Aqueous solution of ticagrelor, its preparation and use

Abstract

The present invention provides an aqueous ticagrelor composition with 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 injection or drip.Preferably, the aqueous ticagrelor intravenous composition of the present invention is used as a drug in the treatment of ticagrelor-responsive diseases in a ready-to-use form or in a form suitable for dilution before intravenous administration.

Description

[Technical field]

[0001] The present invention is located in the field of pharmaceutical compositions and medical applications of pharmaceutical compositions. The present invention also relates to a method for producing pharmaceutical compositions and unit dose forms. The active ingredient of the present invention is ticagrelor. Until now, only ticagrelor tablets were available, but the advantage of the present invention is that stable ticagrelor iv formulations are provided. A further advantage of the present invention is that water-soluble ticagrelor solutions with improved stability suitable for use in the pharmaceutical trade are provided. The present invention has the advantage that patients with ticagrelor-responsive disease can be effectively treated even if they are unconscious or have swallowing problems. The ready-to-use liquid ticagrelor formulations provided by the present invention can eliminate the time required to crush tablets and dissolve the powder. This is particularly important in emergency situations requiring urgent treatment. It can also improve dose titration. [Background technology]

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

[0003] Ticagrelor was developed by AstraZeneca and approved for market entry by the European Medicines Agency in 2010 and the US Food and Drug Administration in 2011. It is marketed as a tablet in the US under the name Brilinta® and in the EU under the name Brilique®, and is not available in liquid form. Ticagrelor is an oral, reversible, direct-acting P2Y12 receptor antagonist that works by inhibiting platelet activation. Brilinta® tablets, in combination 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. In the US, Brilinta® 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 is known to be highly susceptible to degradation when exposed to light, heat and oxygen, and its limited solubility makes it extremely difficult to formulate in an aqueous solution. Although there remains a high need for liquid ticagrelor formulations, to our knowledge no commercial product with the desired solubility and long-term stability to meet the pharmaceutical industry's requirements has been successfully developed.

[0005] Sigfridsson et al. J Pharm Sci 100: 2194-2202, 2011 discloses a composition that is believed to be suitable for intravenous administration. The composition is based on nanoparticles of ticagrelor in combination with polyvinylpyrrolidone, the disodium salt of Aerosol AOT to stabilize the active ingredient, and 5 percent mannitol to obtain a nanosuspension. Aerosol AOT is believed to correspond to the sodium salt of dioctyl sulfosuccinate. The nanosuspension is reported to be stable for at least 10 months, but it has also been reported that the particles tend to aggregate and settle during storage. Therefore, samples are sonicated before intravenous administration. This is cumbersome for use as a pharmaceutical product and poses safety risks.

[0006] In the same paper, Sigfridsson et al. also reported that the concentration of ticagrelor in phosphate buffer at pH 7.4 under normal laboratory conditions of light and temperature decreased after one month, thus counter-indicating that considering a solution instead of a suspension.

[0007] The product characteristics of the drug Brilique® 60 mg film-coated tablets (Brilique INN-ticagrelor) state that for patients who are unable to swallow tablets, the tablets can be crushed, mixed with water and taken immediately. Alternatively, the mixture can be administered to the stomach via a nasogastric tube. The disadvantage of this formulation is that it is not readily available to the patient, and preparation is required immediately before administration. The formulation does not have long-term storage stability and the tablet particles settle on standing. Therefore, for emergency use, especially if the patient is unconscious, it is not a solution.

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

[0009] Yaye et al. (2014) studied the degradation of ticagrelor when exposed to heat, pH, peroxide, and light. They identified multiple degradants, DP1 to DP9, indicating that the molecule is highly susceptible to degradation. [Prior art documents] [Non-patent literature]

[0010] [Non-Patent Document 1] Sigfridsson et al. (J Pharm Sci 100: 2194-2202, 2011) Summary of the Invention [Problem to be solved by the invention]

[0011] In view of the above, it can be seen that there remains a need for a ticagrelor formulation that has good solubility of ticagrelor and excellent storage stability, especially in emergency use. The object of the present invention is to solve at least one or more of the problems described above. In particular, the object of the present invention is to provide a formulation containing ticagrelor as an active ingredient, which has improved solubility combined with long-term stability. Ticagrelor must be readily available to patients, and the formulation developed must use ingredients that are deemed acceptable by regulatory authorities (e.g., FDA Inactive Ingredients Guide-IIG restrictions). [Means for solving the problem]

[0012] In a first aspect of the present invention, the present invention provides an aqueous ticagrelor solution comprising ticagrelor and a solubilizer for ticagrelor, the solution having a storage stability of at least 3 months at 40°C and 75% relative humidity or at 25°C and 60% relative humidity.

[0013] Preferably, the solubilizer is cyclodextrin or Vitamin E TPGS.

[0014] The aqueous pharmaceutical ticagrelor solution according to an embodiment of the present invention preferably comprises an inclusion complex of ticagrelor in cyclodextrin, the aqueous pharmaceutical ticagrelor solution comprising: Ticagrelor at 0.10 to 14.0 mg / ml, Cyclodextrin (a solubilizer for ticagrelor) in an amount of 20-100 mg / ml to solubilize ticagrelor in a selected amount of aqueous pharmaceutical solution; and the pH of the composition is 5.5 to 9 (including the end point), 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.

[0015] Preferably, the osmotic pressure is 300 to 900 mOsm / kg.

[0016] Preferably, the cyclodextrin is selected from hydroxypropyl-β-cyclodextrin and sulfobutylether-β-cyclodextrin.

[0017] Preferably, organic co-solvents are excluded.

[0018] In yet another aspect, the present invention provides an aqueous pharmaceutical ticagrelor solution for use as a medicament. Preferably, the composition is administered as an infusion.

[0019] Preferably, the medicament is used for 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.

[0020] Preferably, the pharmaceutical agent contains, in addition to ticagrelor, acetylsalicylic acid or a salt thereof as a second active ingredient and is used for dual antiplatelet therapy (DAPT).

[0021] In yet another aspect, the present invention provides a ready-to-use infusion container comprising a composition of the present embodiments.

[0022] Preferably, the ready-to-use infusion container of the present embodiment contains 3000-16000 mg of cyclodextrin.

[0023] Preferably, a ready-to-use infusion container of an embodiment of the present invention contains 5% w / v dextrose or 0.9% w / v sodium chloride.

[0024] Preferably, the infusion container is a bag or a bottle.

[0025] In yet another aspect, the present invention provides a method for producing an aqueous pharmaceutical ticagrelor composition according to an embodiment of the present invention, comprising the steps of: - preparing an aqueous solution, preferably containing a buffer, more preferably a phosphate buffer, having a pH of 5.5-9; - Introducing an amount of cyclodextrin (solubilizer for tikageler) to encapsulate a predetermined amount of tikageler; - A certain amount of tikageler is added, thereby obtaining an inclusion complex of tikageler in cyclodextrin.

[0026] Preferably, heating is performed before adding tikageler.

[0027] Preferably, the D90 particle size of the tikageler is less than 10 micrometers when tested using a Malvern Mastersizer.

[0028] Alternatively, the aqueous ticagrelor composition of the present invention comprises ticagrelor as an active ingredient, the composition being a solution containing a water-soluble inclusion complex of ticagrelor in cyclodextrin, the composition being characterized in that it has a pH of 6-8 and a storage stability of at least 3 months at 40° C. and 75% relative humidity.

[0029] Preferably, the alternative aqueous ticagrelor composition has an osmolality of 350-900 mOsm / kg.

[0030] Preferably, the cyclodextrin in the alternative aqueous ticagrelor composition is selected from hydroxypropyl-β-cyclodextrin and sulfobutyl ether derivatives of β-cyclodextrin.

[0031] Preferably, the alternative aqueous ticagrelor composition contains 15-40% w / w cyclodextrin, preferably 15-40% w / w hydroxypropyl-β-cyclodextrin.

[0032] Preferably, the alternative aqueous ticagrelor composition contains 2 to 15 mg / ml of ticagrelor.

[0033] Preferably, the alternative aqueous ticagrelor composition is provided for infusion and has a volume of 15 to 30 ml.

[0034] Preferably, the alternative aqueous ticagrelor composition is provided for injection and has a volume of 5 to 15 ml.

[0035] Preferably, the alternative aqueous ticagrelor composition is provided with the proviso that organic co-solvents are excluded (not included). Preferably, the aqueous ticagrelor composition is free of polyethylene glycol.

[0036] Preferably, the ticagrelor has a D90 particle size of less than 10 micrometers as tested using a Malvern mastersizer.

[0037] More preferably, the alternative aqueous tikageler composition of the present invention contains 5 to 15 mg / ml tikageler, 15 to 40% w / w hydroxypropyl-β-cyclodextrin, 5 mM to 20 mM phosphate buffer, and optionally a tonicity adjuster, and has a pH of 5.5 to 8.

[0038] In yet another aspect, the alternative aqueous ticagrelor compositions of the present invention are used in ticagrelor-responsive medical treatments, preferably in ticagrelor-responsive medical treatments administered as an injection or infusion, nasogastric solution or drink.

[0039] Preferably, the alternative aqueous ticagrelor compositions of the present invention are used to treat acute coronary syndrome (ACS) or myocardial infarction (MI), ischemic stroke, transient ischemic attack (TIA), or to reduce platelet-tumor cell interactions in patients in need thereof.

[0040] Preferably, an alternative aqueous ticagrelor composition of an embodiment of the present invention preferably comprises acetylsalicylic acid or a salt thereof as a second active ingredient in addition to ticagrelor and is used for dual antiplatelet therapy (DAPT).

[0041] In yet another aspect, the present invention provides a unit dose composition for administering (delivering) 50 to 180 mg of ticagrelor, comprising an alternative aqueous ticagrelor composition according to an embodiment of the present invention.

[0042] Preferably, the unit dose composition contains 2000-4000 mg of cyclodextrin.

[0043] Preferably, the unit dose composition contains 5% dextrose in water as a diluent.

[0044] In yet another aspect, the present invention provides a method for producing an aqueous ticagrelor composition of the present invention, comprising the steps of: - preparing an aqueous solution, preferably containing a buffer, having a pH of 5.5 to 9, - introducing an amount of cyclodextrin for encapsulating a predetermined amount of ticagrelor; - A predetermined amount of ticagrelor is added, thereby obtaining an inclusion complex of ticagrelor in cyclodextrin.

[0045] Preferably, heating is performed before adding the ticagrelor.

[0046] In yet another aspect, the present invention provides an aqueous ticagrelor solution for intravenous administration for use in treating 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.

[0047] In yet another aspect, the present invention provides an aqueous ticagrelor solution for intravenous administration, preferably comprising, in addition to ticagrelor, acetylsalicylic acid or a salt thereof as a second active ingredient, for use in dual antiplatelet therapy (DAPT).

[0048] Preferably, the aqueous intravenous ticagrelor solution of the present invention for use as a medicament has a storage stability of at least 3 months under accelerated storage conditions of 40° C. and 75% relative humidity. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0049] The present invention provides a solution to the problem of obtaining a clear aqueous ticagrelor formulation with improved storage stability. The ticagrelor formulation of the present invention is suitable for intravenous administration. The cyclodextrin component is acceptable for medical use according to the Inactive Ingredients Guide (also known as the IIG List). This includes inactive ingredients and amounts that have been reviewed and approved by the Food and Drug Administration list for a dosage form and / or specific route of administration. D-α-tocopherol polyethylene glycol succinate, known as Vitamin E TPGS, is approved by the Food and Drug Administration (FDA) as a safe adjuvant.

[0050] All terms (including technical and scientific terms) used in the description of the present invention have the meanings commonly understood by those skilled in the art to which the present invention pertains, unless otherwise defined. Furthermore, definitions of terms are included to better understand the description of the present invention.

[0051] As used herein, the following terms have the following meanings: As used herein, "A," "an," and "the" refer to both the singular and the plural unless the context indicates otherwise. For example, "a surfactant" refers to one or more surfactants.

[0052] As used herein, "about" refers to a measurable value of a parameter, amount, duration, etc., and is intended to include a variation of no more than plus or minus 10% of the specified value, preferably no more than plus or minus 5%, more preferably no more than plus or minus 3%, even more preferably no more than plus or minus 1%, and even more preferably no more than plus or minus 0.1%, within the scope of the described invention. However, it will be apparent that the term "about" also specifically describes the value to which it refers. As used herein, "Include", "comprising" and "comprises" are inclusive or open-ended terms that identify, but do not exclude, the presence of what follows, such as components and the presence of additional unnamed components, features, elements, components, steps that are well known or described in the art.

[0053] The recitation of numerical ranges with endpoints (limits) includes all numbers and fractions subsumed within the range, as well as the endpoints.

[0054] As used herein, the term "% w / w" refers to weight percent, which is the weight ratio of the component to the total weight of the composition.

[0055] From a first perspective, the present invention provides an aqueous tikageler solution comprising tikageler and a solubilizer for tikageler, the solution having a storage stability of at least 3 months at 40 ° C and 75% relative humidity or at 25 ° C and 60% relative humidity. Most preferably, the solubilizer is cyclodextrin or vitamin E TPGS.

[0056] Preferably, the present invention provides an aqueous ticagrelor composition containing ticagrelor as an active ingredient, characterized in that the composition is a solution containing a water-soluble inclusion complex of ticagrelor in cyclodextrin, the pH of the composition is 5.5 to 9, preferably 5.8 to 8.5, more preferably 6.0 to 8.2, even more preferably 6.2 to 8.1, and most preferably 7.0 to 8.0. The pH range of 7.0 to 8.0 is particularly important for the physiological acceptability of the intravenous formulation to the patient.

[0057] As used herein, the term "ticagrelor" refers to ticagrelor in free form, its pharma- ceutically acceptable solvates, hydrates, enantiomers, polymorphs or mixtures thereof. Preferably, ticagrelor is used in free form.

[0058] The chemical structure of ticagrelor is: JPEG2025515559000001.jpg69127

[0059] Ticagrelor has six stereocenters, and therefore has 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, called polymorphs I, II, III and IV, are available. Each polymorph exhibits 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. In the literature, polymorph form II is described as the most stable crystalline form of ticagrelor.

[0060] Ticageler has low solubility in aqueous media, which is independent of pH. This property of not ionizing in the physiological pH range makes the development of liquid formulations particularly difficult.

[0061] The inventors have discovered that tikageler can be solubilized by using cyclodextrin. Long-term storage stability is achieved by using an aqueous solution with a pH range of 5.5 to 9, particularly pH 7.0 to 8.0. The use of organic cosolvents or surfactants is avoided, thereby reducing the risk of degradation. In particular, the use of polyethylene glycol is avoided. The present invention provides a clear tikageler formulation with good solubility and long-term storage stability required for pharmaceutical and medical formulations.

[0062] The term "inclusion complex" as used herein means a chemical complex in which one compound, the host, has a cavity that can accommodate a guest compound. The interaction between the host and the guest involves van der Waals bonding. A suitable compound for providing this inclusion complex is cyclodextrin.

[0063] Cyclodextrins are cyclic carbohydrates derived from starch, and unmodified cyclodextrins differ from each other by the number of glucopyranose units linked together into a cylindrical structure. The parent cyclodextrins contain six, seven or eight glucopyranose units and are called α-, β- and γ-cyclodextrins, respectively. Each cyclodextrin subunit has secondary hydroxyl groups at positions 2 and 3 and a primary hydroxyl group at position 6. Cyclodextrins can be depicted as hollow truncated cones with a hydrophilic exterior and a hydrophobic interior cavity. In aqueous solution, these hydrophobic cavities provide havens for hydrophobic organic compounds, which can accommodate all or part of the structure. This process, known as inclusion complexation, increases the apparent aqueous solubility and stability of complexed drugs, although the degree of stabilization varies from drug to drug. The complexes are stabilized by hydrophobic interactions and do not involve the formation of covalent bonds.

[0064] Chemical modifications of the parent cyclodextrin (usually to the hydroxyl moieties) result in derivatives with improved safety while maintaining or enhancing the complexing ability of the cyclodextrin. Many derivatized cyclodextrins have been produced, but only two are commercially viable. The 2-hydroxypropyl derivative (HP-β-CD or HPβCD) is a neutral molecule commercially developed by Janssen and others, and the sulfoalkyl ether derivative (SAE-β-CD or SAE-CD) was developed by CyDex Pharmaceuticals, Inc. SAE-CD is a class of negatively charged cyclodextrins that differ in the type of alkyl spacer, salt form, degree of substitution, and starting parent cyclodextrin. The sodium salt of the sulfobutyl ether derivative of β-cyclodextrin (SBE7-β-CD), with an average of about seven substituents per cyclodextrin molecule, is commercialized as CAPTISOL® cyclodextrin by CyDex Pharmaceuticals, Inc. (Kansas).

[0065] Preferably, the cyclodextrin is selected from hydroxypropyl-β-cyclodextrin and sulfobutyl ether derivatives of β-cyclodextrin.

[0066] More preferably, the cyclodextrin is hydroxypropyl-β-cyclodextrin. The results of selecting HPβCD cyclodextrin were superior to those of selecting SBECD cyclodextrin. The amount of HPβCD required to solubilize tikageler was less than that of SBECD cyclodextrin. Compared to SBECD, HPβCD gave clear aqueous tikageler solutions over a wider concentration range. The results are shown in Example 1.

[0067] In a preferred embodiment, ticagrelor is the only active pharmaceutical ingredient present in the composition. Alternatively, additional active ingredients can be included. Preferably, the additional active ingredient is not prasugrel.

[0068] The present invention provides an aqueous liquid formulation comprising an inclusion complex of tikageler and an aqueous liquid carrier. Concentrated ticagrelor compositions for bolus injection or short-term infusion

[0069] Preferably, the aqueous ticagrelor composition of the present invention is provided for injection and has a volume of 15 to 40 ml, more preferably a volume of 20 to 35 ml, and most preferably a volume of 25 to 30 ml. This volume range is typical for use in intravenous administration of compositions according to embodiments of the present invention and aqueous ticagrelor compositions.

[0070] The aqueous ticagrelor solution of the present invention can be administered as an injection instead of intravenously. The volume for this purpose is preferably between 5 and 15 ml. Injections are particularly suitable for the treatment of acute conditions, as they make ticagrelor rapidly available within a short period of time.

[0071] In a preferred embodiment, the aqueous ticagrelor composition contains 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 suitable for treatment by injection or short-term infusion. If a smaller amount is selected, a larger volume is administered to patients in need of ticagrelor-responsive medical indications. Higher amounts of ticagrelor can cause problems with the solubility of the active ingredient, especially when administered by injection in small amounts.

[0072] Most preferably, the aqueous tikageler solution contains 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 sufficient to provide a therapeutically required amount of cyclodextrin and a clear tikageler solution. This range is acceptable for medical administration.

[0073] In a preferred embodiment of the above aqueous tikageler composition according to the present invention, organic co-solvents are excluded (not included). It is not necessary to use organic co-solvents to improve the solubility of tikageler. Avoiding organic co-solvents improves the suitability of the product for intravenous administration. The aqueous solution does not contain polyethylene glycol.

[0074] Preferably, the aqueous ticagrelor composition has an osmolality of 350-900 mOsm / kg, which is advantageous for intravenous administration to patients in need of ticagrelor treatment.

[0075] In a preferred embodiment of the aqueous ticagrelor composition, the D90 particle size of ticagrelor is less than 10 micrometers, more preferably the D90 particle size is less than 9 micrometers, even more preferably the D90 particle size is less than 8 micrometers, and most preferably the D90 particle size is less than 7 micrometers. The selection of the particle size makes it easier to incorporate ticagrelor into cyclodextrin and improves the solubility of ticagrelor in the cyclodextrin inclusion complex.

[0076] Methods for measuring particle size of active ingredients are well known to those skilled in the formulation art. The method used in the present invention is the Malvern Mastersizer dry powder method.

[0077] The shelf life of the aqueous ticagrelor solution according to the present invention is longer than that of currently available solutions obtained by crushing Brilinta® tablets and mixing them with water. The storage stability achieved by the present invention is particularly important for the use of aqueous ticagrelor solutions in pharmaceutical supply and storage.

[0078] In a preferred embodiment of the aqueous ticagrelor composition, the composition has a storage stability of at least 3 months under accelerated storage conditions at 40° C. and 75% relative humidity (RH). More preferably, the storage stability is at least 6 months, even more preferably at least 9 months, and most preferably at least 12 months. A satisfactory stability of 6 months at 40° C. and 75% RH corresponds to a storage period of 24 months at room temperature at 25° C.

[0079] As used herein, "storage stable" means total impurity levels of less than 0.5%.

[0080] Most preferably, the aqueous ticagrelor composition is a solution consisting of the following components: Ticagrelor at 5-15mg / ml; 15-40% w / w of hydroxypropyl-β-cyclodextrin, 5mM to 20mM phosphate buffer, The pH is 5.5 to 8.

[0081] The composition is simple and easy to manufacture. The limited number of components reduces the formation of impurities and by-products.

[0082] The aqueous ticagrelor composition may optionally contain a tonicity adjuster such as sodium chloride. Preferably, the aqueous ticagrelor composition has an osmotic pressure of 350 to 900 mOsm / kg, more preferably 360 to 800 mOsm / kg, even more preferably 370 to 700 mOsm / kg, and most preferably 380 to 600 mOsm / kg.

[0083] In some embodiments, the aqueous pharmaceutical ticagrelor solution comprises a 5% w / v dextrose solution.

[0084] In yet another aspect, the present invention provides an aqueous ticagrelor composition for use in ticagrelor-responsive medical treatment. The aqueous ticagrelor composition is as described above.

[0085] Preferably, the aqueous ticagrelor composition is provided for intravenous administration, and the composition is administered as an injection or short-term infusion. This form is advantageous for unconscious patients who require immediate treatment. The short-term infusion is preferably for 5 to 30 minutes, more preferably 10 to 25 minutes, and most preferably 15 to 20 minutes.

[0086] In another embodiment, the aqueous ticagrelor composition is provided as a solution for nasal gastric administration or as a drink, which is advantageous for conscious patients who have difficulty swallowing.

[0087] Preferably, the aqueous ticagrelor composition according to 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.

[0088] The advantages of the aqueous compositions according to embodiments of the present invention in medical therapy are that they act faster than tablets, have higher bioavailability than tablets, and provide a solution for patients who have difficulty swallowing tablets. Intravenous infusion or injection is advantageous, especially in acute situations. The availability of ready-to-use aqueous solutions according to embodiments of the present invention is preferable to crushing tablets and adding them to water, and to dissolving orally disintegrating tablets in water, in terms of time savings and accuracy of administration.

[0089] More preferably, the aqueous ticagrelor composition according to the present invention is for use in monotherapy or dual antiplatelet therapy (DAPT). Preferably, the dual antiplatelet therapy includes, in addition to ticagrelor, acetylsalicylic acid or a salt thereof as a second active ingredient.

[0090] In a further aspect, the present invention provides a unit dose composition for delivering 15 to 180 mg of ticagrelor comprising an aqueous ticagrelor solution according to an embodiment of the present invention. The dose of ticagrelor for administration to a patient can range from 15 mg to 180 mg, more preferably from 30 mg to 90 mg, and most preferably from 65 to 75 mg.

[0091] Preferably, the unit dose composition contains from 2000 to 4000 mg of cyclodextrin, more preferably from 2200 to 3000 mg of cyclodextrin, even more preferably from 2400 to 2800 mg of cyclodextrin, and most preferably 2500 mg of cyclodextrin.

[0092] In a preferred embodiment of the unit dose composition for bolus injection or short-term infusion according to the present invention, the unit dose composition contains 5% dextrose in water (D5W) as a diluent. Saline and Ringer's lactate solution were not suitable as diluents as they gave cloudy solutions.

[0093] As used herein, "saline" is a general term referring to a solution of 0.90% w / v sodium chloride, 308 mOsm / l or 9.0 g / l. Synonyms are normal saline or isotonic saline.

[0094] As used here, "Ringer's lactate solution" refers to 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 Ringer's lactate 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. Ringer's lactate solution has an osmolality of 273 mOsm / l and a pH of 6.5.

[0095] 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 advantage of the composition of the present invention is that it is advantageous for people who cannot take in water orally and who have developed or are at risk of developing dehydration or hypovolemia.

[0096] In a further aspect, the present invention provides a method for treating a patient suffering from a ticagrelor-responsive disease. The patient is treated with a clear, aqueous ticagrelor solution having a stability of at least 1 month, preferably 3 months, more preferably at least 6 months. Preferably, the clear, aqueous ticagrelor solution is a ready-to-use solution. More preferably, a ticagrelor-cyclodextrin inclusion complex is provided in which ticagrelor is encapsulated in cyclodextrin. Preferably, the clear, aqueous ticagrelor solution has a pH of 5.5-9, more preferably a physiological pH of 7-8. More preferably, the clear, aqueous ticagrelor solution contains a buffer, most preferably a phosphate buffer.

[0097] From a fourth aspect, the present invention provides a method for producing an aqueous ticagrelor composition according to an embodiment of the present invention, comprising the steps of: - Prepare an aqueous solution with a pH of 5.5-9, - introducing an amount of cyclodextrin for encapsulating a predetermined amount of ticagrelor; - Add a predetermined amount of ticagrelor to obtain an inclusion complex of ticagrelor in cyclodextrin.

[0098] The aqueous solution preferably has a pH of 5.8-8.5, more preferably 6.0-8.2, most preferably 7.0-8.0. To maintain this pH range, the solution preferably contains a buffer.

[0099] Preferably, a heating step is applied before adding the ticagrelor, which is beneficial in reducing the amount of cyclodextrin required to dissolve the selected amount of ticagrelor. The ticagrelor is preferably added to the solution at a temperature of 30-45°C.

[0100] From a fifth aspect, the present invention provides a medical use of a ticagrelor intravenous composition.

[0101] 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 patients in need thereof.

[0102] The present invention further provides an aqueous ticagrelor solution for intravenous administration for use in dual antiplatelet therapy (DAPT), preferably comprising, in addition to ticagrelor, acetylsalicylic acid or a salt thereof as a second active ingredient.

[0103] In a preferred embodiment, the aqueous ticagrelor intravenous solution has a storage stability of at least 3 months at accelerated storage conditions of 40° C. and 75% relative humidity.

[0104] The components of the aqueous ticagrelor intravenous solution are preferably as described above.

[0105] Dilute Ticagrelor Compositions for Injection In a further aspect, the present invention provides an aqueous pharmaceutical ticagrelor solution comprising an inclusion complex of ticagrelor in cyclodextrin, the aqueous pharmaceutical ticagrelor solution comprising 0.10-14.0 mg / ml ticagrelor and 20-100 mg / ml cyclodextrin in an amount to solubilize the ticagrelor in a selected volume of the aqueous pharmaceutical solution, the composition having a pH (including endpoint) of 5.5-9, and the aqueous pharmaceutical solution having a volume of 25-1000 ml.

[0106] Surprisingly, it was found that ticagrelor can be solubilized in aqueous media at dilute concentrations, which is of interest in the pharmaceutical field for the treatment of ticagrelor-responsive conditions.

[0107] Preferably, the aqueous pharmaceutical ticagrelor solution contains 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, and most preferably 0.4-5.0 mg / ml or 0.5-2.0 mg / ml ticagrelor. In a preferred embodiment, ticagrelor is the only active ingredient present in the aqueous pharmaceutical ticagrelor solution.

[0108] In a preferred embodiment, the osmotic pressure is 300 to 900 mOsm / kg, more preferably 50 to 850 Osm / kg, even more preferably 400 to 800 mOsm / kg, and most preferably 450 to 750 mOsm / kg.

[0109] 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.

[0110] Preferably, the pH of the aqueous pharmaceutical ticagrelor solution is 6.0 to 8.5, more preferably 6.5 to 8.0, even more preferably 6.8 to 7.8, and most preferably about 7.5.

[0111] 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, and most preferably 100 to 250 ml.

[0112] In a preferred embodiment, organic co-solvents such as polyethylene glycol are excluded from the composition of the present invention. In a preferred embodiment, surfactants are excluded from the composition of the present invention. In a most preferred embodiment, organic co-solvents and surfactants are excluded (not included) from the composition of the present invention.

[0113] The diluted aqueous pharmaceutical tikageler solution according to the embodiment of the present invention has a storage stability of at least 3 months at 25 ° C and a relative humidity of 60%. More preferably, the aqueous pharmaceutical tikageler solution has a storage stability of at least 4, 5, 6, 12, 18 or 24 months measured at 25 ° C and a relative humidity of 60%.

[0114] In some embodiments, the aqueous pharmaceutical ticagrelor solution comprises a pharma- ceutically 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, more preferably 0.0108M to .010M, and most preferably 10 mM. More preferably, the buffer is a 10 millimolar (mM) phosphate buffer. 1 millimole = 1 mM = 1 mmol per liter.

[0115] In some embodiments, the aqueous pharmaceutical ticagrelor solution comprises a 5% w / v dextrose solution.

[0116] In a further aspect, the aqueous pharmaceutical tikageler solution according to an embodiment of the present invention is used as a medicament.

[0117] In a preferred embodiment, the aqueous pharmaceutical ticagrelor solution is administered as an infusion.

[0118] Preferably, the aqueous pharmaceutical ticagrelor solution according to the present invention is used to treat acute coronary syndrome (ACS), myocardial infarction (MI), ischemic stroke, transient ischemic attack (TIA) or to reduce platelet-tumor cell interactions in patients in need thereof.

[0119] Preferably, the aqueous pharmaceutical ticagrelor solution according to an embodiment of the present invention preferably contains acetylsalicylic acid or a salt thereof as a second active ingredient in addition to ticagrelor and is used for dual antiplatelet therapy (DAPT).

[0120] 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.

[0121] Preferably, the composition contains 3000-16000 mg, more preferably 4000-15000 mg, even more preferably 5000-10000 mg, and most preferably 6000-8000 mg of cyclodextrin. The cyclodextrin is preferably hydroxypropyl-β-cyclodextrin. Most preferably, the cyclodextrin is (2-hydroxypropyl)-β-cyclodextrin.

[0122] Preferably, the composition contains 5% w / v dextrose or 0.9% w / v sodium chloride, these diluents contributing to the suitability of the composition for use in intravenous administration.

[0123] Preferably, the ready-to-use infusion container is a bag or a bottle.

[0124] In a preferred embodiment, the only active ingredient present in the ready-to-use infusion container is ticagrelor.

[0125] In a final aspect, the present invention provides a method for producing an aqueous pharmaceutical ticagrelor composition according to an embodiment of the present invention, comprising the following steps: - preparing an aqueous solution, preferably containing a buffer, more preferably a phosphate buffer, having a pH of 5.5-9; - introducing an amount of cyclodextrin for encapsulating a predetermined amount of tikageler; - A predetermined amount of tikageler is added, thereby obtaining an inclusion complex of tikageler in cyclodextrin.

[0126] Preferably, heating is performed before adding tikageler, which is beneficial for obtaining a tikageler-cyclodextrin inclusion complex.

[0127] In a preferred embodiment, the tikageler used in the method according to the present invention has a D90 particle size of less than 10 micrometers as tested using a Malvern Mastersizer.

[0128] Alternative solubilizers for ticagrelor The inventors have discovered that Vitamin E TPGS can be used as a solubilizer for ticagrelor in the preparation of aqueous ticagrelor solutions with improved storage stability.

[0129] In a final aspect, the present invention provides an aqueous ticagrelor solution comprising ticagrelor and a solubilizer for ticagrelor, the solubilizer being vitamin E TPGS, the solution having a storage stability of at least 3 months when measured at 40°C and 75% relative humidity or 25°C and 60% relative humidity.

[0130] Preferably, the aqueous solution of ticagrelor containing Vitamin E TPGS as a solubilizing agent is used as a pharmaceutical, preferably for parenteral administration, more preferably for intravenous administration.

[0131] Preferably, the aqueous ticagrelor solution containing Vitamin E TPGS as a solubilizing agent does not contain any organic co-solvents.

[0132] Preferably, the aqueous solution of ticagrelor containing vitamin E TPGS as a solubilizing agent contains 0.6 to 20 mg of ticagrelor per ml of solution. More preferably, the concentration of ticagrelor is 1.0 to 15 mg / ml, even more preferably 5.0 to 10 mg / ml, and most preferably 6.0 to 9.0 mg / ml.

[0133] Preferably, the above ticagrelor aqueous solution contains 2.5 to 10.0 w / v% vitamin E TPGS.

[0134] Preferably, the aqueous ticagrelor solution contains 2.5 w / v Vitamin E TPGS in water and 10 mg of ticagrelor per ml of solution.

[0135] Preferably, the aqueous tikagrelor solution contains 5.0 w / v Vitamin E TPGS in water and 10-12 mg of ticagrelor per ml of solution.

[0136] Preferably, the aqueous tikagrelor solution contains 10.0 w / v Vitamin E TPGS in water and 10-15 mg of ticagrelor per ml of solution.

[0137] The present invention will be further described below with reference to examples, but the present invention is not limited to the following examples. EXAMPLES

[0138] Example 1 In the first example, the solubilization of ticagrelor was compared using two different types of cyclodextrin. Unbuffered stock solutions of HPβCD or SBECD were prepared in water at target concentrations of 20 w / w%, 25 w / w%, 30 w / w%, 35 w / w% and 40 w / w%. Ticagrelor was added slowly while vortexing. Ticagrelor was used at concentrations of 5, 10 or 14 mg / ml in ultrapure water (Milli-Q). Ticagrelor-cyclodextrin solutions were placed on a shaking platform. No sonication or heating was applied.

[0139] The results in Tables 1 and 2 show that HPβCD can dissolve ticagrelor over a wider range of cyclodextrin and ticagrelor concentrations tested. Clear aqueous solutions containing 5 mg / ml ticagrelor in HPβCD were obtained at 25 w / w%, 30 w / w%, 35 w / w% and 40 w / w% HPβCD.

[0140] [Table 1]

[0141] [Table 2]

[0142] In conclusion, ticagrelor can be dissolved by placing it on a shaking table. No sonication was applied. HPβCD 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 for at least 3 days at room temperature and for several days at 4°C.

[0143] Example 2 After the experiment of Example 1, further optimization was performed to select an appropriate pH range to ensure the long-term stability of the aqueous tikageler-cyclodextrin inclusion complex.

[0144] The following compositions were prepared as shown in Table 3. [Table 3]

[0145] HPβCD was dissolved in a separately prepared buffer solution of pH 4.5, 5.5 or 6.5 in water. After a clear solution was obtained, tikageler was dissolved in this buffer solution with constant stirring. The tikageler in the buffer solution was filtered through a 0.22 micron filter and filled into USP Type I glass vials. The vials were stored stoppered. All precautions were observed during manufacturing, e.g. N 2 Purging and direct exposure to light were avoided. Vials were stored at 40°C and 75% relative humidity (RH).

[0146] To determine the stability of the formulation, each batch was evaluated using the related substance method by HPLC. The data for each batch are listed below in Table 4.

[0147] The impurities in the drug product were analyzed by gradient HPLC using a YMC-Pack Pro C18 column (100x4.6mm, S-3μm 12nm). Good separation was obtained for all impurities.

[0148] 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.

[0149] Regioisomeric 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.

[0150] Acetal impurity: 2-[[(3aR,4S,6S,6aS)-6-[7-[[1R,2S)-2-(3,4-difluorophenyl)-cyclopropyl]amino]-5-(propylsulfanyl)-3H-[1,2,3]triazolo-[4,5-d]pyrimidin-3-yl]-2,2-dimethyltetrahydro-2H-3aHcyclopenta[d][1,3]dioxol-4-yl]oxy]ethan-1-ol. This is a process related impurity.

[0151] Triol impurity: (1S,2R,3S,4R)-4-(7-((1R,2S)-2-(3,4-difluorophenyl)cyclopropylamino)-5-(propylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)cyclopentane-1,2,3-triol. This is a process related impurity.

[0152] After 4 weeks at 40°C and 75% RH, only the redimeric impurity was observed to increase at a level of approximately 0.3%. The specification limit is 0.3%. Therefore, to further optimize the product stability, a pH range of 7-8 was investigated.

[0153] Example 3 Following the experiment of Example 2, a storage stability study at pH 7.5 was carried out.

[0154] First, HPβCD was dissolved in a pH 7.5 phosphate buffer solution prepared in water. After a clear solution was obtained, ticagrelor was dissolved in the solution under constant stirring. The solution was filtered through a 0.22 micrometer filter and filled into USP Type I amber glass vials. The vials were stored with stoppers. During the preparation, N 2 All precautions were taken, such as purging and avoiding direct exposure to light.

[0155] [Table 4]

[0156] [Table 5]

[0157] [Table 6]

[0158] From the stability study results summarized in Table 6, it was concluded that good storage stability was obtained under accelerated storage conditions of 40°C and 75% relative humidity. The rediomer impurity was well controlled and other impurities were not of concern.

[0159] Example 4 In yet another experiment, heating at 40°C was applied to optimize HPβCD concentrations below 40% w / w to facilitate dissolution of the target ticagrelor dose at this concentration, where a clear solution is difficult to obtain.

[0160] Table 7 shows the direct physical stability data obtained from a 5 mg / ml concentrate of ticagrelor and the data from the aggregation test (20 μl of sample material in 1 ml dilution). Table 7 includes data on assay, purity, osmolality and pH.

[0161] [Table 7]

[0162] For the 5 mg / ml ticagrelor formulation, 32.5% w / w HPβCD was chosen because of poor physical stability when diluted with saline. The undiluted concentrate was stable in the refrigerator even at HPβCD concentrations as low as 22.5% w / w. This concentration resulted in a nearly isotonic formulation.

[0163] In conclusion, 5-15 mg / ml of ticagrelor can be dissolved without heating in a concentration range of 20-40% w / w HPβCD. Good solubility was obtained even at lower concentrations of HPβCD, e.g. 15-20% w / w, by heating to give a clear solution.

[0164] At least 15% w / w HPβCD was required to obtain a clear, storage-stable ticagrelor solution of a suitable concentration for injection or intravenous administration.

[0165] Example 5 From the results obtained in Example 4, it can be seen that the concentrations of the excipients are such that the resulting ticagrelor solution is hypertonic. The osmolality and pH of several batches were checked. Each solution has 19 mM phosphate buffer and pH 7.5. The results are shown in Table 8.

[0166] [Table 8]

[0167] Dilution tests were performed to find a suitable diluent.

[0168] 5 mg / ml ticagrelor-cyclodextrin solutions containing various amounts of HPβCD were diluted with saline, 5% dextrose solution or Ringer's lactate solution. Stability was screened. The results of ticagrelor concentration: 0.1 mg / ml when diluted with dextrose or saline are summarized in Table 9.

[0169] [Table 9]

[0170] Furthermore, we performed screening to examine the effect of buffer concentration on pH and osmolality. The results are summarized in Table 10.

[0171] [Table 10]

[0172] It was concluded that the pH 7.5 phosphate buffer had little effect on osmolality at different buffer concentrations. Except for the 0.19 mM buffer, the buffer strength was too weak to change the pH.

[0173] Example 6 In yet another example, the effect of particle size on solubility was tested. Two different particle sizes of the active ingredient ticagrelor (5.5 micrometers and 15 micrometers) were screened. pH and osmolality were not affected. As summarized in Table 11, the smaller the particles, the shorter the dissolution time.

[0174] Micronized tikageler significantly improves dissolution time. Therefore, micronized tikageler with a D90 of less than 10 micrometers is desirable. As used herein, the term "D90" means that at least 90% of the particles present are smaller than the target particle size. However, it is understood that there may be variation in the input particle size distribution (PSD) of tikageler, which will affect the dissolution rate of tikageler.

[0175] [Table 11]

[0176] Example 7 A 12-week / 3-month stability study was conducted to optimize the HPβCD concentration and pH of the intravenous solution. A composition of 32.5% w / w HPβCD containing 5 mg / ml ticagrelor at pH 7-8 was prepared, stored, and its stability was tested periodically. A comparison of the stability profiles at three different pH values ​​(7, 7.5, and 8) was performed as follows. The buffer concentration was kept constant at 19 mM for all manufacturing processes in the three formulations. The results are summarized in Tables 12 to 14.

[0177] [Table 12]

[0178] [Table 13]

[0179] [Table 14]

[0180] From the above data, it was concluded that the tikageler solution in HPβCD was stable in the pH range of 7 to 8.

[0181] Example 8 To investigate the potential effect of packaging materials on the stability of the ticagrelor-cyclodextrin inclusion complex, a composition containing 32.5% w / w HPβCD was prepared using the same procedures and precautions as in the above test, and samples were placed in clear and amber glass vials and stored at 40 ° C / 75% RH. The results are shown in Tables 15 and 16.

[0182] Accelerated storage stability testing showed no significant differences between the two after three months. All samples remained clear aqueous solutions. The pH of the samples remained stable and impurities did not change significantly.

[0183] Both clear and amber glass vials can be used.

[0184] When compared to the results of accelerated storage stability tests of tikageler solutions without cyclodextrin, it is clear that the use of cyclodextrin is important to achieve good stability. In the absence of cyclodextrin, 6 to 8 impurities were generated during storage. These impurities were not found in the selected formulation.

[0185] [Table 15]

[0186] [Table 16]

[0187] Surprisingly, it was concluded that ticagrelor solutions could be stabilized by HPβCD in both amber and clear glass vials.

[0188] Example 9 Further embodiments provided by the present invention are summarized in Table 17. Further improvements were attempted at different concentrations to achieve higher solubility of tikageler. For example, at 40% w / wHPβCD, a solubility of 13 mg / ml of tikageler was possible.

[0189] [Table 17]

[0190] As a result of the investigation, it was observed that a concentration of 5-13mg / ml of ticagrelor solution can be achieved using 20-40% w / w HPβCD. The volume of the filling contents can be modified based on the required dosage.

[0191] Surprisingly, it was found that the target dose of ticagrelor in a small volume of 5-15 mg / ml can be achieved by adjusting the HPβCD% to the full available volume of the ready-to-inject formulation. The ability to accommodate the ticagrelor dose in a volume of 5-15 ml is very important, as this is the typical bolus injection volume.

[0192] Example 10 In yet another example, the maximum solubility of tikageler in HPβCD solution was investigated without the use of heat. The results are summarized in Table 18. Depending on the amount of ticagrelor administered to the patient and the sample volume limitations dictated by administration by injection or infusion, 2000-4000 mg of HPβCD per 10 ml vial will be required to dissolve 65-75 mg of ticagrelor.

[0193] [Table 18]

[0194] Surprisingly, the solutions shown in Table 18 are compatible with diluents, particularly to provide an infusion solution containing 5% dextrose in water.

[0195] Example 11 In another embodiment of the present invention, a very stable and transparent solution of tikageler is obtained by applying appropriate heat to the solution during preparation, providing a completely transparent solution of the desired concentration of HPβCD and tikageler in the formulation.

[0196] To investigate the effect of temperature and holding time, new compositions were prepared as shown in Table 19 below.

[0197] [Table 19]

[0198] The first step was to prepare a pH 7.5 phosphate buffer solution and heat this buffer solution to 40°C-45°C. HPβCD was added to the buffer solution with continuous mixing. Once a clear solution was obtained, tikageler was dispersed in the HPβCD solution and mixed until a clear solution was obtained. Depending on the batch size, this usually takes between 30 minutes and 4 hours. The solution was then filtered through a 0.22 micron filter and packaged into appropriate clear or amber glass vials.

[0199] [Table 20]

[0200] [Table 21]

[0201] [Table 22]

[0202] Holding time studies at temperatures between 25°C and 45°C showed that ticagrelor could be stabilized even at 30% w / w HPβCD, even after prolonged heating of the solution and after the bulk was kept at elevated temperatures.

[0203] Example 12 Aqueous ticagrelor solution for oral administration This example illustrates an aqueous ticagrelor formulation provided for oral administration, the composition of which is shown in Table 23.

[0204] [Table 23]

[0205] The manufacturing process for this oral solution is simple. Dissolve the preservatives in propylene glycol. Dissolve HPβCD in water and add ticagrelor with continuous stirring and mix with the propylene glycol solution. Add the remaining ingredients to the solution and adjust the pH to 7-8.

[0206] Ready-to-use formulation Example 13 To make a ready-to-use aqueous ticagrelor composition, several diluted ticagrelor compositions were made and tested for solubility and stability.

[0207] [Table 24]

[0208] [Table 25]

[0209] [Table 26]

[0210] [Table 27]

[0211] [Table 28]

[0212] Manufacturing process for ready-to-use infusion products The manufacturing process to produce a ready-to-use solution is as follows: In each case, the aforementioned solvent is prepared and placed in a beaker and heated to 40°C, then HPβCD is added and stirred to obtain a clear solution. The active ingredient ticagrelor is then added with stirring at 40°C for a period of time to obtain a clear solution. The solution is filtered through a 0.22 micron filter and aseptically filled into sterile glass bottles or infusion bags.

[0213] To obtain a stable ready-to-use infusion solution of ticagrelor, 24 mg / ml to 350 mg / ml of HPβCD was required. The amount of cyclodextrin required varied depending on the volume of the infusion medium.

[0214] Ticagrelor is an active ingredient that is insoluble in water. The more it is present in a diluted aqueous solution, the greater the tendency for it to precipitate. As the dilution factor of ticagrelor increases from 30 ml to 100 ml to 200 ml, the amount of cyclodextrin must be increased proportionately. However, for volumes of 650 ml and above, 16 g of cyclodextrin was found to be sufficient to keep ticagrelor in aqueous solution.

[0215] Note that no organic co-solvents, surfactants or other solubilizing agents were used.

[0216] Alternative preparation method starting from concentrated tikageler solution One 8 ml vial containing 65 mg / vial of ticagrelor and approximately 3 g of HPβCD can be diluted with 25 ml of 5 w / v% dextrose to obtain a final volume of 33 ml of a clear solution.

[0217] However, this was not possible when a 0.9 w / v% NaCl solution was used as a diluent for the concentrated tikageler solution.

[0218] This is important in medical procedures where concentrated ticagrelor aqueous compositions are mixed with other drugs, as ticagrelor may precipitate, rendering the combination product unsuitable for intravenous administration.

[0219] Alternative solubilizers for ticagrelor Example 14 Aqueous ticagrelor solutions were prepared using vitamin E TPGS as a solubilizing agent for ticagrelor. Water-soluble vitamin E TPGS was added to water to obtain aqueous vitamin E TPGS solutions with different concentrations of 2.5, 5.0, and 10.0 w / v%. Ticagrelor was added in small portions to these solutions, which were kept at a temperature of 45°C + / - 5°C.

[0220] [Table 29]

[0221] 20 ml of each dilution was then used in the second stage of testing: 10 mg of ticagrelor was added to each 20 ml dilution, or reduced to 5 mg if dissolution took too long.

[0222] [Table 30]

[0223] The following was observed: 10 mg of ticagrelor dissolved after 5 to 10 minutes. 2.5% Vitamin E TPGS solution, saturated at 11.6 mg / ml; 5.0% Vitamin E TPGS solution, saturated at 14.9 mg / ml; 10.0% Vitamin E solution in TPGS, saturated at 19.8 mg / ml.

[0224] The resulting aqueous tikageler solution can be stored for at least 3 months at 40°C and 75% relative humidity or at 25°C and 60% relative humidity.

[0225] Although it is soluble, its storage stability is insufficient. Polyethylene glycol can dissolve tikageler, but polyethylene glycol is easily decomposed and impurities are produced.

Claims

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

2. 2. The aqueous pharmaceutical ticagrelor solution of claim 1, comprising an inclusion complex of ticagrelor in cyclodextrin, the aqueous pharmaceutical ticagrelor solution comprising 0.10-14.0 mg / ml ticagrelor and 20-100 mg / ml cyclodextrin (solubilizer for ticagrelor) in an amount to solubilize the ticagrelor in a selected volume of the aqueous pharmaceutical solution, the aqueous pharmaceutical ticagrelor solution composition having a pH (including endpoint) of 5.5-9, the aqueous pharmaceutical solution having a volume of 25-1000 ml, and having 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, having an osmotic pressure of 300 to 900 mOsm / kg.

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

5. The aqueous pharmaceutical tikageler solution according to any one of claims 2 to 3, which does not contain an organic cosolvent.

6. The aqueous pharmaceutical tikageler solution according to any one of claims 2 to 5, which is used as a pharmaceutical.

7. The aqueous pharmaceutical ticagrelor solution according to claim 6, wherein the composition is administered as an infusion.

8. The 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. Use in dual antiplatelet therapy (DAPT), preferably comprising acetylsalicylic acid or a salt thereof as a second active ingredient in addition to ticagrelor, Aqueous pharmaceutical ticagrelor solution according to any one of claims 6 to 8.

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

11. 11. The ready-to-use infusion container according to claim 10, containing 3,000 to 16,000 mg of cyclodextrin.

12. 12. A ready-to-use infusion container according to claim 10 or 11, containing 5% w / v dextrose 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 producing the aqueous pharmaceutical ticagrelor composition according to any one of claims 2 to 13, comprising the following steps: - preparing an aqueous solution, preferably containing a buffer, more preferably a phosphate buffer, having a pH of between 5.5 and 9; - Introducing an amount of cyclodextrin (solubilizer for tikageler) to include a predetermined amount of tikageler; - A certain amount of tikageler is added to obtain an inclusion complex of tikageler in cyclodextrin.

15. The method of claim 14, wherein heating is performed before adding tikagrelor.

16. The method of claim 14 or 15, wherein the D90 particle size of the ticagrelor is less than 10 micrometers when tested using a Malvern Mastersizer.

17. An aqueous ticagrelor composition comprising ticagrelor as an active ingredient, The aqueous ticagrelor composition of claim 1, characterized in that the composition is a solution containing a water-soluble inclusion complex of ticagrelor in cyclodextrin, the pH of the composition is 6 to 8, and the storage stability is at least 3 months at 40°C and 75% relative humidity.

18. The aqueous ticagrelor composition of claim 17, having an osmotic pressure of 350 to 900 mOsm / kg.

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

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

21. Aqueous tikageler according to any one of claims 17 to 20, comprising 2 to 15 mg / ml of tikageler.

22. The aqueous tikageler 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 tikageler 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 tikageler composition according to any one of claims 17 to 23, which does not contain an organic cosolvent.

25. The aqueous tikageler composition according to any one of claims 17 to 24, wherein the D90 particle size of the tikageler is less than 10 micrometers as tested using a Malvern Mastersizer.

26. 26. An aqueous ticagrelor solution according to any one of claims 17 to 25, comprising 5 to 15 mg / ml ticagrelor, 15 to 40% w / w hydroxypropyl-β-cyclodextrin, 5 mM to 20 mM phosphate buffer, and an optional tonicity adjuster, and having a pH of 5.5 to 8.

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

28. An aqueous ticagrelor composition according to any one of claims 17 to 27, for use in ticagrelor-responsive medical treatment, administered as an injection or infusion, nasal, gastric or beverage.

29. The 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, preferably comprising, in addition to ticagrelor, acetylsalicylic acid or a salt thereof as a second active ingredient for use in dual antiplatelet therapy (DAPT).

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

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

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

34. A method for producing the aqueous ticagrelor composition of any one of claims 17 to 30, comprising the steps of: - preparing an aqueous solution having a pH of 5.5-9, preferably containing a buffer; - introducing an amount of cyclodextrin to include 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 performed before adding ticagrelor.

36. Aqueous solution of ticagrelor 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 patients in need thereof.

37. Preferably, in addition to ticagrelor, an aqueous solution of ticagrelor for intravenous administration for use in dual antiplatelet therapy (DAPT) containing acetylsalicylic acid or a salt thereof as a second active ingredient.

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

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