Ticagrelor iv for use in the prevention of thromboembolic events

Abstract

The invention provides a pharmaceutical composition comprising ticagrelor for use in the reduction or prevention of thromboembolic events before and / or during and / or following a neurovascular arterial procedure of a patient in need thereof, comprising administering to the patient an effective amount of the pharmaceutical composition comprising ticagrelor, characterized in, that the pharmaceutical composition is an aqueous solution comprising a solubilizer for ticagrelor and the pharmaceutical composition is administered intravenously; wherein the patient is suffering from a cerebral aneurysm, a brain artery sclerosis, a neck artery sclerosis, a neurovascular carotid arterial dissection or a carotid artery dissection.

Description

[0001] TICAGRELOR IV FOR USE IN NEUROVASCULAR ARTERIAL PROCEDURES TECHNICAL FIELD The present invention is situated in the field of medical uses of pharmaceutical compositions. The active ingredient concerned is ticagrelor. The route of administration is intravenous administration. The invention is advantageous as a liquid ticagrelor formulation, particularly a formulation provided for intravenous administration, is complementary to a tablet formulation. Where hereto ticagrelor was limited to the field of cardiologymainly, the present invention expands the use of ticagrelor iv toneurovascular arterial procedures. The present invention is advantageous inthe field of neurovascular surgery, particularly in patients with an intracranialaneurysm, a brain artery sclerosis, an arteriovenous fistula, or a neck arterysclerosis requiring a surgical intervention such as a stent or a flow diverterwith increased risk of a thromboembolic event. Use of a storage stable, aqueous ticagrelor iv formulation is advantageous in this situation that requires an acute intervention to remediate a high-risk situation. This is an improvement over an extemporaneous preparation of a ticagrelor solution provided for iv administration. BACKGROUND Thromboembolism is the name for a condition wherein a blood clot (thrombus) formed in a blood vessel breaks loose, and carried by the blood stream contributes to a blockage of a blood vessel. This is a dangerous condition that can affect multiple organs, causing organ damage and even death. Several surgical interventions carry an increased risk of a thromboembolic event. These include neurovascular arterial procedures, such as a vascularintervention in the treatment of an intracranial aneurysm, a brain arterysclerosis, or a neck artery sclerosis. The vascular intervention may comprisethe placement of a vascular stent or a flow diverter.Intracranial aneurysm is one of the most common cerebrovascular diseases,with an incidence of approximately 2–7% in adults. The main risk ofintracranial aneurysm includes rupture and aneurysm subarachnoidhaemorrhage, which has high mortality and morbidity. The overall annual rupture rate of intracranial aneurysm is about 1%.The treatment targeting intracranial aneurysms is delicate. It requires abalance between the risk of an intracranial aneurysm rupture and the risk of clots breaking loose during a surgical intervention to a blood vessel leading to thrombosis. Similar risks are associated with surgical interventions related to thetreatment of neck artery sclerosis. The placement of a stent carries the riskof clot formation, leading to a blockage of a blood vessel in the brain. Left untreated, neck artery sclerosis can lead to blockage of the neck artery and deprivation of the brain of oxygen. To reduce or prevent thromboembolic events a suitable antiplatelet therapy is required.Most antiplatelet medication, such as aspirin, clopidogrel, prasugrel andticagrelor, only commercially exists in the form of tablets. These do not offerthe possibility to medicate unconscious patients. This includes patientsundergoing a surgical procedure, which leaves them vulnerable to unpredictable and often inadequate platelet inhibition during the procedure. Tablets are also a problem for patients having difficulties swallowing (dysphagia).Currently, the preferred antiplatelet therapy drugs are mainly aspirin andclopidogrel, both in tablet form. Unfortunately, some patients are resistantto aspirin or clopidogrel. Clopidogrel or aspirin resistance were believed to be the main cause of ischemic cerebrovascular events after interventional therapy reported in the literature. A disadvantage of clopidogrel is also that it is a precursor drug that requires liver metabolism activation.Cangrelor is an antiplatelet agent provided for intravenous administration.Although it is fast acting, it is also short acting. Cangrelor has a very short half-life of 3 to 6 minutes with an offset of its antiplatelet effects within 60 minutes. However, the switching of a tablet to an intravenous formulation involving two different active pharmaceutical ingredients may also provideunwanted complications. Cangrelor is mostly used in patients who have notpreviously used an anti-platelet agent. In view of the above, there is a need for further improvements. In view of the above, there remains a need in the art for an antiplateletmedication that can be administered intravenously for use in the preventionor treatment of cerebrovascular events. The objective of the present invention is to solve at least one or moreproblems as described above. In particular, the invention aims to provide apharmaceutical composition in a form suitable for intravenous administrationfor use in the prevention or treatment of cerebrovascular events. In particular, the invention aims to provide a pharmaceutical composition witha faster onset of therapeutic effect compared to tablets for use in theprevention or treatment of cerebrovascular events. SUMMARY OF THE INVENTIONThe present invention provides a pharmaceutical composition comprisingticagrelor for use in the reduction or prevention of thromboembolic eventsbefore and / or during and / or following a neurovascular arterial procedure ofa patient in need thereof, comprising administering to the patient an effective amount of the pharmaceutical composition comprising ticagrelor, characterized in, that the pharmaceutical composition is an aqueous solution comprising a solubilizer for ticagrelor and the pharmaceutical composition is administered intravenously; wherein the patient is suffering from a cerebral aneurysm, a brain artery sclerosis, a neck artery sclerosis, a neurovascular carotid arterial dissection or a carotid artery dissection. The invention has for effect that patients with a ticagrelor-responsivecondition can be treated effectively even if unconscious or even if havingproblems swallowing. This is especially important in emergency situationswhere a therapeutic effect is urgently needed. The invention also allows dosetitration.In a preferred embodiment, the solubilizer for ticagrelor is a cyclodextrin;preferably the cyclodextrin is a hydroxypropylbetacyclodextrin (HPbCD). In a preferred embodiment, the solubilizer for ticagrelor is vitamin E TPGS. In a preferred embodiment, P2Y12 reactive units (PRUs) during ticagrelor administration are below 200, preferably below 100. In a preferred embodiment, ticagrelor is administered intravenously within 5 days preceding the neurovascular arterial procedure.In a preferred embodiment, ticagrelor is administered intravenously followingthe neurovascular arterial procedure; preferably within 6 hours post- procedure.In a preferred embodiment, the patient is suffering from a cerebralaneurysm, a brain artery sclerosis, a neck artery sclerosis, a neurovascular carotid arterial dissection or a carotid artery dissection.In a preferred embodiment, the patient is administered an infusion of 5-80mg ticagrelor post-procedure.In a preferred embodiment, 20-50 mg ticagrelor is administered twice daily following the intravenous administration of ticagrelor. In a preferred embodiment, the patient is clopidogrel resistant. In a preferred embodiment, ticagrelor is administered as monotherapy. In a preferred embodiment, ticagrelor is administered as part of a dual antiplatelet therapy in combination with aspirin. In a preferred embodiment, the patient has undergone a vascular stent implantation. In a preferred embodiment, the pharmaceutical composition is infused duringthe neurovascular arterial procedure in a therapeutically effective amount.DETAILED DESCRIPTION OF THE INVENTION Unless otherwise defined, all terms used in the description of the invention, including technical and scientific terms, have the meaning as commonly understood by a person skilled in the art to which the invention pertains. Furthermore, definitions of the terms are included to better understand the description of the present invention. As used here, the following terms have the following meaning: “A”, “an”, and “the” as used here refer to both the singular and the plural, unless the context indicates otherwise. “A surfactant” refers, by way of example, to one or more than one surfactant. “About” as used herein, referring to a measurable value such as a parameter, an amount, a duration and the like, is intended to include variations of plus or minus 10% or less, preferably plus or minus 5% or less, more preferablyplus 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 of the specified value, as far as such variations are suitable for carrying out in the described invention. It will be clear, however, that the value to which the term “about” relates is itself also specifically described. “Include”, “comprising” and“comprises” are used herein are inclusive or open terms that specify thepresence of what follows, e.g. a component and the presence of additional, unnamed components, features, elements, parts, steps, which are well known in the art or described therein, and do not exclude them. The recitation of numerical ranges by endpoints includes all numbers and fractions that are included within that range, as well as the endpoints mentioned.The term “% w / w” as used herein means percentage by weight in which theweight ratio of an ingredient to the total weight of a composition is expressedas a percentage.The invention provides a solution to the problem of limited bioavailability anda slow onset of therapeutic effect provided by ticagrelor tablets for use in the reduction or prevention of thromboembolic events following a neurovascular arterial procedure of a patient in need thereof. The present invention provides an aqueous ticagrelor solution provided for intravenousadministration for use in neurovascular arterial procedure of a patient in needthereof. By the term “provided for intravenous administration” as used herein, is meant a composition that is compatible for administration into a bloodstream. This particularly relates to the osmolality and pH of the formulation to be compatible. No dilution or pH adjustment are required, the formulation is ready-to-use. Preferably the patient is a human patient. Preferably the aqueous ticagrelor solution is prepared from micronized ticagrelor with D90 of less than 90 micrometers. A method for the measurement of particle size of an active ingredient, is well-known to a person skilled in the art of formulations. The method used in the presentinvention is by Malvern Mastersizer dry powder method.In particular, the present invention provides a pharmaceutical compositioncomprising ticagrelor for use in the reduction or prevention ofthromboembolic events before and / or during and / or following aneurovascular arterial procedure of a patient in need thereof, comprising administering to the patient an effective amount of the pharmaceutical composition comprising ticagrelor, characterized in, that the pharmaceutical composition is an aqueous solution comprising a solubilizer for ticagrelor andthe pharmaceutical composition is administered intravenously; wherein thepatient is suffering from a cerebral aneurysm, a brain artery sclerosis, a neck artery sclerosis, a neurovascular carotid arterial dissection or a carotid artery dissection. Ticagrelor is a well-known active ingredient. It is a platelet aggregation inhibitor used for the prevention of thrombotic events, such as myocardial infarctions or strokes, in patients with acute coronary syndromes. 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)pyrimidin-3-yl}-5-(2 hydroxyethoxy)cyclopentane-1,2-diol.By the term “ticagrelor” as used herein, is meant ticagrelor in free form as well as to its pharmaceutically acceptable solvates, hydrates, enantiomers, polymorphs, or mixtures thereof. Preferably ticagrelor is used in its free form. Ticagrelor was developed by AstraZeneca and was approved for entry on the market by the European Medicines Agency in 2010 and by the US Food and Drug Administration in 2011. As drug it is marketed in tablet form under the name Brilinta®in the USA and Brilique®in the EU. It is not commercially available in liquid form. Ticagrelor is an oral, reversible, direct-acting P2Y12 receptor antagonist that works by inhibiting plateletactivation. Brilinta® tablets, together with aspirin, have shown tosignificantly reduce the risk of major adverse cardiovascular (CV) events (heart attack, stroke or CV death), in patients with acute coronarysyndrome (ACS) or a history of heart attack. In the US, Brilinta® tabletsare also indicated for the reduction of the risk of a first heart attack orstroke in high-risk patients with coronary artery disease. Ticagrelor is highly susceptible to degradation when exposed to light, heatand oxygen. In addition, its limited solubility is a great challenge to be ableto formulate it as an aqueous solution. Although the need for a liquid ticagrelor formulation remains high, to our knowledge a successful commercial product of desired solubility and long-term stability in correspondence with requirements of the pharmaceutical industry has not been successful. By experimentation it was found that ticagrelor can be solubilized using a suitable solubilizer. Preferably this solubilizer is a cyclodextrin or a vitamin E TPGS. Cyclodextrins are cyclic carbohydrates derived from starch. The unmodified cyclodextrins differ by the number of glucopyranose units joined together in the cylindrical structure. The parent cyclodextrins contain 6, 7, or 8 glucopyranose units and are referred to as α-, β-, and γ-cyclodextrin respectively. Each cyclodextrin subunit has secondary hydroxyl groups at the 2 and 3-positions and a primary hydroxyl group at the 6-position. The cyclodextrins may be pictured as hollow truncated cones with hydrophilic exterior surfaces and hydrophobic interior cavities. In aqueous solutions, these hydrophobic cavities provide a haven for hydrophobic organic compounds, which can fit all, or part of their structure into these cavities. This process, known as inclusion complexation, may result in increased apparent aqueous solubility and stability for the complexed drug; 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. Chemical modification of the parent cyclodextrins (usually at the hydroxyl moieties) has resulted in derivatives with sometimes improved safety while retaining or improving the complexation ability of the cyclodextrin. Of the numerous derivatized cyclodextrins prepared to date, only two appear to be commercially viable; the 2-hydroxypropyl derivatives (HP-β-CD or HPβCD), neutral molecules being commercially developed by Janssen and others, and the sulfoalkyl ether derivatives (SAE-β-CD or SAE-CD), being developed byCyDex Pharmaceuticals, Inc. The SAE-CDs are a class of negatively chargedcyclodextrins, which vary in the nature of the alkyl spacer, the salt form, the degree of substitution and the starting parent cyclodextrin. The sodium salt of the sulfobutyl ether derivative of beta-cyclodextrin, with an average of about 7 substituents per cyclodextrin molecule (SBE7-β-CD), is being commercialized by CyDex Pharmaceuticals, Inc. (Kansas) as CAPTISOL® cyclodextrin. In a preferred embodiment the cyclodextrin is selected from a hydroxypropyl-beta-cyclodextrin and a sulfobutylether of a beta- cyclodextrin. More preferably the cyclodextrin is a hydroxypropyl-beta- cyclodextrin. Most preferably the cyclodextrin is (2-hydroxypropyl)-beta- cyclodextrin. In a preferred embodiment, ticagrelor is the only active pharmaceutical ingredient present in the composition. Alternatively, an additional active ingredient can be included. Preferably the additional active ingredient is not prasugrel. In a preferred embodiment the aqueous ticagrelor composition for iv administration in the treatment of a neurovascular arterial event comprises0,1 to 15 mg / ml ticagrelor; more preferably 1-14 mg / ml ticagrelor or 2-13mg / ml; even more preferably 3-12 mg / ml ticagrelor or 4-11 mg / mlticagrelor; most preferably 5-10 mg / ml ticagrelor. A ticagrelor iv compositionfor use in the treatment of a neurovascular arterial event may be used byinjection, a short-term infusion or a long-term infusion. The short-terminfusion is preferably between 1 and 30 minutes, more preferably between1,5 and 25 minutes; most preferably between 2 and 5 minutes.In a preferred embodiment the aqueous ticagrelor composition for iv administration in the treatment of a neurovascular arterial event comprises comprising 15–40% w / w, more preferably 20-35% w / w, even more preferably 22-34% w / w, most preferably 23-33% w / w hydroxypropyl-beta- cyclodextrin. The amount of cyclodextrin selected is an amount sufficient to enclose a therapeutically relevant amount of cyclodextrin and to provide a clear ticagrelor solution. In a preferred embodiment the aqueous ticagrelor composition for iv administration in the treatment of a neurovascular arterial event does not comprise an organic co-solvent. The use of organic co-solvents is not required to improve the solubility of ticagrelor. The avoidance of organic co- solvents provides a better compatibility of the product for an intravenous administration. In particular, the aqueous ticagrelor composition for ivadministration in the treatment of a neurovascular arterial event is devoid ofpolyethylene glycol. This is advantageous for storage stability as thepresence of polyethylene glycol in an aqueous ticagrelor solution was found prone to generate impurities when stored for a longer period of time. In particular, the aqueous ticagrelor composition for iv administration in thetreatment of a neurovascular arterial event has an osmolality between 350-900 mOsm / kg. This osmolality is advantageous in an intravenous administration to a patient in need of ticagrelor iv treatment. In a preferred embodiment the aqueous ticagrelor composition for iv administration in the treatment of a neurovascular arterial event has a pH of 5,5 to 9,0, more preferably has a pH of 7,0 to 8,0. This pH selection was advantageous for the long-term storage stability of ticagrelor iv compositions. In addition, it provides a physiologically acceptable pH. In a preferred embodiment the aqueous ticagrelor composition for iv administration in the treatment of a neurovascular arterial event has a storage stability of at least 3 months in accelerated storage conditions at 40 °C and 75 % Relative Humidity (RH). More preferably said storage stability is at least 6 months; even more preferably at least 9 months; most preferably at least 12 months. A satisfactory stability of 6 months at 40°C and 75% RHcorresponds to a shelf life of 24 months at room temperature of 25 °C.“Storage stability” as used herein means that the total impurity level is below 0,5%. A storage stable composition has the advantage over an extemporaneous compounded composition that the product does not need preparation just prior to a medical treatment. This is time saving. Most preferably the aqueous ticagrelor composition for iv administration inthe treatment of a neurovascular arterial event is a solution consisting of:5 - 15 mg / ml ticagrelor,15 – 40 % w / w of a hydroxypropyl-beta-cyclodextrin,5 mM-20 mM of buffer, wherein the pH is between 5,5 and 8 Most preferably the aqueous ticagrelor composition for iv administration inthe treatment of a neurovascular arterial event is a solution consisting of:5 - 15 mg / ml ticagrelor,15 – 40 % w / w of a hydroxypropyl-beta-cyclodextrin,5 mM-20 mM of phosphate buffer, wherein the pH is between 5,5 and 8. Alternatively, the aqueous ticagrelor composition for iv administration inthe treatment of a neurovascular arterial event is a solution consisting of:0,10 – 14,0 mg / ml ticagrelor and20 – 100 mg / ml of cyclodextrin in a quantity for solubilization of theticagrelor in the selected volume of aqueous pharmaceutical solution,wherein the composition has a pH between 5,5 – 9,0 endpoints included,and the aqueous pharmaceutical solution has a volume of 25 to 1000 ml. The composition provided above is simple and easy to manufacture. The limited number of ingredients reduced the formation of impurities and sideproducts. This is advantageous for the availability of ticagrelor iv solutions topatients requiring treatment of a neurovascular arterial event. Optionally the aqueous ticagrelor composition for iv administration in thetreatment of a neurovascular arterial event may include a tonicity modifier,such as sodium chloride. Preferably the osmolality of the aqueous ticagrelorcomposition for iv administration in the treatment of a neurovascular arterialevent is between 350-900 mOsm / kg, more preferably between 360 – 800mOsm / kg, even more preferably between 370-700 mOsm / kg, most preferably between 380 and 600 mOsm / kg. In a preferred embodiment the aqueous ticagrelor composition for iv administration in the treatment of a neurovascular arterial event, comprisesvitamin E TPGS as the solubilizer for ticagrelor. It was found that use ofvitamin E TPGS is advantageous for solubilization of the poorly water soluble ticagrelor. With the term “vitamin E TPGS” as used herein is meant a water miscible form of vitamin E having a hydrophobic vitamin E part and a hydrophilic polyethylene glycol chain. Vitamin E TPGS is also known as D-alpha- tocopheryl polyethylene glycol succinate or Tocophersolan. Vitamin E TPGS has been approved by the Food and Drug Administration of the US as a safe adjuvant and finds use in drug delivery systems as surfactant, solubilizer or stabilizer. US 2680749 discloses TPGS molecules in which the polyethylene glycols have average molecular weights of 400, 1000, and those varying between 600 and 6000. Vitamin E TPGS molecules in which the polyethylene glycol chains have an average molecular weight (MW) of about 1000 are commercially available from Eastman Chemical Company, (Kingsport, Tennessee). Ticagrelor iv may find use in the treatment of neurovascular arterialprocedures. Ticagrelor iv may provide antiplatelet therapy before, during orafter a surgical procedure aimed at resolving a non-ruptured intracranial aneurysm. Alternatively, ticagrelor iv may provide antiplatelet therapybefore, during or after a surgical procedure for treatment of a brain or a neckartery sclerosis. In a preferred embodiment of the ticagrelor composition for use in thereduction or prevention of thromboembolic events before and / or duringand / or following a neurovascular arterial procedure of a patient in need thereof, P2Y12 reactive units (PRUs) during ticagrelor administration are below 200, more preferably below 150, even more preferably below 110. Most preferably P2Y12 reactive units are between 0 and 100.P2Y12 reactive units (PRUs) as an indication of platelet function can bemeasured by VerifyNow P2Y12 Test (Accriva Diagnostics). Platelet reactivity was expressed in P2Y12 reaction units (PRUs), and in % inhibition. It was calculated as ((1-(P2Y12 receptor blockade / basal platelet reactivity) x 100). In the scientific literature it is reported that the risk of complications may be correlated with high PRUs. For ticagrelor advice is to keep the PRU between0 and 100.In a preferred embodiment of the invention, ticagrelor is administered intravenously within 5 days preceding the neurovascular arterial procedure. More preferably ticagrelor iv is administered within 4 days, even morepreferably within 3 days, most preferably within 2 days or within 1 daypreceding the neurovascular arterial procedure. For emergency surgery a patient may have received ticagrelor iv just prior to surgery. An antidote or absorption technology may be used to reduce the level of ticagrelor in the blood. Preferably ticagrelor is administered intravenously following theneurovascular arterial procedure; preferably within 6, 5 or 4 hours post-procedure. More preferably within 3 hours post-procedure, most preferablywithin 2 hours post-procedure.A patient may be conscious and capable of swallowing a tablet 4 to 6 hours after surgery. Hence oral anti-platelet therapy can be started. The availabilityof a ticagrelor iv has the advantage that ticagrelor treatment can be startedwhen a patient is still in recovery, unconscious or comatose. This may be anadvantage for reducing the risk of thrombosis following the procedure.With the term “cerebral aneurysm” or “brain aneurysm” as used herein, is meant a ballooning arising from a weakened area in the wall of a blood vessel in the brain. A brain aneurysm that expands results in the blood vessel wall becoming too thin, resulting in a rupture of the aneurysm and bleeding into the space around the brain.In a preferred embodiment, the pharmaceutical composition is used in thetreatment of a patient suffering from a cerebral aneurysm.With the term “brain artery sclerosis” or cerebral artery sclerosis” as used herein, is meant a disease that occurs when the arteries in the brain becomehard, thick, and narrow due to the buildup of deposits or plaques inside theartery walls. The buildup decreases the amount of blood flow to certain areasof the brain. Some of the main components of the plaques are connectivetissue, extracellular matrix, including collagen, proteoglycans, fibronectin, and elastic fibers: crystalline cholesterol, cholesteryl esters, and phospholipids: cells such as monocyte derived macrophages, T-lymphocytes, and smoot muscle cells. The plaque that builds up can lead to further complications such as stroke, as the plaque disrupts blood flow within the intracranial arterioles. This causes the downstream sections of the brain that would normally be supplied by the blocked artery to suffer from ischemia.Diagnosis of the disease can be done through imaging technology such asangiograms or magnetic resonance imaging.In a preferred embodiment, the pharmaceutical composition is used in thetreatment of a patient suffering from a brain artery sclerosis.With the term “neck artery sclerosis” or “carotid artery sclerosis” as usedherein, is meant a disease withing the arteries transporting blood and oxygento the brain. Deposits or plaques clog the blood vessels. The clog increases the risk of stroke. Stroke is a medical emergency that occurs when the brain loses all or much of its blood supply. During a stroke, the brain may not get enough oxygen and brain cells begin to die. Carotid artery disease oftendevelops slowly. The first sign of the condition might be a stroke or transientischemic attack (TIA). A TIA is a temporary shortage of blood flow to the brain. Treatment of carotid artery disease may involve lifestyle changes,medicines, or surgery.In a preferred embodiment, the pharmaceutical composition is used in thetreatment of a patient suffering from a neck artery sclerosis.The treatment of a patient may involve the placement of a neurovascular stent. A neurovascular stent is a small, tube-like, flexible device that is made of either metal or polymer. A stent can be placed within a blood vessel to enhance blood flow. The stent can be an intracranial stent, i.e. a stent placed in a blood vessel in the brain, or a carotid artery stent, i.e. a stent placed ina blood vessel in a neck artery supplying blood to the brain.The surgical procedure for the treatment of an aneurysm may comprise aneurysm embolization by coiling, stenting, or flow diversion. Embolization is a minimally invasive procedure to treat an aneurysm by filling it with material to close off the sac and reduce the risk of bleeding. It is performed from within an artery, thus in an endovascular way, through a steerable catheter inserted into the blood stream and guided to the desired location. Tiny coils, glue, or mesh stents are used to close off the aneurysm.In a preferred embodiment, the pharmaceutical composition is used in thetreatment of a patient suffering from a neurovascular dissection. Theneurovascular dissection may be a brain artery dissection or a carotid artery dissection. A dissection is a structural failure of an arterial wall that results in an intramural bleed, which forms an intramural hematoma that dissects the vessel wall. In a preferred embodiment of the invention, the patient is post-procedureadministered a bolus infusion of 5-80 mg ticagrelor. The first infusion withticagrelor is potentially followed by one or more infusions. Preferably the oneor more infusions comprise the administration of 5-80 mg ticagrelor.In a preferred embodiment of the invention, the treatment comprises the administration of 20-50 mg ticagrelor twice daily following the last intravenous administration of ticagrelor. A switch-over from iv to oral administration of ticagrelor is advantageous for the comfort of the patient. Apatient on tablet medication can more easily be sent home as no assistanceis required for the administration of intravenous medication. In a preferred embodiment of the invention, the composition is used in thetreatment of a patient who is clopidogrel resistant.Clopidogrel resistance is a condition in which the drug clopidogrel is less effective than normal in people who are treated with it. Residual platelet aggregation greater than 50% relative to baseline is defined as poor response after clopidogrel when measured using light transmission aggregometry using 20 μM ADP stimulation. Platelet aggregation may be assessed as follows. Blood collected in blood-citrate tubes was centrifuged at 120 g for 5 min to recover platelet-richplasma and further centrifuged at 850 g for 10 min to recover platelet-poorplasma. The PRP and PPP were stored at room temperature to be used within 2 h. Platelets were stimulated with 20 μM ADP, and the aggregation was assessed using a Chronolog Lumi-Aggregometer (Model 490-4D) with the Aggro / Link software package (Chronolog, Havertown, Pennsylvania). Aggregation was expressed as the maximum percent change in light transmittance from baseline, using platelet-poor plasma as a reference.Ticagrelor iv is preferably administered as monotherapy. Alternatively,ticagrelor iv use is part of a dual antiplatelet therapy in combination withaspirin. In a preferred embodiment, the patient has undergone vascular stent implantation. In a preferred embodiment, the pharmaceutical composition is infused duringthe neurovascular arterial procedure in a therapeutically effective amount.In a second aspect, the invention provides a method of treatment of a patient with an aneurysm in need of anti-platelet therapy comprising the step of administering a therapeutically active dose to the patient in need thereof, thereby controlling thromboembolism complications without increasing hemorrhagic complications during perioperative and postoperative interventional aneurysm therapy. References 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, 1077.2. 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, 3. Imaging of artherosclerosis: magnetic resonance imaging. Roberto Corti, Valentin Fuster. European Heart Journal, Volume 32, Issue 14, July 2011, pages 1709-1719.4. Gurbel PA, Bliden KP, Guyer K, et al. Platelet reactivity in patients andrecurrent events post-stenting: Results of the PREPARE POST-STENTINGStudy. J Am Coll Cardiol2005; 46: 1820–1826. pages 445-452.EXAMPLESPharmaceutical ticagrelor compositions for use in the reduction or preventionof thromboembolic events before and / or during and / or following aneurovascular arterial procedure of a patient in need thereof are provided inthe examples below. Example 1 : Vitamin E TPGS as solubilizer for ticagrelor Table 1: Ticagrelor iv compositions Formulation Weight ticagrelor Volume (mL) Concentrationadded (mg) (mg ticagrelor / ml) 2,5 %30 50 0,600vitamin E TPGS 5,0 % 30 50 0,600 vitamin E TPGS 10,0 %30 50 0,600vitamin E TPGSAqueous ticagrelor solutions, using vitamin E TPGS as solubilizer, wereprepared as follows. Water soluble vitamin E TPGS was added to water to obtain different concentrations of 2,5 and 5,0 and 10,0 w / v% aqueous vitamin E TPGS solutions. To these solutions, kept at a temperature of 45°C+ / - 5°C, portions of ticagrelor were gradually added. 3 mg ticagrelor portionswere added step-by-step to a 50 ml aqueous vitamin E TPGS solution (1ststage). 20 ml of each diluent were then used in a 2ndstage study. To 20 ml of each diluent 10 mg ticagrelor portions were added. This was reduced to 5 mg when the dissolution was taking longer. Table 2: Aqueous ticagrelor iv solutions Formulation Weight ticagrelorVolume (mL) Concentration added (mg) of 0,6 mg / ml (mg ticagrelor ticagrelor / ml) solution from Table 1 2,5 % vitamin E220 20 11,600TPGS (232 / 20) 5,0 % vitamin E286 20 14,900TPGS (298 / 20) 10,0 % vitamin E384 20 19,800TPGS (396 / 20) The following was observed: 10 mg ticagrelor dissolved after 5-10 minutes.2,5 % vitamin E TPGS solution saturated at 11,6 mg / ml5,0 % vitamin E TPGS solution saturated at 14,9 mg / ml10,0 % vitamin E TPGS solution saturated at 19,8 mg / ml The aqueous ticagrelor solutions obtained are stored at 40 °C and 75 % Relative Humidity or at 25 °C and 60 % Relative Humidity, for a period of at least 3 months.Example 2: Cyclodextrin as solubilizer for ticagrelorThe following compositions are suitable as ready-to-use ticagrelor aqueouscompositions for iv administration.Table 3 : ready to use ticagrelor compositions in waterRTU Infusion RTU Infusion RTU Infusion Formulation Formulation Formulation mg / bottle mg / bottle mg / bottle 0.65 mg / ml TCG 0.325 mg / ml TCG 0.10 mg / ml TCG concentration concentration concentration Composition 3.1 Composition 3.2 Composition 3.3 Ticagrelor 65 65 65Hydroxy Propyl8000 16000 16000beta cyclodextrin (HPβCD) Water 100 ml 200 ml 650 mlpH 7.33 7.40 7.57Osmolarity96 90 22(mOsmol / kg) Clarity Clear solution Clear solution Clear solutionTable 4 : ready to use ticagrelor compositions in aqueous phosphate bufferRTU Infusion RTU Infusion RTU Infusion Formulation Formulation Formulation mg / bottle mg / bottle mg / bottle 0.65 mg / ml TCG 0.325 mg / ml TCG 0.10 mg / ml TCG concentration concentration concentration Composition 3.4 Composition 3.5 Composition 3.6 Ticagrelor 65 65 65Hydroxy Propyl8000 16000 16000beta cyclodextrin (HPβCD) Phosphate buffer100 ml 200 ml 650 mlpH 7.5 (10 mMbuffer) pH 7.58 7.45 7.6Osmolarity105 220 280(mOsmol / kg) Clarity Clear solution Clear solution Clear solutionTable 5 : ready to use ticagrelor compositions in diluted saline waterRTU Infusion RTU Infusion RTU Infusion Formulation Formulation Formulation mg / bottle mg / bottle mg / bottle 0.65 mg / ml TCG 0.325 mg / ml TCG 0.10 mg / ml TCG concentration concentration concentration Composition 3.7 Composition 3.8 Composition 3.9 Ticagrelor 65 65 65Hydroxy Propyl beta cyclodextrin8000 16000 16000(HPβCD) Normal Saline 200 ml (0.9 w / v% Nacl in100 ml 650 ml water) pH 6.57 6.6 6.90Osmolarity 415 518 314 (mOsmol / kg) Clarity Clear solution Clear solution Clear solutionTable 6 : ready to use ticagrelor compositions in dextrose solutionRTU Infusion RTU Infusion RTU Infusion Formulation Formulation Formulation mg / bottle mg / bottle mg / bottle 0.65 mg / ml TCG 0.325 mg / ml TCG 0.10 mg / ml TCG concentration concentration concentration Composition 13.10 Composition 13.11 Composition 13.12 Ticagrelor 65 65 65Hydroxy Propyl8000 16000 16000beta cyclodextrin (HPβCD) Dextrose 5 w / v% 100 ml 200 ml 650 mlpH 5.12 5.6 6.61Osmolarity512 425 336(mOsmol / kg) Clarity Clear solution Clear solution Clear solutionTable 7 : preferred ticagrelor solution for infusionRTU Infusion Formulation mg / bottle 2 mg / ml TCG concentration Composition 13.13 Ticagrelor (TCG) 65Hydroxy Propyl beta cyclodextrin (HPβCD) 3000Dextrose 5 w / v % 30 ml pH 7.05Osmolarity (mOsmol / kg) 674Clarity Clear solutionThe exemplified ready-to-use solutions were made as follows. In all cases a solvent as mentioned is prepared and taken in a beaker and heated to 40 °C, then HPβCD is added to obtain a clear solution under stirring. After this the active ingredient ticagrelor is added at 40 °C under constant stirring until a clear solution is obtained. This solution is filtered through a 0.22-micron filter and filled aseptically in a sterile glass bottle or an infusion bag. 24 mg / ml to 350 mg / ml HPβCD was required to obtain a stable Ticagrelor solution ready for infusion. The amount of cyclodextrin required was depending upon the volume of the targeted infusion medium. Ticagrelor is an active ingredient that is insoluble in water. The more it is in a diluted aqueous solution, the more tendency it has to precipitate. A proportional increase in cyclodextrin was required as the dilution factor forticagrelor increased, when going from 30 ml to 100 ml to 200 ml. However,for a 650 ml volume and higher an amount of 16 g of cyclodextrin was foundsufficient to solubilize the ticagrelor.Note that no organic co-solvent, surfactant or other solubilizer were used.The aqueous ticagrelor solutions obtained were stored at 40 °C and 75 %Relative Humidity or at 25 °C and 60 % Relative Humidity, for a period of atleast 3 months and were found stable.Development of storage stable ticagrelor solutions In the following examples the experimental work for obtaining storage stable ticagrelor solutions is explained. Example 3In the present example two different types of cyclodextrin were used andcompared for the solubilization of ticagrelor. An unbuffered stock solution of HPβCD or SBECD was made in water at the target concentrations of 20%w / w, 25% w / w, 30% w / w, 35% w / w and 40% w / w. Ticagrelor was addedslowly under vortex. Ticagrelor was used at concentrations of 5, 10 or 14 mg / ml in milli Q water. The ticagrelor-cyclodextrin solutions were left on a shaking platform. No sonification or heat was applied.From the results in Tables 8 and 9 it follows that HPβCD was able to dissolveticagrelor in a broader range of cyclodextrin and ticagrelor concentrations tested. Clear aqueous solutions with 5 mg / ml ticagrelor in HPβCD wereobtained with 25% w / w, 30% w / w, 35% w / w and 40% w / w HPβCD.Table 8: Solubility of ticagrelor in HPβCD TicagrAppearance of Ticagrelor in cyclodextrinHPβCD elor conc. inconc. Floccul MilliQ After Afte Afte ation (%(mg / After After 5 min r 30 r 60 overnigtestw / w) l) 3h of h m of min min shaki t shaki o shaking ng f of shakin shakin ng g g 5+ + + + + passed40 % 10 - + / - + / - + / - + passed14 - + / - + / - + / - + / -* n.a.5 + / - + / - + / - + / - + passed35 % 10 - + / - + / - + / - + didnot pass 14 - + / - + / - + / - + / - n.a.5 - + / - + / - + / - + passed30 % 10 - - - - - n.a.14 - - - - - n.a.5 - + / - + / - + / - +* did25 %not pass 10 - - - - - n.a.14 - - - - - n.a.5 - + / - + / - + / - - n.a.20 % 10 - - - - - n.a.14 - - - - - n.a.+ clear, appeared completely dissolved- translucent solution with precipitation+ / - clear solution with precipitation* after one hour of sonicationTable 9: Solubility of ticagrelor in SBECD TicagrelAppearance of Ticagrelor inSBECDor conc. cyclodextrin Flocculaticonc. inAfter Afte Afte Afte After on test MilliQ (mg / ml r 5min r r 3 overnig (%w / w ) h of of 30mi 60mi shaki ht shaki n ) shakin ngn of n ofshakin shakin g g g g 5- ++ ++ passe40 % / - / - / - d 10 - - - - - n.a.14 - - - - - n.a.5 - ++ +n.a. / - / - -35 % / - 10 - - - - - n.a.14 - - - - - n.a.5 - - - - - n.a.30 % 10 - - - - - n.a.14 - - - - - n.a.5 - - - - - n.a.25 % 10 - - - - - n.a.14 - - - - - n.a.5 - - - - - n.a.20 % 10 - - - - - n.a.14 - - - - - n.a.+ clear, appeared completely dissolved- translucent solution with precipitation+ / - clear solution with precipitationAs a conclusion Ticagrelor could be dissolved by leaving it on a shakingplatform. No sonication was applied. HPβCD can be used at Ticagrelorconcentrations 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 least for the threedays testing at room temperature and several days at 4°C.Example 4 After the experiments depicted in Example 3, further optimization was caried out with the selection of a suitable pH range to ensure long-term stability of the aqueous ticagrelor-cyclodextrin inclusion complex.The following composition as provided in Table 10 was prepared.Table 10: Composition for storage stability testing. mg / ml Ticagrelor 6HPβCD 40%w / w 452Acetate or Phosphate Buffer pH 4.5 Q.S to 1 ml to 6.5 HPβCD was dissolved in a buffer solution of pH 4.5, 5.5 or 6.5 prepared separately in water. Once a clear solution was obtained, ticagrelor was dissolved in the buffer solution under constant stirring. The ticagrelor in buffer solution was filtered through a 0.22 micron filtered and filled in USP Type I glass vials. The vials were stoppered and stored. All precautions were taken during manufacturing, such as N2 purging and avoiding direct exposure to light. The vials were stored at 40°C and 75 % Relative Humidity (RH). To determine the stability of the formulations, batches were evaluated using a related substance method on HPLC. The data of these batches is enumerated below in Table 11. A Gradient HPLC method was used to analyze impurities in formulations usinga YMC-Pack Pro C18 column (100x4.6 mm, S-3 μm 12 nm). Good separationwas obtained for all the impurities.Amine impurity: (1S,2S,3R,5S)-3-(7-amino-5-(propylsulfanyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)-5-(2-hydroxyethoxy)cyclopentane- 1,2-diol. This is a process related degradant impurity.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]pyrimidin-7-yl)amino)-5-(2-hydroxyethoxy)cyclopentane-1,2-diol. This is a processrelated degradant impurity.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]pyrimidin-3-yl]-2,2-dimethyltetrahydro-2H-3aHcyclopenta[d][1,3] dioxol-4-yl]oxy]ethan-1-ol. This is a process related impurity. 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]pyrimidin-3- yl)cyclopentane-1,2,3-triol. This is a process related impurity. It was observed that only regiomer impurity increased in 4 weeks 40°C and 75 % RH at almost 0.3% level; specification limit 0.3 %. Hence to optimize the stability of the product further, investigations were carried out at pH 7 to 8. Example 5 Following the experiment described in example 4, a storage stability study at pH 7.5 was conducted. First HPβCD was dissolved in a phosphate buffer solution of pH 7.5 prepared separately 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 in USP Type I amber colored glass vials. The vials were stoppered and stored. All precautions were taken during manufacturing, such as N2 purging and avoiding direct exposure to light.

[0002] 

[0003] Table 12: Composition for storage stability testing. mg / ml Ticagrelor 6HPβCD 40% w / w 452Phosphate buffer pH 7.5 Q.S to 1 mlTable 13: Storage stability study of ticagrelor-cyclodextrin inclusion complex in aqueous solution at pH 7.5 stored at 40°C and 75 % Relative Humidity. Time point T=0 T=4T=8 T=12 T=24 40 °C and 75 % RH weeks weeks weeks Weeks Assay ticagrelor (%) 104.27 104.47 102.59 102.31 104.39Relative retention timeImpurity ID impurity impurity impurity impurity impurity(minutes) (%): (%): (%): (%): (%):0.45 Amine 0.04 0.05 0.05 0.05 0.07impurity 0.97 Triol 0.04 0.05 0.05 0.04 0.05impurity 1.03 Regiomer 0.00 0.01 0.04 0.08 0.16impurity 1.49 Acetal 0.05 0.05 0.05 0.05 0.05impurity Total Impurities (%) 0.31 0.32 0.29 0.41 0.35Sum Impurities >0.05 0.11 0.14 0.15 0.23 0.33(%) Based on the results of the stability study, as summarized in Table 13, it was concluded that good storage stability was obtained at accelerated storage conditions of 40°C and 75 % Relative Humidity. The regiomer impurity was well under control and no other impurity was of a concern. Example 6In a further experiment, to optimize the concentration of HPβCD below40% w / w, heat at 40°C was applied at concentrations where a clear solution was difficult to obtain to help dissolve the target ticagrelor dose.Direct physical stability data as obtained from the ticagrelor 5 mg / mlconcentrate and with the flocculation test (20 µl sample material in 1 mldiluent) are shown in Table 14. Table 7 contains data on assay, purity,osmolality and pH.Table 14: Physical stability of ticagrelor 5 mg / ml batches with varyingHPβCD concentrations. Data are sorted by HPβCD strength. Ticagrelorconcentration when diluted into dextrose or saline: 0.1 mg / ml.HPβCDAppearance, undiluted AppearanceAppearance strength inin NaCl(% w / w) 5% dextrose0.9% 32.5 Clear solution ClearClear solution solution 30.0 Clear solution ClearTurbid solution 27.5 Turbid; clear after heatingClear Turbid to 40°Csolution 25.0 Turbid; clear after heatingClear Turbid to 40°Csolution 22.5 Turbid; clear after heatingClear Turbid to 40°Csolution Because of the poor physical stability results when diluted in saline, 32.5% w / w HPβCD was chosen for a 5 mg / ml ticagrelor formulation. Undilutedconcentrate remained stable even in the refrigerator with a HPβCDconcentration as low as 22.5 % w / w. Such a concentration yielded a nearly isotonic formulation. In conclusion, it was possible to dissolve 5-15 mg / ml ticagrelor together with HPβCD in the concentration range of 20-40 % w / w, without the use of heat. It was possible to achieve good solubility with lower concentrations of HPβCD such as 15-20 % w / w with application of heat to achieve a clear solution. At least 15% w / w HPβCD was required to provide a clear, storage stable ticagrelor solution with a concentration that is relevant for injection or intravenous administration. Example 7 From the results obtained in Example 6 it follows that the concentration of excipients may be such that the resulting ticagrelor solution is hypertonic. The osmolality and pH of several batches was checked. The solutions hada 19 mM phosphate buffer and pH 7.5. The results are provided in Table15. Table 15: pH and osmolality determination in undiluted batches. HPβCD Assay Total pH Osmolality strength (%) impurities undiluted undiluted (% w / w) (%) (mOsm / kg) 32.5 99.26 0.41 7.68 81330.0 107.64 0.44 7.74 63827.5 104.27 0.42 7.69 54925.0 103.23 0.41 7.69 49322.5 98.15 0.39 7.67 392Dilution studies were conducted to search for suitable diluents. 5 mg / ml ticagrelor-cyclodextrin solutions with varying amounts of HPβCDwere diluted with normal saline, 5 % dextrose solution or Ringer’s lactate solution. The stability was screened. The ticagrelor concentration whendiluted into dextrose or saline: 0.1 mg / ml The results are summarized inTable 16. Table 16: Diluent tests HPβCDAppearance, undiluted Appearance inAppearance strength5% dextrose in NaCl(% w / w)0.9% 32.5 Clear solution Clear solution Clearsolution 30.0 Clear solution Clear solution Turbid27.5 Turbid; clear after heating to Clear solution Turbid40°C 25.0 Turbid; clear after heating to Clear solution Turbid40°C 22.5 Turbid; clear after heating to Clear solution Turbid40°C In addition, a screening was conducted on the impact of buffer strength on pH and osmolality. The results are summarized in Table 17. Table 17: Impact of buffer strength on pH, osmolality, assay, and impurities. Phosphate pH pH Osmolalit Osmolality Assa Total buffer pH sampl placeb y sample placebo y impuritie 7.5 e o (mOsm / k (mOsm / kg (%) s (%) strength g) ) (mM) 19 7.70 7.71 758 790 102.58 0.4210 7.69 7.72 724 692 102.98 0.425 7.66 7.73 703 725 100.49 0.400.19 7.18 7.45 809 771 102.23 0.42It was concluded that a phosphate buffer of pH 7,5 at different buffer strengths had little effect on the osmolality. Except at 0.19 mM buffer strength. This buffer strength was too weak, which lead to a change in pH. Example 8 In a further example the impact of particle size on solubility was tested. Two different particle size diameters for the ticagrelor active ingredient were screened, 5.5 and 15 micrometers. The pH and osmolality were not affected. Smaller particles showed a faster dissolution time, as summarized in Table 18. The micronized ticagrelor showed significant improvement on the dissolution time. Consequently, a micronized ticagrelor with D90 of less than 10 micrometers is preferred.With the term “D90” as used herein, is meant that at least 90 % of theparticles present have a size that is less than the target particle size. However, it is understood that variations in input particle size distribution (PSD) of ticagrelor would be possible and it will have an impact on the dissolution rate of ticagrelor. Table 18: Impact of particle size Particle distribution, D90DissolutionpH Osmolality(0.9) time (mOsm / kg) 5.5 µm, micronized 33 min 7.68 75115 µm, unmicronized 125 min 7.70 753Example 9 To optimize the HPβCD concentration and the pH of the solution for intravenous use, a 12 week / 3 months stability study was conducted. A composition of 32,5% w / w HPβCD with 5 mg / ml ticagrelor at pH 7 to 8 was prepared and stored. Its stability was tested at regular intervals.A comparison of stability profile at 3 different pH – 7, 7.5 and 8- wascarried out as below, the manufacturing process for all 3 formulations waskept constant with buffer strength at 19 mM. The results are summarizedin Tables 19 to 21Table 19: Storage stability in amber glass vials – pH 7 Amber colour USP Type I HPβCD 40% w / w 19 mM pH 7 Phosphate BufferT0 1M 2M 3MDescription clear clear clear clearAssay 98.95 99.73 99.81 98.51pH 7.33 7.34 7.34 7.30RRT Impurity % % % %0.45 Amine 0.04 0.04 0.04 0.06impurity 0.97 Triol 0.05 0.02 0.04 0.04impurity 1.03 Regiomer 0.00 0.03 0.06 0.111.49 Acetal 0.05 0.05 0.05 0.05impurity Total 0.41 0.27 0.34 0.40Sum Impurities >0.050.22 0.05 0.11 0.22(%)Table 20: Storage stability in amber glass vials – pH 7.5Amber colour USP Type I HPβCD 40% w / w 19 mM pH 7.5 Phosphate BufferT0 1M 2M 3MDescription clear clear clear clearAssay 104.27 104.47 102.59 102.31pH 7.40 7.50 7.48 7.55RRT Impurity % % % %0.45 Amine impurity0.04 0.05 0.05 0.050.97 Triol impurity0.04 0.05 0.05 0.041.03 Regiomer 0.00 0.01 0.04 0.081.49 Acetal impurity0.05 0.05 0.05 0.05Total 0.31 0.32 0.29 0.41Sum Impurities >0.05 (%) 0.11 0.14 0.15 0.23Table 21: Storage stability in amber glass vials – pH 8.0Amber colour USP Type I HPβCD 40% w / w 19 mM pH 8 Phosphate bufferT0 1M 2M 3MDescription clear clear clear clearAssay 103.25 105.88 105.46 104.46pH 8.07 8.10 8.04 8.03RRT Impurity % % % %0.45 Amine impurity0.04 0.05 0.05 0.070.97 Triol impurity0.06 0.03 0.05 0.051.03 Regiomer 0.00 0.01 0.03 0.061.49 Acetal impurity0.05 0.05 0.05 0.05Total 0.43 0.26 0.32 0.37Sum Impurities >0.05 (%) 0.25 0.09 0.15 0.23From the above data it was concluded that the ticagrelor solution in HPβCD was stable in the pH range of 7 to 8. Example 10 To study the potential impact of the packaging material on the stability of the ticagrelor-cyclodextrin inclusion complex a composition with 32.5%w / w HPβCD was prepared with procedures and precaution’s similar toprevious trials, samples were stored in transparent clear glass vials and amber colored glass vials at a temperature of 40 °C / 75% RH. The resultsare shown in Table 22 and Table 23.The results of the accelerated storage stability test indicated that after 3 months, no significant difference was observed between the two. All the samples remained clear aqueous solutions. The pH of the samples remained stable. Impurities did not change significantly. It seems that both clear and amber colored glass vials can be used. Compared to the results of the accelerated storage stability test on ticagrelor solutions, without the use of cyclodextrin, it is clear that the use of cyclodextrin is important to achieve a good stability. Without the cyclodextrin, 6 to 8 different impurities developed on storage. These impurities were not seen in the selected composition. Table 22: Study of the potential impact of packaging. Stability in amber color USP Type I glass. Amber colour USP Type I Glass vials HPβCD 32.5% w / w 5 mM pH 7.5 Phosphate BufferT0 1M 2M 3MDescription clear clear clear clearAssay 98.34 100.24 99.89 98.93pH 7.66 7.70 7.69 7.66RRT Impurity % % % %0.45 Amine 0.04 0.04 0.04 0.06impurity 0.97 Triol impurity 0.04 0.02 0.04 0.051.03 Regiomer 0.00 0.01 0.02 0.041.49 Acetal 0.05 0.05 0.04 0.05impurity Total 0.40 0.22 0.28 0.33Sum Impurities >0.050.18 0.05 0.00 0.16(%) Table 23: Study of the potential impact of packaging. Stability clear glassvials USP Type I.Clear USP Type I Glass vials HPβCD 32.5% w / w 5 mM pH 7.5 Phosphate bufferT0 1M 2M 3MDescription clear clear clear clearAssay 98.34 101.71 99.69 98.25pH 7.65 7.65 7.63 7.58RRT Impurity % % % %0.45 Amine 0.04 0.04 0.04 0.06impurity 0.97 Triol impurity 0.05 0.03 0.05 0.051.03 Regiomer 0.00 0.01 0.02 0.041.49 Acetal 0.05 0.04 0.04 0.05impurityTotal 0.40 0.22 0.28 0.33Sum Impurities >0.050.22 0.00 0.05 0.16(%) Surprisingly it could be concluded that ticagrelor solutions can be stabilized with HPβCD in both amber colored and clear glass vials. Example 11 Further embodiments of the invention are provided as summarized in Table 24. Further improvement in achieving higher solubility of ticagrelor was tried with different concentrations, such as with 40% w / w HPβCD, a ticagrelor solubility of 13 mg / ml was also possible. Table 24: clear aqueous solutions with ticagrelor-cyclodextrin inclusion complex considering 65 mg dose. N HPβ Ticagre Fin HPβC HPβ Appeara Flocculat Flocculat r CD lor al D CD nce ion ion (% (mg / ml Vol mg / g / via in saline, in w / w) ) ml ml l 1:2 dextrose , 1:2 A32.5 7.5 10 367.3.67 Clear,Clear Clear25 colorless B32.5 5 15 367.5.50 Clear,Clear Clear25 colorless C22.5 5 15 254. 3.81 Clear, Clear Clear25 colorless C40 13 5 452 3.39 Clear, Clear Clearcolorless D33 8.25 9.2 372. 3.43 Clear, Clear Clear3 colorless E30 7.5 10 339 3.39 Clear, Clear Clearcolorless Density 1.130 gm / ccBased on the investigations it was observed that a concentration of 5 – 13mg / ml ticagrelor solution could be achieved using 20-40% w / w HPβCD. The volume of the fill content can be changed based on the dose required. Surprisingly it was found that the target dose of 5 -15 mg / ml ticagrelor contained in a small volume could be achieved by adjusting the HPβCD % and total available volume of the formulation ready to inject. Being able to contain the ticagrelor dose in a volume of 5-15 ml is highly relevant as it is a typical bolus injection volume. Example 12 In a further example, the maximum solubility of ticagrelor in an HPβCD solution, without the use of heat, was investigated. The results are summarized in Table 25. Depending on the amount of ticagrelor to be delivered to a patient and the restriction of the sample volume as determined by an administration by injection or infusion, it follows that to dissolve 65-75 mg ticagrelor an amount of 2000-4000 mg of HPβCD per vial of 10 ml may be required. Table 25: Concentration of HPΒCD, dose and volume of formulations HPβCD HPβCD mg / ml Ticagrel 75 HPβCD 65 HPβCD % w / w %w / v HPβCD or mg mg / vial mg mg / vial mg / ml dose dose 17 19.21 192.10 4 18.75 3600 16.253121 ml ml 22.5 25.42 254.20 5 15.00 3813 13 ml 3304ml 30 33.90 339.00 8 9.37 3176 8.122752 ml ml 33 37.29 372.90 9 8.33 3107 7.222692 ml ml 40 45.2 452.00 13 7.76 3507 5 ml 2260ml Density of the HPβCD solution 1.130 gm / ccSurprisingly the solutions provided in Table 25 were compatible withdiluents to provide infusions, specifically with dextrose 5% in water. Example 13 In another embodiment of this invention, a highly stable clear solution of ticagrelor could be obtained by applying appropriate heat to the solution during preparation thus providing a completely clear solution of theformulation at desired HPβCD and ticagrelor concentrations.To investigate the impact of temperature and hold time, a new composition was prepared as per below Table 26. Table 26: Composition for temperature impact assessment. mg / ml Ticagrelor 8HPβCD 30% w / w 329Phosphate Buffer pH 7.5 in water Q.S to 1 mlIn first step a phosphate buffer at pH 7.5 was prepared and the buffered solution was heated to 40°C -45°C. HPβCD was added to the buffered solution under continuous mixing. Once a clear solution was obtained, ticagrelor was dispersed into the HPβCD solution and mixed until a clear solution was obtained. It usually took 30 mins to 4 hours depending on batch size. Then this solution was filtered through a 0.22-micron filter and packed in suitable clear or amber colored glass vials Table 27: Bulk hold study at 45°C Time points @ 45°C- Bulk hold in T=1h T=110hGlass vials Assay Ticagrelor (%) 107.87 109.10Relative retention Impurity Average contenttime:impurity (%):0.45 Amine 0.05 0.07impurity 0.97 Triol impurity 0.04 0.051.33 0.07 0.031.47 Acetal 0.04 0.04impurity Total Impurities (%) 0.20 0.28Sum Impurities >0.05 (%) 0.12 0.11Table 28: Bulk Hold study at 25°C and 40°C Bulk solution @ sealed vials Ticagrelor 8 mg / ml in 30 % w / wHPβCD, phosphate buffer pH 7.5, 25°C and 40 °CTime point T=1M,T=1M, 25 °C 40 °CAssay Ticagrelor (%) 107.22 105.16Relative retention time: Impurity Average contentimpurity (%):0.13 Amine 0.06 0.06impurity 0.96 Triol 0.01 0.00impurity 1.03 0.02 0.021.07 Regiomer 0.03 0.08impurity 1.33 0.03 0.081.78 Acetal 0.03 0.00impurity Total Impurities (%) 0.23 0.28Sum Impurities >0.05 (%) 0.06 0.21Table 29: Bulk hold at 30°C Time point T0 T4WAssay Ticagrelor (%) 105.60 106.14 RelativeImpurity Average content impurity (%):retention time:0.45 Amine impurity 0.06 0.060.98 Triol impurity 0.05 0.041.06 Regiomer 0.00 0.00impurity 1.50 Acetal impurity 0.04 0.04Total Impurities (%) 0.21 0.21Sum Impurities >0.05 (%) 0.10 0.06The hold time study at temperatures between 25°C - 45°C indicated howeven 30% w / w HPβCD was capable of stabilizing ticagrelor, even after heating the solution for a prolonged period of time or keeping the bulk at an elevated temperature. Manufacturing process for a ready-to-use infusion formulation A manufacturing process to make the exemplified ready-to-use solutions of Tables 3-7 was as follows. In all cases a solvent as mentioned is prepared and taken in a beaker and heated to 40 °C, then HPβCD is added to obtain a clear solution under stirring. After this the active ingredient Ticagrelor is added at 40 °C under constant stirring until a clear solution is obtained. This solution is filtered through a 0.22-micron filter and filled aseptically in a sterile glass bottle or an infusion bag. 24 mg / ml to 350 mg / ml HPβCD was required to obtain a stable Ticagrelor solution ready for infusion. The amount of cyclodextrin required was depending upon the volume of the targeted infusion medium. Ticagrelor is an active ingredient that is insoluble in water. The more it is in a diluted aqueous solution, the more tendency it has to precipitate. A proportional increase in cyclodextrin was required as the dilution factor for ticagrelor increased, when going from 30 ml to 100 ml to 200 ml. However, for a 650 ml volume and higher an amount of 16 g of cyclodextrin was found sufficient to hold the ticagrelor in the aqueous solution. Note that no organic co-solvent, surfactant or other solubilizer were used. Alternative preparation method starting from a concentrated ticagrelor solution It is possible to dilute 1 vial of 8 ml containing 65 mg / vial ticagrelor and about 3 g HPβCD with 25 ml 5 w / v% dextrose and obtain a clear solution with a final volume of 33 ml. However, this was not possible with a 0,9w / v% NaCl solution as diluent for the concentrated ticagrelor solution. Thisis of importance in medical treatments where a concentrated ticagrelor aqueous composition would be mixed with another medicine. It can lead to precipitation of ticagrelor, rendering the combination product unsuitable for intravenous administration.Solubility studies with other solventsExample 14 Solubility studies were performed using different solvents. Formulations A-E, shown in Table 30, were prepared by adding ticagrelor (final concentration of 1.8 mg / ml) to a tube (e.g., Eppendorf or conical) followed by adding the listed solvent(s) diluted in distilled water (final volumes of 10 ml). The tubes were then vortexed and sonicated in a temperature controlled water bath, if necessary. After 60 min, the tubes were collected for solubility observation. The samples were checked again after 24 hrs. Table 30: Solubility studies with other solvents Test Solvent (v / v%, remainderV* S* W*֠ Solubilized / # distilled water) Clear Solution A1,2-propanediol 20% Y Y Y NB Ethanol 20% Y Y Y NC Polysorbate 80 100% Y Y Y ND 20 w / v% Hydroxypropyl- Y Y Y Yβ-cyclodextrin EPEG 400 50% Y Y Y YBased on the investigations it was observed that ticagrelor was only solubilized with cyclodextrin or polyethylene glycol (PEG). Solubility, but inadequate storage stability Polyethylene glycol can solubilize ticagrelor. However, polyethylene glycol was found sensitive to degradation, and this led to impurities. Example 15Two clear 1.8 mg / ml ticagrelor formulations were prepared aftersonication for hours: formulation 1 (example 15), 1.8 mg / ml ticagrelor in20% w / w hydroxypropyl-β-cyclodextrin (HPβCD), remainder distilledwater; formulation 2 (example 15), 1.8 mg / ml ticagrelor in 50% w / wPEG400, remainder distilled water. The two formulations were aliquoted and stored under room temperature and 40°C. The formulations were immediately analyzed by LC-UV afterpreparation (Figures 1 and 2). They were analyzed again for 3 times overa 6-month stability period (Figures 3 and 4).Ticagrelor was found to be stable in formulation 1 (example 15), i.e., 1.8mg / ml ticagrelor in 20% w / w HPβCD, for at least 6 months at both roomtemperature and at 40°C (Figures 5 to 6).In formulation 2 (example 15), i.e., 1.8 mg / ml Ticagrelor in 50% w / wPEG400, ticagrelor was not stable at both room temperature and 40°C. Intensive potential degradation product peaks were observed informulation 2 (example 15) in LC-UV chromatograms (Figures 4 to 6).DESCRIPTION OF FIGURESFigure 1: depicts LC-UV chromatograms of ticagrelor Formulation 1(Example 15) and Blank control on day 0.Figure 2: LC-UV chromatograms of ticagrelor Formulation 2 (Example 15)and Blank Control on Day 0.Figure 3: LC-UV chromatograms of ticagrelor Formulation 1 (Example 15)and Blank Control on Day 188 (Room Temperature).Figure 4: LC-UV chromatograms of ticagrelor Formulation 1 (Example 15)and Blank Control on Day 188 (40°C). Figure 5: LC-UV chromatograms of ticagrelor Formulation 2 (Example 15) and Blank Control on Day 188 (Room Temperature).Figure 6: LC-UV chromatograms of ticagrelor Formulation 2 (Example 15)and Blank Control on Day 188 (40°C).

Claims

CLAIMS1. A pharmaceutical composition comprising ticagrelor for use in thereduction or prevention of thromboembolic events before and / or duringand / or following a neurovascular arterial procedure of a patient in needthereof, comprising administering to the patient an effective amount ofthe pharmaceutical composition comprising ticagrelor, characterized in,that the pharmaceutical composition is an aqueous solution comprising asolubilizer for ticagrelor, the pharmaceutical composition is administered intravenously, wherein the patient is suffering from a cerebral aneurysm, a brain artery sclerosis, a neck artery sclerosis, a neurovascular carotid arterial dissection or a carotid artery dissection.

2. Pharmaceutical composition for use according to claim 1, wherein the solubilizer for ticagrelor is a cyclodextrin; preferably the cyclodextrin is a hydroxypropylbetacyclodextrin (HPbCD).

3. Pharmaceutical composition for use according to claim 1, wherein the solubilizer for ticagrelor is vitamin E TPGS.

4. Pharmaceutical composition for use according to any of claims 1 to 3, wherein P2Y12 reactive units (PRUs) during ticagrelor administration are below 200, preferably below 100.

5. Pharmaceutical composition for use according to any of claims 1 to 4, wherein ticagrelor is administered intravenously within 5 days preceding the neurovascular arterial procedure.

6. Pharmaceutical composition for use according to any of claims 1 to 5, wherein ticagrelor is administered intravenously following the neurovascular arterial procedure; preferably within 6 hours post- procedure.

7. Pharmaceutical composition for use according to any of claims 1 to 6,wherein post-procedure the patient is administered an infusion of 5-80 mgticagrelor.

8. Pharmaceutical composition for use according to claim 7, comprising the oral administration of 20-50 mg ticagrelor twice daily following the intravenous administration of ticagrelor.

9. Pharmaceutical composition for use according to any of claims 1 to 8, wherein the patient is clopidogrel resistant.

10. Pharmaceutical composition for use according to any of claims 1 to 9, wherein ticagrelor is administered as monotherapy.

11. Pharmaceutical composition for use according to any of claims 1 to 9, wherein ticagrelor is administered as part of a dual antiplatelet therapy in combination with aspirin.

12. Pharmaceutical composition for use according to any of claims 1 to 11, wherein the patient has undergone a vascular stent implantation.

13. Pharmaceutical composition for use according to any of claims 1 to 12,wherein the pharmaceutical composition is infused during theneurovascular arterial procedure in a therapeutically effective amount.

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