Method of thrombosis treatment or prevention with application of dabigatran etexilate or its salt with improved efficiency in comparison with standard treatment with warfarin

FIELD: medicine.

SUBSTANCE: invention relates to medicine, namely to neurology and cardiology, and deals with treatment or prevention of thrombosis. For this purpose dabigatran etexilate is introduced in a dose from 150 to 300 mg twice per day.

EFFECT: method provides prevention of thromboembolic complications and development of stroke in patients with atrial fibrillation, who have creatinine clearance less than 80 ml/min with an absence of additional factors of risk of massive bleeding.

7 cl, 7 tbl, 4 ex, 3 dwg

 

The scope of the invention

The present invention relates to methods of application of etexilate of dabigatran, not necessarily in the form of its pharmaceutically acceptable salts, which provide advantages compared with standard treatment with warfarin or other antagonists of vitamin K.

The background to the present invention

Atrial fibrillation (AF) is a common cardiac arrhythmia that increases the risk of stroke and other embolic events and deaths. From MA suffer 2.2 million people in the United States and 4.5 million people in Europe. MA is the most common cardiac arrhythmia and a major risk factor for stroke. The incidence of AF increases with age and about 6% of people over 65 years suffer from MA. Patients with AF at risk of blood clots due to the rapid irregular heartbeat. MA increases the chance of stroke in 5 times. As a consequence of stroke may be the exhaustion, the first aim of treatment is to reduce the risk of formation of blood clots and embolism. Patients suffering from MA and risk (medium to high level) of a stroke, the recommended long-term anticoagulant treatment with vitamin K antagonists (AVK or kumudini), such as warfarin. Risk factors for stroke, thrombosis is or embolism include age older than 65 years, earlier history of stroke or temporary ischemic attack, hypertension, diabetes, or heart failure. Other risk factors for stroke-known medical practitioners, as well as described below.

AVK, such as warfarin reduces risk of stroke by 64% compared to control, but increase the risk of bleeding (see, for example, article Hart R.G., Pearce L.A. and M.I. Aguilar, Meta-analysis: Antithrombotic therapy to prevent stroke in patients who have nonvalvular atrial fibrillation, Ann of Intern Med., t, cc. 857-867 (2007). Compared with placebo warfarin reduces mortality. Thus, warfarin is recommended for patients with atrial fibrillation and risk of stroke (see Fuster V., and others, ACC/AHA/ESC 2006 guidelines for the management of patients with atrial fibrillation - executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the European Society of Cardiology Committee for Practice Guidelines (Writing Committee to Revise the 2001 Guidelines for the Management of patients Patient with Arial Fibrillation), J. Am. Coll. Cardiol., t, cc.854-906 (2006).

Treatment using AVK, such as warfarin, is cumbersome due to the many interactions of diet and medicines, as well as in connection with the need to conduct frequent laboratory tests. Thus, AVK often not used; and in most cases patients interrupt treatment (see, for example, articles Birman-Deych E, Radford MJ, Nilasena DS, Gage BF, Use and Effectiveness of Warfarin in Medicare : with Atrial Fibrillation, Stroke, v.37, cc. 1070-1074 (2006), Hylek EM, Evas-Molina C, Shea C, Henault LE, Regan S., Major Hemorrhage and Tolerability of Warfarin in the First Year of Therapy Among Elderly Patients with Atrial Fibrillation, Circulation, t, cc. 2689-2696 (2007). In addition, many patients, even taking warfarin, observed anomalous anticoagulation (see Connolly S.J., Pogue j, Eikelboom j, Flaker G., Commerford p, M.G. Franzosi, Healey J.S., Yusuf, S., ACTIVE W Investigators, Benefit of oral anticoagulant over antiplatelet therapy in atrial fibrillation depends on the quality of international normalized ratio control achieved by centers and countries as measured by time in therapeutic range, Circulation, t, No. 20, cc. 2029-2037 (2008). Thus, despite the fact that warfarin reduces the risk of stroke in atrial fibrillation, it increases the risk of bleeding, its use is difficult. Thus, despite the fact that anticoagulation therapy with warfarin leads to a significant reduction in the risk of stroke, only half of patients who meet the criteria for participation in the trials that took place course of treatment because of various bureaucratic problems and limitations of the application of AVC. Therefore, there is a need for new effective, safe and more easy to use anticoagulants.

Saltimbanque in this context, patents, applications for the grant of a patent and the documents are fully included in the present invention as references.

A brief description of the present invention

The present invention provides methods of preventing or treating thrombosis in patient who, need a specific treatment, in conjunction with the prevention of unwanted bleeding. The methods include the introduction of an effective amount of etexilate of dabigatran, not necessarily in the form of its pharmaceutically acceptable salt to a patient who had not undergone surgery within 10 days, 42 days, 50 days, or 90 days. The above composition when introduced according to the methods of the present invention are effective in prevention or treatment of thrombosis. At the same time, the methods of the present invention provide the advantage compared to currently used methods, which is to prevent unwanted bleeding in patients.

In another embodiment, the present invention methods can be used for the prevention of stroke in patients suffering from atrial fibrillation. The methods include the administration to the patient an effective amount of etexilate of dabigatran, for example, doses of more than 150 mg 2 times a day up to 300 mg 2 times a day, not necessarily in the form of its pharmaceutically acceptable salts. The risk of unwanted bleeding in the specified patient is reduced primarily compared with warfarin treatment. Risk factors for stroke-known medical practitioners and also described in this context below.

How truly the image is the shadow include the introduction of pharmaceutical compositions, comprising a therapeutically effective amount of etexilate of dabigatran, not necessarily in the form of its pharmaceutically acceptable salts. In addition, the pharmaceutical compositions can include pharmaceutically acceptable carrier. Basically, the daily dose from 100 mg to 600 mg of etexilate of dabigatran, not necessarily in the form of its pharmaceutically acceptable salts, provides an optimal balance between the weakening of thromboembolism and low degree of bleeding. First of all, the introduction of etexilate of dabigatran at a dose of 100 to 200 mg 2 times a day provides the optimal balance between the weakening of thromboembolism and low degree of bleeding.

The authors unexpectedly, it was found that the optimal balance between the weakening of thromboembolism and low degree of bleeding in patients without additional risk factors for cases of massive bleeding is ensured by the introduction of etexilate of dabigatran in a dose of from 140 to 160 mg, preferably 150 mg, or from 210 to 230 mg, preferably 220 mg 2 times a day.

In more detail, the present invention relates to a method for preventing stroke in a patient suffering from atrial fibrillation, and the patient has no risk factors for cases of massive bleeding, and this method is the introduction to the patient from more than 150 mg to 300 mg of etexilate of dabigatran 2 times in su the key, not necessarily in the form of its pharmaceutically acceptable salts.

Another object of the present invention relates to the use of etexilate of dabigatran, not necessarily in the form of its pharmaceutically acceptable salts, for obtaining a medicinal product intended for the prevention of stroke in patients suffering from atrial fibrillation, and the patient has no risk factors for cases of massive bleeding, but such application is the introduction to the patient from more than 150 mg to 300 mg of etexilate of dabigatran 2 times a day, not necessarily in the form of its pharmaceutically acceptable salts.

Similarly, the present invention relates to a medicinal product intended for the prevention of stroke in patients suffering from atrial fibrillation, and the patient has no risk factors for cases of massive bleeding, when this drug consists of more than 150 mg to 300 mg of etexilate of dabigatran, not necessarily in the form of its pharmaceutically acceptable salts, and the specified drug primarily intended for the introduction of 2 times per day.

In yet another embodiment, the present invention proposes a method prophylactically treatment of thrombosis in a patient in need of specific treatment, as well as a way to reduce the risk of cases of masses who ate bleeding, hemorrhagic stroke, intracranial stroke or mortality cases compared with standard treatment with warfarin, while this method is the introduction to the patient from more than 150 mg to 300 mg of etexilate of dabigatran 2 times a day, not necessarily in the form of its pharmaceutically acceptable salts, and the patient had undergone surgery within 10 days, 42 days, 50 days, or 90 days. In addition, this method can be used for the patient, creatinine clearance, which is more than 30 ml/min on the Contrary, it is important to note that may interrupt the introduction of etexilate of dabigatran or its salts, if the creatinine clearance of the patient is 30 ml/min or less.

In one embodiment of the above method a case of massive hemorrhage is a bleeding life threat. In another embodiment, this method can be used for a patient with an increased risk of bleeding compared with the General population, or for a patient who has at least one risk factor in cases of massive bleeding, or has no risk factors for cases of bleeding. The above methods may also include examination of the patient for the presence of cases of bleeding, which includes: (a) the introduction of the patient from more than 150 mg to 300 mg of etexilate dub is Gatran 2 times a day, not necessarily in the form of its pharmaceutically acceptable salts, (b) the examination of the patient for the presence of bleeding and (C) the introduction of the patient 110 mg of etexilate of dabigatran 2 times a day, not necessarily in the form of its pharmaceutically acceptable salts, if during the examination of the patient revealed a case of bleeding. Stage surveys can only be conducted for at least 3 months, at least 6 months or at least 1 year.

The present invention relates also to a method for preventing stroke in a patient who has at least one risk factor for stroke, thrombosis or embolism, and to a method of reducing the risk of cases of massive bleeding or mortality compared with standard treatment with warfarin, while this method is the introduction to the patient from more than 150 mg to 300 mg of etexilate of dabigatran 2 times a day, not necessarily in the form of its pharmaceutically acceptable salts. Risk factors for stroke, thrombosis or embolism is chosen from the group including: (a) aged at least 75 years, (b) previous history of stroke, (b) previously transferred transient ischemic disorders of cerebral circulation, (d) transferred thromboembolic complication, (d) left ventricular dysfunction, (e) age at least 65 years of age and high blood pressure, (g) age at measures is 65 years of age and diabetes, (C) age at least 65 years of age and coronary heart disease and (to) age at least 65 years of age and the disease of the peripheral arteries. In one embodiment of the above method a case of massive hemorrhage is a bleeding life threat. In another embodiment of this method the patient is suffering from atrial fibrillation. These methods may also include examination of the patient for the presence of cases of bleeding, which includes: (a) the introduction of the patient from more than 150 mg to 300 mg of etexilate of dabigatran 2 times a day, not necessarily in the form of its pharmaceutically acceptable salts, (b) the examination of the patient for the presence of cases of bleeding and (C) the introduction of the patient more than 110 mg of etexilate of dabigatran 2 times a day, not necessarily in the form of its pharmaceutically acceptable salts, if during the examination the patient identified risk cases of massive bleeding. Stage surveys can only be conducted for at least 3 months, at least 6 months or at least 1 year.

In the present invention it is also proposed a method of preventing or treating thrombosis in a patient in need of specific treatment, while this method is the introduction to the patient from more than 150 mg to 300 mg of etexilate of dabigatran 2 times a day, not necessarily in the form of its pharmaceutically receiving the emnd salt, as the patient's condition does not meet the conditions required for the standard treatment warfarin, or if the patient is contraindicated for treatment with warfarin.

According to one any of the methods described above, etexilate of dabigatran, not necessarily in the form of its pharmaceutically acceptable salts, can be entered for at least 3 months, at least 6 months, at least 9 months, at least 12 months or for at least 48 months.

Another variant of implementation of the present invention relates to a method of reducing the risk of adverse effects in a patient who is in a state after treatment with warfarin, with the specified method includes: (a) terminating introduction of warfarin patient and (b) the introduction of the patient from more than 150 mg to 300 mg of etexilate of dabigatran 2 times a day, not necessarily in the form of its pharmaceutically acceptable salts. In one embodiment, the condition is stroke prevention in atrial fibrillation (PIMA). In another embodiment, an undesirable effect is bleeding.

The present invention relates also to a method for preventing stroke in a patient suffering from atrial fibrillation, with this method is the introduction to the patient from more than 150 mg to 300 mg of etexilate of dabigatran 2 times a day, not necessarily in the form of its pharmaceutically who priemlemoj salt, and change the doses if necessary, ensure the level of dabigatran in the plasma of the patient in the range from about 20 ng/ml to approximately 180 ng/ml, the patient is subjected to a reduced risk of cases of massive bleeding compared with standard treatment with warfarin. Levels of dabigatran in the plasma can be approximately 43 ng/ml to approximately 143 ng/ml, from about 50 ng/ml to approximately 120 ng/ml, from about 50 ng/ml to approximately 70 ng/ml, or from about 60 ng/ml to about 100 ng/ml, and levels of dabigatran in plasma can be determined by methods using standardized lyophilized of dabigatran. In another embodiment of this method a case of massive bleeding is a life threatening case of hemorrhage.

In the present invention it is also proposed a method of prophylaxis or treatment of thrombosis, as well as the way to prevent cases of massive bleeding, hemorrhagic stroke, intracranial stroke or mortality in a patient in need of specific treatment, while this method is the introduction to the patient from more than 150 mg to 300 mg of etexilate of dabigatran 2 times a day, not necessarily in the form of its pharmaceutically acceptable salts, and change the doses if necessary, ensure the level of dabigatran plasma is the range from about 20 ng/ml to approximately 180 ng/ml, the patient is exposed to a reduced risk of massive bleeding compared with standard treatment with warfarin, and the patient had undergone surgery within 10 days, 42 days, 50 days, or 90 days. Levels of dabigatran in the plasma can be approximately 43 ng/ml to approximately 143 ng/ml, from about 50 ng/ml to approximately 120 ng/ml, from about 50 ng/ml to approximately 70 ng/ml, or from about 60 ng/ml to about 100 ng/ml, and levels of dabigatran in plasma can be determined by methods using standardized lyophilized of dabigatran. In one embodiment of this method a case of massive bleeding is a life-threatening.

Another object of the present invention relates to the use of etexilate of dabigatran or its pharmaceutically acceptable salt for a medicinal product intended for the treatment of atrial fibrillation, with etexilate of dabigatran administered in a dose from 150 mg to 300 mg 2 times a day, not necessarily in the form of its pharmaceutically acceptable salts. According to this method, etexilate of dabigatran, not necessarily in the form of its pharmaceutically acceptable salts, can be entered for at least 3 months, at least 6 months, at least 9 months, at least 1 months at least 24 months, at least 48 months or 10 years.

In another embodiment, the present invention features pharmaceutical form, containing more than 150 mg to 300 mg of etexilate of dabigatran, not necessarily in the form of its pharmaceutically acceptable salts, for the treatment of atrial fibrillation. The present invention relates to a medicinal product for the treatment of atrial fibrillation, the bioequivalence of which is from 80 to 125% of the specified dosage forms in the treatment 2 times a day.

The present invention also includes a kit comprising: (a) a drug intended for the treatment of atrial fibrillation containing solid dosage forms containing more than 150 mg to 300 mg of etexilate of dabigatran, not necessarily in the form of its pharmaceutically acceptable salts, and (b) instructions for use one solid dosage forms 2 times a day.

In one embodiment, the present invention features a drug for the prevention of stroke in patients with atrial fibrillation and risk of stroke comprising a fixed dose of dabigatran equivalent dose of more than 150 mg to 300 mg of etexilate of dabigatran 2 times a day, the value of the primary parameter of cases of stroke or systemic embolism does not lower the efficiency zamaskirovannogo of correction the spent treatment with warfarin over the average period of the survey after stroke or systemic embolism in 2 years and not below the effectiveness of standard treatment warfarin.

In another embodiment, the present invention features a drug for the treatment of stroke in patients with atrial fibrillation and risk of stroke comprising a fixed dose of dabigatran equivalent dose of more than 150 mg to 300 mg of etexilate of dabigatran, 2 times a day, with reduced primary parameter massive bleeding compared with option zamaskirovannogo adjusted treatment with warfarin during the middle period of examination of the patient during 2,0 years.

In yet another embodiment, the present invention features a drug for the treatment of atrial fibrillation in patients with stroke risk, including fixed dose of dabigatran equivalent dose of more than 150 mg to 300 mg of etexilate of dabigatran 2 times a day, with reduced primary parameter mortality, compared with the parameter zamaskirovannogo adjusted treatment with warfarin over the average period of the survey during 2,0 years.

The present invention also includes the above medicines, including prodrug of dabigatran, bioequivalence of which is in the range from 80 to 125% in respect of etexilate of dabigatran dose from 150 mg to 300 mg 2 times a day, or a prodrug of dabigatran, bioequivalence of which is in the range from 80 to 125%, and the number of methanesulfonate of etexilate of dabigatran matches from more than 150 mg to 300 mg of etexilate of dabigatran in the treatment 2 times a day.

In the present invention are also methods mentioned above, according to which etexilate of dabigatran, not necessarily in the form of its pharmaceutically acceptable salt, is administered in combination with an antiplatelet agent, such as antiplatelet agent is aspirin, in quantities less than or equal to 100 mg per day. The preferred antiplatelet agent is aspirin, dipyridamole, clopidogrel, abciximab, eptifibatide, tirofiban, epoprostenol, streptokinase or plasminogen activator.

In the present invention are also methods mentioned above, according to which etexilate of dabigatran, not necessarily in the form of its pharmaceutically acceptable salt, is administered in combination with anti-arrhythmic agent, for example, anti-arrhythmic agent is a blocker of potassium channels blocker of sodium channels, β-blocker or calcium channel blocker. The preferred antiarrhythmic agents are quinidine, procainamide, disopyramide, lidocaine, meksiletin, tocainide, phenytoin, flecainide, enkainid, propafenone, moratsizin, propranolol, esmolol, metoprolol, timolol, atenolol, amiodaron, sotalol, dofetilide, ibutilide, verapamil, diltiazem, amiodarone, brutily, verapamil, adenosine or digoxin.

In another embodiment, the present invention also proposes the way PR is the prevention or treatment of thrombosis in a patient, in need of such treatment, as well as a way to reduce the risk of cases of death from cardiovascular disease compared with standard treatment with warfarin, while this method is the introduction to the patient from more than 150 mg to 300 mg of etexilate of dabigatran 2 times a day, not necessarily in the form of its pharmaceutically acceptable salts. Similarly, the present invention relates also to a method of preventing or treating thrombosis in a patient in need of specific treatment, as well as to a method of reducing the risk of cases of death from cardiovascular disease compared with standard treatment with warfarin, while this method is the introduction to the patient from more than 150 mg to 300 mg of etexilate of dabigatran 2 times a day, not necessarily in the form of its pharmaceutically acceptable salts. The present invention relates also to a method of preventing or treating thrombosis in a patient in need of such treatment, as well as to a method of reducing the risk of cases of death from all causes compared with standard treatment with warfarin, while this method is the introduction to the patient from more than 150 mg to 300 mg of etexilate of dabigatran 2 times a day, not necessarily in the form of its pharmaceutically acceptable salts.

All methods described in this context, can the be used for the treatment of thrombosis, and thromboembolism, systemic embolism, or systemic embolism, etc.

Brief description of drawings

Figure 1. Cases of thrombosis and massive bleeding in clinical trials PETRO and PETRO-Ex. Subject - age = sum (completion date of testing date of randomization +1) all randomized subjects/365,25.

Figure 2. The cumulative risk of stroke or systemic embolism with the introduction of dabigatran at doses of 110 mg and 150 mg 2 times daily and warfarin (W denotes warfarin, D110 denotes dabigatran at a dose of 110 mg 2 times a day, D150 denotes dabigatran at a dose of 150 mg 2 times a day) and

Figure 3. The influence of dabigatran on the primary option compared with warfarin in accordance with an important subgroups of patients.

Detailed description of embodiments of the present invention

Etexilate of dabigatran is a compound of formula (I)

and is a direct oral thrombin inhibitor, suitable for prevention of thromboembolism in patients undergoing total knee replacement or hip, and is also suitable for the prevention of stroke, especially in patients suffering from atrial fibrillation. There are also other indications, see, for example, published application US No. 2008/0015176, 2008/0039391 and 2008/0200514. The compound of formula (I) described in the application WO 98/37075 corresponding patents US is the No. 6087380, 6469039, 6414008 and 6710055, which describes compounds with inhibiting thrombin and prolonged thrombin time activity, N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)amides of 1-methyl-2-[N-[4-(N-n-getselectionrange)phenyl]aminomethyl]benzimidazole-5-icarbonell acid. Etexilate of dabigatran is a double prodrug of dabigatran, the compounds of formula (II)

i.e. etexilate of dabigatran becomes active compound, dabigatran only in the body. Etexilate of dabigatran is preferably introduced in the form of his methansulfonate, although the scope of the present invention also includes and other salts of pharmaceutically acceptable acids (see, for example, the application US No. 2006/0183779).

Dabigatran is a new direct oral thrombin inhibitor, characterized by advantages in comparison with warfarin and other AVK. Etexilate of dabigatran is an oral prodrug that is rapidly turning under the action of serum esterase in dabigatran, highly efficient direct competitive inhibitor of thrombin. The half-life in the serum is 12 to 17 h and thus is not required to conduct a periodic review of the patient's condition (see Stangier J, Clinical pharmacokinetics and pharmacodynamics of the oral direct thrombin inhibitor dabigatran etexilate, Clin. Pharmacokinet, t, cc. 285-295 (2008)). Dabigatran evaluated in premeability trials involving patients with atrial fibrillation, and also assessed the effectiveness of the prevention of venous thromboembolism after orthopedic surgery, with recommended dose of 150 mg 2 times per day. and 220 mg 1 time per day. (see article Ezekowitz M.D., and others, Dabigatran with or without concomitant aspirin compared with warfarin alone in patients with nonvalvular atrial fibrillation (PETRO study), Am. J. Cardiol., t, cc. 1419-1426 (2007), Eriksson B.I. and others, Dabigatran etexilate versus enoxaparin for prevention of venous thromboembolism after total hip replacement: a randomized, double-blind; non-inferiority trial*,"Lancet, t, cc. 949-956 (2007)). Tests PETRO described below. Clinical trials RELY described below, represent a large-scale randomized trial when comparing the introduction of dabigatran at a dose of 110 mg 2 times daily and warfarin at a dose of 150 mg 2 times per day.

As described above, treatment with warfarin is complex, and the impossibility of an adequate analysis of the patients ' state associated with risk. Warfarin is characterized by a narrow therapeutic window, slow start and completion of actions, and is also associated with unpredictable response to dose. He also interacts with the most common food, drugs and alcohol, which leads to a change of its therapeutic action, exposing patients to the risk of cases of bleeding or thrombosis. Thus, during warfarin treatment is necessary the exact individual dosages and more frequent and the Alize. Due to significant limitations on the battery there is a need for oral anticoagulant with a rapid onset of action, minimal interactions with medications and predictable anticoagulant effect, not requiring analysis. Direct oral thrombin inhibitor, etexilate of dabigatran meets the specified requirements. Start anticoagulation action is observed after 1 h after injection of dabigatran that is administered 1 or 2 times a day without analysis of the patient's condition.

Etexilate of dabigatran does not interact with food. Oral bioavailability is low, with an average of 6.5%. During metabolism, etexilate of dabigatran under the action of esterases tissues become active connection dabigatran. The maximum levels are observed within 2-3 hours after oral administration. The half-life in plasma is 12 to 17 h after administration of multiple doses. Dabigatran characterized by a low degree of interaction with other drugs, as this prodrug is not subject to metabolism, induces not and did not inhibit the enzyme cytochrome P-450 involved in the metabolism of drugs. Dabigatran in medium associated with plasma proteins (25-35%). The equilibrium state is reached after 2-3 days the to with the introduction of 2 times per day. Approximately 80% of dabigatran excreted by the kidneys in unchanged form. The remainder undergoes conjugation with glucuronic acid with the formation of acylglucuronide, which are excreted mainly in the bile.

Dabigatran directly and reversibly binds to the thrombin with its active site and prevents the cleavage of fibrinogen to fibrin, thus blocks the final stage of the coagulation cascade and formation of thrombus. Dabigatran, unlike heparin also inhibits thrombin associated with Tiberina or degradation products of fibrin. Dabigatran characterized by a dose-dependent prolongation of activated partial thromboplastin time (artt), clotting time acarina and clotting time, thrombin. Anticoagulant simultaneously affect plasma concentrations. As in the case of other direct thrombin inhibitors, the correlation between art and concentrations of dabigatran in the plasma is non-linear with substantial variability and smooth response at high concentrations in plasma. The clotting time acarina and clotting time, thrombin are characterized by a steeper linear correlations with concentrations of dabigatran and less variability.

Dabigatran recommended in Europe for the prevention of thromboembolism after surgery on the hip and the number is not. In these cases, etexilate of dabigatran enter for a limited period of time during which the patient is exposed to the risk of thromboembolism, then the introduction of a stop. These intervals treatment options are limited and generally range from 10 days up to a maximum of 42 days.

Due to the safety and efficacy of dabigatran it is suitable to prevent or eliminate unwanted cases of bleeding. In one embodiment, the present invention proposes a method of prophylaxis or treatment of thrombosis in patients in need of specific treatment, the patient had not undergone surgery, first of all operations on the hip and knee, for at least about 50 days, at least about 60 days, at least about 70 days or more. The method includes the introduction of etexilate of dabigatran or its pharmaceutically acceptable salt in a daily dose of 100 mg to 600 mg

In other embodiments, the methods can be used for prevention of thrombosis, embolism, or stroke in patients suffering from atrial fibrillation (AF). The method includes the introduction of a daily dose of an effective amount of etexilate of dabigatran, not necessarily in the form of its pharmaceutically acceptable salt to a patient, while the PAC is enta decreases the risk of unwanted bleeding, first of all, compared with the treatment of the patient with warfarin.

Before the publication of the results of clinical trials PETRO in the art have been described different ways of dosages and magnitude of doses required for the prevention of stroke in patients with AF. However, medical experience in treating a particular patient suffering from MA, it is not possible to choose the appropriate dosage. This decision is difficult when the doctor has to choose the appropriate method of treatment of a patient suffering from MA and which has at least one risk factor cases unwanted bleeding, as described below.

Therefore, an important object of the present invention is to develop a method for preventing stroke in a patient suffering from atrial fibrillation, while, in addition, the patient has at least one risk factor in cases of massive bleeding.

Patients with AF are characterized by the presence of additional risk factors for thrombosis, embolism and stroke. Risk factors for stroke, thrombosis or embolism include previously deferred stroke, previously transferred transient ischemic disorders of cerebral circulation, moved thromboembolic complication, dysfunction of the left ventricle, the age of graynamore 65 years of age and high blood pressure, age at least 65 years of age and presence of diabetes, age at least 65 years of age and coronary heart disease and age at least 65 years of age and the disease of the peripheral arteries.

However, the method according to the present invention mainly relates to the prevention of thrombosis, embolism or stroke, preferably of stroke in patients who have risk factors for cases of massive bleeding. One important risk factor in cases of massive bleeding is aged at least 75 years. Another risk factor in cases of massive bleeding is previous cases of bleeding, etc. furthermore, an additional risk factor in cases of massive bleeding is reduced creatinine clearance less than 80 ml/min, preferably less than 50 ml/min, most preferably less than 30 ml/min Other risk factors for cases of massive bleeding well-known physicians and are described below.

The method comprises the administration to the patient an effective amount of etexilate of dabigatran, not necessarily in the form of its pharmaceutically acceptable salts.

The treatment of these patients at risk cases of massive bleeding is primarily suitable, because the risk of massive bleeding in such patients is reduced compared with warfarin treatment.

MA is a chronic condition is receiving, currently no cure, but the intensity of the symptoms, which can be reduced. Patients with AF require treatment etexilate of dabigatran throughout life. Thus, there is a need for the definition of a range of doses, suitable for long-term treatment etexilate of dabigatran patients with AF. In addition, there is a need for the definition of a range of doses and treatment (posologie), which will allow to optimize the prevention of thrombosis and to minimize the risk factors, primarily cases of bleeding, especially in patients with established risk factor for cases of massive bleeding. In the treatment of MA suitability of the patient with risk factors such as stroke and bleeding, to treat determines an experienced therapist. In one embodiment, the physician determines the possibility of treating etexilate of dabigatran of a patient suffering from MA and characterized by the presence of additional risk factors.

Pharmaceutically effective amount or therapeutically effective amount for the methods and applications described in this context, including the prevention of thrombosis, embolism or stroke in a patient suffering from MA (characterized by the absence or presence of risk factors for cases of massive bleeding) and/or n is subjected to surgical intervention within a certain period of time, mostly within 10 days, 42 days, 50 days, or 90 days, is a daily dose of from 100 to 600 mg, including 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg, 230 mg, 240 mg, 250 mg, 260 mg, 270 mg, 280 mg, 290 mg, 300 mg, 310 mg, 320 mg, 330 mg, 340 mg, 350 mg, 375 mg, 390 mg, 400 mg, 425 mg, 450 mg, 475 mg, 500 mg, 525 mg, 550 mg, 575 mg, and 600 mg of etexilate of dabigatran, not necessarily in the form of its pharmaceutically acceptable salts. In preferred embodiments, etexilate of dabigatran, not necessarily in the form of its pharmaceutically acceptable salt, is administered at a daily dose of 75 mg 2 times a day up to 300 mg 2 times a day, including a daily dose of 100 mg 2 times a day, 110 mg 2 times a day, 115 mg 2 times a day, 120 mg 2 times a day, 125 mg 2 times a day, 130 mg 2 times a day, 135 mg 2 times daily, 140 mg 2 times a day, 145 mg 2 times a day, 150 mg 2 times a day, 155 mg 2 times a day, 160 mg 2 times a day, 170 mg 2 times a day, 180 mg 2 times a day, 190 mg 2 times a day, 200 mg 2 times per day, 210 mg 2 times a day, 220 mg 2 times per day, 230 mg 2 times a day, and in any specified dose of 75 mg 2 times a day up to 300 mg 2 times a day. In one preferred embodiment, etexilate of dabigatran, not necessarily in the form of its pharmaceutically acceptable salts is administered in a daily dose of 150 mg 2 times daily or 220 mg 2 times a day.

Another object of the present invention is the treatment etexilate of dabigatran that meets pointed to by the m above requirements and is suitable for treatment within 3 months and more. Due to the chronic nature of the disease, the duration of treatment increases even more. Another object of the present invention is to develop such a course of treatment that is suitable for patients of different age, sex, body weight and physical condition.

Dabigatran can be processed into pharmaceutical compositions, see, for example, published application US No. 2005/0038077, 2005/0095293, 2005/0107438, 2006/0183779 and 2008/0069873. In addition, dabigatran you can type in combination with other active ingredients, see, for example, published application US No. 2006/0222640, 2009/0048173 and 2009/0075949.

The definition of used terms and legend

Terms not specifically defined in the present context, have the meanings known to experts in the art from the point of view of the subject and the context of the present invention. However, used in the description and the accompanying claims, unless otherwise specified, the terms and symbols have the following meanings.

The terms "weak hemorrhage" and "the case of weak bleeding" refers to bleeding that does not meet the criteria for massive bleeding.

The terms "massive hemorrhage" and "a case of massive bleeding" refers to a decrease in the level of hemoglobin in the end is th least 2.0 g/l or transfusion of at least two units of blood, or symptomatic bleeding in a critical Department or authority.

The term "life threatening bleeding" or "a case of life threatening bleeding" refers to a subset of cases of massive bleeding, including fatal bleeding, symptomatic intracranial bleeding, bleeding leading to reduced hemoglobin greater than 5.0 g/or requiring transfusion of more than 4 units of blood or requiring inotropic agents or surgery.

The term "warfarin" means an anticoagulant that acts as an inhibitor of the vitamin-K dependent coagulation factors and which is available under the trade names Coumadin, Jantoven, Marevan and Waran. Warfarin is a racemic mixture of R - and S-enantiomers of 3-(α-acetonylbenzyl)-4-hydroxycoumarin. Warfarin is a synthetic derivative of coumarin, a natural compound in the majority of plants. Warfarin reduces the coagulation of blood by inhibiting epoxydodecane of vitamin K, an enzyme that converts oxidized vitamin K in its restored form.

The term "standard treatment warfarin" denotes the number of input patient warfarin according to the instructions of the ACC/AHA/ESC Practice Guidelines (Fuster and others, JACC, t, No. 4, SS. 854-906 (15 August 2006), see, for example, s, recommendation grade 1, paragraphs 3 and 4)included in this opisanie as a reference. In clinical trials RELY standard treatment in what Harinam used as the comparison drug.

The term "etexilate of dabigatran" refers to a compound of formula (I), including pharmaceutically acceptable salts. The value of a single dose of etexilate of dabigatran in the form of any salt in mg refers to the free base, i.e. the free base of formula (I). Dose prodrugs of etexilate of dabigatran determine based on the weight of free base.

The term "dabigatran" refers to a compound of formula (II) in free base form.

The term "MA" denotes atrial fibrillation of the heart.

The term "PIM" means the prevention of stroke in atrial fibrillation.

The term "nakupenda atrial fibrillation" refers to MA in the absence of rheumatic mitral stenosis valves or artificial heart valves.

The term "thrombosis" or "pulmonary" refers to an embolism or stroke. The term "thrombosis" refers to a blood clot (thrombus) inside a blood vessel, obstructing the flow of blood through the circulatory system. In the removal of a clot from the vessel wall is formed embolus. The term "thrombosis" refers to the formation in a blood vessel of a clot that breaks off from the wall of the vessel and transported by the blood stream with the possibility of blockage of the other vessel. The clot can block the vessel in the lungs (pulmonary emb the lia), the brain (stroke), gastrointestinal tract, kidney or leg.

The term "systemic embolism, not related to the Central nervous system" or "SE"indicates that the piece of blood clot, detached from the main bunch, often in the left division of the atrium, is carried by blood flow and blocks the plot circulation in contrast to the brain (the blocking of cerebral circulation develops stroke).

The term "hemorrhagic stroke" refers to bleeding in the brain.

The term "subarachnoid hemorrhage" or "subarachnoid hemorrhage" refers to hemorrhage in podavlennoe space of the brain, in the area between the arachnoid membrane and mild cerebral membrane surrounding the brain.

The term "subdural hemorrhage or subdural bleeding" refers to hemorrhage in the inner meningeal layer of the Dura mater, the outer protective covering of the brain that surrounds the brain.

The term "intracranial hemorrhage" or "HFR" stands for hemorrhagic stroke, including subdural hemorrhage and subarachnoid hemorrhage. Gemorragicheskii stroke is a bleeding inside the brain, and subdural hemorrhage and subarachnoid hemorrhage on the surface of the brain, but outside of it, and HFR includes all three of these different types of bleeding.

The term "between Narodnoe normalized ratio" or "MOT" means the ratio of prothrombin time (PT) of the patient to a normal (control) sample, raised to the power value of the international sensitivity index of the thromboplastin (ISI) ISI used analytical system: MTL=(ROstudiesPWstandards)ISI. Prothrombin time indicates the time required for the formation of a clot in plasma after addition of tissue factor (isolated from an animal's body). This value is a measure of the quality of the external path (and also the common way) coagulation. Speed external paths largely depends on the levels of factor VII in the body. Factor VII has a short half-life period and for its synthesis of needed vitamin K. Prothrombin time increases as a result of lack of vitamin K that may be associated with warfarin, impaired absorption or lack of colonization of bacteria in the gut (as in newborns). In addition, PV increases with insufficient synthesis of factor VII (liver disease) or increased consumption (disseminated intravascular coagulation). The high level of the MTL, such as MNS=5 indicates a high risk of bleeding, while the MNF=0,5 indicates a high risk of clot formation. A normal range for healthy people is 0.9-1.3 and for patients taking warfarin, is 2.0 to 3.0, although the required value of the MTL may exceed the criminal code of the related values in certain situations, such as artificial heart valve or combined treatment with warfarin and low-molecular heparin (enoxaparin) in the mode of intraoperative treatment.

The term "mortality from all causes" refers to death from any cause, including death from cardiovascular disease and death from other causes in contrast to vascular diseases.

The term "death from other causes in contrast to vascular disease" refers to death from cancer, trauma, respiratory disorders, infectious diseases, other causes not related to the vascular system.

The term "death from vascular disease" includes, but is not limited to, death from cardiovascular disease, death from stroke, pulmonary embolism, peripheral embolism, bleeding and the cause is unknown, classified as a disease.

The term "death from cardiovascular disease" includes one sub-group deaths from cardiovascular diseases and includes sudden death/death from arrhythmia (e.g., registered stop Sredets, registered of ventricular fibrillation/fibrillation, a history of myocardial infarction or other) or death as a result of insufficient pumping ability of the heart (for example, heart failure/acute behold the Dechen weakness, the cardiac tamponade, myocardial infarction, or other).

The term "risk factors for stroke, thrombosis or embolism" refers to the risk factors, statistically increases the risk of stroke, thrombosis or embolism. These factors include MA, formerly a history of stroke, previously transferred transient ischemic disorders of cerebral circulation, moved thromboembolic complication, left ventricular dysfunction, age at least 65 years of age and high blood pressure, age at least 65 years of age and presence of diabetes, age at least 65 years of age and coronary heart disease, and age at least 65 years of age and the disease of the peripheral arteries. Accordingly, the risk factors of stroke, thrombosis and embolism include age, heredity, gender, earlier history of stroke, previously transferred transient ischemic cerebrovascular disease, prior heart attack, high blood pressure, Smoking, diabetes, disease of the carotid or other artery, atrial fibrillation or other heart disease, sickle cell anemia, elevated blood cholesterol, intake of food high in saturated fats, hydrogenated fats, sodium and cholesterol, physical inactivity and obesity.

National Association for the study in the Ulta (USA) suggests, the patient is exposed to high risk of stroke", if it is present at least 3 of the following risk factors: blood pressure 140/90 or more, the cholesterol level of 240 or more, diabetes, Smoking, atrial fibrillation, overweight, lack of exercise, strokes among family members.

National Association for the study of stroke (USA) suggests that the patient is exposed to the "average risk of stroke", if it is 4-6 the following factors: blood pressure 120-139/80-89, cholesterol 200-239, marginal rates for diabetes, attempts to quit Smoking, lack of disturbance, palpitation, slightly overweight, the presence of rare physical exercise, the likely absence of stroke in family members.

National Association for the study of stroke (USA) suggests that the patient is exposed to low risk of stroke", if it is present at least 6-8 the following factors: blood pressure 120/80 or less, a cholesterol level of 200 or less, no diabetes, no Smoking, non-infringement heartbeat, normal body weight, regular exercise, no strokes in family members.

The term "risk factors for massive bleeding" refers to the various risk factors is, which statistically increases the patient's risk cases of massive bleeding. The risk factors for cases of massive bleeding well-known therapist in this field of medicine. For security purposes, therapist needs to identify the risk factors for cases of massive bleeding for each patient. For example, the risk factors for cases of massive bleeding can be grouped by demographic (age, gender, and stay in the facility for nursing care). For example, patient age 75 years and older is a risk factor in cases of massive bleeding. These risk factors include

alcohol/drug dependence, comorbidities (anemia, cancer, stroke, transient ischemic attack, myocardial infarction, hypertension, heart failure/cardiomyopathy, ischemic heart disease, diabetes, liver failure, or peptic ulcer disease) and associated risks of damage (risk of falls, disturbance of cognitive functions or surgical intervention during an admission). The risk factors for cases of massive bleeding are also present in patients with previous massive bleeding or with reduced creatinine clearance, for example less than 80 ml/min, less than 50 ml/min or less than 30 ml/min

The term "2 times daily" refers to the introduction day the th dose as 2 separate doses, separated in time by at least 4 hours, preferably for at least 6 hours and more preferably for at least 8 hours So the dose of 150 mg 2 times daily means daily dose of 300 mg, which is administered 2 times per day as a single dose 150 mg

The doses mentioned in this context, calculated on the amount of free base of etexilate of dabigatran (i.e. compounds of formula (I)). If etexilate of dabigatran injected in the form of one of its pharmaceutically acceptable salts, the amount of salt used should be calculated from the specified dose. For example, if etexilate of dabigatran injected in the form of methansulfonate, the dose of 110 mg corresponds 172,95 mg methansulfonate of etexilate of dabigatran.

The term "pharmaceutically acceptable salt" means a salt of the compound of the present invention, which in the opinion of a specialist in the field of medicine is suitable for contact with the tissues of humans and lower animals and does not cause unwanted toxicity, irritation, allergic response and the like, characterized by the corresponding ratio of benefit/risk, mainly is soluble or dispersible in water or oil, and is effective when used as directed. The term includes pharmaceutically acceptable acid additive salts and pharmaceutical is viable is basically additive salt. Since the compound of the present invention can be used in free base form and in salt form, in practice, in salt form means the application in free base form. A list of suitable salts described, for example, article S.M. Birge and others, J. Pharm. Sci., t, cc.1-19 (1977), which is fully incorporated into the present description by reference. The most preferred acid salt additive of the present invention is a salt methanesulfonic acid and etexilate of dabigatran, which in this context is also called the methanesulfonate of etexilate of dabigatran.

The term "prevention" refers to preventing the emergence or development and refers to a statistical reduction in the risk of events. The term "prevention" is synonymous with the term "risk reduction" or "the presence of a low morbidity. The terms "risk reduction" or "having a low incidence" refers to a statistical reduction or decrease in event frequency by at least 1% or more. Preferably the decrease is 7% or more, 10% or more, 20% or more, 26% or more, 34% or more, 50% or more, 64% or more and 74% or more. These include reducing the confidence interval more than 50%, more than 75%, 80%, 90%, 95%, 98% and 99%. The preferred one is camping confidence interval of 95%.

The methods of the present invention provide a safe and therapeutically effective amount of etexilate of dabigatran, not necessarily in the form of its pharmaceutically acceptable salts. The term "safe and therapeutically effective amount" refers to the number of etexilate of dabigatran, not necessarily in the form of its pharmaceutically acceptable salts, the introduction of which, according to the present invention does not cause serious complications, such as a case of massive bleeding that cannot be stopped medikamente ways, and the specified number provides a significant improvement of patients through the prevention or treatment of thrombosis. It is established that a therapeutically effective amount may vary from patient to patient depending on his age, weight, severity of symptoms, General health, physical condition, etc. Usually therapeutically effective amount of etexilate of dabigatran, not necessarily in the form of its pharmaceutically acceptable salts, is daily dose from about 100 mg to about 600 mg, more preferably a therapeutically effective amount of etexilate of dabigatran, not necessarily in the form of its pharmaceutically acceptable salt is orally 2 times per day from 75 mg to about 200 mg, and Naib is more preferably a therapeutically effective amount of etexilate of dabigatran, not necessarily in the form of its pharmaceutically acceptable salts, is an oral dose of 110 mg or 150 mg 2 times a day. Patients characterized by the presence of at least one risk factor for the case of massive bleeding, such as described and defined in this context, it is preferable to introduce a dose of 110 mg 2 times a day etexilate of dabigatran, perhaps in the form of pharmaceutically acceptable acid additive salts.

therapeutically effective amount can also be determined by the level of dabigatran in the blood plasma of the patient, not necessarily in the form of its pharmaceutically acceptable salts. Typically the level in plasma is approximately 20 ng/ml to about 180 ng/ml, from about 43 ng/ml to approximately 143 ng/ml, from about 50 ng/ml to about 120 ng/ml, from about 50 ng/ml to about 70 ng/ml, or from about 60 ng/ml to about 100 ng/ml.

Due to the dual nature of the prodrugs of the term "biosimilar therapeutically effective amount of etexilate of dabigatran" refers to any composition of etexilate of dabigatran in the form of a free base or its pharmaceutically acceptable salts or any derivative prodrugs of dabigatran formula (III), as specified in this context, in the form of a free base or its pharmaceutically acceptable the salts, which provides levels of dabigatran plasma comparable to that achieved with the introduction of etexilate of dabigatran as the comparison drug. Depending on national or regional regulatory bioequivalence is established when the compliance levels of the investigational medicinal product or composition in the plasma of a particular interval in percent. According to the instructions of the Department of supervision of food and drugs U.S. and European medicines Agency bioequivalence corresponds to the interval from 80 to 125% and approved at the instructions in the respective agencies.

Determination of levels of dabigatran plasma

Despite the fact that usually do not require clinical analysis of dabigatran, you can use a reliable laboratory method laboratory analysis of the pharmacodynamic effects of dabigatran for some methods of the present invention. This method of analysis to determine levels of dabigatran in plasma can be used to study not only the kinetics of activity of the drug in the body, but also to optimize the dose and POSOLOGY medicines that you can use to avoid overdose and analysis of the pharmacodynamic effects of etexilate of dabigatran.

Odie is the specified method comprises freeze-dried form of dabigatran, which can be used as a comparator drug in the determination of the pharmacodynamic effects of etexilate of dabigatran, primarily in the method for quantitative determination of dabigatran in blood samples. The method consists in determining the time of formation of blood clots that are initiated purified human thrombin. Thus, for measuring the concentration of dabigatran plasma aliquot portion of the sample of plasma was diluted with physiological saline solution, and then initiate coagulation by adding a constant amount of human thrombin high degree of purification in the α-form, and the measured coagulation time is directly proportional to changes depending on the concentration of dabigatran in the sample. In this application this method is called "method using standardized lyophilized of dabigatran".

To determine the concentration of dabigatran in the tested blood sample according to this method, you should obtain a calibration curve, i.e. the dependence of the coagulation time of the concentration of dabigatran in standard samples: upon receipt of the specified calibration curve using different standards of dabigatran or Comparators with a certain concentration. These standards of dabigatran are stabilin the mi, i.e. the number of dabigatran does not change during storage at -20°C or more and you can use them in the way to obtain a reliable calibration curve.

Etexilate of dabigatran able to crystallize and form a different polymorphic form is hygroscopic (i.e. formed of various hydrated forms) and poorly soluble in water. Thus, the freeze-dried form of dabigatran formula (II) used as calibration substances for dabigatran. To obtain a lyophilized form of dabigatran a certain number of medicines on the basis of dabigatran dissolved in an aqueous acid solution, diluted with water and the resulting solution was used as a concentrated solution to obtain different samples of a drug comparison of dabigatran. Appropriate aliquot parts of concentrated solution of dabigatran add in antikoagulyantnuu human plasma obtained from healthy volunteers (pooled human plasma) according to methods known in the art, thus obtain solutions with different concentrations of dabigatran. Certain amounts of these various solutions are transferred into suitable test tubes and lyophilizer to dryness in a special setup for lyophilization, you get a stable liofilizirovanny the e form of dabigatran with known concentrations, suitable for obtaining the calibration curve. Specified the dried dabigatran dissolves quickly and thus it can be used as the comparison drug to determine the concentration of dabigatran in blood samples with unknown concentrations at the time of coagulation, which is measured after adding equal amounts of thrombin person of high purity in the α-form in the sample with an unknown concentration. These standard samples lyophilizing of dabigatran and thrombin person of high purity in the α-form can be packaged in kits. The accuracy of analysis can be determined by periodic analysis of the sample using a known quantity of dabigatran.

the pH of the Aqueous solution of the acid used for dissolution of dabigatran, is preferably ≤3, more preferably ≤2. Although you can use many different acids, the preferred acids are hydrochloric acid, Hydrobromic acid, phosphoric acid, methanesulfonate acid, acetic acid, fumaric acid, citric acid, tartaric acid or maleic acid, preferably hydrochloric acid. Antikoagulyantnuu human plasma can be obtained according to any of the standard ways, and it preferably is is antikoagulyantna plasma man containing citrate, or antikoagulyantna human plasma containing EDTA.

An example analysis is given below. Chronometric analysis of coagulation was performed using two ball coagulometer Behnk CL4 (Behnk Elektronik, Germany) according to the instructions. Used analysis method Hemoclot Thrombin Inhibitor (HYPHEN BioMed, France). From the set used 2 of the following reagent: (1) lyophilized normal plasma containing citrate (reagent 1) and (2) freeze-dried thrombin person of high purity in the α-form with stabilizing additives (reagent 2).

The efficiency of coagulation analysis of plasma samples with dabigatran was evaluated by using Analyse-it for Excel, version 2.09, software Analyse-it software, Ltd. RO Box 103, Leeds LS27 7WZ England, UK.

Stage And

Getting drugs comparison of lyophilized dabigatran of 5.55 mg of Dabigatran formula (II) was dissolved in 200 ál of 1M Hcl and was diluted in ultrapure water to a final volume of 50 ml of the concentrated solution of dabigatran with a concentration of 111 mg/ml was stored at 4°C. To obtain drugs comparison of dabigatran used human plasma containing citrate and obtained from healthy volunteers (pooled human plasma). Aliquot parts of concentrated solution of dabigatran diluted plasma brow of the ESA, containing citrate, got solutions with different final concentrations dabigatran 100, 500, 1500 and 2000 nm. Aliquot part of human plasma with a volume of 500 μl with concentrations of dabigatran 100, 500, 1500, or 2000 nm was transferred into polypropylene tubes and liofilizirovanny on the vacuum unit with the centrifuge Christ Alpha RVC, Tour SMS-2 dry during priblisitelno 8 h (pressure of 8 mbar). Lyophilized samples of dabigatran kept at -20°C.

Stage B

Obtaining standards (calibration curve)

In each vial containing drugs comparison of dabigatran at concentrations of 0 (control), 100, 500, 1500 and 2000 nm, obtained at the stage And added to 0.5 ml of ultrapure water, gently mixed and kept at room temperature for 15 minutes comparator Drug in the plasma was diluted in the ratio 1:8, for example, 100 μl of standard and 700 μl of physiological NaCl solution. In the cell of coagulometer was added 50 μl of the sample of the comparison drug (definition of double repetition). The dimension of each drug comparison described in stage D.

Stage

Obtaining reagents

Expected required amount of reagents for the number of samples that must be analyzed within 1 day. Dissolve the contents of each vial with reagent 1 and reagent 2 in 1 ml of ultrapure water, gently mixed and well the Wali at room temperature for 15 minutes Below is the stability of the obtained reagents: reagent 1: from +18°C to 25°C (24 h), from +2°to +8°C (48 h) and -20°C (2 months) and reagent 2: from +18°C to 25°C (24 h), from +2°to +8°C (48 h) and -20°C (2 months).

Stage D

Collection and preparation of plasma samples

In the sample of blood was added 0,109 M anticoagulant, citrate, chinatravel salt of citric acid, the ratio of blood/citrate 9:1. After centrifugation for 20 min at 2.5 g supernatant plasma was separated by decantation. Below is the stability of the plasma: from +18°C to 25°C (8 h), from 2°C to 8°C (24 h), ≤-20°C (up to 6 months). Samples were thawed at 37°C for no more than 45 minutes Kept otchajannye samples at room temperature. The plasma samples must be diluted at a ratio of 1:8, for example, 100 μl of standard and 700 μl of physiological NaCl solution.

Stage D

The method of analysis

The following method of analysis was performed first using samples of Comparators, obtained in stage B. After obtaining the calibration curve appropriately analyzed the plasma samples obtained at the stage,

Samples (drug comparison or plasma) was carefully mixed with shaking. Bore 50 μl of each plasma sample (obtained in stage B or G) in 2 of the cell (each sample was measured in two repetitions). In the cuvette was added 100 μl of reagent 1 (predvaritelnogo is incubated at 37°C). At the same time included a timer for incubation for 1 min After completion of the incubation period the cell was added 100 μl of reagent 2 (pre-incubated at 37°C). Included a stopwatch and measure the time until the stop of rotation of the bowl coagulometer Behnk CL4 (the formation of blood clots with). Software instrument calculates the average time of blood clots (C) in a double loop. The results of both measurements and the average time of blood clots were printed on the printer.

Stage E

Obtaining a calibration curve

The coagulation times obtained by analyzing samples of Comparators at a concentration of 0 (control), 100, 500, 1500 and 2000 nm (you can use a wider range of concentrations and additional concentration, for example, 250 nm)was applied on the graph depending on the concentration of the standard dabigatran in the form of scatter plots of data using a spreadsheet program (MS Excel or similar programs). A calibration curve was obtained by the method of simple linear regression. In the determination of coagulation time of the corresponding concentration of dabigatran in the plasma sample can be determined directly using the calibration curve. You can use a quality control system using lyophilizer is the R samples of dabigatran at certain concentrations, for example, 100, 500 and 1500 nm. The use of quality control systems to measure the time of coagulation and subsequent determination of the appropriate concentration of dabigatran using the calibration curve allows us to estimate the accuracy of the analysis. The precision of the assay was evaluated by comparing the control sample with a known desired concentration of dabigatran and with the calculated concentration according to quality control using the coagulation time and the calibration curve.

The pharmaceutical compositions of the present invention, containing etexilate of dabigatran, not necessarily in the form of its pharmaceutically acceptable salts, are delivered into the body in a period of time sufficient to provide the desired physiological effect, i.e. prevention or treatment of thrombosis. Typically, the pharmaceutical composition is administered in the form of oral composition 2 times a day. Song you can enter a specific time or unlimited periods of time.

With the introduction of the method according to the present invention etexilate of dabigatran, not necessarily in the form of its pharmaceutically acceptable salts, provides to the patient a safe and therapeutically effective method of prevention or treatment of thrombosis. Etexilate of dabigatran, not necessarily in the form of its pharmaceutically acceptable salts, can in order to prevent the development of thrombosis and thus is not there are cases of unwanted bleeding.

Dabigatran can be processed into pharmaceutical compositions, for example, see published application US No. 2005/0038077, 2005/0095293, 2005/0107438, 2006/0183779 and 2008/0069873. In addition, dabigatran you can type in combination with other active ingredients, for example, see published application US No. 2006/0222640, 2009/0048173 and 2009/0075949. Standard pharmaceutically acceptable carrier or diluent can be used to provide storage conditions, introduction, and/or provide the desired effect of therapeutic ingredients. Suitable carrier must be stable, i.e. it should not interact with other ingredients in the composition. Such media are known in the art. Detailed description of the composition and selection of pharmaceutically acceptable carriers, stabilizers, etc. given in the book Remington''s Pharmaceutical Sciences (18thed., Mack Pub. Co.: Eaton, Pennsylvania, 1990), included in the present description by reference.

In addition, it was found that etexilate of dabigatran or its pharmaceutically acceptable salt can be entered together with the antiplatelet agent. Antiplatelet agents include cyclo-oxygenase inhibitors such as aspirin, an inhibitor of receptor for adenosine diphosphate (ADP), phosphodiesterase inhibitors, inhibitors of glycoprotein MF/IIIA inhibitors reuptake of adenosine, etc. In one embodiment, antitr miitary agent is aspirin, which is injected in a dose of 100 mg per day or less.

The following examples are provided for illustration and does not limit the nature and scope of the invention.

Experimental part

The test results PETRO and PETRO-ex

The efficacy and safety of etexilate of dabigatran for patients with atrial fibrillation has been evaluated in clinical trials phase 2 "Prevention of cases of embolism and thrombosis in patients with persistent atrial fibrillation" (PETRO). These tests represents a 12-week treatment etexilate of dabigatran, separately or in combination with aspirin (ASA) compared with standard anticoagulant therapy with warfarin in the absence of aspirin in patients with chronic atrial fibrillation. In this test 502 patients randomized in groups of treatment with warfarin (international normalized ratio (MTL) 2-3) or etexilate of dabigatran (50 mg 2 times a day, 150 mg 2 times a day and 300 mg 2 times a day) and three doses of aspirin (0, 81 mg or 325 mg 1 time per day). The primary outcome parameters were cases of bleeding and changes in D-dimer. During the tests was observed 2 cases of systemic embolism, both in the group of patients who entered etexilate of dabigatran dose of 50 mg 2 times a day. 4 cases (6%) massive bleeding registered arowana in the group of patients which introduced etexilate of dabigatran at a dose of 300 mg 2 times a day and aspirin ASA. Minor bleeding was dependent on the dose. Elevated transaminases (more than three times the upper limit of normal (VPN)) observed at 0.9 per cent (4 out of 432) of patients who entered etexilate of dabigatran. Changing levels of D-dimer in patients who have introduced etexilate of dabigatran, was comparable to the change in patients who were administered warfarin.

To determine long-term safety of etexilate of dabigatran to patients who are randomized to the treatment group by etexilate of dabigatran during testing PETRO and who completed the test without complications, were invited to take part in extended testing, testing PETRO-Ex, the results of which are presented below.

Ways

Clinical trials PETRO-Ex was performed in 52 centres in the USA, Denmark, the Netherlands and Sweden. The Protocol was developed in the coordination Committee. Data management and statistical analysis was performed on the company Boehringer Ingelheim. The statistical analysis plan was developed by the coordinating Committee. All authors agreed on the assessment results.

The main objective was to assess long-term safety and efficacy dabigatran in patients with atrial fibrillation, defined by the frequency of cases of massive bleeding, systems the second thromboembolic disease and impaired liver function.

PETRO-Ex is a long-term, extended randomized trial involving patients who were tested PETRO in the treatment dabigatran and completed tests according to the Protocol. Unlike tests PETRO, who conducted a double-blind regarding the dosage of etexilate of dabigatran, testing PETRO-Ex were open label. Tests PETRO-Ex began at a time when continued testing PETRO and researchers have not yet been acquainted with the course of treatment of patients prior to completion of the test PETRO. After that the results could be found.

The data summarized descriptive, hypothesis is not used. The cases were analyzed on the basis of treatment after onset of symptoms. The frequency of cases was registered in the number of patients who have manifested symptoms of cases, and normalized per 100 patient-years in the respective treatment group. Risk events were compared in different groups at risk with a confidence interval of 95% (two-factor analysis).

Patients included in the trial if they meet all the following criteria: age >18 years prior to the treatment dabigatran during testing PETRO without premature termination of treatment, paroxysmal, persistent or permanent (chronic) atrial fibrillation is travmaticheskoje origin, registered on electrocardiogram prior to inclusion in the trial PETRO, at least one additional risk factor for stroke: hypertension, diabetes, heart failure or left ventricular dysfunction, ischemic stroke in anamnesis or transient ischemic stroke, age over 75 years of age and coronary heart disease in history (i.e. of myocardial infarction, angina, positive stress test, surgery for coronary artery bypass grafting or atherosclerotic damage(I), diagnosed by the method of coreografia). Informed written consent was obtained from all patients.

Patients were excluded from testing if they have diagnosed heart disease, suggesting a significant increase in the risk thromboembolitic complications (e.g., clinically significant stenosis of the mitral valve or artificial heart valve), cardiostimulation planned for the period of patient participation in trials, contraindications to anticoagulation therapy (intracranial bleeding disorder, bleeding in the gastrointestinal tract during the previous 3 months, previous serious bleeding during warfarin treatment with a therapeutic international normalized ratio (MTL), regular use of nonsteroidal protivo sporitelny funds hemorrhagic diathesis), as well as other massive bleeding within the last 6 months (except for bleeding in the gastrointestinal tract) and severe renal failure with glomerular filtration rate<30 ml/min

Patients completing the trial PETRO, who has introduced a dose of 50 mg twice per day, included in the group with a dose of 150 mg per day during testing, PETRO-Ex (N=93 patients). All other patients were first injected the same dose of etexilate of dabigatran which they obtained during the tests PETRO. Patients, the dose of which was reduced to 50 mg per day on the basis of glomerular filtration rate<50 ml/min during the test PETRO, was excluded from long-term trials, the patients, the dose of which was lowered to another level, continued to enter the indicated dose once a day.

Results

Of the 432 patients who participated in trials PETRO, who has introduced dabigatran, 396 completed the trial according to the Protocol, of which 361 patients (91%) was included in the tests PETRO-Ex. Patients from group treatment with warfarin during testing PETRO excluded from trials PETRO-Ex. In early tests PETRO-Ex mean age of the patients was 69,7±8.2 years, 16.3% of patients were women, the mean duration of atrial fibrillation in patients was 4.2 years, patients attended an average of 2 risk factor of stroke. Aspirin in the course of the trials PETRO-Ex used on the basis of the opinion of the researcher.

Due to the high frequency of massive bleeding in the group of patients who were administered 300 mg of the drug twice a day (N=162), after a few months of extended testing with the introduction of aspirin or without Independent review Committee data and safety subjects tests (DSMB) recommended and the management Committee approved the transfer of all patients who were administered 300 mg of the drug twice a day, for treatment of 300 mg daily or 150 mg twice a day. Likewise because of the increased frequency of thromboembolic complications in the group of patients who were administered doses less than 300 mg/day (N=103), on the recommendation of the DSMB these patients are recommended to transfer to a course of treatment with increasing doses: 300 mg daily or 150 mg twice a day. The management Committee approved this recommendation. The majority of patients have introduced etexilate dabigatran at a dose of 150 mg twice a day (683,9 patient-years), and then 300 mg / day (198,7 patient-years), 300 mg twice a day (82,0 patient-years), 150 mg a day (58,5 patient-years) and 50 mg twice a day (23,5 patient-years). The net effect reflects both tests together, PETRO and PETRO-Ex.

Cases of embolism and stroke were significantly decreased in the group that was administered etexilate dabigatran at a dose of 150 mg twice a day (1% per year) and 300 mg twice a day (1.2% per year). During the Le is to be placed at a dose of ≤150 mg/day of etexilate of dabigatran annual frequency of thromboembolic complications is more than 5.0 per 100 patient-years.

The frequency of cases of massive bleeding was significantly increased in the group which introduced etexilate of dabigatran at a dose of 300 mg twice a day, compared with the group that was administered the drug at a dose of 150 mg twice daily and 300 mg once daily (12,2 compared to 4.2 and compared with 2.5% in the year). Three cases of massive bleeding was observed in the group that was administered a dose of 150 mg per day. Together with the data on the group which was administered 50 mg twice a day, the frequency of events of massive bleeding in the group that was administered the drug at doses of ≤150 mg/day, was 3.7% per year (figure 1). The frequency of bleeding events was significantly increased in the joint introduction of aspirin (8,5% compared to 3.2% per annum, the risk-2,70, confidence interval 1,49-4,86). Five cases of massive bleeding led to the death of the 4 cases at a dose of 150 mg twice a day and 1 case at a dose of 300 mg per day. Three of these fatal cases were intracranial bleeding, one case of bleeding in the gastrointestinal tract and one case of aortic dissection. Also reported one case of intracranial bleeding, not fatal.

Table 1.
Total test results PETRO and PETRO-Ex
Dose of etexilate of dabigatran50 mg once a day50 mg twice a day150 mg per day300 mg per day150 mg twice a day300 mg twice a dayThe total number of
The number of treated subjects110510390356162432
The total exposure (person-year)0,0523,5158,52198,68683,8882,011046,66
Massive bleeding003(5,1)5(2,5)29(4,2)10(12,2)44(4,2)
Of them without the introduction of aspirin00 3(6,5)3(2,1)18(3,2)4(6,3)26(3,2)
With the introduction of aspirin0002(3,6)11(8,7)6(32,7)19(8,5)
Stroke and systemic embolism03(12,8)3(5,1)5(2,5)7(1,0)1(1,2)20(1,9)
Transient ischemic disorders of cerebral circulation00001(0,1)01(0,1)
Myocardial infarction0001(0,5)6(0,9)07(0,7)
Other serious adverse reactions from the heart0 01(0,5)7(1,0)1(1,2)11(1,1)
Adverse events that led to premature termination of trials05(21,3)8(13,7)19(9,6)67(9,8)21(25,6)120(11,5)
ALT or AST > 3×RPC and Beal>2×RPC within 30 days0001(0,5)3 (0,4)04 (0,4)
ALT or>2 VPN002(3,4)3(1,5)21(3,1)4(4,9)30(2,9)
ALT or ACT>3×RPC0003(1,5)13(1,9)2(2,4)18(1,7)
ALT or ACT>5×RPC 0003(1,5)7(1,0)1(1,2)11(1,1)
ALT - alaninetransaminase, ACT - aspartatamino, Beale total bilirubin, CNS - Central nervous system, RPC - upper limit

The data presented in table 1, are illustrated in figure 1.

During the tests in 18 patients (1.7% per year) was observed elevated levels of hepatic transaminases, ACT or ALT>3 CENSUS, of whom 11 patients (1.1% per year) was observed in transaminases (ACT or ALT) >5×RPC. Four patients (0.4% in the year) was observed concomitant increase in bilirubin >2×RPC and transaminases >3×RPC within 30 days. All the described cases were observed for other clinical reasons.

All 9 of 18 cases of ALT or ACT>3×RPC after the survey was delivered explanatory clinical diagnosis. In 10 out of 16 cases, treatment of the liver were associated with the continued introduction of dabigatran, and in 5 cases of violations observed after stopping the introduction of dabigatran, one patient with impaired liver function during treatment died from heart failure and sepsis, which was associated with impaired liver function. The second patient with an unknown outcome was the replacement of the EN of the trials of dabigatran (due to bleeding) three weeks before the development of liver dysfunction (after treatment). Detailed descriptions of individual patients with impaired liver function and other hepatobiliary disorders shown in table 2.

Table 2.
Patients with impaired liver function
The abnormal liver functionCancel or continue the introduction of the investigational medicinal productThe end result/ comments
AgeFloorALT/RPCACT/RPCOther diagnoses
72W>3×>3×[single deterioration]InterruptRecovery
67M->5×#Adenocarcinoma of the pancreasCancelThe death is case capacity
78W>5×-[single deterioration]ContinuationRecovery
76M>5×#>5×#CholelithiasisInterruptRecovery
69M>5×>5×CholelithiasisInterruptRecovery
65M>3×-DiarrheaContinuationrecovery
78M->5×SepsisContinuation2 months after the deterioration of the liver function, the patient died from heart failure
62 M->3×[single deterioration]ContinuationRecovery

The abnormal liver functionOther diagnosesCancel or continue the introduction of the investigational medicinal productThe end result/ comments
AgeFloorALT /RPCACT /RPC
78M>3×-[single deterioration]ContinuationRecovery
64W>5×>3×[single deterioration]InterruptRecovery
81M>5× >3×[single deterioration][Cancel]Dabigatran was cancelled due to bleeding for 3 weeks prior to deterioration of liver function
74W>3×#>5×#Gall stonesContinuationRecovery
51M->3×CholelithiasisContinuationRecovery
73M>3×-HepatitisContinuationRecovery
73W>5×#>5×#CholelithiasisContinuationRecovery
68W>3×-[ed the border deterioration] InterruptRecovery
68M->5×[single deterioration]InterruptRecovery
63M->5×[single deterioration]ContinuationRecovery
# with a simultaneous increase of bilirubin level >2×VPN
ALT - alaninetransaminase, ACT - aspartatamino, bilirubin - total bilirubin, F - female, M - male, RPC - upper limit

Serious side effects registered in 184 patients (51%), including cases of bleeding and thrombosis. The most common reported side effects are cardiac abnormalities (80 patients, 22%), followed by infections (34 patients, 9,4%), nervous system disorders (33 patients, 9,1%) and disorders of the gastrointestinal tract (28 patients, 7,8%). Other adverse effects except bleeding and blood clots were observed.

Cases of massive bleeding

<> The incidence of bleeding was increased in proportion to the input dose. Cases of massive bleeding was most often observed in patients who were administered 150 mg or more etexilate of dabigatran twice a day, the highest frequency of bleeding was observed in patients who were administered 300 mg of etexilate of dabigatran twice a day. Dose 300 mg twice a day is unbearable. At a dose of 150 mg twice daily cases of massive bleeding slightly increased compared with the previous trials of anticoagulants in patients with atrial fibrillation (table 3). All five cases of bleeding with fatal outcome with the introduction of dabigatran (0.5% per year) registered with the introduction of 150 mg twice a day (4 patients) or with the introduction of 300 mg per day (1 patient). The incidence of intracranial bleeding 0.4% in the year is within the range from 0.1% to 0.6% compared with published values from other antitromboticeskih tests. There was also an increased risk of bleeding in the joint introduction of aspirin. In clinical trials RELY described in detail below, doses of aspirin above 100 mg per day is not allowed.

Table 3
Compared the e previous trials of patients with AF and testing PETRO-Ex
SPORTIF III (2003)12SPORTIF V (2005)13ACTIVE W (2006)15BAFTA (2007)20PETRO-Ex
Test drug
th means or influence
Warfarin compared with csillagos
ran
Warfarin compared with ximelagatran
but m
Clopidrogel + ASA aspirin compared
in warfare
Mr.
ASPI
Rin ASA 75 mg/day compared to the Wharf
enom
Etexilate of dabigatran 150 mg twice a day compared with the 300 mg twice a day compared with 300 mg once daily compared with 150 mg once daily
N, number of participants340739226706973361
Age (average)~70 years71,6 yearsto 70.2 yearsat 81.4 years69.7 years
Men69%69% 66%55%73%
The average period of examination of the patients1,45 year1,66 year1.3 years2.7 years2.5 years
Myocardial infarction1,1% (ximelagatran) 0,6% (warfarin)1,0% (csillagos
RAS) to 1.4% (warfarin)
0,6% (Wharf
Rin)
1,1% (warfarin)0,7% (etexilate of dabigatran all doses)
The liver >3×ULN (per 100 patients per year6% (ximelagatran) 1% (warfarin)6% (ximelagatran) 0,8% (warfarin)--1.7% (etexilate of dabigatran all doses)

SPORTIF III (2003)12SPORTIF V (2005)13ACTIVE W (2006)15BAFTA (2007)20PETRO-Ex
Test drug
th means or influence
Warfarin compared with ximelagatran
Mr.
Warfarin compared with ximelagatran
Mr.
Clopidrogel + ASA aspirin compared with warfarinThe ASA aspirin 75 mg/day compared with warfare
Mr.
Etexilate of dabigatran 150 mg twice a day compared with the 300 mg twice a day compared with 300 mg once daily compared with 150 mg once daily
Cases of massive bleeding (per 100 patients per year)1.3% (ximelagatran 36 mg twice daily) to 1.7% (warfarin)2,4% (ximelagatran 36 mg twice daily) to 3.1% (warfarin)2,2% (warfarin)1,9% (warfarin)3,2%* (etexilate of dabigatran, 150 mg twice daily)
Stroke and systemic embolism (per 100 patients per year)1,6% (ximelagatran 36 mg twice daily) to 2.3% (warfarin)1,6% (csillagos
RAS 36 mg twice a day) 1,2% (warfarin)
1,5% (warfarin)1,7% (warfarin)1,0% (etexilate of dabigatran 150 mg twice a day)
* cases of bleeding without the simultaneous introduction the aspirin
ACTIVE W: trials for the treatment MA clopidrogel together with irbesartan for prevention of vascular complications, BAFTA trials in Birmingham in the treatment of MA in elderly patients, PETRO Ex - extensive testing of the prevention of cases of embolism and trombley in patients with persistent AF, SPORTIF - trials of stroke prevention by oral administration of a thrombin inhibitor in patients with MA, RPC - upper limit

Effectiveness in the prevention of thromboembolism

Some evidence suggests that etexilate of dabigatran may show efficacy in stroke prevention. At the two highest doses, the incidence of stroke and systemic thromboembolism is approximately 1% per year, which is the best published result for patients with atrial fibrillation at risk of stroke from a moderate to a high degree. These data are similar or improved compared with the results obtained in the standard oral therapy with warfarin. At present, they are large-scale trials in the third phase using the specified dose. It is interesting to note that the frequency of strokes at a dose of 300 mg once a day higher than the dose of 150 mg twice a day, although these differences are not statistically significant.

Risk-Paul is and

Data of these long-term trials with open-label use of multiple doses of etexilate of dabigatran allow us to estimate the limits of both the efficiency and security. Doses of 150 mg per day or less lead to unacceptably high complication rates of thromboembolism with low frequency of bleeding, while a dose of 600 mg per day lead to unacceptably high frequency of bleeding, but low risk of stroke. The ratio of the risk-benefit in the case of a dose of 150 mg twice a day improved in comparison with the dose of 300 mg once daily with a lower frequency of strokes, but a higher risk of bleeding. In pharmacokinetic studies divided doses observed peak ratios in plasma concentrations of 2:1 compared to a ratio of 6:1 in case of equal total dose entered once per day, which is a possible explanation for the observed differences. At the dose of 150 mg twice a day there is a better balance frequency of thromboembolism and bleeding in patients who have no additional risk factors for massive bleeding.

From the data presented in table 1 and figure 1 shows that the introduction of etexilate of dabigatran twice a day is preferred. Due to the low oral bioavailability of etexilate of dabigatran with one hand and put the flax high clearance of dabigatran on the other hand, the scheme of injection twice a day provides a more constant level of concentration of dabigatran in plasma.

As shown by direct comparison of the courses of introduction of 300 mg once daily and 150 mg twice a day, the total number of thromboembolic complications is reduced with the introduction of twice a day with the introduction of the same daily dose. Thus, the introduction of twice a day is preferable to the introduction of once a day for a comparable daily doses.

The data presented in table 1 and figure 1, allow you to compare different doses of etexilate of dabigatran in relation to the incidence of thromboembolism and the risk of massive bleeding. The first option presents a number of complications of thromboembolism per 100 years, and the second parameter as the number of cases of bleeding in 100 years. "Year" or "person-year" represents the sum of the (date of the last injection of the medicinal product - the date of first injection drug +1) for all patients participating in trials/365,25.

When comparing data, it was found that with the introduction of etexilate of dabigatran dose of 50 mg twice a day there is more than 12 cases per 100 years, which is insufficient to achieve a satisfactory reduction of cases of thromboembolism.

In addition, the introduction of etexilate of dabigatran at a dose of 300 mg twice a day, although SN is measure the incidence of thromboembolism (approximately 1 case per 100 years), but there is a high incidence of bleeding (more than 12 per 100 years)that is less suitable for a given dose during long-term treatment.

On the other hand, a dose of 150 mg once a day and 300 mg once daily reduces protection against cases of thromboembolism (approximately 5 cases for dose of 150 mg once a day and more than 2 cases for doses of 300 mg once daily), and the number of cases of bleeding remains approximately at the same level compared with the dose of 150 mg twice a day.

In the case of the introduction of etexilate of dabigatran at a dose of 150 mg twice a day, on the one hand, provides better protection against cases of thromboembolism compared with the dose of 150 mg / day and 300 mg per day, and on the other hand, provides better protection from bleeding compared with the introduction of 300 mg twice a day while maintaining the same level of protection against thromboembolism that with the introduction of 300 mg twice a day. Thus, in patients who have no additional risk of massive bleeding, as described in this context, the above-described preferred dose of 140 mg twice daily 160 mg twice per day, preferably 150 mg twice a day, is suitable for the treatment of atrial fibrillation in humans within 3 months, preferably 6 months, more than before occhialino for 9 months, even more preferably within 12 months, most preferably for a period of 24 months, more preferably 48 months and more preferably for 10 years or more.

Due to the nature of the prodrugs, the introduction of the present invention can be used in the case of other esters of dabigatran or salts of the formula (III)

where R stands for any residue of ester with a molecular weight of up to 300, preferably of the formula-C(O)-O-(C1-C8)alkyl or-C(O)-O-(C3-C8)cycloalkyl, and alkyl optionally contain branched or unbranched chain, and the alkyl and cycloalkyl contain optional substituent R', denotes -(C1-C8)alkyl or -(C3-C8)cycloalkyl, where alkyl contains branched or unbranched chain, and the alkyl and cycloalkyl optionally substituted.

Any composition or modification of the compounds of formula (I) or (III) installed bioavailability of 80% to 125%, preferably from 80% to 120%, evaluated by the introduction of etexilate of dabigatran of the present invention may provide the same or comparable favorable properties. "Bioavailability" refers to the results of the analysis to assess the bioequivalence recommended by Management under the control over food and drug cf is the funds of the United States or the European medicines Agency, for assessing and referring to the class of generic products with reference to already registered (approved) the original product.

The present invention also includes a standard dosage form of etexilate of dabigatran ranging from 140 mg to 160 mg, preferably 150 mg, and from 210 to 230 mg, preferably 220 mg, for the treatment of atrial fibrillation (AF). In a preferred embodiment, a standard dosage form is a solid form such as tablet, capsule, granules, powder, etc. for Example, these compositions are described below in the section of the Composition. In the most preferred embodiment of the present invention, the solid form is a capsule containing etexilate of dabigatran deposited on the isolated pellets cores from tartaric acid. The most preferred variant of the present invention is described below in the section Composition.

More than 300 subjects completed tests PETRO and PETRO-Ex. These subjects were from different age groups and gender, and had a different body weight and health status. However, it was found that the results described above, equally apply to all entities.

The results of clinical trials RELY

Tests RELY (The Randomized Evaluation of Long-term Anticoagulation Therapy) was a long-term randomize is consistent anticoagulation tests, in the course of which were compared two doses of dabigatran with warfarin in patients with AF who have attended an increased risk of stroke. The plan test data was published in an article Ezekowitz MD, Connolly S.J., Parekh a, Reilly P.A., Varrone j, Wang s, Oldgren j, Themeles e, Wallentin L. and Yusuf, S., Rationale and design of the RE-LY: Randomized evaluation of long-term anticoagulant therapy, warfarin, compared to dabigatran, Am. Heart J., 157, cc.805-810 (2009), included in this description by reference.

In the tests for equal efficiency 18113 patients suffering from atrial fibrillation, the presence of the risk of stroke, randomized and blind were administered fixed doses of dabigatran 110 mg or 150 mg twice a day, were used for comparison group, in which the blind was administered to warfarin. The average duration of examination of the patients was 2.0 years, and as the primary parameter was estimated cases of stroke or systemic embolism. The frequency of the primary parameter was 1.70 percent per year, with the introduction of warfarin and compared to 1.55% per year, with the introduction of dabigatran 110 mg (relative risk of 0.91, 95 percent confidence interval in the range of 0.75 to 1.12, p [equal efficiency]<0.001) and 1,11% per year, with the introduction of dabigatran at a dose of 150 mg (relative risk of 0.66, 95 percent confidence interval in the range of 0.53-of 0.82, p [advantage]<0,001. The frequency of bleeding was of 3.46% per year, with the introduction of warfarin and compared to 2.74% in the year when BB is Denia of dabigatran at a dose of 110 mg (p=0.002) and 3.22% per year, with the introduction of dabigatran at a dose of 150 mg (p=0.32). The rate of hemorrhagic stroke was 0,38% per year, with the introduction of warfarin and compared to 0.12% in the year with the introduction of dabigatran at a dose of 110 mg (p<0,001) and 0.10% per year, with the introduction of dabigatran at a dose of 150 mg (0.14 to 0,49, p<0,001). The mortality rate was 4.13 percent per year, with the introduction of warfarin and compared with 3,74% per year, with the introduction of dabigatran at a dose of 110 mg (p<0,12) and 3.63 percent per year, with the introduction of dabigatran at a dose of 150 mg (p<0,047).

Thus, in patients with AF, with the introduction of dabigatran at a dose of 110 mg was observed a similar incidence of stroke and systemic embolism, as with the introduction of warfarin, but there was observed a decrease in the frequency of massive bleeding. The introduction of dabigatran at a dose of 150 mg is associated with a lower incidence of stroke and systemic embolism compared with the introduction of warfarin, but with a similar incidence of bleeding. Accordingly, dabigatran at a dose of 110 mg is characterized by a high safety profile compared with warfarin, and dabigatran at a dose of 150 mg is characterized by increased efficacy compared with warfarin.

Podroba description of the tests RELY

Ways

Patients included in trials of 951 clinical center in 44 countries. Mostly patients included in the trial if they were observed atrial fibrillation recorded on the electrocardiogram in oment examination or within 6 months and at least one of the following violations: a history of stroke or transient ischemic stroke, the ejection fraction of the left ventricle is less than 40%, the symptoms of heart failure class 2 or higher according to the classification of new York heart Association within 6 months, aged at least 75 years of age or aged at least 65 years old, presence of diabetes, hypertension or coronary heart disease. The reasons for the exclusion of the patient from tests include severe heart valve, stroke within 14 days or severe stroke within 6 months, the condition with an increased risk of bleeding, creatinine clearance less than 30 ml/min, liver disease in its active form or pregnancy.

After obtaining written informed consent of all participants randomized trials in groups which were administered one of two doses of dabigatran or warfarin, using a Central interactive automated telephone system. Dabigatran gave blind in unmarked capsules containing 110 mg or 150 mg medicines that were taken two times per day. Warfarin was issued in packs of tablets with an open label, containing 1 mg, 3 mg and 5 mg, and the dose was installed in accordance with local MTL from 2.0 to 3.0 and at least with animalism MTL per month. Time in therapeutic range was calculated by the method of Rosendale (Rosendaal F.R., and others, A method to determine the optimal intensity of oral anticoagulant therapy, Thromb. Haemost, 69, cc.236-239 (1993)), except MTL in the first week and after the termination of the test. The data passed in the centres, together with recommendations on the optimal control of the MNF. Permitted joint introduction of aspirin (less than 100 mg/day) or other antiplatelet agents. Quinidine is prohibited within 2 years after the start of the test because of the possibility of its interaction with dabigatran.

Patients were examined 14 days after randomization, after 1 and 3 months, every 3 months during the first year and then every 4 months until the completion of the test. Liver function was evaluated every month during the first year of the survey. In accordance with the pre-installed liver for 6000 patients who entered dabigatran, and examined for 6 months or more, the Committee on monitoring data recommended to reduce the frequency analysis of the liver to regular visits to the doctor.

As the primary parameters in the tests used cases of stroke and systemic embolism. The primary security setting was massive bleeding. As a secondary parameter used stroke, systemic embolism and death. Other p is the parameters included myocardial infarction, pulmonary embolism, transient ischemic stroke, and hospitalization. The set of primary parameters advantage of the benefits included a combination of stroke, systemic embolism, pulmonary embolism, myocardial infarction, fatal accidents or massive bleeding. Stroke was defined as a sudden case of focal neurological deficit affecting the main cerebral artery and classified as ischemic, hemorrhagic or uncertain case. Hemorrhagic transformation of ischemic stroke is not treated as hemorrhagic stroke. Intracranial bleeding includes hemorrhagic stroke and subdural or subarachnoid hemorrhage. Systemic embolism is an acute thrombosis of blood vessels in the limbs or body, which is confirmed by visualization, surgical technique or as the result of the autopsy. Massive bleeding was defined as a decrease in hemoglobin level of at least 2.0 g/l or transfusion of at least 2 units of blood, or symptomatic bleeding in a critical Department or authority. Life-threatening bleeding is a sequence of massive bleeding, including fatal bleeding, symptomatic intracranial bleeding, bleeding with a decrease in hemoglobin level of more than kemna 5.0 g/l or requiring transfusion of more than 4 units blood or requiring inotropic agents or urgent surgical intervention. All other types of bleeding was considered as insignificant.

All primary and secondary parameters were analyzed by double-blind method. International Council of experts reviewed the documents in the original language after anonymization of data or documents translated by a group of independent translators, documents disguise and considered all cases of transient ischemic disorders of cerebral circulation in order to evaluate the possibility of a stroke patient. To identify possible unregistered complications, patients are regularly distributed questionnaires to describe the symptoms and side effects and reports of hospitalization were evaluated in relation to unregistered primary and secondary symptoms.

Statistical analysis

The primary analysis was performed to estimate not lower the effectiveness of any dose of dabigatran in respect of warfarin using the Cox proportional hazards model. To study means corresponded to the condition of not lower the efficiency, the upper limit of the one-sided confidence interval of the relative risk of 97.5% (dabigatran/warfarin) should be less than 1,46. The specified limit is not less efficiency was determined the ene by the method of meta-analysis of trials using vitamin K antagonists in atrial fibrillation compared with control using the lower limit of the confidence interval of the relative risk 95% (warfarin/control). The limit value of 1.46 ensures that there is a 50% advantage of vitamin K antagonists compared with control with respect to the reduction of cases of stroke or systemic embolism. To assess both doses of dabigatran compared with warfarin was planning to check is whether the maximum of the two values of p less than 0.025 according to univariate analysis, in this case, both hypotheses were excluded. If univariate analysis, the maximum of the two values R exceed 0.025, at least two values of R is less of 0.0125, confirmed by statistical significance. All analyses were conducted using data on patients from the ITT population (including treatment). Planned to include in the test 15000 patients that estimates would provide 84% power analysis when evaluating no less the effectiveness of each dose of dabigatran. Two changes to the Protocol were carried out by the control Group during the inclusion of patients in trials without regard to the expected results of treatment. These changes included the requirement of a balanced number of patients who did not enter warfarin (introduction of warfarin during the period of less than 61 days), and patients who were administered warfarin for a long time, and increase the number of patients to 18,000 to increase the power of statistical analysis when comparing each dose of dabigatran comparedwith warfarin. An independent Committee on monitoring data were evaluated by open data and conducted two interim efficacy analysis with the aim to recommend the completion of the test, if the advantage of dabigatran exceeded 3 standard deviations, and repeated the analysis after 3 months.

Characteristics of patients and their examination

In trials participated 18113 patients, the test is performed on 22 December 2005 to 15 December 2007 Group patients were aligned at the baseline (table 4). The average age was 71 years, males accounted for 64%. Half of the patients had previously introduced warfarin. The average CHADS2 score (risk of stroke) accounted for 2.1.

The last visits of the patients for examination took place in the period from 15 December 2008 to 15 March 2009, the Average time of the survey was 2.0 years, and surveys completed by 99.9%, 20 patients did not visit a doctor. The percentage of interruptions test with the introduction of dabigatran at a dose of 110 mg, dabigatran at a dose of 150 mg and warfarin was 14%, 15% and 10% for one year and 23%, 25% and 19% for 2.5 years, respectively. Continuous introduction of aspirin in the tests conducted 23.5%, 21.6% and 23.1% of patients who entered dabigatran 110 mg, dabigatran at a dose of 150 mg and warfarin, respectively. The average time in therapeutic range for patients who were administered warfarin, was 64%

Table 4.
Characteristics baseline
Dabigatran 110 mg twice a day.Dabigatran 150 mg twice a day.Warfarin
The number of randomized patients601560766022
Average age (years) (CO)71,4 (8,6)71,5 (8,8)71,6 (8,6)
The average body weight (kg) (CO)82,9 (19,9)82,46 (19,4)at 82.70 (19,7)
The mean systolic pressure (mmHg) (CO)130, 8mm (17,5)131,0 (17,6)131,2 (17,4)
Average diastolic blood pressure (mmHg) (CO)77,0 (10,6)77,0 (10,6)77,1 (10,4)
Men (%)3865 (64,3)3840 (63,2)3809 (63,3)
Type atrial fibrillation
persistent (%)1950 (32,4)1909 (31,4)1930 (32,0)
paroxysmal (%)1929 (32,1)1978 (32,6)2036 (33,8)
permanent (%)2132 (35,4)2188 (36,0)2055 (34,1)
Assessment CHADS2** (AVG.) (CO)2,1 (1,1)2,2 (1,2)2,1 (1,1)
0-1 (%)1958 (32,6)1958 (32,2)1862 (30,9)
2 (%)2088 (34,7)2137 (35,2)2230 (37,0)
3-6 (%)1968 (32,7)1981 (32,6)1933 (32,1)
Stroke or transient ischemic cerebrovascular disease history (%)1195 (19,9) 1233 (20,3)1195 (19,8)
Myocardial infarction in anamnesis (%)1008 (16,8)1029 (16,9)968 (16,1)
Heart failure (%)1937 (32,2)1934 (31,8)1922 (31,9)
Diabetes mellitus (%)1409 (23,4)1402 (23,1)1410 (23,4)

Dabigatran 110 mg twice a day.Dabigatran 150 mg twice a day.Warfarin
Hypertension (%)4738 (78,8)4795 (78,9)4750 (78,9)
Drugs before testing
Aspirin2404 (40,0)2352 (38,7)2442 (40,6)
Receptor blockers or angiotensin inhibitor
angiotensinconverting enzyme I
3987 (66,3)4053 (66,7) 3939 (65,5)
Beta blocker3784 (62,9)3872 (63,7)3719 (61,8)
Amiodarone624 (10,4)665 (10,9)644 (10,7)
Statin2698 (44,9)2667 (43,9)2673 (44,4)
The inhibitor of proton pump812 (13,5)847 (13,9)832 (13,8)
Receptor antagonist N2225 (3,7)241 (4,0)256 (4,3)
Patients who did not enter warfarin*3011 (50,1)3049 (50,2)2929 (48,6)
* when testing the patient did not enter the antagonist of vitamin K within a period of less than 2 months.
** CHADS2 score represents an estimate of the total risk score: 1 point - congestive heart failure, hypertension, age > 75, diabetes mellitus and 2 points for stroke or transient ischemic cerebrovascular disease in history (16)
The way is - inhibitors of HMG-CoA reductase

Primary

Stroke or systemic embolism was observed in 182 patients who entered dabigatran at a dose of 110 mg (1,55% per year), 133 patients who were administered dabigatran at a dose of 150 mg (1,11% per year) and the 198 patients who were administered warfarin (1.70 percent per year) (table 5 and figure 2). Both doses of dabigatran are not less effective compared with warfarin (p<0,001). Dabigatran at a dose of 150 mg was more effective compared with warfarin (relative risk (RR) of 0.66, 95 percent confidence interval (CI) from 0.53 to 0.82, p<0,001), however, dabigatran at a dose of 110 mg characterized by a lower efficiency (RR 0.91, 95% CI 0.75 to 1.12, p=0.37). The rate of hemorrhagic stroke is 0,38% per year, with the introduction of warfarin compared to 0.12% in the year with the introduction of dabigatran at a dose of 110 mg (RR AT 0.31, 95% CI 0.17 to 0.56, p<0,001) and 0.10% per year, with the introduction of dabigatran at a dose of 150 mg (RR OF 0.26, 95% CI of 0.14 to 0,49, p<0,001).

Other parameters

The mortality rate in each case was 4.13 percent per year, with the introduction of warfarin compared with 3,74% per year, with the introduction of dabigatran at a dose of 110 mg (RR OF 0.90, 95% CI from 0.79 to 1.03, p=0,12) and 3.63 percent per year, with the introduction of dabigatran at a dose of 150 mg (RR TO 0.88, 95% CI from 0.77 to 1.00, p=0,047). The frequency of myocardial infarction was 0.54 percent per year with the introduction of arfarin and increased with the introduction of dabigatran, 0,73% per year at the dose of 110 mg (RR OF 1.35, 95% CI from 0.98 to to 1.87, p=0,069) and 0.74% in the year at the dose of 150 mg (RR OF 1.38, 95% CI 1.00 to 1.91 a, p=0,048).

Bleeding

The frequency of massive bleeding was of 3.46% per year, with the introduction of warfarin compared to 2.74% in the year with the introduction of dabigatran at a dose of 110 mg (RR OF 0.79, 95% CI from 0.68 and 0.92, p=0.002) and 3.22% per year, with the introduction of dabigatran at a dose of 150 mg (RR OF 0.93, 95% CI from 0.81 to 1.07, p=0.32) (table 6). Frequency representing life-threatening bleeding, intracranial bleeding and total bleeding increases with the introduction of warfarin compared with the introduction of dabigatran at any dose. With the introduction of dabigatran at a dose of 150 mg, the frequency of bleeding in the gastrointestinal tract is increased in comparison with the introduction of warfarin.

All values of R indicate a higher efficiency. Hemorrhagic stroke indicates the stroke in table 5 and a massive/a life threatening bleeding and part intracranial bleeding in table 6.

Parameter risk-benefit includes significant vascular disorders, massive bleeding and death. Frequency specified final option is to 7.99% per year, with the introduction of warfarin compared with 7,37% per year, with the introduction of dabigatran at a dose of 110 mg (RR OF 0.92, 95% CI from 0.84 to 1.01, p=0,097) and 7,22% per year with the introduction of dabigatran dose of 150 mg (RR of 0.90, 95% CI from 0.82 to 0.99, p=0.04).

Comparing doses of dabigatran

Compared with a dose of 110 mg dabigatran at a dose of 150 mg reduces the risk of stroke or systemic embolism (p=0.004). This difference is determined largely by the decrease in the number of strokes ischemic or uncertain etiology, and the frequency of hemorrhagic stroke is approximately equal in both groups. For two doses, there were no differences in the number of deaths from cardiovascular disease or overall mortality. On the other hand, compared with 110 mg, dabigatran at a dose of 150 mg increases the risk of massive bleeding (p=0.04) and also increases the number of cases of bleeding in the gastrointestinal tract, minor, and General bleeding. The clinical benefits of approximately equal for the two doses.

Side effects and analysis of liver function

With the introduction of dabigatran increased side effects such as dyspepsia (table 7). Increased levels of aspartate or alanine aminotransferase in serum more than 3 times compared with the upper limit of normal (VPN) with the introduction of any dose of dabigatran was observed no more than the introduction of warfarin.

Table 7
Interrupt test drugs, Autry is atelinae effects and the analysis of liver function
Dabigatran 110 mg (%) N=6015Dabigatran 150 mg (%) N=6076Warfarin (%) N=6022
Interrupt test Lek. tools
In the first yearXXXX (14)XXXX (15)XXXX (10)
For two yearsXXXX (23)XXXX (25)XXXX (19)
The reason for the interrupt test:
The patient's decisionXXX (7,3)XXX (7,8)XXX (6,2)
Cases complicationsXXX (3,2)XXX (2,7)XXX (2,2)
ESR**156 (2,6)158 (2,6)95 (1,6)
Violations in the digestive tract†XXX (2,7)XXX (2,8) XXX (0,8)
Bleeding in the digestive tractXXX (1,0)XXX (1,4)XXX (0,9)
Negative effects*
Dyspepsia**367 (6,1)345 (5,7)83 (1,4)
Dizziness457 (7,6)458 (7,6)555 (9,3)
Shortness of breath497 (8,3)525 (8,7)550 (9,2)
Peripheral edema446 (7,5)442 (7,3)453 (7,6)
Fatigue370 (6,2)367 (6,1)353 (5,9)

Dabigatran 110 mg (%) N=6015Dabigatran 150 mg (%) N=6076Warfarin (%) N=6022
Cough319 (5,3)310 (5,1)345 (5,8)
Breast pain is letke 288 (4,8)355 (5,9)342 (5,7)
Back pain295 (4,9)289 (4,8)331 (5,5)
Arthralgia249 (4,2)313 (5,2)328 (5,5)
Rhinopharyngitis314 (5,2)309 (5,1)327 (5,5)
Diarrhea355 (5,9)367 (6,1)327 (5,5)
Atrial fibrillation303 (5,1)313 (5,2)326 (5,4)
Urinary tract infections242 (4,0)253 (4,2)315 (5,3)
Infection of the upper respiratory tract266 (4,4)261 (4,3)297 (5,0)
Analysis of abnormal liver function
ALT or ACT>3×RPC121 (2,0)111 (1,8) 126 (2,1)
ALT or ACT>3×VPN with simultaneous increase of bilirubin level >2×RPC11 (0,2)14 (0,2)22 (0,4)
Hepatobiliary negative effects
Hepatobiliary disorders (MPD)¶25 (0,4)28 (0,5)25 (0,4)
Hepatobilary disorders (OE)£121 (2,0)123 (2,0)132 (2,2)
† Including pain, vomiting and diarrhea.
* Including negative effects that is registered at more than 5% of the total population.
Based on the reports testing
** Observed less often with the introduction of warfarin than the introduction of any dose of dabigatran (p<0,001).
ALT - alanine aminotransferase, ACT - aspartate aminotransferase, MA - negative effect, ESR is a serious negative effect, RPC - upper limit of normal.
¶ Clinical and/or biochemical liver dysfunction, requiring hospitalization.
£ Jaundice, nausea and vomiting, pain in abdomen, itching, drowsiness and fatigue.

Important subgroups

For many of the following subgroups of the E. there was a significant interaction with treatment dabigatran at any dose (figure 3). There was no significant interaction of treatment effectiveness by dabigatran with previous treatment with warfarin. Although 80% of dabigatran is excreted through the kidneys was not observed interaction with baseline calculated creatinine clearance.

Discussion of results

During the tests RELY two blind treatment with a fixed dose of dabigatran (110 mg twice daily and 150 mg twice daily) was compared with an optimized dose of warfarin in patients with atrial fibrillation and risk of stroke. Both doses of dabigatran are not less effective compared with warfarin in relation to the primary parameter of efficacy: stroke or systemic embolism. In addition, a higher dose is greater effectiveness in terms of stroke or systemic embolism, and a lower dose is characterized by a greater effectiveness against massive bleeding. Moreover, a higher dose of dabigatran characterized by a reduction in the number of total deaths and deaths result from cardiovascular disease compared with warfarin.

All previously conducted studies with the aim of developing a safe and effective alternative to warfarin treatment for patients with atrial fibrillation were characterized by various limitations. The combination of clopidrogel and ASPI is ina was characterized by greater efficiency compared with aspirin alone, see The ACTIVE Investigators, Effect of Clopidogrel Added to Aspirin in Patients with Atrial Fibrillation, N. Engl. J. Med. 360 (2009), but lower efficacy compared with warfarin, see ACTIVE Writing Group of the ACTIVE Investigators, Clopidogrel plus aspirin versus oral anticoagulation for atrial fibrillation in the Atrial Fibrillation Clopidogrel Trial with Irbesartan for Prevention of Vascular Events (ACTIVE W): a randomized controlled trial, Lancet, 367, cc.1903-1912 (2005). Subcutaneous administration of idraparinux was associated with greater efficacy compared with warfarin, but with a significantly higher risk of bleeding, see Amadeus Investigators and others, Comparison of idraparinux with vitamin K antagonists for prevention of thromboembolism in patients with atrial fibrillation: a randomized, open-label, non-inferiority trial, Lancet, 371(9609), cc.315-321, 26 January (2008). Ximelagatran, which is earlier direct thrombin inhibitor, has similar efficacy and safety compared with warfarin, but, as was found to be hepatotoxic, see Deiner NS, Executive Steering Committee Stroke Prevention Using the Oral Direct Thrombin Inhibitor Ximelagatran in Patients with Non-Valvular Atrial Fibrillation Pooled Analysis from the SPORTIF III and V Studies, Cerebrovasc. Dis., 21, cc.279-293 (2006). On the contrary, in the case of dabigatran, serial analysis of the liver showed no signs of hepatotoxicity.

The most serious complication of treatment with warfarin is intracranial bleeding, primarily hemorrhagic stroke. Compared with aspirin in the introduction of warfarin the risk of intracranial bleeding dual standby is carried out (Hart, R.G., see above). Thus, an important advantage of both doses of dabigatran is to reduce the frequency of these complications compared with warfarin more than 2/3 times without compromising effectiveness against ischemic stroke. The frequency of massive bleeding in the introduction of warfarin in these tests is increased in comparison with some previous tests (Deiner NS, see above, The ACTIVE Investigators, see above; ACTIVE Writing Group of the ACTIVE Investigators, see above). This was partly due to a broader definition of massive bleeding in these trials. With the introduction of higher doses of dabigatran increased frequency of bleeding in the gastrointestinal tract, despite the overall decline in the frequency of bleeding in other parts of the body. To increase the absorption of dabigatran require a lower pH value. Therefore, the capsule dabigatran contain covered dabigatran the pellets to the kernel of tartaric acid. With such acidity can be related increase in the incidence of symptoms of dyspepsia in the introduction of both doses of dabigatran and an increased risk of bleeding in the gastrointestinal tract at a dose of 150 mg.

The advantage of dabigatran can partly be explained by the dose twice a day, when the half-life of elimination from 12 to 17 h reduces the variability of anticoagulation really is, first of all, compared with warfarin, which is difficult to control. Warfarin inhibits coagulation in a wide range (inhibits factors II, VII, IX, X, proteins C and S). Selectively inhibiting only thrombin, dabigatran can provide antithrombotic efficiency while maintaining some other hemostatic mechanisms in coagulation system to reduce the potential for bleeding.

A limited test was the use of warfarin with an open label that could make doubt in reports or evaluation of events, as well as the relatively short time period of the survey. The decision not to mask the recommended dose of warfarin is associated with in order to provide the most realistic doses of warfarin, and that cancels the masking of warfarin often happened during the development of complications. Control anticoagulation with the introduction of warfarin compared with previous large-scale clinical trials (therapeutic range 64%), despite the fact that half of the patients warfarin has not previously been introduced, i.e. in this group satisfactory control is the least likely (Rosendaal F.R., and others, see above, The ACTIVE Investigators, see above).

The total evaluation of the results in relation to the overall benefits and risks comparable to two doses of dabigatran. However, this General characteristic is Bukovina fact, that a lower risk of coronary heart disease with the introduction of dabigatran at a dose of 150 mg is balanced by a lower risk of bleeding with the introduction of dabigatran at a dose of 110 mg These data suggest that the dose of dabigatran, in principle, can be optimized in accordance with the risk for each individual patient, although this concept was not specifically tested in the course of our ongoing trials. The results of clinical trials suggest that the introduction of etexilate of dabigatran at a dose of 150 mg twice a day, perhaps in the form of its pharmaceutically acceptable acid additive salts, especially preferred for patients who have no additional risk factors for massive bleeding, as described in this context.

Thus, the comparison of two doses of dabigatran with warfarin when administered to patients suffering from atrial fibrillation risk of stroke. Dabigatran at a dose of 110 mg has similar frequency of stroke and systemic embolism and lower frequency of massive bleeding compared with warfarin. Dabigatran at a dose of 150 mg is characterized by a lower incidence of stroke and systemic embolism and similar frequency of massive bleeding.

Contraindications, special warnings and precautions

There is a number of contraindications for treatment dabigatran, which include known hypersensitivity to dabigatran, etexilate of dabigatran or one of the excipients of the product, patients with severe renal insufficiency (creatinine clearance<30 ml/min), the manifestation of bleeding, active bleeding, patients with hemorrhagic diathesis or spontaneous or pharmacological hemostasis disorders, damage to the organs with the risk of clinically significant bleeding, including hemorrhagic stroke within the last 6 months, patients with persistent spinal or epidural catheter within the first hour after removal and simultaneous therapy with quinidine, verapamil and tpile other joint inhibitors of P-gp.

Disturbances of liver function: patients suffering from abnormal liver function moderate and severe (and With the child-Pugh score), or from liver disease, which is expected disturbance of vital functions, including, but not limited to, a sustained increase in the level of liver enzymes >2 upper limit of normal (VPN) or hepatitis a, b or C, or other disturbance of the vital functions, were excluded from the trials. Thus, the use of etexilate of dabigatran generally not recommended in this population.

The risk of bleeding: due to the pharmacological mode of action use of etexilate of dabigatran can in principle the e lead to an increased risk of bleeding complications. In addition, it is known that factors such as renal function or co-administration of strong inhibitors of P-gp increases the level of dabigatran in the plasma in different degrees. As was established in various clinical trials, raising the level of dabigatran in plasma does not always lead to increased risk of bleeding. In those cases, when it is known that these factors increase the risk of bleeding and exceed the clinical benefit shall be provided with appropriate recommendations. If different contingency factors can lead to unknown risk of bleeding, we recommend that you carefully examine the patient for signs and symptoms of bleeding complications.

The present invention preferably relates to a method of treatment of patients in whom there is no increased risk of bleeding complications. For these patients the recommended dose for prevention of stroke is 150 mg twice a day.

Detailed examination (identification of the symptoms of bleeding or anaemia) is usually required in the following situations, which may increase the risk of bleeding: (a) recent biopsy, major trauma or recent surgery on the brain, spinal or ophthalmic surgery, (b) treatment increase the risk of bleeding as the simultaneous treatment of etexilate of dabigatran and treatment affecting the and hemostasis or coagulation, may increase the risk of bleeding, (C) bacterial endocarditis, hereditary or acquired disease associated with bleeding, active stage of ulcerative disease and angiodysplastic disease of the gastrointestinal tract and hemorrhagic stroke (6 months).

Furthermore, increasing the risk of bleeding may occur due to specific pharmacokinetic or pharmacodynamic interaction with some of simultaneously introduced drugs and together with the introduction of etexilate of dabigatran not you should enter the following medicines: nefrackzionirovannam heparin and derivatives of heparin, low molecular weight heparins (NMG), fondaparinux, desirudin, thrombolytic agents, antagonists of receptor GPIIb/IIIa, dextran, sulfinpirazon, rivaroxaban, prasugrel and antagonists of vitamin K. it Should be noted that nefrackzionirovannam heparin can be entered in the dose necessary to maintain the patient with venous or arterial catheter. It is known that oral administration of strong inhibitors of P-gp, such as verapamil, quinidine or amiodarone, together with etexilate of dabigatran increases the concentration of dabigatran in the plasma, which can also increase the risk of bleeding.

Composition

Etexilate of dabigatran preferably processed in the form of methane is sulfonate (WO 03/074056). The following examples are presented to illustrate the standard dosage forms of the present invention and methods for their production, which are used in the clinical studies described in this context.

The method of obtaining pharmaceutical compositions used in the above clinical trials, includes a number of stages. First, got the engine 1 from pharmaceutically acceptable organic acid. In the present invention for obtaining core 1 used tartaric acid. From the obtained cores 1 then called isolated nuclei from tartaric acid 3, when sprayed insulating suspension 2. Suspension of dabigatran 4, received accordingly, sprayed on these cores with the coating 3 in one or more stages, using the method of coating. Finally, the thus obtained pellets active compound 5 was Packed in suitable capsules.

Determination of particle size of tartaric acid by the method of air-jet sieving

Device for measuring and parameters

Device for measuring: air-jet system screening, for example, Alpine AND 200 LS

Sieves with the desired cell size

Used weight: 10 g/sieve

Duration: 1 min/sieve, then 1 min for each sieve to the maximum mass loss of 0.1 g

Sample preparation/the floor is giving product

The substance was transferred into a mortar and all the lumps were destroyed by the intense rubbing. The sieve with a rubber gasket installed on the scales, the mass value was zeroed and on the sieve was weighed 10.0 g of powdery substances. Sieve together with the content of the rubber gasket and the cover was installed in the device. The timer was set to 1 min, and the material was processed in an air-jet sieve system during a specified period of time. Then the residue was weighed and the results recorded. The above procedure was repeated to reduce the mass of the residue after the air-jet sieving <0,1,

Example 1

Getting the original pellets

480 kg of Water were heated to 50°C. and with stirring was added 120 kg Arabian gum in the standard vessel for mixing with a convex bottom and a mixing rod. Stirring is continued at constant temperature until a clear solution is formed. After a clear solution is formed (usually 1-2 hours), with stirring, was added 600 kg of tartaric acid. Tartaric acid was added at a constant temperature with continuous stirring. After complete addition, the mixture was continued to stir for about 5-6 hours

1000 kg of Tartaric acid were loaded into a slowly rotating (3 rotations per minute) horizontal unperforated tray device for restylene and powder-coating (for example, Driamat 2000/2 .5). Before spraying selected sample acid for analysis in an air-jet system sifting. This acid is a particle of tartaric acid size in the range from 0.4 to 0.6 mm, Obtained as described above, the acid solution and the resin was sprayed on the particles of tartaric acid. During spraying, the air flow was 1000 m3/h and the temperature - 35-75°C. the Pressure was 2 mbar, the speed of rotation of the pallet 9 revolutions per minute. Nozzles should be placed at a distance of 350-450 mm from the content.

A solution of acid and gum sprayed alternately in the following stages. After spraying approximately 4.8 kg of a solution of acid and gum particles tartaric acid with a size of 0.4-0.6 mm and distribution solution, approximately 3.2 kg of powdered tartaric acid was applied to wet the particles of tartaric acid. Specified powdered tartaric acid consists of fine particles of tartaric acid size <50 μm. In total required 800 kg of powdered tartaric acid. After application and distribution of powdered tartaric acid, the material was dried to achieve a product temperature of approximately 40°C. and Then sprayed the acid solution and gums.

The described cycle is repeated until the complete consumption of the acid solution and gums. After the process is complete, the pellets sour what you was dried in a tray during rotation of 3 revolutions per minute for 240 minutes To prevent the formation of lumps after drying was enabled periodic rotation at a speed of 3 rpm for 3 min each 1 h, i.e. the pallet is rotated with a speed of 3 rpm for 3 min with an interval of 1 hour and then rotate off. Pellets acid is then transferred to a dryer and dried at 60°C for 48 hours Then determined the distribution of particle size sieve analysis. Particles with a diameter of 0.6-0.8 mm corresponded to the desired product. This fraction should be >85%.

Example 2

The allocation of the original pellets

To obtain an insulating suspension ethanol (666,1 kg) were loaded into the mixer and with stirring was added hypromellose (33,1 kg), the rotation speed of approximately 600 rpm, before the formation of the solution. Then in the same conditions was added 0.6 kg dimetikona. Before applying with stirring was added talc (33,1 kg) and received a suspension.

Pellets of acid and gum mass 1200 kg poured in apparatus for coating (e.g., GS-Coater, model 600/1200) and in the rotating pallet inflicted insulating suspension described above, in the continuous mode for several hours at a speed of 32 kg/h in the case of 1200 kg of a mixture or 21 kg/h in the case of 600 kg of the mixture. The pellets were dried in a continuous mode in air flow at 70°C.

After complete consumption the program content device GS-Coater isolated source pellets were fractionally during sifting. The product fraction with a particle diameter of <1.0 mm was kept and used in the next stage.

Example 3

Obtaining a suspension of etexilate of dabigatran

Hydroxypropylcellulose (26,5 kg) loaded in isopropanol (720 kg) in the tank for mixing a volume of 1200 liters, equipped with a propeller-type stirrer, and stirred until dissolved (approximately 12-60 hours, at approximately 500 rpm). After formation of a transparent solution under stirring (400 rpm) was added etexilate of dabigatran (132,3 kg) methansulfonate (polymorphic form I) and the mixture was stirred for another 20-30 minutes and Then under stirring was added talc (to 21.15 kg) and stirring continued at the same speed for about 10-15 minutes above the stage is preferably conducted in an atmosphere of nitrogen.

The formation of lumps prevented by homogenization using UltraTurrax stirrer within 60-200 minutes the Temperature of the suspension should not exceed 30°C during the whole process of obtaining.

The suspension was stirred until ready for further processing to eliminate sedimentation (at approximately 400 rpm).

If the suspension is kept at temperatures below 30°C, it can be used in the next stage within 48 hours If, for example, a suspension was obtained and stored at 22°C, it can be used on the next stage within no more than 60 hours If the suspension is kept, for example, at 35°C, it can be used in the next stage within 24 hours

Example 4

Obtaining pellets containing the active substance etexilate of dabigatran

Used horizontal tray non-perforated container (GS Coater, model 600). In contrast to the method in the fluidized bed, the suspension was sprayed onto a fluidized bed of pellets in a rotating pan method "spray top". The composition was sprayed through a nozzle with a diameter of 1.4 mm Dry air was passed through the layer of pellets through the so-called submerged blades and released through openings in the rear wall of the container.

In the horizontal pallet loaded pellets of tartaric acid (320 kg), obtained as described in example 2, and layer pellets were heated. After reaching a temperature of 43°C was started sputtering. Obtained as described in example 3 suspension (900 kg) was sprayed during the first 2 h at spray rates of 20 kg/h, and then at a speed of 24 kg/h and a pressure of 0.8 bar. The suspension was stirred continuously. The temperature of the air was at least 75°C. the Flow of air supplied was approximately 1900 m3/PM

Then the pellets were dried in a horizontal pallet (5 rpm), the temperature of the air flow was at least 30°C, not more than 50°C, the flow of air supplied status is wlel 500 m 3/h for about 1-2 hours

The obtained pellets (325 kg) is then loaded into a horizontal pan and was heated to 43°C. the Suspension obtained previously (900 kg), as described in example 3 was sprayed during the first 2 h with a speed of 20 kg/h, and then at 24 kg/h at a pressure of 0.8 bar. The suspension is continuously stirred. The temperature of the air was not more than 75°C. the Flow of air supplied was approximately 1900 m3/PM

Then the pellets were dried in a horizontal pallet (5 rpm) at a temperature of the air flow of at least 30°C. but not higher than 50°C, the flow of air supplied was 500 m3/h for about 1-2 hours

Dry pellets were then passed through a vibrating sieve with a mesh size of 1.6 mm and kept in containers with desiccant until further use.

Component[mg] per capsule
Methanesulfonate of etexilate of dabigatran172,95(1)
Arabian gum8,86
Tartaric acid177,14
Hydroxyethylmethylcellulose 29104,46
Dimethylpolysiloxane 3500,08
Talc34,41
Hydroxypropylcellulose34,59
Capsule GPMC90(3)
The total number of522,42
(1)equivalent to 150 mg free etexilate of dabigatran
(2)the mass of the capsule is approximately 90 mg

First of all, the preferred implementation of the present invention described above, in the General case described below. The present invention relates to a method for prevention of stroke in patients suffering from atrial fibrillation, and the patient has no risk factors for massive bleeding, and this method includes the introduction of patient etexilate of dabigatran dose of >150 mg twice daily 300 mg twice a day, preferably 220 mg twice a day, not necessarily in the form of its pharmaceutically acceptable salts. First of all, the method includes the introduction of etexilate of dabigatran dose of >150 mg twice daily 300 mg twice a day, preferably 220 mg twice a day, in the form of pharmaceutical compositions, described in the context of the above example.

the present invention also relates to the use of etexilate of dabigatran, not necessarily in the form of its pharmaceutically acceptable salts, for obtaining a medicinal product intended for the prevention of stroke in patients suffering from atrial fibrillation, and the patient has no risk factors for massive bleeding, and the specified application includes the introduction of etexilate of dabigatran dose of >150 mg twice daily 300 mg twice a day, preferably 220 mg twice a day, not necessarily in the form of its pharmaceutically acceptable salts. Above all, preferred applications include the introduction of etexilate of dabigatran dose of >150 mg twice daily 300 mg twice a day, preferably 220 mg twice a day, in the form of pharmaceutical compositions, described in this context as an example.

The present invention also relates to a medicinal product for the prevention of stroke in patients suffering from atrial fibrillation, and the patient has no risk factors for massive bleeding, and this drug consists of >150 mg to 300 mg of etexilate of dabigatran, preferably 220 mg of etexilate of dabigatran, not necessarily in the form of its pharmaceutically acceptable salts. First of all preferred drug is intended for administration twice a day. First of all preferred drug p is ecstasy etexilate of dabigatran in a dose of from > 150 mg to 300 mg of etexilate of dabigatran, preferably 220 mg of etexilate of dabigatran, which is injected twice a day in the form of a pharmaceutical composition, described in this context as an example.

1. The use of etexilate of dabigatran, not necessarily in the form of pharmaceutically acceptable salts, for the prevention of stroke in patients suffering from atrial fibrillation, and the introduction of etexilate of dabigatran dose of >150 mg to 300 mg twice a day, not necessarily in the form of a pharmaceutically acceptable salt, is the patient whose creatinine clearance is less than 80 ml/min and no additional risk factors for massive bleeding.

2. The use of etexilate of dabigatran, not necessarily in the form of pharmaceutically acceptable salts. according to claim 1, and a creatinine clearance of the patient is more than 50 ml/min

3. The use of etexilate of dabigatran, not necessarily in the form of pharmaceutically acceptable salts, for the prevention of stroke in patients with atrial fibrillation according to claim 1 or 2, and introduction, if necessary, adjusted to maintain the level of dabigatran in the plasma of the patient from approximately 20 ng/ml to about 180 ng/ml

4. The use of etexilate of dabigatran, not necessarily in the form of pharmaceutically acceptable salts, for the prevention of stroke in patients with atrial the arrhythmia according to items 1, 2 or 3, and the level of dabigatran in plasma is approximately 43 ng/ml to approximately 143 ng/ml.

5. The use of etexilate of dabigatran, not necessarily in the form of pharmaceutically acceptable salts, for the prevention of stroke in patients with atrial fibrillation according to one of claims 1 to 4, and the level of dabigatran in plasma is approximately 50 ng/ml to about 120 ng/ml

6. The use of etexilate of dabigatran, not necessarily in the form of pharmaceutically acceptable salts, for the prevention of stroke in patients with atrial fibrillation according to one of claims 1 to 5, and the level of dabigatran in plasma is approximately 50 ng/ml to about 70 ng/ml

7. The use of etexilate of dabigatran, not necessarily in the form of pharmaceutically acceptable salts, for the prevention of stroke in patients with atrial fibrillation according to one of claims 1 to 4, and the level of dabigatran in plasma is approximately 60 ng/ml to about 100 ng/ml



 

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FIELD: chemistry.

SUBSTANCE: invention relates to pharmaceutics and medicine and use of tricyclic imidazo[1,2-a]benzimidazole derivatives of general formula I or 1,3-disubstituted 2-aminobenzimidazolium halides of general formula II as an agent having cardioprotective action with high efficiency.

EFFECT: high efficiency.

3 cl, 1 tbl, 2 ex

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely to anaesthesiology, resuscitation and cardiology, and concerns a preventing anaesthetic management in the patients suffering complicated myocardial infarction by spinal-epidural analgesia. That is ensured by a primary reduction of the angious status by a single administration of narcotic analgesics into a subarachnoid space. To provide a further analgesic effect to manage a cardiac discomfort accompanied by objective criteria of hypertension of sympathetic vegetative nervous system (vegetation index (Kerdo index), heart rate, blood pressure, RPP variations), the narcotic analgesics are administered into the epidural space in a lumbar spine once or twice for three to seven days.

EFFECT: complex of anaesthetic manipulations provides the total anaesthesia at all the treatment stages in the patients with the complicated clinical course of myocardial infarction, prevented recurrences of the angious attacks and reduced risk of iatrogenic complications.

1 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compound with structural formula (I) or to its pharmaceutically acceptable salt, where R represents cyanogroup. Invention also relates to method of obtaining said compound and to pharmaceutical composition against platelet aggregation based on the compound.

EFFECT: obtained is novel compound and based on its pharmaceutical composition, which can be applied in medicine for production of medication for prevention or treatment of diseases of cardiac and cerebral vessels, such as coronary syndromes, myocardial infarction and myocardial ischemia, caused by aggregation of platelets.

13 cl, 3 tbl, 13 ex

FIELD: medicine.

SUBSTANCE: as a medication, providing the said stimulation, the application of streptozotocin is suggested in experiment on rats. The preparation is introduced single time intraperitoneally in a dose of 60 mg/kg two weeks after performing coronaroocclusion to the animals.

EFFECT: effective stimulation of endogenic mechanisms of development of capillaries in the cardiac muscle in postinfarction remodelling.

1 ex, 1 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: present group of inventions refers to medicine, namely to therapy and pharmacology, and can be used to increase pharmacological activity and therapeutic efficacy of drug preparations of activated-potentiated forms of hyperdiluted antibodies. That is ensured by administering a pharmaceutical composition containing activated potentiated pathogenic antigen and endothelial NO-synthase antibodies.

EFFECT: administering this composition provides higher therapeutic efficacy ensured by a synergetic effect of the ingredients of the composition.

10 cl, 18 ex

FIELD: medicine.

SUBSTANCE: invention represents a method of treating obliterating arterial sclerosis of the lower extremities combined with the ischemic heart disease involving administering drug preparations into a patient's body; the method is characterised by the fact that ozonised perftoran 200 ml is administered sequentially intravenously once a day, every second day, in a number of three infusions in a combination with oral administration of carvedilol 25 mg a day twice and rosuvastatin 10 mg once a day; if the patient shows high tolerability, a dose of carvedilol is increased to 50 mg, while a dose of rosuvastatin - to 20 mg a day for 12 days within the therapeutic course.

EFFECT: invention provides the recovery of central, peripheral and coronary blood circulation in the involved extremity tissues and the cardiac muscle over a short period of time by activating the enzyme NO-oxidase, reducing an ability of thrombocytes to aggregation and increasing a percentage of high-density lipoproteins, reducing a percentage of low-density lipoproteins and adjusting the systemic atherosclerotic process in arterial walls of greater and smaller diameters.

1 ex

FIELD: medicine.

SUBSTANCE: invention can be used to identify a high risk of developing impaired glucose tolerance in patients with stable effort angina with underlying administering beta-adrenergic blocking agents with no additional vasodilating properties. Therapy is preceded by conducting 2 exercise tests on the same day to achieve a threshold load power according to the same protocol, initially and 2 hours after administering a single dose of the beta-adrenergic blocking agents. If observing an interval gain of 120 seconds and more from the beginning of the load to the angina attack and/or reduction of an ischemic ST segment on the electrocardiogram not less than 1 mm at the 2nd load as compared to the 1st load, a risk of impaired glucose tolerance is considered to be high. A glucose tolerance test is carried out in these patients 4-5 weeks after the scheduled administration of the beta-adrenergic blocking agents. If impaired glucose tolerance is detected, administering the beta-adrenergic blocking agents is withdrawn. If the 2nd load as compared to the 1st load shows an interval to the angina attack and/or reduction of the ischemic ST segment on the electrocardiogram at a depth not less than 1 mm increasing less than by 120 seconds, a risk of developing impaired glucose tolerance is considered to be negligible. Treatment of these patients with the beta-adrenergic blocking agents is continued without the glucose tolerance test required.

EFFECT: method provides preventing carbohydrate metabolic disorders by the early identification of the high risk of developing impaired glucose tolerance in the given patients by detecting a compensatory increase of the glucose consumption with insulin resistance and a lower availability of free fatty acids to provide myocardial energy needs.

6 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to method of obtaining suspension of polymorphic form I of salt of methanesulfonic acid and dabigatran etexilate of formula I . Method is characterised by the following: polymorphic form I of dabigatran etexilate methanesulfonate with melt temperature tmelt 180±3°C is suspended in mixture with talc in solution of hydroxypropylcellulose in isopropyl alcohol at temperature in the range from 12 to 22°C with obtaining suspension by method of circulation dispersion at temperature not higher than 30°C. Invention also relates to obtained in said way suspension for obtaining dabigatran etexilate methanesulfonate pellets. Invention also relates to dabigatran etexilate methanesulfonate pellets used for thrombin inhibition, and to method of obtaining said pellets by dispersion of said suspension on isolated tartaric acid cores in fluidised bed.

EFFECT: claimed invention provides industrial method of obtaining pellets of dabigatran etexilate methanesulfonate, presents only in one polymorphic form.

27 cl, 5 ex

FIELD: medicine.

SUBSTANCE: thrombosis is prevented in the patients suffering cardiovascular diseases and chronic pain by prescribing the preparation tenoxicam 20 mg 1 tablet a day in the period of exacerbation of pain syndrome.

EFFECT: method enables reducing a risk of thrombotic complications and managing pain syndrome in the patients suffering cardiovascular diseases and chronic pain.

3 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compound with structural formula (I) or to its pharmaceutically acceptable salt, where R represents cyanogroup. Invention also relates to method of obtaining said compound and to pharmaceutical composition against platelet aggregation based on the compound.

EFFECT: obtained is novel compound and based on its pharmaceutical composition, which can be applied in medicine for production of medication for prevention or treatment of diseases of cardiac and cerebral vessels, such as coronary syndromes, myocardial infarction and myocardial ischemia, caused by aggregation of platelets.

13 cl, 3 tbl, 13 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds or their pharmaceutically acceptable salts, where compound has formula 1-a, in which R1 and R3 are absent, m represents integer number from 1 to 2, n represents integer number from 1 to 3, A represents , B represents or , where X2 represents O or S, R4a is absent, R4b is selected from the group, consisting of: , , , , and ; Rk is selected from C1-6alkyl and C1-6halogenalkyl, L and E are such as given in i.1 of the invention formula; or compound is such as given in b) of i.1 of the invention formula. Invention also relates to pharmaceutical composition, which contains said compounds.

EFFECT: compounds by i1, possessing inhibiting activity with respect to anti-apoptosis protein Bcl-XL.

27 cl, 6 dwg, 2 tbl, 126 ex

FIELD: medicine.

SUBSTANCE: claimed invention relates to biotechnology and represents a polypeptide construction for treatment, prevention and relief of disorders, associated with an adhesion of platelets and platelet-mediated aggregation or its dysfunction, which includes one or more single-domain antibodies, aimed against the von Willebrand factor (vWF), and one or more single-domain antibodies aimed against serum albumen (SA). The invention also relates to nucleic acid, coding such polypeptide construction, to compositions, containing the said construction, and to its application for obtaining medications for prevention, treatment and relief of the said disorders.

EFFECT: claimed invention makes it possible to extend an assortment of medications for treatment, prevention and relief of disorders, associated with the platelet adhesion and platelet-associated aggregation or its dysfunction.

15 cl, 30 dwg, 32 tbl, 69 ex

FIELD: chemistry.

SUBSTANCE: invention relates to the chemistry of sulphur-containing and terpene compounds and specifically to 2-({[(1S,2R,5S)-6,6-dimethylbicyclo[3.1.1]hept-2-yl]methyl}thionyl)ethanoic acid of structural formula I: . 2-({[(1S,2R,5S)-6,6-dimethylbicyclo[3.1.1]hept-2-yl]methyl}thionyl)ethanoic acid can also be used in medical practice as an agent for preventing haemophilia.

EFFECT: obtaining a novel compound which can be used in medicine as an agent having antiaggregant action, for preserving blood preparations and preventing thrombosis.

3 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to medicine, more specifically to a pharmaceutical composition possessing antithrombotic, thrombolytic, immunomodulatory, anti-inflammatory action, normalising lipid and carbohydrate metabolism, more specifically to the pharmaceutical composition of the substance Pijavitum (hereinafter referred to Pijavitum) made from lyophilised medicinal leech. The above pharmaceutical composition is presented in the form of an enteric coated tablet.

EFFECT: coating prevents the active ingredients of Pijavitum from destruction under action of the enzymes and acid medium of the stomach.

FIELD: medicine.

SUBSTANCE: claimed group of inventions relates to medicine, in particular to hematology, and can be applied for prevention of formation and/or stabilisation of pathological thrombi. Claimed is application of, at least, one antibody, which inhibits factor XII. Also claimed is pharmaceutical preparation, which contains, at least, one antibody inhibiting factor XII.

EFFECT: inventions make it possible to prevent growth of three-dimensional intra-luminal thrombus without manifestations of effect of hemostasis.

7 cl, 7 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to medicine, particularly to experimental pharmacology, and concerns methods for controlled platelet aggregation decrease in vitro. That is ensured by administering mexidol to plasma containing 200-220 thousand/mcl of platelets immediately after plasma sampling. Mexidol is used in the concentration of 0.1 to 0.8 mg/ml of an incubation mixture. The incubation is conducted for 10-15 minutes at room temperature.

EFFECT: method provides platelet aggregation to a desired value.

FIELD: chemistry.

SUBSTANCE: invention relates to biotechnology and can be used to produce biologically active collagen peptides from marine hydrobionts. Patiria pectinifera starfish is dehydrated with 96% ethyl alcohol and then demineralised with 1-2 N solution of an inorganic acid with ratio of the raw material to inorganic acid of 1:(3-5) for 1-3 days. The demineralised raw material is washed from traces of acid and water-soluble impurities with distilled water, after which the material is hydrolysed with an alkali solution with ratio of raw material to the alkali solution of 1:(3-5) in order to remove non-collagen proteins and washed with distilled water at temperature of 2-4°C. The obtained starfish collagen shells are homogenised. The homogenate is diluted with distilled water; pH of the suspension is brought to a value equal to 8.0-8.5 with an alkali solution and hydrolysed with 1% collagenase solution with ratio of homogenate to enzyme of (100-200):1 and temperature of 30-40°C for 3-5 hours, pH 8.5-7.0. The enzyme is inactivated at 80-90°C for 10-15 minutes. The hydrolysate solution is filtered to remove non-hydrolysed collagen, subjected to ultra-filtration through a 30 kD membrane filter to remove the inactivated enzyme; the end product, having antitumour, anticoagulant, wound-healing, anti-inflammatory, antioxidant activity, capacity to inhibit collagenase and angiotensin converting enzyme and which is a complex of collagen peptides with a high-molecular weight component weighing 22-23 kD, is concentrated in a vacuum and lyophilised.

EFFECT: obtaining a product, having antitumour, anticoagulant, wound-healing, anti-inflammatory and antioxidant activity.

2 cl, 7 tbl, 2 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to method of obtaining suspension of polymorphic form I of salt of methanesulfonic acid and dabigatran etexilate of formula I . Method is characterised by the following: polymorphic form I of dabigatran etexilate methanesulfonate with melt temperature tmelt 180±3°C is suspended in mixture with talc in solution of hydroxypropylcellulose in isopropyl alcohol at temperature in the range from 12 to 22°C with obtaining suspension by method of circulation dispersion at temperature not higher than 30°C. Invention also relates to obtained in said way suspension for obtaining dabigatran etexilate methanesulfonate pellets. Invention also relates to dabigatran etexilate methanesulfonate pellets used for thrombin inhibition, and to method of obtaining said pellets by dispersion of said suspension on isolated tartaric acid cores in fluidised bed.

EFFECT: claimed invention provides industrial method of obtaining pellets of dabigatran etexilate methanesulfonate, presents only in one polymorphic form.

27 cl, 5 ex

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