearin L2SM®3,39 g
Purified water160,5 g
Ink suspension
Talc5,85 g
Titanium dioxide1,80 g
Magnesium stearatea 7.92 g
Purified water75,90 g

The method of preparation of the suspension for coating

For coatings used in the following conditions:

The initial temperature45°C
The final temperature35°C
The speed of the peristaltic pump22 rpm
The speed of the drumPosition 2-3
Pressure atomization1,5-2,0 bar.
The nozzle diameter0.8 mm
Subsequent drying in a drying
camera16 hours at 40°
Weight gain pills5%

For the preparation of polymer suspension of sodium lauryl sulfate was added into the water until dissolved, stirring was carried out using a magnetic stirrer. Then dispersible stearin and then the polymer Eudragit®EPO. Total cooking time was 15 minutes.

To prepare the pigment suspension talc, titanium dioxide and magnesium stearate were added to purified water in this order with constant stirring on a magnetic stirrer. Total cooking time was 15 minutes.

After these two dispersions were prepared, the ink suspension was added to the polymer suspension was stirred using a magnetic stirrer at an average speed for 30 minutes.

The obtained coated two-layer tablets were resistant to mechanical friction caused by the covering system due to friction between the pellets and between the pellets and the inner surface of the cover drum. Coated two-layer tablet have the same pharmacotechnical the ski parameters and the parameters of the release of each active ingredient, as uncoated bilayer tablet. Assessment and uniformity the contents of each of the active ingredients was in the range of from 90 to 110%.

Example 3: Methodology for determination of pharmacokinetic parameters

1. Uniformity of weight: for analysis, we used analytical balance AG245 (Mettler-Toledo, Columbus, USA). Were selected 20 tablets and independently from each other weighted, calculated mean, standard deviation and coefficient of variation obtained weights. Standard deviation equal to 7.5%, was valid for tablets weighing 180 mg and 5.0% for tablets weighing 360 mg

2. Strength tablets: analysis, we used the Durometer RTV-311 (Pharma Test, Hainburg, Germany). To measure the strength of the tablets were taken 10 tablets and individual values was recorded to calculate the value of fracture strength, standard deviation and coefficient of variation.

3. Friability: used for the analysis device for determining friability TAR10 (Erweka GmbH, Austria). Were selected 20 tablets, weighed on an analytical balance AG245, the obtained values were recorded, and the tablets were placed in the device for determining friability for 5 minutes at 25 rpm then the tablets were removed from the instrument, was purified from the powder particles, which could be caused by abrasion, and again weighed using the same analytical balance. Looseness of vechicle is and the difference between initial weight and final weight percent, the value was less than 1%.

4. Destruction: used for the analysis disintegrator PTZ-E (Pharma Test, Hainburg, Germany), took 6 pills and put each in a separate compartment, placed in a basket to achieve the effect. The study was performed in a water bath at a temperature of 37±1°C, as media for the destruction of used treated water of the same temperature. Calculated value, standard deviation and coefficient of variation.

5. Loss on drying: analysis was performed using thermovision MA-30 (Sartorius, Goettingen, Germany). Three tablets were ground in a glass mortar, and the obtained powder was placed on a heating element thermovision. The process was completed in 60 minutes at a temperature of 90°C, the weight loss indicated the water content, expressed as a percentage.

6. The size of the tablets: the measurements were made using Vernier calipers, measure the diameter and thickness of ten tablets. To calculate the mean, standard deviation and coefficient of variation.

7. Sliding speed and angle of repose: these options was determined using the PTG cars (Pharma Test, Hainburg, Germany). Sliding speed determines the ability of a powder or granules to flow vertically under certain conditions. The angle of repose is the characteristic which is related to the friction between the particles or to the resistance to movement between the hour is Izumi. Thus, the instrument provides a measurement of both parameters, immediately after filling funnel specified machine mix that you want to analyze. The mixture flows through the hopper and forms a cone at the base of the machine, measured the time required for the mixture spilled (sliding speed), as well as the height and diameter of the forming cone, which makes it possible to calculate the angle of repose (α) according to the following formula:

tan(α)=Height of the cone/0,5×base diameter

8. Volume and fluid density: analysis was carried out using the equipment for the titration of STAV (J.Engelsmann, Ludwigshafen, Germany). A sufficient amount of the mixture was placed in granulated cylinder mechanism, so that the volume was 50-100 ml, weighed mass of the investigated volume. The amount of mass was determined before and after sampling. Bulk density was calculated by dividing mass by volume after sampling. Density values were determined by dividing the mass by the volume to the selection and the fluid density was determined by dividing the mass by the volume after sampling. Both density is expressed in mg/ml

9. Index of Carr (compressibility factor) and the index Hausner: both index was calculated based on the values of bulk density (ρ) and fluid bulk density (ρ) by the following formulas:

The compressibility factor (%)=100×(ρ-ρ)/ρ

Index Hausner=ρ/ρ

Example 4: Analytical IU the odes

Investigation of the solubility

Simvastatin

EquipmentUSP II, blade
The temperature of the water bath37°C±0.5°C
WednesdaySR 10 mm sodium phosphate, pH 7.0 with 0.5% lauryl sulfate
The approximate solution volume900 ml
The blade rotation speed100 rpm

Primary data
EquipmentUSP II, blade
Samples6 individual tablets (1 for each vessel)
The sampling timeThe kinetics of dissolution (minimum 3 points)
The volume of samples to be taken5.0 ml of the middle solution
Filtering sampleFilters made of PVDF, 0.45 μm
The analysis sampleHPLC (without prior dilution of the sample)
The square is defined by calculating the integral of the peak

Calculationsn-1
Q=[CnV+ΣCiS]
i=1
where
Q=accumulated amount of dissolved simvastatin (mg)
Withn=concentration of simvastatin in the interval of sampling n (mg/ml)
V=the individual volume of the vascular system (ml)
n-1
ΣCi=total concentration of simvastatin
i=1 interval sampling at n-1 (mg/ml)
S= volume of the aliquot sample

Conditions of chromatography
EquipmentKontron Instruments, Bletchley, UK
ColumnTracer Exel (Sant Cudat, Spain) 120 ODS 5 µm
15×0.4 cm (control column)
The mobile phaseACN:SR 0,033 M anhydrous phosphate nartia, pH 4.5 6:35
The flow velocity1 ml/min
The amount of applied sample50 µl
DetectorUV, 240 nm
The temperature of the columnTHE
Total time chromatography18 min
The delay time of the active ingredient10 min

Lisinopril digidot
EquipmentUSP II, blade
The temperature of the water bath37°C±0.5°C
WednesdaySR 30 mm potassium phosphate, pH 2,0
The approximate solution volume500 ml
The blade rotation speed100 rpm
Samples6 individual tablets (1 for each vessel)
The sampling timeThe kinetics of dissolution (which minimum 3 points)
The volume of samples to be taken5.0 ml of the middle solution
Filtering sampleFilters made of PVDF, 0.45 μm
The analysis sampleHPLC (without prior dilution of the sample)
Primary dataThe square is defined by calculating the integral of the peak

EquipmentUSP II, blade
CalculationsAs for simvastatin, to calculate the accumulated amount of dissolved substances and the percentage release was represented graphically

Conditions of chromatography
EquipmentKontron Instruments
ColumnTracer Exel C8 5 μm 15×0.4 cm (control column)
The mobile phaseCAN:SR 0,033 M anhydrous phosphate nartia, pH 2,0 9:91
The flow velocity 1 ml/min
The volume of the applied sample50 µl
DetectorUV, 215 nm
The temperature of the columnTHE
Total time chromatography18 min
The delay time of the active ingredient8 min

Folic acid
EquipmentUSP II, blade
The temperature of the water bath37°C±0.5°C
WednesdaySR 0.5 M sodium acetate, pH 2,0
The approximate solution volume250 ml
The blade rotation speed50 rpm
Samples6 individual tablets (1 for each vessel)
The sampling timeThe kinetics of dissolution (minimum 3 points)
The volume of samples to be taken 5.0 ml of the middle solution
Filtering sampleFilters made of PVDF, 0.45 μm
The analysis sampleHPLC (without prior dilution of the sample)
Primary dataThe square is defined by calculating the integral of the peak

EquipmentUSP II, blade
CalculationsAs for simvastatin, to calculate the accumulated amount of dissolved substances and the percentage release was represented graphically

Conditions of chromatography
EquipmentKontron Instruments
ColumnTracer Exel C8 5 μm 15×0.4 cm (control column)
The mobile phaseMethanol: SR 0.03 M phosphate anhydrous, nartia, pH 2,0 22:78
The flow velocity1 ml/min
The amount of deposited samples 80 ál
DetectorUV, 280 nm
The temperature of the columnTHE
Total time chromatography20 min
The delay time of the active ingredient9 min

Research and uniformity of content

Simvastatin

Study: 3 tablets were weighed individually in different flasks with a volume of 100 ml, was added 90 ml of mobile phase. The solutions were treated with ultrasound for 5 minutes, left to the solution cooled, and brought to 100 ml by adding mobile phase. 2 ml of solution was collected and transferred into 10 ml of mobile phase, the final concentration was 20 μg/ml Solution was filtered through a filter made of poly (vinylidene fluoride) with a pore size of 0.45 μm and was placed in a vessel for HPLC.

The uniformity of content: 5 tablets were ground and the equivalent amount of the mixture was added to 5 mg of active ingredient was dissolved in about 40 ml of mobile phase. The solution was treated with ultrasound for 5 minutes, left to the cooled solution was brought to 50 ml by adding mobile phase. 2 ml of solution was collected and transferred into 10 ml of mobile phase, the final concentration was 20 µg/mlrefer filtered through filters of poly (vinylidene fluoride) with a pore size of 0.45 μm and was placed in a vessel for HPLC.

Lisinopril dihydrate

Analysis: 3 tablets separately weighed into flasks of 50 ml volume containing 40 ml of mobile phase. The solution was treated with ultrasound for 5 minutes, left to the cooled solution was brought to 50 ml by adding mobile phase. 2 ml of solution was collected and transferred into 10 ml of mobile phase, the final concentration was 20 μg/ml Solution was filtered through a filter made of poly (vinylidene fluoride) with a pore size of 0.45 μm and was placed in a vessel for HPLC.

The uniformity of content: 5 tablets were ground and the equivalent amount of the mixture was added to 1 mg of active ingredient was dissolved in about 20 ml of the mobile phase. The solution was treated with ultrasound for 5 minutes, left to the cooled solution was brought to 25 ml by adding mobile phase. 2 ml of solution was collected and transferred into 10 ml of mobile phase, the final concentration was 20 μg/ml Solution was filtered through a filter made of poly (vinylidene fluoride) with a pore size of 0.45 μm and was placed in a vessel for HPLC.

Folic acid

Study: three tablets separately weighed into flasks of 100 ml capacity containing 90 ml of mobile phase. The solutions were treated with ultrasound for 5 minutes, left to the solution cooled, and brought to 100 ml by adding mobile phase. The final concentration was 4 μg/ml Solution was filtered through filters of p is divinelyinspired with pore size of 0.45 μm and was placed in a vessel for HPLC.

The uniformity of content: 5 tablets were ground and took 55 mg of the mixture (55,55 µg R.A.) and was dissolved in 20 ml of mobile phase. The solution was treated with ultrasound for 5 minutes, leave to cool it, and brought the volume up to 25 ml Final concentration was of 4.44 mg/ml Solution was filtered through a filter made of poly (vinylidene fluoride) with a pore size of 0.45 μm and was placed in a vessel for HPLC.

Example 5: the release Profiles of the active ingredients

The figure 2 shows the release profiles in vitro for each of the active ingredients of two-layer tablets prepared by direct compression and for active ingredients separately in accordance with the compartments. The order of the values of the dissolution rate for each of the ingredients bilayer tablets was the same as for the individual active ingredients.

The figure 3 shows the release profiles in vitro for each of the active ingredients of two-layer tablets prepared by wet granulation and the active ingredients separately in accordance with the compartments. In this case, it should be noted that there was a slowing of the rate of dissolution for each of the active ingredients of two-layer tablets, compared to the individual active ingredients, the release of the entire dose could take more than 30 minutes.

1. Two-layer tablet for prophylact the key to cardiovascular disorders, including a first compartment containing as an active ingredient, the pharmaceutically acceptable compound of simvastatin and a second compartment containing as active ingredients and pharmaceutically acceptable compound of lisinopril and pharmaceutically acceptable compound of folic acid, while the first and second compartments are isolated from each other.

2. The tablet according to claim 1, in which the pharmaceutically acceptable compound of simvastatin is a free simvastatin, pharmaceutically acceptable connection lisinopril selected from the group including lisinopril and lisinopril dihydrate, and pharmaceutically acceptable compound folic acid is a free folic acid or folic acid dihydrate.

3. The tablet according to claim 2, in which the pharmaceutically acceptable compound of simvastatin is a free simvastatin, pharmaceutically acceptable connection lisinopril is a lisinopril dihydrate, and pharmaceutically acceptable compound folic acid is a free folic acid.

4. The tablet according to claim 2, in which the pharmaceutically acceptable compound of simvastatin is a free simvastatin, pharmaceutically acceptable connection lisinopril is a free is ing lisinopril, and pharmaceutically acceptable compound folic acid is a free folic acid.

5. The tablet according to claim 3, in which a free simvastatin present in an amount of from 2.5 to 20 mg, inclusive, lisinopril dihydrate is present in an amount of from 1 to 10 mg, inclusive, and free folic acid is present in an amount of from 0.1 to 1 mg, inclusive.

6. The tablet according to claim 4, in which a free simvastatin present in an amount of from 2.5 to 20 mg, inclusive, free lisinopril is present in an amount of from 1 to 10 mg, inclusive, and free folic acid is present in an amount of from 0.1 to 1 mg, inclusive.

7. The tablet according to claim 5, in which a free simvastatin present in an amount of 5 to 10 mg, inclusive, lisinopril dihydrate is present in an amount of from 2.5 to 5 mg inclusive, and free folic acid is present in an amount of from 0.2 to 0.5 mg, inclusive.

8. The tablet according to claim 6, in which a free simvastatin present in an amount of 5 to 10 mg inclusive, free lisinopril is present in an amount of from 2.5 to 5 mg inclusive, and free folic acid is present in an amount of from 0.2 to 0.5 mg, inclusive.

9. The tablet according to any one of pp.5-8, which is obtained by direct compression.

10. The tablet according to any one of pp.5-8, which is obtained by wet granulation.

11. T is bleda according to claim 9, in which the first compartment further includes as fillers baking powder, a substance that promotes sliding, thinner, moving the substance and the substance that helps to release and the second compartment further includes as fillers thinner, baking powder, a substance that promotes sliding, and the substance that helps to release.

12. The tablet according to claim 11, in which the baking powder the first compartment selected from the group comprising croscarmellose sodium, glycolate, starch sodium, crosspovidone, sodium lauryl sulfate, microcrystalline cellulose PH 101, microcrystalline cellulose PH 102, and mixtures thereof, and has a weight of from 2 to 10% inclusive of the total weight of the first compartment; a substance that promotes sliding of the first compartment selected from the group comprising colloidal anhydrous silica, maize starch, talc, magnesium trisilicate, and mixtures thereof and has a weight of from 0.1 to 10% inclusive by weight of compartment; diluent first compartment selected from groups, including selectonemenu microcrystalline cellulose, microcrystalline cellulose PH 101, microcrystalline cellulose PH 102, anhydrous lactone, gidratirovannuyu lactose, calcium phosphate, dicalcium phosphate, tricalcium phosphate, mannitol, sorbitol, sucrose, trehalose, xylitol, starch to kurusu, kaolin, bentonite and mixtures thereof, and has a weight of from 20 to 90% of the total weight of the first compartment; moving the substance of the first compartment selected from the group comprising talc, sodium benzoate, poloxamer and mixtures thereof, and has a weight of from 1 to 10% inclusive of the total weight of the first compartment; a substance that helps to release the first compartment selected from the group comprising magnesium stearate, sodium fumarate, calcium stearate, zinc stearate, stearic acid, polyethylene glycols with a molecular weight ≥6000 and mixtures thereof, and has a weight of from 0.25 to 5% inclusive of the total weight of the first compartment; diluent second compartment selected from the group comprising selectonemenu microcrystalline cellulose, microcrystalline cellulose PH 101, microcrystalline cellulose PH 102, anhydrous lactose, gidratirovannuyu lactose, calcium phosphate, dicalcium phosphate, tricalcium phosphate, mannitol, sorbitol, sucrose, trehalose, xylitol, corn starch, kaolin, bentonite and mixtures thereof, and has a weight of from 20 to 95% inclusive by weight of the second compartment; a substance that promotes sliding of the second compartment selected from the group comprising colloidal anhydrous silica, maize starch, talc, trisilicate magnesium and mixtures thereof, and has a weight of from 0.1 to 10% inclusive by weight of the second compartment; baking powder Deut is th compartment selected from the group including croscarmellose sodium, glycolate, starch sodium, crosspovidone, sodium lauryl sulfate, microcrystalline cellulose PH 101, microcrystalline cellulose PH 102, and mixtures thereof, and has a weight of from 2 to 5% inclusive of the total weight of compartment, and the substance that helps to release second compartment selected from the group comprising magnesium stearate, sodium fumarate, calcium stearate, zinc stearate, stearic acid, polyethylene glycols with a molecular weight ≥6000 and mixtures thereof.

13. Tablet of claim 10, in which the first compartment further includes as fillers baking powder, a substance that promotes sliding, diluent, binder, solvent, moving the substance and the substance that helps to release and the second compartment further includes as fillers baking powder, a substance that promotes sliding, diluent, binder and a substance that helps to release.

14. Tablet in item 13, in which the baking powder the first compartment selected from the group comprising crosspovidone, crosscarmellose sodium, glycolate, starch sodium, sodium lauryl sulfate, microcrystalline cellulose PH 101, microcrystalline cellulose PH 102, and mixtures thereof, and has a weight of from 2 to 10% inclusive of the total weight of the first compartment; substance, the method is adequate slip, first compartment selected from the group comprising colloidal anhydrous silica, maize starch, talc, magnesium trisilicate, and mixtures thereof, and has a weight of from 0.1 to 10% inclusive of the total weight of the first compartment; diluent first compartment selected from the group comprising selectonemenu microcrystalline cellulose, microcrystalline cellulose PH 101, microcrystalline cellulose PH 102, anhydrous lactone, gidratirovannuyu lactose, calcium phosphate, dicalcium phosphate, tricalcium phosphate, mannitol, sorbitol, sucrose, trehalose, xylitol, corn starch, kaolin, bentonite and mixtures thereof, and has a weight of from 20 up to 90% inclusive by weight of the first compartment; binder first compartment selected from the group comprising povidone k-30, hypromellose, carboxymethyl cellulose, pretreated with gelatin starch, paste, corn starch and mixtures thereof, and has a weight of from 0.5 to 20% inclusive of the total weight of the first compartment; the solvent of the first compartment selected from the group comprising sodium lauryl sulfate, Polysorbate 80, lauroyl macrogol-32 glycerides and mixtures thereof, and has a weight of from 0.1 to 3% of the total weight of the first compartment; moving the substance of the first compartment selected from the group including talc, sodium benzoate, poloxamer and mixtures thereof, and has the EU from 1 to 10% inclusive of the total weight of the first compartment; a substance that helps to release the first compartment selected from the group comprising magnesium stearate, sodium fumarate, calcium stearate, zinc stearate, stearic acid, polyethylene glycols with a molecular weight ≥6000 and mixtures of the aforementioned substances, and has a weight of from 0.25 to 5% inclusive of the total weight of the first compartment; baking powder second compartment selected from the group comprising crosspovidone, crosscarmellose sodium, glycolate, starch sodium, sodium lauryl sulfate, microcrystalline cellulose PH 101, microcrystalline cellulose PH 102, and mixtures thereof, and has a weight of from 2 to 5% inclusive of the total weight of the second compartment; a substance that promotes sliding of the second compartment selected from the group comprising colloidal anhydrous silica, maize starch, talc, magnesium trisilicate, and mixtures thereof, and has a weight of from 0.1 to 10% inclusive by weight of the second compartment; diluent second compartment selected from the group comprising selectonemenu microcrystalline cellulose, microcrystalline cellulose PH 101, microcrystalline cellulose PH 102, and mixtures thereof, and has a weight of from 20 to 50% inclusive of the total weight of the second compartment; binder of the second compartment selected from the group comprising povidone k-30, hypromellose, carboxymethylcellulose,pre-processed gelatin starch, pasty maize starch and mixtures thereof, and has a weight of from 0.5 to 20% inclusive of the total weight of the second compartment; a substance that helps to release second compartment selected from the group comprising magnesium stearate, sodium fumarate, calcium stearate, zinc stearate, stearic acid, polyethylene glycols with a molecular weight ≥6000
and mixtures thereof, and has a weight of from 0.25 to 5% inclusive of the total weight of the second compartment.

15. Tablet section 12 or 14, which further includes a protective coating, protecting it from light and moisture.

16. Tablet indicated in paragraph 15, in which the protective coating obtained with the use of film-forming polymers.

17. The tablet according to clause 16, in which the film-forming polymers selected from the group comprising acrylic polymers and cellulose derivatives.

18. Tablet 17, in which the acrylic polymer is the main bottled methacrylate copolymer.

19. Tablet 17, in which the derivative of cellulose selected from the group comprising hydroxymethylcellulose, hydroxypropylcellulose, methylcellulose, hydroxyethyl cellulose and mixtures thereof.

20. Tablet p or 19, which optionally further includes at least one moving substance.

21. Tablet p or 19, which optionally additionally contains at least one cm is gitel.

22. Tablet p or 19, which optionally additionally contains at least one cloud.

23. The tablet according to claim 1, which has a total weight of from 150 to 400 mg, inclusive.

24. The tablet according to item 23, which has a total weight of 180 to 380 mg, inclusive.

25. The tablets according to any one of claims 1 to 24 for obtaining a medicinal product intended for the prevention of cardiovascular disorders, including apoplexy and paralysis, diseases or complications, causing an increased risk of apoplexy or paralysis.

26. Use A.25 in which these diseases or complications selected from the group comprising diseases or complications associated with age older than 55 years, angina, stroke, atherosclerosis, syndrome Charcot, diabetes, ischemic heart disease, peripheral vascular disease, altered platelet function, hemodialysis, hypercholesterolemia, hypertension, myocardial infarction, congestive heart failure, ischemia, nephropathy, elevated levels of homocysteine in plasma, heart, or restenosis, diseases or complications associated with Smoking, obesity and sedentary lifestyle.

27. Method of prevention of cardiovascular disorders, including apoplexy and paralysis, diseases or complications, causing an increased risk of apoplexy or paroli is a, involving the introduction of a tablet according to any one of claims 1 to 24.

28. The method according to item 27, in which the disease or complication selected from the group including a disease or complication associated with age older than 55 years, angina, stroke, atherosclerosis, syndrome Charcot, diabetes, ischemic heart disease, peripheral vascular disease, altered platelet function, hemodialysis, hypercholesterolemia, hypertension, myocardial infarction, congestive heart failure, ischemia, nephropathy, elevated levels of homocysteine in plasma, heart, or restenosis, disease or complication associated with Smoking, obesity and sedentary lifestyle.



 

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FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to medicine, pharmacology and biology and concerns use of Trecresan as an acid phospholipase A1 modulator.

EFFECT: invention allows extending the range of acid phospholipase A1 modulators.

5 tbl, 2 ex

Transdermal plaster // 2445084

FIELD: medicine.

SUBSTANCE: invention refers to medicine, particularly pharmaceutical preparations, namely: plasters for transdermal application. Substance of invention consists in the fact that a transdermal plaster representing a matrix system and comprising a lining layer, a matrix layer and a lightproof protective coating in the following proportions is produced: 6.72 wt % of hypoxene substance, 15.11 wt % of sodium metabisulphite in propylene glycol with 0.067% of sodium metabisulphite, as well as 56.0 wt % of 95% ethanol and 22.17 wt % of PVP K30. The plaster aims at the transdermal introduction of hypoxene. A plaster area is 25 cm2.

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6 dwg, 1 tbl

FIELD: food industry.

SUBSTANCE: present invention relates to prevention of subsequent diseases by way of a specific nutritive composition prescription to children at an age of up to 3 years. One proposes the composition application; for production of the nutritive composition for: prevention and/or therapy of visceral adiposopathy and/or prevention and/or therapy of visceral fat mass accumulation up to an excessive quantity where the nutritive composition is prescribed for administration to a child at an age of 0 - 36 months. The composition contains a lipid, a protein components and a digestible carbohydrates component. The lipid component accounts for 35 - 55% of the total calorie content and contains less than 14.5 wt % of linoleic acid of the total fatty acids weight, the weight ratio of linoleic acid (LA) to alfa-linolenic acid (ALA) is 2 - 6. The protein component accounts for 5 - 15% of the total calorie content, the digestive carbohydrates component for 30-60% of the total calorie content. Additionally the composition may contain galactooligosaccharides, long chain polyunsaturated fatty acids (LC-PUFA) and 10-50 wt % of medium-chain fatty acids (MCFA).

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18 cl, 5 tbl, 4 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of formula

and ,

where the ring X represents benzole or pyridine; R1 represents substituted alkyl; R2 represents optionally substituted aryl or optionally substituted 4-7-member monocyclic heterocyclic group or optionally substituted condensed group of heterocyclic group with the benzole ring where the substitutes of optionally substituted aryl, optionally substituted 4-7-member monocyclic heterocyclic group and optionally substituted condensed group of heterocyclic group with the benzole ring are selected from a group consisting of; (1) alkyl optionally substituted by a group selected from halogen and alkoxycarbonyl, (2) alkoxy optionally substituted by halogen, (3) halogen, (4) 4-7-member monocyclic heterocyclic group or (5) amino, optionally mono- or disubstituted alkyl, and (6) hydroxyl, R3 represents hydrogen or alkyl: R4 represents hydrogen, halogen or alkyl; R5 represents hydrogen or alkyl; R6 and R7 are identical or different, and each represents hydrogen or halogen; or pharmaceutically acceptable salt. Also, the invention refers to a IKur blocker containing the compounds described above as an active ingredient, and also to a preventive and therapeutic agent for cardiac arrhythmia and atrial fibrillation.

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12 cl, 13 ex

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19 cl, 3 tbl, 7 ex

FIELD: medicine.

SUBSTANCE: invention refers to experimental medicine and can be used for developing molecular methods of treating coronary insufficiency. For this purpose, the simulated myocardial ischemia requires experimental myocardial injections of an endotheliocyte growth factor gene in the form of the phVEGF165 vector at 50-100 mcg/cm2 of an ischemic region at an area pitch of 5 mm. 2-dimethylaminoethanol is added to the vector preparation to provide more effective myocardiocyte transfection.

EFFECT: unlike peptide growth factors requiring the regular administration, the use of a gene construct with the endotheliocyte growth factor gene introduced in a single dose according to the developed method provides the intensified myocardial construct delivery and the activation of a greater number of cells involved in angiogenesis that promotes repaired perfusion in the ischemic myocardium region.

2 ex, 4 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to medicine, namely to combined drugs, and can be used for treating arterial hypertension. The drug is prepared by direct compression. A preparation with low residual humidity is more storage stable, shows high processibility and biological availability. The combined hypotensive drug contains a combination of enalapril maleate and hydrochlorthiazide as an agent, and lactose anhydride, microcrystalline cellulose, povidone, colloidal silicon dioxide, croscarmellose sodium and stearic acid salt as excipients. The optimum proportions of the components makes, wt %: The agent 11.0-18.0; Lactose anhydride 56.0-78.0; Microcrystalline cellulose 5.0-15.0; Povidone 2.0-4.0; Colloidal silicon dioxide 0.5-1.0; Magnesium stearate 0.5-1.0; Croscarmellose sodium 3.0-5.0.

EFFECT: making the drug preparation for treating arterial hypertension.

12 cl, 1 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to medicine, pharmacology and biology and concerns application of Trecresan as an agent to decrease cholesterol esterase activity.

EFFECT: invention allows extending the range of agents used to decrease cholesterol esterase activity.

4 tbl, 2 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel substituted methyl-amines of general formula 1, having serotonin 5-HT6 receptor antagonist properties. In formula 1 , W is naphthalene, indolysin or quinoline; R1 is hydrogen, fluorine, chlorine, methyl; R2 is hydrogen, fluorine, methyl, phenyl, thiophen-2-yl, furan-2-yl, pyridyl, piperazin-1-yl or 4-methylpiperazin-1-yl; R3 is methyl; or W is benzene, R3 assumes the value given above; R1 is 3-Cl, R2 is 3-piperazin-1-yl or 3-(4-methylpiperazin-1-yl); or R1 is hydrogen, R2 is phenyl or pyridyl; or R1 is hydrogen, fluorine, chlorine, methyl; R2 is 4-piperazin-1-yl or 4-(4-methylpiperazin-1-yl); or W is oxazole, R3 is optionally substituted methyl; R1 is chlorine or fluorine, R2 is methyl, or R1 is hydrogen, fluorine, chlorine, methyl; R2 is piperazin-1-yl, 4-methylpiperazin-1-yl, or R1 is chlorine, fluorine or methyl; R2 is furan-2-yl, or R1 is hydrogen, fluorine, chlorine, methyl; R2 is furan-2-yl, R3 is (tetrahydrofuran-2-yl)methyl, or R1 is hydrogen, fluorine, chlorine, methyl; R2 is thiophen-2-yl, R3 is 2-methoxyethyl, or R1 is chlorine or fluorine, R2 is thiophen-2-yl, R3 is methyl.

EFFECT: compounds can be used to treat central nervous system (CNS) diseases, such as psychiatric disorders, schizophrenia, anxiety disorders, as well as for improving mental capacity, for treating obesity or for studying the molecular mechanism of inhibiting serotonin 5-HT6 receptors.

15 cl, 27 dwg, 2 tbl, 25 ex

FIELD: chemistry.

SUBSTANCE: compounds activate glucokinase and can be used to prepare medicine for treating of metabolic disorders, for lowering blood glucose level, for treating hyperglycemia, for treating IGT, for treating Syndrome X, for treating impaired fasting glucose (IFG), for treating type 2 diabetes, for treating type 1 diabetes, for delaying the progression of impaired glucose tolerance (IGT) to type 2 diabetes, for delaying the progression of non-insulin requiring type 2 diabetes to insulin requiring type 2 diabetes, for treating dyslipidemia, for treating hyperlipidemia, for treating hypertension, for lowering food intake, for appetite regulation, for for treating obesity, for regulating feeding behaviour, or for enhancing the secretion of enteroincretins. In compounds of formula , A denotes , R3 is selected from a group consisting of phenoxy and benzyloxy, each possibly substituted with one or more substitutes independently selected from R12; R12 is F, CI, Br, -CF3, -CN methyl, ethyl, isopropyl, tert-butyl, methoxy, methylthio, ethoxy, cyclopropyl-methoxy, -NHC(O)CH3 or -S(O)2-CH3; R30 is methyl, ethyl, propyl, isopropyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, methoxy, ethoxy, propoxy, butoxy, tert-butoxy, benzyloxy or cyclopropyl-methoxy, each possibly substituted with one or more substitutes independently selected from R12; R8 is methylthio, isopropylthio, ethylthio or 2-methylpropylthio, each substituted with one or more substitutes independently selected from R34; R34 is carboxy.

EFFECT: improved properties of the compound.

13 cl, 1 tbl, 242 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to a method of treating hypertension, congestive cardiac failure, stenocardia, myocardial infarction, atherosclerosis, stroke. A method of treating involves introduction to a patient requiring such treatment of the solid oral dosage form containing a therapeutically effective amount of aliskiren or its pharmaceutically acceptable salt in which the active ingredient makes more than 46 wt % of total weight of the oral dosage form. The oral dosage form is presented in the form of a tablet or a film-coated tablet and produced by methods other than wet granulation with excipients by means of water and/or a water solution of a binding agent.

EFFECT: realisation of the specified purpose.

12 cl, 2 ex

FIELD: medicine, pharmaceutics.

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

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

14 cl, 2 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: declared formulation of the combined pharmaceutical chondroprotective drug presented in a solid dosage form contains as active substances sodium chondroitin sulphate and glucosamine sulphate sodium chloride, a binding agent, antifriction substances, an aerating agent, an excipient; the composition is film-coated. The ingredients are taken in proportions, wt %: sodium chondroitin sulphate - 10-35, glucosamine sulphate sodium chloride - 15-45, the binding agent (low-molecular povidone and potato starch) - 3.1-11, the antifriction substances (aerosil, calcium stearate and talc) - 2.7-5, the aerating agent (kollidon) - 1.7-10, the excipient (ludipress) - 10-44.2. The coating ingredients are taken in proportions, wt %: film-forming material (hypromellose) - 1-2, a plasticiser (macrogol and propylene glycol) - 1-1.8, a pigment (titanium dioxide) - 0.5-1.

EFFECT: auxiliary ingredients enables high release rate of a tabletted mass, complete drug absorption and shelf-life stability of all measures.

3 dwg, 3 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to medicine, and concerns a coformulated drug exhibiting antituberculous action and representing a solid dosage form which contains as an active principle a formulation of rifampicin, isoniazid, pyrazinamide, and a zinc-containing compound, and pharmaceutically acceptable excipients. The zinc-containing compound is zinc salt, preferentially zinc sulphate.

EFFECT: pharmaceutical composition under the invention is characterised by high efficacy and provides synergetic antimycobacterial activity when using the formulation of rifampicin, isoniasid, pyrazinamide and zinc sulphate as an antituberculous drug as compared with a formulation of standard antituberculous drugs.

9 cl, 3 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to field of medicine, namely to anti-tuberculosis composition. Claimed is pharmaceutical composition which includes sodium salt of para-aminosalicylic acid, zinc sulfate, sorbitol, polyvinylpyrrolodone, citric acid, stearic acid salt, sodium carboxymethyl starch, colloidal silicon dioxide and polyethylene glycol in amounts stated in invention formula.

EFFECT: pharmaceutical composition is characterised by high therapeutic activity, satisfactory technological characteristics and has storage term more than 2 years.

8 cl, 1 tbl, 1 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to field of chemical-pharmaceutical industry, namely to novel anti-tuberculosis medication. Claimed medication contains as active substance 4-thioureidoiminomethyperidinium perchlorate in effective and safe quantity and pharmaceutically acceptable auxiliary substances. Also claimed is method of its obtaining, which makes it possible to obtain target product with high yield. Novel medication, obtained by claimed method, possesses high tuberculostatic activity and low toxicity, preserves its stability in long-term storage.

EFFECT: invention can be used for treatment of all forms of pulmonary and extra-pulmonary tuberculosis, as well as in prophylaxis in composition of combined tuberculosis therapy.

12 cl, 8 tbl, 16 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to stable solid medication, containing olmesartan medoxomil and amlodipine or its pharmaceutically acceptable salt. Said solid medication is, in fact, free of reducing sugars. Stable solid medication optionally can additionally contain hydrochlortiazide or its pharmacologically acceptable salt. Medicinal form is intended for treatment or prevention of diseases caused by hypertension.

EFFECT: solid medicinal form in accordance with invention has improved solubility properties in comparison with lactose-containing composition.

42 cl, 2 dwg, 4 tbl, 2 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention claims per oral drug form of neramexam with modified release, which is applied for long therapy of patients with such diseases and states as dimentia in Alzheimer's disease and neuropathic pain. Neramexane is dispersed inside hard matrix, which contains release-regulating filler. Filler is selected from copolymer of polyvinylpyrrolidone and vinyl acetate, hydroxypropylmethylcellulose. Hydroxypropylmethylcellulose is present in mixture with microsrystalline cellulose. Content of said filler is selected in such a way as to obtain profile of neramexan release in vitro, characterised by dissolution time of, at least, 1 hour for amount of neramexane, constituting 50 wt %.

EFFECT: profile of release ensures concentrations of neramexane in plasma with fluctuation index 0,4 or lower with introduction of matrix tablet of neramexane one time per day at steady state.

23 cl, 4 tbl, 7 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to chemical-pharmaceutical industry, namely to creation of pharmaceutical composition in form of hard peroral drug form for treatment of gastrointestinal tract diseases. Pharmaceutical composition contains the following ingredients: trimebutin maleate, lactose, colloidal silicon dioxide, talc, corn starch, magnesium stearate.

EFFECT: obtained pharmaceutical composition ensures high clinical effect.

5 cl, 2 ex, 1 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to medicine, and consists in development of a new dosage of the preparation 6-methyl-2-ethyl-3-hydroxypyridine succinate providing modified release of an active substance. A unit dosage form contains 6-methyl-2-ethyl-3-hydroxypyridine succinate in amount 30.0-70.0 wt %, as a release modifier - cellulose derivatives and/or polyacrylic resins in amount 1.0-20.0 wt %, as an excipient - microcrystalline cellulose in amount 20.0-50.0 wt % and lubricants. The unit dosage form represents a tablet or a capsule consisting of a variety of small dense spheroids containing 6-methyl-2-ethyl-3-hydroxypyridine succinate as a major component. A combination of matrix and instant, coated and uncoated spheroids enables preparation of a drug in the various dosage forms with controlled release rate.

EFFECT: invention allows to produce the unit dosage forms of the preparation 6-methyl-2-ethyl-3-hydroxypyridine succinate for certain treatment regimens of various diseases.

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed invention relates to pharmaceutical composition for obtaining tablets, which includes in one standard form, for instance, in one tablet, the following ingredients: (a) active ingredient, such as (S)-1-[(3-hydroxy-1-adamantyl)amino]acetyl-2-cyano-pyrrolidin (vildagliptin), or its pharmaceutically acceptable salt, (b) hydroxypropylmethylcellulose, whose apparent viscosity in 1% solution constitutes from 80000 cP to 120000 cP (nominal value 100000 cP), (c) microcrystalline cellulose and (d) magnesium stearate.

EFFECT: composition possesses high stability and efficiency.

35 cl, 42 tbl, 26 dwg

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