Use of milbexian in the treatment and prevention of thrombotic disorders in patients with cardiovascular or cerebrovascular disease.

Abstract

A therapeutically effective activated factor XI inhibitor useful in methods for preventing thrombotic disorders in human patients with cardiovascular or cerebrovascular disease.

Description

[Technical Field]

[0001] (Cross-reference of related applications) This application claims priority to U.S. Provisional Application No. 63 / 497,088 filed April 19, 2023, priority to U.S. Provisional Application No. 63 / 497,101 filed April 19, 2023, priority to U.S. Provisional Application No. 63 / 578,508 filed August 24, 2023, priority to U.S. Provisional Application No. 63 / 582,313 filed September 13, 2023, and priority to U.S. Provisional Application No. 63 / 497,111 filed April 19, 2023. All of the aforementioned applications are incorporated herein by reference. [Background technology]

[0002] This disclosure relates to the use of milbexian to treat or prevent thrombotic disorders in human patients with cardiovascular or cerebrovascular disease without significantly impairing the normal blood coagulation process.

[0003] [Technical field] Thromboembolism and its associated complications represent a significant global healthcare burden. Despite advances in modern medicine, stroke remains a leading cause of death and disability worldwide. In 2019 alone, stroke-related disability-adjusted life years and 6.55 million deaths in Western countries accounted for a substantial portion of healthcare expenditures (Katan et al, Global burden of stroke, SeminNeurol., 2018, vol. 38, pp. 208-211). Thrombi can partially or completely block arteries and veins, causing localized ischemic complications. They can also embolize cerebral arteries and lungs, leading to stroke and other life-threatening conditions. Thrombosis contributes to the morbidity and mortality of cardiovascular disease, particularly in coronary artery disease (CAD), atrial fibrillation (AF), stroke, peripheral artery disease (PAD), deep vein thrombosis (DVT), pulmonary embolism (PE), acute myocardial infarction (AMI), and venous thromboembolism (VTE). Arterial and venous thrombosis are the leading causes of mortality and morbidity. Arterial thrombosis causes myocardial infarction (MI) and stroke, while venous thrombosis (VT) leads to venous thromboembolism (VTE) and pulmonary embolism (PE). Ischemic heart disease and stroke together account for approximately 25% of global deaths (Lozano et al. Global and regional mortality from 235 causes of death for 20 age groups in 1990 and 2010: A systematic analysis for the Global Burden of Disease Study 2010. Lancet. 2012;380:2095-2128). Meanwhile, the estimated incidence of VTE, consisting of deep vein thrombosis (DVT) and pulmonary embolism (PE), is 115 to 269 cases per 100,000 people worldwide (Day ISCfWT Thrombosis: A major contributor to the global disease burden. J. Thromb. Haemost. 2014;12:1580-1590).

[0004] The overall composition of thrombi differs significantly from that of arterial thrombi. Venous thrombi are primarily composed of red blood cells and fibrin fibers, accounting for 63% and 35% of their volume, respectively, while arterial thrombi are mainly composed of fibrin and platelets. Platelets have a relatively high wall shear rate (approximately 10%). 2 ~10 5 s -1 It plays a crucial role in the formation of arterial thrombi, often forming what are called "white thrombi," which are formed at low shear rates (10-100 s). In patients with coronary artery disease, thrombi generally form due to the rupture of atherosclerotic plaques or the exposure of pro-coagulation components (e.g., collagen and lipid-rich activated macrophages that express tissue factor), and if a thrombus forms and causes occlusion, it leads to myocardial infarction. Primary arterial thrombosis can develop in the brain or other circulatory systems through a similar mechanism. In contrast, at low shear rates (10-100 s), -1 Venous thrombi, formed in the arteries, are mainly composed of red blood cells and fibrin and are called "red thrombi." Venous thrombosis is generally thought to be the result of a combination of increased blood coagulation, vascular endothelial damage, and blood stasis (Virchow's triad). The overall composition of pulmonary embolism differed significantly from that of arterial thrombosis, but did not show a significant difference from that of venous thrombosis (Cheynysh et al., The distinctive structure and composition of arterial and venous thrombi and pulmonary emboli, Scientific Reports, 2020, vol. 10, pp.5112). Therefore, antiplatelet therapy is considered a favorable option for the prevention of arterial thrombosis, while anticoagulant therapy (vitamin K anticoagulants, heparin, or direct activated factor X inhibitors) is recommended for the treatment of venous thrombosis. However, there are also situations where arterial and venous thrombosis show similarities, as described below. (1) Special circumstances in which fibrin-dominant thrombi form in the left atrial appendage of patients with atrial fibrillation (AF) (characterized by low pressure and low shear, and receiving oxygenated venous blood from the post-pulmonary capillary circulation) (Wysokinski et al., Atrial fibrillation and thrombosis: immunohistochemical differences between in situ and embolized thrombi. J Thromb Haemost, 2004, vol. 2, pp.1637-1644) and in the coronary artery system of patients with myocardial infarction (MI) (Yamashita et al., Detection of von Willebrand factor and tissue factor in platelets-fibrin-rich coronary thrombi in acute myocardial infarction. Am J Cardiol 97(1):26-28); (2) Aspirin may be effective in preventing venous thromboembolism (VTE) (suggesting that platelets play an essential role in thrombus formation in the venous system). (3) High frequency of co-occurrence of major cardiovascular (CV) risk factors (mainly hypertension) in patients with retinal vein occlusion (RVO) (Janssen et al., Retinal vein occlusion: a form of venous thrombosis or a complication of atherosclerosis? A meta-analysis of thrombophilic factors. Thromb Haemost. 2005, vol. 93, pp. 1021-1026).

[0005] The (1) extrinsic pathway and (2) intrinsic pathway are well known as the two main pathways that trigger the blood coagulation cascade. Both pathways initiate a series of cascade reactions and form thrombi. The purpose of this is to isolate and contain the triggering factors from the blood, thereby preventing further contact with plasma components and stopping the thrombus formation process (Figure 1). Hemostasis is a normal physiological process in which the coagulation cascade repairs the site of vascular injury in order to suppress bleeding after injury. Platelets are responsible for primary hemostasis, and coagulation is responsible for secondary hemostasis (strengthening of platelet thrombi). On the other hand, thrombosis refers to various pathological conditions in which thrombi form in the vascular lumen due to the normal physiological blood coagulation process, obstructing normal blood flow. In both hemostasis and thrombosis, thrombin generation and fibrin formation are the final stages, but there are important differences in the pathways involved (Figure 1).

[0006] Hemostasis typically begins when tissue factor (TF) present in the vascular adventitia is exposed to the blood. When vascular damage that could cause bleeding occurs, a series of soluble plasma proteins are activated and act sequentially as an enzyme activation cascade to form a platelet-fibrin thrombus. In such situations, the concentration of TF is relatively high, leading to rapid and powerful thrombin production, and a hemostatic clot is quickly formed to isolate the inducing TF from the blood. This interrupts the activation of the coagulation pathway via a feedback mechanism, preventing the progression to a pathological state.

[0007] Although the concentration of TF in this context is lower than during hemostasis, the contact time with blood components is often longer than during hemostasis. Whether coagulation is induced by TF associated with the rupture of atherosclerotic plaque, activated monocytes / macrophages expressed at the site of injury or inflammation, or by implantable medical devices or neutrophil extracellular traps (NETs), the situation differs depending on the feedback mechanism of the coagulation cascade for thrombus growth and thrombus stability (Figure 1). This blood clot or thrombus obstructs blood flow to distal tissues and organs, causing ischemia and necrosis, and manifests as clinical symptoms including acute coronary syndrome (ACS), stroke, or deep vein thrombosis (DVT) (Badimon et al., Factor XI / XIa Inhibition: The Arsenal in Development for a New Therapeutic Target in Cardio- and Cerebrovascular Disease, J Cardiovasc Dev Dis., 2022, vol. 9, p. 437).

[0008] The TF pathway is understood to play a larger role in the "initiation" and "amplification" phases of coagulation and to function more in normal hemostasis than in thrombosis. FXI has a dual role: one is located directly below FXII in the intrinsic pathway, and the other is activated by thrombin (and FXIIa, if present) in the amplification pathway. However, the intrinsic pathway is activated when it plays a crucial role in thrombotic disorders. Increased activity of FXII, FXI, or kallikrein in plasma has been reported to be associated with atherosclerosis (Colhoun et al., Activated factor XII levels and factor XII 46C>T genotype in relation to coronary artery calcification in patients with type 1 diabetes and healthy subjects. Atherosclerosis. 2002;163:363-369) and myocardial infarction (MI) (Doggen et al., Levels of intrinsic coagulation factors and the risk of myocardial infarction among men: Opposite and synergistic effects of factors XI and XII. Blood. 2006;108:4045-4051).

[0009] Analysis of genetically determined FXI levels has shown that the highest FXI levels are associated with a higher risk of ischemic stroke (Gill et al. Genetically determined FXI (Factor XI) levels and risk of stroke. Stroke 2018;49 (11):2761-2763). On the other hand, severe FXI deficiency is associated with a reduced risk of stroke and deep vein thrombosis (Salomon et al., Reduced incidence of ischemic stroke in patients with severe factor XI deficiency. Blood. 2008;111:4113-4117; Salomon et al., Patients with severe factor XI deficiency have a reduced incidence of deep-vein thrombosis. Thromb. Haemost. 2011;105:269-273). Congenital FXI deficiency has a low incidence of both arterial and venous thrombotic events, and unpredictable major bleeding is rare (i.e., the bleeding tendency is lower compared to deficiencies of other coagulation factors such as factor X) (Gailani et al., Factor XI as a therapeutic target. Arterioscler Thromb Vasc Biol. 2016;36(7):1316-1322; Peyvandi et al. European Network of Rare Bleeding Disorders Group. Coagulation factor activity and clinical bleeding severity in rare bleeding disorders: results from the European Network of Rare Bleeding Disorders. J Thromb Haemost. 2012;(4):615-621).In a mouse model of atherosclerosis with severe FXI deficiency (apoE / FXI double knockout mice), a significant suppression of atherosclerosis was observed compared to apoE knockout mice, suggesting the potential for pharmacological inhibition of factor XI to be applied to human treatment (Shnerb Ganor 2016).

[0010] The significant human and economic burdens posed by thromboembolic events strongly indicate the need for new and superior treatment options in the management of thrombotic diseases. The challenge lies in developing drugs that possess potent antithrombotic effects while minimizing bleeding risk, which requires an extremely delicate balance in regulating hemostatic mechanisms. In the clinical treatment of thrombotic diseases, the clinical benefits of current anticoagulants are well established. Non-cardiogenic strokes, particularly those resulting from extra-aortic atherosclerosis or intracranial small vessel disease, are generally treated with antiplatelet monotherapy or dual antiplatelet therapy (SAPT / DAPT) (Greco et al., Antithrombotic Therapy for Primary and Secondary Prevention of Ischemic Stroke, JACC, 2023, vol. 82, pp. 1538-1557). In recent years, the advent of direct oral anticoagulants (DOACs) has significantly improved treatment options. DOACs are easy to administer, potent, and demonstrate efficacy comparable to VKAs, often with a lower risk of bleeding. Despite significant progress in the development of safer and more effective anticoagulants (e.g., direct oral anticoagulants (DOACs)), bleeding complications in the treatment of thromboembolism remain a major concern, occurring in approximately 5% of elderly patients with atrial fibrillation (AF) (Ruff et al. Comparison of the efficacy and safety of new oral anticoagulants with warfarin in patients with atrial fibrillation: A meta-analysis of randomised trials. Lancet. 2014;383:955-962). This is one reason why an unacceptably high percentage of AF patients (approximately 30%) do not receive necessary prophylactic anticoagulation therapy.Furthermore, even among patients receiving anticoagulation therapy, approximately half are not receiving the appropriate dose (Alamneh et al., Suboptimal Use of Oral Anticoagulants in Atrial Fibrillation: Has the Introduction of Direct Oral Anticoagulants Improved Prescribing Practices? Am. J. Cardiovasc. Drugs. 2016;16:183-200).

[0011] Therefore, improving the benefit-risk ratio remains a meaningful goal in the development of antithrombotic drugs. To achieve this, it is necessary to select molecular targets that have a significant difference in hemostasis and thrombus formation. Since FXI is thought to play a more important role in thrombus formation than in hemostasis, a novel approach of inhibiting its production and activity is being investigated as a new therapeutic strategy. The above includes (a) antisense oligonucleotides (ASOs) that act on the liver to stop the synthesis of FXI in the liver (e.g., IONIS-FXI). RX and IONIS-FXI-L RX(b) small molecule compounds that target the active site of factor XI or the heparin allosteric site on activated factor XI (e.g., asundexane, milbexian, ONO-7648, EP-7041, BMS962212, sulfated pentagalloyl glucose (SPGG)) (for SPGG, see Horani et al., J Thromb Haemost. 2019 vol. 12, pp. 2110-2122), (c) monoclonal antibodies that act by inhibiting or suppressing activation (e.g., xisomab, avelacimab, osocimab, MK-2060, REGN9933, BAY1831865), and (d) aptamers (see Badimon et al. above). These strategies differ not only in their mechanism of action but also in their route of administration (oral or parenteral), onset time, and duration of effect. Parenteral administration is essential for ASOs, aptamers, and monoclonal antibodies, while small molecule drugs can be administered either parenterally or orally. The variety of onset and duration of action provides a wide range of treatment options depending on the patient's condition. For acute thrombotic events, drugs with a short onset of action are suitable, while drugs with a short duration of action are desirable in situations with a high risk of bleeding complications (such as trauma or surgery).

[0012] Despite significant advances in our understanding of platelet function mechanisms and the interaction between coagulation and thrombus formation, challenges remain in the treatment of vascular occlusive diseases. This is due to the complexity of diverse diseases, as well as the influence of immunological and inflammatory processes on hemostasis and thrombus formation. Despite the success of novel DOACs, there remains a strong medical need for more effective and safer antithrombotic drugs. While pharmacological advances have significantly impacted the outcomes of thrombotic events, they have also led to the undesirable side effect of bleeding. This problem is further complicated by the lack of clear biomarkers to assess the balance of treatment risks and benefits, particularly in combination therapies.

[0013] Milvexian (BMS-986177 / JNJ-70033093) is a direct-acting inhibitor that shows high affinity for human activating factor XI (Dilger et al., Discovery of milvexian, a high-affinity, orally bioavailable inhibitor of factor XIa in clinical studies for antithrombotic therapy. J Med Chem 2022;65(3):1770-85). Milvexian is expressed by formula (I): [ka] It is a macrocyclic compound having the following structure.

[0014] Milbexian is its chemical name (5R,9S)-9-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazole-1-yl)phenyl)-6-oxopyrimidine-1(6H)-yl)-2 1 -(difluoromethyl)-5-methyl-2 1 Also known as H-3-aza-1(4,2)-pyridina-2(5,4)-pyrazolacronafane-4-one

[0015] Milbexian and methods for producing milbexian are described in U.S. Patent No. 9,453,018, all of which are incorporated herein by reference. Solvates, crystalline, and amorphous forms of milbexian are also known to those skilled in the art (see, for example, WO2021207659 and WO2022081473). Amorphous solid dispersion compositions of milbexian in one or more polymers are described in WO2020210629, all of which are incorporated herein by reference.

[0016] In clinical trials of milbexian (milbexian, placebo, or control), 4,114 participants were included in the intervention study. Of these 4,114 participants, 3,229 received milbexian, of which 660 were included in the Phase 1 trial of milbexian, and 2,569 were included in the Phase 2 and early Phase 2 trials of milbexian. In the clinical development of milbexian, the following four types of serious bleeding were identified as adverse events: gastrointestinal bleeding, procedure-related bleeding, bleeding associated with neurological disorders (hemorrhagic changes in ischemic stroke and subdural hematoma), and hematuria. The results of a Phase II trial of milvexian in patients who underwent TKR (total knee arthroplasty) were published in 2021 (Weitz, et al., Milvexian for the Prevention of Venous Thromboembolism, N. Engl. J. Med. 2021, 385, 2161-2172), and the results of a Phase II trial using milvexian in addition to antiplatelet monotherapy or dual antiplatelet therapy (SAPT / DAPT) to prevent non-cardioembolic stroke, particularly those caused by atherosclerosis of the extracranial aorta or intracranial small vessel lesions, were published in 2023 (Sharma et al., Safety and efficacy of factor XIa inhibition with milvexian for secondary stroke prevention (AXIOMATIC-SSP): a phase 2, international, randomised, double-blind, placebo-controlled, dose-finding trial, The Lancet Neurology, 2023, vol. 23). (pp. 46-59). In two Phase II trials (AXIOMATIC-TKR and AXIOMATIC-SSP), Milbexian was evaluated in different patient populations. [Overview of the Initiative]

[0017] This disclosure provides a therapeutic regimen comprising the FXIa inhibitor milbexian and, as appropriate, one or more antiplatelet therapies, which reduces the risk of arterial and / or venous thrombosis in patients with a history of cardiovascular or cerebrovascular disease by treating and preventing thrombus formation and embolism, while suppressing thrombin generation without impairing hemostatic function.

[0018] The method disclosed herein meets the need for anticoagulation therapy in patients with cardiovascular or cerebrovascular disease who are at high risk of bleeding.

[0019] In some embodiments, the Disclosure provides a method for treating or preventing thrombotic disorders in human patients with cardiovascular or cerebrovascular disease, the method comprising administering to a human patient an immediate-release tablet containing 25 mg, 50 mg, or 100 mg of milbexian (or a pharmaceutically acceptable salt or solvate thereof) and a pharmaceutically acceptable excipient, the immediate-release tablet may be administered in combination with antiplatelet therapy as appropriate, and the immediate-release tablet is administered twice daily.

[0020] In some embodiments of the methods disclosed herein, milbexian (or a pharmaceutically acceptable salt or solvate thereof) is administered orally as a solid pharmaceutical composition comprising milbexian (or a pharmaceutically acceptable salt or solvate thereof) and a pharmaceutically acceptable excipient.

[0021] In other embodiments of the method disclosed herein, administration does not statistically significantly increase the incidence of major hemorrhagic complications. [Brief explanation of the drawing]

[0022] [Figure 1]Figure 1 shows the coagulation pathway. Explanation of terms: FXII = factor XII; FXIIa = activated factor XII; FXI = factor XI; FXIa = activated factor XI; FIX = factor IX; FIXa = activated factor IX; FVIIa = activated factor VII; FVII = factor VII; FX = factor X; FXa = activated factor X. See Kakkar et al., FXI inhibition: The Holy Grail of Haemostasis-Sparing Anticoaulation, EMJ, 2021, vol. 6, pp. 12-20; and Fredenburgh et al., FXIa as a Target for New Anticoagulants, Hamostaseologie, 2021, vol. 41, pp. 104-110.

[0023] [Figure 2] Figure 2 shows thrombus formation and vascular adverse events (e.g., ischemic stroke) associated with atrial fibrillation.

[0024] [Figure 3] Figure 2 shows the activated partial thromboplastin time, as described in Example 2. Figure 3 shows the relationship between the mean percentage change (±SD) from baseline of aPTT due to treatment and time. Within the dose range of milbexian (25 mg once daily to 200 mg twice daily), a dose-dependent increase in the percentage change from baseline of aPTT was observed. A statistical summary of the measured values ​​and percentage changes from baseline of aPTT in the PD analysis population is shown in Table 6. Values ​​after a specified time interval were used for the PD biomarker data analysis. At 4 hours, all test values ​​collected between 0.5 and 6 hours were included; at 12 hours, all test values ​​collected between 6 and 12 hours were included; and at 24 hours, all test values ​​collected between 12 and 72 hours were included.

[0025] [Figure 4]Figure 4 shows Kaplan-Meier curves for the time to ischemic stroke and / or any other stroke in all randomly selected subjects (see Example 2).

[0026] [Figure 5] Figure 5 shows Kaplan-Meier curves for the time to ischemic stroke and / or any other stroke in all randomly selected subjects (see Example 2).

[0027] [Figure 6]Figure 6 shows the median plasma concentrations (ng / mL) of milbexian at specified sampling times from day 1 to day 14, on a linear scale for each administration group (25 mg, 50 mg, or 200 mg once daily, or 25 mg, 50 mg, 100 mg, or 200 mg twice daily). In subjects who received milbexian at doses of 25 mg to 200 mg twice daily or twice daily, an increase in milbexian concentration was observed with increasing dose. For example, the concentration before administration on day 4 reached 1,570.71 ng / mL in the group receiving 100 mg twice daily and 3,699.01 ng / mL in the group receiving 200 mg twice daily. Similar dose-dependent increases were observed with once-daily administration regimens. For example, before administration on day 4, the group receiving 50 mg once daily had a concentration of 220.23 ng / mL, while the group receiving 200 mg once daily had a concentration of 228.63 ng / mL (PK analysis population (AXIOMATIC-TKR)). At 12 hours post-administration on day 4, the groups receiving 50 mg / 200 mg once daily showed higher plasma concentrations than the groups receiving 25 mg / 100 mg twice daily, respectively. However, at 12 hours post-administration on day 7, the once-daily group showed lower concentrations than the group receiving twice-daily. On day 4, the Tmax for the group receiving milbexian 25 mg / 100 mg twice daily was approximately 2 hours after administration, compared to approximately 4 hours after administration for the group receiving milbexian 50 mg / 200 mg once daily. These values ​​were consistent with the results obtained in a study with healthy subjects, where the median Tmax was 2-3 hours after once-daily administration and approximately 3 hours after twice-daily administration. The mean trough plasma concentration of milbexian reached a steady state around day 4 when patients were administered 25 mg, 50 mg, or 100 mg twice daily as capsules containing an amorphous solid dispersion produced by spray drying (AXIOMATIC-TKR Phase 2 trial). The administration of 25 mg or 100 mg is as described in WO2020210629 (see Example 3).

[0028] [Figure 7]Figure 7 shows the median aPTT baseline ratio at the prescribed sampling time points from day 1 to day 14 for each treatment group (25 mg, 50 mg, or 200 mg once daily, or 25 mg, 50 mg, 100 mg, or 200 mg twice daily). With milbexian, a prolongation of aPTT was observed with increasing dose. In this study, the group receiving milbexian 50 mg twice daily had a lower incidence of VTE and a prolongation of aPTT of approximately 2.3 times compared to the enoxaparin group. Furthermore, with higher doses of milbexian (e.g., higher than 50 mg twice daily), the incidence of VTE was even lower, and aPTT was further prolonged. At the maximum dose of 200 mg twice daily, the aPTT ratio was approximately 3.4 times (AXIOMATIC-TKR Phase 2 trial) (see Example 3).

[0029] [Figure 8] Figure 8 shows the median percentage change (%) from baseline in factor XI coagulation activity at the specified sampling time points from day 1 to day 14, for each treatment group (25 mg, 50 mg, or 200 mg once daily, or 25 mg, 50 mg, 100 mg, or 200 mg twice daily). A decrease in factor XI coagulation activity was observed with increasing dose across all dose ranges of milbexian studied. The group receiving 50 mg of milbexian twice daily had a lower incidence of VTE than the enoxaparin group, and factor XI coagulation activity decreased by an average of approximately 18%. At the maximum dose (200 mg twice daily), factor XI coagulation activity decreased by an average of approximately 79% (AXIOMATIC-TKR Phase 2 trial) (see Example 3).

[0030] [Figure 9]Figure 9A shows the highest thrombin concentration measured by mean peak height as a baseline ratio, Figure 9B shows the median area under the total thrombin production (ETP) curve as a baseline ratio, and Figure 9C shows the median time until the waveform rises in TGA measurements as a baseline ratio, for each administration group (25 mg, 50 mg, or 200 mg once daily, or 25 mg, 50 mg, 100 mg, or 200 mg twice daily) for each specified sampling time from day 1 to day 14. With milbexian administration, a clear and firm decrease in thrombin production was observed with increasing dose. When 200 mg was administered twice daily, the baseline ratio of mean peak height was 0.18 from day 10 to day 14, compared to 0.27 when 100 mg was administered twice daily (Figure 9A). As the dose increased, the peak and area under the curve (total thrombin production) of thrombin generation decreased (Figure 9B), and the time until the waveform rose increased with increasing dose (Figure 9C), indicating a delay in the time to the onset of thrombus formation (AXIOMATIC-TKR Phase 2 trial) (see Example 3).

[0031] [Figure 10A] Figure 10A shows the plasma concentration of milbexian on day 1, as a function of time from BID administration, for the film-coated direct-compression tablets (2 x 100 mg) of the present disclosure, compared to the plasma concentration of milbexian on day 1, as a function of time from BID administration, for capsules (2 x 100 mg) containing milbexian (see Example 4).

[0032] [Figure 10B] Figure 10B shows the plasma concentration of milbexian on day 5, function of time from BID administration, for the film-coated direct-compression tablets (2 x 100 mg) of this disclosure, compared to the plasma concentration of milbexian on day 5, function of time from BID administration, for capsules (2 x 100 mg) containing milbexian (see Example 4).

[0033] [Figure 10C]Figure 10C shows the plasma concentration of milbexian on day 1, as a function of time from BID administration, for the film-coated direct-compression tablets (1 x 25 mg) of the present disclosure, compared with the plasma concentration of milbexian on day 1, as a function of time from BID administration, for the capsule (1 x 25 mg) containing milbexian (see Example 4).

[0034] [Figure 10D] Figure 10D shows the plasma concentration of milbexian on day 5, function of time from BID administration, for the film-coated direct-compression tablets (1x25 mg) of this disclosure, compared to the plasma concentration of milbexian on day 5, function of time from BID administration, for capsules (1x25 mg) containing milbexian (see Example 4).

[0035] [Figure 11] Figure 11 shows the odds ratio plot obtained from the model-based meta-analysis described in "Dosage Selection" of Example 1B. [Modes for carrying out the invention]

[0036] As used herein, the term "atrial fibrillation (AF)" refers to a supraventricular tachyarrhythmia characterized by uncoordinated atrial excitation, resulting in impaired mechanical function of the atria. As used herein, atrial fibrillation also includes atrial flutter. In AF, numerous atrial waves propagating in different directions within the atria cause disordered atrial depolarization without effective atrial contraction. On an electrocardiogram, AF is characterized by the replacement of consistent P waves with rapid fibrillation waves (f waves) of varying size, shape, and timing, occurring at 350–600 beats / min, and may be accompanied by an irregular and rapid ventricular response if atrioventricular conduction is preserved. The ventricular response to AF varies depending on the electrophysiological characteristics of the atrioventricular node, the state of vagal and sympathetic nerve tone, and the effects of medications. Conventionally, an appearance lasting at least 30 seconds, or present throughout a 12-lead electrocardiogram, is considered sufficient evidence for a clinical diagnosis of AF. The latest classification proposed by the European Society of Cardiology (ESC) is as follows: (1) Initial atrial fibrillation: Regardless of the duration of the arrhythmia or the presence or severity of AF-related symptoms, this refers to the first time a patient experiences atrial fibrillation. (2) Paroxysmal atrial fibrillation: AF that usually resolves spontaneously within 48 hours. Although attacks can last up to 7 days, 48 ​​hours is a clinically important time point, and beyond this point, the likelihood of spontaneous recovery decreases, necessitating consideration of anticoagulant therapy. (3) Persistent atrial fibrillation: When AF persists for more than 7 days, or when it requires termination by pharmacological or electrical cardioversion. (4) Long-term persistent atrial fibrillation: If AF has persisted for at least one year at the time treatment aimed at restoring sinus rhythm is being considered. (5) Persistent atrial fibrillation: When the patient (and physician) accept the persistence of AF. Atrial flutter occurs when certain electrical signals are not properly transmitted to the ventricles of the heart. The rapid heartbeat associated with atrial flutter also increases the risk of blood clots and stroke. Atrial fibrillation and atrial flutter often occur simultaneously.

[0037] The terms used herein include: "patient with atrial fibrillation," "patient with atrial fibrillation or atrial flutter," "patient with a history of atrial fibrillation or atrial flutter," "patient with a history or current symptoms of atrial fibrillation or atrial flutter," or "patient with a recent history or current symptoms of atrial fibrillation or atrial flutter," or "patient with paroxysmal or persistent atrial fibrillation or atrial flutter," or "patient with a history or current symptoms of paroxysmal or persistent atrial fibrillation or atrial flutter," or "patient with a recent history or current symptoms of paroxysmal or persistent atrial fibrillation or atrial flutter." "Patients" or "Patients with paroxysmal or persistent atrial fibrillation or atrial flutter who have recently experienced either of these, are currently in sinus rhythm, or are scheduled for defibrillation" or "Patients with paroxysmal or persistent atrial fibrillation or atrial flutter who have recently experienced either of these, are currently in sinus rhythm, or are scheduled for defibrillation" means patients who have previously experienced atrial fibrillation or atrial flutter once or more times and / or patients who have experienced atrial fibrillation or atrial flutter when using milbexian or a pharmaceutically acceptable salt and are indicated for anticoagulation therapy. More specifically, this term refers to patients who have documented the presence of both atrial fibrillation or atrial flutter and sinus rhythm within six months prior to the initiation of treatment. At the time of initiation of administration of milbexian or a pharmaceutically acceptable salt, the patient may be in sinus rhythm or in a state of atrial fibrillation or atrial flutter. In some embodiments, the patient is a patient with a recent history or current condition of non-persistent atrial fibrillation or atrial flutter. In some embodiments, the patient has paroxysmal atrial fibrillation (i.e., AF that occurs intermittently and resolves spontaneously within 7 days). In some embodiments, the patient has persistent atrial fibrillation (i.e., AF that lasts longer than 7 days and may require electrical shock to restore sinus rhythm). In some embodiments, the patient has long-term persistent atrial fibrillation (i.e., AF that lasts longer than 1 year). In some embodiments, the patient has permanent / chronic atrial fibrillation (i.e., a patient who is always in a state of AF and for whom all attempts to restore sinus rhythm have failed).In some embodiments, patients with a recent history of atrial fibrillation or atrial flutter also have co-existing coronary artery disease (CAD) and / or peripheral artery disease (PAD). In some embodiments, patients with a recent history of paroxysmal, persistent, or irreversible atrial fibrillation or atrial flutter received such diagnosis within one year prior to the first dose of the milbexian regimen described herein. Among patients, those with a history of atrial fibrillation or atrial flutter are further: (i) 75 years of age or older, (ii) A history of stroke with clinical symptoms (e.g., a history of symptomatic or asymptomatic stroke of any type (ischemic, hemorrhagic, lacunar, or of unknown cause)), or a history of intracerebral microhemorrhage (CMB) (wherein in the case of ischemic stroke, it must have occurred at least 7 days prior to the first dose of the milbexian regimen described herein, and in the case of hemorrhagic stroke / hemorrhagic transformation, it must have occurred at least 3 months prior). Having one or more risk factors in category (A) selected from; and / or below: (i) 65-74 years old; (ii) Hypertension (for example, a history of antihypertensive drug use within 6 months prior to screening, or a persistently high systolic blood pressure of over 140 mmHg or a high diastolic blood pressure of over 90 mmHg); (iii) Diabetes (for example, having a history of diabetes and currently taking medication for diabetes); (iv) Atherosclerotic vascular diseases (arteriosclerosis, CAD, MI, PAD, PCI, CABG); and (v) Congestive heart failure (e.g., symptomatic heart failure, a history of hospitalization primarily due to heart failure (regardless of ejection fraction (EF)), or an EF of less than 40% regardless of a history of hospitalization due to heart failure (the most recent EF within one year prior to the first dose of the milbexian regimen described herein)) The patient has two or more cardiovascular risk factors in category (B), selected from the group consisting of the following. A normal ejection fraction is 50% or higher. If the ejection fraction is less than 40%, the heart is not pumping enough blood and may be presenting with heart failure. The terms "persistent" and "intermittent" are used synonymously. More specifically, this term refers to patients who are medically stable and suitable for chronic antithrombotic drug therapy. The term CMB is defined as a lesion that appears as a circular low-signal area less than 10 mm in size on T2*-weighted MRI images and is clearly distinguishable from vascular flow voids, leptomeningeal hemosiderosis, and non-hemorrhagic subcortical calcification.

[0038] A patient with "persistent atrial fibrillation or atrial flutter" is defined as a patient in whom the corresponding waveform is confirmed on all scheduled ECG examinations throughout the period of administration of delonedarone or a pharmaceutically acceptable salt thereof.

[0039] "Cerebrovascular disorder" refers to neurological disorders caused by impaired blood flow to the brain, resulting in damage or death of brain cells due to oxygen deprivation. In some embodiments, cerebrovascular disorder includes transient ischemic attacks (TIAs). In some embodiments, cerebrovascular disorder includes stroke. How a stroke or TIA affects the body depends on which part of the brain is affected by the interruption of blood supply.

[0040] In some embodiments, the term “stroke” refers to an acute neurological disorder that causes necrosis of brain tissue (cerebral infarction) due to insufficient blood flow and oxygen supply to the brain. Stroke can be either ischemic or hemorrhagic. In ischemic stroke, blood supply to a part of the brain is cut off because a blood vessel is blocked by either a locally formed thrombus in an abnormal artery (e.g., atherosclerosis) or an embolus formed upstream and traveling through the bloodstream. In hemorrhagic stroke, a blood vessel ruptures, disrupting normal blood flow and causing blood to leak into a specific area of ​​the brain, damaging that area. The vast majority of strokes are sudden and rapidly progressing, causing brain damage within minutes (complete stroke). Less common, however, is a progressive stroke in which the area of ​​necrotic brain tissue continuously expands and the stroke continues to worsen over hours to days. Ischemic stroke can also be either lacunar or non-lacunar in nature. When an ischemic stroke is caused by arterial occlusion due to an embolus presumed to originate from a thrombus formed in the heart or its valves, it may be a cardiogenic embolic stroke. In some embodiments, ischemic stroke is a non-cardiogenic embolic stroke. The definition of ischemic stroke is based on the 2013 guidelines (Sacco et al., An updated definition of stroke for the 21st century Stroke, 44 (2013), pp. 2064-2089).

[0041] In some embodiments, "stroke" refers to ischemic stroke, hemorrhagic stroke, or stroke of unknown cause. In clinical trials, stroke severity is measured using the National Institutes of Health Stroke Scale (NIHSS) score (Kamel et al., Validation of the International Classification of Diseases, Tenth Revision Code for the National Institutes of Health Stroke Scale Score. Circ Cardiovasc Qual Outcomes, 2023, vol. 16, e009215). Stroke severity is classified as follows: 1-4 = mild stroke, 5-15 = moderate stroke, 16-20 = moderate to severe stroke, 21-42 = severe stroke.

[0042] In some embodiments, ischemic stroke refers to neurological disorders accompanied by clinical symptoms, resulting from non-lacunar acute cerebral infarction detected by neuroimaging (CT or MRI).

[0043] In some embodiments, ischemic stroke is further identified as having a National Institutes of Health Stroke Scale (NIHSS) score of 7 or less.

[0044] In another embodiment, ischemic stroke is further identified as having a National Institutes of Health Stroke Scale (NIHSS) score of 8–15.

[0045] In another embodiment, ischemic stroke is further identified as having a National Institutes of Health Stroke Scale (NIHSS) score of 15 or less.

[0046] In other embodiments, the ischemic stroke is further characterized by the presence of atherosclerotic plaque in the associated intracranial or carotid artery, ulcers or thrombi in the nutrient arteries, which are confirmed by imaging studies (either Doppler ultrasound, CTA, MRA, or catheter angiography).

[0047] In yet another embodiment, ischemic stroke is further identified by a modified Ranking Scale. For example, in some embodiments, ischemic stroke is identified by a modified Ranking Scale (mRS) score of 3 or less, 4 or less, 5 or less, or 6 or less.

[0048] In some embodiments, MI is defined according to the fourth universal definition of MI, with the exception of Type 2 myocardial infarction (Thygesen et al., Fourth universal definition of myocardial infarction (2018) Eur. Heart J., 40 (2019), pp. 237-269).

[0049] In some embodiments, cardiovascular death is classified as a death in which the primary cause of death is MI, stroke, other thromboembolism of the vascular bed, heart failure, primary arrhythmia, or cardiovascular procedure.

[0050] As used herein, the term "activated partial thromboplastin time (aPTT)" refers to an indicator of the intrinsic and common pathways of the coagulation cascade. It represents the time, in seconds, for plasma to coagulate after the addition of phospholipids, intrinsic pathway activators, and calcium. The name "activated partial thromboplastin time" originates from the original method of this test. In the original method, only phospholipid concentration was controlled (as opposed to forms that controlled both phospholipid and surface activator concentrations), and the term "partial thromboplastin" was used at the time for phospholipid preparations that promoted coagulation but did not correct the prolongation of coagulation time in hemophilic plasma. The term "partial" means that phospholipids are present but tissue factor is absent. Normal values ​​and reference ranges vary depending on the combination of reagents and instruments, particularly the phospholipid composition.

[0051] In some embodiments, the aPTT is measured as follows. A plasma sample is incubated with Actin FS (aPTT assay reagent) containing a standard amount of phospholipid and a contact factor (ellagic acid) that activates the intrinsic system for 3 minutes, calcium chloride is then added to initiate coagulation, and the formation of fibrin thrombus is optically measured. The time to thrombus formation (in seconds) is reported as the activated partial thromboplastin time (aPTT).

[0052] When milvexian was orally administered to healthy human subjects multiple times, the aPTT was prolonged depending on the dose and concentration. The average maximum change in aPTT from baseline increased approximately 1.1 - 4.1 fold after administration of 5 - 500 mg once daily for 2 weeks and increased 3.4 fold after administration of 200 mg twice daily for 2 weeks. Single or multiple administrations of milvexian to human subjects had no effect on the prothrombin time, and the maximum average change rate from baseline was approximately 5%. Here, the prothrombin time (PT) test used in this specification measures the time until a thrombus is formed in a blood sample

[0053] The "Factor XI coagulation activity" used in this specification is measured using a one - stage coagulation method based on aPTT. Serial diluted normal plasma is mixed with FXI - deficient plasma, the coagulation time is measured according to a standard aPTT protocol, and a reference range is set. The sample plasma is processed in the same manner and compared with the above - mentioned reference plasma.

[0054] In some embodiments, the Factor XI coagulation activity is measured as follows. The Factor XI (FXI) activity applies the measurement principle of the activated partial thromboplastin time (aPTT) and uses Actin FS (Siemens Healthcare) for BCS (登録商標)Measurements were taken using an XP analyzer (Siemens Healthcare). A 6-point calibration curve was created using a secondary standard material (standard human plasma, Siemens Healthcare Diagnostics Inc.) with known FXI concentrations assigned by the manufacturer, covering a range of approximately 5% to 150%. Approximately 100% of the reference standard plasma was used for BCS (Body Conditioning). (登録商標) The sample was diluted with physiological saline using an XP analyzer to a pre-set FXI calibration level. The calibration curve was fitted using a log / lin regression curve with FXI activity rate (%) plotted on the x-axis and coagulation time (seconds) on the y-axis. The sample to be tested was mixed with FXI-deficient plasma (less than 1% FXI, with at least 75% of all other factors) to normalize all other factors. After adding aPTT reagent (Actin FS) and incubating the mixture, calcium chloride was added to the mixture, and the optically measured thrombus formation time was compared to the time on the calibration curve. The sample was BCS (登録商標) Measurements were taken using XP after basic dilution (1:10) with physiological saline.

[0055] The "thrombin generation test (TGA)" used herein is a comprehensive coagulation test that evaluates the thrombogenic potential of plasma samples and has been shown to potentially reflect thrombotic or bleeding tendencies more accurately than conventional coagulation tests. In conventional TGA, coagulation via the extrinsic pathway is initiated by adding tissue factor, phospholipids, and calcium to citrated plasma. In this study, a kaolin slurry was used to initiate intrinsic coagulation in an in vitro thrombin generation test (TGA) using human platelet-rich plasma. Thrombin generation was continuously monitored via products released by the cleavage of a thrombin-specific fluorescent substrate. Using the obtained thrombogram, several relevant parameters were calculated, including intrinsic thrombin generation ability (defined as the area under the curve between thrombin concentration and time). In some embodiments, single or multiple oral administration of milbexian to human subjects inhibits intrinsic thrombin generation, but only slightly inhibits extrinsic thrombin generation.

[0056] As used herein, “prevention” means reducing the occurrence of a risk. In some embodiments, prevention includes eliminating the occurrence of a risk (i.e., reducing the occurrence of a risk to zero). Therefore, “prevention” includes prophylactic treatment to reduce the probability of clinical disease development. In some embodiments, the treatment regimens described herein are administered to patients at risk of developing thromboembolic disease to prevent the development of thromboembolic disease (primary prevention). In some embodiments, the treatment regimens described herein are administered as secondary prevention to patients after the initial onset of a thrombotic condition (e.g., secondary prevention of cardiovascular events in patients with a history of acute myocardial infarction or acute coronary syndrome). In clinical practice, aspirin and clopidogrel (or other thienopyridine derivatives) may be used in combination to prevent secondary thrombosis.

[0057] In some embodiments, “prevention” is synonymous with “reduced risk” or “reduced incidence” of adverse events of atherosclerosis (e.g., MACE). A reduction in risk or incidence means that the incidence of adverse events of atherosclerosis is reduced numerically and / or statistically significantly by at least 1%. Preferably, the reduction is 2% or more, 3% or more, 4% or more, 5% or more, 6% or more, 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 reductions include those with confidence intervals of 50% or more, 75% or more, 80% or more, 90% or more, 95% or more, 98% or more, and 99% or more. A confidence interval of 95% or more is desirable.

[0058] Within the scope of this disclosure, “prevention” means prophylactic treatment to reduce and / or minimize the risk of disease and / or disease recurrence by administering to a patient a therapeutically effective amount of milbexian or a pharmaceutically acceptable salt or solvate thereof. Patients receiving prophylactic treatment may be selected based on factors known to be at higher risk of clinically developing the disease compared to the general population. Prophylactic treatment may be administered whether or not clinical symptoms of the disease are present. “Prophylactic” treatment may be classified into (a) primary prevention and (b) secondary prevention. Primary prevention is defined as treatment to reduce or minimize the risk of disease in patients who have not yet developed clinical disease, while secondary prevention is defined as treatment to reduce or minimize the risk of recurrence or secondary development of the same or similar clinical disease.

[0059] As used herein, the term “treatment” means improving the signs or symptoms of a patient’s disease or condition, and / or preventing the patient’s disease or condition. Unless otherwise specified, as used herein, the terms “treatment,” “procedure,” etc., include the management and care of a patient aimed at combating a disease, condition, or disorder, and include administering milbexian to prevent the onset of symptoms or complications, to alleviate symptoms or complications, or to resolve the disease, condition, or disorder. Accordingly, “treatment” or “procedure” refers to the treatment of a human disease condition and includes (a) suppression of the disease, i.e., cessation of its progression; and / or (b) relief of the disease, i.e., reduction of the condition.

[0060] As used herein, "risk factor" refers to a demographic factor that influences the underlying risk of a particular event, regardless of any drug treatment.

[0061] As used herein, the term "atherosclerosis" refers to major cardiovascular adverse events (MACE), major vascular adverse events (MAVE), arrhythmogenic cardiomyopathy, major lower extremity adverse events (MALE), or a combination thereof.

[0062] As used herein, the terms “major cardiovascular adverse event” or “MACE” mean cardiovascular death, non-fatal myocardial infarction, ischemic stroke, or a combination thereof.

[0063] As used herein, the terms “major vascular adverse events” or “MAVE” refer to cardiovascular death, non-fatal myocardial infarction, ischemic stroke, MALE, symptomatic VTE, or a combination thereof.

[0064] As used herein, the terms “Major Lower Limb Adverse Event” or “MALE” refer to acute limb ischemia (ALI), major non-traumatic vascular amputation, or a combination thereof.

[0065] As used herein, the term "symptomatic VTE" refers to pulmonary embolism, deep vein thrombosis, or a combination thereof.

[0066] As used herein, “medically acceptable salt” refers to a derivative of a compound modified by the formation of an acid salt or base salt thereof. Examples of medically acceptable salts include, but are not limited to, inorganic or organic acid salts of basic functional groups (e.g., amines) and alkali or organic salts of acidic functional groups (e.g., carboxylic acids). Medically acceptable salts include, for example, non-toxic conventional salts or quaternary ammonium salts of parent compounds formed from non-toxic inorganic or organic acids. For example, conventional non-toxic salts include those produced from inorganic acids (e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, and nitric acid) and organic acids (e.g., acetic acid, propionic acid, succinic acid, glycolic acid, stearic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, pamoic acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, sulfanilic acid, 2-acetoxybenzoic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethanedisulfonic acid, oxalic acid, and isethionic acid). Medicinally acceptable salts of milbexian can be synthesized using conventional chemical methods. Generally, such salts can be produced by reacting milbexian with a stoichiometric amount of a suitable base or acid in water, an organic solvent, or a mixture of the two. Generally, non-aqueous solvents such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are suitable. Suitable salts are listed in Remington's Pharmaceutical Sciences, 18th Edition, Mack Publishing Company, Easton, Pa. (1990), which is incorporated herein by reference.

[0067] As used herein, the term "standard treatment" refers to a treatment process that is generally considered appropriate by medical professionals for the treatment of a particular disease (e.g., acute coronary syndrome) and is widely used by healthcare professionals.

[0068] As used herein, "safe" means that, compared to antiplatelet therapy alone, the regulatory authority determines that the reduction in the risk of human atherosclerotic events outweighs the increased risk of adverse events (e.g., serious bleeding), and that a pure clinical benefit is obtained.

[0069] As used herein, "effective" means that the regimen in question demonstrates a reduction in the risk of atherosclerotic events and a therapeutic effect compared to antiplatelet therapy alone.

[0070] The absolute rate of risk reduction (ARR) is calculated by subtracting the proportion of patients with a poor prognosis in the treatment group (i.e., the group receiving the regimen) from the proportion of patients with a poor prognosis in the control group (i.e., the group not receiving the regimen). For example, if the incidence rate in the control group is 20% (i.e., 20% of patients in the control group have a poor prognosis) and the incidence rate in the treatment group is 12% (i.e., 12% of patients have a poor prognosis), then the absolute rate of risk reduction (ARR) is 8% (i.e., 20% - 12%).

[0071] Relative risk (RR) refers to the percentage of adverse outcomes (e.g., ischemic stroke) in the treatment group (i.e., the group that received the regimen) divided by the percentage of adverse outcomes in the control group (i.e., the group that did not receive the regimen). For example, if 20% of patients in the control group experience adverse events and 12% of patients in the treatment group experience adverse events, the RR = 0.12 / 0.20 = 0.6. Therefore, an RR of less than 1 indicates a reduction in risk.

[0072] As used herein, the term "relative risk reduction (RRR)" is an indicator that shows how much the treatment group has reduced the risk of adverse outcomes compared to the control group. For example, if 20% of patients in the control group experience adverse events and 12% of patients in the treatment group experience adverse events, then the RRR = (1-RR)*100% = [1-(0.12 / 0.20)]*100% = 0.4*100% = 40%. Therefore, an RRR greater than 0% indicates a reduction in risk.

[0073] In some embodiments, the "Bleeding Academic Research Consortium (BARC) bleeding criteria" are described in Roxana Mehran, et al. Standardized Bleeding Definitions for Cardiovascular Clinical Trials, Circulation. 2011;123:2736-2747, which is incorporated herein by reference.

[0074] In another embodiment, the “Bleeding Academic Research Consortium (BARC) bleeding criteria” are described in Pascal Vranckx, et al. Validation of BARC Bleeding Criteria in Patients With Acute Coronary Syndromes J Am Coll Cardiol 2016;67:2135-44, which is incorporated herein by reference.

[0075] In some embodiments, the GUSTO bleeding criteria are described in "An international randomized trial comparing four thrombolytic strategies for acute myocardial infarction. GUSTO investigators, N Engl J Med 1993;329:673-82," which is incorporated herein by reference.

[0076] In some embodiments, the GUSTO bleeding criteria are described in Pascal Vranckx, et al. Validation of BARC Bleeding Criteria in Patients With Acute Coronary Syndromes J Am Coll Cardiol 2016;67:2135-44, which disclosure is incorporated herein by reference.

[0077] In some embodiments, the TIMI bleeding criteria are described in Rao AK, Pratt C, Berke A, et al. Thrombolysis in Myocardial Infarction (TIMI) Trial-phase I: hemorrhagic manifestations and changes in plasma fibrinogen and the fibrinolytic system in patients treated with recombinant tissue plasminogen activator and streptokinase. J Am Coll Cardiol 1988;11: 1-11, which disclosure is incorporated herein by reference.

[0078] In some embodiments, the TIMI bleeding criteria are described in Pascal Vranckx, et al. Validation of BARC Bleeding Criteria in Patients With Acute Coronary Syndromes J Am Coll Cardiol 2016;67:2135-44, which disclosure is incorporated herein by reference.

[0079] In some embodiments, "Type 3 of the Bleeding Academic Research Consortium (BARC) bleeding criteria" refers to (a) obvious bleeding + a hemoglobin decrease of 3 to <5 g / dL associated with bleeding, and transfusion due to obvious bleeding; (b) obvious bleeding + a hemoglobin decrease of ≥5 g / dL associated with bleeding, cardiac tamponade, bleeding requiring surgical intervention, bleeding requiring intravenous administration of vasoactive agents, or (c) intracranial hemorrhage confirmed by subcutaneous examination, imaging, or lumbar puncture, and intraocular hemorrhage with visual impairment. See, for example, Roxana Mehran, et al. Standardized Bleeding Definitions for Cardiovascular Clinical Trials, Circulation. 2011;123:2736-2747.

[0080] In some embodiments, "Type 5 of the Bleeding Academic Research Consortium (BARC) bleeding criteria" refers to (a) bleeding that is likely to be fatal, or (b) bleeding that is clearly fatal (obvious bleeding or confirmed by autopsy or imaging). See, for example, Roxana Mehran, et al. Standardized Bleeding Definitions for Cardiovascular Clinical Trials, Circulation. 2011;123:2736-2747.

[0081] In some embodiments, "Type 2 of the Bleeding Academic Research Consortium (BARC) bleeding criteria" refers to a clear sign of bleeding that requires medical attention, diagnosis, hospitalization, or treatment by a healthcare professional. See, for example, Roxana Mehran, et al. Standardized Bleeding Definitions for Cardiovascular Clinical Trials, Circulation. 2011;123:2736-2747.

[0082] In some embodiments, the "ISTH criteria (major bleeding or clinically significant non-major bleeding (CRNM))" are as follows: Major bleeding in ISTH in non-surgical patients is characterized by the presence of clinical symptoms. i. Fatal bleeding and / or ii. Bleeding in vital sites or organs (e.g., intracranial, intraspinal, intraocular, retroperitoneal, intra-articular or pericardial, or intramuscular bleeding associated with compartment syndrome, and / or iii. Bleeding resulting in a decrease in hemoglobin levels of 20 g / L (1.24 mmol / L) or more, or bleeding requiring 2 or more units of whole blood transfusion or red blood cell transfusion. It is defined as follows. ISTH's definition of CRNM bleeding is a sign or symptom of bleeding (e.g., bleeding discovered solely by imaging, or bleeding greater than expected from the clinical context) that does not meet ISTH's definition of major bleeding, but follows: i. Medical intervention by healthcare professionals is required. ii. Reaching a condition requiring hospitalization or advanced medical care. iii. Face-to-face assessments should be encouraged, rather than those conducted by telephone or electronic communication. It is defined as bleeding that satisfies at least one of the following criteria.

[0083] For example, when using approximation terms (e.g., "approximately" or "about") to refer to quantity, duration, or degree of effect, it is understood that these may mean values ​​within ±5%, ±7.5%, ±10%, ±12.5%, ±15%, ±17.5%, or ±20% of a given number.

[0084] In some embodiments, the Disclosure provides a method for treating or preventing thrombotic disorders in human patients with cardiovascular or cerebrovascular disease, characterized by administering to the human patient an immediate-release tablet containing 25 mg, 50 mg, or 100 mg of milbexian (or a pharmaceutically acceptable salt or solvate thereof) and a pharmaceutically acceptable excipient, the immediate-release tablet may be administered in combination with antiplatelet therapy as appropriate, and the immediate-release tablet being administered twice daily.

[0085] In some embodiments, the thrombotic disorder is a thromboembolic disorder selected from arterial thromboembolism, venous thromboembolism, or thromboembolism in the cardiac chambers or peripheral circulation.

[0086] In some embodiments, thrombotic disease is thromboembolism.

[0087] In some embodiments, the thrombotic disease is arterial thromboembolism.

[0088] In some embodiments, arterial thromboembolism refers to coronary artery thrombosis, cerebral artery thrombosis, arterial embolism, stroke, acute ischemic stroke, transient ischemic attack (TIA), myocardial infarction, cerebral embolism, acute coronary syndrome, atherosclerosis, peripheral occlusive arterial disease, cardiovascular death, or a combination thereof.

[0089] In some embodiments, the thrombotic disease is venous thromboembolism.

[0090] In some embodiments, venous thromboembolism is defined as deep vein thrombosis, venous thromboembolism, pulmonary embolism, death, or a combination thereof.

[0091] In some embodiments, thrombotic disorders are thromboembolic events in the cardiac chambers or peripheral circulation.

[0092] In some embodiments, thrombotic disorders include unstable angina, acute coronary syndrome, atrial fibrillation, myocardial infarction, transient ischemic attack, stroke, atherosclerosis, peripheral occlusive arterial disease, venous thrombosis, deep vein thrombosis, thrombophlebitis, arterial embolism, coronary artery thrombosis, cerebral artery thrombosis, cerebral embolism, renal embolism, pulmonary embolism, or thrombosis resulting from medical implants, medical devices, or medical procedures in which thrombus formation is promoted by exposure of blood to an artificial surface.

[0093] In some embodiments, the thrombotic disorder is a stroke and / or a systemic embolism other than that of the central nervous system (CNS).

[0094] In some embodiments, the thrombotic disorder is unstable angina.

[0095] In some embodiments, the thrombotic disorder is acute coronary syndrome.

[0096] In some embodiments, thrombotic disease is chronic coronary disease.

[0097] In some embodiments, the thrombotic disorder is chronic coronary syndrome.

[0098] In some embodiments, the thrombotic disorder is atrial fibrillation.

[0099] In some embodiments, the thrombotic disease is myocardial infarction.

[0100] In some embodiments, the thrombotic disorder is a transient ischemic attack.

[0101] In some embodiments, the thrombotic disease is a stroke.

[0102] In some embodiments, the thrombotic disease is atherosclerosis.

[0103] In some embodiments, thrombotic disease is peripheral occlusive arterial disease.

[0104] In some embodiments, the thrombotic disease is venous thrombosis.

[0105] In some embodiments, the thrombotic disorder is deep vein thrombosis.

[0106] In some embodiments, the thrombotic disease is thrombophlebitis.

[0107] In some embodiments, thrombotic disease is arterial embolism.

[0108] In some embodiments, the thrombotic disease is coronary artery thrombosis.

[0109] In some embodiments, the thrombotic disease is cerebral artery thrombosis.

[0110] In some embodiments, thrombotic disease is cerebral embolism.

[0111] In some embodiments, the thrombotic disease is renal embolism.

[0112] In some embodiments, the thrombotic disease is pulmonary embolism.

[0113] In some embodiments, thrombosis is caused by medical implants, medical devices, or medical procedures, such that thrombus formation is promoted by exposure of blood to an artificial surface.

[0114] In some embodiments, thrombotic disorders include arterial thromboembolism associated with acute coronary syndrome. In some embodiments, thrombotic disorders include arterial thromboembolism associated with chronic coronary disease. In some embodiments, thrombotic disorders include arterial thromboembolism associated with chronic coronary syndrome.

[0115] In some embodiments, the methods described herein are performed on human patients with cardiovascular or cerebrovascular disease.

[0116] In some embodiments, cardiovascular disease or cerebrovascular disease is cerebrovascular disease. In some embodiments, cerebrovascular disease is selected from non-cardiogenic ischemic stroke or transient ischemic attack (TIA).

[0117] In another embodiment, cardiovascular disease or cerebrovascular disease is a cardiovascular disease.

[0118] In some embodiments, the cardiovascular disease is atrial fibrillation or atrial flutter.

[0119] In another embodiment, the cardiovascular disease is acute coronary syndrome. In another embodiment, the cardiovascular disease is chronic coronary disease. In another embodiment, the cardiovascular disease is chronic coronary syndrome.

[0120] In certain embodiments, the Disclosure relates to a method for preventing cerebrovascular or cardiovascular adverse events in human patients with acute coronary syndrome (ACS), the method characterized by measuring the baseline factor XI coagulation activity of the patient, and then implementing a regimen comprising (i) a pharmaceutical composition comprising 25 mg of milbexian (or a pharmaceutically acceptable salt or solvate thereof); and (ii) an antiplatelet therapy selected from the group consisting of aspirin, P2Y12 inhibitors, and combinations thereof; administering the pharmaceutical composition twice daily.

[0121] In some embodiments, antiplatelet therapy is dual antiplatelet therapy (DAPT), which includes once-daily administration of aspirin (75-100 mg) and administration of a P2Y12 inhibitor. In some embodiments, antiplatelet therapy is antiplatelet monotherapy (SAPT). In some embodiments, the above method includes the implementation of antiplatelet therapy consisting of dual antiplatelet therapy and antiplatelet monotherapy. In some embodiments, antiplatelet therapy includes DAPT.

[0122] In some embodiments, DAPT includes the administration of aspirin and prasugrel. In some embodiments, DAPT includes the administration of aspirin and prasugrel for 12 months.

[0123] In some embodiments, DAPT includes the administration of aspirin and clopidogrel. In some embodiments, aspirin and clopidogrel are administered for 21 days to 12 months. In some embodiments, DAPT includes the administration of aspirin and clopidogrel. In some embodiments, aspirin and clopidogrel are administered for 21 days. In some embodiments, aspirin and clopidogrel are administered for 6 months. In some embodiments, aspirin and clopidogrel are administered for 12 months.

[0124] In some embodiments, DAPT includes the administration of aspirin and ticagrelor. In some embodiments, DAPT includes the administration of aspirin and ticagrelor for 12 months. In some embodiments, DAPT includes the administration of aspirin (75-100 mg) once daily for the first 12 months, followed by administration of a P2Y12 inhibitor, and then aspirin monotherapy for 6-12 months.

[0125] In some embodiments, DAPT includes once-daily administration of aspirin (75-100 mg) for the first 21 days and administration of a P2Y12 inhibitor, followed by 6 months of aspirin monotherapy.

[0126] In some embodiments, DAPT includes once-daily administration of aspirin (75-100 mg) for the first 21 days and administration of a P2Y12 inhibitor, followed by 12 months of aspirin monotherapy.

[0127] In some embodiments, DAPT includes once-daily administration of aspirin (75-100 mg) for the first 21 days, followed by once-daily administration of 75 mg of clopidogrel, and then 6 months of aspirin monotherapy.

[0128] In some embodiments, DAPT includes once-daily administration of aspirin (75-100 mg) for the first 12 months, followed by once-daily administration of ticagrelor (90 mg), and then once-daily administration of aspirin (75-100 mg) for 12 months.

[0129] In some embodiments, DAPT includes once-daily administration of aspirin (75-100 mg) and once-daily administration of ticagrelor (90 mg) for the first 12 months, followed by once-daily administration of ticagrelor (90 mg) for 23 months.

[0130] In some embodiments, DAPT includes once-daily administration of aspirin (75-100 mg) and twice-daily administration of 75 mg of ticagrelor. In some embodiments, 75-100 mg of aspirin is administered once daily and 75 mg of ticagrelor is administered twice daily for 12 months.

[0131] In some embodiments, DAPT includes once-daily administration of aspirin (81-100 mg) and once-daily administration of ticagrelor (90 mg). In some embodiments, 81-100 mg of aspirin is administered once daily and 90 mg of ticagrelor is administered twice daily for three years.

[0132] In some embodiments, antiplatelet therapy includes 30 to 90 days of aspirin administration followed by clopidogrel monotherapy. In some embodiments, antiplatelet therapy includes 60 days of aspirin administration followed by clopidogrel monotherapy. In some embodiments, antiplatelet therapy includes 90 days of aspirin administration followed by clopidogrel monotherapy.

[0133] In some embodiments, antiplatelet therapy includes SAPT.

[0134] In some embodiments, SAPT includes the administration of aspirin. In some embodiments, aspirin monotherapy is administered once daily. In some embodiments, aspirin monotherapy is administered once daily for 3 months to 3 years. In some embodiments, aspirin monotherapy is administered once daily for 3 months. In some embodiments, aspirin monotherapy is administered once daily for 6 months. In some embodiments, aspirin monotherapy is administered once daily for 12 months. In some embodiments, aspirin monotherapy is administered once daily for 24 months. In some embodiments, aspirin monotherapy is administered once daily for 36 months. In some embodiments, aspirin monotherapy is administered twice daily.

[0135] In some embodiments, SAPT includes the administration of a P2Y12 inhibitor. In some embodiments, the P2Y12 inhibitor is selected from prasugrel, clopidogrel, seratogrel, or ticagrelor. In some embodiments, the P2Y12 inhibitor is administered as monotherapy for 3 to 6 months.

[0136] In some embodiments, SAPT includes administration of clopidogrel. In some embodiments, SAPT includes administration of ticagrelor. In some embodiments, SAPT includes ticagrelor monotherapy followed by administration of 20 mg of aspirin twice daily.

[0137] In some embodiments, SAPT includes once-daily administration of aspirin (75-100 mg). In some embodiments, 75-100 mg of aspirin is administered once daily for 12 months.

[0138] In some embodiments, SAPT includes once-daily administration of ticagrelor (90 mg). In some embodiments, 90 mg of ticagrelor is administered twice daily for three years.

[0139] In some embodiments, SAPT includes administration of clopidogrel. In some embodiments, aspirin monotherapy is administered first, followed by clopidogrel monotherapy for at least a further two months.

[0140] In some embodiments, the methods disclosed herein relate to the primary prevention of cerebrovascular adverse events or cardiovascular adverse events.

[0141] In some embodiments, the methods disclosed herein relate to the secondary prevention of cerebrovascular adverse events or cardiovascular adverse events.

[0142] In some embodiments of the methods of this disclosure, a cerebrovascular adverse event or a cardiovascular adverse event includes one or more of stroke, heart attack, or death.

[0143] In some embodiments of the methods of this disclosure, the cerebrovascular adverse event or cardiovascular adverse event occurs in an organ selected from the heart, brain, limbs, blood circulation system, or blood vessels.

[0144] In some embodiments of the methods of this disclosure, the cerebrovascular adverse event or cardiovascular adverse event includes one or more major cardiovascular adverse events (MACE) selected from the group consisting of cardiovascular death, non-fatal myocardial infarction, ischemic stroke, and combinations thereof.

[0145] In other embodiments of the methods of the present disclosure, cerebrovascular or cardiovascular adverse events include one or more major vascular adverse events (MAVE) selected from the group consisting of MACE; major lower limb adverse events (MALE) including one or more selected from acute limb ischemia, chronic limb ischemia, or major amputation; symptomatic venous thromboembolic adverse events; and combinations thereof.

[0146] In some embodiments of the method of this disclosure, the cerebrovascular adverse event or cardiovascular adverse event is selected from the group consisting of arrhythmogenic cardiomyopathy, non-fatal myocardial infarction, ischemic stroke, and combinations thereof.

[0147] In some embodiments of the methods of this disclosure, cerebrovascular adverse events or cardiovascular adverse events include cardiovascular death.

[0148] In some embodiments of the methods disclosed herein, cerebrovascular adverse events or cardiovascular adverse events include arrhythmogenic cardiomyopathy.

[0149] In certain embodiments, this disclosure relates to a method for preventing cerebrovascular or cardiovascular adverse events in human patients with chronic coronary syndrome (CCS) or chronic coronary disease (CCD), characterized by measuring the patient's baseline factor XI coagulation activity, and then administering to the human patient (i) approximately 25 mg to approximately 100 mg of milbexian twice daily (BID), and (ii) implementing a regimen including antiplatelet therapy. As used herein, “chronic coronary disease (CCD)” is a diverse group of conditions including obstructive or non-obstructive CAD (regardless of whether there has been a history of myocardial infarction (MI) or revascularization), ischemic heart disease diagnosed solely by non-invasive tests, and chronic angina syndrome with various underlying causes. Care for CCD patients encompasses a range of services, from post-acute care for patients experiencing chest pain, acute coronary syndrome (ACS), or both, to CCD-related management for outpatients (Virani et al., 2023 AHA / ACC / ACCP / ASPC / NLA / PCNA Guideline for the Management of Patients With Chronic Coronary Disease, Circulation, 2023, Vol. 148, pp. e9-e119). In this specification, "chronic coronary syndrome (CCS)" refers to the following clinical conditions in patients suspected of having CCS or with a confirmed diagnosis of CCS.(i) Patients suspected of having CAD who have symptoms of "stable" angina and / or dyspnea; (ii) Patients suspected of having CAD who have newly developed heart failure (HF) or left ventricular (LV) dysfunction; (iii) Stable, asymptomatic or symptomatic patients less than one year after ACS onset, or patients who have recently undergone revascularization; (iv) Asymptomatic or symptomatic patients more than one year after initial consultation or revascularization; (v) Patients with suspected angina with coronary spasm or microangiopathy (see Section 6); and (vi) Asymptomatic patients in whom CAD was discovered at screening (Wijns et al., 2019 Guidelines on Chronic Coronary Syndromes ESC Clinical Practice Guidelines, European Heart Journal, 2019, 00, pp. 1-71).

[0150] In some embodiments, human patients with chronic coronary syndrome (CCS) or chronic coronary disease (CCD) also have atrial fibrillation.

[0151] In some embodiments, milbexian is administered at a dose of 25.0 mg twice daily. In some embodiments, milbexian is administered at a dose of 50.0 mg twice daily. In some embodiments, milbexian is administered at a dose of 75.0 mg twice daily. In some embodiments, milbexian is administered at a dose of 100.0 mg twice daily.

[0152] In some embodiments, antiplatelet therapy for CCS or CCD includes SAPT for secondary prevention in patients with CCS or CCD. In some embodiments, SAPT for secondary prevention in patients with CCS or CCD includes administering 75-100 mg of aspirin once daily for 6 months. In some embodiments, SAPT for secondary prevention in patients with CCS or CCD includes administering 75 mg of clopidogrel once daily for 6 months. In some embodiments, SAPT for CCS or CCD includes administering 75 mg of clopidogrel once daily for 24 months. In some embodiments, SAPT for CCS or CCD includes administering 325 mg of aspirin once daily for 24 months. In some embodiments, SAPT for CCS or CCD includes administering 90 mg of ticagrelor twice daily and aspirin, for 3 years. In some embodiments, SAPT for CCS or CCD includes administering 60 mg of ticagrelor twice daily and aspirin, for three years. In some embodiments, antiplatelet therapy for CCS or CCD includes DAPT, which includes administering 60 mg of prasugrel followed by aspirin and clopidogrel. In some embodiments, antiplatelet therapy for CCS or CCD includes DAPT, which includes administering 600 mg of clopidogrel followed by aspirin and clopidogrel.

[0153] In some embodiments, antiplatelet therapy for CCS includes administering 180 mg of ticagrelor followed by 30 days of DAPT with aspirin and 90 mg of ticagrelor twice daily. In some embodiments, antiplatelet therapy for CCS or CCD includes administering 300 mg to 600 mg of clopidogrel followed by 30 days of DAPT with aspirin and 75 mg of clopidogrel once daily.

[0154] In some embodiments, antiplatelet therapy for CCS or CCD includes DAPT. In some embodiments, DAPT for CCS or CCD includes the administration of aspirin and a second antithrombotic agent. In some embodiments, aspirin and a P2Y12 inhibitor are administered for 6 months for CCS or CCD.

[0155] In some embodiments, antiplatelet therapy for CCS or CCD includes DAPT. In some embodiments, antiplatelet therapy for CCS or CCD includes DAPT administered for 3 to 12 months. In some embodiments, antiplatelet therapy for CCS or CCD includes DAPT administered for 3 months. In some embodiments, antiplatelet therapy for CCS or CCD includes DAPT administered for 12 months. In some embodiments, antiplatelet therapy for CCS or CCD includes DAPT administered for 60 days, followed by P2Y12 monotherapy. In some embodiments, antiplatelet therapy for CCS or CCD includes DAPT administered for 60 days, followed by ticagrelor monotherapy for 23 months. In some embodiments, antiplatelet therapy for CCS or CCD includes DAPT administered for 60 days, followed by aspirin monotherapy for 12 months. In some embodiments, antiplatelet therapy for CCS or CCD includes administration of aspirin and clopidogrel for 60 days, followed by clopidogrel monotherapy for 12 months. In some embodiments, antiplatelet therapy for CCS or CCD includes a 60-day course of aspirin and prasugrel, followed by 12 months of clopidogrel monotherapy.

[0156] In some embodiments, antiplatelet therapy for CCS or CCD includes 12 months of administration of aspirin and clopidogrel, followed by 18 months of aspirin monotherapy. In some embodiments, antiplatelet therapy for CCS or CCD includes 12 months of administration of aspirin and prasugrel, followed by 18 months of aspirin monotherapy. In some embodiments, antiplatelet therapy for CCS or CCD includes 30 months of administration of aspirin and clopidogrel. In some embodiments, antiplatelet therapy for CCS or CCD includes 30 months of administration of aspirin and prasugrel.

[0157] In some embodiments, DAPT for CCS or CCD includes a 3-month course of aspirin and ticagrelor, followed by ticagrelor monotherapy. In some embodiments, DAPT for CCS or CCD includes a 12-month course of aspirin and ticagrelor. In some embodiments, DAPT for CCS or CCD includes a 6-month course of once-daily administration of aspirin (75-100 mg) and twice-daily administration of 75 mg of clopidogrel.

[0158] In some embodiments, antiplatelet therapy for CCS or CCD includes the administration of SAPT after DAPT. In some embodiments, antiplatelet therapy for CCS or CCD includes the administration of SAPT after DAPT for the first 1 to 12 months. In some embodiments, antiplatelet therapy for CCS or CCD includes the administration of SAPT after DAPT for the first 3 to 6 months. In some embodiments, antiplatelet therapy for CCS or CCD includes the administration of SAPT after DAPT for the first 3 months. In some embodiments, antiplatelet therapy for CCS or CCD includes the administration of SAPT after DAPT for the first 6 months. In some embodiments, antiplatelet therapy for CCS or CCD includes aspirin monotherapy after DAPT for the first 1 month. In some embodiments, antiplatelet therapy for CCS or CCD includes P2Y12 inhibitor monotherapy after DAPT for the first 3 months.

[0159] In some embodiments, antiplatelet therapy for CCS or CCD includes administering aspirin (75-100 mg) once daily and clopidogrel (75 mg) twice daily for 12 months, followed by administering aspirin (75-100 mg) once daily for 12 months.

[0160] In some embodiments, antiplatelet therapy for CCS or CCD includes triple therapy administered weekly, followed by dual therapy including clopidogrel and dabigatran for up to six months. In some embodiments, antiplatelet therapy for CCS or CCD includes triple therapy administered weekly, followed by dual therapy including clopidogrel and dabigatran for up to six months. In some embodiments, antiplatelet therapy for CCS or CCD includes triple therapy administered weekly, followed by dual therapy including clopidogrel and an activated factor X inhibitor for up to six months. In some embodiments, antiplatelet therapy for CCS or CCD includes triple therapy administered weekly, followed by dual therapy including clopidogrel and apixaban for up to six months. In some embodiments, antiplatelet therapy for CCS or CCD includes triple therapy administered weekly, followed by dual therapy including clopidogrel and rivaroxaban for up to six months. In some embodiments, antiplatelet therapy for CCS or CCD includes triple therapy for one week, followed by dual therapy including clopidogrel and edoxaban for up to six months.

[0161] In some embodiments, the methods disclosed herein relate to the primary prevention of cerebrovascular adverse events or cardiovascular adverse events.

[0162] In some embodiments, the methods disclosed herein relate to the secondary prevention of cerebrovascular adverse events or cardiovascular adverse events.

[0163] In some embodiments of the methods of this disclosure, a cerebrovascular adverse event or a cardiovascular adverse event includes one or more of the following: stroke, heart attack, or death.

[0164] In some embodiments of the methods of this disclosure, the cerebrovascular adverse event or cardiovascular adverse event occurs in an organ selected from the heart, brain, limbs, blood circulation system, or blood vessels.

[0165] In some embodiments of the methods of this disclosure, the cerebrovascular adverse event or cardiovascular adverse event includes one or more major cardiovascular adverse events (MACE) selected from the group consisting of cardiovascular death, non-fatal myocardial infarction, ischemic stroke, and combinations thereof.

[0166] In other embodiments of the method of the present disclosure, cerebrovascular or cardiovascular adverse events include one or more major lower limb adverse events (MALE) selected from the group consisting of MACE; major lower limb adverse events (MALE) including one or more of acute limb ischemia, chronic limb ischemia, or major amputation; symptomatic venous thromboembolic events; and combinations thereof.

[0167] In some embodiments of the method of this disclosure, the cerebrovascular adverse event or cardiovascular adverse event is selected from the group consisting of arrhythmogenic cardiomyopathy, non-fatal myocardial infarction, ischemic stroke, and combinations thereof.

[0168] In some embodiments of the methods of this disclosure, cerebrovascular adverse events or cardiovascular adverse events include cardiovascular death.

[0169] In some embodiments of the methods of this disclosure, cerebrovascular adverse events or cardiovascular adverse events include arrhythmogenic cardiomyopathy.

[0170] In some embodiments, this disclosure relates to methods for treating or preventing cerebrovascular or cardiovascular adverse events in human patients with acute coronary syndrome.

[0171] In some embodiments, the human patient is female. In other embodiments, the human patient is male.

[0172] In some embodiments, the human patient is at least 40 years old.

[0173] In another embodiment, the human patient is at least 50 years old.

[0174] In another embodiment, the human patient is at least 60 years old.

[0175] In another embodiment, the human patient is at least 70 years old.

[0176] In some embodiments, the method of the present disclosure is characterized by administering to a human patient (i) a pharmaceutical composition comprising 25 mg of milbexian (or a pharmaceutically acceptable salt or solvate thereof), or a pharmaceutical composition comprising 12.5 mg to 200 mg of milbexian (or a pharmaceutically acceptable salt or solvate thereof); and (ii) implementing a regimen comprising antiplatelet therapy selected from the group consisting of aspirin, P2Y12 inhibitors, and combinations thereof.

[0177] In some embodiments, the method of the present disclosure is characterized by administering to a human patient a regimen comprising (i) administering a pharmaceutical composition comprising 25 mg of milbexian (or a pharmaceutically acceptable salt or solvate thereof) twice daily; and (ii) implementing an antiplatelet therapy selected from the group consisting of aspirin, P2Y12 inhibitors, and combinations thereof.

[0178] In some embodiments, the pharmaceutical composition contains milbexian.

[0179] In some embodiments, the pharmaceutical composition includes a solvate of milbexian.

[0180] In another embodiment, the pharmaceutical composition contains a pharmaceutically acceptable salt of milbexian.

[0181] In embodiments of the methods disclosed herein, if a pharmaceutical composition contains a solvate or pharmaceutically acceptable salt of milbexian, the specific amount is based on milbexian. That is, the amount of solvate or pharmaceutically acceptable salt in a pharmaceutical composition contains a specific amount of milbexian. For example, a pharmaceutical composition containing 25 mg of milbexian (or a pharmaceutically acceptable salt or solvate thereof) means a pharmaceutical composition containing 25 mg of milbexian, or an amount of a pharmaceutically acceptable salt or solvate of milbexian equivalent to 25 mg of milbexian.

[0182] In some embodiments of the methods of the present disclosure, the regimen is characterized by administering a pharmaceutical composition containing 12.5 mg of milbexian (or a pharmaceutically acceptable salt or solvate thereof) twice daily.

[0183] In some embodiments of the methods of the present disclosure, the regimen is characterized by administering a pharmaceutical composition containing 25 mg of milbexian (or a pharmaceutically acceptable salt or solvate thereof) twice daily.

[0184] In some embodiments of the methods of this disclosure, the regimen is characterized by administering a pharmaceutical composition containing 50 mg of milbexian (or a pharmaceutically acceptable salt or solvate thereof) twice daily.

[0185] In some embodiments of the methods of this disclosure, the regimen is characterized by administering a pharmaceutical composition containing 100 mg of milbexian (or a pharmaceutically acceptable salt or solvate thereof) twice daily.

[0186] In some embodiments of the methods of this disclosure, the regimen is characterized by administering a pharmaceutical composition containing 12.5 mg to 200 mg of milbexian (or a pharmaceutically acceptable salt or solvate thereof) twice daily.

[0187] In some embodiments of the methods of the present disclosure, an embodiment in which a composition comprising milbexian (or a pharmaceutically acceptable salt or solvate thereof, in milbexian equivalent) is administered to a human patient twice daily, one of the two doses being given in the morning and the other in the evening, and these doses being given at approximately the same time each day (i.e., within ±1 hour).

[0188] In some embodiments of the method disclosed herein, immediate-release tablets of milbexian may be administered in combination with antiplatelet therapy as appropriate.

[0189] In some embodiments, the regimens used in the methods of disclosure include antiplatelet therapies selected from the group consisting of administration of aspirin, P2Y12 inhibitors, and combinations thereof.

[0190] In some embodiments of the methods disclosed herein, antiplatelet therapy includes antiplatelet monotherapy (SAPT).

[0191] In some embodiments of the methods disclosed herein, antiplatelet therapy includes dual antiplatelet therapy (DAPT).

[0192] In some embodiments, antiplatelet therapy includes 21 days of dual antiplatelet therapy (DAPT), followed by antiplatelet monotherapy (SAPT).

[0193] In some embodiments of the method of the present disclosure, the regimen includes combination therapy with aspirin and clopidogrel from day 1 to day 21, followed by aspirin monotherapy from day 22 to day 90.

[0194] In some embodiments of the method of this disclosure, the regimen includes a DAPT of more than 90 days (with or without de-escalation to SAPT).

[0195] In some embodiments of the method of this disclosure, the regimen includes a DAPT of more than 90 days with de-escalation to SAPT.

[0196] In other embodiments of the method disclosed herein, the regime includes a DAPT of more than 90 days without de-escalation to SAPT.

[0197] In some embodiments of the method of this disclosure, the regime includes a DAPT of no more than 90 days, with de-escalation to SAPT.

[0198] In some embodiments of the method disclosed herein, the regimen includes SAPT.

[0199] In some embodiments of the methods of the present disclosure, the regimen includes the administration of aspirin and / or clopidogrel without any adjustment of the dose of milbexian.

[0200] In some embodiments, aspirin is used in antiplatelet monotherapy.

[0201] In some embodiments of antiplatelet monotherapy, aspirin is administered at a dose of 50 to 150 mg per day, for example, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 81 mg, 85 mg, 90 mg, 95 mg, 100 mg, 105 mg, 110 mg, 115 mg, 120 mg, 125 mg, 130 mg, 135 mg, 140 mg, 145 mg, or 150 mg per day.

[0202] In some embodiments of antiplatelet monotherapy, aspirin is administered at a dose of 75-100 mg per day, for example, 75 mg, 80 mg, 81 mg, 85 mg, 90 mg, 95 mg, or 100 mg per day.

[0203] In some embodiments of antiplatelet monotherapy, aspirin is administered at a dose of 75 mg per day.

[0204] In some embodiments of antiplatelet monotherapy, aspirin is administered at a dose of 81 mg per day.

[0205] In some embodiments of antiplatelet monotherapy, aspirin is administered at a dose of 100 mg per day.

[0206] In another embodiment, a P2Y12 inhibitor is used for antiplatelet monotherapy.

[0207] In some embodiments of antiplatelet monotherapy, the P2Y12 inhibitor is clopidogrel, ticagrelor, or prasugrel.

[0208] In some embodiments of antiplatelet monotherapy, the P2Y12 inhibitor is clopidogrel.

[0209] In some embodiments of antiplatelet monotherapy, clopidogrel is administered at a dose of 75 mg to 600 mg per day, for example, 75 mg, 150 mg, 225 mg, 300 mg, 375 mg, 450 mg, 525 mg, or 600 mg per day.

[0210] In some embodiments of antiplatelet monotherapy, the P2Y12 inhibitor is ticagrelor.

[0211] In some embodiments of antiplatelet monotherapy, the P2Y12 inhibitor is prasugrel.

[0212] In some embodiments, ticlopidine is used for antiplatelet monotherapy.

[0213] In some embodiments, ticlopidine is administered at a dose of 250 to 500 mg per day, for example, 150 mg or 500 mg per day.

[0214] In other embodiments of the methods disclosed herein, antiplatelet therapy includes dual antiplatelet therapy.

[0215] In some embodiments, aspirin and ticlopidine are used in dual antiplatelet therapy.

[0216] In some embodiments, dual antiplatelet therapy uses aspirin and a P2Y12 inhibitor.

[0217] In some embodiments of dual antiplatelet therapy, aspirin is administered at a dose of 50 to 150 mg per day, for example, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 81 mg, 85 mg, 90 mg, 95 mg, 100 mg, 105 mg, 110 mg, 115 mg, 120 mg, 125 mg, 130 mg, 135 mg, 140 mg, 145 mg, or 150 mg per day.

[0218] In some embodiments of dual antiplatelet therapy, aspirin is administered at a dose of 75-100 mg per day, for example, 75 mg, 80 mg, 81 mg, 85 mg, 90 mg, 95 mg, or 100 mg per day.

[0219] In some embodiments of dual antiplatelet therapy, aspirin is administered at a dose of 75 mg per day.

[0220] In some embodiments of dual antiplatelet therapy, aspirin is administered at a dose of 81 mg per day.

[0221] In some embodiments of dual antiplatelet therapy, aspirin is administered at a dose of 100 mg per day.

[0222] In some embodiments of dual antiplatelet therapy, the P2Y12 inhibitor is clopidogrel, ticagrelor, or prasugrel.

[0223] In some embodiments of dual antiplatelet therapy, the P2Y12 inhibitor is clopidogrel.

[0224] In some embodiments of dual antiplatelet therapy, clopidogrel is administered at a dose of 75 mg to 600 mg per day, for example, 75 mg, 150 mg, 225 mg, 300 mg, 375 mg, 450 mg, 525 mg, or 600 mg per day.

[0225] In some embodiments of dual antiplatelet therapy, clopidogrel is administered at an initial loading dose.

[0226] In some embodiments, the initial loading dose is 300-600 mg per day.

[0227] In some embodiments of dual antiplatelet therapy, clopidogrel is administered at a dose of 75 mg per day.

[0228] In some embodiments of dual antiplatelet therapy, clopidogrel is administered at a dose of 150 mg per day.

[0229] In some embodiments of dual antiplatelet therapy, clopidogrel is administered at a dose of 225 mg per day.

[0230] In some embodiments of dual antiplatelet therapy, clopidogrel is administered at a dose of 300 mg per day.

[0231] In some embodiments of dual antiplatelet therapy, clopidogrel is administered at a dose of 375 mg per day.

[0232] In some embodiments of dual antiplatelet therapy, clopidogrel is administered at a dose of 450 mg per day.

[0233] In some embodiments of dual antiplatelet therapy, clopidogrel is administered at a dose of 525 mg per day.

[0234] In some embodiments of dual antiplatelet therapy, clopidogrel is administered at a dose of 600 mg per day.

[0235] In some embodiments, the present disclosure relates to a method for preventing cardiovascular adverse events in a human patient diagnosed with acute coronary syndrome, comprising administering to the human patient a regimen comprising (i) a pharmaceutical composition comprising 25 mg of milbexian (or a pharmaceutically acceptable salt or solvate thereof) and one or more pharmaceutically acceptable excipients, and (ii) an antiplatelet therapy selected from the group consisting of aspirin, P2Y12 inhibitors, and combinations thereof; Administering the aforementioned pharmaceutical composition twice a day; and The cardiovascular adverse event must be selected from one or more of the following groups: all-cause mortality (ACM); cardiovascular (CV) death; myocardial infarction (MI); unstable angina (UA); any stroke or any stroke (ischemic, hemorrhagic, or of unknown cause); ischemic stroke; acute limb ischemia (ALI); large vessel (non-traumatic) limb amputation; symptomatic venous thromboembolism (VTE: pulmonary embolism (PE), deep vein thrombosis (DVT)); coronary revascularization due to ischemia; stent thrombosis; hospitalization for any cause (classified as (1) planned or unplanned, (2) hospitalization due to arterial thromboembolism or venous thromboembolism, or hospitalization not falling under either category); and transient ischemic attack (TIA). This relates to a method characterized by the following.

[0236] In some embodiments of the above method, the regimen, compared to the placebo group, resulted in a relative risk reduction (RRR) of symptomatic venous thromboembolism (VTE: pulmonary embolism (PE), deep vein thrombosis (DVT)) in patients being at least 25%, for example, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, or 50%, with no increase in bleeding risk observed.

[0237] In another embodiment of the above method, a cardiovascular adverse event is one or more of CV death, MI, or ischemic stroke.

[0238] In some embodiments, the present disclosure relates to a method for reducing the incidence of one or more thrombotic adverse events selected from new-onset ischemic stroke, MI, or all-cause death in a human patient diagnosed with acute coronary syndrome, the method comprising administering to the human patient (i) a pharmaceutical composition comprising from about 25 mg to about 100 mg of milvexian (or a pharmaceutically acceptable salt or solvate thereof) and one or more pharmaceutically acceptable excipients, and (ii) a regimen comprising an antiplatelet therapy selected from the group consisting of aspirin, a P2Y12 inhibitor, and combinations thereof, twice daily.

[0239] In some embodiments of the above method, as a result of implementing the regimen, the relative risk is 0.85 or less compared to placebo, for example, 0.85, 0.84, 0.83, 0.82, 0.81, 0.8, 0.79, 0.78, 0.77, 0.76, 0.75, 0.74, 0.73, 0.72, 0.71, or 0.7 compared to placebo.

[0240] In other embodiments, the present disclosure relates to a method for preventing ischemic stroke in a human patient diagnosed with acute coronary syndrome, the method comprising administering to the human patient (i) a pharmaceutical composition comprising 25 mg of milvexian (or a pharmaceutically acceptable salt or solvate thereof) and one or more pharmaceutically acceptable excipients, and (ii) an antiplatelet therapy selected from the group consisting of aspirin, a P2Y12 inhibitor, and combinations thereof; and implementing a regimen comprising administering the pharmaceutical composition twice daily.

[0241] In some embodiments of the above method, as a result of implementing the regimen, the relative risk reduction rate (RRR) in the onset of ischemic stroke in the patient is at least 25% compared to the placebo group, for example, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49% or 50%, and no increase in the bleeding risk is observed.

[0242] In some embodiments of the above method, the clinical benefit of the regimen—a reduction in the incidence of clinical ischemic stroke—is maintained over a 90-day treatment period.

[0243] In some embodiments, the Disclosure provides a method for preventing one or more strokes and non-central nervous system (CNS) systemic embolic events in a human patient having atrial fibrillation or atrial flutter, characterized by administering to the human patient a composition comprising 50 mg or 100 mg of milbexian (or a pharmaceutically acceptable salt or solvate thereof, in milbexian equivalent); and administering the composition twice daily.

[0244] In other embodiments, the Disclosure relates to a method for preventing one or more cardiovascular adverse events in patients with a history of atrial fibrillation or atrial flutter, Each event is selected from a group consisting of cardiovascular death, myocardial infarction, stroke, and systemic embolism other than that of the central nervous system (CNS), and the method is characterized by administering a composition containing 50 mg or 100 mg of milbexian (or a pharmaceutically acceptable salt or solvate thereof, in milbexian equivalent) to a human patient; and administering the composition twice daily.

[0245] In some embodiments, the methods of this disclosure are performed on human patients.

[0246] In some embodiments, the human patient is at least 18 years old.

[0247] In another embodiment, the human patient is at least 75 years old.

[0248] In other embodiments, the human patient is between 64 and 74 years old, for example, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, or 74 years old.

[0249] In some embodiments, the patient has a history of atrial fibrillation or atrial flutter.

[0250] In some embodiments, the patient has a history of paroxysmal atrial fibrillation.

[0251] In another embodiment, the patient has a history of persistent atrial fibrillation that is not due to a reversible cause.

[0252] In some embodiments, the patient has a history of persistent atrial fibrillation (i.e., AF that lasts for more than 7 days and may require electrical shock to restore sinus rhythm).

[0253] In some embodiments, the patient has a history of long-term persistent atrial fibrillation (i.e., AF that has persisted for more than one year).

[0254] In some embodiments, the patient has a history of persistent / chronic atrial fibrillation (i.e., is a patient who is always in a state of AF and whose every attempt to restore sinus rhythm has failed).

[0255] In some embodiments, the patient has a history of paroxysmal, persistent, or long-lasting atrial fibrillation.

[0256] In some embodiments, a patient's atrial fibrillation is indicated by electrocardiogram findings (e.g., 12-lead electrocardiogram, rhythm strip, Holter electrocardiogram, pacemaker data analysis). In some embodiments, the patient has medical evidence of atrial fibrillation for a period from one year to at least one day prior to the detection of atrial fibrillation on an electrocardiogram.

[0257] In some embodiments, the methods disclosed herein are performed on patients who have undergone electrical defibrillation or ablation.

[0258] In some embodiments, the patient has a history of atrial fibrillation.

[0259] In another embodiment, the patient has a history of atrial flutter.

[0260] In other embodiments, the patient has a history of both atrial fibrillation and atrial flutter.

[0261] In some embodiments, the methods of the present disclosure relate to the prevention of one or more strokes and systemic embolism events outside the central nervous system (CNS).

[0262] In some embodiments, the methods of the present disclosure prevent strokes.

[0263] In some embodiments, the methods of the present disclosure prevent systemic embolism events outside the central nervous system (CNS).

[0264] In some embodiments, the methods of the present disclosure prevent strokes and systemic embolism events outside the central nervous system (CNS).

[0265] In some embodiments, the methods of the present disclosure relate to the prevention of major cardiovascular adverse events. In some embodiments, each event is selected from the group consisting of cardiovascular death, myocardial infarction, stroke, and systemic embolism outside the central nervous system (CNS).

[0266] In some embodiments, the methods of the present disclosure relate to the prevention of systemic embolism outside the central nervous system (CNS).

[0267] In some embodiments, the methods of the present disclosure relate to the prevention of non-fatal myocardial infarction.

[0268] In other embodiments, the methods of the present disclosure relate to the prevention of non-fatal stroke.

[0269] In other embodiments, the methods of the present disclosure relate to the prevention of cardiovascular death.

[0270] In other embodiments, the methods of the present disclosure relate to the prevention of non-fatal myocardial infarction, non-fatal stroke, and cardiovascular death.

[0271] In certain embodiments, the methods of this disclosure relate to the prevention of one or more all-cause mortality, myocardial infarction, stroke, and systemic embolisms other than CNS.

[0272] In some embodiments, the methods disclosed herein relate to the prevention of all-cause mortality.

[0273] In some embodiments, the methods disclosed herein relate to the prevention of myocardial infarction.

[0274] In some embodiments, the methods disclosed herein relate to the prevention of stroke.

[0275] In some embodiments, the methods disclosed herein relate to the prevention of systemic embolism other than CNS.

[0276] In some embodiments, the methods of the present disclosure relate to the prevention of emergency hospitalization due to cardiovascular death, myocardial infarction, stroke, unexpected revascularization (including ischemic limb amputation), or ischemic events (including DVT and PE) in human patients with a history of atrial fibrillation or atrial flutter.

[0277] In some embodiments, the methods disclosed herein relate to the prevention of cardiovascular death in human patients having atrial fibrillation or atrial flutter.

[0278] In some embodiments, the methods disclosed herein relate to the prevention of myocardial infarction in human patients having atrial fibrillation or atrial flutter.

[0279] In some embodiments, the methods disclosed herein relate to the prevention of stroke in human patients having atrial fibrillation or atrial flutter.

[0280] In some embodiments, the methods disclosed herein relate to the prevention of non-CNS embolisms in human patients having atrial fibrillation or atrial flutter.

[0281] In some embodiments, the methods disclosed herein relate to the prevention of unplanned revascularization (including ischemic limb amputation) in human patients with atrial fibrillation or atrial flutter.

[0282] In some embodiments, the methods disclosed herein relate to the prevention of emergency hospitalization due to ischemic events (including deep vein thrombosis and pulmonary embolism) in human patients with atrial fibrillation or atrial flutter.

[0283] In some embodiments, the methods disclosed herein relate to the prevention of conditions corresponding to stroke or non-CNS systemic embolism in human patients having atrial fibrillation or atrial flutter.

[0284] In some embodiments, the methods disclosed herein relate to the prevention of cardiovascular death, myocardial infarction, stroke, or non-CNS embolism in human patients having atrial fibrillation or atrial flutter.

[0285] In some embodiments, the methods disclosed herein relate to the prevention of all-cause mortality, myocardial infarction, stroke, or non-CNS embolism in human patients having atrial fibrillation or atrial flutter.

[0286] In some embodiments, the methods of the present disclosure relate to the prevention of conditions in human patients with atrial fibrillation or atrial flutter that result in cardiovascular death, myocardial infarction, stroke, unexpected revascularization (including ischemic limb amputation), or emergency hospitalization due to ischemic events (including thrombotic events such as deep vein thrombosis (DVT) and pulmonary embolism (PE)).

[0287] In some embodiments of the method of this disclosure, a patient is administered a pharmaceutical composition comprising 50 mg or 100 mg of milbexian (or a pharmaceutically acceptable salt or solvate thereof, in milbexian equivalent), said composition, which is administered twice daily.

[0288] When a pharmaceutical composition contains a solvate or pharmaceutically acceptable salt of milbexian, the specific amount is based on milbexian. That is, the amount of solvate or pharmaceutically acceptable salt in a pharmaceutical composition contains a specific amount of milbexian. For example, a pharmaceutical composition containing 100 mg of milbexian (or its pharmaceutically acceptable salt or solvate) means a pharmaceutical composition containing 100 mg of milbexian, or an amount of a pharmaceutically acceptable salt or solvate of milbexian equivalent to 100 mg of milbexian.

[0289] In some embodiments, a patient is administered a pharmaceutical composition containing 50 mg of milbexian, which is administered twice daily.

[0290] In some embodiments, the patient is administered a pharmaceutical composition comprising 50 mg of a pharmaceutically acceptable salt or solvate of milbexian in terms of milbexian equivalent, said composition, which is administered twice daily.

[0291] In some embodiments, the patient is administered a pharmaceutical composition containing 50 mg of a pharmaceutically acceptable salt of milbexian in milbexian equivalent, and the composition is administered twice daily.

[0292] In some embodiments, the patient is administered a pharmaceutical composition containing 50 mg of a pharmaceutically acceptable milbexian solvate, in terms of milbexian equivalent, which is administered twice daily.

[0293] In some embodiments, a patient is administered a pharmaceutical composition containing 100 mg of milbexian, which is administered twice daily.

[0294] In some embodiments, the patient is administered a pharmaceutical composition containing 100 mg of a pharmaceutically acceptable salt or solvate of milbexian in terms of milbexian equivalent, and the composition is administered twice daily.

[0295] In some embodiments, the patient is administered a pharmaceutical composition containing 100 mg of a pharmaceutically acceptable salt of milbexian in milbexian equivalent, and the composition is administered twice daily.

[0296] In some embodiments, the patient is administered a pharmaceutical composition containing 100 mg of a pharmaceutically acceptable milbexian solvate in milbexian equivalent, and the composition is administered twice daily.

[0297] In some embodiments of the method of the present disclosure, a pharmaceutical composition comprising milbexian (or a pharmaceutically acceptable salt or solvate thereof, in milbexian equivalent) is administered to a human patient, with the first dose being administered within 7 days after the onset of acute coronary syndrome.

[0298] In some embodiments of the method of the present disclosure, a pharmaceutical composition comprising milbexian (or a pharmaceutically acceptable salt or solvate thereof, in milbexian equivalent) is administered to a human patient twice daily, once in the morning and the other at night.

[0299] In some embodiments, the morning and evening doses are administered at the same time each day.

[0300] In some embodiments of the method of this disclosure, a pharmaceutical composition comprising milbexian (or a pharmaceutically acceptable salt or solvate thereof, in milbexian equivalent) is administered twice daily for at least 13 weeks.

[0301] In some embodiments, a pharmaceutical composition comprising milbexian (or a pharmaceutically acceptable salt or solvate thereof, in milbexian equivalent) is administered twice daily for 13 weeks.

[0302] In another embodiment, a pharmaceutical composition comprising milbexian (or a pharmaceutically acceptable salt or solvate thereof, in milbexian equivalent) is administered twice daily for more than 13 weeks.

[0303] In other embodiments, a pharmaceutical composition comprising milbexian (or a pharmaceutically acceptable salt or solvate thereof, in milbexian equivalent) is administered twice daily for at least 26 weeks, at least 52 weeks, at least 78 weeks, at least 104 weeks, at least 130 weeks, at least 156 weeks, at least 182 weeks, or at least 208 weeks.

[0304] In some embodiments, a pharmaceutical composition comprising milbexian (or a pharmaceutically acceptable salt or solvate thereof, in milbexian equivalent) is administered twice daily for an extended period, i.e., indefinitely.

[0305] In some embodiments of the method of this disclosure, a human patient is administered a pharmaceutical composition containing 12.5 mg to 200 mg of milbexian (or a pharmaceutically acceptable salt or solvate thereof, in milbexian equivalent) twice daily.

[0306] In some embodiments, a patient is administered a pharmaceutical composition containing 12.5 mg to 200 mg of milbexian, and the composition is administered twice daily.

[0307] In some embodiments, the patient is administered a pharmaceutical composition containing a pharmaceutically acceptable salt or solvate of milbexian in an amount of 12.5 mg to 200 mg in milbexian equivalent, and the composition is administered twice daily.

[0308] In some embodiments, the patient is administered a pharmaceutical composition containing 12.5 mg to 200 mg of a pharmaceutically acceptable salt of milbexian in milbexian equivalent, and the composition is administered twice daily.

[0309] In some embodiments, the patient is administered a pharmaceutical composition containing 12.5 mg to 200 mg of a pharmaceutically acceptable milbexian solvate, which is administered twice daily.

[0310] In some embodiments, a patient is administered a pharmaceutical composition containing 25 mg of milbexian, which is administered twice daily.

[0311] In some embodiments, the patient is administered a pharmaceutical composition comprising 25 mg of a pharmaceutically acceptable salt or solvate of milbexian in milbexian equivalent, said composition, twice daily.

[0312] In some embodiments, the patient is administered a pharmaceutical composition containing 25 mg of a pharmaceutically acceptable salt of milbexian in milbexian equivalent, and the composition is administered twice daily.

[0313] In some embodiments, the patient is administered a pharmaceutical composition containing 25 mg of a pharmaceutically acceptable milbexian solvate in milbexian equivalent, and the composition is administered twice daily.

[0314] In some embodiments, the disclosure provides a method for preventing one or more strokes and non-central nervous system (CNS) systemic embolic events in patients with a history of atrial fibrillation or atrial flutter, Administer the patient a film-coated, immediate-release tablet containing 50 mg or 100 mg of milbexian (or a pharmaceutically acceptable salt thereof, in milbexian equivalent) and one or more pharmaceutically acceptable excipients. The film-coated, immediate-release tablets are administered twice daily, regardless of whether or not a meal has been eaten. The patient is at least 18 years old; The patient also had the following: (i) 75 years of age or older or (ii) history of ischemic stroke Do you have one or more risk factors in category (A) selected from the following? Or: (i) 65-74 years old; (ii) hypertension; (iii) diabetes; (iv) A history of coronary artery disease (CAD) (including a history of myocardial infarction or acute coronary syndrome, regardless of whether percutaneous coronary intervention (PCI) has been performed) or a history of peripheral artery disease (PAD); and (v) History of heart failure The present invention provides a method characterized by the coexistence or combination of two or more cardiovascular risk factors belonging to category (B), selected from the group consisting of the following.

[0315] In other embodiments, the Disclosure relates to a method for preventing one or more major cardiovascular adverse events in patients with a history of atrial fibrillation or atrial flutter, Each event is selected from a group consisting of cardiovascular death, myocardial infarction, stroke, and systemic embolism other than that of the central nervous system (CNS). Administer the patient a film-coated, immediate-release tablet containing 50 mg or 100 mg of milbexian or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients. The film-coated, immediate-release tablets are administered twice daily, regardless of whether or not a meal has been eaten. The patient is at least 18 years old; The patient also had the following: (i) 75 years of age or older or (ii) history of ischemic stroke Do you have one or more risk factors in category (A) selected from the following? Or: (i) 65-74 years old; (ii) hypertension; (iii) diabetes; (iv) A history of coronary artery disease (CAD) (including a history of myocardial infarction or acute coronary syndrome, regardless of whether percutaneous coronary intervention (PCI) has been performed) or a history of peripheral artery disease (PAD); and (v) History of heart failure The present invention provides a method characterized by the coexistence or combination of two or more cardiovascular risk factors belonging to category (B), selected from the group consisting of the following.

[0316] In some embodiments of the above method, the primary cardiovascular adverse event is cardiovascular death.

[0317] In some embodiments of the methods of this disclosure, a baseline of a patient's factor XI coagulation activity is measured. As used herein, “baseline of factor XI coagulation activity” means the patient’s factor XI coagulation activity before administration of a regimen comprising a pharmaceutical composition comprising milbexian (or a pharmaceutically acceptable salt or solvate thereof).

[0318] In some embodiments, factor XI (FXI) activity is measured using a modified activated partial thromboplastin time (aPTT) measurement method with Actin FS (Siemens Healthcare) and Siemens BCS. (登録商標) Measurement is performed using an XP analyzer. A 6-point calibration curve is created in the range of approximately 5-150% using a secondary standard material (standard human plasma, Siemens Healthcare Diagnostics Inc.) with a known FXI concentration assigned by the manufacturer. Approximately 100% of the reference standard plasma is used in the BCS. (登録商標) Dilute with physiological saline using an XP analyzer to a pre-set FXI calibration level. The calibration curve is fitted using a log / lin regression curve with FXI activity rate (%) plotted on the x-axis and coagulation time (seconds) on the y-axis. The sample to be tested is mixed with FXI-deficient plasma (less than 1% FXI, with at least 75% of all other factors) to normalize all other factors. After adding aPTT reagent (Actin FS) and incubating the mixture, calcium chloride is added to the mixture, and the optically measured thrombus formation time is compared to the time on the calibration curve. The sample is then processed using the BCS (Body Condition System). (登録商標) The measurement is performed using XP after basic dilution (1:10) with physiological saline.

[0319] In some embodiments of the methods disclosed herein, administration of an immediate-release tablet containing milbexian (or a pharmaceutically acceptable salt or solvate thereof), or a regimen including an immediate-release tablet, reduces the patient's factor XI coagulation activity by approximately 7% to approximately 70% compared to baseline.

[0320] In another embodiment, the method of this disclosure results in a reduction of approximately 7% to approximately 20% of the patient's factor XI coagulation activity compared to baseline, upon administration.

[0321] In some embodiments, the method of this disclosure, upon administration, reduces the patient's factor XI coagulation activity by approximately 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, and 3% relative to baseline. It decreases by 5%, approximately 36%, approximately 37%, approximately 38%, approximately 39%, approximately 40%, approximately 41%, approximately 42%, approximately 43%, approximately 44%, approximately 45%, approximately 46%, approximately 47%, approximately 48%, approximately 49%, approximately 50%, approximately 51%, approximately 52%, approximately 53%, approximately 54%, approximately 55%, approximately 56%, approximately 57%, approximately 58%, approximately 59%, approximately 60%, approximately 61%, approximately 62%, approximately 63%, approximately 64%, approximately 65%, approximately 66%, approximately 67%, or approximately 68%, approximately 69%, or approximately 70%.

[0322] In other embodiments, the method of the present disclosure, upon administration, reduces the patient's factor XI coagulation activity by approximately 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, or 20% compared to baseline.

[0323] In other embodiments, the method of the present disclosure, upon administration, reduces the patient's factor XI coagulation activity by the rate shown in the examples herein.

[0324] In some embodiments of the methods of the present disclosure, administration of an immediate-release tablet containing milbexian (or a pharmaceutically acceptable salt or solvate thereof), or a regimen containing an immediate-release tablet, results in an extension of activated partial thromboplastin time (aPTT) of approximately 27% to approximately 64% relative to baseline, or an extension of the patient's activated partial thromboplastin time (aPTT) of 2.1 to 2.6 relative to baseline.

[0325] In some embodiments of the method of this disclosure, administration prolongs the activated partial thromboplastin time (aPTT) by approximately 27% to 64% compared to baseline.

[0326] In some embodiments of the method of the present disclosure, administration prolongs the activated partial thromboplastin time (aPTT) by approximately 27% to approximately 64% relative to baseline, for example, approximately 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, or 64%. As used herein, "baseline" refers to the patient's aPTT before any regimen is administered.

[0327] In another embodiment, administration prolongs the patient's activated partial thromboplastin time (aPTT), with a baseline ratio of 2.1–2.6, e.g., 2.1, 2.2, 2.3, 2.4, 2.5, or 2.6.

[0328] In some embodiments of the methods disclosed herein, administration results in an extension of the activated partial thromboplastin time (aPTT) as shown in the examples herein.

[0329] In some embodiments, aPTT is determined as follows: A plasma sample is incubated for 3 minutes with Actin FS (aPTT assay reagent) containing a standard amount of phospholipids and a contact factor (ellagic acid) that activates the intrinsic pathway. Calcium chloride is then added to initiate coagulation, and fibrin thrombus formation is optically measured. The time to thrombus formation (in seconds) is reported as the activated partial thromboplastin time (aPTT).

[0330] In some embodiments of the methods disclosed herein, the pharmaceutical composition comprising milbexian (or a pharmaceutically acceptable salt or solvate thereof) is a solid oral pharmaceutical composition.

[0331] In some embodiments of the methods of this disclosure, the solid oral pharmaceutical composition includes an amorphous solid dispersion (SDP) produced by spray drying, comprising free milbexian and a pH-dependent enteric polymer as the main components.

[0332] In some embodiments of the method of this disclosure, the SDP contains free milbexian and a pH-dependent enteric polymer in a weight ratio of 3:1 (milbexian:polymer).

[0333] In some embodiments of the methods of this disclosure, the pH-dependent enteric polymer is trimellitic cellulose acetate (CAT), cellulose phthalate acetate (CAP), hydroxypropyl methylcellulose phthalate (HPMCP), ES grade of hydroxypropyl methylcellulose (HPMC ES), LF, LG, MF, MG, or HF grade of hydroxypropyl methylcellulose acetate succinate (HPMC-AS) (e.g., Aqoat®), polyvinyl acetate phthalate (PVAP) (e.g., Sureteric® and Opadry®), and shellac resin (e.g., SSB® Aquagold), or polyvinylpyrrolidone (PVP).

[0334] In some embodiments of the method of this disclosure, the pH-dependent enteric polymer is MG grade hydroxypropyl methylcellulose-AS.

[0335] In some embodiments of the method of the present disclosure, the solid oral pharmaceutical composition further includes a binder (e.g., microcrystalline cellulose (MCC), silicified microcrystalline cellulose (SMCC), or a combination thereof).

[0336] In some embodiments of the method of the present disclosure, the solid oral pharmaceutical composition further includes a volume extender (e.g., lactose monohydrate).

[0337] In some embodiments of the method of the present disclosure, the solid oral pharmaceutical composition further includes a disintegrant.

[0338] In some embodiments of the method of the present disclosure, the solid oral pharmaceutical composition further includes a lubricant.

[0339] In some embodiments of the method disclosed herein, the solid oral pharmaceutical composition is a tablet.

[0340] In some embodiments of the methods disclosed herein, the solid oral pharmaceutical composition is an immediate-release tablet.

[0341] In some embodiments of the methods disclosed herein, the solid oral pharmaceutical composition is a tablet obtained by direct compression.

[0342] In some embodiments of the methods disclosed herein, the solid oral pharmaceutical composition is a tablet produced by rotary compression.

[0343] In some embodiments of the methods disclosed herein, the solid oral pharmaceutical composition is a film-coated tablet.

[0344] In some embodiments of the methods of this disclosure, the film coating includes polyvinyl alcohol, titanium dioxide, polyethylene glycol-polyvinyl alcohol graft copolymer, and talc.

[0345] In some embodiments of the method of this disclosure, the film coating includes a polyethylene glycol-polyvinyl alcohol graft copolymer.

[0346] In some embodiments, the film coating includes polyvinyl alcohol, iron oxide, macrogol (PEG) polyvinyl alcohol graft copolymer, and talc.

[0347] In some embodiments, the film coating includes OpadryQX 321A220063 Yellow, a film coating material comprising polyvinyl alcohol, iron oxide, macrogol (PEG)-polyvinyl alcohol graft copolymer, and talc.

[0348] In some embodiments, the solid oral pharmaceutical composition is a tablet having the composition and / or properties shown in Table A. [Table 1]

[0349] As used herein, the term "disintegration time" refers to the time required for a tablet to disintegrate into particles under specified conditions. In some embodiments, the disintegration time is measured using a disk with distilled water at 37°C and the apparatus described in Eur. Ph. (PTZ-E Pharma Test, Hainburg, Germany).

[0350] In some embodiments where the solid pharmaceutical composition is a tablet, the disintegration time of the tablet in water is less than 60 seconds at 37°C.

[0351] In some embodiments where the solid pharmaceutical composition is a tablet, the disintegration time of the tablet in water is less than 20 seconds at 37°C.

[0352] In another embodiment where the solid pharmaceutical composition is a tablet, the disintegration time of the tablet in water is less than 15 seconds at 37°C.

[0353] In another embodiment where the solid pharmaceutical composition is a tablet, the disintegration time of the tablet in water is less than 10 seconds at 37°C.

[0354] In some embodiments of the method disclosed herein, the solid pharmaceutical composition is a capsule.

[0355] In some embodiments of the methods of this disclosure, a human patient to whom a pharmaceutical composition comprising milbexian (or a pharmaceutically acceptable salt or solvate thereof) is administered is a person who is unable to swallow tablet dosage forms.

[0356] In some embodiments of the method disclosed herein, the solid oral pharmaceutical composition is dispersed in an aqueous medium for administration to form an aqueous dispersion.

[0357] In some embodiments of the method of the present disclosure, the solid oral pharmaceutical composition is a tablet dispersed in an aqueous medium for forming an aqueous dispersion for administration.

[0358] In some embodiments of the method disclosed herein, the solid oral pharmaceutical composition is a tablet for oral administration as an aqueous dispersion by dispersing it in an aqueous medium at 37°C in less than one minute.

[0359] In the above embodiment, in which the solid oral pharmaceutical composition is dispersed in an aqueous medium to form an aqueous dispersion, the aqueous medium is water, physiological saline, phosphate buffer, plant juice, or fruit juice such as applesauce.

[0360] In the above embodiment, the solid oral pharmaceutical composition is a tablet dispersed in an aqueous medium to form an aqueous dispersion, the aqueous medium is water, saline solution, phosphate buffer, plant juice, or fruit juice such as applesauce.

[0361] In some embodiments of the method of the present disclosure, in which the solid oral pharmaceutical composition is dispersed in an aqueous medium to form an aqueous dispersion for administration, the aqueous dispersion is administered to a human patient via a nasogastric tube or spoon.

[0362] In some embodiments of the method of the present disclosure, the solid oral pharmaceutical composition is a tablet dispersed in an aqueous medium to form an aqueous dispersion for administration, the aqueous dispersion is administered to a human patient via a nasogastric tube or spoon.

[0363] In some embodiments of the methods of this disclosure, oral administration of a pharmaceutical composition containing milbexian (or a pharmaceutically acceptable salt or solvate thereof) results in a plasma half-life of approximately 13 to 16 hours for milbexian. Methods for measuring the half-life in the plasma of human patients are well known to those skilled in the art.

[0364] In some embodiments of the methods of this disclosure, when a pharmaceutical composition comprising milbexian (or a pharmaceutically acceptable salt or solvate thereof) is administered to a human patient, the plasma concentration of milbexian reaches a steady state in approximately 3 to 6 days. As used herein, “steady state” means a steady state plasma concentration as defined by a regulatory body (e.g., the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA)).

[0365] In some embodiments, the terminal phase half-life (t) of mirbexian in plasma is defined as 1 / 2 The duration is approximately 13 to 16 hours.

[0366] In some embodiments of the method of this disclosure, administration of 25 mg of milbexian twice daily to a human patient results in a steady state of milbexian plasma concentration being reached in approximately 3 days.

[0367] In some embodiments of the method of this disclosure, administration of 100 mg of milbexian twice daily to a human patient results in a steady state of milbexian plasma concentration being reached in approximately 4 days.

[0368] In some embodiments of the method of this disclosure, administration of 100 mg of milbexian twice daily to a human patient results in a steady state of milbexian plasma concentration being reached in approximately 5 days.

[0369] In some embodiments of the method of this disclosure, administration of 100 mg of milbexian twice daily to a human patient results in a steady state of milbexian plasma concentration being reached in approximately 6 days.

[0370] In some embodiments, the terminal phase half-life (t) of mirbexian in plasma is defined as1 / 2 The duration is approximately 13 to 16 hours.

[0371] In some embodiments, administering 100 mg of milbexian twice daily to human patients as monotherapy resulted in the following plasma concentrations of milbexian: (i) Steady state C max (ii) Steady state C max (iii) The mean (standard deviation) is 1760 (566) ng / mL, and the steady-state AUC 0-24 (iv) Steady-state AUC 0-24 The mean (standard deviation) is 36200 (12900) ng*h / mL. It reaches a steady state characterized by one or more of the following:

[0372] In another embodiment, the steady state after administering 100 mg of milbexian twice daily to a human patient as monotherapy is C max It is characterized by being in the range of approximately 1194 ng / mL to approximately 2326 ng / mL.

[0373] In another embodiment, the steady state after administering 100 mg of milbexian twice daily to a human patient as monotherapy was defined as having a mean (standard deviation) C max It is characterized by having a concentration of 1760 (566) ng / mL.

[0374] In another embodiment, the steady state after administering 100 mg of milbexian twice daily to a human patient as monotherapy is AUC 0-24 It is characterized by being in the range of approximately 23,300 ng*h / mL to approximately 49,100 ng*h / mL.

[0375] In another embodiment, the steady state after administering 100 mg of milbexian twice daily to a human patient as monotherapy is characterized by a mean (standard deviation) steady-state AUC of 36200 (12900) ng*h / mL.

[0376] In some embodiments, administering 100 mg of milbexian twice daily to human patients in addition to standard antiplatelet therapy results in the following plasma concentrations of milbexian: (i) Steady state C max (ii) Steady state C max (iii) The mean (standard deviation) is 1670 (536) ng / mL, and the steady-state AUC 0-24 (iv) Steady-state AUC 0-24 The mean (standard deviation) is 35,000 (12,100) ng*h / mL. It reaches a steady state characterized by one or more of the following:

[0377] In another embodiment, the steady state after administering 100 mg of milbexian twice daily to a human patient in addition to standard antiplatelet therapy is C max It is characterized by being in the range of approximately 1134 ng / mL to approximately 2206 ng / mL.

[0378] In another embodiment, the steady state after administering 100 mg of milbexian twice daily to human patients in addition to standard antiplatelet therapy was, mean (standard deviation) C max It is characterized by having a concentration of 1670 (536) ng / mL.

[0379] In another embodiment, the steady state after administering 100 mg of milbexian twice daily to human patients in addition to standard antiplatelet therapy is AUC 0-24 It is characterized by being in the range of approximately 22,900 ng*h / mL to approximately 47,100 ng*h / mL.

[0380] In another embodiment, the steady state after administering 100 mg of milbexian twice daily to human patients in addition to standard antiplatelet therapy is characterized by a mean (standard deviation) AUC of 35,000 (12,100) ng*h / mL.

[0381] In some embodiments, administering 25 mg of milbexian twice daily to human patients as monotherapy resulted in the following plasma concentrations of milbexian: (i) Steady state C max (ii) Steady state C max (iii) The mean (standard deviation) is 394 (131) ng / mL, and the steady-state AUC 0-24 (iv) The mean (standard deviation) AUC of the steady state is in the range of approximately 5230 ng*h / mL to approximately 10650 ng*h / mL. 0-24 The value is 7940 (2710) ng*h / mL. It reaches a steady state characterized by one or more of the following:

[0382] In another embodiment, the steady state after administering 25 mg of milbexian twice daily to a human patient as monotherapy is C max It is characterized by being in the range of approximately 283 ng / mL to approximately 525 ng / mL.

[0383] In another embodiment, the steady state after administering 25 mg of milbexian twice daily to a human patient as monotherapy is C max It is characterized by having a mean (standard deviation) of 394 (131) ng / mL.

[0384] In another embodiment, the steady state after administering 25 mg of milbexian twice daily to a human patient as monotherapy is AUC 0-24 It is characterized by having a concentration in the range of approximately 5230 ng*h / mL to approximately 10650 ng*h / mL.

[0385] In another embodiment, the steady state after administering 25 mg of milbexian twice daily to a human patient as monotherapy is characterized by a mean (standard deviation) AUC of 7940 (2710) ng*h / mL.

[0386] In some embodiments, administering 25 mg of milbexian twice daily to human patients in addition to standard antiplatelet therapy results in the following plasma concentrations of milbexian: (i) Steady state C max (ii) Steady state C max (iii) The mean (standard deviation) of the ng / mL is 346 (129) ng / mL, and the steady-state AUC 0-24 (iv) Steady-state AUC 0-24 The mean (standard deviation) is 7290 (2940) ng*h / mL. It reaches a steady state characterized by one or more of the following:

[0387] In another embodiment, the steady state after administering 25 mg of milbexian twice daily to a human patient in addition to standard antiplatelet therapy is C max It is characterized by a concentration in the range of approximately 217 ng / mL to approximately 475 ng / mL.

[0388] In another embodiment, the steady state after administering 25 mg of milbexian twice daily to a human patient in addition to standard antiplatelet therapy is C max It is characterized by having a mean (standard deviation) of 346 (129) ng / mL.

[0389] In another embodiment, the steady state after administering 25 mg of milbexian twice daily to human patients in addition to standard antiplatelet therapy is AUC 0-24 It is characterized by having a concentration in the range of approximately 4350 ng*h / mL to approximately 10230 ng*h / mL. In another embodiment, the steady state after administering 25 mg of milbexian twice daily to a human patient is characterized by a mean (standard deviation) AUC of 7290 (2940) ng*h / mL.

[0390] In some embodiments of the methods of this disclosure, when a pharmaceutical composition comprising milbexian (or a pharmaceutically acceptable salt or solvate thereof) is administered to a human patient, the plasma concentration of milbexian reaches a steady state in approximately 4 to 6 days.

[0391] In some embodiments of the method of the present disclosure, when a pharmaceutical composition comprising milbexian (or a pharmaceutically acceptable salt or solvate thereof) is administered to a human patient, the plasma concentration of milbexian reaches a steady state in approximately 4 to 6 days, with the administration being performed twice daily.

[0392] In some embodiments of the method of this disclosure, administration of a pharmaceutical composition containing milbexian (or a pharmaceutically acceptable salt or solvate thereof) to a human patient results in a steady state of plasma concentration of milbexian being reached in approximately 3 days.

[0393] In some embodiments of the method of this disclosure, administration of a pharmaceutical composition containing milbexian (or a pharmaceutically acceptable salt or solvate thereof) to a human patient results in a steady state of plasma concentration of milbexian being reached in approximately 4 days.

[0394] In some embodiments of the method of this disclosure, administration of a pharmaceutical composition containing milbexian (or a pharmaceutically acceptable salt or solvate thereof) to a human patient results in a steady state of plasma concentration of milbexian being reached in approximately 5 days.

[0395] In some embodiments of the method of this disclosure, administration of a pharmaceutical composition containing milbexian (or a pharmaceutically acceptable salt or solvate thereof) to a human patient results in a steady state of plasma concentration of milbexian being reached in approximately 6 days.

[0396] In some embodiments of the method of the present disclosure, a pharmaceutical composition comprising milbexian (or a pharmaceutically acceptable salt or solvate thereof) is administered to a human patient, thereby reaching a steady state in plasma concentrations of milbexian in approximately 4 days, with the administration being performed twice daily.

[0397] In some embodiments of the method of the present disclosure, a pharmaceutical composition comprising milbexian (or a pharmaceutically acceptable salt or solvate thereof) is administered to a human patient, thereby reaching a steady state in plasma concentrations of milbexian in approximately 5 days, with the administration being performed twice daily.

[0398] In some embodiments of the method of the present disclosure, a pharmaceutical composition comprising milbexian (or a pharmaceutically acceptable salt or solvate thereof) is administered to a human patient, thereby reaching a steady state in plasma concentrations of milbexian in approximately 6 days, with the administration being performed twice daily.

[0399] In some embodiments of the methods disclosed herein, a pharmaceutical composition comprising milbexian (or a pharmaceutically acceptable salt or solvate thereof) is administered regardless of the timing of meals.

[0400] In some embodiments of the methods described herein, administration does not statistically significantly increase major hemorrhagic complications. In the embodiments described above, “statistically significant increase” means an increase compared to the patient’s baseline major bleeding, i.e., major bleeding before administration of the pharmaceutical composition containing milbexian (or a pharmaceutically acceptable salt or solvate thereof).

[0401] In some embodiments of the methods described herein, when evaluated based on ISTH criteria, such administration does not statistically significantly increase the incidence of major hemorrhagic complications.

[0402] In some embodiments of the methods described herein, when evaluated based on the CRNM bleeding criteria, the administration does not statistically significantly increase the incidence of major hemorrhagic complications.

[0403] In some embodiments of the methods described herein, when evaluated based on the ISTH CRNM bleeding criteria, the administration does not statistically significantly increase the incidence of major hemorrhagic complications.

[0404] In some embodiments of the methods described herein, when evaluated based on ISTH major bleeding or CRNM bleeding criteria, the administration does not statistically significantly increase the incidence of major bleeding complications.

[0405] In some embodiments of the methods described herein, when evaluated based on the GUSTO, BARC, or TIMI bleeding criteria, such administration does not statistically significantly increase the incidence of major hemorrhagic complications.

[0406] In some embodiments of the methods described herein, when evaluated based on BARC bleeding criteria types 3c and 5, the administration does not statistically significantly increase the incidence of major bleeding complications.

[0407] In some embodiments of the methods described herein, when evaluated based on BARC bleeding criteria types 3b, 3c, and 5, such administration does not statistically significantly increase the incidence of major bleeding complications.

[0408] In some embodiments of the methods described herein, when evaluated based on BARC bleeding criteria type 3b, the administration does not statistically significantly increase the incidence of major bleeding complications.

[0409] In some embodiments of the methods described herein, when evaluated based on BARC bleeding criteria type 3c, the administration does not statistically significantly increase the incidence of major bleeding complications.

[0410] In some embodiments of the methods described herein, when evaluated based on BARC bleeding criteria type 5, the administration does not statistically significantly increase the incidence of major bleeding complications.

[0411] In some embodiments of the method described herein, such administration does not statistically significantly increase the GUSTO bleeding criteria for "severe bleeding or life-threatening bleeding."

[0412] In some embodiments of the method described herein, such administration does not statistically significantly increase non-CABG-related major bleeding based on the TIMI bleeding criteria.

[0413] In some embodiments of the methods described herein, such administration does not statistically increase clinically significant non-major bleeding.

[0414] In some embodiments of the method described herein, such administration does not statistically increase clinically significant non-major bleeding based on an assessment of BARC bleeding criteria type 2, 3a, or 4.

[0415] In some embodiments of the method described herein, such administration does not statistically increase clinically significant non-major bleeding based on ISTH criteria.

[0416] In some embodiments of the methods described herein, when evaluated based on moderate bleeding according to the GUSTO bleeding criteria, the administration does not statistically increase clinically significant non-major bleeding.

[0417] In some embodiments of the methods described herein, when evaluated based on CABG-related major bleeding according to the TIMI bleeding criteria, the administration does not statistically increase clinically significant non-major bleeding.

[0418] In some embodiments of the methods described herein, when evaluated based on minor bleeding according to the TIMI bleeding criteria, the administration does not statistically increase clinically significant non-major bleeding.

[0419] In some embodiments of the methods described herein, when evaluated based on the TIMI bleeding criteria for "bleeding requiring treatment," the administration does not statistically increase clinically significant non-major bleeding.

[0420] In some embodiments of the methods described herein, when evaluated based on major bleeding according to the TIMI bleeding criteria, the administration does not statistically increase clinically significant non-major bleeding.

[0421] In some embodiments of the methods described herein, when evaluated based on major or minor bleeding according to the TIMI bleeding criteria, the administration does not statistically increase clinically significant non-major bleeding.

[0422] In some aspects of the methods of this disclosure, the relative risk of bleeding meeting type 3 or 5 of the Bleeding Academic Research Consortium (BARC) bleeding criteria with this regimen is 3 or less, for example, ≤3.0, ≤2.9, ≤2.8, ≤2.7, ≤2.6, ≤2.5, ≤2.4, ≤2.3, ≤2.2, ≤2.1, ≤2.0, ≤1.9, ≤1.8, ≤1.7, ≤1.6, ≤1.5, ≤1.4, ≤1.3, ≤1.2, ≤1.1, ≤1.0, ≤0.9, ≤0.8, ≤0.7, ≤0.6, or ≤0.5, compared to placebo with antiplatelet therapy.

[0423] In some aspects of the methods of this disclosure, the relative risk of bleeding meeting type 3 or 5 of the Bleeding Academic Research Consortium (BARC) bleeding criteria with this regimen is 3 or less, for example, ≤3.0, ≤2.9, ≤2.8, ≤2.7, ≤2.6, ≤2.5, ≤2.4, ≤2.3, ≤2.2, ≤2.1, ≤2.0, ≤1.9, ≤1.8, ≤1.7, ≤1.6, ≤1.5, ≤1.4, ≤1.3, ≤1.2, ≤1.1, ≤1.0, ≤0.9, ≤0.8, ≤0.7, ≤0.6, or ≤0.5, compared to placebo with antiplatelet therapy.

[0424] In some embodiments of the method of this disclosure, the relative risk of serious bleeding corresponding to type 3 or 5 of the Bleeding Academic Research Consortium (BARC) bleeding criteria is independent of the amount of milbexian administered.

[0425] In other embodiments of the method of this disclosure, the human patient does not have severe bleeding that corresponds to type 3 or 5 of the Bleeding Academic Research Consortium (BARC) bleeding criteria.

[0426] In some aspects of the methods of this disclosure, the relative risk of bleeding meeting type 2 of the Bleeding Academic Research Consortium (BARC) bleeding criteria with this regimen is 2.6 or less, for example, 2.6 or less, 2.5 or less, 2.4 or less, 2.3 or less, 2.2 or less, 2.1 or less, 2.0 or less, 1.9 or less, 1.8 or less, 1.7 or less, 1.6 or less, 1.5 or less, 1.4 or less, 1.3 or less, 1.2 or less, 1.1 or less, 1.0 or less, 0.9 or less, 0.8 or less, 0.7 or less, 0.6 or less, or 0.5 or less.

[0427] In some aspects of the methods of this disclosure, the relative risk of bleeding meeting type 2 of the Bleeding Academic Research Consortium (BARC) bleeding criteria with this regimen is 2.6 or less, compared to placebo administered with antiplatelet therapy, for example, 2.6 or less, 2.5 or less, 2.4 or less, 2.3 or less, 2.2 or less, 2.1 or less, 2.0 or less, 1.9 or less, 1.8 or less, 1.7 or less, 1.6 or less, 1.5 or less, 1.4 or less, 1.3 or less, 1.2 or less, 1.1 or less, 1.0 or less, 0.9 or less, 0.8 or less, 0.7 or less, 0.6 or less, or 0.5 or less.

[0428] In some embodiments of the method of this disclosure, the relative risk of bleeding corresponding to type 2 of the Bleeding Academic Research Consortium (BARC) bleeding criteria is independent of the amount of milbexian administered.

[0429] In other embodiments of the method of this disclosure, the human patient does not have bleeding that falls under type 2 of the Bleeding Academic Research Consortium (BARC) bleeding criteria.

[0430] In some aspects of the methods of this disclosure, the relative risk of bleeding meeting the ISTH criteria for major bleeding or clinically significant non-major bleeding (CRNM) with this regimen is 3 or less, for example, ≤3.0, ≤2.9, ≤2.8, ≤2.7, ≤2.6, ≤2.5, ≤2.4, ≤2.3, ≤2.2, ≤2.1, ≤2.0, ≤1.9, ≤1.8, ≤1.7, ≤1.6, ≤1.5, ≤1.4, ≤1.3, ≤1.2, ≤1.1, ≤1.0, ≤0.9, ≤0.8, ≤0.7, ≤0.6, or ≤0.5, compared to placebo in addition to standard treatment.

[0431] In some aspects of the methods of this disclosure, the relative risk of bleeding meeting the ISTH criteria for major bleeding or clinically significant non-major bleeding (CRNM) with this regimen is 3 or less, for example, ≤3.0, ≤2.9, ≤2.8, ≤2.7, ≤2.6, ≤2.5, ≤2.4, ≤2.3, ≤2.2, ≤2.1, ≤2.0, ≤1.9, ≤1.8, ≤1.7, ≤1.6, ≤1.5, ≤1.4, ≤1.3, ≤1.2, ≤1.1, ≤1.0, ≤0.9, ≤0.8, ≤0.7, ≤0.6, or ≤0.5, compared to placebo with antiplatelet therapy.

[0432] The administration of milbexian as described in this disclosure is generally safe and well-tolerated. For example, administration of milbexian at doses of 25 mg, 50 mg, or 100 mg does not result in clinically significant QTc interval prolongation. Administration of milbexian at doses of 25 mg, 50 mg, or 100 mg does not result in a ΔΔQTc of 10 milliseconds or more. In some embodiments, administration of milbexian at doses of 25 mg, 50 mg, or 100 mg results in a ΔΔQT of less than 10 milliseconds. In some embodiments, administration of milbexian at doses of 25 mg, 50 mg, or 100 mg results in a ΔΔQTc of less than 9 milliseconds. In some embodiments, administration of milbexian at doses of 25 mg, 50 mg, or 100 mg results in a ΔΔQTc of less than 8 milliseconds. In some embodiments, administration of milbexian at doses of 25 mg, 50 mg, or 100 mg results in a QTc ΔΔQTc of less than 7 milliseconds. In some embodiments, administration of milbexian at doses of 25 mg, 50 mg, or 100 mg results in a ΔΔQTc of less than 6 milliseconds. In some embodiments, administration of milbexian at doses of 25 mg, 50 mg, or 100 mg results in a ΔΔQTc of less than 5 milliseconds. In some embodiments, administration of milbexian at doses of 25 mg, 50 mg, or 100 mg results in a ΔΔQTc of less than 4 milliseconds.

[0433] Administration of milbexian at a dose of 25 mg does not result in clinically significant QTc interval prolongation. In some embodiments, administration of milbexian at a dose of 25 mg results in a ΔΔQTc of less than 10 milliseconds. In some embodiments, administration of milbexian at a dose of 25 mg results in a ΔΔQTc of less than 9 milliseconds. In some embodiments, administration of milbexian at a dose of 25 mg results in a ΔΔQTc of less than 8 milliseconds. In some embodiments, administration of milbexian at a dose of 25 mg results in a ΔΔQTc of less than 7 milliseconds. In some embodiments, administration of milbexian at a dose of 25 mg results in a ΔΔQTc of less than 6 milliseconds. In some embodiments, administration of milbexian at a dose of 25 mg results in a ΔΔQTc of less than 5 milliseconds. In some embodiments, administration of milbexian at a dose of 25 mg results in a ΔΔQTc of less than 4 milliseconds.

[0434] Administration of milbexian at a dose of 50 mg does not result in clinically significant QTc interval prolongation. In some embodiments, administration of milbexian at a dose of 50 mg results in a ΔΔQTc of less than 10 milliseconds. In some embodiments, administration of milbexian at a dose of 50 mg results in a ΔΔQTc of less than 9 milliseconds. In some embodiments, administration of milbexian at a dose of 50 mg results in a ΔΔQTc of less than 8 milliseconds. In some embodiments, administration of milbexian at a dose of 50 mg results in a ΔΔQTc of less than 7 milliseconds. In some embodiments, administration of milbexian at a dose of 50 mg results in a ΔΔQTc of less than 6 milliseconds. In some embodiments, administration of milbexian at a dose of 50 mg results in a ΔΔQTc of less than 5 milliseconds. In some embodiments, administration of milbexian at a dose of 50 mg results in a ΔΔQTc of less than 4 milliseconds.

[0435] Administration of milbexian at a dose of 100 mg does not result in a clinically significant QTc interval prolongation. In some embodiments, administration of milbexian at a dose of 100 mg results in a ΔΔQTc of less than 10 milliseconds. In some embodiments, administration of milbexian at a dose of 100 mg results in a ΔΔQTc of less than 9 milliseconds. In some embodiments, administration of milbexian at a dose of 100 mg results in a ΔΔQTc of less than 8 milliseconds. In some embodiments, administration of milbexian at a dose of 100 mg results in a ΔΔQTc of less than 7 milliseconds. In some embodiments, administration of milbexian at a dose of 100 mg results in a ΔΔQTc of less than 6 milliseconds. In some embodiments, administration of milbexian at a dose of 100 mg results in a ΔΔQTc of less than 5 milliseconds. In some embodiments, administration of milbexian at a dose of 100 mg results in a ΔΔQTc of less than 4 milliseconds.

[0436] This disclosure relates to a method for preventing stroke and non-CNS systemic embolism in adult patients with atrial fibrillation (AF), characterized in that the method involves administering 100 mg of milbexian to the patient twice daily. This disclosure relates to a method for preventing stroke and non-CNS systemic embolism in multiple adult patients with atrial fibrillation (AF), characterized in that the method involves administering 100 mg of milbexian to the patient twice daily.

[0437] This disclosure relates to one method for preventing one thrombotic event in adult patients with acute coronary syndrome (ACS), characterized by administering 25 mg of milbexian in a BID in combination with antiplatelet therapy. This disclosure relates to multiple methods for preventing multiple thrombotic events in adult patients with acute coronary syndrome (ACS), characterized by administering 25 mg of milbexian in a BID in combination with antiplatelet therapy.

[0438] Those skilled in the art will be able to recognize or confirm, within the scope of ordinary experimentation, many equivalents to the embodiments described herein.

[0439] All publications, patents, and patent applications referenced herein are incorporated by reference to the same extent as when each individual publication, patent, or patent application is specifically and individually indicated to be incorporated by reference.

[0440] [Pattern] In this specification, references to methods of using milbexian or compositions containing milbexian for treating or preventing the symptoms of the Disclosure are understood to also refer to (i) milbexian or compositions containing milbexian for use in methods of treating or preventing the symptoms of the Disclosure; and / or (ii) the use of milbexian or compositions containing milbexian in the manufacture of a medicament for treating or preventing the symptoms of the Disclosure.

[0441] Model Group 1 Embodiment 1. Use of milbexian for the treatment or prevention of thrombotic disease in human patients with cardiovascular disease or cerebrovascular disease, characterized in that the human patient is administered an immediate-release tablet containing 25 mg, 50 mg, or 100 mg of milbexian (or a pharmaceutically acceptable salt or solvate thereof) and a pharmaceutically acceptable excipient, the immediate-release tablet may be administered in combination with antiplatelet therapy as appropriate, and the immediate-release tablet is administered twice daily. Embodiment 2. Use of milbexian according to Embodiment 1, wherein administration of an immediate-release tablet containing milbexian (or a pharmaceutically acceptable salt or solvate thereof), or a regimen including an immediate-release tablet, reduces the patient's factor XI coagulation activity by approximately 7% to approximately 20% compared to baseline, or by approximately 27% to approximately 64% compared to baseline. Embodiment 3. Use of milbexian according to Embodiment 1 or Embodiment 2, by administration of an immediate-release tablet containing milbexian (or a pharmaceutically acceptable salt or solvate thereof), or by a regimen including an immediate-release tablet, which results in an extension of activated partial thromboplastin time (aPTT) of approximately 27% to approximately 64% relative to baseline, or an extension of the patient's activated partial thromboplastin time (aPTT) of 2.1 to 2.6 relative to baseline. Embodiment 4. Use of milbexian in any one of the embodiments described above, wherein administration does not statistically significantly increase the incidence of major hemorrhagic complications. Embodiment 5. Use of any one of the above embodiments of milbexian, wherein the disintegration time of the immediate-release tablet in water is less than 20 seconds at 37°C. Embodiment 6. Use of milbexian in any one of the embodiments described above, wherein administration results in a plasma half-life of milbexian of approximately 13 hours to approximately 16 hours. Embodiment 7. Use of milbexian in any one of the embodiments described above, wherein the plasma concentration of milbexian reaches a steady state in approximately 3 to 6 days after administration. Embodiment 8. Use of milbexian in any one of the embodiments described above, wherein the plasma concentration of milbexian reaches a steady state in approximately 4 to 6 days after administration. Embodiment 9. Use of milbexian in any one of the embodiments described above, wherein the immediate-release tablet is administered regardless of the timing of meals. Embodiment 10. Use of a milbexian in any one of the embodiments described above, wherein the thrombotic disorder is a thromboembolic disorder selected from arterial thromboembolism, venous thromboembolism, or thromboembolism in the intracardiac chamber or peripheral circulation. Apparatus 11. Use of any one of the above-described apparatuses, wherein the thromboembolic disorder is unstable angina, acute coronary syndrome, atrial fibrillation, myocardial infarction, transient ischemic attack, stroke, atherosclerosis, peripheral occlusive arterial disease, venous thrombosis, deep vein thrombosis, thrombophlebitis, arterial embolism, coronary artery thrombosis, cerebral artery thrombosis, cerebral embolism, renal embolism, pulmonary embolism, or thrombosis resulting from a medical implant, medical device or medical procedure in which thrombus formation is promoted by exposure of blood to an artificial surface. Apparatus 12. Use of milbexian according to Apparatus 10, wherein the thrombotic disease is arterial thromboembolism. Apparatus 13. Use of the milbexian of Apparatus 12, wherein arterial thromboembolism is selected from coronary artery thrombosis, cerebral artery thrombosis, arterial embolism, cerebral embolism, acute ischemic stroke, transient ischemic attack (TIA), myocardial infarction, stroke, acute coronary syndrome, atherosclerosis, peripheral occlusive arterial disease, cardiovascular death, or a combination thereof. Apparatus 14. Use of milbexian according to Apparatus 10, wherein the thrombotic disease is venous thromboembolism. Apparatus 15. Use of the milbexian of Apparatus 14, wherein venous thromboembolism is selected from deep vein thrombosis, venous thromboembolism, pulmonary embolism, death, or a combination thereof. Apparatus 16. Use of any one of the milbexian of Apparatus 1 to 9, wherein the thrombotic disorder is a stroke and / or a systemic embolism other than that of the central nervous system (CNS). Embodiment 17. Use of any one of the above embodiments of a milbexian in which a human cardiovascular patient also has a cerebrovascular disease. Embodiment 18. Use of the milbexian of Embodiment 17, wherein the cerebrovascular disease is selected from non-cardiogenic ischemic stroke or transient ischemic attack (TIA). Embodiment 19. Use of any one of the above embodiments of a milbexian in which a human patient has a cardiovascular disease. Apparatus 20. Use of milbexian according to Apparatus 19, wherein the cardiovascular disease is atrial fibrillation or atrial flutter. Apparatus 21. Use of the milbexian of Apparatus 19, wherein the cardiovascular disease is acute coronary syndrome. Apparatus 22. Use of Milbexian according to Apparatus 11, wherein the thrombotic disorder is caused by a medical implant, medical device, or medical procedure in which thrombus formation is promoted by exposure of blood to an artificial surface. Embodiment 23. Use of milbexian according to any one of the embodiments described above, wherein the immediate-release tablet contains 50 mg or 100 mg of milbexian (or a pharmaceutically acceptable salt or solvate thereof). Apparatus 24. Use of milbexian according to Apparatus 10, wherein thrombotic diseases include arterial thromboembolism associated with acute coronary syndrome. Embodiment 25. Use of milbexian according to any one of Embodiments 1 to 9, characterized in that a human patient is given a regimen comprising (i) an immediate-release tablet containing 25 mg of milbexian (or a pharmaceutically acceptable salt or solvate thereof); and (ii) an antiplatelet therapy selected from the group consisting of aspirin, P2Y12 inhibitors, and combinations thereof, wherein the immediate-release tablet is administered twice daily. Embodiment 26. Use of milbexian according to Embodiment 25, wherein the antiplatelet therapy is the administration of a P2Y12 inhibitor. Embodiment 27. Use of milbexian according to Embodiment 26, wherein the P2Y12 inhibitor is clopidogrel, ticagrelor, or prasugrel. Embodiment 28. Use of milbexian in any one of the embodiments described above, wherein the antiplatelet therapy is the administration of aspirin. Embodiment 29. Use of milbexian in any one of the embodiments described above, in which a human patient is treated with a combination therapy of aspirin and clopidogrel for at least 90 days. Embodiment 30. Use of milbexian according to Embodiment 29, wherein the patient is treated with aspirin and / or clopidogrel without adjusting the dose of milbexian. Embodiment 31. Use of milbexian in any one of the embodiments described above, wherein the human patient is unable to swallow tablet dosage forms. Embodiment 32. Use of milbexian according to any one of the embodiments described above, wherein the immediate-release tablets are dispersed in an aqueous medium to form an aqueous dispersion. Embodiment 33. Use of the milbexian according to Embodiment 32, wherein the aqueous medium is physiological saline, phosphate buffer, plant juice, or fruit juice such as applesauce. Embodiment 34. Use of milbexian according to Embodiment 32 or Embodiment 33, wherein the aqueous dispersion is administered to a human patient via a nasogastric tube or spoon. Embodiment 35. Use of milbexian according to any one of Embodiments 32 to 34, wherein the immediate-release tablet is dispersed in an aqueous medium at 37°C in less than 1 minute to be administered orally as an aqueous dispersion. Embodiment 36. Use of milbexian in any one of the embodiments described above, wherein administration of milbexian does not result in a significant prolongation of the QTc interval.

[0442] Appearance Group 2 Embodiment 1. A method for preventing one or more strokes and non-central nervous system (CNS) systemic embolism events in a human patient having atrial fibrillation, the method comprising administering to a human patient a pharmaceutical composition containing approximately 100 mg of milbexian (or a pharmaceutically acceptable salt or solvate thereof, in milbexian equivalent); the pharmaceutical composition being administered twice daily. Embodiment 2. A method for preventing one or more major cardiovascular adverse events in a human patient with atrial fibrillation, Each event is selected from a group consisting of cardiovascular death, myocardial infarction, stroke, and systemic embolism other than that of the central nervous system (CNS); The method involves administering a pharmaceutical composition containing approximately 100 mg of milbexian (or a pharmaceutically acceptable salt or solvate thereof, in milbexian equivalent) to a human patient; the composition is administered twice daily. Embodiment 3. The method of Embodiment 2, wherein the primary cardiovascular adverse event is cardiovascular death. Embodiment 4. The method according to any one of Embodiments 1 to 3, wherein the patient has atrial fibrillation and also has coexisting coronary artery disease (CAD) and / or peripheral artery disease (PAD). Embodiment 5. The method according to any one of Embodiments 1 to 4, wherein the pharmaceutical composition is a solid oral pharmaceutical composition comprising milbexian (or a pharmaceutically acceptable salt or solvate thereof) and one or more pharmaceutically acceptable excipients. Embodiment 6. The method of Embodiment 5, wherein the solid oral pharmaceutical composition is an immediate-release tablet. Embodiment 7. The method of Embodiment 6, wherein the disintegration time of the immediate-release tablet in water is less than 20 seconds at 37°C. Embodiment 8. The method according to any one of Embodiments 5 to 7, wherein administration results in a plasma half-life of milbexian of approximately 13 hours to approximately 16 hours. Embodiment 9. The method according to any one of Embodiments 5 to 7, wherein, during repeated administration, the half-life of milbexian in plasma becomes approximately 13 hours to approximately 16 hours upon administration. Embodiment 10. Any one of the above embodiments, wherein the plasma concentration of milbexian reaches a steady state in approximately 4 to 6 days after administration. Embodiment 11. Any one of the above embodiments, wherein a pharmaceutical composition comprising milbexian (or a pharmaceutically acceptable salt or solvate thereof) is administered regardless of the timing of meals. Embodiment 12. Any one of the embodiments described above, wherein a composition comprising milbexian (or a pharmaceutically acceptable salt or solvate thereof) is administered twice daily for at least 13 weeks. Embodiment 13. Any one of the embodiments described above, wherein a composition comprising milbexian (or a pharmaceutically acceptable salt or solvate thereof) is administered once in the morning and once at night. Embodiment 14. Any one of the embodiments described above, wherein the morning and evening doses are administered at the same time every day. Apparatus 15. A method for preventing one or more strokes and non-central nervous system (CNS) systemic embolism events in a human patient with atrial fibrillation, the method comprising administering to the patient a film-coated immediate-release tablet containing approximately 100 mg of milbexian or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients. The film-coated, immediate-release tablets are administered twice daily, regardless of whether or not a meal has been eaten. The patient is at least 18 years old; The patient also had the following: (i) 75 years of age or older or (ii) history of ischemic stroke Do you have one or more risk factors in category (A) selected from the following? Or: (i) 65-74 years old; (ii) hypertension; (iii) diabetes; (iv) A history of coronary artery disease (CAD) (including a history of myocardial infarction or acute coronary syndrome, regardless of whether percutaneous coronary intervention (PCI) has been performed) or a history of peripheral artery disease (PAD); and (v) History of heart failure A method in which two or more cardiovascular risk factors from category (B), selected from the group consisting of the above, are present or combined. Embodiment 16. A method for preventing one or more major cardiovascular adverse events in a human patient with atrial fibrillation, Each event is selected from a group consisting of cardiovascular death, myocardial infarction, stroke, and systemic embolism other than that of the central nervous system (CNS). The method is characterized by administering to the patient a film-coated immediate-release tablet containing 100 mg of milbexian or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients. The film-coated, immediate-release tablets are administered twice daily, regardless of whether or not a meal has been eaten. The patient is at least 18 years old; The patient also had the following: (i) 75 years of age or older or (ii) history of ischemic stroke Do you have one or more risk factors in category (A) selected from the following? Or: (i) 65-74 years old; (ii) hypertension; (iii) diabetes; (iv) A history of coronary artery disease (CAD) (including a history of myocardial infarction or acute coronary syndrome, regardless of whether percutaneous coronary intervention (PCI) has been performed) or a history of peripheral artery disease (PAD); and (v) History of heart failure A method in which two or more cardiovascular risk factors from category (B), selected from the group consisting of the above, are present or combined. Embodiment 17. The method of Embodiment 16, wherein the major cardiovascular adverse events are stroke and systemic embolism other than that of the central nervous system (CNS). Embodiment 18. Any one of Embodiments 15 to 17, wherein the film-coated, ready-release tablet has a water disintegration time of less than 20 seconds at 37°C. Embodiment 19. Any one of embodiments 15 to 18, wherein the half-life of administered milbexian in plasma is 13 to 16 hours. Embodiment 20. Any one of embodiments 15 to 18, wherein the half-life of administered milbexian in plasma is 13 to 16 hours during repeated administration. Embodiment 21. Any one of Embodiments 15 to 20, wherein a composition comprising milbexian (or a pharmaceutically acceptable salt or solvate thereof) is administered twice daily for at least 13 weeks. Embodiment 22. Any one of Embodiments 15 to 21, wherein a composition comprising milbexian (or a pharmaceutically acceptable salt or solvate thereof) is administered once in the morning and once at night. Embodiment 23. The method of Embodiment 22, wherein the morning and evening doses are administered at the same time every day. Embodiment 24. Any one of the embodiments described above, wherein administration reduces the patient's factor XI coagulation activity by approximately 27% to approximately 64% compared to baseline. Embodiment 25. Any one of the above embodiments, wherein administration prolongs the patient's activated partial thromboplastin time (aPTT) to a baseline ratio of 2.1 to 2.6. Embodiment 26. A method for preventing stroke in a human patient having atrial fibrillation, the method comprising administering to a human patient a pharmaceutical composition containing about 100 mg of milbexian (or a pharmaceutically acceptable salt or solvate thereof, in milbexian equivalent), and administering the pharmaceutical composition twice daily. Apparatus 27. A method for preventing one or more systemic embolisms other than those of the central nervous system (CNS) in a human patient having atrial fibrillation, the method comprising administering to a human patient a pharmaceutical composition containing approximately 100 mg of milbexian (or a pharmaceutically acceptable salt or solvate thereof, in milbexian equivalent), and administering the pharmaceutical composition twice daily. Embodiment 28. A method for preventing one or more cardiovascular adverse events in a human patient with atrial fibrillation, Each event is selected from a group consisting of cardiovascular death, myocardial infarction, stroke, and systemic embolism other than that of the central nervous system (CNS). The method involves administering a pharmaceutical composition containing approximately 100 mg of milbexian (or a pharmaceutically acceptable salt or solvate thereof, in milbexian equivalent) to a human patient; the composition is administered twice daily. Appearance 29. The method of Appearance 28, wherein the primary cardiovascular adverse event is cardiovascular death. Embodiment 30. The method of Embodiment 28, wherein the primary cardiovascular adverse event is myocardial infarction. Embodiment 31. The method of Embodiment 28, wherein the primary cardiovascular adverse event is stroke. Embodiment 32. The method of Embodiment 28, wherein the primary cardiovascular adverse event is systemic embolism other than that of the central nervous system (CNS). Embodiment 33. Any one of embodiments 26 to 32, wherein the patient has atrial fibrillation and also has coexisting coronary artery disease (CAD) and / or peripheral artery disease (PAD). Embodiment 34. The method of Embodiment 33, wherein the patient has atrial fibrillation and also has co-existing coronary artery disease (CAD). Embodiment 35. The method of Embodiment 33, wherein the patient has atrial fibrillation and also has concomitant peripheral artery disease (PAD). Embodiment 36. Any one of Embodiments 26 to 35, wherein the pharmaceutical composition is a solid oral pharmaceutical composition comprising milbexian (or a pharmaceutically acceptable salt or solvate thereof) and one or more pharmaceutically acceptable excipients. Embodiment 37. The method of Embodiment 36, wherein the solid oral pharmaceutical composition is an immediate-release tablet. Embodiment 38. The method of Embodiment 37, wherein the underwater disintegration time of the immediate-release tablet is less than 20 seconds at 37°C. Embodiment 39. Any one of Embodiments 26 to 38, wherein administration results in a plasma half-life of milbexian of approximately 13 to 16 hours. Embodiment 40. A method according to any one of Embodiments 26 to 39, wherein, during repeated administration, the plasma half-life of milbexian becomes approximately 13 hours to approximately 16 hours upon administration. Embodiment 41. Any one of Embodiments 26 to 40, wherein the plasma concentration of milbexian reaches a steady state in approximately 4 to 6 days after administration. Embodiment 42. Any one of Embodiments 26 to 41, wherein a pharmaceutical composition comprising milbexian (or a pharmaceutically acceptable salt or solvate thereof) is administered regardless of the timing of meals. Embodiment 43. Any one of Embodiments 26 to 42, wherein the patient is unable to swallow tablet dosage forms. Embodiment 44. Any one of Embodiments 26 to 43, wherein a pharmaceutical composition is dispersed in an aqueous medium to form an aqueous dispersion. Embodiment 45. The method of Embodiment 44, wherein the aqueous medium is physiological saline, phosphate buffer, plant juice, or fruit juice such as applesauce. Embodiment 46. The method according to Embodiment 44 or Embodiment 45, wherein the aqueous dispersion is administered to a human patient via a nasogastric tube or spoon. Embodiment 47. Any one of Embodiments 44 to 46, wherein milbexian is administered orally as an aqueous dispersion by dispersing the pharmaceutical composition in an aqueous medium at 37°C for less than 60 seconds. Embodiment 48. Any one of Embodiments 26 to 47, wherein a composition comprising milbexian (or a pharmaceutically acceptable salt or solvate thereof) is administered twice daily for at least 13 weeks. Embodiment 49. Any one of Embodiments 26 to 48, wherein a composition comprising milbexian (or a pharmaceutically acceptable salt or solvate thereof) is administered once in the morning and once at night. Embodiment 50. The method of Embodiment 49, wherein the morning and evening doses are administered at the same time every day. Embodiment 51. Any one of Embodiments 26 to 50, wherein administration reduces the patient's factor XI coagulation activity by approximately 27% to approximately 64% compared to baseline. Embodiment 52. Any one of Embodiments 26 to 51, wherein administration prolongs the patient's activated partial thromboplastin time (aPTT) and the baseline ratio is 2.1 to 2.6. Apparatus 53. A method for preventing stroke in a human patient having atrial fibrillation, the method comprising administering to the patient a film-coated immediate-release tablet containing approximately 100 mg of milbexian or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients, The film-coated, immediate-release tablets are administered twice daily, regardless of whether or not a meal has been eaten. The patient is at least 18 years old; The patient also had the following: (i) 75 years of age or older or (ii) history of ischemic stroke Do you have one or more risk factors in category (A) selected from the following? Or: (i) 65-74 years old; (ii) hypertension; (iii) diabetes; (iv) A history of coronary artery disease (CAD) (including a history of myocardial infarction or acute coronary syndrome, regardless of whether percutaneous coronary intervention (PCI) has been performed) or a history of peripheral artery disease (PAD); and (v) History of heart failure A method in which two or more cardiovascular risk factors from category (B), selected from the group consisting of the above, are present or combined. Apparatus 54. A method for preventing systemic embolic events other than those of the central nervous system (CNS) in a human patient with atrial fibrillation, the method comprising administering to the patient a film-coated immediate-release tablet containing approximately 100 mg of milbexian or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients. The film-coated, immediate-release tablets are administered twice daily, regardless of whether or not a meal has been eaten. The patient is at least 18 years old; The patient also had the following: (i) 75 years of age or older or (ii) history of ischemic stroke Do you have one or more risk factors in category (A) selected from the following? Or: (i) 65-74 years old; (ii) hypertension; (iii) diabetes; (iv) A history of coronary artery disease (CAD) (including a history of myocardial infarction or acute coronary syndrome, regardless of whether percutaneous coronary intervention (PCI) has been performed) or a history of peripheral artery disease (PAD); and (v) History of heart failure A method in which two or more cardiovascular risk factors from category (B), selected from the group consisting of the above, are present or combined. Embodiment 55. Any one of embodiments 53 to 54, wherein the patient has atrial fibrillation and also has coexisting coronary artery disease (CAD) and / or peripheral artery disease (PAD). Embodiment 56. The method of Embodiment 55, wherein the patient has atrial fibrillation and also has co-existing coronary artery disease (CAD). Embodiment 57. The method of Embodiment 55, wherein the patient has atrial fibrillation and also has concomitant peripheral artery disease (PAD). Embodiment 58. Any one of Embodiments 53 to 57, wherein the underwater disintegration time of a film-coated, ready-release tablet is less than 20 seconds at 37°C. Embodiment 59. One of the methods described in Embodiments 53 to 58, wherein administration results in a plasma half-life of milbexian of approximately 13 to 16 hours. Embodiment 60. A method according to any one of Embodiments 53 to 59, wherein, during repeated administration, the half-life of milbexian in plasma becomes approximately 13 hours to approximately 16 hours upon administration. Embodiment 61. Any one of Embodiments 53 to 60, wherein the plasma concentration of milbexian reaches a steady state in approximately 4 to 6 days after administration. Embodiment 62. Any one of embodiments 53 to 61, wherein a film-coated immediate-release tablet is administered regardless of the timing of meals. Embodiment 63. Any one of embodiments 53 to 62, wherein the patient is unable to swallow tablet dosage forms. Embodiment 64. Any one of Embodiments 53 to 63, wherein film-coated immediate-release tablets are dispersed in an aqueous medium to form an aqueous dispersion. Embodiment 65. The method of Embodiment 64, wherein the aqueous medium is physiological saline, phosphate buffer, plant juice, or fruit juice such as applesauce. Embodiment 66. Embodiment 65 or the method of Embodiment 65, wherein the aqueous dispersion is administered to a human patient via a nasogastric tube or spoon. Embodiment 67. Any one of Embodiments 53 to 66, wherein milbexian is administered orally as an aqueous dispersion by dispersing a film-coated immediate-release tablet in an aqueous medium at 37°C in less than 60 seconds. Embodiment 68. Any one of embodiments 53 to 67, wherein a film-coated immediate-release tablet is administered twice daily for at least 13 weeks. Embodiment 69. Any one of embodiments 53 to 68, wherein a film-coated immediate-release tablet is administered once in the morning and once at night. Embodiment 70. The method of Embodiment 69, wherein the morning and evening doses are administered at the same time every day. Embodiment 71. Any one of Embodiments 53 to 70, wherein administration reduces the patient's factor XI coagulation activity by approximately 27% to approximately 64% compared to baseline. Embodiment 72. Any one of embodiments 53 to 71, wherein administration prolongs the patient's activated partial thromboplastin time (aPTT) and the baseline ratio is 2.1 to 2.6. Embodiment 73. Any one of the above embodiments, characterized in that standard antiplatelet therapy is further administered to the patient. Embodiment 74. The method of Embodiment 73, wherein the standard antiplatelet therapy is selected from aspirin, adenosine diphosphate (ADP) receptor inhibitors; adenosine reuptake inhibitors; platelet glycoprotein receptor antagonists; phosphodiesterase inhibitors; or protease-activated receptor (PAR-1) antagonists. Embodiment 75. Any one of embodiments 73 and 74, wherein the standard antiplatelet therapy is selected from aspirin, clopidogrel, ticagrelor, ticlopidine, prasugrel, dipyridamole, absiximab, eptifivatide, tyrofiban, cilostazol, or volapaxar. Embodiment 76. Any one of embodiments 73 to 75, wherein the standard antiplatelet therapy is selected from aspirin, clopidogrel, ticagrelor, or prasugrel. Embodiment 77. Any one of embodiments 73 to 76, wherein the standard antiplatelet therapy is selected from clopidogrel, ticagrelor, or prasugrel. Embodiment 78. Any one of embodiments 73 to 77, wherein standard antiplatelet therapy includes antiplatelet monotherapy (SAPT). Embodiment 79. The method of Embodiment 78, wherein the antiplatelet monotherapy includes aspirin or a P2Y12 inhibitor selected from clopidogrel, ticagrelor, and prasugrel. Embodiment 80. Any one of Embodiments 73 to 77, wherein standard antiplatelet therapy includes dual antiplatelet therapy (DAPT). Embodiment 81. The method of Embodiment 80, wherein the dual antiplatelet therapy includes aspirin and a P2Y12 inhibitor (selected from clopidogrel, ticagrelor, or prasugrel). Embodiment 82. Any one of Embodiments 80 and 81, wherein the combination therapy of two antiplatelet agents includes aspirin and a P2Y12 inhibitor (selected from clopidogrel, ticagrelor, or prasugrel). Embodiment 83. Any one of Embodiments 80 to 82, wherein the combination therapy of two antiplatelet agents includes aspirin and clopidogrel. Appearance 84. One of the methods described in Appearances 80 to 83, in which dual antiplatelet therapy (DAPT) is performed for 21 days, followed by antiplatelet monotherapy (SAPT). Embodiment 85. Any one of Embodiments 80 to 83, wherein dual antiplatelet therapy (i.e., administration of aspirin and a P2Y12 inhibitor) is administered for more than 90 days, with or without de-escalation to SAPT. Apparatus 86. Use of milbexian to prevent one or more strokes and non-central nervous system (CNS) systemic embolic events in a human patient having atrial fibrillation, the method comprising administering to a human patient a pharmaceutical composition containing about 100 mg of milbexian (or a pharmaceutically acceptable salt or solvate thereof, in milbexian equivalent); the pharmaceutical composition being administered twice daily. Appearance 87. Use of milbexian to prevent one or more major cardiovascular adverse events in a human patient with atrial fibrillation, Each event is selected from a group consisting of cardiovascular death, myocardial infarction, stroke, and systemic embolism other than that of the central nervous system (CNS). The method involves administering a pharmaceutical composition containing 100 mg of milbexian (or a pharmaceutically acceptable salt or solvate thereof, in milbexian equivalent) to a human patient; the composition is administered twice daily. Appearance 88. Use of milbexian as in Appearance 87, where the primary cardiovascular adverse event is cardiovascular death. Apparatus 89. Use of any one of the milbexian described in Apparatus 86-88, in which the patient has atrial fibrillation and also has coronary artery disease (CAD) and / or peripheral artery disease (PAD). Embodiment 90. Use of milbexian according to any one of Embodiments 86 to 89, wherein the pharmaceutical composition is a solid oral pharmaceutical composition comprising milbexian (or a pharmaceutically acceptable salt or solvate thereof) and one or more pharmaceutically acceptable excipients. Embodiment 91. Use of milbexian according to Embodiment 90, wherein the solid oral pharmaceutical composition is an immediate-release tablet. Appearance 92. Use of the milbexian of Appearance 91, wherein the disintegration time of the immediate-release tablet in water is less than 20 seconds at 37°C. Embodiment 93. Use of any one of the milbexian embodiments 86 to 92, wherein administration results in a plasma half-life of milbexian of approximately 13 to 16 hours. Embodiment 94. Use of milbexian in any one of Embodiments 86 to 93, wherein, during repeated administration, the half-life of milbexian in plasma is approximately 13 hours to approximately 16 hours. Embodiment 95. Use of any one of the milbexian embodiments 86 to 94, wherein the plasma concentration of milbexian reaches a steady state in approximately 4 to 6 days after administration. Embodiment 96. Use of milbexian according to any one of Embodiments 86 to 95, wherein a pharmaceutical composition comprising milbexian (or a pharmaceutically acceptable salt or solvate thereof) is administered regardless of the timing of meals. Embodiment 97. Use of milbexian according to any one of Embodiments 86 to 96, wherein a composition comprising milbexian (or a pharmaceutically acceptable salt or solvate thereof) is administered twice daily for at least 13 weeks. Embodiment 98. Use of milbexian according to any one of Embodiments 86 to 97, wherein a composition comprising milbexian (or a pharmaceutically acceptable salt or solvate thereof) is administered once in the morning and once at night. Embodiment 99. Use of milbexian according to any one of Embodiments 86-98, wherein the morning and evening doses are administered at the same time each day. Apparatus 100. Use of milbexian to prevent one or more strokes and non-central nervous system (CNS) systemic embolisms in human patients with atrial fibrillation, the method comprising administering to the patient a film-coated immediate-release tablet containing 100 mg of milbexian or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients. The film-coated, immediate-release tablets are administered twice daily, regardless of whether or not a meal has been eaten. The patient is at least 18 years old; The patient also had the following: (i) 75 years of age or older or (ii) history of ischemic stroke Do you have one or more risk factors in category (A) selected from the following? Or: (vi) 65-74 years old; (vii) hypertension; (viii) diabetes; (ix) A history of coronary artery disease (CAD) (including a history of myocardial infarction or acute coronary syndrome, regardless of whether percutaneous coronary intervention (PCI) has been performed) or a history of peripheral artery disease (PAD); and (x) History of heart failure A method in which two or more cardiovascular risk factors from category (B), selected from the group consisting of the above, are present or combined. Embodiment 101. Use of milbexian to prevent one or more major cardiovascular adverse events in a human patient with atrial fibrillation, Each event is selected from a group consisting of cardiovascular death, myocardial infarction, stroke, and systemic embolism other than that of the central nervous system (CNS). The method is characterized by administering to the patient a film-coated immediate-release tablet containing 100 mg of milbexian or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients. The film-coated, immediate-release tablets are administered twice daily, regardless of whether or not a meal has been eaten. The patient is at least 18 years old; The patient also had the following: (i) 75 years of age or older or (ii) history of ischemic stroke Do you have one or more risk factors in category (A) selected from the following? Or: (i) 65-74 years old; (ii) hypertension; (iii) diabetes; (iv) A history of coronary artery disease (CAD) (including a history of myocardial infarction or acute coronary syndrome, regardless of whether percutaneous coronary intervention (PCI) has been performed) or a history of peripheral artery disease (PAD); and (v) History of heart failure The individual has two or more cardiovascular risk factors in category (B), selected from the group consisting of the following: Appearance 102. Use of milbexian as in Appearance 101, wherein the primary cardiovascular adverse event is cardiovascular death. Embodiment 103. Use of any one of Embodiments 100 to 102, wherein the film-coated, ready-release tablet has a water disintegration time of less than 20 seconds at 37°C. Embodiment 104. Use of any one of the milbexian embodiments 100 to 103, wherein the half-life of the administered milbexian in plasma is 13 to 16 hours. Embodiment 105. Use of any one of the milbexian embodiments 100 to 104, wherein the half-life of the administered milbexian in plasma is 13 to 16 hours during repeated administration. Embodiment 106. Use of milbexian according to any one of Embodiments 100 to 105, wherein a composition comprising milbexian (or a pharmaceutically acceptable salt or solvate thereof) is administered twice daily for at least 13 weeks. Embodiment 107. Use of milbexian according to any one of Embodiments 86 to 106, wherein a composition comprising milbexian (or a pharmaceutically acceptable salt or solvate thereof) is administered once in the morning and once at night. Embodiment 108. Use of milbexian according to Embodiment 107, wherein the morning and evening doses are administered at the same time each day. Apparatus 109. Use of any one of the milbexian formulations from Apparatus 86 to 108, wherein administration reduces the patient's factor XI coagulation activity by approximately 27% to approximately 64% compared to baseline. Embodiment 110. Use of any one of the milbexian formulations from Embodiments 86 to 109, wherein administration prolongs the patient's activated partial thromboplastin time (aPTT) with a baseline ratio of 2.1 to 2.6. Embodiment 111. Use of milbexian for the prevention of stroke in human patients with atrial fibrillation, the method comprising administering to a human patient a pharmaceutical composition containing about 100 mg of milbexian (or a pharmaceutically acceptable salt or solvate thereof, in milbexian equivalent); the pharmaceutical composition being administered twice daily. Embodiment 112. A method for using milbexian to prevent one or more systemic embolisms other than those in the central nervous system (CNS) in a human patient having atrial fibrillation, the method comprising administering to a human patient a pharmaceutical composition containing about 100 mg of milbexian (or a pharmaceutically acceptable salt or solvate thereof, in milbexian equivalent); the pharmaceutical composition being administered twice daily. Embodiment 113. Use of milbexian to prevent one or more major cardiovascular adverse events in a human patient with atrial fibrillation, Each event is selected from a group consisting of cardiovascular death, myocardial infarction, stroke, and systemic embolism other than that of the central nervous system (CNS). The method involves administering a pharmaceutical composition containing approximately 100 mg of milbexian (or a pharmaceutically acceptable salt or solvate thereof, in milbexian equivalent) to a human patient; the composition is administered twice daily. Appearance 114. Use of any one of the milbexian formulations in Appearances 111-113, wherein the primary cardiovascular adverse event is cardiovascular death. Appearance 115. Use of any one of the milbexian formulations in Appearances 111 to 113, wherein the primary cardiovascular adverse event is myocardial infarction. Apparatus 116. Use of any one of the milbexian formulations described in Apparatus 111 to 113, wherein the primary cardiovascular adverse event is stroke. Apparatus 117. Use of any one of the milbexian described in Apparatus 111 to 113, wherein the primary cardiovascular adverse event is systemic embolism other than that of the central nervous system (CNS). Apparatus 118. Use of any one of the milbexian described in Apparatus 111-117, in which the patient has atrial fibrillation and also has coronary artery disease (CAD) and / or peripheral artery disease (PAD). Apparatus 119. Use of the milbexian according to Apparatus 118, in which the patient has atrial fibrillation and also co-existing coronary artery disease (CAD). Apparatus 120. Use of the milbexian of Apparatus 118 in a patient who has atrial fibrillation and also has concomitant peripheral artery disease (PAD). Embodiment 121. Use of milbexian according to any one of Embodiments 111 to 120, wherein the pharmaceutical composition is a solid oral pharmaceutical composition comprising milbexian (or a pharmaceutically acceptable salt or solvate thereof) and one or more pharmaceutically acceptable excipients. Embodiment 122. Use of milbexian according to Embodiment 121, wherein the solid oral pharmaceutical composition is an immediate-release tablet. Embodiment 123. Use of the milbexian of Embodiment 122, wherein the disintegration time of the immediate-release tablet in water is less than 20 seconds at 37°C. Embodiment 124. Use of any one of the milbexian embodiments 111 to 123, wherein administration results in a plasma half-life of approximately 13 to 16 hours. Embodiment 125. Use of any one of the milbexian embodiments 111 to 124, wherein, during repeated administration, the half-life of milbexian in plasma becomes approximately 13 hours to approximately 16 hours upon administration. Embodiment 126. Use of any one of the milbexian embodiments 111 to 125, wherein the plasma concentration of milbexian reaches a steady state in approximately 4 to 6 days after administration. Embodiment 127. Use of milbexian according to any one of Embodiments 111 to 126, wherein a pharmaceutical composition containing milbexian (or a pharmaceutically acceptable salt or solvate thereof) is administered regardless of the timing of meals. Embodiment 128. Use of milbexian according to any one of Embodiments 111 to 127, wherein the patient is unable to swallow tablet dosage forms. Embodiment 129. Use of any one of the milbexian embodiments 111 to 128, wherein the pharmaceutical composition is dispersed in an aqueous medium to form an aqueous dispersion. Embodiment 130. Use of the milbexian of Embodiment 129, wherein the aqueous medium is physiological saline, phosphate buffer, plant juice, or fruit juice such as applesauce. Embodiment 131. Use of milbexian according to Embodiment 129 or Embodiment 130, wherein the aqueous dispersion is administered to a human patient via a nasogastric tube or spoon. Embodiment 132. A use of milbexian according to any one of Embodiments 129 to 131, wherein milbexian is administered orally as an aqueous dispersion by dispersing the pharmaceutical composition in an aqueous medium at 37°C for less than 60 seconds. Embodiment 133. Use of milbexian according to any one of Embodiments 111 to 132, wherein a composition comprising milbexian (or a pharmaceutically acceptable salt or solvate thereof) is administered twice daily for at least 13 weeks. Embodiment 134. Use of milbexian according to any one of Embodiments 111 to 133, wherein a composition comprising milbexian (or a pharmaceutically acceptable salt or solvate thereof) is administered once in the morning and once at night. Embodiment 135. Use of milbexian according to Embodiment 134, wherein the morning and evening doses are administered at the same time each day. Embodiment 136. Use of any one of the milbexian formulations from Embodiments 111 to 135, wherein administration reduces the patient's factor XI coagulation activity by approximately 27% to approximately 64% compared to baseline. Embodiment 137. Use of any one of the milbexian formulations from Embodiments 111 to 136, wherein administration prolongs the patient's activated partial thromboplastin time (aPTT) with a baseline ratio of 2.1 to 2.6. Apparatus 138. Use of milbexian for the prevention of stroke in a human patient with atrial fibrillation, the method comprising administering to the patient a film-coated immediate-release tablet containing approximately 100 mg of milbexian or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients, The film-coated, immediate-release tablets are administered twice daily, regardless of whether or not a meal has been eaten. The patient is at least 18 years old; The patient also had the following: (i) 75 years of age or older or (ii) history of ischemic stroke Do you have one or more risk factors in category (A) selected from the following? Or: (i) 65-74 years old; (ii) hypertension; (iii) diabetes; (iv) A history of coronary artery disease (CAD) (including a history of myocardial infarction or acute coronary syndrome, regardless of whether percutaneous coronary intervention (PCI) has been performed) or a history of peripheral artery disease (PAD); and (v) History of heart failure The individual has two or more cardiovascular risk factors in category (B), selected from the group consisting of the following: Apparatus 139. Use of milbexian to prevent systemic embolic events other than those of the central nervous system (CNS) in human patients with atrial fibrillation, the method comprising administering to the patient a film-coated immediate-release tablet containing approximately 100 mg of milbexian or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients. The film-coated, immediate-release tablets are administered twice daily, regardless of whether or not a meal has been eaten. The patient is at least 18 years old; The patient also had the following: (i) 75 years of age or older or (ii) history of ischemic stroke Do you have one or more risk factors in category (A) selected from the following? Or: (i) 65-74 years old; (ii) hypertension; (iii) diabetes; (iv) A history of coronary artery disease (CAD) (including a history of myocardial infarction or acute coronary syndrome, regardless of whether percutaneous coronary intervention (PCI) has been performed) or a history of peripheral artery disease (PAD); and (v) History of heart failure The individual has two or more cardiovascular risk factors in category (B), selected from the group consisting of the following: Apparatus 140. Use of any one of the milbexian described in Apparatus 138-139, in which the patient has atrial fibrillation and also has coronary artery disease (CAD) and / or peripheral artery disease (PAD). Apparatus 141. Use of the milbexian of Apparatus 140 in a patient who has atrial fibrillation and also has co-existing coronary artery disease (CAD). Apparatus 142. Use of milbexian according to Apparatus 140 in a patient who has atrial fibrillation and also has concomitant peripheral artery disease (PAD). Embodiment 143. Use of any one of the milbexian embodiments 138 to 142, wherein the film-coated, ready-release tablet has a water disintegration time of less than 20 seconds. Embodiment 144. Use of any one of the milbexian embodiments 138 to 143, wherein administration results in a plasma half-life of milbexian of approximately 13 to 16 hours. Embodiment 145. Use of any one of the milbexian embodiments 138 to 144, wherein, during repeated administration, the half-life of milbexian in plasma becomes approximately 13 hours to approximately 16 hours upon administration. Embodiment 146. Use of any one of the milbexian embodiments 138 to 145, wherein the plasma concentration of milbexian reaches a steady state in approximately 4 to 6 days after administration. Embodiment 147. Use of milbexian according to any one of Embodiments 138-146, wherein a film-coated immediate-release tablet is administered regardless of meal timing. Apparatus 148. Use of milbexian according to any one of Apparatus 138-147, wherein the patient is unable to swallow tablet dosage forms. Embodiment 149. Use of any one of the milbexian embodiments 138 to 148, wherein film-coated immediate-release tablets are dispersed in an aqueous medium to form an aqueous dispersion. Embodiment 150. Use of the milbexian of Embodiment 149, wherein the aqueous medium is physiological saline, phosphate buffer, plant juice, or fruit juice such as applesauce. Embodiment 151. Use of milbexian according to Embodiment 149 or Embodiment 150, wherein the aqueous dispersion is administered to a human patient via a nasogastric tube or spoon. Embodiment 152. A use of milbexian according to any one of Embodiments 138 to 151, wherein milbexian is administered orally as an aqueous dispersion by dispersing a film-coated immediate-release tablet in an aqueous medium at 37°C in less than 60 seconds. Embodiment 153. Use of milbexian according to any one of Embodiments 138-152, wherein film-coated immediate-release tablets are administered twice daily for at least 13 weeks. Embodiment 154. Use of milbexian according to any one of Embodiments 138 to 153, in which a film-coated immediate-release tablet is administered once in the morning and once at night. Embodiment 155. Use of milbexian according to Embodiment 154, wherein the morning and evening doses are administered at the same time each day. Embodiment 156. Use of any one of the milbexian formulations from Embodiments 138 to 155, wherein administration reduces the patient's factor XI coagulation activity by approximately 27% to approximately 64% compared to baseline. Embodiment 157. Use of any one of the milbexian formulations from Embodiments 138 to 156, wherein administration prolongs the patient's activated partial thromboplastin time (aPTT) with a baseline ratio of 2.1 to 2.6. Embodiment 158. Use of any one of the milbexian embodiments 86 to 157, characterized by further administering standard antiplatelet therapy to the patient. Apparatus 159. Use of milbexian according to Apparatus 158, wherein standard antiplatelet therapy is selected from aspirin, adenosine diphosphate (ADP) receptor inhibitors; adenosine reuptake inhibitors; platelet glycoprotein receptor antagonists; phosphodiesterase inhibitors; or protease-activated receptor (PAR-1) antagonists. Apparatus 160. Use of milbexian according to Apparatus 158 and 159, wherein the standard antiplatelet therapy is selected from aspirin, clopidogrel, ticagrelor, ticlopidine, prasugrel, dipyridamole, absiximab, eptifivatide, tyrofiban, cilostazol, or volapaxar. Embodiment 161. Use of any one of the milbexian described in Embodiments 158-160, wherein standard antiplatelet therapy is selected from aspirin, clopidogrel, ticagrelor, or prasugrel. Embodiment 162. Use of any one of the milbexian formulations in Embodiments 158-161, wherein standard antiplatelet therapy is selected from clopidogrel, ticagrelor, or prasugrel. Embodiment 163. Use of any one of the milbexian formulations in Embodiments 158-162, wherein standard antiplatelet therapy includes antiplatelet monotherapy (SAPT). Embodiment 164. Use of milbexian according to Embodiment 163, wherein monotherapy with an antiplatelet agent includes aspirin or a P2Y12 inhibitor selected from clopidogrel, ticagrelor, or prasugrel. Apparatus 165. Use of any one of milbexian from Apparatus 158-164, in which standard antiplatelet therapy includes dual antiplatelet therapy (DAPT). Embodiment 166. Use of milbexian according to Embodiment 165, wherein the combination therapy of two antiplatelet agents includes aspirin and a P2Y12 inhibitor (selected from clopidogrel, ticagrelor, or prasugrel). Embodiment 167. Use of milbexian in any one of Embodiments 165 and 166, wherein the combination therapy includes aspirin and a P2Y12 inhibitor (selected from clopidogrel, ticagrelor, or prasugrel). Embodiment 168. Use of milbexian in any one of Embodiments 165 to 167, wherein the combination therapy includes aspirin and clopidogrel as antiplatelet agents. Apparatus 169. Use of milbexian as described in one of Apparatus 165-168, in which dual antiplatelet therapy (DAPT) is performed for 21 days, followed by antiplatelet monotherapy (SAPT). Embodiment 170. Use of milbexian according to any one of Embodiments 165-168, wherein dual antiplatelet therapy (i.e., administration of aspirin and a P2Y12 inhibitor) is performed for more than 90 days, with or without de-escalation to SAPT. Apparatus 171. A method for preventing one or more strokes and systemic embolisms other than those of the central nervous system (CNS) in a human patient having atrial fibrillation, the method comprising administering to a human patient a pharmaceutical composition containing about 100 mg of milbexian or a pharmaceutically acceptable salt thereof; the pharmaceutical composition being administered twice daily. Embodiment 172. A method for preventing one or more cardiovascular adverse events in a human patient with atrial fibrillation, Each event is selected from a group consisting of cardiovascular death, myocardial infarction, stroke, and systemic embolism other than that of the central nervous system (CNS). The method involves administering a pharmaceutical composition containing approximately 100 mg of milbexian or a pharmaceutically acceptable salt thereof to a human patient; the composition is administered twice daily. Embodiment 173. A method for reducing the risk of one or more strokes and non-central nervous system (CNS) systemic embolisms in a human patient having atrial fibrillation, the method comprising administering to a human patient a pharmaceutical composition containing about 100 mg of milbexian or a pharmaceutically acceptable salt thereof; the pharmaceutical composition being administered twice daily. Embodiment 174. A method for reducing the risk of one or more cardiovascular adverse events in a human patient with atrial fibrillation, Each event is selected from a group consisting of cardiovascular death, myocardial infarction, stroke, and systemic embolism other than that of the central nervous system (CNS). The method involves administering a pharmaceutical composition containing approximately 100 mg of milbexian or a pharmaceutically acceptable salt thereof to a human patient; the composition is administered twice daily. Apparatus 175. A method for preventing one or more strokes and non-central nervous system (CNS) systemic embolism events in a human patient with a history of atrial fibrillation, the method comprising administering to a human patient a pharmaceutical composition containing 100 mg of milbexian (or a pharmaceutically acceptable salt or solvate thereof, in milbexian equivalent); the pharmaceutical composition being administered twice daily. Apparatus 176. A method for preventing one or more major cardiovascular adverse events in a patient with a history of atrial fibrillation, Each event is a cardiovascular death, myocardial infarction, stroke, or systemic embolism other than that of the central nervous system (CNS). The method involves administering a pharmaceutical composition containing 100 mg of milbexian (or a pharmaceutically acceptable salt or solvate thereof, in milbexian equivalent) to a human patient; the composition is administered twice daily. Apparatus 177. The method of Apparatus 176, wherein the primary cardiovascular adverse event is cardiovascular death. Apparatus 178. Any one of the methods described in Apparatus 171 to 177, wherein the patient has a history of atrial fibrillation and also has coexisting coronary artery disease (CAD) and / or peripheral artery disease (PAD). Embodiment 179. Any one of Embodiments 171 to 178, wherein the pharmaceutical composition contains 100 mg of milbexian (or a pharmaceutically acceptable salt or solvate thereof, in milbexian equivalent). Embodiment 180. Any one of Embodiments 171 to 179, wherein the pharmaceutical composition is a solid oral pharmaceutical composition comprising milbexian (or a pharmaceutically acceptable salt or solvate thereof) and one or more pharmaceutically acceptable excipients. Embodiment 181. The method of Embodiment 180, wherein the solid oral pharmaceutical composition is an immediate-release tablet. Embodiment 182. The method of Embodiment 181, wherein the disintegration time of the immediate-release tablet in water is less than 20 seconds at 37°C. Embodiment 183. Any one of Embodiments 180 to 182, wherein administration results in a plasma half-life of milbexian of approximately 13 to 16 hours. Embodiment 184. Any one of Embodiments 171 to 183, wherein the plasma concentration of milbexian reaches a steady state in approximately 4 to 6 days after administration. Embodiment 185. Any one of Embodiments 171 to 184, wherein a pharmaceutical composition comprising milbexian (or a pharmaceutically acceptable salt or solvate thereof) is administered regardless of the timing of meals. Apparatus 186. A method for preventing one or more strokes and systemic embolic events other than those of the central nervous system (CNS) in patients with a history of atrial fibrillation, The method is characterized by administering to the patient a film-coated immediate-release tablet containing 100 mg of milbexian or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients. The film-coated, immediate-release tablets are administered twice daily, regardless of whether or not a meal has been eaten. The patient is at least 18 years old; The patient also had the following: (i) 75 years of age or older, or (ii) a history of ischemic stroke or asymptomatic cerebral infarction. Do you have one or more risk factors in category (A) selected from the following? Or: (i) 65-74 years old; (ii) hypertension; (iii) diabetes; (iv) A history of coronary artery disease (CAD) (including a history of myocardial infarction or acute coronary syndrome, regardless of whether percutaneous coronary intervention (PCI) has been performed) or a history of peripheral artery disease (PAD); and (v) History of heart failure A method in which two or more cardiovascular risk factors from category (B), selected from the group consisting of the above, are present or combined. Apparatus 187. A method for preventing one or more cardiovascular adverse events in a patient with a history of atrial fibrillation, Each event is selected from a group consisting of cardiovascular death, myocardial infarction, stroke, and systemic embolism other than that of the central nervous system (CNS). The method is characterized by administering to the patient a film-coated immediate-release tablet containing 100 mg of milbexian or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients. The film-coated, immediate-release tablets are administered twice daily, regardless of whether or not a meal has been eaten. The patient is at least 18 years old; The patient also had the following: (i) 75 years of age or older, or (ii) a history of ischemic stroke or asymptomatic cerebral infarction. Do you have one or more risk factors in category (A) selected from the following? Or: (i) 65-74 years old; (ii) hypertension; (iii) diabetes; (iv) A history of coronary artery disease (CAD) (including a history of myocardial infarction or acute coronary syndrome, regardless of whether percutaneous coronary intervention (PCI) has been performed) or a history of peripheral artery disease (PAD); and (v) History of heart failure The individual has two or more cardiovascular risk factors in category (B), selected from the group consisting of the following: Apparatus 188. The method of Apparatus 187, wherein the cardiovascular adverse event is cardiovascular death. Embodiment 189. Any one of Embodiments 186 to 188, wherein the underwater disintegration time of the film-coated, ready-release tablet is less than 20 seconds. Embodiment 190. Any one of embodiments 186 to 189, wherein the half-life of administered milbexian in plasma is 13 to 16 hours. Embodiment 191. Any one of Embodiments 171 to 190, wherein administration reduces the patient's factor XI coagulation activity by approximately 27% to approximately 64% compared to baseline. Embodiment 192. Any one of Embodiments 171 to 191, wherein administration prolongs the patient's activated partial thromboplastin time (aPTT) to a baseline ratio of 2.1 to 2.6. Embodiment 193. Any one of Embodiments 171 to 192, wherein a composition comprising milbexian (or a pharmaceutically acceptable salt or solvate thereof) is administered twice daily for at least 13 weeks. Embodiment 194. Any one of Embodiments 171 to 193, wherein a composition comprising milbexian (or a pharmaceutically acceptable salt or solvate thereof) is administered once in the morning and once at night. Embodiment 195. The method of Embodiment 194, wherein the morning and evening doses are administered at the same time every day. Apparatus 196. Use of milbexian in a method for preventing one or more systemic embolic events other than those of the central nervous system (CNS) in a human patient with a history of atrial fibrillation, the method comprising administering to a human patient a pharmaceutical composition containing 100 mg of milbexian (or a pharmaceutically acceptable salt or solvate thereof, in milbexian equivalent); the pharmaceutical composition being administered twice daily. Apparatus 197. The use of milbexian in a method for preventing one or more cardiovascular adverse events in a patient with a history of atrial fibrillation, Each event is selected from a group consisting of cardiovascular death, myocardial infarction, stroke, and systemic embolism other than that of the central nervous system (CNS). The method involves administering a pharmaceutical composition containing 100 mg of milbexian (or a pharmaceutically acceptable salt or solvate thereof, in milbexian equivalent) to a human patient; the composition is administered twice daily. Apparatus 198. Use of milbexian as in Apparatus 197, where the cardiovascular adverse event is cardiovascular death. Apparatus 199. Use of any one of the milbexian described in Apparatus 196-198, in which the patient has a history of atrial fibrillation and also has co-existing coronary artery disease (CAD) and / or peripheral artery disease (PAD). Embodiment 200. Use of milbexian according to any one of Embodiments 196 to 199, wherein the pharmaceutical composition contains 100 mg of milbexian (or a pharmaceutically acceptable salt or solvate thereof, in milbexian equivalent). Embodiment 201. Use of milbexian according to any one of Embodiments 196 to 200, wherein the pharmaceutical composition is a solid oral pharmaceutical composition comprising milbexian (or a pharmaceutically acceptable salt or solvate thereof) and one or more pharmaceutically acceptable excipients. Embodiment 202. Use of milbexian according to Embodiment 201, wherein the solid oral pharmaceutical composition is an immediate-release tablet. Embodiment 203. Use of the milbexian of Embodiment 202, wherein the disintegration time in water of the immediate-release tablet is less than 20 seconds at 37°C. Embodiment 204. Use of one of the milbexian embodiments 201 to 203, wherein administration results in a plasma half-life of approximately 13 to 16 hours. Embodiment 205. Use of any one of the milbexian embodiments 196 to 204, wherein the plasma concentration of milbexian reaches a steady state in approximately 6 days after administration. Embodiment 206. Use of milbexian according to any one of Embodiments 196 to 205, wherein a pharmaceutical composition comprising milbexian (or a pharmaceutically acceptable salt or solvate thereof) is administered regardless of the timing of meals. Apparatus 207. Use of milbexian in a method for preventing stroke and one or more systemic embolic events other than those affecting the central nervous system (CNS) in patients with a history of atrial fibrillation, The method is characterized by administering to the patient a film-coated immediate-release tablet containing 100 mg of milbexian or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients. The film-coated, immediate-release tablets are administered twice daily, regardless of whether or not a meal has been eaten. The patient is at least 18 years old; The patient also had the following: (i) 75 years of age or older, or (ii) a history of ischemic stroke or asymptomatic cerebral infarction. Do you have one or more risk factors in category (A) selected from the following? Or: (i) 65-74 years old; (ii) hypertension; (iii) diabetes; (iv) A history of coronary artery disease (CAD) (including a history of myocardial infarction or acute coronary syndrome, regardless of whether percutaneous coronary intervention (PCI) has been performed) or a history of peripheral artery disease (PAD); and (v) History of heart failure The individual has two or more cardiovascular risk factors in category (B), selected from the group consisting of the following: Apparatus 208. Use of milbexian in a method for preventing one or more cardiovascular adverse events in a patient with a history of atrial fibrillation, Each event is a cardiovascular death, myocardial infarction, stroke, or systemic embolism other than that of the central nervous system (CNS). The method is characterized by administering to the patient a film-coated immediate-release tablet containing 100 mg of milbexian or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients. The film-coated, immediate-release tablets are administered twice daily, regardless of whether or not a meal has been eaten. The patient is at least 18 years old; The patient also had the following: (i) 75 years of age or older, or (ii) a history of ischemic stroke or asymptomatic cerebral infarction. Do you have one or more risk factors in category (A) selected from the following? Or: (i) 65-74 years old; (ii) hypertension; (iii) diabetes; (iv) A history of coronary artery disease (CAD) (including a history of myocardial infarction or acute coronary syndrome, regardless of whether percutaneous coronary intervention (PCI) has been performed) or a history of peripheral artery disease (PAD); and (v) History of heart failure The individual has two or more cardiovascular risk factors in category (B), selected from the group consisting of the following: Appearance 209. Use of milbexian as in Appearance 208, where the cardiovascular adverse event is cardiovascular death. Embodiment 210. Use of any one of the milbexian embodiments 207 to 209, wherein the film-coated, ready-release tablet has a water disintegration time of less than 20 seconds. Embodiment 211. Use of any one of the milbexian embodiments 207 to 210, wherein the half-life of the administered milbexian in plasma is 13 to 16 hours. Embodiment 212. Use of any one of the milbexian formulations described in Embodiments 196-211, wherein administration reduces the patient's factor XI coagulation activity by approximately 27% to approximately 64% compared to baseline. Embodiment 213. Use of any one of the milbexian formulations from Embodiments 196 to 212, wherein administration prolongs the patient's activated partial thromboplastin time (aPTT) with a baseline ratio of 2.1 to 2.6. Embodiment 214. Use of milbexian according to any one of Embodiments 196 to 213, wherein a composition comprising milbexian (or a pharmaceutically acceptable salt or solvate thereof) is administered twice daily for at least 13 weeks. Embodiment 215. Use of milbexian according to any one of Embodiments 196 to 214, wherein a composition comprising milbexian (or a pharmaceutically acceptable salt or solvate thereof) is administered once in the morning and once at night. Embodiment 216. Use of milbexian according to Embodiment 215, wherein the morning and evening doses are administered at the same time each day. Embodiment 217. Any one of the above embodiments, wherein administration of milbexian does not result in a clinically significant prolongation of the QTc interval. Embodiment 218. Use of milbexian in any one of the embodiments described above, wherein administration of milbexian does not result in a clinically significant prolongation of the QTc interval. Embodiment 219. Use of milbexian according to any one of the embodiments described above, wherein administration of milbexian does not result in a clinically significant change in prothrombin time, and the maximum mean percentage change from baseline is approximately 5%. Embodiment 220. Administration brings about a steady-state AUC or C max The use of any one of the above embodiments of milbexian, in which no clinically relevant effects are observed for any bleeding due to milbexian exposure, as evaluated by [method]. Embodiment 221. Use of any one of the above embodiments of milbexian in which administration causes minimal impairment of hemostatic function in human patients. Embodiment 222. Any one of the above embodiments, wherein administration of milbexian does not result in a clinically significant change in prothrombin time, and the maximum mean change from baseline is approximately 5%. Embodiment 223. Administration brings about a steady-state AUC or C max One of the above-described methods, which evaluates that no clinically relevant effect is observed for any bleeding caused by exposure to Milbexian. Embodiment 224. Any one of the above embodiments, wherein the impairment of hemostatic function due to administration in a human patient is minimized. Embodiment 225. Any one of Embodiments 171 to 195, wherein the regimen includes an immediate-release tablet. Embodiment 226. The method of Embodiment 225, wherein the disintegration time of the immediate-release tablet in water is less than 20 seconds at 37°C. Embodiment 227. Any one of Embodiments 171 to 195, wherein administration results in the terminal phase half-life of milbexian in plasma being approximately 13 hours to approximately 16 hours. Embodiment 228. Any one of Embodiments 171 to 195, wherein the regimen is implemented regardless of the timing of meals. Embodiment 229. Any one of Embodiments 171 to 195, wherein an immediate-release tablet is dispersed in an aqueous medium to form an aqueous dispersion. Embodiment 230. The method of Embodiment 229, wherein the aqueous medium contains water or applesauce. Apparatus 231. A method for preventing stroke or systemic embolism other than that of the central nervous system (CNS) in human patients with atrial fibrillation, This method involves implementing a regimen in human patients that includes oral administration of milbexian (approximately 100 mg) twice daily; This method yielded the following clinical results: (1) The plasma concentration profile of mirbexian reaches a steady state within approximately 6 days; (2)(i) Steady state C max(ii) Steady state C max (iii) The mean (standard deviation) is 1760 (566) ng / mL, and the steady-state AUC 0-24 (iv) Steady-state AUC 0-24 The steady state of the plasma concentration profile of mirbexian is reached, characterized by a mean (standard deviation) of 36200 (12900) ng*h / mL; (3) No clinically significant prolongation of the QTc interval is observed; (4) AUC or C in a steady state max No clinically relevant effects are observed for any bleeding resulting from exposure to Milbexian, as assessed by the following criteria; (5) Minimal impairment of hemostatic function in human patients; (6) No clinically significant change in prothrombin time is observed, and the maximum mean change from baseline is approximately 5%; or (7) Any combination of the clinical outcomes described above It is characterized by achieving at least one of the following. Embodiment 232. A method for preventing one or more strokes or systemic embolisms other than those of the central nervous system (CNS) in a human patient having atrial fibrillation, the method characterized by implementing a regimen comprising orally administering approximately 100 mg of milbexian twice daily to the human patient. Embodiment 233. A method for preventing one or more cardiovascular deaths, myocardial infarctions, strokes, or systemic embolisms other than those of the central nervous system (CNS) in a human patient having atrial fibrillation, the method being characterized by implementing a regimen comprising orally administering approximately 100 mg of milbexian twice daily to the human patient. Embodiment 234. A method for preventing stroke in a human patient having atrial fibrillation, the method characterized by implementing a regimen that includes orally administering approximately 100 mg of milbexian to the human patient twice daily. Embodiment 235. A method for preventing ischemic stroke in a human patient having atrial fibrillation, the method characterized by implementing a regimen comprising orally administering approximately 100 mg of milbexian to the human patient twice daily. Embodiment 236. A method for preventing systemic embolism other than that of the central nervous system (CNS) in a human patient having atrial fibrillation, the method characterized by implementing a regimen comprising orally administering 100 mg of milbexian twice daily to the human patient. Embodiment 237. A method for preventing one or more all-cause mortality, myocardial infarction, stroke, and non-central nervous system (CNS) systemic embolisms in a human patient having atrial fibrillation, the method being characterized by implementing a regimen comprising orally administering approximately 100 mg of milbexian twice daily to the human patient. Embodiment 238. A method for preventing cardiovascular death in a human patient having atrial fibrillation, the method characterized by implementing a regimen comprising orally administering approximately 100 mg of milbexian to the human patient twice daily. Embodiment 239. A method for preventing all-cause mortality in a human patient having atrial fibrillation, the method characterized by implementing a regimen comprising orally administering approximately 100 mg of milbexian twice daily to the human patient. Embodiment 240. A method for preventing cardiovascular death, myocardial infarction, stroke, acute limb ischemia, deep vein thrombosis, or pulmonary embolism in a human patient having atrial fibrillation, the method characterized by implementing a regimen comprising orally administering approximately 100 mg of milbexian twice daily to the human patient. Embodiment 241. A method for preventing myocardial infarction in a human patient having atrial fibrillation, the method characterized by implementing a regimen comprising orally administering approximately 100 mg of milbexian to the human patient twice daily. Embodiment 242. A method for preventing acute limb ischemia in a human patient having atrial fibrillation, the method characterized by implementing a regimen that includes orally administering approximately 100 mg of milbexian twice daily to the human patient. Embodiment 243. A method for preventing deep vein thrombosis in a human patient having atrial fibrillation, the method characterized by implementing a regimen comprising orally administering approximately 100 mg of milbexian twice daily to the human patient. Embodiment 244. A method for preventing pulmonary embolism in a human patient having atrial fibrillation, the method characterized by implementing a regimen comprising orally administering 100 mg of milbexian twice daily to the human patient. Embodiment 245. Any one of Embodiments 231 to 244, wherein the plasma concentration profile of milbexian reaches a steady state in approximately 3 to 6 days after administration. Embodiment 246. Any one of Embodiments 231 to 245, wherein the plasma concentration profile of milbexian reaches a steady state in approximately 6 days after administration. Apparatus 247. Upon administration, the following occurs: (i) Steady state C max The range is approximately 1194 ng / mL to approximately 2326 ng / mL. (ii) Steady state C max The mean (standard deviation) is 1760 (566) ng / mL; (iii) Steady-state AUC 0-24 The value is in the range of approximately 23,300 ng*h / mL to approximately 49,100 ng*h / mL; or (iv) Steady-state AUC 0-24 The mean (standard deviation) is 36200 (12900) ng*h / mL. One of the methods in embodiments 231 to 246, which provides a steady-state plasma concentration profile of milbexian characterized by the following: Embodiment 248. Any one of Embodiments 231 to 247, wherein administration does not result in a clinically significant prolongation of the QTc interval. Apparatus 249. Administration brings about steady-state AUC or C maxOne of the methods described in aspects 231 to 248, which evaluates that no clinically relevant effect is observed for any bleeding caused by exposure to Milbexian. Embodiment 250. Any one of Embodiments 231 to 249, wherein the impairment of hemostatic function due to administration is minimized in human patients. Embodiment 251. One of the methods described in Embodiments 231 to 249, wherein administration does not result in a clinically significant change in prothrombin time, and the maximum mean change from baseline is approximately 5%. Embodiment 252. Any one of Embodiments 231 to 251, wherein the regimen includes an immediate-release tablet. Embodiment 253. The method of Embodiment 252, wherein the disintegration time of the immediate-release tablet in water is less than 20 seconds at 37°C. Embodiment 254. Any one of Embodiments 231 to 253, wherein administration results in a terminal phase half-life of milbexian in plasma of approximately 13 to 16 hours. Embodiment 255. Any one of Embodiments 231 to 254, wherein the regimen is implemented regardless of the timing of meals. Embodiment 256. Any one of Embodiments 252 to 255, wherein an immediate-release tablet is dispersed in an aqueous medium to form an aqueous dispersion. Embodiment 257. The method of Embodiment 256, wherein the aqueous medium contains water or applesauce. Apparatus 258. Use of milbexian in a method for preventing stroke or systemic embolism other than that of the central nervous system (CNS) in a human patient having atrial fibrillation, The method involves implementing a regimen in which human patients are orally administered approximately 100 mg of milbexian twice daily; This method yielded the following clinical results: (1) The plasma concentration profile of mirbexian reaches a steady state within approximately 6 days; (2)(i) Steady state C max (ii) Steady state C max (iii) The mean (standard deviation) is 1760 (566) ng / mL, and the steady-state AUC 0-24(iv) Steady-state AUC 0-24 Reaching a steady state in the plasma concentration profile of mirbexian, characterized by a mean (standard deviation) of 36200 (12900) ng*h / mL; (3) The patient's QTc change from baseline is less than 10 milliseconds; (4) AUC or C in a steady state max No clinically relevant effects are observed for any bleeding resulting from exposure to Milbexian, as assessed by the following criteria; (5) Minimal impairment of hemostatic function in human patients; (6) No clinically significant change in prothrombin time is observed, and the maximum mean change from baseline is approximately 5%; or (7) Any combination of the results described above It is characterized by achieving at least one of the following. Apparatus 259. Use of milbexian in a method for preventing one or more strokes or systemic embolisms other than those of the central nervous system (CNS) in patients with a history of atrial fibrillation, the method characterized by implementing a regimen comprising orally administering approximately 100 mg of milbexian twice daily to a human patient. Apparatus 260. Use of milbexian in a method for preventing one or more cardiovascular death, myocardial infarction, stroke, or systemic embolism other than that of the central nervous system (CNS) in a human patient having atrial fibrillation, the method being characterized by implementing a regimen comprising orally administering about 100 mg of milbexian to the human patient twice daily. Embodiment 261. Use of milbexian in a method for preventing stroke in a human patient with a history of atrial fibrillation, the method characterized by implementing a regimen comprising orally administering approximately 100 mg of milbexian to the human patient twice daily. Embodiment 262. Use of milbexian in a method for preventing ischemic stroke in a human patient with a history of atrial fibrillation, the method characterized by implementing a regimen comprising orally administering approximately 100 mg of milbexian to the human patient twice daily. Embodiment 263. Use of milbexian in a method for preventing systemic embolism other than that of the central nervous system (CNS) in a human patient with a history of atrial fibrillation, the method characterized by implementing a regimen comprising orally administering approximately 100 mg of milbexian to the human patient twice daily. Embodiment 264. Use of milbexian in a method for preventing one or more all-cause deaths, myocardial infarctions, strokes, or systemic embolisms other than those of the central nervous system (CNS) in human patients having atrial fibrillation, the method being characterized by implementing a regimen comprising orally administering approximately 100 mg of milbexian to a human patient twice daily. Embodiment 265. Use of milbexian in a method for preventing cardiovascular death in a human patient having atrial fibrillation, the method characterized by implementing a regimen comprising orally administering approximately 100 mg of milbexian to the human patient twice daily. Embodiment 266. Use of milbexian in a method for preventing all-cause mortality in a human patient having atrial fibrillation, the method characterized by implementing a regimen comprising orally administering approximately 100 mg of milbexian twice daily to the human patient. Apparatus 267. Use of milbexian in a method for preventing cardiovascular death, myocardial infarction, stroke, acute limb ischemia, deep vein thrombosis, or pulmonary embolism in a human patient with a history of atrial fibrillation, the method being characterized by implementing a regimen comprising orally administering approximately 100 mg of milbexian twice daily to a human patient. Embodiment 268. Use of milbexian in a method for preventing myocardial infarction in a human patient with a history of atrial fibrillation, the method characterized by implementing a regimen comprising orally administering approximately 100 mg of milbexian to the human patient twice daily. Embodiment 269. Use of milbexian in a method for preventing acute limb ischemia in a human patient with a history of atrial fibrillation, the method characterized by implementing a regimen comprising orally administering approximately 100 mg of milbexian to the human patient twice daily. Embodiment 270. Use of milbexian in a method for preventing deep vein thrombosis in a human patient with a history of atrial fibrillation, the method characterized by implementing a regimen comprising orally administering approximately 100 mg of milbexian to the human patient twice daily. Embodiment 271. Use of milbexian in a method for preventing pulmonary embolism in a human patient with a history of atrial fibrillation, the method characterized by implementing a regimen comprising orally administering approximately 100 mg of milbexian to the human patient twice daily. Embodiment 272. Use of any one of the milbexian embodiments 258 to 271, wherein the plasma concentration profile of milbexian reaches a steady state in approximately 4 to 6 days after administration. Embodiment 273. Use of any one of the milbexian embodiments 258 to 272, wherein the plasma concentration profile of milbexian reaches a steady state in approximately 6 days after administration. Appearance 274. Upon administration, the following occurs: (i) Steady state C max The concentration should be in the range of approximately 1194 ng / mL to approximately 2326 ng / mL; (ii) Steady state C max The mean (standard deviation) is 1760 (566) ng / mL; (iii) Steady-state AUC 0-24 The value is in the range of approximately 23,300 ng*h / mL to approximately 49,100 ng*h / mL; or (iv) Steady-state AUC 0-24 The mean (standard deviation) is 36200 (12900) ng*h / mL. The use of milbexian in any one of embodiments 258 to 273, which results in a steady-state plasma concentration profile of milbexian characterized by the following: Embodiment 275. Use of any one of the milbexian embodiments 258-274, wherein administration does not result in a clinically significant prolongation of the QTc interval. Apparatus 276. Administration brings about steady-state AUC or C max The use of milbexian in any of the embodiments 258-275, wherein no clinically relevant effects are observed for any bleeding due to milbexian exposure, as evaluated by [method]. Embodiment 277. Use of any one of the milbexian embodiments 258 to 275 in which administration causes minimal impairment of hemostatic function in human patients. Apparatus 278. Use of any one of the milbexian formulations from Apparatus 258 to 275, wherein administration does not result in a clinically significant change in prothrombin time and the maximum mean change from baseline is approximately 5%. Embodiment 279. Use of any one of the milbexian regimens from Embodiments 258 to 278, wherein the regimen includes an immediate-release tablet. Appearance 280. Use of the milbexian of Appearance 279, wherein the disintegration time in water of the immediate-release tablet is less than 20 seconds at 37°C. Embodiment 281. Use of any one of the milbexian embodiments 258 to 275, wherein administration results in a terminal phase half-life of milbexian in plasma of approximately 13 to 16 hours. Embodiment 282. Use of any one of the Milbexian regimens from Embodiments 258 to 275, wherein the regimen is implemented regardless of the timing of meals. Embodiment 283. Use of any one of the milbexian embodiments 279 to 282, wherein the immediate-release tablets are dispersed in an aqueous medium to form an aqueous dispersion. Embodiment 284. Use of the Milbexian of Embodiment 283, wherein the aqueous medium contains water or applesauce. Embodiment 285. Any one embodiment of Embodiments 1 to 284, wherein "100 mg of milbexian" is replaced with "50 mg of milbexian". Embodiment 286. Any one embodiment of Embodiments 1 to 284, wherein "100 mg of milbexian" is replaced with "75 mg of milbexian". Embodiment 287. Any one embodiment of Embodiments 1 to 284, wherein "100 mg of milbexian" is replaced with "87.5 mg of milbexian".

[0443] Group 3 of the morphology Embodiment 1. A method for preventing one or more strokes and non-central nervous system (CNS) systemic embolic events in human patients with a history of atrial fibrillation or atrial flutter, the method comprising administering to a human patient a pharmaceutical composition containing approximately 50 mg, approximately 75.0 mg, approximately 87.5 mg, or approximately 100 mg of milbexian (or a pharmaceutically acceptable salt or solvate thereof, in milbexian equivalent); the pharmaceutical composition being administered twice daily. Apparatus 2. A method for preventing one or more major cardiovascular adverse events in patients with a history of atrial fibrillation or atrial flutter, Each event is selected from a group consisting of cardiovascular death, myocardial infarction, stroke, and systemic embolism other than that of the central nervous system (CNS). The method involves administering to a human patient a pharmaceutical composition containing approximately 25 mg, 50 mg, 75.0 mg, 87.5 mg, or 100 mg of milbexian (or a pharmaceutically acceptable salt or solvate thereof, in milbexian equivalent); the pharmaceutical composition is administered twice daily. Embodiment 3. The method of Embodiment 2, wherein the primary cardiovascular adverse event is cardiovascular death. Embodiment 4. The method according to any one of Embodiments 1 to 3, wherein the patient has a history of atrial fibrillation or atrial flutter and also has coexisting coronary artery disease (CAD) and / or peripheral artery disease (PAD). Embodiment 5. The method according to any one of Embodiments 1 to 4, wherein the pharmaceutical composition contains about 100 mg of milbexian (or a pharmaceutically acceptable salt or solvate thereof, in milbexian equivalent). Embodiment 6. The method according to any one of Embodiments 1 to 4, wherein the pharmaceutical composition contains approximately 87.5 mg of milbexian (or a pharmaceutically acceptable salt or solvate thereof, in milbexian equivalent). Embodiment 7. The method according to any one of Embodiments 1 to 4, wherein the pharmaceutical composition contains approximately 75 mg of milbexian (or a pharmaceutically acceptable salt or solvate thereof, in milbexian equivalent). Embodiment 8. The method according to any one of Embodiments 1 to 4, wherein the pharmaceutical composition contains about 50 mg of milbexian (or a pharmaceutically acceptable salt or solvate thereof, in milbexian equivalent). Embodiment 9. Any one of Embodiments 1 to 8, wherein the pharmaceutical composition is a solid oral pharmaceutical composition comprising milbexian (or a pharmaceutically acceptable salt or solvate thereof) and one or more pharmaceutically acceptable excipients. Embodiment 10. The method of Embodiment 9, wherein the solid oral pharmaceutical composition is an immediate-release tablet. Embodiment 11. The method of Embodiment 10, wherein the underwater disintegration time of the immediate-release tablet is less than 20 seconds at 37°C. Embodiment 12. One of the methods described in Embodiments 5 to 11, wherein administration results in a plasma half-life of milbexian of approximately 13 to 16 hours. Embodiment 13. A method according to any one of Embodiments 5 to 11, wherein, during repeated administration, the half-life of milbexian in plasma becomes approximately 13 hours to approximately 16 hours upon administration. Embodiment 14. Any one of the above embodiments, wherein the plasma concentration of milbexian reaches a steady state in approximately 3 to 6 days after administration. Embodiment 15. Any one of the above embodiments, wherein a pharmaceutical composition comprising milbexian (or a pharmaceutically acceptable salt or solvate thereof) is administered regardless of the timing of meals. Embodiment 16. Any one of the embodiments described above, wherein a composition comprising milbexian (or a pharmaceutically acceptable salt or solvate thereof) is administered twice daily for at least 13 weeks. Embodiment 17. Any one of the embodiments described above, wherein a composition comprising milbexian (or a pharmaceutically acceptable salt or solvate thereof) is administered once in the morning and once at night. Embodiment 18. Any one of the embodiments described above, wherein the morning and evening doses are administered at the same time every day. Apparatus 19. A method for preventing one or more strokes and non-central nervous system (CNS) systemic embolic events in a patient with a history of atrial fibrillation or atrial flutter, the method comprising administering to the patient a film-coated immediate-release tablet containing approximately 50 mg, approximately 75.0 mg, approximately 87.5 mg, or approximately 100 mg of milbexian or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients. The film-coated, immediate-release tablets are administered twice daily, regardless of whether or not a meal has been eaten. The patient is at least 18 years old; The patient also had the following: (i) 75 years of age or older or (ii) history of ischemic stroke Do you have one or more risk factors in category (A) selected from the following? Or: (i) 65-74 years old; (ii) hypertension; (iii) diabetes; (iv) A history of coronary artery disease (CAD) (including a history of myocardial infarction or acute coronary syndrome, regardless of whether percutaneous coronary intervention (PCI) has been performed) or a history of peripheral artery disease (PAD); and (v) History of heart failure It is characterized by having two or more cardiovascular risk factors from category (B), selected from the group consisting of the above. Apparatus 20. A method for preventing one or more major cardiovascular adverse events in patients with a history of atrial fibrillation or atrial flutter, Each event is selected from a group consisting of cardiovascular death, myocardial infarction, stroke, and systemic embolism other than that of the central nervous system (CNS). The method involves administering to the patient a film-coated immediate-release tablet containing approximately 50 mg, approximately 75.0 mg, approximately 87.5 mg, or 100 mg of milbexian or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients. The film-coated, immediate-release tablets are administered twice daily, regardless of whether or not a meal has been eaten. The patient is at least 18 years old; The patient also had the following: (i) 75 years of age or older or (ii) history of ischemic stroke Having one or more risk factors in category (A) selected from; or below: (i) 65-74 years old; (ii) hypertension; (iii) diabetes; (iv) A history of coronary artery disease (CAD) (including a history of myocardial infarction or acute coronary syndrome, regardless of whether percutaneous coronary intervention (PCI) has been performed) or a history of peripheral artery disease (PAD); and (v) History of heart failure It is characterized by having two or more cardiovascular risk factors from category (B), selected from the group consisting of the above. Embodiment 21. The method of Embodiment 20, wherein the major cardiovascular adverse events are stroke and systemic embolism other than that of the central nervous system (CNS). Embodiment 22. Any one of Embodiments 19 to 21, wherein the film-coated, ready-release tablet has a water disintegration time of less than 20 seconds. Embodiment 23. Any one of embodiments 19 to 22, wherein the half-life of administered milbexian in plasma is 13 to 16 hours. Embodiment 24. Any one of embodiments 19 to 23, wherein the half-life of administered milbexian in plasma is 13 to 16 hours during repeated administration. Embodiment 25. Any one of Embodiments 19 to 24, wherein a composition comprising milbexian (or a pharmaceutically acceptable salt or solvate thereof) is administered twice daily for at least 13 weeks. Embodiment 26. Any one of Embodiments 19 to 25, wherein a composition comprising milbexian (or a pharmaceutically acceptable salt or solvate thereof) is administered once in the morning and once at night. Embodiment 27. The method of Embodiment 26, wherein the morning and evening doses are administered at the same time every day. Embodiment 28. Any one of the embodiments described above, wherein administration reduces the patient's factor XI coagulation activity by approximately 27% to approximately 64% compared to baseline. Embodiment 29. Any one of the above embodiments, wherein administration prolongs the patient's activated partial thromboplastin time (aPTT) to a baseline ratio of 2.1 to 2.6. Embodiment 30. A method for preventing stroke in a human patient with a history of atrial fibrillation or atrial flutter, characterized in that the human patient is administered a pharmaceutical composition containing approximately 50 mg of milbexian (or a pharmaceutically acceptable salt or solvate thereof, in milbexian equivalent), and the pharmaceutical composition is administered twice daily. Embodiment 31. A method for preventing stroke in a human patient with a history of atrial fibrillation or atrial flutter, characterized in that the human patient is administered a pharmaceutical composition containing approximately 75 mg of milbexian (or a pharmaceutically acceptable salt or solvate thereof, in milbexian equivalent), and the pharmaceutical composition is administered twice daily. Embodiment 32. A method for preventing stroke in a human patient with a history of atrial fibrillation or atrial flutter, characterized in that the human patient is administered a pharmaceutical composition containing approximately 87.5 mg of milbexian (or a pharmaceutically acceptable salt or solvate thereof, in milbexian equivalent), and the pharmaceutical composition is administered twice daily. Embodiment 33. A method for preventing stroke in a human patient with a history of atrial fibrillation or atrial flutter, characterized in that the human patient is administered a pharmaceutical composition containing approximately 100 mg of milbexian (or a pharmaceutically acceptable salt or solvate thereof, in milbexian equivalent), and the pharmaceutical composition is administered twice daily. Embodiment 34. A method for preventing one or more systemic embolic events other than those of the central nervous system (CNS) in a human patient with a history of atrial fibrillation or atrial flutter, characterized in that the method involves administering a pharmaceutical composition containing approximately 50 mg of milbexian (or a pharmaceutically acceptable salt or solvate thereof, in milbexian equivalent) to the human patient, and administering the pharmaceutical composition twice daily. Embodiment 35. A method for preventing one or more systemic embolic events other than those of the central nervous system (CNS) in a human patient with a history of atrial fibrillation or atrial flutter, characterized in that the method involves administering a pharmaceutical composition containing approximately 75 mg of milbexian (or a pharmaceutically acceptable salt or solvate thereof, in milbexian equivalent) to the human patient, and administering the pharmaceutical composition twice daily. Embodiment 36. A method for preventing one or more systemic embolic events other than those of the central nervous system (CNS) in a human patient with a history of atrial fibrillation or atrial flutter, characterized in that the method involves administering a pharmaceutical composition containing approximately 87.5 mg of milbexian (or a pharmaceutically acceptable salt or solvate thereof, in milbexian equivalent) to the human patient, and administering the pharmaceutical composition twice daily. Embodiment 37. A method for preventing one or more systemic embolic events other than those of the central nervous system (CNS) in a human patient with a history of atrial fibrillation or atrial flutter, characterized in that the method involves administering a pharmaceutical composition containing approximately 100 mg of milbexian (or a pharmaceutically acceptable salt or solvate thereof, in milbexian equivalent) to the human patient, and administering the pharmaceutical composition twice daily. Apparatus 38. A method for preventing one or more cardiovascular adverse events in a patient with a history of atrial fibrillation or atrial flutter, Each event is selected from a group consisting of cardiovascular death, myocardial infarction, stroke, and systemic embolism other than that of the central nervous system (CNS). The method is characterized by administering a pharmaceutical composition containing 50 mg of milbexian (or a pharmaceutically acceptable salt or solvate thereof, in milbexian equivalent) to a human patient, and administering the pharmaceutical composition twice daily. Appearance 39. The method of Appearance 38, wherein the cardiovascular adverse event is cardiovascular death. Appearance 40. The method of Appearance 38, wherein the primary cardiovascular adverse event is myocardial infarction. Appearance 41. The method of Appearance 38, wherein the primary cardiovascular adverse event is stroke. Apparatus 42. The method of Apparatus 38, wherein the primary cardiovascular adverse event is systemic embolism other than that of the central nervous system (CNS). Apparatus 43. A method for preventing one or more cardiovascular adverse events in a patient with a history of atrial fibrillation or atrial flutter, Each event is selected from a group consisting of cardiovascular death, myocardial infarction, stroke, and systemic embolism other than that of the central nervous system (CNS). The method involves administering a pharmaceutical composition containing approximately 100 mg of milbexian (or a pharmaceutically acceptable salt or solvate thereof, in milbexian equivalent) to a human patient; the composition is administered twice daily. Appearance 44. The method of Appearance 43, wherein the cardiovascular adverse event is cardiovascular death. Appearance 45. The method of Appearance 43, wherein the cardiovascular adverse event is myocardial infarction. Appearance 46. The method of Appearance 43, wherein the cardiovascular adverse event is stroke. Apparatus 47. The method of Apparatus 43, wherein the cardiovascular adverse event is a systemic embolism other than that of the central nervous system (CNS). Apparatus 48. Any one of the methods in Apparatus 30 to 47, wherein the patient has a history of atrial fibrillation or atrial flutter and also has coexisting coronary artery disease (CAD) and / or peripheral artery disease (PAD). Apparatus 49. The method of Apparatus 48, wherein the patient has a history of atrial fibrillation or atrial flutter and also has co-existing coronary artery disease (CAD). Apparatus 50. The method of Apparatus 48, wherein the patient has a history of atrial fibrillation or atrial flutter and also has concomitant peripheral artery disease (PAD). Embodiment 51. Any one of Embodiments 30 to 50, wherein the pharmaceutical composition is a solid oral pharmaceutical composition comprising milbexian (or a pharmaceutically acceptable salt or solvate thereof) and one or more pharmaceutically acceptable excipients. Embodiment 52. The method of Embodiment 51, wherein the solid oral pharmaceutical composition is an immediate-release tablet. Embodiment 53. The method of Embodiment 52, wherein the underwater disintegration time of the immediate-release tablet is less than 20 seconds. Embodiment 54. Any one of Embodiments 30 to 53, wherein administration results in a plasma half-life of milbexian of approximately 13 to 16 hours. Embodiment 55. A method according to any one of Embodiments 30 to 54, wherein, during repeated administration, the half-life of milbexian in plasma becomes approximately 13 hours to approximately 16 hours upon administration. Embodiment 56. Any one of Embodiments 30 to 55, wherein the plasma concentration of milbexian reaches a steady state in approximately 3 to 6 days after administration. Embodiment 57. Any one of Embodiments 30 to 56, wherein a pharmaceutical composition comprising milbexian (or a pharmaceutically acceptable salt or solvate thereof) is administered regardless of the timing of meals. Embodiment 58. Any one of Embodiments 30 to 57, wherein the patient is unable to swallow tablet dosage forms. Embodiment 59. Any one of Embodiments 30 to 58, wherein a pharmaceutical composition is dispersed in an aqueous medium to form an aqueous dispersion. Embodiment 60. The method of Embodiment 59, wherein the aqueous medium is physiological saline, phosphate buffer, plant juice, or fruit juice such as applesauce. Embodiment 61. The method according to Embodiment 59 or Embodiment 60, wherein the aqueous dispersion is administered to a human patient via a nasogastric tube or spoon. Embodiment 62. Any one of Embodiments 59 to 61, wherein milbexian is administered orally as an aqueous dispersion by dispersing the pharmaceutical composition in an aqueous medium in less than 60 seconds. Embodiment 63. Any one of Embodiments 30 to 62, wherein a composition comprising milbexian (or a pharmaceutically acceptable salt or solvate thereof) is administered twice daily for at least 13 weeks. Embodiment 64. Any one of Embodiments 30 to 63, wherein a composition comprising milbexian (or a pharmaceutically acceptable salt or solvate thereof) is administered once in the morning and once at night. Embodiment 65. The method of Embodiment 64, wherein the morning and evening doses are administered at the same time every day. Embodiment 66. Any one of Embodiments 30 to 65, wherein administration reduces the patient's factor XI coagulation activity by approximately 27% to approximately 64% compared to baseline. Embodiment 67. Any one of embodiments 30 to 66, wherein administration prolongs the patient's activated partial thromboplastin time (aPTT) and the baseline ratio is 2.1 to 2.6. Apparatus 68. A method for preventing stroke in a patient with a history of atrial fibrillation or atrial flutter, the method comprising administering to the patient a film-coated immediate-release tablet containing approximately 50 mg of milbexian or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients, The film-coated, immediate-release tablets are administered twice daily, regardless of whether or not a meal has been eaten. The patient is at least 18 years old; The patient also had the following: (i) 75 years of age or older or (ii) history of ischemic stroke Do you have one or more risk factors in category (A) selected from the following? Or: (i) 65-74 years old; (ii) hypertension; (iii) diabetes; (iv) A history of coronary artery disease (CAD) (including a history of myocardial infarction or acute coronary syndrome, regardless of whether percutaneous coronary intervention (PCI) has been performed) or a history of peripheral artery disease (PAD); and (v) History of heart failure It is characterized by having two or more cardiovascular risk factors from category (B), selected from the group consisting of the above. Apparatus 69. A method for preventing systemic embolic events other than those affecting the central nervous system (CNS) in patients with a history of atrial fibrillation or atrial flutter, the method comprising administering to the patient a film-coated immediate-release tablet containing approximately 50 mg of milbexian or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients. The film-coated, immediate-release tablets are administered twice daily, regardless of whether or not a meal has been eaten. The patient is at least 18 years old; The patient also had the following: (i) 75 years of age or older or (ii) history of ischemic stroke Do you have one or more risk factors in category (A) selected from the following? Or: (i) 65-74 years old; (ii) hypertension; (iii) diabetes; (iv) A history of coronary artery disease (CAD) (including a history of myocardial infarction or acute coronary syndrome, regardless of whether percutaneous coronary intervention (PCI) has been performed) or a history of peripheral artery disease (PAD); and (v) History of heart failure It is characterized by having two or more cardiovascular risk factors from category (B), selected from the group consisting of the above. Apparatus 70. A method for preventing stroke in a patient with a history of atrial fibrillation or atrial flutter, the method comprising administering to the patient a film-coated immediate-release tablet containing approximately 75 mg of milbexian or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients, The film-coated, immediate-release tablets are administered twice daily, regardless of whether or not a meal has been eaten. The patient is at least 18 years old; The patient also had the following: (i) 75 years of age or older or (ii) history of ischemic stroke Do you have one or more risk factors in category (A) selected from the following? Or: (i) 65-74 years old; (ii) hypertension; (iii) diabetes; (iv) A history of coronary artery disease (CAD) (including a history of myocardial infarction or acute coronary syndrome, regardless of whether percutaneous coronary intervention (PCI) has been performed) or a history of peripheral artery disease (PAD); and (v) History of heart failure It is characterized by having two or more cardiovascular risk factors from category (B), selected from the group consisting of the above. Apparatus 71. A method for preventing systemic embolic events other than those affecting the central nervous system (CNS) in patients with a history of atrial fibrillation or atrial flutter, the method comprising administering to the patient a film-coated immediate-release tablet containing approximately 75 mg of milbexian or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients. The film-coated, immediate-release tablets are administered twice daily, regardless of whether or not a meal has been eaten. The patient is at least 18 years old; The patient also had the following: (i) 75 years of age or older or (ii) history of ischemic stroke Do you have one or more risk factors in category (A) selected from the following? Or: (i) 65-74 years old; (ii) hypertension; (iii) diabetes; (iv) A history of coronary artery disease (CAD) (including a history of myocardial infarction or acute coronary syndrome, regardless of whether percutaneous coronary intervention (PCI) has been performed) or a history of peripheral artery disease (PAD); and (v) History of heart failure It is characterized by having two or more cardiovascular risk factors from category (B), selected from the group consisting of the above. Apparatus 72. A method for preventing stroke in a patient with a history of atrial fibrillation or atrial flutter, the method comprising administering to the patient a film-coated immediate-release tablet containing approximately 87.5 mg of milbexian or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients, The film-coated, immediate-release tablets are administered twice daily, regardless of whether or not a meal has been eaten. The patient is at least 18 years old; The patient also had the following: (i) 75 years of age or older or (ii) history of ischemic stroke Do you have one or more risk factors in category (A) selected from the following? Or: (i) 65-74 years old; (ii) hypertension; (iii) diabetes; (iv) A history of coronary artery disease (CAD) (including a history of myocardial infarction or acute coronary syndrome, regardless of whether percutaneous coronary intervention (PCI) has been performed) or a history of peripheral artery disease (PAD); and (v) History of heart failure It is characterized by having two or more cardiovascular risk factors from category (B), selected from the group consisting of the above. Apparatus 73. A method for preventing systemic embolic events other than those affecting the central nervous system (CNS) in patients with a history of atrial fibrillation or atrial flutter, the method comprising administering to the patient a film-coated immediate-release tablet containing approximately 87.5 mg of milbexian or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients. The film-coated, immediate-release tablets are administered twice daily, regardless of whether or not a meal has been eaten. The patient is at least 18 years old; The patient also had the following: (i) 75 years of age or older or (ii) history of ischemic stroke Do you have one or more risk factors in category (A) selected from the following? Or: (i) 65-74 years old; (ii) hypertension; (iii) diabetes; (iv) A history of coronary artery disease (CAD) (including a history of myocardial infarction or acute coronary syndrome, regardless of whether percutaneous coronary intervention (PCI) has been performed) or a history of peripheral artery disease (PAD); and (v) History of heart failure It is characterized by having two or more cardiovascular risk factors from category (B), selected from the group consisting of the above. Apparatus 74. A method for preventing stroke in a patient with a history of atrial fibrillation or atrial flutter, the method comprising administering to the patient a film-coated immediate-release tablet containing approximately 100 mg of milbexian or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients, The film-coated, immediate-release tablets are administered twice daily, regardless of whether or not a meal has been eaten. The patient is at least 18 years old; The patient also had the following: (i) 75 years of age or older or (ii) history of ischemic stroke Do you have one or more risk factors in category (A) selected from the following? Or: (i) 65-74 years old; (ii) hypertension; (iii) diabetes; (iv) A history of coronary artery disease (CAD) (including a history of myocardial infarction or acute coronary syndrome, regardless of whether percutaneous coronary intervention (PCI) has been performed) or a history of peripheral artery disease (PAD); and (v) History of heart failure It is characterized by having two or more cardiovascular risk factors from category (B), selected from the group consisting of the above. Apparatus 75. A method for preventing systemic embolic events other than those affecting the central nervous system (CNS) in patients with a history of atrial fibrillation or atrial flutter, the method comprising administering to the patient a film-coated immediate-release tablet containing approximately 100 mg of milbexian or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients. The film-coated, immediate-release tablets are administered twice daily, regardless of whether or not a meal has been eaten. The patient is at least 18 years old; The patient also had the following: (i) 75 years of age or older or (ii) history of ischemic stroke Do you have one or more risk factors in category (A) selected from the following? Or: (i) 65-74 years old; (ii) hypertension; (iii) diabetes; (iv) A history of coronary artery disease (CAD) (including a history of myocardial infarction or acute coronary syndrome, regardless of whether percutaneous coronary intervention (PCI) has been performed) or a history of peripheral artery disease (PAD); and (v) History of heart failure It is characterized by having two or more cardiovascular risk factors from category (B), selected from the group consisting of the above. Apparatus 76. Any one of the methods of Apparatus 68 to 75, wherein the patient has a history of atrial fibrillation or atrial flutter and also has coexisting coronary artery disease (CAD) and / or peripheral artery disease (PAD). Apparatus 77. The method of Apparatus 76, wherein the patient has a history of atrial fibrillation or atrial flutter and also has co-existing coronary artery disease (CAD). Apparatus 78. The method of Apparatus 76, wherein the patient has a history of atrial fibrillation or atrial flutter and also has concomitant peripheral artery disease (PAD). Embodiment 79. Any one of Embodiments 68 to 78, wherein the film-coated, ready-release tablet has a water disintegration time of less than 20 seconds at 37°C. Embodiment 80. Any one of Embodiments 68 to 79, wherein administration results in a plasma half-life of milbexian of approximately 13 hours to approximately 16 hours. Embodiment 81. A method according to any one of Embodiments 68 to 80, wherein, during repeated administration, the plasma half-life of milbexian becomes approximately 13 hours to approximately 16 hours upon administration. Embodiment 82. Any one of Embodiments 68 to 81, wherein the plasma concentration of milbexian reaches a steady state in approximately 3 to 6 days after administration. Embodiment 83. Any one of embodiments 68 to 82, wherein a film-coated immediate-release tablet is administered regardless of the timing of meals. Embodiment 84. Any one of embodiments 68 to 83, wherein the patient is unable to swallow tablet dosage forms. Embodiment 85. Any one of Embodiments 68 to 84, wherein film-coated ready-release tablets are dispersed in an aqueous medium to form an aqueous dispersion. Embodiment 86. The method of Embodiment 85, wherein the aqueous medium is physiological saline, phosphate buffer, plant juice, or fruit juice such as applesauce. Embodiment 87. The method according to Embodiment 85 or Embodiment 86, wherein the aqueous dispersion is administered to a human patient via a nasogastric tube or spoon. Embodiment 88. Any one of Embodiments 68 to 87, wherein milbexian is administered orally as an aqueous dispersion by dispersing a film-coated immediate-release tablet in an aqueous medium in less than 60 seconds. Embodiment 89. Any one of embodiments 68 to 88, wherein a film-coated immediate-release tablet is administered twice daily for at least 13 weeks. Embodiment 90. One of the methods described in Embodiments 68 to 89, wherein a film-coated immediate-release tablet is administered once in the morning and once at night. Embodiment 91. The method of Embodiment 90, wherein the morning and evening doses are administered at the same time every day. Embodiment 92. Any one of Embodiments 68 to 91, wherein administration reduces the patient's factor XI coagulation activity by approximately 27% to approximately 64% compared to baseline. Embodiment 93. Any one of embodiments 68 to 91, wherein administration prolongs the patient's activated partial thromboplastin time (aPTT) and the baseline ratio is 2.1 to 2.6. Embodiment 94. Any one of the above embodiments, characterized in that standard antiplatelet therapy is further administered to the patient. Embodiment 95. The method of Embodiment 94, wherein the standard antiplatelet therapy is selected from aspirin, adenosine diphosphate (ADP) receptor inhibitors; adenosine reuptake inhibitors; platelet glycoprotein receptor antagonists; phosphodiesterase inhibitors; or protease-activated receptor (PAR-1) antagonists. Embodiment 96. Any one of embodiments 94 and 95, wherein the standard antiplatelet therapy is selected from aspirin, clopidogrel, ticagrelor, ticlopidine, prasugrel, dipyridamole, absiximab, eptifivatide, tyrofiban, cilostazol, or volapaxar. Embodiment 97. Any one of embodiments 94 to 97, wherein the standard antiplatelet therapy is selected from aspirin, clopidogrel, ticagrelor, or prasugrel. Embodiment 98. Any one of embodiments 94 to 97, wherein the standard antiplatelet therapy is selected from clopidogrel, ticagrelor, or prasugrel. Embodiment 99. Any one of Embodiments 94 to 98, wherein standard antiplatelet therapy includes antiplatelet monotherapy (SAPT). Embodiment 100. The method of Embodiment 99, wherein the antiplatelet monotherapy includes aspirin or a P2Y12 inhibitor selected from clopidogrel, ticagrelor, and prasugrel. Embodiment 101. Any one of Embodiments 94 to 98, wherein standard antiplatelet therapy includes dual antiplatelet therapy (DAPT). Embodiment 102. The method of Embodiment 101, wherein the dual antiplatelet therapy includes aspirin and a P2Y12 inhibitor (selected from clopidogrel, ticagrelor, or prasugrel). Embodiment 103. Any one of Embodiments 101 and 102, wherein the dual antiplatelet therapy includes aspirin and a P2Y12 inhibitor (selected from clopidogrel, ticagrelor, or prasugrel). Embodiment 104. Any one of Embodiments 101 to 103, wherein the combination therapy of two antiplatelet agents includes aspirin and clopidogrel. Apparatus 105. One of the methods described in Apparatus 101 to 104, in which dual antiplatelet therapy (DAPT) is performed for 21 days, followed by antiplatelet monotherapy (SAPT). Embodiment 106. Any one of Embodiments 101 to 104, wherein dual antiplatelet therapy (i.e., administration of aspirin and a P2Y12 inhibitor) is administered for more than 90 days, with or without de-escalation to SAPT. Embodiment 107. Use of milbexian to prevent one or more strokes and non-central nervous system (CNS) systemic embolic events in human patients with a history of atrial fibrillation or atrial flutter, wherein the method involves administering to a human patient a pharmaceutical composition containing approximately 50 mg, approximately 75.0 mg, approximately 87.5 mg, or approximately 100 mg of milbexian (or a pharmaceutically acceptable salt or solvate thereof, in milbexian equivalent); the pharmaceutical composition is administered twice daily. Apparatus 108. Use of milbexian to prevent one or more cardiovascular adverse events in a patient with a history of atrial fibrillation or atrial flutter, Each event is selected from a group consisting of cardiovascular death, myocardial infarction, stroke, and systemic embolism other than that of the central nervous system (CNS). The method involves administering to a human patient a pharmaceutical composition containing approximately 50 mg, approximately 75.0 mg, approximately 87.5 mg, or 100 mg of milbexian (or a pharmaceutically acceptable salt or solvate thereof, in milbexian equivalent); the composition is administered twice daily. Appearance 109. Use of milbexian as in Appearance 108, wherein the cardiovascular adverse event is cardiovascular death. Apparatus 110. Use of any one of the milbexian described in Apparatus 107-109, in which the patient has a history of atrial fibrillation or atrial flutter and also has co-existing coronary artery disease (CAD) and / or peripheral artery disease (PAD). Embodiment 111. Use of milbexian according to any one of Embodiments 107 to 110, wherein the pharmaceutical composition contains 100 mg of milbexian (or a pharmaceutically acceptable salt or solvate thereof, in milbexian equivalent). Embodiment 112. Use of milbexian according to any one of Embodiments 107 to 110, wherein the pharmaceutical composition contains 87.5 mg of milbexian (or a pharmaceutically acceptable salt or solvate thereof, in milbexian equivalent). Embodiment 113. Use of milbexian according to any one of Embodiments 107 to 110, wherein the pharmaceutical composition contains 75 mg of milbexian (or a pharmaceutically acceptable salt or solvate thereof, in milbexian equivalent). Embodiment 114. Use of milbexian according to any one of Embodiments 107 to 110, wherein the pharmaceutical composition contains 50 mg of milbexian (or a pharmaceutically acceptable salt or solvate thereof, in milbexian equivalent). Embodiment 115. Use of milbexian according to any one of Embodiments 107 to 114, wherein the pharmaceutical composition is a solid oral pharmaceutical composition comprising milbexian (or a pharmaceutically acceptable salt or solvate thereof) and one or more pharmaceutically acceptable excipients. Embodiment 116. Use of milbexian according to Embodiment 115, wherein the solid oral pharmaceutical composition is an immediate-release tablet. Embodiment 117. Use of the milbexian of Embodiment 116, wherein the disintegration time in water of the immediate-release tablet is less than 20 seconds. Embodiment 118. Use of any one of the milbexian embodiments 107 to 117, wherein administration results in a plasma half-life of milbexian of approximately 13 to 16 hours. Embodiment 119. Use of any one of the milbexian embodiments 107 to 118, wherein, during repeated administration, the half-life of milbexian in plasma becomes approximately 13 hours to approximately 16 hours upon administration. Embodiment 120. Use of milbexian according to any one of Embodiments 107 to 119, wherein the plasma concentration of milbexian reaches a steady state in approximately 3 to 6 days after administration. Embodiment 121. Use of milbexian according to any one of Embodiments 107 to 120, wherein a pharmaceutical composition containing milbexian (or a pharmaceutically acceptable salt or solvate thereof) is administered regardless of the timing of meals. Embodiment 122. Use of milbexian according to any one of Embodiments 107 to 121, wherein a composition comprising milbexian (or a pharmaceutically acceptable salt or solvate thereof) is administered twice daily for at least 13 weeks. Embodiment 123. Use of milbexian according to any one of Embodiments 107 to 122, wherein a composition comprising milbexian (or a pharmaceutically acceptable salt or solvate thereof) is administered once in the morning and once at night. Embodiment 124. Use of milbexian according to any one of Embodiments 107 to 123, wherein the morning and evening doses are administered at the same time every day. Apparatus 125. Use of milbexian to prevent one or more strokes and non-central nervous system (CNS) systemic embolic events in patients with a history of atrial fibrillation or atrial flutter, the method characterized by administering to the patient a film-coated immediate-release tablet containing approximately 50 mg, approximately 75.0 mg, approximately 87.5 mg, or 100 mg of milbexian or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients. The film-coated, immediate-release tablets are administered twice daily, regardless of whether or not a meal has been eaten. The patient is at least 18 years old; The patient also had the following: (i) 75 years of age or older or (ii) history of ischemic stroke Do you have one or more risk factors in category (A) selected from the following? Or: (i) 65-74 years old; (ii) hypertension; (iii) diabetes; (iv) A history of coronary artery disease (CAD) (including a history of myocardial infarction or acute coronary syndrome, regardless of whether percutaneous coronary intervention (PCI) has been performed) or a history of peripheral artery disease (PAD); and (v) History of heart failure The individual has two or more cardiovascular risk factors in category (B), selected from the group consisting of the following: Apparatus 126. Use of milbexian to prevent one or more major cardiovascular adverse events in patients with a history of atrial fibrillation or atrial flutter, Each event is selected from a group consisting of cardiovascular death, myocardial infarction, stroke, and systemic embolism other than that of the central nervous system (CNS). The method is characterized by administering to the patient a film-coated immediate-release tablet containing approximately 50 mg, approximately 75.0 mg, approximately 87.5 mg, or 100 mg of milbexian or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients. The film-coated, immediate-release tablets are administered twice daily, regardless of whether or not a meal has been eaten. The patient is at least 18 years old; The patient also had the following: (i) 75 years of age or older or (ii) history of ischemic stroke Do you have one or more risk factors in category (A) selected from the following? Or: (i) 65-74 years old; (ii) hypertension; (iii) diabetes; (iv) A history of coronary artery disease (CAD) (including a history of myocardial infarction or acute coronary syndrome, regardless of whether percutaneous coronary intervention (PCI) has been performed) or a history of peripheral artery disease (PAD); and (v) History of heart failure The individual has two or more cardiovascular risk factors in category (B), selected from the group consisting of the following: Appearance 127. Use of milbexian as in Appearance 126, where the primary cardiovascular adverse event is cardiovascular death. Embodiment 128. Use of any one of the milbexian embodiments 125 to 127, wherein the film-coated, ready-release tablet has a water disintegration time of less than 20 seconds. Embodiment 129. Use of any one of the milbexian embodiments 125 to 128, wherein the half-life of the administered milbexian in plasma is 13 to 16 hours. Embodiment 130. Use of any one of the milbexian embodiments 125 to 129, wherein the half-life of the administered milbexian in plasma is 13 to 16 hours during repeated administration. Embodiment 131. Use of milbexian according to any one of Embodiments 125 to 130, wherein a composition comprising milbexian (or a pharmaceutically acceptable salt or solvate thereof) is administered twice daily for at least 13 weeks. Embodiment 132. Use of milbexian according to any one of Embodiments 105 to 131, wherein a composition comprising milbexian (or a pharmaceutically acceptable salt or solvate thereof) is administered once in the morning and once at night. Embodiment 133. Use of milbexian according to Embodiment 132, wherein the morning and evening doses are administered at the same time each day. Embodiment 134. Use of any one of the milbexian formulations described in Embodiments 107 to 133, wherein administration reduces the patient's factor XI coagulation activity by approximately 27% to approximately 64% compared to baseline. Embodiment 135. Use of any one of the milbexian formulations from Embodiments 107 to 134, wherein administration prolongs the patient's activated partial thromboplastin time (aPTT) with a baseline ratio of 2.1 to 2.6. Embodiment 136. Use of milbexian to prevent stroke in human patients with a history of atrial fibrillation or atrial flutter, characterized in that the human patient is administered a pharmaceutical composition containing approximately 50 mg of milbexian (or a pharmaceutically acceptable salt or solvate thereof, in milbexian equivalent), and the pharmaceutical composition is administered twice daily. Embodiment 137. Use of milbexian to prevent stroke in human patients with a history of atrial fibrillation or atrial flutter, characterized in that the human patient is administered a pharmaceutical composition containing approximately 75 mg of milbexian (or a pharmaceutically acceptable salt or solvate thereof, in milbexian equivalent), and the pharmaceutical composition is administered twice daily. Embodiment 138. Use of milbexian to prevent stroke in human patients with a history of atrial fibrillation or atrial flutter, characterized in that the human patient is administered a pharmaceutical composition containing approximately 87.5 mg of milbexian (or a pharmaceutically acceptable salt or solvate thereof, in milbexian equivalent), and the pharmaceutical composition is administered twice daily. Embodiment 139. Use of milbexian to prevent stroke in human patients with a history of atrial fibrillation or atrial flutter, characterized in that the human patient is administered a pharmaceutical composition containing approximately 100 mg of milbexian (or a pharmaceutically acceptable salt or solvate thereof, in milbexian equivalent), and the pharmaceutical composition is administered twice daily. Embodiment 140. Use of milbexian to prevent one or more systemic embolic events other than those of the central nervous system (CNS) in human patients with a history of atrial fibrillation or atrial flutter, characterized in that the human patient is administered a pharmaceutical composition containing approximately 50 mg of milbexian (or a pharmaceutically acceptable salt or solvate thereof, in milbexian equivalent), and the pharmaceutical composition is administered twice daily. Embodiment 141. Use of milbexian to prevent one or more systemic embolic events other than those of the central nervous system (CNS) in a human patient with a history of atrial fibrillation or atrial flutter, characterized in that the human patient is administered a pharmaceutical composition containing approximately 75 mg of milbexian (or a pharmaceutically acceptable salt or solvate thereof, in milbexian equivalent), and the pharmaceutical composition is administered twice daily. Embodiment 142. Use of milbexian to prevent one or more non-central nervous system (CNS) systemic embolism events in human patients with a history of atrial fibrillation or atrial flutter, characterized in that the human patient is administered a pharmaceutical composition containing approximately 87.5 mg of milbexian (or a pharmaceutically acceptable salt or solvate thereof, in milbexian equivalent), and the pharmaceutical composition is administered twice daily. Embodiment 143. Use of milbexian to prevent one or more systemic embolic events other than those of the central nervous system (CNS) in human patients with a history of atrial fibrillation or atrial flutter, characterized in that the human patient is administered a pharmaceutical composition containing approximately 100 mg of milbexian (or a pharmaceutically acceptable salt or solvate thereof, in milbexian equivalent), and the pharmaceutical composition is administered twice daily. Apparatus 144. Use of milbexian to prevent one or more major cardiovascular adverse events in patients with a history of atrial fibrillation or atrial flutter, Each event is selected from a group consisting of cardiovascular death, myocardial infarction, stroke, and systemic embolism other than that of the central nervous system (CNS). The method is characterized by administering a pharmaceutical composition containing approximately 50 mg of milbexian (or a pharmaceutically acceptable salt or solvate thereof, in milbexian equivalent) to a human patient, and administering the composition twice daily. Apparatus 145. Use of milbexian to prevent one or more cardiovascular adverse events in a patient with a history of atrial fibrillation or atrial flutter, Each event is selected from a group consisting of cardiovascular death, myocardial infarction, stroke, and systemic embolism other than that of the central nervous system (CNS). The method is characterized by administering a pharmaceutical composition containing approximately 75 mg of milbexian (or a pharmaceutically acceptable salt or solvate thereof, in milbexian equivalent) to a human patient, and administering the composition twice daily. Apparatus 146. Use of milbexian to prevent one or more cardiovascular adverse events in a patient with a history of atrial fibrillation or atrial flutter, Each event is selected from a group consisting of cardiovascular death, myocardial infarction, stroke, and systemic embolism other than that of the central nervous system (CNS). The method is characterized by administering a pharmaceutical composition containing approximately 87.5 mg of milbexian (or a pharmaceutically acceptable salt or solvate thereof, in milbexian equivalent) to a human patient, and administering the composition twice daily. Apparatus 147. Use of milbexian to prevent one or more cardiovascular adverse events in a patient with a history of atrial fibrillation or atrial flutter, Each event is selected from a group consisting of cardiovascular death, myocardial infarction, stroke, and systemic embolism other than that of the central nervous system (CNS). The method is characterized by administering a pharmaceutical composition containing approximately 100 mg of milbexian (or a pharmaceutically acceptable salt or solvate thereof, in milbexian equivalent) to a human patient, and administering the composition twice daily. Appearance 148. Use of any one of the milbexian described in Appearances 144-147, wherein the cardiovascular adverse event is cardiovascular death. Appearance 149. Use of any one of the milbexian formulations in Appearances 144 to 147, wherein the cardiovascular adverse event is myocardial infarction. Appearance 150. Use of any one of the milbexian described in Appearances 144 to 147, wherein the cardiovascular adverse event is stroke. Appearance 151. Use of any one of the milbexian described in Appearances 144 to 147, wherein the cardiovascular adverse event is a systemic embolism other than that of the central nervous system (CNS). Apparatus 152. Use of any one of the milbexian described in Apparatus 136-151, in which the patient has a history of atrial fibrillation or atrial flutter and also has co-existing coronary artery disease (CAD) and / or peripheral artery disease (PAD). Apparatus 153. Use of milbexian as in Apparatus 152, in a patient with a history of atrial fibrillation or atrial flutter and co-existing coronary artery disease (CAD). Apparatus 154. Use of milbexian as in Apparatus 152, in a patient with a history of atrial fibrillation or atrial flutter and coexisting peripheral artery disease (PAD). Embodiment 155. Use of milbexian according to any one of Embodiments 136 to 154, wherein the pharmaceutical composition is a solid oral pharmaceutical composition comprising milbexian (or a pharmaceutically acceptable salt or solvate thereof) and one or more pharmaceutically acceptable excipients. Embodiment 156. Use of milbexian according to Embodiment 155, wherein the solid oral pharmaceutical composition is an immediate-release tablet. Embodiment 157. Use of the milbexian of Embodiment 156, wherein the disintegration time in water of the immediate-release tablet is less than 20 seconds. Embodiment 158. Use of any one of the milbexian embodiments 136 to 157, wherein administration results in a plasma half-life of milbexian of approximately 13 to 16 hours. Embodiment 159. Use of any one of the milbexian embodiments 136 to 158, wherein, during repeated administration, the half-life of milbexian in plasma becomes approximately 13 hours to approximately 16 hours upon administration. Embodiment 160. Use of any one of the milbexian embodiments 136 to 159, wherein the plasma concentration of milbexian reaches a steady state in approximately 3 to 6 days after administration. Embodiment 161. Use of milbexian according to any one of Embodiments 136 to 160, wherein a pharmaceutical composition containing milbexian (or a pharmaceutically acceptable salt or solvate thereof) is administered regardless of the timing of meals. Embodiment 162. Use of milbexian according to any one of Embodiments 136 to 161, wherein the patient is unable to swallow tablet dosage forms. Embodiment 163. Use of any one of the milbexian embodiments 136 to 162, wherein the pharmaceutical composition is dispersed in an aqueous medium to form an aqueous dispersion. Embodiment 164. Use of the milbexian of Embodiment 163, wherein the aqueous medium is physiological saline, phosphate buffer, plant juice, or fruit juice such as applesauce. Embodiment 165. Use of milbexian according to Embodiment 163 or Embodiment 164, wherein the aqueous dispersion is administered to a human patient via a nasogastric tube or spoon. Embodiment 166. A use of milbexian according to any one of Embodiments 163 to 165, wherein milbexian is administered orally as an aqueous dispersion by dispersing the pharmaceutical composition in an aqueous medium at 37°C for less than 60 seconds. Embodiment 167. Use of milbexian according to any one of Embodiments 136 to 166, wherein a composition comprising milbexian (or a pharmaceutically acceptable salt or solvate thereof) is administered twice daily for at least 13 weeks. Embodiment 168. Use of milbexian according to any one of Embodiments 136 to 167, wherein a composition comprising milbexian (or a pharmaceutically acceptable salt or solvate thereof) is administered once in the morning and once at night. Embodiment 169. Use of milbexian according to Embodiment 168, wherein the morning and evening doses are administered at the same time each day. Embodiment 170. Use of any one of the milbexian formulations from Embodiments 136 to 169, wherein administration reduces the patient's factor XI coagulation activity by approximately 27% to approximately 64% compared to baseline. Embodiment 171. Use of any one of the milbexian formulations from Embodiments 136 to 170, wherein administration prolongs the patient's activated partial thromboplastin time (aPTT) with a baseline ratio of 2.1 to 2.6. Apparatus 172. Use of milbexian to prevent stroke in patients with a history of atrial fibrillation or atrial flutter, the method comprising administering to the patient a film-coated immediate-release tablet containing approximately 50 mg of milbexian or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients, The film-coated, immediate-release tablets are administered twice daily, regardless of whether or not a meal has been eaten. The patient is at least 18 years old; The patient also had the following: (i) 75 years of age or older or (ii) history of ischemic stroke Do you have one or more risk factors in category (A) selected from the following? Or: (i) 65-74 years old; (ii) hypertension; (iii) diabetes; (iv) A history of coronary artery disease (CAD) (including a history of myocardial infarction or acute coronary syndrome, regardless of whether percutaneous coronary intervention (PCI) has been performed) or a history of peripheral artery disease (PAD); and (v) History of heart failure The individual has two or more cardiovascular risk factors in category (B), selected from the group consisting of the following: Apparatus 173. Use of milbexian to prevent systemic embolic events other than those of the central nervous system (CNS) in patients with a history of atrial fibrillation or atrial flutter, the method comprising administering to the patient a film-coated immediate-release tablet containing approximately 50 mg of milbexian or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients. The film-coated, immediate-release tablets are administered twice daily, regardless of whether or not a meal has been eaten. The patient is at least 18 years old; The patient also had the following: (i) 75 years of age or older or (ii) history of ischemic stroke Do you have one or more risk factors in category (A) selected from the following? Or: (i) 65-74 years old; (ii) hypertension; (iii) diabetes; (iv) A history of coronary artery disease (CAD) (including a history of myocardial infarction or acute coronary syndrome, regardless of whether percutaneous coronary intervention (PCI) has been performed) or a history of peripheral artery disease (PAD); and (v) History of heart failure The individual has two or more cardiovascular risk factors in category (B), selected from the group consisting of the following: Apparatus 174. Use of milbexian to prevent stroke in patients with a history of atrial fibrillation or atrial flutter, characterized in that the patient is administered a film-coated immediate-release tablet containing approximately 75 mg of milbexian or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients. The film-coated, immediate-release tablets are administered twice daily, regardless of whether or not a meal has been eaten. The patient is at least 18 years old; The patient also had the following: (i) 75 years of age or older or (ii) history of ischemic stroke Do you have one or more risk factors in category (A) selected from the following? Or: (i) 65-74 years old; (ii) hypertension; (iii) diabetes; (iv) A history of coronary artery disease (CAD) (including a history of myocardial infarction or acute coronary syndrome, regardless of whether percutaneous coronary intervention (PCI) has been performed) or a history of peripheral artery disease (PAD); and (v) History of heart failure The individual has two or more cardiovascular risk factors in category (B), selected from the group consisting of the following: Apparatus 175. Use of milbexian to prevent systemic embolic events other than t...

Claims

1. A method for treating or preventing thrombotic disorders in human patients with cardiovascular or cerebrovascular disease, comprising administering to the human patient an immediate-release tablet containing 25 mg, 50 mg, or 100 mg of milbexian (or a pharmaceutically acceptable salt or solvate thereof) and a pharmaceutically acceptable excipient, wherein the immediate-release tablet may be administered in combination with antiplatelet therapy as appropriate, and the immediate-release tablet is administered twice daily.

2. The method according to claim 1, wherein administration of an immediate-release tablet containing milbexian (or a pharmaceutically acceptable salt or solvate thereof), or a regimen including an immediate-release tablet, reduces the patient's factor XI coagulation activity by approximately 7% to approximately 20% or by approximately 27% to approximately 64% compared to baseline.

3. The method according to claim 1, wherein administration of an immediate-release tablet containing milbexian (or a pharmaceutically acceptable salt or solvate thereof), or a regimen including an immediate-release tablet, results in an extension of activated partial thromboplastin time (aPTT) of approximately 27% to approximately 64% relative to baseline, or an extension of the patient's activated partial thromboplastin time (aPTT) to 2.1 to 2.6 relative to baseline.

4. The method according to claim 1, wherein administration does not statistically significantly increase the incidence of major hemorrhagic complications.

5. The method according to claim 1, wherein the disintegration time in water for immediate release is less than 20 seconds.

6. The method according to claim 1, wherein administration results in a plasma half-life of milbexian of approximately 13 to 16 hours.

7. The method according to claim 1, wherein, upon administration, the plasma concentration of milbexian reaches a steady state in approximately 3 to 6 days.

8. The method according to claim 1, wherein the immediate-release tablet is administered regardless of the timing of meals.

9. The method according to claim 1, wherein the thrombotic disorder is a thromboembolic disorder selected from arterial thromboembolism, venous thromboembolism, or thromboembolism in the cardiac chambers or peripheral circulation.

10. The method according to claim 1, wherein a human patient has a cerebrovascular disease.

11. The method according to claim 10, wherein the cerebrovascular disease is selected from non-cardiogenic ischemic stroke or transient ischemic attack (TIA).

12. The method according to claim 1, wherein a human patient has a cardiovascular disease.

13. The method according to claim 12, wherein the cardiovascular disease is atrial fibrillation or atrial flutter.

14. The method according to claim 12, wherein the cardiovascular disease is acute coronary syndrome.

15. The method according to claim 1, wherein the immediate-release tablet comprises 50 mg or 100 mg of milbexian (or a pharmaceutically acceptable salt or solvate thereof).

16. The method according to claim 9, wherein thrombotic diseases include arterial thromboembolism associated with acute coronary syndrome.

17. The method according to claim 1, characterized in that a human patient is given a regimen comprising (i) administration of an immediate-release tablet containing 25 mg of milbexian (or a pharmaceutically acceptable salt or solvate thereof), and (ii) an antiplatelet therapy selected from the group consisting of aspirin, P2Y12 inhibitors, and combinations thereof, wherein the immediate-release tablet is administered twice daily.

18. The method according to claim 17, wherein a P2Y12 inhibitor is used for antiplatelet therapy.

19. The method according to claim 17, wherein aspirin is used for antiplatelet therapy.

20. The method according to claim 1, wherein administration of milbexian does not result in a clinically significant prolongation of the QTc interval.

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