Intravenous administration of the ticagrelor composition in patients previously administered an opioid to treat coagulopathy and avoid reduced ticagrelor uptake

Abstract

This invention provides a ticagrelor pharmaceutical composition for treating or preventing coagulation in patients in need of co-administering an opioid active ingredient, the pharmaceutical composition being combined with a pharmaceutically acceptable carrier, characterized in that the ticagrelor pharmaceutical composition is administered intravenously after administration of the opioid active ingredient, thereby avoiding delayed or reduced ticagrelor uptake caused by the opioid active ingredient; wherein the ticagrelor pharmaceutical composition comprises an inclusion complex of ticagrelor and cyclodextrin. This invention also provides lyophilized forms of ticagrelor pharmaceutical compositions and liquid ticagrelor compositions for lyophilization. This invention provides a kit comprising a combination of lyophilized ticagrelor compositions and suitable diluents. This invention provides a method for preparing lyophilized forms of ticagrelor pharmaceutical compositions. The reconstituted lyophilized ticagrelor compositions are particularly suitable for overcoming delayed or reduced ticagrelor absorption caused by concomitant opioid use.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical compositions and their uses. The active ingredient involved is ticagrelor. This invention has advantages for patients requiring combined anticoagulant therapy for pain management or sedation. This invention provides a solution to the problem of opioid active ingredients affecting the absorption of oral P2Y12 anticoagulants. This is particularly important for patients requiring immediate onset of action to reduce coagulation-related complications. This invention is an improvement on the temporary preparation of ticagrelor solution. Background Technology

[0002] Fentanyl is a potent synthetic opioid used to relieve severe and chronic pain, and as an adjunct to general or local anesthesia. Its analgesic and anesthetic activity derives from stimulation of μ-opioid receptors, leading to inhibition of adenylate cyclase and downregulation of cyclic adenosine 3',5'-monophosphate (cAMP), as well as decreased calcium channel activity and increased potassium channel activity. μ-opioid receptors are abundant in the central nervous system, mediating analgesia there, and also in the nerve cells of the intestine, regulating peristalsis in the secretion and transport of fluids and electrolytes. They are also expressed in blood cells, vascular cells, and skin. Given the widespread distribution of μ-opioid receptors, it is likely that fentanyl can also modulate the activity of many other cells, including platelets.

[0003] Recent studies have shown that opioids, such as fentanyl, morphine, oxycodone, hydrocodone, and codeine, can delay gastric emptying and slow the absorption of oral P2Y12 platelet inhibitors. Furthermore, nausea and vomiting are more frequent in patients receiving opioids, which may further reduce the uptake of oral P2Y12 platelet inhibitors.

[0004] Optimal platelet suppression is one of the most important goals in the acute treatment of patients with segmental elevation myocardial infarction (STEMI). Opioids are widely used in routine practice, especially in the United States, for example, to reduce chest pain while waiting for angiography and determining the need for percutaneous coronary intervention (PCI). Antiplatelet therapy is administered to patients prior to PCI to reduce in-stent thrombosis. However, fentanyl has been observed to delay or reduce platelet suppression by oral P2Y12 inhibitors, especially when the time interval between the co-administration of opioids and antiplatelet agents is short. Because the goal of non-elective PCI is to be performed within 90 minutes of the patient's arrival in the emergency room, the so-called "surgery-to-balloon dilation" time window, the risk of myocardial infarction or in-stent thrombosis may not be adequately reduced.

[0005] In healthy adults, co-administration of 5 mg intravenous morphine with a 600 mg loading dose of clopidogrel reduced the AUC and Cmax of clopidogrel's thiol metabolites by 34%. Mean platelet aggregation was higher up to 2 to 4 hours after morphine co-administration.

[0006] In healthy adults, co-administration of 5 mg intravenous morphine with a 60 mg loading dose of prasugrel reduced the Cmax of the active metabolite of prasugrel by 31%, while there was no change in the inhibition of AUC, Tmax, or ADP-induced platelet aggregation. In stable patients with ACS more than 1 year after co-administration of morphine, ADP-induced platelet aggregation was higher up to 2 hours after the 60 mg loading dose of prasugrel. In patients with a 2-hour delay in platelet aggregation onset (5 of 11 patients), Tmax was delayed after co-administration with morphine, and the level of the active metabolite of prasugrel was significantly reduced 30 minutes after administration (5 ng / mL vs. 120 ng / mL).

[0007] In healthy adults, co-administration of 5 mg intravenous morphine with a loading dose of 180 mg ticagrelor resulted in an observed reduction of mean ticagrelor exposure by up to 25%, and by up to 36% in ACS patients undergoing PCI. Tmax was delayed by 1–2 hours. Exposure to the active metabolite was reduced to a similar extent. In healthy adults, co-administration of morphine did not delay or reduce platelet inhibition. In ACS patients co-administered with morphine, mean platelet aggregation was higher up to 3 hours after the loading dose.

[0008] In ACS patients undergoing PCI, co-administration of intravenous fentanyl with a loading dose of 180 mg ticagrelor had similar effects on ticagrelor exposure and platelet inhibition.

[0009] In the presence of an interaction between opioids and oral P2Y12 inhibitors, there may be other medical indications.

[0010] Since 2019, the U.S. Food and Drug Administration (FDA) has mandated that manufacturers of oral P2Y12 platelet inhibitors (clopidogrel, prasugrel, and ticagrelor) include a warning on their product labels: absorption may be delayed or reduced when taken with opioid receptor agonists. The drug labels for clopidogrel, prasugrel, and ticagrelor tablets recommend considering parenteral antiplatelet therapy for patients requiring co-administration of morphine or other opioid agonists in cases of acute coronary syndrome.

[0011] The known parenteral administration of ticagrelor is via crushed tablets administered through a nasogastric tube. This method offers some improvement. However, its preparation is time-consuming and can cause considerable discomfort to patients. This method involves administering a suspension, which is non-uniform, prone to sedimentation, and results in inconsistent dosage.

[0012] Current medical practice involves increasing the dosage of P2Y12 inhibitors and monitoring patients more closely. Increased dosage may lead to increased adverse reactions and an increased risk of bleeding. Closer monitoring and follow-up place a burden on hospital resources.

[0013] Cangrelor IV is the only known P2Y12 inhibitor available for intravenous administration. It acts directly, with the platelet-depressant (PD) effect starting in approximately 2 minutes, reaching its maximal effect in approximately 2 minutes, and exhibiting a maximum platelet inhibition of at least 98%. However, its half-life is 3–6 minutes, and platelet function returns to baseline within approximately 1 hour after discontinuation. This means that repeated injections or continuous infusions are necessary if the effect is to last for at least several hours. Furthermore, cangrelor is contraindicated in some patients due to allergy to cangrelor or any component of the product.

[0014] In view of the above, there is a need for further improvements. This invention aims to address at least one of the aforementioned problems. Specifically, this invention aims to provide a solution to drug-drug interactions between opioids and oral P2Y12 inhibitors, such as ticagrelor. This invention aims to reduce the risk of insufficient platelet inhibition and the resulting thrombotic complications. This invention aims to provide optimized formulations for time-sensitive acute scenarios. Summary of the Invention

[0015] In a first aspect, the present invention provides a ticagrelor pharmaceutical composition for treating or preventing coagulation in patients in need who have previously received an opioid active ingredient, characterized in that the ticagrelor pharmaceutical composition is administered intravenously after administration of the opioid active ingredient, thereby avoiding delayed or reduced ticagrelor uptake caused by the opioid active ingredient. The use of the ticagrelor IV composition provides improved bioavailability compared to currently available ticagrelor compositions. Intravenous administration overcomes the effects of the opioid active ingredient, which is known to delay or reduce oral ticagrelor uptake, with an average bioavailability of 36%.

[0016] Preferably, ticagrelor is administered within three hours of the administration of the active ingredient in the opioid.

[0017] Preferably, the ticagrelor pharmaceutical composition is used to treat patients with ST-segment elevation myocardial infarction or non-ST-segment elevation myocardial infarction. Preferably, the patient has been given fentanyl before angiography and before anticoagulant therapy. Preferably, the patient is undergoing non-elective PCI.

[0018] Alternatively, ticagrelor drug combinations can be used to treat patients who have undergone joint replacement surgery.

[0019] Alternatively, ticagrelor drug compositions are used to treat patients with Gram-positive bacteremia following abuse of a drug substance containing an opioid active ingredient.

[0020] Preferably, the ticagrelor pharmaceutical composition used in embodiments of the present invention comprises an inclusion complex of ticagrelor and cyclodextrin.

[0021] Preferably, the ticagrelor pharmaceutical composition used in the embodiments of the present invention is a lyophilized ticagrelor composition; preferably, it is a lyophilized ticagrelor composition according to the embodiments of the present invention.

[0022] Preferably, the reconstitution time of the lyophilized ticagrelor composition is less than 5 minutes.

[0023] Preferably, an effective amount of ticagrelor is administered intravenously over 5 minutes.

[0024] In a second aspect, the present invention provides a liquid composition containing ticagrelor for lyophilization, comprising ticagrelor in free form, a filler, and an alcohol:water mixture, wherein the ratio of the alcohol to the water is 25:75 to 50:50 (%w / w). Preferably, the alcohol is tert-butanol (TBA). This composition is particularly suitable for preparing lyophilized ticagrelor pharmaceutical compositions.

[0025] Preferably, the lyophilized liquid composition containing ticagrelor according to an embodiment of the present invention comprises a 50 mg / 15 ml to 100 mg ticagrelor / 15 ml solution and / or a 6.5 mg / ml to 8.0 mg ticagrelor / ml composition.

[0026] Preferably, the filler is mannitol, and the mannitol is present in the liquid composition containing ticagrelor for lyophilization at an amount of 20 to 75 mg / ml.

[0027] More preferably, the liquid composition containing ticagrelor for lyophilization according to an embodiment of the present invention comprises: 6.5 mg ticagrelor / ml, 232.5 mg / ml TBA, 33.5 mg mannitol / ml, and the balance being water for injection.

[0028] In a further aspect, the present invention provides a method for manufacturing a lyophilized form of a ticagrelor pharmaceutical composition, comprising the steps of: providing a liquid composition containing ticagrelor according to an embodiment of the present invention; lyophilizing the liquid composition containing ticagrelor; and recovering the resulting lyophilized form of the ticagrelor composition.

[0029] The present invention also provides a lyophilized ticagrelor pharmaceutical composition obtained by a method according to embodiments of the invention. Preferably, the composition comprises 30 mg to 100 mg of ticagrelor and 20 mg to 75 mg of mannitol, and the ticagrelor is present in free form. This formulation is particularly suitable for time-sensitive acute scenarios where it is important to avoid delays or reductions in platelet inhibition. This formulation provides an alternative to liquid ticagrelor IV formulations containing a high content of cyclodextrin. Cyclodextrin-free formulations may be more suitable for long-term use.

[0030] In a further aspect, the present invention provides a kit of parts comprising a ticagrelor pharmaceutical composition according to an embodiment of the present invention in combination with a suitable diluent solution, said suitable diluent solution comprising:

[0031] 0.1 M phosphate buffer solution with pH 7.4-7.5

[0032] 4% - 4.4 w / w% polyethylene glycol (15)-hydroxy stearate (Kolliphor HS 15) and 30% - 40 v / v% polyethylene glycol (PEG-400).

[0033] Alternatively, the present invention provides a kit comprising a ticagrelor pharmaceutical composition according to an embodiment of the present invention in combination with a suitable diluent solution comprising:

[0034] Phosphate buffer solution with pH 7.4-7.5

[0035] 4% polyoxyethylene dehydrated sorbitan monooleate (40 mg / ml) and

[0036] 40 / v% propylene glycol (400 mg / ml).

[0037] The present invention also provides a method for preparing a lyophilized form of a ticagrelor pharmaceutical composition, comprising the following steps: providing a liquid composition containing ticagrelor, comprising an inclusion complex of ticagrelor and cyclodextrin (preferably hydroxypropyl β-cyclodextrin (HPBCD)); lyophilizing the liquid composition containing ticagrelor and recovering the resulting lyophilized form of the ticagrelor composition; wherein the ticagrelor pharmaceutical composition comprises an inclusion complex of ticagrelor and cyclodextrin (preferably hydroxypropyl β-cyclodextrin (HPBCD)).

[0038] The present invention further provides a lyophilized composition containing ticagrelor, comprising ticagrelor and cyclodextrin, preferably an inclusion complex of hydroxypropyl β-cyclodextrin (HPBCD). Invention Details

[0040] Unless otherwise defined, all terms used in the description of this invention, including technical and scientific terms, shall have the meanings commonly understood by one of ordinary skill in the art to which this invention pertains. Furthermore, definitions of terms are included to facilitate a better understanding of the description of this invention.

[0041] As used herein, the following terms have the following meanings: “a,” “an,” and “the” as used herein refer to both the singular and the plural, unless the context otherwise indicates. “A surfactant” means, for example, one or more surfactants.

[0042] As used herein, “about” refers to a measurable value, such as a parameter, quantity, duration, etc., and is intended to include variations of ±10% or less, preferably ±5% or less, more preferably ±3% or less, even more preferably ±1% or less, and even more preferably ±0.1% or less, provided such variation is suitable for carrying out in the described invention. However, it will be clear that the value referred to by the term “about” is itself specifically described. As used herein, “include,” “comprising,” and “comprises” are inclusive or open-ended terms that explicitly indicate the presence of what follows, such as components and additional, unnamed components, features, elements, parts, steps, etc., that are well known in the art or described herein, and do not exclude them.

[0043] The description of a numerical range by endpoints includes all numbers and fractions included in that range, as well as the endpoints mentioned.

[0044] As used herein, the term "% w / w" refers to weight percentage, where the weight ratio of an ingredient to the total weight of the composition is expressed as a percentage.

[0045] Ticagrelor is the well-known active ingredient. It is a platelet aggregation inhibitor used in patients with acute coronary syndrome to prevent thrombotic events such as myocardial infarction or stroke. 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.

[0046] Ticagrelor was developed by AstraZeneca and approved for marketing by the European Medicines Agency in 2010 and the U.S. Food and Drug Administration in 2011. It is marketed as a tablet in the United States under the name Brilinta. ® and in Europe for Brilique ® It is not commercially available in liquid form. Ticagrelor is an oral, reversible, direct-acting P2Y drug. 12 Receptor antagonists work by inhibiting platelet activation. Brilinta® tablets, together 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 a history of acute coronary syndrome (ACS) or heart attack. In the United States, Brilinta... ® Tablets are also suitable for use in high-risk patients with coronary artery disease to reduce the risk of a first heart attack or stroke.

[0047] Ticagrelor has shown high degradability when exposed to light, heat, and oxygen, and its limited solubility poses a significant challenge when formulated into aqueous solutions. Despite the continued high demand for ticagrelor liquid formulations, to our knowledge, no successful commercial product has yet achieved the desired solubility and long-term stability required by the pharmaceutical industry.

[0048] Sigfridsson et al. (J Pharm Sci 100: 2194-2202, 2011) disclosed a composition deemed suitable for intravenous administration. This composition is based on a combination of ticagrelor nanoparticles, polyvinylpyrrolidone, and Aerosol AOT disodium salt (for stabilizing the active ingredient), along with 5% mannitol to obtain a nanosuspension. Aerosol AOT is believed to correspond to sodium dioctyl sulfosuccinate. Although the nanosuspension has been reported to have stability of at least 10 months, there have also been reports of a tendency for some particle aggregation and precipitation during storage. Therefore, the sample is sonicated prior to intravenous administration. This is cumbersome for pharmaceutical use and poses safety risks.

[0049] The same publication by Sigfridsson et al. also mentions that the concentration of ticagrelor in a phosphate buffer solution at pH 7.4 decreased after one month under normal laboratory light and temperature conditions.

[0050] Despite the long-standing need for intravenous formulations to overcome the drawbacks of oral P2Y12 inhibitors such as ticagrelor tablets, no feasible disclosures have been provided in the literature. Commercially available ticagrelor is only available in the form of (orally dispersible) tablets.

[0051] In a first aspect, the present invention provides a ticagrelor pharmaceutical composition for treating or preventing coagulation in patients in need who are co-administering an opioid active ingredient, said pharmaceutical composition being combined with one or more pharmaceutically acceptable carriers, characterized in that the ticagrelor pharmaceutical composition is administered intravenously after administration of the opioid active ingredient, thereby avoiding delay or reduction in ticagrelor uptake caused by the opioid active ingredient.

[0052] This invention overcomes the problem of reduced absorption of oral P2Y12 inhibitors caused by decreased gastric motility associated with opioid use.

[0053] The present invention provides a ticagrelor pharmaceutical composition for intravenous administration, which is used to treat time-sensitive acute scenarios requiring antiplatelet therapy, particularly ticagrelor therapy.

[0054] As used herein, the term "provided for intravenous administration" refers to a composition compatible with the bloodstream. This particularly relates to the osmotic pressure and pH of the formulation to be compatible. No dilution or pH adjustment is required; the formulation is ready to use.

[0055] Preferably, the patient is a human patient.

[0056] Preferably, the ticagrelor aqueous solution is prepared from micronized ticagrelor with a D90 of less than 90 micrometers. Methods for measuring the particle size of the active ingredient are well known to those skilled in the art. The method used in this invention is the Malvern particle size analyzer dry powder method.

[0057] According to embodiments of the present invention, the ticagrelor pharmaceutical composition comprising an opioid active ingredient and ticagrelor is administered at an interval of less than four hours, preferably less than three hours, more preferably less than two hours, and most preferably less than one hour.

[0058] The ticagrelor pharmaceutical composition used according to an embodiment of the present invention, wherein the patient suffers from ST-segment elevation myocardial infarction.

[0059] The ticagrelor drug composition used according to an embodiment of the present invention, wherein the patient suffers from non-ST-segment elevation myocardial infarction.

[0060] The ticagrelor pharmaceutical composition used according to an embodiment of the present invention, wherein the patient suffers from ST-segment elevation myocardial infarction.

[0061] The ticagrelor pharmaceutical composition used according to a prior embodiment of the invention, wherein fentanyl is administered to the patient before angiography and before anticoagulant therapy.

[0062] The ticagrelor drug composition used in the first two embodiments of the present invention, wherein the patient is undergoing non-elective PCI.

[0063] Alternatively, the ticagrelor pharmaceutical composition used according to embodiments of the present invention is used in cases where the patient has undergone joint replacement surgery (knee or hip). Opioids are used for pain management after joint replacement. Furthermore, antithrombotic drugs, including ticagrelor, are prescribed for the prevention or treatment of arterial or venous thrombosis. The present invention provides a solution to address drug-drug interactions between opioids and oral P2Y12 inhibitors (e.g., ticagrelor tablets).

[0064] The use of commonly injected drugs (such as heroin and fentanyl) in the United States has increased. Injection drug use (IDU) can lead to life-threatening methicillin-resistant Staphylococcus aureus (MRSA) bloodstream infections (BSI). A surveillance study reported that 24.1% of 7,646 MRSA BSI cases diagnosed between 2015 and 2017 were related to injection drug use. The prevalence of endocarditis in IDU-related BSI was significantly higher (40.4%) compared to other non-IDU-related BSI (10.8%) (p<0.001). Especially in these cases, the effectiveness of antiplatelet therapy with ticagrelor is particularly important due to the serious health risks involved.

[0065] Antiplatelet therapy has been proposed as a novel approach to combating bloodstream infections of Staphylococcus aureus (SA), including both methicillin-sensitive (MSSA) and methicillin-resistant Staphylococcus aureus (MRSA). This invention provides a solution to the problem of substance abuse or opioid use due to pain medication / sedation that may affect the efficacy of P2Y12 antiplatelet drugs such as oral ticagrelor or clopidogrel.

[0066] The ticagrelor pharmaceutical composition used according to an embodiment of the present invention comprises an inclusion complex of ticagrelor and cyclodextrin.

[0067] Cyclodextrin is a suitable solubilizer for ticagrelor by forming a ticagrelor-cyclodextrin inclusion complex. Preferably, the cyclodextrin is HPbCD. This cyclodextrin can be used to solubilize ticagrelor in an aqueous environment. A therapeutically relevant amount of the active ingredient ticagrelor can be dissolved as long as sufficient cyclodextrin is used. An aqueous composition containing a ticagrelor and HPbCD inclusion complex at pH 6-8 is prepared. Accelerated storage stability tests show accelerated storage stability for at least 3 months, measured under accelerated storage conditions of 40°C and 75% relative humidity.

[0068] In a further aspect, the present invention provides a ticagrelor pharmaceutical composition for use according to embodiments of the invention, for treating patients with Gram-positive bacteremia following opioid substance abuse. Intravenous administration of ticagrelor avoids the delayed or reduced absorption caused by opioid use.

[0069] The ticagrelor pharmaceutical composition used according to the prior embodiments of the present invention is preferably an aqueous solution of ticagrelor, comprising water, ticagrelor as the active ingredient, and a suitable amount of cyclodextrin for solubilizing ticagrelor, wherein the aqueous solution has a pH of 5.5-9 and an osmotic pressure of 300-900 mOsm / kg.

[0070] The ticagrelor pharmaceutical composition used according to the prior embodiments of the present invention preferably has a pH of 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 because the intravenous formulation is physiologically acceptable to the patient.

[0071] More preferably, the aqueous pharmaceutical composition used according to embodiments of the present invention comprises

[0072] 0.10–14.0 mg / ml ticagrelor and

[0073] Cyclodextrin at a concentration of 20–100 mg / ml is used to solubilize ticagrelor in a selected volume of aqueous drug solution (for solubilizing ticagrelor), wherein the volume of the aqueous drug solution is 25 to 1000 ml.

[0074] Preferably, the cyclodextrin is selected from hydroxypropyl-β-cyclodextrin and sulfobutyl ether-β-cyclodextrin. Most preferably, the cyclodextrin is hydroxypropyl-β-cyclodextrin. Preferably, no organic co-solvent is included. Preferably, polyethylene glycol is excluded from the aqueous ticagrelor composition. Preferably, the D90 particle size of ticagrelor is less than 10 micrometers when tested using a Malvern particle size analyzer.

[0075] More preferably, the aqueous ticagrelor composition used in the embodiments of the present invention comprises the following:

[0076] 5-15 mg / ml ticagrelor

[0077] 15–40% w / w hydroxypropyl-β-cyclodextrin

[0078] 5 mM-20 mM buffer solution

[0079] Optionally includes a tension modifier.

[0080] The pH value is between 5.5 and 8.

[0081] And the osmotic pressure is 300-900 mOsm / kg.

[0082] More preferably, the aqueous ticagrelor composition used in the embodiments of the present invention comprises the following:

[0083] 5-15 mg / ml ticagrelor

[0084] 15–40% w / w hydroxypropyl-β-cyclodextrin

[0085] 5 mM-20 mM phosphate buffer,

[0086] Optionally includes a tension modifier.

[0087] The pH value is between 5.5 and 8.

[0088] And the osmotic pressure is 300-900 mOsm / kg.

[0089] In a preferred embodiment, the pharmaceutical composition used in this invention is free of polyethylene glycol. This is advantageous for storage stability, as polyethylene glycol, found in aqueous ticagrelor solutions, is prone to impurities during prolonged storage.

[0090] The ticagrelor pharmaceutical composition used in the prior embodiments of the present invention, wherein the ticagrelor pharmaceutical composition is a lyophilized ticagrelor composition.

[0091] According to the ticagrelor pharmaceutical composition used in the prior embodiments of the present invention, the reconstitution time of the lyophilized ticagrelor composition is less than 5 minutes, preferably less than 3 minutes, and most preferably less than 1 minute.

[0092] In a second aspect, the present invention provides a ticagrelor pharmaceutical composition comprising an inclusion complex of ticagrelor and cyclodextrin, characterized in that the pharmaceutical composition is in lyophilized form.

[0093] In a further aspect, the present invention provides a liquid composition containing ticagrelor, comprising ticagrelor, a filler, and an alcohol:water mixture, wherein the ratio of the alcohol to the water is 25:75 to 50:50. The alcohol:water mixture ratio is preferably 30:70. This ratio is expressed as % w:w.

[0094] The alcohol is preferably tert-butanol (TBA).

[0095] Preferably, the liquid composition containing ticagrelor comprises ticagrelor, a filler, and a tert-butanol:water mixture, wherein the ratio of TBA to water is 25:75 to 50:50. The TBA:water mixture ratio is preferably 30:70. This ratio is expressed as % w:w.

[0096] Ticagrelor has six stereocenters, thus existing in various crystalline and amorphous forms. In a preferred embodiment of the invention, the active ingredient is crystalline ticagrelor. Specifically, four non-solventizable crystalline forms are obtained, named polymorphs I, II, III, and IV. These polymorphs exhibit different physical and chemical properties. In a preferred embodiment, polymorph II is used. Its X-ray powder diffraction pattern is characterized by characteristic 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° (±0.1°) 2Q. Polymorph II is described in the literature as the most stable crystalline form of ticagrelor.

[0097] The above-mentioned liquid composition containing ticagrelor is used as a stock solution for preparing lyophilized ticagrelor, wherein ticagrelor exists in free form. Preferably, ticagrelor polymorph II is used.

[0098] The concentration of ticagrelor in the liquid composition containing ticagrelor is preferably from 50 mg / 15 ml to 100 mg / 15 ml; more preferably from 55 mg / 15 ml to 95 mg / 15 ml; even more preferably from 60 mg / 15 ml to 90 mg / 15 ml; and most preferably 60 mg / 15 ml or 90 mg / 15 ml. 15 ml is a typical volume content (fill volume) for vials used for lyophilization.

[0099] In a preferred embodiment, the liquid composition containing ticagrelor comprises a filler selected from sucrose or mannitol. Preferably, the filler is present in an amount of 20 to 75 mg / ml; more preferably 25 to 65 mg / ml; even more preferably 30 to 60 mg / ml; and most preferably 33.5 or 50 mg / ml. Preferably, mannitol is present in an amount of 20 to 75 mg / ml; more preferably 25 to 65 mg / ml; even more preferably 30 to 60 mg / ml; and most preferably 33.5 or 50 mg / ml.

[0100] In a preferred embodiment, the liquid composition containing ticagrelor consists of 6.5 mg / ml ticagrelor, 232.5 mg / ml TBA, 33.5 mg / ml mannitol, and water for injection to a final volume of 1.0 ml. 10 ml of this ticagrelor-containing composition is filled into a vial and lyophilized.

[0101] In an alternative embodiment, the liquid composition containing ticagrelor consists of 60 or 90 mg / 15 ml ticagrelor, 3.5-4.5% w / w Kolliphor HS15 surfactant, optionally 5% w / v mannitol, and water for injection to a final volume of 15 ml.

[0102] Synonyms for Kolliphor HS15 include macrogol (15)-hydroxystearate, polyethylene glycol (15)-hydroxystearate, and polyoxyethylene-modified 12-hydroxystearate. The CAS number for Kolliphor HS15 is 70142-34-6. This nonionic surfactant is available from BASF. It is FDA approved for use in parenteral medications.

[0103] In a further aspect, the present invention provides a kit comprising a ticagrelor pharmaceutical composition according to an embodiment of the present invention in combination with a suitable diluent solution. The suitable diluent solution comprises:

[0104] 0.1 M phosphate buffer solution with pH 7.4-7.5

[0105] 4%-4.4 w / w% polyethylene glycol (15)-hydroxy stearate (Kolliphor HS 15) and 30%-40 v / v% polyethylene glycol (PEG-400).

[0106] In a further aspect, the present invention provides a method for preparing a lyophilized form of a ticagrelor pharmaceutical composition, comprising the steps of: providing a liquid composition containing ticagrelor, comprising ticagrelor, a filler, and an alcohol:water mixture, wherein the ratio of the alcohol to the water is 25 / 75 to 50 / 50; lyophilizing the liquid composition containing ticagrelor; and recovering the resulting lyophilized form of the ticagrelor composition, wherein the ticagrelor is in free form. Preferably, the liquid composition containing ticagrelor for lyophilization is a composition as previously disclosed.

[0107] The present invention also provides a method for preparing a lyophilized form of a ticagrelor pharmaceutical composition, comprising the following steps: providing a liquid composition containing ticagrelor, comprising an inclusion complex of ticagrelor and cyclodextrin (preferably hydroxypropyl β-cyclodextrin (HPBCD)); lyophilizing the liquid composition containing ticagrelor and recovering the resulting lyophilized form of the ticagrelor composition; wherein the ticagrelor pharmaceutical composition comprises an inclusion complex of ticagrelor and cyclodextrin (preferably hydroxypropyl β-cyclodextrin (HPBCD)).

[0108] The present invention further provides a lyophilized composition containing ticagrelor, comprising an inclusion complex of ticagrelor and cyclodextrin (preferably hydroxypropyl β-cyclodextrin (HPBCD)).

[0109] The invention is further illustrated by the following embodiments. These embodiments are not limiting. Example

[0110] Suitable ticagrelor pharmaceutical compositions for use in the present invention are provided in the examples below. In the first part, a liquid ticagrelor pharmaceutical solution with improved stability for intravenous administration is provided. These were previously disclosed in co-pending application PCT / EP2023 / 063071, which is incorporated herein by reference. In the second part, several lyophilized ticagrelor formulations and formulations for lyophilization are provided. These have the advantage that they may be free of cyclodextrin. These are particularly suitable for use over extended periods of treatment, i.e., beyond a single intravenous administration.

[0111] Provides an aqueous solution of ticagrelor for intravenous administration.

[0112] Example 1: Vitamin E TPGS as a solubilizer for ticagrelor

[0113] Table 1: Ticagrelor IV Combinations

[0114]

[0115] Using vitamin E TPGS as a solubilizer, ticagrelor aqueous solutions were prepared as follows: Water-soluble vitamin E TPGS was added to water to obtain aqueous solutions of different concentrations: 2.5 w / v%, 5.0 w / v%, and 10.0 w / v. The ticagrelor fraction was gradually added to these solutions, which were maintained at 45°C ± 5°C. 3 mg of the ticagrelor fraction was gradually added to 50 ml of vitamin E TPGS aqueous solution (Phase 1). Then, in the Phase 2 study, 20 ml of various diluents were used. 10 mg of the ticagrelor fraction was added to 20 ml of various diluents. When dissolution took a long time, the ticagrelor concentration was reduced to 5 mg.

[0116] Table 2: Ticagrelor IV aqueous solution

[0117]

[0118] The results were as follows: 10 mg ticagrelor dissolved after 5-10 minutes.

[0119] 2.5% Vitamin E TPGS solution saturated at 11.6 mg / ml

[0120] 5.0% Vitamin E TPGS solution saturated at 14.9 mg / ml

[0121] 10.0% Vitamin E TPGS solution saturated at 19.8 mg / ml

[0122] The obtained ticagrelor aqueous solution should be stored at 40°C and 75% relative humidity or 25°C and 60% relative humidity for at least 3 months.

[0123] Example 2: Cyclodextrin as a solubilizer for ticagrelor

[0124] The following compositions are suitable as ready-to-use aqueous ticagrelor compositions for intravenous administration.

[0125] Table 3: Ready-to-use ticagrelor compositions in water

[0126]

[0127] Table 4: Ready-to-use ticagrelor compositions in aqueous phosphate buffer solutions

[0128]

[0129] Table 5: Ready-to-use ticagrelor compositions in diluted physiological saline

[0130]

[0131] Table 6: Ready-to-use ticagrelor compositions in dextran solution

[0132]

[0133] Table 7: Preferred ticagrelor infusion solutions

[0134]

[0135] Exemplary ready-to-use solutions are prepared as follows. In all cases, the mentioned solvent is prepared and placed in a beaker and heated to 40 °C, then HPβCD is added with stirring to obtain a clear solution. Subsequently, the active ingredient ticagrelor is added at 40 °C with continuous stirring until a clear solution is obtained. This solution is filtered through a 0.22-micron filter and aseptically filled into sterile glass vials or infusion bags.

[0136] A stable ticagrelor solution of 24 mg / ml to 350 mg / ml HPβCD is required for infusion. The amount of cyclodextrin required depends on the volume of the target infusion medium.

[0137] Ticagrelor is an active ingredient that is insoluble in water. The more it is in an aqueous solution, the more likely it is to precipitate. As the dilution factor of ticagrelor increases, the amount of cyclodextrin required increases proportionally from 30 ml to 100 ml and then to 200 ml. However, for volumes of 650 ml and above, 16 g of cyclodextrin has been found to be sufficient to solubilize ticagrelor.

[0138] Please note that no organic cosolvents, surfactants, or other solubilizers were used.

[0139] The resulting ticagrelor aqueous solution was stored at 40°C and 75% relative humidity or 25°C and 60% relative humidity for at least 3 months and was found to be stable.

[0140] Developing a storage-stable ticagrelor solution

[0141] The experimental procedures for obtaining a storage-stable ticagrelor solution are explained in the following examples.

[0142] Example 3

[0143] In this embodiment, two different types of cyclodextrins were used, and their solubilization effects on ticagrelor were compared. 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 slowly added under vortex. Ticagrelor was used in milliQ water at concentrations of 5, 10, or 14 mg / ml. The ticagrelor-cyclodextrin solution was placed on a shaking platform. No sonication or heating was applied.

[0144] The results in Tables 8 and 9 show that HPβCD can dissolve ticagrelor in a wider range of cyclodextrin and ticagrelor concentrations tested. Clear aqueous solutions containing 5 mg / ml ticagrelor were obtained using 25 w / w%, 30 w / w%, 35 w / w%, and 40 w / w% HPβCD.

[0145] Table 8: Solubility of ticagrelor in HPβCD

[0146]

[0147] + Clarified, showing complete dissolution

[0148] - A translucent solution with precipitate

[0149] + / - Clear solution with precipitate

[0150] After one hour of ultrasound treatment

[0151] Table 9: Solubility of ticagrelor in SBECD

[0152]

[0153] + Clarified, showing complete dissolution

[0154] - A translucent solution with precipitate

[0155] + / - Clear solution with precipitate

[0156] In conclusion, ticagrelor can be dissolved by placing it on a shaking platform. No sonication is applied. HPβCD can be used at a 5 mg / ml ticagrelor concentration, using 40% w / w, 35% w / w, or 30% w / w cyclodextrin in milliQ water. These solutions remain clear at room temperature for at least three days and remain clear at 4°C for several days.

[0157] Example 4

[0158] Following the experiments described in Example 3, further optimization was performed by selecting an appropriate pH range to ensure the long-term stability of the aqueous ticagrelor-cyclodextrin inclusion complex.

[0159] Prepare the following compositions as provided in Table 10.

[0160] Table 10: Compositions used for storage stability testing.

[0161]

[0162] HPβCD was dissolved in buffer solutions prepared in water at pH 4.5, 5.5, or 6.5. Once a clear solution was obtained, ticagrelor was dissolved in the buffer solution with continuous stirring. The ticagrelor in the buffer solution was filtered through a 0.22-micron filter and filled into USP Type I glass vials. The vials were sealed and stored. All protective measures, such as N2 purging and avoidance of direct exposure to light, were taken during manufacturing. The vials were stored at 40 °C and 75% relative humidity (RH).

[0163] To determine the stability of the formulation, each batch was evaluated using the related substances method on HPLC. The data for these batches are listed in Table 11 below.

[0164] Impurities in the formulation were analyzed using gradient HPLC with a YMC-Pack Pro C18 column (100x4.6mm, S-3μm 12nm). All impurities were well separated.

[0165] Amine impurity: (1S,2S,3R,5S)-3-(7-amino-5-(propylthio)-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.

[0166] Regioisomer impurity: (1S,2S,3R,5S)-3-((3-((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)-5-(propylthio)-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.

[0167] Acetal impurity: 2-[[(3aR,4S,6S,6aS)-6-[7-[[1R,2S)-2-(3,4-difluorophenyl)-cyclopropyl]amino]-5-(propylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl]-2,2-dimethyltetrahydro-2H-3aHcyclopenta[d][1,3]dioxacyclopenten-4-yl]oxy]eth-1-ol.

[0168] These are process-related impurities.

[0169] 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.

[0170] These are process-related impurities.

[0171] It was observed that only regiomeric impurities increased by approximately 0.3% at 40 °C and 75% RH over 4 weeks; the specification limit was 0.3%. Therefore, studies were conducted at pH 7 to 8 to further optimize product stability.

[0172] Example 5

[0173] Storage stability was studied at pH 7.5, following the experiment described in Example 4.

[0174] First, HPβCD was dissolved separately in a phosphate buffer solution prepared in water at pH 7.5. Once a clear solution was obtained, ticagrelor was dissolved in the solution with continuous stirring. The solution was filtered through a 0.22-micron filter and filled into USP Type I amber glass vials. The vials were sealed and stored. All protective measures, such as N2 purging and avoidance of direct exposure to light, were taken during manufacturing.

[0175] Table 11

[0176]

[0177] Table 12: Compositions used for storage stability testing.

[0178]

[0179] Table 13: Storage stability study of ticagrelor-cyclodextrin inclusion complexes stored in aqueous solution at pH 7.5 at 40 °C and 75% relative humidity.

[0180]

[0181] Based on the results of the stability studies, as summarized in Table 13, it is concluded that good storage stability was achieved under accelerated storage conditions of 40°C and 75% relative humidity. Regiomeric impurities were well controlled, and no other impurities warranted attention.

[0182] Example 6

[0183] In further experiments, in order to optimize the concentration of HPβCD to below 40% w / w, heating at 40°C was applied to help dissolve the target dose of ticagrelor when it was difficult to obtain a clear solution.

[0184] The direct physical stability data obtained by ticagrelor 5 mg / ml concentrate and flocculation test (20 µl sample material in 1 ml diluent) are shown in Table 14. Table 14 contains data on content, purity, osmotic pressure, and pH.

[0185] Table 14: Physical stability of 5 mg / ml ticagrelor batches with different HPβCD concentrations. Data are sorted by HPβCD concentration. Ticagrelor concentration when diluted to dextran or physiological saline: 0.1 mg / ml.

[0186]

[0187] Due to the varying physical stability results when diluted in physiological saline, 32.5% w / w HPβCD was chosen for the 5 mg / ml ticagrelor formulation. The undiluted concentrate remains stable, even in a refrigerator, with HPβCD concentrations as low as 22.5% w / w. Such concentrations produce a nearly isotonic formulation.

[0188] In summary, 5–15 mg / ml ticagrelor can be dissolved together with HPβCD at concentrations ranging from 20–40% w / w without heating. A clear solution can be obtained by using lower concentrations of HPβCD, such as 15–20% w / w, and applying heat to achieve good solubility.

[0189] At least 15% w / w HPβCD is required to provide a clear, storage-stable ticagrelor solution with concentrations associated with injection or intravenous administration.

[0190] Example 7

[0191] The results obtained from Example 6 demonstrate that the excipient concentration allows for a hypertonic ticagrelor solution. Osmolarity and pH were examined in several batches. The solution was prepared with 19 mM phosphate buffer and pH 7.5. The results are provided in Table 15.

[0192] Table 15: pH and osmotic pressure measurements of undiluted batches.

[0193]

[0194] Dilution studies were conducted to identify a suitable diluent.

[0195] Solutions of ticagrelor-cyclodextrin at 5 mg / ml with varying amounts of HPβCD were diluted with physiological saline, 5% dextran solution, or lactated Ringer's solution. Stability screening was performed. The ticagrelor concentration at dilution in dextran or physiological saline was 0.1 mg / ml. The results are summarized in Table 16.

[0196] Table 16: Diluent Test

[0197]

[0198] In addition, the effects of buffer concentration on pH and osmotic pressure were screened. The results are summarized in Table 17.

[0199] Table 17: Effects of buffer concentration on pH, osmotic pressure, content and impurities.

[0200]

[0201] The conclusion is that, except for the 0.19 mM buffer concentration, different buffer concentrations of pH 7.5 phosphate buffer have little effect on osmotic pressure. A 0.19 mM buffer concentration is too weak, causing pH variations.

[0202] Example 8

[0203] In a further embodiment, the effect of particle size on solubility was tested. Two different particle diameters, 5.5 μm and 15 μm, of the active ingredient ticagrelor were screened. pH and osmotic pressure were unaffected. Smaller particles exhibited faster dissolution times, as summarized in Table 18.

[0204] Micronized ticagrelor exhibits a significant improvement in dissolution time. Therefore, micronized ticagrelor with a D90 of less than 10 micrometers is preferred.

[0205] As used herein, the term "D90" refers to the presence of at least 90% of particles having a size smaller than the target particle size. However, it should be understood that variations in the input particle size distribution (PSD) of ticagrelor are possible and will affect the dissolution rate of ticagrelor.

[0206] Methods for measuring the particle size of active ingredients are well known to those skilled in the art of pharmaceutical formulation. The method employed in this invention is the Malvern particle size analyzer dry powder method.

[0207] Table 18: Effect of Particle Size

[0208]

[0209] Example 9

[0210] To optimize HPβCD concentration and pH of the solution for intravenous use, a 12-week / 3-month stability study was conducted. Combinations of 32.5% w / w HPβCD with 5 mg / ml ticagrelor at pH 7 to 8 were prepared and stored. Stability was tested at fixed intervals.

[0211] The stability characteristics of the three formulations at three different pH values ​​(7, 7.5, and 8) were compared below. All three formulations were manufactured using the same process, and the buffer concentration was 19 mM. The results are summarized in Tables 19 to 21.

[0212] Table 19: Storage stability in amber glass vials – pH 7

[0213]

[0214] Table 20: Storage stability in amber glass vials – pH 7.5

[0215]

[0216] Table 21: Storage stability in amber glass vials – pH 8.0

[0217]

[0218] The data above indicate that ticagrelor solutions in HPβCD are stable in the pH range of 7 to 8.

[0219] Example 10

[0220] To investigate the potential impact of packaging materials on the stability of ticagrelor-cyclodextrin inclusion complexes, compositions with 32.5% w / w HPβCD were prepared using similar procedures and protective measures as in previous experiments. Samples were stored in clear glass vials and amber glass vials at 40 °C / 75% RH. The results are shown in Tables 22 and 23.

[0221] The results of the accelerated storage stability test showed no significant difference between the two after 3 months. All samples remained clear aqueous solutions. The pH of the samples remained stable. There were no significant changes in impurities.

[0222] It seems that both clear and amber glass bottles can be used.

[0223] Compared to the accelerated storage stability test results of ticagrelor solution without cyclodextrin, the use of cyclodextrin is clearly important for achieving good stability. In the absence of cyclodextrin, six to eight different impurities are generated during storage. These impurities were not observed in the selected composition.

[0224] Table 22: Study on the potential impact of packaging. Stability of amber USP Type I glass.

[0225]

[0226] Table 23: Study on the potential impact of packaging. Stability of transparent glass vials, USP Type I.

[0227]

[0228] Surprisingly, it can be concluded that ticagrelor solution is stable with HPβCD in amber and clear glass vials.

[0229] Example 11

[0230] Further embodiments of the invention are provided, as summarized in Table 24. Further improvements to ticagrelor, achieving higher solubility, were explored using different concentrations, for example, 40% w / w HPβCD; a solubility of 13 mg / ml for ticagrelor was also possible.

[0231] Table 24: Clear aqueous solutions containing ticagrelor-cyclodextrin inclusion complexes, considering a dose of 65 mg.

[0232]

[0233] Density 1.130 gm / cc

[0234] Based on research, concentrations of 5-13 mg / ml ticagrelor solution have been observed using 20-40% w / w HPβCD. The volume of the filling contents can be varied based on the desired dosage.

[0235] Surprisingly, it was found that by adjusting the HPβCD% and total available volume of the formulation prepared for injection, a target dose of 5-15 mg / ml ticagrelor could be achieved in a small volume. The ability to deliver a ticagrelor dose in a 5-15 ml volume is highly relevant, as this is a typical bolus injection volume.

[0236] Example 12

[0237] In a further embodiment, the maximum solubility of ticagrelor in HPβCD solution without heating was investigated. The results are summarized in Table 25.

[0238] Depending on the amount of ticagrelor to be delivered to the patient and the limitations of the sample volume determined by injection or infusion administration, a dose of 2000-4000 mg HPβCD may be required per 10 ml vial to dissolve 65-75 mg of ticagrelor.

[0239] Table 25: Concentration, Dosage, and Formulation Volume of HPβCD

[0240]

[0241] The density of the HPβCD solution is 1.130 gm / cc.

[0242] Surprisingly, the solutions provided in Table 25 are compatible with diluents for providing infusions, particularly with 5% dextrose aqueous solution.

[0243] Example 13

[0244] In another embodiment of the invention, a highly stable ticagrelor clear solution can be obtained by applying appropriate heat to the solution during preparation, thereby providing a completely clear formulation solution with the desired HPβCD and ticagrelor concentrations.

[0245] To investigate the effects of temperature and holding time, new compositions were prepared according to Table 26 below.

[0246] Table 26: Compositions used for temperature effect assessment.

[0247]

[0248] In the first step, a phosphate buffer solution with pH 7.5 is prepared, and the buffer solution is heated to 40°C–45°C. HPβCD is added to the buffer solution under continuous mixing. Once a clear solution is obtained, ticagrelor is dispersed into the HPβCD solution and mixed until a clear solution is obtained. This typically takes 30 minutes to 4 hours, depending on the batch size. The solution is then filtered through a 0.22-micron filter and packaged in suitable clear or amber glass vials.

[0249] Table 27: Study on preservation of the original solution at 45℃

[0250]

[0251] Table 28: Studies on stock solution preservation at 25℃ and 40℃

[0252]

[0253] Table 29: Preservation of the stock solution at 30°C

[0254]

[0255] Storage time studies at temperatures between 25 °C and 45 °C showed that 30% w / w HPβCD was able to stabilize ticagrelor even after the solution was heated for a long period of time or after the stock solution was placed at elevated temperatures.

[0256] Method for manufacturing ready-to-use infusion formulations

[0257] The exemplary ready-to-use solutions in Tables 3-7 are prepared as follows. In all cases, the mentioned solvent is prepared and placed in a beaker and heated to 40°C, then HPβCD is added to obtain a clear solution with stirring. Subsequently, the active ingredient ticagrelor is added at 40°C with continuous stirring until a clear solution is obtained. This solution is filtered through a 0.22-micron filter and aseptically filled into sterile glass vials or infusion bags.

[0258] A stable ticagrelor solution of 24 mg / ml to 350 mg / ml HPβCD is required for infusion. The amount of cyclodextrin required depends on the volume of the target infusion medium.

[0259] Ticagrelor is an active ingredient that is insoluble in water. The more diluted it is in an aqueous solution, the more likely it is to precipitate. As the dilution factor of ticagrelor increases, the amount of cyclodextrin required increases proportionally from 30 ml to 100 ml to 200 ml. However, for volumes of 650 ml and above, an amount of 16 g of cyclodextrin has been found sufficient to hold ticagrelor in the aqueous solution.

[0260] Please note that organic cosolvents, surfactants, or other solubilizers should not be used.

[0261] Optional preparation methods starting from concentrated ticagrelor compositions

[0262] One 8ml vial containing 65 mg ticagrelor and approximately 3 g HPβCD can be diluted with 25 ml of 5 w / v dextrose to obtain a clear solution with a final volume of 33 ml. However, this cannot be achieved using 0.9 w / v % NaCl solution as a diluent for the concentrated ticagrelor solution. This is crucial in medical treatments where the concentrated aqueous ticagrelor composition will be mixed with another drug. It can cause precipitation of ticagrelor, making the combination product unsuitable for intravenous administration.

[0263] Solubility studies with other solvents

[0264] Solubility studies were conducted using different solvents. Formulation AE, as shown in Table 30A, was prepared as follows: Ticagrelor (final concentration 1.8 mg / mL) was added to a tube (e.g., an Eppendorf tube or conical tube), followed by the addition of the listed solvent diluted in distilled water (final volume 10 mL). The tube was then vortexed and, if necessary, sonicated in a temperature-controlled water bath. After 60 minutes, the tube was collected for solubility observation. The sample was examined again after 24 hours.

[0265] Table 30: Solubility Study of A with Other Solvents

[0266]

[0267] Based on the research, it was observed that ticagrelor can be solubilized with either cyclodextrin or polyethylene glycol (PEG).

[0268] Soluble, but lacks storage stability.

[0269] Polyethylene glycol (PEG) can dissolve ticagrelor. However, PEG has been found to be prone to degradation, leading to the formation of impurities.

[0270] Example 14

[0271] Two clarified 1.8 mg / mL ticagrelor formulations were prepared after several hours of sonication: Formulation 1 (Example 14), 1.8 mg / mL ticagrelor in 20% hydroxypropyl-β-cyclodextrin (HPbCD) (w / w), with the remainder being water; and Formulation 2 (Example 14), 1.8 mg / mL ticagrelor in 50% PEG400 (w / w), with the remainder being water.

[0272] The two formulations were aliquoted and stored at room temperature and 40°C, respectively. LC-UV analysis of the formulations was performed immediately after preparation. Figure 1 and Figure 2 During the 6-month stability period, they were analyzed three more times. Figure 3 and Figure 4 ).

[0273] The results showed that ticagrelor in formulation 1 (Example 14), i.e., 1.8 mg / mL ticagrelor in 20% HPbCD (w / w), was stable for at least 6 months at room temperature and at 40°C. Figures 5 to 6 ).

[0274] In formulation 2 (Example 14), i.e., 1.8 mg / mL ticagrelor in 50% PEG400 (w / w), ticagrelor is unstable at room temperature and 40°C. (LC-UV chromatogram) Figures 4 to 6 In formulation 2 (Example 14), a strong peak of potential degradation products was observed. Attached Figure Description

[0275] Figure 1 LC-UV chromatograms of ticagrelor formulation 1 (Example 14) and blank control on day 0 were depicted.

[0276] Figure 2 LC-UV chromatograms of ticagrelor formulation 2 (Example 14) and blank control on day 0.

[0277] Figure 3 LC-UV chromatograms of ticagrelor formulation 1 (Example 14) and blank control on day 188 (room temperature).

[0278] Figure 4 LC-UV chromatograms of ticagrelor formulation 1 (Example 14) and blank control on day 188 (40°C).

[0279] Figure 5 LC-UV chromatograms of ticagrelor formulation 2 (Example 14) and blank control on day 188 (room temperature).

[0280] Figure 6 LC-UV chromatograms of ticagrelor formulation 2 (Example 14) and blank control on day 188 (40°C).

[0281] Lyophilized form of ticagrelor composition for reconstitution and intravenous use

[0282] Solubility Study

[0283] Solubility in a solvent:water mixture

[0284] Solubility studies were conducted as follows.

[0285]

[0286] The density of TBA, 0.781 g / ml, was used for calculations.

[0287]

[0288] The density of TBA is 0.775 g / ml, which was used for calculation.

[0289]

[0290] The density of TBA is 0.775 g / ml, which was used for calculation.

[0291]

[0292] Kolliphor HS15 density

[0293]

[0294]

[0295] Observation results:

[0296]

[0297] Lyophilization using tert-butanol: Experiment 1

[0298] Based on the above solubility studies, the following experiments were selected for formulation and lyophilization processes.

[0299] Batch size: 300 ml; Fill volume: 15 mL

[0300]

[0301] The density of TBA is 0.775 g / ml, which was used for calculation.

[0302]

[0303] Observations after freeze-drying: No collapse was observed in any of the freeze-dried vials. A white, compact, cake-like substance was observed (which turned into a loose powder after shaking).

[0304] Reconstruction Research

[0305] A. Reconstruction was performed using 30% PEG 400 and 70% phosphate buffer (pH 7.4).

[0306] The reconstitution mediator was prepared by mixing 30% PEG 400 into 70% phosphate buffer (pH 7.4). 15 ml and 20 ml of the reconstitution mediator were added to lyophilized product vials using a plastic syringe. The vials were allowed to reconstitute for approximately 2–3 minutes. A milky white solution was observed in all the reconstituted vials.

[0307] B. Reconstruction was performed using 4% Kolliphor HS 15, 30% PEG 400, and phosphate buffer (pH 7.4).

[0308] The reconstitution mediator was prepared by mixing 4% Kolliphor HS 15 and 30% PEG 400 in phosphate buffer (pH 7.4). 15 ml of the reconstitution mediator was added to a lyophilized product vial using a plastic syringe. The vial was reconstituted for approximately 2–3 minutes. Visible particles were observed in all reconstituted vials. A further 5 ml (total 20 ml) of the reconstitution mediator was added and mixed to obtain a clear solution, but the clarity did not improve; undissolved particles were observed.

[0309] Lyophilization using Kolliphor HS 15: Experiment 2

[0310] Based on the following solubility studies, conduct formulation and lyophilization feasibility tests.

[0311] Batch size: 300 mL, fill volume: 15 mL

[0312]

[0313] Kolliphor HS15 density 1.048 g / ml used for calculation

[0314]

[0315] Observations after freeze-drying: No collapse was observed in any of the freeze-dried vials. A compact, white, cake-like substance was observed in all vials. No vial rupture was observed at the end of the freeze-drying cycle.

[0316] The reconstitution mediator was prepared by mixing 30% PEG 400 in 70% phosphate buffer (pH 7.4). 15 ml of the reconstitution mediator was added to each lyophilized product vial using a plastic syringe. The vials were allowed to reconstitute for approximately 2–3 minutes. Clear solutions without any visible particles were observed in all reconstituted vials.

[0317] Optimization of freeze-drying cycle using Kolliphor HS 15: Experiment 3

[0318] Based on the observations from Experiment 2, a batch with a similar composition was used, but with a reduced lyophilization cycle time. Details are provided below. Batch size: 300 mL, fill volume: 15 mL. In this composition, the concentration of Kolliphor HS15 was increased to 4.4% w / v.

[0319]

[0320]

[0321] Observations after freeze-drying: No collapse was observed in any of the freeze-dried vials. A compact, white, cake-like substance was observed in all vials. No spillage or vial breakage was observed.

[0322] The reconstitution mediator was prepared by mixing 30% PEG 400 in 70% 0.1M phosphate buffer (pH 7.4). 15 ml of the reconstitution mediator was added to each lyophilized product vial using a plastic syringe. The vials were allowed to reconstitute for approximately 2–3 minutes. A clear solution formed in all reconstituted vials without any visible particles.

[0323] Stability assessment test 4 was conducted using the Kolliphor HS15 freeze-drying test.

[0324] Based on the observations of Experiments 2 and 3 above, since the expected results (compact disc-like material and clear reconstruction) were achieved, Experiment 3 was repeated to conduct chemical analysis and stability studies on the finished product and the reconstruction diluent.

[0325] Batch size: 700 ml; Fill volume: 15 mL

[0326]

[0327]

[0328] Observations after freeze-drying: No collapse was observed in any of the freeze-dried vials. A white, compact, cake-like substance was observed (which became a loose, free-flowing cake-like substance after shaking). No vial breakage was observed at the end of the freeze-drying cycle.

[0329] Reconstruction Research

[0330]

[0331] Procedure: Add batch amounts of sodium dihydrogen phosphate and anhydrous disodium hydrogen phosphate to 500 ml of water for injection and dissolve using a top-mounted stirrer to obtain a clear solution. The pH of the 0.1 M phosphate buffer solution was observed to be 7.39.

[0332] Preparation of reconstitution solution: (batch size – 700 mL)

[0333] Step 1 - Place 490 ml (70%) of the above-prepared pH 7.4 0.1M phosphate buffer into a beaker, add 210 ml of PEG 400 (30%), and mix for 10 minutes with a top stirrer.

[0334] Step 2 - Filter the bulk solution with nitrogen using a 0.22 μm polyvinylidene fluoride (PVDF) sterile filter.

[0335] Step 3 - Fill the filtered solution into a 20 ml clear, colorless USP Type 1 glass vial (20 mm neck), with a target filling volume of "not less than 15 mL". Purge the top space of the vial with nitrogen, plug the vial with a West 20 mm stopper-coated stopper, and seal it with an aluminum flip-top sealing ring.

[0336] Using a plastic syringe, add 15 ml of the reconstituted solution prepared above to each lyophilized product vial. Reconstitute the vial (by shaking) for approximately 20–30 seconds. Clear solutions without any visible particles were observed in all reconstituted vials.

[0337] Stability results of freeze-drying test 4 (Kolliphor HS15 as solubilizer):

[0338]

[0339]

[0340] Based on the accelerated stability results over the aforementioned 6 months (6M), amine impurities were observed to increase from 0.06% w / w at time T0 to 0.22% w / w under 6M accelerated conditions (40℃ / 75%RH). All impurities remained within the set specifications.

[0341] Lyophilization test for stability evaluation using TBA, Test 5 (the composition does not contain solubilizer).

[0342] As an alternative to the Kolliphor HS 15 formulation (Test 4), further testing was conducted similar to that of the Test-1 composition, with tert-butanol as a solubilizer (TBA:water; 30:70 ratio), and the details of the study are shown below.

[0343] Batch size: 1200 mL; Fill volume: 15 mL

[0344]

[0345]

[0346] Observation results after freeze-drying:

[0347] Note similar observations to those in Experiment-1, and additionally, 30 to 5 vials were found to have cracks in the walls and bottoms of the glass vials.

[0348] Product overflow was observed inside the freeze dryer during the drying process.

[0349] After the freeze-drying cycle, melting regression was observed in all the remaining vials.

[0350] Although the compositions of Experiments 1 and 5 were identical, more vial breakage and lyophilized cake melting and regression were observed in Experiment 5. This is likely due to the increased batch size, and it indicates that we need to evaluate the impact of batch size on the proposed lyophilization cycle. Therefore, further experiments to be optimized will focus on these aspects, followed by reconstitution diluent evaluation and stability studies.

[0351] Optimization of lyophilization cycle using tert-butanol - Experiment 1:

[0352] Fill volume selection: Target concentration: 65mg / vial

[0353]

[0354] Based on the above solubility study, a filling volume of 10.0 ml and a bulk solution concentration of 6.5 mg / ml were selected for preparation and lyophilization.

[0355] Batch size: 1200 ml; Fill volume: 10.0 mL

[0356]

[0357] The density of TBA is 0.775 g / ml, which was used for calculation.

[0358]

[0359] Results observed after freeze-drying:

[0360] Compared to previous batches, there was very little powder overflow.

[0361] No collapse or melting regression was observed in any of the freeze-dried vials.

[0362] A white, compact, cake-like substance was observed (which turned into a loose powder after shaking).

[0363] No vials were damaged during or after the freeze-drying process.

[0364] In some vials, the powder was observed to be sticky on the walls and bottom of the vials.

[0365] Optimization of lyophilization cycle using tert-butanol - Experiment 2:

[0366] Batch size: 800 ml; Fill volume: 10 mL

[0367]

[0368] The density of TBA is 0.775 g / ml, which was used for calculation.

[0369]

[0370] Observations after freeze-drying: Powder overflow was minimal. No collapse or melting regression was observed in any of the freeze-dried vials. A white, compact cake-like substance was observed (which became loose powder after shaking). One vial broke at the bottom. Powder stickiness was observed on the walls and bottom of some vials (but less than in the previous batch).

[0371] Optimization of lyophilization cycle using tert-butanol—Experiment 3

[0372] Batch size: 800 ml; Fill volume: 10 mL

[0373]

[0374] The density of TBA is 0.775 g / ml, which was used for calculation.

[0375]

[0376] Observations after freeze-drying: Powder overflow was minimal. No collapse or melting regression was observed in any of the freeze-dried vials. A white, compact cake-like substance was observed (which became a loose powder upon shaking). No vials broke during or after freeze-drying. In a few vials, powder stickiness was observed on the walls and bottom of the vials.

[0377] Based on the three freeze-drying cycles described above, Experiment 3 performed well across all parameters, including minimal powder spillage (which can be controlled in further freeze-drying cycle optimization studies), no vial breakage, no meltback issues, and reduced powder-via-via adhesion. Therefore, the vials from Experiment 3 will be considered for remodeling studies using the recommended diluent.

[0378] Reconstruction was performed using a mixture of 30% PEG-400 and water for injection.

[0379] composition:

[0380]

[0381] operate:

[0382] Step 1:Prepare the required amount of diluent as described in the table above.

[0383] Step 2: Use a syringe to add the required amount of diluent (15 mL) to the vial for reconstitution.

[0384] Step 3: Shake the bottle vigorously for 3 minutes to reconstruct the contents.

[0385] Reconstruction was performed using a mixture of 50% PEG-400 and water for injection.

[0386] composition:

[0387]

[0388] operate:

[0389] Step 1: Prepare the required amount of diluent as described in the table above.

[0390] Step 2: Use a syringe to add the required amount of diluent (15 mL) to the vial for reconstitution.

[0391] Step 3: Shake the bottle vigorously for 3 minutes to reconstruct the contents.

[0392] Reconstruction was performed using a mixture of Kolliphor HS 15-4% and water for injection.

[0393] composition:

[0394]

[0395] operate:

[0396] Step 1: Prepare the required amount of diluent as described in the table above.

[0397] Step 2: Use a syringe to add the required amount of diluent (15 mL) to the vial for reconstitution.

[0398] Step 3: Shake the bottle vigorously for 2 minutes to reconstruct the contents.

[0399] Reconstruction was performed using a mixture of 30% PEG-400, 20% propylene glycol, and water for injection.

[0400] composition:

[0401]

[0402] operate:

[0403] Step 1: Prepare the required amount of diluent as described in the table above.

[0404] Step 2: Use a syringe to add the required amount of diluent (15 mL) to the vial for reconstitution.

[0405] Step 3: Shake the bottle vigorously for 3 minutes to reconstruct the contents.

[0406] Based on the aforementioned reconstruction study, clear solutions were obtained in water for injection only in Kolliphor HS 15- 4% and 30% PEG-400+ Kolliphor HS 15- 4%.

[0407] Therefore, the second group (Group-2) remodeling studies were conducted using only Kolliphor HS 15-4% in phosphate buffer and 30% PEG-400+ Kolliphor HS 15-4% in phosphate buffer.

[0408] Reconstruct dilution group-2

[0409] A. Reconstitute using a mixture of Kolliphor HS 15-4% and phosphate buffer, and bring the volume to 15 ml.

[0410] composition:

[0411]

[0412] operate:

[0413] Step 1: Prepare the required amount of diluent as shown in the table above.

[0414] Step 2: Use a syringe to add the required amount of diluent (15 mL) to the vial for reconstitution.

[0415] Step 3: Shake the bottle vigorously for 3 minutes to reconstruct the contents of the bottle.

[0416] Reconstitute using a mixture of 30% PEG-400+Kolliphor HS 15-4% and phosphate buffer, and bring the volume to 15 ml.

[0417] composition:

[0418]

[0419] operate:

[0420] Step 1: Prepare the required amount of diluent as described in the table above.

[0421] Step 2:Use a syringe to add the required amount of diluent (15 mL) to the vial for reconstitution.

[0422] Step 3: Shake the bottle vigorously for 3 minutes to reconstruct the contents.

[0423] Restructuring the Research Plan (Group 3)

[0424] Reconstitute using a mixture of Kolliphor HS 15-4.4% and water for injection, and bring the volume to 15 ml.

[0425] composition:

[0426]

[0427] operate:

[0428] Step 1: Prepare the required amount of diluent as described in the table above.

[0429] Step 2: Use a syringe to add the required amount of diluent (15 mL) to the vial for reconstitution.

[0430] Observation results:

[0431] Reconstruct the contents of the vial for 2 minutes. Foaming was observed.

[0432] The vial was then set aside, and the solution was found to be clear after 10 minutes.

[0433] Reconstitute using a mixture of Kolliphor HS 15-4.4% and water for injection, and bring the volume to 15 ml.

[0434] composition:

[0435]

[0436] operate:

[0437] Step 1: Prepare the required amount of diluent as described in the table above.

[0438] Step 2: Use a syringe to add the required amount of diluent (15 mL) to the vial for reconstitution.

[0439] Observation results:

[0440] After reconstitution and vigorous shaking for 3 minutes, the solution was found to be clear with very few undissolved particles.

[0441]

[0442] Based on the above findings, a reconstituted solution containing 4.4% Kolliphor in water for injection (adjusted to 15 mL) was selected, and its stability was investigated. The stability results will be mentioned in the following sections.

[0443]

[0444] As part of further improvement and research, ticagrelor lyophilized formulations were prepared without the use of solubilizers and by reducing the mannitol concentration in the composition. Experiments A and B, numbered 19, were conducted as follows.

[0445] Experiment A

[0446] Batch number: 19, Batch size: 500 mL

[0447] Filling volume: 6.5 ml in 20 ml vials

[0448] Description: Lyophilized batch of ticagrelor for injection, mannitol concentration 5 mg / ml, formulation does not contain Kolliphor HS-15.

[0449]

[0450] Water for injection will be removed during the freeze-drying process.

[0451] $: TBA density 0.775 g / ml is used for calculation.

[0452]

[0453] Observation results: After the freeze-drying cycle unloading, a white, compact freeze-dried cake-like substance was observed. Subsequently, this batch was used for reconstruction tests, and the different tests are shown in Table 68 below.

[0454]

[0455] Based on satisfactory lyophilization and diluent screening, the following composition appears to be the optimal design for this product. Laboratory-scale batches of ticagrelor for injection, with 40% TBA, a drug concentration of 10 mg / ml, and 5 mg / ml mannitol, were used for reproducibility and commercial viability. Tween 80 is polyoxyethylene sorbitan monooleate.

[0456] Batch number: #020, Batch size: 750 mL

[0457] Fill volume: 6.5 ml in a 20 ml vial

[0458] Description: Lyophilized batch of ticagrelor for injection, containing 40% TBA, drug concentration of 10 mg / ml, and mannitol 5 mg / mL.

[0459]

[0460] Water for injection will be removed during the freeze-drying process.

[0461] $: TBA density 0.775 g / ml is used for calculation.

[0462]

[0463] Table 71: Reconstruction experiments using the final lyophilized ticagrelor vials from B. No. #20

[0464]

[0465] Tween 80 is a polysorbate, a nonionic surfactant and emulsifier derived from polyethoxylated sorbitol and oleic acid; synonyms: polysorbate 80; polyoxyethylene dehydrated sorbitol monooleate; CAS number 9005-65-6.

[0466] Solutions for lyophilization containing cyclodextrin as a solubilizer

[0467] As an alternative to aqueous solutions based on tert-butanol or surfactants as solubilizers for use in freeze-drying processes, compositions are prepared using cyclodextrin as a solubilizer.

[0468] Table 72: Solutions for lyophilization using cyclodextrin as a solubilizer

[0469]

[0470] Density assumed to be 1.130, target concentration 90 mg / vial

[0471] Manufacturing process

[0472] HPBCD was dissolved in WFI under continuous stirring. TCG was added in a vortex to form a clear solution, followed by mannitol as a packing agent. The solution was filtered through a 0.22-micron filter. The solution was then filled into USP Type I glass vials and lyophilized according to the following parameters.

[0473] Table 73: Lyophilization process of aqueous solutions containing ticagrelor-cyclodextrin inclusion complexes.

[0474] The solutions in Table 72 were lyophilized using the following parameters.

[0475]

[0476] A well-formed cake can be reconstituted using a suitable diluent (e.g., water for injection with a suitable pH of 5.5 to 8). This diluent may contain some surfactants to facilitate obtaining a clear solution.

Claims

1. A ticagrelor pharmaceutical composition for treating or preventing coagulation in patients in need who have previously received an opioid active ingredient, characterized in that... The ticagrelor pharmaceutical composition is administered intravenously after administration of the opioid active ingredient, thereby avoiding delayed or reduced ticagrelor uptake caused by the opioid active ingredient; wherein the ticagrelor pharmaceutical composition comprises an inclusion complex of ticagrelor and cyclodextrin.

2. The ticagrelor pharmaceutical composition for use according to claim 1, wherein ticagrelor is administered within three hours of the administration of the opioid active ingredient.

3. The ticagrelor pharmaceutical composition for use according to claim 1 or 2, wherein the patient suffers from ST-segment elevation myocardial infarction or non-ST-segment elevation myocardial infarction.

4. The ticagrelor pharmaceutical composition for use according to claim 3, wherein fentanyl is administered to the patient prior to recording angiography and prior to anticoagulant treatment.

5. The ticagrelor pharmaceutical composition for use according to claim 3 or 4, wherein the patient is undergoing non-elective PCI.

6. The ticagrelor pharmaceutical composition for use according to claim 1 or 2, wherein the patient has undergone joint replacement surgery.

7. The ticagrelor pharmaceutical composition for use according to claim 1 or 2, wherein the patient has contracted Gram-positive bacteremia following abuse of a pharmaceutical substance containing an opioid active ingredient.

8. The ticagrelor pharmaceutical composition for use according to any one of claims 1 to 7, wherein the ticagrelor pharmaceutical composition is a lyophilized ticagrelor composition.

9. The ticagrelor pharmaceutical composition for use according to claim 8, wherein the reconstitution time of the lyophilized ticagrelor composition is less than 5 minutes.

10. The ticagrelor pharmaceutical composition for use according to any one of claims 1 to 9, wherein an effective amount of ticagrelor is administered intravenously over 5 minutes.

11. A liquid composition containing ticagrelor for lyophilization, comprising ticagrelor in free form, a filler, and an alcohol:water mixture, wherein the ratio of the alcohol to the water is 25:75 to 50:50 (% w / w).

12. The liquid composition containing ticagrelor for lyophilization according to claim 11, wherein the alcohol is tert-butanol (TBA).

13. The lyophilized liquid composition containing ticagrelor according to claim 11 or 12, comprising 30 mg ticagrelor / 15 ml composition to 100 mg ticagrelor / 15 ml composition or 6.5 mg ticagrelor / ml composition to 8 mg ticagrelor / ml composition.

14. The liquid composition containing ticagrelor for lyophilization according to any one of claims 11 to 13, wherein the filler is mannitol, and the mannitol is present in an amount of 2.5 to 75 mg mannitol / ml of composition.

15. The ticagrelor-containing liquid composition for lyophilization according to any one of claims 11 to 14, wherein the ticagrelor-containing liquid composition comprises 6.5 mg ticagrelor / ml, 310 mg / ml TBA, 5 mg mannitol / ml and the remainder water for injection.

16. A method for preparing a lyophilized form of a ticagrelor pharmaceutical composition, comprising the following steps: Provide a liquid composition containing ticagrelor according to any one of claims 11 to 15; freeze-dry the liquid composition containing ticagrelor and recover the resulting freeze-dried form of the ticagrelor composition.

17. A lyophilized ticagrelor pharmaceutical composition obtained by the method according to claim 16.

18. The lyophilized ticagrelor pharmaceutical composition of claim 17, wherein the composition comprises 30 mg to 100 mg of ticagrelor and 25 mg to 75 mg of mannitol, and wherein the ticagrelor is present in free form.

19. The ticagrelor pharmaceutical composition for use according to any one of claims 1 to 8, wherein the ticagrelor pharmaceutical composition is a lyophilized ticagrelor composition according to claim 17 or 18.

20. The ticagrelor pharmaceutical composition for use according to claim 19, wherein the reconstitution time of the lyophilized ticagrelor composition is less than 5 minutes.

21. The ticagrelor pharmaceutical composition for use according to any one of claims 19 to 20, wherein an effective amount of ticagrelor is administered intravenously over 5 minutes.

22. A kit comprising a ticagrelor pharmaceutical composition according to claim 17 or 18 in combination with a suitable diluent solution, said suitable diluent solution comprising: Aqueous, 0.1 M phosphate buffer solution with pH 7.4-7.

5. 4%-4.4 w / w% polyethylene glycol (15)-hydroxystearate (Kolliphor HS 15) and 30%-40 v / v% polyethylene glycol (PEG-400).

23. A kit comprising a ticagrelor pharmaceutical composition according to claim 17 or 18 in combination with a suitable diluent solution, said suitable diluent solution comprising: Aqueous phosphate buffer solution with pH 7.4-7.5 4% polyoxyethylene dehydrated sorbitan monooleate (40 mg / ml) and 40 v / v% propylene glycol (400 mg / ml).

24. A method for preparing a lyophilized form of a ticagrelor pharmaceutical composition, comprising the following steps: A liquid composition containing ticagrelor is provided, comprising an inclusion complex of ticagrelor and cyclodextrin, preferably hydroxypropyl β-cyclodextrin (HPBCD); The liquid composition containing ticagrelor is lyophilized, and the resulting lyophilized ticagrelor composition is recovered; wherein the ticagrelor pharmaceutical composition comprises an inclusion complex of ticagrelor and cyclodextrin, preferably hydroxypropyl β-cyclodextrin (HPBCD).

25. A lyophilized composition containing ticagrelor, comprising ticagrelor and cyclodextrin, preferably an inclusion complex of hydroxypropyl β-cyclodextrin (HPBCD).

Images