Pharmaceutical preparation containing low-molecular thrombin inhibitor and its pre-medicine

FIELD: pharmaceutics.

SUBSTANCE: the set of components is suggested containing: (a) pharmaceutical preparation including low-molecular thrombin inhibitor or its pharmaceutically acceptable derivative in the mixture with pharmaceutically acceptable adjuvant, solvent or carrier; and (b) pharmaceutical preparation including pre-medicine of low-molecular thrombin inhibitor or pharmaceutically acceptable derivative of this pre-medicine in the mixture with pharmaceutically acceptable adjuvant, solvent or carrier, where components (a) and (b), each of them, should be taken in the form suitable to be introduced together; it is, also, suggested to apply this set of components for treating the state at which it is necessary or preferably to inhibit thrombin. The innovation enables to treat thrombotic states such as thrombosis of deep veins and pulmonary embolism.

EFFECT: higher efficiency of application.

30 cl, 1 tbl

 

The scope of the invention

This invention relates to a new use of low molecular weight thrombin inhibitors.

Background of the invention the level of equipment

Blood clotting is a key process involved in hemostasis (i.e., the prevention of blood loss from a damaged vessel), and thrombosis (formation of blood clot in a blood vessel, sometimes leading to blockage of the vessel).

Coagulation is the result of a complex group of enzymatic reactions. One of the last stages in this group of reactions is the conversion of proferment of prothrombin to the active enzyme thrombin.

It is known that thrombin plays a Central role in coagulation. He activates the platelets, leading to platelet aggregation, converts fibrinogen into fibrin monomers, which spontaneously polymerize the polymers of fibrin, and activates factor XIII, which, in turn, knits these polymers with the formation of insoluble fibrin. Further, thrombin activates factor V and factor VIII, resulting in the formation of thrombin from prothrombin by the mechanism of “positive feedback”.

Thus, it is known and/or expected effective thrombin inhibitors are useful as anticoagulants, and therefore applicable in therapeutic treatment of thrombosis and related diseases.

p> Early development of a low molecular weight thrombin inhibitors described Claesson in Blood Coagul. Fibrinol. (1994) 5, 411. Later low-molecular weight thrombin inhibitors have been described in U.S. patent No. 4346078; international patent applications WO 93/11152, WO 93/18060, WO 93/05069, WO 94/20467, WO 94/29336, WO 95/35309, WO 95/23609, WO 96/03374, WO 96/06832, WO 96/06849, WO 96/25426, WO 96/32110, WO 97/01338, WO 02284, WO 97/15190, WO 97/30708, WO 97/40024, WO 97/46577, WO 98/06740, WO 97/49404, WO 97/11693, WO 97/24135, WO 97/47299, WO 98/01422, WO 98/57932, WO 99/29664, WO 98/06741, WO 99/37668, WO 99/37611, WO 98/37075, WO 99/00371, WO 99/28297, WO 99/29670, WO 99/40072, WO 99/54313, WO 96/31504, WO 00/01704 and WO 00/08014; and in applications to the European patent 648780, 468231, 559046, 641779, 185390, 526877, 542525, 195212, 362002, 364344, 530167, 293881, 686642, 669317, 601459 and 623596.

In particular, international patent application WO 94/29336 describes a group of compounds comprising HOOC-CH2-(R)Cgl-Aze-Pab-H (where Cgl is cyclohexylglycine, Aze is a 5-azetidin-2-carboxylic acid, and Pab-H is a 4-aminomethyl-amidines), which is also known as melagatran (see Example 1 in WO 94/29336). International patent application WO 97/23499 describes prodrugs, in particular, melagatran.

None of these documents describes or does not involve the introduction of active thrombin inhibitor in combination with a prodrug of this inhibitor of thrombin, or even in combination with the prodrug of any inhibitor of thrombin.

Deep vein thrombosis (DVT) and pulmonary embolism (PE) are the main clause is allemani health, which can lead to serious consequences. In particular, E may be fatal or may lead to the development of pulmonary hypertension and heart failure due to repeated embolism. DVT can lead to post-venous insufficiency and ulcers in the affected part of the body (such as the leg). Both these States are widely distributed, which significantly affects health care costs worldwide.

After orthopedic surgery is a significant incidence of DVT and EL. For example, in patients undergoing total hip replacement arthroplasty, the frequency of DVT in the absence of prophylaxis of thrombosis may be so high that reaches from 45 to 57%. Further, the frequency of proximal DVT can range from 23 to 36%, and the frequency of lethal ELECTRICITY from 0.34%to 6%. In patients undergoing total replacement of the knee joint, in the absence of prophylaxis of postoperative thrombosis the incidence of DVT ranges from 40 to 84%, proximal DVT from 9%to 20%, and lethal ELECTRICITY from 0.2 to 0.7%. In patients undergoing General surgery, in the absence of prophylaxis of postoperative thrombosis the incidence of DVT is approximately 25% (Reference: Chest (1998) 114, 531S - 560S).

Injected subcutaneously (P.K.) in low doses nefrackzionirovannam heparin is the most widely COI is leseman modern prophylactic treatment of venous thromboembolism, resulting from orthopedic and General surgery. It was shown that the incidence of DVT after total replacement of the hip joint is reduced (see the link on the Chest above).

It was shown that the use of low molecular weight heparin (NMG) in the prevention of DVT after surgery total replacement of the hip joint and the knee joint further reduces the incidence of disease (compared to nefrackzionirovannam heparin in low doses, without concomitant increase in bleeding (see link on the Chest above).

However, it was shown that long-term treatment with heparins increases the risk of osteoporosis. Heparin can also cause heparin-induced thrombocytopenia” (HDE), depend on the level of endogenous inhibitor of thrombin, anti-thrombin in the plasma and does not inactivate associated with clot thrombin.

It was also shown that oral anticoagulants, such as warfarin (an antagonist of vitamin K), is effective in reducing DVT after extensive surgery (see the link on the Chest above). However, due to the risk of bleeding and the need for frequent laboratory monitoring for patients with high risk and/or for long term use use of this substance is usually back. The vitamin K antagonists also find a significant risk of interaction is interaction with other drugs and certain foods, and their use requires monitoring of the coagulation status of the patient's blood.

It was shown that antiplatelet agents such as aspirin, have limited effectiveness in preventing DVT (see the link on the Chest above).

Comparative clinical trial conducted in the course of operations total replacement of the hip joint showed that subcutaneous administration of the thrombin inhibitor hirudin is far superior to nefrackzionirovannam heparin and MWF in reducing the frequency of total and proximal DVT without an accompanying increase in bleeding (see Eriksson et al, Lancet, 347, 635 (1996) and J. Bone Joint. Surg., Sep., 11 (1996)). However, hirudin is expensive and has immunogenic potential.

The closest analogue of the present invention is a pharmaceutical preparation containing melagatran and agent, enhances the absorption is intended for treatment of thromboembolism, as well as a method of treatment of a patient in need of protivodiabeticescoy treatment with this drug (WO 96/16671).

However, there is a need for effective treatment of thrombotic conditions such as DVT.

Description of the invention

The inventors have unexpectedly discovered that the introduction of low molecular weight thrombin inhibitor, in combination with the prodrug inhibitor of thrombin (or its prodrug) actuator is t to a significant anticoagulant effect.

According to the first aspect of the invention proposed a set of components:

(a) a pharmaceutical preparation comprising a low molecular weight thrombin inhibitor or its pharmaceutically acceptable derivative in a mixture with a pharmaceutically acceptable adjuvant, diluent or carrier; and

(b) a pharmaceutical product comprising a prodrug of low molecular weight thrombin inhibitor, or a pharmaceutically acceptable derivative of the prodrugs in a mixture with a pharmaceutically acceptable adjuvant, diluent or carrier,

where components (a) and (b), each taken in a form suitable for administration in combination with each other.

Preferably the prodrug component (b) is a prodrug of the active low-molecular weight thrombin inhibitor component (a).

According to another aspect of the invention, a method of manufacturing a set of components, as defined in this description of the invention, which combine the component (a)as defined above, with a component (b)as defined above, thus making these two components suitable for administration in combination with each other.

The term “combine with each other two components, the authors of the invention include the fact that the components (a) and (b) can be:

(I) taken as a separate preparations (i.e. n is dependent from one another), which are then combined for use in combination with each other in combination therapy; or

(II) packaged and presented together as separate components of “combination packaging” for use in combination with each other in combination therapy.

Thus, further proposed a set of components that contains:

(1) one of the components (a) and (b), as it is defined here, along with

(2) instructions for use of this component in combination with the second of these two components.

The feature sets described herein may contain more than one drug, including an appropriate quantity/dose thrombin inhibitor, and/or more than one drug, including an appropriate quantity/dose of the corresponding prodrugs, to ensure repeated dosing. If there is more than one drug (containing thrombin inhibitor or a prodrug), these drugs can be the same or different in regard to the dose of the inhibitor of thrombin/prodrugs, chemical composition and/or physical form.

According to another aspect of the invention, a method for treatment of the condition in which it is required or desirable inhibition of thrombin, wherein the patient suffering from such condition or subject to it, enter:

(a) pharmaceutical is such a drug, includes low molecular weight thrombin inhibitor or its pharmaceutically acceptable derivative in a mixture with a pharmaceutically acceptable adjuvant, diluent or carrier; in combination with

(b) a pharmaceutical preparation comprising a prodrug of low molecular weight thrombin inhibitor, or a pharmaceutically acceptable derivative of the prodrugs in a mixture with a pharmaceutically acceptable adjuvant, diluent or carrier.

To avoid confusion, the term “treatment”as used here, includes therapeutic and/or prophylactic treatment.

“Pharmaceutically acceptable derivatives” of thrombin inhibitors and prodrugs include salts (for example, pharmaceutically acceptable non-toxic salts of the accession of organic or inorganic acids) and the solvate. It should be understood that the term pharmaceutically acceptable derivatives of the active thrombin inhibitors include such derivatives, which have the same biological function and/or activity of this inhibitor of thrombin, but, for the purposes of the invention, does not include prodrugs of thrombin inhibitor.

The term “administered in combination with the authors of the invention include the fact that appropriate preparations containing thrombin inhibitor and/or a prodrug administered sequentially, what about separately and/or simultaneously, during the course of treatment of the relevant condition, which may be acute or chronic. Preferably this term includes the fact that these two drugs injected (possibly repeatedly) close enough in time that the patient had a favorable effect, which is great during the course of treatment of the relevant condition, than when any of these two drugs injected (possibly repeatedly) alone, in the absence of another drug, during the same course of treatment. Determining whether the combination of more favorable effect in relation to the particular condition and during the course of treatment will depend on the condition which must be treated or prevented, but can be successfully carried out by a specialist routine method.

Thus, the term “in combination with” includes that one or the other of the two drugs can be introduced (possibly repeatedly) before, after and/or at the same time as the introduction of another component. When used in this context, the terms “administered simultaneously” and “administered at the same time” include that individual dose thrombin inhibitor and prodrug is administered one after another period of up to 48 hours (e.g. 24 hours).

Components (a) and (b), as they are described in the application materials, can also be represented (that is, p is ugotovlena in the form of the drug) in the form of a combined preparation (i.e. presented as a single drug, includes low molecular weight thrombin inhibitor and prodrug).

Thus, next offered a pharmaceutical drug, which includes low molecular weight thrombin inhibitor or its pharmaceutically acceptable derivative) and the prodrug of low molecular weight thrombin inhibitor (or a pharmaceutically acceptable derivative of this prodrug) in a mixture with a pharmaceutically acceptable adjuvant, diluent or carrier.

The term “low molecular weight thrombin inhibitor” to be understood by experts in this field. It is understood that this term includes any composition (e.g., chemical compound, which inhibits thrombin to the experimentally determined level in the analysis of in vivo and/or in vitro and which has a molecular weight of less than 2000, preferably less than 1000.

Preferred low molecular weight thrombin inhibitors include low molecular weight thrombin inhibitors based on peptides based on amino acids and/or on the basis of peptides.

The specialist will be clear that the term “low molecular weight thrombin inhibitors based on peptides based on amino acids and/or on the basis of peptides” includes low molecular weight thrombin inhibitors, peptide bonded in the amount of from one to four and includes a low molecular weight is inhibitory thrombin, described in the review Claesson in Blood Coagul. Fibrin. (1994) 5, 411, and thrombin inhibitors described in U.S. patent No. 4346078, international patent applications WO 93/11152, WO 93/18060, WO 93/05069, WO 94/20467, WO 94/29336, WO 95/35309, WO 95/23609, WO 96/03374, WO 96/06832, WO 96/06849, WO 96/25426, WO 96/32110, WO 97/01338, WO 97/02284, WO 97/15190, WO 97/30708, WO 97/40024, WO 97/46577, WO 98/06740, WO 97/49404, WO 97/11693, WO 97/241135, WO 97/47299, WO 98/01422, WO 98/57932, WO 99/29664 WO 98/06741, WO 99/37668, WO 99/37611, WO 98/37075, WO 99/00371, WO 99/28297, WO 99/29670, WO 99/40072, WO 99/54313, WO 96/31504, WO 00/01704 and WO 00/08014 and applications to the European patent 648780, 468231, 559046, 641779, 185390, 526877, 542525, 195212, 362002, 364344, 530167, 293881, 686642, 669317, 601459 and 623596, descriptions of all of these documents are included here fully by reference.

Preferred low molecular weight thrombin inhibitors based on peptides include HOOC-CH2-(R)Cha-Pic-Nag-H (where h is cyclohexylamine, Pic is a (S)-pipecolinic acid, and Nag is eramaten known as inogatran, see international patent application WO 93/11152) and, especially, HOOC-CH2-(K)Cgl-Aze-Pab-H (known as melagatran, see above, and international patent application WO 94/29336).

The term “prodrug” low molecular weight thrombin inhibitor includes any compound which, after oral or parenteral administration is converted in the course of metabolism in vivo with the formation of low molecular weight thrombin inhibitor (as it is defined here) in experimentally op is Delaema quantity within a certain time (for example within the interval between meals medicines from 6 to 24 hours (i.e. from one to four times per day)) after oral or parenteral introduction. Prodrugs of thrombin inhibitor of melagatran that may be mentioned include those described in international patent application WO 97/23499. Preferred prodrugs are prodrugs of formula R1O2C-CH2-(R)Cgl-Aze-Pab-OH (see above list of abbreviations or WO 97/23499), where R1represents a C1-10alkyl or benzyl, as, for example, linear or branched C1-6alkyl (for example With1-4alkyl, especially methyl, propyl and, in particular, ethyl), and Oh group replaces one of the hydrogens amidino in b.

Specialists in this field will be clear that the term “state in which it is required or desirable inhibition of thrombin” includes the following :

Treatment and/or prophylaxis of thrombosis and hypercoagulability in blood and tissues of animals, including humans. It is known that hypercoagulation may lead to thromboembolic disease. Conditions associated with hypercoagulation and thromboembolic diseases that may be mentioned include hereditary or acquired resistance to activated protein C, as, for example, the mutation of factor V (factor V Leiden), and hereditary or acquired deficiencies of anti-thrombin III, protein C, protein S, heparin cofactor II. Other conditions about which we know that they are connected is a hypercoagulation and thromboembolic disease, include circulating antibodies to phospholipids (lupus anticoagulant), homocysteinemia caused by heparin thrombocytopenia and disorders of fibrinolysis.

Treatment of conditions in which there is an undesirable excess of thrombin without symptoms of hypercoagulation, for example in neurodegenerative diseases such as Alzheimer's disease.

Specific painful conditions that may be mentioned include therapeutic and/or prophylactic treatment of venous thrombosis (e.g. DVT) and pulmonary embolism, thrombosis of arteries (e.g. in myocardial infarction, unstable angina, caused by thrombosis, stroke and thrombosis of peripheral arteries and systemic embolism usually from the atrium during arterial fibrillation or from the left ventricle after transmural myocardial infarction, or caused by congestive heart failure; prevention of re-occlusion (thrombosis) after thrombolyse, percutaneous intraluminal angioplasty (NDA) and coronary artery bypass operations; the prevention of re-thrombosis after microsurgery and vascular surgery in General.

Additional indications include therapeutic and/or prophylactic treatment of disseminated intravascular coagulation caused by bacteria, m is divine injuries, intoxication or any other mechanism; anticoagulants treatment when blood is in contact with foreign surfaces in the body such as vascular grafts, vascular stents, vascular catheters, mechanical and biological artificial valves or any other medical device; and anticoagulants treatment when blood is in contact with medical devices outside the body, such as during cardiovascular surgery using cardiopulmonary bypass or dialysis; therapeutic and/or prophylactic treatment of respiratory distress syndrome in adults and idiopathic fibrosis of the lungs after treatment with radiation or chemotherapy, septic shock, septicemia, inflammatory reactions that include swelling, but limited to, acute or chronic atherosclerosis, such as coronary artery lesions, lesions of the cerebral arteries, lesions of peripheral artery disease, reperfusion injury and restenosis after percutaneous intraluminal angioplasty (NDA).

The preferred condition include thrombosis, especially DVT, including distal and proximal DVT. The present invention is particularly useful in the prophylaxis of DVT, which is the result of surgical operas the tion, such as gastrointestinal or orthopedic surgery (such as hip replacement or knee replacement). This includes DVT, resulting immobilized after surgery.

According to this invention thrombin inhibitors, prodrugs of thrombin inhibitors and derivatives of both, can be administered orally, intravenously, subcutaneously, transbukkalno, rectal, transdermal, nose, trachea, bronchi, topically, by any other parenteral route or via inhalation, in the form of a pharmaceutical preparation containing a thrombin inhibitor or prodrug in a pharmaceutically acceptable dosage form. Depending on the disorder and the patient should be treated, and the route of administration, the composition can be injected at various doses.

Preferred delivery methods are system. For melagatran and its derivatives are the preferred routes of administration are parenteral, preferably intravenous, and especially subcutaneous. For prodrugs of melagatran the preferred routes of administration are oral.

When therapeutic treatment of mammals, and especially humans, thrombin inhibitors, prodrugs of thrombin inhibitors and derivatives of those should usually be entered as supplied with the ski drugs in a mixture with a pharmaceutically acceptable adjuvant, diluent or carrier, which may be selected with due regard to the intended route of administration and conventional pharmaceutical practice.

Suitable drugs for use in the introduction of thrombin inhibitors known in the field and include drugs known from U.S. patent No. 4346078; international patent applications WO 93/11152, WO 93/18060, WO 93/05069, WO 94/20467, WO 94/29336, WO 95/35309, WO 95/23609, WO 96/03374, WO 96/06832, WO 96/06849, WO 96/25426, WO 96/32110, WO 97/01338, WO 97/02284, WO 97/15190, WO 97/30708, WO 97/40024, WO 97/46577, WO 98/06740, WO 97/49404, WO 97/11693, WO 97/24135, WO 97/47299, WO 98/01422 WO 98/57932, WO 99/29664, WO 98/06741, WO 99/37668, WO 99/37611, WO 98/37075, WO 99/00371, WO 99/28297, WO 99/29670, WO 99/40072, WO 99/54313, WO 96/31504, WO 00/01704 and WO 00/08014; and applications to the European patent 648780, 468231, 559046, 641779, 185390, 526877, 542525, 195212, 362002, 364344, 530167, 293881, 686642, 669317, 601459 and 623596, the description of all documents included in this description by this reference.

Suitable for using drugs with melagatran, its derivatives and prodrugs are described in the literature, for example as described, inter alia, in the international patent applications WO 94/29336, WO 96/14084, WO 96/16671, WO 97/23499, WO 97/39770, WO 97/45138, WO 98/16252, WO 99/27912 and WO 99/27913, the description of these documents is incorporated here by this reference. In other words, the preparation of suitable preparations can be carried out by a specialist standard way to use is by routine methods.

The amount of thrombin inhibitor, prodrug or derivative of any of them in the product will depend on the severity of the condition and the patient should be treated, but also from the connection(s)that apply, but they can be in the standard manner defined by the expert.

Suitable doses of thrombin inhibitors, prodrugs and derivatives of both therapeutic and/or prophylactic treatment of patients with mammals, especially humans, can be a routine manner determined by the physician or other specialist and include the appropriate dose, discussed in the documents relating to the prior art that disclose the above-mentioned inhibitors of thrombin, the description of which is included here by reference.

In the case of melagatran suitable dose of the active compounds, prodrugs and their derivatives with therapeutic and/or prophylactic treatment of patients with mammals, especially humans, include dose, which give the average concentration in the blood plasma of up to 5 mmol/l, for example in the range from 0.001 to 5 mmol/l, during the course of treatment of the relevant condition. Suitable doses may thus be in the range from 0.1 mg once daily to 25 mg three times per day and/or up to 100 mg, parenteral introduced by infusion over a 24-hour period, for melagatran, and in the interval the e from 0.1 mg once daily 100 mg three times a day for prodrugs of melagatran, including prodrugs specifically mentioned above.

In any case, the doctor or specialist will be able to determine the actual dosage which will be most appropriate for the individual patient, and which is likely to vary depending on the state, which should be treated, and the age, weight, sex, and the susceptibility of a particular patient to be treated. The above dosages are examples of average case; you can, of course, be some cases when using higher or lower ranges of dosages, and they are included in the scope of this invention.

The sequence in which can be entered preparations containing thrombin inhibitor and prodrug (i.e. whether, and at what point in time, sequential, separate and/or simultaneous introduction) can be determined by a doctor or specialist. For example, this sequence may depend on many factors, which will be clear to the specialist, as, for example, that one or other of the drugs cannot be administered to the patient at any time during the course or period of treatment, for practical reasons (for example, a patient is unconscious and thus unable to take oral medication containing either thrombin inhibitor, or a prodrug).

For example, in the treatment of thrombosis is (e.g. DVT), resulting from surgery, such as gastrointestinal or orthopedic surgery, and when the active thrombin inhibitor is melagatran, preferably a preparation containing melagatran, it is administered parenterally within two days (for example, within 24 hours from surgery (before or after surgery) and, in particular, immediately before (for example, within 2 hours) and/or up to 12 hours after surgery (for example, at least one hour after the operation), and then to the period from 3 to 7 (e.g., from 0 to 2, and from 1 to 2) days after this surgery, and a drug containing the prodrug administered orally within 7 days after surgery (preferably, as only completed one introduction of melagatran) before the deadline, for example, from 11 to 40 days, preferably 9 days, more preferably up to 8 days.

The described method can have the advantage that in the treatment of conditions in which it is required or desirable inhibition of thrombin, it may be more appropriate for a physician and/or patient, more effective, less toxic, to have a wider range of activity, be more effective, have fewer side effects, or it may have other useful pharmacological, the properties compared with similar treatments of such conditions, known from the prior art.

The present invention is illustrated but in no way limited by the following example.

Example 1

Clinical trial of combined therapy melagatran and EtOOC-CH2-(R)Cgl-Aze-Pab-OH

In Sweden conducted a multicenter randomized controlled preliminary study with parallel groups. The study was open to evaluate drugs, but blind for patients of all staff in the study sites and for the person conducting the monitoring of the experiment in relation to doses of melagatran and prodrugs of melagatran, EtOOC-CH2-(R)Cgl-Aze-Pab-OH (R; see WO 97/23499).

Dalteparin (Fragmin®, Pharmacia-decision Upjohn) was used as reference compound.

For inclusion was approached by patients for whom it was planned optional primary total hip replacement or knee replacement surgery, they were randomly distributed into three groups, each of which received different doses of melagatran and P or dalteparin. In total, the study included 135 patients, of which 105 patients could be used to assess in relation to thromboembolic phenomena using the Central estimate is made locally of phlebogram.

About 32 patients in each treatment group was evaluated in accordance with the Protocol. PR is changed stratified randomization, center and type of surgery, in order to ensure that approximately equal numbers of patients received each of the products when evaluating all involved centers (used in all six centers) for both types of surgery (hip or knee). Each centre received investigational drugs in blocks of four, separately for hip and knee joints. Within each block, the order of the studied drugs was randomized.

The study used the following drugs:

Melagatran - 5, 10, or 20 mg/ml in aqueous salt solution.

R - suitable weight (see below) in a tablet containing from 59 to 63 mg of corn starch, 115 mg microcrystalline cellulose and 2 mg of sodium fumarate.

The study used the following doses of melagatran and P:

Treatment And subcutaneously melagatran (1 mg) twice a day for 2 days, followed by oral administration of R (6 mg) twice a day for 6 to 9 days.

Treatment B is subcutaneously melagatran (2 mg) twice a day for 2 days, followed by oral administration of R (12 mg) twice a day for 6 to 9 days.

Treatment In the subcutaneous melagatran (4 mg) twice a day for 2 days, followed by oral administration of R (24 mg) twice a day for 6 to 9 days.

PAC the coefficients, receiving melagatran and P, received treatment on the day of surgery. The patient received the first injection after induction of anaesthesia prior to surgery. For patients with knee joint preoperative injection of melagatran did before overlay harness. The second injection was done on the same day in the evening. The patient received one injection of melagatran in the morning and one in the evening for the next 24 hours, until then, until he started oral administration of P twice a day. The first oral dose R always taken in the morning. Thus, the total period of treatment ranged from 8 to 11 days.

Treatment G - dalteparin (Fragmin®): one subcutaneous injection of 5000 units in the evening on the day before surgery, in the continuation of one subcutaneous injection every evening during the treatment period from 8 to 11 days.

Recorded concentration of melagatran in plasma.

The results of clinical trials, expressed as the incidence of thromboembolism after surgery for hip or knee joint, shown in the table below:

 Treatment AndTreatment BThe treatmentTreatment G
 (n)(%)(n)(%) (n)(%)(n)(%)
result6/29216/24254/24165/2719

These data show that the combination of subcutaneous insertion of melagatran and oral input R is effective for the prevention of VTE after orthopedic surgery.

1. The feature set contains:

(a) a pharmaceutical preparation comprising a low molecular weight thrombin inhibitor or its pharmaceutically acceptable derivative in a mixture with a pharmaceutically acceptable adjuvant, diluent or carrier;

(b) a pharmaceutical product comprising a prodrug of low molecular weight thrombin inhibitor, or a pharmaceutically acceptable derivative of the prodrugs in a mixture with a pharmaceutically acceptable adjuvant, diluent or carrier,

where components (a) and (b) each taken in a form suitable for administration in combination with each other.

2. The set of components according to claim 1, where the prodrug component (b) is a prodrug inhibitor of thrombin component (a).

3. The set of components according to claim 1 or 2, where the components (a) and (b) are suitable for sequential, separate and/or simultaneous use in electionseare, where required or desirable inhibition of thrombin.

4. The set of components according to claim 3, where the state represents a deep vein thrombosis.

5. The set of components according to any one of claims 1, 2 and 4, where the thrombin inhibitor is melagatran.

6. The set of components according to claim 3, where the thrombin inhibitor is melagatran.

7. The set of components according to claim 5, where the product containing a thrombin inhibitor or its derivative, is a parenteral drug, and a drug containing the prodrug or derivative, is an oral drug.

8. The set of components according to claim 5, where the prodrug has the formula

R1O2C-CH2-(R)Cgl-Aze-Pab-OH,

where R1represents a linear or branched C1-6alkyl, and the group HE replaces one of the hydrogens amidino in Pab.

9. The set of components of claim 8, where R1represents methyl, ethyl or propyl.

10. The set of components of claim 9, where R' represents ethyl.

11. The set of components according to any one of claims 1, 2, 4 and 6-10, where the product containing a thrombin inhibitor or its derivative, is a parenteral drug, and a drug containing the prodrug or derivative, is an oral drug.

12. A method of manufacturing a set of components according to any one of claims 1 to 11, in which to will beyrout component (a), as defined in any one of claims 1 to 11, with the component (b)as defined in any one of claims 1 to 11, thus making these two components suitable for administration in combination with each other.

13. The set of components containing

(1) one of the components (a) and (b)as defined in any one of claims 1 to 11, together with

(2) instructions for use of this component in combination with the second of these two components.

14. Pharmaceutical preparation comprising a low molecular weight thrombin inhibitor or its pharmaceutically acceptable prodrug derivative and a low molecular weight thrombin inhibitor, or a pharmaceutically acceptable derivative of the prodrugs in a mixture with a pharmaceutically acceptable adjuvant, diluent or carrier.

15. Pharmaceutical drug through 14, where the prodrug has the formula

R1About2C-CH2-(R)gl-Aze-Pab-OH,

where R1represents a linear or branched C1-6alkyl, and the group HE replaces one of the hydrogens amidino in Pab.

16. The pharmaceutical preparation according to item 15, where R1represents methyl, ethyl or propyl.

17. The pharmaceutical preparation according to item 16, where R1represents ethyl.

18. A method of treating a condition in which it is required or desirable inhibition of thrombin, wherein the patient suffering from this with the standing or prone to it, enter

(a) a pharmaceutical preparation comprising a low molecular weight thrombin inhibitor or its pharmaceutically acceptable derivative in a mixture with a pharmaceutically acceptable adjuvant, diluent or carrier; in combination with

(b) a pharmaceutical preparation comprising a prodrug of low molecular weight thrombin inhibitor, or a pharmaceutically acceptable derivative of the prodrugs in a mixture with a pharmaceutically acceptable adjuvant, diluent or carrier.

19. The method according to p, where the component (a) is administered prior to the administration of the component (b).

20. The method according to p or 19, where the prodrug has the formula

R1O2C-CH2-(R)Cgl-Aze-Pab-OH,

where R1represents a linear or branched C1-6alkyl, and the group HE replaces one of the hydrogens amidino in Pab.

21. The method according to claim 20, where R1represents methyl, ethyl or propyl.

22. The method according to item 21, where R1represents ethyl.

23. The method according to any of PP-22, where the state represents a deep vein thrombosis.

24. The method according to item 23, where thrombosis is the result of a surgical operation.

25. The method according to paragraph 24, where a surgical operation is a gastro-intestinal surgery or orthopedic surgery.

26. The method according to paragraph 24, or 2, where component (a) is administered parenterally before and/or after surgery, and the component (b) is administered orally after this surgery.

27. A method of treating a condition in which it is required or desirable inhibition of thrombin, wherein the patient suffering from such condition or affected by it, enter the product according to any one of p-17.

28. The method according to item 27, where the state represents a deep vein thrombosis.

29. The method according to p, where thrombosis is the result of a surgical operation.

30. The method according to clause 29, where a surgical operation is a gastro-intestinal surgery or orthopedic surgery.

Priority from 21.04.99 installed according to claim 2 and 3-13, when they depend on item 2.

Priority from 03.12.1999 installed according to claims 1, 3-13, when they are dependent on claim 1, and PP-30.



 

Same patents:

FIELD: medicine, combustiology, resuscitation.

SUBSTANCE: during the first 2 d since the moment of trauma one should intravenously inject infusion solution of vasaprostan additionally to conventional anti-shock therapy at 1 mcg/kg patient's body weight daily. The present innovation favors to normalize capillary walls' tonicity, decrease their permeability and improve the values of blood hemoconcentration and viscosity.

EFFECT: higher efficiency of correction.

1 ex, 1 tbl

The invention relates to the field of pharmaceutical industry and relates to a method of obtaining a suppository "Epiproct", featured in complex therapy of inflammatory processes of the rectum, prostatitis, hemorrhoids, treatment for anal fissures
The invention relates to medicine, in particular to surgery, and can be used for the treatment of thrombophlebitis
The invention relates to medicine, namely to surgery, and can be used for sclerochronological the treatment of acute superficial variationality lower extremities
The invention relates to medicine, namely to create herbal medicines for the treatment of patients with systemic vascular diseases of the lower and upper extremities

The invention relates to medicine, namely to surgery, and can be used for intraoperative stem sclerotherapy catheter

The invention relates to medicine, in particular to vascular surgery, and can be used for sclerotherapy of varicose veins of the lower extremities

The invention relates to compounds of the formula I, in all stereoisomeric forms and mixtures in any ratio, where NV denotes maleic acid, to a method for producing compounds of formula I, which lies in the fact that compounds of the formula II exercise anionic exchange with maleic acid and/or maleate

The invention relates to the field of medicine and is suitable for treatment of bleeding (hemorrhoid, nasal, uterine, lung, ulcers, gastrointestinal tract, operations, injuries and other), gipoprotrombinemii (bleeding, hemorrhagic diathesis), obstructive jaundice, hepatitis, cirrhosis of the liver, prolonged diarrhea, infants, intestinal atony, hemorrhagic disease of the newborn, increased fragility of vessels, dysproteinemia

FIELD: pharmaceutical industry, medicine.

SUBSTANCE: invention relates to peroral immediate-released drug in solid form, containing low molecular thrombin inhibitor based on peptide with pH-depending solubility. Claimed drug has size particle less than 300 mum and contains combination of microcrystal cellulose and sodium glycolate starch in amount of more than 35 mass % (calculates as preparation mass).

EFFECT: drug with reduced dependence of thrombin inhibitor dissolution from pH and increased releasing rate from tablet.

17 cl, 3 ex, 3 dwg

FIELD: medicine, pharmaceutics, pharmacology.

SUBSTANCE: one should apply mammalian anti-HBP-antibodies. The ways are being suggested to identify monoclonal antibody bound, at least, with one epitope upon native HBP (heparin-binding protein) and methods to detect whether a mammal produces HBR being bound with a monoclonal antibody and, also, the kits for the above-mentioned purpose. The present innovation provides the opportunity to apply the mentioned antibodies in preventing and treating disorders associated with bradykinin releasing.

EFFECT: higher efficiency of application.

25 cl, 11 dwg, 3 ex, 1 tbl

FIELD: pharmaceutical chemistry.

SUBSTANCE: invention relates to (i) essentially crystalline melagatran in the form of hydrate, which is characterized by x-ray diffraction pattern on powder having crystalline peaks with following d values: 21.1, 10.5, 7.6, 7,0, 6.7, 6.4, 6.2, 5.7, 5.4, 5.3, 5.22, 5,19, 5.07, 4.90, 4.75, 4,68, 4.35, 4.19, 4.00, 3.94, 3.85, 3.81, 3.73, 3.70, 3.63, 3.52, 3.39, 3.27, 3,23, 3.12, 3.09, 3.06, 2.75, 2.38, and 2.35 Å and/or water content 4.3%; and (ii) essentially crystalline melagatran in the form of anhydrate, which is characterized by x-ray diffraction pattern on powder having crystalline peaks with following d values: 17.8, 8.9, 8.1, 7.5, 6.9, 6.3, 5.9, 5.6, 5.5, 5.4, 5.3, 5.2, 5.0, 4.71, 4.43, 4.38, 4.33, 4.14, 4.12, 4.05, 3.91, 3.73, 3.61, 3.58, 3.56, 3.47, 3.40, 3.36, 3,28, 3.24, 3.17, 3.09, 3.01, 2.96, 2.83, 2.54, 2.49, 2.41, 2.38, and 2.35 Å. Invention also relates to a method for preparation of indicated form, a method for interconversion of anhydrite form, to use of indicated compounds as pharmaceutical agent, and to preparation of drugs. Pharmaceutical preparation is suitable for treatment of condition, in case of which inhibition of thrombin is needed or desirable. Invention provides a method for treatment of such condition.

EFFECT: increased chemical stability and solid state stability as compared to amorphous forms of melagatran.

14 cl, 4 dwg, 3 tbl, 9 ex

The invention relates to pharmaceutical industry and relates to the creation of a means for inhibiting reproduction enveloped viruses
The invention relates to biotechnology, in particular to a technology for primary protease inhibitor type Konitza of the bodies of cattle, and can be used in biochemistry, cell and molecular biology, as well as in the medical industry as a substance to obtain drugs

The invention relates to medicine, surgery, anesthesiology and critical care medicine and can be used for postoperative pain management of patients with pancreatic necrosis after omentoplasty with multiple programmed rehabilitation by relaparotomy
The invention relates to medicine, namely to the development of new dosage forms for oral administration
The invention relates to pharmaceutical compositions, in particular to pharmaceutical compositions comprising an inhibitor illegitimates (ARI) and angiotensin-converting enzyme (ACE), which is applicable for the prevention and treatment of complications of diabetes

FIELD: medicine, pharmaceutics.

SUBSTANCE: it is suggested to apply Pro-Gly-Pro tripeptide known as anticoagulant to keep stable norglycemia and stable normoinsulinemia in circulation at no side effects because the above-mentioned tripepetide is being natural human and animal metabolite.

EFFECT: higher efficiency of application.

3 cl, 5 ex, 2 tbl

Up!