Pharmaceutical solution with reduced n-nitroso-landiolol impurity

Abstract

The present invention relates to a sterile, storage stable pharmaceutical solution comprising landiolol or a pharmaceutically acceptable salt thereof, and one or more solvents, wherein said solution is in a container selected from the group consisting of a vial with an elastomeric closure for injection, specifically, an elastic lid comprising a septum, a rubber stopper, or an elastic membrane, an infusion bag, and a syringe, and wherein the solution has N-nitroso-landiolol impurity content of less than 4500 ng per g landiolol..

Description

[0001] AP028P

[0002] -1- PHARMACEUTICAL SOLUTION WITH REDUCED N-NITROSO-LANDIOLOL IMPURITY FIELD OF THE INVENTION

[0003] The present invention relates to a sterile, storage stable pharmaceutical solution comprising landiolol or a pharmaceutically acceptable salt thereof and one or more solvents, wherein said solution is in a container selected from the group consisting of a vial with an elastomeric closure for injection, specifically, an elastic lid comprising a septum, a rubber stopper, or an elastic membrane; an infusion bag; or a syringe, and wherein the solution has a N-nitroso-landiolol impurity content of less than 4500 ng per g landiolol.

[0004] BACKGROUND OF THE INVENTION

[0005] N-nitrosamines (NA) are organic compounds that feature a nitroso group (NO+) bonded to a deprotonated amine. NA impurities have been found to be mutagenic and potentially carcinogenic in humans.

[0006] Various regulatory agencies have recommended control strategies to prevent or restrict the presence of NA impurities in pharmaceutical products as much as possible and, where necessary, improve pharmaceutical manufacturing processes. Companies should evaluate the risk of NAs being present in medicines and carry out appropriate tests.

[0007] N-nitroso compounds (NOCs) are NA impurities formed by secondary or tertiary amine groups in active pharmaceutical ingredients (APIs) which react with nitrites of drug components during the manufacture of the drug or during its storage. Some examples of the excipients that could carry trace levels of nitrate or nitrite are sodium starch glycolate, croscarmellose sodium, pre-gelatinized starch, polyvinylpyrrolidone (PVP), cross polyvinylpyrrolidone (cPVP), or lactose, among others. Since functional amine groups are irreplaceable for the function of most APIs, they cannot be substituted easily.

[0008] Limits for the daily intake of NOCs are defined, for example, in Article 5(3) of Regulation (EC) No 726 / 2004 of the European Union, which defines a limit of e.g. 400 ng / day for N-nitroso-landiolol.

[0009] Landiolol is an ultrashort-acting beta blocker. Beta blockers (P-blockers) are a class of medications that are used in the treatment of various conditions related to the heart and vascular system. Beta blockers are competitive antagonists that block theAP028P

[0010] -2-receptor sites for the endogenous catecholamines epinephrine (adrenaline) and norepinephrine (noradrenaline) on adrenergic beta receptors.

[0011] Common heart-related conditions for which beta blockers are well-established include angina pectoris, acute coronary syndromes, hypertension (high blood pressure), heart failure, and tachyarrhythmias (abnormal heart rhythm) such as for example atrial fibrillation. They are also used in the management of other heart diseases, such as hypertrophic obstructive cardiomyopathy, mitral valve stenosis or prolapse, and dissecting aneurysm, and to protect the heart from a second heart attack after a first heart attack (secondary prevention). Additionally, beta blockers find applications in vascular surgery, the treatment of anxiety states, cases of thyrotoxicosis, glaucoma, migraines, and esophageal varices.

[0012] The beta blocker landiolol is an ultra-short-acting, |31-superselective intravenous adrenergic antagonist. Landiolol is registered as an antiarrhythmic agent to treat supraventricular tachycardia and for the rapid control of ventricular rate in patients with atrial fibrillation or atrial flutter in perioperative, postoperative, or other circumstances where short-term control of the ventricular rate with a short acting agent is desirable, and to treat non-compensatory sinus tachycardia where, in the physician's judgment the rapid heart rate requires specific intervention.

[0013] Pharmaceutical compositions comprising landiolol or its pharmaceutically acceptable salt, e.g., landiolol hydrochloride (HCI), are available for example under the brand names Rapibloc®, Raploc®, Runrapiq®, Landibloc®, Onoact®, and Corebeta®. Landiolol is available as a liquid formulation in ampoules (e.g. Rapibloc® 20) or as freeze-dried formulation in vials (e.g., Rapibloc® 300, Onoact®, Rapiblyk®).

[0014] However, high levels of N-nitroso-landiolol have been observed in pharmaceutical solutions comprising landiolol produced, assembled and stored in ampoules, which, when administered to patients, may lead to an uptake of N-nitroso-landiolol above the defined daily intake limit of 400 ng / day.

[0015] EP1652533A1 discloses landiolol hydrochloric acid solution in vials. The landiolol hydrochloride solution is sterilized and placed in vials. Optionally, the solution can be freeze-dried. EP1652533A1 does not disclose information on storage stability, nor on nitrosamine impurities.AP028P

[0016] -3- US2016361422 and W02009079679A2 describe a storage-stable pharmaceutical solution comprising landiolol and cyclodextrin. W02009079679A2 does not disclose information on storage containers nor on nitrosamine impurities.

[0017] WO2025153663 discloses a storage stable pharmaceutical solution comprising complexed landiolol encapsulated or dissolved in lipophilic matrix and specifically discloses that said solution is in a vial closed with an elastomeric stopper and aluminum overseal. WO2025153663 does not disclose information on nitrosamine impurity.

[0018] To protect patients from potential cancer risk and ensure access to essential drugs, the manufacture and provision of pharmaceutical products with a low concentration of NOCs is of great importance but remains technically challenging. Therefore, there is still a strong and yet unmet need for a pharmaceutical landiolol solution with reduced nitrosamine impurity content.

[0019] SUMMARY OF THE INVENTION

[0020] It is the objective of the present invention to provide a sterile, storage stable landiolol solution with reduced nitrosamine impurity content.

[0021] The problem is solved by the present invention.

[0022] The inventors have surprisingly found that while landiolol solutions in ampoules contained significant amounts of N-nitroso-landiolol due to degradation of landiolol to N-nitroso-landiolol, such degradation can be significantly reduced by production, assembly and storage of landiolol solution in vials closed with an elastomeric closure, in infusion bags, or in syringes.

[0023] Herein provided is a sterile, storage stable pharmaceutical solution comprising landiolol or the pharmaceutically acceptable salt thereof, specifically landiolol HCI, in a vial closed with an elastomeric closure, or in an infusion bag, or in a syringe, which has a reduced amount of N-nitroso-landiolol.

[0024] According to the invention there is provided a sterile, storage stable pharmaceutical solution comprising landiolol or a pharmaceutically acceptable salt thereof and one or more solvents, wherein said solution

[0025] a. is in a container selected from the group consisting of a vial with an elastomeric closure for injection, an infusion bag, and a syringe; and

[0026] b. has N-nitroso-landiolol impurity content of less than 4500 ng per g landiolol. In an embodiment of the invention, the pharmaceutical solution comprises landiolol hydrochloride (HCI).AP028P

[0027] -4- In an embodiment of the invention, the pharmaceutical solution is storage stable for at least one month, specifically up to 3 months, specifically up to 6 months, specifically up to 12 months, specifically up to 18 months, specifically up to 24 months, specifically up to 30 months, specifically up to 36 months, specifically at a temperature in the range of 2-8°C.

[0028] In a further embodiment of the invention, the pharmaceutical solution is storage stable for at least one month, specifically up to 3 months, specifically up to 4 months at a temperature in the range of 22-28°C.

[0029] According to a further embodiment, the pharmaceutical solution further comprises one or more cyclodextrin(s), and / or salts, and / or a buffer.

[0030] In a further embodiment, said cyclodextrin is HPBCD or SBECD, or pharmaceutically acceptable salts thereof.

[0031] In a further embodiment, said cyclodextrin has a concentration of 0.5 to 600 mg / ml, specifically 5 to 140 mg / ml, more specifically 10 to 30 mg / ml.

[0032] According to a further embodiment, the landiolol or landiolol HCI is present at a concentration of 0.1 mg / ml to 20 mg / ml, specifically 6 to 12 mg / ml, more specifically 0.5 mg / ml, 6 mg / ml, 10 mg / ml, 11 mg / ml, or 12 mg / ml.

[0033] In an alternative embodiment, landiolol free base is present at a concentration of 0.1 mg / ml to 20 mg / ml, specifically approx. 5.6 to 11.2 mg / ml, more specifically approx.

[0034] 0.46 mg / ml, 5.6 mg / ml, or approx. 9.35 mg / ml, 10.3 mg / ml, or 11.2 mg / ml.

[0035] According to a further embodiment, the solvent is ethanol, or water, preferably the solvent is miscible with water.

[0036] According to a further embodiment, the pharmaceutical solution further comprises a saccharide, a sugar alcohol, and / or a salt.

[0037] According to a further embodiment, the pharmaceutical solution further comprises a buffer with a pH ranging from pH 5.0-7.5, specifically phosphate buffer, and / or citrate buffer.

[0038] According to a further embodiment, the pharmaceutical solution further comprises a tonicity agent and / or an osmotic agent and / or a stabilizing agent, specifically, sodium chloride, or macrogol.

[0039] In a further embodiment, the vial is made of plastic or glass, specifically borosilicate glass, or soda-lime-silica glass, optionally plastic or glass coated with one or more types of polymers.AP028P

[0040] -5- According to a further embodiment, the inside wall of the vial is coated, specifically coated with polymer or silicon.

[0041] According to a further embodiment, the elastomeric closure for injection is a lid comprising a septum, an elastic membrane, or a rubber stopper.

[0042] In a further embodiment, the infusion bag is made of plastic.

[0043] According to a further embodiment, the syringe is made of plastic, or glass.

[0044] DETAILED DESCRIPTION

[0045] Nitrosamine impurities in pharmaceutical products have been found to be mutagenic and potentially carcinogenic for humans. One example is N-nitroso-landiolol impurity formed in the P-blocker landiolol which is produced, assembled and stored in ampoules.

[0046] A sterile, storage stable pharmaceutical solution comprising landiolol or its pharmaceutically acceptable salt e.g., landiolol HCI, with only a low amount of N-nitroso-landiolol impurity was surprisingly achieved by production, assembly and storage of the pharmaceutical solution in a vial closed with an elastomeric closure, infusion bag, or syringe.

[0047] Unless indicated or defined otherwise, all terms used herein have their usual meaning in the art, which will be clear to the skilled person. Reference is for example made to standard handbooks, such as Remington: The Science and Practice of Pharmacy, 23rd edition, 2020.

[0048] The terms “comprise”, “contain”, “have” and “include” as used herein can be used synonymously and shall be understood as an open definition, allowing further members or parts or elements. “Consisting” is considered as a closest definition without further elements of the consisting definition feature. Thus “comprising” is broader and contains the “consisting” definition.

[0049] The term “about” or around as used herein refers to the same value or a value differing by + / - 5 % of the given value.

[0050] As used herein and in the claims, the singular form, for example “a”, “an” and “the” includes the plural, unless the context clearly dictates otherwise.

[0051] It is intended that reference to a range of numbers disclosed herein (for example, 1 to 10) also incorporates reference to all rational numbers within that range (for example, 1, 1.1, 2, 3, 3.9, 4, 5, 6, 6.5, 7, 8, 9 and 10) and also any range of rational numbers within that range (for example, 2 to 8, 1.5 to 5.5, and 3.1 to 4.7). These areAP028P

[0052] -6-only examples of what is specifically intended and all possible combinations of numerical values between the lowest value and the highest value enumerated are considered to be expressly stated in this application in a similar manner.

[0053] The term “pharmaceutical solution” as used herein refers to a liquid pharmaceutical or a liquid pharmaceutical composition. The pharmaceutical solution may be an aqueous solution. Herein, the pharmaceutical solution comprises landiolol or a pharmaceutically acceptable salt thereof and is a stable and sterile liquid for the purpose of administrating and transferring an effective amount of the ingredient compound landiolol to the human body.

[0054] The pharmaceutical solution of the present invention is a ready-to-use formulation, or a ready-to-dilute formulation. A person skilled in the art is familiar with the difference between a ready-to-use formulation and a ready-to-dilute formulation, that is, a ready-to-use formulation can be administered as is to a patient, while a ready-to-dilute formulation may require dilution before administering to a patient. The person skilled in the art is further familiar with an alternative term for ready-to-dilute formulation, that is concentrate. The terms ready-to-dilute and concentrate can be used interchangeably.

[0055] According to a specific embodiment, the pharmaceutical solutions comprising landiolol described herein are for parenteral or intrapulmonary administration.

[0056] The term “parenteral” as used herein refers to subcutaneous, intracutaneous, intravenous, intramuscular, intraarticular, intraarterial, intrasynovial, intrasternal, intrathecal, intralesional, intraperitoneal, intratracheal, intracranial, or intracoronary administration.

[0057] The term “intrapulmonary”, as used herein refers to employing inhalable technology or pulmonary delivery systems such as for inhalable routes of administration.

[0058] According to one embodiment, the pharmaceutical solutions comprising landiolol described herein are for intranasal routes of administration.

[0059] The pharmaceutical solution of the present invention is a sterile solution.

[0060] The term “sterile” as used in the context of the invention means a solution that has been brought to a state of sterility and has not been subsequently exposed to microbiological contamination, i.e. the sterility of the liquid solution present in the container has not been compromised.AP028P

[0061] -7- Herein, the pharmaceutical solution may be in a vial with an elastomeric closure, specifically an elastic lid, specifically, an elastic lid which comprises a septum, an elastic membrane, or a rubber stopper. Said elastomeric closure prevents microbial contamination and maintains sterility of the pharmaceutical solution when used under sterile conditions, specifically when solution is withdrawn one or multiple times, more specifically, when using a syringe with a needle. A person skilled in the art is familiar with a method to withdraw a solution from a vial under sterile conditions, including, but not limited to, cleaning the elastic lid with an antiseptic solution prior to insertion of a sterile needle.

[0062] The pharmaceutical solution of the present invention is storage stable.

[0063] The term “storage stable” as used herein refers to a pharmaceutical solution, which can be stored at appropriate temperature for commercially relevant periods of time (e.g., one month, two months, three months, or longer) without any significant degradation or change of the contained active substance taking place. That is, compositions of the invention as described herein are safe and effective for human use, even after commercially relevant storage periods. As is known in the art, ‘appropriate temperature’ for pharmaceutical manufacturing and storage refers to a temperature range between 8°C and 30°C. Ideally, storage areas would be temperature controlled between 2°C and 8°C. A person skilled in the art may refer to a storage temperature between 2-8°C as ‘controlled cold temperature’. Pharmaceutical products which are storage stable can be maintained at appropriate temperature for commercially relevant periods of time. In the examples of the present invention, storage stability was measured at a temperature range of around 5°C and 25°C.

[0064] Storage stability of pharmaceutical products is routinely assessed in pharmaceutical production and can e.g. be measured using techniques such as chromatography, for example, by Reverse Phase-High-Performance Liquid Chromatography (RP-HPLC) with UV detection and gradient elution.

[0065] The term ’’storage stable solution”, as used herein, refers to a pharmaceutical solution comprising landiolol or a pharmaceutically acceptable salt thereof, specifically, landiolol HCI, which is substantially free of N-nitroso-landiolol impurity or only contains levels of N-nitroso-landiolol of less than 4500 ng / g landiolol.

[0066] As a non-limiting example, N-nitroso-landiolol impurity can be measured using liquid chromatography-mass spectrometry approaches, e.g. LC-MS / MS.AP028P

[0067] -8- Non-limiting examples for analysis instruments to detect N-nitroso-landiolol impurity used herein are e.g. AB Sciex 4500 Triple Quadrupole MS or Agilent Ultivo LC / TQ Triple Quadrupole MS.

[0068] The term “detection limit or limit of detection or LOD” as used herein refers to the lowest concentration of a substance that can be reliably detected by an analytical method, distinguishing it from background noise. Detection limits may differ for measurements if different analysis instruments are used. Further differences may be caused by differences in substance concentrations, e.g. landiolol concentrations, excipient composition, and matrix effects.

[0069] In a specific embodiment, the detection limit of N-nitroso-landiolol impurity of the ready-to-use formulation in vials is 34 ng N-nitroso landiolol / g landiolol HCL

[0070] In another specific embodiment, the detection limit of N-nitroso-landiolol impurity of the ready-to-use formulation in infusion bags and pre-filled syringes is 14 ng N-nitroso landiolol / g landiolol HCL

[0071] The term “limit of quantification or LOQ” as used herein refers to the lowest concentration of a substance that can be measured with acceptable precision and accuracy. Limits of quantification may differ for measurements if different analysis instruments are used. Further differences may be caused by differences in substance concentrations, e.g. landiolol concentrations, excipient composition, and matrix effects.

[0072] In a specific embodiment, the limit of quantification of N-nitroso-landiolol impurity of the ready-to-use formulation in vials, infusion bags and pre-filled syringes is 40 ng N-nitroso landiolol / g landiolol HCL

[0073] The term ’’storage stable solution”, as used herein, refers to a pharmaceutical solution comprising landiolol or a pharmaceutically acceptable salt thereof, specifically, landiolol HCI, which is substantially free of N-nitroso-landiolol impurity or only contains levels of N-nitroso-landiolol of less than 4500 ng / g landiolol, specifically less than 4400, 4300, 4200, 4100, 4000, 3900, 3800, 3700, 3600, 3500, 3400, 3300, 3200, 3100, 3000, 2900, 2800, 2700, 2600, 2500, 2400, 2300, 2200, 2100, 2000, 1900, 1800, 1700, 1600, 1500, 1400, 1300, 1200, 1100, 1000, 900, 800, 700, 600, 500, 400, 300, 250, 240, 230, 225, or 220 ng N-nitroso-landiolol per g (ng / g) landiolol, specifically when stored between 2 and 34°C, specifically, at 5°C ± 3°C, or at 18°C ± 3°, or at 25°C ± 4°C, or at 30°C ± 4°C for at least 1 month.AP028P

[0074] -9- The pharmaceutical solution comprising landiolol or a pharmaceutically acceptable salt thereof, specifically landiolol HCI, may be a ready-to-use formulation which is substantially free of N-nitroso-landiolol impurity or only contains levels of N-nitroso-landiolol of less than 4500 ng / g landiolol, specifically less than 4400, 4300, 4200, 4100, 4000, 3900, 3800, 3700, 3600, 3500, 3400, 3300, 3200, 3100, 3000, 2900, 2800, 2700, 2600, 2500, 2400, 2300, 2200, 2100, 2000, 1900, 1800, 1700, 1600, 1500, 1400, 1300, 1200, 1100, 1000, 900, 800, 700, 600, 500, 400, 300, 200, 100, 90, 80, 70, 60, 50, 40, or 35 ng N-nitroso-landiolol per g landiolol, specifically when stored between 2 and 27°C, specifically, at 5°C ± 3°C, or at 25°C ± 2°C for at least 1 month. Preferably, the pharmaceutical solution comprising landiolol or a pharmaceutically acceptable salt thereof is a ready-to-use formulation which is substantially free of N-nitroso-landiolol impurity or only contains levels of N-nitroso-landiolol of less than 250 ng N-nitroso-landiolol per g landiolol or landiolol HCI, more preferably, of less than 140 ng / g.

[0075] Alternatively, the pharmaceutical solution comprising landiolol or a pharmaceutically acceptable salt thereof is a ready-to-dilute formulation which is substantially free of N-nitroso-landiolol impurity or only contains levels of N-nitroso-landiolol of less than 4500 ng / g landiolol, specifically less than 4400, 4300, 4200, 4100, 4000, 3900, 3800, 3700, 3600, 3500, 3400, 3300, 3200, 3100, 3000, 2900, 2800, 2700, 2600, 2500, 2400, 2300, 2200, 2100, 2000, 1900, 1800, 1700, 1600, 1500, 1400, 1300, 1200, 1100, 1000, 900, 800, 700, 600, 500, 400, 300, 250, 240, 230, 225, or 220 ng N-nitroso-landiolol per g (ng / g) landiolol, specifically when stored between 2 and 29°C, specifically, at 5°C ± 3°C, or at 25°C ± 4°C for at least 1 month. Preferably, the pharmaceutical solution comprising landiolol or a pharmaceutically acceptable salt thereof may be a ready-to-dilute formulation which is substantially free of N-nitroso-landiolol impurity or only contains levels of N-nitroso-landiolol of less than 250 ng N-nitroso-landiolol per g landiolol or landiolol HCI, more preferably, of less than 140 ng / g.

[0076] In one embodiment, the solution is storage stable for a period of 1 to 55 months, specifically 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, or 55 months, specifically up to 1, 3, 6, or 12 months, specifically up to 18 months, specifically up to 24 months, specifically up to 30 months, specifically up to 36 months, specifically up to 42 months, specifically up to 50 months, specifically up to 55 months, specifically, at a temperature in the range of 2-8°C.AP028P

[0077] -10- In another embodiment, the solution is storage stable for a period of 1 to 4 months, specifically 1 , 2, 3, or 4 months at a temperature in the range of 22-28°C.

[0078] The term “substantially free of nitrosamine impurities” refers to N-nitroso-landiolol impurity of less than 25 ng / g landiolol, specifically, less than 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, 1, or contains 0 ng / g landiolol, more specifically less than 22, 21, 20, 19, or 18 ng / g landiolol.

[0079] The pharmaceutical solution of the present invention comprises landiolol or a pharmaceutically acceptable salt thereof.

[0080] The term “landiolol” as used herein refers to landiolol (CAS 133242-30-5), chemical name [(4S)-2,2-dimethyl-1 ,3-dioxolan-4-yl]methyl 3-[4-[(2S)-2-hydroxy-3-[2-(morpholine-4-carbonylamino)ethylamino]propoxy]phenyl]propanoate, with the molecular formula C25H39N3O8, and molecular weight of 509.59 g / mol.

[0081] In a specific embodiment, landiolol is present at a concentration of around 0.1 mg / ml to 30 mg / ml, specifically of around 0.5 to 15 mg / ml, more specifically 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, or 30 mg / ml.

[0082] As is known in the art, methods to measure active pharmaceutical ingredient (API) concentration in pharmaceutical compositions are e.g. spectroscopy methods, such as near-infrared (NIR) spectrometry, or ultraviolet (UV)-visible (Vis) absorption spectroscopy.

[0083] The term “landiolol” as used herein also refers to a pharmaceutically acceptable salt thereof.

[0084] The term “salt” is commonly known in the field and as used herein refers to a chemical compound comprising an ionic assembly of positively charged cations and negatively charged anions, which results in a compound with no net electric charge. A common example is table salt, with positively charged sodium ions and negatively charged chloride ions.

[0085] A “pharmaceutically acceptable salt” of landiolol is, for example, landiolol hydrochloride (HCI) with CAS 144481-98-1, chemical name (— )-[(S)-2,2-dimethyl-1 ,3-dioxolan-4-yl]methyl 3-[4-[(S)-2-hydroxy-3-(2-morpholinocarbonylamino) ethylamino] propoxy] phenylpropionate monohydrochloride, the empirical formula C25H39N3O8HCI and a molecular weight of 546.06 g / mol, or any other pharmaceutically acceptable salt of landiolol.AP028P

[0086] -11- In a preferred embodiment, the pharmaceutical solution comprises landiolol hydrochloride (HCI).

[0087] A person skilled in the art is familiar with the conversion of a value obtained as ng / g landiolol HCI to ng / g landiolol free base. The conversion is performed based on the molecular weights of 509.59 g / mol of landiolol free base and of 546.06 g / mol of landiolol HCI. A value with the unit ng / g landiolol HCI is multiplied by the factor of 1.07 based on the different molecular weights to receive the value with the unit of ng / g landiolol free base. The ratio of the HCI to the free base is 1.07, illustrating that one mole of the hydrochloride has a mass higher by the factor of 1.07 than one mole of the free base. As a non-limiting example, 100 ng / g landiolol HCI is equal to 107 ng / g landiolol free base. On the other hand, as a non-limiting example, 100 ng / g landiolol in a pharmaceutical composition is equal to 93,45 ng / g landiolol free base.

[0088] The pharmaceutical solution of the present invention comprises one or more solvents.

[0089] The term “solvent” as used herein refers to substances which can suspend, extract, or dissolve other substances without bringing any change into the chemistry of either the substance or the solvent. As is known in the art, solvents may be mixable with water, salts, sugar alcohols (e.g., mannitol), and sugars (e.g., saccharides). A person skilled in the art is familiar with solvents used for pharmaceutical solutions, e.g., as a non-limiting example, ethanol 96%.

[0090] In a further specific embodiment, the solvent is ethanol or water, preferably, the solvent is miscible with water.

[0091] In a specific embodiment, the ready-to-dilute formulation of the pharmaceutical solution described herein comprises between 300 to 400 mg / ml ethanol, specifically 320 mg / ml ethanol.

[0092] In another specific embodiment, the ready-to-use formulation of the pharmaceutical solution described herein does not comprise ethanol.

[0093] According to one embodiment, the pharmaceutical solution may comprise one or more cyclodextrin(s), and / or salts, and / or a buffer.

[0094] Cyclodextrin may be contained in the pharmaceutical solution of the present invention.

[0095] The term “cyclodextrin” as used herein refers to cyclodextrins, its pharmaceutically acceptable salts, and functional cyclodextrin derivatives. CyclodextrinsAP028P

[0096] -12-

[0097] can be, but are not limited to a-cyclodextrin, p-cyclodextrin, y-cyclodextrin, or functional derivatives and mixtures thereof. Functional cyclodextrin derivatives is taken to mean all pharmaceutically acceptable derivatives of cyclodextrins in which the essential structure and size of the cyclodextrin molecules are retained. Considered as functional cyclodextrin derivatives in particular are esters with pharmaceutically acceptable acids and ethers, especially low-alkyl ethers. Particularly preferred cyclodextrin derivatives are (2-hydroxypropyl)-p-cyclodextrin (HPBCD) and (sulfobutylether)-7p cyclodextrin (SBECD), or a pharmaceutically acceptable salt thereof.

[0098] In a specific embodiment of the invention there is a sterile, storage stable pharmaceutical solution comprising landiolol or a pharmaceutically acceptable salt thereof, one or more solvents, and one or more cyclodextrin(s) selected from HPBCD or SBECD or its pharmaceutically acceptable salts, wherein said solution

[0099] a. is in a container selected from the group consisting of a vial with an elastomeric closure for injection, an infusion bag, and a syringe; and

[0100] b. has N-nitroso-landiolol impurity content of less than 4500 ng per g landiolol. According to a specific embodiment, the ready-to-use formulation of the pharmaceutical solution comprises cyclodextrin at a concentration of 0.5 mg / ml to 35 mg / ml, specifically 1 mg / ml to 30 mg / ml, more specifically 1 mg / ml to 26 mg / ml.

[0101] Specifically, the ready-to-use pharmaceutical solution comprises HPBCD or its pharmaceutically acceptable salt at a concentration of 0.5 mg / ml to 35 mg / ml, specifically 1 mg / ml to 30 mg / ml, more specifically 1 mg / ml to 26 mg / ml, even more specifically 26 mg / ml, 17mg / ml, 15 mg / ml, 10 mg / ml, or 5 mg / ml.

[0102] Specifically, the ready-to-use pharmaceutical solution comprises SBECD or its pharmaceutically acceptable salt at a concentration of 0.5 mg / ml to 35 mg / ml, specifically 1 mg / ml to 30 mg / ml, more specifically 1 mg / ml to 26 mg / ml, even more specifically 26 mg / ml, 17mg / ml, 15 mg / ml, 10 mg / ml, or 5 mg / ml.

[0103] According to a further specific embodiment, the ready-to-dilute pharmaceutical solution comprises cyclodextrin at a concentration of 1 mg / ml to 600 mg / ml, specifically 120 to 160 mg / ml, more specifically 140 mg / ml.

[0104] Specifically, the ready-to-dilute pharmaceutical solution comprises HPBCD or its pharmaceutically acceptable salt at a concentration of 1 mg / ml to 600 mg / ml, specifically 120 to 160 mg / ml, more specifically 140 mg / ml.AP028P

[0105] -13- Specifically, the ready-to-dilute pharmaceutical solution comprises SBECD or its pharmaceutically acceptable salt at a concentration of 1 mg / ml to 600 mg / ml, specifically 120 to 160 mg / ml, more specifically 140 mg / ml.

[0106] In a further specific embodiment, the pharmaceutical solution further comprises a buffer. Buffers in pharmaceutical compositions regulate the pH of the solution. Regulation of pH ensures the quality and performance of drug formulations, since changes of pH can influence the overall thermodynamic parameters of reactions, chemical stability and solubility. As is known in the art, a wide variety of buffer solutions is available in pharmaceutical manufacturing. One non-limiting example for a common biological buffer is phosphate-buffered saline (PBS) containing Na2PO4 and sodium chloride (NaCI). Further non-limiting examples of a buffer or of buffer components are citrate, sodium I potassium phosphate, e.g. trisodium phosphate (Na3PO4), sodium hydrogen phosphate, e.g. disodium hydrogen phosphate (Na2HPO4), monopotassium phosphate (KH2PO4), acetate, TRIS, succinate, sodium hydroxide, glacial acetic acid, hydrochloric acid, sodium acetate dihydrate, potassium chloride, potassium dihydrogen phosphate, disodium hydrogen phosphate anhydride, citric acid, sodium citrate dihydrate, or any other physiologically acceptable buffer.

[0107] The pharmaceutical solution described herein may comprise NaOH / HCL According to an embodiment, the buffer can be Na2HPO4, and / or NaH2PO4, and / or KH2PO4, and / or citrate buffer.

[0108] In a specific embodiment, the buffered pharmaceutical solution as described herein has a pH ranging from pH 5.0 to 7.5. Specifically, the buffered ready-to-use formulation of the pharmaceutical solution as described herein has a pH ranging from pH 6.5 to 6.6. More specifically, the ready-to-use formulation comprising HPBCD has a pH of 6.5. More specifically, the ready-to-use formulation comprising SBECD has a pH of 6.6. In a specific embodiment, the ready-to-use formulation of the pharmaceutical solution described herein comprises NaOH / HCI for pH adjustment.

[0109] Specifically, the buffered ready-to-dilute formulation of the pharmaceutical solution as described herein has a pH ranging from pH 6.5 to 7.5. In a specific embodiment, the ready-to-dilute formulation of the pharmaceutical solution described herein comprises KH2PO4 and / or Na2HPO4. In another specific embodiment, the ready-to-use formulation of the pharmaceutical solution described herein comprises 5 mM Na2HPO4X 2H2O and / or NaH2PC>4 x 2H2O.AP028P

[0110] -14- In a specific embodiment, the pharmaceutical solution comprises a buffer comprising citrate or phosphate, wherein the buffer has a concentration of 1 mM to 100 mM, specifically 60 mM citrate or phosphate. In a specific embodiment, the ready-to-use formulation of the pharmaceutical solution described herein comprises a phosphate buffer, specifically, the buffer has a concentration of 5 mM, or 10 mM.

[0111] In an embodiment, the pharmaceutical solution described herein may comprise NaCI / KCI at a concentration between 0.5 mg / ml to 10 mg / ml.

[0112] In a specific embodiment, the ready-to-use formulation of the pharmaceutical solution described herein comprises NaCI / KCI at a concentration of 0.5 mg / ml to 10 mg / ml, specifically, the ready-to-use formulation comprises around 7 mg / ml NaCI if it further comprises HPBCD, more specifically, the ready-to-use formulation comprises 6 mg / ml NaCI if it further comprises SBECD. In another embodiment, the ready-to-use formulation of the pharmaceutical solution described herein comprises NaCI, but does not comprise KCL

[0113] In a specific embodiment, the ready-to-dilute formulation of the pharmaceutical solution described herein comprises around 2 mg / ml NaCI and 0.05 mg / ml KCL In another embodiment, the ready-to-dilute formulation of the pharmaceutical solution described herein may not comprise NaCI / KCI.

[0114] In an embodiment, the pharmaceutical solution comprises an osmotic agent and / or a tonicity agent and / or a stabilizing agent, specifically, macrogol. The terms “osmotic agent” and “tonicity agent” as described herein can be used interchangeably.

[0115] Macrogol, or polyethylene glycol (PEG) is known to a person skilled in the art as a commonly used stabilizing agent in pharmaceutical compositions. Macrogol may further be used as osmotic agent or tonicity agent. One non-limiting example is macrogol 300, which has a molecular mass of 300 g / mol.

[0116] In a specific embodiment, the ready-to-dilute formulation of the pharmaceutical solution as described herein comprises PEG at 300 mg / ml.

[0117] According to an embodiment, the pharmaceutical solution comprises sugar, specifically, monosaccharides or oligosaccharides, and / or sugar alcohol, and / or salt.

[0118] One non-limiting example for a pharmaceutical composition comprising landiolol in a vial comprises 8-12 mg / ml landiolol, 120-160 mg cyclodextrin, specifically HPBCD, 250-350 mg / mL macrogol, 300-340 mg / ml ethanol, 1.5-2.5 mg / ml NaCI, 0.03-0.08 mg / ml KCI, 0.1 -0.5 mg / ml Na2HPO4, 0.1 -0.5 mg / ml KH2PO4, and water for injection (WFI).AP028P

[0119] -15- In a specific embodiment, the pharmaceutical solution comprises 10 mg / ml landiolol HCI, 140 mg cyclodextrin, specifically HPBCD, 300 mg / mL macrogol, 320 mg / ml ethanol, 2 mg / ml NaCI, 0.05 mg / ml KCI, 0.3 mg / ml Na2HPO4, 0.3 mg / ml KH2PO4, and water for injection (WFI).

[0120] One further non-limiting example for a pharmaceutical composition comprising landiolol in a vial refers to 8-12 mg / ml landiolol, 120-160 mg cyclodextrin (HPBCD), 250-350 mg / mL macrogol, 300-340 mg / ml Ethanol, 1.5-2.5 mg / ml NaCI, 0.03-0.08 mg / ml KCI, 0.1 -0.5 mg / ml Na2HPO4, 0.1 -0.5 mg / ml KH2PO4, and water for injection (WFI).

[0121] In a specific embodiment, a pharmaceutical solution comprising landiolol in a vial encompasses 10 mg / ml landiolol HCI, 140 mg cyclodextrin (HPBCD), 300 mg / mL macrogol, 320 mg / ml ethanol, 2.1 mg / ml NaCI, 0.05 mg / ml KCI, 0.3 mg / ml Na2HPO4, 0.3 mg / ml KH2PO4, and water for injection (WFI).

[0122] One further non-limiting example for a pharmaceutical solution comprising landiolol in a vial refers to 4-8 mg / mL landiolol, 20-35 mg / ml cyclodextrin, NaCI 5.0-8.5 mg / ml, Na2HPO4 (as dihydrate) 0.12-0.20 mg / ml, NaH2PO4 (as dihydrate) 0.3-0.8 mg / ml.

[0123] In a specific embodiment, a pharmaceutical solution comprises 6 mg / mL landiolol HCI, 26 mg / ml cyclodextrin, 6.0 -7.5 mg / ml NaCI, 5 mM Na2HPO4 (as dihydrate), 5mM NaH2PO4 (as dihydrate), and cyclodextrin, which can be, but is not limited to, HPBCD or SBECD or its salts.

[0124] In a specific embodiment, the pharmaceutical solution comprises 11 mg / ml landiolol HCI, 300 mg / ml PEG 300, 140 mg / ml HPBCD, 320mg / ml ethanol, 0.05 mg / ml KH2PO4, and 0.3 mg / ml Na2HPO4, and optionally 0.05 mg / ml KCI, and / or 2 mg / ml NaCI and has a pH value in the range of 6.5 to 7.5.

[0125] In a specific embodiment, the pharmaceutical solution comprises 6 mg / ml landiolol HCI, 5 mM phosphate buffer, and 26 mg / ml cyclodextrin, specifically HPBCD or SBECD or it salts, and optionally, 7-7.5 mg / ml NaCI (if comprising HPBCD) or 6 mg / ml NaCI (if comprising SBECD), and / or NAOH / HCI for pH adjustment, and has a pH value of 6.5 (if comprising HPBCD) or 6.6 (if comprising SBECD).

[0126] In a specific embodiment, the pharmaceutical solution comprises 6mg / mL landiolol HCI, 5mM NaP, 26 mg / mL SBECD, and 6 mg / mL NaCI,

[0127] In a specific embodiment, the pharmaceutical solution comprises 6mg / mL landiolol HCI, 5mM NaP, 17 mg / mL SBECD, and 6.6 mg / mL NaCI.AP028P

[0128] -16- In a specific embodiment, the pharmaceutical solution comprises 6mg / mL landiolol HCI, 5mM NaP, 15 mg / mL SBECD, and 6.7 mg / mL NaCL

[0129] In a specific embodiment, the pharmaceutical solution comprises 6mg / mL landiolol HCI, 5mM NaP, 10 mg / mL SBECD, and 7.1 mg / mL NaCL

[0130] In a specific embodiment, the pharmaceutical solution comprises 6mg / mL landiolol HCI, 5mM NaP, 5 mg / mL SBECD, and 7.4 mg / mL NaCL

[0131] One non-limiting example for a pharmaceutical composition comprising landiolol in a pre-filled syringe comprises 4-8 mg / ml landiolol HCI, 20-35 mg / ml cyclodextrin, 5-8.5 mg / ml NaCI, Na2HPO4 x 2H2O, NaH2PO4 x 2H2O, and water for injection.

[0132] One non-limiting example for a pharmaceutical composition comprising landiolol in a infusion bag comprises 4-8 mg / ml landiolol HCI, 20-35 mg / ml cyclodextrin, 5-8.5 mg / ml NaCI, Na2HPO4 x 2H2O, NaH2PO4 x 2H2O, and water for injection.

[0133] In a specific embodiment, the pharmaceutical solution comprises 6 mg / ml landiolol HCI, 26 mg / ml cyclodextrin, specifically SBECD sodium salt, 6mg / ml NaCI, Na2HPO4 x 2H2O, NaH2PO4 x 2H2O, and water for injection.

[0134] Specifically, landiolol HCI is present at a concentration of 0.1 mg / ml to 30 mg / ml, specifically 0.5 to 15 mg / ml, more specifically 0.5, 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, or 30 mg / ml.

[0135] According to a specific embodiment, the pharmaceutical solution described herein is a landiolol ready-to-use formulation comprising about 6 mg / ml landiolol HCL Said formulation can further comprise one or more of cyclodextrin, such as, but not limited to HPBCD or SBECD; or its pharmaceutically acceptable salts, NaCI, and / or phosphate buffer, such as Na2HPO4, NaH2PO4, NaOH, and / or H3PO4.

[0136] According to a specific embodiment, the pharmaceutical solution described herein is a landiolol ready-to-dilute formulation containing about 10 mg / ml landiolol HCL Said ready-to-dilute formulation can further comprise one or more of cyclodextrin, specifically HPBCD or its pharmaceutically acceptable salts, macrogol, ethanol, NaCI, KCI, and a phosphate buffer, such as Na2HPO4, and / or KH2PO4, and WFL

[0137] The pharmaceutical solution of the present invention is in a container selected from the group consisting of a vial, an infusion bag, and a syringe. Alternatively, the pharmaceutical solution of the present invention may be in a pressurized metered dose inhaler. The pharmaceutical solution of the present invention is not in an ampoule.AP028P

[0138] -17- The terms “vial”, “infusion bag”, “syringe”, and “dose inhaler” are containers for pharmaceutical solutions known to those in the art.

[0139] A “vial” is a container for liquids or solids. Vials can be made of glass, or plastic. Commonly used vials for pharmaceutical solutions are e.g. 2-ml vials, 5-ml vials, 10-ml, 20-ml, 50-ml or 100-ml vials.

[0140] The vial can have a screw-on cap, a crimp closure, or an elastomeric closure for injection. Non-limiting examples for an elastomeric closure are a lid comprising a septum, a rubber stopper, or an elastic membrane.

[0141] An unopened vial can provide for sterile storage of pharmaceutical solutions. Once opened under non-sterile conditions, air, moisture or water can reach the stored pharmaceutical solution and may contaminate it. Opened and closed under sterile conditions, the elastomeric closure maintains sterility of the pharmaceutical solution, therefore, a vial operated under sterile conditions can be used more than once while maintaining sterility of the pharmaceutical solution within. The elastomeric closure for injection may be a lid comprising a septum, an elastic membrane, or a rubber stopper.

[0142] An elastic lid comprising a septum or an elastic membrane is characterized in that the elasticity of the closure causes the opening caused by the insertion of a needle for withdrawal of solution to be closed following removal of the needle.

[0143] The elastomeric closure further may be a rubber stopper which may be resealable. A rubber stopper may be made of polymer, specifically bromobutyl.

[0144] According to one embodiment, the vial is made of glass, specifically, borosilicate glass or soda-lime-silica glass, or plastic.

[0145] Vials can be made of glass or plastic, e.g., borosilicate glass, specifically, Type I Borosilicate Glass with high chemical resistance according to ISO 9187-1, or can be made from polyethylene or polypropylene plastic.

[0146] According to a further embodiment, the vial is optionally coated with one or more polymers.

[0147] According to another embodiment, the inside wall of the vial is coated, specifically, coated with polymer or silicon.

[0148] Production, assembly, and storage of a landiolol solution in a vial as disclosed in the present invention has surprisingly avoided N-nitroso-landiolol degradation products or led to a significantly reduced concentration of N-nitroso-landiolol compared to the production, assembly, and storage of a landiolol or landiolol HCI solution in an ampoule.AP028P

[0149] -18- The person skilled in the art is familiar with the manufacturing process leading to a pharmaceutical product. Such exemplary process can be as follows, involving in the sequential order production, assembly, and storage of the product.

[0150] The term “production” as used herein may refer to the process of

[0151] (1) production of the active pharmaceutical ingredient (API),

[0152] (2) subsequent drug formulation to obtain a pharmaceutical solution comprising the API and one or more solvents, and

[0153] (3) optionally, filtering to ensure sterility of the pharmaceutical solution.

[0154] The term “assembly” as used herein refers to the process of filling the sterile pharmaceutical solution into a primary packaging container such as a vial, ampoule, syringe, or infusion bag, and subsequent closure of said container. Importantly, the assembled pharmaceutical product is sterile. The person skilled in the art is familiar with the difference between the assembly of a vial and an ampoule. A vial with an elastomeric closure, a syringe, or infusion bag as described herein is not heated up or exposed to heat during the assembly process, specifically, during the closure. In contrast, an ampoule as described herein is subjected to heat to seal the ampoule. One example for sealing the ampoule is by melting the top part.

[0155] The term “storage” as used herein refers to the storage of the pharmaceutical product under appropriate conditions, e.g., at an appropriate temperature as described herein.

[0156] Significant reduction as used herein means that N-nitroso-landiolol impurity of a pharmaceutical landiolol solution in a vial, an infusion bag, or in a syringe is at least 50, 60, 70, 80, 90, or 95% less compared to a pharmaceutical landiolol solution in an ampoule at the same storage conditions.

[0157] A person skilled in the art is familiar with the difference between a vial and an ampoule. An “ampoule”, or “ampule” is a single-use container with a sealed neck. Ampoules can be of glass or plastic, e.g., borosilicate glass, specifically, Type I Borosilicate Glass with high chemical resistance according to ISO 9187-1, or can be polyethylene or polypropylene plastic ampoules. The neck of an ampoule is sealed using an open flame to melt the glass or plastic. This leads to an airtight obstruction which prevents air, moisture and water from contaminating the liquid or solid inside the ampoule. The seal is unfastened by cracking the top off the neck, which causes a tidy break without any additional glass shards or slivers. Ampoules cannot be reused onceAP028P

[0158] -19-the sealed neck is snapped off to have access to the drug or any other stored liquid or solid.

[0159] An “infusion bag” or “injection bag” as used herein refers to a bag to be filled with pharmaceutical or medical solutions. An infusion bag is designed to be used for intravenous infusion and may be compatible with intravenous infusion transfer sets. Infusion bags may be made from medical-grade soft polyvinylchloride (PVC), ethylene vinyl acetate (EVA) or polypropylene film materials, or other suitable materials. An infusion bag may be filled with, e.g., ready-to-use product, sodium chloride, or dextrose solution. Infusion bags may be provided with two separate ports for injection and infusion, e.g., an inlet and an outlet port or a combined inlet / outlet port. The pharmaceutical solution, e.g. in the present invention the solution comprising landiolol or the pharmaceutically acceptable salt thereof, is added to the infusion bag via an injection port or through an infusion pump which administers the solution. Alternatively, the infusion bag may be filled with a premixed pharmaceutical composition. The patient receives the pharmaceutical composition via the infusion port. Commonly used infusion bags for pharmaceutical solutions are e.g. 50-ml, 100-ml or 250-ml infusion bags.

[0160] In a specific embodiment, the infusion bag is made of plastic.

[0161] A “syringe” as used herein refers to a syringe as a container for storage and delivery of a pharmaceutical solution. One non-limiting example for a syringe as a storage container for a pharmaceutical composition can be a pre-filled syringe for injection. The syringe can be connected to an appropriate injection connection, such as an infusion bag port, and the required dose can be delivered directly into the infusion bag. Alternatively, the syringe can be connected to an infusion pump which administers the pharmaceutical solution of the syringe.

[0162] Syringes can be made from glass e.g., borosilicate glass, or plastic, e.g., polymers such as cyclic olefin polymer (COP) or cyclic olefin copolymer (COC). Syringes may be coated with one or more polymers. Coating of the inside wall of the syringe may be with polymer or silicon.

[0163] Commonly used syringes for pharmaceutical solutions are, for example, but not limited to 2 ml or 50 ml syringes.

[0164] In a specific embodiment, the syringe is made of plastic, or glass. According to a further specific embodiment, the syringe is made of a polymer such as cyclic olefin polymer (COP), or cyclic olefin copolymer (COC).AP028P

[0165] -20- A “dose inhaler”, “metered dose inhaler (MDI)” or “pressurized metered dose inhaler (pMDI)” as used herein refers to a drug supply device designed to deliver small droplets of typically less than 5 pm in diameter that contain a single drug dose. The device consists of three main parts: the reservoir which contains the drug solution, the metering valve, and the spray actuator responsible for creating the aerosol cloud (Chandel et aL, Biomedicine & Pharmacotherapy, vol 112, 2019, or, de Boer et aL, Inhaled Medicines, chapter 4, 2021).

[0166] In a specific embodiment, the pharmaceutical solution of the present invention is in a pressurized metered dose inhaler.

[0167] The pharmaceutical solution of the present invention has nitrosamine (NA) impurities of less than 4500 ng n-nitroso-landiolol per g (ng / g) landiolol free base , specifically less than 4400, 4300, 4200, 4100, 4000, 3900, 3800, 3700, 3600, 3500, 3400, 3300, 3200, 3100, 3000, 2900, 2800, 2700, 2600, 2500, 2400, 2300, 2250, 2200, 2100, 2000, 1900, 1800, 1700, 1600, 1500, 1400, 1300, 1200, 1100, 1000, 900, 800, 700, 600, 500, 400, 300, 200, 100, 75, 50, 40, 35, or 30 ng n-nitroso-landiolol ng / g landiolol.

[0168] The pharmaceutical solution of the present invention has nitrosamine (NA) impurities of less than 4500 ng n-nitroso-landiolol per g (ng / g) landiolol HCI, specifically less than 4400, 4300, 4200, 4100, 4000, 3900, 3800, 3700, 3600, 3500, 3400, 3300, 3200, 3100, 3000, 2900, 2800, 2700, 2600, 2500, 2400, 2300, 2250, 2200, 2100, 2000, 1900, 1800, 1700, 1600, 1500, 1400, 1300, 1200, 1100, 1000, 900, 800, 700, 600, 500, 400, 300, 200, 100, 75, 50, 40, 35, or 30 ng n-nitroso-landiolol ng / g landiolol.

[0169] The term ’’nitrosamine impurity” or ‘nitrosamine impurities’, as used herein refers to a class of compound(s) having the chemical structure of a nitroso group bonded to an amine RI-N(-R2)-N=O, which can be formed by a nitrosating reaction between an amine group and nitrous acid.

[0170] A person skilled in the art is familiar with “N-nitroso-compounds” (NOCs) or “N-nitrosamine impurity”. Nitrosamine impurities are organic compounds that refer to any molecule containing the nitroso (N-N=O) functional group. In organic chemistry, “nitroso” refers to a functional group in which the nitric oxide (N-N=O) group is attached to an organic moiety. Essentially, nitroso groups can be categorized as C-nitroso compounds (e.g., nitroso alkanes; R-N=O), S-nitroso compounds (nitroso thiols; RS-N=O), N-nitroso compounds (e.g., nitrosamines, RN(-R')-N=O), and O-nitroso compounds (alkyl nitrites;AP028P

[0171] -21- RO-N=O). NOCs in pharmaceutical compositions are formed through the interaction between secondary or tertiary amines with a nitrosating agent such as nitrite. It is well known that compounds that comprise a secondary dialkylamino- or a tertiary trialkylamino-group are at risk of reacting to form N-nitrosamine-derivatives that may be highly toxic and may be carcinogenic. It has been proposed that e.g. during storage of the corresponding final dosage forms of pharmaceuticals comprising secondary or tertiary amines, the amino-groups are converted into highly toxic N-nitrosamines. The concentration of NOCs may be measured compared to a free base of landiolol, specifically, in ng per g (ng / g) landiolol, or, compared to landiolol hydrochloride (HCI), specifically, in ng per g (ng / g) landiolol HCI.

[0172] Standard analytical techniques to measure NOCs, especially of N-nitroso-landiolol impurity, in pharmaceutical products include chromatography methods, e.g. high performance liquid chromatography (HPLC), or ultra high performance liquid chromatography (UHPLC), gas chromatography (GC), and ultraviolet spectroscopy. As a non-limiting example, HPLC or UHPLC may utilize fully or superficially porous particles with particle sizes ranging from 1.7-10 pm, or surface-modified particles modified with various organic molecules. Since N-nitrosamine impurities have low detection and quantification limits, advanced analytical techniques, such as liquid chromatography mass spectrometry (LC-MS), specifically, the LC-MS / MS SCIEX® QTRAP® 6500+ system, gas chromatography mass spectrometry (GC-MS), and capillary electrophoresis (CE) have been tested to accurately detect and quantify N-nitrosamine-related impurities in pharmaceutical products (Machuri KM. et al., Chem. Res. Toxicol.

[0173] 2024, 37, 1456-1483).

[0174] As is known in the art, limits for the daily human intake of NOCs are defined, for example, in Article 5(3) of Regulation (EC) No 726 / 2004 of the European Union, which defines a limit of e.g. 400 ng / day for N-nitroso-landiolol.

[0175] Landiolol free base with a molecular weight of 509.59 g / mol and landiolol HCI with a molecular weight of 546.06 g / mol result in the ratio 1.07 of the hydrochloride to the free base, illustrating that one mole of landiolol HCI has a mass higher by the factor of 1.07 than one mole of landiolol free base, e.g, that 100 ng / g landiolol HCI is equal to 107 ng / g landiolol free base. On the other hand, 100 ng / g landiolol free base is equal to approx. 93,46 ng / g landiolol HCI. A person skilled in the art can convert values stated for landiolol free base to values for landiolol HCI and vice versa.AP028P

[0176] -22- As a non-limiting example, a limit of 400 ng / day for landiolol HCI is set, which would result in a limit of ~430 ng / g API free base and a lower maximum daily dose of ~0.93 g / day.

[0177] The pharmaceutical solution following production and assembly in a vial, an infusion bag, or a syringe as described herein may be substantially free from N-nitroso-landiolol impurity or may exhibit a maximum concentration of around 25 ng N-nitroso-landiolol impurity per g landiolol free base, specifically 25, 24, 23, 22, 21 , 20, 19, 18, 17, 16, or 15 ng N-nitroso-landiolol impurity perg landiolol, more specifically 10 ng N-nitroso-landiolol impurity per g landiolol.

[0178] The pharmaceutical solution following production and assembly in a vial, an infusion bag, or a syringe as described herein may be substantially free from N-nitroso-landiolol impurity or may exhibit a maximum concentration of around 25 ng N-nitroso-landiolol impurity per g landiolol HCI or less, specifically 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, or 15 ng N-nitroso-landiolol impurity per g landiolol HCI, more specifically 10 ng N-nitroso-landiolol impurity per g landiolol HCI or less.

[0179] Upon storage for 1 month (or four weeks) in a vial with air atmosphere in either upright or inverted position, the pharmaceutical solution may exhibit N-nitroso-landiolol impurity content of less than 50 ng / g landiolol or landiolol HCI when stored at 5°C, or less than 100 ng / g landiolol or landiolol HCI when stored at 25°C.

[0180] Specifically, after one month (or four weeks) of storage in a vial with air atmosphere and at 25°C, the pharmaceutical solution described herein may exhibit a maximum concentration of N-nitroso-landiolol of less than 90 ng / g landiolol or landiolol HCI.

[0181] Upon storage for 1 month in either upright or inverted position of the vial with N2 atmosphere, the pharmaceutical solution may exhibit no substantial increase of N-nitroso-landiolol or a N-nitroso-landiolol content of less than 45 ng / g landiolol or landiolol HCI when stored at 5°C, or less than 95 ng / g landiolol or landiolol HCI when stored at 25°C.

[0182] Specifically, after one month (or four weeks) of storage in a vial infused with N2 and at 25°C, the pharmaceutical solution described herein may exhibit a maximum concentration of N-nitroso-landiolol of less than or equal to 92 ng / g landiolol or landiolol HCI.AP028P

[0183] -23- The examples described herein are illustrative of the present invention and are not intended to be limitations thereon. Different embodiments of the present invention have been described according to the present invention. Many modifications and variations may be made to the techniques described and illustrated herein without departing from the scope of the invention.

[0184] EXAMPLES

[0185] Example 1: Highly increased N-nitroso-landiolol formation in ampoules A pharmaceutical solution comprising land iolol hydrochloride (HCI) was produced and assembled in ampoules and stored at a temperature of either 5°C or at 18-25°C.

[0186] The pharmaceutical solution had the following formulation:

[0187] 10 mg / ml landiolol HCI, 140 mg cyclodextrin (HPBCD), 300 mg macrogol, 320 g ethanol, 2.1 mg NaCI, 0.05 mg KCI, 0.3 mg Na2HPC>4, KH2PO4 and WFI.

[0188] The formation of N-nitroso-landiolol impurity was determined at different time points (Table 1). Table 1 shows the formation of N-nitroso-landiolol in the pharmaceutical solution comprising landiolol hydrochloride (HCI) upon production and assembly in ampoules and following storage at 5°C or 18-25°C for up to 55 months. N-nitroso-landiolol impurity is depicted in ng / g landiolol HCI. Values above 6000 ng / g landiolol HCI were above the detectable range and are indicated by >6000. ppb, part per billion.

[0189] N-nitroso-landiolol impurity formed due to assembly in ampoules (storage time 0 months) and gradually increased during a time span of 55 months.

[0190] Table 1: Highly increased N-nitroso-landiolol formation in ampoules

[0191] Storage Storage N-nitroso-landiolol

[0192] temperature time [ng / g landiolol HCI,

[0193] [°C] [months] PPb]

[0194] 0 1553

[0195] 19 5397

[0196] 5°C

[0197] 26 >6000

[0198] 29 >6000

[0199] 0 5429

[0200] 6 >6000

[0201] 18-25°C

[0202] 26 >6000

[0203]

[0204] 55 >6000AP028P

[0205] -24- Example 2: Limited N-nitroso-landiolol formation in vials Pharmaceutical solutions comprising landiolol hydrochloride (HCI) as ready-to-use formulation and as ready-to-dilute (concentrate) formulation were assembled in vials. Vials contained either pharmaceutical solution and air (‘air atmosphere’), or nitrogen (‘N2 atmosphere’).

[0206] Vials were either stored in an upright or in an inverted position. In an upright position, the solution is not in contact with the closure. In an inverted position, the vial is positioned upside down with the closure downside so that the solution is in contact with the closure.

[0207] Landiolol ready-to-dilute formulation in vial

[0208] The formation of N-nitroso-landiolol in ready-to-dilute formulation was determined following assembly in vials (storage time 0 months), and after 1 month, 3 months, 6 months, 9 months and 12 months storage time at 5°C or 25°C (Tables 2 and 3).

[0209] Landiolol ready-to-dilute formulation: 10 mg / ml landiolol HCI, 140 mg / ml cyclodextrin HPBCD, 300 mg / ml macrogol, 320 mg / ml ethanol, 2 mg / ml NaCI, 0.05 mg / ml KCI, 0.3 mg / ml Na2HPC>4, KH2PO4, and WFI.

[0210] Tables 2 and 3 show the formation of N-nitroso-landiolol impurity in a pharmaceutical solution comprising landiolol hydrochloride (HCI) upon assembly in vials and storage at 5°C or 25°C for up to 12 months and 40°C up to 6 months. N-nitroso-landiolol impurity is depicted in ng / g landiolol HCI and was measured using LC-MS / MS (AB Sciex 4500 triple quadrupole MS). Vials contained either pharmaceutical solution and air (‘air atmosphere’, Table 2), or nitrogen (‘N2 atmosphere’, Table 3), and were either stored in an upright or inverted position.

[0211] Table 2: Limited N-nitroso-landiolol formation in ready-to-dilute formulation in vials with air atmosphere

[0212] Air atmosphere N-nitroso-landiolol [ng / g landiolol HCI] Storage Storage UPRIGHT position INVERTED position temperature time

[0213] [°C] [months]

[0214] 0 22

[0215] 1 44 41

[0216] 5°C 3 73 69

[0217] 6 62 88

[0218] 9 61 62

[0219]

[0220] 12 74 65AP028P

[0221] -25- 0 22

[0222] 1 89 92

[0223] 3 226 228

[0224] 25°C

[0225] 6 393 398

[0226] 9 545 566

[0227] 12 802 791

[0228] 0 22

[0229] 40°C 1 624 659

[0230] 3 2240 2207

[0231]

[0232] 6 3681 3635

[0233] Table 3: Limited N-nitroso-landiolol formation in ready-to-dilute formulation in vials with N2 atmosphere

[0234] N2N-nitroso-landiolol HCI [ng / g]

[0235] atmosphere

[0236] Storage Storage UPRIGHT position INVERTED position temperature time

[0237] [°C] [months]

[0238] 0 18

[0239] 1 40 42

[0240] 3 65 64

[0241] 5°C

[0242] 6 47 54

[0243] 9 64 59

[0244] 12 65 61

[0245] 0 18

[0246] 1 92 86

[0247] 3 221 204

[0248] 25°C

[0249] 6 359 348

[0250] 9 474 453

[0251] 12 699 652

[0252] 0 18

[0253] 1 480 499

[0254] 40°C

[0255] 3 1411 1285

[0256]

[0257] 6 2106 1718

[0258] Landiolol readv-to-use formulation in vial

[0259] Formation of N-nitroso-landiolol in landiolol HCI ready-to-use solution was determined following 6 and 12 months storage at 5°C or 4 months storage at 25°C (T able 4). Vials contained either pharmaceutical solution and air (‘air atmosphere’), or nitrogen (‘N2 atmosphere’), and were either stored in an upright or inverted position.

[0260] Landiolol ready-to-use formulation: 6 mg / ml landiolol HCI, 26 mg / ml cyclodextrin (HPBCD or SBECD sodium salt), 6-7.5 mg / ml NaCI, Na2HPC>4X 2H2O, NaH2PO4x 2H2O or sodium citrate dihydrate, citric acid monohydrate and water for injection.AP028P

[0261] -26- Tested ready-to-use formulations were prepared in the same generic manner as follows. The required amount of phosphate or citrate buffer components were dissolved in 1800 ml of water for injection (WFI). Cyclodextrins (HPBCD or SBECD sodium salt) and sodium chloride were dissolved in the same solution, which was subsequently purged with nitrogen for 10 min to reach the residual oxygen <0.5 mg / L. For samples with “air atmosphere” the nitrogen purging step was omitted.

[0262] The pH of the solution was measured and adjusted with 0.1 M NaOH or 1M HCI to prescribed pH (6.5 for HPBCD-based formulation, 6.6 to SBECD-based formulation). Landiolol HCI was added and magnetically stirred until fully dissolved. The solution was made up to a final volume of 2200 ml with WFI, and pH was measured and adjusted to respective values. The solutions were purged again with N2 (with exception of samples with air atmosphere), filtered via PVDF 0.22 pm membrane filter and filled into 50mL glass Type 1 vials. The headspace was either flushed with N2 (N2 atmosphere), or kept unflushed (air atmosphere) and closed with bromobutyl stoppers. Prepared vials were placed into stability chambers at temperatures outlined in Table 4 below. N-nitroso-landiolol impurity was measured using LC-MS / MS (Agilent Ultivo LC / TQ triple quadrupole MS). Detection limits differed between the ready-to-dilute formulation and the ready-to-use formulation due to differences in analysis instruments (e.g., AB Sciex 4500 Triple Quadrupole MS, Agilent Ultivo LC / TQ Triple Quadrupole MS), and differences in landiolol concentrations, excipient composition, and matrix effects.

[0263] Table 4 shows the formation of N-nitroso-landiolol impurity in a pharmaceutical solution comprising landiolol hydrochloride (HCI) upon production and assembly in vials and storage at 5°C for 6 months and 12 months or 25°C for 4 months. The determined amount of the N-nitroso-landiolol impurity was below the limit of detection. Vials contained either pharmaceutical solution with air (‘air atmosphere’), or with nitrogen (‘N2 atmosphere’), and were either stored in an upright or inverted position. ‘< limit of detection’ indicates that the measurement was below the detection limit of 34 ng N-nitroso landiolol / g landiolol HCI.AP028P

[0264] -27- Table 4: Limited N-nitroso-landiolol formation in ready-to-use formulation in vials with air or N2 atmosphere

[0265] Vial Storage Storage N-nitroso-landiolol HCI [ng / g] headspace temperature [°C] time UPRIGHT INVERTED [months] position position

[0266] N2 6 < limit of < limit of atmosphere detection detection

[0267] 5°C ± 3°C

[0268] 12 < limit of < limit of detection detection

[0269] 4 < limit of < limit of 25°C ± 2°C

[0270] detection detection Air 6 < limit of < limit of

[0271] 5°C ± 3°C

[0272] atmosphere detection detection

[0273] 4 < limit of < limit of 25°C ± 2°C

[0274]

[0275] detection detection

[0276] Table 5 shows the formation of N-nitroso-landiolol impurity in pharmaceutical solutions comprising 6 mg / mL landiolol hydrochloride (HCI), 5 mM NaP, a varying SBECD concentration from 5 mg / mL up to 26 mg / mL, a varying NaCI concentration from 6 mg / mL up to 7.4 mg / mL and a pH of 6.8 upon production and assembly in vials and storage at 25°C ± 2°C for 1 , 2 and 3 months. The determined amount of the N-nitroso-landiolol impurity was below the limit of quantification. Vials contained the pharmaceutical solution with air (‘air atmosphere’), and were stored in an inverted position. ‘< limit of quantification’ indicates that the results obtained were below the quantification limit of 40 ng N-nitroso landiolol / g landiolol HCI.

[0277] Table 5: Limited N-nitroso-landiolol formation in ready-to-use formulation in vials with air atmosphere in a 10 mL vial.

[0278] Formulation Vial Storage Storage N-nitroso-landiolol headspace temperature time HCI [ng / g]

[0279] [°C] [months] INVERTED position 6mg / mL Landiolol HCI, Air 25°C ± 2°C 1 < limit of quantification 5mM NaP, 26 mg / mL atmosphere 2 < limit of quantification SBECD, 6 mg / mL NaCI, 3 < limit of quantification pH 6.8

[0280] 6mg / mL Landiolol HCI, Air 25°C ± 2°C 1 < limit of quantification 5mM NaP, 17 mg / mL atmosphere 2 < limit of quantification SBECD, 6.6 mg / mL NaCI, 3 < limit of quantification pH 6.8

[0281] 6mg / mL Landiolol HCI, Air 25°C ± 2°C 1 < limit of quantification 5mM NaP, 15 mg / mL atmosphere 2 < limit of quantification SBECD, 6.7 mg / mL NaCI, 3 < limit of quantification

[0282]

[0283] pH 6.86mg / mL Landiolol HCI, Air 25°C ± 2°C 1 < limit of quantification 5mM NaP, 10 mg / mL atmosphere 2 < limit of quantification SBECD, 7.1 mg / mLNaCI, 3 < limit of quantification pH 6.8

[0284] 6mg / mL Landiolol HCI, Air 25°C ± 2°C 1 < limit of quantification 5mM NaP, 5 mg / mL atmosphere 2 < limit of quantification SBECD, 7.4 mg / mL NaCI, 3 < limit of quantification

[0285]

[0286] pH 6.8

[0287] Example 3: Limited N-nitroso-iandioioi formation in pre-fiiied syringes and infusion bags

[0288] Landiolol ready-to-use formulation: 6 mg / ml landiolol HCI, 26 mg / ml cyclodextrin (SBECD sodium salt), 6mg / ml NaCI, Na2HPO4 x 2H2O, NaH2PO4 x 2H2O, water for injection.

[0289] The tested ready-to-use formulation was prepared as follows. The required amount of phosphate buffer components was dissolved in 3400 ml of water for injection (WFI). SBECD, sodium salt and sodium chloride were dissolved in the same solution.

[0290] The pH of the solution was measured and adjusted with 0.1 M NaOH or 1M HCI to a target pH of 6.8. The solution was filled up to a volume of 3700 mL with water for injection, the pH was measured and adjusted to a prescribed value of 6.8. The bulk solution was filtered via a PVDF 0.22 pm membrane filter and filled into either 50mL prefilled syringes made of a Cyclo-olefin-copolymer, closed with a bromobutyl plunger, or cyclo-olefin-polymer infusion bags. Prepared vials were placed into stability chambers at temperatures outlined in table 6 below. N-nitroso-landiolol impurity was measured using LC-MS / MS (Agilent Ultivo LC / TQ triple quadrupole MS). Detection and quantification limits differed between the ready-to-dilute formulation and the ready-to-use formulation due to differences in analysis instruments (e.g., AB Sciex 4500 Triple Quadrupole MS, Agilent Ultivo LC / TQ Triple Quadrupole MS), and differences in landiolol concentrations, excipient composition, and matrix effects.

[0291] Table 6 shows the formation of N-nitroso-landiolol impurity in a pharmaceutical solution comprising landiolol hydrochloride (HCI) upon production and assembly in infusion bags and pre-filled syringes after a storage time of 0 - 3 months at 5°C or 25°C. The determined amount of the N-nitroso-landiolol impurity was below the limit of detection or limit of quantification. Pre-filed syringes and infusion bags contained the pharmaceutical solution with air (‘air atmosphere’). Pre-filed syringes were stored in an upright position whereby the plunger was in an upright “up-position”. Infusion bags werestored in a lying flat position. ‘< limit of detection’ indicates that the measurement was below the detection limit of 14 ng N-nitroso landiolol / g landiolol HCI. ‘< limit of quantification’ indicates that the measurement was below the quantification limit of 40 ng N-nitroso landiolol / g landiolol HCL

[0292] Table 6: Limited N-nitroso-landiolol formation in ready-to-use formulation in prefilled syringes and infusion bags with air atmosphere

[0293] Air Atmosphere Storage time N-nitroso-landiolol H Cl [ng / g] Storage [months] Prefilled syringes i.v. Bags temperature [°C]

[0294] 0 < limit of detection < limit of detection 1 < limit of detection < limit of detection 5°C ± 3°C

[0295] 3 < limit of detection < limit of detection 6 < limit of detection < limit of detection 0 < limit of detection < limit of detection 1 < limit of detection < limit of

[0296] 25°C ± 2°C quantification

[0297] 3 < limit of < limit of

[0298]

[0299] quantification quantification

[0300] Results and discussion

[0301] Vials, infusion bags, pre-filled syringes (PFS) and ampoules are used in the pharmaceutical industry as alternative containers for packaging.

[0302] The inventors surprisingly showed that N-nitroso-landiolol impurity of landiolol or its pharmaceutically acceptable salt was almost unmeasurable in vials, infusion bags and PFS while N-nitroso-landiolol impurity in ampoules was extremely high even immediately after filling and assembly. It was also shown that a notable increase of N-nitroso-landiolol impuritiesin vials, pre-filled syringes and infusion bags could be avoided even over months of storage.

[0303] As confirmed above, in ampoules, landiolol HCI had a high N-nitroso-landiolol impurity of 1553 to 5429 ng / g landiolol HCI already immediately after its assembly, i.e. immediately after sealing of the ampoules.

[0304] When assembled in vials, PFS or infusion bags, surprisingly, a significantly lower N-nitroso-landiolol concentration of only around 20 ng / g landiolol HCI, or even less was measured.-30- N-nitroso-landiolol impurity was also not significantly present even after storage in vials for several months. N-nitroso-landiolol impurity concentrations in ready-to-dilute solutions stored at 18-25°C were only around 200-230 ng / g even after 3 months, and landiolol HCI in vials only contained around 75 ng / g N-nitroso-landiolol after storage at 5°C.

[0305] N-nitroso-landiolol concentrations in landiolol ready-to-use solutions in vials were even under the detection limit after 4 to 6 months of storage at 5°C or 25°C.

[0306] When assembled in prefilled syringes, or in infusion bags, N-nitroso-landiolol concentrations were under the limit of quantification of 40 ng N-nitroso landiolol / g landiolol HCI after a storage time of 3 months at a storage temperature of 25°C.

[0307] In contrast, the N-nitroso-landiolol impurity content in ampoules increased so much that even the upper detection limits (more than 6000 ng / g landiolol HCI) were exceeded after 6 months of storage at 18-25°C.

Claims

AP028P-31- CLAIMS1. A sterile, storage stable pharmaceutical solution comprising landiolol or a pharmaceutically acceptable salt thereof and one or more solvents, wherein said solutiona. is in a container selected from the group consisting of a vial with an elastomeric closure for injection, an infusion bag, and a syringe; andb. has N-nitroso-landiolol impurity content of less than 4500 ng per g landiolol.

2. The pharmaceutical solution of claim 1, wherein the solution comprises landiolol hydrochloride (HCI).

3. The pharmaceutical solution of claim 1 or 2, wherein the solution is storage stable for at least one month, specifically up to 3 months, specifically up to 6 months, specifically up to 12 months, specifically up to 18 months, specifically up to 24 months, specifically up to 30 months, specifically up to 36 months, specifically at a temperature in the range of 2-8°C.

4. The pharmaceutical solution of claim 1 or 2, wherein the solution is storage stable for at least one month, specifically up to 3 months, specifically up to 4 months at a temperature in the range of 22-28°C.

5. The pharmaceutical solution of any one of claims 1 to 4, further comprising one or more cyclodextrin(s), and / or salts, and / or a buffer.

6. The pharmaceutical solution of claim 5, wherein the cyclodextrin is HPBCD or SBECD, or its pharmaceutically acceptable salts.

7. The pharmaceutical solution of claim 5 or 6, wherein the cyclodextrin has a concentration of 0.5 to 600 mg / ml, specifically 5 to 140 mg / ml, more specifically 10 to 30 mg / ml.

8. The pharmaceutical solution of any one of claims 1 to 7, wherein the landiolol is a landiolol hydrochloride (HCI) present at a concentration of 0.1 mg / ml to 20 mg / ml, specifically 6 to 12 mg / ml, more specifically 0.5 mg / ml, 6 mg / ml, 10 mg / ml, 11 mg / ml or 12 mg / ml.

9. The pharmaceutical solution of any one of claims 1 to 8, wherein the solvent is ethanol, or water, preferably, the solvent is miscible with water.

10. The pharmaceutical solution of any one of claims 1 to 9, further comprising a saccharide, sugar alcohol, or salt.AP028P-32- 11. The pharmaceutical solution of any one of claims 1 to 10, further comprising a buffer with a pH ranging from pH 5.0-7.5, specifically phosphate buffer and / or citrate buffer.

12. The pharmaceutical solution of any one of claims 1 to 11, further comprising a tonicity agent and / or an osmotic agent and / or a stabilizing agent, specifically, sodium chloride, or macrogol.

13. The pharmaceutical solution of any one of claims 1 to 12, wherein the vial is made of plastic or glass, specifically borosilicate glass, or soda-lime-silica glass, optionally, coated with polymer.

14. The pharmaceutical solution of any one of claims 1 to 13, wherein the inside wall of the vial is coated, specifically coated with polymer or silicon.

15. The pharmaceutical solution of any one of claims 1 to 13, wherein the elastomeric closure for injection is a lid comprising a septum, an elastic membrane, or a rubber stopper.

16. The pharmaceutical solution of any one of claims 1 to 12, wherein the infusion bag is made of plastic.

17. The pharmaceutical solution of any one of claims 1 to 12, wherein the syringe is made of plastic, or glass.

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