WO2023222184A1 - Aqueous ticagrelor solution, method of manufacturing and uses - Google Patents
Aqueous ticagrelor solution, method of manufacturing and uses Download PDFInfo
- Publication number
- WO2023222184A1 WO2023222184A1 PCT/EP2022/063185 EP2022063185W WO2023222184A1 WO 2023222184 A1 WO2023222184 A1 WO 2023222184A1 EP 2022063185 W EP2022063185 W EP 2022063185W WO 2023222184 A1 WO2023222184 A1 WO 2023222184A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- ticagrelor
- aqueous
- cyclodextrin
- solution
- composition according
- Prior art date
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- OEKWJQXRCDYSHL-FNOIDJSQSA-N ticagrelor Chemical compound C1([C@@H]2C[C@H]2NC=2N=C(N=C3N([C@H]4[C@@H]([C@H](O)[C@@H](OCCO)C4)O)N=NC3=2)SCCC)=CC=C(F)C(F)=C1 OEKWJQXRCDYSHL-FNOIDJSQSA-N 0.000 title claims abstract description 222
- 229960002528 ticagrelor Drugs 0.000 title claims abstract description 219
- 238000004519 manufacturing process Methods 0.000 title claims description 11
- 239000000203 mixture Substances 0.000 claims abstract description 116
- 229920000858 Cyclodextrin Polymers 0.000 claims abstract description 102
- 239000000243 solution Substances 0.000 claims abstract description 79
- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical compound O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 claims abstract description 43
- 239000004480 active ingredient Substances 0.000 claims abstract description 18
- 238000001990 intravenous administration Methods 0.000 claims abstract description 18
- 238000011282 treatment Methods 0.000 claims abstract description 17
- 238000002347 injection Methods 0.000 claims abstract description 15
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- 238000001802 infusion Methods 0.000 claims abstract description 12
- 238000003860 storage Methods 0.000 claims description 37
- 238000000034 method Methods 0.000 claims description 17
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- 208000010125 myocardial infarction Diseases 0.000 claims description 16
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- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 14
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- 208000032109 Transient ischaemic attack Diseases 0.000 claims description 12
- 201000010875 transient cerebral ischemia Diseases 0.000 claims description 12
- ODLHGICHYURWBS-LKONHMLTSA-N trappsol cyclo Chemical compound CC(O)COC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)COCC(O)C)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1COCC(C)O ODLHGICHYURWBS-LKONHMLTSA-N 0.000 claims description 10
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 claims description 9
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- WHGYBXFWUBPSRW-FOUAGVGXSA-N beta-cyclodextrin Chemical compound OC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)CO)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1CO WHGYBXFWUBPSRW-FOUAGVGXSA-N 0.000 claims description 5
- 239000002904 solvent Substances 0.000 claims description 5
- NZAQRZWBQUIBSF-UHFFFAOYSA-N 4-(4-sulfobutoxy)butane-1-sulfonic acid Chemical class OS(=O)(=O)CCCCOCCCCS(O)(=O)=O NZAQRZWBQUIBSF-UHFFFAOYSA-N 0.000 claims description 4
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- XYLIQTKEYHWYGG-XUNGLMTJSA-N (1s,2r,3s,4r)-4-[7-[[(1r,2s)-2-(3,4-difluorophenyl)cyclopropyl]amino]-5-propylsulfanyltriazolo[4,5-d]pyrimidin-3-yl]cyclopentane-1,2,3-triol Chemical compound C1([C@@H]2C[C@H]2NC=2N=C(N=C3N([C@H]4[C@@H]([C@H](O)[C@@H](O)C4)O)N=NC3=2)SCCC)=CC=C(F)C(F)=C1 XYLIQTKEYHWYGG-XUNGLMTJSA-N 0.000 description 1
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/69—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
- A61K47/6949—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes
- A61K47/6951—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes using cyclodextrin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/60—Salicylic acid; Derivatives thereof
- A61K31/612—Salicylic acid; Derivatives thereof having the hydroxy group in position 2 esterified, e.g. salicylsulfuric acid
- A61K31/616—Salicylic acid; Derivatives thereof having the hydroxy group in position 2 esterified, e.g. salicylsulfuric acid by carboxylic acids, e.g. acetylsalicylic acid
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
Abstract
The present invention provides an aqueous ticagrelor composition comprising ticagrelor as active ingredient, characterized, in that the composition is a solution comprising a water-soluble inclusion complex of ticagrelor in a cyclodextrin, wherein the composition has a pH between 5,5 to 9 The aqueous ticagrelor solution is preferably provided for intravenous administration, either by injection or infusion. Preferably a ticagrelor intravenous composition according to the invention is used as a medicine in the treatment of a ticagrelor responsive disease.
Description
AQUEOUS TICAGRELOR SOLUTION, METHOD OF MANUFACTURING AND USES TECHNICAL FIELD The present invention is situated in the field of pharmaceutical compositions and medical uses of pharmaceutical compositions. The present invention also relates to the manufacturing of pharmaceutical compositions and unit dose forms. The active ingredient concerned is ticagrelor. The invention is advantageous as it provides a stable ticagrelor iv formulation, where hereto only ticagrelor tablets are available. The invention has for effect that patients with a ticagrelor-responsive disease can be treated effectively even if unconscious or even if having problems swallowing. BACKGROUND Ticagrelor is a well-known active ingredient. It is a platelet aggregation inhibitor used for the prevention of thrombotic events, such as myocardial infarctions or strokes, in patients with acute coronary syndromes. Its chemical name is (1S,2S,3R,5S)‐3‐{7‐[(1R,2S)‐2‐(3,4‐ difluorophenyl)cyclopropylamino]5‐(propylthio)‐3H‐(1,2,3) triazolo (4,5‐D) pyrimidin‐ 3‐yl}‐5‐(2 hydroxyethoxy)cyclopentane‐1,2‐diol. Ticagrelor was developed by AstraZeneca and was approved for entry on the market by the European Medicines Agency in 2010 and by the US Food and Drug Administration in 2011. As drug it is marketed in tablet form under the name Brilinta® in the USA and Brilique® in the EU. It is not commercially available in liquid form. Ticagrelor is an oral, reversible, direct- acting P2Y12 receptor antagonist that works by inhibiting platelet activation. Brilinta® tablets, together with aspirin, have shown to significantly reduce the risk 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 the reduction of the risk of a first heart attack or stroke in high-risk patients with coronary artery disease. Ticagrelor has shown to be highly susceptible to degradation when exposed to light, heat and oxygen, plus its limited solubility is a great challenge in formulating it as an aqueous solution. Although the need for a liquid ticagrelor formulation remains high, to our knowledge a successful commercial product of desired solubility and long-term stability in correspondence with requirements of the pharmaceutical industry has not been successful. Sigfridsson et al. (J Pharm Sci 100: 2194-2202, 2011) disclosed a composition deemed suitable for intravenous administration. The composition is based on nanoparticles of ticagrelor, a combination of polyvinylpyrrolidone and the disodium salt of Aerosol AOT for stabilization of the active ingredient, and 5 percent mannitol to obtain a nanosuspension. Aerosol AOT is believed to correspond to dioctyl sulfosuccinate sodium salt. Although the
nanosuspension is reported to have a stability of at least 10 months, it is also reported that there is some tendency for particle aggregation and sedimentation during storage. Therefor, samples are sonicated prior to an intravenous administration. This is cumbersome for a pharmaceutical use and presents a safety risk. The same publication of Sigfridsson et al. also mentions that ticagrelor concentrations in phosphate buffered solution at pH 7.4 declined after 1 month under normal laboratory conditions of light and temperature. Thus, the investigation of a solution as alternative to a suspension, is counter-indicated. In the product characteristics for the medicinal product Brilique 60 mg film-coated tablets (Brilique INN-ticagrelor) it is disclosed that tablets can be crushed, mixed with water and drunk immediately, for patients who are unable to swallow the tablets. Alternatively, the mixture may be administered via a nasogastric tube into the stomach. The disadvantage of this formulation is that it is not readily available to patients. A preparation is needed just prior before administration. The formulation does not have a long-term storage stability and the tablet particles settle on standing. For emergency use, especially when a patient is unconscious, this is not a solution. Cheong-Weon Cho et al., 2019 studied self-micro emulsifying drug delivery systems (SMEDDS) for oral delivery to overcome the poor ticagrelor solubility barriers. Ticagrelor solubility was studied in oily and hydrophilic excipients. A combination of surfactants was selected to obtain an emulsion system: Capmul MCM/Cremophor EL/Transcutol P. Ticagrelor is used to inhibit platelet aggregation in patients with acute coronary syndrome, but its poor solubility and low bioavailability limit its in vivo efficacy. Yaye et al., 2014 studied the degradation of ticagrelor when exposed to heat, pH, peroxide and light . They identified numerous degradants DP1 to DP9 indicating that the molecule is highly suseptible to degradation. In view of the above, there remains a need in the art for storage stable ticagrelor formulations with good ticagrelor solubility, particularly for emergency use. The objective of the present invention is to solve at least one or more problems as described above. In particular, the invention aims to provide a formulation comprising ticagrelor as active ingredient that has improved solubility in combination with long-term stability. Ticagrelor should be readily available to patients and the formulation developed should make use of ingredients that regulatory agencies find acceptable (e.g. within the FDA’s Inactive Ingredient Guide - IIG limits). SUMMARY OF THE INVENTION In a first aspect the invention provides an aqueous ticagrelor composition comprising
ticagrelor as active ingredient, remarkable in that the composition is a solution comprising a water-soluble inclusion complex of ticagrelor in a cyclodextrin, wherein the composition has a pH between 5,5 to 9. One or more of the following embodiments can be used to further define the aqueous ticagrelor composition according to the invention. For example, the osmolality is between 350-900 mOsm/kg. For example, the cyclodextrin is selected from a hydroxypropyl-beta-cyclodextrin and a sulfobutylether derivative of a beta-cyclodextrin. For example, the aqueous ticagrelor comprises 15 – 40% w/w cyclodextrin; preferably comprising 15 – 40% w/w hydroxypropyl-beta-cyclodextrin. For example, the aqueous ticagrelor composition comprises 2-15 mg/ml ticagrelor. For example, the composition is provided for infusion and has a volume of 15 to 30 ml. For example, the composition is provided for injection and has a volume of 5 to 15 ml. For example, the aqueous ticagrelor composition is with the proviso that organic co-solvents are excluded. For example, the ticagrelor has a D90 particle size below 10 micrometers when tested using Malvern mastersizer For example, the aqueous ticagrelor composition is with a storage stability of at least 3 months at 40 °C and 75 % Relative Humidity. For example, the aqueous ticagrelor solution consists of 5-15 mg/ml ticagrelor, 15 – 40 % w/w of a hydroxypropyl-beta-cyclodextrin, 5 mM-20 mM of phosphate buffer, optionally including a tonicity modifier, wherein the pH is between 5,5 and 8. In a second aspect the invention provides in a medical use of an aqueous ticagrelor solution. The invention provides an aqueous ticagrelor composition according to an embodiment of the invention, for use in a ticagrelor responsive medical treatment. For example, the aqueous ticagrelor composition is for use in a ticagrelor responsive medical treatment wherein the composition is administered as an injection, infusion, nasal gastric fluid, or drink. For example, the aqueous ticagrelor composition is for use in the treatment of acute coronary syndrome (ACS), myocardial infarction (MI), ischemic stroke, transient ischemic attack (TIA) or for the reduction of platelet-tumor cell interactions in a patient in need thereof. For example, the aqueous ticagrelor composition is for use in a dual antiplatelet therapy (DAPT), preferably comprising acetyl salicylic acid or salts thereof as second active ingredient in addition to ticagrelor.
In a third aspect the invention provides a unit dose composition for delivery of 15-180 mg ticagrelor comprising a composition according to an embodiment of the invention. In an embodiment, the unit dose comprises 2000-4000 mg of cyclodextrin. In an embodiment, the unit dose comprises 5% dextrose water as diluent. In a fourth aspect the invention provides a method for the manufacturing of an aqueous ticagrelor composition according to an embodiment of the invention comprising the steps of: - preparing an aqueous solution of pH 5,5-9 preferably comprising a buffering agent, more preferably comprising a phosphate buffer, - introducing a cyclodextrin amount for inclusion of a pre-determined amount of ticagrelor, - adding the pre-determined amount of ticagrelor, thereby obtaining an inclusion complex of ticagrelor in cyclodextrin. In an embodiment, heating is applied prior to the addition of ticagrelor. In a further aspect, the 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 the reduction of platelet- tumor cell interactions in a patient in need thereof. In an embodiment, the solution has a storage stability of at least 3 months in accelerated storage conditions at 40 °C and 75 % Relative Humidity. In a final aspect, the invention provides an aqueous ticagrelor solution for intravenous administration, for use in a dual antiplatelet therapy (DAPT), preferably comprising acetyl salicylic acid or salts thereof as second active ingredient in addition to ticagrelor. In an embodiment, the solution has a storage stability of at least 3 months in accelerated storage conditions at 40 °C and 75 % Relative Humidity. DETAILED DESCRIPTION OF THE INVENTION The invention provides a solution to the problem of obtaining clear and storage stable aqueous ticagrelor formulations. The ticagrelor formulations of the invention are suitable for administration as an injection, infusion, nasal gastric liquid or drink. The ingredients are acceptable for medical use according to the IIG-list. Unless otherwise defined, all terms used in the description of the invention, including technical and scientific terms, have the meaning as commonly understood by a person skilled in the art
to which the invention pertains. Furthermore, definitions of the terms are included to better understand the description of the present invention. As used here, the following terms have the following meaning: “A”, “an”, and “the” as used here refer to both the singular and the plural, unless the context indicates otherwise. “A surfactant” refers, by way of example, to one or more than one surfactant. “About” as used herein, referring to a measurable value such as a parameter, an amount, a duration and the like, is intended to include variations of plus or minus 10% or less, preferably plus or minus 5% or less, more preferably plus or minus 3% or less, even more preferably plus or minus 1% or less, and even more preferably plus or minus 0.1% or less of the specified value, as far as such variations are suitable for carrying out in the described invention. It will be clear, however, that the value to which the term “about” relates is itself also specifically described. “Include”, “comprising” and “comprises” are used herein are inclusive or open terms that specify the presence of what follows, e.g. a component and the presence of additional, unnamed components, features, elements, parts, steps, which are well known in the art or described therein, and do not exclude them. The recitation of numerical ranges by endpoints includes all numbers and fractions that are included within that range, as well as the endpoints mentioned. The term “% w/w” as used herein means percentage by weight in which the weight ratio of an ingredient to the total weight of a composition is expressed as a percentage. In a first aspect the invention provides an aqueous ticagrelor composition comprising ticagrelor as active ingredient, characterized, in that the composition is a solution comprising a water-soluble inclusion complex of ticagrelor in a cyclodextrin, wherein the composition has a pH between 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; most preferably 7,0 to 8,0. The pH range of 7,0 to 8,0 is especially important because of the physiological acceptance for iv formulation to patients. By the term “ticagrelor” as used herein, is meant ticagrelor in free form as well as to its pharmaceutically acceptable solvates, hydrates, enantiomers, polymorphs, or mixtures thereof. Preferably ticagrelor is used in its free form. Ticagrelor has the following chemical structure:
Ticagrelor has six stereocenters and consequently there are many crystalline and amorphous forms. In a preferred embodiment of the present invention, the active agent is crystalline ticagrelor. Especially, four non- solvated crystalline forms are available, named as Polymorph I, II, III and IV. The polymorphs present different physical and chemical properties. In a preferred embodiment, polymorph II is used. Its X-ray powder diffraction patterns is characterized by specific peaks at 5.5° (±0.1°), 6.8° (±0.1°), 10.6° (±0.1°), 13.5° (±0.1°), 14.9° (±0.1°), 18.3° (±0.1°), 19.2° (±0.1°), 22.7° (±0.1°), 24.3° (±0.1°) and 27.G (±0.1°) 2Q. The polymorph II form is described in literature as the most stable crystalline form of ticagrelor. Ticagrelor has a low and pH-independent solubility in aqueous media. This property of not ionizing in the physiological pH range, makes the development of liquid formulations especially challenging. The inventor has found that ticagrelor could be solubilized using a cyclodextrin. Long-term storage stability could be obtained using an aqueous solution of pH of 5,5 to 9, and importantly in the range of pH 7,0 to 8,0. The use of an organic co-solvent or surfactant were avoided, which reduced degradation risks. The invention provides a clear ticagrelor formulation with good solubility and long-term storage stability as required for formulations in the pharmaceutical and medical field. In a preferred embodiment, ticagrelor is the only active pharmaceutical ingredient present in the composition. Alternatively, an additional active ingredient can be included. The present invention provides an aqueous liquid formulation comprising an inclusion complex of ticagrelor and an aqueous liquid carrier. Preferably the aqueous ticagrelor composition is provided for infusion and has a volume of 15 to 30 ml. This volume range is typical for a composition according to an embodiment of the invention and use in an intravenous administration of the aqueous ticagrelor composition. Alternatively, to an intravenous administration, the aqueous ticagrelor solution can be administered as an injection. For this purpose, the volume is preferably between 5 to 15 ml.
An injection is particularly suitable for treatment of an acute situation, as the ticagrelor is made available rapidly, over a short period of time. In a preferred embodiment the aqueous ticagrelor composition comprises 2-15 mg/ml ticagrelor; more preferably 4-14 mg/ml ticagrelor; even more preferably 6-13 mg/ml ticagrelor; most preferably 7-12 mg/ml ticagrelor. This amount of ticagrelor is relevant for therapy by injection or infusion. A selection of a lower amount requires a higher volume to be administered to a patient in need of a ticagrelor responsive medical indication. A higher amount of ticagrelor causes problems with the solubility of the active ingredient, especially in cases of an administration by injection which involves a small volume. By the term “inclusion complex” as used herein, is meant a chemical complex in which one chemical compound, the host, has a cavity into which a guest compound can be accommodated. The interaction between the host and guest involves van der Waals bonding. Compounds suitable for providing an inclusion complex are cyclodextrins. Cyclodextrins are cyclic carbohydrates derived from starch. The unmodified cyclodextrins differ by the number of glucopyranose units joined together in the cylindrical structure. The parent cyclodextrins contain 6, 7, or 8 glucopyranose units and are referred to as α-, β-, and γ-cyclodextrin respectively. Each cyclodextrin subunit has secondary hydroxyl groups at the 2 and 3-positions and a primary hydroxyl group at the 6-position. The cyclodextrins may be pictured as hollow truncated cones with hydrophilic exterior surfaces and hydrophobic interior cavities. In aqueous solutions, these hydrophobic cavities provide a haven for hydrophobic organic compounds, which can fit all, or part of their structure into these cavities. This process, known as inclusion complexation, may result in increased apparent aqueous solubility and stability for the complexed drug; however, the degree of stabilization will vary from drug to drug. The complex is stabilized by hydrophobic interactions and does not involve the formation of any covalent bonds. Chemical modification of the parent cyclodextrins (usually at the hydroxyl moieties) has resulted in derivatives with sometimes improved safety while retaining or improving the complexation ability of the cyclodextrin. Of the numerous derivatized cyclodextrins prepared to date, only two appear to be commercially viable; the 2-hydroxypropyl derivatives (HP-β- CD or HPβCD), neutral molecules being commercially developed by Janssen and others, and the sulfoalkyl ether derivatives (SAE-β-CD or SAE-CD), being developed by CyDex Pharmaceuticals, Inc. The SAE-CDs are a class of negatively charged cyclodextrins, which vary in the nature of the alkyl spacer, the salt form, the degree of substitution and the starting parent cyclodextrin. The sodium salt of the sulfobutyl ether derivative of beta-cyclodextrin, with an average of about 7 substituents per cyclodextrin molecule (SBE7-β-CD), is being commercialized by CyDex Pharmaceuticals, Inc. (Kansas) as CAPTISOL® cyclodextrin.
Preferably the cyclodextrin is selected from a hydroxypropyl-beta-cyclodextrin and a sulfobutylether derivative of a beta-cyclodextrin. More preferably the cyclodextrin is hydroxypropyl-beta-cyclodextrin. The selection of the HPβCD cyclodextrin was superior to SBECD cyclodextrin. A lower amount of HPβCD was required to solubilize ticagrelor as compared to SBECD cyclodextrin. A broader range of HPβCD concentrations provided clear aqueous ticagrelor solutions as compared to SBECD. The results are provided in Example 1. Most preferably the aqueous ticagrelor solution comprising 15–40% w/w, more preferably 20- 35% w/w, even more preferably 22-34% w/w, most preferably 23-33% w/w hydroxypropyl- beta-cyclodextrin. The amount of cyclodextrin selected is an amount sufficient to enclose a therapeutically relevant amount of cyclodextrin and to provide a clear ticagrelor solution. This range is acceptable for medical administration. In a preferred embodiment of the aqueous ticagrelor composition according to the invention, organic co-solvents are excluded. The use of organic co-solvents is not required to improve the solubility of ticagrelor. The avoidance of organic co-solvents provides a better compatibility of the product for an intravenous administration. Preferably the aqueous ticagrelor composition has an osmolality between 350-900 mOsm/kg. This osmolality is advantageous in an intravenous administration to a patient in need of ticagrelor treatment. In a preferred embodiment of the aqueous ticagrelor composition, the ticagrelor has a D90 particle size below 10 micrometers; more preferably the D90 particle size is below 9 micrometers; even more preferably the D90 particle size is below 8 micrometer; most preferably the D90 particle size is below 7 micrometer. Selection of the indicated particle size makes it easier to incorporate ticagrelor in cyclodextrin. The solubility of ticagrelor included in a cyclodextrin inclusion complex is improved. A method for the measurement of particle size of an active ingredient, is well-known to a person skilled in the art of formulations. The method used in the present invention is by Malvern Mastersizer dry powder method. The storage periods obtained for an aqueous ticagrelor solution according to an embodiment of the invention are prolonged over currently available solutions obtained by crushing Brillinta® tablets and mixing them with water. The storage stability achieved is particularly relevant for use of the ticagrelor aqueous solutions in pharmaceutical supplies and storage. In a preferred embodiment of the aqueous ticagrelor composition, the composition has a storage stability of at least 3 months in accelerated storage conditions at 40 °C and 75 %
Relative Humidity (RH). More preferably said storage stability is at least 6 months; even more preferably at least 9 months; most preferably at least 12 months. A satisfactory stability of 6 months at 40°C and 75% RH corresponds to a shelf life of 24 months at room temperature of 25 °C. “Storage stability” as used herein means that the total impurity level is below 0,5%. Most preferably the aqueous ticagrelor composition is a solution consisting of: 5 - 15 mg/ml ticagrelor, 15 – 40 % w/w of a hydroxypropyl-beta-cyclodextrin, 5 mM-20 mM of phosphate buffer, wherein the pH is between 5,5 and 8. The composition provided above is simple and easy to manufacture. The limited number of ingredients reduced the formation of impurities and side products. Optionally the aqueous ticagrelor composition may including a tonicity modifier, such as sodium chloride. Preferably the osmolality of the aqueous ticagrelor composition between 350- 900 mOsm/kg, more preferably between 360 – 800 mOsm/kg, even more preferably between 370-700 mOsm/kg, most preferably between 380 and 600 mOsm/kg. In a further aspect the invention provides an aqueous ticagrelor composition for use in a ticagrelor responsive medical treatment; wherein the aqueous ticagrelor composition is as previously described. Preferably the aqueous ticagrelor composition is provided for intravenous administration and the composition is administered as an injection or infusion. This form is advantageous for unconscious patients who need immediate treatment. In alternative embodiment the aqueous ticagrelor composition is provided as a solution for nasal gastric administration or as a drink. This form is advantageous for conscious patients that have difficulties with swallowing. Preferably the aqueous ticagrelor composition according to an embodiment of the invention is provided for use in the treatment of acute coronary syndrome (ACS), myocardial infarction (MI), ischemic stroke, transient ischemic attack (TIA) or for the reduction of platelet-tumor cell interactions in a patient in need thereof. An aqueous composition according to an embodiment of the invention has the advantage in a medical therapy that it is faster acting than a tablet; has a higher bio availability than a tablet and provides a solution to patients who have difficulties swallowing a tablet. Especially in acute situations, an intravenous infusion or injection is advantageous. The availability of a ready-
to-use aqueous solution according to an embodiment of the invention is preferred over the crushing of a tablet and addition to water and over dissolving an orodispersible tablet in water, because of time-savings and accuracy of dosing. More preferably the aqueous ticagrelor composition according to an embodiment of the invention is for use in a monotherapy or in a dual antiplatelet therapy (DAPT). Preferably the dual antiplatelet therapy comprises acetyl salicylic acid or salts thereof as second active ingredient in addition to ticagrelor. In a further aspect the invention provides a unit dose composition for delivery of 15-180 mg ticagrelor comprising an aqueous ticagrelor solution according to an embodiment to the invention. The dose of ticagrelor for administration to a patient may range from 15 mg to 180 mg, more preferably from 30 mg to 90 mg and most preferably from 65 to 75 mg. Preferably the unit dose composition comprises 2000-4000 mg of cyclodextrin, more preferably 2200-3000 mg of cyclodextrin, even more preferably 2400–2800 mg of cyclodextrin, most preferably 2500 mg of cyclodextrin. In a preferred embodiment of a unit dose composition according to the invention, the unit dose composition comprises 5% dextrose in water (D5W) as diluent. Normal saline and Ringer’s lactate solution were not suitable as diluent because they provided turbid solutions. “Normal saline” as used herein, refers to the commonly used phrase for a solution of 0,90% w/v sodium chloride, 308 mOsm/l or 9,0 g per liter. Synonyms are physiological saline or isotonic saline. “Ringer’s lactate solution” as used herein, refers to sodium lactate solution, also called 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 ion, 109-111 mEq of chloride ion, 28-29 mEq of lactate ion, 4-5 mEq of potassium ion and 2-3 mEq of calcium ion. Ringer’s lactate has an osmolarity of 273 mOsm/l and a pH of 6.5. The unit dose compositions according to an embodiment of the invention provide for treatment with ticagrelor together with a good fluid balance with minimal hypotonicity or hypertonicity. The compositions are advantageous for people who cannot take fluids orally and have developed or are in danger of developing dehydration or hypovolemia. In a further aspect, the invention provides a method of treatment of a patient suffering from a ticagrelor-responsive disease, wherein the patient is treated with a clear and aqueous ticagrelor solution having a stability of at least one month, preferably three months, even more preferably at least six months. Preferably the clear and aqueous ticagrelor solution is a
ready-to-use solution. More preferably ticagrelor is enclosed in a cyclodextrin thereby providing a ticagrelor-cyclodextrin inclusion complex. Preferably the clear and aqueous ticagrelor solution has a pH of 5,5-9; more preferably a physiological pH of 7-8. More preferably the clear and aqueous ticagrelor solution comprises a buffering agent, most preferably a phosphate buffer. In a fourth aspect, the invention provides a method for the manufacturing of an aqueous ticagrelor composition according to an embodiment of the invention, comprising the steps of: - preparing an aqueous solution of pH 5,5-9 - introducing a cyclodextrin amount for inclusion of a pre-determined amount of ticagrelor, - adding the pre-determined amount of ticagrelor, thereby obtaining an inclusion complex of ticagrelor in cyclodextrin. 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 the indicated pH range the solution is preferably comprising a buffering agent. Preferably a heating step is applied prior to the addition of ticagrelor. This is beneficial for the reduction of the amount of cyclodextrin needed to dissolve a selected amount of ticagrelor. Ticagrelor is preferably added to a solution at a temperature of 30 to 45°C. In a fifth aspect, the invention provides medical uses for the ticagrelor iv compositions. The 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 the reduction of platelet-tumor cell interactions in a patient in need thereof. The invention also provides an aqueous ticagrelor solution for intravenous administration, for use in a dual antiplatelet therapy (DAPT), preferably comprising acetyl salicylic acid or salts thereof as second active ingredient in addition to ticagrelor. In a preferred embodiment, the aqueous ticagrelor iv solution has a storage stability of at least 3 months in accelerated storage conditions at 40 °C and 75 % Relative Humidity. The ingredients of the aqueous ticagrelor iv solution are preferably as previously described. The invention is further illustrated by way of examples. The examples are non-exhaustive. EXAMPLES
Example 1 In a first example two different types of cyclodextrin were used and compared for the solubilization of ticagrelor. An unbuffered stock solution of HPβCD or SBECD was made in water at the target concentrations of 20 w/w%, 25 w/w%, 30 w/w%, 35 w/w% and 40 w/w%. Ticagrelor was added slowly under vortex. Ticagrelor was used at concentrations of 5, 10 or 14 mg/ml in milli Q water. The ticagrelor-cyclodextrin solutions were left on a shaking platform. No sonification or heat was applied. From the results in Table 1 and 2 it follows that HPβCD was able to dissolve ticagrelor in a broader range of cyclodextrin and ticagrelor concentrations tested. Clear aqueous solutions with 5 mg/ml ticagrelor in HPβCD were obtained with 25 w/w%, 30 w/w%, 35 w/w% and 40w/w% HPβCD. Table 1: Solubility of ticagrelor in HPβCD
+ clear, appeared completely dissolved - translucent solution with precipitation +/- clear solution with precipitation * after one hour of sonication Table 2: Solubility of ticagrelor in SBECD
+ clear, appeared completely dissolved - translucent solution with precipitation +/- clear solution with precipitation As a conclusion Ticagrelor could be dissolved by leaving it on a shaking platform. No sonication was applied. HPβCD can be used at Ticagrelor concentrations of 5 mg/ml, using cyclodextrin at 40% w/w, 35% w/w or 30% w/w in milliQ water. These solutions remained clear at least for the three days testing at room temperature and several days at 4°C. Example 2 After the experiments depicted in Example 1, further optimization was caried out with the selection of a suitable pH range to ensure long-term stability of the aqueous ticagrelor- cyclodextrin inclusion complex. The following composition as provided in Table 3 was prepared. Table 3: Composition for storage stability testing.
HPβCD was dissolved in a buffer solution of pH 4.5, 5.5 or 6.5 prepared separately in water. Once a clear solution was obtained, ticagrelor was dissolved in the buffer solution under constant stirring. The ticagrelor in buffer solution was filtered through a 0.22 micron filtered and filled in USP Type I glass vials. The vials were stoppered and stored. All precautions were taken during manufacturing, such as N2 purging and avoiding direct exposure to light. The vials were stored at 40 °C and 75 % Relative Humidity (RH). To determine the stability of the formulations, batches were evaluated using a related substance method on HPLC. The data of these batches is enumerated below in Table 4. A Gradient HPLC method was used to analyze impurities in formulations using a YMC-Pack Pro C18 column (100x4.6mm, S-3μm 12nm). Good separation was obtained for all the impurities. Amine impurity: (1S,2S,3R,5S)-3-(7-amino-5-(propylsulfanyl)-3H-[1,2,3]triazolo[4,5- d]pyrimidin-3-yl)-5-(2-hydroxyethoxy)cyclopentane-1,2-diol. This is a process related degradant impurity. Regiomer impurity: (1S, 2S, 3R, 5S)-3-((3-((1R,2S)-2-(3,4-Difluorophenyl) cyclopropyl)-5- (propylsulfanyl)-3H-[1,2,3]triazolo [4,5-d]pyrimidin-7-yl)amino)-5-(2- hydroxyethoxy)cyclopentane-1,2-diol. This is a process related degradant impurity. Acetal impurity: 2-[[(3aR,4S,6S,6aS)-6-[7-[[1R,2S)-2-(3,4-difluorophenyl)- cyclopropyl]amino]-5-(propylsulfanyl)-3H-[1,2,3]triazolo-[4,5-d]pyrimidin-3-yl]-2,2- dimethyltetrahydro-2H-3aHcyclopenta[d][1,3] dioxol-4-yl]oxy]ethan-1-ol. This is a process related impurity. Triol impurity: (1S,2R,3S,4R)-4-(7-((1R,2S)-2-(3,4-difluorophenyl) cyclopropylamino)-5- (propylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)cyclopentane-1,2,3-triol. This is a process related impurity. It was observed that only regiomer impurity increased in 4 weeks 40 °C and 75 % RH at almost 0.3% level; specification limit 0.3 %. Hence to optimize the stability of the product further, investigations were carried out at pH 7 to 8. Example 3 Following the experiment described in example 2, a storage stability study at pH 7.5 was conducted. First HPβCD was dissolved in a phosphate buffer solution of pH 7.5 prepared separately in water. Once a clear solution was obtained ticagrelor was dissolved in the solution under constant stirring. The solution was filtered through a 0.22 micrometer filter and filled in USP Type I amber colored glass vials. The vials were stoppered and stored. All precautions were taken during manufacturing, such as N2 purging and avoiding direct exposure to light.
Table 4: Stability test of ticagrelor-cyclodextrin inclusion complex in aqueous solution at pH 4.5, 5.5 and 6.5 after storage at 40 *C and 75 % RH
Table 5: Composition for storage stability testing.
Table 6: Storage stability study of ticagrelor-cyclodextrin inclusion complex in aqueous solution at pH 7.5 stored at 40 °C and 75 % Relative Humidity.
Based on the results of the stability study, as summarized in Table 6, it was concluded that good storage stability was obtained at accelerated storage conditions of 40 °C and 75 % Relative Humidity. The regiomer impurity was well under control and no other impurity was of a concern. Example 4 In a further experiment, to optimize the concentration of HPβCD below 40% w/w, heat at 40 °C was applied at concentrations where a clear solution was difficult to obtain to help dissolve the target ticagrelor dose. Direct physical stability data as obtained from the ticagrelor 5mg/ml concentrate and with the flocculation test (20 µl sample material in 1 ml diluent) are shown in Table 7. Table 7 contains data on assay, purity, osmolality and pH. Table 7: Physical stability of ticagrelor 5 mg/ml batches with varying HPβCD concentrations. Data are sorted by HPβCD strength. Ticagrelor concentration when diluted into dextrose or saline: 0.1 mg/ml.
Because of the poor physical stability results when diluted in saline, 32.5 % w/w HPβCD was chosen for a 5 mg/ml ticagrelor formulation. Undiluted concentrate remained stable even in the refrigerator with a HPβCD concentration as low as 22.5 % w/w. Such a concentration yielded a nearly isotonic formulation. In conclusion, it was possible to dissolve 5-15 mg/ml ticagrelor together with HPβCD in the concentration range of 20-40 % w/w, without the use of heat. It was possible to achieve good solubility with lower concentrations of HPβCD such as 15-20 % w/w with application of heat to achieve a clear solution. At least 15% w/w HPβCD was required to provide a clear, storage stable ticagrelor solution with a concentration that is relevant for injection or intravenous administration. Example 5 From the results obtained in Example 4 it follows that the concentration of excipients may be such that the resulting ticagrelor solution is hypertonic. The osmolality and pH of several batches was checked. The solutions had a 19mM phosphate buffer and pH 7.5. The results are provided in Table 8. Table 8: pH and osmolality determination in undiluted batches.
Dilution studies were conducted to search for suitable diluents.
5 mg/ml ticagrelor-cyclodextrin solutions with varying amounts of HPβCD were diluted with normal saline, 5% dextrose solution or Ringer’s lactate solution. The stability was screened. The ticagrelor concentration when diluted into dextrose or saline: 0.1mg/ml The results are summarized in Table 9. Table 9: Diluent tests
In addition, a screening was conducted on the impact of buffer strength on pH and osmolality. The results are summarized in Table 10. Table 10: Impact of buffer strength on pH, osmolality, assay, and impurities.
It was concluded that a phosphate buffer of pH 7,5 at different buffer strengths had little effect on the osmolality. Except at 0.19 mM buffer strength. This buffer strength was too weak, which lead to a change in pH. Example 6 In a further example the impact of particle size on solubility was tested. Two different particle size diameters for the ticagrelor active ingredient were screened, 5.5 and 15 micrometers. The pH and osmolality were not affected. Smaller particles showed a faster dissolution time, as summarized in Table 11. The micronized ticagrelor showed significant improvement on the dissolution time. Consequently, a micronized ticagrelor with D90 of less than 10 micrometers is preferred.
With the term “D90” as used herein, is meant that at least 90% of the particles present have a size that is less than the target particle size. However, it is understood that variations in input particle size distribution (PSD) of ticagrelor would be possible and it will have an impact on the dissolution rate of ticagrelor. Table 11: Impact of particle size
Example 7 To optimize the HPβCD concentration and the pH of the solution for intravenous use, a 12 week/3 months stability study was conducted. A composition of 32,5% w/w HPβCD with 5 mg/ml ticagrelor at pH 7 to 8 was prepared and stored. Its stability was tested at regular intervals. A comparison of stability profile at 3 different pH – 7, 7.5 and 8- was carried out as below, the manufacturing process for all 3 formulations was kept constant with buffer strength at 19mM. The results are summarized in Tables 12 to 14 Table 12: Storage stability in amber glass vials – pH 7
Table 13: Storage stability in amber glass vials – pH 7.5
Table 14: Storage stability in amber glass vials – pH 8.0
From the above data it was concluded that the ticagrelor solution in HPβCD was stable in the pH range of 7 to 8. Example 8 To study the potential impact of the packaging material on the stability of the ticagrelor- cyclodextrin inclusion complex a composition with 32.5%w/w HPβCD was prepared with procedures and precaution’s similar to previous trials, samples were stored in transparent clear glass vials and amber colored glass vials at a temperature of 40 °C /75% RH. The results are shown in Table 15 and Table 16.
The results of the accelerated storage stability test indicated that after 3 months, no significant difference was observed between the two. All the samples remained clear aqueous solutions. The pH of the samples remained stable. Impurities did not change significantly. It seems that both clear and amber colored glass vials can be used. Compared to the results of the accelerated storage stability test on ticagrelor solutions, without the use of cyclodextrin, it is clear that the use of cyclodextrin is important to achieve a good stability. Without the cyclodextrin, 6 to 8 different impurities developed on storage. These impurities were not seen in the selected composition. Table 15: Study of the potential impact of packaging. Stability in amber color USP Type I glass.
Table 16: Study of the potential impact of packaging. Stability clear glass vials USP Type I.
Surprisingly it could be concluded that ticagrelor solutions can be stabilized with HPβCD in both amber colored and clear glass vials. Example 9 Further embodiments of the invention are provided as summarized in Table 17. Further improvement in achieving higher solubility of ticagrelor was tried with different concentrations, such as with 40% w/w HPβCD, a ticagrelor solubility of 13 mg/ml was also possible. Table 17: clear aqueous solutions with ticagrelor-cyclodextrin inclusion complex considering 65 mg dose.
Density 1.130 gm/cc Based on the investigations it was observed that a concentration of 5 – 13 mg/ml ticagrelor solution could be achieved using 20-40% w/w HPβCD. The volume of the fill content can be changed based on the dose required. Surprisingly it was found that the target dose of 5 -15 mg/ml ticagrelor contained in a small volume could be achieved by adjusting the HPβCD % and total available volume of the formulation ready to inject. Being able to contain the ticagrelor dose in a volume of 5-15 ml is highly relevant as it is a typical bolus injection volume. Example 10
In a further example, the maximum solubility of ticagrelor in an HPβCD solution, without the use of heat, was investigated. The results are summarized in Table 18. Depending on the amount of ticagrelor to be delivered to a patient and the restriction of the sample volume as determined by an administration by injection or infusion, it follows that to dissolve 65-75 mg ticagrelor an amount of 2000-4000 mg of HPβCD per vial of 10 ml may be required. Table 18: Concentration of HPΒCD, dose and volume of formulations
Density of the HPβCD solution 1.130 gm/cc Surprisingly the solutions provided in Table 18 were compatible with diluents to provide infusions, specifically with dextrose 5% in water. Example 11 In another embodiment of this invention, a highly stable clear solution of ticagrelor could be obtained by applying appropriate heat to the solution during preparation thus providing a completely clear solution of the formulation at desired HPβCD and ticagrelor concentrations. To investigate the impact of temperature and hold time, a new composition was prepared as per below Table 19. Table 19: Composition for temperature impact assessment.
In first step a phosphate buffer at pH 7.5 was prepared and the buffered solution was heated to 40°C -45°C. HPβCD was added to the buffered solution under continuous mixing. Once a clear solution was obtained, ticagrelor was dispersed into the HPβCD solution and mixed until a clear solution was obtained. It usually took 30 mins to 4 hours depending on batch size.
Then this solution was filtered through a 0.22-micron filter and packed in suitable clear or amber colored glass vials Table 20: Bulk hold study at 45°C
Table 21: Bulk Hold study at 25°C and 40°C
Table 22: Bulk hold at 30°C
The hold time study at temperatures between 25°C - 45°C indicated how even 30% w/w HPβCD was capable of stabilizing ticagrelor, even after heating the solution for a prolonged period of time or keeping the bulk at an elevated temperature. Example 12: Aqueous ticagrelor solution for oral administration In the present example an aqueous ticagrelor formulation is presented that is provided for oral administration. The composition is provided in Table 23. Table 23: Composition of an aqueous ticagrelor formulation for oral administration
The process of manufacturing such oral solutions is straight forward. Preservatives are dissolved in propylene glycol. HPβCD was dissolved in water and ticagrelor is added into it under continuous stirring and then mixed with solution of propylene glycol. The remaining items were added in the solution and pH is adjusted to 7-8.
Claims
CLAIMS 1. An aqueous ticagrelor composition comprising ticagrelor as active ingredient, characterized, in that the composition is a solution comprising a water-soluble inclusion complex of ticagrelor in a cyclodextrin, wherein the composition has a pH between 5,5 to 9.
2. An aqueous ticagrelor composition according to claim 1, wherein the osmolality is between 350-900 mOsm/kg.
3. Aqueous ticagrelor composition according to claim 1 or 2, wherein the cyclodextrin is selected from a hydroxypropyl-beta-cyclodextrin and a sulfobutylether derivative of a beta-cyclodextrin.
4. Aqueous ticagrelor according to any of claims 1 to 3, comprising 15 – 40% w/w cyclodextrin; preferably comprising 15 – 40% w/w hydroxypropyl-beta-cyclodextrin.
5. Aqueous ticagrelor composition according to any of claims 1 to 4, comprising 2-15 mg/ml ticagrelor.
6. Aqueous ticagrelor composition according to any of claims 1 to 5, wherein the composition is provided for infusion and has a volume of 15 to 30 ml.
7. Aqueous ticagrelor composition according to any of claims 1 to 5, wherein the composition is provided for injection and has a volume of 5 to 15 ml.
8. Aqueous ticagrelor composition according to any of claims 1 to 7, with the proviso that organic co-solvents are excluded.
9. Aqueous ticagrelor composition according to any of claims 1 to 8, wherein the ticagrelor has a D90 particle size below 10 micrometers when tested using Malvern mastersizer
10. Aqueous ticagrelor composition according to any of claims 1 to 9, with a storage stability of at least 3 months at 40 °C and 75 % Relative Humidity.
11. Aqueous ticagrelor solution according to any of claims 1 to 10, consisting of 5-15 mg/ml ticagrelor, 15 – 40 % w/w of a hydroxypropyl-beta-cyclodextrin, 5 mM-20 mM of phosphate buffer, optionally including a tonicity modifier, wherein the pH is between 5,5 and 8.
12. Aqueous ticagrelor composition according to any of claims 1 to 11, for use in a ticagrelor responsive medical treatment.
13. Aqueous ticagrelor composition according to any of claims 1 to 12, for use in a ticagrelor responsive medical treatment wherein the composition is administered as an injection, infusion, nasal gastric fluid, or drink.
14. Aqueous ticagrelor composition according to claim 12 or 13, for use in the treatment of acute coronary syndrome (ACS), myocardial infarction (MI), ischemic stroke, transient ischemic attack (TIA) or for the reduction of platelet-tumor cell interactions in a patient in need thereof.
15. Aqueous ticagrelor composition according to any of claims 12 to 14, for use in a dual antiplatelet therapy (DAPT), preferably comprising acetyl salicylic acid or salts thereof as second active ingredient in addition to ticagrelor.
16. A unit dose composition for delivery of 15-180 mg ticagrelor comprising a composition according to any of claims 1 to 15.
17. Unit dose composition according to claim 16, comprising 2000-4000 mg of cyclodextrin.
18. Unit dose composition according to claim 16 or 17, comprising 5% dextrose water as diluent.
19. A method for the manufacturing of an aqueous ticagrelor composition according to any of claims 1 to 15, comprising the steps of: - preparing an aqueous solution of pH 5,5-9 preferably comprising a buffering agent, more preferably comprising a phosphate buffer, - introducing a cyclodextrin amount for inclusion of a pre-determined amount of ticagrelor, - adding the pre-determined amount of ticagrelor, thereby obtaining an inclusion complex of ticagrelor in cyclodextrin.
20. Method according to claim 19, wherein heating is applied prior to the addition of ticagrelor.
21. 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 the reduction of platelet-tumor cell interactions in a patient in need thereof.
22. Aqueous ticagrelor solution for intravenous administration, for use in a dual antiplatelet therapy (DAPT), preferably comprising acetyl salicylic acid or salts thereof as second active ingredient in addition to ticagrelor.
23. Aqueous ticagrelor solution according to claim 21 or 22, wherein the solution has a storage stability of at least 3 months in accelerated storage conditions at 40 °C and 75 % Relative Humidity.
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| PCT/EP2023/063071 WO2023222660A1 (en) | 2022-05-16 | 2023-05-16 | Aqueous ticagrelor solutions, method of manufacturing and uses |
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20100291056A1 (en) * | 2009-05-13 | 2010-11-18 | Mosher Gerold L | Pharmaceutical Compositions Comprising Prasugrel and Cyclodextrin Derivatives and Methods of Making and Using the Same |
| CN110917167A (en) * | 2018-09-19 | 2020-03-27 | 河南天晟泰丰医药科技有限公司 | Ticagrelor enteric sustained-release soft capsule and preparation method thereof |
| WO2021096444A1 (en) * | 2019-11-13 | 2021-05-20 | Santa Farma İlaç Sanayi̇ A.Ş. | Pharmaceutical compositions comprising ticagrelor |
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- 2022-05-16 WO PCT/EP2022/063185 patent/WO2023222184A1/en unknown
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
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| US20100291056A1 (en) * | 2009-05-13 | 2010-11-18 | Mosher Gerold L | Pharmaceutical Compositions Comprising Prasugrel and Cyclodextrin Derivatives and Methods of Making and Using the Same |
| CN110917167A (en) * | 2018-09-19 | 2020-03-27 | 河南天晟泰丰医药科技有限公司 | Ticagrelor enteric sustained-release soft capsule and preparation method thereof |
| WO2021096444A1 (en) * | 2019-11-13 | 2021-05-20 | Santa Farma İlaç Sanayi̇ A.Ş. | Pharmaceutical compositions comprising ticagrelor |
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| SIGFRIDSSON ET AL., J PHARM SCI, vol. 100, 2011, pages 2194 - 2202 |
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