Intravenous administration of ticagrelor compositions in a patient who was previously administered an opioid in order to treat coagulation and avoid reduced ticagrelor uptake

Abstract

The invention provides a pharmaceutical ticagrelor composition for use in the treatment or prevention of coagulation in a patient in need thereof who is co- administered an opioid active ingredient, in combination with a pharmaceutically acceptable carrier, characterized in that the pharmaceutical ticagrelor composition is administered intravenously following the administration of the opioid active ingredient thereby avoiding delayed or reduced ticagrelor uptake provided by the opioid active ingredient; wherein the pharmaceutical ticagrelor composition comprises an inclusion complex of ticagrelor and a cyclodextrin. The invention also provides pharmaceutical ticagrelor composition in lyophilized form and liquid ticagrelor compositions for lyophilization. The invention provides kits comprising a ticagrelor composition in lyophilized form in combination with a suitable diluent. The invention provides methods of manufacturing the pharmaceutically ticagrelor composition in lyophilized form. The reconstituted lyophilized ticagrelor compositions are particularly suitable for use in overcoming delays or reduction in ticagrelor absorption by concomitant opioid drug use.

Description

[0001] OVERCOMING DELAYS OR REDUCTIONS IN TICAGRELOR ABSORPTION BYCONCOMMITTANT OPIOID DRUG USETECHNICAL FIELD The present invention is situated in the field of pharmaceutical compositions and their uses. The active ingredient concerned is ticagrelor. The present invention is advantageous for patients in need of pain treatment or sedation in combination with anti-coagulation therapy. The present invention provides a solution to the problem of opioid active ingredients impacting the absorption of oral P2Y12 anti-coagulants. This is especially important for patients in need of urgent onset of therapeutic effect to mitigate coagulationrelated complications. The present invention is an improvement over anextemporaneous preparation of a ticagrelor solution. BACKGROUND Fentanyl is a potent synthetic opioid used to alleviate severe and chronic pain, as well as an adjunct to general or local anesthesia. Its analgesic and anesthetic activity arise from the stimulation of the ^-opioid receptors, resulting in the inhibition of adenyl cyclase and downregulation of cyclic adenosine 3’, 5’-monophosphate (cAMP), as well as decreased calcium channel activity and increased potassium channel activity. The ^-opioid receptors are abundantly distributed within the central nervous system, where they mediate analgesia, and in the nerve cells of the intestines, where they regulate gastrointestinal tract motility in the secretion or transport of fluids and electrolytes. They are also expressed in blood cells, blood vessel cells, and skin. Given the widespread distribution of ^-opioid receptors, it is likely that fentanyl may also regulate the activity of many other cells, including platelets. It has recently been discovered that opioids, such as fentanyl, morphine,oxycodone, hydrocodone, and codeine, delay gastric emptying and slow-down drug absorption of oral P2Y12 platelet inhibitors. Moreover, nausea and vomiting are more frequently seen in patients receiving opioids, which may further reduce the uptake of oral P2Y12 platelet inhibitors. Optimal platelet inhibition is one of the most important goals in the acute treatment of segment (ST)-elevation myocardial infarction (STEMI) patients.Opioids are widely used in daily practice, especially in the US, for instance toreduce chest pain while waiting for an angiogram and determining the need for a percutaneous coronary intervention (PCI). Prior to the percutaneouscoronary intervention, patients are administered anti-platelet therapy toreduce stent thrombosis. However, it was observed that fentanyl may delayor reduce platelet inhibition by oral P2Y12 inhibitors, especially when thetimeframe between co-administration of the opioid medication and the anti- platelet medication is short. As the aim in non-elective PCI procedures is to perform the procedure within 90 minutes from presentation of the patient to the emergency room, so-called “door to balloon” time window, the risk of a myocardial infarction or stent thrombosis may be insufficiently reduced. Co-administration of 5 mg intravenous morphine with 600 mg loading dose of clopidogrel in healthy adults decreased the AUC and Cmaxof clopidogrel’s thiol metabolites by 34%. Mean platelet aggregation was higher up to 2 to 4 hours with morphine coadministration. Co-administration of 5 mg intravenous morphine with 60 mg loading dose of prasugrel in healthy adults decreased the Cmaxof prasugrel's active metabolite by 31% with no change in AUC, Tmax, or inhibition of ADP- induced platelet aggregation. ADP induced platelet aggregation was higher up to 2 hours following 60 mg loading dose of prasugrel in stable patients more than 1 year after an ACS who were co-administered morphine. In the patients with a 2-hour delay in the onset of platelet aggregation (5 of 11), Tmax was delayed and prasugrel active metabolite levels were significantly lower at 30 min (5 vs 120 ng / mL) following co-administration with morphine. Co-administration of 5 mg intravenous morphine with 180 mg loading dose of ticagrelor decreased observed mean ticagrelor exposure by up to 25% in healthy adults and up to 36% in ACS patients undergoing PCI. Tmaxwas delayed by 1-2 hours. Exposure of the active metabolite decreased to a similar extent. Morphine co-administration did not delay or decrease platelet inhibition in healthy adults. Mean platelet aggregation was higher up to 3hours post loading dose in ACS patients co- administered with morphine.Co-administration of intravenous fentanyl with 180 mg loading dose of ticagrelor in ACS patients undergoing PCI resulted in similar effects on ticagrelor exposure and platelet inhibition. Other medical indications may exist where there is an interaction between opioid drugs and an oral P2Y12 inhibitor. Since 2019, the Food and Drug Administration has obliged the manufacturers of oral P2Y12 platelet inhibitors (clopidogrel, prasugrel, ticagrelor) to include information in the product labels warning that absorption may be delayed orreduced when taken with an opioid receptor agonist. On the label ofclopidogrel, prasugrel, and ticagrelor tablets, it is advised to consideradministration of a parenteral anti-platelet agent in acute coronary syndrome to patients requiring co-administration of morphine or other opioid agonists. A known parenteral use of ticagrelor is the use of crushed tablets and their administration by gastric nasal tube. This provides some improvement.However, it is time consuming to prepare and provides considerablediscomfort to a patient. It involves the administration of a suspension, which is inhomogeneous, may provide sedimentation and inconsistent dosing.Current medical practice is the increase of the P2Y12 dose inhibitor and closermonitoring of the patient. Dose increase may lead to an increase of adverse effects. The bleeding risk is increased. A closer monitoring and follow-up is a burden on hospital resource. Cangrelor iv is the only known P2Y12 inhibitor available in a form for intravenous administration. It is direct acting, onset of PD effect is around 2 minutes, time to maximal effect is about 2 minutes and maximum platelet inhibition is at least 98%. However, its half-life is 3-6 minutes and plateletfunction return to baseline after discontinuation in about 1 hour. This meansthat repeated injections or continuous infusion are required if the effect is tolast for at least several hours. In addition, in some patients cangrelor iscontraindicated due to hypersensitivity to cangrelor or a component of theproduct.In view of the above, there is a need for further improvements. The presentinvention aims to solve at least one of the problems outlined above. In particular, the present invention aims to provide a solution to the drug-drug interaction between opioid drugs and oral P2Y12 inhibitors, such as ticagrelor. The present invention aims to reduce the risk of insufficient platelet inhibition and resulting thrombotic complications. The present invention aims toprovide optimized formulations for use in time-sensitive acute scenarios.SUMMARY OF THE INVENTIONIn a first aspect, the invention provides a pharmaceutical ticagrelorcomposition for use in the treatment or prevention of coagulation in a patient in need thereof who was previously administered an opioid active ingredient, characterized in that the pharmaceutical ticagrelor composition is administered intravenously following the administration of the opioid active ingredient thereby avoiding delayed or reduced ticagrelor uptake provided bythe opioid active ingredient. The use of a ticagrelor iv composition providesan improved bioavailability over currently available ticagrelor compositions. The intravenous administration overcomes the impact of opioid active ingredients, which are known to delay or reduce oral ticagrelor uptake, which on average has a bioavailability of 36%. Preferably ticagrelor was administered within less than three hours of the opioid active ingredient administration. Preferably the pharmaceutical ticagrelor composition is used for thetreatment of a patient suffering from an ST-elevated myocardial infarction ora non ST-elevated myocardial infarction. Preferably, said patient was administered fentanyl prior to recording an angiogram and prior to anti-coagulant treatment. Preferably said patient is receiving a non-elective PCI.Alternatively, the pharmaceutical ticagrelor composition is used for thetreatment of a patient who has undergone surgery for a joint replacement.Alternatively, the pharmaceutical ticagrelor composition is used for thetreatment of a patient who has contracted a Gram-positive bacteremiafollowing drug substance abuse comprising an opioid active ingredient. Preferably, the pharmaceutical ticagrelor composition for use in an embodiment of the invention comprises an inclusion complex of ticagrelor and a cyclodextrin.Preferably the pharmaceutical ticagrelor composition for use in anembodiment of the invention, is a lyophilized ticagrelor composition;preferably a lyophilized ticagrelor composition according to an embodiment of the invention. Preferably, the lyophilized ticagrelor composition has a reconstitution time of less than 5 minutes. Preferably an effective amount of ticagrelor is administered intravenously within 5 minutes. In a second aspect, the invention provides a liquid ticagrelor-containing composition for lyophilization, comprising ticagrelor in free form, a bulkingagent and an alcohol: water mixture, wherein the ratio of said alcohol to saidwater is from 25:75 to 50:50 (% w / w). Preferably the alcohol is tertiary butylalcohol (TBA). This composition is particularly suitable for the preparation ofpharmaceutical ticagrelor compositions in lyophilized form. Preferably, the liquid ticagrelor-containing composition for lyophilizationaccording to an embodiment of the invention, comprises from 50 mg / 15 mlto 100 mg ticagrelor / 15 ml solution and or 6.5 mg / ml to 8.0 mg ticagrelor / mlof composition.Preferably, the bulking agent is mannitol and said mannitol is present theliquid ticagrelor-containing composition for lyophilization in an amount of 20 to 75 mg / ml. More preferably the liquid ticagrelor-containing composition for lyophilization according to an embodiment of the invention, consists of 6.5 mgticagrelor / ml, 232.5 mg / ml TBA, 33.5 mg mannitol / ml and remainder waterfor injection. In a further aspect, the invention provides a method of manufacturing a pharmaceutical ticagrelor composition in lyophilized form, comprising thesteps of: providing a liquid ticagrelor-containing composition according to anembodiment of the invention; lyophilizing said liquid ticagrelor containing composition and recovering the resultant ticagrelor composition in lyophilized form.The present invention also provides a pharmaceutical ticagrelor compositionin lyophilized form, obtained by a method according to an embodiment of theinvention. Preferably the composition comprises 30 mg to 100 mg ticagrelorand 20 to 75 mg mannitol and the ticagrelor is present in free form. Thisformulation is particularly suitable for use in time-sensitive acute scenarios where it is of importance to avoid delays or reductions in platelet inhibition. This formulation provides an alternative to liquid ticagrelor iv formulations comprising elevated amounts of cyclodextrin. A cyclodextrin-free formulation may be better suitable for prolonged use.In a further aspect, the invention provides a kit of parts comprising apharmaceutical ticagrelor composition according to an embodiment of the invention, in combination with a suitable diluent solution, said suitable diluent solution comprising: an aqueous, 0,1 M phosphate buffered solution of pH 7.4-7.5 4% -4.4 w / w% polyethylene glycol (15)-hydroxystearate (Kolliphor HS 15) and 30%-40 v / v% polyethylene glycol (PEG-400).Alternatively, the invention provides a kit of parts comprising apharmaceutical ticagrelor composition according to an embodiment of the invention, in combination with a suitable diluent solution, said suitable diluent solution comprising: an aqueous, phosphate buffered solution of pH 7.4-7.5 4% polyoxyethylene sorbitan monooleate (40 mg / ml) and40 / v% propylene glycol (400 mg / ml).The invention also provides a method of manufacturing a pharmaceuticalticagrelor composition in lyophilized form, comprising the steps of: providing a liquid ticagrelor-containing composition comprising an inclusion complex of ticagrelor and a cyclodextrin, preferably hydroxypropylbetacyclodextrin (HPBCD); lyophilizing said liquid ticagrelor containing composition and recovering the resultant ticagrelor composition in lyophilized form; wherein the pharmaceutical ticagrelor composition comprises an inclusion complex of ticagrelor and a cyclodextrin, preferably hydroxypropylbetacyclodextrin (HPBCD).The invention further provides a lyophilized ticagrelor-containingcomposition, comprising an inclusion complex of ticagrelor and a cyclodextrin, preferably hydroxypropylbetacyclodextrin (HPBCD). DETAILED DESCRIPTION OF THE INVENTION Unless otherwise defined, all terms used in the description of the invention, including technical and scientific terms, have the meaning as commonly understood by a person skilled in the art to which the invention pertains. Furthermore, definitions of the terms are included to better understand the description of the present invention. As used here, the following terms have the following meaning: “A”, “an”, and “the” as used here refer to both the singular and the plural, unless the context indicates otherwise. “A surfactant” refers, by way of example, to one or more than one surfactant. “About” as used herein, referring to a measurable value such as a parameter, an amount, a duration and the like, is intended to include variations of plus or minus 10% or less, preferably plus or minus 5% or less, more preferablyplus or minus 3% or less, even more preferably plus or minus 1% or less,and even more preferably plus or minus 0.1% or less of the specified value, as far as such variations are suitable for carrying out in the described invention. It will be clear, however, that the value to which the term “about” relates is itself also specifically described. “Include”, “comprising” and“comprises” are used herein are inclusive or open terms that specify thepresence of what follows, e.g. a component and the presence of additional, unnamed components, features, elements, parts, steps, which are well known in the art or described therein, and do not exclude them. The recitation of numerical ranges by endpoints includes all numbers and fractions that are included within that range, as well as the endpoints mentioned.The term “% w / w” as used herein means percentage by weight in which theweight ratio of an ingredient to the total weight of a composition is expressedas a percentage. Ticagrelor is a well-known active ingredient. It is a platelet aggregation inhibitor used for the prevention of thrombotic events, such as myocardial infarctions or strokes, in patients with acute coronary syndromes. Its chemical name is (1S,2S,3R,5S)-3-{7-[(1R,2S)-2-(3,4-difluorophenyl)cyclopropylamino]5-(propylthio)-3H-(1,2,3) triazolo (4,5-D)pyrimidin-3-yl}-5-(2 hydroxyethoxy)cyclopentane-1,2-diol. Ticagrelor was developed by AstraZeneca and was approved for entry on the market by the European Medicines Agency in 2010 and by the US Food and Drug Administration in 2011. As drug it is marketed in tablet form under the name Brilinta®in the USA and Brilique®in the EU. It is not commercially available in liquid form. Ticagrelor is an oral, reversible, direct-acting P2Y12^receptor antagonist that works by inhibiting platelet activation.^Brilinta®tablets, together with aspirin, have shown to significantly reduce the risk ofmajor adverse 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®^tablets are also indicated for the reduction of the risk ofa first heart attack or stroke in high-risk patients with coronary artery disease. Ticagrelor has shown to be highly susceptible to degradation when exposed to light, heat and oxygen, plus its limited solubility is a great challenge in formulating it as an aqueous solution. Although the need for a liquid ticagrelor formulation remains high, to our knowledge a successful commercial product of desired solubility and long-term stability in correspondence with requirements of the pharmaceutical industry has not been successful. Sigfridsson et al. (J Pharm Sci 100: 2194-2202, 2011) disclosed a composition deemed suitable for intravenous administration. The composition is based on nanoparticles of ticagrelor, a combination of polyvinylpyrrolidone and the disodium salt of Aerosol AOT for stabilization of the active ingredient, and 5 percent mannitol to obtain a nanosuspension. Aerosol AOT is believed to correspond to dioctyl sulfosuccinate sodium salt. Although the nanosuspension is reported to have a stability of at least 10 months, it is also reported that there is some tendency for particle aggregation and sedimentation during storage. Therefore, samples are sonicated prior to an intravenous administration. This is cumbersome for a pharmaceutical use and presents a safety risk. The same publication of Sigfridsson et al. also mentions that ticagrelor concentrations in phosphate buffered solution at pH 7.4 declined after 1 month under normal laboratory conditions of light and temperature. Although there is a long-felt need for an intravenous formulation to overcome drawbacks of oral P2Y12 inhibitors, such as ticagrelor tablets, no enabling disclosure is provided in the literature. Commercially ticagrelor is only available in the form of (orodispersible) tablets.In a first aspect the present invention provides a pharmaceutical ticagrelorcomposition for use in the treatment or prevention of coagulation in a patient in need thereof who is co-administered an opioid active ingredient, in combination with one or more pharmaceutically acceptable carriers, characterized in that the pharmaceutical ticagrelor composition isadministered intravenously following the administration of the opioid activeingredient thereby avoiding delayed or reduced ticagrelor uptake provided by the opioid active ingredient. The present invention overcomes the problem of reduced absorption of an oral P2Y12 inhibitor caused by gastric motility reduction related to opioid use. The present invention provides pharmaceutical ticagrelor compositions provided for intravenous administration for use in the treatment of time- sensitive acute scenarios requiring anti-platelet therapy, particularly ticagrelor therapy. By the term “provided for intravenous administration” as used herein, is meant a composition that is compatible for administration into a bloodstream. This particularly relates to the osmolality and pH of the formulation to be compatible. No dilution or pH adjustment are required, the formulation is ready-to-use. Preferably the patient is a human patient. Preferably the aqueous ticagrelor solution is prepared from micronized ticagrelor with D90 of less than 90 micrometers. A method for the measurement of particle size of an active ingredient, is well-known to a person skilled in the art of formulations. The method used in the presentinvention is by Malvern Mastersizer dry powder method. The pharmaceutical ticagrelor composition for use according to an embodiment of the invention, comprises the co-administration of the opioid active ingredient and ticagrelor is less than four hours apart, preferably less than three hours apart, more preferably less than two hours apart, most preferably less than one hour apart. The pharmaceutical ticagrelor composition for use according to an embodiment of the invention, wherein the patient is suffering from an ST- elevated myocardial infarction. The pharmaceutical ticagrelor composition for use according to anembodiment of the invention, wherein the patient is suffering from a non ST-elevated myocardial infarction. The pharmaceutical ticagrelor composition for use according to an embodiment of the invention, wherein the patient is suffering from an ST- elevated myocardial infarction. The pharmaceutical ticagrelor composition for use according to the previous embodiment of the invention, wherein the patient was administered fentanyl prior to recording an angiogram and prior to anti-coagulant treatment. The pharmaceutical ticagrelor composition for use according to the previous two embodiments of the invention, wherein the patient is receiving a non- elective PCI. Alternatively, the pharmaceutical ticagrelor composition for use according to an embodiment of the invention, wherein the patient has undergone surgeryfor a joint replacement (knee joint or hip joint). Opioids are in use in painmanagement after a joint replacement. In addition, antithrombotic medicinesare prescribed for the prevention or treatment of arterial or venous thrombi, including ticagrelor. The present invention provides a solution to drug-drug interactions between an opioid and an oral P2Y12 inhibitor, such as ticagrelor tablets. The US has seen an increase in the use of commonly injected drugs, such as heroin and fentanyl. Injection drug use (IDU) can lead to the life-threatening methicillin-resistant Staphylococcus aureus (MRSA) blood stream infections(BSI). A surveillance study reported that of the 7646 MRSA BSIs identifiedduring 2015-2017, 24.1% were related to injection drug use. The prevalence of endocarditis (40.4%) was significantly greater (p<0,001) among IDU- related BSIs compared to other non-IDU related BSIs (10.8%). Especially in these cases it is very important that the anti-platelet therapy with ticagrelor is effective because of the serious health risks involved. Anti-platelet therapy has been proposed as a new tool for fightingStaphylococcus Aureus (SA) blood stream infections, including methicillinsensitive (MSSA) and methicillin resistant Staphylococcus Aureus (MRSA) blood stream infections. The present invention provides a solution to the problem that opioid drug use, from substance abuse or from pain medication / sedation, may impact the efficacy of a P2Y12 anti-platelet medication, such as oral ticagrelor or clopidogrel. The pharmaceutical ticagrelor composition for use according to an embodiment of the invention, wherein the pharmaceutical ticagrelor composition comprises an inclusion complex of ticagrelor and a cyclodextrin. Cyclodextrin is a suitable solubilizer for ticagrelor through the formation of ticagrelor-cyclodextrin inclusion complexes. Preferably the cyclodextrin is HPbCD. The cyclodextrin can be used to solubilize ticagrelor in an aqueous environment. Provided enough cyclodextrin is used, a therapeutically relevant amount of ticagrelor active ingredient can be dissolved. Aqueous compositions comprising an inclusion complex of ticagrelor and HPbCD, at pH 6-8, were prepared. Accelerated storage stability tests showed an accelerated storage stability of at least 3 months measured in accelerated storage conditions at 40°C and 75% Relative Humidity. In a further aspect, the invention provides a pharmaceutical ticagrelor composition for use according to an embodiment of the invention, in the treatment of a patient who has contracted a Gram-positive bacteremiafollowing an opioid drug substance abuse. Administration of ticagrelorintravenously avoids a delay or decrease in absorption as a consequence ofthe opioid drug use.The pharmaceutical ticagrelor composition for use according to the previousembodiment of the invention, is preferably an aqueous ticagrelor solution,comprising, water, ticagrelor as active ingredient, and a cyclodextrin in a suitable amount for solubilization of the ticagrelor, wherein the aqueous solutions has a pH of 5.5-9, and an osmolality of 300-900 mOsm / kg. The pharmaceutical ticagrelor composition for use according to anembodiment of the invention preferably has a pH between 5.8 to 8.5; morepreferably 6.0 to 8.2; even more preferably 6.2 to 8.1; most preferably 7.0 to 8.0. The pH range of 7.0 to 8.0 is especially important because of the physiological acceptance for iv formulation to patients. More preferably the aqueous pharmaceutical composition for use accordingto an embodiment of the invention comprises0.10 – 14.0 mg / ml ticagrelor and20 – 100 mg / ml of cyclodextrin in a quantity for solubilization of the ticagrelorin the selected volume of aqueous pharmaceutical solution (solubilizer forticagrelor), wherein the aqueous pharmaceutical solution has a volume of 25to 1000 ml. Preferably the cyclodextrin is selected from a hydroxypropyl-beta-cyclodextrin and a sulfobutylether beta-cyclodextrin. Most preferably thecyclodextrin is a hydroxypropyl-beta-cyclodextrin. Preferably organic co-solvents are excluded. Preferably polyethylene glycol is excluded from theaqueous ticagrelor composition. Preferably the ticagrelor has a D90 particlesize below 10 micrometers when tested using Malvern mastersizer.More preferably, the aqueous ticagrelor composition for use in an embodiment of the invention consists of^ 5-15 mg / ml ticagrelor,^^15 – 40 % w / w of a hydroxypropyl-beta-cyclodextrin,^^ 5 mM-20 mM of buffer,^ optionally including a tonicity modifier,^^ wherein the pH is between 5.5 and 8; and the osmolality is 300-900 mOsm / kg. More preferably, the aqueous ticagrelor composition for use in an embodiment of the invention consists of^ 5-15 mg / ml ticagrelor,^^15 – 40 % w / w of a hydroxypropyl-beta-cyclodextrin,^^5 mM-20 mM of phosphate buffer,^ optionally including a tonicity modifier,^^ wherein the pH is between 5.5 and 8; and the osmolality is 300-900 mOsm / kg. In a preferred embodiment the pharmaceutical composition for use in the invention, is devoid of polyethylene glycol. This is advantageous for storage stability as the presence of polyethylene glycol in an aqueous ticagrelor solution was found prone to generate impurities when stored for a longer period of time. The pharmaceutical ticagrelor composition for use according to the previous embodiment of the invention, wherein the pharmaceutical ticagrelorcomposition is a lyophilized ticagrelor composition.The pharmaceutical ticagrelor composition for use according to the previous embodiment of the invention, wherein the lyophilized ticagrelor composition has a reconstitution time of less than 5 minutes, preferably less than 3 minutes, most preferably less than 1 minute. In a second aspect the invention provides a pharmaceutical ticagrelor composition comprising an inclusion complex of ticagrelor and a cyclodextrin, characterized in that the pharmaceutical composition is in lyophilized form. In a further aspect the invention provides a liquid ticagrelor-containingcomposition, comprising ticagrelor, a bulking agent and a alcohol:watermixture, wherein the ratio of said alcohol to said water is from 25:75 to50:50. The alcohol:water mixture preferably has a ratio of 30:70. The ratiois expressed in % w:w.The alcohol is preferably t-butyl alcohol (TBA).Preferably the liquid ticagrelor-containing composition comprises ticagrelor,a bulking agent and t-butyl alcohol:water mixture, wherein the ratio of saidTBA to said water is from 25:75 to 50:50. The TBA:water mixture preferably has a ratio of 30:70. The ratio is expressed in % w:w.Ticagrelor has six stereocenters and consequently there are many crystallineand amorphous forms. In a preferred embodiment of the present invention, the active agent is crystalline ticagrelor. Especially, four non-solvated crystalline forms are available, named as Polymorph I, II, III and IV. The polymorphs present different physical and chemical properties.^In a preferred embodiment, polymorph II is used. Its X-ray powder diffraction patterns is characterized by specific peaks at 5.5° (±0.1°), 6.8° (±0.1°), 10.6° (±0.1°), 13.5° (±0.1°), 14.9° (±0.1°), 18.3° (±0.1°), 19.2° (±0.1°), 22.7° (±0.1°),24.3° (±0.1°) and 27.G (±0.1°) 2Q. The polymorph II form is described inliterature as the most stable crystalline form of ticagrelor. The liquid ticagrelor-containing composition described above is used as a bulk solution for preparing lyophilized ticagrelor, wherein the ticagrelor is present in free form. Preferably ticagrelor polymorph II form is used. The concentration of ticagrelor in the liquid ticagrelor-containing compositionis preferably from 50 mg / 15 ml to 100 mg / 15 ml; more preferably 55 mg / 15ml to 95 mg / 15 ml; even more preferably 60 mg / 15 ml to 90 mg / 15 ml;most preferably 60 mg / 15 ml or 90 mg / 15 ml. 15 ml is the typical volumecontent of a vial for lyophilization (fill volume).In a preferred embodiment the liquid ticagrelor-containing compositioncomprises a bulking agent selected from sucrose or mannitol. Preferably thebulking agent is present in an amount of 20 to 75 mg / ml; more preferably25 to 65 mg / ml; even more preferably 30 to 60 mg / ml; most preferably 33.5 or 50 mg / ml. Preferably mannitol is present in an amount of 20 to 75 mg / ml; more preferably 25 to 65 mg / ml; even more preferably 30 to 60 mg / ml; most preferably 33.5 or 50 mg / ml. In a preferred embodiment the liquid ticagrelor-containing composition consists of 6.5 mg / ml ticagrelor, 232.5 mg / ml TBA, 33.5 mg / ml mannitol and water for injection q.s. to 1.0 ml. Vials are filled with 10 ml of this ticagrelor- containing composition for lyophilization.In an alternative embodiment the liquid ticagrelor-containing compositionconsists of 60 or 90 mg / 15 ml ticagrelor, 3.5-4.5% w / w Kolliphor HS15surfactant, optionally 5% w / v mannitol, and water for injection q.s. to 15 ml.Synonyms for Kolliphor HS15 are Macrogol (15)-hydroxystearate, polyethylene glycol (15)-hydroxystearate, polyoxyethylated 12- hydroxystearic acid. The CAS-number of Kolliphor HS15 is 70142-34-6. This non-ionic surfactant is available from BASF. It is approved by the FDA for use in parenteral drugs. In a further aspect the invention provides a kit of parts comprising the pharmaceutical ticagrelor composition according to an embodiment of the invention, in combination with a suitable diluent solution. The suitable diluentsolution comprises:an aqueous, 0.1 M phosphate buffered solution of pH 7.4-7.54% -4.4 w / w% polyethylene glycol (15)-hydroxystearate (Kolliphor HS 15)and 30%-40 v / v% polyethylene glycol (PEG-400).In a further aspect the invention provides a method of manufacturing apharmaceutically ticagrelor composition in lyophilized form, comprising thesteps of: providing a liquid ticagrelor-containing composition comprisingticagrelor, a bulking agent and a alcohol:water mixture, wherein the ratio ofsaid alcohol to said water is from 25 / 75 to 50 / 50; lyophilizing said liquidticagrelor containing composition and recovering the resultant ticagrelor composition in lyophilized form, wherein the ticagrelor is in free form. Preferably the liquid ticagrelor-containing composition for lyophilization is a composition as previously disclosed above.The invention also provides a method of manufacturing a pharmaceuticalticagrelor composition in lyophilized form, comprising the steps of: providing a liquid ticagrelor-containing composition comprising an inclusion complex of ticagrelor and a cyclodextrin, preferably hydroxypropylbetacyclodextrin (HPBCD); lyophilizing said liquid ticagrelor containing composition and recovering the resultant ticagrelor composition in lyophilized form; wherein the pharmaceutical ticagrelor composition comprises an inclusion complex of ticagrelor and a cyclodextrin, preferably hydroxypropylbetacyclodextrin (HPBCD).The invention further provides a lyophilized ticagrelor-containingcomposition, comprising an inclusion complex of ticagrelor and a cyclodextrin, preferably hydroxypropylbetacyclodextrin (HPBCD). The invention is further illustrated by the following examples. The examples are non-limiting. EXAMPLES Pharmaceutical ticagrelor compositions suitable for use in the presentinvention are provided in the examples below. In a first part, liquidpharmaceutical ticagrelor solutions with improved stability are provided for iv administration. These were previously disclosed in a co-pending application PCT / EP2023 / 063071, which is incorporated herein by reference. In a second part, several lyophilized ticagrelor formulations and formulations for lyophilization are provided. These have the advantage that they may be cyclodextrin free. These may be particularly suitable for use over an extended period of treatment, i.e. beyond a single iv administration. Aqueous ticagrelor solutions provided for intravenous administration Example 1 : Vitamin E TPGS as solubilizer for ticagrelor Table 1: Ticagrelor iv compositions Formulation Weight ticagrelor Volume (mL) Concentrationadded (mg) (mg ticagrelor / ml) 2.5 %30 50 0.600vitamin E TPGS 5.0 %30 50 0.600vitamin E TPGS 10.0 %30 50 0.600vitamin E TPGS Aqueous ticagrelor solutions, using vitamin E TPGS as solubilizer, were prepared as follows. Water soluble vitamin E TPGS was added to water to obtain different concentrations of 2.5 and 5.0 and 10.0 w / v% aqueous vitamin E TPGS solutions. To these solutions, kept at a temperate of 45°C+ / - 5°C, portions of ticagrelor were gradually added. 3 mg ticagrelor portionswere added step-by-step to a 50 ml aqueous vitamin E TPGS solution (1ststage). 20 ml of each diluent were then used in a 2ndstage study. To 20 ml of each diluent 10 mg ticagrelor portions were added. This was reduced to 5 mg when the dissolution was taking longer. Table 2: Aqueous ticagrelor iv solutions Formulation WeightVolume (mL) Concentration ticagrelor of 0.6 mg / ml (mg added (mg) ticagrelor ticagrelor / ml) solution from Table 1 2.5 % vitamin E TPGS 220 20 11.600(232 / 20) 5.0 % vitamin E TPGS 286 20 14.900(298 / 20) 10.0 % vitamin E384 20 19.800TPGS (396 / 20) The following was observed: 10 mg ticagrelor dissolved after 5-10 minutes. 2.5% vitamin E TPGS solution saturated at 11.6 mg / ml 5.0% vitamin E TPGS solution saturated at 14.9 mg / ml 10.0% vitamin E TPGS solution saturated at 19.8 mg / ml The aqueous ticagrelor solutions obtained are stored at 40 °C and 75 % Relative Humidity or at 25 °C and 60 % Relative Humidity, for a period of at least 3 months. Example 2: Cyclodextrin as solubilizer for ticagrelor The following compositions are suitable as ready-to-use ticagrelor aqueous compositions for iv administration. Table 3 : ready to use ticagrelor compositions in water RTU Infusion RTU Infusion RTU Infusion Formulation Formulation Formulation mg / bottle mg / bottle mg / bottle 0.65 mg / ml TCG 0.325 mg / ml TCG 0.10 mg / ml TCG concentration concentration concentration Composition 3.1 Composition 3.2 Composition 3.3 Ticagrelor 65 65 65Hydroxy Propyl8000 16000 16000beta cyclodextrin (HPβCD) Water 100 ml 200 ml 650 mlpH 7.33 7.40 7.57Osmolarity96 90 22(mOsmol / kg) Clarity Clear solution Clear solution Clear solutionTable 4 : ready to use ticagrelor compositions in aqueous phosphate bufferRTU Infusion RTU Infusion RTU Infusion Formulation Formulation Formulation mg / bottle mg / bottle mg / bottle 0.65 mg / ml TCG 0.325 mg / ml TCG 0.10 mg / ml TCG concentration concentration concentration Composition 3.4 Composition 3.5 Composition 3.6 Ticagrelor 65 65 65Hydroxy Propyl8000 16000 16000beta cyclodextrin (HPβCD) Phosphate buffer100 ml 200 ml 650 mlpH 7.5 (10mM buffer) pH 7.58 7.45 7.6Osmolarity105 220 280(mOsmol / kg) Clarity Clear solution Clear solution Clear solutionTable 5 : ready to use ticagrelor compositions in diluted saline waterRTU Infusion RTU Infusion RTU Infusion Formulation Formulation Formulation mg / bottle mg / bottle mg / bottle 0.65 mg / ml TCG 0.325 mg / ml TCG 0.10 mg / ml TCG concentration concentration concentration Composition 3.7 Composition 3.8 Composition 3.9 Ticagrelor 65 65 65Hydroxy Propyl beta cyclodextrin8000 16000 16000(HPβCD) Normal Saline (0.9 w / v % Nacl 100 ml 200 ml 650 mlin water) pH 6.57 6.6 6.90Osmolarity 518 415 314(mOsmol / kg) Clarity Clear solution Clear solution Clear solutionTable 6 : ready to use ticagrelor compositions in dextrose solutionRTU Infusion RTU Infusion RTU Infusion Formulation Formulation Formulation mg / bottle mg / bottle mg / bottle 0.65 mg / ml TCG 0.325 mg / ml TCG 0.10 mg / ml TCG concentration concentration concentration Composition 13.10 Composition 13.11 Composition 13.12 Ticagrelor 65 65 65Hydroxy Propyl8000 16000 16000beta cyclodextrin (HPβCD) Dextrose 5 w / v % 100 ml 200 ml 650 mlpH 5.12 5.6 6.61Osmolarity512 425 336(mOsmol / kg) Clarity Clear solution Clear solution Clear solutionTable 7 : preferred ticagrelor solution for infusion RTU Infusion Formulation mg / bottle 2 mg / ml TCG concentration Composition 13.13 Ticagrelor (TCG) 65Hydroxy Propyl beta cyclodextrin (HPβCD) 3000Dextrose 5 w / v % 30 ml pH 7.05Osmolarity (mOsmol / kg) 674Clarity Clear solutionThe exemplified ready-to-use solutions were made as follows. In all cases a solvent as mentioned is prepared and taken in a beaker and heated to 40 °C, then HPβCD is added to obtain a clear solution under stirring. After this the active ingredient ticagrelor is added at 40 °C under constant stirring until a clear solution is obtained. This solution is filtered through a 0.22-micron filter and filled aseptically in a sterile glass bottle or an infusion bag. 24 mg / ml to 350 mg / ml HPβCD was required to obtain a stable Ticagrelor solution ready for infusion. The amount of cyclodextrin required was depending upon the volume of the targeted infusion medium. Ticagrelor is an active ingredient that is insoluble in water. The more it is in a diluted aqueous solution, the more tendency it has to precipitate. A proportional increase in cyclodextrin was required as the dilution factor for ticagrelor increased, when going from 30 ml to 100 ml to 200 ml. However,for a 650 ml volume and higher an amount of 16 g of cyclodextrin was foundsufficient to solubilize the ticagrelor. Note that no organic co-solvent, surfactant or other solubilizer were used. The aqueous ticagrelor solutions obtained were stored at 40 °C and 75 % Relative Humidity or at 25 °C and 60 % Relative Humidity, for a period of at least 3 months and were found stable. Development of storage stable ticagrelor solutions In the following examples the experimental work for obtaining storage stable ticagrelor solutions is explained. Example 3 In the present example two different types of cyclodextrin were used and compared for the solubilization of ticagrelor. An unbuffered stock solution of HPβCD or SBECD was made in water at the target concentrations of 20 w / w%, 25 w / w%, 30 w / w%, 35 w / w% and 40 w / w%. Ticagrelor was added slowly under vortex. Ticagrelor was used at concentrations of 5, 10 or 14 mg / ml in milliQ water. The ticagrelor-cyclodextrin solutions were left on a shaking platform. No sonification or heat was applied.From the results in Table 8 and 9 it follows that HPβCD was able to dissolveticagrelor in a broader range of cyclodextrin and ticagrelor concentrations tested. Clear aqueous solutions with 5 mg / ml ticagrelor in HPβCD were obtained with 25 w / w%, 30 w / w%, 35 w / w% and 40w / w% HPβCD. Table 8: Solubility of ticagrelor in HPβCD TicagrAppearance of Ticagrelor in cyclodextrinHPβCD elor conc. inconc. Floccul MilliQ After Afte Afte ation (%(mg / After After 5 min r 30 r 60test3h of overnigh w / w) ml) of min min haki sh t s aki of o shaking ng f shakin shakin ng g g 5+ + + + + passed40%10 - + / - + / - + / - + passed14 - + / - + / - + / - + / -* n.a.5 + / - + / - + / - + / - + passed35%10 - + / - + / - + / - + didnot pass 14 - + / - + / - + / - + / - n.a.5 - + / - + / - + / - + passed30%10 - - - - - n.a.14 - - - - - n.a.5 - + / - + / - + / - +* did25% not pass 10 - - - - - n.a.14 - - - - - n.a.5 - + / - + / - + / - - n.a.20%10 - - - - - n.a.14 - - - - - n.a.+ clear, appeared completely dissolved- translucent solution with precipitation+ / - clear solution with precipitation* after one hour of sonicationTable 9: Solubility of ticagrelor in SBECD TicagrelAppearance of Ticagrelor inSBECDor conc. cyclodextrin Flocculaticonc. inAfter Afte Afte After After on test MilliQ (mg / ml 5min r r 3 overnig ) h of (%w / w) of 30mi 60mi n sha ht shaki kin shakin ngof n ofshakin shakin g g g g5 - ++ ++ passe40% / - / - / - d 10 - - - - - n.a.14 - - - - - n.a.5 - ++ +- n.a.35% / - / - / - 10 - - - - - n.a.14 - - - - - n.a.5 - - - - - n.a.30%10 - - - - - n.a.14 - - - - - n.a.5 - - - - - n.a.25%10 - - - - - n.a.14 - - - - - n.a.5 - - - - - n.a.20%10 - - - - - n.a.14 - - - - - n.a.+ clear, appeared completely dissolved- translucent solution with precipitation+ / - clear solution with precipitationAs a conclusion Ticagrelor could be dissolved by leaving it on a shakingplatform. No sonication was applied. HPβCD can be used at Ticagrelorconcentrations of 5 mg / ml, using cyclodextrin at 40% w / w, 35% w / w or 30%w / w in milliQ water. These solutions remained clear at least for the threedays testing at room temperature and several days at 4°C.Example 4 After the experiments depicted in Example 3, further optimization was caried out with the selection of a suitable pH range to ensure long-term stability of the aqueous ticagrelor-cyclodextrin inclusion complex.The following composition as provided in Table 10 was prepared.Table 10: Composition for storage stability testing. mg / ml Ticagrelor 6HPβCD 40%w / w 452 Acetate or Phosphate Buffer pH 4.5 Q.S to 1 ml to 6.5 HPβCD was dissolved in a buffer solution of pH 4.5, 5.5 or 6.5 prepared separately in water. Once a clear solution was obtained, ticagrelor was dissolved in the buffer solution under constant stirring. The ticagrelor in buffer solution was filtered through a 0.22 micron filtered and filled in USP Type I glass vials. The vials were stoppered and stored. All precautions were taken during manufacturing, such as N2 purging and avoiding direct exposure to light. The vials were stored at 40°C and 75 % Relative Humidity (RH). To determine the stability of the formulations, batches were evaluated using a related substance method on HPLC. The data of these batches is enumerated below in Table 11. A Gradient HPLC method was used to analyze impurities in formulations using a YMC-Pack Pro C18 column (100x4.6mm, S-3μm 12nm). Good separation was obtained for all the impurities.Amine impurity: (1S,2S,3R,5S)-3-(7-amino-5-(propylsulfanyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)-5-(2-hydroxyethoxy)cyclopentane- 1,2-diol. This is a process related degradant impurity.Regiomer impurity: (1S, 2S, 3R, 5S)-3-((3-((1R,2S)-2-(3,4-Difluorophenyl)cyclopropyl)-5-(propylsulfanyl)-3H-[1,2,3]triazolo [4,5-d]pyrimidin-7-yl)amino)-5-(2-hydroxyethoxy)cyclopentane-1,2-diol. This is a processrelated degradant impurity.Acetal impurity: 2-[[(3aR,4S,6S,6aS)-6-[7-[[1R,2S)-2-(3,4-difluorophenyl)-cyclopropyl]amino]-5-(propylsulfanyl)-3H-[1,2,3]triazolo- [4,5-d]pyrimidin-3-yl]-2,2-dimethyltetrahydro-2H-3aHcyclopenta[d][1,3] dioxol-4-yl]oxy]ethan-1-ol. This is a process related impurity. Triol impurity: (1S,2R,3S,4R)-4-(7-((1R,2S)-2-(3,4-difluorophenyl) cyclopropylamino)-5-(propylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3- yl)cyclopentane-1,2,3-triol. This is a process related impurity. It was observed that only regiomer impurity increased in 4 weeks 40°C and 75 % RH at almost 0.3% level; specification limit 0.3 %. Hence to optimize the stability of the product further, investigations were carried out at pH 7 to 8. Example 5 Following the experiment described in example 4, a storage stability study at pH 7.5 was conducted. First HPβCD was dissolved in a phosphate buffer solution of pH 7.5 prepared separately in water. Once a clear solution was obtained ticagrelor was dissolved in the solution under constant stirring. The solution was filtered through a 0.22 micrometer filter and filled in USP Type I amber colored glass vials. The vials were stoppered and stored. All precautions were taken during manufacturing, such as N2 purging and avoiding direct exposure to light. Table 11

[0002] 

[0003] Table 12: Composition for storage stability testing. mg / ml Ticagrelor 6HPβCD 40% w / w 452Phosphate buffer pH 7.5 Q.S to 1 mlTable 13: Storage stability study of ticagrelor-cyclodextrin inclusion complex in aqueous solution at pH 7.5 stored at 40°C and 75 % Relative Humidity. Time point T=0 T=4T=8 T=12 T=24 40 °C and 75 % RH weeks weeks weeks Weeks Assay ticagrelor (%) 104.27 104.47 102.59 102.31 104.39Relative retention timeImpurity ID impurity impurity impurity impurity impurity(minutes) (%): (%): (%): (%): (%):0.45 Amine 0.04 0.05 0.05 0.05 0.07impurity 0.97 Triol impurity 0.04 0.05 0.05 0.04 0.051.03 Regiomer 0.00 0.01 0.04 0.08 0.16impurity 1.49 Acetal 0.05 0.05 0.05 0.05 0.05impurity Total impurities (%) 0.31 0.32 0.29 0.41 0.35Sum impurities >0.05 (%) 0.11 0.14 0.15 0.23 0.33Based on the results of the stability study, as summarized in Table 13, it was concluded that good storage stability was obtained at accelerated storageconditions of 40 °C and 75 % Relative Humidity. The regiomer impurity was wellunder control and no other impurity was of a concern. Example 6In a further experiment, to optimize the concentration of HPβCD below 40%w / w, heat at 40°C was applied at concentrations where a clear solution was difficult to obtain to help dissolve the target ticagrelor dose.Direct physical stability data as obtained from the ticagrelor 5 mg / mlconcentrate and with the flocculation test (20 µl sample material in 1 ml diluent)are shown in Table 14. Table 14 contains data on assay, purity, osmolality andpH.Table 14: Physical stability of ticagrelor 5 mg / ml batches with varying HPβCDconcentrations. Data are sorted by HPβCD strength. Ticagrelor concentrationwhen diluted into dextrose or saline: 0.1 mg / ml.HPβCDAppearance, undiluted AppearanceAppearance strength inin NaCl(% w / w) 5% dextrose0.9% 32.5 Clear solution ClearClear solution solution 30.0 Clear solution ClearTurbid solution 27.5 Turbid; clear after heating toClear Turbid 40°C solution 25.0 Turbid; clear after heating toClear Turbid 40°C solution 22.5 Turbid; clear after heating toClear Turbid 40°C solution Because of the poor physical stability results when diluted in saline, 32.5 % w / wHPβCD was chosen for a 5 mg / ml ticagrelor formulation. Undiluted concentrateremained stable even in the refrigerator with a HPβCD concentration as low as22.5 % w / w. Such a concentration yielded a nearly isotonic formulation. In conclusion, it was possible to dissolve 5-15 mg / ml ticagrelor together with HPβCD in the concentration range of 20-40 % w / w, without the use of heat. It was possible to achieve good solubility with lower concentrations of HPβCD such as 15-20 % w / w with application of heat to achieve a clear solution. At least 15% w / w HPβCD was required to provide a clear, storage stable ticagrelor solution with a concentration that is relevant for injection or intravenous administration. Example 7 From the results obtained in Example 6 it follows that the concentration of excipients may be such that the resulting ticagrelor solution is hypertonic. The osmolality and pH of several batches was checked. The solutions had a 19mM phosphate buffer and pH 7.5. The results are provided in Table 15. Table 15: pH and osmolality determination in undiluted batches. HPβCD Assay Total pH Osmolality strength (%) impurities undiluted undiluted (% w / w) (%) (mOsm / kg) 32.5 99.26 0.41 7.68 81330.0 107.64 0.44 7.74 63827.5 104.27 0.42 7.69 54925.0 103.23 0.41 7.69 49322.5 98.15 0.39 7.67 392Dilution studies were conducted to search for suitable diluents. 5 mg / ml ticagrelor-cyclodextrin solutions with varying amounts of HPβCD were diluted with normal saline, 5% dextrose solution or Ringer’s lactate solution. The stability was screened. The ticagrelor concentration when diluted intodextrose or saline: 0.1mg / ml The results are summarized in Table 16.Table 16: Diluent tests HPβCDAppearance, undiluted Appearance inAppearance strength5% dextrose in NaCl(% w / w)0.9% 32.5 Clear solution Clear solution Clearsolution 30.0 Clear solution Clear solution Turbid27.5 Turbid; clear after heating to Clear solution Turbid40°C 25.0 Turbid; clear after heating to Clear solution Turbid40°C 22.5 Turbid; clear after heating to Clear solution Turbid40°C In addition, a screening was conducted on the impact of buffer strength on pH and osmolality. The results are summarized in Table 17. Table 17: Impact of buffer strength on pH, osmolality, assay, and impurities. Phosphate pH pH Osmolality Osmolality Assay Total buffer pH samp placebo sample placebo (%) impurities 7.5 le (mOsm / kg) (mOsm / kg) (%) strength (mM) 19 7.70 7.71 758 790 102.58 0.4210 7.69 7.72 724 692 102.98 0.425 7.66 7.73 703 725 100.49 0.400.19 7.18 7.45 809 771 102.23 0.42It was concluded that a phosphate buffer of pH 7.5 at different bufferstrengths had little effect on the osmolality, except at 0.19 mM bufferstrength. This buffer strength was too weak, which led to a change in pH. Example 8In a further example the impact of particle size on solubility was tested. Twodifferent particle size diameters for the ticagrelor active ingredient were screened, 5.5 and 15 micrometers. The pH and osmolality were not affected. Smaller particles showed a faster dissolution time, as summarized in Table 18. The micronized ticagrelor showed significant improvement on the dissolution time. Consequently, a micronized ticagrelor with D90 of less than 10 micrometers is preferred. With the term “D90” as used herein, is meant that at least 90% of the particles present have a size that is less than the target particle size. However, it is understood that variations in input particle size distribution (PSD) of ticagrelor would be possible and it will have an impact on the dissolution rate of ticagrelor. A method for the measurement of particle size of an active ingredient, is well- known to a person skilled in the art of formulations. The method used in thepresent invention is by Malvern Mastersizer dry powder method Table 18: Impact of particle size Particle distribution, D90DissolutionpH Osmolality(0.9) time (mOsm / kg) 5.5µm, micronized 33 min 7.68 75115µm, unmicronized 125 min 7.70 753Example 9 To optimize the HPβCD concentration and the pH of the solution for intravenous use, a 12 week / 3 months stability study was conducted. A composition of 32.5% w / w HPβCD with 5 mg / ml ticagrelor at pH 7 to 8 was prepared and stored. Its stability was tested at regular intervals.A comparison of stability profile at 3 different pH – 7, 7.5 and 8- was carriedout as below, the manufacturing process for all 3 formulations was kept constantwith buffer strength at 19 mM. The results are summarized in Tables 19 to 21Table 19: Storage stability in amber glass vials – pH 7Amber colour USP Type I HPβCD 40%w / w 19mM pH 7 Phosphate BufferT0 1M 2M 3MDescription clear clear clear clearAssay 98.95 99.73 99.81 98.51pH 7.33 7.34 7.34 7.30RRT Impurity % % % %0.45 Amine 0.04 0.04 0.04 0.06impurity 0.97 Triol 0.05 0.02 0.04 0.04impurity 1.03 Regiomer 0.00 0.03 0.06 0.111.49 Acetal 0.05 0.05 0.05 0.05impurity Total 0.41 0.27 0.34 0.40Sum impurities >0.050.22 0.05 0.11 0.22(%)Table 20: Storage stability in amber glass vials – pH 7.5Amber colour USP Type I HPβCD 40%w / w 19mM pH 7.5 Phosphate BufferT0 1M 2M 3MDescription clear clear clear clearAssay 104.27 104.47 102.59 102.31pH 7.40 7.50 7.48 7.55RRT Impurity % % % %0.45 Amine impurity0.04 0.05 0.05 0.050.97 Triol impurity0.04 0.05 0.05 0.041.03 Regiomer 0.00 0.01 0.04 0.081.49 Acetal impurity0.05 0.05 0.05 0.05Total 0.31 0.32 0.29 0.41Sum impurities >0.05 (%) 0.11 0.14 0.15 0.23Table 21: Storage stability in amber glass vials – pH 8.0Amber colour USP Type I HPβCD 40%w / w 19mM pH 8 Phosphate bufferT0 1M 2M 3MDescription clear clear clear clearAssay 103.25 105.88 105.46 104.46pH 8.07 8.10 8.04 8.03RRT Impurity % % % %0.45 Amine impurity0.04 0.05 0.05 0.070.97 Triol impurity0.06 0.03 0.05 0.051.03 Regiomer 0.00 0.01 0.03 0.061.49 Acetal impurity0.05 0.05 0.05 0.05Total 0.43 0.26 0.32 0.37Sum impurities >0.05 (%) 0.25 0.09 0.15 0.23From the above data it was concluded that the ticagrelor solution in HPβCD wasstable in the pH range of 7 to 8. Example 10 To study the potential impact of the packaging material on the stability of the ticagrelor-cyclodextrin inclusion complex a composition with 32.5%w / w HPβCD was prepared with procedures and precaution’s similar to previous trials, samples were stored in transparent clear glass vials and amber colored glass vials at a temperature of 40 °C / 75% RH. The results are shown in Table 22 and Table 23. The results of the accelerated storage stability test indicated that after 3 months, no significant difference was observed between the two. All the samples remained clear aqueous solutions. The pH of the samples remained stable. Impurities did not change significantly. It seems that both clear and amber colored glass vials can be used. Compared to the results of the accelerated storage stability test on ticagrelor solutions, without the use of cyclodextrin, it is clear that the use of cyclodextrin is important to achieve a good stability. Without the cyclodextrin, 6 to 8 different impurities developed on storage. These impurities were not seen in the selected composition. Table 22: Study of the potential impact of packaging. Stability in amber color USP Type I glass. Amber colour USP Type I Glass vials HPβCD 32.5%w / w 5mM pH 7.5 Phosphate BufferT0 1M 2M 3MDescription clear clear clear clearAssay 98.34 100.24 99.89 98.93pH 7.66 7.70 7.69 7.66RRT Impurity % % % %0.45 Amine 0.04 0.04 0.04 0.06impurity 0.97 Triol impurity 0.04 0.02 0.04 0.051.03 Regiomer 0.00 0.01 0.02 0.041.49 Acetal 0.05 0.05 0.04 0.05impurity Total 0.40 0.22 0.28 0.33Sum impurities >0.050.18 0.05 0.00 0.16(%) Table 23: Study of the potential impact of packaging. Stability clear glass vials USP Type I. Clear USP Type I Glass vials HPβCD 32.5%w / w 5mM pH 7.5 Phosphate bufferT0 1M 2M 3MDescription clear clear clear clearAssay 98.34 101.71 99.69 98.25pH 7.65 7.65 7.63 7.58RRT Impurity % % % %0.45 Amine 0.04 0.04 0.04 0.06impurity 0.97 Triol impurity 0.05 0.03 0.05 0.051.03 Regiomer 0.00 0.01 0.02 0.041.49 Acetal 0.05 0.04 0.04 0.05impurity Total 0.40 0.22 0.28 0.33Sum impurities >0.050.22 0.00 0.05 0.16(%) Surprisingly it could be concluded that ticagrelor solutions can be stabilized with HPβCD in both amber colored and clear glass vials. Example 11 Further embodiments of the invention are provided as summarized in Table 24. Further improvement in achieving higher solubility of ticagrelor was tried with different concentrations, such as with 40% w / w HPβCD, a ticagrelor solubility of 13 mg / ml was also possible. Table 24: clear aqueous solutions with ticagrelor-cyclodextrin inclusion complex considering 65 mg dose. N HPβC Ticagrel Fin HPβC HPβC Appearan Flocculati Flocculati r D or al D D ce on on (% (mg / ml Vol mg / g / vial in saline, in w / w) ) ml ml 1:2 dextrose, 1:2 A32.5 7.5 10 367.23.67 Clear,Clear Clear5 colorless B32.5 5 15 367.25.50 Clear,Clear Clear5 colorlessC 22.5 5 15 254.2 3.81 Clear, Clear Clear5 colorless C40 13 5 452 3.39 Clear, Clear Clearcolorless D33 8.25 9.2 372.3 3.43 Clear, Clear Clearcolorless E30 7.5 10 339 3.39 Clear, Clear Clearcolorless Density 1.130 gm / ccBased on the investigations it was observed that a concentration of 5 – 13mg / ml ticagrelor solution could be achieved using 20-40% w / w HPβCD. The volume of the fill content can be changed based on the dose required. Surprisingly it was found that the target dose of 5-15 mg / ml ticagrelor contained in a small volume could be achieved by adjusting the HPβCD % and total available volume of the formulation ready to inject. Being able to contain the ticagrelor dose in a volume of 5-15 ml is highly relevant as it is a typical bolus injection volume. Example 12 In a further example, the maximum solubility of ticagrelor in an HPβCD solution, without the use of heat, was investigated. The results are summarized in Table 25. Depending on the amount of ticagrelor to be delivered to a patient and the restriction of the sample volume as determined by an administration by injection or infusion, it follows that to dissolve 65-75 mg ticagrelor an amount of 2000- 4000 mg of HPβCD per vial of 10 ml may be required. Table 25: Concentration of HPΒCD, dose and volume of formulations HPβCD HPβCD mg / ml Ticagrelo 75 mg HPβCD 65 mg HPβCD % w / w %w / v HPβCDr mg / mldose mg / vial dose mg / vial 17 19.21 192.10 4 18.75 3600 16.253121 ml ml22.5 25.42 254.20 5 15.00 3813 13 ml 3304ml 30 33.90 339.00 8 9.37 3176 8.122752 ml ml 33 37.29 372.90 9 8.33 3107 7.222692 ml ml 40 45.2 452.00 13 7.76 3507 5 ml 2260ml Density of the HPβCD solution 1.130 gm / ccSurprisingly the solutions provided in Table 25 were compatible with diluents toprovide infusions, specifically with dextrose 5% in water. Example 13 In another embodiment of this invention, a highly stable clear solution of ticagrelor could be obtained by applying appropriate heat to the solution during preparation thus providing a completely clear solution of the formulation atdesired HPβCD and ticagrelor concentrations.To investigate the impact of temperature and hold time, a new composition was prepared as per below Table 26. Table 26: Composition for temperature impact assessment. mg / ml Ticagrelor 8HPβCD 30% w / w 329Phosphate Buffer pH 7.5 in water Q.S to 1 mlIn first step a phosphate buffer at pH 7.5 was prepared and the buffered solution was heated to 40°C -45°C. HPβCD was added to the buffered solution under continuous mixing. Once a clear solution was obtained, ticagrelor was dispersed into the HPβCD solution and mixed until a clear solution was obtained. It usually took 30 mins to 4 hours depending on batch size. Then this solution was filtered through a 0.22-micron filter and packed in suitable clear or amber colored glass vials Table 27: Bulk hold study at 45°C Time points @ 45°C- Bulk hold in T=1h T=110hGlass vials Assay Ticagrelor (%) 107.87 109.10Relative retention Impurity Average contenttime:impurity (%):0.45 Amine 0.05 0.07impurity 0.97 Triol impurity 0.04 0.051.33 0.07 0.031.47 Acetal 0.04 0.04impurity Total Impurities (%) 0.20 0.28Sum Impurities >0.05 (%) 0.12 0.11Table 28: Bulk Hold study at 25°C and 40°C Bulk solution @ sealed vials Ticagrelor 8 mg / ml in 30 % w / wHPβCD, phosphate buffer pH 7.5, 25°C and 40 °CTime point T=1M,T=1M, 25 °C 40 °CAssay Ticagrelor (%) 107.22 105.16Relative retention time: Impurity Average contentimpurity (%):0.13 Amine 0.06 0.06impurity 0.96 Triol 0.01 0.00impurity 1.03 0.02 0.021.07 Regiomer 0.03 0.08impurity 1.33 0.03 0.081.78 Acetal 0.03 0.00impurityTotal Impurities (%) 0.23 0.28Sum Impurities >0.05 (%) 0.06 0.21Table 29: Bulk hold at 30°C Time point T0 T4WAssay Ticagrelor (%) 105.60 106.14RelativeImpurity Average content impurity (%):retention time:0.45 Amine impurity 0.06 0.060.98 Triol impurity 0.05 0.041.06 Regiomer 0.00 0.00impurity 1.50 Acetal impurity 0.04 0.04Total Impurities (%) 0.21 0.21Sum Impurities >0.05 (%) 0.10 0.06The hold time study at temperatures between 25°C - 45°C indicated how even30% w / w HPβCD was capable of stabilizing ticagrelor, even after heating the solution for a prolonged period of time or keeping the bulk at an elevated temperature. Manufacturing process for a ready-to-use infusion formulation A manufacturing process to make the exemplified ready-to-use solutions of Tables 3-7 was as follows. In all cases a solvent as mentioned is prepared and taken in a beaker and heated to 40 °C, then HPβCD is added to obtain a clear solution under stirring. After this the active ingredient Ticagrelor is added at 40 °C under constant stirring until a clear solution is obtained. This solution is filtered through a 0.22-micron filter and filled aseptically in a sterile glass bottle or an infusion bag. 24 mg / ml to 350 mg / ml HPβCD was required to obtain a stable ticagrelor solution ready for infusion. The amount of cyclodextrin required was depending upon the volume of the targeted infusion medium. Ticagrelor is an active ingredient that is insoluble in water. The more it is in a diluted aqueous solution, the more tendency it has to precipitate. A proportional increase in cyclodextrin was required as the dilution factor for ticagrelorincreased, when going from 30 ml to 100 ml to 200 ml. However, for a 650 mlvolume and higher an amount of 16 g of cyclodextrin was found sufficient to hold the ticagrelor in the aqueous solution. Note that no organic co-solvent, surfactant or other solubilizer were used. Alternative preparation method starting from a concentrated ticagrelor solution It is possible to dilute 1 vial of 8 ml containing 65 mg / vial ticagrelor and about 3 g HPβCD with 25 ml 5 w / v % dextrose and obtain a clear solution with a final volume of 33 ml. However, this was not possible with a 0.9 w / v% NaCl solution as diluent for the concentrated ticagrelor solution. This is of importance in medical treatments where a concentrated ticagrelor aqueous composition would be mixed with another medicine. It can lead to precipitation of ticagrelor, rendering the combination product unsuitable for intravenous administration.Solubility studies with other solventsSolubility studies were performed using different solvents. Formulations A-E, shown in Table 30A, were prepared by adding ticagrelor (final concentration of 1.8 mg / mL) to a tube (e.g., Eppendorf or conical) followed by adding the listed solvent(s) diluted in distilled water (final volumes of 10 ml). The tubes were then vortexed and sonicated in a temperature controlled water bath, if necessary. After 60 min, the tubes were collected for solubility observation. The samples were checked again after 24 hrs.Table 30A Solubility studies with other solventsTest Solvent (v / v%, remainderV* S* W*֠ Solubilized / # distilled water) Clear Solution A1,2-propanediol 20% Y Y Y NB Ethanol 20% Y Y Y NC Polysorbate 80 100% Y Y Y ND 20% w / v Hydroxypropyl- Y Y Y Yβ-cyclodextrin EPEG 400 50% Y Y Y YBased on the investigations it was observed that ticagrelor was only solubilized with cyclodextrin or polyethylene glycol (PEG). Solubility, but inadequate storage stability Polyethylene glycol can solubilize ticagrelor. However, polyethylene glycol was found sensitive to degradation, and this led to impurities. Example 14 Two clear 1.8 mg / mL Ticagrelor formulations were prepared after sonication forhours: formulation 1 (Example 14), 1.8 mg / mL ticagrelor in 20%hydroxypropyl-β-cyclodextrin (HPbCD) (w / w), remainder water; formulation 2 (Example 14), 1.8 mg / mL ticagrelor in 50% PEG400 (w / w), remainder water. The two formulations were aliquoted and stored under room temperature and 40°C. The formulations were immediately analyzed by LC-UV after preparation (Figures 1 and 2). They were analyzed again for 3 times over a 6-month stabilityperiod (Figures 3 and 4).Ticagrelor was found to be stable in formulation 1 (Example 14), i.e., 1.8 mg / mLTicagrelor in 20% HPbCD (w / w), for at least 6 months at both room temperatureand at 40°C (Figures 5 to 6).In formulation 2 (Example 14), i.e., 1.8 mg / mL Ticagrelor in 50% PEG400(w / w), Ticagrelor was not stable at both room temperature and 40°C. Intensivepotential degradation product peaks were observed in formulation 2 (Example14) in LC-UV chromatograms (Figures 4 to 6).DESCRIPTION OF FIGURES Figure 1 depicts LC-UV chromatograms of Ticagrelor Formulation 1 (Example 14) and Blank control on day 0.Figure 2. LC-UV chromatograms of Ticagrelor Formulation 2 (Example 14) andBlank Control on Day 0.Figure 3. LC-UV chromatograms of Ticagrelor Formulation 1 (Example 14) andBlank Control on Day 188 (Room Temperature) Figure 4. LC-UV chromatograms of Ticagrelor Formulation 1 (Example 14) and Blank Control on Day 188 (40°C). Figure 5. LC-UV chromatograms of Ticagrelor Formulation 2 (Example 14) and Blank Control on Day 188 (Room Temperature). Figure 6. LC-UV chromatograms of Ticagrelor Formulation 2 (Example 14) and Blank Control on Day 188 (40°C)

[0004] Ticagrelor compositions in lyophilized form for reconstitution and intravenous use Solubility studies Solubility in solvent: water mixture Solubility studies are performed as per below Table 30: Solubility plan with TBA and water mixture (10:90 v / v) Components %w / w mL / vialTrial 1 (g / vial) Ticagrelor 0.6 0.09 0.09Tertiary Butyl alcohol (TBA) 10.00 1.50 1.16*Water for injection 90.00 13.5 13.5Total 100% 15 14.7525*TBA density 0.781 g / ml used for calculation. Table 31: Solubility plan with TBA and water mixture (20:80 v / v) Components %v / v mL / vialTrial 2 (g / vial) Ticagrelor 0.6 0.09 0.09Tertiary Butyl alcohol (TBA) 20.00 3.00 2.33*Water for injection 80.00 12.00 12Total 100% 15.00 14.415*TBA density 0.775 g / ml used for calculation. Table 32: Solubility plan with TBA and water mixture (30:70 v / v) Components %v / v mL / vialTrial 3 (g / vial) Ticagrelor 0.600 0.09 0.09Tertiary Butyl alcohol (TBA) 30.00 4.50 3.49*Water for injection 70.00 10.50 10.5Total 100% 15.00 14.078*TBA density 0.775 g / ml used for calculation. Table 33: Solubility plan with Kolliphor HS15 and water mixtureComponents %w / w Trial 4 (mg / vial)Ticagrelor - 90Kolliphor HS15 4% 628.8*Water for injection q.s. to 15 mL q.s. to 15 mLTotal 15 15*Kolliphor HS15 density Table 34: Solubility trials observations Observations ProcedureTrial 1 Trial 2 Trial 3 Trial 4 Step-1: Transferred 90 mg of drugNil Nil Nil Nilsubstance to 20 ml glass vial.Step-2: Addedrequired quantity of solvent to step 1Nil Nil Nil Niland close the vial with rubber stoppers. Clear, Light Clear, Light Pale Clear Pale pink pink color colorlessStep-3: Vortexcolor solution solution is formed solution the vial to get a is formed within 5 min. of is formed Nil clear solution. within 5 min. vortex within 5 of vortex min. of vortex. Solution Added WFI slowly Clear Clear becomes under mixing, colorless colorless precipitated. Haziness was solution solution Vial was observed during after 30 continued to addition of water min of vortexed for and it gradually mixingStep-4: Added30 minutes, increased with required no further addition of quantity of improvement water. water (as in clarity. Solution was clear mentioned in up to addition of below table) to 10 ml water. the clear After adding solution to step remaining water, 3 and vortex. solution becomes precipitated. Vial was continued to vortexed for 30 minutes, no improvement in clarity. Clear colorlessStep-5: AddedClear c solution 5% MannitolNil Nilolorless s with visual (750 mg) olution observed. particulate matter was observed. Keep the clear Clear Clear solution forNil Nilcolorless colorless overnight at RT solution solution (approx.12 hr) (kept in for observation water shaker over nigh) but fibrous matter was observed in solution. Observations: Table 35: Solubility study with different ratios of TBA and Water 10:90 (TBA: 20:80 (TBA: 30:70 (TBA: Kolliphor HS15 Components Water) Water) Water) 4% Trial 1 Trial 2 Trial 3 Trial 4Ticagrelor (mg)90 90 90 90Kolliphor HS15 TBA (mL) 1.5 3.0 4.54% (628.8 mg in 15 mL) Water (mL) 13.5 12.0 10.5 q.s. to 15 mLObservation Precipitated Precipitated Solution SolutionClear solution Clear solutionAddition of 5% Clear solution MannitolN / A N / A Clear solutionwith little (750 mg) fibrous matter Observation Clear colorless after 12NIL NILClear colorless solution with hours solution little fibrous matterLyophilization using Tertiary butyl alcohol: Trial-1Based on above solubility study, below trial is selected for formulation and lyophilization process. Batch Size: 300 ml Fill volume: 15 mL Table 36: Formula composition A. Trial-1 Ingredients Concentration (mg / mL) Batch quantity (mg) Ticagrelor 6.00 1.80Tertiary butyl alcohol232.67* 69.80Mannitol 5% 50 15.00WFI Q.S to 1.0 mL Q.S to 300.0 mL Primary packing material Clear Glass vial 30 ml tubular glass vialRubber stopper 20 mm uncoated rubber stopper*TBA density 0.775 g / ml used for calculation. Table 37: Lyophilization cycle parameters A. Stages Temp. Ramp Vacuum (°C) (min) Hold (min) (mTorr) Pre-freeze 5 -- -- --5 45 90 --Thermal Treatment-5 40 120 --(Freezing)-35 120 200 ---15 80 200 ---35 80 200 --Evacuation (shelf -35 driven)-- -- 150-35 10 30 150Primary drying -30 40 500 150-15 160 3400 150Secondary drying5 120 90 15020 60 150 150Total cycle (hours) 95.95 hoursObservations after lyophilization: No collapse was observed in any of the lyophilized vials. White compact cake (loose powder after shake) was observed. Reconstitution study A.Reconstitution with 30% PEG 400 and 70% phosphate buffer (pH 7.4) Reconstitution vehicle was prepared by mixing 30% PEG 400 in 70% phosphate buffer (pH 7.4). 15 ml & 20 ml of reconstitution vehicle was added in to the lyophilized product vial using plastic syringe. Vial was reconstituted for approximately 2-3 minutes. In all the reconstituted vials, milky white solution was observed. B. Reconstitution with 4% Kolliphor HS 15, 30% PEG 400 and phosphate buffer (pH 7.4) Reconstitution vehicle was prepared by mixing 4% Kolliphor HS 15, 30% PEG 400 in phosphate buffer (pH 7.4). 15 ml of reconstitution vehicle was added in to the lyophilized product vial using plastic syringe. Vial was reconstituted forapproximately 2 - 3 minutes. In all the reconstituted vials, visual particles wereobserved. To this further 5 ml (total 20 ml) of reconstitution vehicle is addedand mixed to get clear solution, but there is no improvement in clarity; undissolved particles were seen.Lyophilization using Kolliphor HS 15: Trial-2Based on the solubility studies below trial is executed for formulation and lyophilization feasibility. Batch Size: 300 mL, Fill volume: 15 mL Table 38: Formula composition B. Trial-2 Ingredients Concentration Batch (mg / mL) Quantity (g) Ticagrelor 6.00 1.80Kolliphor HS15 41.92* 12.58Mannitol 50 15WFI Q.S to 1.0 Q.S to 300.0 mL mL Primary packing material Clear Glass vial 30 ml tubular glass vialRubber stopper 20 mm uncoated rubberstopper *Kolliphor HS15 density 1.048 g / ml used for calculation Table 39: Lyophilization cycle parameters B. Stages Temp. Ramp in) Ho Vacuum (°C) (m ld (min) (mTorr) Pre-freeze 5 -- -- --5 10 10 ---5 40 120 --Thermal Treatment-35 120 40 --(Freezing)-45 80 200 ---15 80 200 ---45 80 200 --Evacuation (shelf -45 driven)-- -- 300-45 10 500 300Primary drying-17 160 1900 2005 70 90 150Secondary drying20 60 600 5035 15 1400 50Total cycle time 99.75 hours.Oobservations after lyophilization: No collapse was observed in any of thelyophilized vials. White compact cake was observed in all the vials. No vialbreakage was observed at the end of lyo cycle. Reconstitution vehicle was prepared by mixing 30% PEG 400 in 70% phosphate buffer (pH 7.4). 15 ml of reconstitution vehicle was added in to the lyophilized product vial using plastic syringe. Vial was reconstituted for approximately 2 - 3 minutes. In all the reconstituted vials a clear solution without any visual particles was observed. Optimization of Lyophilization cycle using Kolliphor HS 15: Trial-3Based on Trial-2 observations a batch with similar composition was used but toreduce the lyophilisation cycle time. The details are provided below. Batch Size:300 mL, Fill volume: 15 ml. In this composition Kolliphor HS15 concentration was increased to 4.4%w / v. Table 40: Formula composition C. Trial-3 Concen Batch Ingredients tration (mg / mL) %W / V Quantity (g) Ticagrelor 6.00 0.6 1.80Kolliphor HS15 44.0 4.4 13.20Mannitol 50.0 5.0 15.0WFI Q.S to 1.0 Q.S to mL N / A 300.0 mL Primary packing material Clear Glass vial 30 ml tubular glass vialRubber stopper 20 mm uncoated rubber stopperTable 41: Lyophilization cycle parameters B. No.: ROY02-FD / 170-004 Stages Temp. Ramp Vacu ) (min) Ho um (°C ld (min) (mTorr) Pre-freeze 5 -- -- --5 10 60 --Thermal Treatment-10 90 120 --(Freezing)-45 120 200 ---15 90 200 ---45 90 200 --Evacuation (shelf -45 driven)0 0 300-45 0 10 300Primary drying-17 150 1200 2005.0 60 90 150 Secondary drying20.0 60 500 10035.0 30 1200 100Total lyo cycle time 74.67 hours.Observations after lyophilization: No collapse was observed in any of thelyophilized vials. White compact cake was observed in all the vials. No spillageand no vial breakage was observed. Reconstitution vehicle was prepared by mixing 30% PEG 400 in 70% 0.1M phosphate buffer (pH 7.4). 15 ml of reconstitution vehicle was added in to the lyophilized product vial using plastic syringe. Vial was reconstituted forapproximately 2 - 3 minutes. In all the reconstituted vials clear solution isformed without any visual particles.Lyophilization of trial using Kolliphor HS15 for stability evaluation Trial-4From above trial-2 and trial-3 observations, as the expected results were achieved (compact cake & clear reconstitution) a repetition of trial-3 was executed to perform the chemical analysis and stability loading of finished product along with reconstitution diluent. Batch Size: 700 ml Fill volume: 15 mL Table 42: Formula composition C. (Trial-4)Ingredients Concentration Batch (mg / mL) quantity (g) Ticagrelor 6.00 4.20Kolliphor HS15 44.0 30.80Mannitol 5% 50.0 35.00WFI Q.S to 1.0 mLQ.S to 700.0 mL Primary packing material Clear Glass vial 30 ml tubular glass vialRubber stopper 20 mm uncoated rubberstopper Table 43: Lyophilization cycle parameters B. Stages Temp. Ramp Hold Vacuum (°C) (min) (min) (mTorr) Pre-freeze 5 -- -- --5 15 60 --Thermal Treatment-10 90 120 --(Freezing)-45 120 200 ---15 90 200 ---45 90 200 -- Evacuation (shelf -45 driven)-- -- 300-45 0 10 300Primary drying-17 150 1200 2005 60 90 150Secondary drying20 60 500 10035 30 1200 100Observations after lyophilization: No collapse was observed in any of the lyophilized vials. White compact cake (loose free flowing cake after shake) wasobserved. No vial breakage was observed at the end of lyophilisation cycle.Reconstitution Study Table 44: Formula composition for 0.1 M phosphate buffer preparation Ingredients Batch qty. (g)Monobasic sodium dihydrogen phosphate 1.56Di sodium hydrogen phosphate anhydrous 5.45 Water for injection Q.S to 500.0 mLProcedure: Batch quantity of monobasic sodium dihydrogen phosphate and disodium hydrogen phosphate anhydrous is added in 500 ml of water for injection and dissolved to get clear solution using overhead stirrer. The observed pH of 0.1M phosphate buffer solution is 7.39. Preparation of reconstitution solution: (Batch size – 700 mL)Step 1- Taken 490 ml (70 %) of above prepared 0.1M phosphate buffer of pH7.4 in a beaker, to this 210 ml of PEG 400 (30%) was added and mixed for 10 min under overhead stirrer. Step 2- Filtered the bulk solution using 0.22 μm Polyvinylidene fluoride (PVDF)sterile grade filter with aid of nitrogen gas. Step 3- The filtered solution was filled in to 20 ml clear colorless, USP type-1glass vial, 20 mm neck, with a target fill volume of “Not less than 15 mL” purged the head space with nitrogen gas and stoppered the vials with west 20 mm plug coated stopper and sealed with aluminum flip-off seals. 15 ml of above prepared reconstitution solution was added in to the lyophilized product vial using plastic syringe. Vial was reconstituted (by shaking) forapproximately 20 – 30 sec. In all the reconstituted vials clear solution withoutany visual particles were observed.Stability results of lyophilisation Trial-4 (Kolliphor HS15 as solubilizer): Table 45: Stability results for batch ROY02-FD / 170-005 Ticagrelor for injection90mg / vial Storage Condi^on RTIni^al Test parameters / Sta^on (1M 1W) Descrip^on of lyo cake White lyophilized cakeAssay (%w / w) 101.7pH of diluent 8.068pH of recons^tuted solu^on 7.963Volume of diluent 14.98Related substances, @RRT, (%w / w) Amine impurity@ 0.46 0.06Oxida^ve impurity 1@0.71 0.01Oxida^ve impurity 2@0.72 0.01Triol impurity@0.95 0.04Acetal impurity@1.48 0.02Total impuri^es 0.34AR Number: ROY02 / AR001 / 22Unknown impuri^es <0.05% are not reported but included in Total impuri^es.

[0005] 

[0006] From above 6 months (6M) accelerated stability results, it is observed thatamine impurity is increased from 0.06%w / w at T0 time point to 0.22%w / w at 6M accelerated (40°C / 75%RH) condition. All the impurities were well within the set specifications.Lyophilization trial using TBA for stability evaluation, Trial-5 (without solubiliserin the composition)As an alternative to Kolliphor HS 15 formulation (trial-4), further trials wereundertaken similar to that of trial-1 composition i.e. Tertiary butanol as solubilizer (TBA : water; 30:70 ratio), The study details are captured below. Batch Size: 1200 mL; Fill volume: 15 mL Table 47: Formula composition B. (Trial-5) Ingredients Concentration (mg / mL) Batch quantity (g) Ticagrelor 6.00 7.20Tertiary butanol232.67 279.20Mannitol 5% 50.0 60.00WFI Q.S to 1.0 mL Q.S to 1200.0 mL Primary packing material Clear Glass vial 30 ml tubular glass vial Rubber stopper 20 mm uncoated rubber stopper Table 48: Lyophilization cycle parameters, Stages Temp. Ramp Hold (m Vacuum (°C) (min) in) (mTorr) Pre-freeze 5 -- -- --5 45 90 --Thermal Treatment-5 40 120 --(Freezing)-35 120 200 ---15 80 200 ---35 80 200 --Evacuation (shelf -35 driven)-- -- 150-35 10 30 150Primary drying-30 40 500 150-15 160 2500 200Secondary drying5 120 90 20030 60 90 200 Observations after lyophilization: Similar observations as that of trial-1 was noticed and additionally thirty to five vials were found broken at walls and bottom of the glass vialsProduct spillage was observed inside the lyophilizer chamber during drying.Melt back was observed in remaining all the vials after lyophilization cycle.Though the composition of trial-1 & trial-5 were same but more vial breakageand lyophilized cake melt back was observed in trial-5, this might be dueincreased batch size and it indicates us to evaluate the batch size impact on theproposed lyophilization cycle. Hence further trials to be optimized focusing theseaspects followed by reconstitution diluents evaluation and stability loading. Optimization of Lyophilization cycle using Tertiary butyl alcohol-Trial-1:Fill volume selection: Target strength 65 mg / vialTable 49: Solubility of ticagrelor 65mg in TBA : water (30:70 v / v) mixtureTrial Trial-1 Trial-2Components %v / v mg / mL g / 10 mL %v / v mg / mL g / 15mL Ticagrelor NA 6.5 65.0 NA 4.333 65.0Mannitol NA 33.5 335.0 NA 22.333 335.0TBA 30.0 232.5 2.325 30.0 232.5 3.4875WFI 70.0 700.0 7.000 70.0 700.0 10.50Observations Clear colorless solution Clear colorless solutionBased on solubility study as above, fill volume 10.0 ml and bulk solution concentration 6.5 mg / ml was selected for formulation and lyophilization process. Batch Size: 1200 ml Fill volume: 10.0 mL Table 50: Formula composition A. Trial-1Ingredients Concentration Batch (mg / mL) quantity (g) Ticagrelor 6.5 7.80Tertiary butyl alcohol232.5* 279.00Mannitol 3.35% 33.5 40.20WFI Q.S to 1.0 Q.S to mL 1200.0 mL Primary packing material Clear Glass vial 25 ml tubular glass vialRubber stopper 20 mm uncoated rubberstopper *TBA density 0.775 g / ml used for calculation. Table 51: Lyophilization cycle parameters Stages Temp. Ramp °C) (min) H Vacuum ( old (min) (mTorr) Pre-freeze 5 45 90 ---5 40 120 --Thermal Treatment-45 160 200 --(Freezing)-15 120 200 ---45 120 200 --Evacuation (shelf-45 -- --driven) 120 -45 10 300 120Primary drying-35 80 900 300-15 160 1700 300-15 0 1098 450Secondary drying10 90 200 45020 60 200 450Total Cycle Time (hours) 101.55 hours Observations after lyophilization: Compared to previous batches powder spillage is very less. No collapse and melt back was observed in any of the lyophilized vials. White compact cake (loose powder after shake) was observed. No vials were broken during and after lyophilization. Powder stickiness on walls and bottom of the vials were observed in some vials. Optimization of Lyophilization cycle using Tertiary butyl alcohol-Trial-2: Batch Size: 800 ml Fill volume: 10 mL Table 52: Formula composition A. Trial-2 Ingredients Concentration Batch (mg / mL) quantity (g) Ticagrelor 6.5 5.20Tertiary butyl alcohol232.5* 186.00Mannitol 3.35% 33.5 26.80WFI Q.S to 1.0 Q.S to 800.0 mL mL Primary packing material Clear Glass vial 25 ml tubular glass vialRubber stopper 20 mm uncoated rubberstopper *TBA density 0.775 g / ml used for calculation. Table 53: Lyophilization cycle parameters B. No.: ROY02-FD / 170-009 Stages Temp. Ramp Vacuum (°C) (min) Hold (min) (mTorr) Pre-freeze 5 45 90 ---5 40 120 --Thermal Treatment-45 160 200 --(Freezing)-15 120 200 ---45 120 200 --Evacuation (shelf-45 -- --driven) 180 -45 10 130 180-30 70 120 180Primary drying-20 60 1560 180-20 5 1250 2500 90 180 350Secondary drying20 60 200 35020 60 200 350Total Cycle Time (Hours) 88.17 HoursObservations after lyophilization: Powder spillage is very minimal. No collapseand melt back was observed in any of the lyophilized vials. White compact cake(loose powder after shake) was observed. One vial was broken at the bottom ofthe vial. Powder stickiness on walls and bottom of the vials were observed insome vials. (But reduced compared to previous batch).Optimization of Lyophilization cycle using Tertiary butyl alcohol-Trial-3 Batch Size: 800 ml Fill volume: 10 mL Table 54: Formula composition B. Trial-3 Ingredients Concentration Batch (mg / mL) quantity (g) Ticagrelor 6.5 5.20Tertiary butyl alcohol232.5* 186.00Mannitol 3.35% 33.5 26.80WFI Q.S to 1.0 Q.S to 800.0 mL mL Primary packing material Clear Glass vial 25 ml tubular glass vialRubber stopper 20 mm coated rubberstopper *TBA density 0.775 g / ml used for calculation. Table 55: Lyophilization cycle parameters B. Trial 3 ( Batch No.#10)Stages Temp. Ramp Vacuum (°C) (min) Hold (min) (mTorr) Pre-freeze 5 40 10 ---5 40 120 -- Thermal Treatment-45 160 200 --(Freezing)-15 120 200 ---45 120 200 --Evacuation (shelf-45 -- --driven) 180 -45 10 30 180Primary drying-30 70 120 180-22 60 3060 180-5 90 300 230Secondary drying 20 60 500 230Total Cycle Time (Hours) 91.83 hoursObservations after lyophilization: Powder spillage is very minimal. No collapseand melt back was observed in any of the lyophilized vials. White compact cake(loose powder after shake) was observed. No vials were broken during and afterlyophilization. Powder stickiness on walls and bottom of the vials were observed in few vials.Based on the above three lyophilization cycles, trial 3 found to be goodconsidering in terms all parameters such as minimal powder spillage (It can be controlled in further lyo cycle optimization studies), no vial breakage, no melt back issues and stickiness of powder to vials were reduced. Hence vials from trial 3 will be considered for reconstitution study as per recommended diluents. Reconstitution with 30% PEG-400 and Water for injection mixture Composition: Table 56: Reconstitution with 30% PEG-400 and Water for Injection mixture q.s. to 15 mL Components Quantity / 15 mLPEG-400 4.5 mLWater for Injection q.s. to 15 mLTarget concentration of drug after reconstitution. (mg / mL) 4.333 Procedure:Step-1: Prepare required quantity of diluent as mentioned in the above table.Step-2: Add required quantity of diluent (15 mL) to the vial using syringe forreconstitution.Step-3: Reconstitute the vial contents by shaking the vial vigorously for 3minutes. Reconstitution with 50% PEG-400 and Water for Injection mixture Composition: Table 57: Reconstitution with 50% PEG-400 and Water for Injection mixture q.s. to 15 mLComponents Quantity / 15 mLPEG-400 7.5 mLWater for Injection q.s. to 15 mLTarget concentration of drug after reconstitution. (mg / mL) 4.333 Procedure:Step-1: Prepare required quantity of diluent as mentioned in the above table.Step-2: Add required quantity of diluent (15 mL) to the vial using syringe forreconstitution.Step-3: Reconstitute the vial contents by shaking the vial vigorously for 3minutes.Reconstitution with Kolliphor HS 15- 4% and Water for Injection mixtureComposition: Table 58: Reconstitution with Kolliphor HS 15- 4% and Water for Injectionmixture q.s. to 15 mLComponents Quantity / 15 mLKolliphor HS 15 0.6 gWater for Injection q.s. to 15 mLTarget concentration of drug after reconstitution. (mg / mL) 4.333 Procedure:Step-1: Prepare required quantity of diluent as mentioned in the above table.Step-2: Add required quantity of diluent (15 mL) to the vial using syringe forreconstitution.Step-3: Reconstitute the vial contents by shaking the vial vigorously for 2minutes.Reconstitution with 30% PEG – 400 + 20% propylene glycol and Water forInjection mixture Composition: Table 59: Reconstitution with 30% PEG – 400 + 20% propylene glycol andWater for Injection mixture q.s. to 15 mLComponents Quantity / 15 mLPEG-400 4.5 mLpropylene glycol 3.0 mLWater for Injection q.s. to 15 mLTarget concentration of drug after reconstitution. (mg / mL) 4.333 Procedure:Step-1: Prepare required quantity of diluent as mentioned in the above table.Step-2: Add required quantity of diluent (15 mL) to the vial using syringe forreconstitution.Step-3: Reconstitute the vial contents by shaking the vial vigorously for 3minutes.Based on the above reconstitution study, a clear solution was only obtained inKolliphor HS 15- 4% and 30% PEG-400 + Kolliphor HS 15- 4% in Water forInjection. So the second set (set-2) of reconstitution study was performed only withKolliphor HS 15- 4% in phosphate buffer and 30% PEG-400 + Kolliphor HS15- 4% in phosphate buffer.Reconstitution dilution set-2A.Reconstitution with Kolliphor HS 15- 4% and phosphate buffer mixture q.s.to 15 mlComposition: Table 60: Reconstitution with Kolliphor HS 15- 4% and phosphate buffermixture q.s. to 15 mLComponents Quantity / 15 mLKolliphor HS 15 0.6 gPhosphate buffer mixture q.s. to 15 mLTarget concentration of drug after reconstitution. (mg / mL) 4.333 Procedure: Step-1: Prepare required quantity of diluent as mentioned in the above table. Step-2: Add required quantity of diluent (15 mL) to the vial using syringe for reconstitution. Step-3: Reconstitute the vial contents by shaking the vial vigorously for 3 minutes.Reconstitution with 30% PEG-400 + Kolliphor HS 15- 4% and phosphatebuffer mixture q.s. to 15 mlComposition: Table 61: Reconstitution with 30% PEG-400 + Kolliphor HS 15- 4% andphosphate buffer mixture q.s. to 15 mLComponents Quantity / 15 mLKolliphor HS 15 0.6 gPEG-400 4.5 mLPhosphate buffer mixture q.s. to 15 mLTarget concentration of drug after reconstitution. (mg / mL) 4.333 Procedure:Step-1: Prepare required quantity of diluent as mentioned in the above table.Step-2: Add required quantity of diluent (15 mL) to the vial using syringe forreconstitution.Step-3: Reconstitute the vial contents by shaking the vial vigorously for 3minutes.Reconstitution study plans (set-3)Reconstitution with Kolliphor HS 15- 4.4% and water for injection mixture q.s.to 15 mlComposition: Table 62: Reconstitution with Kolliphor HS 15- 4.4% and water for injectionmixture q.s. to 15 mLComponents Quantity / 15 mLKolliphor HS 15 0.66 gWater for injection q.s. to 15 mLTarget concentration of drug after reconstitution. (mg / mL) 4.333 Procedure:Step-1: Prepare required quantity of diluent as mentioned in the above table.Step-2: Add required quantity of diluent (15 mL) to the vial using syringe forreconstitution. Observation: Reconstitute the vial contents for 2 minutes. Foam was observed. Then vial was kept aside and after 10 minutes solution was found to be clear.Reconstitution with Kolliphor HS 15- 4.4% and water for injection mixture q.s.to 15 mlComposition: Table 63: Reconstitution with Kolliphor HS 15- 4.4% and phosphate buffermixture q.s. to 15 mLComponents Quantity / 15 mLKolliphor HS 15 0.66 gPhosphate buffer mixture q.s. to 15 mLTarget concentration of drug after reconstitution. (mg / mL) 4.333 Procedure:Step-1: Prepare required quantity of diluent as mentioned in the above table.Step-2: Add required quantity of diluent (15 mL) to the vial using syringe forreconstitution. Observation: On reconstitution and vigorous shaking for 3 minutes solution was found to be clear with very few undissolved particles. Table 64: Reconstitution study with various diluent proportions & its observations No of Trials Reconstitution diluents set-1 Trial No. Trial Details ObservationsReconstitution with 30% PEG- On reconstitution and vigorous Trial-1 400 and Water for Injection shaking for 3 minutes, mixture q.s. to 15 mLsolution was precipitated Reconstitution with 50% PEG- On reconstitution and vigorous Trial-2 400 and Water for Injection shaking for 3 minutes, a hazy mixture q.s. to 15 mLsolution was observed On reconstitution the solution was shaken for 2 minutes, Reconstitution with Kolliphor HS foam was observed and then Trial-315- 4% in Water for Injection,left idle for 10 minutes, foam 15mL went to the supernatant, and the solution was found to be clear On reconstitution the solution Reconstitution with 30% PEG- was shaken for 2 minutes, foam was observed and then Trial-4400 + Kolliphor HS 15- 4% inWater for Injection mixture q.s. left idle for 10 minutes, foam to 15 mLwent to the supernatant, and the solution was found to be clear Reconstitution with 30% PEG- 400 + 20% P On reconstitution and vigorous Trial-5 ropylene Glycol in Water for Injection mixture q.s. shaking for 3 minutes, a hazy to 15 mLsolution was observedTrial No. Reconstitution diluents set-2On reconstitution and vigorous rial-6Reshaking for 3 minutes, Tconstitution with Kolliphor HS15- 4% in pH 7.5 buffer, 15 mLsolution appeared clear but undissolved particles were present. Reconstitution with 30% PEG- On reconstitution and vigorous Trial-7400 + Kolliphor HS 15- 4% in pHshaking for 3 minutes, 7.5 buffer mixture q.s. to 15 mLsolution was clear with few undissolved particles present. Trial No. Reconstitution diluents set-3On reconstitution the solution was shaken for 2 minutes, Reconstitution with Kolliphor HSfoam was observed and then Trial-815- 4.4% and water for injectionleft idle for 10 minutes, foam mixture q.s. to 15 mLwent to the supernatant, and the solution was found to be clear Reconstitution with Kolliphor HS On reconstitution and vigorous Trial-915- 4.4% and phosphate buffershaking for 3 minutes, mixture q.s. to 15 mLsolution was clear with few undissolved particles present. Based on above study results, reconstituted solution with Kolliphor 4.4% in water for injection (q.s to 15 mL) is selected and loaded for stability. Stability results are mentioned in below section. Table 65: Trial 3: Batch #10 Stability results Ticagrelor for injection 65 mg / vial Storage Condi^on RT 25℃ / 60%RH 30℃ / 65%RH 40°C / 75%RHTest parameters / Sta^onIni^al 2 M 3 M 2 M 3 M 1 M 2 M 3 MOrienta^on I I I I I I I IAssay (%w / w) 97.3 103.2 101.9 104.3 100.6 100.6 102.2 102.6Related substances, @RRT (%w / w) Amine impurity@0.05 0.06 0.05 0.07 0.05 0.060.14 0.05 0.06 Unknown @ 1.03 ND <0.03 <0.03 <0.03 <0.03 ND <0.03 <0.03Regiomer impurity0.01 0.02 0.03 0.04 0.08 0.13@ 1.05 0.01 0.07 Unknown @ 1.56 0.04 ND ND ND 0.03 0.05 ND NDUnknown @ 1.57 0.03 ND ND ND ND 0.03 ND NDTotal impuri^es 0.30 0.35 0.34 0.33 0.41 0.41 0.43 0.50 / AR006 / AR019 / AR024 / AR025 / AR021 / AR026 / AR Number: ROY02 22 2222 AR020 / 22 AR018 / 22 22 22 22 Unknown impuri^es <0.03% are not men^oned in above table but included in Total impuri^es. As a part of further improvement and investigations a ticagrelor lyophilised formulation was prepared as follows without a solubiliser and by reducing the mannitol concentration in the composition. Trial A with B. No. 19 was executed as below. Trial ABatch No: 19, Batch Size: 500 mLFill volume: 6.5 ml in 20 ml vialDescription: Lyo batch of Ticagrelor for Injection with mannitol concentration of 5 mg / mlwithout Kolliphor HS-15 in the formulation Table 66: Composition SNo Ingredients Mg / mL Mg / vial1 Ticagrelor 10 mg 65 mg2 Tertiary butyl alcohol (TBA 40.0%) $ 310 mg 2015 mg3 Mannitol 5.0 mg 32.5 mg4 Water for injection* Q.s to mL Q.s to 6.5 mL*: Water for injection will be removed during lyophilization. $: TBA density 0.775g / ml used for calculation. Table 67: Lyophilization cycle parameters Stages Temp. Ramp Vacuum (°C) (min) Hold (min) (mTorr) Pre-freeze 5 -- -- --5 30 60 --Thermal Treatment-5 30 60 --(Freezing)-40 180 120 ---15 80 180 ---40 150 240 --Evacuation (shelf driven) -40 -- -- 380-35 10 30 380Primary drying-20 30 2400 380-10 30 720 280Secondary drying10 60 120 15040 60 600 50Total cycle time 86.5 hoursObservation: White compact lyophilized cake was observed after unloading the lyo cycle.This batch was then used to reconstitute with different trials as indicated in below table 68.Trial Diluent Préparations Observation & conclusioncomposition AAlcohol 300Drug product vial Clear samples with few particles mg / ml reconstituted with 10 ml of at bottom Water Qs.1 ml diluent and shaken for 10 minutes BTween 80 40Drug product vial Clear samples with few particles mg / ml reconstituted with 10 ml of at bottom Water Qs 1 ml diluent and shaken for 10 minutesC Tween 80 (40Drug product vial Reconstituted sample was mg / ml) reconstituted with 10 ml of found to be clear colourless Alcohol 300 diluent and shaken for 1 with no traces of particles mg / ml minute Water Qs 1 mlD Tween 80 (40Drug product vial Reconstituted sample was mg / ml) reconstituted with 10 ml of found to be clear colourless Propylene Glycol diluent and shaken for 1 400 mg / ml minute. Water Q.s to 1 ml Based on satisfactory lyophilization and diluent screening, the following composition appears to be the best design for the product. Lab scale batch ofTicagrelor for Injection with 40% TBA, drug concentration 10 mg / ml andmannitol 5 mg / ml for reproducibility and commercial feasibility. Tween 80 ispolyoxyethylene sorbitan monooleate. Batch No: #020, Batch Size: 750 mL Fill volume: 6.5 ml in 20 ml vial Description: Lyo batch of Ticagrelor for Injection with 40%TBA, drug concentration 10 mg / ml and Mannitol 5 mg / mL. Table 69: Composition for B.No: 020 batchS No Ingredients Mg / mL Mg / vial1 Ticagrelor 10 mg 65 mg2 Tertiary butyl alcohol (TBA 40.0%) $ 310 mg 2015 mg3 Mannitol 5.0 mg 32.5 mg4 Water for injection* Q.s to mL Q.s to 6.5 mL*: Water for injection will be removed during lyophilization. $: TBA density 0.775g / ml used for calculation. Table 70: Lyophilization cycle parameters of 020 Stages Temp. Ramp Hold (min) Vacuum (°C) (min) (mTorr) Pre-freeze 5 -- -- --5 30 60 --Thermal Treatment-5 30 60 --(Freezing)-40 180 120 ---15 80 180 ---40 150 240 --Evacuation (shelf driven) -40 -- -- 380-35 10 30 380Primary drying-20 30 2400 380-10 30 720 280 Secondary drying10 60 120 15040 60 600 50Total cycle time 86.5 hoursTable 71: Reconstitution trials using final lyophilised Ticagrelor vials from B. No. #20 Trial Details Diluent composition Reconstitution Diluent pH after mg / mL procedure Observation pH reconstitution Disodium hydrogen phosphate di 7.208 hydrate Drug product Sodium vial Clear dihydrogen reconstituted colourless 1 (Not phosphate di 2.269 with 10 ml of sample with autoclaved)7.522 7.5hydrate diluent and foam on the Tween 80 42.4reconstitution top of the Propylene glycol 414.4time was found solution to be 3 minutes. Q.s WFI to 1 ml Disodium hydrogen phosphate di 7.208 hydrate Sodium dihydrogen phosphate di 2.269 Drug product hydrate vial Clear Tween 80 42.4reconstituted colourless 2 with 10 ml of sample with (Autoclaved) diluent an7.528 7.524Propylene glycol 414.4d foam on the reconstitution top of the Q.s time was found solution WFI to 1 to be 3 minutes. ml Propylene glycol 414.4Q.s WFI to 1 mlTween 80 is a polyethylene sorbitol ester, non ionic surfactant and anemulsifier derived from polyethoxylated sorbitan and oleic acid; synonym: polysorbate 80; polyoxyethylene sorbitan monooleate; CAS number 9005-65- 6. Solutions for lyophilization comprising cyclodextrin as solubilizer As an alternative to aqueous solutions based on tertiary butyl alcohol or a surfactant as solubilizer for use in a lyophilization process, compositions were prepared with a cyclodextrin as solubilizer. Table 72: solution for lyophilization using a cyclodextrin as solubilizer Formula composition S. No. IngredientsConcentration (mg / mL) Batch quantity (gm) 1. Ticagrelor 6.00 1.802. HPBCD [40%w / w] 432 129.603. Mannitol 2.5% 25 7.54. WFI Q.S to 1.0 mL Q.S to 300.0 mLPrimary packing material 5. Clear Glass vial Schott Kaisha 30 ml tubular glass vial6. Rubber stopper West pharma 20 mm uncoated rubber stopperDensity assumed 1.130, target strength 90 mg / vial Manufacturing process Dissolve HPBCD in WFI under constant stirring. Add TCG in the vortex to form a clear solution, add bulking agent mannitol. Filter the solution through 0.22 microns filter. Fill the solution in USP Type I glass vials and lyophilize the solution as per below parameters. Table 73: Lyophilization process of an aqueous solution comprising a ticagrelor-cyclodextrin inclusion complex.The solution of Table 72 was lyophilized using the following parameters. Lyophilization cycle parameters Stages Temp. Ramp Hold Vacuum (°C) (min) (min) (mTorr) Pre-freeze 5 -- -- --5 45 90 --Thermal Treatment-5 40 120 --(Freezing)-35 120 200 ---15 80 200 ---35 80 200 --Evacuation (shelf -35 driven)-- -- 150-35 10 30 150Primary drying-30 40 500 150-15 160 3400 150Secondary drying5 120 90 15020 60 150 150A nice cake was formed which can be reconstituted with suitable diluent such as water for injection with suitable pH 5.5 to 8, the diluent may contain somesurfactants to facilitate obtaining a clear solution.

Claims

CLAIMS 1. A pharmaceutical ticagrelor composition for use in the treatment orprevention of coagulation in a patient in need thereof who was previously administered an opioid active ingredient, characterized in that thepharmaceutical ticagrelor composition is administered intravenously following the administration of the opioid active ingredient thereby avoiding delayed or reduced ticagrelor uptake provided by the opioid active ingredient; wherein the pharmaceutical ticagrelor compositioncomprises an inclusion complex of ticagrelor and a cyclodextrin.

2. The pharmaceutical ticagrelor composition for use according to claim 1,wherein ticagrelor was administered within less than three hours of the opioid active ingredient administration.

3. The pharmaceutical ticagrelor composition for use according to claim 1or 2, wherein the patient is suffering from an ST-elevated myocardialinfarction or a non ST-elevated myocardial infarction.

4. The pharmaceutical ticagrelor composition for use according to claim 3,wherein the patient was administered fentanyl prior to recording an angiogram and prior to anti-coagulant treatment.

5. The pharmaceutical ticagrelor composition for use according to claim 3or 4, wherein the patient is receiving a non-elective PCI.

6. The pharmaceutical ticagrelor composition for use according to claim 1or 2, wherein the patient has undergone surgery for a joint replacement.

7. The pharmaceutical ticagrelor composition for use according to claim 1or 2, wherein the patient has contracted a Gram-positive bacteremia following drug substance abuse comprising an opioid active ingredient.

8. The pharmaceutical ticagrelor composition for use according to any ofclaims 1 to 7, wherein the pharmaceutical ticagrelor composition is alyophilized ticagrelor composition.

9. The pharmaceutical ticagrelor composition for use according to claim 8,wherein the lyophilized ticagrelor composition has a reconstitution time of less than 5 minutes.

10. The pharmaceutical ticagrelor composition for use according to any ofclaims 1 to 9, wherein an effective amount of ticagrelor, is administeredintravenously within 5 minutes.

11. A liquid ticagrelor-containing composition for lyophilization, comprisingticagrelor in free form, a bulking agent and an alcohol:water mixture,wherein the ratio of said alcohol to said water is from 25:75 to 50:50 (% w / w).

12. The liquid ticagrelor-containing composition for lyophilization accordingto claim 11, wherein the alcohol is tertiary butyl alcohol (TBA).

13. The liquid ticagrelor-containing composition for lyophilization accordingto claim 11 or 12, comprising 30 mg ticagrelor / 15 ml composition to 100mg ticagrelor / 15 ml composition or 6.5 mg ticagrelor / ml composition to8 mg ticagrelor / ml composition.

14. The liquid ticagrelor-containing composition for lyophilization accordingto any of claims 11 to 13, wherein the bulking agent is mannitol and saidmannitol is present in an amount of 2.5 to 75 mg mannitol / mlcomposition.

15. The liquid ticagrelor-containing composition for lyophilization accordingto any of claims 11 to 14, wherein said liquid ticagrelor-containingcomposition consists of 6.5 mg ticagrelor / ml, 310 mg / ml TBA, 5 mgmannitol / ml and remainder water for injection.

16. A method of manufacturing a pharmaceutical ticagrelor composition inlyophilized form, comprising the steps of: providing a liquid ticagrelor-containing composition according to any of claims 11 to 15; lyophilizing said liquid ticagrelor containing composition and recovering the resultant ticagrelor composition in lyophilized form.

17. A pharmaceutical ticagrelor composition in lyophilized form, obtained bythe method according to claim 16.

18. The pharmaceutical ticagrelor composition in lyophilized form accordingto claim 17, wherein the composition comprises 30 mg to 100 mgticagrelor and 25 to 75 mg mannitol and the ticagrelor is present in freeform.

19. The pharmaceutical ticagrelor composition for use according to any ofclaims 1 to 8, wherein the pharmaceutical ticagrelor composition is alyophilized ticagrelor composition according to claim 17 or 18.

20. The pharmaceutical ticagrelor composition for use according to claim 19,wherein the lyophilized ticagrelor composition has a reconstitution time of less than 5 minutes.

21. The pharmaceutical ticagrelor composition for use according to any ofclaims 19 to 20, wherein an effective amount of ticagrelor, is administeredintravenously within 5 minutes.

22. A kit of parts comprising a pharmaceutical ticagrelor compositionaccording to claim 17 or 18, in combination with a suitable diluent solution, said suitable diluent solution comprising: an aqueous, 0,1 M phosphate buffered solution of pH 7.4-7.5 4% - 4.4 w / w% polyethylene glycol (15)-hydroxystearate (Kolliphor HS15) and 30%-40 v / v% polyethylene glycol (PEG-400).23.A kit of parts comprising a pharmaceutical ticagrelor composition according to claim 17 or 18, in combination with a suitable diluentsolution, said suitable diluent solution comprising: an aqueous, phosphate buffered solution of pH 7.4-7.5 4% polyoxyethylene sorbitan monooleate (40 mg / ml) and40 v / v% propylene glycol (400 mg / ml).

24. A method of manufacturing a pharmaceutical ticagrelor composition inlyophilized form, comprising the steps of: providing a liquid ticagrelor-containing composition comprising an inclusion complex of ticagrelor and a cyclodextrin, preferably hydroxypropylbetacyclodextrin (HPBCD); lyophilizing said liquid ticagrelor containing composition and recovering the resultant ticagrelor composition in lyophilized form; wherein the pharmaceutical ticagrelor composition comprises an inclusion complex of ticagrelor and a cyclodextrin, preferably hydroxypropylbetacyclodextrin (HPBCD). 25.A ticagrelor-containing composition in lyophilized form, comprising an inclusion complex of ticagrelor and a cyclodextrin, preferably hydroxypropylbetacyclodextrin (HPBCD).

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