Prevention and treatment of thrombotic diseases with 5-amino-2,3-dihydro-1,4-phthalazinedione

Abstract

This disclosure relates to 5-amino-2,3-dihydro-1,4-phthalazinedione and its pharmaceutically acceptable salts for the prevention or treatment of thrombotic diseases. The invention particularly relates to the use of 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt for this purpose. Pharmaceutical compositions, advantageous formulation techniques, and therapeutic methods are disclosed.

Description

Technical Field

[0001] The present disclosure relates to 5-amino-2,3-dihydro-1,4-phthalazinedione and pharmaceutically acceptable salts thereof for the prevention or treatment of thrombotic diseases. The present invention particularly relates to the use of the sodium salt of 5-amino-2,3-dihydro-1,4-phthalazinedione for this purpose. Pharmaceutical compositions, advantageous formulation techniques, and treatment methods are disclosed.

Background Art

[0002] Thrombotic diseases are frequently occurring and highly concerning pathological events or secondary complications associated with other diseases. Thrombosis is a cardiovascular disease or disorder in which a thrombus is formed within a blood vessel. Thrombosis can occur in any blood vessel. The most common is venous thrombosis (venous thrombosis or phlebitis of venous thrombosis), especially deep vein thrombosis (DVT) in the deep veins of the lower extremities. During pregnancy, lower extremity venous thrombosis is a common complication. Thrombosis as part of a coagulation disorder also plays a major role in sepsis.

[0003] A thrombus is formed by blood coagulation, but this process is originally a defense mechanism. After trauma, the coagulation system protects the body from death by bleeding. That is, the blood coagulates to close the wound. This process is called hemostasis. Unlike the coagulation system, blood in a blood vessel without damage should not aggregate and should flow freely. In this case, a thrombus can inhibit blood flow, cause thromboembolism, and be a trigger for pulmonary embolism. When the natural coagulation ability of blood abnormally increases, the risk of thrombosis and embolism further increases.

[0004] There may be congenital and extrinsic factors that promote thrombus formation. The so-called Virchow's triad explains the causes of venous thrombosis.

[0005] Changes in blood composition These causes include coagulation disorders (hypercoagulation), hereditary hypercoagulation, such as activated protein C resistance (APCR), mutations in coagulation factor V, and hereditary or drug-induced thrombolytic impairment, as well as foods, drugs, or toxins that affect blood coagulation, such as contraceptives, pregnancy, dehydration, and antiphospholipid antibody syndrome.

[0006] Decreased blood flow velocity (stasis, immobility, low circulation) This may be due to dilated veins (varicose veins) or varicose veins, limbs exposed to external pressure, immobilization due to bed restraint (such as after surgery or wearing a cast), prolonged sitting in a restricted state (e.g., long-haul flights), lack of exercise, being overweight, dehydration, unfamiliar strenuous exercise, hormonal contraceptives, smoking, a history of thrombosis, pregnancy, cancer, chemotherapy, frequent intravenous injections with vascular damage (e.g., heroin abuse), above-average body size, or atrial fibrillation.

[0007] endothelial damage This could be due to trauma or surgery, age-related degenerative changes, inflammatory changes in blood vessels, diabetes, CO-induced hypoxic endothelial injury, or tumor infiltration.

[0008] Typical symptoms include swelling and warmth accompanied by a feeling of tension, redness and tightness of the skin, sometimes blueness, pressure and pain in the affected limb, and excessive heat in the swollen limb.

[0009] The most dangerous complication is thromboembolism, especially when it affects the lungs (pulmonary embolism). A significant percentage of thromboembols are fatal. Thromboembolism is the third leading cause of fatal cardiovascular disease, after myocardial infarction and stroke.

[0010] Recently, pulmonary embolism has attracted attention as one of the highest risk factors in SARS-CoV-2 infection. To assess the risk of severe illness, the biomarker D-dimer is routinely monitored. D-dimer has shown a good ability to predict severe illness and even fatal outcomes (Reference: Zhan et al. (2021) Clin Appl Thrombosis Hemostasi 27:1-10).

[0011] Preventive drug therapy is mainly based on anticoagulants, such as heparin (unfractionated heparin (UFH), low molecular weight heparin (LMWH), very low molecular weight heparin (ULMWH)), vitamin K antagonists such as 4-hydroxycoumarin (warfarin, coumatetralyl, dicumarol, fenprocumon, brodifacum, thiochromatol, asenocoumarol, etc.), and indanedione (fluindione, phenindione, pindone, chlorofacinone, difacinone, anisindione, etc.).

[0012] Other classes of drugs used for preventive purposes include direct thrombin inhibitors (such as hirudin, bivalirudine, repirudine, decildin, argatroban, inogatran, melagatran, xymelagatran, dabigatran, DNA aptamers, benzofuran dimers, benzofuran trimers, and polymer lignins) and direct factor Xa inhibitors (such as rivaroxaban, apixaban, and edoxaban).

[0013] Antiplatelet agents such as ADP receptor inhibitors (clopidogrel, cangrelol, prasugrel, ticagrelor, ticlopidine, etc.), adenosine reuptake inhibitors (dipyridamole), glycoprotein IIB / IIIA inhibitors (absiximab, eptifavatide, tirofiban), irreversible COX inhibitors (acetylsalicylic acid, triflusal, etc.), PDE inhibitors (cilostazol), PAR-1 antagonists (borapaxal), or thromboxane inhibitors (thromboxane receptor antagonists such as tertroban or thromboxane synthase inhibitors) are commonly administered to prevent arterial thrombosis.

[0014] While antithrombotic drugs offer excellent preventative effects, they present several challenges. They are associated with adverse side effects, the most common being an increased risk of bleeding (particularly gastrointestinal bleeding due to COX inhibitors). Furthermore, common side effects include skin necrosis, limb gangrene, purple digit syndrome, vitamin K depletion, and heparin-induced thrombocytopenia. Some of these drugs exhibit undesirable interactions with other medications. Additionally, some of these drugs are very expensive (such as clopidogrel), limiting their use to only severe cases. A practical problem is that many of these drugs must be administered by injection (intravenous or subcutaneously). Therefore, they are not very popular among patients, and their use purely for preventative purposes (i.e., not anticipating thrombosis cases) is impractical.

[0015] For thrombolysis, fibrinolytic agents such as streptokinase, urokinase, and recombinant tissue plasminogen activators (alteplase, leteplase, tenecteplase, anistreplase) are prescribed.

[0016] In light of the SARS-CoV-2 pandemic and any further viral pandemics that may occur in the future, there is a medical need for preventive (and therapeutic) drugs, and these drugs should meet the following profile. • Excellent preventive effect against thrombosis • No effect on hemostasis • No or very minor side effects (high safety profile) • Can be taken orally Ideally, the medication should also act on other causes or symptoms of the underlying condition, e.g., anti-inflammatory, antiviral. • Relatively low cost

[0017] Surprisingly, this problem is solved by 5-amino-2,3-dihydro-1,4-phthalazinedione or a pharmaceutically acceptable salt thereof.

[0018] Accordingly, the present invention relates to 5-amino-2,3-dihydro-1,4-phthalazinedione or one of its pharmaceutically acceptable salts, hydrates, or solvates for use in the prevention and treatment of thrombotic diseases. [Overview of the project]

[0019] 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt was tested in a double-blind, placebo-controlled phase II clinical trial in patients with moderate to severe COVID-19. In this trial, D-dimer was measured by default as a biomarker indicating the occurrence or indication of thrombosis. Analysis of collected blood samples showed that 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt significantly reduced D-dimer levels. This was consistent with the favorable results obtained when 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt was used in combination with standard treatment compared to placebo and standard treatment (see: EudraCT-No.:2021-000344-21). This will be explained in Example 1.

[0020] Previous studies in other indications have shown that 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt is effective and safe when administered in two divided doses at a daily dose of 100 to 1000 mg (e.g., WO2018 / 082814, WO2022 / 008093, EudraCT-No.:2014-004606-15, EudraCT-No.:2017-003484-36). Accordingly, the present invention relates to 5-amino-2,3-dihydro-1,4-phthalazinedione or one of its pharmaceutically acceptable salts, hydrates, or solvates for use in the prevention and treatment of thrombotic diseases, with a daily dose in the range of 100 mg to 1000 mg, preferably in the range of 300 mg to 800 mg, and more preferably in the range of 450 mg to 700 mg for patients requiring such a dose.

[0021] In this clinical trial, no evidence of clinical parameters or side effects indicating that 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt affects hemostasis was found. Furthermore, no such side effects have been reported in previous in vitro, in vivo, or clinical trials. Therefore, this disclosure relates to 5-amino-2,3-dihydro-1,4-phthalazinedione or one of its pharmaceutically acceptable salts, hydrates, or solvates for use in the prevention and treatment of thrombotic disorders without affecting hemostasis.

[0022] In an in vitro cell culture model, different concentrations of 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt were added. Subsequently, the amount of thrombomodulin released into the supernatant was measured. The results showed that 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt significantly increased thrombomodulin release in a dose-dependent manner. The results are shown in Example 2.

[0023] Therefore, 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt has shown clear prophylactic and therapeutic antithrombotic effects in these studies. The results of this study are presumed to be predictive not only for thrombosis in COVID-19 but also for other thrombotic diseases.

[0024] 5-Amino-2,3-dihydro-1,4-phthalazinedione (luminol) belongs to the pharmaceutical class of phthalazinediones. Compounds of this class are known for their beneficial anti-inflammatory effects. 5-Amino-2,3-dihydro-1,4-phthalazinedione is also known by the name luminol. Luminol has excellent chemiluminescent properties. Luminol is widely used as a detection means in diagnostic assays and in forensic medicine, such as for tracking blood stains. In the medical field, 5-amino-2,3-dihydro-1,4-phthalazinedione has been developed in the form of its sodium salt. In some countries, this agent has been approved as a therapeutic for a wide range of acute and chronic inflammatory diseases, for example, inflammatory diseases such as bacterial or viral, especially acute intestinal infections, hepatitis B and C, gastroenteritis, prostatitis, endometriosis, pharyngitis, bronchial asthma, pneumonia, periodontitis, pyelonephritis, etc., autoimmune diseases such as Crohn's disease, ulcerative colitis, systemic lupus erythematosus, and scleroderma. Furthermore, there still exists a long list of scientific and patent literature on indications for which 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt has been tested or for which usefulness has been suggested (see: WO2004 / 041169, WO2007 / 018546, WO2012 / 127441, WO2017 / 202496, WO2018 / 082814:ao).

[0025] In an in vitro model, 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt was able to suppress viral replication in a dose-dependent manner (WO2021 / 249667).

[0026] Most conventional immunomodulatory drugs have shown severe side effects or at least have problems with long-term treatment, but 5-amino-2,3-dihydro-1,4-phthalazinedione and its pharmaceutically acceptable salts have good tolerance and a high safety margin with respect to dosage.

[0027] Pharmacologically acceptable salts of 5-amino-2,3-dihydro-1,4-phthalazinedione are used to improve solubility and bioavailability. Sodium, potassium, and lithium salts have been reported for therapeutic use (see WO2010 / 082858). The crystal structures of lithium, sodium, potassium, rubidium, and cesium salts are described in Guzei et al. (2013) Journal of Coordination Chemistry, 66, 3722-3739. Therefore, this patent application also refers to the use of any pharmaceutically acceptable salt of 5-amino-2,3-dihydro-1,4-phthalazinedione.

[0028] In particular, this application discloses one of 5-amino-2,3-dihydro-1,4-phthalazinedione or a pharmaceutically acceptable salt thereof for use in the prevention and treatment of thrombotic diseases, wherein the pharmaceutically acceptable salt of 5-amino-2,3-dihydro-1,4-phthalazinedione is 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt.

[0029] In another embodiment, the present invention relates to 5-amino-2,3-dihydro-1,4-phthalazinedione or one of its pharmaceutically acceptable salts for use in the prevention and treatment of thrombotic diseases, wherein the prophylactic or therapeutic effect of 5-amino-2,3-dihydro-1,4-phthalazinedione or one of its pharmaceutically acceptable salts is monitored by analysis of D-dimer concentration in a blood sample.

[0030] In a preferred embodiment, the monitoring is performed by measuring the D-dimer concentration in DDU (D-dimer units).

[0031] 5-amino-2,3-dihydro-1,4-phthalazinedione is often used as a hydrate, for example, a sodium salt dihydrate. Therefore, this patent application also refers to the use of all hydrates and other solvates of 5-amino-2,3-dihydro-1,4-phthalazinedione and its pharmaceutically acceptable salts. Any of 5-amino-2,3-dihydro-1,4-phthalazinedione or its pharmaceutically acceptable salts may form complexes with suitable ligands. Therefore, this patent application also refers to such complexes. Within the scope of this disclosure, all hydrates and solvates are included in the term "5-amino-2,3-dihydro-1,4-phthalazinedione or any of its pharmaceutically acceptable salts."

[0032] Anhydrous formulations are often preferred to ensure reproducibility and standardized API production and to improve the stability of the activator. Anhydrous 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt is described as a crystalline polymorph in WO2011 / 107295 (Form I, Form II) and WO2016 / 096143 (Form III). These crystalline polymorphs are substantially free of phase impurities and were characterized by X-ray powder diffraction. This method yields a characteristic d value indicating interplanar interplanar spacing [Å] and a corresponding set of 2-theta (2θ) angles [°] at which Bragg reflections occur. This provides a unique and clear fingerprint of each polymorph.

[0033] In morphology I, the following values ​​were determined. d values: 13.5; 6.9; 5.2; 4.6; 3.9; 3.5; 3.4; 3.3; 3.1; 3.0 and / or 2θ values: 6.5; 12.7; 16.9; 19.3; 22.8; 25.8; 26.6; 27.2; 28.7; 30.3. Morphology II is characterized by the following values: d values: 12.9; 7.9; 7.1; 6.5; 5.3; 4.0; 3.7; 3.6; 3.3; 3.2 and / or 2θ values: 6.8; 11.2; 12.5; 13.7; 16.7; 22.4; 24.3; 24.9; 27.2; 27.8. The following values ​​were obtained for Form III. d values: 13.131; 7.987; 7.186; 6.566; 6.512; 5.372; 3.994; 3.662; 3.406; 3.288; 3.283; 3.222; 3.215; 3.127; 2.889 and / or 2θ values: 6.73; 11.07; 12.31; 13.48; 13.59; 16.49; 22.24; 24.29; 26.14; 27.10; 27.14; 27.67; 27.72; 28.52; 30.93.

[0034] The use of form I of the anhydrous 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt is preferred.

[0035] 5-amino-2,3-dihydro-1,4-phthalazinedione also exhibits pleomorphism. Form I (Paradies (1992) Ber. Bunsen-Ges. Phys. Chem 96:1027-1031) and Form II (WO2017 / 140430) have been disclosed.

[0036] Accordingly, this patent application also refers to the use of all crystalline forms and polymorphs of 5-amino-2,3-dihydro-1,4-phthalazinedione and its pharmaceutically acceptable salts, in accordance with the disclosure. The use of form II of 5-amino-2,3-dihydro-1,4-phthalazinedione is preferred.

[0037] Similar therapeutic effects are known for various phthalazinediones, which are derivatives of 5-amino-2,3-dihydro-1,4-phthalazinedione and their pharmaceutically acceptable salts. One example is 6-amino-2,3-dihydrophthalazine-1,4-dione (isoluminol). A summary of suitable phthalazinediones is provided in WO2007 / 018546. It is reasonable to assume that these compounds would exhibit equivalent efficacy when used for therapeutic purposes based on this disclosure.

[0038] Tautomerism refers to the phenomenon in organic compounds in which the structure rapidly interconverts due to the formal movement of hydrogen atoms or protons within the compound. This involves the exchange of single bonds with adjacent double bonds. These single-bonded forms are called tautomers. For example, keto-enol tautomerism occurs in 5-amino-2,3-dihydro-1,4-phthalazinedione (Proescher and Moody (1939) J Lab Clin Med, 1183-1189). Therefore, this patent application also refers to the use of all tautomers of 5-amino-2,3-dihydro-1,4-phthalazinedione and its pharmaceutically acceptable salts.

[0039] As used throughout this application, the term "5-amino-2,3-dihydro-1,4-phthalazinedione or any of its pharmaceutically acceptable salts" encompasses all of the aforementioned molecular variants of 5-amino-2,3-dihydro-1,4-phthalazinedione, i.e., any of its pharmaceutically acceptable salts or solvates, hydrates, crystalline polymorphs, or tautomers.

[0040] Unless otherwise specified, the technical or scientific terms used in this invention have the meanings that those skilled in the relevant technical field assign to them.

[0041] The term “composition” or “pharmaceutical composition” includes at least one active ingredient in at least one pharmaceutically acceptable defined dose and form of administration, at least one pharmaceutically acceptable excipient, and all agents produced directly or indirectly from the components outlined below, as combinations, accumulations, complexes, or crystals, or as a result of other reactions or interactions, and optionally at least one further pharmaceutical product listed below.

[0042] In this application, the term "excipient" is used to refer to components in a pharmaceutical composition other than the pharmacologically active ingredient. The selection of an appropriate excipient depends on various factors, including dosage form, dose, desired solubility, and stability of the composition.

[0043] The terms “effect,” “therapeutic effect,” “action,” “therapeutic action,” “potency,” and “effectiveness” relating to the substances or pharmaceutical compositions of this disclosure, or other active substances described herein, refer to beneficial results that causally occur in an organism to which the substance has been previously administered.

[0044] According to this disclosure, the terms “effective dose” and “therapeutic effective dose” refer to an amount of the substance of the present invention sufficient to produce a desired beneficial effect in a subject requiring such treatment.

[0045] The terms “treatment” and “therapy” include administering at least one of the substances of the present invention alone or in combination with at least one other pharmaceutical product, regardless of the order of administration. Such administration is intended to substantially prevent the formation of occlusive thrombi or to improve the condition of a thrombotic disorder.

[0046] The terms “prevention” or “preventive treatment” include administering at least one of the substances of the present invention alone or in combination with at least one other pharmaceutical product, regardless of the time order of administration, to prevent or suppress the onset of symptoms resulting from thrombotic disorders. In particular, it refers to a patient’s medical condition in which the onset of such symptoms is expected to occur with a reasonable probability in the distant or near future.

[0047] The terms “subject” and “patient” refer to an individual who has symptoms or impairments related to a thrombotic disorder and who is confirmed or suspected of having such a diagnosis. “Individual” refers to a mammal, in particular a human.

[0048] In particular, this application discloses either 5-amino-2,3-dihydro-1,4-phthalazinedione or any pharmaceutically acceptable salt thereof for use in the prevention and treatment of thrombotic diseases, wherein thrombotic diseases are selected from the group including venous thrombosis, deep vein thrombosis, Paget-Schlotter disease, Budd-Chiari syndrome, portal vein thrombosis, renal vein thrombosis, cerebral venous sinus thrombosis, jugular vein thrombosis, cavernous sinus thrombosis, thrombophlebitis, peripartum thrombosis, painful leukocytoma, arterial thrombosis, peripheral artery disease, acute limb ischemia, hepatic artery thrombosis, disseminated intravascular coagulation syndrome and thrombotic microangiopathy.

[0049] Venous thrombosis is a type of thrombosis that affects the veins of a patient.

[0050] A common form of venous thrombosis is deep vein thrombosis (DVT). This is a disease in which blood clots form in the deep veins, most commonly occurring in the legs and pelvis (Phillippe (2017) Am J Managed Care 23:S376-382). Symptoms include pain, swelling, redness, and vein dilation in the affected area (Kruger et al. (2019) Med J Australia 210:516-524). The greatest threat is when the blood clot detaches from the affected vein and travels to the lungs, causing pulmonary embolism, which can be life-threatening.

[0051] Paget-Schlotter disease is a specific form of deep vein thrombosis of the upper extremities. It typically occurs in the axillary vein and / or subclavian vein (Hughes (1949) Surgery, Gynecology & Gynecology 88:89-127).

[0052] Budd-Chiari syndrome is a rare disease caused by obstruction of the hepatic veins that supply blood to the liver. In most cases, it is caused by acquired hypercoagulation. It is often secondary to tumors (see GarciA Pagan et al. (2023) New Engl J Med 388:1307-1316).

[0053] Portal vein thrombosis is a disease in which a blood clot forms in the hepatic portal vein. This causes increased portal pressure and decreased blood flow to the liver (DeLeve et al. (2009) Hepatology 49:1729-1764).

[0054] Renal vein thrombosis (RVT) is a condition in which blood clots form in the veins that drain blood from the kidneys. It can affect one or both kidneys. It mainly occurs in newborns with blood clotting disorders and adults with nephrotic syndrome (Totowa (2005) "Handbook of Urological Emergencies: A Practical Guide" Wessels et al. eds, Humana Press, 171-180).

[0055] Cerebral venous sinus thrombosis (CVST) is a disease in which blood clots form in the sinuses of the dura mater surrounding the central nervous system. Symptoms include severe headache, visual disturbances, stroke symptoms, and seizures (Silvis et al. (2017) Nat Rev Neurol 13:555-565).

[0056] Jugular vein thrombosis often occurs as a result of infection, intravenous drug use, or as a sequela of malignant tumors. Complications include systemic sepsis, pulmonary embolism, and papilledema.

[0057] Cavernous sinus thrombosis (CST) is a condition in which blood clots form in the cavernous sinuses at the base of the brain (where oxygen-deprived blood returns to the heart). It can be caused by infections that spread to the nose, sinuses, ears, teeth, etc.

[0058] Thrombophlebitis is inflammation of the veins associated with blood clots. Typical symptoms include pain, redness of the skin, inflammation, edema, hardening of the veins, and tenderness. One cause is elevated estrogen levels during pregnancy, estrogen replacement therapy, or the use of oral contraceptives. Other major causes include prolonged immobility and air travel.

[0059] Perinatal thrombosis is a type of stroke that occurs in infants between 140 days of gestation and 28 days postpartum (Raju et al. (2007) Pediatrics 120:609-616). Causes include trauma during childbirth, placental abruption, infection, and maternal health problems. Affected infants may exhibit stroke symptoms, seizures, coordination disorders, and delayed language development in the early postnatal period (Aden (2009) Stroke 40:1948-1949).

[0060] Phlegmasia alba dolens includes various forms of deep vein thrombosis (DVT). It can occur in late pregnancy and immediately after childbirth and is an acute condition that causes compression of the left common iliac vein.

[0061] Arterial thrombosis is a disease in which blood clots form in the arteries. It is a condition in which blood flow to an organ or part of the body is suddenly blocked. Symptoms include pain in the affected area and a temporary decrease in organ function.

[0062] Peripheral artery disease (PAD) is a condition in which arteries other than those supplying blood to the heart and brain become pathologically narrowed. It most commonly affects the legs, but can also occur in the arms, neck, and kidneys. Intermittent claudication is a common syndrome seen in the elderly.

[0063] Acute limb ischemia (ALI) is a condition in which blood flow to the limbs is suddenly interrupted within 14 days of symptom onset (Olinic et al. (2019) J Clin Med 8(8)). ALI is caused by embolism or thrombosis, but rarely by trauma. Typical symptoms include pain, pallor, paresthesia, extreme coldness, absence of pulse, and paralysis (Brearly (2013) BMJ 346:f2681).

[0064] Hepatic artery thrombosis (TAF) develops when a blood clot forms in the artery that supplies blood to the liver. It can occur as a complication after liver transplantation. Smoking is a major risk factor and can lead to a severe increase in serum aminotransferase levels.

[0065] Disseminated intravascular coagulation (DIC) is a disease in which blood clots form throughout the body, blocking small blood vessels. Symptoms include chest pain, shortness of breath, leg pain, speech difficulties, or paralysis of specific body parts. These symptoms are commonly seen in septic diseases.

[0066] Coagulation disorders in septic diseases appear during the pathophysiological course of sepsis. In the early stages of sepsis, coagulation activation is inhibited by three anticoagulant pathways: antithrombin, protein C, and tissue factor pathway inhibitors. As sepsis progresses, these three mechanisms break down, resulting in a hypercoagulable state. Impairment of the fibrinolytic system contributes to this hypercoagulable state. Therefore, restoring coagulation balance to prevent the progression to the severe stages of sepsis is an important treatment in sepsis management (Tsante et al. (2023) Life 13:350).

[0067] Thrombotic microangiopathy (TMA) is a disease in which blood clots form due to endothelial damage in capillaries and arterioles. Hemolytic uremic syndrome and thrombotic thrombocytopenic purpura are also included in TMA.

[0068] In this specification, for all the disorders and symptoms described above, the pharmaceutically acceptable salt of 5-amino-2,3-dihydro-1,4-phthalazinedione is preferably 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt.

[0069] Accordingly, the present invention relates to either 5-amino-2,3-dihydro-1,4-phthalazinedione or any pharmaceutically acceptable salt thereof for use in the prevention or treatment of thrombotic diseases, which are selected from the group including venous thrombosis, deep vein thrombosis, Paget-Schlotter disease, Budd-Chiari syndrome, portal vein thrombosis, renal vein thrombosis, cerebral venous sinus thrombosis, jugular vein thrombosis, cavernous sinus thrombosis, thrombophlebitis, peripartum thrombosis, painful leukocytoma, arterial thrombosis, peripheral artery disease, acute limb ischemia, hepatic artery thrombosis, disseminated intravascular coagulation syndrome, and coagulation disorders.

[0070] In another aspect, the present invention relates to 5-amino-2,3-dihydro-1,4-phthalazinedione or any pharmaceutically acceptable salt, hydrate, or solvate thereof for use in the prevention or treatment of thrombotic disorders caused by viral infections.

[0071] In a preferred embodiment, the present invention relates to 5-amino-2,3-dihydro-1,4-phthalazinedione or one of its pharmaceutically acceptable salts, hydrates, or solvates for use in the prevention or treatment of thrombotic disorders when the thrombotic disorder is caused by SARS-CoV-2 infection.

[0072] In preferred embodiments, the present invention relates to 5-amino-2,3-dihydro-1,4-phthalazinedione or any pharmaceutically acceptable salt, hydrate, or solvate thereof for use in the prevention or treatment of thrombotic disorders when they occur in sepsis or septic diseases.

[0073] The most common biomarker for ongoing or impending thrombotic disease is the so-called D-dimer (DD), a physiologically occurring degradation product during fibrinolysis. When the soluble protein fibrinogen coagulates due to the enzyme thrombin, a thrombus is formed. The resulting fibrin monomers spontaneously polymerize in a semi-twisted structure to form protofibrils. The tensile strength of the fibrin network is enhanced by factor XIIIa (transglutaminase), which cross-links adjacent monomers. Fibrin formation also triggers the activation of plasminogen. The resulting enzyme plasmin breaks down individual fibrin fibers into non-covalent trimer complexes (DDEs). Plasmin further cleaves DDEs into D-dimers (DD) and fragment E (Weitz et al. (2017) J Am Coll Cardiology 70:2411-2420).

[0074] DD can be detected in whole blood or plasma using monoclonal antibodies that recognize epitopes on cross-linked D-dimers that are not present in the D domains of fibrinogen and non-cross-linked fibrin monomers. Three commonly used diagnostic methods are whole blood agglutination, enzyme-linked immunosorbent assay (ELISA), enzyme-linked immunofluorescence assay (ELFA), and latex agglutination (Tripodi (2011) Clin Chem 57:1256-1262).

[0075] The enzyme thrombomodulin (TM) is encoded by the THBD gene and is primarily expressed in endothelial cells. TM plays a crucial role in maintaining vascular homeostasis by regulating the coagulation system. Intravascular injury and inflammation mediate inflammation by triggering procoagulation signaling, necrotizing endothelial cells, and blood cell-derived injury-associated patterns (DAMPs). In the hypercoagulable state following endothelial injury, TM is released into the vascular lumen by the proteolysis of endothelial components (Watanabe-Kusonoki et al. (2020) FrontiersImmunol 11:575890).

[0076] TM is composed of three domains, each with a different function: TMD1 (lectin-like domain), TMD2 (six epidermal growth factor-like structures), and TMD3 (serine and threonine-rich domain). In response to thrombin production, TM on endothelial cells acts as a thrombin receptor, reducing fibrin coagulation properties and platelet activation. The thrombin-TM complex activates protein C, and activated protein C (APC) inactivates factor Va and factor VIIIa, thereby suppressing thrombin production. Thus, TM is a natural feedback inhibitor against excessive intravascular coagulation (Esmon and Owen (2004) J Thromb Haemost 2:209-213).

[0077] To prevent unnecessary coagulation, endothelial cells express anticoagulant factors such as tissue factor pathway inhibitors and TM, as well as platelet activation regulators such as NO, prostacyclin, and ADPase, in a steady state. In cases of vascular injury, crosstalk between the activated coagulation system and inflammatory signaling causes mutual amplification (Foley et al. (2016) Circ Res 118:1392-1408).

[0078] Clinical application of recombinant TM (rTM) in disseminated intravascular coagulation (DIC) can help prevent tissue damage. rTM neutralizes DAMPs such as histones and high-mobility group box 1 (HMGB1), suppresses excessive complement system activation, protects the endothelium, and acts on both the innate and adaptive immune systems. Neutrophil extracellular traps (NETs) promote immunothrombosis by organizing platelets as part of the innate immune system to contain infectious invaders. However, excessive immunothrombosis can cause intravascular damage (Watanabe-Kusonoki et al. (2020) FrontiersImmunol 11:575890). Immunothrombotic thrombi are primarily composed of fibrin. rTM inhibits NET formation after treatment with LPS-primed platelets by suppressing TLR4 signaling (Shimomura et al. (2016) JIntensive Care 4:48). When it binds to neutrophils, it inhibits NET formation mediated by autoantibodies (Watanabe-Kusoniki et al. (2020) J Autoimmun 108:102390).

[0079] It can be reasonably inferred that the same effect as when rTM is administered can be obtained by pharmacochemically increasing the TM concentration in the blood. This is shown in Example 2.

[0080] In another embodiment, the present disclosure relates to a pharmaceutical composition for use in the prevention or treatment of thrombotic diseases, comprising one of 5-amino-2,3-dihydro-1,4-phthalazinedione or a pharmaceutically acceptable salt, hydrate, or solvate thereof, and at least one pharmaceutically acceptable excipient. The pharmaceutically acceptable salt is preferably 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt.

[0081] In another aspect, the present invention relates to a pharmaceutical composition for use in the prevention or treatment of thrombotic diseases, the pharmaceutical composition being suitable for administration by inhalation, oral, parenteral, intraperitoneal, intravenous, intraarterial, intramuscular, topical, transdermal, subcutaneous, intradermal, sublingual, conjunctival, vaginal, rectal, intrathecal, pharyngeal or nasal administration, or by intubation.

[0082] "Pharmacologically acceptable excipients" refer to natural or synthetic compounds added to pharmaceutical formulations along with the active ingredient. These not only help increase the volume of the formulation, improve desirable pharmacokinetic properties, and enhance the stability of the formulation, but also exert beneficial effects in the manufacturing process.

[0083] In another embodiment, the present invention relates to a pharmaceutical composition for use in the prevention or treatment of thrombotic diseases, wherein the at least one pharmaceutically acceptable excipient is selected from the group comprising carriers, binders, colorants, buffers, preservatives, antioxidants, coatings, sweeteners, thickeners, pH adjusters, acidity adjusters, acidulants, solvents, isotonic agents, disintegrants, flow enhancers, lubricants, emulsifiers, solubilizers, stabilizers, diluents, anticaking agents, adsorbents, penetration enhancers, foaming agents, defoaming agents, opacifying agents, fatliquoring agents, viscosity enhancers, hydrotropes, aromatics, and flavorings.

[0084] Generally, one or more pharmaceutically acceptable carriers are added to a pharmaceutically active drug. Any carrier or combination known in the art is suitable. For solid dosage forms, examples include vegetable and animal fats, waxes, paraffin, starch, tragacanth, cellulose derivatives, polyethylene glycol, silicone, bentonite, silica, talc, and zinc oxide. For liquid dosage forms and emulsions, suitable carriers include, for example, solvents, solubilizers, and emulsifiers (water, ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butyl glycol, cottonseed oil, peanut oil, olive oil, castor oil, sesame oil, glycerol fatty acid esters, polyethyl glycol, sorbitan fatty acid esters, etc.). The suspension according to the present invention may use a diluent (e.g., water, ethanol, or propylene glycol), ethoxylated isostearyl alcohol, polyoxyethylene and polyoxyethylene sorbitan esters, microcrystalline cellulose, bentonite, agar, tragacanth, or other carriers well known in the art.

[0085] A binder is a substance that binds or adheres powders together, increasing their cohesive force through granular formation. Binders function as the "adhesive" of a formulation. They enhance the cohesive force of the diluent or filler provided.

[0086] Suitable binders include, for example, starches derived from wheat, corn, rice, or potatoes; natural sugars such as gelatin, glucose, sucrose, or β-lactose; sweeteners derived from corn; natural and synthetic gums such as acacia, tragacanth, or ammonium calcium alginate; sodium alginate; carboxymethylcellulose; sodium carboxymethylcellulose; hydroxypropyl carboxymethylcellulose; polyethylene glycol; polyvinylpyrrolidone; magnesium aluminum silicate; and waxes. The proportion of the binder in the composition is in the range of 1 to 30% by weight, preferably 2 to 20% by weight, more preferably 3 to 10% by weight, and most preferably 3 to 6% by weight.

[0087] Colorants are excipients that impart color to pharmaceutical formulations. These excipients may also be food colorants. Colorants can be adsorbed onto suitable adsorbents such as clay or aluminum oxide. A further advantage of colorants is that they facilitate cleaning by making any spilled aqueous solution on the nebulizer and / or mouthpiece visible. The amount of colorant can be varied in the range of 0.01 to 10% relative to the weight of the pharmaceutical composition, but is preferably in the range of 0.05 to 6%, more preferably 0.1 to 4%, and most preferably 0.1 to 1%.

[0088] Suitable pharmaceutical colorants include, for example, curcumin, riboflavin, riboflavin-5'-phosphate, tartrazine, alkannin, quinolion yellow WS, fast yellow AB, sodium riboflavin-5'-phosphate, yellow 2G, sunset yellow FCF, orange GGN, cochineal, carminic acid, citrus red 2, carmoisine, amaranth, ponseau 4R, ponseau SX, ponseau 6R, erythrosine, red 2G, alura red AC, indanthrene blue RS, patent blue V, indigo carmine, brilliant blue FCF, chlorophyll and chlorophyllin, copper complexes of chlorophyll and chlorophyllin, green S, fast green FCF, plain caramel, caustic sulfite caramel, and ammonia caramel. Examples include ammonium sulfite caramel, black PN, carbon black, vegetable carbon, brown FK, brown HT, alpha-carotene, beta-carotene, gamma-carotene, annatto, bixin, norbixin, paprika oleoresin, capsanthin, capsorbin, lycopene, beta-apo-8'-carotenal, beta-apo-8'-carotenate ethyl ester, flavoxanthin, lutein, cryptoxanthin, rubixanthin, violaxanthin, rhodoxanthin, canthaxanthin, zeaxanthin, citranaxanthin, astaxanthin, betanin, anthocyanin, saffron, calcium carbonate, titanium dioxide, iron oxide, iron hydroxide, aluminum, silver, gold, pigment rubin, tannin, orcein, ferrous gluconate, and ferrous lactate.

[0089] Furthermore, buffer solutions are preferred for liquid formulations, especially pharmaceutical liquid formulations. The terms buffer, buffer system, and buffer solution, particularly in aqueous solutions, refer to the system's ability to resist pH changes due to the addition of acids or bases, or dilution with solvents. Preferred buffer systems include formic acid, lactic acid, benzoic acid, oxalic acid, fumaric acid, aniline, acetate buffer, citrate buffer, glutamate buffer, phosphate buffer, succinic acid, pyridine, phthalic acid, histidine, MES (2-(N-morpholino)ethanesulfonic acid), maleic acid, cacodylic acid (dimethylarsenic acid), carbonic acid, ADA (N-(2-acetamido)iminodiacetic acid), PIPES (4-piperazine-bis-ethanesulfonic acid), and BIS-TRIS propane (1,3-bis[tris(hydroxylated)). The group may be selected from the following: ((methyl)methylamino)propane), ethylenediamine, ACES (2-[(amino-2-oxoethyl)amino]ethanesulfonic acid), imidazole, MOPS (3-(N-morpholino)propanesulfonic acid), diethylmalonic acid, TES (2-[tris(hydroxymethyl)methyl]aminoethanesulfonic acid), HEPES (N-2-hydroxyethylpiperazine-N'-2-ethanesulfonic acid), and other buffers with pKa values ​​of 3.8 to 7.7.

[0090] Preferably, the buffers are carbonate buffers such as acetate buffers, dicarboxylic acid buffers such as fumarates, tartrates, and phthalates, and tricarboxylic acid buffers such as citrates.

[0091] Further groups of preferred buffers include inorganic buffers such as sulfates, borates, carbonates, oxalates, calcium hydroxide, and phosphate buffers. Another group of preferred buffers includes nitrogen-containing buffers such as imidazole, diethylenediamine, and piperazine. Even more preferred buffers include sulfonic acid buffers such as TES, HEPES, ACES, PIPES, [(2-hydroxy-1,1-bis-(hydroxymethyl)ethyl)amino]-1-propanesulfonic acid (TAPS), 4-(2-hydroxyethyl)piperazine-1-propanesulfonic acid (EEPS), MOPS, and N,N-bis-(2-hydroxyethyl)-2-aminoethanesulfonic acid (BES). Another group of preferred buffers includes glycine, glycylglycine, glycylglycylglycine, N,N-bis-(2-hydroxyethyl)glycine, and N-[2-hydroxy-1,1-bis(hydroxymethyl)ethyl]glycine (tricine). Amino acid buffers such as glycine, alanine, valine, leucine, isoleucine, serine, threonine, phenylalanine, tyrosine, tryptophan, lysine, arginine, histidine, aspartic acid, glutamic acid, asparagine, glutamine, cysteine, methionine, proline, 4-hydroxyproline, N,N,N-trimethyllysine, 3-methylhistidine, 5-hydroxylysine, o-phosphoserine, γ-carboxyglutamic acid, [ε]-N-acetyllysine, [ω]-N-methylarginine, citrulline, ornithine, and their derivatives are also preferred. KH2PO4 buffer is particularly preferred.

[0092] Preservatives for liquid and / or solid dosage forms may be used as needed. These include sorbic acid, potassium sorbate, sodium sorbate, calcium sorbate, methylparaben, ethylparaben, methylethylparaben, propylparaben, benzoic acid, sodium benzoate, potassium benzoate, calcium benzoate, heptylparahydroxybenzoic acid, sodium methylparahydroxybenzoate, sodium ethylparahydroxybenzoate, sodium propylparahydroxybenzoate, benzyl alcohol, benzalkonium chloride, phenylethyl alcohol, cresol, cetylpyridinium chloride, chlorobutanol, thiomersal (2-(ethylmercurithiodesodium)benzoate), sulfur dioxide, sodium sulfite, sodium bisulfite, sodium metabisulfite, potassium metabisulfite, potassium sulfite, calcium sulfite, and sulfur dioxide. These may be selected from, but are not limited to, calcium carbonate, potassium bisulfite, biphenyl, orthophenylphenol, orthophenyl sodium phenol, thiabendazole, nisin, natamycin, formic acid, sodium formate, calcium formate, hexamine, formaldehyde, dimethyl dicarbonate, potassium nitrite, sodium nitrite, sodium nitrate, potassium nitrate, acetic acid, potassium acetate, sodium acetate, sodium diacetate, calcium acetate, ammonium acetate, dehydroacetic acid, sodium dehydroacetate, lactic acid, propionic acid, sodium propionate, calcium propionate, potassium propionate, boric acid, sodium tetraborate, carbon dioxide, malic acid, fumaric acid, lysozyme, copper(II) sulfate, chlorine, chlorine dioxide, and other suitable substances or compositions known to those skilled in the art.

[0093] In liquid and topical dosage forms, it is particularly preferable to add a sufficient amount of antioxidant. Suitable examples of antioxidants include sodium metabisulfite, α-tocopherol, ascorbic acid, maleic acid, sodium ascorbate, ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, fumaric acid, or propyl gallic acid. Preferably, sodium metabisulfite, α-tocopherol, and ascorbyl palmitate are used.

[0094] Tablets or pills are usually coated; that is, the coating constitutes the outer layer. This can be a film coating, a sugar coating with sugars, or a compression coating. Pharmaceutically acceptable varnishes or waxes, HPMC (hydroxypropyl methylcellulose), MC (methylcellulose), or HPC (hydroxypropylcellulose) can be used. Such coatings help to mask the taste or make them easier to swallow or identify. Coatings often contain plasticizers or pigments. Capsules usually have a gelatinous outer layer that encloses the active ingredient. The specific composition and thickness of this gelatinous layer determine the absorption rate after the capsule is taken. Of particular interest are sustained-release formulations, which are known in the art.

[0095] Suitable sweeteners can be selected from the group consisting of mannitol, glycerol, acesulfame potassium, aspartame, cyclamate, isomalt, isomaltitol, saccharin and its sodium, potassium, and calcium salts, sucralose, alitame, thaumatin, glycyrrhizin, neohesperidin dihydrochalcone, steviol glycosides, neotame, aspartame-acesulfame salts, maltitol, maltitol syrup, lactitol, xylitol, and erythritol.

[0096] Suitable thickeners can be selected from the group consisting of polyvinylpyrrolidone, methylcellulose, hydroxypropyl methylcellulose, hydroxypropylcellulose, dextrin, polydextrose, modified starch, alkali-modified starch, bleached starch, oxidized starch, enzyme-treated starch, monostarch phosphate, distarch phosphate esterified with sodium trimetaphosphate or phosphorus oxychloride, distarch phosphate, acetylated distarch phosphate, starch acetic acid esterified with acetic anhydride, starch acetic acid esterified with vinyl acetate, acetylated distarch adipate, acetylated distarch glycerol, distarch glycerin, hydroxypropyl starch, hydroxypropyl distarch glycerin, hydroxypropyl distarch phosphate, hydroxypropyl distarch glycerol, sodium octenyl succinate starch, acetylated oxidized starch, and hydroxyethylcellulose.

[0097] Examples of pH adjusters suitable for liquid formulations include buffering agents such as sodium hydroxide, hydrochloric acid, sodium dihydrogen phosphate, or disodium hydrogen phosphate.

[0098] Appropriate acidity adjusters include acetic acid, potassium acetate, sodium acetate, sodium diacetate, calcium acetate, carbon dioxide, malic acid, fumaric acid, sodium lactate, potassium lactate, calcium lactate, ammonium lactate, magnesium lactate, citric acid, monosodium citrate, disodium citrate, trisodium citrate, monosodium citrate, dipotassium citrate, monocalcium citrate, tricalcium citrate, tartaric acid, monosodium tartrate, dipotassium tartrate, sodium tartrate, potassium tartrate, orthophosphate, lecithin citrate, magnesium citrate, ammonium malate, sodium malate, sodium hydrogen malate, calcium malate, calcium hydrogen malate The following can be selected from the group consisting of: adipic acid, sodium adipate, potassium adipate, ammonium adipate, succinic acid, sodium fumarate, potassium fumarate, calcium fumarate, ammonium fumarate, 1,4-heptonolactone, triammonium citrate, ferric ammonium citrate, calcium glycerophosphate, isopropyl citrate, potassium carbonate, potassium bicarbonate, ammonium carbonate, ammonium bicarbonate, magnesium carbonate, magnesium bicarbonate, ferrous carbonate, ammonium sulfate, potassium aluminum sulfate, ammonium aluminum sulfate, sodium hydroxide, potassium hydroxide, ammonium hydroxide, magnesium hydroxide, and gluconic acid.

[0099] Oxidizing agents are inorganic chemical substances that produce or become acids. Suitable examples include ammonium chloride and calcium chloride.

[0100] Suitable solvents can be selected from, but are not limited to, water, carbonated water, water for injection, water containing an isotonic agent, physiological saline, isotonic physiological saline, alcohols, particularly ethyl alcohol and n-butyl alcohol, and mixtures thereof.

[0101] Suitable isotonic agents include, for example, pharmaceutically acceptable salts, particularly sodium chloride and potassium chloride; sugars, such as glucose or lactose; sugar alcohols, such as mannitol and sorbitol; citrates; phosphates; borates; and mixtures thereof.

[0102] Suitable disintegrants can be selected from the group consisting of starch, cold water-soluble starches such as carboxymethyl starch, cellulose derivatives such as methylcellulose and sodium carboxymethylcellulose, microcrystalline cellulose and cross-linked microcrystalline cellulose such as croscarmellose sodium, natural and synthetic gums such as guar gum, agar, karaya (Indian tragacanth), locust bean gum, tragacanth, clay such as bentonite, alginates such as xanthan gum, alginic acid and sodium alginate, and foaming compositions. Water expansion is promoted by, for example, starch, cellulose derivatives, alginates, polysaccharides, dextran, and cross-linked polyvinylpyrrolidone. The amount of disintegrant in the composition can vary in the range of 1% to 40% by weight, preferably 3% to 20% by weight, and most preferably 5% to 10% by weight.

[0103] A fluidizer is a substance that prevents the individual supplements from sticking together and improves the fluidity of the granules, resulting in a smooth and uniform flow. Suitable fluidizers include silicon dioxide, magnesium stearate, sodium stearate, starch, and talc. The amount of fluidizer in the composition can be varied in the range of 0.01 to 10% by weight, but is preferably 0.1 to 7% by weight, more preferably 0.2 to 5% by weight, and most preferably 0.5 to 2% by weight.

[0104] The term "lubricant" refers to a substance added to a dosage form, such as tablets or granules, to facilitate removal from a press mold or exit nozzle. Lubricants reduce friction or wear. Because lubricants need to be present on the surface of the granules and between the granules and the parts of the press mold, they are usually added immediately before pressing. The amount of lubricant in the composition can vary in the range of 0.05 to 15% by weight, but is preferably in the range of 0.2 to 5% by weight, more preferably 0.3 to 3% by weight, and most preferably 0.3 to 1.5% by weight. Suitable lubricants include metal stearate salts such as sodium oleate, sodium stearate, calcium stearate, potassium stearate, and magnesium stearate, stearic acid, sodium benzoate, sodium acetate, sodium chloride, boric acid, high melting point waxes, and polyethylene glycol.

[0105] Emulsifiers can be selected from, for example, the following anionic and nonionic emulsifiers: anionic emulsifiers, waxes, cetyl alcohol, cetyl stearyl alcohol, stearic acid, oleic acid, polyoxyethylene polyoxypropylene block polymer, 2 to 60 moles of ethylene oxide adduct to castor oil and / or hydrogenated castor oil, wool wax oil (lanolin), sorbitan esters, polyoxyethylene alkyl esters, polyoxyethylene sorbitan fatty acid esters, polyoxyethensorbitan monolaurate, polyoxyethensorbitan monooleate, polyoxyethensorbitan monopalmitate, polyoxyethensorbitan monostearate, polyoxyethensorbitan tristearate, polyoxyethenstearate, polyvinyl alcohol, metatartaric acid, calcium tartrate, alginic acid, sodium alginate, potassium alginate, ammonium alginate, calcium alginate, propane-1,2-Diol alginic acid, carrageenan, processed Eukema seaweed, locust bean gum, tragacanth gum, acacia gum, karaya gum, gellan gum, ghati gum, glucomannan, pectin, amidated pectin, ammonium phospholipids, brominated vegetable oil, sucrose acetate isobutyrate, glycerol ester of wood ginseng, disodium phosphate, trisodium phosphate, tetrasodium phosphate, dicalcium phosphate, calcium dihydrogen phosphate, trisodium phosphate, pentapotassium phosphate, sodium polyphosphate, sodium calcium polyphosphate, ammonium polyphosphate, β-cyclodextrin, powdered cellulose, methylcellulose, ethylcellulose, hydroxypropylcellulose, hydroxypropyl methylcellulose, ethylmethylcellulose, carboxymethylcellulose, carboxymethylcellulose Sodium ethyl hydroxyethyl cellulose, croscarmellose, enzymatic hydrolyzed carboxymethylcellulose, monoglycerides and diglycerides of fatty acids, glyceryl monostearate, glyceryl distearate, acetate esters of monoglycerides and diglycerides of fatty acids, lactate esters of monoglycerides and diglycerides of fatty acids, citrate esters of monoglycerides and diglycerides of fatty acids, tartaric acid esters of monoglycerides and diglycerides of fatty acids, monoacetyl tartaric acid esters of monoglycerides and diglycerides of fatty acids, mixed esters of acetate and tartaric acid of monoglycerides and diglycerides of fatty acids, succinyl monoglycerides, sucrose esters of fatty acids, sucrose esters, polyglycerol esters of fatty acids, polyglycerolpropane-1 polyricinoleate,2-diol fatty acid esters, propylene glycol fatty acid esters, emulsified fatty acid esters of glycerol and propane-1, heat-oxidized soybean oil reacted with mono and diglyceride fatty acids, sodium dioctyl sulfosuccinate, sodium stearoyl-2-lactate, calcium stearoyl-2-lactate, stearyl tartrate, stearyl citrate, sodium stearoyl fumarate, calcium stearoyl fumarate, stearyl tartrate, stearyl citrate, sodium stearoyl fumarate, calcium stearoyl fumarate Um, sodium lauryl sulfate, ethoxylated mono and diglycerides, methyl glucoside-coconut oil ester, sorbitan monostearate, sorbitan tristearate, sorbitan monolaurate, sorbitan monooleate, sorbitan monopalmitate, sorbitan trioleate, sodium calcium polyphosphate, calcium polyphosphate, ammonium polyphosphate, cholic acid, choline salt, distem glycerol, sodium octenyl succinate starch, acetylated oxidized starch. Preferably, phospholipids such as glycerin monooleate, stearic acid, and lecithin.

[0106] Suitable surfactant solubilizers include, for example, diethylene glycol monoethyl ester, polyethylene propylene glycol copolymer, cyclodextrins such as α-cyclodextrin and β-cyclodextrin, glyceryl monostearates such as Soltol HS15 (BASF's macrogol-15-hydroxystearate, PEG660-15 hydroxystearate), sorbitan esters, polyoxyethylene glycol, polyoxyethylene sorbitan monooleate, polyoxyethylene oxystearate triglyceride, polyvinyl alcohol, sodium dodecyl sulfate, and (anionic) glyceryl monooleate.

[0107] Stabilizers are substances that can be added to prevent undesirable changes. While stabilizers are not true emulsifiers, they can contribute to the stability of emulsions. Suitable examples of stabilizers include oxystearin, xanthan gum, agar, oat gum, guar gum, tara gum, polyoxyethylene stearate, aspartame acesulfame salt, amylase, protease, papain, bromelain, ficin, invertase, polydextrose, polyvinylpyrrolidone, polyvinylpolypyrrolidone, triethyl citrate, maltitol, and maltitol syrup.

[0108] Diluents or bulking agents are inert substances added to pharmaceuticals to handle trace amounts of active ingredients. Examples of suitable diluents include water, mannitol, pregelatinized starch, starch, microcrystalline cellulose, powdered cellulose, silicified microcrystalline cellulose, dicalcium phosphate dihydrate, calcium phosphate, calcium carbonate, hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl methylcellulose, polyethylene glycol, xanthan gum, gum arabic, or combinations thereof.

[0109] Anticaking agents (anti-adhesion agents) are added to supplements or supplement compositions to prevent clumping, facilitate packaging, transport, release from at least one chamber of a dispensing cap, and ingestion. Suitable examples include tricalcium phosphate, powdered cellulose, magnesium stearate, sodium bicarbonate, sodium ferrocyanide, potassium ferrocyanide, calcium ferrocyanide, bone phosphate, sodium silicate, silicon dioxide, calcium silicate, magnesium trisilicate, talc powder, sodium aluminosilicate, potassium aluminum silicate, calcium aluminosilicate, bentonite, aluminum silicate, stearic acid, and polydimethylsiloxane.

[0110] Adsorbents are substances that absorb oil from water. Suitable examples include natural adsorbents such as peat moss, sawdust, and feathers, other carbon-containing natural materials, and synthetic adsorbents such as polyethylene and nylon. Adsorbents are used to protect tablets / capsules from moisture by performing limited liquid adsorption (absorption of liquids or gases by adsorption) in a dry state.

[0111] Penetration enhancers are often used in topical dosage forms. Suitable penetration enhancers include all pharmaceutically acceptable ones known in the art, such as azeos such as laurocapram and 1-dodecyl azacycloheptan-2-one; sulfoxides such as dimethyl sulfoxide, DMAC, and DMF; pyrrolidones such as 2-pyrrolidone and N-methyl-2-pyrrolidone; alcohols such as ethanol, 1,2-propanediol, and decanol; glycols such as propylene glycol, diethylene glycol, and tetraethylene glycol; oleic acid, lauric acid, and lauridyl sulfate. Examples of suitable surfactants include, but are not limited to, sodium sulfate, myristic acid, isopropylmyristic acid, fatty acids such as capric acid, nonionic surfactants such as polyoxyethylene-2-oleyl ether and polyoxyethylene-2-stearyl ether, terpenes, terpenoids, oxazolidinones, urea, ceramide analogs, azone analogs, menthol derivatives, etherified derivatives, esterified derivatives, transcarbam, carbamate salts, TXA derivatives, DDAIP (dodecyl 2-(dimethylamino)propanoate), DDAK, natural essential oils (all of which are described in Chen et al. (2014) Asian J. Pharm. Sc. 9, 51-64), citrate esters (e.g., triethyl citrate), hydrophobic polypeptides, α-bisabolol, dimethyl isosorbide (Arlasove DMI), and ethoxydiglycol. Preferably, it is 1,2-propanediol.

[0112] In some herbal medicine preparations, it is desirable for the liquid oral dosage form to generate foam upon dissolution. This effect can be enhanced by adding a foaming agent that lowers the surface tension of the liquid and promotes foam formation. It can also be enhanced by adding a foaming agent that inhibits foam aggregation and improves colloidal stability. Alternatively, foam can be stabilized by a foaming agent. Suitable examples include mineral oil, quillaja extract, triethyl citrate, sodium lauryl ether sulfate, sodium lauryl sulfate, and ammonium lauryl sulfate.

[0113] Furthermore, some liquid oral dosage forms may foam slightly during preparation. While this does not affect the intended use, it may impact patient adherence in the case of pharmaceuticals and commercial success in the case of dietary supplements. Therefore, it may be desirable to add a pharmaceutically acceptable antifoaming agent. Examples include polydimethylsiloxane and silicone oil in dietary supplements, and simethicone in pharmaceuticals.

[0114] An opaque agent is a substance that makes a liquid formulation opaque as needed. The opaque agent must have a refractive index significantly different from that of the solvent (most often water). At the same time, it must be inert to the other components of the composition. Suitable examples include titanium dioxide, talc, calcium carbonate, behenic acid, cetyl alcohol, or mixtures thereof.

[0115] Suitable fatliquoring agents include, for example, decyl oleate, hydrated castor oil, light mineral oil, mineral oil, polyethylene glycol, and sodium lauryl sulfate.

[0116] Examples of viscosity improvers include cetyl alcohol, cetyl ester wax, hydrated castor oil, microcrystalline wax, nonionic emulsifying wax, beeswax, paraffin, and stearyl alcohol.

[0117] Suitable hydrotropes are alcohols such as ethanol and isopropyl alcohol, or polyols such as glycerin.

[0118] Suitable aromatic and fragrance substances include, in particular, essential oils. Essential oils generally refer to volatile extracts obtained from plants or parts of plants that have their own characteristic fragrances. Essential oils can be extracted from plants or parts of plants by steam distillation.

[0119] Appropriate examples include essential oils and equivalent aromatic substances such as achillea, sage, cedar, clove, chamomile, anise, aniseed, star anise, thyme, tea tree, peppermint, mint oil, menthol, cineole, borneol, gingerol, eucalyptus, mango, fig, lavender oil, chamomile flower, pine needle, cypress, orange, rose, rosewood, plum, currant, cherry, birch leaf, cinnamon, lime, grapefruit, and Angeline, Juniper, Valerian, Lemon, Lemon Balm, Lemongrass, Palmarosa, Cranberry, Pomegranate, Rosemary, Ginger, Pineapple, Guava, Echinacea, Hedera Helix Leaf Extract, Blueberry, Persimmon, Melon, Alpha-Pinene or Beta-Pinene, Alpha-Pinene Oxide, Alpha-Camphorenic Aldehyde, Alpha-Citronellol, Alpha-Isoamyl Cinnamic, Alpha-Cinnamic Terpinene, Alpha-Terpineol, Alpha-Terpinene, Aldehyde C16 α-Phellandrene, Amyl cinnamic aldehyde, Amyl salicylic acid, Anisaldehyde, Basil, Anethole, Bay, Benzyl acetate, Benzyl alcohol, Bergamot, Bitter orange peel, Black pepper, Calamus, Camphor, Cananga oil, Cardamom, Carnation, Carvacrol, Carveol, Cassia, Castor oil, Cedarwood, Cinnamaldehyde, Cinnamic alcohol, Cis-pinan, Citral, Citronella, Citronellal, Citronellol dextrose, Citronellol, Citronellyl acetate; Citronellyl nitrile, Satsuma mandarin, Clary sage, Clove buds, Coriander, Corn Cottonseed, d-dihydrocarbone, decylaldehyde, diethyl phthalate, dihydroanethole, dihydrocarbeol, dihydrolinalool, dihydromyrcene, dihydromyrcenol, dihydromyrcenyl acetate; dihydroterpineol, dimethyl salicylate, dimethyloctanal, dimethyloctanol, dimethyloctanyl acetate, diphenyl oxide, dipropylene glycol, d-limonene, d-pulegone, estragole, ethyl vanillin, eucalyptol; Eucalyptus citriodora, Eucalyptus globulus, eugenol, evening primrose, fencol, fennel, phenylol, fish, florazone,Galaxolide, Geraniol, Geranium, Geranyl Acetate, Geranyl Nitrile, Guaiacol, Guaiac Wood, Gourdung Balsam, Heliotropin, Herbanate, Hiba, Hydroxycitronellal, i-Carvone, i-Methyl Acetate, Ionone, Isobutylquinoline, Isobornyl Acetate, Isobornyl Methyl Ether, Isoeugenol, Isolongifolene, Jasmine, Lavender, Limonene, Linalool Oxide, Linalool, Linalool, Linalyl Acetate, Flaxseed, Litsea Cubeba, i-Methyl Acetate, Longifolene, Man Darrin, Mentha, Menthane Hydroperoxide, Menthol Crystals, Menthol Laevo, Menthone Laevo, Methylanthranilic Acid, Methyl Cedyl Ketone, Methyl Chavicol, Methyl Hexyl Ether, Methyl Ionone, Methyl Salicylate, Minerals, Mint, Musk Ambrette, Musk Ketone, Muscoxylol, Myrcene, Nerol, Neryl Acetate, Nonyl Aldehyde, Nutmeg, Orris Root, Para-Cymene, Para-Hydroxyphenyl Butanone Crystals, Patchouli, p-Cymene, Pennyroyal Oil, Pepper, Perillaldehyde, Petitgrain, Phenyl E Chil alcohol, phenylethyl propionate, phenylethyl-2-methyl butyrate, pimento berry, pimento leaf, pinan hydroperoxide, pinanol, pine ester, pine, pinene, piperonal, piperonyl acetate, piperonyl alcohol, prinol, prinyl acetate, pseudo-ionone, rodinol, rodinyl acetate, rosalin, lily, sandalwood, sandenol, sassafras, sesame, soybean, spearmint, spices, spike lavender, spirantol, starflower, tea seed, terpenoids, terpineol, Examples include terpinolene, terpinyl acetate, tert-butylcyclohexyl acetate, tetrahydrolinalool, tetrahydrolinalyl acetate, tetrahydromyrcenolate, tulasi, thymol, tomato, trans-2-hexenol, trans-anethole, turmeric, turmeric oil, vanillin, vetiver, vitalisal, white cedar, white grapefruit, wintergreen, or mixtures thereof, as well as menthol, a mixture of peppermint and star anise oil, or a mixture of menthol and cherry flavor.

[0120] These aromatic or flavoring substances can be included in the composition in an amount ranging from 0.0001 to 10% by weight (especially within the composition) relative to the whole composition, preferably 0.001 to 6% by weight, more preferably 0.001 to 4% by weight, and most preferably 0.01 to 1% by weight. Depending on the application or individual case, it may be advantageous to use different amounts.

[0121] According to the present invention, all of the aforementioned excipients and classes of excipients can be used without limitation, either alone or in any conceivable combination, as long as they do not hinder the use of the present invention, do not cause toxic effects, or violate the laws of their respective countries.

[0122] In another aspect of the present invention, this application relates to any of the 5-amino-2,3-dihydro-1,4-phthalazinedione or any pharmaceutically acceptable salt thereof, or a pharmaceutical composition, for use in orally administered formulations in the prevention or treatment of thrombotic diseases.

[0123] 5-amino-2,3-dihydro-1,4-phthalazinedione or any pharmaceutically acceptable salt thereof, or pharmaceutical formulations suitable for oral administration of the pharmaceutical compositions according to this disclosure, may be administered as individual units such as tablets, soft gelatin capsules, hard gelatin capsules, sugar-coated tablets or pills, powders or granules, juices, syrups, drips, teas, solutions or suspensions in aqueous or non-aqueous liquids, edible foams or mousses, or oil-in-water or water-in-oil emulsions.

[0124] In oral dosage forms such as tablets and capsules, the active ingredient can be mixed with a non-toxic and pharmaceutically acceptable inert carrier such as ethanol, glycerol, or water. Powders are prepared by grinding the compound into appropriate fine particles and mixing it with a pharmaceutically acceptable carrier such as starch or edible carbohydrates such as mannitol in a similar manner. Flavorings, preservatives, dispersants, colorants, etc., may also be added.

[0125] Tablets are formulated by manufacturing, granulating or dry-compressing a powder mixture, adding lubricants and disintegrants, and compressing the mixture into tablets. Powder mixtures are manufactured by mixing a properly ground compound with the aforementioned diluents or bases, and optionally with binders such as carboxymethylcellulose, alginates, gelatin, and polyvinylpyrrolidone, dissolution inhibitors such as paraffin, absorption enhancers such as quaternary salts, and / or absorbents such as bentonite, kaolin, and dicalcium phosphate. Powder mixtures can be granulated by moistening them with a binder such as syrup, starch paste, acacia mucilage, or a solution of cellulose or polymer material, and compressing them through a sieve. As an alternative to granulation, the powder mixture can also be passed through a tablet press to crush any unevenly shaped lumps and form granules. To prevent the granules from adhering to the tablet mold, lubricants such as stearic acid, stearates, talc, or mineral oil can be added. The lubricated mixture is then compressed to obtain tablets. The compounds relating to this disclosure can also be mixed with a free-flowing, inert excipient and directly compressed to obtain tablets without going through a granulation process or a dry compression process.

[0126] In another aspect of the present invention, 5-amino-2,3-dihydro-1,4-phthalazinedione or any pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to the present invention, is provided in hard gelatin capsules. These are produced by preparing a powder mixture as described above and filling it into a molded gelatin cover. The powder mixture may be supplemented with solids such as highly dispersed silica, talc, magnesium stearate, calcium stearate, and polyethylene glycol. Similarly, disintegrants or solubilizers such as agar, calcium carbonate, and sodium carbonate may be added to improve the availability of the drug after capsule ingestion. Furthermore, suitable binders and / or colorants may be added to the mixture as needed.

[0127] In another aspect of the present invention, either 5-amino-2,3-dihydro-1,4-phthalazinedione or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to the present invention, is encapsulated in a soft gelatin capsule (SGC). The SGC dissolves as it passes through the gastrointestinal tract. The SGC mainly consists of gelatin with varying amounts of plasticizers such as glycerol or sorbitan added. The release rate depends on the specific formulation of the SGC carrier material. The SGC is also suitable for the sustained release of active drugs. The SGC is particularly useful for administering active drugs that are poorly soluble in water.

[0128] In another aspect of the present invention, either 5-amino-2,3-dihydro-1,4-phthalazinedione or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to the present invention, is incorporated into a chewable tablet or hard caramel. In this case, the substance is incorporated into the matrix of the tablet or caramel.

[0129] In another aspect of the present invention, this application relates to a pharmaceutical composition for use in the prevention or treatment of thrombotic diseases in an inhalation formulation, either 5-amino-2,3-dihydro-1,4-phthalazinedione or any pharmaceutically acceptable salt thereof, or as disclosed herein.

[0130] For effective inhalation prophylaxis or treatment of thrombotic diseases affecting the respiratory system at some stage of the disease course, it is advantageous that 5-amino-2,3-dihydro-1,4-phthalazinedione or any pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to this disclosure, reach the patient's alveoli. Therefore, the particle size must be small enough to reach the lowest part of the airways in the lung tissue. The optimal inhalation device for administering pharmaceutically active substances by inhalation is the so-called mesh nebulizer. Within the scope of this application, substantially all mesh nebulizers known in the art can be used, from relatively simple disposable mesh nebulizers for coughs, colds, or bronchodilation, to advanced high-end mesh nebulizers for the clinical or home treatment of serious diseases or symptoms of the lower respiratory tract.

[0131] Suitable commercially available mesh nebulizers, jet nebulizers, ultrasonic nebulizers, dry powder inhalers, and (pressurized) metered-dose inhalers include PARIeFlow rapid, PARILC STAR, PARIVelox, PARIVelox Junior (PARIGmbH, Starnberg, Germany), Philips Respironics I-neb, Philips InnoSpire Go (Eindhoven, Netherlands), VENTA-NEB -ir, OPTI-NEB, M-neb dose + mesh nebulizer inhaler MN-300 / 8, M-NebFlow+, M-neb mesh nebulizer MN-300 / X (NEBU-TEC, Eisenfeld, Germany), Hcmed Deepro HCM-86C and HCM860 (HCmedInnovations Co.,Ltd, Taipei, Taiwan), OMRON MicroAir U22 and U100 (OMRON, Kyoto, Japan), Aerogen Solo, Aerogen Ultra and Aerogen PRO (Aerogen, Galway, Ireland), KTMEDNePlusNE-SM1 (KTMED Inc., Seoul, South Korea), Vectura Bayer Breelib tm (Bayer AG, Leverkusen, Germany), VecturaFox, MPV Truma, MicroDrop Smarty (MPV MEDICAL GmbH, Kirchheim, Germany), MOBIMESH (APEX Medical, New Taipei City, Taiwan), B.Well WN-114, TH-134, TH-135 (B.Well Swiss AG, Widnou, Switzerland), Babybelle Asia BBU01 (Babybelle Asia Ltd., Hong Kong), CA-MIKiwi Hoka (CA-MIsri, Langhirano, Italy), Diagnosis PRO MESH (Diagnosis SA, Białystok, Poland), DIGIO 2 (DigiO 2 International Co., Ltd.), New Taipei City, Taiwan), feellife AIR PLUS, AEROCENTRE+, AIR 360+, AIR GARDEN, AIRICU, AIR MASK, AIRGEL BOY, AIR ANGEL, AIRGEL GIRL, AIR PRO 4 (FeellifeHealthInc., Shenzhen, China), Hannox MA-02 (HannoxInternational Corp., Taipei, Taiwan), Health and LifeHL100 and HL100A (HEALTH & LIFE Co., Ltd., New Taipei City, Taiwan), HonsunNB-810B (Honsun Co., Ltd., Nantong City, China), K-jump KN-9100 (K-jumpHealth Co., Ltd., New Taipei City, Taiwan), microlifeNEB-800 (Microlife AG, Widnau, Switzerland), OK Biotech Docspray (OK Biotech Co., Ltd., Hsinchu, China), Prodigy Mini-Mist (Prodigy Diabetes Care, LLC, Charlotte, USA), QuatekNM211, NE203, NE320 and NE403 (Big EagleHolding Ltd., Taipei, Taiwan), SimzoNBM-1 and NBM-2 (Simzo Electronic Technology Ltd., Dongguan, China), Mexus BBU01 and BBU02 (Tai YuInternational Manufactory Ltd., Dongguan, China), TaiDoc TD-7001 (TaiDoc Technology Co., New Taipei City, Taiwan), Vibralung and HIFLO Miniheart CirculaireII (Westmed Medical Group, Purchase, USA), KEJIAN (Xuzhou Kejian Hi-Tech Co., Ltd., Xuzhou, China), YM-252, Examples include, but are not limited to, the P&S-T45 and P&S-360 (TEKCELEO, Valbonne, France), Maxwell YS-31 (Maxwell India, Jaipur, India), and Kernmed JLN-MB001 (Kernmed, Damersheim, Germany).

[0132] Preferably, it is a mesh nebulizer or a vibrating mesh nebulizer equipped with piezoelectric activation of the spraying process.

[0133] Accordingly, in another aspect of the present invention, this application relates to the use of 5-amino-2,3-dihydro-1,4-phthalazinedione or any pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to the present disclosure, in a formulation administered by inhalation using a vibrating mesh nebulizer, for the prevention or treatment of thrombotic diseases.

[0134] Mesh nebulizers can be classified into two groups based on their interaction with the patient: continuous mode devices and trigger-activated devices. In continuous mode mesh nebulizers, the sprayed aerosol is continuously released into the mouthpiece, and the patient needs to inhale the supplied aerosol. In trigger-activated devices, a certain amount of aerosol is released only during active, deep inspiration. This results in significantly more active substance-containing aerosol being inhaled and reaching the lower airway than in continuous mode devices. In trigger-activated devices, because the aerosol release is not synchronized with the respiratory cycle, a large amount of active substance-containing aerosol is released into the surroundings or lost as it passes through the upper airway.

[0135] Therefore, trigger-operated mesh nebulizers, particularly vibrating mesh nebulizers, are preferred.

[0136] Particularly preferred is a trigger-operated mesh nebulizer with piezoelectric action for the spraying process.

[0137] Recommended mesh nebulizer models include PARIeFlow rapid, Philips Respironics I-neb, Philips InnoSpire Go, M-neb dose + mesh nebulizer inhaler MN-300 / 8, Hcmed Deepro HCM-86C and HCM860, OMRON MicroAir U100, Aerogen Solo, KTMEDNePlusNE-SM1, VecturaFox, and Vectura Bayer Breelib. TM That is the case.

[0138] The most preferred vibrating mesh nebulizers are PARIEFlow rapid, PARIVelox, Philips Respironics I-neb, M-neb dose + mesh nebulizer inhalation MN-300 / 8, Aerogen Solo, VecturaFox, and Vectura Bayer Breelib. TM These are high-end models.

[0139] The average droplet size is typically characterized by its MMAD (Central Mass Aerodynamic Diameter). The size of individual droplets is called the MAD (Mass Aerodynamic Diameter). This value indicates whether 50% of the diameter of the sprayed particles (droplets) is smaller or larger than this value. Particles with an MMAD greater than 10 μm usually do not reach the lower respiratory tract and often become lodged in the throat. Particles with an MMAD between 5 μm and 10 μm usually reach the bronchi but not the alveoli. Particles with an MMAD between 100 nm and 1 μm do not deposit in the alveoli and are quickly expelled in the exhaled breath. Therefore, the optimal range for MMAD is 1 μm to 5 μm. Recent publications recommend a narrower range of 3.0 μm to 4.0 μm (Amirav et al. (2010) J Allergy ClinImmunol 25:1206-1211; Hydler et al. (2012) Respiratory Medicine 66:356-360).

[0140] Another generally accepted quality parameter is the proportion of particles with a diameter of 1 μm to 5 μm in the generated aerosol (FPM: particulate matter mass). FPM is a measure of particle distribution and is calculated by subtracting the proportion of particles with a diameter of less than 1 μm in the generated aerosol from the total proportion of particles with a diameter of less than 5 μm in the generated aerosol (FPF: particulate matter fraction).

[0141] In another aspect of the present invention, the present invention relates to a method for producing an aerosol according to the disclosure of the present invention for the prevention or treatment of thrombotic diseases, comprising the following steps.

[0142] Fill the spray chamber of a mesh nebulizer with 0.1 ml to 5 ml of an aqueous solution containing either 5-amino-2,3-dihydro-1,4-phthalazinedione or any pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to this disclosure, and optionally at least one pharmaceutically acceptable excipient.

[0143] The mesh of the mesh nebulizer is vibrated at a frequency of 80kHz to 200kHz.

[0144] The generated aerosol is discharged from the side of the mesh nebulizer opposite the spray chamber.

[0145] The vibration frequency of a vibrating mesh nebulizer is typically in the range of 80kHz to 200kHz, but 90kHz to 180kHz is preferred, 100kHz to 160kHz is more preferred, and 105kHz to 130kHz is most preferred (see Chen, The Aerosol Society: DDL2019, Gardenshire et al (2017) A Guide to Aerosol Delivery Devices for Respiratory Therapists, 4th edition).

[0146] Therefore, the method described above is also disclosed in the vibration frequency range.

[0147] Accordingly, the method according to the present disclosure is characterized in that at least 80% by weight, preferably at least 85% by weight, and most preferably at least 90% by weight, of 5-amino-2,3-dihydro-1,4-phthalazinedione or one of its pharmaceutically acceptable salts, or of the pharmaceutical composition according to the present disclosure, contained in the aqueous solution, is sprayed into the resulting aerosol.

[0148] The method of the present invention is particularly effective in spraying a high concentration of pharmacologically active substance from a provided aqueous solution in a short time. This is an important feature for patient compliance. A significant percentage of patients find the inhalation process unpleasant, tiring, and physically burdensome. On the other hand, effective and accurate inhalation administration requires the active cooperation of the patient. Therefore, it is desirable to administer a therapeutically sufficient amount in the shortest possible time. Surprisingly, it has been shown that 95% of the substance in the aqueous solution can be sprayed in 3 minutes. This is an ideal time for high patient compliance.

[0149] Therefore, the method according to this disclosure is characterized in that at least 80%, preferably at least 85%, and most preferably at least 90% of the generated aerosol is produced within 3 minutes of starting spraying with a mesh nebulizer.

[0150] Pharmacologically active substances are typically supplied in a single dosing container for each nebulization method, but nebulizers and / or mouthpieces can be used for a certain period and need to be replaced at regular intervals. It is recommended to clean the nebulizer and mouthpiece after each nebulization. However, patient compliance cannot be taken for granted. Even after thorough cleaning, aerosol deposits are always present in the nebulization chamber, outlet, and / or mouthpiece. Since aerosols are produced from aqueous solutions, these deposits carry the risk of creating a bioburden of bacteria that can contaminate inhaled aerosols. The deposits can also clog the holes in the mesh membrane of mesh nebulizers. Generally, nebulizers and / or mouthpieces need to be replaced every 1-2 weeks. Therefore, it is convenient to supply the medication and nebulizer as a combined product.

[0151] Accordingly, in another aspect of the present invention, the present invention also relates to a kit comprising a mesh nebulizer and a pharmaceutically acceptable container comprising an aqueous solution containing an effective amount of 5-amino-2,3-dihydro-1,4-phthalazinedione or any pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to the present disclosure, for the prevention or treatment of thrombotic diseases, and optionally at least one pharmaceutically acceptable excipient.

[0152] In the alternative kit, either 5-amino-2,3-dihydro-1,4-phthalazinedione or any pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to this disclosure, is provided not in the form of an aqueous solution, but in two separate containers: one for the solid form of the activator and the other for the aqueous solution. The final aqueous solution is freshly prepared by dissolving the activator in the final aqueous solution. The final aqueous solution is then filled into the spray chamber of a mesh nebulizer. These two containers may be completely separated containers, such as two vials or a dual-chamber vial. To dissolve the activator, for example, a hole may be made in the membrane between the two chambers to allow the contents of both chambers to be mixed.

[0153] Accordingly, the present invention also discloses a kit comprising a mesh nebulizer, a first pharmaceutically acceptable container containing water for injection or physiological saline, and a second pharmaceutically acceptable container containing a solid of either 5-amino-2,3-dihydro-1,4-phthalazinedione or any pharmaceutically acceptable salt thereof, or an effective dose of a pharmaceutical composition according to the present disclosure, for the prevention or treatment of thrombotic disorders. In this case, the first pharmaceutically acceptable container and / or the second pharmaceutically acceptable container optionally contain at least one pharmaceutically acceptable excipient.

[0154] The aerosol produced by the method according to the present invention is administered using a mouthpiece or self-administered. If necessary, such a mouthpiece may be included in addition to the aforementioned kit.

[0155] A syringe equipped with a needle is commonly used to transfer the prepared or final aqueous solution into the spray chamber of a mesh nebulizer. First, the aqueous solution is drawn into the syringe and then injected into the spray chamber. Such syringes and / or needles can be included in the aforementioned kit as needed. Common syringes made of polyethylene, polypropylene, or cyclic olefin copolymers can be used, but are not limited to those made of polyethylene, polypropylene, or cyclic olefin copolymers, and common gauges for stainless steel needles are 14-27.

[0156] In yet another aspect of the present invention, any of 5-amino-2,3-dihydro-1,4-phthalazinedione or any pharmaceutically acceptable salt thereof, or a pharmaceutical composition, as disclosed, for use in the prevention or treatment of thrombotic diseases, wherein the substance, composition, or combination is applied in the form of liposomes, micelles, multilayer vesicles, or cyclodextrin complexes.

[0157] In yet another aspect of the present invention, the present invention discloses 5-amino-2,3-dihydro-1,4-phthalazinedione or any pharmaceutically acceptable salt thereof, or a composition according to the present invention, for use in the prevention or treatment of thrombotic disorders that have been refractory to prior treatment with at least one other pharmaceutically active agent.

[0158] In yet another aspect of the present invention, the present invention discloses 5-amino-2,3-dihydro-1,4-phthalazinedione or any pharmaceutically acceptable salt thereof, or a composition according to the present invention, for use in the prevention or treatment of thrombotic diseases, wherein the substance or the pharmaceutical composition is formulated as a suppository.

[0159] To prepare a formulation using 5-amino-2,3-dihydro-1,4-phthalazinedione as a suppository, first melt a mixture of low-melting-point wax and a fatty acid glyceride such as cocoa butter, and then uniformly disperse 5-amino-2,3-dihydro-1,4-phthalazinedione by stirring or other mixing methods. Transfer the molten, homogeneous mixture to a suitable mold and cool until solidified.

[0160] In yet another aspect of the present invention, the present invention relates to 5-amino-2,3-dihydro-1,4-phthalazinedione or any pharmaceutically acceptable salt thereof, or a composition according to the present invention, for use in liquid dosage form for the prevention or treatment of thrombotic diseases.

[0161] This application also discloses parenteral administration of either 5-amino-2,3-dihydro-1,4-phthalazinedione or any pharmaceutically acceptable salt thereof, or a composition according to the present invention, for use in the form of intravenous, intra-arterial, or intraperitoneal injection for the prevention or treatment of thrombotic diseases.

[0162] These liquid dosage forms include solutions, suspensions, and emulsions. Examples include water or water / propylene glycol solutions for parenteral injection, or solutions, suspensions, and emulsions for oral administration with added sweeteners or emulsifiers.

[0163] These liquid dosage forms can be stored in vials, infusion bags, ampoules, cartridges, and pre-filled syringes. Suitable additives include solubilizers, stabilizers, buffers, tonicity modifiers, volume extenders, viscosity enhancers / decreasers, surfactants, chelating agents, and adjuvants.

[0164] A preferred dosage form according to the present invention is a delayed-release formulation, i.e., a formulation in which the release of at least one active agent is delayed. These are also known as sustained-release (SR), extended-release (ER, XR), or controlled-release / continuous-release (CR) formulations. Suitable formulations and carriers are known to those skilled in the art (Kleinsorge (1995) Retardformulierungen in der medikamentosen Therapie. Leipzig, Barth 8th ed.). Most commonly, the active agent is embedded in a matrix of an insoluble substance such as acrylic or chitin. Thus, the active agent must exit through openings in the matrix. In some formulations, holes are laser-drilled on one side, with a porous membrane on the opposite side. Gastric juice attacks this porous membrane and flows in, pushing the active agent through the holes on the opposite side. In other formulations, the active agent dissolves in the matrix and swells on the matrix to form a gel. The active agent is then released through the pores of the gel. Other examples include specially coated tablets with gastric acid resistance, delayed capsules containing delayed pellets of the active drug released after the capsule casing dissolves, multi-unit pellet systems (MUPS), oral osmotic systems, resonates, coacervation, and microencapsulation. Such delayed formulations allow for control over the drug release site and pharmacokinetics. For example, it is often desirable that the active drug does not dissolve before reaching a specific site in the intestinal tract. Because the pH changes during passage through the intestinal tract, the dissolution process can be designed in a pH-dependent manner. In therapeutic applications where it is necessary to promote the absorption of the active drug from the intestinal mucosa and enhance its bioavailability, it may be preferable to use a neutral form of the active drug rather than a salt.

[0165] Accordingly, this application also refers to 5-amino-2,3-dihydro-1,4-phthalazinedione or any pharmaceutically acceptable salt thereof, or a composition according to the present invention, for use in the prevention or treatment of thrombotic diseases, wherein the substance or the pharmaceutical composition is formulated as a sustained-release agent.

[0166] In yet another aspect of the present invention, it is provided that 5-amino-2,3-dihydro-1,4-phthalazinedione or any pharmaceutically acceptable salt thereof, or a composition according to the present invention, be used for the prevention or treatment of thrombotic disorders, wherein the substance, composition, or combination is formulated as a lyophilized product. The lyophilized product can be reconstituted with water for injection, saline solution, or a water / ethanol solution and administered by injection.

[0167] Common applications of intravenous injection include infusion pumps, subcutaneous needles, infusion chambers, peripheral cannulas (peripheral venous catheters), and compression bags.

[0168] Generally, aqueous solutions or physiological saline are preferred. In the case of poorly soluble drugs as described in the present invention, ethanol or an ethanol / water mixture can also be used.

[0169] Further suitable liquid dosage forms include drops, gels, and hydrogels.

[0170] A gel is a colloid in which a solid dispersed phase forms a network with a fluid continuous phase, creating a viscous, semi-rigid sol. Gel properties vary widely, from soft and weak to hard and tough. In a steady state, a gel is defined as a substantially dilute crosslinked system that does not exhibit fluidity. While gels are nearly liquid by weight, they behave like solids due to a three-dimensional crosslinking network within the liquid. This crosslinking within the fluid creates the gel's viscosity and contributes to its adhesiveness. A gel is essentially a dispersion of liquid molecules in a solid medium.

[0171] Hydrogels are networks of hydrophilic polymer chains, sometimes existing as colloidal gels with water as the dispersion medium. Three-dimensional solids are formed when these hydrophilic polymer chains are linked together by crosslinking. This inherent crosslinking ensures that the structural integrity of the hydrogel network does not collapse even with high concentrations of water. Hydrogels are highly absorbent (containing over 90% water) natural or synthetic polymer networks. Furthermore, due to their high water content, hydrogels possess flexibility very similar to that of natural tissues. In the medical field, hydrogels can encapsulate chemical systems and, in response to external factors such as pH changes, release specific pharmacologically active substances into the environment. Release almost always occurs via a gel-sol transition, returning the hydrogel to a liquid state.

[0172] Suitable gel-forming agents can be selected from the group including, but are not limited to, agar, algin, alginic acid, bentonite, carbomer, carrageenan, hectorite, hydroxyethylcellulose, hydroxypropylcellulose, polyvinyl alcohol, polyvinylpyrrolidone, and sodium carbomer.

[0173] In yet another aspect of the present invention, the present invention relates to 5-amino-2,3-dihydro-1,4-phthalazinedione or any pharmaceutically acceptable salt thereof, or a composition according to the present invention, for use in a sublingual tablet formulation for the prevention or treatment of thrombotic diseases.

[0174] Sublingual administration can be an alternative to oral administration because it avoids hepatic metabolism. For some medications, particularly those used to treat acute illnesses, rapid onset of pharmacological effects is often required. Sublingual tablets disintegrate rapidly and usually disintegrate sufficiently even with small amounts of saliva, offering improved dissolution and bioavailability.

[0175] Drugs need to be lipophilic enough to pass through the lipid bilayer, but they should not be so lipophilic that they cannot escape once they enter the lipid bilayer. According to the diffusion model of absorption, the flux across the lipid bilayer is directly proportional to the concentration gradient. Therefore, low solubility in saliva leads to decreased absorption, and vice versa. Generally, drugs formulated for sublingual administration ideally have a molecular weight of less than 500 to promote diffusion. Because the pH range in the oral cavity is narrow (5.0-7.0), the pH of aqueous saliva can be controlled by adding an appropriate buffer to the formulation of ionized drugs.

[0176] Taste masking is necessary to avoid the unpleasant taste and smell of medication. Sweeteners, flavorings, and other taste masking agents are essential ingredients. Sugar-based excipients dissolve rapidly in saliva, generating endothermic heat of dissolution. They are ideal for sublingual tablets when used in combination with other flavorings, as they create a pleasant sensation in the mouth.

[0177] Typical techniques for manufacturing sublingual tablets include direct compression, compression molding, freeze-drying, and hot-melt extrusion (Khan et al. (2017) J Pharmaceut Res16:257-267).

[0178] If swallowing is to be avoided, the active ingredient can be administered locally to the pharynx and throat using sublingual tablets. The majority of the active ingredient is absorbed through the pharyngeal mucosa.

[0179] In yet another embodiment of the present invention, a pharmaceutical composition comprising 5-amino-2,3-dihydro-1,4-phthalazinedione or one of its pharmaceutically acceptable salts for use in the prevention or treatment of thrombotic diseases is provided in the form of topical application, such as a cream, emulsion, lotion, gel, hydrogel, paste, powder, ointment, ointment, application, film, liposome, skin patch, transdermal patch, transdermal spray or suspension.

[0180] In a further aspect of the present invention, a method for preventing or treating a thrombotic disease is disclosed, in which an effective amount of 5-amino-2,3-dihydro-1,4-phthalazinedione or any pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable composition according to the present disclosure, is administered to a patient in need. [Examples]

[0181] Example 1: In a Phase IIa clinical trial, the efficacy of 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt form I 300 mg in combination with standard care (SoC) was evaluated compared to placebo in combination with SoC in hospitalized patients with moderate to severe COVID-19 (EudraCT number: 2021-000344-21, IND153604). This was a randomized, double-blind, placebo-controlled trial enrolling participants at 20 IEC-approved sites in six countries (Bulgaria, France, Hungary, Italy, Romania, and Spain). A list of participating sites is available on clinicaltrials.gov (NCT04932941). This study was partially funded by the COVID-19 Horizon Europe Work Programme (Project number: 101046182). The funders of this study were not involved in the design, data collection, data analysis, data interpretation, or report writing of the study.

[0182] Patients aged 18 or older who tested positive for SARS-CoV-2 and exhibited symptoms suggestive of moderate or severe systemic illness were eligible for registration, while asymptomatic or mild COVID-19 patients, or those with severe COVID-19 on day 1, were excluded. Detailed registration and exclusion criteria can be found at clinicaltrials.gov (NCT04932941).

[0183] Patients were randomly assigned in a 2:1 ratio to receive either 300 mg of 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt form I twice daily or placebo twice daily, using an interactive web response system (IWRS) based on a randomization scheme developed by an open-label independent statistician. Stratification factors included baseline COVID-19 severity and age group (under 65 years vs. 65 years and older).

[0184] Hard gelatin capsules containing 50 mg of 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt form I and placebo capsules were supplied in identical blister packaging, matched in color and size, and affixed with blind labels.

[0185] In this proof-of-concept trial, the sample size was determined using a two-tailed type I chi-squared test with an error α = 10%, and the randomization ratio was set to 2:1. To achieve a statistical power of 83%, 114 patients (76 in group A and 38 in group B) were required. Considering an early termination rate of approximately 5%, the required sample size for randomization was a total of 120 patients (80 in group A and 40 in group B). Because the early termination rate exceeded the estimated 5%, the number of patients eligible for randomization increased during the trial period, reaching 114 evaluable patients on day 14. Sample size was estimated using nQuery8 version 8.6.1.0.

[0186] The standard treatments used in this study were largely balanced between the two groups, with oxygen therapy being the most frequently used treatment in over 99% of patients. Other common treatments included dexamethasone (61.4%), sodium chloride (54.5%), paracetamol (38.6%), methylprednisolone, ceftriaxone, pantoprazole, and ascorbic acid (all 35.6%). The use of systemic antiviral drugs was also balanced between the two groups, with 52 patients (39.4%) receiving antiviral medication, the most frequently administered being remdesivir (28.8%).

[0187] Patients received treatment for 28 days. By day 14, the majority of patients showed improvement in their condition (69 out of 82 in the verum group and 31 out of 43 in the placebo group). After discharge, these patients were given medication (verum or placebo) to continue self-treatment at home for the remainder of their stay. A follow-up examination was conducted at 60 days.

[0188] In addition to the clinical outcome parameters of this study, exposure-response analysis was performed to establish a pharmacokinetic (PK) model of 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt form I. For this purpose, the biomarker D-dimer was determined.

[0189] D-dimer levels are an important marker for predicting the severity of COVID-19. Elevated D-dimer levels are associated with thromboembolic complications. To monitor the expression of this biomarker during the study period, blood samples were collected on days 1, 7, 14, 21, 28, and 60. D-dimer concentrations were measured using monoclonal antibodies in plasma via ELISA (Olson (2015) Adv Clin Chem. 69:1-46; Johnson et al. (2019) Am J. Hematol). The results are shown in Table 1. [Table 1]

[0190] D-dimer concentrations vary considerably among individuals, with outliers existing in both directions. To facilitate comparison of results, the median values ​​for each group are shown in ng / mL DDU (D-dimer units).

[0191] The group administered 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt + SoC had significantly lower D-dimer levels throughout the study period compared to the group administered placebo + SoC. The curve is not smooth, which may be due to the inability to collect blood samples from all patients at every time point. Therefore, the composition and size of each group differ slightly. Furthermore, patients in both groups who died during the study period typically only had elevated D-dimer levels while alive. These patients died within the first 14 days. After discharge, patients were not administered SoC further. This may explain the transient rebound in both groups. After 60 days, all surviving patients had recovered, their D-dimer levels had normalized, and no differences were detected between the groups.

[0192] In a post-hoc analysis, the effect of administration of 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt + SoC on the biomarker D-dimer was modeled (Saarmetrics GmbH, University of Saarland, Saarbrücken, Germany). The results showed that administration of 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt + SoC had a significant effect in significantly reducing D-dimer levels compared to placebo (p<0.001) (Figure 1).

[0193] Figure 1 shows that 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt reduces D-dimers during the increase and recovery phases of the placebo curve. This can be interpreted as 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt having both a preventive effect (reduced D-dimer formation, thus lowering the risk of thrombotic events) and a therapeutic effect (formed fibrin thrombi or their respective coils are more rapidly broken down and removed).

[0194] Example 2: Effects of 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt in an in vitro cell system The effects of different concentrations of 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt on thrombomodulin release were tested in cell lines compared to a control group. Commercially available coronary artery smooth muscle cells (n=3) pooled from human donors were cultured according to the manufacturer's recommendations. To mimic vascular inflammation, cells were stimulated with IL-1β, TNF-α, and IFN-γ. B cells were cultured in 96-well plates until confluence. (Details are described in Kunkel et al. (2004) FASEB J 18:1279-1281). 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt (type I) was provided by the applicant. A stock solution of 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt was prepared in PBS (phosphate-buffered saline) and thawed before the experiment. It was added at the specified concentration 1 hour before stimulation and cultured for 48 hours. Each plate contained a positive control, a negative control (unstimulated cells), and a solvent control (buffer solution). Thrombomodulin concentration was measured using direct ELISA (enzyme-linked immunosorbent assay). Soluble factors from the supernatant were quantified using capture ELISA.

[0195] The cytotoxic effects of 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt were monitored for 24 hours using an SRB (sulforhodamine B) assay. No cytotoxic effects were observed for any substance or combination during this period (data not shown).

[0196] The following concentrations and combinations of 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt were tested. 62.5μM-250μM-1mM-4mM

[0197] The measurement was repeated three times, and the average value was divided by the average value of the control sample. The control sample was set to 100%. The following results were obtained. [Table 2]

[0198] The results are shown in Figure 2.

[0199] These results indicate that prophylactic administration of an effective concentration of 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt can significantly increase thrombomodulin release from cardiovascular smooth muscle cells in a dose-dependent manner. Therefore, it is suggested that adding 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt before stimulation can prevent thrombus formation in blood vessels under pro-inflammatory conditions. Thus, it is reasonable to infer that the use of 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt can prevent thrombus formation and the development of thrombotic diseases. [Brief explanation of the drawing]

[0200] [Figure 1] Figure 1 shows the modeled changes in plasma D-dimer concentration (ng / mL DDU) during the course of a clinical trial. Black line: 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt + SoC Gray line: placebo + SoC [Figure 2] Figure 2 shows the percentage change in thrombomodulin concentration in the supernatant compared to the control after adding 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt at different concentrations. Values ​​are normalized to 100% (control).

Claims

1. 5-amino-2,3-dihydro-1,4-phthalazinedione, or one of its pharmaceutically acceptable salts, hydrates, or solvates, for use in the prevention and treatment of thrombotic diseases.

2. The pharmaceutically acceptable salt is 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt, or one of a pharmaceutically acceptable salt, hydrate, or solvate thereof, according to claim 1.

3. 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt is provided as one of crystalline anhydride polymorphs I, II, or III, characterized by the following crystallographic values ​​determined by X-ray powder mapping. For morphology I, the d values ​​were: 13.5; 6.9; 5.2; 4.6; 3.9; 3.5; 3.4; 3.3; 3.1; 3.0 and / or 2θ values: 6.5; 12.7; 16.9; 19.3; 22.8; 25.8; 26.6; 27.2; 28.7; 30.3 For morphology II, the d values ​​were: 12.9; 7.9; 7.1; 6.5; 5.3; 4.0; 3.7; 3.6; 3.3; 3.2 and / or 2θ values: 6.8; 11.2; 12.5; 13.7; 16.7; 22.4; 24.3; 24.9; 27.2; 27.8, and, For morphology III, the d values ​​are: 13.131; 7.987; 7.186; 6.566; 6.512; 5.372; 3.994; 3.662; 3.406; 3.288; 3.283; 3.222; 3.215; 3.127; 2.889 and / or The 2θ values ​​are: 6.73; 11.07; 12.31; 13.48; 13.59; 16.49; 22.24; 24.29; 26.14; 27.10; 27.14; 27.67; 27.72; 28.52; 30.

93. 5-amino-2,3-dihydro-1,4-phthalazinedione for use according to claim 2, or one of its pharmaceutically acceptable salts, hydrates, or solvates.

4. 5-amino-2,3-dihydro-1,4-phthalazinedione, or one of its pharmaceutically acceptable salts, hydrates, or solvates, for use according to any one of claims 2 or 3, wherein the daily dose for patients requiring the use is in the range of 100 mg to 1000 mg.

5. 5-amino-2,3-dihydro-1,4-phthalazinedione or one of its pharmaceutically acceptable salts, hydrates or solvates for use according to any one of claims 1 to 4, wherein the thrombotic disorder is caused by a viral infection.

6. 5-amino-2,3-dihydro-1,4-phthalazinedione or one of its pharmaceutically acceptable salts, hydrates or solvates for use according to claim 5, wherein the thrombotic disorder is caused by SARS-CoV-2 infection.

7. One of 5-amino-2,3-dihydro-1,4-phthalazinedione or a pharmaceutically acceptable salt thereof for use according to any one of claims 1 to 4, wherein the thrombotic disease is selected from the group including venous thrombosis, deep vein thrombosis, Paget-Schlotter disease, Budd-Chiari syndrome, portal vein thrombosis, renal vein thrombosis, cerebral venous sinus thrombosis, jugular vein thrombosis, cavernous sinus thrombosis, thrombophlebitis, peripartum thrombosis, painful leukodysplasia, arterial thrombosis, peripheral artery disease, acute limb ischemia, hepatic artery thrombosis, disseminated intravascular coagulation syndrome, coagulation disorders in septic diseases, and thrombotic microangiopathy.

8. A pharmaceutical composition comprising 5-amino-2,3-dihydro-1,4-phthalazinedione, or one of its pharmaceutically acceptable salts, hydrates, or solvates, and at least one pharmaceutically acceptable excipient, for use in the prevention or treatment of thrombotic diseases.

9. The pharmaceutical composition according to claim 8, which is suitable for administration by inhalation, oral administration, parenteral administration, intraperitoneal administration, intra-arterial administration, intramuscular administration, local administration, transdermal administration, subcutaneous administration, intradermal administration, sublingual administration, conjunctival administration, vaginal administration, rectal administration, intrathecal administration, intrapharyngeal administration, intranasal administration, or intubation.

10. The pharmaceutical composition according to any one of claims 8 or 9, wherein the at least one pharmaceutically acceptable excipient is selected from the group comprising carriers, binders, colorants, buffers, preservatives, antioxidants, coatings, sweeteners, thickeners, pH adjusters, acidity adjusters, acidifying agents, solvents, isotonic agents, disintegrants, flow enhancers, lubricants, emulsifiers, solubilizers, stabilizers, diluents, anti-solidification agents, adsorbents, permeation enhancers, foaming agents, defoaming agents, opacifying agents, fats, viscosity enhancers, hydrotropes, aromatic substances, and flavoring substances.

11. 5-amino-2,3-dihydro-1,4-phthalazinedione for use according to claim 1, or one of its pharmaceutically acceptable salts, hydrates or solvates, or the pharmaceutical composition for use according to claim 8, wherein the oral dosage form of the substance or the pharmaceutical composition is in the form of a tablet, sublingual tablet, soft gelatin capsule, hard gelatin capsule, sugar-coated tablet or pill, powder or granules, juice, syrup, drop, tea, solution or suspension in an aqueous or non-aqueous liquid, food foam or mousse, lozenge, or water-in-oil or oil-in-water emulsion.

12. The substance or the pharmaceutical composition is administered by inhalation using a vibrating mesh nebulizer, a metered-dose inhaler, a jet nebulizer, or a dry powder inhaler, and the 5-amino-2,3-dihydro-1,4-phthalazinedione for use according to claim 1, or one of its pharmaceutically acceptable salts, hydrates, or solvates, or the pharmaceutical composition for use according to claim 8.

13. The substance or the pharmaceutical composition is formulated as a sustained-release agent, comprising 5-amino-2,3-dihydro-1,4-phthalazinedione for use according to claim 1, or one of its pharmaceutically acceptable salts, hydrates, or solvates, or the pharmaceutical composition for use according to claim 8.

14. The substance or the pharmaceutical composition is administered in the form of liposomes, micelles, multilayer vesicles or cyclodextrin complexes, and is 5-amino-2,3-dihydro-1,4-phthalazinedione for use according to claim 1, or one of its pharmaceutically acceptable salts, hydrates or solvates, or the pharmaceutical composition for use according to claim 8.

15. The substance or the pharmaceutical composition is administered topically in the form of a cream, emulsion, lotion, gel, hydrogel, paste, powder, ointment, ointment, application, film, liposome, skin patch, transdermal patch, transdermal spray, or suspension, and is 5-amino-2,3-dihydro-1,4-phthalazinedione or one of its pharmaceutically acceptable salts, hydrates, or solvates, or the pharmaceutical composition for use according to claim 8.

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