Ticagrelor iv for use in the treatment, reduction or prevention of an ischemic event in a patient undergoing a percutaneous coronary intervention (PCI)

Abstract

The invention provides a pharmaceutical composition comprising ticagrelor for use in the treatment, reduction or prevention of an ischemic event in a patient undergoing a percutaneous coronary intervention (PCI) comprising administering to the patient an effective amount of ticagrelor for initiating or maintaining P2Y12 inhibition in the percutaneous coronary intervention (PCI), characterized in, that the pharmaceutical composition is an aqueous ticagrelor solution comprising a solubilizer in an effective amount for the solubilization of ticagrelor and the pharmaceutical composition is provided for intravenous administration; and wherein the effective amount of ticagrelor is administered intravenously.

Description

[0001] TICAGRELOR IV FOR USE IN THE TREATMENT, REDUCTION OR PREVENTIONOF AN ISCHEMIC EVENT IN A PATIENT UNDERGOING A PERCUTANEOUSCORONARY INTERVENTION (PCI) TECHNICAL FIELD The present invention is situated in the field of medical uses ofpharmaceutical compositions. The present invention relates to a storagestable, aqueous pharmaceutical ticagrelor solution for use in the treatmentof ischemic events in a patient, comprising ST-segment elevation myocardialinfarction or acute ischemic stroke, by administering the P2Y12 inhibitorticagrelor intravenously in a percutaneous coronary intervention (PCI). Useof a storage stable, aqueous ticagrelor iv formulation is advantageous in this situation that requires an acute intervention to remediate a high-risksituation. This is an improvement over an extemporaneous preparation of aticagrelor solution provided for iv administration.The present invention relates to a pharmaceutical ticagrelor composition foranti-platelet therapy comprising administration of the P2Y12 inhibitor ticagrelor intravenously. BACKGROUND Myocardial infarction (Ml) is a leading cause of hospital admissions and mortality around the world. If left untreated, Ml results in irreversible damage to the heart muscle due to a lack of blood flow (ischemia) and thus oxygen. A primary goal of therapy with Ml is therefore to expedite restoration of normal coronary blood flow with the aim of decreasing heart muscle damage through reperfusion therapy. Reperfusion therapy typically involves the use of therapeutics to increase blood flow and reduce thrombosis combined with techniques such as percutaneous coronary intervention, abbreviated as PCI. A PCI procedure is used to treat blockages in a coronary artery. Narrowed or blocked sections of the artery are blocked, restoring blood flow to the heart. Early reperfusion and PCI is preferable and associated with improved outcomes, with medical Guidelines suggesting PCI should be performed within 12 hours of Ml symptom onset. Several treatment strategies are available to deal with thrombus formationand fall into two classes - protein-based therapeutics and small moleculetherapeutics. Examples of small molecule therapeutics include the P2Y12 receptor inhibitors clopidogrel, ticagrelor, prasugrel and cangrelor. TheseP2Y12 receptor inhibitors are known for their ability to inhibit platelets andprevent blood clots. Clopidogrel and prasugrel are irreversible antagonists ofthe P2Y12 receptor. A disadvantage of clopidogrel and prasugrel is that theyare precursor drugs which require liver metabolism activation. This causes adelay in the onset of action. In addition, a patient may be clopidogrel resistant.Clopidogrel, prasugrel and ticagrelor are only commercially available in theform of tablets. These do not offer the possibility to medicate unconscious patients. This includes patients on a ventilator or patients undergoing a surgical procedure, which leaves them vulnerable to unpredictable and often inadequate platelet inhibition. Tablets are also a problem for patients havingdifficulties swallowing (dysphagia). Oral medication may also be at risk offood effects. When undergoing emergent primary percutaneous coronary intervention(PCI), crushing tablets is a known way to obtain faster absorption and achievea more rapid and higher antiplatelet effect in 30-120 minutes ofadministration. The bioavailability of prasugrel is reduced when it is administered via an enteral route as stomach acidity is bypassed. Cangrelor is commercially available as a formulation 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. It could also be used to bridge an oral medicationto intravenous administration with Cangrelor. However, the switching of atablet to an intravenous formulation involving two different active pharmaceutical ingredients may also provide unwanted complications. Cangrelor is mostly used in patients who have not previously used an anti- platelet agent. Fast and accurate platelet inhibition is an important therapeutic goal in the acute treatment of patients with a myocardial infarction. Platelet inhibitory effects induced by oral P2Y12-receptor antagonists are delayed in patients undergoing primary percutaneous coronary intervention (PCI) due to haemodynamic changes and delayed gastro-intestinal absorption. In addition to receiving anti-platelet medication, patients with a myocardial infarction also receive pain medication. Recent studies have shown that concomitant use of opioids, such as morphine and fentanyl, althoughrecommended in treatment guidelines, delay gastro-intestinal absorption ofP2Y12 inhibitors. Use of crushed ticagrelor tablets instead of full tablets improved the situation somewhat. However, in the initial phase of treatmentthe delayed onset of therapeutic effect presents risks to the patient. Also,when patients receive pain medication prior to a PCI procedure, for instance for recording an angiogram and the PCI procedure follows shortly thereafter, within 1 hour, platelet inhibition may be inefficient still.In view of the above, there is a need for further improvements. There remainsa need in the art for an antiplatelet therapy with fast and reliable onset ofaction. 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 a percutaneous coronary intervention (PCI). SUMMARY OF THE INVENTION The present invention provides a pharmaceutical composition comprisingticagrelor for use in the treatment, reduction or prevention of an ischemicevent in a patient undergoing a percutaneous coronary intervention (PCI)comprising administering to the patient an effective amount of ticagrelor for initiating or maintaining P2Y12 inhibition in the percutaneous coronaryintervention (PCI), characterized in, that the pharmaceutical compositionis an aqueous ticagrelor solution comprising a solubilizer in an effectiveamount for the solubilization of ticagrelor and the pharmaceuticalcomposition is provided for intravenous administration. In use the composition is administered intravenously.The invention has for effect that patients in need of a percutaneous coronaryintervention (PCI) can be treated rapidly, reliably, and effectively even ifunconscious or even if having problems swallowing. This is especially important in emergency situations where a therapeutic effect is urgently needed. Intravenous ticagrelor administration provides a fast onset of therapeutic effect. It has improved bioavailability over a tablet or crushed tablet. In addition, it avoids the first-pass effect and is not hampered by delayed gastro-intestinal absorption.In a preferred embodiment, the solubilizer for ticagrelor is a cyclodextrin;more preferably the cyclodextrin is a hydroxypropyl-beta-cyclodextrin (HPbCD).In a preferred embodiment, the solubilizer for ticagrelor is D-alpha-tocopherylpolyethylene glycol succinate (vitamin E TPGS).In a preferred embodiment, the aqueous pharmaceutical ticagrelorcomposition has a pH of 5,5 to 9,0.In a preferred embodiment, the aqueous pharmaceutical ticagrelorcomposition is devoid of polyethylene glycol.In a preferred embodiment, the aqueous ticagrelor solution consists of:0,10 – 14,0 mg / ml ticagrelor and20 – 100 mg / ml of cyclodextrin in a quantity for solubilization of the ticagrelorin the selected volume of aqueous pharmaceutical solution, wherein thecomposition has a pH between 5,5 – 9,0 endpoints included, andthe aqueous pharmaceutical solution has a volume of 25 to 1000 ml.In a preferred embodiment, the aqueous pharmaceutical ticagrelorcomposition has a storage stability of at least 3 months as measured in accelerated storage conditions at 40 °C and 75 % Relative Humidity (RH).In a preferred embodiment, the patient has P2Y12 reactive units (PRUs) priorto ticagrelor administration of more than 100, preferably more than 200.The use of an intravenous ticagrelor formulation allows for dose titration andadjustment. The activity of the ticagrelor P2Y12 antagonist can rapidly bereversed in case of emergency surgery.In a preferred embodiment, the patient is comatose, intubated ormechanically ventilated.In a preferred embodiment, ticagrelor is administered intravenously followingthe percutaneous coronary intervention; preferably within 6 hours post- procedure.In a preferred embodiment, the patient was stented.In a preferred embodiment, the patient prior to receiving ticagrelorintravenously was administered pain medication comprising paracetamol (iv) and excluding morphine and fentanyl.In a preferred embodiment, the patient is administered a bolus infusion of 5-80 mg ticagrelor (loading dose), optionally followed by one or more maintenance infusions of 20-80 mg ticagrelor.In a preferred embodiment, the loading dose is administered in less than 10minutes, preferably less than 5 minutes, more preferably less than 2 minutes.In a preferred embodiment, the pharmaceutical composition for usecomprises the oral administration of 20-50 mg ticagrelor twice daily followingthe last intravenous administration of ticagrelor and provided the patient isconscious.In a preferred embodiment, the patient is clopidogrel resistant.In a preferred embodiment, ticagrelor is administered as anti-plateletmonotherapy or as part of a dual antiplatelet therapy in combination with aspirin.In a preferred embodiment, aspirin is administered intravenously.In a further aspect the invention provides a composition comprising ticagrelorfor use in a method for the treatment of pain in a patient in need of P2Y12inhibition, wherein the composition is administered intravenously in a therapeutically effective amount with the proviso that the treatment does not include morphine and fentanyl, and wherein a therapeutically effectiveamount of pain medication comprising paracetamol is administered.In a preferred embodiment, the pain medication further comprises ibuprofen.In a preferred embodiment, paracetamol and ibuprofen are administeredintravenously in combination. 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 before, during or followingpercutaneous coronary intervention (PCI) of a patient in need thereof.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.In particular, the present invention provides a pharmaceutical compositioncomprising ticagrelor for use in the treatment, reduction or prevention of anischemic event in a patient undergoing a percutaneous coronary intervention(PCI) comprising administering to the patient an effective amount ofticagrelor for initiating or maintaining P2Y12 inhibition in the percutaneouscoronary intervention (PCI), characterized in, that the pharmaceuticalcomposition is an aqueous ticagrelor solution comprising a solubilizer in aneffective amount for the solubilization of ticagrelor and the pharmaceuticalcomposition is provided for intravenous administration. In use the composition is administered intravenously. 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 becompatible. No dilution or pH adjustment are required, the formulation isready-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.Intravenous administration delivers a fast onset of therapeutic effect over an oral dosage. It allows treatment of patients which cannot take oral medication, for instance because they cannot swallow, are on ventilation, or are unconscious. 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 liquidticagrelor formulation remains high, to our knowledge a successful commercial product of desired solubility in correspondence with requirements of the pharmaceutical industry has not been successful. In a preferred embodiment, ticagrelor is the only active pharmaceutical ingredient present in the composition. Alternatively, an additional active ingredient can be included. Preferably theadditional active ingredient is not prasugrel or a cysteine-aspartic proteaseinhibitor. More preferably the additional active ingredient is not a cysteine- aspartic protease inhibitor selected from (S)-3-({1-[(S)-1-((S)-2-{[1-(4- amino-3-chlorophenyl)-methanoyl]-amino}-3,3-dimethyl-butanoyl)- pyrrolidin-2yl]-methanoyl}-amino)-4-oxo-butyric acid (VRT-043198), (S)-3- ({1-[(S)-1-((S)-2-{[1-(4-amino-3-chlorophenyl)-methanoyl]-amino}-3,3- dimethyl-butanoyl)-pyrrolidin-2yl]-methanoyl}-amino)-4-oxo-butyric acid (VRT-043198), or emricasan. In a preferred embodiment the aqueous ticagrelor composition provided for iv administration comprises 0,1 to 15 mg / ml ticagrelor; more preferably 1- 14 mg / ml ticagrelor or 2-13 mg / ml; even more preferably 3-12 mg / mlticagrelor or 4-11 mg / ml ticagrelor; most preferably 5-10 mg / ml ticagrelor.By extensive experimentation it was found that ticagrelor can be solubilized in an aqueous composition 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. Morepreferably the cyclodextrin is a hydroxypropyl-beta-cyclodextrin. Mostpreferably the cyclodextrin is (2-hydroxypropyl)-beta-cyclodextrin (HPbCD).In a preferred embodiment the aqueous ticagrelor composition provided for iv administration comprises 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 an alternative embodiment, the solubilizer for ticagrelor is D-alpha- tocopheryl polyethylene glycol succinate, also known as vitamin E TPGS. 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 orstabilizer. US 2680749 discloses TPGS molecules in which the polyethyleneglycols have average molecular weights of 400, 1000, and those varyingbetween 600 and 6000. Vitamin E TPGS molecules in which the polyethyleneglycol chains have an average molecular weight (MW) of about 1000 arecommercially available from Eastman Chemical Company, (Kingsport, Tennessee). In a preferred embodiment the aqueous ticagrelor composition provided for iv administration 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 according to an embodiment of the invention is devoidof polyethylene 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 iv composition according to anembodiment of the invention 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. Optionally the aqueous ticagrelor iv composition according to an embodimentof the invention comprises a tonicity modifier, such as sodium chloride.Preferably the osmolality of the aqueous ticagrelor iv composition accordingto an embodiment of the invention is between 350-900 mOsm / kg, morepreferably between 360 – 800 mOsm / kg, even more preferably between 370-700 mOsm / kg, most preferably between 380 and 600 mOsm / kg. In a preferred embodiment the aqueous ticagrelor iv composition accordingto an embodiment of the invention has a storage stability of at least 3 monthsin 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% RH corresponds 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. In a preferred embodiment the aqueous ticagrelor iv composition according to an embodiment of the invention 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. No pH adjustment is required beforeadministration to the patient. This is time saving.Most preferably the aqueous ticagrelor iv composition according to anembodiment of the invention 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 iv composition according to anembodiment of the invention 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 iv composition according to anembodiment of the invention 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 cardiovascular arterial event. An aqueous ticagrelor iv composition according to an embodiment of the invention is provided for the provision of antiplatelet therapy before, during or after a PCI procedure. In a preferred embodiment the aqueous ticagrelor iv composition according to an embodiment of the invention is used in the treatment of a patienthaving P2Y12 reactive units (PRUs) below 200, more preferably below 150,even more preferably below 110, prior to ticagrelor iv administration. Mostpreferably P2Y12 reactive units are between 0 and 100, after ticagrelor iv administration.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. In a preferred embodiment of the invention, ticagrelor is administeredintravenously within 5 days preceding the PCI procedure. More preferablyticagrelor iv is administered within 4 days, even more preferably within 3 days, most preferably within 2 days or within 1 day preceding the PCI procedure. For emergency surgery a patient may have received ticagrelor iv just prior tosurgery. An antidote or absorption technology, such as CytoSorb©, may beused to reduce the level of ticagrelor in the blood to a level suitable for havinga reduced bleeding risk. An antidote for ticagrelor is bentracimab, also knownas PB2452. It is a neutralizing recombinant human immunoglobulin G1 monoclonal antibody antigen-binding fragment that binds ticagrelor and itsmajor active circulating metabolite M8, also known as AR-C124910XX, withhigh affinity and specificity. CytoSorb® consists of a porous polymer beadsadsorption system. Preferably the pharmaceutical composition according to an embodiment ofthe invention is administered intravenously to a patient who has P2Y12reactive units (PRUs) prior to ticagrelor administration of more than 100,preferably more than 200. Preferably the pharmaceutical composition according to an embodiment of the invention is administered intravenously to a patient who is comatose, intubated or mechanically ventilated. Preferably the pharmaceutical ticagrelor iv composition according to an embodiment of the invention is administered intravenously following the percutaneous coronary intervention; preferably within 6 hours post- procedure, more preferably within 4 hours post-procedure, even more preferably within 3 hours post-procedure, most preferably within 2 hours post-procedure. The availability of an iv formulation allows the restart of antiplatelet therapy earlier than is possible with tablets; it acts faster than crushed tablets. Treatment can be started when the patient is still in recovery, unconscious or comatose thereby reducing the risk of thrombosis following the procedure. Preferably the pharmaceutical composition according to an embodiment of the invention is administered intravenously to a patient who prior to receiving ticagrelor intravenously was administered pain medication comprising morphine or fentanyl. Use of the iv ticagrelor overcomes delays in bioavailability due to sedatives such as morphine or fentanyl. A faster onset of platelet inhibition is provided. Preferably the pharmaceutical composition according to an embodiment of the invention is administered intravenously to a patient who prior to receiving ticagrelor intravenously was administered pain medication comprising paracetamol, preferably comprising paracetamol iv.Most preferably no opioid medication, such as morphine or fentanyl, was usedin a treatment according to an embodiment of the invention. This isadvantageous to avoid addiction. It is also of importance to avoid delayed onset of therapeutic action in a situation with acute risk of thrombosis. A ticagrelor iv composition for use in the treatment of a cardiovascular arterial event may be used by injection, a short-term infusion or a long-term infusion. The short-term infusion is preferably between 1 and 20 minutes, more preferably between 3 and 15 minutes; most preferably between 5 and 10 minutes. Preferably the pharmaceutical composition according to an embodiment of the invention is administered intravenously as a bolus infusion. Preferably the bolus infusion is administered in less than 10 minutes, more preferably in less than 5 minutes, even more in less than 3 minutes, most preferably in less than 2 minutes. Most preferably the bolus infusion is administered as an injection. The effect is a faster onset of therapeutic effect compared to ticagrelor oral or crushed ticagrelor tablets. Optionally the ticagrelor loading is followed by one or more maintenanceinfusions of ticagrelor iv.Preferably the pharmaceutical composition according to an embodiment of the invention is administered intravenously after the PCI procedure and intravenous ticagrelor administration is followed by oral administration of 20- 50 mg ticagrelor twice daily as the patient can take oral medication. This switch-over from iv to oral is advantageous as there is no change in pharmaceutical active ingredient. In a preferred embodiment of the invention, ticagrelor is administered as anti-platelet monotherapy or as part of a dual antiplatelet therapy in combination with aspirin.In a preferred embodiment of the invention, the aspirin is administeredintravenously. In a preferred embodiment of the invention, the patient was stented. Preferably ticagrelor is administered intravenously following the PCIprocedure; preferably within 6-, 5- or 4-hours post-procedure. Morepreferably within 3 hours post-procedure, most preferably within 2 hourspost-procedure. The availability of a ticagrelor iv has the advantage that ticagrelor treatment can be started when a patient is still in recovery, unconscious or comatose. This may be advantages for reducing the risk of thrombosis following the procedure. A patient may be conscious and capable of swallowing a tablet 4 to 6 hoursafter surgery. Hence oral anti-platelet therapy can be started consecutivelyto iv administration. 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 oral 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. A patient on tablet medication can easier be sent home as no assistance is 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. In a preferred embodiment, the pharmaceutical composition is infused duringthe cardiovascular arterial procedure in a therapeutically effective amount.In a further aspect, the invention provides in a ticagrelor therapy wherein drug-drug interaction with opioid pain medication is avoided. The present invention provides a composition comprising ticagrelor for use in a method for the treatment of a patient in need of P2Y12 inhibition, wherein the composition is administered intravenously in a therapeutically effective amount with the proviso that the treatment does not include morphine and fentanyl, and wherein a therapeutically effective amount of pain medication comprising paracetamol is administered. Preferably the pain medication further comprises ibuprofen. More preferably paracetamol and ibuprofen are administered intravenously in combination. EXAMPLESPharmaceutical ticagrelor compositions for use in the reduction or preventionof thromboembolic events before and / or during and / or following a PCIprocedure of a patient in need thereof are provided in the 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 0,600vitamin 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 temperate 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 / mlThe 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 in 100 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 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 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 added slowly 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 were obtained with 25 w / w%, 30 w / w%, 35 w / w% and 40w / w% HPβCD. Table 8: Solubility of ticagrelor in HPβCD TicagrAppearance of Ticagrelor in cyclodextrinHPβCD elor conc. inconc. Floccul MilliQ After Afte Afte ation (%g / A After (mfter 5 min r 30 r 60 overntestw / w) ) 3 igh ml h of of min min haki s t s haki of o shaking ng f 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 on test MilliQ l Afte After (mg / m r 5min r r 3h o overnig ) f (% of 30mi 60mi shakin ht w / w) shaki 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 using a YMC-Pack Pro C18 column (100x4.6mm, S-3μm 12nm). Good separation was 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 and75 % 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 filteredthrough a 0.22 micrometer filter and filled in USP Type I amber colored glassvials. 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 time Impurityimpurity impurity impurity impurity impurity(minutes) ID (%): (%): (%): (%): (%):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 6, it was concluded that good storage stability was obtained at accelerated storageconditions of 40 °C and 75 % Relative Humidity. The regiomer impurity waswell under control and no other impurity was of a concern. Example 6In a further experiment, to optimize the concentration of HPβCD below 40%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 varying HPβCDconcentrations. Data are sorted by HPβCD strength. Ticagrelor concentrationwhen 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 heating toClear Turbid 40°C solution 25.0 Turbid; clear after heating toClear Turbid 40°C solution 22.5 Turbid; clear after heating toClear Turbid 40°C solution 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 had a19 mM phosphate buffer and pH 7.5. The results are provided in Table 15.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 HPβCD were 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 the particles 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. 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 thepresent invention is by Malvern Mastersizer dry powder method.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- was carriedout as below, the manufacturing process for all 3 formulations was keptconstant with buffer strength at 19 mM. The results are summarized in Tables19 to 21Table 19: Storage stability in amber glass vials – pH 7Amber 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 19mM 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 theticagrelor-cyclodextrin inclusion complex a composition with 32.5% w / wHPβCD was prepared with procedures and precaution’s similar to previoustrials, samples were stored in transparent clear glass vials and amber colored glass vials at a temperature of 40 °C / 75% RH. The results are shown inTable 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 0.05impurity Total 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 HPβC Ticagrel Fin HPβC HPβC Appeara Flocculati Flocculati r D or al D D nce on on (% (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 Ticagrelo 75 HPβCD 65 HPβCD % w / w% w / vHPβCDr mg / mlmg mg / vial mg mg / vial 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 / cc Surprisingly the solutions provided in Table 18 were compatible with diluentsto 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°CBulk 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 (%) 105.60 106.14RelativeImpurity 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 0,9 w / v%NaCl solution as diluent for the concentrated ticagrelor solution. This is ofimportance 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 solventsSolubility 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 TestSolvent (% v / v, remainder V* 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 glycolwas found sensitive to degradation, and this led to impurities.Example 14Two clear 1.8 mg / ml ticagrelor formulations were prepared after sonicationfor hours: formulation 1 (Example 14), 1.8 mg / ml ticagrelor in 20% w / whydroxypropyl-β-cyclodextrin (HPβCD), remainder distilled water;formulation 2 (Example 14), 1.8 mg / ml ticagrelor in 50% w / w PEG400,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 over a6-month stability period (Figures 3 and 4).Ticagrelor was found to be stable in formulation 1 (Example 14), 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 14), 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 in formulation2 (Example 14) in LC-UV chromatograms (Figures 4 to 6).DESCRIPTION OF FIGURESFigure 1: depicts LC-UV chromatograms of ticagrelor Formulation 1 (Example14) and Blank control on day 0.Figure 2: LC-UV chromatograms of ticagrelor Formulation 2 (Example 14)and Blank Control on Day 0.Figure 3: LC-UV chromatograms of ticagrelor Formulation 1 (Example 14)and Blank Control on Day 188 (Room Temperature).Figure 4: LC-UV chromatograms of ticagrelor Formulation 1 (Example 14)and Blank Control on Day 188 (40°C).Figure 5: LC-UV chromatograms of ticagrelor Formulation 2 (Example 14)and Blank Control on Day 188 (Room Temperature).Figure 6: LC-UV chromatograms of ticagrelor Formulation 2 (Example 14)and Blank Control on Day 188 (40°C).

Claims

CLAIMS1. A pharmaceutical composition comprising ticagrelor for use in thetreatment or prevention of an ischemic event in a patient undergoing apercutaneous coronary intervention (PCI) comprising administering tothe patient an effective amount of ticagrelor for initiating or maintainingP2Y12 inhibition, characterized in, that the pharmaceuticalcomposition is an aqueous ticagrelor solution comprising a solubilizer inan effective amount for the solubilization of ticagrelor and thepharmaceutical composition is provided for intravenous administration; and wherein the effective amount of ticagrelor is administered intravenously.

2. Pharmaceutical composition for use according to claim 1, wherein thesolubilizer for ticagrelor is a cyclodextrin; preferably the cyclodextrin is a hydroxypropyl-beta-cyclodextrin (HPbCD).

3. Pharmaceutical composition for use according to claim 1, wherein the solubilizer for ticagrelor is D-alpha-tocopheryl polyethylene glycol succinate (vitamin E TPGS).

4. Pharmaceutical composition for use according to any of claims 1 to 3,wherein the aqueous pharmaceutical ticagrelor composition has a pH of 5,5 to 9,0.

5. Pharmaceutical composition for use according to any of claims 1 to 4,wherein the aqueous pharmaceutical ticagrelor composition is devoid of polyethylene glycol.

6. Pharmaceutical composition for use according to any of the claims 1, 2and 4, wherein the aqueous ticagrelor solution consists 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 endpointsincluded, and the aqueous pharmaceutical solution has a volume of 25 to 1000 ml.

7. Pharmaceutical composition for use according to any of claims 1 to 6,wherein the aqueous pharmaceutical ticagrelor composition has a storage stability of at least 3 months as measured in accelerated storage conditions at 40 °C and 75 % Relative Humidity (RH).

8. Pharmaceutical composition for use according to any of claims 1 to 7, wherein the patient has P2Y12 reactive units (PRUs) prior to ticagreloradministration of more than 100, preferably more than 200.

9. Pharmaceutical composition for use according to any of claims 1 to 8, wherein the patient is comatose, intubated or mechanically ventilated.

10. Pharmaceutical composition for use according to any of claims 1 to 9,wherein ticagrelor is administered intravenously following the percutaneous coronary intervention; preferably within 6 hours post- procedure.

11. Pharmaceutical composition for use according to any of claims 1 to 10, wherein the patient was stented.

12. Pharmaceutical composition for use according to any of claims 1 to 11, wherein the patient prior to receiving ticagrelor intravenously was administered pain medication comprising paracetamol (iv) andexcluding morphine and fentanyl.

13. Pharmaceutical composition for use according to any of claims 1 to 12, wherein the patient is administered a bolus infusion of 5-80 mgticagrelor (loading dose), optionally followed by one or moremaintenance infusions of 20-80 mg ticagrelor.

14. Pharmaceutical composition for use according to claim 13, wherein theloading dose is administered in less than 10 minutes, preferably lessthan 5 minutes, preferably less than 2 minutes.15 Pharmaceutical composition for use according to claim 13 or 14,comprising the oral administration of 20-50 mg ticagrelor twice daily following the last intravenous administration of ticagrelor and providedthe patient is conscious.

16. Pharmaceutical composition for use according to any of claims 1 to 15,wherein the patient is clopidogrel resistant.

17. Pharmaceutical composition for use according to any of claims 1 to 16, wherein ticagrelor is administered as anti-platelet monotherapy or as part of a dual antiplatelet therapy in combination with aspirin.

18. Pharmaceutical composition for use according to claim 17, wherein aspirin is administered intravenously.

19. A composition comprising ticagrelor for use in a method for the treatment of pain in a patient in need of P2Y12 inhibition, wherein the composition is administered intravenously in a therapeutically effective amount with the proviso that the treatment does not include morphine and fentanyl, and wherein a therapeutically effective amount of painmedication comprising paracetamol is administered.

20. The composition for use according to claim 19, wherein the pain medication further comprises ibuprofen.

21. The composition for use according to claim 20, wherein paracetamol and ibuprofen are administered intravenously in combination.

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