Capsule and drug preparation for preventing cardiovascular diseases

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pharmaceutical industry, particularly a drug preparation for preventing the development of cardiovascular diseases in individuals of a high-risk group. A capsule for preventing the development of cardiovascular diseases in individuals of a high-risk group which contains acetylsalicylic acid tablets coated by partially hydrolised polyvinyl alcohol (PVA), tablets of simvastatin and pravastatin coated by hydroxypropyl methylcellulose (HPMC) and tablets of lisinopril, ramipril or perindopril coated by partially hydrolised polyvinyl chloride. Using the capsule in producing the drug preparation for preventing the development of cardiovascular diseases in individuals of a high-risk group.

EFFECT: capsule is stable at variable temperature and relative humidity, as well as resistant to decomposition of the active ingredients under exposure to light.

8 cl, 29 tbl, 9 ex

 

The technical field to which the invention relates.

The invention relates to pharmaceutical compositions for the prevention of cardiovascular disease in patients from high-risk groups. More specifically, this invention relates to a capsule that contains a set of components, such as acetylsalicylic acid, an inhibitor of the reductase 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-COA), selected from such compounds as simvastatin and pravastatin, an inhibitor of angiotensin converting enzyme (ACE)inhibitors, selected from such compounds as lisinopril, ramipril and perindopril.

The level of technology

Cardiovascular diseases are the leading cause of mortality and morbidity in the developed world, and this cause of mortality and morbidity comes first the rest of the world. Although the risk factors for cardiovascular disease are well known, management options are not yet optimal, even in the most developed countries of the world. Changes in dietary habits and lifestyle will undoubtedly reduce the risk of cardiovascular disease. However, as yet there have not been enough effort to find the most efficient and cost-effective ways of achieving change in the human OBR who see life. On the other hand, prevention and treatment of cardiovascular diseases are costly activities and their value continues to increase.

It is well known that inaccurate compliance with prescribed regimens medication during the course of remedial measures, and self-treatment of patients is a significant problem in the treatment of such chronic diseases as cardiovascular disease. The proportion of patients who follow prescribed a regimen of drugs is estimated at 50% in the developed world. A lack of consistency in the implementation of medical advice in the area of treatment is fraught with consequences, affecting directly the patients themselves and the society in General. For patients this may reduce the effectiveness of the treatment, which necessitates the treatment of subacute symptoms and creates difficulties for clinicians in their assessment of the effectiveness of remedial measures and identify the most appropriate when such treatment dosages of medicines. For society in General, this problem threatens the growth of the volumes of chemical waste, increasing health care costs and increased incidence of self-medication among patients.

The complexity of dosing and adverse effects pre whom are associated with drugs factors most complicate compliance with prescribed medical regimens medication. There has been a rapid increase in both the complexity of dosing, and adverse effects during implementation of the methods of complex therapy for treating one or more diseases in one patient, which leads to less rigorous adherence to medical appointments for treatment.

In this context, Wald and law (Br.Med.J. 326, No.7404, 1419-23, 2003) formulated the concept of "multi-component pill", implying that the given term combination of such drugs as statins, anti-hypertensive tools, aspirin and vitamins, for example folic acid, intended for once daily administration. The concept of "statins" includes compounds that are inhibitors of the reductase 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-COA). Chemical name for aspirin is acetylsalicylic acid. Acceptance of this multicomponent tablets recommended by these authors as a way of achieving an important effect in the prevention of cardiovascular disease while minimizing the adverse effects that were found on the basis of a meta-analysis of non-system short-term clinical studies. The practice of receiving multi-component tablets, containing the x several active substances, in order to reduce risk factors for cardiovascular disease so as to prevent significant increased incidence of heart attacks and strokes. The authors concluded that taking multicomponent tablets will not harm patients and that the widespread use of such means of drug delivery will have a more significant impact on the prevention of cardiovascular diseases among the population of Western countries than any other event in the specified direction. At the same time, the authors estimated that, due to the use of multicomponent tablets may reduce the number of occurrence of coronary heart disease and stroke 88% and 80%, respectively.

The authors investigated the impact of receiving a multicomponent tablets to patients with appropriate symptoms. Thus, the number of candidates for the study included the patients with the syndrome of acute heart failure or the onset of cerebral ischemia, patients with chronic stable angina, seizures transient vascular insufficiency and those suffering from diabetes. Among those not affected by the primary disease, the most determining factor is age as 96% of the mortality associated with acute coronary syndrome or Insa is Tom, occurs in persons older than 55 years, and preventive treatment of persons in this age group gave the opportunity for almost all of them to avoid death. Thus, the best results of preventive treatment are achieved in patients with disease due to vascular insufficiency and in the age group over 55 years of age.

In this regard, we have published several patents relating to the application of multicomponent tablets for the prevention of cardiovascular diseases.

In the patent application US 2004219208 disclosed drug delayed release of the active substance-containing antagonist of angiotensin II in combination with one or more medicinal component, selected from among the compounds used as hypertensive drugs, hypoglycemic drugs, that reduces the content of lipids, antithrombotic drugs, facilitating a state of menopause, and drugs.

In the patent US 6576256 mentioned the combination of means for lowering cholesterol in the blood, such as an inhibitor of reductase HMG-COA, an inhibitor system the renin-angiotensin-for example, ACE inhibitor, aspirin, and at least one vitamin selected from the group consisting of vitamin B6, vitamin B12 and folic acid.

In the bid, medium, small the patent W003/020243 described the combination of means for reducing the amount of lipids the inhibitor system of the renin - angiotensin and aspirin, as well as at least one vitamin selected as an optional component from the group consisting of vitamin B6, vitamin B12 and folic acid.

In the patent application WO 2004/080488 disclosed combination of acetylsalicylic acid reductase inhibitors HMG-COA and anti-hypertensive means selected from calcium antagonists, ACE inhibitors, antagonists of angiotensin II and diuretics.

In the patent application WO 2005/011586 presents a combination of an antagonist of β-adrenergic receptor or diuretic, or both of these components, with means of lowering cholesterol in the blood, such as inhibitor of reductase HMG-COA, an inhibitor system the renin - angiotensin, for example, ACE inhibitor, and aspirin.

In the patent application WO 2005/0025673 considered a combination of hypoglycemic agents on the basis of biguanide, such as Metformin, a means of reducing cholesterol in the blood, selected from an inhibitor of reductase HMG-COA, compounds that increase the secretion of bile acids, compounds based on probucol and fibrin acid, and antihypertensive drug selected from inhibitors of the system renin-angiotensin, which in turn can be selected from ACE inhibitors, antagonist of angiotensin II and renin inhibitors, β-BL is kotorov, diuretics and calcium channel antagonists. The invention also relates to the availability and other optional components, such as means of preventing aggregation of platelets from a group of salicylates, such as acetyl salicylic acid and other similar compounds, and various vitamin derivatives.

In the patent application WO 2006/020522 mentioned various combinations of medicines that are designed to receive the patient during the emergence of several dangerous symptoms, which are symptoms of cardiovascular disease. In several of these options offers a combination of aspirin, statin, and data combinations in addition to other compounds of optional ACE inhibitor.

In the patent application WO 2006/135415 disclosed nanoparticles present in the composition of microemulsions, which are used in combinations of drugs can be aspirin, policosanol, atenolol, metoprolol, nadolol, propranolol, diltiazem, nifedipine, verapamil, captopril, enalapril, lisinopril, losartan, losartan in combination with hydrochlorthiazide, olmesartan, lovastatin, pravastatin, simvastatin, atorvastatin, connection, amplifying secretion of bile acid, cholestyramine, colestipol, gemfibrozil, clofibrate, probucol, anti-inflammatories and antibiotics at all. In the cave compositions may also be present in food supplements selected choline, folic acid, vitamin B6, vitamin B12, Niacin, Niacin chromium, vitamin C, vitamin E, coenzyme Q10 and fat intake of ω-3 or their combinations.

In the patent CN 1785196 offers a combination of aspirin, folic acid, simvastatin and ramipril.

In the patent application US 2006177504 disclosed combination of one or more anti-inflammatory drugs and one or more drugs for the prevention of stroke and cardiovascular diseases, such as aspirin, clopidogrel, ticlopidine, a mixture of dipyridamole with aspirin, dipyridamole, Cilostazol, pentoxifylline, reductase inhibitors HMG-COA, ACE inhibitors, angiotensin receptor blockers, calcium channel blockers, and vasodilators, anti-hypertensive drugs, to prevent platelet aggregation and oral medications that delay the clotting of blood at all.

In the patent application WO 2006/105806 claimed compositions containing a statin, the connection, the vast production and activity of angiotensin, anti-inflammatory agent and at least one antioxidant. The specified statin may be selected from lovastatin, simvastatin, pravastatin and fluvastatin, and the specified connection, the vast production and activity of angiotensin, the can is to be selected from antagonists of angiotensin II and ACE inhibitors, such as valsartan, losartan, irbesartan, trandolapril, perindopril or ramipril, while anti-inflammatory agent is preferably acetylsalicylic acid, and the antioxidant is a vitamin selected from vitamin a, vitamin C and vitamin E.

In the patent application WO 2007/011524 presents data on daily administration to patients drugs, containing hypoglycemic agent, representing the derived biguanide, preferably Metformin, a means of reducing the content of lipids, preferably, simvastatin, anti-hypertensive agent, preferably lisinopril and aspirin. In this case, all the active ingredients are separate from each other under a common blister shell.

In the patent application WO 2007/027454 related to new dihydropyrimidinase connections, describes their combination with antiplatelet drugs, ACE inhibitors and means of reducing the lipid content mentioned among other groups of pharmaceuticals. Aspirin is mentioned among antiplatelet agents, ramipril and lisinopril referred to as ACE inhibitors, simvastatin and pravastatin are mentioned as a means of reducing the lipid content.

In the patent application US 2007116756 claimed compositions containing therapeuti Eskom number hypercholesterinemia means, the inhibitor system of the renin-angiotensin, diuretic, aspirin and, optionally, at least one blocker β-adrenergic receptor presented in option a single dose. In addition, in the aforementioned application describes operations of manufacturing these compositions, their use and the treatment of patients suffering from cardiovascular diseases.

In the patent application WO 2007/092270 mentioned combination of drugs, or combination therapy with these medications, including antiplatelet blocker β-adrenergic receptor inhibitor system the renin-angiotensin-aldosterone ("RAAS inhibitor") and/or means for modifying cholesterol, and aspirin is indicated in the number of possible antiplatelet agents and statins specified number of modifications of cholesterol. A RAAS inhibitor is a compound selected from ACE inhibitors, antagonists of angiotensin II and/or blockers aldosterone (spironolactone, eplerenone or its derivatives). The application States that these combinations of drugs or combination therapy with their help reduce mortality and morbidity associated with pathology of the coronary artery.

Patent CN 101024082 relates to various compositions on the basis of sex hormones, funds reduced the deposits of lipid, antihypertensive drugs, hypoglycemic agents and anticoagulants for use in the prevention and treatment of cardiovascular diseases. Statins indicated a means of reducing the lipid content, the inhibitors listed as antihypertensive agents, and aspirin was mentioned as an anticoagulant.

Patent application US 2003/0049314 relates to an oral dosage form containing a combination of therapeutically effective standard dose means of reducing lipid, a therapeutically effective standard dose of the inhibitor system of the renin-angiotensin, therapeutically effective standard dose of aspirin and a pharmaceutically acceptable carrier.

In India, the firm Torrent Pharma has developed the manufacture of a pharmaceutical product "CVpill"representing the first multicomponent dosage form for the prevention of cardiovascular diseases. Dosage form "CVpill" comes in the form of a single set, which consists of capsule and tablet. Capsule contains 10 mg of atorvastatin in powder, 5 mg ramipril powder and aspirin weight 75 mg made in intersolubility shell. As active substances for the slow release of this tablet contains 50 mg of metoprolol succinate. Capsule and tablet is edu must be taken at the same time once a day.

The patent IN 2003MU00153 relates to a combined dosage form, which may contain: a) the statin and aspirin, (b) a statin, aspirin and β-blocker, statin, aspirin, β-blocker and ACE inhibitor, and d) a statin, aspirin, β-blocker and an antagonist of angiotensin II. In all cases, each of the components laid separately in the appropriate blister shell.

Currently, specialists in the field of medicine indicate the need to create combinations consisting of acetylsalicylic acid, hypercholesterinemia means, preferably reductase inhibitors HMG-COA, and antihypertensive agents, preferably inhibitors, and providing optimal dose within them these three active ingredients that are enclosed in a single dosage form, intended for the prevention of cardiovascular disease in those at high risk (Schaeffer B. et al., The role of inhibitors of the reductase 3-hydroxy-3-methylglutaryl-coenzyme A, inhibitors of angiotensin converting enzyme, inhibitors of cyclooxygenase-2 and aspirin in the treatment of cardiovascular diseases anti-inflammatory and immunomodulatory drugs. Am J Cardiol. 2003 Jun 19; 91(12A): 12H-18H. Overview; Takeda, T. et al., The relationship between the effects of statins, aspirin and modulator of angiotensin I to the levels of high-sensitivity C-reactive protein. Atherosclerosis. 2003 Jul; 169(1): 155-8; Hippsley-Cox, J. et al., The effect of combinations of drugs for a full list of causes of mortality in patients with coronary heart disease: Analysis by the method of "case - control". BMJ. 2005 May 7; 330(7499): 1059-63; Kulkarni S. p. et al., Long-term medication in the treatment of cardiovascular diseases. Am Heart J. 2006 Jan; 151(1): 185-91; Gaziano T.A. et al., Prevention of cardiovascular disease complex medicines in developing countries:

analysis of economic efficiency. Lancet. 2006 Aug 19; 368(9536): 679-86. Review; and Chaudry NICHOLAS et al., Whether on a Pro Bono basis to provide additional preventive medications to patients after myocardial infarction? The economic analysis. Health Aff (Millwood). 2007 Jan-Feb; 26(1): 186-94). In particular, under the persons in the group of high risk of cardiovascular disease, defined as individuals over the age of 55 years, patients have a condition that develops on the background of angina, stroke, atherosclerosis, syndrome Charcot, diabetes, ischemic heart disease, peripheral vascular disease, disorders of platelet function, hemodialysis, hypercholesterolemia, hypertension, myocardial infarction, congestive heart failure, ischemia, nephropathy, stop certaily restenosis, nicotine addiction of the smoker, obesity, physical inactivity.

Despite the fact that in all known from the prior art inventions in varying degrees claimed combination of acetylsalicylic acid reductase inhibitors HMG-COA and ACE inhibitors, only in the patent application WO 2004/080488 describes a specific example of a combination of three active ingredients without additional components. Thus, in example 18 describes the combination of components in the form of tablets containing 100 mg of aspirin, 10 mg simvastatin 20 mg lisinopril, and in example 19 in a similar manner describes a different combination of components in the form of tablets containing 100 mg aspirin, 40 mg of simvastatin and 8 mg of perindopril. However, these examples are stated very briefly and not the explanation, which would be sufficient to implement in practice represented in the examples of the combinations of components.

On the other hand, depending on the characteristics of the health status and medical history of the particular patient, the experts in the field of medicine, you may need to have a wide range of various multi-component dosage forms, providing the choice of such a medicinal product which is best suited for the treatment of this particular patient. In both RA and is one of the main difficulties that constraining the implementation of such methods of therapy, as it is often difficult to determine what combination of drugs in terms of their quantitative composition satisfies the necessary conditions of treatment of the individual patient. Due to the sensitivity of public opinion to the problems of health care in General and in connection with expressed community requirements in terms of use considerably more individual approach in the treatment of patients, the relevance of this situation is intensifying day by day.

However, any of the currently existing technological solutions in the field of pharmacology, associated with the practical implementation of the above inventions, obstructed, due to difficulties in the implementation of varying dosages of the components of the dosage forms, which leads to additional costs and time when the quantitative adjustment of the compositions in the manufacturing process of pharmaceutical products.

Therefore, on the other hand, there is a need to make available for public consumption and medical professional using a combination of acetylsalicylic acid reductase inhibitors HMG-COA and ACE inhibitors, taken in fixed doses and prisoners in a single dosage form providing the ability to adjust these fixed dose components of the dosage form depending on the individual characteristics of each patient or social subgroups. Thus, based on all the above preconditions are formulated subject to the decision of tasks associated with the size of dosage forms and compatibility within them various components.

Disclosure of inventions

In this sense, the present invention offers a number of new compositions in the form of capsules containing a variable number of tablets of acetylsalicylic acid, a variable number of tablets inhibitor of reductase HMG-COA and a variable number of tablets ACE inhibitor, it is also possible to adjust the number of tablets of each active ingredient, depending on the specific patient or social subgroups for which are specified composition.

The choice in favor of simvastatin and pravastatin as reductase inhibitors HMG-COA was determined in the present invention is their most widespread use in the treatment of patients suffering from hypercholesterolemia. In this respect, applied in the form of a sodium salt of pravastatin is extremely beneficial as part of the composition from the viewpoint of solubility in water. Lisinopril, ramipril and perindopril similarly appear among the most prescribed ACE inhibitors in the treatment of hypertension. From the point of view of production technology of pharmaceutical preparations lisinopril about lady advantage relative to other compounds in this group, which is that its receipt accompanied with fewer impurities, and that when used in the form of dihydrate he is among the compounds that are most soluble in water. Likewise used in the form of albuminous salt of perindopril is also freely soluble in water, thereby providing greater ease of absorption.

The present invention relates to the production of combined therapeutic compositions intended for the prevention of cardiovascular diseases and containing acetylsalicylic acid reductase inhibitors HMG-COA and ACE inhibitors in fixed doses, as well as made with the possibility of adjustment to the indicated doses of these components of the composition to the amounts prescribed in specific patients or members of certain social subgroups.

In addition, these compositions of the present invention have an advantageous difference, which is that due to capsulerebel excluded decomposition of the active ingredients when exposed to light. This advantage becomes even more significant due to the fact that these active ingredients, in turn, is made in the form of tablets in the shell, which eliminates the symptoms of incompatibility between the different components. Based on the total weight of the specified tablet, the share of shell in the usual case we have from 1 to 12% by weight, preferably 2-6%. The composition of the shell includes a film-forming substance, such as a film-forming polymer such as partially hydrolyzed polyvinyl alcohol, hydroxypropylmethyl cellulose or similar connection. The shell of the pill may have additional typical fillers.

During research it was found that upon contact with moisture acetylsalicylic acid is decomposed with the formation of salicylic acid. Then on the surface of the tablets ACE inhibitor sublimating acetylsalicylic acid, causing chemical decomposition of the indicated inhibitor. It was found that the film sheath containing partially hydrolyzed polyvinyl alcohol (under the trade designations Opadry AMB™, use)that may be due to its waterproofing properties to protect the tablets containing acetylsalicylic acid, and the ACE inhibitor. In accordance with the present invention, the material of the shell to protect the tablets containing the inhibitor of reductase HMG-COA can serve as a pigmented film coating consisting, for example, from hydroxypropylmethyl cellulose (under the trade designations Opadry Orange™, use), which camouflages dark color content of the tablets. Shell under the brand of what value is the CA may also contain one or more pigments.

Finally, the compositions of the present invention are safe, stable and efficient. They are also distinguished by malonaselennostju that allows patients to easily swallow the dosage form. In accordance with one embodiments of the present invention provides an immediate release of the active agent dosage form after oral administration.

Finally, it is proved Toxicological safety in conjunction with the absence of pharmacodynamic and pharmacokinetic interactions, the presence of the benefits of combination therapy involving the use of acetylsalicylic acid reductase inhibitors HMG-COA, such as simvastatin and pravastatin, as well as with ACE inhibitors such as lisinopril, perindopril and ramipril, as well as predictability and insignificant side effects, the degree of symptoms which may be affected in a clinical setting without risk to the health of patients, suggest that the combination of the components of the present invention provide an impetus to the development of innovative, safe and effective treatment methods.

Simvastatin in their chemical structure corresponds to a mixture of (4R,6R)-6-[2-[(1S,2S,6R,8S,8aR)-1,2,6,7,8,8A-hexahydro-8-hydroxy-2,6-dimethyl-1-naphthyl]ethyl]tetrahydro-4-hydroxy-2H-Piran-2-he sloneg the ether with 2,2-dimethylmaleic acid (item who). Pravastatin according to its chemical structure corresponds to(3R,5R)-7-{(1S,2S,6S,8S,8aR)-1,2,6,7,8,8A-hexahydro-6-hydroxy-2-methyl-8-[(S)-2-methylbutoxy]-1-naphthyl} - for 3,5-dihydroxy heptane acid (item who). Lisinopril according to its chemical structure corresponds to 1-[N2-(S)-1-carboxy-3-phenylpropyl]-L-Proline (item who). Ramipril according to its chemical structure corresponds to 1-ethyl ether (2S,3aS,6aS)-1-[(S)-N-[(S)-1-carboxy-3-phenylpropyl]octahydrocyclopenta[b]pyrrole-2-carboxylic acid (item who). Perindopril according to its chemical structure corresponds to 1-ethyl ether (2S,3aS,7aS)-1-[(S)-N-[(S)-1-carboxybutyl]alanyl]hexahydro-2-indoline carboxylic acid (item who).

The present invention relates to a capsule made taking into account the individual characteristics of each patient or social subgroups and intended for the prevention of cardiovascular diseases, characterized in that it contains:

(i) a) w a pill(s) in the envelope containing the(their) 40.5 mg of acetylsalicylic acid and x tablet(s) in the envelope containing the (their) 81 mg acetylsalicylic acid, while w is an integer selected from 0 and 1, and x is an integer selected from 0, 1 and 2, so that the total number of acetylsalicylic acid is in the range from 40,5 to 162 mg, and w+x is 1 and is 2; or

b) y the tablet(s) in the shell, containing(a) 50 mg of acetylsalicylic acid and z tablet(s) in the shell, containing (a) 100 mg acetylsalicylic acid, is an integer selected from 0 and 1, and z is an integer selected from 0, 1 and 2, so that the total number of acetylsalicylic acid is in the range from 50 to 100 mg, and w+x is 1 or 2;

(ii) a) s pill(C) in the shell, containing(a) 20 mg of simvastatin and t tablet(s) in the shell, containing (a) 40 mg of simvastatin, in this case, s is an integer selected from 0, 1 and 2, and t is an integer selected from 0, 1 and 2, so that the total number of simvastatin is in the range from 20 to 80 mg, and s+t is 1 or 2;or

b) u tablet(s) in the shell, containing (a) 20 mg of pravastatin or its pharmaceutically acceptable salts, and v the tablet(s) in the shell, containing (a) 40 mg of pravastatin or its pharmaceutically acceptable salt, in this case u is an integer selected from 0, 1 and 2, and v is an integer selected from 0, 1 and 2, so that the total number of provastatin or its pharmaceutically acceptable salt is in the range from 20 to 80 mg, and u+v is 1 or 2; and

(iii) a) R tablet(s) in the shell, containing (a) 5 mg of lisinopril or its hydrated form, q tablet(s) in the envelope containing the Yu(their) 10 mg lisinopril or its hydrated form, and r tablet(s) in the shell, containing (a) 20 mg of lisinopril or its hydrated form, while p is an integer selected from 0 and 1, q is an integer selected from 0 and 1, and r is an integer selected from 0, 1 and 2, so that the total number of lisinopril or its hydrated form is in the range from 5 to 40, and p+q+r is 1, 2 or 3; or

b) k tablet(s) in the shell, containing(a) 2.5 mg of ramipril, m tablet(s) in the shell, containing(a) 5 mg ramipril, and n tablet(s) in the shell, containing (a) 10 mg ramipril, k is an integer selected from 0 and 1, m is an integer selected from 0 and 1, n is an integer selected from 0, 1 and 2, so that the total number of ramipril is in the range from 2.5 to 20 mg, and k+m+n is 1, 2 or 3; or

in) h tablet(s) in the envelope containing 2 mg of perindopril or its pharmaceutically acceptable salt, i tablet(s) in the envelope containing the(their) 4 mg perindopril or its pharmaceutically acceptable salts, and j the tablet(s) in the envelope containing the(their) 8 mg perindopril or its pharmaceutically acceptable salt, when h is an integer selected from 0 and 1, i is an integer selected from 0 and 1, and j is an integer selected from 0, 1 and 2, so that the total number perindo the Rila or its pharmaceutically acceptable salt is in the range from 2 to 16 mg, h+i+j is 1, 2 or 3;

and:

these tablets containing acetylsalicylic acid coated film-coated, containing partially hydrolyzed polyvinyl alcohol;

these tablets containing simvastatin, coated film-coated, containing hypromellose;

these tablets containing pravastatin or its pharmaceutically acceptable salt, covered with a film cover, containing hypromellose;

these tablets containing lisinopril or its hydrated form, covered with a film cover, containing partially hydrolyzed polyvinyl alcohol;

these tablets containing ramipril, coated film-coated, containing partially hydrolyzed polyvinyl alcohol;

these tablets containing perindopril or its pharmaceutically acceptable salt, covered with a film cover, containing partially hydrolyzed polyvinyl alcohol.

Preferred among the pharmaceutically acceptable salt of pravastatin are salts with alkali or alkaline earth metals. The most preferred salt is sodium salt. Lisinopril is usually available in the dihydrate form, so this form of lisinopril is preferred for use in the present invention. PR is doctitle including pharmaceutically acceptable salts of perindopril are alkali metal salts and alkylamine salt, the most preferred is its salt with tert-butylamine, also known as erbenova salt.

In accordance with the private embodiment of the present invention, all tablets are made with unmodified mode of release of active substances. In the sense in which the term "unmodified mode release" is used in the context of the present invention, it is understood that the term applies to the profile of the solubility and bioavailability of the active ingredient, provided that the ingredient was not subjected to additional modifications, whether chemical or physical, with the specific intent to change the profile of solubility or bioavailability relative to the specified profile, specific to the ingredient in the usual form. Also have in mind that unmodified release means almost instant release of the active ingredients. Next, we mean that the traditional or normal release implies the absence of the tablet effect is slow, delayed or prolonged release of the active ingredient. Immediate release means quick dissolving tablets in vitro and in the stomach or in the upper part of the gastrointestinal tract. In a preferred embodiment, immediately you shall order his means, that at least 80% of the active ingredient is released within 60 minutes, preferably within 30 minutes after administration of the dosage form. Method validation is the test for solubility, shown in example 6 in respect of simvastatin and pravastatin, in example 7 in respect of the ACE inhibitor.

In a preferred embodiment of the present invention, these capsules are characterized in that they contain:

(1) one tablet in the shell, containing 81 mg acetylsalicylic acid, two coated tablet, each comprising 20 mg simvastatin and one tablet in the shell, containing 5 mg lisinopril dihydrate;

(2) one tablet in the shell, containing 81 mg acetylsalicylic acid, two coated tablet, each comprising 20 mg simvastatin and one tablet in the shell, containing 10 mg lisinopril dihydrate;

(3) one tablet in the shell, containing 81 mg acetylsalicylic acid, two coated tablet, each comprising 20 mg simvastatin and one tablet in the shell, containing 20 mg lisinopril dihydrate;

(4) one tablet in the shell, containing 81 mg acetylsalicylic acid, two coated tablet, each comprising 20 mg simvastatin and one tablet in the shell, containing 2.5 mg of ramipril;

(5) one tablet in the shell, the content is Asa 81 mg acetylsalicylic acid, two tablets in the shell, each comprising 20 mg simvastatin and one tablet in the shell, containing 5 mg ramipril;

(6) one tablet in the shell, containing 81 mg acetylsalicylic acid, two coated tablet, each comprising 20 mg simvastatin and one tablet in the shell, containing 10 mg ramipril;

(7) one tablet in the shell, containing 81 mg acetylsalicylic acid, two coated tablet, each comprising 20 mg simvastatin and one tablet in the shell, containing 2 mg of perindopril erbumine;

(8) one tablet in the shell, containing 81 mg acetylsalicylic acid, two coated tablet, each comprising 20 mg simvastatin and one tablet in the shell, containing 4 mg of perindopril erbumine;

(9) one tablet in the shell, containing 81 mg acetylsalicylic acid, two coated tablet, each comprising 20 mg simvastatin and one tablet in the shell, containing 8 mg of perindopril erbumine;

(10) one tablet in the shell, containing 81 mg acetylsalicylic acid, two coated tablet, each of which contains 20 mg of sodium salt of pravastatin, and one tablet in the shell, containing 5 mg lisinopril dihydrate;

(11) one tablet in the shell, containing 81 mg acetylsalicylic acid, two coated tablet, each of which soda is separated by 20 mg of sodium salt of pravastatin, and one tablet in the shell, containing 10 mg lisinopril dihydrate;

(12) one tablet in the shell, containing 81 mg acetylsalicylic acid, two coated tablet, each of which contains 20 mg of sodium salt of pravastatin, and one tablet in the shell, containing 20 mg lisinopril dihydrate;

(13) one tablet in the shell, containing 81 mg acetylsalicylic acid, two coated tablet, each of which contains 20 mg of sodium salt of pravastatin, and one tablet in the shell, containing 2.5 mg of ramipril;

(14) one tablet in the shell, containing 81 mg acetylsalicylic acid, two coated tablet, each of which contains 20 mg of sodium salt of pravastatin, and one tablet in the shell, containing 5 mg ramipril;

(15) one tablet in the shell, containing 81 mg acetylsalicylic acid, two coated tablet, each of which contains 20 mg of sodium salt of pravastatin, and one tablet in the shell, containing 10 mg ramipril;

(16) one tablet in the shell, containing 81 mg acetylsalicylic acid, two coated tablet, each of which contains 20 mg of sodium salt of pravastatin, and one tablet in the shell, containing 2 mg of perindopril erbumine;

(17) one tablet in the shell, containing 81 mg acetylsalicylic acid, two coated tablet, each of which contains 20 mg nutrie the Oh salt of pravastatin, and one tablet in the shell, containing 4 mg of perindopril erbumine;

(18) one tablet in the shell, containing 81 mg acetylsalicylic acid, two coated tablet, each of which contains 20 mg of sodium salt of pravastatin, and one tablet in the shell, containing 8 mg of perindopril erbumine;

(19) one tablet in the shell, containing 100 mg acetylsalicylic acid, two coated tablet, each comprising 20 mg simvastatin and one tablet in the shell, containing 5 mg lisinopril dihydrate;

(20) one tablet in the shell, containing 100 mg acetylsalicylic acid, two coated tablet, each comprising 20 mg simvastatin and one tablet in the shell, containing 10 mg lisinopril dihydrate;

(21) one tablet in the shell, containing 100 mg acetylsalicylic acid, two coated tablet, each comprising 20 mg simvastatin and one tablet in the shell, containing 20 mg lisinopril dihydrate;

(22) one tablet in the shell, containing 100 mg acetylsalicylic acid, two coated tablet, each comprising 20 mg simvastatin and one tablet in the shell, containing 2.5 mg of ramipril;

(23) one tablet in the shell, containing 100 mg acetylsalicylic acid, two coated tablet, each comprising 20 mg simvastatin and one tablet in the shell, tereasa 5 mg ramipril;

(24) one tablet in the shell, containing 100 mg acetylsalicylic acid, two coated tablet, each comprising 20 mg simvastatin and one tablet in the shell, containing 10 mg ramipril;

(25) one tablet in the shell, containing 100 mg acetylsalicylic acid, two coated tablet, each comprising 20 mg simvastatin and one tablet in the shell, containing 2 mg of perindopril erbumine;

(26) one tablet in the shell, containing 100 mg acetylsalicylic acid, two coated tablet, each comprising 20 mg simvastatin and one tablet in the shell, containing 4 mg of perindopril erbumine;

(27) one tablet in the shell, containing 100 mg acetylsalicylic acid, two coated tablet, each comprising 20 mg simvastatin and one tablet in the shell, containing 8 mg of perindopril erbumine;

(28) one tablet in the shell, containing 100 mg acetylsalicylic acid, two coated tablet, each of which contains 20 mg of sodium salt of pravastatin, and one tablet in the shell, containing 5 mg lisinopril dihydrate;

(29) one tablet in the shell, containing 100 mg acetylsalicylic acid, two coated tablet, each of which contains 20 mg of sodium salt of pravastatin, and one tablet in the shell, containing 10 mg lisinopril dihydrate;

(30) one t who bleda in the shell, containing 100 mg acetylsalicylic acid, two coated tablet, each of which contains 20 mg of sodium salt of pravastatin, and one tablet in the shell, containing 20 mg lisinopril dihydrate;

(31) one tablet in the shell, containing 100 mg acetylsalicylic acid, two coated tablet, each of which contains 20 mg of sodium salt of pravastatin, and one tablet in the shell, containing 2.5 mg of ramipril;

(32) one tablet in the shell, containing 100 mg acetylsalicylic acid, two coated tablet, each of which contains 20 mg of sodium salt of pravastatin, and one tablet in the shell, containing 5 mg ramipril;

(33) one tablet in the shell, containing 100 mg acetylsalicylic acid, two coated tablet, each of which contains 20 mg of sodium salt of pravastatin, and one tablet in the shell, containing 10 mg ramipril;

(34) one tablet in the shell, containing 100 mg acetylsalicylic acid, two coated tablet, each of which contains 20 mg of sodium salt of pravastatin, and one tablet in the shell, containing 2 mg of perindopril erbumine;

(35) one tablet in the shell, containing 100 mg acetylsalicylic acid, two coated tablet, each of which contains 20 mg of sodium salt of pravastatin, and one tablet in the shell, containing 4 mg of perindopril erbumine;

(36) on the on the tablet in the shell, containing 100 mg acetylsalicylic acid, two coated tablet, each of which contains 20 mg of sodium salt of pravastatin, and one tablet in the shell, containing 8 mg of perindopril erbumine.

In further preferred variants of implementation of the present invention, these capsules are different in that they are made of solid gelatin.

In other further preferred embodiments, the implementation of the present invention, these capsules are different in that they are made of cellulose.

In accordance with the private embodiment of the present invention, these capsules or tablets do not contain additional active substances, i.e. these capsules contain components i), ii) and iii).

In a preferred embodiment of the present invention, these capsules are used for the prevention of cardiovascular disease in subjects from high-risk groups, preferably in persons over the age of 55 years, patients have a condition that develops on the background of angina, stroke, atherosclerosis, syndrome Charcot, diabetes, ischemic heart disease, peripheral vascular disease, disorders of platelet function, hemodialysis, hypercholesterolemia, hypertension, myocardial infarction, congestive heart failure, ischemia, nephro atii, cardiac arrest or restenosis, nicotine addiction, Smoking, obesity, physical inactivity.

Capsules of the present invention provide a simple variation of the dose at the discretion of the physician within the defined arithmetic progression intervals, subject to the availability of a minimum number of tablets in a capsule and depending on the individual characteristics of each patient or social subgroups subject to preventive treatment. Dose acetylsalicylic acid was determined on the basis of the magnitude of the weight 81 mg prescribed standard USA (tablet weight 81 g under the brand name Aspirin®, manufacturer - the company Saint-Joseph), and the size and weight of 100 mg, prescribed in the international standard. The range of possible doses are presented in Table 1.

Table 1.
Intervals doses
Acetylsalicylic acid (intervals doses: 40,5-162 mg 50-200 mg, 40.5; 50 mg)
w, 40.5 mg1010
x, 81 mg011 2
Only40.5 mg81 mg121,5 mg162 mg
, 50 mg1010
z 100 mg0112
Only50 mg100 mg150 mg200 mg

Reductase inhibitors HMG-COA (intervals dose: 20-80 mg, 20 mg)
Simvastatin
s, 20 mg1010
t 40 mg0112
Only20 mg40 mg60 mg80 mg

Reductase inhibitors HMG-COA (intervals dose: 20-80 mg, 20 mg)
Sodium salt of pravastatin
u, 20 mg1010
v 40 mg0112
Only20 mg40 mg60 mg80 mg

0 0
ACE inhibitors
The lisinopril dihydrate (intervals dose: 5-40 mg, 5 mg)
R, 5 mg10101010
q, 10 mg0110110
r, 20 mg00011112
Only5 mg10 mg15 mg20 mg25 mg30 mg35 mg40 mg
Ramipril (intervals doses: 2.5 to 20 mg, 2.5 mg)
k, 2.5 mg10101010
m, 5 mg01100110
n, 10 mg0011112
Only2,55 mg7,510 mg12,515 mgof 17.520 mg
mgmgmgmg
Erbenova salt of perindopril (intervals doses: 2-16 mg, 2 mg)
h, 2 mg10101010
i, 4 mg0110011 0
j, 8 mg00011112
Only2 mg4 mg6 mg8 mg10 mg12 mg14 mg16 mg

Capsules of the present invention can be made of different materials. The most common material for the manufacture of capsules is a standard hard gelatin and cellulose. To cellulose capsules can be attributed, not implying that limit the scope of the claims according to the invention, the capsules of alkylsilanes, for example methylcellulose, carboxymethylcellulose, hydroxypropylcellulose, and the preferred option is hypromellose (HPMC).

Thus, in one embodiment, the practical implementation of the present invention applies to terrorisation capsules (iron oxides, represented by a black iron oxide pigment or red iron oxide pigment, or mixtures thereof of 0.12-1.66% of titanium dioxide 0,37-2,33%; gelatin - else), and cellulose capsules (HPMC - 99%; carragenin - 0,2%; potassium chloride - 0,15%; pigments - 0,65%). Composition as terdoslavich and cellulose capsules do not involve restrictions on the scope of the claims of the present invention.

Tablets normally contain pharmaceutically acceptable excipients such as diluents, binders, rippers, lubricants, additives that affect the slip, antioxidants, pH regulators and film-forming polymers, and similar components.

Among the diluents may be mentioned, without implying that necessarily limit the scope of the claims according to the invention, calcium phosphate, dicalcium phosphate, tricalcium phosphate, calcium sulfate, microcrystalline cellulose, kaolin, bentonite, starch, magnesium carbonate, several saccharides such as mannitol, lactose anhydrous, spray dried or moisture-containing, sorbitol, sucrose, Inositol, presswise sugar, trehalose, xylitol, and the like compounds, and mixtures thereof.

Among the binders may be mentioned, without implying that necessarily limit the scope of the claims according to the invention, gum Arabic, microcrystalline cellulose, cellulose-containing solutions, such as HPMC, gelatin solutions with a concentration of 10-20%glucose solutions with concentration is the situation 20-50%, polyvinylpyrrolidone, starch paste with starch content of 10-20%, sorbitol, tragacanth gum, polyethylene glycol, maltodextrin, polymethacrylates, and the like compounds, and mixtures thereof.

The leavening agents may be mentioned, without implying that necessarily limit the scope of the claims according to the invention, corn or potato starch, methylcellulose, cellulose generally, the carboxymethyl cellulose-based calcium, powdered mineral clay, such as bentonite/wigum, wetting agents such as sodium lauryl sulfate, superathletes, so named because of its low concentration in which they are used (usually 2-4%), such as croscarmellose, crosspovidone, starch, glycolate sodium and similar compounds, and mixtures thereof.

Among the lubricants may be mentioned, without implying that necessarily limit the scope of the claims according to the invention, polyethylene glycol, poloxamer, magnesium stearate, calcium stearate, hydrogenated vegetable oil, talc, glyceryl begent and similar compounds, and mixtures thereof.

Among the additives that affect the slide, we can mention, not implying that necessarily limit the scope of the claims according to the invention, the colloidal silica (one percent), talc, stearyl fumarate, sodium, corn is a starch and the like compounds, as well as mixtures thereof.

Among the antioxidants may be mentioned, without implying that necessarily limit the scope of the claims according to the invention, bottled hydroxyanisol, bottled hydroxytoluene, ascorbic acid, askorbinovoyj sodium, Galloway propyl, metabisulfite, sodium or potassium, fumaric acid and similar compounds, and mixtures thereof.

The pH regulators may be mentioned, without implying that necessarily limit the scope of the claims according to the invention, sodium bicarbonate, magnesium oxide, calcium phosphate, citric acid, potassium citrate, and the like compounds, and mixtures thereof.

Among the film-forming polymers may be mentioned, without implying that necessarily limit the scope of the claims according to the invention, polyvinylacetate, some derivatives of cellulose such as cellulose acetate, hypromellose, ethylcellulose, acetate succinate methylcellulose, polymethacrylates, copolymers of methacrylic acid, polyvinyl alcohol and the like compounds, and mixtures thereof.

Brief description of drawings

The drawing shows a capsule that represents the object of the present invention and having in its composition one tablet in the shell, containing 100 mg of acetylsalicylic acid (A), two tablets in the shell, each of Kotor is x contains 20 mg of simvastatin (S), and one tablet in the shell, containing 2.5 mg of ramipril (R).

The implementation of the invention

The present invention is additionally illustrated by the following examples which are not intended to limit the scope of the claims of the invention.

Example 1: Capsules made of hard gelatin containing one tablet in the shell, containing 100 mg acetylsalicylic acid, two coated tablet, containing 20 mg of simvastatin, and one tablet in the shell containing 2.5, 5 or 10 mg of ramipril.

(a) the Manufacture of pellets in the shell, containing acetylsalicylic acid

These tablets were made by standard pharmaceutical manufacturing operations carried out in the following order. Acetylsalicyloyl acid, starch, glycolate sodium and microcrystalline cellulose 101 sifted through a sieve in the proper proportions, and then all three of these components were mixed with the addition of pre-sifted talc and mixed again with subsequent pressing and resulting core tablets are coated membrane by applying a specified core of an aqueous solution of film-forming means Opadry AMB OY-B-28920 white pigment. Thus, we have obtained coated tablets containing 100 mg of acetylsalicylic acid. The composition of the decree is those tablets are presented in Table 2. The composition of the film-forming means Opadry AMB OY-B-28920 white pigment shown in Table 3. Ingredients aqueous solution of film-forming means Opadry AMB OY-B-28920 white pigment based coating membrane on one tablet containing 100 mg of acetylsalicylic acid, is shown in Table 4.

Table 2.
The composition of the tablets in the shell, containing 100 mg of acetylsalicylic acid
CoreComponentsAcetylsalicylic acid100,000 mg
Microcrystalline cellulose 10120,000 mg
Starch, glycolate sodium3,750 mg
Talc1,250 mg
The total weight of the core125,000 mg
The shellFilm-forming means Opadry AMB OY-B-28920 white pigment6,250 mg
The total weight of the tablet with Obolo is Oh 131,250 mg

Table 3.
The composition of the film-forming means Opadry AMB OY-B-28920 white pigment
Partially hydrolyzed polyvinyl alcohol45,50%
Titanium dioxide32,00%
Talc20,00%
Soy lecithin2,00%
Xanthan gum0,50%
Only100,00%

Table 4.
Ingredients aqueous solution of film-forming means Opadry AMB OY-B-28920 white pigment based coating membrane on one tablet containing 100 mg of acetylsalicylic acid
The tool Opadry AMB OY-B-28920 white pigment6,250 mg
Distilled water56,250 mg

b) manufacture of the other tablets in the shell, containing 20 mg simvastatin

These tablets were made by standard pharmaceutical manufacturing operations carried out in the following order. Fine simvastatin, lactose monohydrate, reptitiously starch 1500, ascorbic acid and citric acid was sieved through a sieve in the proper proportions, and then all these components are mixed with each other by adding distilled water, followed by drying and sieving, thereby Sifting 1. In parallel was prepared granulate containing 0.4% of bottled hydroxyanisole (hereinafter referred to as BGA). The specified granules were prepared from microcrystalline cellulose 102, which after sifting mixed with a solution of BHA in ethyl alcohol followed by drying and sieving to obtain thus granulate containing 0.4% BHA. Then there was prepared a mixture containing microcrystalline cellulose 102, the specified granules containing 0.4% BHA, colloidal anhydrous silica, talc and magnesium stearate, which after preparation was subjected to sieving to obtain such Prosea 2. Sifting 1 and Sifting 2 were mixed, followed by compressing the mixture in the core tablet and the creation around him membrane by applying an aqueous solution of film-forming means Opadry 06023821 with orange pig is entom. Thus, we have obtained coated tablets containing 20 mg of simvastatin. The composition of these tablets are shown in Table 5. The composition of the film-forming means Opadry 06023821 with orange pigment shown in Table 6. The list of ingredients for the preparation of granules containing 0.4% BHA and is taken as the manufacture of one coated tablet, containing 20 mg of simvastatin, are presented in Table 7. The list of ingredients for cooking Prosea 1 corresponding to one tablet in the shell, containing 20 mg of simvastatin, are presented in Table 8. The list of ingredients for the preparation of aqueous film-forming means Opadry 06023821 corresponding to one tablet in the shell, containing 20 mg of simvastatin, are presented in Table 9.

Table 5.
The composition of the tablets in the shell, containing 20 mg simvastatin
CoreComponentsFine simvastatin20,000 mg
The lactose monohydrate45,000 mg
Reptitiously starch 1500 10,000 mg
Ascorbic acid5,000 mg
Citric acid2,500 mg
Microcrystalline cellulose 10211,960 mg
Bottled hydroxyanisol0,040 mg
Colloidal anhydrous silica0,500 mg
Talc4,000 mg
Magnesium stearate1,000 mg
The total weight of the core100,000 mg
About-
shell
the tool Opadry 06023821 with orange pigment3,000 mg
The total weight of the tablet shell103,000 mg

Table 6.
Composition means Opadry 06023821 with orange pigment
Hypromellose 60637,80%
The guy who ramallosa E15LVP 12,59%
Red iron oxide pigment0,19%
Yellow iron oxide pigment0,77%
Triethyl citrate8,14%
Titanium dioxide4,72%
Talcfor 33.27%
Povidone K2,52%
Only100,00%

Table 7.
The list of ingredients for the preparation of granules containing 0.4% BHA and is taken as the manufacture of one coated tablet comprising 20 mg simvastatin
Microcrystalline cellulose10,000 mg
Bottled hydroxyanisol0,040 mg
Ethyl alcohol 96°3,750 mg

Table 8.
The list of ingredients for cooking Prosea 1 corresponding to one tablet in the shell, containing 20 mg of simvastatin.
Fine simvastatin20,000 mg
The lactose monohydrate45,000 mg
Reptitiously starch 150010,000 mg
Ascorbic acid5,000 mg
Citric acid2,500 mg
Distilled water17,000 mg

Table 9.
The list of ingredients for the preparation of aqueous film-forming means Opadry 06023821 corresponding to one tablet in the shell, containing 20 mg of simvastatin.
The tool Opadry 06023821 with orange pigment3,000 mg
Distilled water27,000 mg

C) the Manufacture of pellets in the shell, containing 2.5. 5 and 10 mg ramipril

These tablets were made through the your standard for the pharmaceutical industry operations, carried out in the following order. Ramipril, sodium bicarbonate and reptitiously starch 1500 sifted in a dry state and mixed in the proper proportions. Then, in two stages (pre-mixing and secondary mixing) was added pre-sifted microcrystalline cellulose 101, when added to this mixture of each portion of the microcrystalline cellulose was produced by dry mixing. The hypromellose was added in distilled water, followed by stirring of the solution, drying, and sieving the sediment with getting Prosea 1. Then added a pre-sifted microcrystalline cellulose 101, produced mixing with the addition of pre-sifted stearyl fumarata sodium, again produced a stirring, followed by compressing the mixture in the core tablet and the creation around him membrane by applying an aqueous solution of film-forming means Opadry AMB with a yellow pigment. Thus, we have obtained coated tablet, containing 2.5, 5, and 10 mg of ramipril. The composition of these tablets are presented respectively in Tables 10, 11 and 12. The strength of these tablets on the destruction of the fracture was 9-11 kPa at the time of the destruction in the range of 0.5-2 min Composition tools Opadry AMB yellow pigment used to create obolos and around tablets, contains 2.5, 5, and 10 mg of ramipril, are presented in Tables 13, 14, 15, respectively. The list of ingredients for cooking Prosea 1 corresponding to one tablet in the shell, containing 2.5, 5, and 10 mg of ramipril, are presented in Tables 16, 17, 18, respectively. The list of ingredients for the preparation of an aqueous solution Opadry AMB yellow pigment corresponding to one tablet in the shell, containing 2.5, 5, and 10 mg of ramipril, is presented in Table 19.

Table 10.
The composition of the coated tablet containing 2.5 mg of ramipril
CoreComponentsRamipril2,500 mg
The hypromellose0,500 mg
Sodium bicarbonate1,000 mg
Reptitiously starch 150010,000 mg
Microcrystalline cellulose 10186,200 mg
Stearyl fumarate sodium0.800 to mg
The total weight of the core101,000 mg
The shellThe tool Opadry AMB yellow pigment4,000 mg
The total weight of the tablet shell105,000 mg

Table 11.
The composition of the coated tablet containing 5 mg ramipril
CoreComponentsRamipril5,000 mg
The hypromellose0,500 mg
Sodium bicarbonate2,000 mg
Reptitiously starch 150010,000 mg
Microcrystalline cellulose 10182,700 mg
Stearyl fumarate sodium0.800 to mg
The total weight of the core101,000 mg
The shell The tool Opadry AMB yellow pigment4,000 mg
The total weight of the tablet shell105,000 mg

Table 12.
The composition of the coated tablet containing 10 mg ramipril
CoreComponentsRamipril10,000 mg
The hypromellose0,500 mg
Sodium bicarbonate4,000 mg
Reptitiously starch 150010,000 mg
Microcrystalline cellulose 10175,700 mg
Stearyl fumarate sodium0.800 to mg
The total weight of the core101,000 mg
The shellThe tool Opadry AMB yellow pigment4,000 mg
Total weight the tablet shell 105,000 mg

Table 13.
Composition means OpadryAMB 80W32039 with yellow pigment for tablets in the shell, containing 2.5 mg of ramipril
Partially hydrolyzed polyvinyl alcohol45,52%
Titanium dioxide30,70%
Talc20,00%
Soy lecithin2,00%
Yellow iron oxide pigment1,30%
Xanthan gum0,48%
Only100,00%

Table 14.
Composition means OpadryAMB 80W32656 with yellow pigment for tablets in the shell, containing 5 mg ramipril
Partially hydrolyzed polyvinyl alcohol45,52%
Titanium dioxideto 29.61%
Talc20,00%
Soy lecithin2,39%
Yellow iron oxide pigment2,00%
Xanthan gum0,48%
Only100,00%

Table 15.
Composition means OpadryAMB 80W32880 with yellow pigment for tablets in the shell, containing 10 mg ramipril
Partially hydrolyzed polyvinyl alcohol45,52%
Titanium dioxide27,20%
Talc20,00%
Soy lecithin4,80%
Yellow iron oxide pigment2,00%
Xanthan gum0,48%
Only100,00%

Table 16.
The list of ingredients for cooking Prosea 1 corresponding to one tablet in the shell, containing 2.5 mg of ramipril
Ramipril2,500 mg
The hypromellose0,500 mg
Sodium bicarbonate1,000 mg
Reptitiously starch 150010,000 mg
Microcrystalline cellulose 101 (pre-mixing)32,000 mg
Microcrystalline cellulose 101 (secondary mix)25,000 mg
Distilled water45,000 mg

Table 17.
The list of ingredients for cooking Prosea 1 corresponding to one tablet in the shell, containing 5 mg ramipril
Ramipril5,000 mg
The hypromellose0,500 mg
Bicarbonate NAT is s 2,000 mg
Reptitiously starch 150010,000 mg
Microcrystalline cellulose 101 (pre-mixing)28,500 mg
Microcrystalline cellulose 101 (secondary mix)25,500 mg
Distilled water40,000 mg

Table 18.
The list of ingredients for cooking Prosea 1 corresponding to one tablet in the shell, containing 10 mg ramipril
Ramipril10,000 mg
The hypromellose0,500 mg
Sodium bicarbonate4,000 mg
Reptitiously starch 150010,000 mg
Microcrystalline cellulose 101 (pre-mixing)21,500 mg
Microcrystalline cellulose 101 (secondary smesi the tion) 25,000 mg
Distilled water35,000 mg

Table 19.
The list of ingredients for the preparation of an aqueous solution OpadryAMB with yellow pigment corresponding to one tablet in the shell containing 2.5, 5 and 10 mg ramipril
The tool Opadry AMB yellow pigment4,000 mg
Distilled water36,000 mg

g) Operation capsulization

Coated tablet containing ramipril, simvastatin and acetylsalicylic acid were placed in a ratio of 1:2:1, respectively, made of hard gelatin capsules size #0, using for this purpose the setup for capsulization. Were involved in three of the hopper at the rate of one hopper on one type of tablet. The filled capsules were made using a punch to push the pellets inside the capsule, with the specified installation for capsulization was equipped with a system of quality control that is configured for rejection of capsules with the wrong number of the prisoners in their table is current.

d) Evaluation of stability

Each batch of capsules, obtained during the execution of steps (a)-(g) and Packed in aluminum-aluminum (ALM/ALM) blister shell and polyvinyl/grades (PVC/PVDC) aluminum blister shell was placed in conditions with variable temperature and relative humidity for a period of 3 months. Below is information regarding formed during storage of impurities and inclusions or degradation products found in the store under different conditions.

1. Stability of tablets containing acetylsalicylic acid

At the beginning of the storage period
Salicylic acidThe content of other impuritiesThe total impurity content
0,60%Not determined0,60%

3 months later
ConditionsParty capsulesSalicylic acidThe content of other impuritiesThe total content of CR is Mesa
25°C 60% RHALM/ALM0,35%Not determined0,4%
PVC/PVDC0,34%Not determined0,4%
30°C 65% RHALM/ALM1,43%Not determined1,4%
PVC/PVDC0,56%Not determined0,6%
40°C 75% RHALM/ALM0,76%Not determined0,8%
PVC/PVDC1,76%Not determined1,8%

2. Stability of tablets containing simvastatin

At the beginning of the storage period
LovastatinAdmixture AndAdmixture WithWith the holding of other impurities The total impurity content
Party capsules0,11%Not determined0,06%0,17%

Impurity A=simvastatina Spartakiada

Impurity C=anhydrous simvastatin

3 months later
ConditionsParty capsulesL(1)Admixture AndAdmixture WithThe content of other impuritiesThe total impurity content
25°C 60%OBALM/ ALM0,02%0,28%n (2)0,05%0,43%
PVC/ PVDC0,02%0,31%n (2)0,05%0,47%
30°C 65%OBALM/ ALM0,02%0,22%0,29%0,63%
PVC/ PVDC0,02%0,26%0,02%0,31%0,69%
40°C 75%OBALM/ ALM0,02%0,21%0,06%1,13%1,50%
PVC/ PVDC0,02%0,36%0,12%1,69%2,31%

Admixture And - Lovastatin

Admixture With - Not determined

3. Stability of tablets containing ramipril

At the beginning of the storage period
Impurity DUnknown impuritiesThe total impurity content
0,04%0,05%0,21%

Impurity D=ramipril of diketopiperazine

tr>
3 months later
ConditionsParty capsulesBGAAA(1)Impurity DImpurity EThe total impurity content
25°C 60% RHALM/ ALMn.d. (2)n.d. (2)0,1%0,1%<0,l%
PVC/ PVDCn.d. (2)n.d. (2)0,1%0,1%n.d. (3)

3 months later
ConditionsParty capsulesBGAAA(1)Impurity DImpurity EThe total impurity content
30°C 65% RHALM/ALMn.d. (2)n.d. (2)0,1%0,1%0,1%
PVC/PVDCn.d. (2)n.d. (2)0,1%0,2%<0,1%
40°C 75% RHALM/ALM0,2%0,1%0,1%0,2%n.d. (3)
PVC/PVDC1,1%n.d. (2)0,4%0,7%0,2%

(1) acetylsalicylic acid

(2) was not determined

(3) was not determined

Impurity E=ramipril dokily

Example 2: Capsules made of hard gelatin containing one tablet in the shell, containing 100 mg acetylsalicylic acid, two coated tablet, containing 20 mg of simvastatin, and one tablet in the shell, containing 10 mg of ramipril.

By analogy with example 1, were made the same capsule, differing only in the composition of the tablet of ramipril, which is presented in Table 20. The tensile strength of these tablets with destruction by crushing amounted 9-11 kPa at the time of the destruction in the interval 1-2 minutes

Table 20.
The composition of the coated tablet containing 10 mg ramipril
CoreComponentsRamipril10,000 mg
The hypromellose1,000 mg
Reptitiously starch 15008,000 mg
Microcrystalline cellulose 10178,200 mg
Starch of glycolate sodium2,000 mg
Stearyl fumarate sodium800 mg
The total weight of the core100,000 mg
About-
shell
Tool AM IN 80W32880 with yellow pigment4,000 mg
The total weight of the tablet shell104,000 mg

Example 3: Capsules made of hard gelatin containing one tablet in the shell, containing 100 mg acetylsalicylic acid, two table the TCI in the shell, comprising 20 mg simvastatin and one tablet in the shell, containing 20 mg lisinopril dihydrate.

By analogy with example 1, were made the same capsule, differing only in the composition of the tablets lisinopril dihydrate, which is presented in Table 21. The tensile strength of these tablets with destruction by crushing amounted to 5, 5 and 7.5 kPa at the time of the destruction of less than 1 minutes

Table 21.
The composition of the coated tablet, containing 20 mg lisinopril dihydrate
CoreComponentsThe dihydrate lisinopril20,000 mg
Corn starch5,000 mg
Reptitiously starch 15005,000 mg
Mannitol25,000 mg

CoreComponentsPhosphate dihydrate calcium44,500 mg
Magnesium stearate 500 mg
The total weight of the core100,000 mg
About-
shell
Tool CA 80W32039 with yellow pigment4,000 mg
The total weight of the tablet shell104,000 mg

Example 4: Capsules made of hard gelatin containing one tablet in the shell, containing 100 mg acetylsalicylic acid, two coated tablet, containing 20 mg of simvastatin, and one tablet in the shell, containing 10 mg of ramipril.

By analogy with example 1, were made the same capsule, differing only in the composition of the tablet of ramipril, which is presented in Table 22. The tensile strength of these tablets with destruction by crushing amounted 9-11 kPa at the time of the destruction in the range of 0.5-2 minutes

Table 22.
The composition of the coated tablet containing 10 mg ramipril
CoreComponentsRamipril10,000 mg
Reptitiously starch 150010,000 mg
Microcrystalline cellulose 10179,200 mg
Stearyl fumarate sodium800 mg
The total weight of the core100,000 mg
About-
shell
Tool CA 80W32880 with yellow pigment4,000 mg
The total weight of the tablet shell104,000 mg

Example 5: Capsules made of hard gelatin containing one tablet in the shell, containing 100 mg acetylsalicylic acid, two coated tablet, containing 20 mg of simvastatin, and one tablet in the shell, containing 10 mg of ramipril.

By analogy with example 1, were made the same capsule, differing only in the composition of the tablets simvastatin, which are presented in Table 23.

Table 23.
The composition of the tablets in the shell, containing 20 mg simvastatin
Core Fine simvastatin20,000 mg
The lactose monohydrate51,960 mg
Reptitiously starch 150010,000 mg
Ascorbic acid5,000 mg
Citric acid2,500 mg
Microcrystalline cellulose 1015,000 mg
Bottled hydroxyanisol0,040 mg
Colloidal anhydrous silica0,500 mg
Talc4,000 mg
Magnesium stearate1,000 mg
The total weight of the core100,000 mg
The shellThe tool Opadry 06023821 with yellow pigment3,000 mg
The total weight of the tablet shell103,000 mg

Example 6: Test solubility tablets symb is a statin

Test the solubility was carried out in respect of the tablet of simvastatin mentioned in example 4. To this end, one tablet of simvastatin was placed in capsules size #0, made of solid gelatin and cellulose. The capsules are then placed in a buffered aqueous medium at pH 7, containing 0.5% dodecyl sulfate, sodium phosphate sodium concentration of 0.01 N at 37°C. the results Obtained are presented in Table 24.

Table 24.
Test the solubility for tablets simvastatin
Time (min)Material capsules
Hard gelatinCellulose
518,78±47,39%0,00%
1569,69±13,98%57,17±15,02%
3085,05±of 7.36%90,31±3,95%

Example 7: Test solubility tablet ramipril

One tablet of ramipril specified in example 4 was placed in capsules size #0, made of solid gelatin and a is wlosy. The capsules are then placed in a buffer solution of HCl with a concentration of 0.1 N at 37°C. the results Obtained are presented in Table 25.

Table 25.
Test the solubility for tablets ramipril
Time (min)Material capsules
Hard gelatinCellulose
586,29±2,41%6,93±83,65%
1590,17±1,93%84,68±2,65%
3091,22±1,80%89,49±2,37%

Example 8: Test solubility tablets acetylsalicylic acid

One tablet with acetylsalicylic acid found in example 4 was placed in a buffered aqueous medium at pH 4.5 and 37°C. the results Obtained are presented in Table 26.

Table 26.
Test the solubility for tablets with acetylsalicylic acid
0 min0%
5 min40%
15 min90%
30 min96%

Example 9: Capsules made of hard gelatin containing one tablet in the shell, containing 100 mg acetylsalicylic acid, two coated tablet, containing 20 mg of simvastatin, and one tablet in the shell, containing 2.5, 5, and 10 mg of ramipril.

By analogy with example 1, were made the same capsule, differing only in the composition of the tablets in the shell, containing 2.5, 5, and 10 mg of ramipril, which are presented in Tables 27, 28 and 29, respectively.

Table 27.
The tablet shell containing 2.5 mg ramipril
CoreComponentsRamipril2,500 mg
The hypromellose0,441 mg
Reptitiously starch 150017,559 mg
Microcrystalline the cellulite, tighten the 200 80,000 mg
Stearyl fumarate sodium0,500 mg
The total weight of the core101,000 mg
About-
shell
The tool Opadry AMB 80W32039 with yellow pigment4,000 mg
The total weight of the tablet shell105,000 mg

Table 28.
The tablet shell containing 5 mg ramipril
CoreComponentsRamipril5,000 mg
The hypromellose0,882 mg
Reptitiously starch 150019,618 mg
Microcrystalline cellulose 20075,000 mg
Stearyl fumarate sodium0,500 mg
The total weight of the core 101,000 mg
About-
shell
The tool Opadry AMB 80W32039 with yellow pigment4,000 mg
The total weight of the tablet shell105,000 mg

Table 29.
The tablet shell containing 10 mg ramipril
CoreComponentsRamipril10,000 mg
The hypromellose1,764 mg
Reptitiously starch 150018,736 mg
Microcrystalline cellulose 20070,000 mg
Stearyl fumarate sodium0,500 mg
The total weight of the core101,000 mg
About-
shell
The tool Opadry AMB 80W32039 with yellow pigment4,000 mg
The total weight of the tablet shell105,000 mg

1. Capsule for the prevention of cardiovascular disease in subjects from high-risk groups, including:
w tablets in the shell that contains 40.5 mg of acetylsalicylic acid, and x tablets in the shell, containing 81 mg of acetylsalicylic acid, the total amount of acetylsalicylic acid 40,5÷162 mg, where w is an integer selected from 0 and 1, x is an integer selected from 0, 1 and 2, and w+x is 1 or 2, or tablets in the shell, containing 50 mg of acetylsalicylic acid, and z tablets in the shell, containing 100 mg of acetylsalicylic acid, the total amount of acetylsalicylic acid 50-200 mg where y is an integer selected from 0 and 1, z is an integer selected from 0, 1 and 2, and y+z is 1 or 2;
's tablets in the shell, containing 20 mg of simvastatin, and t tablets in the shell, containing 40 mg of simvastatin, when the total number of simvastatin 20÷80 mg, where s is an integer selected from 0, 1 and 2, t is an integer selected from 0, 1 and 2, a s+t is 1 or 2, or u tablets in the shell, containing 20 mg of pravastatin or its pharmaceutically acceptable salts, and v tablets in the shell, containing 40 mg of pravastatin or its pharmaceutically praml is my salt, when the total number of pravastatin or its pharmaceutically acceptable salt 20÷80 mg, where u is an integer selected from 0, 1 and 2, v is an integer selected from 0, 1 and 2, a u+v is 1 or 2, and
R tablets in the shell, containing 5 mg of lisinopril or its hydrated form, q tablets in the shell, containing 10 mg lisinopril or its hydrated form, and r tablets in the shell, containing 20 mg lisinopril or its hydrated form, for a total of lisinopril or its hydrated form is 5÷40 mg, where p is an integer selected from 0 and 1, q is an integer selected from 0 and 1, r is an integer selected from 0, 1 and 2, a p+q+r is 1, 2 or 3, or k tablets in the shell, containing 2.5 mg of ramipril, m tablets in the shell, containing 5 mg of ramipril, and n tablets in the shell, containing 10 mg of ramipril, when the total number of ramipril 2,5÷20 mg, where k is an integer selected from 0 and 1, m is an integer selected from 0 and 1, n is an integer selected from 0, 1 and 2, a k+m+n is 1, 2 or 3, or h tablets in the shell, containing 2 mg of perindopril or its pharmaceutically acceptable salts, of the first tablets in the shell that contains 4 mg perindopril or its pharmaceutically acceptable salts, and j pellets in the shell, containing 8 mg perindo the Rila or its pharmaceutically acceptable salt, when the total number of perindopril or its pharmaceutically acceptable salt 2÷16 mg, h is an integer selected from 0 and 1, i is an integer selected from 0 and 1, j is an integer selected from 0, 1 and 2, a h+i+j is 1, 2 or 3, with:
these tablets containing acetylsalicylic acid coated film-coated, containing partially hydrolyzed polyvinyl alcohol;
these tablets containing simvastatin, coated film-coated, containing hypromellose;
these tablets containing pravastatin or its pharmaceutically acceptable salt, covered with a film cover, containing hypromellose;
these tablets containing lisinopril or its hydrated form, covered with a film cover, containing partially hydrolyzed polyvinyl alcohol;
these tablets containing ramipril, coated film-coated, containing partially hydrolyzed polyvinyl alcohol;
these tablets containing perindopril or its pharmaceutically acceptable salt, covered with a film cover, containing partially hydrolyzed polyvinyl alcohol.

2. The capsule according to claim 1, including:
one tablet in the shell, containing 81 mg of acetylsalicylic acid or one tablet in the shell, the content is concerned 100 mg acetylsalicylic acid
two tablets in the shell, each of which contains 20 mg of simvastatin or two tablets in the shell, each of which contains 20 mg of sodium salt of pravastatin, and
one tablet in the shell, which contains 5, 10 or 20 mg of lisinopril dihydrate or one tablet in the shell containing 2.5, 5 or 10 mg of ramipril, or one tablet in the shell, containing 2, 4 or 8 mg albuminous salt of perindopril.

3. The capsule according to claim 1, which contains a combination of elements selected from the following groups:
one tablet in the shell, containing 81 mg acetylsalicylic acid, two coated tablet, each comprising 20 mg simvastatin and one tablet in the shell, containing 5 mg lisinopril dihydrate;
one tablet in the shell, containing 81 mg acetylsalicylic acid, two coated tablet, each comprising 20 mg simvastatin and one tablet in the shell, containing 10 mg lisinopril dihydrate;
one tablet in the shell, containing 81 mg acetylsalicylic acid, two coated tablet, each comprising 20 mg simvastatin and one tablet in the shell, containing 20 mg lisinopril dihydrate;
one tablet in the shell, containing 81 mg acetylsalicylic acid, two coated tablet, each comprising 20 mg simvastatin and one tablet in the shell, containing 2.5 mg of ramipril;
one tablet is in the shell, contains 81 mg acetylsalicylic acid, two coated tablet, each comprising 20 mg simvastatin and one tablet in the shell, containing 5 mg ramipril;
one tablet in the shell, containing 81 mg acetylsalicylic acid, two coated tablet, each comprising 20 mg simvastatin and one tablet in the shell, containing 10 mg ramipril;
one tablet in the shell, containing 81 mg acetylsalicylic acid, two coated tablet, each comprising 20 mg simvastatin and one tablet in the shell, containing 2 mg of perindopril erbumine;
one tablet in the shell, containing 81 mg acetylsalicylic acid, two coated tablet, each comprising 20 mg simvastatin and one tablet in the shell, containing 4 mg of perindopril erbumine;
one tablet in the shell, containing 81 mg acetylsalicylic acid, two coated tablet, each comprising 20 mg simvastatin and one tablet in the shell, containing 8 mg of perindopril erbumine;
one tablet in the shell, containing 81 mg acetylsalicylic acid, two coated tablet, each of which contains 20 mg of sodium salt of pravastatin, and one tablet in the shell, containing 5 mg lisinopril dihydrate;
one tablet in the shell, containing 81 mg acetylsalicylic acid, two coated tablet, each is th of which contains 20 mg of sodium salt of pravastatin, and one tablet in the shell, containing 10 mg lisinopril dihydrate;
one tablet in the shell, containing 81 mg acetylsalicylic acid, two coated tablet, each of which contains 20 mg of sodium salt of pravastatin, and one tablet in the shell, containing 20 mg lisinopril dihydrate;
one tablet in the shell, containing 81 mg acetylsalicylic acid, two coated tablet, each of which contains 20 mg of sodium salt of pravastatin, and one tablet in the shell, containing 2.5 mg of ramipril;
one tablet in the shell, containing 81 mg acetylsalicylic acid, two coated tablet, each of which contains 20 mg of sodium salt of pravastatin, and one tablet in the shell, containing 5 mg ramipril;
one tablet in the shell, containing 81 mg acetylsalicylic acid, two coated tablet, each of which contains 20 mg of sodium salt of pravastatin, and one tablet in the shell, containing 10 mg ramipril;
one tablet in the shell, containing 81 mg acetylsalicylic acid, two coated tablet, each of which contains 20 mg of sodium salt of pravastatin, and one tablet in the shell, containing 2 mg of perindopril erbumine;
one tablet in the shell, containing 81 mg acetylsalicylic acid, two coated tablet, each of which contains 20 mg of sodium salt of pravastatin, and is on the pill in the shell, contains 4 mg perindopril of erbumine;
one tablet in the shell, containing 81 mg acetylsalicylic acid, two coated tablet, each of which contains 20 mg of sodium salt of pravastatin, and one tablet in the shell, containing 8 mg of perindopril erbumine;
one tablet in the shell, containing 100 mg acetylsalicylic acid, two coated tablet, each comprising 20 mg simvastatin and one tablet in the shell, containing 5 mg lisinopril dihydrate;
one tablet in the shell, containing 100 mg acetylsalicylic acid, two coated tablet, each comprising 20 mg simvastatin and one tablet in the shell, containing 10 mg lisinopril dihydrate;
one tablet in the shell, containing 100 mg acetylsalicylic acid, two coated tablet, each comprising 20 mg simvastatin and one tablet in the shell, containing 20 mg lisinopril dihydrate;
one tablet in the shell, containing 100 mg acetylsalicylic acid, two coated tablet, each comprising 20 mg simvastatin and one tablet in the shell, containing 2.5 mg of ramipril;
one tablet in the shell, containing 100 mg acetylsalicylic acid, two coated tablet, each comprising 20 mg simvastatin and one tablet in the shell, containing 5 mg ramipril;
one tablet in the shell containing 100 mg of acetylsalicylic acid, two tablets in the shell, each comprising 20 mg simvastatin and one tablet in the shell, containing 10 mg ramipril;
one tablet in the shell, containing 100 mg acetylsalicylic acid, two coated tablet, each comprising 20 mg simvastatin and one tablet in the shell, containing 2 mg of perindopril erbumine;
one tablet in the shell, containing 100 mg acetylsalicylic acid, two coated tablet, each comprising 20 mg simvastatin and one tablet in the shell, containing 4 mg of perindopril erbumine;
one tablet in the shell, containing 100 mg acetylsalicylic acid, two coated tablet, each comprising 20 mg simvastatin and one tablet in the shell, containing 8 mg of perindopril erbumine;
one tablet in the shell, containing 100 mg acetylsalicylic acid, two coated tablet, each of which contains 20 mg of sodium salt of pravastatin, and one tablet in the shell, containing 5 mg lisinopril dihydrate;
one tablet in the shell, containing 100 mg acetylsalicylic acid, two coated tablet, each of which contains 20 mg of sodium salt of pravastatin, and one tablet in the shell, containing 10 mg lisinopril dihydrate;
one tablet in the shell, containing 100 mg acetylsalicylic acid, two coated tablet, each of Kotor is x contains 20 mg of sodium salt of pravastatin, and one tablet in the shell, containing 20 mg lisinopril dihydrate;
one tablet in the shell, containing 100 mg acetylsalicylic acid, two coated tablet, each of which contains 20 mg of sodium salt of pravastatin, and one tablet in the shell, containing 2.5 mg of ramipril;
one tablet in the shell, containing 100 mg acetylsalicylic acid, two coated tablet, each of which contains 20 mg of sodium salt of pravastatin, and one tablet in the shell, containing 5 mg ramipril;
one tablet in the shell, containing 100 mg acetylsalicylic acid, two coated tablet, each of which contains 20 mg of sodium salt of pravastatin, and one tablet in the shell, containing 10 mg ramipril;
one tablet in the shell, containing 100 mg acetylsalicylic acid, two coated tablet, each of which contains 20 mg of sodium salt of pravastatin, and one tablet in the shell, containing 2 mg of perindopril erbumine;
one tablet in the shell, containing 100 mg acetylsalicylic acid, two coated tablet, each of which contains 20 mg of sodium salt of pravastatin, and one tablet in the shell, containing 4 mg of perindopril erbumine;
one tablet in the shell, containing 100 mg acetylsalicylic acid, two coated tablet, each of which contains 20 mg of sodium salt of pravastatin, and the bottom tablet in the shell, containing 8 mg of perindopril erbumine.

4. The capsule according to any one of claims 1 to 3, in which the material for its production is solid gelatin.

5. The capsule according to any one of claims 1 to 3, in which the material for its production is cellulose.

6. The capsule according to any one of claims 1 to 3, in which all tablets are made with unmodified mode of release of active substances.

7. The use of a capsule according to any one of claims 1 to 6 in the manufacture of a medicine for the prevention of cardiovascular disease in subjects from high-risk groups.

8. The use according to claim 7, in which these subjects from high-risk groups are those aged over 55 years, patients have a condition that develops on the background of angina, stroke, atherosclerosis, syndrome Charcot, diabetes, ischemic heart disease, peripheral vascular disease, disorders of platelet function, hemodialysis, hypercholesterolemia, hypertension, myocardial infarction, congestive heart failure, ischemia, nephropathy, cardiac arrest or restenosis, nicotine addiction, Smoking, obesity, physical inactivity.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: disclosed are novel 4-dimethyl aminobutyric acid derivatives of formula (I) (pharmaceutically acceptable salts thereof), where values of A1, A2, R1, m and n are given in the claim, which inhibit activity of carnitine palmitoyltransferase (CPT), and more specifically CPT2.

EFFECT: compounds are an agent of pharmaceutical compositions, having CPT2 inhibiting activity.

18 cl, 71 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to novel substituted 4-aryl-1,4-dihydro-1,6-naphthyridine-3-carboxamides, method for production thereof, use thereof to produce a medicinal agent which inhibits MR activity.

EFFECT: improved method.

11 cl, 9 ex

FIELD: chemistry; pharmaceutics.

SUBSTANCE: present invention relates to 6-substituted isoquinoline and isoquinolinone derivatives of formula or stereoisomer and/or tautomer forms thereof, and/or pharmaceutically acceptable salts thereof, where R1 is H or OH; R2 is R', (C7-C8)alkyl, (C1-C6)alkylene-R', (C2-C6)alkenyl; or R2 is (C1-C6)alkyl, under the condition that in said alkyl residue, at least one hydrogen is substituted with OH or OCH3; or R2 is (C1-C6)alkylene, bonded with cycloalkylamine, where (C1-C4)alkylene forms a second bond with another carbon atom of the cycloalkylamine ring and, together with carbon atoms of the cycloalkyalmine, forms a second 5-8-member ring; R3, R5 and R8 denote H; R4 is H, (C1-C6)alkyl or (C1-C6)alkylene-R'; R6 and R6' independently denote H, (C1-C8)alkyl, (C1-C6)alkylene-R' or C(O)O-(C1-C6)alkyl; R7 is H, halogen or (C1-C6)alkyl; n equals 1; m equals 3 or 5; r equals 0 or 1 and L is O(CH2)p, where p=0; where R' is (C3-C8)cycloalkyl, (C6)aryl; where in residues R2-R8 (C6)aryl is unsubstituted or substituted with one or more suitable groups independently selected from halogen, (C1-C6)alkyl, O-(C1-C6)alkyl, where the alkyl group can be substituted with 1-3 halogen atoms. The invention also relates to use of the compound of formula (I) and a medicinal agent based on the compound of formula (I).

EFFECT: obtaining novel 6-substituted isoquinoline and isoquinolinone derivatives suitable for treating and/or preventing diseases associated with Rho-kinase and/or Rho-kinase-mediated myosin light chain phosphatase phosphorylation.

36 cl, 5 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pharmaceutics and medicine, more specifically to a new 3-(2,2,2-trimethylhydrazinium)propionate derivative, 3-(2,2,2-trimethylhydrazinium)potassium propionate 5-bromnicotinate (CH3)3N+HCH2CH2COOKRCOO- wherein .

EFFECT: preparing the compound showing high endothelioprotective activity.

1 tbl, 2 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pharmaceutics and medicine, more specifically to a new chemical compound, a 3-(2,2,2-trimethylhydrazinium)propionate derivative, namely 3-(2,2,2-trimethylhydrazinium)potassium propionate 5-nicotinate hydroxide showing endothelioprotective activity.

EFFECT: preparing the compound which can find application in medicine in the integrated treatment for endothelial dysfunction correction in cardiovascular diseases.

1 tbl, 2 ex

FIELD: chemistry.

SUBSTANCE: crystalline form of aliskiren hemifumarate is characterized by the picture of X-ray diffraction in powder demonstrating the following main peaks, given at degrees 2 Teta+/- 0.3 degree: 3.8, 6.5, 7.7, 8.0, 15.6 and 17.4. said form is obtained from solution with weight ratio (weight/weight) acetonyl : ethanol, being in the interval from 90:10 to 75:25 (for instance, 80:20) at suitable temperature in the interval from 15 to 40°C, for instance, by cooling from 37°C to 35°C and especially after dimming - by further cooling to 20°C, ensuring aliskiren hemifumarate crystallisation, filtered and dried under vacuum, for instance, at 10 mbar and 40°C. Crystalline form of aliskiren hemifumarate is applied for obtaining pharmaceutical composition, suitable for treating disease in warm-blooded animal, modulated by rennin inhibition.

EFFECT: stable aliskiren form, with long storage term, purity, improved parameters of fluidity.

10 cl, 16 tbl, 12 dwg, 13 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: pharmaceutical composition by invention possesses antagonistic activity with respect to angiotensin II. Pharmaceutical composition contains 30-80 wt % of inrbesartan or its pharmaceutically acceptable salt as active ingredient and more than 10 wt % of loosening agent in terms of complete composition weight. Pharmaceutical composition does not contain silicon-containing antiadhesive. Pharmaceutical composition of irbesartan is made in form of tablet with film coating. Also described is method of irbesartan tablet manufacturing.

EFFECT: irbesartan tablet possesses dissolution profile at which 80 wt % or more of irbesartan dissolve not later than after 30 min.

25 cl, 1 dwg, 10 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to a pharmaceutical composition for treating cardiovascular diseases which contains a therapeutically effective amount of metoprolol succinate as an active substance, and excipients - a combination of hypromellose type 2910 and hypromellose type 2208 taken in the relation of 1:(0.18-472.5), a filler, a glidant, a lubricant. Said pharmaceutical composition is presented in the form of a coated tablet.

EFFECT: said composition is characterised by modified release of the active substance; it is storage-stable and has high mechanical strength.

4 cl, 2 tbl, 12 ex

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely pulmonology, and concerns treating chronic obstructive pulmonary disease accompanied by bronchiectasia. That is ensured by the endotracheal introduction of berodual 2 ml, 0.25% novocaine 5 ml, 1% diphenylhydramine 1 ml, and 1% dioxidine 15 ml; the procedure is performed for 15-20 min; the therapeutic course makes 10-15 daily instillations.

EFFECT: endotracheal introduction of such complex of the therapeutic preparations provides the effective treatment with no side effects, particularly antibiotic-induced bronchial spasm.

2 ex, 1 tbl

FIELD: medicine.

SUBSTANCE: group of inventions refers to medicine. Group of inventions involves the use of lisuride or terguride or their enantiomers, or their salts or hydrates for treating and preventing pulmonary arterial hypertension, endogenic or exogenic induced glomerular sclerosis, as well as secondary Reynaud's syndrome; the use of lisuride or terguride or their enantiomers, or their salts or hydrates for treating and preventing said diseases; a pharmaceutical composition for treating and preventing said diseases containing a compound specified in a group consisting of lisuride, terguride, their enantiomers, as well as their salts or hydrates, together with a pharmaceutically compatible carriers, excipients and/or solvents.

EFFECT: group of inventions provides higher therapeutic and preventive effectiveness.

6 cl, 10 ex, 3 dwg

FIELD: chemistry.

SUBSTANCE: invention relates to novel tetrahydroisoquinoline derivatives of general formula (I) or pharmacologically acceptable salts thereof, where R1 is a phenyl aminocarbonyl group which can be substituted with 1-3 groups independently selected from a substituting group A, a heteroaryl aminocarbonyl group, where the heteroaryl is pyridine, pyrazine, thiazole, pyrazole or isoxazole, which can be substituted with 1 group selected from a substituting group A, benzoxazol-2-yl group, which can be substituted with 1 group selected from a substituting group A, benzothiazol-2-yl group, (C1-C6 alkyl which can be monosubstituted with a C3-C6 cycloalkyl group), aminocarbonyl group, (C3-C6 cycloalkyl)aminocarbonyl group or adamantyl aminocarbonyl group; R2 independently represents a C1-C6 alkyl group; R3 is a heterocyclic group, where the heterocycle is oxazole, oxadiazole, pyrazole, isoxazole or tetrazole, which can be substituted with 1 group selected from a substituting group A, a group of formula -C(=O)-O-R4, or a group of formula -C(=O)-N(R5)R6; R4 is a hydrogen atom, a C1-C6 alkyl group which can be substituted with 1-2 groups independently selected from a substituting group B; R5 is a hydrogen atom, a C1-C6 alkyl group which can be substituted with 1 group selected from a substituting group B, a C3-C6 cycloalkyl group which is monosubstituted with a carboxyl group, or a heterocyclic group, where the heterocycle is tetrazole, which can be substituted with 1 group selected from a substituting group A; R6 is a hydrogen atom or a C1-C6 alkyl group; in those cases when both R5 and R6 represent a C1-C6 alkyl group, which can be substituted with 1 group selected from a substituting group B, their carbon atoms can be bonded to each other to form a 5-member saturated ring; X is an oxygen atom, a methylene group, a group of formula -NH-, a methylene group which is monosubstituted with a C1-C6 alkyl group, or a group of formula -N(R7)-; R7 is a C1-C6 alkyl group; L is a single bond, a methylene group, a 1,1-dimethylmethylene group, an ethylene group, a group of formula - CH=, or a methylene group which is monosubstituted with a C1-C6 alkyl group; … denotes a single bond or a double bond (however, … denotes a single bond when L is a group of formula -CH=); m equals 1 or 2; n equals 0 or 1; substituting group A is a group of substitutes selected from a halogen atom, a C1-C6 alkyl group, a C1-C6 halogenated alkyl group, a C1-C6 alkoxy group, a C1-C6 halogenated alkoxy group, a C1-C6 alkylthio group, a carboxyl group, a di-(C1-C6 alkyl)amino group, a cyano group, a hydroxy group, a C1-C6 alkylthionyl group and an oxo group; and substituting group B is a group of substitutes selected from a carboxyl group and a hydroxy group. The invention also relates to a pharmaceutical composition based on the compound of formula (I), use of the compound of formula (I) and a method of treating and/or preventing a disease.

EFFECT: obtaining novel tetrahydroisoquinoline derivatives, having excellent inhibiting action on acyl-coenzyme A: diacylglycerol-acyltransferase and excellent food intake suppression.

31 cl, 113 ex

FIELD: chemistry.

SUBSTANCE: disclosed are novel 4-dimethyl aminobutyric acid derivatives of formula (I) (pharmaceutically acceptable salts thereof), where values of A1, A2, R1, m and n are given in the claim, which inhibit activity of carnitine palmitoyltransferase (CPT), and more specifically CPT2.

EFFECT: compounds are an agent of pharmaceutical compositions, having CPT2 inhibiting activity.

18 cl, 71 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (IX) wherein radicals and symbols have values given in the claim, and pharmaceutically acceptable salts or tautomers thereof. Said compounds are inhibitors of poly(ADP-ribose)polymerase (PARP) and can be used to treat cancer, inflammatory diseases, reperfusion injuries, ischaemic conditions, stroke, renal failure, cardiovascular diseases, vascular diseases other than cardiovascular diseases, diabetes mellitus, neurodegenerative diseases, retroviral infections, retinal damage, skin senescence and UV-induced skin damage, and as chemo- or radiosensitisers for cancer treatment. The invention also relates to a pharmaceutical composition containing said compounds, use of said compounds and a method of treating said diseases.

EFFECT: high efficiency of using the compounds.

10 cl, 18 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pharmaceutical industry and represents a biologically compatible polysaccharide gel composition possessing the properties of prolonged release and containing triamcinolone acetonide engrafted to hyaluronic acid by covalent binding of triamcinolone acetonide and hyaluronic acid.

EFFECT: invention provides controlled release of the active ingredient representing triamcinolone acetonide.

19 cl

FIELD: medicine.

SUBSTANCE: invention refers to a lyophilised DNA compound to be applied for treating an ischemic disease and to a method of treating an ischemic disease in an individual. The lyophilised DNA compound contains plasmid DNA, salt and carbohydrate wherein said plasmid DNA contains HGF gene, or its version, and wherein said HGF gene, or its version is specified in a group consisting of flHGF, dHGF, NK1, NK2, NK4 or their mixture. The method of treating an ischemic disease in a human or a mammal involves the introduction of a composition recovered from the lyophilised DNA compound by direct injection.

EFFECT: invention enables effective treatment of the ischemic disease in the human or the mammal.

14 cl, 5 dwg, 2 tbl, 5 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel substituted 4-aryl-1,4-dihydro-1,6-naphthyridine-3-carboxamides, method for production thereof, use thereof to produce a medicinal agent which inhibits MR activity.

EFFECT: improved method.

11 cl, 9 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel pyrimidine derivatives of general formula (I-a), having the capacity to simulate axonal growth coupled with the capacity to stimulate angiogenesis and can be used in treating spinal chord damage, damage to the central nervous system as a result of head injuries, ischaemic stroke, ischemic heart disease, peripheral arterial occlusive disease, vascular dementia, cerebrovascular dementia or senile dementia. In the compound of formula (I-a): R0 is a group where R3 and R4 denote a hydrogen atom; R1 is a methyl group; R2 is a methyl group; R5 is a hydrogen atom; R6 is a hydrogen atom; R7 is a methyl group; E is an oxygen atom; is a benzyl group, a cyclohexyl methyl group, an isobutyl group, a cyclohexane carbonyl group, an acetyl group, a phenylsulphonyl group, a cyclohexyl group, a piperidine-1-carbonyl group, a methylbenzyl group, a phenyl group, a fluorobenzyl group, a methoxybenzyl group or a trifluorobenzyl group; or a pharmaceutically acceptable salt thereof.

EFFECT: high efficiency of using the compounds.

4 cl, 16 dwg, 27 tbl, 148 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pharmaceutical industry, namely a preparation for treating ischemic and haemorrhagic stroke. The preparation for treating ischemic and haemorrhagic stroke recovered from swine brains with simulated haemorrhagic hemispheric stroke after common carotid arterial occlusive disease on the same side (ischemic stroke). A method for producing the preparation for treating ischemic and haemorrhagic stroke involves grinding of swine brains with pre-simulated haemorrhagic hemispheric stroke after common carotid arterial occlusive disease on the same side (ischemic stroke), homogenisation in a buffer at pH 7.3-7.6, separation of insoluble fragments from the homogenate, extraction of mixed lipid components; cleaning and sterilising filtration of the product frozen at temperature -30°C and lyophilisation.

EFFECT: preparation is effective for treating ischemic and haemorrhagic stroke.

2 cl, 1 ex

FIELD: medicine.

SUBSTANCE: claimed is application of carbon-containing nanoparticles, representing carbon nanocapsule 10 nm in size, containing iron particles, for destructuring atherosclerotic lesions, formed on the walls of blood vessels. It is demonstrated that claimed carbon-containing nanoparticles, applied on the surface of atherosclerotic lesion, are capable of penetrating into its internal layers and modifying its structure: presence of nanoparticles in it combines with presence in it of segments of sparse collagen structures.

EFFECT: invention can be used for creation of novel efficient medication which makes it possible to destructure atherosclerotic lesions, formed on the walls of blood vessels.

4 dwg

FIELD: medicine.

SUBSTANCE: invention refers to a method for detection of genetic predisposition in an individual with no clinical implications of ischemic heart disease (IHD) to developing myocardial infarction (MI). The invention may be used in cardiology for detection of genetic predisposition to developing myocardial infarction (MI). A combination of two pathogenetically MI-related polymorphisms representing single nucleotide substitutes C1019T in connexin-37 (Cx37) gene and G894T in endothelial NO-CHHTa3bi.(eNOS) gene are examined. A high degree of risk of developing MI in an individual being examined is stated by a combination of homozygous genotype TT in C1019T polymorphism of Cx37 gene and homozygous genotype GG in G894T polymorphism of eNOS gene.

EFFECT: invention enables specifying a group of high risk of developing MI among almost healthy persons for the purpose of taking primary prevention actions.

2 dwg, 7 tbl, 4 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a new compound of 2-[3-(2,2-difluorobenzo[1,3]dioxol-5-ylamino)-5-(2,6-dimethylpyridin-4-yl)-[1,2,4]triazol4-yl]-N-ethylacetamide and/or pharmaceutically acceptable salts, or hydrate, or solvates, as well as to a method for preparing it; a pharmaceutical composition based on this compound and using its in therapy for prevention and treatment of mental disorders, intellectual disorders or diseases, inflammatory diseases or conditions wherein α7 nicotinic receptor modulation is considered to be favourable. The invention also refers to a product containing such compound and α7-nicotinic receptor agonist.

EFFECT: preparing the compounds applicable in therapy for prevention or treatment of mental disorders, intellectual disorders or diseases, inflammatory diseases or conditions wherein α7 nicotinic receptor modulation is considered to be favourable.

6 cl, 1 tbl, 4 ex

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