Liquid ticagrelor formulation

Abstract

A liquid oral formulation comprising: a) a therapeutically effective amount of ticagrelor, b) more than 60% propylene glycol, c) an antioxidant d) optionally, a co-solvent and e) 0.03% anionic surfactant selected from sodium lauryl sulfate and / or sodium docusate or 0.05% of a non-ionic surfactant selected from d-α-tocopheryl polyethylene glycol 1000 succinate, is described. Furthermore, the liquid oral formulation is colored and characterized by UV-vis spectra. The method of preparing under limited light or non-light exposure is presented.

Description

[0001] LIQUID TICAGRELOR FORMULATION

[0002] FIELD OF THE INVENTION

[0003] The present invention relates to a liquid formulation of ticagrelor to the use thereof in the therapy and prevention of blood cloths in a patient and a method for preparing thereof. In particular, the liquid formulation of ticagrelor further comprises 0.03% and anionic surfactant or 0.05% a nonionic surfactant.

[0004] BACKGROUND OF THE INVENTION

[0005] Ticagrelor is known chemically as (lS,2S,3R,5S)-3-(7-(((lR,2S)-2-(3,4-Difluorophenyl) cyclopropylamino)-5-(propylthio) 3H-[l,2,3]triazolo[4,5-d] pyrimidin-3-yl)-5-(2- hydroxyethoxy) cyclopentane-l,2-diol and is a selective P2Y12-receptor antagonist (anti -platelet agent). It can selectively and reversibly block the P2Y12 receptor, inhibiting platelet aggregation and preventing amplification of platelet activation.

[0006] Ticagrelor is classified as a BCS class IV molecule. According to the biopharmaceutical classification system (BCS) of drugs, Ticagrelor is hydrophobic with a Log P of 3.9. Ticagrelor, being a class IV compound is expected to exhibit least oral bioavailability, low solubility and intestinal permeability among all pharmaceutical classes of drugs. Ticagrelor presents poor solubility in water, at approximately 10 pg / mL and is potentially photosensitive.

[0007] Oral formulations of ticagrelor in the form of tablets are known. The tablets are round film-coated tablets and have strengths of the active ingredient of 60 mg and 90 mg. Nevertheless, there is a need for a new pharmaceutical form which would enable a patient with difficulty in swallowing.

[0008] However, such oral liquid formulations of ticagrelor are not available. Developing a liquid formulation of ticagrelor suitable for use is challenging due to the low solubility and instability of ticagrelor, especially in solutions containing water. Thus, an improved oral formulation which can be used to treat patients with ticagrelor via administration through a nasogastric and / or a gastronomy tube or via a glass of water, which avoid sticking to nasogastric and / or gastronomy tube or to the glass. SUMMARY OF THE INVENTION

[0009] It is therefore an object of the present invention to provide a new liquid oral formulation comprising a therapeutically effective amount of ticagrelor, without the foregoing disadvantages inherent in the known oral formulations of ticagrelor.

[0010] In one aspect, the present invention provides a liquid oral formulation comprising: a) a therapeutically effective amount of ticagrelor, b) more than 60% propylene glycol, c) an antioxidant d) optionally, a co-solvent and e) 0.03% anionic surfactant selected from sodium lauryl sulfate or sodium docusate or 0.05% a non-ionic surfactant selected from d-a-tocopheryl polyethylene glycol 1000 succinate. Preferably, a liquid oral formulation of the invention may comprise more than 70% propylene glycol. More preferably, may comprise more than 80% propylene glycol. Even more preferably, more than 90% propylene glycol.

[0011] In some embodiments, the color of the formulation of the present invention is determined by visual inspection. In some embodiments, the color is determined by assessing UV-vis absorbance values. Preferably, the present invention provides a liquid oral formulation, wherein said liquid oral formulation exhibits absorbance peaks at about 475 nm and at about 500 nm in the UV-vis spectra.

[0012] In another aspect, the present invention provides a liquid oral formulation, wherein said formulation is a ready- to-use formulation or diluted in water for oral administration or for administration via feeding tubes.

[0013] Preferably, the liquid oral formulation may further comprise a flavoring agent and / or sweetening agent. The flavoring agents may be selected from menthol containing natural flavors. The sweetening agents may be selected from sodium saccharin, sodium cyclamate, neohesperidin dihydrochalcone, neotame, aspartame etc.

[0014] In a further aspect, the present invention provides for a method for preparing the liquid oral formulation by: i) dissolving the anionic surfactant and / or the non-ionic surfactant to at least one part of propylene glycol, ii) optionally adding the co-solvent, iii) dissolving ticagrelor, iv) optionally, dissolve sweetening agents and / or flavoring agents, v) bringing to volume with propylene glycol, vi) optionally, packing in an opaque container.

[0015] Preferably dissolving the anionic surfactant and / or the non-ionic surfactant in step i) and step ii) further comprises applying heat. Preferably, heat at about 25-90°C.

[0016] In the above-mentioned method of preparing, the order of addition of each component of step i), step ii) and step iii) is not particularly limited.

[0017] Preferably, the present invention method for preparing the liquid oral formulation, in steps i) to vi) are protected from light exposure. More preferably, the present invention method for preparing the liquid oral formulation, in steps i) to vi) are performed under artificial lighting having a wavelength of more than 500 nm.

[0018] In a further aspect, the present invention provides for a method for preparing the liquid oral formulation by dissolving ticagrelor and pharmaceutical acceptable excipients and / or solvents, under limited-light or non-light exposure. Preferably, under artificial lighting having a wavelength of more than 500 nm or dark rooms.

[0019] It’s within the scope of this invention to provide a liquid oral formulation as described for use in the therapy of blood clots in a patient wherein the effective amount of the formulation is administered to a in need of treatment in an adjustable dose.

[0020] Furthermore, methods of preparing and using the formulations of the present invention are also described, as are methods of treatment of atherothrombotic events using the described formulations.

[0021] It’s within the scope of this invention to provide a pharmaceutical kit comprising: (i) an opaque container comprising a liquid oral formulation according to any of the preceding embodiments, (ii) optionally a calibrated device, and optionally (iii) instructions for administration. Preferably, the calibrated device is selected from an oral syringe, a dropper and a spoon.

[0022] Embodiment 1 : A liquid oral formulation comprising: a) a therapeutically effective amount of ticagrelor, b) more than 60% propylene glycol, c) an antioxidant d) optionally, a co-solvent and e) 0.03% anionic surfactant selected from sodium lauryl sulfate or sodium docusate or 0.05% a non-ionic surfactant selected from d-a-tocopheryl polyethylene glycol 1000 succinate.

[0023] Embodiment 2: A liquid oral formulation according to embodiment 1, wherein the co-solvent is selected from polyethylene glycol having an average molecular weight of about 200-600 or mixtures thereof.

[0024] Embodiment 3 : A liquid oral formulation according to Embodiments 1 and 2, wherein ticagrelor less than 10%.

[0025] Embodiment 4: A liquid oral formulation according to Embodiment 1, wherein the antioxidant is selected from butylated hydroxytoluene and / or butylated hydroxyanisole.

[0026] Embodiment 5: A liquid oral formulation according to Embodiments 1-4, characterized by absorbance peaks at about 475 nm and at about 500 nm in the UV-vis spectra. Embodiment 6: A liquid oral formulation according to previous Embodiments, further comprising a flavouring agent and / or a sweeting agent.

[0027] Embodiment 7: A liquid oral formulation according to previous Embodiments, wherein said formulation is a ready- to-use formulation or is diluted in water.

[0028] Embodiment 8: A method for preparing a liquid oral formulation according to any of the preceding Embodiments comprising i) dissolving the anionic surfactant and / or the non-ionic surfactant to at least one part of propylene glycol, ii) optionally adding the co-solvent, iii) dissolving ticagrelor, iv) optionally, dissolve sweetening agents and / or flavoring agents, v) bringing to volume with propylene glycol, vi) optionally, packing in an opaque container. Embodiment 9: A method for preparing a liquid oral formulation according to Embodiment 8, wherein steps i) to vi) are performed under limited-light or non-light exposure.

[0029] Embodiment 10: A method for preparing a liquid oral formulation according to Embodiment 9, wherein limited-light exposure is performed under artificial lighting having a wavelength of more than 500 nm.

[0030] Embodiment 11 : A method for preparing a liquid oral formulation according to Embodiments 8, 9, 10, wherein dissolving further comprises applying heat from 25 to 90°C.

[0031] Embodiment 12. A method for preparing a liquid oral formulation according to any of the preceding Embodiments, wherein the opaque container is a covered amber glass container.

[0032] Embodiment 13 : A liquid oral formulation according to any of the preceding Embodiments for use in the therapy of blood clots in a subject wherein the effective amount of the formulation is administered to a subject in need of treatment in less than 10 mL dosage volume.

[0033] Embodiment 14: A liquid oral formulation according to Embodiment 13, wherein the dosage is a volume of 1 ml.

[0034] Embodiment 15: A pharmaceutical kit comprising: (i) an opaque container comprising a liquid oral formulation according to any of the preceding Embodiments, (ii) optionally a calibrated device, and optionally (iii) instructions for administration.

[0035] BRIEF DESCRIPTION OF DRAWINGS

[0036] FIG. 1 : Visible range spectrum of samples Ticagrelor liquid oral formulation of 90 mg / mL, at t=0 (circle & line plot), Ambient-clear vial-24hrs (triangle & line plot), Ambient-amber vial-24hrs (triangle & line plot), Ambient-opaque vial-24hrs (half-circle & line plot) and Blanc (square & line plot)

[0037] FIG. 2: Visible range spectrum of samples Ticagrelor liquid oral formulation of 90 mg / mL, at t=0 (circle & line plot), Dark-clear vial-24hrs (triangle & line plot), Dark-amber vial-24hrs (triangle & line plot) and Dark- opaque vial -24hrs (half-circle & line plot) and Blanc (square & line plot)

[0038] FIG. 3 : Visible range spectrum of samples Ticagrelor liquid oral formulation of 90 mg / mL, at t=0 (circle & line plot), Sunlight-clear vial-24hrs (triangle & line plot), Sunlight-amber vial-24hrs (triangle & line plot), Sunlight- opaque vial-24hrs (half-circle & line plot) and Blanc (square & line plot)

[0039] DETAILED DESCRIPTION OF THE INVENTION

[0040] Liquid oral formulations of ticagrelor have been developed and are reported herein.

[0041] It has been determined that pharmaceutically acceptable and stable liquid formulations of ticagrelor, are prepared, within the scope of this invention. A liquid oral formulation comprising: a) a therapeutically effective amount of ticagrelor, b) more than 60% propylene glycol, c) an antioxidant d) optionally, a co-solvent and e) 0.03% anionic surfactant selected from sodium lauryl sulfate and / or sodium docusate or 0.05% of a non-ionic surfactant selected from d-a-tocopheryl polyethylene glycol 1000 succinate, is described.

[0042] The formulation comprises 60% w / w propylene glycol. Propylene glycol is chosen as a suitable solvent because it dissolves ticagrelor and enhances the active ingredient’s stability in solution, in a small dosage form. The provision of a relatively small dosage form (1 mL dosage form) represents a clinical advantage because it may be expected to increase patient convenience and to avoid exposure of patients to excipients.

[0043] In some embodiments, the liquid oral formulation has a dose volume of equal to or less than 10 mL, preferably equal to or less than 5 mL, more preferably equal to or less than 4 mL, more preferably equal to or less than 3 mL, even more preferably equal to or less than 2 mL, preferably equal to or less than I mL. In some embodiments, the liquid oral formulation of the invention comprises more than 60% (w / w) propylene glycol based on the total formulation. In some embodiments the liquid oral formulation comprises more than 70% (w / w) propylene glycol based on the total formulation. Preferably, the liquid oral formulation comprises more than 80% (w / w) propylene glycol based on the total formulation. Even more preferably, the liquid oral formulation comprises more than 90% (w / w) propylene glycol based on the total formulation.

[0044] Here, the formulation for oral administration of the present invention is a non-aqueous solution. Within the scope of the invention, a “non-aqueous solution” is defined as a solution in which any liquid other than water acts as a solvent. The co-solvent are organic solvents suitable for dissolving ticagrelor and there is no limitation in the number of solvents. The co-solvent may be mixtures formed by a mixture of two or more organic and / or inorganic solvents. Preferably the co-solvents are selected from polyethylene glycol, ethanol, glycerol, propylene glycol and mixtures thereof. A polyethylene glycol with molecular weight of 200 - 600, is preferred. In a preferred embodiment of the invention, a cosolvent is selected from polyethylene glycol with molecular weight of 200 and / or 400.

[0045] In another aspect of the invention, the formulation of the present invention may have a low moisture content, due to the instability of ticagrelor in water. In a preferred embodiment formulations of the present invention can have a moisture content that is less than 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.25%, 0.1%, 0.05%, 0.025%, 0.01%, to 0% by weight or volume of the formulation.

[0046] An antioxidant typically is oxidized and degraded in preference to the active ingredient. The antioxidant protects ticagrelor from decomposition and enhances the stability of ticagrelor. Within the scope of this invention the antioxidant may be selected from butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA) and propyl gallate, among others. Preferably, the antioxidant is selected from butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), propyl gallate and mixtures thereof. More preferably, the antioxidant is selected from butylated hydroxytoluene and / or butylated hydroxyanisole.

[0047] Preferably, the liquid oral formulation of the invention may further comprise a flavoring agent and / or sweetening agent. The flavoring agents may be selected from menthol containing natural flavors. The sweeting agents may be selected from sodium saccharin, sodium cyclamate, neohesperidin dihydrochalcone, neotame, aspartame etc.

[0048] Within the scope of this invention the liquid oral formulation further comprises 0.03% anionic surfactant or 0.05% non-ionic surfactant.

[0049] Typically, the surfactant enhances the solubility of ticagrelor in the liquid formulation while maintaining the stability of the composition. In one aspect of the invention, the liquid formulation comprises 0.03% of an anionic surfactant, selected from sodium lauryl sulfate or sodium docusate.

[0050] In another aspect of the invention, the liquid formulation comprises 0.05% a non-ionic surfactant selected from d-a-tocopheryl polyethylene glycol 1000 succinate. It has been surprisingly found that when the formulation of the present invention comprises 0.03% of an anionic surfactant, selected from sodium lauryl sulfate or sodium docusate or 0.05% a nonionic surfactant selected from d-a-tocopheryl polyethylene glycol 1000 succinate, the formulation showed enhanced stability.

[0051] The term “stable”, as used herein, refers to remaining in a state or condition that is suitable for administration to a patient. The formulation described herein exhibits negligible drop in drug concentration at 9 months of accelerated conditions ie at temperature of 40°C and humidity 75% RH and negligible formation of impurities as shown in Example 3. The concentration of ticagrelor in the oral liquid formulation of Example 3 is of 90 mg / mL. Any deviation from the specifications is expected to have greater effect due to the high concentration of ticagrelor I the oral formulation.

[0052] In another aspect of the invention, the formulation of the present invention is a ready- to-use formulation or it can be diluted in water.

[0053] The term, “ready to use” as used herein, refers to formulations that contain ticagrelor in dissolved or in solubilized form. Within the scope of this invention liquid formulation is intended to be used as such, especially when the person in need is under fluid restriction.

[0054] In another aspect of the invention, the formulation of the present invention exhibit at least an absorbance curve with maximum at approximately 255nm in the UV spectra. More preferably, the formulation of the present invention exhibits at least an absorbance curve with maximum at approximately 255nm and at approximately 291nm in the UV spectra. The absorbance was calculated using a UV-Vis Spectrometer at wavelength range of 230 - 400nm. A plastic cuvette of 2.5ml may be used and the empty cuvette may be used as blank sample. Absorbance can be determined using a UV-visible spectrophotometer according to known techniques. The techniques described herein, should not be considered limiting.

[0055] Visual inspection is a method in liquid formulation production to ensure safety. It is used as a friendly user and time-saving method. The color of the solution can be evaluated by visual inspection. Furthermore, UV-Vis Spectroscopy is an analytical method used to measure how much a chemical substance absorbs light. It is especially useful in colored solutions, which can be considered as a fingerprint of the solution. It is performed by measuring the intensity of light that passes through a sample with respect to the intensity of light through a reference sample or blank. Practically the method is used to obtain the absorbance spectra of the compound in solution. UV- Vis Spectroscopy is a well-known method.

[0056] Within the scope of this invention color stability was determined. A liquid oral formulation of the invention was evaluated for color stability after 24h, in three different conditions and three different packaging containers. A liquid oral formulation according to some embodiments, is characterized by absorbance peaks at about 475 nm and at about 500 nm in the UV-vis spectra.

[0057] In details, in ambient lighting conditions, it is showed that a clear vial container yielded a significantly different Visible spectrum than the initial sample (t=0) (FIG. 1). Moreover, it is shown in Fig.l that the formulation in the clear vial exhibited less intensity in its coloring after one day in ambient lighting conditions (light yellow appearance), whereas, when stored in an amber glass vial yielded a Vis spectrum similar to that of the initial sample. Nevertheless, the spectrum’s main peak exhibited notably lower intensity, therefore the amber glass vial container did not completely protect it from light exposure. When the liquid oral formulation was stored in an opaque container for example an amber glass vial covered with aluminum foil or nontransparent plastic cover, yielded a spectrum practically identical to that of the initial sample (t=0). As presented in FIG. 2 shielding the formulation from light exposure limited-light or non-light exposure (Dark conditions) and storing it for 24 hours, led to practically identical Visible spectra regardless of the type of container that was used. No difference in the appearance / color of the liquid oral formulation in Dark condition was observed. Limited-light or non-light exposure condition was achieved in dark rooms, cabinets or performed under artificial lighting having a wavelength of more than 500 nm.

[0058] In some embodiments, a method for preparing the liquid oral formulation comprising dissolving a therapeutically effective amount of ticagrelor and pharmaceutical acceptable excipients and / or solvents, under limited-light or non-light exposure, is provided. Preferably, under artificial lighting having a wavelength of more than 500 nm or dark rooms. Preferably, the method for preparing further comprises packaging in opaque containers.

[0059] Moreover, as presented in FIG. 3, at direct sunlight conditions can be discerned that the corresponding clear vial stored liquid oral formulation exhibited significantly less intensity in its coloring after one day in direct sunlight conditions (light yellow appearance). When the liquid oral formulation was stored in an amber glass vial yielded a Vis spectrum similar to that of the initial sample, however the spectrum’s main peak exhibited lower intensity. When the liquid oral formulation was stored in an opaque container, for example an amber glass vial covered with aluminum foil or non-transparent plastic cover, yielded a spectrum practically identical to that of the initial sample (t=0).

[0060] Within the scope of this invention liquid formulation, may be orally administrated upon further dilution in water. Depending on the patient’s need, the liquid formulation may be orally administrated after being diluted with drinking water such as mineral water, tap water and the like to facilitate drinking. The formulations of the present invention may be manufactured in a concentrated form, such as so that upon dilution with water, the aqueous form of the present invention may be produced for oral administration.

[0061] In some case a subject in need of a therapeutic dosage form receives one or multiple dosages over time. Typically, the invention’s formulation comprises 30-90 mg / mL ticagrelor. Preferably, a suitable concentration of ticagrelor in the solution, but not limited to, is within the range of 60-90 mg / mL.

[0062] It is within the scope of this invention, a pharmaceutical kit comprising: (i) an opaque container comprising a liquid oral formulation according to any of the preceding Embodiments, (ii) optionally a calibrated device, and optionally (iii) instructions for administration. Preferably, the calibrated device is selected from an oral syringe, a dropper and a spoon.

[0063] Within the scope of this invention liquid formulation may be orally administrated by esophagostomy or gastrostomy feeding tube, upon dilution using suitable media, preferably water. The liquid formulation of the invention is compatible with administration via a tube. Giving medications containing Ticagrelor through a esophagostomy or gastrostomy feeding tube can be challenging. The sticky clumps of amorphous Ticagrelor formed may stick to the glass and the feeding tubes’ surfaces, thereby resulting in clogging of the tubes or undelivered Ticagrelor left in the tube. The present invention is explained in more detail in the following by referring to Examples, which are not to be construed as limitative.

[0064] EXAMPLES

[0065] The liquid oral formulation as described herein may be illustrated by the following examples which are not to be construed as limiting the scope of the invention. EXAMPLE 1

[0066] In Example 1, liquid oral formulations of 90 mg / mL ticagrelor were prepared. The variations represent independently prepared formulations. Table 1. Illustrative quantitative composition of 90 mg / mL of ticagrelor liquid oral formulation

[0067] *Density of Solution: 1.064 g / mL

[0068] 1 Dose = 1 mL; Contains 90.00 mg of Ticagrelor.

[0069] General manufacturing process: Step A: Add more than half of the required amount of propylene glycol to a mixing container.

[0070] Step B: In the solution of Step A, add SLS and / or sodium docusate, and BHA and / or BHT.

[0071] Mix until the ingredients are dissolved and a clear solution is formed. Step C: In the solution of Step B, add PEG-200 and / or PEG-400 and mix well.

[0072] Step D: In the solution of Step C, add ticagrelor, optionally apply mild heat and mix until dissolved.

[0073] A, clear yellow solution is formed.

[0074] Step E: In the solution of Step D, add the flavoring and mix well. Top up to the required volume using propylene glycol.

[0075] Step F : Allow the solution of Step E to settle and pack in amber glass bottles.

[0076] EXAMPLE 2

[0077] Example 2, liquid oral formulations of 60 mg / mL ticagrelor, were prepared according to the general manufacturing process, as in Example 1. Table 2. Illustrative quantitative composition of 60 mg / mL of ticagrelor liquid oral formulation EXAMPLE 3

[0078] Example 3, liquid oral formulations of 90 mg / mL ticagrelor, were prepared according to the general manufacturing process, as in Example 1. Table 3. Illustrative quantitative composition of 90 mg / mL of ticagrelor liquid oral formulation

[0079] *Density of Solution: 1.052 g / mL

[0080] 1 Dose = 1 mL; Contains 90.00 mg of Ticagrelor.

[0081] EXAMPLE 4

[0082] The formulation of Example 1, wherein SLS and BHA were chosen as a surfactant and anti-oxidant correspondingly, was checked for its stability performance under Accelerated Conditions 40°C / 75% RH. The results are presented below:

[0083] Method of Impurities Analysis Preparation of buffer: Dissolve 1.36 g of potassium phosphate monobasic in 1000 mL of water, and then adjust the pH to 4.0 with dilute orthophosphoric acid solution.

[0084] Mobile phase A: 70:30 (v / v) buffer: acetonitrile. Mix well, filter and degas.

[0085] Mobile phase B: 35:65 (v / v) water: acetonitrile. Mix well, filter and degas. Diluent: 50:50 (v / v) water: acetonitrile. Mix well.

[0086] Needle wash (if applicable): 10:90 (v / v) water: acetonitrile. Mix well, filter and degas.

[0087] Seal wash (if applicable): 90: 10 (v / v) water: acetonitrile. Mix well, filter and degas.

[0088] System: HPLC with UV / DAD

[0089] Preparation of Standard stock solution (0.3 mg / mL Ticagrelor): Accurately weigh 30 mg of Ticagrelor reference standard or working standard and transfer quantitively into a 100 mL volumetric flask. Dissolve with diluent by means of sonication and make up to the mark with diluent.

[0090] Preparation of Standard solution (0.003 mg / mL Ticagrelor): Transfer 5 mL of the Standard stock solution into a 50 mL volumetric flask. Dilute to volume with diluent and mix well. Then transfer 5 mL of this solution into a 50 mL volumetric flask with diluent. Filter the standard through a 0.45 pm qualified filter.

[0091] Table 4. Stability data of Example 1 formulation

[0092] All other formulations were checked for stability and found to comply with the specifications, with similar results. EXAMPLE 5

[0093] The measurement of sample of formulation as per Example 1, absorption in the Visible range at t=0 (day of sample preparation) and t=24 hours after storage was conducted to evaluate the effect of light exposure to the sample. Three different degrees of natural light exposure were set to be tested; storage of the sample in ambient lighting conditions (referred as “Ambient”, i.e., on a laboratory bench), in direct sunlight exposure conditions (referred as “Sunlight”) and away from any natural light (referred as “Dark”, i.e., inside a closed cabinet).

[0094] Also, three different types of sample storage containers were set to be tested in order to determine which of them would better protect the sample; a simple clear, glass vial, an amber glass vial and an opaque vial (covered amber glass).

[0095] Instrument type used: UV-Vis Spectrometer, Agilent, Cary 60

[0096] Wavelength range: 380 - 800nm

[0097] Cuvette: plastic, 2.5ml volume for UV-Vis range

[0098] Used as blank sample: Placebo (colorless)

[0099] It was concluded that: Exposure of sample Ticagrelor liquid oral formulation 90mg / ml of Example 1 to light (ambient or direct sunlight conditions), for 24 hours, while stored in a clear glass vial, led to significantly different Visible spectrum compared to the t=0 sample. The compromised samples were characterized by a lighter yellow color appearance. Storing the solution in an amber glass vial led to slightly better sample stability, however, both for the ambient and the direct sunlight conditions, it still led to a notably different Visible spectrum compared to the t=0 sample. The best sample stability was observed when Ticagrelor liquid oral formulation 90mg / ml as per example 1, was stored away from light (Dark conditions) and container wise, when an opaque container was used as compared in FIG 1-3.

Claims

CLAIMS1. A liquid oral formulation comprising: a) a therapeutically effective amount of ticagrelor, b) more than 60% propylene glycol, c) an antioxidant d) optionally, a co-solvent and e) 0.03% anionic surfactant selected from sodium lauryl sulfate or sodium docusate or 0.05% a non-ionic surfactant selected from d-a-tocopheryl polyethylene glycol 1000 succinate.

2. A liquid oral formulation according to claim 1, wherein the co-solvent is selected from polyethylene glycol having an average molecular weight of about 200-600 or mixtures thereof.

3. A liquid oral formulation according to claims 1 to 2, wherein ticagrelor less than 10%.

4. A liquid oral formulation according to claims 1 to 3, wherein the antioxidant is selected from butylated hydroxytoluene and / or butylated hydroxyanisole.

5. A liquid oral formulation according to claims 1 to 4, characterized by absorbance peaks at about 475 nm and at about 500 nm in the UV-vis spectra.

6. A liquid oral formulation according to any of the preceding claims, further comprising a flavouring agent and / or a sweeting agent.

7. A liquid oral formulation according to any of the preceding claims, wherein said formulation is a ready- to-use formulation or is diluted in water.

8. A method for preparing a liquid oral formulation according to any of the preceding claims, comprising: i) dissolving the anionic surfactant and / or the non-ionic surfactant to at least one part of propylene glycol, ii) optionally adding the co-solvent, iii) dissolving ticagrelor, iv) optionally, dissolve sweetening agents and / or flavoring agents,v) bringing to volume with propylene glycol, vi) optionally, packing in an opaque container.

9. A method for preparing a liquid oral formulation according to claim 8, wherein steps i) to vi) are performed under limited-light or non-light exposure.

10. A method for preparing a liquid oral formulation according to claim 9, wherein limited-light exposure is performed under artificial lighting having a wavelength of more than 500 nm.

11. A method for preparing a liquid oral formulation according to claims 8 to 10, wherein dissolving further comprises applying heat from 25 to 90°C.

12. A method for preparing a liquid oral formulation according to any of the preceding claims, wherein the opaque container is a covered amber glass container.

13. A liquid oral formulation according to any of the preceding claims, for use in the therapy of blood clots in a subject wherein the effective amount of the formulation is administered to a subject in need of treatment in less than 10 mL dosage volume.

14. A liquid oral formulation according to claim 13, wherein the dosage is a volume of 1 ml.

15. A pharmaceutical kit comprising: (i) an opaque container comprising a liquid oral formulation according to any of the preceding claims, (ii) optionally a calibrated device, and optionally (iii) instructions for administration.

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