Ticagrelor IV formulations for treatment of gram-positive bacteremia

Abstract

The present invention relates to providing an aqueous ticagrelor solution for intravenous administration for use in the treatment of Gram-positive bacterial infections in the bloodstream of a patient in need thereof. The pharmaceutical composition is beneficial to further improving the effectiveness of bacteremia treatment, especially the effectiveness of MSSA and MRSA bacteremia and thrombocytopenia related to bacteremia.

Description

TECHNICAL FIELD

[0001] The present invention belongs to the field of pharmaceutical compositions and medical uses of pharmaceutical compositions. The present invention is advantageous as it provides a solution of iv ticagrelor with sufficient solubility and storage stability of ticagrelor for the treatment of patients inflicted with Gram-positive bacterial bloodstream infections (bacteremia). The present invention increases the effectiveness of medical treatment and can help to save lives. BACKGROUND

[0002] The active ingredient ticagrelor is well known. 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 has the following chemical structure:

[0003]

[0004] Ticagrelor has an established use in cardiology. It is used in patients with acute coronary syndrome for the prevention of thrombotic events, such as myocardial infarction or stroke.

[0005] Recently, non-cardiological uses of ticagrelor have been proposed. Lancelloti et al. reported that ticagrelor has antibiotic properties ex vivo at concentrations much higher than those encountered when treating a cardiac condition (JAMA Cardiol. 2019, 4(6): 596-599). The minimum bactericidal concentration was 20 micrograms / ml for methicillin-sensitive Staphylococcus aureus (MSSA), glycopeptide intermediate Staphylococcus aureus (GISA), methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant E. Faecalis (VRE); 30 micrograms / ml for methicillin-resistant Staphylococcus epidermis (MRSE); and 40 micrograms / ml for Enterococcus faecalis and Staphylococcus agalactiae.

[0006] In WO2018046174, Lancelotti and Oury disclose the use of triazolo(4,5-D)pyrimidine derivatives for the treatment of bacterial infections. Ticagrelor is part of a long list of defined triazolo(4,5-D)pyrimidine derivatives (Figure 1). It is disclosed that the invented triazolo(4,5-D)pyrimidine derivatives can exhibit effects through different types of formulations. However, no specific ticagrelor composition or ticagrelor use in the treatment of bloodstream infections is disclosed.

[0007] Ulloa et al. (J Infect Dis. 2021, 224(9): 1566-1569) report the first experimental use of ticagrelor in a single human patient for the treatment of a Staphylococcus aureus bacterial infection. In addition to antibiotic treatment with cefazolin plus ertapenem, 90 mg of ticagrelor tablets were orally administered twice a day from day 5. In total, ticagrelor tablets were taken for a total of 3 months. The patient was in the hospital for 35 days.

[0008] Although the results are very promising, the use of tablets can be unacceptable in regular clinical practice, as several countries have guidelines that prescribe the use of intravenous formulations for the treatment of bacteremia, especially in the case of deep bacterial infections that cannot be removed by surgery (complex bacteremia). Tablets and other oral intake modalities have the disadvantage of limited bioavailability. The oral bioavailability of ticagrelor is 36% (30-42% confidence interval) with large variations between individuals (Teng and Maya, J Drug Assess. 2014, 3(1): 43-). Therefore, there is a need for an improved formulation, especially in emergency or life-threatening situations.

[0009] It is generally known that intravenous administration is faster (shorter half-life) than oral, has 100% bioavailability and less variation. It would be beneficial to have a ticagrelor formulation suitable for intravenous administration; preferably in a ready-to-use formulation. However, ticagrelor is notoriously difficult to handle. The active ingredient is prone to degradation when exposed to light, heat and oxygen. In addition, its limited solubility is a huge challenge in the development of pharmaceutical formulations. Ticagrelor has a low and pH-independent solubility in aqueous media. This property of not ionizing in the physiological pH range makes the development of liquid formulations particularly challenging. Yaye et al. (J Pharm Biomed Anal. 2015; 105: 74-83) studied the degradation of ticagrelor upon exposure to heat, pH, peroxide and light. They identified a number of degradants DP1 to DP9, indicating that the molecule is very prone to degradation.

[0010] Ticagrelor is commercially available in the form of tablets. 60 and 90 mg tablets are available in the United States under the trade name Brilinta® and in the European Union under the trade name BRILLIQUE®. Ticagrelor cannot be commercially obtained in liquid form.

[0011] In the product characteristics of the medical product Brilique 60 mg or 90 mg film-coated tablets (Brilique INN - Ticagrelor), it is disclosed that for patients who are unable to swallow tablets, the tablets can be crushed, mixed with water and immediately drunk. Alternatively, the mixture can be administered into the stomach through a nasogastric tube. The disadvantage of this formulation is that it is not readily available to the patient. It needs to be prepared just before administration. The formulation does not have long-term storage stability and the tablet particles settle upon standing, which excludes the formulation for intravenous administration. Furthermore, the formulation is not sterile.

[0012] Sigfridsson et al. (J Pharm Sci. 2011, 100(6): 2194-2202) disclose a composition based on ticagrelor nanoparticles, the combination of the disodium salt of Aerosol AOT and polyvinylpyrrolidone and the combination of 5% mannitol to obtain a nanosuspension. Aerosol AOT is considered to correspond to the sodium salt of dioctyl sulfosuccinic acid. Although the nanosuspension is reported to have a stability of at least 10 months, there is also reported a tendency of some particle aggregation and sedimentation during storage. Therefore, the sample should be sonicated before intravenous administration. This is cumbersome and poses a safety risk for pharmaceutical use. Especially in cases where acute treatment is required, the formulation is not robust for hospital use.

[0013] The same publication of Sigfridsson et al. also mentions that the concentration of ticagrelor in a phosphate buffer solution at pH 7.4 decreases after 1 month under normal laboratory conditions of light and temperature.

[0014] Na et al. (Int J Nanomedicine. 2019, 14: 1193-1212) investigated a self-microemulsifying drug delivery system (SMEDDS) for oral delivery to overcome the obstacle of poor solubility of ticagrelor. Ticagrelor solubility was investigated in oily and hydrophilic excipients. A combination of surfactants was chosen to obtain an emulsion system: Capmul MCM / Cremophor EL / Transcutol P. However, oily substances and surfactants are considered not suitable for a formulation for intravenous administration.

[0015] Teng and Maya disclose the use of a single iv infusion of ticagrelor 15 mg (150 mL solution of ticagrelor for infusion: 0.1 mg / ml, given at 300 mL / h for 30 min) in healthy volunteers (J Drug Assess. 2014, 3(1): 43-50). No information on the composition or stability is provided. It is speculated that it is a freshly prepared composition to allow comparison of the pharmacokinetics of oral and iv administration. No use in patients is reported.

[0016] In view of the above, there is still a need in the art for a ticagrelor iv formulation for the treatment of gram-positive bacterial infections in the bloodstream of ill patients.

[0017] It is an object of the present invention to solve at least one or more of the problems as described above. In particular, the present invention aims at providing a ticagrelor iv formulation for the treatment of gram-positive bacteremia. The ticagrelor iv should be readily available to patients and the formulation preferably utilizes ingredients found acceptable by regulatory agencies (e.g. within the FDA's inactive ingredient guide - IIG limits) to enable market introduction and patient availability. SUMMARY

[0018] In a first aspect, the present invention provides a pharmaceutical ticagrelor composition for use in the treatment of gram-positive bacteremia in a patient in need thereof by administering the pharmaceutical composition at a therapeutically effective concentration, characterized in that the pharmaceutical ticagrelor composition is an aqueous ticagrelor solution, the pharmaceutical ticagrelor composition has a storage stability of at least 3 months at 25°C and 60% relative humidity or at 40°C and 75% relative humidity, and is administered intravenously by injection or infusion.

[0019] The availability of a ticagrelor iv composition with sufficient solubility of ticagrelor and limited degradation for the treatment of gram-positive bacteremia infections is advantageous, as intravenous administration provides 100% bioavailability, allows easier dose adjustment, and can be applied even when the patient is unconscious. Intravenous formulations are advantageous for the treatment of deep bacterial infections that cannot be removed by surgery.

[0020] Preferably, the pharmaceutical ticagrelor composition has a pH of 5.5 to 9.0 and an osmolality between 300-900 mOsm / kg.

[0021] Preferably, the pharmaceutical ticagrelor composition comprises a water-soluble inclusion complex of ticagrelor in a cyclodextrin; preferably the cyclodextrin is hydroxypropyl-β-cyclodextrin.

[0022] Preferably, organic cosolvents are excluded.

[0023] Preferably, the pharmaceutical ticagrelor composition comprises 1-15 mg / ml ticagrelor and 15-40% w / w cyclodextrin.

[0024] Preferably, the pharmaceutical ticagrelor composition has a volume of 1-15 ml for administration by injection or a volume of 10-50 ml for administration by short-term infusion of up to 30 minutes.

[0025] Preferably, the pharmaceutical ticagrelor composition comprises 0.10-14 mg / ml ticagrelor and 20-100 mg / ml cyclodextrin.

[0026] Preferably, the pharmaceutical ticagrelor composition has a volume of 25 to 1000 ml for administration by infusion for at least 30 minutes.

[0027] Preferably, the Gram-positive bacteremia is Staphylococcus, Streptococcus or Enterococcus bacteremia; preferably, the Gram-positive bacteremia is Staphylococcus aureus bacteremia; more preferably, the Gram-positive bacteremia is an antibiotic resistant bacterial infection; most preferably, the Gram-positive bacteremia is methicillin sensitive (MSSA) or methicillin resistant Staphylococcus aureus (MRSA).

[0028] Preferably, the patient is further administered an antibiotic selected from cefazolin, ceftaroline, daptomycin, ertapenem, linezolid, minocycline, oxacillin, telavancin, trimethoprim-sulfamethoxazole, vancomycin or combinations thereof.

[0029] Preferably, the intravenous administration of ticagrelor is initiated within 4 days of the bacterial bloodstream infection.

[0030] Preferably, the dose of ticagrelor is adjusted according to the level of alpha toxin produced by the Gram-positive bacterial strain present in the bloodstream infection.

[0031] Preferably, the patient has a blood platelet count of 50,000 to 150,000 platelets per microliter of blood (thrombocytopenia).

[0032] Preferably, the treatment further comprises administering an effective amount of blood platelets for treating the thrombocytopenia.

[0033] Preferably, the blood platelets are pre-treated with ticagrelor.

[0034] In another aspect, the present application provides a container comprising the pharmaceutical composition of ticagrelor according to the first aspect.

[0035] Preferably, the container is a plastic bag or a glass bottle.

[0036] In a further aspect, the present application provides a ready-to-use ticagrelor product for use in the treatment of Gram-positive bacteremia in a patient in need thereof by administering said pharmaceutical composition in a therapeutically effective concentration, wherein the intravenous administration is by infusion.

[0037] Preferably, the ready-to-use ticagrelor product is a ready-to-use container comprising 25-1000 mL of an aqueous solution, 0.10-14 mg / ml ticagrelor and 20-100 mg / ml of a cyclodextrin; preferably hydroxypropyl-beta-cyclodextrin.

[0038] It is beneficial to have a ready-to-use iv formulation, especially for use in the treatment of severe bacteremia which can lead to life-threatening thrombocytopenia (loss of blood platelets). Furthermore, the patient can be unconscious and not able to take tablets. DETAILED DESCRIPTION

[0039] Unless otherwise defined, all terms (including technical and scientific terms) used in the description of the present application have the meaning commonly understood by one of ordinary skill in the art in the field of the present application. Furthermore, definitions of common terms in the art are found at the end of the specification.

[0040] As used herein, the following terms have the following meanings:

[0041] Unless otherwise indicated, the use of “a” or “an” herein refers to both the singular and the plural. For example, “surfactant” refers to one or more than one surfactant.

[0042] As used herein, "about" means a measurable amount, e.g., a parameter, amount, duration, etc., that varies slightly from a specified value, and is intended to include values that are ±10% or less, preferably ±5% or less, more preferably ±3% or less, even more preferably ±1% or less, even more preferably ±0.1% or less of the specified value, as long as such variations are appropriate in the context of the invention being described. However, it will be clear to those skilled in the art that the value "about" the value itself is also specifically described. As used herein, "Include," "comprising" and "comprises" are synonymous with "containing", "containing", or "contains" and are inclusive or open-ended terms that specifies the presence of stated elements, features, elements, components, steps, and the like, but do not preclude the presence or addition of one or more other stated or unstated elements, features, elements, components, steps, and the like.

[0043] Numerical ranges expressed in terms of "between" are inclusive of the numbers recited as endpoints.

[0044] The term "% w / w" as used herein means weight percent, wherein the weight ratio of an ingredient to the total weight of the composition is expressed as a percentage.

[0045] Bacterial bloodstream infections, known as bacteremia, are notoriously difficult to treat, particularly when they are caused by Gram-positive bacteria, such as methicillin-resistant Staphylococcus aureus strains. Methicillin-resistant Staphylococcus aureus strains produce large amounts of alpha toxins. These toxins attack blood platelets, making them insufficient to trigger the immune system against bacterial infection. In addition, large amounts of platelets can be damaged and lost (thrombocytopenia). This leads to an increased risk of bleeding and life-threatening situations (Alhurayri et al. Toxins, 2021, 13(10): 726).

[0046] The standard method to treat bacterial infections in the bloodstream is with antibiotics. For hospital-incurred bacteremia infections, intravenous formulations are used. Intravenous formulations have the benefit of 100% bioavailability over oral drugs. They allow for a rapid start of treatment. Intravenous formulations are sought, particularly for treating bloodstream infections caused by bacterial infection sources that cannot be surgically removed and are difficult to reach.

[0047] Recently, it has been proposed that ticagrelor tablets are considered for use in the treatment of bacteremia infections. However, ticagrelor tablets have a bioavailability of only 36%, with large variations between humans. Intravenous formulations are not commercially available to date. Past development efforts have failed to solubilize ticagrelor at medically relevant concentrations. In addition, limited storage stability is insufficient to surpass freshly prepared compositions.

[0048] The present invention provides aqueous ticagrelor solutions which are provided for intravenous administration. Suitable aqueous ticagrelor solutions for use in the present invention are described in co-pending applications PCT / EP2022 / 063185 and PCT / EP2023 / 055736, which are incorporated herein by reference.

[0049] The aqueous ticagrelor solutions used in the present invention have sufficient storage stability which makes them suitable for commercialization. Without sufficient storage stability it is not possible to produce the solution, package it, store it, transport it to the site of use, store it until needed and use it for treating a patient. The sufficient storage stability which avoids the need for the solution to be prepared and used on demand is considered to require at least 3 months of storage stability as measured under storage stability conditions of 25°C and 60% relative humidity or under accelerated storage stability conditions of 40°C and 70% relative humidity.

[0050] More preferably, the storage stability is at least 6 months; even more preferably at least 9 months; most preferably at least 12 months. A satisfactory stability of 6 months at 40°C and 75% RH corresponds to a shelf life of 24 months at room temperature of 25°C.

[0051] “Storage stability” as used herein refers to a total impurity level of below 0.5%.

[0052] The aqueous ticagrelor solutions can advantageously be used for treating Gram-positive bacteremia by intravenous administration of an effective amount of the aqueous ticagrelor solution to a patient in need thereof. Depending on the concentration of ticagrelor, the intravenous administration is by injection or infusion.

[0053] The present invention provides in an improved way a solution to the problem of treating Gram-positive bacteremia with ticagrelor.

[0054] In particular, the present invention provides a pharmaceutical ticagrelor composition for use in the treatment of Gram-positive bacteremia in a patient in need thereof by administering the pharmaceutical composition in a therapeutically effective concentration, characterized in that the pharmaceutical ticagrelor composition is an aqueous ticagrelor solution, the pharmaceutical ticagrelor composition has a storage stability of at least 3 months at 25°C and 60% relative humidity or at 40°C and 75% relative humidity, and is administered intravenously by injection or infusion.

[0055] The term “bacteremia” as used herein refers to a bacterial infection in the bloodstream.

[0056] The term "gram-positive bacteria" as used herein means bacteria that give a positive result in a Gram stain test, which is a test known to the person skilled in the art for classifying bacteria according to the type of their cell wall. Gram-positive bacteria take up the crystal violet stain used in the test and appear purple when viewed by light microscopy. This is because the thick peptidoglycan layer in the bacterial cell wall retains the stain after it has been washed away from the rest of the sample during the decolorizing stage of the test. In contrast, gram-negative bacteria are unable to retain the purple stain after the decolorizing step; the alcohol used in this stage degrades the outer membrane of gram-negative cells, making the cell wall more porous and unable to retain the crystal violet stain. Their peptidoglycan layer is much thinner and is sandwiched between the inner and outer cell membranes, making them take up counterstains such as safranin or carbol fuchsin and appear red or pink.

[0057] In a preferred embodiment, the bacteraemia is staphylococcal, streptococcal or enterococcal bacteraemia. Preferably, the bacteraemia is Staphylococcus aureus bacteraemia. More preferably, the bacteraemia is an antibiotic resistant bacterial infection of gram-positive bacteria. Most preferably, the bacteraemia is methicillin-sensitive (MSSA) or methicillin-resistant Staphylococcus aureus (MRSA) bacteraemia. MRSA bacteraemia is notoriously difficult to treat. Mortality is at least 20%.

[0058] The patient is preferably a mammal, more preferably a human.

[0059] The present application is advantageous because it makes available a storage-stable liquid formulation of ticagrelor which is suitable for administration into a vein. A vein is a tube that forms part of the blood circulation system of a patient's body, which carries blood and blood platelets, also known as thrombocytes. The use of a liquid formulation that provides for intravenous administration in the treatment of bacteraemia improves the bioavailability of ticagrelor to blood platelets in the bloodstream, thereby providing protection against bacterial attack. Since blood platelets are important in the immune system, their protection is considered important to help fight against gram-positive bacterial bloodstream infections.

[0060] Preferably, the pH of the product is such that pH adjustment prior to administration is not required. The aqueous ticagrelor solution as described above preferably has a pH of 5.5 to 9.0, more preferably 6.0 to 8.5, even more preferably 6.5 to 8.0, most preferably 6.8 to 7.8.

[0061] Preferably, the osmolality of the product is such that no adjustment prior to administration is required. The aqueous ticagrelor solution used in the present application preferably has an osmolality of 300 to 900 mOsm / kg; more preferably 400-850 mOsm / kg, most preferably 450-800 mOsm / kg. An osmolality between 300-900 mOsm / kg allows for intravenous administration without prior adjustment of the formulation. This osmolality is compatible with the direct iv administration of ticagrelor formulations in the treatment of bacteremia. These parameters are beneficial for the compatibility with the patient's blood stream.

[0062] In a preferred embodiment, the pharmaceutical ticagrelor composition further comprises a buffer. The buffer is preferably a phosphate buffer. The aqueous ticagrelor solution used in the present application more preferably has 5 mM-20 mM phosphate buffer. This buffer strength was found to be advantageous for obtaining the desired storage stability of the aqueous ticagrelor solution.

[0063] The solubilization of ticagrelor in the composition according to the present application is performed using a solubilizing agent. Preferably, the solubilizing agent is a cyclodextrin. Preferably, the cyclodextrin is hydroxypropyl-β-cyclodextrin. Cyclodextrins, especially hydroxypropyl-β-cyclodextrin were found to provide a water-soluble inclusion complex of ticagrelor.

[0064] Preferably, the aqueous pharmaceutical ticagrelor solution according to the embodiments of the present application has a volume of 5-1000 ml. This volume spans the range of several types of intravenous administration, wherein small volumes are typically administered by bolus injection. Larger volumes are administered by infusion.

[0065] The aqueous ticagrelor solution for intravenous administration is preferably free of any other solvent or surfactant. In particular, co-solvents consisting of oil, ethanol, propylene glycol, polyethylene glycol are excluded. Preferably, also polymers consisting of poloxamer, polyvinylpyrrolidone or combinations thereof are excluded. The exclusion of polyethylene glycol is particularly advantageous as it is prone to form impurities upon storage, especially upon exposure to temperatures above 35°C.

[0066] In a preferred embodiment, salts are excluded from the aqueous ticagrelor solution for intravenous administration. The exclusion of salts is beneficial to avoid potential salting-out of ticagrelor from the cyclodextrin inclusion complex.

[0067] Ticagrelor solution for injection or short-term infusion

[0068] In a preferred embodiment, the administration of ticagrelor is by injection or short-term infusion.

[0069] Preferably, the aqueous pharmaceutical ticagrelor solution for use according to embodiments of the application for administration by injection or short-term infusion comprises 1-15 mg / ml ticagrelor. More preferably the solution comprises 2-14 mg / ml ticagrelor. Even more preferably the solution comprises 3-12 mg / ml ticagrelor. Most preferably the solution comprises 5-10 mg / ml ticagrelor.

[0070] Preferably, the composition according to embodiments of the application comprises 15-40% w / w hydroxypropyl-β-cyclodextrin. The use of this amount of cyclodextrin facilitates solubilisation of ticagrelor and provides a solution with sufficient storage stability.

[0071] Most preferably, the pharmaceutical ticagrelor composition comprises 1-15 mg / ml ticagrelor and 15-40% w / w cyclodextrin.

[0072] In a preferred embodiment, the ticagrelor used to prepare the ticagrelor solution of the application has a D90 particle size below 10 microns as measured using a Malvern mastersizer. A small particle size was found to facilitate easy incorporation of the ticagrelor into the cyclodextrin and thus provide solubility (solubility).

[0073] The short-term infusion is carried out for up to 30 minutes, preferably up to 25 minutes, more preferably up to 20 minutes, even more preferably up to 15 minutes.

[0074] Preferably, the pharmaceutical ticagrelor composition according to embodiments of the application has a volume of 10-50 ml for administration by short-term infusion for up to 30 minutes.

[0075] This range of concentrations of ticagrelor is sufficient for use in the treatment of bacteremia by intravenous administration. When the concentration is too low, an unacceptably large volume will need to be administered to provide an effective dose. This can prolong administration in an uncomfortable manner. When the concentration is too high, solubility and storage stability are difficult to maintain. Furthermore, the product needs to be diluted before use.

[0076] The solutions provided above work faster than tablets, have higher bioavailability, and can be administered to patients who have difficulty swallowing or are unconscious. Direct administration into a vein allows the ticagrelor to come into direct contact with blood platelets. Doses are easier to adjust according to the level of toxin being released by the bacterial strain of interest.

[0077] Preferably, the aqueous ticagrelor composition used in the present application is a solution consisting of:

[0078] 5-15 mg / ml ticagrelor,

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

[0080] 5mM-20mM phosphate buffer,

[0081] wherein the pH is between 5.5 and 8.

[0082] The compositions provided above are simple and easy to manufacture. The limited number of ingredients reduces the formation of impurities and by-products.

[0083] Surprisingly, it was found that a 5% dextrose solution is a suitable diluent that is compatible with the above-described concentrated aqueous dilution of the ticagrelor-cyclodextrin inclusion complex. Alternatives tested failed to provide a clear ticagrelor solution. This can be problematic with mixtures having antibiotic formulations. The problem is solved by formulating an alternative ticagrelor iv solution suitable for administration by infusion, as described below.

[0084] Ticagrelor infusion solution

[0085] Alternatively, for injection or short-term infusion, intravenous administration of the aqueous ticagrelor solution is by infusion over a period of at least 30 minutes.

[0086] Preferably, the ticagrelor iv composition comprises 0.10-14 mg / ml ticagrelor and 20-100 mg / ml cyclodextrin. Preferably, the cyclodextrin is hydroxypropyl-β-cyclodextrin. The amount of cyclodextrin selected is the amount that is used for solubilization of the ticagrelor in the selected volume of aqueous pharmaceutical solution.

[0087] Preferably, the aqueous pharmaceutical ticagrelor solution has a pH between 6.0-8.5, more preferably 6.5-8.0, even more preferably 6.8-7.8, most preferably about 7.5.

[0088] Preferably, the aqueous pharmaceutical ticagrelor solution comprises 0.1-10.0 mg / ml ticagrelor, more preferably 0.2-8 mg / ml ticagrelor, even more preferably 0.3-6.0 mg / ml ticagrelor, most preferably 0.4-5.0 mg / ml ticagrelor or 0.5 mg-2.0 mg / ml ticagrelor. In a preferred embodiment, the ticagrelor is the only active ingredient present in the aqueous pharmaceutical ticagrelor solution.

[0089] Preferably, the ticagrelor iv composition has a volume of 25 to 1000 ml, more preferably 50 to 750 ml, even more preferably 75 to 500 ml, most preferably 100 to 250 ml.

[0090] Surprisingly, it was found that ticagrelor can be solubilized in aqueous media at dilute concentrations. This is of interest in the pharmaceutical art for treating ticagrelor-responsive conditions.

[0091] More preferably, the aqueous pharmaceutical ticagrelor solution has a storage stability of at least 4, 5, 6, 12, 18 or 24 months measured at 25 °C and 60% relative humidity.

[0092] In some embodiments, the aqueous pharmaceutical ticagrelor solution comprises a 5 w / v% dextrose solution.

[0093] Preferably, the composition comprises 3000-16000 mg, more preferably 4000-15000 mg, even more preferably 5000-10000 mg, most preferably 6000-8000 mg of cyclodextrin. The cyclodextrin is preferably hydroxypropyl-β-cyclodextrin. Most preferably, the cyclodextrin is (2-hydroxypropyl)-β-cyclodextrin.

[0094] Use as a medicament

[0095] In preferred embodiments, the bacteremia is staphylococcal, streptococcal or enterococcal bacteremia. Staphylococci, streptococci and enterococci are all bacteria that can enter the blood stream of a patient and cause an infection.

[0096] Preferably, the bacteremia is Staphylococcus aureus bacteremia; more preferably, the bacteremia is an antibiotic resistant bacterial infection; most preferably, the bacteremia is methicillin sensitive (MSSA) or methicillin resistant Staphylococcus aureus (MRSA). Intravenous administration of ticagrelor to the bloodstream is particularly useful for the treatment of staphylococcal infections. This is believed to be caused by the blocking of receptors on blood platelets present in the bloodstream by ticagrelor, which would otherwise be attacked by alpha toxin produced by Staphylococcus aureus bacteria, especially methicillin resistant Staphylococcus aureus (MRSA). The iv route of administration provides a rapid response to a severe systemic invasion and provides a rapid action protection of blood platelets against bacterial attack. The inventors believe that this effect supports the survival of blood platelets. The protective effect can reduce the development and severity of thrombocytopenia in patients with bacteremia. It can also prevent the development of infective (bacterial) endocarditis. Infective (bacterial) endocarditis is an infection caused by bacteria that enter the bloodstream and settle on the endocardium or heart valves.

[0097] As used herein, the term "thrombocytopenia" means a lower than normal number of blood platelets (thrombocytes) in the blood. In a bacterial bloodstream infection, a patient can suffer a loss of blood platelets due to the bacterial attack. A healthy person has a blood platelet count of 150,000 to 450.000 platelets per microliter of blood. In the present invention, a level of 150,000 platelets per microliter of blood will be taken as the threshold for thrombocytopenia.

[0098] In a preferred embodiment, the aqueous ticagrelor composition for intravenous administration according to embodiments of the present application is administered to a patient having a blood platelet count of between 50,000 and 150,000 platelets per microliter of blood (thrombocytopenia). More preferably, the platelet count is between 60,000 and 140,000 blood platelets per microliter of blood; even more preferably between 70,000 and 130,000 blood platelets per microliter of blood; most preferably between 80,000 and 125,000 blood platelets per microliter of blood.

[0099] Intravenous administration of ticagrelor can prevent prolonged bacteremia-derived thrombocytopenia and the absence of a relative increase in blood platelet count. This can reduce mortality in patients with bacteremia.

[0100] It is therefore also important to start protection at an early stage of the bacterial infection when the blood platelet count would otherwise drop significantly. In a preferred embodiment of the present application, intravenous administration of ticagrelor is started within 4 days of the bacterial bloodstream infection. Preferably, intravenous administration of ticagrelor is started 4, 3, 2 or 1 day after the bacterial bloodstream infection. Since it can be difficult to establish the exact time of infection, the diagnosis of a Gram-positive bloodstream infection can be taken as a reference point to initiate ticagrelor administration. Bacterial bloodstream infection can be diagnosed by checking for the presence of bacteria in blood or blood culture samples.

[0101] It is also advantageous to check the level of alpha toxin emitted by the relevant bacterial strain and to adjust the dose of ticagrelor to the patient accordingly. In the case of high alpha toxin levels, the receptors targeted by alpha toxin, such as the ADAM10 receptor targeted by alpha toxin of S. aureus, are occupied, which is advantageous to reduce the impact of the bacterial infection. This protection of blood platelets can improve the clinical outcome.

[0102] In a preferred embodiment, the patient is also administered an antibiotic selected from the group consisting of cefazolin, ceftaroline, daptomycin, ertapenem, linezolid, minocycline, oxacillin, telavancin, trimethoprim-sulfamethoxazole, vancomycin or combinations thereof. The adjunctive therapy of ticagrelor iv in combination with an antibiotic is advantageous to provide different modes of action against the bacterial infection. Ticagrelor iv can be administered before, during or together with the antibiotic(s). For intravenous administration, a small volume of aqueous ticagrelor solution, preferably 1-15 ml, can be added to the infusion solution of the antibiotic.

[0103] Preferably, the treatment also comprises administering an effective amount of blood platelets. Providing additional blood platelets can be beneficial, in particular in case the blood platelet count has dropped dramatically. The addition of blood platelets serves to replace the platelets lost due to the bacterial attack.

[0104] To protect the platelet add-on, it is advantageous to pre-treat with ticagrelor. Preferably, the platelets are pre-treated with ticagrelor; i.e. before administration to the patient. This avoids that the supplementation of platelets is only transient and cannot support the immune system against blood stream infections.

[0105] Preferably, the platelet supplementation is provided by intravenous administration. The pre-treatment with ticagrelor can be obtained by injecting ticagrelor into the blood platelet solution before administration. The pre-treatment of blood platelets with ticagrelor has the advantage that receptors targeted by bacterial toxins, such as the ADAM10 receptor targeted by alpha toxin in S. aureus infections, are at least partially unavailable. This targeted (alpha) toxin-platelet interface interaction with ticagrelor can contribute to improve clinical outcome of bacteremia treatment, in particular in staphylococcal bacteremia.

[0106] In a preferred embodiment, the platelets used are prepared by freeze-drying. Freeze-drying of platelets can advantageously be obtained as disclosed in US2021100846. The product is commercially available under the trade name Thrombosomes®. The use of freeze-dried platelets is advantageous because they can be stored in dry form at ambient temperature for several years. They can be rehydrated with sterile water within minutes for immediate infusion. In a preferred embodiment of the present application, the freeze-dried platelets are reconstituted / rehydrated with an aqueous ticagrelor solution, thereby providing ticagrelor pre-treated platelets for intravenous administration.

[0107] Preferably, the effective amount administered to the patient is less than 60 mg ticagrelor / day. More preferably, the effective amount administered to the patient is less than 50 mg, even more preferably less than 40 mg, most preferably less than 30 mg ticagrelor / day.

[0108] Ready-to-use ticagrelor iv

[0109] In another aspect, the present application provides a ready-to-use aqueous solution of ticagrelor for administration by infusion, consisting of an aqueous 5% dextrose solution and an inclusion complex of ticagrelor in cyclodextrin (with 1-100 mg ticagrelor and 2000-3000 mg cyclodextrin), optionally with a buffer and / or a tonicity adjuster.

[0110] The term "ready-to-use" as used herein means a product that does not require adjustment of the composition, e.g. change of pH, osmolality, volume or ticagrelor concentration, before administration.

[0111] Preferably, the ready-to-use aqueous ticagrelor solution according to the embodiments of the present application has a storage stability of at least 3 months at 25°C and 60% relative humidity.

[0112] Preferably, ready-to-use ticagrelor compositions are provided for administration of 20-65 mg ticagrelor per day to a bacteremic patient in need thereof. The administration can be once a day. More preferably, ready-to-use compositions are provided for 10-30 mg ticagrelor administration.

[0113] The present application also provides a method of preparing a ready-to-use aqueous ticagrelor composition for intravenous administration in the treatment of bacteremia according to embodiments of the present application. The method comprises the following steps:

[0114] An aqueous solution is provided consisting of:

[0115] 5-15 mg / ml ticagrelor,

[0116] 15-40% w / w hydroxypropyl-beta-cyclodextrin,

[0117] 5 mM - 20 mM phosphate buffer,

[0118] optionally comprising a tonicity adjusting agent,

[0119] wherein the pH is between 6.0 and 8.0;

[0120] diluting the aqueous ticagrelor solution into an aqueous 5% dextrose solution, thereby obtaining the ready-to-use aqueous ticagrelor composition for intravenous administration.

[0121] Preferably, the aqueous ticagrelor solution has a volume of 10 ml and is diluted into 25 ml of a 5% dextrose solution.

[0122] Packaging

[0123] In another aspect, the present application provides a container comprising a medical ticagrelor composition according to embodiments of the present application. Preferably, the container is a plastic bag (infusion bag) or a glass bottle.

[0124] The present application provides an infusion bag comprising a ready-to-use ticagrelor solution according to embodiments of the present application.

[0125] The present application also provides a ready-to-use container comprising 25-1000 mL of an aqueous solution, 0.10-14 mg / ml ticagrelor and 20-100 mg / ml of a cyclodextrin; preferably hydroxypropyl-beta-cyclodextrin, for use in the treatment of Gram-positive bacteremia in a patient in need thereof by administering the medical composition in a therapeutically effective concentration, wherein the intravenous administration is by infusion.

[0126] The present application is illustrated by the following non-limiting examples.

[0127] Example

[0128] Example 1

[0129] In the first example, two different types of cyclodextrins were used and the solubilization of ticagrelor was compared. Unbuffered stock solutions of HPpCD or SBECD were prepared in water at target concentrations of 20 w / w%, 25 w / w%, 30 w / w%, 35 w / w% and 40 w / w%. Ticagrelor was added slowly under vortex. Ticagrelor was used at concentrations of 5, 10 or 14 mg / ml in milli Q water. The ticagrelor-cyclodextrin solutions were left on a shaking platform. No ultrasound or heating was applied.

[0130] From the results in Tables 1 and 2 it can be seen that HPpCD was able to solubilize ticagrelor in a wider range of cyclodextrin and ticagrelor concentrations tested. With 25 w / w%, 30 w / w%, 35 w / w% and 40 w / w% HPpCD clear aqueous solutions with 5 mg / ml ticagrelor in HPpCD were obtained.

[0131] In summary, ticagrelor can be solubilized by leaving it on a shaking platform. No ultrasound was applied. HPpCD can be used at a ticagrelor concentration of 5 mg / ml using 40% w / w, 35% w / w or 30% w / w cyclodextrin in milli Q water. These solutions remained clear at least for three days at room temperature and for several days at 4°C.

[0132] Table 1 : Solubility of ticagrelor in HPpCD

[0133]

[0134] + clear, looks completely dissolved

[0135] - translucent solution with precipitate

[0136] + / - clear solution with precipitate

[0137] * after 1 hour of ultrasound

[0138] Table 2: Solubility of ticagrelor in SBECD

[0139]

[0140] + clear, looks completely dissolved

[0141] - translucent solution with precipitate

[0142] + / - clear solution with precipitate

[0143] Example 2

[0144] Following the experiments depicted in Example 1, further optimization was performed by selecting the appropriate pH range to ensure long-term stability of the aqueous ticagrelor-cyclodextrin inclusion complex.

[0145] The following compositions as provided in Table 3 were prepared.

[0146] Table 3: Compositions used for storage stability testing.

[0147]

[0148] HPpCD was dissolved in buffer solutions 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 the buffer solution was filtered through a 0.22 micron filter and filled in USP Type I glass vials. The vials were stoppered and stored. All precautions were taken during manufacturing, such as N2purging and avoiding direct exposure to light. The vials were stored at 40°C and 75% relative humidity (RH).

[0149] To determine the stability of the formulations, the batches were evaluated using the related substances method on HPLC. The data for these batches are listed in Table 4 below.

[0150] The gradient HPLC method was used to analyze the impurities in the formulations using a YMC-Pack Pro C18 column (100 x 4.6 mm, S-3 μm 12 nm). Good separation was obtained for all impurities.

[0151] 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.

[0152] Regioisomer 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 process-related degradant impurity.

[0153] 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-3a-cyclopenta[d][1,3]dioxol-4-yl]oxy]ethan-1 -ol.

[0154] This is a process related impurity.

[0155] 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.

[0156] This is a process related impurity.

[0157] It was observed that only regioisomer impurity increased at almost 0.3% level within 4 weeks at 40°C and 75% RH; specification limit 0.3%. Therefore, to further optimize the stability of the product, studies were carried out at pH 7 to 8.

[0158] Example 3

[0159] After the experiments described in Example 2, storage stability studies at pH 7.5 were carried out.

[0160] HPpCD was first dissolved in a phosphate buffer solution at 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 micron filter and filled into USP Type I amber glass vials. The vials were stoppered and stored. All precautions were taken during manufacturing, such as N2purging and avoiding direct exposure to light.

[0161]

[0162] Table 5: Compositions used for storage stability testing.

[0163]

[0164] Table 6: Storage stability studies of ticagrelor-cyclodextrin inclusion complex in aqueous solution at pH 7.5 stored at 40°C and 75% relative humidity

[0165]

[0166] Based on the results of the stability study, as summarized in Table 6, it was concluded that good storage stability was achieved under accelerated storage conditions of 40°C and 75% relative humidity. Regioisomer impurities were well controlled, and no other impurities were of concern.

[0167] Example 4

[0168] In further experiments, to optimize the concentration of HPβCD below 40% w / w, heating at 40°C was applied to help dissolve the target ticagrelor dose at concentrations where a clear solution was difficult to obtain.

[0169] Direct physical stability data obtained from ticagrelor 5 mg / ml concentrate and flocculation testing (20 µl sample material in 1 ml diluent) are shown in Table 7. Table 7 contains data on assay, purity, osmolality, and pH.

[0170] Table 7: Physical stability of ticagrelor 5 mg / ml batches with varying HPβCD concentrations. Data are sorted by HPβCD intensity. Ticagrelor concentration when diluted into dextrose or saline: 0.1 mg / ml.

[0171]

[0172] Due to poor physical stability results when diluted in saline, 32.5% w / w HPβCD was selected for the 5 mg / ml ticagrelor formulation. The undiluted concentrate remained stable even in the refrigerator with HPβCD concentrations as low as 22.5% w / w. This concentration resulted in a nearly isotonic formulation.

[0173] In summary, 5-15 mg / ml ticagrelor can be dissolved with a concentration range of 20-40% w / w HPβCD without the use of heat. By applying heat, good solubility can be achieved with lower concentrations of HPβCD (e.g., 15-20% w / w) to achieve clear solutions.

[0174] At least 15% w / w HPβCD is required to provide a clear, storage-stable solution of ticagrelor at concentrations relevant to injection or intravenous administration.

[0175] Example 5

[0176] As can be seen from the results obtained in Example 4, the concentration of the excipients can be such that the resulting ticagrelor solution is hypertonic. Several batches were checked for osmotic pressure and pH. The solution had 19 mM phosphate buffer and pH 7.5. The results are provided in Table 8.

[0177] Table 8: pH and osmolality determination in undiluted batches.

[0178]

[0179] Dilution studies were performed to find a suitable diluent.

[0180] A 5 mg / ml solution of ticagrelor-cyclodextrin with varying amounts of HPpCD was diluted with normal saline, 5% dextrose solution or Ringer's lactate solution. Stability was screened. The concentration of ticagrelor when diluted into dextrose or saline was 0.1 mg / ml. The results are summarized in Table 9.

[0181] Table 9: Diluent testing

[0182]

[0183] In addition, the effect of buffer strength on pH and osmolality was screened. The results are summarized in Table 10.

[0184] Table 10: Effect of buffer strength on pH, osmolality, assay and impurities.

[0185]

[0186] The conclusion is that phosphate buffer at pH 7.5 has little effect on osmolality at different buffer strengths, with the exception of 0.19 mM buffer strength. This buffer strength is too weak, which results in a change in pH.

[0187] Example 6

[0188] In another example, the effect of particle size on solubility was tested.

[0189] Two different particle sizes diameters of the ticagrelor active ingredient, 5.5 and 15 microns, were screened. The pH and osmolality were not affected. The smaller particles showed a faster disintegration time, as summarized in Table 11.

[0190] Micronized ticagrelor showed a significant improvement in disintegration time. Therefore, micronized ticagrelor with a D90 of less than 10 microns is preferred.

[0191] As used herein, the term "D90" means that at least 90% of the particles present have a size of less than the target particle size. However, it is to be understood that variations in the input particle size distribution (PSD) of ticagrelor will be possible and it will have an impact on the disintegration rate of ticagrelor.

[0192] Table 11: Effect of particle size

[0193]

[0194] Example 7

[0195] To optimize the pH and HPpCD concentration of the solution for intravenous use, a 12-week / 3-month stability study was performed. Compositions of 32.5% w / w HPpCD with 5 mg / ml of ticagrelor at pH 7 to 8 were prepared and stored. Their stability was tested periodically.

[0196] The comparison of the stability profiles at 3 different pH (7, 7.5 and 8) was performed with a constant manufacturing process for all 3 formulations, with a buffer strength of 19 mM. The results are summarized in Tables 12 to 14.

[0197] Table 12: Storage stability in amber glass vials - pH 7

[0198]

[0199] Table 13: Storage stability in amber glass vials - pH 7.5

[0200]

[0201] Table 14: Storage stability in amber glass vials - pH 8.0

[0202]

[0203] From the above data it was concluded that the solution of ticagrelor in HPpCD is stable in the pH range of 7 to 8.

[0204] Example 8

[0205] To investigate the potential impact of the packaging material on the stability of the ticagrelor-cyclodextrin inclusion complex, compositions with 32.5% w / w HPpCD were prepared with similar procedures and precautions as in the previous trial; samples were stored at a temperature of 40 °C / 75% RH in clear, transparent glass vials and amber glass vials. The results are shown in Tables 15 and 16.

[0206] The results of the accelerated storage stability test showed that no significant difference was observed between the two after 3 months. All samples remained clear, aqueous solutions. The pH of the samples remained stable. There was no significant change in impurities.

[0207] It appears that both clear and amber glass vials can be used.

[0208] It is clear from the results of the accelerated storage stability testing of the ticagrelor solution without the use of cyclodextrin that the use of cyclodextrin is important for achieving good stability. Six to eight different impurities were generated upon storage without cyclodextrin. These impurities were not seen in the selected compositions.

[0209] Table 15: Study of potential impact of packaging. Stability in amber USP Type I glass.

[0210]

[0211] Table 16: Study of potential impact of packaging. Stability in clear glass vials USP Type I.

[0212]

[0213] It can surprisingly be concluded that ticagrelor solutions can be stabilized with HPpCD in both amber and clear glass vials.

[0214] Example 9

[0215] Further improvements to achieve higher solubility of ticagrelor were tried with different concentrations such as with 40% w / w HPpCD; 13 mg / ml ticagrelor solubility is also possible are provided as summarized in Table 17.

[0216] Table 17: Clear aqueous solutions with ticagrelor-cyclodextrin inclusion complex considering 65 mg dose.

[0217]

[0218] Density 1.130 gm / cc

[0219] Based on the studies, it was observed that concentrations of 5-13 mg / ml ticagrelor solutions can be achieved using 20-40% w / w HPpCD. The volume of fill content can be varied based on the required dose.

[0220] It was surprisingly found that by adjusting the HPpCD% and the total available volume of the formulation for the intended injection, the target dose of 5-15 mg / ml ticagrelor contained in a small volume can be achieved. The ability to contain the ticagrelor dose in a volume of 5-15 mL is highly relevant as it is the typical bolus volume.

[0221] Example 10

[0222] In another example, the maximum solubility of ticagrelor in HPpCD solution without the use of heat was studied. The results are summarized in Table 18.

[0223] Depending on the amount of ticagrelor to be delivered to the patient and the limitations of the sample volume as determined by administration through injection or infusion, therefore, to solubilize 65-75 mg of ticagrelor, a quantity of HPpCD of 2000-4000 mg per 10 mL vial can be required.

[0224] Table 18: Concentration of HPpCD, dose, and volume of formulation

[0225]

[0226] Density of HPpCD solution 1.130 gm / cc

[0227] Surprisingly, the solutions provided in Table 18 are compatible with diluents to provide infusions, in particular with 5% dextrose in water.

[0228] Example 11

[0229] In another embodiment of the present application, highly stable clear solutions of ticagrelor can be obtained by applying appropriate heat to the solution during its preparation, thereby providing a completely clear solution of the formulation at the required concentrations of HPpCD and ticagrelor.

[0230] To investigate the effect of temperature and holding time, new compositions were prepared as follows in Table 19.

[0231] Table 19: Compositions for temperature effect evaluation.

[0232]

[0233] In a first step, a phosphate buffer at pH 7.5 was prepared and the buffer solution was heated to 40-45°C. HPpCD was added to the buffer solution under continuous mixing. Once a clear solution was obtained, ticagrelor was dispersed into the HPpCD solution and mixed until a clear solution was obtained. Typically 30 minutes to 4 hours were required, depending on the batch size. The solution was then filtered through a 0.22 micron filter and packaged in suitable clear or amber glass vials.

[0234] Table 20: Bulk holding study at 45°C

[0235]

[0236] Table 21: Bulk holding study at 25°C and 40°C

[0237]

[0238] Table 22: Bulk holding at 30°C

[0239]

[0240] The holding time study at temperatures between 25°C and 45°C showed how even 30% w / w HPpCD is able to stabilize ticagrelor even after heating the solution for an extended period of time or keeping the bulk at elevated temperatures.

[0241] Ready-to-use formulation

[0242] Example 13

[0243] To formulate ready-to-use ticagrelor aqueous compositions, several diluted ticagrelor compositions were prepared and tested for solubility and stability

[0244] Table 24: Ready-to-use ticagrelor compositions in water

[0245]

[0246] Table 25: Ready-to-use ticagrelor compositions in aqueous phosphate buffer

[0247]

[0248] Table 26: Ready-to-use ticagrelor compositions in diluted saline

[0249]

[0250] Table 27: Ready-to-use ticagrelor compositions in dextrose solution

[0251]

[0252] Table 28: Most preferred ticagrelor iv compositions for use in the present invention

[0253]

[0254] The compositions have a storage stability of at least 3 months at 25°C and 60% relative humidity.

[0255] Method for manufacturing a ready-to-use infusion formulation

[0256] The manufacturing process for preparing the exemplary ready-to-use solutions is as follows. In all cases, the solvent as described was prepared and placed in a beaker and heated to 40°C, then the HPpCD was added to obtain a clear solution under stirring. Thereafter, the active ingredient ticagrelor was added at 40°C under constant stirring until a clear solution was obtained. This solution was filtered through a 0.22 micron filter and aseptically filled in sterile glass vials or infusion bags.

[0257] 24 mg / ml to 350 mg / mL HPpCD is required to obtain a stable ticagrelor solution ready for infusion. The amount of cyclodextrin required depends on the volume of the target infusion medium.

[0258] Ticagrelor is a water-insoluble active ingredient. The more it is diluted in aqueous solution, the greater its tendency to precipitate. As the dilution factor of ticagrelor increases, the amount of cyclodextrin required increases proportionally, when going from 30 mL to 100 mL to 200 mL. However, for 650 ml volumes and above, an amount of 16 grams of cyclodextrin was found to be sufficient to keep ticagrelor in aqueous solution.

[0259] Note that no organic co-solvents, surfactants or other solubilizers were used.

[0260] Alternative preparation method starting from a concentrated ticagrelor solution

[0261] A 8 mL vial containing 65 mg / vial ticagrelor and about 3 g HPpCD can be diluted with 25 mL 5 w / v% dextrose and a clear solution is obtained with a final volume of 33 mL.

[0262] However, this is not possible in the case of a 0.9 w / v% NaCl solution as diluent for a concentrated ticagrelor solution.

[0263] This is important in medical treatments where the concentrated ticagrelor aqueous composition will be mixed with another drug product. It can lead to precipitation of ticagrelor, making the combination product unsuitable for intravenous administration.

[0264] Example 14 - Aqueous ticagrelor solution for intravenous administration in the treatment of bacteremia

[0265] An aqueous ticagrelor solution for intravenous administration is prepared with the following composition:

[0266] 5-15 mg / ml ticagrelor

[0267] 20-40% w / w HPpCD

[0268] q.s. to 1 mL acetate or phosphate buffer pH 4.5 to 6.5

[0269] pH solution: 6-8

[0270] Osmolality solution: 350-900 mOsm / kg

[0271] Packaged in glass vials containing 5-15 mL of the aqueous ticagrelor solution.

[0272] Storage stability: at least 3 months at 40°C and 75% relative humidity

[0273] Based on blood culture, a human patient is diagnosed with MRSA bacteremia at a hospital.

[0274] Within 4 days of obtaining a positive test result, the patient is administered intravenously a first 30 mg ticagrelor in the form of an aqueous iv solution. The administration is repeated twice daily for multiple days until the bacteremia is cleared.

[0275] Example 15 - Aqueous ticagrelor solution for intravenous administration in the treatment of bacteremia and bacteremia-associated thrombocytopenia

[0276] Based on blood culture and blood platelet count, a human patient is diagnosed with MRSA bacteremia and bacteremia-associated thrombocytopenia.

[0277] The patient is administered intravenously a ready-to-use aqueous ticagrelor composition as provided in Table 28, which has a storage stability of at least 3 months at 25 °C and 60% relative humidity, in a therapeutically effective amount. The administration is repeated until the bacteremia is cleared and the thrombocytopenia is resolved.

[0278] Example 16 - Aqueous ticagrelor solution for intravenous administration in the treatment of bacteremia

[0279] A human patient is diagnosed with gram-positive bacteremia. After diagnosis, the patient is administered intravenously a ready-to-use ticagrelor iv composition as provided in Table 28, in a therapeutically effective amount.

[0280] Example 17 - Aqueous ticagrelor solution for intravenous administration in the treatment of bacteremia-associated thrombocytopenia

[0281] A human patient is diagnosed with gram-positive bacteremia. The patient has a blood platelet count of 80,000 to 120,000 platelets per microliter of blood. An aqueous ticagrelor iv composition having a storage stability of at least 3 months at 25 °C and 60% relative humidity is mixed with the blood platelets of an infusion bag. The mixture is administered to the bacteremic patient by infusion in a therapeutically effective amount. The treatment is repeated at least until the bacteremia is cleared and the blood platelet count is restored to a level of above 150,000 platelets per microliter of blood.

Claims

1. A pharmaceutical ticagrelor composition for treating Gram-positive bacteremia in a patient in need thereof by administering the pharmaceutical composition at a therapeutically effective concentration, characterized in that The pharmaceutical ticagrelor composition is an aqueous ticagrelor solution having a storage stability of at least 3 months at 25° C. and 60% relative humidity or at 40° C. and 75% relative humidity, and is administered intravenously by injection or infusion.

2. The pharmaceutical ticagrelor composition according to claim 1, wherein the pharmaceutical composition has a pH of 5.5 to 9.0 and an osmolality between 300-900 mOsm / kg.

3. The pharmaceutical ticagrelor composition according to claim 1 or 2, comprising a water-soluble inclusion complex of ticagrelor in a cyclodextrin; preferably, the cyclodextrin is hydroxypropyl-β-cyclodextrin.

4. The pharmaceutical ticagrelor composition according to any one of claims 1 to 3, with the proviso that organic co-solvents are excluded.

5. The pharmaceutical ticagrelor composition according to claims 1-4, comprising 1-15 mg / ml ticagrelor and 15-40% w / w cyclodextrin.

6. The pharmaceutical ticagrelor composition according to claim 5, having a volume of 1-15 ml for administration by injection, or having a volume of 10-50 ml for administration by short-term infusion of up to 30 minutes.

7. The pharmaceutical ticagrelor composition according to claims 1-4, comprising 0.10-14 mg / ml ticagrelor and 20-100 mg / ml cyclodextrin.

8. The pharmaceutical ticagrelor composition according to claim 7, having a volume of 25 to 1000 ml for administration by infusion over at least 30 minutes.

9. The pharmaceutical ticagrelor composition according to any one of claims 1 to 8, wherein the Gram-positive bacteremia is Staphylococcus, Streptococcus or Enterococcus bacteremia; preferably, the Gram-positive bacteremia is Staphylococcus aureus bacteremia; more preferably, the Gram-positive bacteremia is an antibiotic-resistant bacterial infection; most preferably, the Gram-positive bacteremia is methicillin-susceptible (MSSA) or methicillin-resistant Staphylococcus aureus (MRSA).

10. The pharmaceutical ticagrelor composition according to any one of claims 1 to 9, wherein the patient is further administered an antibiotic selected from cefazolin, ceftaroline, daptomycin, ertapenem, linezolid, minocycline, oxacillin, telavancin, trimethoprim-sulfamethoxazole, vancomycin, or a combination thereof.

11. The pharmaceutical ticagrelor composition according to any one of claims 1 to 10, wherein the intravenous administration of ticagrelor is initiated within 4 days of the bacterial bloodstream infection.

12. The pharmaceutical ticagrelor composition according to any one of claims 1 to 11, wherein the dosage of ticagrelor is adjusted according to the level of alpha toxin produced by Gram-positive bacterial strains present in bloodstream infections.

13. The pharmaceutical ticagrelor composition according to any one of claims 1 to 12, wherein the patient has a blood platelet count of 50,000 to 150,000 platelets per microliter of blood (thrombocytopenia).

14. The pharmaceutical ticagrelor composition of claim 13, wherein the treatment further comprises administering an effective amount of blood platelets to treat thrombocytopenia.

15. The pharmaceutical ticagrelor composition of claim 14, wherein blood platelets are pretreated with ticagrelor.

16. A container comprising the pharmaceutical ticagrelor composition according to any one of claims 1 to 15.

17. The container according to claim 16, wherein the container is a plastic bag or a glass bottle.

18. A ready-to-use container comprising 25-1000 mL of an aqueous solution, 0.10-14 mg / ml of ticagrelor, and 20-100 mg / ml of a cyclodextrin; preferably hydroxypropyl-β-cyclodextrin, for use in treating Gram-positive bacteremia in a patient in need thereof by administering the pharmaceutical composition at a therapeutically effective concentration, wherein the administration is intravenous by infusion.

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