Ticagrelor IV for use in the treatment, reduction, or prevention of ischemic events in patients who have undergone percutaneous coronary intervention (PCI)

Abstract

The present invention provides a pharmaceutical composition comprising ticagrelor for use in the treatment, reduction, or prevention of ischemic events in a patient who has undergone percutaneous coronary intervention (PCI), comprising the step of administering an effective amount of ticagrelor to the patient to initiate or maintain P2Y12 inhibition during percutaneous coronary intervention (PCI); wherein the pharmaceutical composition is an aqueous ticagrelor solution comprising a solubilizing agent in an effective amount for solubilizing ticagrelor; wherein the pharmaceutical composition is provided by intravenous administration, and the effective amount of ticagrelor is administered intravenously.

Description

Technology Field

[0001] The present invention falls within the field of medical uses of pharmaceutical compositions. The present invention relates to a storage-stable, aqueous pharmaceutical ticagrelor solution for use in the treatment of ischemic events in patients, including those with ST-segment elevation myocardial infarction or acute ischemic stroke, by administering the P2Y12 inhibitor ticagrelor intravenously during percutaneous coronary intervention (PCI). The use of a storage-stable, aqueous ticagrelor IV formulation is advantageous in situations requiring acute intervention to manage high-risk situations. This is an improvement over the immediate preparation of ticagrelor solutions provided for IV administration.

[0002] The present invention relates to a pharmaceutical ticagrelor composition for antiplatelet therapy comprising intravenous administration of the P2Y12 inhibitor ticagrelor. Background Technology

[0003] Myocardial infarction (MI) is a leading cause of hospitalization and mortality worldwide. If left untreated, MI causes irreversible damage to the heart muscle due to insufficient blood flow (ischemia) and consequently, oxygen deficiency. Therefore, the primary goal of MI treatment is to rapidly restore normal coronary blood flow through reperfusion therapy, aiming to reduce heart muscle damage. Reperfusion therapy typically involves the use of therapeutic agents to reduce thrombosis and increase blood flow, often in conjunction with techniques such as transcutaneous coronary intervention, commonly abbreviated as PCI. PCI procedures are used to treat blockages in the coronary arteries. They open narrowed or blocked sections of the arteries to restore blood flow to the heart. Early reperfusion and PCI are desirable and associated with improved outcomes, and medical guidelines recommend performing PCI within 12 hours of the onset of MI symptoms.

[0004] Several treatment strategies are available to manage thrombosis and are divided into two classes: protein-based therapies and small molecule therapies. Examples of small molecule therapies include the P2Y12 receptor inhibitors clopidogrel, ticagrelor, prasugrel, and cangrelor. These P2Y12 receptor inhibitors are known for their ability to inhibit platelets and prevent blood clotting. Clopidogrel and prasugrel are irreversible antagonists of the P2Y12 receptor. A disadvantage of clopidogrel and prasugrel is that they are precursor drugs that require hepatic metabolic activation. This results in a delayed onset of action. Additionally, patients may be resistant to clopidogrel.

[0005] Clopidogrel, prasugrel, and ticagrelor are commercially available only in tablet form. They do not offer the possibility of treating unconscious patients. This includes patients on mechanical ventilation or those who have undergone surgical procedures, who are vulnerable to unpredictable and often insufficient platelet suppression. Tablets also pose a problem for patients with dysphagia (difficulty swallowing). Oral medications may also carry a risk of food effects.

[0006] In cases of emergency primary percutaneous coronary intervention (PCI), tablet crushing is a method known to achieve faster absorption and a more rapid and higher antiplatelet effect within 30 to 120 minutes of administration. Since prasugrel bypasses gastric acid, its bioavailability is reduced when administered via the intestinal route.

[0007] Cangrelor is commercially available as an intravenous formulation. Although it acts quickly, it also acts briefly. Cangrelor has a very short half-life of 3 to 6 minutes, so its antiplatelet effect is offset within 60 minutes. Additionally, it can be used as a bridge from oral medications to intravenous administration of cangrelor. However, switching from a tablet to an intravenous formulation containing two different active pharmaceutical ingredients can also lead to unwanted complications. Cangrelor is primarily used in patients who have not previously used antiplatelet agents.

[0008] Rapid and accurate platelet inhibition is an important therapeutic goal in the acute treatment of patients with myocardial infarction. The platelet inhibitory effect induced by oral P2Y12-receptor antagonists is delayed in patients who have undergone primary percutaneous coronary intervention (PCI) due to hemodynamic changes and delayed gastrointestinal absorption.

[0009] In addition to receiving antiplatelet medications, patients with myocardial infarction also receive pain medications. Recent studies have recommended the concomitant use of opioids, such as morphine and fentanyl, in treatment guidelines, but this delays the gastrointestinal absorption of P2Y12 inhibitors. The use of crushed ticagrelor tablets instead of whole tablets has improved the situation to some extent. However, in the early stages of treatment, the delayed onset of therapeutic effect poses a risk to the patient. Furthermore, if a patient receives pain medication before a PCI procedure—for example, for angiographic recording—and the PCI procedure follows within one hour, platelet suppression may still be insufficient.

[0010] From the above perspective, further improvements are needed. There is still a need in the field for antiplatelet therapies that initiate action quickly and reliably.

[0011] The object of the present invention is to solve at least one of the problems described above. In particular, the present invention aims to provide a pharmaceutical composition in a form suitable for intravenous administration for use in percutaneous coronary intervention (PCI).

[0012] The present invention provides a pharmaceutical composition comprising ticagrelor for use in the treatment, reduction, or prevention of ischemic events in a patient who has undergone transcutaneous coronary intervention (PCI), comprising the step of administering an effective amount of ticagrelor to the patient to initiate or maintain P2Y12 inhibition during transcutaneous coronary intervention (PCI); wherein the pharmaceutical composition is an aqueous ticagrelor solution comprising an effective amount of a solubilizing agent for solubilizing ticagrelor, and the pharmaceutical composition is provided for intravenous administration. When used, the composition is administered intravenously.

[0013] The present invention has the effect of enabling rapid, reliable, and effective treatment of patients requiring percutaneous coronary intervention (PCI), even when they are unconscious or have difficulty swallowing. This is particularly important in emergency situations where a therapeutic effect is urgently required.

[0014] Intravenous ticagrelor administration 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 delayed gastrointestinal absorption.

[0015] In a preferred embodiment, the solubilizing agent for ticagrelor is cyclodextrin, and more preferably, the cyclodextrin is hydroxypropyl-beta-cyclodextrin (HPβCD).

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

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

[0018] In a preferred embodiment, the aqueous pharmaceutical ticagrelor composition is free of polyethylene glycol.

[0019] In a preferred embodiment, the aqueous ticagrelor solution is

[0020] 0.10 - 14.0 mg / mL of ticagrelor, and

[0021] The aqueous pharmaceutical solution is composed of 20 to 100 mg / mL of cyclodextrin as an amount for solubilizing ticagrelor in a selected volume, the composition has a pH between 5.5 and 9.0, includes an endpoint, and the aqueous pharmaceutical solution has a volume of 25 to 1000 mL.

[0022] In a preferred embodiment, the aqueous pharmaceutical ticagrelor composition has a storage stability of at least 3 months when measured under accelerated storage conditions of 40°C and 75% relative humidity (RH).

[0023] In a preferred embodiment, the patient has a P2Y12 reaction unit (PRU) greater than 100, preferably greater than 200, before administration of ticagrelor.

[0024] The use of intravenous ticagrelor formulations allows for dose titration and adjustment. The activity of ticagrelor P2Y12 antagonists can be rapidly reversed in emergency surgical situations.

[0025] In a preferred embodiment, the patient is in a coma, intubated, or mechanically ventilated.

[0026] In a preferred embodiment, ticagrelor is administered intravenously after transcutaneous coronary intervention, preferably within 6 hours after the procedure.

[0027] In a preferred embodiment, the patient underwent a stent procedure.

[0028] In a preferred embodiment, before receiving ticagrelor intravenously, the patient was administered a pain medication containing paracetamol (iv), excluding morphine and fentanyl.

[0029] In a preferred embodiment, the patient is administered a bolus injection of 5-80 mg of ticagrelor (loading dose), and optionally, one or more maintenance injections of 20-80 mg of ticagrelor are subsequently followed.

[0030] In a preferred embodiment, the loading dose is administered for less than 10 minutes, preferably less than 5 minutes, and more preferably less than 2 minutes.

[0031] In a preferred embodiment, the pharmaceutical composition for use comprises oral administration of 20-50 mg of ticagrelor twice daily after the last intravenous administration of ticagrelor, provided that the patient is conscious.

[0032] In a preferred embodiment, the patient is resistant to clopidogrel.

[0033] In a preferred embodiment, ticagrelor is administered as antiplatelet monotherapy or as part of dual antiplatelet therapy combined with aspirin.

[0034] In a preferred embodiment, aspirin is administered intravenously.

[0035] In a further aspect, the present invention provides a composition comprising ticagrelor for use 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 does not include morphine and fentanyl, but a therapeutically effective amount of a pain drug comprising paracetamol is administered.

[0036] In a preferred embodiment, the pain medication further includes ibuprofen.

[0037] In a preferred embodiment, paracetamol and ibuprofen are administered intravenously in combination. Brief explanation of the drawing

[0038] Fig. 1: LC-UV chromatograms of ticagrelor preparation 1 (Example 14) and a blank control on day 0 are shown. Fig. 2: LC-UV chromatograms of ticagrelor preparation 2 (Example 14) and blank control on day 0. Fig. 3: LC-UV chromatograms of ticagrelor preparation 1 (Example 14) and blank control on day 188 (room temperature). Fig. 4: LC-UV chromatograms of ticagrelor preparation 1 (Example 14) and a blank control at day 188 (40°C). Fig. 5: LC-UV chromatograms of ticagrelor preparation 2 (Example 14) and blank control on day 188 (room temperature). Fig. 6: LC-UV chromatograms of ticagrelor preparation 2 (Example 14) and a blank control at day 188 (40°C). Specific details for implementing the invention

[0039] Unless otherwise defined, all terms used in the description of the present invention, including technical and scientific terms, have the meaning commonly understood by those skilled in the art to which the present invention pertains. Furthermore, definitions of terms are included to facilitate a better understanding of the description of the present invention.

[0040] The following terms used in this specification have the following meanings.

[0041] As used herein, “one,” “one,” and “that” mean both singular and plural unless otherwise indicated by the context. “Surfactant” is, for example, one or more than one surfactant.

[0042] The term “about” as used herein to refer to measurable values, such as parameters, amounts, durations, etc., is intended to include a variation of the specified value ± 10% or less, preferably ± 5% or less, more preferably ± 3% or less, more preferably ± 1% or less, and even more preferably ± 0.1% or less, such variation is suitable for performing the described method. However, it will become clear that the value associated with the term “about” is also specifically described in itself. The terms “comprising,” “comprising,” and “comprising” are used herein as comprehensive or open terms to specify, but do not exclude, the presence of what follows, e.g., components and additional unnamed components, characteristics, elements, parts, steps, etc., which are sufficiently known in the art or described herein.

[0043] The reference to a numerical range by an endpoint includes the mentioned endpoint, as well as all numbers and fractions contained within that range.

[0044] As used in this specification, the term "% w / w" refers to a weight-based percentage in which the weight ratio of a component to the total weight of the composition is expressed as a percentage.

[0045] The present invention provides a solution to the problem of slow onset of therapeutic effect and limited bioavailability provided by ticagrelor tablets for use in reducing or preventing thromboembolic events prior to, during, or after percutaneous coronary intervention (PCI) in patients requiring this.

[0046] Ticagrelor is a well-known active ingredient. It is a platelet aggregation inhibitor used to prevent thrombotic events, such as myocardial infarction or stroke, in patients with acute coronary syndrome. Its chemical name is (1S,2S,3R,5S)-3-{7-[(1R,2S)-2-(3,4-difluorophenyl)cyclopropylamino]5-(propylthio)-3H-(1,2,3)triazolo(4,5-D)pyrimidine-3-yl}-5-(2-hydroxyethoxy)cyclopentane-1,2-diol.

[0047] As used herein, "ticagrelor" means the free form of ticagrelor, as well as 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 was marketed after receiving approval from the European Medicines Agency in 2010 and the U.S. Food and Drug Administration in 2011. This drug is called Brilinta in the USA. ® And Brilique in the EU ® It is sold in tablet form under the name. It is not commercially available in liquid form. Ticagrelor is an oral, reversible, direct-acting P2Y 12 As a receptor antagonist, it acts by inhibiting platelet activation. Brilinta in combination with aspirin ® The tablets were confirmed to significantly reduce the risk of major cardiovascular (CV) events (heart attack, stroke, or CV death) in patients with acute coronary syndrome (ACS) or a history of heart attack. In the US, Brilinta ® The tablet is also used to reduce the risk of first heart attack or stroke in high-risk patients with coronary artery disease.

[0049] In particular, the present invention provides a pharmaceutical composition comprising ticagrelor for use in the treatment, reduction, or prevention of ischemic events in a patient undergoing percutaneous coronary intervention (PCI), comprising the step of administering an effective amount of ticagrelor to the patient to initiate or maintain P2Y12 inhibition during percutaneous coronary intervention (PCI), wherein the pharmaceutical composition is an aqueous ticagrelor solution comprising an effective amount of a solubilizing agent for solubilizing ticagrelor, and the pharmaceutical composition is provided by intravenous administration. When used, the composition is administered intravenously.

[0050] As used herein, the term "provided by intravenous administration" refers to a composition suitable for administration into the bloodstream. This relates particularly to the fact that the osmotic pressure and pH of the formulation must be compatible. Dilution or pH adjustment is not required, and the formulation is used immediately.

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

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

[0053] Intravenous administration delivers a rapid onset of therapeutic effect compared to oral administration. This enables the treatment of patients who, for example, cannot take oral medication because they are unable to swallow, are on mechanical ventilation, or are unconscious.

[0054] Ticagrelor is highly sensitive to degradation when exposed to light, heat, and oxygen. Furthermore, its limited solubility poses a significant challenge in formulating it as an aqueous solution. While there is still high demand for liquid ticagrelor formulations, to our knowledge, there have been no successful commercially available products with the desirable solubility to meet the requirements of the pharmaceutical industry.

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

[0056] Alternatively, additional active ingredients may be included. Preferably, the additional active ingredient is not prasugrel or a cysteine-aspartate protease inhibitor. More preferably, the additional active ingredient is not a cysteine-aspartate protease inhibitor selected from (S)-3-({1-[(S)-1-((S)-2-{[1-(4-amino-3-chlorophenyl)-methanoyl]-amino}-3,3-dimethyl-butanoyl)-pyrrolidin-2-yl]-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-2-yl]-methanoyl}-amino)-4-oxo-butyric acid (VRT-043198), or emricacic acid.

[0057] In a preferred embodiment, the aqueous ticagrelor composition provided for iv administration comprises 0.1 to 15 mg / mL of ticagrelor; more preferably 1-14 mg / mL of ticagrelor or 2-13 mg / mL; more preferably 3-12 mg / mL of ticagrelor or 4-11 mg / mL of ticagrelor; and most preferably 5-10 mg / mL of ticagrelor.

[0058] Through extensive experiments, it has been confirmed that ticagrelor can be solubilized in aqueous compositions using a suitable solubilizing agent. Preferably, such a solubilizing agent is cyclodextrin or vitamin E TPGS.

[0059] Cyclodextrin is a cyclic carbohydrate derived from starch. Unmodified cyclodextrins differ in the number of glucopyranose units linked together in a cylindrical structure. Parent cyclodextrins contain 6, 7, or 8 glucopyranose units, which are called α-cyclodextrin, β-cyclodextrin, and γ-cyclodextrin, respectively. Each cyclodextrin subunit has secondary hydroxyl groups at the 2nd and 3rd positions and a primary hydroxyl group at the 6th position. Cyclodextrin may also be described as a hollow truncated cone having a hydrophilic outer surface and a hydrophobic inner cavity. In aqueous solutions, these hydrophobic cavities provide a resting place for hydrophobic organic compounds, into which all or part of their structure can be fitted. This process, known as inclusion complexes, may increase the apparent water solubility and stability of the complex-formed drug, but the degree of solubilization will vary depending on the drug. The complex is stabilized by hydrophobic interactions and does not involve the formation of any covalent bonds.

[0060] Chemical modification of parent cyclodextrins (typically at the hydroxyl moiety) sometimes produces derivatives with improved stability while maintaining or enhancing the cyclodextrin's complexing ability. Of the many derivatized cyclodextrins produced to date, only two are commercially available: 2-hydroxypropyl derivatives (HP-β-CD or HPβCD), which are neutral molecules and are currently under commercial development by Janssen and several other companies, and sulfoalkyl ether derivatives (SAE-β-CD or SAE-CD), which are under development by CyDex Pharmaceuticals, Inc. SAE-CD belongs to a class of negatively charged cyclodextrins, varying in alkyl spacer properties, salt form, degree of substitution, and starting parent cyclodextrins. Sodium salts of sulfobutyl ether derivatives of beta-cyclodextrins (SBE7-β-CD), having an average of about 7 substituents per cyclodextrin molecule, are being developed by CyDex Pharmaceuticals, Inc. It is sold as CAPTISOL® Cyclodextrin in Kansas.

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

[0062] In a preferred embodiment, an 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, and most preferably 23-33% w / w of hydroxypropyl-beta-cyclodextrin. The selected amount of cyclodextrin is sufficient to provide a clear ticagrelor solution containing a therapeutically relevant amount of cyclodextrin.

[0063] In an alternative embodiment, the solubilizing agent for ticagrelor is D-alpha-tocopheryl polyethylene glycol succinate, also known as vitamin E TPGS.

[0064] As used herein, the term “Vitamin E TPGS” refers to a water-miscible form of Vitamin E having a hydrophobic Vitamin E moiety and a hydrophilic polyethylene glycol chain. Vitamin E TPGS is also known as D-alpha-tocopheryl polyethylene glycol succinate or tocopersolan. Vitamin E TPGS is approved by the U.S. Food and Drug Administration as a safe adjuvant and is confirmed for use as a surfactant, solubilizer, or stabilizer in drug delivery systems. US 2680749 discloses TPGS molecules with an average molecular weight of polyethylene glycol that varies between 400, 1000, and 600 to 6000. Vitamin E TPGS with an average molecular weight (MW) of the polyethylene glycol chain of about 1000 is commercially available from Eastman Chemical Company, (Kingsport, Tennessee).

[0065] In a preferred embodiment, the aqueous ticagrelor composition provided for IV administration does not contain an organic co-solvent. The use of an organic co-solvent is not necessary to improve the solubility of ticagrelor. By not using an organic co-solvent, better compatibility of the product for intravenous administration is provided. In particular, the aqueous ticagrelor composition according to an embodiment of the present invention is free of polyethylene glycol. This is advantageous for storage stability, as the presence of polyethylene glycol in aqueous ticagrelor solutions has been found to tend to cause impurities during long-term storage.

[0066] In particular, the aqueous ticagrelor IV composition according to an embodiment of the present invention has an osmolarity between 350 mOsm / kg and 900 mOsm / kg. Such osmolarity is advantageous for intravenous administration to patients requiring ticagrelor IV treatment.

[0067] Optionally, according to an embodiment of the present invention, the aqueous ticagrelor iv composition comprises a growth modifier, such as sodium chloride.

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

[0069] In a preferred embodiment, the aqueous ticagrelor iv composition according to an embodiment of the present invention has a storage stability of at least 3 months under accelerated storage conditions at 40°C and 75% relative humidity (RH). More preferably, the 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 storage life of 24 months at room temperature of 25°C.

[0070] As used in this specification, "storage stability" means that the total impurity level is less than 0.5%.

[0071] Storage-stable compositions have an advantage over ready-to-use compositions in that there is no need to prepare the product immediately before pharmaceutical treatment. This saves time.

[0072] In a preferred embodiment, the aqueous ticagrelor IV composition according to an embodiment of the present invention has a pH of 5.5 to 9.0, and more preferably, a pH of 7.0 to 8.0. This pH selection was advantageous for the long-term storage stability of the ticagrelor IV composition. Additionally, it provides a physiologically acceptable pH. pH adjustment is not required prior to administration to the patient. This saves time.

[0073] Most preferably, the aqueous ticagrelor iv composition according to an embodiment of the present invention is

[0074] 5 - 15 mg / mL of ticagrelor,

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

[0076] It is a solution consisting of 5 mM to 20 mM buffer, and the pH is between 5.5 and 8.

[0077] Most preferably, the aqueous ticagrelor iv composition according to an embodiment of the present invention is

[0078] 5 - 15 mg / mL of ticagrelor,

[0079] 15 - 40% w / w hydroxypropyl-beta-cyclodextrin,

[0080] It is a solution consisting of 5 mM-20 mM phosphate buffer, and the pH is between 5.5 and 8.

[0081] Alternatively, the aqueous ticagrelor iv composition according to an embodiment of the present invention is

[0082] 0.10 - 14.0 mg / mL of ticagrelor, and

[0083] A solution comprising 20 to 100 mg / mL of cyclodextrin in an amount for solubilizing ticagrelor in a selected volume of an aqueous pharmaceutical solution, and

[0084] The composition has a pH between 5,5 and 9,0, including the endpoint, and

[0085] The volume of the aqueous pharmaceutical solution is 25 to 1000 mL.

[0086] The composition provided above is simple and easy to manufacture. The limited number of components reduced the formation of impurities and byproducts. This is advantageous for the availability of ticagrelor IV solution for patients requiring treatment of cardiovascular arterial events.

[0087] An aqueous ticagrelor IV composition according to an embodiment of the present invention is provided for the provision of antiplatelet therapy before, during, or after a PCI procedure.

[0088] In a preferred embodiment, the aqueous ticagrelor IV composition according to an embodiment of the present invention is used in the treatment of a patient whose P2Y12 reaction unit (PRU) is less than 200, more preferably less than 150, and even more preferably less than 110 prior to ticagrelor IV administration. Most preferably, the P2Y12 reaction unit is between 0 and 100 after ticagrelor IV administration.

[0089] As an indicator of platelet function, P2Y12 reactive units (PRUs) can be measured using the VerifyNow P2Y12 test (Accriva Diagnostics). Platelet reactivity is expressed in P2Y12 reactive units (PRUs) and inhibition rate (%). This is calculated as ((1 - (P2Y12 receptor blockade / baseline platelet reactivity) x 100). In the scientific literature, it has been reported that the risk of complications may be correlated with high PRUs.

[0090] In a preferred embodiment of the present 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, more preferably within 3 days, most preferably within 2 days or within 1 day.

[0091] In the case of emergency surgery, the patient may receive ticagrelor IV immediately prior to surgery. Antidotes or adsorption technologies, such as CytoSorbⓒ, may also be used to reduce blood ticagrelor levels to a level suitable for reducing the risk of bleeding. The ticagrelor antidote is ventrasimab, also known as PB2452. This is a neutralizing recombinant human immunoglobulin G1 monoclonal antibody antigen-binding fragment that binds with high affinity and specificity to ticagrelor and its major active circulating metabolite M8, also known as AR-C124910XX. CytoSorbⓒ consists of a porous polymer bead adsorption system.

[0092] Preferably, the pharmaceutical composition according to an embodiment of the present invention is administered intravenously to a patient whose P2Y12 reaction unit (PRU) is greater than 100, preferably greater than 200, prior to ticagrelor administration.

[0093] Preferably, the pharmaceutical composition according to an embodiment of the present invention is administered intravenously to a patient who is in a coma or who is undergoing intubation or mechanical ventilation.

[0094] Preferably, the pharmaceutical ticagrelor IV composition according to an embodiment of the present invention is administered after transcutaneous coronary artery 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.

[0095] The availability of IV formulations allows for the restart of antiplatelet therapy earlier than is possible with tablets, and this acts more rapidly compared to crushed tablets. Treatment can be initiated while the patient is still recovering, unconscious, or comatose, thereby reducing the risk of thrombosis after the procedure.

[0096] Preferably, the pharmaceutical composition according to an embodiment of the present invention is administered intravenously to a patient who has been administered a pain medication containing morphine or fentanyl before receiving ticagrelor intravenously.

[0097] The use of IV ticagrelor overcomes the delay in bioavailability caused by sedatives such as morphine or fentanyl. It provides a faster onset of platelet inhibition.

[0098] Preferably, the pharmaceutical composition according to an embodiment of the present invention is administered intravenously to a patient who has been administered a pain medication comprising paracetamol, preferably paracetamol IV, before receiving ticagrelor intravenously.

[0099] Most preferably, opioid drugs such as morphine or fentanyl were not used in other treatments in embodiments of the present invention. This is advantageous for avoiding addiction. This is important for avoiding the delayed onset of therapeutic action in situations of acute thrombosis risk.

[0100] Ticagrelor IV compositions for use in the treatment of cardiovascular arterial events may be administered via 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.

[0101] Preferably, the pharmaceutical composition according to an embodiment of the present invention is administered intravenously as a bolus injection. Preferably, the bolus injection is administered in less than 10 minutes, more preferably in less than 5 minutes, even more preferably in less than 3 minutes, and most preferably in less than 2 minutes. Most preferably, the bolus injection is administered as an injection. The onset of therapeutic effect is faster compared to oral ticagrelor or crushed ticagrelor tablets.

[0102] Optionally, one or more maintenance infusions of ticagrelor IV are followed after ticagrelor loading.

[0103] Preferably, the pharmaceutical composition according to an embodiment of the present invention is administered intravenously after a PCI procedure, and since the intravenous administration of ticagrelor can be taken by the patient as an oral drug, oral administration of 20-50 mg of ticagrelor twice a day follows.

[0104] Switching from IV to oral is advantageous because there is no change in the pharmaceutically active ingredient.

[0105] In a preferred embodiment of the present invention, ticagrelor is administered as antiplatelet monotherapy or as part of dual antiplatelet therapy in combination with aspirin.

[0106] In a preferred embodiment of the present invention, aspirin is administered intravenously.

[0107] In a preferred embodiment of the present invention, the patient underwent a stent procedure.

[0108] Preferably, ticagrelor is administered intravenously after the PCI procedure, preferably within 6, 5, or 4 hours after the procedure. More preferably within 3 hours after the procedure, and most preferably within 2 hours after the procedure.

[0109] The availability of ticagrelor IV has the advantage that ticagrelor treatment can be initiated while the patient is still recovering, unconscious, or in a coma. This may be advantageous in reducing the risk of thrombosis after the procedure.

[0110] The patient is conscious after surgery and may swallow the tablet 4 to 6 hours after surgery. Therefore, oral antiplatelet therapy can be started sequentially up to IV administration.

[0111] In a preferred embodiment of the present invention, a patient is administered a bolus injection of 5-80 mg of ticagrelor after the procedure. Potentially one or more injections are followed after the first injection of ticagrelor. Preferably, one or more injections comprise the administration of 5-80 mg of ticagrelor.

[0112] In a preferred embodiment of the present invention, treatment involves oral administration of 20-50 mg of ticagrelor twice daily following the last intravenous administration of ticagrelor. The switch from intravenous to oral administration of ticagrelor is advantageous for patient comfort. Patients taking the tablets may be easier to discharge as they do not require assistance with intravenous drug administration.

[0113] In a preferred embodiment of the present invention, the composition is used in the treatment of patients resistant to clopidogrel.

[0114] Clopidogrel resistance is a condition in which the drug clopidogrel is less effective than normal in the person being treated with it. Residual platelet aggregation exceeding 50% of baseline when measured using the light transmission aggregation assay with 20 μM ADP stimulation is defined as a poor response to clopidogrel.

[0115] Platelet aggregation may also be evaluated as follows. Blood collected in a blood-citrate tube is steeped for 5 minutes at a rate of 120 g Recover platelet-rich plasma by centrifugation and 850 for 10 minutes g Platelet-poor plasma was recovered by further centrifugation. PRP and PPP were stored at room temperature and used within 2 hours. Platelets were stimulated with 20 μM ADP, and agglutination was evaluated using a Chronolog Lumi-Aggregometer (model 490-4D) and the Aggro / Link software package (Chronolog, Havertown, Pennsylvania). Agglutination was expressed as the maximum percentage change in light transmittance from the reference point, using platelet-poor plasma as the reference.

[0116] In a preferred embodiment, the pharmaceutical composition is injected during a cardiovascular artery procedure in a therapeutically effective amount.

[0117] In a further embodiment, the present invention provides a ticagrelor regimen to avoid drug-drug interactions with opioid pain medications.

[0118] The present invention provides a composition comprising ticagrelor for use in a treatment method for patients requiring P2Y12 inhibition, wherein the composition is administered intravenously in a therapeutically effective amount, provided that the treatment does not contain morphine and fentanyl, and a therapeutically effective amount of a pain medication comprising paracetamol is administered.

[0119] Preferably, the pain medication further contains ibuprofen.

[0120] More preferably, paracetamol and ibuprofen are administered intravenously in combination.

[0121] Examples

[0122] A pharmaceutical ticagrelor composition for use in the reduction or prevention of thromboembolic events prior to and / or during and / or after a PCI procedure in patients requiring this is provided in the following examples.

[0123] Example 1: Vitamin E TPGS as a ticagrelor solubilizer

[0124] Table 1: Ticagrelor IV composition

[0125]

[0126] Aqueous ticagrelor solutions using vitamin E TPGS as a solubilizer were prepared as follows. Water-soluble vitamin E TPGS was added to water to obtain aqueous vitamin E TPGS solutions at different concentrations of 2.5, 5.0, and 10.0 w / v%. These solutions were maintained at a temperature of 45°C + / -5°C, and fractions of ticagrelor were added gradually. A 3 mg fraction of ticagrelor was added stepwise to 50 mL of aqueous vitamin E TPGS solution (Step 1), and 20 mL of each dilution was subsequently used in the Step 2 study. A 10 mg fraction of ticagrelor was added to each 20 mL dilution. When dissolution was prolonged, this was reduced to 5 mg.

[0127] Table 2: Aqueous ticagrelor IV solution

[0128]

[0129] It was observed as follows: 10 mg ticagrelor dissolved after 5-10 minutes.

[0130] The 2.5% vitamin E TPGS solution was saturated at 11.6 mg / mL.

[0131] The 5.0% vitamin E TPGS solution was saturated at 14.9 mg / mL.

[0132] The 10.0% vitamin E TPGS solution was saturated at 19.8 mg / mL.

[0133] The obtained aqueous ticagrelor solution is stored at 40°C and 75% relative humidity or at 25°C and 60% relative humidity for a period of at least 3 months.

[0134] Example 2: Cyclodextrin as a ticagrelor solubilizer

[0135] The following composition is a ticagrelor aqueous composition prepared for use in IV administration.

[0136] Table 3: Ticagrelor compositions prepared for underwater use

[0137]

[0138] Table 4: Ticagrelor compositions prepared for use in aqueous phosphate buffer

[0139]

[0140] Table 5: Ticagrelor compositions prepared for use in diluted saline solution

[0141]

[0142] Table 6: Ticagrelor compositions prepared for use in dextrose solution

[0143]

[0144] Table 7: Preferred ticagrelor solution for infusion

[0145]

[0146] The prepared solutions for use described above were prepared as follows. In all cases, the solvents mentioned were prepared, placed in a beaker, and heated to 40°C; then, HPβCD was added and a clear solution was obtained under stirring. Subsequently, the active ingredient ticagrelor was added at 40°C under constant stirring until a clear solution was obtained. These solutions were filtered through a 0.22-micron filter and aseptically filled into sterile glass vials or infusion bags.

[0147] 24 mg / mL to 350 mg / mL HPβCD was required to obtain a stable ticagrelor solution prepared for infusion. The amount of cyclodextrin required depended on the volume of the target infusion medium.

[0148] Ticagrelor is an active ingredient that is insoluble in water. The more it is in a diluted aqueous solution, the greater the tendency to precipitate. When the dilution ratio for ticagrelor increased from 30 mL to 100 mL to 200 mL, a proportional increase in cyclodextrin was required. However, it was found that 16 g of cyclodextrin was sufficient to dissolve ticagrelor in volumes of 650 mL or more.

[0149] Note that organic co-solvents, surfactants, or other solubilizing agents were not used.

[0150] The obtained aqueous ticagrelor solution was stored for a period of at least 3 months at 40°C and 75% relative humidity or 25°C and 60% relative humidity and was confirmed to be stable.

[0151] Development of storage-stable ticagrelor solution

[0152] In the following examples, experimental work to obtain a storage-stable ticagrelor solution is described.

[0153] Example 3

[0154] In this example, two different types of cyclodextrin were used, and the solubility of ticagrelor was 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 at concentrations of 5, 10, or 14 mg / mL in milli Q water. The ticagrelor-cyclodextrin solutions were left on a shaking platform. No sonication or heat was applied.

[0155] According to the results in Tables 8 and 9, HPβCD was found to be able to dissolve ticagrelor at a wide range of tested cyclodextrin and ticagrelor concentrations. A clear aqueous solution was obtained using 5 mg / mL ticagrelor in HPβCD at 25 w / w%, 30 w / w%, 35 w / w%, and 40 w / w% HPβCD.

[0156] Table 8: Solubility of ticagrelor in HPβCD

[0157]

[0158] Table 9: Solubility of ticagrelor in SBECD

[0159]

[0160] In conclusion, ticagrelor can be dissolved by placing it on a shaking platform. No sonication was applied. HPβCD can be used at a ticagrelor concentration of 5 mg / mL using cyclodextrin at 40% w / w, 35% w / w, or 30% w / w in milliQ water. These solutions were tested at room temperature and remained clear for at least 3 days and for several days at 4°C.

[0161] Example 4

[0162] After the experiment shown in Example 3, further optimization was performed to select a suitable pH range that ensures the long-term stability of the aqueous ticagrelor-cyclodextrin inclusion complex.

[0163] The following compositions provided in Table 10 were prepared.

[0164] Table 10: Composition for storage stability test.

[0165]

[0166] HPβCD was dissolved in water in individually prepared buffer solutions of pH 4.5, 5.5, or 6.5. Once a clear solution was obtained, ticagrelor was dissolved in the buffer solution under constant stirring. The ticagrelor in the buffer solution was filtered through a 0.22 micron filter and filled into USP Type I glass vials. The vials were plugged and stored. All precautions taken during preparation, such as N2 purging and avoiding direct exposure to light, were taken. The vials were stored at 40°C and 75% relative humidity (RH).

[0167] To determine the stability of the formulation, batches were evaluated using the relevant substance method in HPLC. The data for these batches are listed in Table 11 below.

[0168] A concentration gradient HPLC method was used to analyze impurities in the formulation using a YMC-Pack Pro C18 column (100x4.6mm, S-3 μm 12 nm). Good separation of all impurities was obtained.

[0169] Amine impurity: (1S,2S,3R,5S)-3-(7-amino-5-(propylsulfanyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-3-yl)-5-(2-hydroxyethoxy)cyclopentane-1,2-diol. This is a process-related decomposition product impurity.

[0170] Regiomer impurity: (1S, 2S, 3R, 5S)-3-((3-((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)-5-(propylsulfanyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-7-yl)amino)-5-(2-hydroxyethoxy)cyclopentane-1,2-diol. This is a process-related decomposition product impurity.

[0171] Acetal impurity: 2-[[(3aR,4S,6S,6aS)-6-[7-[[1R,2S)-2-(3,4-difluorophenyl)-cyclopropyl]amino]-5-(propylsulfanyl)-3H-[1,2,3]triazolo-[4,5-d]pyrimidine-3-yl]-2,2-dimethyltetrahydro-2H-3aHcyclopenta[d][1,3]dioxol-4-yl]oxy]ethanol-1-ol.

[0172] This is a process-related impurity.

[0173] Triol impurity: (1S,2R,3S,4R)-4-(7-((1R,2S)-2-(3,4-difluorophenyl)cyclopropylamino)-5-(propylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-3-yl)cyclopentane-1,2,3-triol.

[0174] This is a process-related impurity.

[0175] It was observed that only regiomer impurities increased to a level of nearly 0.3% over 4 weeks at 40℃ and 75% RH, and the specification limit is 0.3%. Therefore, to further optimize product stability, an investigation was conducted at pH 7 to 8.

[0176] Example 5

[0177] Storage stability at pH 7.5 was performed according to the experiment described in Example 4.

[0178] First, HPβCD was dissolved in water in a separately prepared pH 7.5 phosphate buffer solution. Once a clear solution was obtained, ticagrelor was dissolved in the solution under constant stirring. The solution was filtered through a 0.22 micrometer filter and filled into a USP Type I amber glass vial. The vial was stopped and stored. All precautions during preparation, such as N2 purging and avoiding direct exposure to light, were taken.

[0179] Table 11: Stability test of ticagrelor-cyclodextrin inclusion complex in aqueous solutions at pH 4.5, 5.5, and 6.5 after storage at 40°C and 75% RH

[0180]

[0181] Table 12: Composition for storage stability test.

[0182]

[0183] Table 13: Study on the storage stability of ticagrelor-cyclodextrin inclusion complex in an aqueous solution of pH 7.5 stored at 40 ℃ and 75% relative humidity.

[0184]

[0185] Based on the stability study results summarized in Table 6, it was concluded that good storage stability can be obtained under accelerated storage conditions of 40°C and 75% relative humidity. Regiomer impurities were sufficiently controlled, and other impurities were not an issue.

[0186] Example 6

[0187] In additional experiments, to optimize the concentration of HPβCD to less than 40% w / w, heat of 40°C was applied at a concentration where it was difficult to obtain a clear solution to help dissolve the target ticagrelor dose.

[0188] Direct physical stability data obtained from ticagrelor 5 mg / mL concentrate and agglutination tests (20 µL sample material in 1 mL diluent) are provided in Table 14. Table 7 contains data on quantification, purity, osmolarity, and pH.

[0189] Table 14: Physical stability of ticagrelor 5 mg / ml batches according to changes in HPβCD concentration. Data are classified by HPβCD concentration. Ticagrelor concentration when diluted in dextrose or saline: 0.1 mg / ml.

[0190]

[0191] Due to poor physical stability results when diluted in saline solution, 32.5% w / w HPβCD was selected for the 5 mg / mL ticagrelor formulation. The undiluted concentrate remained stable even in the refrigerator at HPβCD concentrations as low as 22.5% w / w. These concentrations produced a nearly isotonic formulation.

[0192] In conclusion, it was possible to dissolve 5-15 mg / mL of ticagrelor with HPβCD in a concentration range of 20-40% w / w without using heat. It was also possible to achieve good solubility by applying heat to obtain a clear solution using low concentrations of HPβCD, such as 15-20% w / w.

[0193] At least 15% w / w HPβCD was required to provide a clear, storage-stable ticagrelor solution at a concentration suitable for injection or intravenous administration.

[0194] Example 7

[0195] From the results obtained in Example 6, it was concluded that the concentration of the excipient could make the final ticagrelor solution hypertonic. The osmolarity and pH of several batches were examined. The solution was 19 mM phosphate buffer and pH 7.5. The results are provided in Table 15.

[0196] Table 15: Determination of pH and osmolarity in undiluted batch.

[0197]

[0198] We conducted dilution studies to find a suitable diluent.

[0199] 5 mg / mL ticagrelor-cyclodextrin solutions with varying amounts of HPβCD were diluted in physiological saline, 5% dextrose solution, or Ringer's lactic acid solution. Stability was screened. Ticagrelor concentration when diluted in dextrose or saline: 0.1 mg / mL. The results are summarized in Table 16.

[0200] Table 16: Diluent Test

[0201]

[0202] In addition, screening was performed on the effect of buffer concentration on pH and osmolarity. The results are summarized in Table 17.

[0203] Table 17: Effect of buffer concentration on pH, osmolarity, quantification, and impurities.

[0204] Phosphate buffer pH

[0205]

[0206] It was concluded that at different buffer concentrations, phosphate buffer at pH 7.5 has little effect on osmolarity. The 0.19 mM buffer concentration is an exception. This buffer concentration is too weak to cause a change in pH.

[0207] Example 8

[0208] In additional examples, the effect of particle size on solubility was tested.

[0209] Two different particle size diameters of 5.5 and 15 micrometers were screened for the ticagrelor active ingredient. pH and osmolarity were unaffected. The smaller particles exhibited faster dissolution times, as summarized in Table 18.

[0210] Micronized ticagrelor showed a significant improvement in dissolution time. In conclusion, micronized ticagrelor having a D90 of less than 10 micrometers is preferred.

[0211] The term "D90" as used herein means that at least 90% of the particles present have a size smaller than the target particle size. However, it is understood that variations in the input particle size distribution (PSD) of ticagrelor are possible and may affect the dissolution rate of ticagrelor.

[0212] Methods for measuring the particle size of active ingredients are well known to those skilled in the art of formulation. The method used in the present invention is the Malvern Mastersizer dry powder method.

[0213] Table 18: Effect of particle size

[0214]

[0215] Example 9

[0216] To optimize the pH and HPβCD concentration of the solution for intravenous use, a 12-week / 3-month stability study was conducted. Compositions of 32.5% w / w HPβCD and 5 mg / mL ticagrelor with a pH of 7 to 8 were prepared and stored. Their stability was tested at regular intervals.

[0217] A comparison of stability profiles at three different pH values ​​of 7, 7.5, and 8 was performed as follows, - the manufacturing process of all three formulations was maintained at a constant buffer concentration of 19 mM. The results are summarized in Tables 19 to 21.

[0218] Table 19: Storage stability in amber glass vials - pH 7

[0219]

[0220] Table 20: Storage stability in amber glass vials - pH 7.5

[0221]

[0222] Table 21: Storage stability in amber glass vials - pH 8.0

[0223]

[0224] From the above data, it was concluded that the ticagrelor solution in HPβCD was stable in the pH range of 7 to 8.

[0225] Example 10

[0226] To investigate the potential effect of packaging materials on the stability of ticagrelor-cyclodextrin inclusion complexes, compositions of 32.5% w / w HPβCD were prepared according to procedures and precautions similar to those in previous tests, and samples were stored in clear glass vials and amber glass vials at a temperature of 40°C / 75% RH. The results are shown in Tables 22 and 23.

[0227] The results of the accelerated storage stability test suggested that no significant deviation was observed between the two samples after 3 months. All samples remained as clear aqueous solutions. The pH of the samples remained stable. Impurities did not change significantly.

[0228] It appears that both clear and amber glass vials can be used.

[0229] When comparing the accelerated storage stability results for ticagrelor solutions with and without the use of cyclodextrin, it is clear that the use of cyclodextrin is important for achieving good stability. Without cyclodextrin, 6 to 8 different impurities were generated during storage. These impurities were not observed in the selected compositions.

[0230] Surprisingly, it can be concluded that ticagrelor solution can be stabilized by HPβCD in both amber and clear glass vials.

[0231] Table 22: Study on the potential impact of packaging materials. Stability in amber USP Type I glass.

[0232]

[0233] Table 23: Study on the potential impact of packaging materials. Stability of clear glass vials in USP Type I.

[0234]

[0235] Example 11

[0236] Further embodiments of the present invention are provided as summarized in Table 24. Further improvements in achieving high solubility of ticagrelor were attempted at different concentrations, for example, using 40% w / w HPβCD, a solubility of ticagrelor of 13 mg / mL was also possible.

[0237] Table 24: Clear aqueous solution in the presence of ticagrelor-cyclodextrin inclusion complex at a dose of 65 mg.

[0238]

[0239] Based on the investigation, it was observed that concentrations of 5–13 mg / mL ticagrelor solution can be achieved using 20–40% w / w HPβCD. The volume of the filling contents can be varied based on the required dose.

[0240] 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 the total available volume of the injectable preparation. The fact that a ticagrelor dose can be contained in a volume of 5–15 mL is very significant, as this is a typical bolus injection volume.

[0241] Example 12

[0242] In additional examples, the maximum solubility of ticagrelor in HPβCD solution was investigated without using heat. The results are summarized in Table 25.

[0243] Depending on the amount of ticagrelor to be administered to the patient and the sample volume limit determined by administration by injection or infusion, an amount of 2000-4000 mg of HPβCD per 10 mL vial may be required to dissolve 65-75 mg of ticagrelor.

[0244] Table 25: HPβCD concentration, formulation dosage, and volume

[0245]

[0246] Surprisingly, the solution provided in Table 18 was compatible with diluents providing the injection solution, particularly 5% dextrose in water.

[0247] Example 13

[0248] In another embodiment of the present invention, a very stable clear solution of ticagrelor can be obtained by applying appropriate heat to the solution during preparation, thereby providing a completely clear solution of a formulation with desirable HPβCD and ticagrelor concentrations.

[0249] To investigate the effects of temperature and holding time, a new composition was prepared according to Table 26 below.

[0250] Table 26: Composition for evaluating temperature effects.

[0251]

[0252] In the first step, a phosphate buffer solution with a pH of 7.5 was prepared, and the buffer solution was heated to 40°C–45°C. HPβCD was added to the buffer solution while mixing continuously. Once a clear solution was obtained, ticagrelor was dispersed in the HPβCD solution and mixed until a clear solution was obtained. Generally, this took 30 minutes to 4 hours depending on the batch size. Next, this solution was filtered through a 0.22-micron filter and packaged in suitable clear or amber glass vials.

[0253] Table 27: Large-scale maintenance study at 45℃

[0254]

[0255] Table 28: Bulk retention study at 25℃ and 40℃

[0256]

[0257] Table 29: Maintaining bulk at 30℃

[0258]

[0259] Studies on holding times at temperatures between 25°C and 45°C suggested that 30% w / w HPβCD could stabilize ticagrelor even after heating the solution for a long period or holding it in large quantities at high temperatures.

[0260] Method for preparing a ready-to-use infusion preparation

[0261] The preparation process for the solution prepared for use, as exemplified in Table 3-7, was as follows. In all cases, the mentioned solvent was prepared, placed in a beaker, and heated to 40°C, after which HPβCD was added and a clear solution was obtained under stirring. Subsequently, the active ingredient ticagrelor was added at 40°C under constant stirring until a clear solution was obtained. This solution was filtered through a 0.22-micron filter and aseptically filled into a sterile glass vial or infusion bag.

[0262] 24 mg / mL to 350 mg / mL of HPβCD was required to obtain a stable ticagrelor solution prepared for infusion. The amount of cyclodextrin required depended on the volume of the target infusion medium.

[0263] Ticagrelor is an active ingredient that is insoluble in water. The more of it in a diluted aqueous solution, the greater the tendency for it to precipitate. As the dilution ratio for ticagrelor increased from 30 mL to 100 mL to 200 mL, a proportional increase in cyclodextrin was required. However, for volumes of 650 mL or more, an amount of 16 g of cyclodextrin was found to be sufficient to retain ticagrelor in the aqueous solution.

[0264] Note that organic co-solvents, surfactants, or other solubilizing agents were not used.

[0265] Alternative manufacturing method starting from concentrated ticagrelor solution

[0266] It is possible to obtain a clear solution with a final volume of 33 mL by diluting one 8 mL vial containing 65 mg / vial of ticagrelor and about 3 g of HPβCD with 25 mL of 5 w / v% dextrose. However, this was not possible when using a 0.9 w / v% NaCl solution as a diluent for the concentrated ticagrelor solution. This is important in medical treatments where concentrated ticagrelor aqueous compositions are mixed with other medicines. This can cause precipitation of ticagrelor, making the combination product unsuitable for intravenous administration.

[0267] Solubility study using different solvents

[0268] Solubility studies were performed using different solvents. The formulation AE shown in Table 30 was prepared by adding ticagrelor (final concentration of 1.8 mg / mL) to a tube (e.g., Eppendorf or Conical) and then adding the listed solvent(s) diluted in distilled water (final volume of 10 mL). Subsequently, if necessary, the tubes were vortexed and sonicated in a temperature-controlled water bath. After 60 minutes, the tubes were collected for solubility observation. The samples were reviewed again after 24 hours.

[0269] Table 30: Solubility studies using different solvents

[0270]

[0271] Based on the investigation, it was observed that ticagrelor was solubilized only by cyclodextrin or polyethylene glycol (PEG).

[0272] Soluble, but insufficient storage stability

[0273] Polyethylene glycol can solubilize ticagrelor. However, polyethylene glycol has been found to be sensitive to degradation, which has resulted in impurities.

[0274] Example 14

[0275] Two clear 1.8 mg / mL ticagrelor preparations were prepared after sonication for several hours: Preparation 1 (Example 14), 1.8 mg / mL ticagrelor in 20% w / w hydroxypropyl-β-cyclodextrin (HPβCD), the remainder being distilled water; Preparation 2 (Example 14), 1.8 mg / mL ticagrelor in 50% w / w PEG400, the remainder being distilled water.

[0276] Two formulations were aliquoted and stored at room temperature and 40°C. The formulations were analyzed immediately by LC-UV after preparation (Figs. 1 and 2). They were analyzed three times during a 6-month stability period (Figs. 3 and 4).

[0277] Ticagrelor was found to be stable for at least 6 months at both room temperature and 40°C in formulation 1 (Example 14), i.e., 1.8 mg / mL ticagrelor in 20% w / w HPβCD (Figs. 5 to 6).

[0278] In Preparation 2 (Example 14), i.e., 1.8 mg / mL ticagrelor in 50% w / w PEG400, ticagrelor was not stable at both room temperature and 40°C. In the LC-UV chromatogram, a strong potential degradation product peak was observed in Preparation 2 (Example 14) (Figs. 4 to 6).

Claims

Claim 1 A pharmaceutical composition comprising ticagrelor for use in the treatment or prevention of ischemic events in a patient who has undergone percutaneous coronary intervention (PCI), comprising the step of administering an effective amount of ticagrelor to the patient to initiate or maintain P2Y12 inhibition, wherein the pharmaceutical composition is an aqueous ticagrelor solution comprising a solubilizing agent in an effective amount for solubilizing ticagrelor, and the pharmaceutical composition is provided for intravenous administration, characterized in that the effective amount of ticagrelor is administered intravenously. Claim 2 A pharmaceutical composition according to claim 1, wherein the solubilizing agent for ticagrelor is cyclodextrin, and preferably the cyclodextrin is hydroxypropyl-beta-cyclodextrin (HPβCD). Claim 3 A pharmaceutical composition according to claim 1, wherein the solubilizing agent for ticagrelor is D-alpha-tocopheryl polyethylene glycol succinate (vitamin E TPGS). Claim 4 In any one of claims 1 to 3, the aqueous pharmaceutical ticagrelor composition is a pharmaceutical composition having a pH of 5.5 to 9.

0. Claim 5 A pharmaceutical composition according to any one of claims 1 to 4, wherein the aqueous pharmaceutical ticagrelor composition is free of polyethylene glycol. Claim 6 A pharmaceutical composition according to any one of claims 1, 2, or 4, wherein the aqueous ticagrelor solution comprises 0.10 to 14.0 mg / mL of ticagrelor and 20 to 100 mg / mL of cyclodextrin in an amount for solubilizing ticagrelor in a selected volume of aqueous pharmaceutical solution, the composition has a pH between 5.5 and 9.0 (including the endpoint), and the aqueous pharmaceutical solution has a volume of 25 to 1000 mL. Claim 7 A pharmaceutical composition according to any one of claims 1 to 6, wherein the aqueous pharmaceutical ticagrelor composition has storage stability of at least 3 months as measured under accelerated storage conditions of 40°C and 75% relative humidity (RH). Claim 8 A pharmaceutical composition according to any one of claims 1 to 7, wherein the patient has a P2Y12 reaction unit (PRU) greater than 100, preferably greater than 200, prior to ticagrelor administration. Claim 9 A pharmaceutical composition according to any one of claims 1 to 8, wherein the patient is in a coma, is intubated, or is mechanically ventilated. Claim 10 A pharmaceutical composition according to any one of claims 1 to 9, wherein ticagrelor is administered intravenously after transcutaneous coronary intervention, preferably within 6 hours after the procedure. Claim 11 A pharmaceutical composition in which, in any one of claims 1 to 10, the patient has undergone a stent procedure. Claim 12 A pharmaceutical composition according to any one of claims 1 to 11, wherein, before receiving ticagrelor intravenously, the patient is administered a pain medication including paracetamol (iv), excluding morphine and fentanyl. Claim 13 A pharmaceutical composition according to any one of claims 1 to 12, wherein a bolus infusion of 5-80 mg ticagrelor (loading dose) is administered to the patient, and optionally one or more maintenance infusions of 20-80 mg ticagrelor are subsequently administered. Claim 14 A pharmaceutical composition according to claim 13, wherein the loading dose is administered for less than 10 minutes, preferably less than 5 minutes, preferably less than 2 minutes. Claim 15 A pharmaceutical composition according to claim 13 or 14, comprising a step of oral administration of 20-50 mg of ticagrelor twice daily, provided the patient is conscious, after the last intravenous administration of ticagrelor. Claim 16 In any one of claims 1 to 15, the patient is resistant to clopidogrel. Pharmaceutical composition. Claim 17 A pharmaceutical composition according to any one of claims 1 to 16, wherein ticagrelor is administered as antiplatelet monotherapy or as part of dual antiplatelet therapy in combination with aspirin. Claim 18 In paragraph 17, a pharmaceutical composition in which aspirin is administered intravenously. Claim 19 A composition comprising ticagrelor for use in a method of treating pain in patients requiring P2Y12 inhibition, wherein the composition is administered intravenously in a therapeutically effective amount, provided that the treatment does not include morphine and fentanyl, but a therapeutically effective amount of a pain drug comprising paracetamol is administered. Claim 20 In paragraph 19, the pain medication is a composition that further comprises ibuprofen. Claim 21 A composition according to claim 20, wherein paracetamol and ibuprofen are administered intravenously in combination.

Images