Injection of ticagrelor for the treatment, reduction, or prevention of ischemic events in patients undergoing percutaneous coronary intervention (PCI)

Abstract

The present invention provides a pharmaceutical composition comprising ticagrelor for treating, reducing, or preventing ischemic events in patients undergoing percutaneous coronary intervention (PCI), comprising administering an effective amount of ticagrelor to the patient to initiate or maintain P2Y12 inhibition during PCI, characterized in that the pharmaceutical composition is an aqueous solution of ticagrelor comprising an effective amount of a solubilizer for solubilizing ticagrelor, and the pharmaceutical composition is provided for intravenous administration; wherein the effective amount of ticagrelor is administered intravenously.

Description

Technical Field

[0001] This invention pertains to the pharmaceutical use of pharmaceutical compositions. Specifically, it relates to a storage-stable aqueous solution of ticagrelor for the treatment of ischemic events, including ST-segment elevation myocardial infarction or acute ischemic stroke, in patients via intravenous administration of the P2Y12 inhibitor ticagrelor during percutaneous coronary intervention (PCI). The use of a storage-stable aqueous injectable formulation of ticagrelor offers advantages in cases requiring acute intervention to resolve high-risk conditions. This invention represents an improvement over readily prepared ticagrelor solutions intended for intravenous administration.

[0002] This invention relates to ticagrelor pharmaceutical compositions for antiplatelet therapy, comprising intravenous administration of the P2Y12 inhibitor ticagrelor. Background Technology

[0003] Myocardial infarction (MI) is a leading cause of hospitalization and death worldwide. If left untreated, MI causes irreversible damage to the heart muscle due to a lack of blood flow (ischemia) and therefore oxygen deprivation. Therefore, the primary goal of MI treatment is to accelerate the restoration of normal coronary blood flow, aiming to reduce myocardial damage through reperfusion therapy. Reperfusion therapy typically involves using therapeutic agents to increase blood flow and reduce thrombus formation, combined with techniques such as percutaneous coronary intervention (PCI). PCI is used to treat coronary artery blockage. The narrowed or blocked portion of the artery is cleared, restoring blood flow to the heart. Early reperfusion and PCI are preferred and associated with improved prognosis; medical guidelines recommend that PCI should be performed within 12 hours of the onset of MI symptoms.

[0004] Several treatment strategies are available for managing thrombosis, falling into two main categories: protein-based therapeutics and small molecule therapeutics. Examples of small molecule therapeutics include P2Y12 receptor inhibitors, such as clopidogrel, ticagrelor, prasugrel, and cangrelorel. These P2Y12 receptor inhibitors are known for their ability to inhibit platelets and prevent blood clots. Clopidogrel and prasugrel are irreversible antagonists of the P2Y12 receptor. A disadvantage of clopidogrel and prasugrel is that they are prodrugs, requiring hepatic metabolic activation. This results in a delayed onset of action. Furthermore, patients may develop resistance to clopidogrel.

[0005] Clopidogrel, prasugrel, and ticagrelor are only available in tablet form. These medications do not offer the possibility of administration to unconscious patients. This includes patients on ventilators or undergoing surgery, who are susceptible to unpredictable and often inadequate platelet suppression. Furthermore, tablets are also problematic for patients with dysphagia (difficulty swallowing). Oral medications may also carry the risk of food effects.

[0006] In emergency percutaneous coronary intervention (PCI), fragmentation agents are a known method for achieving faster absorption and a more rapid and greater antiplatelet effect within 30–120 minutes of administration. When prasugrel is administered via the enteral route, its bioavailability is reduced because it bypasses gastric acid.

[0007] Cangrelor is commercially available in formulations for intravenous administration. While it has a rapid onset of action, its duration of action is also relatively short. Cangrelor has a very short half-life of 3 to 6 minutes, and its antiplatelet effect is offset within 60 minutes. It can also be used to bridge oral medications to intravenous cangrelor. However, converting tablets to intravenous formulations involving two different active pharmaceutical ingredients may also result in undesirable complications. Cangrelor is primarily used in patients who have not previously used antiplatelet agents.

[0008] Rapid and accurate platelet inhibition is an important therapeutic goal in the acute treatment of patients with myocardial infarction. However, due to hemodynamic changes and delayed gastrointestinal absorption, the platelet inhibition induced by oral P2Y12-receptor antagonists is delayed in patients undergoing direct percutaneous coronary intervention (PCI).

[0009] In addition to antiplatelet drugs, patients with myocardial infarction also receive pain medication. Recent studies have shown that the concomitant use of opioids, such as morphine and fentanyl, despite being recommended in treatment guidelines, delays the gastrointestinal absorption of P2Y12 inhibitors. Using crushed ticagrelor tablets instead of whole tablets slightly improves this situation. However, the delayed onset of action poses risks to patients in the early stages of treatment. Furthermore, when patients receive pain medication before PCI procedures, such as for recording angiography, and then undergo PCI shortly thereafter, platelet inhibition may still be ineffective within one hour.

[0010] In light of the above, there is a need for further improvements. There remains a need in this field for antiplatelet therapies that offer rapid and reliable onset of action.

[0011] The object of this invention is to solve at least one or more of the problems described above. Specifically, the invention aims to provide pharmaceutical compositions in a form suitable for intravenous administration for percutaneous coronary intervention (PCI). Summary of the Invention

[0012] This invention provides a pharmaceutical composition comprising ticagrelor for treating, reducing, or preventing ischemic events in patients undergoing percutaneous coronary intervention (PCI), comprising administering an effective amount of ticagrelor to the patient for initiating or maintaining P2Y12 inhibition during PCI, characterized in that the pharmaceutical composition is an aqueous solution of ticagrelor comprising an effective amount of a solubilizer for solubilizing ticagrelor, and the pharmaceutical composition is provided for intravenous administration. In use, the composition is administered intravenously.

[0013] This invention offers the following advantages: patients requiring percutaneous coronary intervention (PCI) can be treated quickly, reliably, and effectively, even if unconscious or with swallowing difficulties. This is especially important in emergency situations where a therapeutic effect is urgently needed.

[0014] Intravenous administration of ticagrelor provides a rapid onset of therapeutic effect. It has improved bioavailability compared to tablets or crushed tablets. Furthermore, it avoids the first-pass effect and is not hindered by gastrointestinal absorption delays.

[0015] In a preferred embodiment, the solubilizer used for ticagrelor is a cyclodextrin; more preferably, the cyclodextrin is hydroxypropyl-β-cyclodextrin (HPbCD).

[0016] In a preferred embodiment, the solubilizer used for ticagrelor is D-α-tocopherol polyethylene glycol succinate (vitamin E TPGS).

[0017] In a preferred embodiment, the pH of the ticagrelor aqueous pharmaceutical composition is 5.5 to 9.0.

[0018] In a preferred embodiment, the ticagrelor aqueous pharmaceutical composition does not contain polyethylene glycol.

[0019] In a preferred embodiment, the ticagrelor aqueous solution comprises the following:

[0020] 0.10–14.0 mg / ml ticagrelor and

[0021] A cyclodextrin concentration of 20–100 mg / ml, in an amount sufficient to solubilize ticagrelor in a selected volume of aqueous drug solution, wherein the pH of the composition is between 5.5 and 9.0 (inclusive), and

[0022] The volume of the aqueous drug solution is 25 to 1000 ml.

[0023] In a preferred embodiment, the ticagrelor aqueous pharmaceutical composition has storage stability of at least 3 months, as measured under accelerated storage conditions of 40°C and 75% relative humidity (RH).

[0024] In a preferred embodiment, the patient has more than 100 P2Y12 response units (PRU) before administration of ticagrelor, preferably more than 200.

[0025] The use of intravenous ticagrelor allows for dose titration and adjustment. In cases of emergency surgery, the activity of the ticagrelor P2Y12 antagonist can be rapidly reversed.

[0026] In a preferred embodiment, the patient is comatose, intubated, or mechanically ventilated.

[0027] In a preferred embodiment, ticagrelor is administered intravenously after percutaneous coronary intervention; preferably within 6 hours after the procedure.

[0028] In the preferred embodiment, the patient has a stent placed.

[0029] In a preferred embodiment, the patient was given an analgesic containing acetaminophen (iv) and free of morphine and fentanyl before receiving intravenous ticagrelor.

[0030] In a preferred embodiment, the patient is given a bolus infusion of 5-80 mg ticagrelor (loading dose), optionally followed by one or more maintenance infusions of 20-80 mg ticagrelor.

[0031] In a preferred embodiment, the loading dose is administered within less than 10 minutes, preferably less than 5 minutes, and more preferably less than 2 minutes.

[0032] In a preferred embodiment, the pharmaceutical composition used comprises oral administration of 20-50 mg ticagrelor twice daily, provided that the patient is conscious, following the last intravenous administration of ticagrelor.

[0033] In a preferred embodiment, the patient is resistant to clopidogrel.

[0034] In a preferred embodiment, ticagrelor is administered as a monotherapy for antiplatelet infection or as part of a dual antiplatelet therapy in combination with aspirin.

[0035] In a preferred embodiment, aspirin is administered intravenously.

[0036] In a further aspect, the present invention provides a composition comprising ticagrelor for use in a method of treating pain in a patient requiring P2Y12 inhibition, wherein the composition is administered intravenously in a therapeutically effective amount, provided that the treatment is free of morphine and fentanyl, and wherein a therapeutically effective amount of analgesics, including acetaminophen, is administered.

[0037] In a preferred embodiment, the analgesic further comprises ibuprofen.

[0038] In a preferred embodiment, acetaminophen and ibuprofen are administered intravenously in combination. Invention Details

[0040] Unless otherwise defined, all terms used in the description of this invention, including technical and scientific terms, shall have the meanings commonly understood by one of ordinary skill in the art to which this invention pertains. Furthermore, definitions of terms are included to facilitate a better understanding of the description of this invention.

[0041] As used herein, the following terms have the following meanings: “a,” “an,” and “the” as used herein refer to both the singular and the plural, unless the context otherwise indicates. “A surfactant” means, for example, one or more surfactants.

[0042] As used herein, “about” refers to a measurable value, such as a parameter, quantity, duration, etc., and is intended to include variations of ±10% or less, preferably ±5% or less, more preferably ±3% or less, even more preferably ±1% or less, and even more preferably ±0.1% or less, provided such variation is suitable for carrying out in the described invention. However, it will be clear that the value referred to by the term “about” is itself specifically described. As used herein, “include,” “comprising,” and “comprises” are inclusive or open-ended terms that explicitly indicate the presence of what follows, such as components and additional, unnamed components, features, elements, parts, steps, etc., that are well known in the art or described herein, and do not exclude them.

[0043] The description of a numerical range by endpoints includes all numbers and fractions included in that range, as well as the endpoints mentioned.

[0044] As used herein, the term "% w / w" refers to weight percentage, where the weight ratio of an ingredient to the total weight of the composition is expressed as a percentage.

[0045] This invention provides a solution to the problem of limited bioavailability and slow onset of action of ticagrelor tablets used to reduce or prevent thromboembolic events before, during, or after percutaneous coronary intervention (PCI) in patients in need.

[0046] Ticagrelor is the well-known active ingredient. It is a platelet aggregation inhibitor used in patients with acute coronary syndrome to prevent thrombotic events such as myocardial infarction or stroke. 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.

[0047] As used herein, the term "ticagrelor" refers to ticagrelor in its free form and its pharmaceutically acceptable solvates, hydrates, enantiomers, polymorphs, or mixtures thereof. Preferably, ticagrelor is used in its free form.

[0048] Ticagrelor was developed by AstraZeneca and approved for marketing by the European Medicines Agency in 2010 and the U.S. Food and Drug Administration in 2011. It is marketed as a tablet in the United States under the name Brilinta. ® and in Europe for Brilique ® It is not commercially available in liquid form. Ticagrelor is an oral, reversible, direct-acting P2Y drug. 12 Receptor antagonists work by inhibiting platelet activation. Brilinta® tablets, together with aspirin, have been shown to significantly reduce the risk of major adverse cardiovascular (CV) events (heart attack, stroke, or CV death) in patients with a history of acute coronary syndrome (ACS) or heart attack. In the United States, Brilinta... ® Tablets are also suitable for use in high-risk patients with coronary artery disease to reduce the risk of a first heart attack or stroke.

[0049] Specifically, the present invention provides a pharmaceutical composition comprising ticagrelor for treating, reducing, or preventing ischemic events in patients undergoing percutaneous coronary intervention (PCI), comprising administering an effective amount of ticagrelor to the patient to initiate or maintain P2Y12 inhibition during PCI. The pharmaceutical composition is characterized by being an aqueous solution of ticagrelor comprising an effective amount of a solubilizer for solubilizing ticagrelor, and the pharmaceutical composition is provided for intravenous administration. In use, the composition is administered intravenously.

[0050] As used herein, the term "provided for intravenous administration" refers to a composition compatible with the bloodstream. This particularly relates to the osmotic pressure and pH of the formulation to be compatible. No dilution or pH adjustment is required; the formulation is ready to use.

[0051] Preferably, the patient is a human patient.

[0052] Preferably, the ticagrelor aqueous solution is prepared from micronized ticagrelor with a D90 of less than 90 micrometers. Methods for measuring the particle size of the active ingredient are well known to those skilled in the art. The method used in this invention is the Malvern particle size analyzer dry powder method.

[0053] Intravenous administration provides a faster onset of action compared to oral dose delivery. It allows for the treatment of patients who cannot take oral medications, such as those who cannot swallow, are on mechanical ventilation, or are unconscious.

[0054] Ticagrelor degrades readily when exposed to light, heat, and oxygen. Furthermore, its limited solubility poses a significant challenge to its formulation into aqueous solutions. While the demand for liquid ticagrelor formulations remains high, to our knowledge, no successful commercial product has yet achieved the desired solubility required by the pharmaceutical industry.

[0055] In a preferred embodiment, ticagrelor is the only active pharmaceutical ingredient present in the composition.

[0056] Alternatively, it may contain an additional active ingredient. Preferably, the additional active ingredient is not prasugrel or a cysteine-aspartic protease inhibitor. 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)-formyloxy]-amino}-3,3-dimethyl-butyryl)-pyrrolidine-2-yl]-formyloxy}-amino)-4-oxo-butyric acid (VRT-043198), (S)-3-({1-[(S)-1-((S)-2-{[1-(4-amino-3-chlorophenyl)-formyloxy]-amino}-3,3-dimethyl-butyryl)-pyrrolidine-2-yl]-formyloxy}-amino)-4-oxo-butyric acid (VRT-043198), or an enricacin cysteine-aspartic protease inhibitor.

[0057] In a preferred embodiment, the aqueous composition of ticagrelor provided for intravenous administration contains 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 / ml ticagrelor or 4-11 mg / ml ticagrelor; most preferably 5-10 mg / ml ticagrelor.

[0058] Extensive experiments have shown that ticagrelor can be solubilized in aqueous compositions using a suitable solubilizer. Preferably, the solubilizer is cyclodextrin or vitamin E TPGS.

[0059] Cyclodextrins are cyclic carbohydrates derived from starch. Unmodified cyclodextrins differ in the number of pyranose units linked together in their cylindrical structure. The parent cyclodextrin contains 6, 7, or 8 pyranose units and is designated α-, β-, and γ-cyclodextrins, respectively. Each cyclodextrin subunit has secondary hydroxyl groups at positions 2 and 3, and a primary hydroxyl group at position 6. Cyclodextrins can be described as hollow truncated pyramids with a hydrophilic outer surface and hydrophobic cavities. In aqueous solution, these hydrophobic cavities provide refuge for hydrophobic organic compounds that can assemble all or part of their structure into these cavities. This process, called inclusion complexation, can lead to increased apparent water solubility and stability of the complexed drug; however, the degree of stability varies from drug to drug. The complex is stable through hydrophobic interactions and does not involve the formation of any covalent bonds.

[0060] Chemical modification of the parent cyclodextrin (typically at the hydroxyl moiety) has yielded derivatives that sometimes offer improved safety while retaining or improving the complexing ability of the cyclodextrin. Of the numerous derivative cyclodextrins prepared to date, only two appear to be commercially viable: a 2-hydroxypropyl derivative (HP-β-CD or HPβCD), a neutral molecule commercially developed by Janssen et al., and a sulfoalkyl ether derivative (SAE-β-CD or SAE-CD), developed by CyDex Pharmaceuticals, Inc. SAE-CD is a class of negatively charged cyclodextrins that vary in the nature of the alkyl spacer, salt form, degree of substitution, and starting parent cyclodextrin. A sodium salt of a sulfobutyl ether derivative of β-cyclodextrin with an average of about 7 substituents per cyclodextrin molecule (SBE7-β-CD) has been commercialized by CyDex Pharmaceuticals, Inc. (Kansas) as CAPTISOL® cyclodextrin.

[0061] In a preferred embodiment, the cyclodextrin is selected from hydroxypropyl-β-cyclodextrin and sulfobutyl ether of β-cyclodextrin. More preferably, the cyclodextrin is hydroxypropyl-β-cyclodextrin. Most preferably, the cyclodextrin is (2-hydroxypropyl)-β-cyclodextrin (HPbCD).

[0062] In a preferred embodiment, the aqueous ticagrelor composition provided for intravenous administration comprises 15-40% w / w, more preferably 20-35% w / w, even more preferably 22-34% w / w, and most preferably 23-33% w / w of hydroxypropyl-β-cyclodextrin. The amount of the selected cyclodextrin is sufficient to encapsulate a therapeutically relevant amount of cyclodextrin and to provide a clear ticagrelor solution.

[0063] In an alternative implementation, the solubilizer used for ticagrelor is D-α-tocopherol polyethylene glycol succinate, also known as vitamin E TPGS.

[0064] As used herein, the term "vitamin E TPGS" refers to an aqueous miscible form of vitamin E having a hydrophobic vitamin E moiety and a hydrophilic polyethylene glycol chain. Vitamin E TPGS is also known as D-α-tocopherol polyethylene glycol succinate or tococelen. Vitamin E TPGS has been approved by the U.S. Food and Drug Administration as a safe adjuvant and can be used as a surfactant, solubilizer, or stabilizer in drug delivery systems. US 2680749 discloses TPGS molecules containing polyethylene glycol with average molecular weights of 400, 1000, and those varying between 600 and 6000. Vitamin E TPGS molecules containing polyethylene glycol chains with an average molecular weight (MW) of approximately 1000 are available from Eastman Chemical Company, (Kingsport, Tennessee).

[0065] In a preferred embodiment, the aqueous ticagrelor composition provided for intravenous administration does not contain an organic co-solvent. There is no need to use an organic co-solvent to improve the solubility of ticagrelor. Avoiding organic co-solvents provides better compatibility for products intended for intravenous administration. Specifically, the aqueous ticagrelor composition according to embodiments of the invention does not contain polyethylene glycol. This is advantageous for storage stability, as the presence of polyethylene glycol in aqueous ticagrelor solutions is found to easily introduce impurities during prolonged storage.

[0066] Specifically, the aqueous ticagrelor IV composition according to embodiments of the present invention has an osmotic pressure between 350 and 900 mOsm / kg. This osmotic pressure is advantageous for intravenous administration to patients requiring ticagrelor IV treatment.

[0067] Optionally, the aqueous ticagrelor IV composition according to embodiments of the present invention comprises a tension modifier, such as sodium chloride.

[0068] Preferably, the osmotic pressure of the aqueous ticagrelor IV composition according to an embodiment of the present invention is between 350-900 mOsm / kg, more preferably between 360-800 mOsm / kg, even more preferably between 370-700 mOsm / kg, and most preferably between 380 and 600 mOsm / kg.

[0069] In a preferred embodiment, the aqueous ticagrelor IV composition according to an embodiment of the invention exhibits storage stability of at least 3 months under accelerated storage conditions of 40°C and 75% relative humidity (RH). More preferably, the storage stability is at least 6 months; even more preferably, at least 9 months; and most preferably, at least 12 months. The satisfactory stability of 6 months at 40°C and 75% RH corresponds to a shelf life of 24 months at room temperature (25°C).

[0070] As used in this article, “storage stability” refers to a total impurity level of less than 0.5%.

[0071] Storage-stable compositions have the advantage over temporary mixtures because the product does not need to be prepared just before medical use. This saves time.

[0072] 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 7.0 to 8.0. This pH selection is advantageous for the long-term storage stability of the ticagrelor IV composition. Furthermore, it provides a physiologically acceptable pH. No pH adjustment is required before administration to the patient, which saves time.

[0073] Most preferably, the aqueous ticagrelor IV composition according to an embodiment of the present invention is a solution comprising:

[0074] 5-15 mg / ml ticagrelor,

[0075] 15-40% w / w hydroxypropyl-β-cyclodextrin,

[0076] 5 mM-20 mM buffer solution,

[0077] The pH ranges between 5.5 and 8.

[0078] Most preferably, the aqueous ticagrelor IV composition according to an embodiment of the present invention is a solution comprising:

[0079] 5-15 mg / ml ticagrelor,

[0080] 15-40% w / w hydroxypropyl-β-cyclodextrin,

[0081] 5 mM-20 mM phosphate buffer,

[0082] The pH ranges between 5.5 and 8.

[0083] Alternatively, the aqueous ticagrelor IV composition according to an embodiment of the present invention is a solution comprising the following:

[0084] 0.10–14.0 mg / ml ticagrelor and

[0085] Cyclodextrin at a concentration of 20–100 mg / ml, in an amount sufficient to solubilize ticagrelor in a selected volume of aqueous drug solution.

[0086] The pH of the composition is between 5.5 and 9.0 (inclusive).

[0087] Furthermore, the volume of the aqueous drug solution is 25 to 1000 ml.

[0088] The compositions provided above are simple and easy to manufacture. The limited number of components reduces the formation of impurities and byproducts. This is advantageous for the availability of ticagrelor IV solution in patients requiring treatment for cardiovascular events.

[0089] An aqueous ticagrelor IV composition according to an embodiment of the present invention is provided for providing antiplatelet therapy before, during or after PCI procedures.

[0090] In a preferred embodiment, the aqueous ticagrelor IV composition according to an embodiment of the invention is used to treat patients whose P2Y12 response units (PRU) are below 200, more preferably below 150, and even more preferably below 110 before ticagrelor IV administration. Most preferably, the P2Y12 response units are between 0 and 100 after ticagrelor IV administration.

[0091] P2Y12 responsive units (PRU), an indicator of platelet function, can be measured using the VerifyNow P2Y12 assay (Accriva Diagnostics). Platelet reactivity is expressed as P2Y12 responsive units (PRU) and inhibition percentage. It is calculated as: ((1 - (P2Y12 receptor blockade / baseline platelet reactivity) × 100). Scientific literature reports that the risk of complications may be associated with high PRU.

[0092] In a preferred embodiment of the invention, ticagrelor is administered intravenously within 5 days prior to the PCI procedure. More preferably, ticagrelor IV is administered within 4 days prior to the PCI procedure, even more preferably within 3 days, and most preferably within 2 or 1 day.

[0093] For emergency surgery, the patient may have already received ticagrelor IV just before the procedure. An antidote or absorption technology (such as CytoSorb®) can be used to lower the blood level of ticagrelor to a level suitable for reducing the risk of bleeding. The antidote for ticagrelor is betracitabine (also known as PB2452). It is a neutralizing recombinant human immunoglobulin G1 monoclonal antibody antigen-binding fragment that binds to ticagrelor and its major active circulating metabolite M8 (also known as AR-C124910XX) with high affinity and specificity. CytoSorb® consists of a porous polymer microsphere adsorption system.

[0094] Preferably, the pharmaceutical composition according to embodiments of the present invention is administered intravenously to patients with a P2Y12 response unit (PRU) of more than 100, preferably more than 200, prior to administration of ticagrelor.

[0095] Preferably, the pharmaceutical composition according to an embodiment of the present invention is administered intravenously to a patient who is in a coma, intubated, or mechanically ventilated.

[0096] Preferably, the ticagrelor IV composition according to an embodiment of the present invention is administered intravenously after percutaneous coronary intervention; preferably within 6 hours after the procedure, more preferably within 4 hours after the procedure, even more preferably within 3 hours after the procedure, and most preferably within 2 hours after the procedure.

[0097] The availability of IV formulations allows for the earlier restart of antiplatelet therapy compared to tablets; it also has a faster onset of action than crushed tablets. Treatment can be initiated while the patient is still in recovery, unconscious, or comatose, thus reducing the risk of postoperative thrombosis.

[0098] Preferably, the pharmaceutical composition according to an embodiment of the invention is administered intravenously to a patient who has received an analgesic containing morphine or fentanyl prior to receiving intravenous ticagrelor.

[0099] The use of intravenous ticagrelor overcomes the delayed bioavailability caused by sedatives such as morphine or fentanyl, providing faster onset of platelet inhibition.

[0100] Preferably, the pharmaceutical composition according to an embodiment of the invention is administered intravenously to a patient who has received an analgesic containing acetaminophen (preferably acetaminophen IV) prior to receiving intravenous ticagrelor.

[0101] Most preferably, opioids, such as morphine or fentanyl, are not used in the treatment according to embodiments of the invention. This helps to avoid addiction. In cases with an acute risk of thrombosis, it is also important to avoid delayed onset of therapeutic effect.

[0102] Ticagrelor IV compositions for the treatment of cardiovascular arterial events can be administered by injection, short-term infusion, or long-term infusion. Short-term infusion is preferably between 1 and 20 minutes, more preferably between 3 and 15 minutes, and most preferably between 5 and 10 minutes.

[0103] Preferably, the pharmaceutical composition according to embodiments of the present invention is administered intravenously via bolus infusion. Preferably, the bolus infusion is administered in less than 10 minutes, more preferably less than 5 minutes, even less than 3 minutes, and most preferably less than 2 minutes. Most preferably, the bolus infusion is administered as an injection. The therapeutic effect is faster compared to oral ticagrelor or crushed ticagrelor tablets.

[0104] Optionally, one or more maintenance infusions of ticagrelor IV follow the loading of ticagrelor.

[0105] Preferably, the pharmaceutical composition according to embodiments of the present invention is administered intravenously after PCI surgery, and 20-50 mg of ticagrelor is administered orally twice daily after intravenous administration, as the patient can take oral medication.

[0106] This switch from IV to oral administration is advantageous because the active pharmaceutical ingredient remains unchanged.

[0107] In a preferred embodiment of the invention, ticagrelor is administered as a monotherapy for antiplatelet therapy or as part of a dual antiplatelet therapy in combination with aspirin.

[0108] In a preferred embodiment of the invention, aspirin is administered intravenously.

[0109] In a preferred embodiment of the invention, the patient has a stent placed in their body.

[0110] Preferably, ticagrelor is administered intravenously after PCI; more preferably, it is administered within 6, 5, or 4 hours after the procedure. More preferably, it is administered within 3 hours after the procedure, and most preferably, it is administered within 2 hours after the procedure.

[0111] The availability of ticagrelor IV offers the following advantages: ticagrelor treatment can be initiated while the patient is still in recovery, unconscious, or comatose. This may help reduce the risk of postoperative thrombosis.

[0112] Patients may become conscious and be able to swallow tablets 4 to 6 hours after surgery. Therefore, oral antiplatelet therapy can be started immediately following intravenous administration.

[0113] In a preferred embodiment of the invention, a bolus infusion of 5-80 mg ticagrelor is administered to the patient postoperatively. The first infusion of ticagrelor may be followed by one or more subsequent infusions. Preferably, each of the one or more infusions comprises the administration of 5-80 mg ticagrelor.

[0114] In a preferred embodiment of the invention, treatment comprises administering 20-50 mg of ticagrelor orally twice daily following the last intravenous administration. Switching from intravenous to oral administration of ticagrelor improves patient comfort. Patients taking tablet medication can be more easily sent home because no assistance is required compared to intravenous administration.

[0115] In a preferred embodiment of the invention, the composition is used to treat patients resistant to clopidogrel.

[0116] Clopidogrel resistance is a condition in which the drug clopidogrel is less effective than normal in people treated with it. A residual platelet aggregation greater than 50% relative to baseline is defined as a poor response after clopidogrel treatment, as measured using a light transmittance aggregation assay when stimulated with 20 μM ADP.

[0117] Platelet aggregation was assessed as follows. Blood collected in blood-citrate tubes was centrifuged at 120 g for 5 minutes to recover platelet-rich plasma, and further centrifuged at 850 g for 10 minutes to recover platelet-poor plasma. PRP and PPP were stored at room temperature for use within 2 hours. Platelets were stimulated with 20 μM ADP, and aggregation was assessed using a Chronolog Lumi-Aggregometer (model 490-4D) with Aggro / Link software package (Chronolog, Havertown, Pennsylvania). Aggregation was expressed as the maximum percentage change in transmittance relative to baseline, using platelet-poor plasma as a reference.

[0118] In a preferred embodiment, the pharmaceutical composition is infused in a therapeutically effective amount during cardiovascular artery surgery.

[0119] In a further aspect, the present invention provides ticagrelor therapy in which drug-drug interactions with opioid analgesics are avoided.

[0120] The present invention provides a composition comprising ticagrelor for use in a method of treating patients requiring P2Y12 inhibition, wherein the composition is administered intravenously in a therapeutically effective amount, provided that the treatment is free of morphine and fentanyl, and wherein the therapeutically effective amount of analgesic comprising acetaminophen is administered.

[0121] Preferably, the analgesic further contains ibuprofen.

[0122] More preferably, acetaminophen and ibuprofen are administered intravenously in combination. Example

[0123] The following examples provide ticagrelor pharmaceutical compositions for reducing or preventing thromboembolic events before, during, and / or after PCI procedures in patients in need.

[0124] Example 1: Vitamin E TPGS as a solubilizer for ticagrelor

[0125] Table 1: Ticagrelor IV Combinations

[0126]

[0127] Using vitamin E TPGS as a solubilizer, ticagrelor aqueous solutions were prepared as follows: Water-soluble vitamin E TPGS was added to water to obtain aqueous solutions of different concentrations: 2.5 w / v%, 5.0 w / v%, and 10.0 w / v. The ticagrelor fraction was gradually added to these solutions, which were maintained at 45°C ± 5°C. 3 mg of the ticagrelor fraction was gradually added to 50 ml of vitamin E TPGS aqueous solution (Phase 1). Then, in the Phase 2 study, 20 ml of various diluents were used. 10 mg of the ticagrelor fraction was added to 20 ml of various diluents. When dissolution took a long time, the ticagrelor concentration was reduced to 5 mg.

[0128] Table 2: Ticagrelor IV aqueous solution

[0129]

[0130] The following was observed: 10 mg ticagrelor dissolved after 5-10 minutes.

[0131] 2.5% Vitamin E TPGS solution saturated at 11.6 mg / ml

[0132] 5.0% Vitamin E TPGS solution saturated at 14.9 mg / ml

[0133] 10.0% Vitamin E TPGS solution saturated at 19.8 mg / ml

[0134] The obtained ticagrelor aqueous solution should be stored at 40°C and 75% relative humidity or 25°C and 60% relative humidity for at least 3 months.

[0135] Example 2: Cyclodextrin as a solubilizer for ticagrelor

[0136] The following compositions are suitable as ready-to-use aqueous ticagrelor compositions for intravenous administration.

[0137] Table 3: Ready-to-use ticagrelor compositions in water

[0138]

[0139] Table 4: Ready-to-use ticagrelor compositions in aqueous phosphate buffer solutions

[0140]

[0141] Table 5: Ready-to-use ticagrelor compositions in diluted physiological saline

[0142]

[0143] Table 6: Ready-to-use ticagrelor compositions in dextran solution

[0144]

[0145] Table 7: Preferred ticagrelor solutions for infusion

[0146]

[0147] An exemplary ready-to-use solution is prepared as follows. In all cases, the solvent mentioned is prepared and placed in a beaker and heated to 40 °C, then HPβCD is added to obtain a clear solution with stirring. Subsequently, the active ingredient ticagrelor is added at 40 °C with continuous stirring until a clear solution is obtained. This solution is filtered through a 0.22-micron filter and aseptically filled into sterile glass vials or infusion bags.

[0148] A stable ticagrelor solution of 24 mg / ml to 350 mg / ml HPβCD is required for infusion. The amount of cyclodextrin required depends on the volume of the target infusion medium.

[0149] Ticagrelor is an active ingredient that is insoluble in water. The more diluted it is in a diluted aqueous solution, the more likely it is to precipitate. As the dilution factor of ticagrelor increases, the amount of cyclodextrin required increases proportionally from 30 ml to 100 ml and then to 200 ml. However, for volumes of 650 ml and above, 16 g of cyclodextrin has been found to be sufficient to solubilize ticagrelor.

[0150] Please note that no organic cosolvents, surfactants, or other solubilizers were used.

[0151] The resulting ticagrelor aqueous solution was stored at 40°C and 75% relative humidity or 25°C and 60% relative humidity for at least 3 months and was found to be stable.

[0152] Developing a storage-stable ticagrelor solution

[0153] The experimental work used to obtain a storage-stable ticagrelor solution is explained in the following implementation plan.

[0154] Example 3

[0155] In this embodiment, two different types of cyclodextrins were used, and their solubilization effects on ticagrelor were compared. Unbuffered stock solutions of HPβCD or SBECD were prepared in water at target concentrations of 20 w / w%, 25 w / w%, 30 w / w%, 35 w / w%, and 40 w / w%. Ticagrelor was slowly added under vortex. Ticagrelor was used in milliQ water at concentrations of 5, 10, or 14 mg / ml. The ticagrelor-cyclodextrin solution was placed on a shaking platform. No sonication or heating was applied.

[0156] The results in Tables 8 and 9 show that HPβCD can dissolve ticagrelor in a wider range of cyclodextrin and ticagrelor concentrations tested. Clear aqueous solutions containing 5 mg / ml ticagrelor were obtained using 25 w / w%, 30 w / w%, 35 w / w%, and 40 w / w% HPβCD.

[0157] Table 8: Solubility of ticagrelor in HPβCD

[0158]

[0159] + Clarified, showing complete dissolution

[0160] - A translucent solution with a precipitate

[0161] + / - Clear solution with precipitate

[0162] After one hour of ultrasound treatment

[0163] Table 9: Solubility of ticagrelor in SBECD

[0164]

[0165] + Clarified, showing complete dissolution

[0166] - A translucent solution with precipitate

[0167] + / - Clear solution with precipitate

[0168] In conclusion, ticagrelor can be dissolved by placing it on a shaking platform. No sonication is applied. At a 5 mg / ml ticagrelor concentration, HPβCD can be used with 40% w / w, 35% w / w, or 30% w / w cyclodextrin in milliQ water. These solutions remain clear at room temperature for at least three days and remain clear at 4°C for several days.

[0169] Example 4

[0170] Following the experiments described in Example 3, further optimization was performed by selecting an appropriate pH range to ensure the long-term stability of the aqueous ticagrelor-cyclodextrin inclusion complex.

[0171] Prepare the following compositions as provided in Table 10.

[0172] Table 10: Components used for storage stability testing.

[0173]

[0174] HPβCD is dissolved in a buffer solution prepared separately in water at pH 4.5, 5.5, or 6.5. Once a clear solution is obtained, ticagrelor is dissolved in the buffer solution with continuous stirring. The ticagrelor in the buffer solution is filtered through a 0.22-micron filter and filled into USP Type I glass vials. The vials are stoppered and stored. All precautions, such as N2 purging and avoidance of direct exposure to light, are taken during manufacturing. The vials are stored at 40 °C and 75% relative humidity (RH).

[0175] To determine the stability of the formulation, batches were evaluated using the related substances method on HPLC. The data for these batches are listed in Table 11 below.

[0176] Impurities in the formulation were analyzed using gradient HPLC with a YMC-Pack Pro C18 column (100x4.6mm, S-3μm 12nm). All impurities were well separated.

[0177] Amine impurity: (1S,2S,3R,5S)-3-(7-amino-5-(propylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)-5-(2-hydroxyethoxy)cyclopentane-1,2-diol. This is a process-related degradation impurity.

[0178] Regioisomer impurity: (1S,2S,3R,5S)-3-((3-((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)-5-(propylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7-yl)amino)-5-(2-hydroxyethoxy)cyclopentane-1,2-diol. This is a process-related degradation impurity.

[0179] Acetal impurity: 2-[[(3aR,4S,6S,6aS)-6-[7-[[1R,2S)-2-(3,4-difluorophenyl)-cyclopropyl]amino]-5-(propylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl]-2,2-dimethyltetrahydro-2H-3aH-cyclopenta[d][1,3]dioxacyclopenten-4-yl]oxy]eth-1-ol.

[0180] These are process-related impurities.

[0181] 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.

[0182] These are process-related impurities.

[0183] It was observed that only regiomeric impurities increased by approximately 0.3% at 40 °C and 75% RH over 4 weeks; the specification limit was 0.3%. Therefore, studies were conducted at pH 7 to 8 to further optimize product stability.

[0184] Example 5

[0185] Storage stability was studied at pH 7.5, following the experiment described in Example 4.

[0186] First, HPβCD was dissolved in a phosphate buffer solution prepared separately in water at pH 7.5. Once a clear solution was obtained, ticagrelor was dissolved in the solution with constant stirring. The solution was filtered through a 0.22-micron filter and filled into USP Type I amber glass vials. The vials were stoppered and stored. All precautions, such as N2 purging and avoidance of direct light exposure, were taken during manufacturing.

[0187]

[0188] Table 12: Components used for storage stability testing.

[0189]

[0190] Table 13: Storage stability study of ticagrelor-cyclodextrin inclusion complexes stored in aqueous solution at pH 7.5 at 40 °C and 75% relative humidity.

[0191]

[0192] Based on the results of the stability studies, as summarized in Table 6, it is concluded that good storage stability was achieved under accelerated storage conditions of 40°C and 75% relative humidity. Regiomeric impurities were well controlled, and no other impurities warranted attention.

[0193] Example 6

[0194] In further experiments, in order to optimize the concentration of HPβCD to below 40% w / w, heating at 40°C was applied to help dissolve the target dose of ticagrelor when it was difficult to obtain a clear solution.

[0195] The direct physical stability data obtained by ticagrelor 5 mg / ml concentrate and flocculation test (20 µl sample material in 1 ml diluent) are shown in Table 14. Table 7 contains data on content, purity, osmotic pressure, and pH.

[0196] Table 14: Physical stability of 5 mg / ml ticagrelor batches with different HPβCD concentrations. Data are sorted by HPβCD concentration. Ticagrelor concentration when diluted to dextran or physiological saline: 0.1 mg / ml.

[0197]

[0198] Due to the varying physical stability results when diluted in physiological saline, 32.5% w / w HPβCD was chosen for the 5 mg / ml ticagrelor formulation. The undiluted concentrate remains stable, even in a refrigerator, with HPβCD concentrations as low as 22.5% w / w. Such concentrations produce a nearly isotonic formulation.

[0199] In summary, 5–15 mg / ml ticagrelor can be dissolved together with HPβCD at concentrations ranging from 20–40% w / w without heating. A clear solution can be obtained by using lower concentrations of HPβCD, such as 15–20% w / w, and applying heat to achieve good solubility.

[0200] At least 15% w / w HPβCD is required to provide a clear, storage-stable ticagrelor solution with concentrations associated with injection or intravenous administration.

[0201] Example 7

[0202] The results obtained from Example 6 demonstrate that the excipient concentration allows for a hypertonic ticagrelor solution. Osmolarity and pH were examined in several batches. The solution was prepared with 19 mM phosphate buffer and pH 7.5. The results are provided in Table 15.

[0203] Table 15: pH and osmotic pressure measurements of undiluted batches.

[0204]

[0205] Dilution studies were conducted to identify a suitable diluent.

[0206] Solutions of ticagrelor-cyclodextrin at 5 mg / ml with varying amounts of HPβCD were diluted with physiological saline, 5% dextran solution, or lactated Ringer's solution. Stability screening was performed. The ticagrelor concentration at dilution in dextran or physiological saline was 0.1 mg / ml. The results are summarized in Table 16.

[0207] Table 16: Diluent Test

[0208]

[0209] In addition, the effects of buffer concentration on pH and osmotic pressure were screened. The results are summarized in Table 17.

[0210] Table 17: Effects of buffer concentration on pH, osmotic pressure, content and impurities.

[0211]

[0212] The conclusion is that pH 7.5 phosphate buffer at different concentrations has little effect on osmotic pressure, except for the 0.19 mM buffer concentration. The 0.19 mM buffer concentration is too weak to cause pH changes.

[0213] Example 8

[0214] In a further implementation, the effect of particle size on solubility was tested.

[0215] Two different particle sizes, 5.5 μm and 15 μm, were screened for the active ingredient of ticagrelor. pH and osmotic pressure were unaffected. Smaller particles exhibited faster dissolution times, as summarized in Table 18.

[0216] Micronized ticagrelor exhibits a significant improvement in dissolution time. Therefore, micronized ticagrelor with a D90 of less than 10 micrometers is preferred.

[0217] As used herein, the term "D90" refers to the presence of at least 90% of particles having a size smaller than the target particle size. However, it should be understood that variations in the input particle size distribution (PSD) of ticagrelor are possible and will affect the dissolution rate of ticagrelor.

[0218] Methods for measuring the particle size of active ingredients are well known to those skilled in the art of pharmaceutical formulation. The method employed in this invention is the Malvern particle size analyzer dry powder method.

[0219] Table 18: Effect of Particle Size

[0220]

[0221] Example 9

[0222] To optimize HPβCD concentration and pH of the solution for intravenous use, a 12-week / 3-month stability study was conducted. Combinations of 32.5% w / w HPβCD with 5 mg / ml ticagrelor at pH 7 to 8 were prepared and stored. Stability was tested at fixed intervals.

[0223] The stability characteristics of the three formulations at three different pH values ​​(7, 7.5, and 8) were compared below. All three formulations were manufactured using the same process, and the buffer concentration was 19 mM. The results are summarized in Tables 19 to 21.

[0224] Table 19: Storage stability in amber glass vials – pH 7

[0225]

[0226] Table 20: Storage stability in amber glass vials – pH 7.5

[0227]

[0228] Table 21: Storage stability in amber glass vials – pH 8.0

[0229]

[0230] The data above indicate that ticagrelor solutions in HPβCD are stable in the pH range of 7 to 8.

[0231] Example 10

[0232] To investigate the potential impact of packaging materials on the stability of ticagrelor-cyclodextrin inclusion complexes, compositions with 32.5% w / w HPβCD were prepared using procedures and precautions similar to those used in previous experiments. Samples were stored in clear glass vials and amber glass vials at 40 °C / 75% RH. The results are shown in Tables 22 and 23.

[0233] The results of the accelerated storage stability test showed no significant difference between the two after 3 months. All samples remained clear aqueous solutions. The pH of the samples remained stable. There were no significant changes in impurities.

[0234] It seems that both clear and amber glass bottles can be used.

[0235] Compared to the accelerated storage stability test results of ticagrelor solution without cyclodextrin, the use of cyclodextrin is clearly important for achieving good stability. In the absence of cyclodextrin, six to eight different impurities are generated during storage. These impurities were not observed in the selected composition.

[0236] Table 22: Study on the potential impact of packaging. Stability of amber USP Type I glass.

[0237]

[0238] Table 23: Study on the potential impact of packaging. Stability of transparent glass vials, USP Type I.

[0239]

[0240] Surprisingly, it can be concluded that ticagrelor solution is stable with HPβCD in amber and clear glass vials.

[0241] Example 11

[0242] Further embodiments of the invention are provided, as summarized in Table 24. Further improvements to ticagrelor, achieving higher solubility, were explored using different concentrations, for example, 40% w / w HPβCD; a solubility of 13 mg / ml for ticagrelor was also possible.

[0243] Table 24: Clear aqueous solutions containing ticagrelor-cyclodextrin inclusion complexes, considering a dose of 65 mg.

[0244]

[0245] Density 1.130 gm / cc

[0246] Based on research, concentrations of 5-13 mg / ml ticagrelor solution have been observed using 20-40% w / w HPβCD. The volume of the filling contents can be varied based on the desired dosage.

[0247] Surprisingly, it was found that by adjusting the HPβCD% and total available volume of the formulation prepared for injection, a target dose of 5-15 mg / ml ticagrelor could be achieved in a small volume. The ability to deliver a ticagrelor dose in a 5-15 ml volume is highly relevant, as this is a typical bolus injection volume.

[0248] Example 12

[0249] In a further implementation, the maximum solubility of ticagrelor in HPβCD solution without heating was investigated. The results are summarized in Table 25.

[0250] Depending on the amount of ticagrelor to be delivered to the patient and the limitations of the sample volume determined by injection or infusion administration, a dose of 2000-4000 mg HPβCD may be required per 10 ml vial to dissolve 65-75 mg of ticagrelor.

[0251] Table 25: Concentration, Dosage, and Formulation Volume of HPβCD

[0252]

[0253] The density of the HPβCD solution is 1.130 gm / cc.

[0254] Surprisingly, the solutions provided in Table 18 are compatible with diluents for providing infusions, particularly with 5% dextrose aqueous solution.

[0255] Example 13

[0256] In another embodiment of the invention, a highly stable ticagrelor clear solution can be obtained by applying appropriate heat to the solution during preparation, thereby providing a completely clear formulation solution with the desired HPβCD and ticagrelor concentrations.

[0257] To investigate the effects of temperature and holding time, new compositions were prepared according to Table 26 below.

[0258] Table 26: Compositions used for temperature effect assessment.

[0259]

[0260] In the first step, a phosphate buffer solution with pH 7.5 is prepared, and the buffer solution is heated to 40°C–45°C. HPβCD is added to the buffer solution under continuous mixing. Once a clear solution is obtained, ticagrelor is dispersed into the HPβCD solution and mixed until a clear solution is obtained. This typically takes 30 minutes to 4 hours, depending on the batch size. The solution is then filtered through a 0.22-micron filter and packaged in suitable clear or amber glass vials.

[0261] Table 27: Study on preservation of the original solution at 45℃

[0262]

[0263] Table 28: Studies on stock solution preservation at 25℃ and 40℃

[0264]

[0265] Table 29: Preservation of the stock solution at 30°C

[0266]

[0267] Storage time studies at temperatures between 25 °C and 45 °C showed that 30% w / w HPβCD was able to stabilize ticagrelor even after the solution was heated for a long period of time or after the stock solution was placed at elevated temperatures.

[0268] Method for manufacturing ready-to-use infusion formulations

[0269] The exemplary ready-to-use solutions in Table 3-7 are prepared as follows. In all cases, the mentioned solvent is prepared and placed in a beaker and heated to 40°C, then HPβCD is added to obtain a clear solution with stirring. Subsequently, the active ingredient ticagrelor is added at 40°C with continuous stirring until a clear solution is obtained. This solution is filtered through a 0.22-micron filter and aseptically filled into sterile glass vials or infusion bags.

[0270] A stable ticagrelor solution of 24 mg / ml to 350 mg / ml HPβCD is required for infusion. The amount of cyclodextrin required depends on the volume of the target infusion medium.

[0271] Ticagrelor is an active ingredient that is insoluble in water. The more diluted it is in a diluted aqueous solution, the more likely it is to precipitate. As the dilution factor of ticagrelor increases, the amount of cyclodextrin required increases proportionally from 30 ml to 100 ml to 200 ml. However, for volumes of 650 ml and above, it has been found that 16 g of cyclodextrin is sufficient to hold ticagrelor in the aqueous solution.

[0272] Please note that organic cosolvents, surfactants, or other solubilizers should not be used.

[0273] Optional preparation methods begin with concentrated ticagrelor solution.

[0274] One 8ml vial containing 65 mg ticagrelor and approximately 3 g HPβCD can be diluted with 25 ml of 5 w / v dextrose to obtain a clear solution with a final volume of 33 ml. However, this cannot be achieved using 0.9 w / v % NaCl solution as a diluent for the concentrated ticagrelor solution. This is crucial in medical treatments where the concentrated aqueous ticagrelor composition will be mixed with another drug. It can cause precipitation of ticagrelor, making the combination product unsuitable for intravenous administration.

[0275] Solubility studies with other solvents

[0276] Solubility studies were conducted using different solvents. Formulation AE, as shown in Table 30, was prepared as follows: Ticagrelor (final concentration 1.8 mg / ml) was added to a tube (e.g., an Eppendorf tube or conical tube), followed by the addition of the listed solvent diluted in distilled water (final volume 10 ml). The tube was then vortexed and sonicated in a temperature-controlled water bath, if necessary. After 60 minutes, the tube was collected for solubility observation. The sample was examined again after 24 hours.

[0277] Table 30: Solubility studies with other solvents

[0278]

[0279] Based on the research, it was observed that ticagrelor can be solubilized with either cyclodextrin or polyethylene glycol (PEG).

[0280] It has good solubility, but its storage stability is insufficient.

[0281] Polyethylene glycol (PEG) can solubilize ticagrelor. However, PEG has been found to be sensitive to degradation, which leads to impurities.

[0282] Example 14

[0283] Two clarified 1.8 mg / ml ticagrelor formulations were prepared after sonication for several hours: Formulation 1 (Example 14), 1.8 mg / ml ticagrelor in 20% w / w hydroxypropyl-β-cyclodextrin (HPβCD), with the remainder in distilled water; and Formulation 2 (Example 14), 1.8 mg / ml ticagrelor in 50% w / w PEG400, with the remainder in distilled water.

[0284] The two formulations were aliquoted and stored at room temperature and 40°C, respectively. LC-UV analysis of the formulations was performed immediately after preparation. Figure 1 and Figure 2 During the 6-month stability period, they were analyzed three more times. Figure 3 and Figure 4 ).

[0285] Ticagrelor was found to be stable in formulation 1 (Example 14), i.e., 1.8 mg / ml ticagrelor in 20% w / w HPβCD, for at least 6 months at room temperature and at 40°C. Figures 5 to 6 ).

[0286] In formulation 2 (Example 14), i.e., 1.8 mg / ml ticagrelor in 50% w / w PEG400, ticagrelor is unstable at room temperature and 40°C. (LC-UV chromatogram) Figures 4 to 6 In formulation 2 (Example 14), a strong peak of potential degradation products was observed. Attached Figure Description

[0287] Figure 1 The LC-UV chromatograms of ticagrelor formulation 1 (Example 14) and blank control on day 0 are depicted.

[0288] Figure 2 LC-UV chromatograms of ticagrelor formulation 2 (Example 14) and blank control on day 0.

[0289] Figure 3 LC-UV chromatograms of ticagrelor formulation 1 (Example 14) and blank control on day 188 (room temperature).

[0290] Figure 4 LC-UV chromatograms of ticagrelor formulation 1 (Example 14) and blank control on day 188 (40°C).

[0291] Figure 5 LC-UV chromatograms of ticagrelor formulation 2 (Example 14) and blank control on day 188 (room temperature).

[0292] Figure 6 LC-UV chromatograms of ticagrelor formulation 2 (Example 14) and blank control on day 188 (40°C).

Claims

1. A pharmaceutical composition comprising ticagrelor for treating or preventing ischemic events in patients undergoing percutaneous coronary intervention (PCI), comprising administering an effective amount of ticagrelor to said patient to initiate or maintain P2Y12 inhibition, characterized in that, The pharmaceutical composition is an aqueous solution of ticagrelor containing an effective amount of a solubilizer for solubilizing ticagrelor, and the pharmaceutical composition is provided for intravenous administration; wherein the effective amount of ticagrelor is for intravenous administration.

2. The pharmaceutical composition for use according to claim 1, wherein the solubilizer for ticagrelor is a cyclodextrin; preferably, the cyclodextrin is hydroxypropyl-β-cyclodextrin (HPbCD).

3. The pharmaceutical composition for use according to claim 1, wherein the solubilizer for ticagrelor is D-α-tocopherol polyethylene glycol succinate (vitamin E TPGS).

4. The pharmaceutical composition for use according to any one of claims 1 to 3, wherein the pH of the ticagrelor aqueous pharmaceutical composition is 5.5 to 9.

0.

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

6. The pharmaceutical composition for use according to any one of claims 1, 2, and 4, wherein the ticagrelor aqueous solution comprises: 0.10–14.0 mg / ml ticagrelor and A concentration of 20–100 mg / ml of cyclodextrin, sufficient to solubilize ticagrelor in a selected volume of aqueous drug solution, wherein the pH of the composition is between 5.5 and 9.0, including the extreme values, and The volume of this aqueous drug solution is 25 to 1000 ml.

7. The pharmaceutical composition for use according to any one of claims 1 to 6, wherein the ticagrelor aqueous pharmaceutical composition has storage stability of at least 3 months, as measured under accelerated storage conditions of 40°C and 75% relative humidity (RH).

8. The pharmaceutical composition for use according to any one of claims 1 to 7, wherein the patient has more than 100, preferably more than 200 P2Y12 response units (PRU) prior to administration of ticagrelor.

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

10. The pharmaceutical composition for use according to any one of claims 1 to 9, wherein ticagrelor is administered intravenously after percutaneous coronary intervention; preferably within 6 hours after the procedure.

11. The pharmaceutical composition for use according to any one of claims 1 to 10, wherein the patient has a stent in place.

12. The pharmaceutical composition for use according to any one of claims 1 to 11, wherein the patient has been given an analgesic containing acetaminophen (iv) and free of morphine and fentanyl prior to receiving intravenous ticagrelor.

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

14. The pharmaceutical composition for use according to claim 13, wherein the loading dose is administered in less than 10 minutes, preferably in less than 5 minutes, and most preferably in less than 2 minutes.

15. The pharmaceutical composition for use according to claim 13 or 14, comprising oral administration of 20-50 mg ticagrelor twice daily after the last intravenous administration of ticagrelor, provided that the patient is conscious.

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

17. The pharmaceutical composition for use according to any one of claims 1 to 16, wherein ticagrelor is administered as an antiplatelet monotherapy or as part of a dual antiplatelet therapy in combination with aspirin.

18. The pharmaceutical composition for use according to claim 17, wherein the aspirin is administered intravenously.

19. A composition comprising ticagrelor, used in a method for treating pain in a patient requiring P2Y12 inhibition, wherein the composition is administered intravenously in a therapeutically effective amount, provided that the treatment is free of morphine and fentanyl, and wherein a therapeutically effective amount of analgesic, including acetaminophen, is administered.

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

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

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