Water-based ticagrelor solution, production method and application

Abstract

The present invention provides an aqueous ticagrelor composition having improved storage stability, comprising ticagrelor as an active ingredient and a solubilizer for ticagrelor, preferably cyclodextrin or vitamin E TPGS. The aqueous ticagrelor solution is preferably provided for intravenous administration by or by injection or infusion. Preferably, the aqueous intravenous composition of ticagrelor according to the present invention, in a ready-to-use form or suitable for dilution prior to intravenous administration, is used as a medicament in the treatment of ticagrelor reactive diseases.

Description

Technical Field

[0001] The present invention is in the field of pharmaceutical compositions and medical uses of pharmaceutical compositions. The present invention also relates to the manufacture of pharmaceutical compositions and unit dosage forms. The active ingredient involved is ticagrelor. The present invention is advantageous because it provides a stable intravenous (iv) formulation of ticagrelor, for which only ticagrelor tablets are available. In addition, the present invention provides an aqueous ticagrelor solution with improved stability relevant to use in the pharmaceutical business. The present invention has the effect that patients with ticagrelor-responsive diseases can be effectively treated even if they lose consciousness or even if they have swallowing problems. The ready-to-use liquid ticagrelor formulation as provided by the present invention avoids the time required to crush tablets and dissolve the powder. This is particularly important in emergency situations where urgent treatment is required. It also allows improved dose titration. Background Art

[0002] Ticagrelor is a well-known active ingredient. It is a platelet aggregation inhibitor used to prevent thrombotic events such as myocardial infarction or stroke in patients with acute coronary syndrome. Its chemical name is (1S, 2S, 3R, 5S) -3-{7-[(1R, 2S) -2-(3, 4-difluorophenyl) cyclopropylamino] 5-(propylthio) -3H-(1, 2, 3) triazole (4, 5-D) pyrimidin-3-yl} -5-(2-hydroxyethoxy) cyclopentane-1, 2-diol.

[0003] Ticagrelor was developed by AstraZeneca and approved for marketing by the European Medicines Agency in 2010 and the US Food and Drug Administration in 2011. As a drug, it is marketed in the United States under the name and in the European Union under the name It is sold in tablet form. It is not commercially available in liquid form. Ticagrelor is an oral, reversible, direct-acting P2Y 12 Receptor antagonists that act by inhibiting platelet activation. The tablets, along with aspirin, have been shown to significantly reduce the risk of major adverse cardiovascular (CV) events (heart attack, stroke, or CV death) in patients with acute coronary syndrome (ACS) or a history of heart attack. The tablets are also indicated for reducing the risk of a first heart attack or stroke in high-risk patients with coronary artery disease.

[0004] Ticagrelor has been shown to be highly susceptible to degradation upon exposure to light, heat and oxygen, and its limited solubility presents a significant challenge when formulating it as an aqueous solution. Although the demand for liquid ticagrelor formulations remains high, to the best of our knowledge, successful commercial products that correspond to the long-term stability and required solubility required by the pharmaceutical industry have not yet been achieved.

[0005] Sigfridsson et al. (J Pharm Sci 100:2194-2202, 2011) disclose a composition that is considered suitable for intravenous administration. The composition is based on a combination of nanoparticles of ticagrelor, polyvinyl pyrrolidone and Aerosol AOT disodium salt (for stabilizing the active ingredient), and 5% mannitol to obtain a nanosuspension. Aerosol AOT is considered to correspond to dioctyl sulfosuccinate sodium salt. Although the nanosuspension is reported to have a stability of at least 10 months, there are also reports that there is a tendency for particle aggregation and precipitation during storage. Therefore, the sample is ultrasonically treated before intravenous administration. This is cumbersome for medical use and poses a safety risk.

[0006] The same publication by Sigfridsson et al. also mentions that the concentration of ticagrelor in phosphate buffer solution at pH 7.4 decreases after 1 month under normal laboratory conditions of light and temperature. Therefore, investigating alternative solutions for suspensions is contrary to what is shown.

[0007] In the product characteristics of the pharmaceutical product Brilique 60 mg film-coated tablets (Brilique INN-ticagrelor), it is disclosed that for patients who cannot swallow tablets, the tablets can be crushed, mixed with water and drunk immediately. Alternatively, the mixture can be administered into the stomach via a nasogastric tube. The disadvantage of this formulation is that it is not easily available to the patient. Preparation is required just before administration. The formulation does not have long-term storage stability and the tablet particles settle when standing. This is not a solution for emergency use, especially when the patient loses consciousness.

[0008] Cheong-Weon Cho et al. studied self-microemulsifying drug delivery system (SMEDDS) for oral delivery to overcome the poor solubility barrier of ticagrelor in 2019. The solubility of ticagrelor in oily and hydrophilic excipients was studied. A combination of surfactants was selected to obtain an emulsifying system: Capmul MCM / Cremophor EL / Transcutol P. Ticagrelor is used to inhibit platelet aggregation in patients with acute coronary syndrome, but its poor solubility and low bioavailability limit its in vivo efficacy.

[0009] Yaye et al. studied the degradation of ticagrelor upon exposure to heat, pH, peroxides and light in 2014. They identified a large number of degradants DP1 to DP9, indicating that the molecule is highly susceptible to degradation.

[0010] In view of the above, there is still a need in the art for storage-stable ticagrelor formulations with good ticagrelor solubility, especially for emergency use. The object of the present invention is to solve at least one or more of the problems as described above. In particular, the present invention aims to provide a formulation comprising ticagrelor as an active ingredient, which has improved solubility combined with long-term stability. Ticagrelor should be easily available to patients, and the developed formulations should use ingredients that are considered acceptable by regulatory agencies (e.g., within the FDA's Inactive Ingredient Guide-IIG (FDA's Inactive Ingredient Guide-IIG) limits). Summary of the invention

[0011] In a first aspect, the present invention provides an aqueous ticagrelor solution comprising ticagrelor and a solubilizer for ticagrelor, and having a storage stability of at least 3 months at 40° C. and 75% relative humidity or 25° C. and 60% relative humidity.

[0012] Preferably, the solubilizing agent is cyclodextrin or Vitamin E TPGS.

[0013] Preferably, the aqueous pharmaceutical ticagrelor solution according to an embodiment of the present invention comprises an inclusion complex of ticagrelor in cyclodextrin,

[0014] The aqueous pharmaceutical ticagrelor solution comprises

[0015] 0.10-14.0mg / ml ticagrelor and

[0016] 20-100 mg / ml of cyclodextrin (solubilizer for ticagrelor) in an amount for solubilizing the ticagrelor in a selected volume of an aqueous pharmaceutical solution

[0017] wherein the composition has a pH between 5.5 and 9 (including endpoints),

[0018] and the aqueous pharmaceutical solution has a volume of 25 to 1000 ml,

[0019] It has a storage stability of at least 3 months at 25°C and 60% relative humidity.

[0020] Preferably, the osmolality is between 300-900 mOsm / kg.

[0021] Preferably, the cyclodextrin is selected from hydroxypropyl-β-cyclodextrin and sulfobutyl ether β-cyclodextrin.

[0022] Organic co-solvents are preferably excluded.

[0023] In a further aspect, the present invention provides an aqueous pharmaceutical ticagrelor solution for use as a medicament. Preferably, the composition is administered by infusion.

[0024] Preferably, the medicament is for use in the treatment of acute coronary syndrome (ACS), myocardial infarction (MI), ischemic stroke, transient ischemic attack (TIA) or for reducing platelet-tumor cell interactions in a patient in need thereof.

[0025] Preferably, the medicinal product is for use in dual antiplatelet therapy (DAPT), which preferably comprises acetylsalicylic acid or a salt thereof as a second active ingredient in addition to ticagrelor.

[0026] In a further aspect, the present invention provides a ready-to-use infusion container comprising a composition according to an embodiment of the present invention.

[0027] Preferably, the ready-to-use infusion container according to an embodiment of the present invention contains 3000-16000 mg of cyclodextrin.

[0028] Preferably, the ready-to-use infusion container according to an embodiment of the present invention contains 5 w / v% glucose or 0.9 w / v% sodium chloride.

[0029] Preferably, the container is a bag or a bottle.

[0030] In a further aspect, the present invention provides a method for manufacturing an aqueous pharmaceutical ticagrelor composition according to an embodiment of the present invention, comprising the following steps:

[0031] - preparing an aqueous solution at pH 5.5-9, preferably comprising a buffer, more preferably comprising a phosphate buffer,

[0032] - introducing an amount of cyclodextrin (solubilizer for ticagrelor) for inclusion of a predetermined amount of ticagrelor,

[0033] - Adding a predetermined amount of ticagrelor, thereby obtaining an inclusion complex of ticagrelor in cyclodextrin.

[0034] Preferably, heating is applied prior to adding ticagrelor.

[0035] Preferably, ticagrelor has a D90 particle size of less than 10 microns when tested using a Malvern particle sizer.

[0036] Alternatively, the aqueous ticagrelor composition according to an embodiment of the present invention comprises ticagrelor as an active ingredient,

[0037] Characterized in that the composition is a solution comprising:

[0038] Water-soluble inclusion complex of ticagrelor in cyclodextrin,

[0039] wherein the composition has a pH between 6 and 8;

[0040] It has a storage stability of at least 3 months at 40°C and 75% relative humidity.

[0041] Preferably, the alternative aqueous ticagrelor composition has an osmolality between 350-900 mOsm / kg.

[0042] Preferably, the cyclodextrin in the alternative aqueous ticagrelor composition is selected from hydroxypropyl-β-cyclodextrin and a sulfobutyl ether derivative of β-cyclodextrin.

[0043] Preferably, the alternative aqueous ticagrelor composition comprises 15-40% w / w cyclodextrin; preferably comprises 15-40% w / w hydroxypropyl-β-cyclodextrin.

[0044] Preferably, the alternative aqueous ticagrelor composition has 2-15 mg / ml ticagrelor.

[0045] Preferably, the alternative aqueous ticagrelor composition is provided for infusion and has a volume of 15 to 30 ml.

[0046] Preferably, the alternative aqueous ticagrelor composition is provided for injection and has a volume of 5 to 15 ml.

[0047] Preferably, the alternative aqueous ticagrelor composition is a condition that excludes organic co-solvents. Preferably, polyethylene glycol is excluded from the aqueous ticagrelor composition.

[0048] Preferably, ticagrelor has a D90 particle size of less than 10 microns when tested using a Malvern mastersizer.

[0049] More preferably, the alternative aqueous ticagrelor composition according to an embodiment of the present invention consists of:

[0050] 5-15mg / ml ticagrelor,

[0051] 15-40% w / w hydroxypropyl-β-cyclodextrin,

[0052] 5mM-20mM phosphate buffer,

[0053] optionally including a tonicity adjusting agent,

[0054] The pH is between 5.5 and 8.

[0055] In a further aspect, an alternative aqueous ticagrelor composition according to an embodiment of the present invention is for use in a ticagrelor-responsive medical treatment; preferably for use in a ticagrelor-responsive medical treatment wherein the composition is administered as an injection or infusion, nasogastric solution or drink.

[0056] Preferably, the alternative aqueous ticagrelor composition according to an embodiment of the present invention is for use in the treatment of acute coronary syndrome (ACS) or myocardial infarction (MI), ischemic stroke, transient ischemic attack (TIA) or for reducing platelet-tumor cell interactions in a patient in need thereof.

[0057] Preferably, the alternative aqueous ticagrelor composition according to an embodiment of the present invention is for use in dual antiplatelet therapy (DAPT), which preferably comprises acetylsalicylic acid or a salt thereof as a second active ingredient in addition to ticagrelor.

[0058] In a further aspect, the present invention provides a unit dose composition for delivering 50-180 mg of ticagrelor comprising an alternative aqueous ticagrelor composition according to an embodiment of the present invention.

[0059] Preferably, the unit dose composition comprises 2000-4000 mg of cyclodextrin.

[0060] Preferably, the unit dose comprises 5% dextrose in water as a diluent.

[0061] In a further aspect, the present invention provides a method for manufacturing an aqueous ticagrelor composition according to an embodiment of the present invention, comprising the following steps:

[0062] - preparing an aqueous solution at pH 5.5-9, preferably comprising a buffer,

[0063] - introducing an amount of cyclodextrin for inclusion of a predetermined amount of ticagrelor,

[0064] - Adding a predetermined amount of ticagrelor, thereby obtaining an inclusion complex of ticagrelor in cyclodextrin.

[0065] Preferably, heating is applied prior to adding ticagrelor.

[0066] In a further aspect, the present invention provides an aqueous ticagrelor solution for intravenous administration for use in the treatment of acute coronary syndrome (ACS), myocardial infarction (MI), ischemic stroke, transient ischemic attack (TIA), or for reducing platelet-tumor cell interactions in a patient in need thereof.

[0067] In a further aspect, the present invention provides an aqueous ticagrelor solution for intravenous administration for use in dual antiplatelet therapy (DAPT), which preferably comprises acetylsalicylic acid or a salt thereof as a second active ingredient in addition to ticagrelor.

[0068] Preferably, the aqueous ticagrelor solution for intravenous administration for use as a pharmaceutical according to an embodiment of the present invention has a storage stability of at least 3 months in an accelerated storage condition at 40° C. and 75% relative humidity. DETAILED DESCRIPTION

[0069] The present invention provides a solution to the following problems: obtaining a clear and improved storage-stable aqueous ticagrelor formulation. The ticagrelor formulation of the present invention is suitable for administration by infusion. According to the Inactive Ingredients Guide (also known as the IIG List), the cyclodextrin component is acceptable for medical use. This contains amounts and inactive ingredients that have been reviewed and approved by the listed Food and Drug Administration for dosage forms and / or special routes of administration. D-α-Tocopherol polyethylene glycol succinate (known as Vitamin E TPGS) has been approved as a safe adjuvant by the U.S. Food and Drug Administration (FDA).

[0070] Unless otherwise defined, all terms used in the specification of the present invention, including technical terms and scientific terms, have the meanings commonly understood by those skilled in the art to which the present invention belongs. Further, definitions of terms are included to better understand the specification of the present invention.

[0071] As used herein, the following terms have the following meanings: Unless the context indicates otherwise, "a, an", "a, an" and "the" as used herein refer to both the singular and the plural. For example, "a surfactant" refers to one or more surfactants.

[0072] As used herein, "about", which refers to a measurable value, such as a parameter, amount, duration, and the like, is intended to include variations of plus or minus 10% or less, preferably plus or minus 5% or less, more preferably plus 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 long as such variations are applicable to the invention described. However, it is apparent that the value to which the term "about" refers is also specifically described. As used herein, "includes", "comprising" and "comprises" are inclusive or open terms that specify, for example, the presence of a component at the back, as well as the presence of additional, unnamed components, features, elements, parts (parts), steps, which are well known in the art or described herein, and do not exclude them.

[0073] The recitation of numerical ranges by endpoints includes all numbers and fractions within the range, as well as the recited endpoints.

[0074] As used herein, the term "% w / w" means percentage by weight, wherein the weight ratio of an ingredient to the total weight of the composition is expressed as a percentage.

[0075] In a first aspect, the present invention provides an aqueous ticagrelor solution comprising ticagrelor and a solubilizer for ticagrelor, having a storage stability of at least 3 months at 40°C and 75% relative humidity or 25°C and 60% relative humidity. Most preferably, the solubilizer is cyclodextrin or vitamin E TPGS.

[0076] Preferably, the present invention provides an aqueous ticagrelor composition comprising ticagrelor as an active ingredient, characterized in that the composition is a solution of a water-soluble inclusion complex of ticagrelor contained in cyclodextrin, wherein the composition has a pH between 5.5 and 9, preferably between 5.8 and 8.5, more preferably between 6.0 and 8.2, even more preferably between 6.2 and 8.1, and most preferably between 7.0 and 8.0. The pH range of 7.0 to 8.0 is particularly important due to the physiological acceptance of intravenous formulations by patients.

[0077] The term "ticagrelor" as used herein refers to ticagrelor in free form and its pharmaceutically acceptable solvate, hydrate, enantiomer, polymorph or mixture thereof. Preferably, ticagrelor in free form is used.

[0078] Ticagrelor has the following chemical structure:

[0079]

[0080] Ticagrelor has six stereocenters, and therefore there are many crystalline and amorphous forms. In a preferred embodiment of the present invention, the active agent is crystalline ticagrelor. In particular, four non-solvated crystalline forms are available, referred to as polymorphs 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 pattern 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. Polymorph II is described in the literature as the most stable crystalline form of ticagrelor.

[0081] 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.

[0082] The inventors have found that ticagrelor can be solubilized using cyclodextrins. Long-term storage stability can be obtained using aqueous solutions with a pH of 5.5 to 9, and importantly in the range of pH 7.0 to 8.0. The use of organic co-solvents or surfactants is avoided, which reduces the risk of degradation. In particular, the use of polyethylene glycol is avoided. The present invention provides a clear ticagrelor formulation with good solubility and long-term storage stability as required for formulations in the pharmaceutical and medical fields.

[0083] As used herein, the term "inclusion complex" refers to a chemical complex in which a chemical compound (host) has a cavity in which a guest compound can be accommodated. The interaction between the host and the guest involves van der Waals bonds. A compound suitable for providing an inclusion complex is a cyclodextrin.

[0084] Cyclodextrins are cyclic carbohydrates derived from starch. The difference between unmodified cyclodextrins lies in the number of glucose pyranose units linked together in the cylindrical structure. The mother cyclodextrin contains 6, 7 or 8 glucose pyranose units and is called α-, β- and γ-cyclodextrin, respectively. Each cyclodextrin subunit has a secondary hydroxyl group at the 2nd and 3rd positions, and a primary hydroxyl group at the 6th position. Cyclodextrins can be depicted as hollow truncated cones with a hydrophilic outer surface and a hydrophobic inner cavity. In aqueous solution, these hydrophobic cavities provide a haven for hydrophobic organic compounds, which can place all or part of their structure into these cavities. This process is called inclusion complexation, which can lead to an apparent aqueous solubility and stability improvement for the complexed drug; however, the degree of stabilization varies from drug to drug. The complex is stabilized by hydrophobic interactions and does not involve the formation of any covalent bonds.

[0085] Chemical modification of the parent cyclodextrin, usually at the hydroxyl moiety, produces derivatives with sometimes improved safety profiles while retaining or improving the complexing ability of the cyclodextrin. Of the numerous derivative cyclodextrins prepared to date, only two appear to be commercially viable; the 2-hydroxypropyl derivative (HP-β-CD or HPβCD), a neutral molecule commercially developed by Janssen et al.; and the sulfoalkyl ether derivative (SAE-β-CD or SAE-CD), developed by CyDex Pharmaceuticals, Inc. SAE-CD is a class of negatively charged cyclodextrins that differ from the starting parent cyclodextrin in the nature of the alkyl spacer, salt form, degree of substitution, and so on. The sodium salt of the sulfobutyl ether derivative of β-cyclodextrin, having an average of about 7 substituents per cyclodextrin molecule (SBE7-β-CD), is being commercialized by CyDex Pharmaceuticals, Inc. (Kansas City, Kansas) as a Cyclodextrins are commercialized.

[0086] Preferably, the cyclodextrin is selected from hydroxypropyl-β-cyclodextrin and sulfobutyl ether derivatives of β-cyclodextrin.

[0087] More preferably, the cyclodextrin is hydroxypropyl-β-cyclodextrin. The choice of HPβCD cyclodextrin is preferred over SBECD cyclodextrin. Compared with SBECD cyclodextrin, a lower amount of HPβCD is required to solubilize ticagrelor. Compared with SBECD, a wider range of HPβCD concentrations provides a clear aqueous ticagrelor solution. The results are provided in Example 1.

[0088] In a preferred embodiment, ticagrelor is the only active pharmaceutical ingredient present in the composition. Alternatively, an additional active ingredient may be included. Preferably, the additional active ingredient is not prasugrel.

[0089] The present invention provides an aqueous liquid formulation comprising an aqueous liquid carrier and an inclusion complex of ticagrelor.

[0090] Concentrated ticagrelor compositions for bolus injection or short-term infusion

[0091] Preferably, the aqueous ticagrelor composition is provided for infusion and has a volume of 15 to 40 ml, more preferably 20 to 35 ml, most preferably 25 to 30 ml. This volume range is typical for compositions according to embodiments of the present invention and for intravenous administration of aqueous ticagrelor compositions.

[0092] Alternatively to intravenous administration, the aqueous ticagrelor solution is administered by injection. For this purpose, the volume is preferably between 5 and 15 ml. Injection is particularly suitable for the treatment of acute situations because ticagrelor becomes available rapidly within a short period of time.

[0093] In a preferred embodiment, the aqueous ticagrelor composition comprises 2-15 mg / ml ticagrelor, more preferably 4-14 mg / ml ticagrelor, even more preferably 6-13 mg / ml ticagrelor, most preferably 7-12 mg / ml ticagrelor or 8-10 mg / ml ticagrelor. This amount of ticagrelor is relevant for therapy by injection or short-term infusion. Selecting a lower amount requires that a higher volume be administered to patients requiring medical indications for ticagrelor responsiveness. Higher amounts of ticagrelor cause solubility problems of the active ingredient, especially in cases involving administration by injection of small volumes.

[0094] Most preferably, the aqueous ticagrelor solution comprises 15-40% w / w, more preferably 20-35% w / w, even more preferably 22-34% w / w, most preferably 23-33% w / w hydroxypropyl-β-cyclodextrin. The amount of cyclodextrin selected is an amount sufficient to encapsulate a therapeutically relevant amount of cyclodextrin and provide a clear ticagrelor solution. This range is acceptable for medical administration.

[0095] In a preferred embodiment of the aqueous ticagrelor composition according to the present invention, organic co-solvents are excluded. It is not necessary to use organic co-solvents to improve the solubility of ticagrelor. Avoiding organic co-solvents provides better compatibility of the product for intravenous administration. The aqueous solution of the present invention does not contain polyethylene glycol.

[0096] Preferably, the aqueous ticagrelor composition has an osmotic pressure concentration between 350-900 mOsm / kg. Such osmotic pressure concentration is conducive to intravenous administration to patients in need of ticagrelor treatment.

[0097] In a preferred embodiment of the aqueous ticagrelor composition, ticagrelor has a D90 particle size below 10 microns; more preferably, the D90 particle size is below 9 microns; even more preferably, the D90 particle size is below 8 microns; most preferably, the D90 particle size is below 7 microns. The indicated particle size is selected to make it easier to incorporate ticagrelor in cyclodextrin. The solubility of ticagrelor included in the cyclodextrin inclusion complex is improved.

[0098] Methods for measuring the particle size of active ingredients are well known to those skilled in the art of formulation. The method used in the present invention is the Malvern Mastersizer dry powder method.

[0099] The shelf life obtained for the aqueous ticagrelor solution according to an embodiment of the present invention is longer than that obtained by pulverization. The currently available solutions obtained by tableting and mixing it with water are longer. The achieved storage stability is particularly relevant for the use of aqueous ticagrelor solutions in pharmaceutical supply and storage.

[0100] In a preferred embodiment of the aqueous ticagrelor composition, the composition has a storage stability of at least 3 months in an accelerated storage condition at 40°C and 75% relative humidity (RH). More preferably, the storage stability is at least 6 months, even more preferably at least 9 months, most preferably at least 12 months. A satisfactory stability of 6 months at 40°C and 75% RH corresponds to a shelf life of 24 months at room temperature of 25°C.

[0101] As used herein, "storage stability" means that the total impurity level is below 0.5%.

[0102] Most preferably, the aqueous ticagrelor composition is a solution consisting of:

[0103] 5-15mg / ml ticagrelor,

[0104] 15-40% w / w hydroxypropyl-β-cyclodextrin,

[0105] 5mM-20mM phosphate buffer,

[0106] The pH is between 5.5 and 8.

[0107] The compositions provided above are simple and easy to manufacture. The limited number of ingredients reduces the formation of impurities and by-products.

[0108] Optionally, the aqueous ticagrelor composition may include a tonicity adjuster, such as sodium chloride. Preferably, the aqueous ticagrelor composition has an osmotic pressure concentration between 350-900 mOsm / kg, more preferably between 360-800 mOsm / kg, even more preferably between 370-700 mOsm / kg, and most preferably between 380 and 600 mOsm / kg.

[0109] In some embodiments, the aqueous pharmaceutical ticagrelor solution comprises a 5 w / v % glucose solution.

[0110] In a further aspect, the present invention provides an aqueous ticagrelor composition for use in a medical treatment of ticagrelor responsiveness; wherein the aqueous ticagrelor composition is as described above.

[0111] Preferably, the aqueous ticagrelor composition is for intravenous administration, and the composition is administered by injection or short-term infusion. This form is advantageous for unconscious patients who need immediate treatment. Short-term infusion is preferably between 5 and 30 minutes, more preferably between 10 and 25 minutes, and most preferably between 15 and 20 minutes.

[0112] In an alternative embodiment, the aqueous ticagrelor composition is provided as a solution for nasogastric administration or as a drink. This form is advantageous for awake patients who have difficulty swallowing.

[0113] Preferably, an aqueous ticagrelor composition according to an embodiment of the present invention is provided for use in the treatment of acute coronary syndrome (ACS), myocardial infarction (MI), ischemic stroke, transient ischemic attack (TIA), or for reducing platelet-tumor cell interactions in a patient in need thereof.

[0114] The aqueous composition according to an embodiment of the present invention has the following advantages in medical treatment: it works faster than tablets; has higher bioavailability than tablets, and provides a solution for patients who have difficulty swallowing tablets. Intravenous infusion or injection is advantageous, especially in acute situations. Compared with crushing tablets and adding them to water and dissolving orodispersible tablets in water, the ready-to-use aqueous solution according to an embodiment of the present invention is more usable because of time saving and accurate dosage.

[0115] More preferably, the aqueous ticagrelor composition according to an embodiment of the present invention is used in monotherapy or dual antiplatelet therapy (DAPT). Preferably, the dual antiplatelet therapy (DAPT) further comprises acetylsalicylic acid or a salt thereof as a second active ingredient in addition to ticagrelor.

[0116] In a further aspect, the present invention provides a unit dose composition for delivering 15-180 mg of ticagrelor, comprising an aqueous ticagrelor solution according to an embodiment of the present invention. The dose range of ticagrelor for administration to a patient may be 15 mg to 180 mg, more preferably 30 mg to 90 mg, and most preferably 65 to 75 mg.

[0117] Preferably, the unit dose composition comprises 2000-4000 mg of cyclodextrin, more preferably 2200-3000 mg of cyclodextrin, even more preferably 2400-2800 mg of cyclodextrin, most preferably 2500 mg of cyclodextrin.

[0118] In a preferred embodiment of the unit dose composition according to the invention for bolus injection or short-term infusion, the unit dose composition comprises 5% dextrose in water (D5W) as diluent. Physiological saline and Ringer's lactate solutions are not suitable as diluents because they provide turbid solutions.

[0119] As used herein, "normal saline" refers to the phrase conventionally used for a solution of 0.90% w / v sodium chloride, 308 mOsm / l or 9.0 g per liter. Synonyms are normal saline or isotonic saline.

[0120] As used herein, "Lactated Ringer's solution" refers to a sodium lactate solution, also known as Hartmann's solution. It is a mixture of sodium chloride, sodium lactate, potassium chloride, and calcium chloride in water. One liter of lactated Ringer's solution contains 130-131 mEq of sodium ions, 109-111 mEq of chloride ions, 28-29 mEq of lactate ions, 4-5 mEq of potassium ions, and 2-3 mEq of calcium ions. Lactated Ringer's solution has an osmotic pressure concentration of 273 mOsm / l and a pH of 6.5.

[0121] The unit dose composition according to an embodiment of the present invention provides a good fluid balance with minimal hypotonicity or hypertonicity for treatment with ticagrelor. The composition is advantageous for people who cannot take fluids orally and who have or are at risk of dehydration or hypovolemia.

[0122] In a further aspect, the present invention provides a method of treating a patient with a ticagrelor-responsive disease, wherein the patient is treated with a clear and aqueous ticagrelor solution having a stability of at least one month, preferably three months, and even more preferably at least six months. Preferably, the clear and aqueous ticagrelor solution is a ready-to-use solution. More preferably, ticagrelor is encapsulated in a cyclodextrin, thereby providing a ticagrelor-cyclodextrin inclusion complex. Preferably, the clear and aqueous ticagrelor solution has a pH of 5.5-9, more preferably a physiological pH of 7-8. More preferably, the clear and aqueous ticagrelor solution comprises a buffer, most preferably a phosphate buffer.

[0123] In a fourth aspect, the present invention provides a method for manufacturing an aqueous ticagrelor composition according to an embodiment of the present invention, comprising the following steps:

[0124] -Prepare an aqueous solution with a pH of 5.5-9

[0125] - introducing an amount of cyclodextrin for inclusion of a predetermined amount of ticagrelor,

[0126] - Adding a predetermined amount of ticagrelor, thereby obtaining an inclusion complex of ticagrelor in cyclodextrin.

[0127] The aqueous solution preferably has a pH of 5.8-8.5, more preferably 6.0-8.2, most preferably 7.0-8.0. In order to maintain the indicated pH range, the solution preferably comprises a buffer.

[0128] Preferably, a heating step is applied before adding ticagrelor. This is beneficial to reduce the amount of cyclodextrin required to dissolve the selected amount of ticagrelor. Preferably, ticagrelor is added to a solution at a temperature of 30 to 45°C.

[0129] In a fifth aspect, the present invention provides a medical use of a ticagrelor intravenous composition.

[0130] The present invention provides an aqueous ticagrelor solution for intravenous administration for use in the treatment of acute coronary syndrome (ACS), myocardial infarction (MI), ischemic stroke, transient ischemic attack (TIA) or for reducing platelet-tumor cell interaction in a patient in need thereof.

[0131] The present invention also provides an aqueous ticagrelor solution for intravenous administration for use in dual antiplatelet therapy (DAPT), which preferably contains acetylsalicylic acid or a salt thereof as a second active ingredient in addition to ticagrelor.

[0132] In a preferred embodiment, the aqueous ticagrelor intravenous solution has a storage stability of at least 3 months in accelerated storage conditions at 40°C and 75% relative humidity.

[0133] The components of the aqueous ticagrelor intravenous solution are preferably as described above.

[0134] Diluted ticagrelor composition for infusion

[0135] In a further aspect, the present invention provides an aqueous pharmaceutical ticagrelor solution comprising an inclusion complex of ticagrelor in cyclodextrin,

[0136] The aqueous pharmaceutical ticagrelor solution comprises

[0137] 0.10-14.0mg / ml ticagrelor and

[0138] 20-100 mg / ml of cyclodextrin, in an amount for solubilizing ticagrelor in a selected volume of an aqueous pharmaceutical solution,

[0139] wherein the composition has a pH between 5.5 and 9 (including endpoints),

[0140] And the aqueous pharmaceutical solution has a volume of 25 to 1000 ml.

[0141] It was unexpectedly found that ticagrelor can be solubilized in aqueous media at dilute concentrations. This is beneficial in the medical field for treating ticagrelor-responsive disorders.

[0142] 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. In a preferred embodiment, ticagrelor is the only active ingredient present in the aqueous pharmaceutical ticagrelor solution.

[0143] In a preferred embodiment, the osmolality is between 300-900 mOsm / kg. More preferably, the osmolality is between 350-850 mOsm / kg, even more preferably 400-800 mOsm / kg, most preferably 450-750 mOsm / kg.

[0144] In a preferred embodiment, the cyclodextrin is selected from hydroxypropyl-β-cyclodextrin and sulfobutyl ether of β-cyclodextrin. More preferably, the cyclodextrin is hydroxypropyl-β-cyclodextrin. Most preferably, the cyclodextrin is (2-hydroxypropyl)-β-cyclodextrin.

[0145] 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 around 7.5.

[0146] Preferably, the aqueous pharmaceutical ticagrelor solution has a volume of 30 to 750 ml, more preferably 40 to 700 ml, even more preferably 50 to 650 ml, most preferably 100-250 ml.

[0147] In a preferred embodiment, organic co-solvents, such as polyethylene glycol, are excluded from the composition according to the invention. In a preferred embodiment, surfactants are excluded from the composition according to the invention. In a most preferred embodiment, organic co-solvents and surfactants are excluded from the composition according to the invention.

[0148] The dilute aqueous pharmaceutical ticagrelor solution according to an embodiment of the present invention has a storage stability of at least 3 months at 25° C. and 60% relative humidity. 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.

[0149] In some embodiments, the aqueous pharmaceutical ticagrelor solution comprises a pharmaceutically acceptable buffer. Preferably, the buffer is a phosphate buffer. In some embodiments, the buffer is present at a concentration of 0.005M to 0.1M, preferably 0.007M to 0.010M, even more preferably 0.0108M to 0.010M, most preferably 10mM. More preferably, 10 millimolar (mM) phosphate buffer. 1 millimolar = 1mM = 1mmol / liter.

[0150] In some embodiments, the aqueous pharmaceutical ticagrelor solution comprises a 5 w / v % glucose solution.

[0151] In a further aspect, the aqueous pharmaceutical ticagrelor solution according to an embodiment of the present invention is for use as a pharmaceutical product.

[0152] In a preferred embodiment, the aqueous pharmaceutical ticagrelor solution is administered by infusion.

[0153] Preferably, the aqueous pharmaceutical ticagrelor solution according to an embodiment of the present invention is used for use in the treatment of acute coronary syndrome (ACS), myocardial infarction (MI), ischemic stroke, transient ischemic attack (TIA) or for reducing platelet-tumor cell interactions in patients in need thereof.

[0154] Preferably, the alternative aqueous pharmaceutical ticagrelor solution according to an embodiment of the present invention is for use in dual antiplatelet therapy (DAPT), which preferably comprises acetylsalicylic acid or a salt thereof as a second active ingredient in addition to ticagrelor.

[0155] In a further aspect, the present invention provides a ready-to-use infusion container comprising a composition according to an embodiment of the present invention.

[0156] 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.

[0157] Preferably, the composition comprises 5 w / v% glucose or 0.9 w / v% sodium chloride.These diluents aid in the compatibility of the composition for use in intravenous administration.

[0158] Preferably, the ready-to-use infusion container is a bag or a bottle.

[0159] In a preferred embodiment, ticagrelor is the only active ingredient present in the ready-to-use infusion container.

[0160] In a final aspect, the present invention provides a method for manufacturing an aqueous pharmaceutical ticagrelor composition according to an embodiment of the present invention, comprising the following steps:

[0161] - preparing an aqueous solution at pH 5.5-9, preferably comprising a buffer, more preferably comprising a phosphate buffer,

[0162] - introducing an amount of cyclodextrin for inclusion of a predetermined amount of ticagrelor,

[0163] - Adding a predetermined amount of ticagrelor, thereby obtaining an inclusion complex of ticagrelor in cyclodextrin.

[0164] Preferably, heating is applied before adding ticagrelor. This is beneficial for obtaining a ticagrelor-cyclodextrin inclusion complex.

[0165] In a preferred embodiment, ticagrelor used in a method according to an embodiment of the present invention has a D90 particle size of below 10 microns when tested using a Malvern mastersizer.

[0166] Alternative solubilizers for ticagrelor

[0167] Furthermore, it was discovered that Vitamin E TPGS can be used as a solubilizer for ticagrelor in preparing aqueous ticagrelor solutions with improved storage stability.

[0168] In a final aspect, the present invention provides an aqueous ticagrelor solution comprising ticagrelor and a solubilizer for ticagrelor, having a storage stability of at least 3 months measured at 40°C and 75% relative humidity or 25°C and 60% relative humidity; wherein the solubilizer is vitamin E TPGS.

[0169] Preferably, the aqueous ticagrelor solution comprising Vitamin E TPGS as a solubilizer is for use as a pharmaceutical product, preferably for parenteral administration, more preferably for intravenous administration.

[0170] Preferably, the aqueous ticagrelor solution comprising Vitamin E TPGS as a solubilizer does not contain an organic co-solvent.

[0171] Preferably, the aqueous ticagrelor solution comprising Vitamin E TPGS as a solubilizer comprises 0.6-20 mg ticagrelor per ml of solution. More preferably, the ticagrelor concentration is 1.0-15 mg / ml, even more preferably 5.0-10 mg / ml, most preferably 6.0-9.0 mg / ml.

[0172] Preferably, the aqueous ticagrelor solution comprises 2.5-10.0 w / v% vitamin E TPGS.

[0173] Preferably, the aqueous ticagrelor solution comprises 2.5 w / v Vitamin E TPGS in water and 10 mg ticagrelor per ml of solution.

[0174] Preferably, the aqueous ticagrelor solution comprises 5.0 w / v Vitamin E TPGS in water and 10-12 mg ticagrelor per ml of solution.

[0175] Preferably, the aqueous ticagrelor solution comprises 10.0 w / v Vitamin E TPGS in water and 10-15 mg ticagrelor per ml of solution.

[0176] The present invention will be further illustrated by the following examples, which are non-exhaustive.

[0177] Example

[0178] Example 1

[0179] In the first example, two different types of cyclodextrins were used and their solubilization properties for ticagrelor were compared. Unbuffered stock solutions of HPβCD or SBECD were made 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 vortexing. Ticagrelor was used at concentrations of 5, 10, or 14 mg / ml in milli Q water. The ticagrelor-cyclodextrin solution was placed on a shaking platform. No ultrasound or heating was applied.

[0180] As can be seen from the results in Tables 1 and 2, HPβCD is able to dissolve ticagrelor over a wider 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 40 w / w% HPβCD.

[0181] Table 1: Solubility of ticagrelor in HPβCD

[0182]

[0183] + Clear, showing complete dissolution

[0184] - Translucent solution with precipitate

[0185] + / - Clear solution with precipitate

[0186] *After one hour of sonication

[0187] Table 2: Solubility of Ticagrelor in SBECD

[0188]

[0189] + Clear, showing complete dissolution

[0190] - Translucent solution with precipitate

[0191] + / - Clear solution with precipitate

[0192] As a conclusion, ticagrelor can be dissolved by placing it on a shaking platform. No ultrasonic treatment was applied. HPβCD can be used at a ticagrelor concentration of 5 mg / ml using cyclodextrin at 40% w / w, 35% w / w or 30% w / w in milliQ water. These solutions remained clear for at least three days tested at room temperature and several days at 4°C.

[0193] Example 2

[0194] Following the experiments depicted in Example 1, further optimization was performed by selecting an appropriate pH range to ensure long-term stability of the aqueous ticagrelor-cyclodextrin inclusion complex.

[0195] The following compositions as provided in Table 3 were prepared.

[0196] Table 3: Compositions used for storage stability testing

[0197]

[0198] HPβCD is dissolved in a buffer solution of pH 4.5, 5.5 or 6.5 prepared separately in water. After obtaining a clear solution, ticagrelor is dissolved in the buffer solution under constant stirring. Ticagrelor in the buffer solution is filtered through a 0.22 micron filter and filled in a USPI type glass vial. The vial is stoppered and stored. All precautions were taken during manufacturing, such as N2 purging and avoiding direct exposure to light. The vials are stored at 40°C and 75% relative humidity (RH).

[0199] To determine the stability of the formulations, batches were evaluated using the related material method on HPLC. The data for these batches are listed in Table 4 below.

[0200] Gradient HPLC was used to analyze the impurities in the formulation using a YMC-Pack Pro C18 column (100x4.6 mm, S-3 μm 12 nm). Good separation was obtained for all impurities.

[0201] 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 degradation impurity.

[0202] 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 process related degradation impurity.

[0203] 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 (2-[[(3aR,4S,6S,6aS)-6-[7-[[1R,2S)-2-(3,4-difluorophenyl)-cyclopropyl]a mino]-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 methyltetrahydro-2H-3aHcyclopenta[d][1,3]dioxol-4-yl]oxy]ethan-1-ol).

[0204] This is a process-related impurity.

[0205] 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.

[0206] This is a process-related impurity.

[0207] It was observed that only the regiomer impurity increased to almost 0.3% level in 4 weeks at 40°C and 75% RH; specification limit 0.3%. Therefore, to further optimize the stability of the product, studies were performed at pH 7 to 8.

[0208] Example 3

[0209] Following the experiments described in Example 2, storage stability studies at pH 7.5 were performed.

[0210] First, HPβCD was dissolved in a phosphate buffer solution of pH 7.5 prepared separately in water. After obtaining a clear solution, ticagrelor was dissolved in the solution under constant stirring. The solution was filtered through a 0.22 micron filter and filled in a USPI type amber glass vial. The vial was stoppered and stored. All precautions were taken during manufacturing, such as N2 purging and avoiding direct exposure to light.

[0211]

[0212] Table 5: Compositions used for storage stability testing

[0213] mg / ml Ticagrelor 6 HPβCD 40%w / w 452 Phosphate buffer pH 7.5 Appropriate amount to 1ml

[0214] Table 6: Storage stability study of ticagrelor-cyclodextrin inclusion compounds in aqueous solution at pH 7.5 stored at 40°C and 75% relative humidity.

[0215]

[0216] Based on the results of the stability studies, as summarized in Table 6, the following conclusions were drawn: Good storage stability was obtained under accelerated storage conditions of 40°C and 75% relative humidity. Regiomer impurities were well under control and no other impurities were of concern.

[0217] Example 4

[0218] 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 when a clear solution was difficult to obtain.

[0219] Direct physical stability data obtained from ticagrelor 5 mg / ml concentrate and by 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.

[0220] 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 glucose or saline: 0.1 mg / ml.

[0221]

[0222] 32.5% w / w HPβCD was selected for the 5 mg / ml ticagrelor formulation due to poor physical stability when diluted in saline. The undiluted concentrate remained stable in the refrigerator even with HPβCD concentrations as low as 22.5% w / w. Such concentrations produced an almost isotonic formulation.

[0223] In summary, 5-15 mg / ml ticagrelor can be dissolved together with HPβCD in a concentration range of 20-40% w / w without the use of heat. Good solubility can be obtained with lower concentrations of HPβCD, such as 15-20% w / w, by applying heat to obtain clear solutions.

[0224] At least 15% w / w HPβCD is required to provide a clear, storage-stable solution of ticagrelor with a concentration relevant for injection or intravenous administration.

[0225] Example 5

[0226] From the results obtained in Example 4, it can be seen that the concentration of the excipients can make the obtained ticagrelor solution hypertonic. Several batches of osmotic pressure concentration and pH were checked. The solution had 19mM phosphate buffer and pH 7.5. The results are provided in Table 8.

[0227] Table 8: pH and osmolality determination in undiluted batches.

[0228]

[0229] Dilution studies were performed to find the appropriate diluent.

[0230] 5 mg / ml ticagrelor-cyclodextrin solutions with varying amounts of HPβCD were diluted by saline, 5% glucose solution or Ringer's lactate solution. Stability was screened. Ticagrelor concentration when diluted into glucose or saline: 0.1 Mg / ml The results are summarized in Table 9.

[0231] Table 9: Diluent Test

[0232]

[0233] In addition, the effect of buffer strength on pH and osmolality was screened. The results are summarized in Table 10.

[0234] Table 10: Effect of buffer strength on pH, osmolarity, assay and impurities.

[0235]

[0236] It was concluded that phosphate buffer at pH 7.5 at different buffer strengths had little effect on osmolarity, except at 0.19 mM buffer strength, which was too weak to cause a change in pH.

[0237] Example 6

[0238] In further examples, the effect of particle size on solubility was tested.

[0239] Two different particle sizes for the ticagrelor active ingredient were screened, 5.5 and 15 microns. pH and osmolality were not affected. Smaller particles showed faster dissolution times, as summarized in Table 11.

[0240] Micronized ticagrelor showed a significant improvement in dissolution time. Therefore, micronized ticagrelor with a D90 of less than 10 microns is preferred.

[0241] As used herein, the term "D90" means that at least 90% of the particles present have a size less than the target particle size. However, it is understood that variations in the input particle size distribution (PSD) of ticagrelor may be possible and will have an impact on the dissolution rate of ticagrelor.

[0242] Table 11: Effect of particle size

[0243]

[0244] Example 7

[0245] To optimize the pH and HPβCD concentration of the solution for intravenous use, a 12 week / 3 month stability study was performed. 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.

[0246] The following comparison of stability profiles at 3 different pH (7, 7.5 and 8) was performed, the manufacturing process of all 3 formulations remained unchanged, with a buffer strength of 19 mM. The results are summarized in Tables 12 to 14

[0247] Table 12: pH 7 - Storage Stability in Amber Glass Vials

[0248]

[0249] Table 13: pH 7.5 - Storage Stability in Amber Glass Vials

[0250]

[0251]

[0252] Table 14: pH 8.0 - Storage Stability in Amber Glass Vials

[0253]

[0254] From the above data, it was concluded that ticagrelor solution in HPβCD was stable in the pH range of 7 to 8.

[0255] Example 8

[0256] To investigate the potential effect of packaging materials on the stability of the ticagrelor-cyclodextrin inclusion complex, a composition with 32.5% w / w HPβCD was prepared by similar procedures and precautions as in the previous experiment, and samples were stored in clear glass vials and amber colored glass vials at a temperature of 40°C / 75%RH. The results are shown in Tables 15 and 16.

[0257] The results of the accelerated storage stability test showed that after 3 months of storage, no significant difference was observed between the two. All samples were still clear aqueous solutions. The pH of the samples was still stable. There was no significant change in impurities.

[0258] It appears that both clear and amber tinted glass vials are available.

[0259] Compared to the results of the accelerated storage stability testing of ticagrelor solutions without cyclodextrin, it is clear that the use of cyclodextrin is important to obtain good stability. In the absence of cyclodextrin, 6 to 8 different impurities were generated on storage. These impurities were not seen in the selected compositions.

[0260] Table 15: Study on the potential effect of packaging. Stability in amber color USPI type glass

[0261]

[0262] Table 16: Potential Effects of Packaging Studies. Clear Glass Vials USPI Type Stability

[0263]

[0264]

[0265] Unexpectedly, it can be concluded that ticagrelor solutions can be stabilized by HPβCD in both amber tinted and clear glass vials.

[0266] Example 9

[0267] Further embodiments of the present invention are provided as summarized in Table 17. Further improvements in obtaining higher solubility of ticagrelor were attempted by different concentrations, for example by 40% w / w HPβCD, a ticagrelor solubility of 13 mg / ml was also possible.

[0268] Table 17: Clear aqueous solutions with ticagrelor-cyclodextrin inclusion complex considering a dose of 65 mg.

[0269]

[0270] Density 1.130gm / cc

[0271] Based on studies, it was observed that concentrations of 5-13 mg / ml of ticagrelor solution could be achieved using 20-40% w / w HPβCD.The volume of the fill contents may be varied based on the desired dose.

[0272] It was unexpectedly found that by adjusting the total available volume of the formulation ready for injection and the HPβCD%, a target dose of ticagrelor 5-15 mg / ml in a small volume could be achieved. Being able to contain the ticagrelor dose in a volume of 5-15 ml is highly relevant as it is a typical bolus volume.

[0273] Example 10

[0274] In a further example, the maximum solubility of ticagrelor in HPβCD solution without the use of heating was studied. The results are summarized in Table 18.

[0275] Depending on sample volume limitations determined by dosing by injection or infusion and the amount of ticagrelor delivered to the patient, an amount of 2000-4000 mg of HPβCD per 10 ml vial may be required to dissolve 65-75 mg of ticagrelor.

[0276] Table 18: HPβCD concentrations, formulation volumes and doses

[0277]

[0278] Density of HPβCD solution 1.130 gm / cc

[0279] Unexpectedly, the solutions provided in Table 18 are compatible with diluents provided for infusion, particularly with 5% dextrose in water.

[0280] Embodiment 11

[0281] In further embodiments of the present invention, highly stable clear solutions of ticagrelor can be obtained by applying appropriate heating to the solution during preparation, thereby providing a completely clear solution of the formulation at the desired HPβCD and ticagrelor concentrations.

[0282] To study the effect of temperature and hold time, new compositions were prepared according to Table 19 below.

[0283] Table 19: Compositions used for temperature impact assessment

[0284] mg / ml Ticagrelor 8 HPβCD 30%w / w 329 Phosphate buffer in water pH 7.5 Appropriate amount to 1ml

[0285] In the first step, a phosphate buffer at pH 7.5 is prepared and the buffer solution is heated to 40°C-45°C. HPβCD is added to the buffer solution under continuous stirring. After a clear solution is obtained, ticagrelor is dispersed into the HPβCD solution and mixed until a clear solution is obtained. This usually takes 30mins to 4 hours, depending on the batch size. The solution is then filtered through a 0.22 micron filter and packaged in suitable clear or amber colored glass vials.

[0286] Table 20: Bulk retention study at 45°C

[0287]

[0288] Table 21: Batch hold studies at 25°C and 40°C

[0289]

[0290]

[0291] Table 22: Batch retention at 30°C

[0292]

[0293] Holding time studies at temperatures between 25°C and 45°C showed that even 30% w / w HPβCD was able to stabilize ticagrelor even when the solution was heated for extended periods of time or the batch was held at elevated temperatures.

[0294] Example 12: Aqueous Ticagrelor Solution for Oral Administration

[0295] In this example, aqueous ticagrelor formulations for oral administration are demonstrated. The compositions are provided in Table 23.

[0296] Table 23: Composition of aqueous ticagrelor formulations for oral administration

[0297]

[0298]

[0299] The process of making such an oral solution is straightforward. The preservative is dissolved in propylene glycol. HPβCD is dissolved in water and ticagrelor is added thereto under constant stirring and then mixed with the solution of propylene glycol. The remaining substances are added to the solution and the pH is adjusted to 7-8.

[0300] Ready-to-use formulations

[0301] Embodiment 13

[0302] To formulate a ready-to-use aqueous ticagrelor composition, several diluted ticagrelor compositions were made and tested for solubility and stability.

[0303] Table 24: Composition of ready-to-use aqueous ticagrelor solution in water

[0304]

[0305] Table 25: Ready-to-use ticagrelor compositions in aqueous phosphate buffer

[0306]

[0307] Table 26: Ready-to-use ticagrelor composition in diluted saline

[0308]

[0309] Table 27: Ready-to-use ticagrelor composition in glucose solution

[0310]

[0311] Table 28

[0312]

[0313] Manufacturing process for ready-to-use infusion formulations

[0314] The manufacturing process for making the ready-to-use solutions of the examples is as follows. In all cases, the solvent is prepared and placed 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. The solution is filtered through a 0.22 micron filter and aseptically filled in a sterile glass bottle or infusion bag.

[0315] 24 mg / ml to 350 mg / ml HPβCD 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.

[0316] Ticagrelor is an active ingredient that is insoluble in water. The more it is in a diluted aqueous solution, the greater its tendency to precipitate. As the dilution factor of ticagrelor increases, when going from 30ml to 100ml to 200ml, the cyclodextrin also needs to be increased proportionally. However, for volumes of 650ml and higher, it was found that an amount of 16g ​​of cyclodextrin was sufficient to keep ticagrelor in aqueous solution.

[0317] Note that no organic co-solvents, surfactants or other solubilizing agents were used.

[0318] Alternative preparation method starting from concentrated ticagrelor solution

[0319] One vial of 8 ml containing 65 mg / vial of ticagrelor and approximately 3 g of HPβCd can be diluted by 25 ml of 5 w / v% glucose and a clear solution with a final volume of 33 ml is obtained.

[0320] However, this was not possible with 0.9 w / v% NaCl solution as diluent for the concentrated ticagrelor solution.

[0321] This is important in medical treatments where concentrated aqueous ticagrelor compositions are mixed with other pharmaceutical products. This can result in precipitation of ticagrelor, making the combination product unsuitable for intravenous administration.

[0322] Alternative solubilizers for ticagrelor

[0323] Embodiment 14

[0324] Aqueous ticagrelor solutions were prepared using Vitamin E TPGS as a solubilizer for ticagrelor. Water-soluble Vitamin E TPGS was added to water to obtain 2.5 and 5.0 and 10.0 w / v% aqueous Vitamin E TPGS solutions of different concentrations. To these solutions, which were maintained at a temperature of 45°C + / - 5°C, portions of ticagrelor were gradually added.

[0325] In the experiment summarized in Table 29, 3 mg ticagrelor portions were added stepwise to 50 ml of aqueous Vitamin E TPGS solution (Stage 1).

[0326] Table 29: Aqueous Ticagrelor Solutions with Vitamin E TPGS as a Solubilizer for Ticagrelor

[0327]

[0328] 20 ml of each diluent was subsequently used in the Phase 2 study. To the 20 ml of each diluent was added a 10 mg portion of ticagrelor. When the dissolution time was longer, this was reduced to 5 mg.

[0329] Table 30: Aqueous Ticagrelor Solutions with Vitamin E TPGS as a Solubilizer for Ticagrelor

[0330]

[0331] The following was observed: 10 mg of ticagrelor dissolved after 5-10 minutes.

[0332] 2.5% Vitamin E TPGS solution saturated at 11.6 mg / ml

[0333] 5.0% Vitamin E TPGS solution saturated at 14.9 mg / ml

[0334] 10.0% Vitamin E TPGS solution saturated at 19.8 mg / ml

[0335] The obtained aqueous ticagrelor solution was stored at 40°C and 75% relative humidity or at 25°C and 60% relative humidity for a period of at least 3 months.

[0336] Solubility, but not sufficient storage stability

[0337] Polyethylene glycol can solubilize ticagrelor. However, it was found that polyethylene glycol is sensitive to degradation and this causes impurities.

Claims

1. An aqueous ticagrelor solution comprising ticagrelor and a solubilizer for ticagrelor, having a storage stability of at least 3 months at 40°C and 75% relative humidity or at 25°C and 60% relative humidity; Preferably, the solubilizing agent is cyclodextrin or Vitamin E TPGS.

2. The aqueous pharmaceutical ticagrelor solution according to claim 1, comprising an inclusion complex of ticagrelor in cyclodextrin, The aqueous pharmaceutical ticagrelor solution comprises 0.10-14.0mg / ml ticagrelor and 20-100 mg / ml of cyclodextrin (a solubilizer for ticagrelor) in an amount for solubilizing said ticagrelor in a selected volume of an aqueous pharmaceutical solution, wherein the composition has a pH between 5.5 and 9, inclusive, and the aqueous pharmaceutical solution has a volume of 25 to 1000 ml, It has a storage stability of at least 3 months at 25°C and 60% relative humidity.

3. The aqueous pharmaceutical ticagrelor solution according to claim 2, wherein the osmotic pressure concentration is between 300-900 mOsm / kg.

4. The aqueous pharmaceutical ticagrelor solution according to claim 2 or 3, wherein the cyclodextrin is selected from hydroxypropyl-β-cyclodextrin and sulfobutyl ether β-cyclodextrin.

5. The aqueous pharmaceutical ticagrelor solution according to any one of claims 2 to 3, with the proviso that organic co-solvents are excluded.

6. The aqueous pharmaceutical ticagrelor solution according to any one of claims 2 to 5, for use as a medicament.

7. The aqueous pharmaceutical ticagrelor solution of claim 6, wherein the composition is administered by infusion.

8. An aqueous pharmaceutical ticagrelor solution according to claim 6 or 7, for use in the treatment of acute coronary syndrome (ACS), myocardial infarction (MI), ischemic stroke, transient ischemic attack (TIA) or for reducing platelet-tumor cell interactions in a patient in need thereof.

9. An aqueous pharmaceutical ticagrelor solution according to any one of claims 6 to 8 for use in dual antiplatelet therapy (DAPT), which preferably comprises acetylsalicylic acid or a salt thereof as a second active ingredient in addition to ticagrelor.

10. A ready-to-use infusion container comprising the composition according to any one of claims 2 to 9.

11. The ready-to-use infusion container according to claim 10, comprising 3000-16000 mg of cyclodextrin.

12. The ready-to-use infusion container according to claim 10 or 11, comprising 5 w / v% glucose or 0.9 w / v% sodium chloride.

13. The ready-to-use infusion container according to any one of claims 10 to 12, wherein the container is a bag or a bottle.

14. A method for manufacturing an aqueous pharmaceutical ticagrelor composition according to any one of claims 2 to 13, comprising the following steps: - preparing an aqueous solution at pH 5.5-9, said aqueous solution preferably comprising a buffer, more preferably a phosphate buffer, - introducing an amount of cyclodextrin (solubilizer for ticagrelor) for inclusion of a predetermined amount of ticagrelor, - Adding a predetermined amount of ticagrelor, thereby obtaining an inclusion complex of ticagrelor in cyclodextrin.

15. The method of claim 14, wherein heating is applied prior to adding ticagrelor.

16. The method according to claim 14 or 15, wherein the ticagrelor has a D90 particle size of less than 10 microns when tested using a Malvern mastersizer.

17. The aqueous ticagrelor composition according to claim 1, comprising Ticagrelor, the active ingredient, It is characterized in that The composition is a solution comprising: a water-soluble inclusion complex of ticagrelor in cyclodextrin, wherein the composition has a pH between 6 and 8; It has a storage stability of at least 3 months at 40°C and 75% relative humidity.

18. The aqueous ticagrelor composition according to claim 17, wherein the osmotic pressure concentration is between 350-900 mOsm / kg.

19. The aqueous ticagrelor composition according to claim 17 or 18, wherein the cyclodextrin is selected from hydroxypropyl-β-cyclodextrin and a sulfobutyl ether derivative of β-cyclodextrin.

20. The aqueous ticagrelor composition according to any one of claims 17 to 19, comprising 15-40% w / w cyclodextrin; preferably 15-40% w / w hydroxypropyl-β-cyclodextrin.

21. The aqueous ticagrelor according to any one of claims 17 to 20, comprising 2-15 mg / ml ticagrelor.

22. The aqueous ticagrelor composition according to any one of claims 17 to 21, wherein the composition is provided for infusion and has a volume of 15 to 30 ml.

23. The aqueous ticagrelor composition according to any one of claims 17 to 21, wherein the composition is provided for injection and has a volume of 5 to 15 ml.

24. The aqueous ticagrelor composition according to any one of claims 17 to 23, with the proviso that organic co-solvents are excluded.

25. The aqueous ticagrelor composition according to any one of claims 17 to 24, wherein the ticagrelor has a D90 particle size of less than 10 microns when tested using a Malvernmastersizer.

26. The aqueous ticagrelor solution according to any one of claims 17 to 25, consisting of: 5-15mg / ml ticagrelor, 15-40% w / w hydroxypropyl-β-cyclodextrin, 5mM-20mM phosphate buffer, optionally including a tonicity adjusting agent, The pH is between 5.5 and 8.

27. The aqueous ticagrelor composition according to any one of claims 17 to 26, for use in a ticagrelor-responsive medical treatment.

28. The aqueous ticagrelor composition according to any one of claims 17 to 27 for use in the medical treatment of ticagrelor responsiveness, wherein the composition is administered as an injection or infusion, nasogastric solution or drink.

29. An aqueous ticagrelor composition according to claim 27 or 28, for use in the treatment of acute coronary syndrome (ACS) or myocardial infarction (MI), ischemic stroke, transient ischemic attack (TIA) or for reducing platelet-tumor cell interactions in a patient in need thereof.

30. An aqueous ticagrelor composition according to any one of claims 27 to 29 for use in dual antiplatelet therapy (DAPT), which preferably comprises acetylsalicylic acid or a salt thereof as a second active ingredient in addition to ticagrelor.

31. A unit dose composition for delivering 50-180 mg of ticagrelor comprising the composition according to any one of claims 27 to 30.

32. The unit dose composition of claim 31 comprising 2000-4000 mg of cyclodextrin.

33. A unit dose composition according to claim 31 or 32 comprising 5% dextrose in water as a diluent.

34. A method for manufacturing an aqueous ticagrelor composition according to any one of claims 17 to 30, comprising the following steps: - preparing an aqueous solution at a pH of 5.5-9, said aqueous solution preferably comprising a buffer, - introducing an amount of cyclodextrin for inclusion of a predetermined amount of ticagrelor, - Adding a predetermined amount of ticagrelor, thereby obtaining an inclusion complex of ticagrelor in cyclodextrin.

35. The method of claim 34, wherein heating is applied prior to adding ticagrelor.

36. An aqueous ticagrelor solution for intravenous administration for use in the treatment of acute coronary syndrome (ACS), myocardial infarction (MI), ischemic stroke, transient ischemic attack (TIA) or for reducing platelet-tumor cell interactions in a patient in need thereof.

37. An aqueous ticagrelor solution for intravenous administration for use in dual antiplatelet therapy (DAPT), which preferably comprises acetylsalicylic acid or a salt thereof as a second active ingredient in addition to ticagrelor.

38. The aqueous ticagrelor solution of claim 36 or 37, wherein the solution has a storage stability of at least 3 months in accelerated storage conditions at 40°C and 75% relative humidity.

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