Ticagrelor IV for use in the prevention of thromboembolic events

Abstract

The present invention provides a pharmaceutical composition containing ticagrelor for use in reducing or preventing thromboembolic events before and / or during and / or after neurovascular arterial procedures in a patient requiring the use of the pharmaceutical composition containing ticagrelor, comprising administering an effective amount of the pharmaceutical composition containing ticagrelor to a patient, wherein the pharmaceutical composition is an aqueous solution containing a solubilizing agent for ticagrelor and the pharmaceutical composition is administered intravenously; wherein the patient suffers from a cerebral aneurysm, cerebral arteriosclerosis, cervical arteriosclerosis, neurovascular carotid dissection or carotid dissection.

Description

Technology Field

[0001] The present invention is in the field of medical use of pharmaceutical compositions. The relevant active ingredient is ticagrelor. The route of administration is intravenous administration. The present invention is advantageous in that the liquid ticagrelor formulation, particularly the formulation provided for intravenous administration, is complementary to the tablet formulation. While ticagrelor has so far been limited mainly to the field of cardiology, the present invention extends the use of ticagrelor IV to neurovascular arterial procedures. The present invention is advantageous in the field of neurovascular surgery, particularly in patients with intracranial aneurysms, cerebral arteriosclerosis, arteriovenous fistulas, or cervical arteriosclerosis who require surgical interventions such as stents or blood flow diverters, which entail an increased risk of thromboembolic events.

[0002] The use of the storage-stable aqueous ticagrelor IV formulation is advantageous in these situations requiring acute intervention to improve high-risk conditions. This is an improvement over the immediate preparation of ticagrelor solutions provided for IV administration. Background Technology

[0003] Thromboembolism is the term used for a condition in which a blood clot (thrombus) formed in a blood vessel breaks off and is carried by the bloodstream, contributing to the blockage of the vessel. This is a dangerous condition that can affect multiple organs, leading to organ damage and even death.

[0004] Some surgical interventions carry an increased risk of thromboembolic events. These include neurovascular procedures, such as vascular interventions in the treatment of intracranial aneurysms, cerebral arteriosclerosis, or cervical arteriosclerosis. Vascular interventions may include the placement of vascular stents or flow diversions.

[0005] Intracranial aneurysms are one of the most common cerebrovascular diseases in adults, with an incidence of approximately 2–7%. Major risks associated with intracranial aneurysms include rupture and aneurysmic subarachnoid hemorrhage, which carry high mortality and morbidity rates. The overall annual rupture rate of intracranial aneurysms is approximately 1%.

[0006] Treatment targeting intracranial aneurysms is sophisticated. It requires a balance between the risk of intracranial aneurysm rupture and the risk of a blood clot breaking off during surgical intervention on the vessel leading to thrombosis.

[0007] A similar risk is associated with surgical interventions related to the treatment of cervical artery sclerosis. The placement of stents carries a risk of thrombus formation, leading to occlusion of blood vessels within the brain. If left untreated, cervical artery sclerosis can lead to occlusion of the cervical arteries and oxygen deprivation in the brain.

[0008] Appropriate antiplatelet therapy is required to reduce or prevent thromboembolic events.

[0009] Most antiplatelet drugs, such as aspirin, clopidogrel, prasugrel, and ticagrelor, are commercially available only in tablet form. These do not offer the possibility of administration to unconscious patients. This includes patients undergoing surgical procedures, who are vulnerable to unpredictable and often inappropriate platelet suppression during the procedure. Tablets also pose a problem for patients with dysphagia (difficulty swallowing).

[0010] Currently, the preferred antiplatelet therapy drugs are primarily aspirin and clopidogrel, both available in tablet form. Unfortunately, some patients are resistant to aspirin or clopidogrel. Resistance to clopidogrel or aspirin has been considered a major cause of ischemic cerebrovascular events reported in the literature following interventional therapy. Another disadvantage of clopidogrel is that it is a prodrug requiring hepatic metabolic activation.

[0011] Cangrelor is an antiplatelet agent provided for intravenous administration. It acts rapidly, but also briefly. Cangrelor has a very short half-life of 3 to 6 minutes, and its antiplatelet effect wears off within 60 minutes. However, switching to an intravenous formulation of tablets containing two different active pharmaceutical ingredients can also lead to unwanted complications. Cangrelor is primarily used in patients who have not previously used antiplatelet agents.

[0012] Considering the above, there is a need for further improvement.

[0013] Considering the above, there is still a need in the industry for antiplatelet drugs that can be administered intravenously for the prevention or treatment of cerebrovascular events.

[0014] The object of the present invention is to solve at least one of the problems described above. In particular, the present invention aims to provide a pharmaceutical composition in a form suitable for intravenous administration for use in the prevention or treatment of cerebrovascular events. In particular, the present invention aims to provide a pharmaceutical composition having a faster onset of therapeutic effect compared to tablets for use in the prevention or treatment of cerebrovascular events.

[0015] Summary of the Invention

[0016] The present invention provides a pharmaceutical composition containing ticagrelor for use in reducing or preventing thromboembolic events before and / or during and / or after a neurovascular arterial procedure in a patient requiring such treatment, comprising administering an effective amount of the pharmaceutical composition containing ticagrelor to a patient, wherein the pharmaceutical composition is an aqueous solution containing a solubilizing agent for ticagrelor and the pharmaceutical composition is administered intravenously; wherein the patient suffers from a cerebral aneurysm, cerebral arteriosclerosis, cervical arteriosclerosis, neurovascular carotid dissection or carotid dissection.

[0017] The present invention has the effect that patients with a ticagrelor-responsive state can be effectively treated even if they are unconscious or have difficulty swallowing. This is particularly important in emergency situations where a therapeutic effect is urgently needed. The present invention also allows for dose titration.

[0018] In a preferred embodiment, the solubilizing agent for ticagrelor is cyclodextrin; preferably, the cyclodextrin is hydroxypropylbetacyclodextrin (HPbCD).

[0019] In a preferred embodiment, the solubilizing agent for ticagrelor is vitamin E TPGS.

[0020] In a preferred embodiment, during ticagrelor administration, the P2Y12 reaction unit (PRU) is less than 200, preferably less than 100.

[0021] In a preferred embodiment, ticagrelor is administered intravenously within 5 days preceding a neurovascular arterial procedure.

[0022] In a preferred embodiment, ticagrelor is administered intravenously after a neurovascular arterial procedure; preferably, within 6 hours after the procedure.

[0023] In a preferred embodiment, the patient suffers from a cerebral aneurysm, cerebral arteriosclerosis, cervical arteriosclerosis, neurovascular carotid artery dissection or carotid artery dissection.

[0024] In a preferred embodiment, a 5-80 mg ticagrelor infusion is administered to the patient after the procedure.

[0025] In a preferred embodiment, 20-50 mg of ticagrelor is administered twice a day after intravenous administration of ticagrelor.

[0026] In a preferred embodiment, the patient is resistant to clopidogrel.

[0027] In a preferred embodiment, ticagrelor is administered as monotherapy.

[0028] In a preferred embodiment, ticagrelor is administered as part of a dual antiplatelet therapy combined with aspirin.

[0029] In a preferred embodiment, the patient received a vascular stent implant.

[0030] In a preferred embodiment, the pharmaceutical composition is injected in a therapeutically effective amount during a neurovascular arterial procedure.

[0031] Detailed description of the invention

[0032] Unless otherwise defined, all terms used in the description of the present invention, including technical and scientific terms, have the meaning generally understood by a person skilled in the art to which the present invention pertains. Additionally, definitions of terms are included to better understand the description of the present invention.

[0033] As used herein, the following terms have the following meanings: The singular form used herein refers to both singular and plural unless otherwise indicated by the context. For example, "surfactant" refers to one or more surfactants.

[0034] As used herein, the term “about” is intended to include a variation of plus or minus 10% or less of a specific value, preferably plus or minus 5% or less, more preferably plus or minus 3% or less, even more preferably plus or minus 1% or less, and even more preferably plus or minus 0.1% or less, insofar as such variation is suitable for carrying out the described invention. However, it will be clear that the value itself to which the term “about” relates is also specifically described. As used herein, “comprising,” and “comprising” are inclusive or open terms that specify, but do not exclude, what follows, e.g., the presence of a component and any additional unnamed components, features, elements, parts, or steps that are well known in the art or described herein.

[0035] The reference to a numerical range by an endpoint includes all numbers and fractions contained within that range, as well as the mentioned endpoint.

[0036] The term "% w / w" as used herein means a weight percentage in which the weight ratio of a component to the total weight of the composition is expressed as a percentage.

[0037] The present invention provides a solution to the problem of limited bioavailability and slow onset of therapeutic effect provided by ticagrelor tablets for use in reducing or preventing thromboembolic events after neurovascular arterial procedures in patients requiring this. The present invention provides an aqueous ticagrelor solution provided for intravenous administration for use in neurovascular arterial procedures in patients requiring this.

[0038] As used herein, the term "provided for intravenous administration" means a composition suitable for administration into the bloodstream. This relates particularly to the osmolality and pH of the formulation being suitable. Dilution or pH adjustment is not required, and the formulation is ready for immediate use.

[0039] Preferably, the patient is a human patient.

[0040] Preferably, the aqueous ticagrelor solution is prepared from finely pulverized ticagrelor with a D90 of less than 90 micrometers. Methods for measuring the particle size of the active ingredient are well known to those skilled in the art of formulation technology. The method used in the present invention is the Malvern Mastersizer dry powder method.

[0041] In particular, the present invention provides a pharmaceutical composition containing ticagrelor for use in reducing or preventing thromboembolic events before and / or during and / or after a neurovascular arterial procedure in a patient requiring such treatment, comprising administering an effective amount of the pharmaceutical composition containing ticagrelor to a patient, wherein the pharmaceutical composition is an aqueous solution containing a solubilizing agent for ticagrelor and the pharmaceutical composition is administered intravenously; wherein the patient suffers from a cerebral aneurysm, cerebral arteriosclerosis, cervical arteriosclerosis, neurovascular carotid dissection or carotid dissection.

[0042] Ticagrelor is a well-known active ingredient. It is a platelet aggregation inhibitor used to prevent thrombotic events, such as myocardial infarction or stroke, in patients with acute coronary syndrome. Its chemical name is (1S,2S,3R,5S)-3-{7-[(1R,2S)-2-(3,4-difluorophenyl)cyclopropylamino]5-(propylthio)-3H-(1,2,3)triazolo(4,5-D)pyrimidine-3-yl}-5-(2-hydroxyethoxy)cyclopentane-1,2-diol.

[0043] As used herein, the term "ticagrelor" refers not only to ticagrelor in its free form but also to its pharmaceutically acceptable solvates, hydrates, enantiomers, polymorphs, or mixtures thereof. Preferably, ticagrelor is used in its free form.

[0044] Ticagrelor was developed by AstraZeneca and received market approval from the European Medicines Agency in 2010 and the U.S. Food and Drug Administration in 2011. As a drug, it is sold in tablet form under the names Brilinta® in the United States and Brilique® in the EU. It is not commercially available in liquid form. Ticagrelor is an oral, reversible, direct-acting P2Y that works by inhibiting platelet activation. 12It is a receptor antagonist. Brilinta® tablets, when combined with aspirin, have been shown to significantly reduce the risk of major adverse cardiovascular (CV) events (heart attack, stroke, or CV death) in patients with a history of acute coronary syndrome (ACS) or heart attack. In the United States, Brilinta® tablets are also used to reduce the risk of the first heart attack or stroke in high-risk patients with coronary artery disease.

[0045] Ticagrelor is highly susceptible to degradation when exposed to light, heat, and oxygen. Furthermore, its limited solubility poses a significant challenge in enabling formulation into aqueous solutions. While the need for liquid ticagrelor formulations remains high, existing knowledge has not yet enabled the development of successful commercial products with the desired solubility and long-term stability to meet the requirements of the pharmaceutical industry.

[0046] Experiments have revealed that ticagrelor can be solubilized using a suitable solubilizing agent. Preferably, this solubilizing agent is cyclodextrin or vitamin E TPGS.

[0047] Cyclodextrins are cyclic carbohydrates derived from starch. Unmodified cyclodextrins differ by the number of glucopyranose units linked together in a cylindrical structure. Parent cyclodextrins contain 6, 7, or 8 glucopyranose units and are referred to as α-, β-, and γ-cyclodextrins, respectively. Each cyclodextrin subunit has secondary hydroxyl groups at the 2- and 3-positions and a primary hydroxyl group at the 6-position. Cyclodextrins can be described as hollow truncated cones with a hydrophilic outer surface and a hydrophobic inner cavity. In aqueous solution, these hydrophobic cavities provide a resting place for hydrophobic organic compounds, which can fit all or part of their structure within these cavities. This process, known as inclusion complexation, can result in increased apparent aqueous solubility and stability for complexed drugs; however, the degree of stabilization will vary from drug to drug. The complex is stabilized by hydrophobic interactions and does not involve the formation of any covalent bonds.

[0048] Chemical modification of the parent cyclodextrin (typically in the hydroxyl moiety) has resulted in derivatives with improved safety while maintaining or improving the complexing ability of the cyclodextrin. Of the numerous derivatized cyclodextrins produced to date, only two appear to be commercially viable: the neutral 2-hydroxypropyl derivative (HP-β-CD or HPβCD) being commercially developed by Janssen et al., and the sulfoalkyl ether derivative (SAE-β-CD or SAE-CD) being developed by CyDex Pharmaceuticals, Inc. SAE-CD is a class of negatively charged cyclodextrins that differs from the starting parent cyclodextrin in the nature of the alkyl spacer, salt form, degree of substitution, and the starting parent cyclodextrin. The sodium salt of the sulfobutyl ether derivative of beta-cyclodextrin has an average of about 7 substituents per cyclodextrin molecule (SBE7-β-CD), and CyDex Pharmaceuticals, Inc. It is being commercialized as CAPTISOL® cyclodextrin by (Kansas).

[0049] In a preferred embodiment, the cyclodextrin is selected from hydroxypropyl-beta-cyclodextrin and sulfobutyl ethers of beta-cyclodextrin. More preferably, the cyclodextrin is hydroxypropyl-beta-cyclodextrin. Most preferably, the cyclodextrin is (2-hydroxypropyl)-beta-cyclodextrin.

[0050] In a preferred embodiment, ticagrelor is the only active pharmaceutical ingredient present in the composition. Alternatively, additional active ingredients may be included. Preferably, the additional active ingredient is not prasugrel.

[0051] In a preferred embodiment, an aqueous ticagrelor composition for IV administration in the treatment of neurovascular arterial events comprises 0.1 to 15 mg / ml ticagrelor; more preferably, 1-14 mg / ml ticagrelor or 2-13 mg / ml ticagrelor; even more preferably, 3-12 mg / ml ticagrelor or 4-11 mg / ml ticagrelor; and most preferably, 5-10 mg / ml ticagrelor. The ticagrelor IV composition for use in the treatment of neurovascular arterial events may be administered by injection, short-term infusion, or long-term infusion. Short-term infusion is preferably between 1 minute and 30 minutes, more preferably between 1.5 minutes and 25 minutes; most preferably between 2 minutes and 5 minutes.

[0052] In a preferred embodiment, an aqueous ticagrelor composition for IV administration in the treatment of neurovascular arterial events comprises 15-40% w / w, more preferably 20-35% w / w, even more preferably 22-34% w / w, and most preferably 23-33% w / w hydroxypropyl-beta-cyclodextrin. The amount of cyclodextrin selected is sufficient to encapsulate a therapeutically relevant amount of ticagrelor and provide a clear ticagrelor solution.

[0053] In a preferred embodiment, the aqueous ticagrelor composition for IV administration in the treatment of neurovascular arterial events does not contain an organic co-solvent. The use of an organic co-solvent to improve the solubility of ticagrelor is not required. The avoidance of organic co-solvents provides better suitability of the product for intravenous administration. In particular, the aqueous ticagrelor composition for IV administration in the treatment of neurovascular arterial events does not contain polyethylene glycol. This is advantageous for storage stability, as the presence of polyethylene glycol in aqueous ticagrelor solutions has been found to be prone to generating impurities when stored for longer periods.

[0054] In particular, aqueous ticagrelor compositions for IV administration in the treatment of neurovascular arterial events have an osmolality between 350 and 900 mOsm / kg. This osmolality is advantageous for intravenous administration to patients requiring ticagrelor IV treatment.

[0055] In a preferred embodiment, the aqueous ticagrelor composition for IV administration in the treatment of neurovascular arterial events has a pH of 5.5 to 9.0, and more preferably a pH of 7.0 to 8.0. This pH selection was advantageous for the long-term storage stability of the ticagrelor IV composition. In addition, it provides a physiologically acceptable pH.

[0056] In a preferred embodiment, an aqueous ticagrelor composition for iv administration in the treatment of neurovascular arterial events has a storage stability of at least 3 months under accelerated storage conditions of 40°C and 75% relative humidity (RH). More preferably, the storage stability is at least 6 months; even more preferably, at least 9 months; and most preferably, at least 12 months. A satisfactory stability of 6 months at 40°C and 75% RH corresponds to a shelf life of 24 months at room temperature of 25°C.

[0057] "Storage stability" as used herein means that the total impurity level is less than 0.5%.

[0058] Storage-stable compositions have an advantage over ready-to-use compositions in that the product does not need to be prepared immediately before medical treatment. This saves time.

[0059] Most preferably, an aqueous ticagrelor composition for IV administration in the treatment of neurovascular arterial events is a solution consisting of the following:

[0060] 5 - 15 mg / ml ticagrelor,

[0061] 15 - 40% w / w hydroxypropyl-beta-cyclodextrin,

[0062] 5 mM-20 mM buffer,

[0063] Here, the pH is between 5.5 and 8.

[0064] Most preferably, an aqueous ticagrelor composition for IV administration in the treatment of neurovascular arterial events is a solution consisting of the following:

[0065] 5 - 15 mg / ml ticagrelor,

[0066] 15 - 40% w / w hydroxypropyl-beta-cyclodextrin,

[0067] 5 mM-20 mM phosphate buffer,

[0068] Here, the pH is between 5.5 and 8.

[0069] Alternatively, an aqueous ticagrelor composition for IV administration in the treatment of neurovascular arterial events is a solution consisting of the following:

[0070] 0.10 - 14.0 mg / ml ticagrelor and

[0071] An amount of cyclodextrin for solubilization of ticagrelor in a volume of selected aqueous pharmaceutical solution of 20 - 100 mg / ml,

[0072] Here, the composition has a pH between 5.5 and 9.0 including the endpoint, and

[0073] Aqueous pharmaceutical solutions have a volume of 25 to 1000 ml.

[0074] The composition provided above is simple and easy to manufacture. The limited number of components has reduced the formation of impurities and byproducts. This is advantageous for the availability of ticagrelor IV solution for patients requiring treatment of neurovascular arterial events.

[0075] Optionally, an aqueous ticagrelor composition for intravenous administration in the treatment of neurovascular arterial events may include an isotonic modifier such as sodium chloride. Preferably, the osmolality of the aqueous ticagrelor composition for intravenous administration in the treatment of neurovascular arterial events is between 350 and 900 mOsm / kg, more preferably between 360 and 800 mOsm / kg, even more preferably between 370 and 700 mOsm / kg, and most preferably between 380 and 600 mOsm / kg.

[0076] In a preferred embodiment, an aqueous ticagrelor composition for IV administration in the treatment of neurovascular arterial events comprises vitamin E TPGS as a solubilizing agent for ticagrelor. The use of vitamin E TPGS has been found to be advantageous for the solubilization of poorly soluble ticagrelor.

[0077] As used herein, the term “Vitamin E TPGS” refers to a water-miscible form of Vitamin E having a hydrophobic Vitamin E moiety and a hydrophilic polyethylene glycol chain. Vitamin E TPGS is also known as D-alpha-tocopheryl polyethylene glycol succinate or tocopersolan. Vitamin E TPGS is approved by the U.S. Food and Drug Administration as a safe adjuvant and is used as a surfactant, solubilizer, or stabilizer in drug delivery systems. US 2680749 discloses TPGS molecules in which the polyethylene glycol has an average molecular weight of 400, 1000, and an average molecular weight that varies between 600 and 6000. Vitamin E TPGS molecules in which the polyethylene glycol chain has an average molecular weight (MW) of about 1000 are commercially available from Eastman Chemical Company (Kingsport, Tennessee).

[0078] Ticagrelor IV may find use in the treatment of neurovascular arterial procedures. Ticagrelor IV can provide antiplatelet therapy before, during, or after surgical procedures to resolve unruptured intracranial aneurysms. Alternatively, ticagrelor IV can provide antiplatelet therapy before, during, or after surgical procedures for the treatment of cervical or cervical arteriosclerosis.

[0079] In a preferred embodiment of a ticagrelor composition for use in reducing or preventing thromboembolic events before and / or during and / or after neurovascular arterial procedures in patients requiring this, the P2Y12 reaction unit (PRU) during ticagrelor administration is less than 200, more preferably less than 150, and even more preferably less than 110. Most preferably, the P2Y12 reaction unit is between 0 and 100.

[0080] P2Y12 Response Units (PRU) as an indicator of platelet function can be measured by the VerifyNow P2Y12 test (Accriva Diagnostics). Platelet reactivity was expressed in P2Y12 Response Units (PRU) and % inhibition. This was calculated as ((1 - (P2Y12 receptor blockade / baseline platelet reactivity) x 100). The scientific literature reports that PRU may correlate with a higher risk of complications. For ticagrelor, the advice is to maintain PRU between 0 and 100.

[0081] In a preferred embodiment of the present invention, ticagrelor is administered intravenously within 5 days preceding a neurovascular arterial procedure. More preferably, ticagrelor IV is administered within 4 days preceding a neurovascular arterial procedure, more preferably within 3 days, most preferably within 2 days or 1 day.

[0082] In the case of emergency surgery, the patient may have received ticagrelor IV immediately before surgery. Antidotes or absorption techniques may be used to reduce ticagrelor levels in the blood.

[0083] Preferably, ticagrelor is administered intravenously after a neurovascular arterial procedure; preferably within 6, 5, or 4 hours after the procedure. More preferably within 3 hours after the procedure, most preferably within 2 hours after the procedure.

[0084] The patient may be conscious and able to swallow tablets 4 to 6 hours after surgery. Thus, oral antiplatelet therapy can be initiated. The availability of ticagrelor IV offers the advantage that ticagrelor treatment can be initiated while the patient is still recovering, unconscious, or in a coma. This may be beneficial in reducing the risk of thrombosis after the procedure.

[0085] The terms "cerebral aneurysm" or "brain aneurysm" as used here refer to a balloon-like expansion originating from a weakened area of ​​the blood vessel wall within the brain. An expanding brain aneurysm results in the blood vessel wall becoming too thin, leading to the rupture of the aneurysm and hemorrhage into the space surrounding the brain.

[0086] In a preferred embodiment, the pharmaceutical composition is used to treat a patient suffering from a cerebral aneurysm.

[0087] The terms "cerebral arteriosclerosis" or "cerebral arteriosclerosis" as used here refer to a disease that occurs when the arteries of the brain harden, thicken, and narrow due to the accumulation of deposits or plaque within the artery walls. This accumulation reduces blood flow to specific areas of the brain. Some of the major components of plaque include the extracellular matrix, which contains connective tissue, collagen, proteoglycans, fibronectin, and elastic fibers; crystalline cholesterol, cholesteryl esters, and phospholipids; and cells such as monocyte-derived macrophages, T-lymphocytes, and smooth muscle cells. As the accumulating plaque obstructs blood flow within the intracranial arterioles, it can lead to additional complications such as stroke. This causes downstream sections of the brain normally supplied by the blocked artery to experience ischemia. Diagnosis of the disease can be performed using imaging techniques such as angiography or magnetic resonance imaging.

[0088] In a preferred embodiment, the pharmaceutical composition is used to treat a patient suffering from cerebral arteriosclerosis.

[0089] The term "carotid artery sclerosis" as used here refers to a disease within the arteries that transport blood and oxygen to the brain. Deposits or plaque block the blood vessels. This blockage increases the risk of stroke. A stroke is a medical emergency that occurs when the brain loses all or part of its blood supply. During a stroke, the brain may not receive sufficient oxygen, and brain cells begin to die. Carotid artery disease often develops slowly. The first signs of the condition may be a stroke or a transient ischemic attack (TIA). A TIA is a temporary lack of blood flow to the brain. Treatment for carotid artery disease may include lifestyle changes, medication, or surgery.

[0090] In a preferred embodiment, the pharmaceutical composition is used to treat a patient suffering from carotid artery sclerosis.

[0091] The patient's treatment may involve the placement of a neurovascular stent. A neurovascular stent is a small, tubular, and flexible device made of either metal or polymer. The stent can be placed within a blood vessel to improve blood flow. The stent may be an intracranial stent, that is, a stent placed in a blood vessel within the brain, or a carotid stent, that is, a stent placed in a blood vessel within the carotid artery that supplies blood to the brain.

[0092] Surgical procedures for the treatment of aneurysms may include coiling, stenting, or aneurysm embolization by diversion. Embolization is a minimally invasive procedure that treats an aneurysm by filling it with material to block the sac and reduce the risk of bleeding. This is performed via a maneuverable catheter inserted into the bloodstream from inside the artery—and thus endovascularly—and guided to the desired location. Microcoils, adhesives, or mesh stents are used to block the aneurysm.

[0093] In a preferred embodiment, the pharmaceutical composition is used to treat a patient suffering from neurovascular dissection. Neurovascular dissection may be cerebral artery dissection or carotid artery dissection. Dissection is a structural failure of the artery wall, resulting in intramural hemorrhage, which forms an intramural hematoma that dissects the blood vessel wall.

[0094] In a preferred embodiment of the present invention, a bolus injection of 5-80 mg ticagrelor is administered to the patient after the procedure. The first injection using ticagrelor potentially leads to one or more injections. Preferably, one or more injections involve the administration of 5-80 mg ticagrelor.

[0095] In a preferred embodiment of the present invention, treatment involves administering 20-50 mg of ticagrelor twice daily following the last intravenous administration of ticagrelor. The transition from intravenous administration of ticagrelor to oral administration is advantageous for patient convenience. Patients taking tablets can be discharged more easily as they do not require assistance with the administration of the intravenous drug.

[0096] In a preferred embodiment of the present invention, the composition is used to treat patients who are resistant to clopidogrel.

[0097] Clopidogrel resistance is a condition in which the drug clopidogrel is less effective than normal in a person being treated with it. When measured using the light transmission aggregation assay with 20 μM ADP stimulation, residual platelet aggregation greater than 50% of baseline is defined as a poor response to clopidogrel.

[0098] Platelet aggregation can be evaluated as follows. Blood collected in blood-citrate tubes was centrifuged at 120 g for 5 minutes to recover platelet-rich plasma and further centrifuged at 850 g for 10 minutes to recover platelet-deficient plasma. PRP and PPP were stored at room temperature for use within 2 hours. Platelets were stimulated with 20 μM ADP, and aggregation was evaluated using a Chronolog Lumi-Aggregometer (model 490-4D) equipped with the Aggro / Link software package (Chronolog, Havertown, Pennsylvania). Aggregation was expressed as the maximum percentage change in light transmittance from baseline, using platelet-deficient plasma as the reference.

[0099] Ticagrelor IV is preferably administered as monotherapy. Alternatively, the use of ticagrelor IV is part of dual antiplatelet therapy combined with aspirin.

[0100] In a preferred embodiment, the patient received a vascular stent implant.

[0101] In a preferred embodiment, the pharmaceutical composition is injected during a neurovascular arterial procedure in a therapeutically effective amount.

[0102] In a second aspect, the present invention provides a method for treating a patient with an aneurysm requiring antiplatelet therapy, comprising the steps of administering a therapeutically active dose to the patient requiring such therapy, thereby controlling thromboembolic complications without increasing hemorrhagic complications during pre-operative and post-operative interventional aneurysm therapy.

[0103] References

[0104] 1. The Effect of Ticagrelor for Endovascular Intervention of Intracranial Aneurysm Patients with or without Clopidogrel Resistant: A Meta-Analysis. Xia et al. Brain Sciences 2022, 12, 1077.

[0105] 2. Utility of P2Y12 Reactive Unit Assessment on Ticagrelor in Cerebral Aneurysms Treated with Intracranial Stenting and Flow Diversion: Cohort Study and Case Report From Two Neurovascular Centers. Bohan et al. World Neurosurgery, Vol. 142, October 2020.

[0106] 3. Imaging of artherosclerosis: magnetic resonance imaging. Roberto Corti, Valentin Fuster. European Heart Journal, Volume 32, Issue 14, July 2011, pages 1709-1719.

[0107] 4. Gurbel PA, Bliden KP, Guyer K, et al. Platelet reactivity in patients and recurrent events post-stenting: Results of the PREPARE POST-STENTING Study. J Am Coll Cardiol2005; 46: 1820-1826. pages 445-452. Specific details for implementing the invention

[0108] Examples

[0109] A pharmaceutical ticagrelor composition for use in reducing or preventing thromboembolic events before and / or during and / or after neurovascular arterial procedures in patients requiring this is provided in the examples below.

[0110] Examples 1 : Tikagrelor Vitamin E as a solubilizing agent for TPGS

[0111] Table 1: Ticagrelor IV composition

[0112] Formulation Weight of added ticagrelor (mg) Volume (mL) Concentration (mg ticagrelor / ml) 2.5% Vitamin E TPGS 30 50 0,600 5.0% Vitamin E TPGS 30 50 0,600 10.0% Vitamin E TPGS 30 50 0,600

[0113] An aqueous ticagrelor solution using vitamin E TPGS as a solubilizer was prepared as follows. Water-soluble vitamin E TPGS was added to water to obtain aqueous vitamin E TPGS solutions at different concentrations of 2.5, 5.0, and 10.0 w / v%. To these solutions maintained at a temperature of 45°C + / - 5°C, the ticagrelor fraction was gradually added. A 3 mg ticagrelor dose was added stepwise to 50 ml of aqueous vitamin E TPGS solution (Step 1). Subsequently, 20 ml of each diluent was used for the Step 2 study. A 10 mg ticagrelor dose was added to 20 ml of each diluent. When dissolution took longer, this was reduced to 5 mg.

[0114] Table 2: Aqueous ticagrelor IV solution

[0115] Formulation Weight of added ticagrelor (mg) Volume of 0.6 mg / ml ticagrelor solution (mL) from Table 1 Concentration (mg ticagrelor / ml) 2.5% Vitamin E TPGS 220 20 11,600 (232 / 20) 5.0% Vitamin E TPGS 286 20 14,900 (298 / 20) 10.0% Vitamin E TPGS 384 20 19,800 (396 / 20)

[0116] The following was observed: 10 mg ticagrelor dissolved after 5-10 minutes.

[0117] The 2.5% vitamin E TPGS solution was saturated at 11.6 mg / ml.

[0118] The 5.0% vitamin E TPGS solution was saturated at 14.9 mg / ml.

[0119] The 10.0% vitamin E TPGS solution was saturated at 19.8 mg / ml.

[0120] The obtained aqueous ticagrelor solution is stored at 40°C and 75% relative humidity or 25°C and 60% relative humidity for a period of at least 3 months.

[0121] Examples 2: Tikagrelor As a solubilizing agent for Korea Cyclodextrin

[0122] The following composition is suitable as an immediately usable ticagrelor aqueous composition for IV administration.

[0123] Table 3: Ticagrelor compositions ready for immediate use in water

[0124] RTU Injection Formulation mg / Vase 0.65 mg / ml TCG Concentration Composition 3.1 RTU Injection Formulation mg / Vase 0.325 mg / ml TCG Concentration Composition 3.2 RTU injection formulation mg / vial 0.10 mg / ml TCG concentration composition 3.3 Tika Greller 65 65 65 Hydroxypropyl beta-cyclodextrin (HPβCD) 8000 16000 16000 water 100 ml 200 ml 650 ml pH 7.33 7.40 7.57 Osmotic concentration (mOsmol / kg) 96 90 22 transparency transparent solution transparent solution transparent solution

[0125] Table 4: Ready-to-use ticagrelor compositions among aqueous phosphate buffers

[0126] RTU injection formulation mg / vial 0.65 mg / ml TCG concentration composition 3.4 RTU injection formulation mg / vial 0.325 mg / ml TCG concentration composition 3.5 RTU injection formulation mg / vial 0.10 mg / ml TCG concentration composition 3.6 Tika Greller 65 65 65 Hydroxypropyl beta-cyclodextrin (HPβCD) 8000 16000 16000 Phosphate buffer pH 7.5 (10 mM buffer) 100 ml 200 ml 650 ml pH 7.58 7.45 7.6 Osmotic concentration (mOsmol / kg) 105 220 280 transparency transparent solution transparent solution transparent solution

[0127] Table 5: Ticagrelor compositions ready for immediate use in diluted saline solution

[0128] RTU injection formulation mg / vial 0.65 mg / ml TCG concentration composition 3.7 RTU injection formulation mg / vial 0.325 mg / ml TCG concentration composition 3.8 RTU injection formulation mg / vial 0.10 mg / ml TCG concentration composition 3.9 Tika Greller 65 65 65 Hydroxypropyl beta-cyclodextrin (HPβCD) 8000 16000 16000 Physiological saline solution (0.9 w / v% NaCl in water) 100 ml 200 ml 650 ml pH 6.57 6.6 6.90 Osmotic concentration (mOsmol / kg) 518 415 314 transparency transparent solution transparent solution transparent solution

[0129] Table 6: Ticagrelor compositions available for immediate use in dextrose solution

[0130] RTU injection formulation mg / vial 0.65 mg / ml TCG concentration composition 13.10 RTU Injection Formulation mg / Vase 0.325 mg / ml TCG Concentration Composition 13.11 RTU injection formulation mg / vial 0.10 mg / ml TCG concentration composition 13.12 Tika Greller 65 65 65 Hydroxypropyl beta-cyclodextrin (HPβCD) 8000 16000 16000 Dextrose 5 w / v% 100 ml 200 ml 650 ml pH 5.12 5.6 6.61 Osmotic concentration (mOsmol / kg) 512 425 336 transparency transparent solution transparent solution transparent solution

[0131] Table 7: Preferred Ticagrelor Solution for Injection

[0132] RTU injection formulation mg / vial 2 mg / ml TCG concentration composition 13.13 Tikagrelor (TCG) 65 Hydroxypropyl beta-cyclodextrin (HPβCD) 3000 Dextrose 5 w / v% 30 ml pH 7.05 Osmotic concentration (mOsmol / kg) 674 transparency transparent solution

[0133] The example ready-to-use solutions were prepared as follows. In all cases, the solvent as described was prepared, placed in a beaker, heated to 40°C, and then HPβCD was added to obtain a clear solution under stirring. Subsequently, the active ingredient ticagrelor was added at 40°C under constant stirring until a clear solution was obtained. This solution was filtered through a 0.22-micron filter and aseptically filled into sterile glass vials or infusion bags.

[0134] To obtain a stable ticagrelor solution for infusion, 24 mg / ml to 350 mg / ml HPβCD was required. The amount of cyclodextrin required depended on the volume of the target infusion medium.

[0135] Ticagrelor is an active ingredient that is insoluble in water. The more diluted the aqueous solution, the greater the tendency to precipitate. When the dilution factor of ticagrelor increased from 30 ml to 100 ml and to 200 ml, a proportional increase in cyclodextrin was required. However, at volumes of 650 ml or more, it was found that 16 g of cyclodextrin was sufficient to solubilize ticagrelor.

[0136] Note that organic co-solvents, surfactants, or other solubilizing agents were not used.

[0137] The obtained aqueous ticagrelor solution was stored at 40°C and 75% relative humidity or 25°C and 60% relative humidity for a period of at least 3 months and was found to be stable.

[0138] Storage stability Tika Greller Development of the solution

[0139] In the following examples, experimental work for obtaining a storage-stable ticagrelor solution is described.

[0140] Examples 3

[0141] In this example, two different types of cyclodextrin were used and compared for the solubilization of ticagrelor. Unbuffered stock solutions of HPβCD or SBECD were prepared at target concentrations of 20% w / w, 25% w / w, 30% w / w, 35% w / w, and 40% w / w in water. Ticagrelor was slowly added under vortexing. Ticagrelor was used at concentrations of 5, 10, or 14 mg / ml in milli Q water. The ticagrelor-cyclodextrin solutions were placed on a shaking platform. No sonication or heat was applied.

[0142] From the results of Tables 8 and 9, it is concluded that HPβCD was able to dissolve ticagrelor at a wider range of cyclodextrin and ticagrelor concentrations tested. Clear aqueous solutions containing 5 mg / ml ticagrelor in HPβCD were obtained at 25% w / w, 30% w / w, 35% w / w, and 40% w / w HPβCD.

[0143] Table 8: Solubility of ticagrelor in HPβCD

[0144] HPβCD concentration in MilliQ (% w / w) Ticagrelor concentration (mg / ml) Appearance of ticagrelor among cyclodextrins Coagulation test 5 minutes after concussion 30 minutes after concussion 60 minutes after concussion 3 hours after concussion After a night of chaos 40% 5 + + + + + passing 10 - + / - + / - + / - + passing 14 - + / - + / - + / - + / -* Not applicable 35% 5 + / - + / - + / - + / - + passing 10 - + / - + / - + / - + Failed to pass 14 - + / - + / - + / - + / - Not applicable 30% 5 - + / - + / - + / - + passing 10 - - - - - Not applicable 14 - - - - - Not applicable 25% 5 - + / - + / - + / - +* Failed to pass 10 - - - - - Not applicable 14 - - - - - Not applicable 20% 5 - + / - + / - + / - - Not applicable 10 - - - - - Not applicable 14 - - - - - Not applicable

[0145] + Transparent, appears to be completely dissolved

[0146] - Translucent solution with precipitate

[0147] Clear solution with + / - precipitate

[0148] * After 1 hour of ultrasonic treatment

[0149] Table 9: Solubility of ticagrelor in SBECD

[0150] SBECD concentration in MilliQ (%w / w) Ticagrelor concentration (mg / ml) Appearance of ticagrelor among cyclodextrins Coagulation test 5 minutes after concussion 30 minutes after concussion 60 minutes after concussion 3 hours after concussion After a night of chaos 40% 5 - + / - + / - + / - + passing 10 - - - - - Not applicable 14 - - - - - Not applicable 35% 5 - + / - + / - + / - - Not applicable 10 - - - - - Not applicable 14 - - - - - Not applicable 30% 5 - - - - - Not applicable 10 - - - - - Not applicable 14 - - - - - Not applicable 25% 5 - - - - - Not applicable 10 - - - - - Not applicable 14 - - - - - Not applicable 20% 5 - - - - - Not applicable 10 - - - - - Not applicable 14 - - - - - Not applicable

[0151] + Transparent, appears to be completely dissolved

[0152] - Translucent solution with precipitate

[0153] Clear solution with + / - precipitate

[0154] In conclusion, ticagrelor could be dissolved by placing it on a shaking platform. Sonication was not applied. HPβCD can be used at a ticagrelor concentration of 5 mg / ml using cyclodextrin at 40% w / w, 35% w / w, or 30% w / w in milliQ water. These solutions remained clear at room temperature for at least 3 days and at 4°C for several days.

[0155] Examples 4

[0156] After the experiment described in Example 3, further optimization was performed by selecting a suitable pH range to ensure the long-term stability of the aqueous ticagrelor-cyclodextrin inclusion complex.

[0157] The following compositions provided in Table 10 were prepared.

[0158] Table 10: Composition for storage stability test

[0159] mg / ml Tika Greller 6 HPβCD 40%w / w 452 Acetate or phosphate buffer pH 4.5 to 6.5 A sufficient amount up to 1 ml

[0160] HPβCD was dissolved in water in separately prepared buffer solutions of pH 4.5, 5.5, or 6.5. Once a clear solution was obtained, ticagrelor was dissolved in the buffer solution under constant stirring. The ticagrelor in the buffer solution was filtered through a 0.22 micron filter and filled into USP Type I glass vials. The vials were plugged and stored. All precautions, such as N2 purging and avoidance of direct exposure to light, were taken during preparation. The vials were stored at 40°C and 75% relative humidity (RH).

[0161] To determine the stability of the formulation, the batches were evaluated using the relevant substance method on HPLC. The data for these batches are listed in Table 11 below.

[0162] To analyze impurities in the formulation, a gradient HPLC method using a YMC-Pack Pro C18 column (100x4.6 mm, S-3 μm 12 nm) was used. Good separation was obtained for all impurities.

[0163] Amine impurity: (1S,2S,3R,5S)-3-(7-amino-5-(propylsulfanyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-3-yl)-5-(2-hydroxyethoxy)cyclopentane-1,2-diol. This is a process-related degradable impurity.

[0164] Regiomer impurity: (1S, 2S, 3R, 5S)-3-((3-((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)-5-(propylsulfanyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-7-yl)amino)-5-(2-hydroxyethoxy)cyclopentane-1,2-diol. This is a process-related degradable impurity.

[0165] Acetal impurity: 2-[[(3aR,4S,6S,6aS)-6-[7-[[1R,2S)-2-(3,4-difluorophenyl)-cyclopropyl]amino]-5-(propylsulfanyl)-3H-[1,2,3]triazolo-[4,5-d]pyrimidine-3-yl]-2,2-dimethyltetrahydro-2H-3aHcyclopenta[d][1,3]dioxol-4-yl]oxy]ethanol-1-ol.

[0166] This is a process-related impurity.

[0167] Triol impurity: (1S,2R,3S,4R)-4-(7-((1R,2S)-2-(3,4-difluorophenyl)cyclopropylamino)-5-(propylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-3-yl)cyclopentane-1,2,3-triol.

[0168] This is a process-related impurity.

[0169] Only regiomer impurities were observed to increase to nearly 0.3% over 4 weeks at 40°C and 75% RH; the specification limit is 0.3%. Therefore, to further optimize the stability of the product, an investigation was conducted at pH 7 to 8.

[0170] Examples 5

[0171] Following the experiment described in Example 4, a storage stability study was performed at pH 7.5.

[0172] First, HPβCD was dissolved in a separately prepared pH 7.5 phosphate buffer solution in water. Once a clear solution was obtained, ticagrelor was dissolved in the solution under constant stirring. The solution was filtered through a 0.22 micrometer filter and filled into a USP Type I amber glass vial. The vial was plugged and stored. During preparation, all precautions were taken, such as N2 purging and avoidance of direct exposure to light.

[0173] Table 11. Stability test of ticagrelor-cyclodextrin inclusion complex in aqueous solution at pH 4.5, 5.5, and 6.5 after storage at 40°C and 75% RH

[0174]

[0175] Table 12: Composition for storage stability test

[0176] mg / ml Tika Greller 6 HPβCD 40% w / w 452 Phosphate buffer pH 7.5 A sufficient amount up to 1 ml

[0177] Table 13: Study on the storage stability of ticagrelor-cyclodextrin inclusion complex in aqueous solution at pH 7.5 stored at 40°C and 75% relative humidity

[0178] At 40℃ and 75% RH T=0 T=4 weeks T=8 weeks T=12 weeks T=24 weeks Ticagrelor content (%) 104.27 104.47 102.59 102.31 104.39 opponent possession Time (minutes) Impurity ID impurities impurities impurities impurities impurities (%): (%): (%): (%): (%): 0.45 Amine impurities 0.04 0.05 0.05 0.05 0.07 0.97 Triol impurities 0.04 0.05 0.05 0.04 0.05 1.03 Regiomer impurities 0.00 0.01 0.04 0.08 0.16 1.49 Acetal impurities 0.05 0.05 0.05 0.05 0.05 Total impurities (%) 0.31 0.32 0.29 0.41 0.35 Total impurities >0.05 (%) 0.11 0.14 0.15 0.23 0.33

[0179] Based on the results of the stability study summarized in Table 13, it was concluded that good storage stability was obtained under accelerated storage conditions of 40°C and 75% relative humidity. Regiomer impurities were well controlled, and no other impurities were a concern.

[0180] Examples 6

[0181] In additional experiments, to optimize HPβCD concentrations of less than 40% w / w, heat of 40°C was applied to help dissolve the target ticagrelor dose at concentrations where it is difficult to obtain a clear solution.

[0182] Direct physical stability data obtained from ticagrelor 5 mg / ml concentrate and from the agglutination test (20 μl sample material in 1 ml diluent) are shown in Table 14. Table 7 contains data regarding content, purity, osmolality, and pH.

[0183] Table 14: Physical stability of ticagrelor 5 mg / ml batches with various HPβCD concentrations. Data are sorted by HPβCD strength. Ticagrelor concentration when diluted with dextrose or saline: 0.1 mg / ml

[0184] HPβCD Strength (% w / w) Appearance, non-diluted Appearance of 5% dextrose Appearance in 0.9% NaCl 32.5 transparent solution transparent solution transparent solution 30.0 transparent solution transparent solution Turbidity 27.5 Cloudy; clear after heating to 40℃ transparent solution Turbidity 25.0 Cloudy; clear after heating to 40℃ transparent solution Turbidity 22.5 Cloudy; clear after heating to 40℃ transparent solution Turbidity

[0185] Due to poor physical stability results when diluted with saline, 32.5% w / w HPβCD was selected for the 5 mg / ml ticagrelor formulation. The undiluted concentrate remained stable in the refrigerator even at HPβCD concentrations as low as 22.5% w / w. These concentrations provided a nearly isotonic formulation.

[0186] In conclusion, it was possible to dissolve 5-15 mg / ml ticagrelor with HPβCD in a concentration range of 20-40% w / w without the use of heat. By applying heat to achieve a clear solution, it was possible to achieve good solubility with lower concentrations of HPβCD, such as 15-20% w / w.

[0187] At least 15% w / w HPβCD was required to provide a clear, storage-stable ticagrelor solution with a concentration suitable for injection or intravenous administration.

[0188] Examples 7

[0189] From the results obtained in Example 6, it is concluded that the concentration of the excipient can make the resulting ticagrelor solution hypertonic. The osmotic concentration and pH of several batches were determined. The solution contained 19 mM phosphate buffer and had a pH of 7.5. The results are provided in Table 15.

[0190] Table 15: Determination of pH and Osmolality in Undiluted Batch

[0191] HPβCD Strength (% w / w) Content (%) Total Impurities (%) Undiluted pH Undiluted osmolality (mOsm / kg) 32.5 99.26 0.41 7.68 813 30.0 107.64 0.44 7.74 638 27.5 104.27 0.42 7.69 549 25.0 103.23 0.41 7.69 493 22.5 98.15 0.39 7.67 392

[0192] Dilution studies were conducted to find a suitable diluent.

[0193] 5 mg / ml ticagrelor-cyclodextrin solutions containing varying amounts of HPβCD were diluted with physiological saline, 5% dextrose solution, or Ringer's lactate solution. Stability was screened. Ticagrelor concentration when diluted with dextrose or saline: 0.1 mg / ml. The results are summarized in Table 16.

[0194] Table 16: Diluent Test

[0195] HPβCD Strength (% w / w) Appearance, non-diluted Appearance of 5% dextrose Appearance in 0.9% NaCl 32.5 transparent solution transparent solution transparent solution 30.0 transparent solution transparent solution Turbidity 27.5 Cloudy; clear after heating to 40℃ transparent solution Turbidity 25.0 Cloudy; clear after heating to 40℃ transparent solution Turbidity 22.5 Cloudy; clear after heating to 40℃ transparent solution Turbidity

[0196] In addition, the effect of buffer strength on pH and osmolality was screened. The results are summarized in Table 17.

[0197] Table 17: Effects of buffer strength on pH, osmolality, content, and impurities

[0198] Phosphate buffer pH 7.5 strength (mM) Sample pH placebo pH Sample osmolality (mOsm / kg) Placebo osmolality (mOsm / kg) Content (%) Total impurities (%) 19 7.70 7.71 758 790 102.58 0.42 10 7.69 7.72 724 692 102.98 0.42 5 7.66 7.73 703 725 100.49 0.40 0.19 7.18 7.45 809 771 102.23 0.42

[0199] It was concluded that phosphate buffer at pH 7.5 had little effect on osmolality at different buffer intensities, except for the 0.19 mM buffer intensity. This buffer intensity was too weak and led to a change in pH.

[0200] Examples 8

[0201] In additional examples, the effect of particle size on solubility was tested.

[0202] Two different particle size diameters of 5.5 and 15 micrometers were screened for the ticagrelor active ingredient. pH and osmolality were unaffected. As summarized in Table 18, smaller particles exhibited faster dissolution times.

[0203] Micronized ticagrelor showed a significant improvement in dissolution time. Consequently, micronized ticagrelor with a D90 of less than 10 micrometers is preferred.

[0204] The term "D90" as used herein means that at least 90% of the particles present have a size smaller than the target particle size. However, it is understood that variations in the input particle size distribution (PSD) of ticagrelor are possible and that this will affect the dissolution rate of ticagrelor.

[0205] Table 18: Effect of particle size

[0206] Particle distribution, D90 (0.9) Dissolution time pH Osmolality (mOsm / kg) 5.5 μm, finely divided 33 minutes 7.68 751 15 μm, undifferentiated 125 minutes 7.70 753

[0207] Examples 9

[0208] To optimize the HPβCD concentration and solution pH for intravenous use, a 12-week / 3-month stability study was conducted. Compositions of 32.5% w / w HPβCD containing 5 mg / ml ticagrelor at pH 7 to 8 were prepared and stored. Their stability was tested at regular intervals.

[0209] A comparison of stability profiles at three different pH values—7, 7.5, and 8—was performed as shown below, and the preparation process for all three formulations was maintained at a constant buffer strength of 19 mM. The results are summarized in Tables 19 to 21.

[0210] Table 19: Storage stability in amber glass vials - pH 7

[0211] Amber USP Type I HPβCD 40% w / w 19 mM pH 7 phosphate buffer 　 　 T0 1M 2M 3M 　 explanation transparency transparency transparency transparency 　 Content 98.95 99.73 99.81 98.51 　 pH 7.33 7.34 7.34 7.30 RRT impurities % % % % 0.45 Amine impurities 0.04 0.04 0.04 0.06 0.97 Triol impurities 0.05 0.02 0.04 0.04 1.03 Leggiomer 0.00 0.03 0.06 0.11 1.49 Acetal impurities 0.05 0.05 0.05 0.05 　 aggregate 0.41 0.27 0.34 0.40 Total impurities >0.05 (%) 0.22 0.05 0.11 0.22

[0212] Table 20: Storage stability in amber glass vials - pH 7.5

[0213] Amber USP Type I HPβCD 40% w / w 19 mM pH 7.5 phosphate buffer 　 　 T0 1M 2M 3M 　 explanation transparency transparency transparency transparency 　 Content 104.27 104.47 102.59 102.31 　 pH 7.40 7.50 7.48 7.55 RRT impurities % % % % 0.45 Amine impurities 0.04 0.05 0.05 0.05 0.97 Triol impurities 0.04 0.05 0.05 0.04 1.03 Leggiomer 0.00 0.01 0.04 0.08 1.49 Acetal impurities 0.05 0.05 0.05 0.05 　 aggregate 0.31 0.32 0.29 0.41 Total impurities >0.05 (%) 0.11 0.14 0.15 0.23

[0214] Table 21: Storage stability in amber glass vials - pH 8.0

[0215] Amber USP Type I HPβCD 40% w / w 19 mM pH 8 phosphate buffer 　 　 T0 1M 2M 3M 　 explanation transparency transparency transparency transparency 　 Content 103.25 105.88 105.46 104.46 　 pH 8.07 8.10 8.04 8.03 RRT impurities % % % % 0.45 Amine impurities 0.04 0.05 0.05 0.07 0.97 Triol impurities 0.06 0.03 0.05 0.05 1.03 Leggiomer 0.00 0.01 0.03 0.06 1.49 Acetal impurities 0.05 0.05 0.05 0.05 　 aggregate 0.43 0.26 0.32 0.37 Total impurities >0.05 (%) 0.25 0.09 0.15 0.23

[0216] From the above data, it was concluded that the ticagrelor solution in HPβCD is stable in the pH range of 7 to 8.

[0217] Examples 10

[0218] To investigate the potential effect of packaging materials on the stability of ticagrelor-cyclodextrin inclusion complexes, compositions containing 32.5% w / w HPβCD were prepared using procedures and precautions similar to those in previous tests, and samples were stored in clear glass vials and amber glass vials at a temperature of 40°C / 75% RH. The results are shown in Tables 22 and 23.

[0219] The results of the accelerated storage stability test indicated that no significant difference was observed between the two after 3 months. All samples were maintained as clear aqueous solutions. The pH of the samples remained stable. Impurities did not change significantly.

[0220] It appears that both clear and amber glass vials can be used.

[0221] When compared to the results of accelerated storage stability tests for ticagrelor solutions without the use of cyclodextrin, it is clear that the use of cyclodextrin is important for achieving good stability. Without cyclodextrin, 6 to 8 different impurities were generated during storage. These impurities were not observed in the selected composition.

[0222] Table 22: Study on the potential impact of packaging. Stability in amber USP Type I glass.

[0223] Amber USP Type I glass vial HPβCD 32.5% w / w 5 mM pH 7.5 phosphate buffer 　 　 T0 1M 2M 3M 　 explanation transparency transparency transparency transparency 　 Content 98.34 100.24 99.89 98.93 　 pH 7.66 7.70 7.69 7.66 RRT impurities % % % % 0.45 Amine impurities 0.04 0.04 0.04 0.06 0.97 Triol impurities 0.04 0.02 0.04 0.05 1.03 Leggiomer 0.00 0.01 0.02 0.04 1.49 Acetal impurities 0.05 0.05 0.04 0.05 　 aggregate 0.40 0.22 0.28 0.33 Total impurities >0.05 (%) 0.18 0.05 0.00 0.16

[0224] Table 23: Study on the potential impact of packaging. Stability of clear glass vials in USP Type I.

[0225] Transparent USP Type I glass vial HPβCD 32.5% w / w 5 mM pH 7.5 phosphate buffer 　 　 T0 1M 2M 3M 　 explanation transparency transparency transparency transparency 　 Content 98.34 101.71 99.69 98.25 　 pH 7.65 7.65 7.63 7.58 RRT impurities % % % % 0.45 Amine impurities 0.04 0.04 0.04 0.06 0.97 Triol impurities 0.05 0.03 0.05 0.05 1.03 Leggiomer 0.00 0.01 0.02 0.04 1.49 Acetal impurities 0.05 0.04 0.04 0.05 　 aggregate 0.40 0.22 0.28 0.33 Total impurities >0.05 (%) 0.22 0.00 0.05 0.16

[0226] Surprisingly, it was concluded that ticagrelor solution could be stabilized with HPβCD in both amber and clear glass vials.

[0227] Examples 11

[0228] Further embodiments of the present invention are provided as summarized in Table 24. Further improvements to achieve higher solubility of ticagrelor were attempted at different concentrations, e.g., 40% w / w HPβCD, and ticagrelor solubility of 13 mg / ml was also possible.

[0229] Table 24: Clear aqueous solution containing ticagrelor-cyclodextrin inclusion complex considering a 65 mg dose

[0230] number HPβCD(% w / w) Ticagrelor (mg / ml) Final volume ml HPβCD mg / ml HPβCDg / vial appearance Saline solution coagulation, 1:2 Dextrose coagulant, 1:2 A 32.5 7.5 10 367.25 3.67 Transparent, colorless transparency transparency B 32.5 5 15 367.25 5.50 Transparent, colorless transparency transparency C 22.5 5 15 254.25 3.81 Transparent, colorless transparency transparency C 40 13 5 452 3.39 Transparent, colorless transparency transparency D 33 8.25 9.2 372.3 3.43 Transparent, colorless transparency transparency E 30 7.5 10 339 3.39 Transparent, colorless transparency transparency

[0231] Density 1.130 gm / cc

[0232] Based on investigations, it was observed that concentrations of 5–13 mg / ml ticagrelor solution can be achieved using 20–40% w / w HPβCD. The volume of the filling contents can be changed based on the required dose.

[0233] Surprisingly, it was found that the target dose of 5-15 mg / ml ticagrelor could be contained in a small volume by adjusting the HPβCD % and the total available volume of the injection-ready formulation. The fact that ticagrelor doses can be contained in a volume of 5-15 ml is highly relevant as it is a typical bolus injection volume.

[0234] Examples 12

[0235] In additional examples, the maximum solubility of ticagrelor in HPβCD solution was investigated without the use of heat. The results are summarized in Table 25.

[0236] It is concluded that, depending on the amount of ticagrelor to be delivered to the patient and the limitations of the sample volume determined by administration by injection or infusion, an amount of 2000-4000 mg of HPβCD per 10 ml vial may be required to dissolve 65-75 mg of ticagrelor.

[0237] Table 25: HPβCD concentration, dose, and volume of formulations

[0238] HPβCD% w / w HPβCD%w / v mg / ml HPβCD Ticagrelor mg / ml 75 mg dose HPβCD mg / vial 65 mg dose HPβCD mg / vial 　 　 　 　 　 　 　 　 17 19.21 192.10 4 18.75 ml 3600 16.25 ml 3121 22.5 25.42 254.20 5 15.00 ml 3813 13 ml 3304 30 33.90 339.00 8 9.37 ml 3176 8.12 ml 2752 33 37.29 372.90 9 8.33 ml 3107 7.22 ml 2692 40 45.2 452.00 13 7.76 ml 3507 5 ml 2260

[0239] Density of HPβCD solution 1.130 gm / cc

[0240] Surprisingly, the solution provided in Table 25 was compatible with a diluent for providing injections, particularly 5% dextrose in water.

[0241] Examples 13

[0242] In another embodiment of the present invention, a very stable transparent ticagrelor solution could be obtained by applying appropriate heat to the solution during preparation, thereby providing a completely transparent solution of the formulation at desired HPβCD and ticagrelor concentrations.

[0243] To investigate the effects of temperature and storage time, a new composition was prepared according to Table 26 below.

[0244] Table 26: Composition for temperature effect evaluation

[0245] mg / ml Tika Greller 8 HPβCD 30% w / w 329 Phosphate buffer in water pH 7.5 A sufficient amount up to 1 ml

[0246] In the first step, a pH 7.5 phosphate buffer was prepared, and the buffer solution was heated to 40–45°C. HPβCD was added to the buffer solution under continuous mixing. Once a clear solution was obtained, ticagrelor was dispersed in the HPβCD solution and mixed until a clear solution was obtained. This typically took 30 minutes to 4 hours, depending on the batch size. Subsequently, this solution was filtered through a 0.22-micron filter and packaged in suitable clear or amber glass vials.

[0247] Table 27: Bulkhold study at 45°C

[0248] At 45℃ - Bulk hold in glass vial T=1 hour T=110 hours Ticagrelor content (%) 107.87 109.10 Rival holding time: impurities Average impurity content (%): 0.45 Amine impurities 0.05 0.07 0.97 Triol impurities 0.04 0.05 1.33 0.07 0.03 1.47 Acetal impurities 0.04 0.04 Total impurities (%) 0.20 0.28 Total impurities >0.05 (%) 0.12 0.11

[0249] Table 28: Bulkhold study at 25°C and 40°C

[0250] Bulk solution in a sealed vial 8 mg / ml ticagrelor in 30% w / w HPβCD, phosphate buffer, pH 7.5, at 25°C and 40°C Point of view T=1M,25℃ T=1M,40℃ Ticagrelor content (%) 107.22 105.16 Rival holding time: impurities Average impurity content (%): 0.13 Amine impurities 0.06 0.06 0.96 Triol impurities 0.01 0.00 1.03 0.02 0.02 1.07 Regiomer impurities 0.03 0.08 1.33 0.03 0.08 1.78 Acetal impurities 0.03 0.00 Total impurities (%) 0.23 0.28 Total impurities >0.05 (%) 0.06 0.21

[0251] Table 29: Bulk hold at 30℃

[0252] Point of view T0 T4W Ticagrelor content (%) 105.60 106.14 Rival holding time: impurities Average impurity content (%): 0.45 Amine impurities 0.06 0.06 0.98 Triol impurities 0.05 0.04 1.06 Regiomer impurities 0.00 0.00 1.50 Acetal impurities 0.04 0.04 Total impurities (%) 0.21 0.21 Total impurities >0.05 (%) 0.10 0.06

[0253] Hold time studies at temperatures between 25°C and 45°C indicated that even 30% w / w HPβCD could stabilize ticagrelor after heating the solution for a long period or holding the bulk at elevated temperatures.

[0254] immediately Available Manufacturing process for injectable formulations

[0255] The preparation process for the ready-to-use solutions exemplified in Table 3-7 was as follows. In all cases, the solvent as described was prepared, placed in a beaker, and heated to 40°C; then, HPβCD was added and a clear solution was obtained under stirring. Subsequently, the active ingredient ticagrelor was added at 40°C under constant stirring until a clear solution was obtained. This solution was filtered through a 0.22-micron filter and aseptically filled into sterile glass vials or infusion bags.

[0256] To obtain a stable ticagrelor solution for infusion, 24 mg / ml to 350 mg / ml HPβCD was required. The amount of cyclodextrin required depends on the volume of the target infusion medium.

[0257] Ticagrelor is an active ingredient that is insoluble in water. The more diluted the aqueous solution, the greater the tendency to precipitate. When the dilution factor of ticagrelor increased from 30 ml to 100 ml and to 200 ml, a proportional increase in cyclodextrin was required. However, at volumes of 650 ml or more, it was found that 16 g of cyclodextrin was sufficient to hold ticagrelor in the aqueous solution.

[0258] Note that organic co-solvents, surfactants, or other solubilizing agents were not used.

[0259] concentration Tika Greller Alternative manufacturing method starting from a solution

[0260] It is possible to obtain a clear solution with a final volume of 33 ml by diluting one 8 ml vial containing 65 mg / vial ticagrelor and approximately 3 g HPβCD with 25 ml of 5 w / v% dextrose. However, this was not possible with a 0.9 w / v% NaCl solution as a diluent for the concentrated ticagrelor solution. This is important in medical treatments where the concentrated ticagrelor aqueous composition is mixed with other medications. This can lead to precipitation of ticagrelor, making the combination product unsuitable for intravenous administration.

[0261] Solubility study using other solvents

[0262] Examples 14

[0263] Solubility studies were performed using different solvents. The formulation AE shown in Table 30 was prepared by adding ticagrelor (final concentration 1.8 mg / ml) to a tube (e.g., Eppendorf or Conical) and then adding the listed solvent(s) diluted in distilled water (final volume 10 ml). The tube was then vortexed and, if necessary, sonicated in a temperature-controlled water bath. After 60 minutes, the tube was collected for solubility observation. The samples were checked again after 24 hours.

[0264] Table 30: Solubility Study Using Other Solvents

[0265] test # Solvent (v / v%, remainder is distilled water) V* S* W* Solubilized / Clear solution A 1,2-Propanediol 20% Y Y Y N B 20% ethanol Y Y Y N C Polysorbate 80 100% Y Y Y N D 20 w / v% hydroxypropyl-β-cyclodextrin Y Y Y Y E PEG 400 50% Y Y Y Y

[0266] Based on the investigation, it was observed that ticagrelor was solubilized only with cyclodextrin or polyethylene glycol (PEG).

[0267] Solubility, but inadequate storage stability

[0268] Polyethylene glycol can solubilize ticagrelor. However, polyethylene glycol was found to be sensitive to degradation, which led to impurities.

[0269] Examples 15

[0270] After sonication for several hours, two clear 1.8 mg / ml ticagrelor formulations were prepared: Formulation 1 (Example 15), 1.8 mg / ml ticagrelor in 20% w / w hydroxypropyl-β-cyclodextrin (HPβCD), the remainder being distilled water; Formulation 2 (Example 15), 1.8 mg / ml ticagrelor in 50% w / w PEG400, the remainder being distilled water.

[0271] The two formulations were aliquoted and stored at room temperature and 40°C. The formulations were analyzed by LC-UV immediately after preparation (Figs. 1 and 2). They were analyzed three times during a 6-month stability period (Figs. 3 and 4).

[0272] Ticagrelor was found to be stable for at least 6 months at both room temperature and 40°C in formulation 1 (Example 15), i.e., 1.8 mg / ml ticagrelor in 20% w / w HPβCD (Figs. 5 to 6).

[0273] In Formulation 2 (Example 15), i.e., 1.8 mg / ml ticagrelor in 50% w / w PEG400, ticagrelor was not stable at both room temperature and 40°C. A strong potential degradation product peak was observed for Formulation 2 (Example 15) in the LC-UV chromatogram (Figs. 4 to 6).

[0274] [Brief explanation of the drawing]

[0275] Fig. 1: LC-UV chromatograms of ticagrelor formulation 1 (Example 15) and a blank control at day 0 are shown.

[0276] Fig. 2: LC-UV chromatograms of ticagrelor formulation 2 (Example 15) and blank control at day 0.

[0277] Fig. 3: LC-UV chromatograms of ticagrelor formulation 1 (Example 15) and blank control at day 188 (room temperature).

[0278] FIG. 4: LC-UV chromatograms of ticagrelor formulation 1 (Example 15) and blank control at day 188 (40°C).

[0279] Fig. 5: LC-UV chromatograms of ticagrelor formulation 2 (Example 15) and blank control at day 188 (room temperature).

[0280] Fig. 6: LC-UV chromatograms of ticagrelor formulation 2 (Example 15) and blank control at day 188 (40°C).

Claims

Claim 1 A pharmaceutical composition comprising ticagrelor for use in reducing or preventing thromboembolic events prior to and / or during and / or after neurovascular arterial procedures in a patient requiring the use of a pharmaceutical composition comprising ticagrelor, wherein the pharmaceutical composition is an aqueous solution comprising a solubilizing agent for ticagrelor, the pharmaceutical composition is administered intravenously, and the patient suffers from a cerebral aneurysm, cerebral arteriosclerosis, cervical arteriosclerosis, neurovascular carotid dissection, or carotid dissection. Claim 2 A pharmaceutical composition according to claim 1, wherein the solubilizing agent for ticagrelor is cyclodextrin; preferably, the cyclodextrin is hydroxypropylbetacyclodextrin (HPbCD). Claim 3 A pharmaceutical composition according to claim 1, wherein the solubilizing agent for ticagrelor is vitamin E TPGS. Claim 4 A pharmaceutical composition according to any one of claims 1 to 3, wherein the P2Y12 reaction unit (PRU) is less than 200, preferably less than 100, during ticagrelor administration. Claim 5 A pharmaceutical composition according to any one of claims 1 to 4, wherein ticagrelor is administered intravenously within 5 days preceding a neurovascular arterial procedure. Claim 6 A pharmaceutical composition according to any one of claims 1 to 5, wherein ticagrelor is administered intravenously after a neurovascular arterial procedure; preferably administered within 6 hours after the procedure. Claim 7 A pharmaceutical composition according to any one of claims 1 to 6, wherein an infusion of 5-80 mg of ticagrelor is administered to the patient after the procedure. Claim 8 A pharmaceutical composition according to claim 7, comprising administering 20-50 mg of ticagrelor orally twice a day after intravenous administration of ticagrelor. Claim 9 A pharmaceutical composition according to any one of claims 1 to 8, wherein the patient is resistant to clopidogrel. Claim 10 A pharmaceutical composition according to any one of claims 1 to 9, wherein ticagrelor is administered as monotherapy. Claim 11 A pharmaceutical composition according to any one of claims 1 to 9, wherein ticagrelor is administered as part of a dual antiplatelet therapy combined with aspirin. Claim 12 A pharmaceutical composition according to any one of claims 1 to 11, wherein the patient has received a vascular stent implant. Claim 13 A pharmaceutical composition according to any one of claims 1 to 12, wherein the pharmaceutical composition is injected in a therapeutically effective amount during a neurovascular arterial procedure.

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