MXPA01010512A - A pharmaceutical formulation comprising a low molecular weight thrombin inhibitor and its prodrug - Google Patents

Abstract

According to the invention there is provided a kit of parts comprising:(a) a pharmaceutical formulation including a low molecular weight thrombin inhibitor, or a pharmaceutically acceptable derivative thereof, in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier;and (b) a pharmaceutical formulation including a produg of a low molecular weight thrombin inhibitor, or a pharmaceutically acceptable derivative of that prodrug, in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier, which components (a) and (b) ar each provided in a form that is suitable for administration in conjunction with the other, as well as the use of such a kit of parts in the treatment of a condition in which inhibition of thrombin is required or desired.

Description

PHARMACEUTICAL FORMULATION COMPRISING MOLECULAR LOW WEIGHT THROMBIN INHIBITOR AND ITS PROFARMACO Field of the Invention This invention relates to a new use of low molecular weight thrombin inhibitors.

BACKGROUND ART Blood coagulation is the key process involved in both haemostasis (i.e., prevention of blood loss from a damaged vessel) and thrombosis (i.e., the formation of a blood clot in a vessel). blood, which sometimes lead to obstruction of the vessel). Coagulation is the result of a complex series of enzymatic reactions. One of the last steps in this series of reactions is the conversion of prothrombin from proenzyme to thrombin from the active enzyme. It is known that thrombin plays a central role in coagulation. It activates platelets, leads to the aggregation of platelets, converts fibrinogen into fibrin monomers, which spontaneously polymerizes in REF. NO.:133625 fibrin polymers, and activates factor XIII, which in turn crosslinks the polymers to form insoluble fibrin. In addition, thrombin activates factor V and factor VIII that lead to a "favorable response" generation of thrombin from the protrobin. Effective thrombin inhibitors are thus known, and / or are expected to be useful as anticoagulants and therefore useful in the therapeutic treatment of thrombosis and related disorders. The anticipated development of low molecular weight thrombin inhibitors has been described by Claesson in Blood Coagul, Fibrinol. (1994) 5, 411. Low molecular weight thrombin inhibitors have been described more recently in U.S. Patent No. 4,346,078; 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 European Patent Applications 648 780, 468 231, 559 046, 641 779, 185 390, 526 877, 542 525, 195 212, 362 002, 364 344, 530 167, 293 881, 686 642, 669 317, 601 459 and 623 596. In particular, the international patent application WO 94/29336 describes a group of compounds, including HOOC-CH2- [R) Cgl-Aze-Pab-H (in which Cgl represents cyclohexylglycine, Aze represents S-acid) azetidine-2-carboxylic acid and Pab-H represents 4-aminomethyl-amidinobenzene), which is also known as melagatran (see Example 1 of WO 94/29336). International Patent Application WO 97/23499 describes prodrugs of melagatran inter alia. None of the documents mentioned above describes or suggest the administration of an active thrombin inhibitor in conjunction with a prodrug of that thrombin inhibitor, or actually in conjunction with a prodrug of any thrombin inhibitor. Deep vein thrombosis (DVT) and pulmonary embolism (PE) are the major health problems, which can lead to serious consequences. In particular, PE can be fatal, or it can result in the development of pulmonary hypertension and heart failure from recurrent embolism. DVT can result in post-thrombotic venous insufficiency and ulcers in the affected part of the body (eg, legs). Both are common conditions, which have a greater impact on the costs of health care worldwide. There is a considerable incidence of DVT and PE that follows orthopedic surgery. For example, in patients suffering from total hip replacement, the DVT incident in the absence of thromboprophylaxis can be as high as 45 to 57%. further, the incidence of proximal DVT may be between 23 and 36%, and that of fatal PE, 0.34 to 6%. In patients suffering from total knee replacement in the absence of thromboprophylaxis, the postoperative incidence of DVT is between 40 and 84%, of proximal DVT is between 9 and 20%, and of fatal PE is between 0.2 and 0.7%. In patients suffering from general surgery in the absence of thromboprophylaxis, the postoperative incidence of DVT is approximately 25%. (Reference: Chest (1998) 114, 531S to 560S.) Unfractionated low-dose subcutaneous heparin (s.c.) is the most widely used common prophylactic treatment for venous thromboembolism resulting from orthopedic and general surgery. The incidence of DVT after total hip replacement has been shown to be reduced (see Chest's previous reference). The use of low molecular weight heparin (LMWH) in DVT prophylaxis following total hip and knee replacement operations has been shown to add reduced incidence (when compared to heparin). unfractionated low dose), without a concomitant increase in bleeding (see Chest's previous reference). However, it has been shown that prolonged treatment with heparins gives rise to an increased risk of osteoporosis. Heparins can also give rise to "heparin-induced thrombocytopenia" (HIT), are dependent on the plasma level of the endogenous thrombin inhibitor, antithrombin, and do not inactivate thrombin bound to the clot. It has also been shown that oral anticoagulants, such as warfarin (a vitamin K antagonist), are effective in reducing DVT after major surgery (see previous Chest reference). However, due to the risk of hemorrhage, and the need for frequent laboratory control, the use of this substance is usually reserved for high-risk patients, and / or for long-term use. Vitamin K antagonists also demonstrate a significant risk of interaction with other drugs and certain foods, and their use requires observation of the patient's blood clotting status. Antiplatelet agents, such as aspirin, have been shown to have limited efficacy in the prevention of DVT (see previous Chest reference). Comparative clinical studies conducted during the course of total hip replacement operations have shown that subcutaneous administration of hirudin as a thrombin inhibitor is superior to unfractionated heparin and LMWH in reducing the frequency of total and proximal DVT without corresponds to the increase in hemorrhage (see Eriksson et al in Lancet, 347, 635 (1996) and J. Bone Joint, Surg., Sep., 11 (1996)). However, hirudin is expensive and has an immunogenic potential. Thus, there is a need for effective treatments of thrombotic conditions such as DVT.

Description of the Invention It has been found, surprisingly, that the administration of a low molecular weight thrombin inhibitor in conjunction with a prodrug of a thrombin inhibitor (or a prodrug thereof) produces a remarkable anticoagulant effect. According to a first aspect of the invention there is provided a set of parts comprising the following components: (a) a pharmaceutical formulation that includes a low molecular weight thrombin inhibitor, or a pharmaceutically acceptable derivative thereof, in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier; and (b) a pharmaceutical formulation that includes a prodrug of a low molecular weight thrombin inhibitor, or a pharmaceutically acceptable derivative of this prodrug, in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier. these components (a) and (b) are each provided in a form that is suitable for administration in conjunction with the other.

It is preferred that the prodrug of component (b) is a prodrug of the active, low molecular weight thrombin inhibitor of component (a). According to a further aspect of the invention, there is provided a method for producing a set of parts as defined herein, this method comprises carrying a component (a), as defined above, in association with a component (b), such as it was previously defined, thus making the two components suitable for administration in conjunction with each other. Taking the two components "in association with each other", it is included that the components (a) and (b) can be: (i) provided as separate formulations (that is, independently of each other), which subsequently were taken together for use in conjunction with each other in combination therapy; or (ii) packaged and presented together as separate components of a "combination package" for use in conjunction with each other in combination therapy. Accordingly, there is further provided a set of parts comprising: (1) one of components (a) and (b) as defined herein; together with (2) instructions for using this component in conjunction with each other of the two components. The sets of parts defined herein may comprise more than one formulation that includes an appropriate amount / dose of thrombin inhibitor, and / or more than one formulation that includes an appropriate amount / dose of the respective prodrug, to provide the repeated dosage. If more than one formulation (comprising prodrug or thrombin inhibitor) is present, such formulations may be the same, or may be different in terms of the dose of thrombin inhibitor / prodrug, chemical composition and / or physical form. A further aspect of the invention provides a method for the treatment of a condition in which inhibition of thrombin is required or desired, which comprises the administration of: (a) a pharmaceutical formulation that includes a low molecular weight thrombin inhibitor , or a pharmaceutically acceptable derivative thereof, in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier; in conjunction with (b) a pharmaceutical formulation including a prodrug of a low molecular weight thrombin inhibitor, or a pharmaceutically acceptable derivative of this prodrug, in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier, to a patient suffering from , or is susceptible to, a condition. For the avoidance of doubt, as used herein, the term "treatment" includes therapeutic and / or prophylactic treatment. The "pharmaceutically acceptable derivatives" of prodrugs and thrombin inhibitors include salts (e.g., pharmaceutically acceptable non-toxic organic or inorganic acid addition salts) and solvates. It will be appreciated that the term derivatives of pharmaceutically acceptable active thrombin inhibitors, include those derivatives that have the same biological function and / or activity as that thrombin inhibitor but, for the purpose of this invention, prodrugs of that thrombin inhibitor are not included. By "administration in conjunction with", it is included that the respective formulations comprising the thrombin inhibitor and / or prodrug, are administered sequentially, separately and / or simultaneously, during the course of treatment of the relevant condition, this Condition can be acute or chronic. Preferably, the term includes that the two formulations are administered (optionally repeatedly) sufficiently narrowly in time for this to be a beneficial effect for the patient, which is greater, during the course of treatment of the relevant condition, than if either of the two formulations is administered (optionally repeatedly) alone, in the absence of the other formulation, over the same course of treatment. The determination of whether a combination provides a greater beneficial effect with respect to, and during the course of the treatment of, a particular condition, will depend on the condition to be treated or prevented, but can be routinely achieved by the skilled person. Thus, the term "in conjunction with" includes that either of the two formulations may be administered (optionally repeatedly) prior to, after and / or at the same time as the administration with the other component. When used in this context, the terms "administered simultaneously" and "administered at the same time as" include those individual doses of the thrombin inhibitor and prodrugs that are administered within 48 hours (eg, 24 hours) to each other.

Components (a) and (b) as described herein may also be presented (ie, formulated) as a combined preparation (i.e., presented as a single formulation including the prodrug and low molecular weight thrombin inhibitor). Accordingly, a pharmaceutical formulation including a low molecular weight thrombin inhibitor (or a pharmaceutically acceptable derivative thereof) and a prodrug of a low molecular weight thrombin inhibitor (or a pharmaceutically acceptable derivative of this prodrug) is further provided. , in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier. The term "low molecular weight thrombin inhibitor" will be understood by those skilled in the art. The term can also be understood to include any combination of matter (eg, chemical compound) which inhibits thrombin to a degree that can be determined experimentally in in vivo and / or in vi tro tests, and which has a lower molecular weight to 2,000, preferably less than 1,000. Preferred low molecular weight thrombin inhibitors include inhibitors of peptide-based, amino-base, and / or peptide-based, low molecular weight thrombin inhibitors. The term "peptide base, amino acid-based, and / or peptide-based, low molecular weight peptide inhibitors" will be well understood by one skilled in the art to include low molecular weight thrombin inhibitors with one another. four peptide bonds, and includes those described in the Claesson in Blood Coagul publication. Fibrin (1994) 5, 411, as well as those described in U.S. Patent No. 4,346,078; 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 European Patent Applications 648 780, 468 231, 559 046, 641 779, 185 390, 526 877, 542 525, 195 212, 362 002, 364 344, 530 167, 293 881, 686 642, 669 317, 601 459 and 623 596, the descriptions of all these documents are incorporated herein by reference. Preferred low molecular weight peptide-based thrombin inhibitors include HOOC-CH2- (R) Cha-Pic-Nag-H (where Cha represents cyclohexylalanine, Foot represents (S) -pipecolinic acid and Nag represents noragmatine; as inogatran, see International Patent Application WO 93/11152) and, especially, HOOC-CH2-. { R) Cgl-Aze-Pab-H (known as melagatran, see above and International Patent Application WO 94/29336). The term "prodrug" of a low molecular weight thrombin inhibitor includes any compound which, following oral or parenteral administration, is metabolized in vi to form a low molecular weight thrombin inhibitor (as defined herein), an experimentally detectable amount, and within a predetermined period (e.g., within a dosage range of between 6 and 24 hours (i.e., one to four times per day)), following oral or parental administration. of melagatran as thrombin inhibitors which may be mentioned include those described in international patent application WO 97/23499. Preferred prodrugs are those of the formula R102C-CH2-. {R) Cgl-Aze-Pab-OH (cf. the list of abbreviations above or in WO 97/23499), wherein R represents benzyl or C? -? or alkyl, such as linear or branched C? -6 alkyl (eg, C? _4 alkyl, especially methyl) , propyl and, particularly, ethyl) and the OH group replaces one of the amidino hydrogens in Pab. The term "condition in which thrombin inhibition is desired or required" will be understood by those skilled in the art to include the following: The treatment and / or prophylaxis of thrombosis and hypercoagulability in the blood and tissues of animals including the man. It is known that hypercoagulability can lead to thromboembolic diseases. Conditions associated with hypercoagulability and thromboembolic diseases which may be mentioned include resistance to activated, inherited or acquired protein C, such as the V mutation factor (factor V Leiden), and inherited or acquired deficiencies in antithrombin III. , protein C, protein S, cofactor of heparin II. Other known conditions that may be associated with hypercoagulability and thromboembolic disease include circulating antiphospholipid antibodies (Lupus anticoagulants), homocysteinemias, heparin-induced thrombocytopenia, and defects in fibrinolysis. The treatment of conditions where there is an excess of undesirable thrombin without signs of hypercoagulability, for example in neurodegenerative diseases such as Alzheimer's disease. The states of the particular disease which may be mentioned, include the therapeutic and / or prophylactic treatment of venous thrombosis (eg, DVT) and pulmonary embolism, arterial thrombosis (eg, in myocardial infarction, unstable angina, seizure stroke based on thrombosis and peripheral arterial thrombosis) and systemic embolism usually of the atrium during arterial fibrillation or from the left ventricle after infarction to the transmural myocardium, or caused by congestive heart failure; reocclusion prophylaxis (ie, thrombosis) after thrombolysis, percutaneous transluminal angiplasty (PTA), and coronary bypass operations; the prevention of rethrombosis after microsurgery and vascular surgery in general.

Additional indications include the therapeutic and / or prophylactic treatment of disseminated intravascular coagulation caused by bacteria, multiple trauma, intoxication or any other mechanism; anticoagulant treatment when blood is in contact with foreign surfaces in the body such as vascular grafts, vascular stents, vascular catheters, mechanical and biological orthopedic valves or any other medical device, and anticoagulant treatment when the blood is in contact with medical devices outside the body such as during cardiovascular surgery using a heart-lung machine or in hemodialysis, therapeutic and / or prophylactic treatment of idiopathic and adult respiratory distress syndrome, pulmonary fibrosis following treatment with radiation or chemotherapy , septic shock, septicemia, inflammatory responses, which include, but are not limited to, edema, acute or chronic atherosclerosis such as coronary artery disease, cerebral arterial disease, peripheral arterial disease, reperfusion injury, and restenosis after angioplasty transluminal percu tandem (PTA).

Preferred conditions include thrombosis, especially DVT, which includes distal and proximal DVT. The present invention finds particular utility in the prophylactic treatment of DVT resulting from surgery, such as gastrointestinal, or orthopedic surgery (for example knee or hip replacement). This includes DVT that results from immobilization after surgery. According to the invention, thrombin inhibitors, prodrugs of thrombin inhibitors, and derivatives of either of the two, can be administered orally, intravenously, subcutaneously, buccally, rectally, dermally, nasally, tracheally, bronchially, topically, by any another parental route, or via inhalation, in the form of a pharmaceutical preparation comprising the prodrug or thrombin inhibitor in a pharmaceutically acceptable dosage form. Depending on the disorder, and the patient, to be treated, as well as the route of administration, the compositions may be administered in various doses. The proffered modes of supply are systemic.

For melagatran and derivatives thereof, preferred modes of administration are parental, more preferably intravenous, and especially subcutaneous. For melagatran prodrugs, the preferred modes of administration are oral. In the therapeutic treatment of mammals, and especially humans, thrombin inhibitors, prodrugs of thrombin inhibitors, and derivatives of either will generally be administered as a pharmaceutical formulation in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier, which they can select with due consideration of the proposed route of administration and standard pharmaceutical practice. Formulations suitable for use in the administration of thrombin inhibitors are known in the art, and include those known from U.S. Patent No. 4,346,078; 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 European Patent Applications 648 780, 468 231, 559 046, 641 779, 185 390, 526 877, 542 525, 195 212, 362 002, 364 344, 530 167, 293 881, 686 642, 669 317, 601 459 and 623,596, the descriptions of all documents are hereby incorporated by reference. The formulations suitable for use with melagratan, derivatives and prodrugs thereof, are described in the literature, for example as described in, inter alia, 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 descriptions of the documents are hereby incorporated by reference. Otherwise, the preparation of suitable formulations can be accomplished in a non-inventive manner by the skilled person using routine techniques. The amounts of the thrombin inhibitor, prodrugs, or derivatives of either, in the formulation will depend on the severity of the condition, and in the patient, to be treated (a), as well as the compound (s) which ( which) is / are employed (s), but can be determined non-inventively by the skilled person. The appropriate dose of thrombin inhibitors, prodrugs and derivatives of any, in the therapeutic and / or prophylactic treatment of mammals, especially of human, patients can be routinely determined by the medical professional or other skilled person, and includes the respective dose discussed. in the prior art documents describing thrombin inhibitors that are mentioned above, the descriptions in which they are hereby incorporated by reference. In the case of melagatran, the appropriate doses of the active compound, prodrugs and derivatives thereof, in the therapeutic and / or prophylactic treatment of mammals, especially humans, patients include those which give an average plasma concentration of up to 5 μmol / L , for example in the range of 0.001 to 5 μmol / L over the course of the treatment of the relevant condition. Accordingly, adequate doses may be in the range of 0.1 mg per day to 25 mg three times per day, and / or up to 100 mg infused parentéricamente during a period of 24 hours, for melagatran, and in the range of 0.1 mg a once a day at 100 mg three times per day for melagatran prodrugs including those mentioned in a specific manner above. In any case, the doctor, or the expert, will be able to determine the current dosage which will be most suitable for an individual patient, which is likely to vary with the condition to be treated, as well as age, Weight, sex and response of the particular patient to be treated. The dosages mentioned above are examples of the average case; these may, of course, be individual examples where the upper and lower dosage ranges are approved, and are within the scope of this invention. The sequence in which the formulations comprising the thrombin inhibitor, and prodrugs, can be administered (ie, if, and at what point, sequential, separate and / or simultaneous administration occurs) can be determined by the physician or person expert For example, the sequence may depend on many factors that will be apparent to the skilled person, such as whether, at any time during the course or period of treatment, one or the other of the formulations can not be administered to the patient for practical reasons (eg, example, the patient is unconscious and therefore can not take an oral formulation comprising either the prodrug or thrombin inhibitor). For example, in the treatment of thrombosis (eg, DVT) resulting from surgery, such as gastrointestinal or orthopedic surgery, and when the active thrombin inhibitor is melagatran, it is preferred that the formulation comprising melagatran be administered parenterally within two days (for example, within 24 hours) of surgery (either prior to or after surgery), and particularly immediately prior to (for example, within 2 hours), and / or within up to 12 hours after surgery (for example, at least one hour after surgery), and thereafter for up to between 3 and 7 (for example, between 0 and 2, such as between 1 and 2) days after that surgery, and that the formulation comprising the prodrug is administered orally within 7 days following that surgery (preferably once the administration of melagatran has been completed) -for up to, for example, between 11 and 40 days, preferably 9 days, in form more preferable up to 8 days. The method described herein may have the advantage that, in the treatment of conditions in which thrombin inhibition is required or desired, it may be more convenient for the physician and / or patient to be more effective than to be less toxic that, having a broader range of activity that is more potent, produces fewer side effects than, or that other pharmacological properties may have on, similar methods known in the prior art for the treatment of such conditions. The invention is illustrated, but not limited in form, by the following example.

Example 1 Clinical Trial - Combination Therapy of Melagatran and EtOOC-CH2- (R) Cgl-Aze-Pab-OH A pilot study of the Swedish multi-center was conducted with a parallel, random, controlled group. The study was open with respect to the drugs under evaluation but was simulated for the patients, all personnel at the study sites, and for the person observing the experiments regarding the dose of melagatran and the prodrug of melagatran, EtOOC -CH2- (R) Cgl-Aze-Pab-OH (P; see WO 97/23499). Dalteparin (Fragmin®, Pharmacia-Upjohn) was used as a reference compound.

Patients scheduled for primary hip or knee replacement, elective, were eligible for inclusion, and were randomly selected in one of three groups, each receiving different doses of melagatran and P, or dalteparin. Throughout the study, the 135 patients were included, of which 105 patients could be used for the evaluation regarding thromboembolic events using the central assessment of the locally performed phlebograms. Approximately 32 patients in each treatment group were evaluated according to the protocol. A randomized stratified distribution, by center and type of surgery, was used to ensure that approximately equal numbers of patients were given with each of the drugs under evaluation in all the participation centers (in all six centers were used) for both types of surgery (hip or knee). Each of the study drugs received in the center in blocks of four, separately for hips and knees. Within each block, the order of study drugs was randomized. The following formulations were used in the study: Melagatran - 5, 10 or 20 mg / ml in aqueous saline. P - appropriate weight (see below) in a tablet also comprising 59 to 63 mg of corn starch, 115 mg of microcrystalline cellulose and 2 mg of sodium stearyl fumarate. The following doses of melagatran and P were used in the study: Treatment A - s.c. melagatran (1 mg) b.i.d. for 3 days, followed by oral administration of P (6 mg) b.i.d. for 6 to 9 days. Treatment B - s.c. melagatran (2 mg) b.i.d. for 3 days, followed by an oral administration of P (12 mg) b.i.d. for 6 to 9 days. Treatment C - s.c. melagatran (4 mg) b.i.d. for 2 days, followed by an oral administration of P (24 mg) b.i.d. for 6 to 9 days. The patients who receive melagatran and P receive the treatment on the day of surgery. The patient receives the first injection after induction of anesthesia immediately before surgery. For knee patients, preoperative melagatran injection occurred before the tourniquets were applied.

The second injection occurred in the afternoon on the same day. The patient receives an injection of melagatran in the morning and one in the afternoon for the next 24 hours, until the oral administration of P begins, twice a day. The first oral dose of P was always taken in the morning. Therefore, the total treatment period was between 8 and 11 days. Treatment D - dalteparin (Fragmin ®): a s.c. of 5000 U during the afternoon of the day before the surgery, continuing with an injection s.c. every afternoon during a treatment period of 8 to 11 days. Plasma concentrations of melagatran were recorded. The results of the trial, in terms of the frequencies of the thromboembolism after the surgery of the hip or knee, are tabulated later: These data show that a combination of melagatran administered subcutaneously and P administered orally, is effective in the prevention of DVT after orthopedic surgery. It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.

Claims (19)

1. CLAIMS Having described the invention as above, the content of the following claims is claimed as property: 1. A set of parts characterized in that it comprises: (a) a pharmaceutical formulation that includes a low molecular weight thrombin inhibitor, or a derivative thereof pharmaceutically acceptable, in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier; and (b) a pharmaceutical formulation including a prodrug of a low molecular weight thrombin inhibitor, or a pharmaceutically acceptable derivative of this prodrug, in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier, components (a) and (b) ) are each provided in a form that is suitable for administration in conjunction with the other.
2. 2. A set of parts according to claim 1, characterized in that the prodrug of component (b) is a prodrug of the thrombin inhibitor of component (a).
3. 3. A set of parts according to claim 1 or claim 2, characterized in that the components (a) and (b) are suitable for sequential, separate and / or simultaneous use in the treatment of a condition in which it is required or desired the inhibition of thrombin.
4. 4. A set of parts according to claim 3, characterized in that the condition is deep vein thrombosis.
5. 5. A set of parts according to any of claims 1 to 4, characterized in that the thrombin inhibitor is melagatran.
6. 6. A set of parts according to claim 5, characterized in that the prodrug is of the formula R102C-CH2- (R) Cgl-Aze-Pab-OH, wherein R1 represents straight or branched C6-6 alkyl and the OH group replaces one of the hydrogens of a idino in Pab.
7. 7. A set of parts according to claim 6, characterized in that R1 represents methyl, ethyl or propyl.
8. 8. A set of parts according to any of the preceding claims, characterized in that the formulation comprising the thrombin inhibitor, or derivative thereof, is a parental formulation and that which comprises the prodrug, or derivative thereof, is an oral formulation.
9. 9. A method for producing a set of parts as defined in any of claims 1 to 8, the method is characterized in that it comprises carrying a component (a) according to any of claims 1 to 8, in association with a component (b) according to any one of claims 1 to 8, thus rendering the two components suitable for administration in conjunction with each other.
10. 10. A set of parts characterized in that it comprises: (i) one of the components (a) and (b) as defined in any of claims 1 to 8; together with (ii) instructions for using this component in conjunction with the other of the two components.
11. 11. A pharmaceutical formulation, characterized in that it includes a low molecular weight thrombin inhibitor (or a pharmaceutically acceptable derivative thereof) and a prodrug of a low molecular weight thrombin inhibitor (or a pharmaceutically acceptable derivative of this prodrug), mixture with a pharmaceutically acceptable adjuvant, diluent or carrier.
12. 12. A method of treating a condition in which the thrombin inhibitor is required or desired, characterized in that it comprises administration of: (a) a pharmaceutical formulation that includes a low molecular weight thrombin inhibitor, or a derivative thereof pharmaceutically acceptable, in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier; in conjunction with (b) a pharmaceutical formulation including a prodrug of a low molecular weight thrombin inhibitor, or a pharmaceutically acceptable derivative of this prodrug, in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier, to a patient suffering from , or is susceptible to such condition.
13. 13. A method in accordance with the claim 12, characterized in that component (a) is administered prior to the start of administration of component (b).
14. 14. A method of treating a condition in which inhibition of thrombin is required or desired, characterized in that it comprises administering a formulation as defined in claim 11 to a patient suffering from, or susceptible to, such a condition.
15. 15. A method according to any of claims 12 to 14, characterized in that the condition is deep vein thrombosis.
16. 16. A method according to claim 15, characterized in that the thrombosis results from the surgery.
17. 17. A method according to claim 16, characterized in that the surgery is gastrointestinal surgery or orthopedic surgery.
18. 18. A method according to claim 16 or claim 17, characterized in that component (a) is administered parentally prior to and / or after surgery and component (b) is administered orally following that surgery.
19. 19. The use of a thrombin inhibitor, or a pharmaceutically acceptable derivative thereof, in the production of a medicament for the treatment or prophylaxis of a condition in which thrombin inhibition is required or desired, the treatment or prophylaxis is characterized in that it comprises administration of: (a) a pharmaceutical formulation that includes a low molecular weight thrombin inhibitor, or a pharmaceutically acceptable derivative thereof, in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier; in conjunction with (b) a pharmaceutical formulation including a prodrug of a low molecular weight thrombin inhibitor, or a derivative of this pharmaceutically acceptable prodrug, in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier, to a patient suffering from , or is susceptible to, such condition.