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WO2019122157A1 - Lyophilisat comprenant de l'esmolol et de l'adénosine pour une utilisation en cardioplégie - Google Patents

Lyophilisat comprenant de l'esmolol et de l'adénosine pour une utilisation en cardioplégie Download PDF

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Publication number
WO2019122157A1
WO2019122157A1 PCT/EP2018/086248 EP2018086248W WO2019122157A1 WO 2019122157 A1 WO2019122157 A1 WO 2019122157A1 EP 2018086248 W EP2018086248 W EP 2018086248W WO 2019122157 A1 WO2019122157 A1 WO 2019122157A1
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WO
WIPO (PCT)
Prior art keywords
lyophilisate
adenosine
esmolol
cardioplegia
kci
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Ceased
Application number
PCT/EP2018/086248
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English (en)
Inventor
Günther Krumpl
Regina SCHÜLLER
Wolfgang Strohmaier
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AOP Orphan IP AG
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Ipsol AG
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Filing date
Publication date
Application filed by Ipsol AG filed Critical Ipsol AG
Publication of WO2019122157A1 publication Critical patent/WO2019122157A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
    • 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
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/216—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acids having aromatic rings, e.g. benactizyne, clofibrate
    • 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
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
    • 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
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
    • A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P41/00—Drugs used in surgical methods, e.g. surgery adjuvants for preventing adhesion or for vitreum substitution

Definitions

  • the invention refers to a lyophilisate comprising esmolol, adenosine and at least one pharmaceutical salt for use in cardioplegia.
  • Cardioplegia refers to paralysis of the heart using chemicals. Typically this is effected in order to stop a heart during cardiac surgery.
  • the heart is subjected to an elective period of global ischaemia to provide the surgeon with a blood- free operating field and a still, flaccid heart.
  • a cardioplegic solution is used for rapid arrest and to help protect the heart from ischaemic injury.
  • hypothermic ischaemic arrest Historically the heart used to be stopped in cardiac surgery by clamping the aorta, inducing ischaemia and cooling the heart down. This was called hypothermic ischaemic arrest. Hypothermic arrest led to an invariably lethal condition called the stone heart in up to one out of ten patients undergoing cardiac surgery. Subsequently, a method of chemically inducing cardiac arrest was developed after decades of research. This ended the occurrence of the condition "stone heart” and made cardiac surgery a much safer procedure. The chemical arrest (cardioplegia) is induced by perfusing the heart with a cardioplegic solution containing moderately high concentrations of potassium (K) in addition to other electrolytes. One of these solutions, known as St.
  • STH Thomas’ Hospital cardioplegia
  • STH has been used as the predominant crystalloid cardioplegic solution world-wide since.
  • STH is used widely in cardiac surgical centres, and relies on an increased potassium concentration to induce arrest; this has been shown to be reasonably effective and safe.
  • potassium induces a’depolarized’ arrest that can be associated with increases in intracellular sodium and calcium concentrations; intracellular overload of these ions can be harmful to the heart.
  • St. Thomas’ Hospital (STH) cardioplegia is relatively safe but it causes a shift in the resting membrane potential to a level that can have detrimental effects, such as increasing the intracellular sodium (Na) and calcium (Ca) concentrations.
  • Na channel and Ca channel blockers in addition to K channel openers are examples of these pharmacological agents.
  • STH cardioplegia causes a shift in the resting membrane of the heart from about -85mV to about -50mV. This is thought to be detrimental because it causes Na and Ca loading which results in ischaemic contracture and poor recovery of the heart.
  • Chang et al (2002 Cardiology, volume 97, pages 138 to 146) disclose a study of interactions of esmolol and adenosine in atrioventricular nodal-dependent supraventricular tachycardia.
  • Adenosine is known to operate via the direct effect on activation of the adenosine-sensitive potassium current.
  • McCully discusses the use of oxygenated multidose delivery of crystalloid esmolol cardioplegia as an alternative to high potassium cardioplegia.
  • the numerous different approaches taken in the art at that date are reviewed in this editorial.
  • oxygenated multidose crystalloid esmolol cardioplegia is critically assessed for its provision of myocardial protection. It is concluded that esmolol cardioplegia might provide a useful alternative to a traditional high potassium depolarizing cardioplegia. Use of adenosine is not disclosed.
  • European Patent EP 2 400 963 B1 discloses a liquid composition comprising esmolol and adenosine for use in cardioplegia.
  • the invention provides a lyophilisate comprising esmolol HCI, adenosine and at least one pharmaceutically acceptable salt.
  • the pharmaceutically acceptable salt is selected from the group consisting of KCI, MgCb, MgS04 and MgCi2H220i4.
  • the pharmaceutically acceptable salt is selected from the group consisting of KCI and MgCl2.
  • the lyophilisate provided herein comprises esmolol HCI, adenosine, KCI and MgCl2.
  • the lyophilisate provided herein comprises esmolol HCI in the range of 800 mg to 850 mg, adenosine in the range of 300 mg to 350 mg, KCI in the range of 150 mg to 200 mg, and MgCb in the range of 4.5 g to 6.0 g.
  • the lyophilisate comprises esmolol HCI in the range of 750 to 900 mg, preferably 800 to 850 mg and even more preferably it comprises about 830 mg of esmolol HCI.
  • the lyophilisate comprises adenosine in the range of 250 to 400 mg, preferably 300 to 350 mg and even more preferably it comprises about 334 mg of adenosine.
  • the lyophilisate comprises KCI in the range of 100 to 250 mg, preferably 150 to 200 mg and even more preferably it comprises about 186 mg of KCI.
  • the lyophilisate comprises MgCb in the range of 4.0 to 6.5 g, preferably 4.5 to 6.0 g and even more preferably it comprises about 5.1 g of MgCl2.
  • the lyophilisate comprises 829.60 mg esmolol HCI, 334.05 mg adenosine, 186.38 mg KCI and 5,082.50 mg MgCl2.
  • the lyophilisate consists of 829.60 mg esmolol HCI, 334.05 mg adenosine, 186.38 mg KCI and 5,082.50 mg MgCl2.
  • a method of preparing the lyophilisate wherein respective amounts of esmolol HCI, adenosine, KCI and MgC are dissolved in H2O generating a dissolution, which is subsequently freeze- dried.
  • respective amounts of esmolol HCI, adenosine, KCI and MgCb are dissolved in 10 to 100 g of H2O, preferably 30 to 60 g H2O and most preferably 50 g H2O.
  • MgCb is dissolved before adding esmolol HCI, adenosine and KCI.
  • adenosine is dissolved in H2O at a temperature of about 40°C before adding esmolol, MgCb and KCI at room temperature.
  • the pH of the dissolution is in the range of 5 to 8.
  • the pH of the dissolution is about 6.5.
  • the dissolution of esmolol HCI, adenosine, KCI and MgCh is stored for at least 5 days, preferably 10 days and even more preferably for at least 12 days before freeze-drying.
  • the lyophilisate provided herein, or a reconstituted solution thereof, are used in cardioplegia.
  • cardioplegia For use in cardioplegia is intended to imply that the composition is capable of effective arrest of a heart, i. e. capable of actually being used to induce cardioplegia if administered to a subject.
  • the cardioplegia is human cardioplegia, i.e. for use specifically implies for use in humans.
  • a method for preparing a liquid pharmaceutical preparation from the lyophilisate described herein comprises dissolving the lyophilisate in 50, 100, 150, 200, 250, 300, 350, 400, 450 or 500 ml_ water and/or a liquid pharmaceutically acceptable solvent, preferably in 100 ml_ water.
  • said liquid pharmaceutical preparation is a reconstituted solution of the lyophilisate.
  • said pharmaceutically acceptable solvent is selected from the group consisting of Ringer solution, Hartmann’s solution and Krebs-Henseleit buffer.
  • the reconstituted lyophilisate is used in crystalloid or blood cardioplegia.
  • a blood-based solution is most suitably used as this is used most frequently in the clinical setting.
  • the liquid pharmaceutical preparation is provided in ampoules or vials containing 100 to 500ml of the liquid pharmaceutical preparation.
  • cardioplegia refers to the intentional and temporary cessation of cardiac activity, primarily for cardiac surgery.
  • the lyophilisate referred to herein specifically comprises esmolol HCI, adenosine and at least one pharmaceutically acceptable salt.
  • Esmolol HCI (ASL-8052) (Esmolol Hydrochloride) is a phenoxypropranolamine.
  • Esmolol is a beta 1 -selective (cardioselective) adrenergic receptor blocking agent with a very short duration of action (half-life in blood is approximately 9 minutes).
  • the molecule has an ester link in the para-position of the phenyl ring that is responsible for the esmolol cardioselectivity and ultra-short duration of action of the drug. It is registered in the UK for the treatment of supraventricular tachycardia, post-operative hypertension and tachycardia syndrome (BNF).
  • Esmolol Hydrochloride is: ( ⁇ )-Methyl p-[2-hydroxy-3- (isopropylamino) propoxy] hydrocinnamate hydrochloride.
  • Esmolol HCI has the empirical formula C16H26NO4CI and a molecular weight of 331 .8. It has one asymmetric center and exists as an enantiomeric pair.
  • Esmolol HCI is a white to off-white crystalline powder. It is a relatively hydrophilic compound which is very soluble in water and freely soluble in alcohol. Its partition coefficient (octanol/water) at pH 7.0 is 0.42 compared to 17.0 for propranolol.
  • Esmolol may be dissolved in water. It is suitably provided as stock (750mmol/L) in aqueous solution.
  • the typical Esmolol stock/buffer contents from commercially available sources comprise: sodium acetate trihydrate, acetic acid, propylene glycol, ethanol, HCI for pH adjustment.
  • Esmolol is widely available and may suitably be obtained from Orpha-Devel bottles undmaschines GmbH, Austria. This supplier typically provides a stock solution in vials at 750mmol/L. Alternatively, it may be obtained as Brevibloc® from Baxter either as a stock solution or as a more dilute preparation.
  • Adenosine is a purine nucleoside. It is an endogenous nucleoside occurring in all cells of the body. Adenosine (CAS 58-61 -7) has the formula C10H 13N5O4 and the systematic name (2R,3R,4S,5R)-2-(6-amino-9H-purin-9-yl)-5-(hydroxymethyl)oxolane- 3,4-diol (or 6-amino-9-beta-D-ribofuranosyl-9-H-purine). It is a white crystalline powder. It is soluble in water and practically insoluble in alcohol. Solubility may be improved by increasing temperature and lowering the pH of the solution.
  • Adenosine is widely available and suitably provided as powder and dissolved in water. It may suitably be obtained as a powder from Sigma Inc. Attention must be paid to purity of compounds to ensure human grade material is used. A number of suppliers provide clinical grade material, for example AdenoscanTM or Adenocard® (from Astellas Pharma Inc. U.S.) is provided as powder to dilute in water.
  • An AdenoscanTM vial contains a sterile, non- pyrogenic solution of adenosine 3 mg/mL and sodium chloride 9 mg/mL in water for Injection, q.s. The pH of the solution is between 4.5 and 7.5.
  • the lyophilisate presented herein further comprises at least one pharmaceutically acceptable salt.
  • Such salts typically are potassium and magnesium but not limited thereto.
  • KCI refers to Potassium chloride (KCI), a metal halide salt composed of potassium and chloride.
  • MgCl2 refers to magnesium chloride.
  • MgS04 refers to magnesium sulfate, an inorganic salt containing magnesium, sulfur and oxygen.
  • MgCi2H220i4 refers to magnesium gluconate, a magnesium salt of gluconic acid.
  • composition of the invention may further comprise one or more other agents which are known to have myocardial protection properties such as natrium channel and/or calcium channel blockers, potassium channel openers, calcium desensitizers may be included as an additional component to the composition of the invention. Any such additional components are suitably used to improve the protection against ischaemia. Inducing arrest is accomplished by the esmolol - adenosine combination and further additional components for arrest are typically not used. It is possible that some embodiments might include a very small concentration of Lidocaine e.g. ⁇ 0.1 mM. This is a non-arresting amount of Lidocaine. Inclusion of such a non-arresting amount of lidocaine would not detract from the invention.
  • agents which are known to have myocardial protection properties such as natrium channel and/or calcium channel blockers, potassium channel openers, calcium desensitizers may be included as an additional component to the composition of the invention. Any such additional components are suitably used to improve the protection against
  • lidocaine was at significantly higher and arresting concentrations such as no less than 0.6mM, thus even in embodiments of the invention which included minimal levels of lidocaine remain distinguished from the prior art since the concentrations used are non- overlapping with (e.g.) Dobson publication GB 2 436 255 A. Most suitably lidocaine is omitted or specifically excluded from the compositions of the invention.
  • the term“dissolution” as used herein refers to a solution in which the components of the lyophilisate of the present invention are dissolved.
  • said dissolution is an aqueous solution and comprises 10, 20, 30, 40, 50, 60, 70 or 80 g H2O, preferably it comprises 50 g H2O.
  • esmolol HCI adenosine and the at least one pharmaceutically acceptable salt are dissolved.
  • the dissolution is the solution which is subsequently subjected to lyophilisation according to the freeze-drying method provided herein.
  • the dissolution typically has a physiological pH.
  • the pH of the dissolution is in the range of 5 to 8, preferably about 6.5.
  • the pH of the dissolution is about 5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0 or 8.5.
  • the dissolution can be stored at 2 to 6°C, even for multiple days. Preferably it is stored at a temperature of at least 4°C. Specifically, it can be stored for at least 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13 or 14 days. Characteristically no precipitate can be seen during this storage period.
  • the dissolution comprises 829.60 mg esmolol HCI, 334.05 mg adenosine, 186.38 mg KCI and 5.082.50 mg MgC .
  • Table 1 depicts the concentrations of esmolol HCI, adenosine, KCI and MgCh when dissolved in 10, 50 or 100 ml_ of water. Therefore, when 829.60 mg esmolol HCI, 334.05 mg adenosine, 186.38 mg KCI and 5.082.50 mg MgC are dissolved in 50ml_ water, they are present in the dissolution at concentrations of 50mM, 20mM, 50mM and 200mM, respectively.
  • lyophilisate refers to a pharmaceutical composition which has been freeze-dried.
  • the principle involved is sublimation of water at temperature and pressure below its triple point, that is, 611 Pascal and 0.0098 °C.
  • the product is at first cooled at low temperature (e.g. -50°C) in such a way that the solvent (water, in most cases) freezes.
  • low temperature e.g. -50°C
  • the pressure in the equipment where the process is carried out is decreased, in such a way that ice sublimation can occur (primary drying).
  • the temperature of the product is increased, and heat is continuously supplied to the product as ice sublimation is an endothermic process.
  • the freeze-drying process is generally carried out in a batch mode: the product is processed either in vials or in trays, loaded onto the shelves of the drying chamber. Product cooling, in the freezing stage, and heating, in the drying stages, is obtained through a technical fluid that flows into the shelves.
  • the desired vacuum level is obtained using a vacuum pump and a condenser, where the vapor leaving the product is removed. In some cases, a controlled leakage of inert gas is used to achieve a better pressure control.
  • the lyophilized pharmaceutical composition presented herein is specifically storage stable at room temperature. Specifically, said lyophilisate is stable for at least 1 month, preferably at least 3 months and even more preferably at least 6 or 12 months.
  • Room temperature refers to any temperature of at least 16°C and maximum 26°C. Specifically, said lyophilisate is even more stable at temperatures below room temperature. Preferably, said lyophilisate is stored at 3 to 9 °C.
  • the lyophilisate presented herein can be directly reconstituted.
  • the term reconstitution as used herein refers to the direct reconstitution of the lyophilisate, wherein the lyophilisate is dissolved in an aqueous solution and/or a liquid pharmaceutically acceptable solvent.
  • the lyophilisate is reconstituted in 10, 50, 100, 150, 200, 250, 300, 350, 400, 450 or 500 ml_ water and/or a liquid pharmaceutically acceptable solvent.
  • the lyophilisate is reconstituted in a low volume of water or pharmaceutically acceptable solvent.
  • this low volume is 50 or 100 ml_.
  • the solution resulting from the reconstitution of the lyophilisate is referred to as the“liquid pharmaceutical preparation”.
  • concentrations of the liquid pharmaceutical preparation are as shown in Table 2 below.
  • Table 2 Concentration of lyophilisate reconstituted in pharmaceutically acceptable solvent
  • liquid pharmaceutically acceptable solvent refers to a physiological solution, suitable for use in the treatment of humans.
  • Said liquid pharmaceutically acceptable solvent is selected from the group consisting of Ringer solution, Hartmann’s solution and Krebs-Henseleit buffer.
  • Ringer solution refers to a solution of several salts dissolved in water for the purpose of creating an isotonic solution relative to the body fluids of humans.
  • Ringer solution typically comprises 8.60 g/L sodium chloride, 0.30 g/L potassium chloride and 0.33g/L calcium chloride dehydrate.
  • Hardmann’s solution refers to a solution also commonly known as Ringer’s lactate solution or sodium lactate solution. It is a mixture of sodium chloride, sodium lactate, potassium chloride, and calcium chloride in water. It is commonly used for replacing fluids and electrolytes in those who have low blood volume or low blood pressure.
  • Krebs-Henseleit Buffer refers to a physiological solution sodium (Na), potassium (K), chloride (Cl), calcium (Ca), MgS04, HCO3, PO4, glucose, albumin, and Thromethamine (THAM).
  • the liquid pharmaceutical preparation can subsequently be diluted with patient blood or a pharmaceutically acceptable solvent to generate an infusion solution.
  • the infusion solution is a pharmaceutical preparation of the liquid pharmaceutical preparation as parenteral formulation.
  • the liquid pharmaceutical preparation is diluted with blood or a pharmaceutically acceptable solvent 1 :2, 1 :4, 1 :5, 1 :8, 1 :10, 1 :20, 1 :30 or 1 :40, preferably 1 :20. Since the lyophilisate can be reconstituted in volumes as low as 50 or 100 ml_, the amount of liquid pharmaceutical preparation needed to induce effective cardioplegia can be efficiently reduced.
  • Exemplary, 50ml_ of liquid pharmaceutical preparation comprising 829,60mg esmolol HCI, 334,05 mg adenosine, 186,38 mg KCI and 5.082,50 mg MgC diluted 1 :20 in 950 ml_ blood, yields an effective concentration of esmolol HCI of 2,5 mM and an effective concentration of adenosine of 1 mM.
  • the subject treated is a human subject.
  • Suitably administration is to a human.
  • Suitably dosages/concentrations provided herein are for human applications.
  • the infusion solutions of the invention are administered according to any suitable technique known in the art. Choice of particular mode of administration is typically made by a skilled operator such as the surgeon.
  • liquid pharmaceutical preparation of the lyophilisate presented herein may be used for intermittent or continuous administration.
  • a lyophilisate was generated.
  • the aim was to generate a lyophilisate which can be reconstituted as liquid pharmaceutical preparation with a volume of 100 - 500mL.
  • adenosine is the limiting component.
  • the solubility of adenosine under the given conditions is about 8.23 g / litre of water, which corresponds to 82.3 mg / 10 mL.
  • the target amount of adenosine in the lyophilisate is 334.05 mg.
  • 334.05 divided by 82.3 is 40.06. This means at least 40.06 mL of water is needed to completely dissolve adenosine.
  • the components of the lyophilisate were dissolved in 50mL water, thereby generating a dissolution.
  • the ingredients were mixed together dry and dissolved with 50 g of water. Alternatively, the ingredients may be added sequentially to 50 g of water, starting with MgCL, if any, which will shift the acidic pH to a stable matrix for esmolol.
  • the solution EsmX0501 is stored in the refrigerator at 3-5 °C. Over several days until the time of freeze-drying, no precipitation was observed.

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Abstract

L'invention concerne un lyophilisat comprenant de l'esmolol, de l'adénosine et au moins un sel pharmaceutique et son utilisation en cardioplégie.
PCT/EP2018/086248 2017-12-21 2018-12-20 Lyophilisat comprenant de l'esmolol et de l'adénosine pour une utilisation en cardioplégie Ceased WO2019122157A1 (fr)

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EP17209552 2017-12-21

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2436255A (en) 2002-12-23 2007-09-19 Global Cardiac Solutions Pty L Organ preconditioning, arrest, protection, preservation and recovery (2)
CN102106846A (zh) * 2009-12-23 2011-06-29 南京海辰药业有限公司 左旋盐酸艾司洛尔药物组合物及其制备方法
EP2400963A1 (fr) * 2009-02-26 2012-01-04 King's College London Compositions pour utilisation dans une cardioplégie contenant de l'esmolol et de l'adénosine
WO2013167657A1 (fr) * 2012-05-10 2013-11-14 Aop Orphan Pharmaceuticals Ag Formulation parentérale d'esmolol

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2436255A (en) 2002-12-23 2007-09-19 Global Cardiac Solutions Pty L Organ preconditioning, arrest, protection, preservation and recovery (2)
EP2400963A1 (fr) * 2009-02-26 2012-01-04 King's College London Compositions pour utilisation dans une cardioplégie contenant de l'esmolol et de l'adénosine
EP2400963B1 (fr) 2009-02-26 2016-05-11 Fallouh, Hazem Compositions pour son utilisation en cardioplegie comprenant esmolol et adenosine
CN102106846A (zh) * 2009-12-23 2011-06-29 南京海辰药业有限公司 左旋盐酸艾司洛尔药物组合物及其制备方法
WO2013167657A1 (fr) * 2012-05-10 2013-11-14 Aop Orphan Pharmaceuticals Ag Formulation parentérale d'esmolol

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
BESSHO; CHAMBERS, JOURNAL OF THORACIC AND CARDIOVASCULAR SURGERY, vol. 122, 2001, pages 993 - 1003
CHANG ET AL., CARDIOLOGY, vol. 97, 2002, pages 138 - 146
MCCULLY, JOURNAL OF THORACIC AND CARDIOVASCULAR SURGERY, vol. 124, 2002, pages 219 - 220

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