Complexed landiolol encapsulated or dissolved in lipophilic matrix

Abstract

The present invention relates to a composition comprising i. landiolol complexed with an oppositely charged excipient; and ii. at least one lipophilic or amphiphilic excipient. Further, the present invention also relates to pharmaceutical composition and the use thereof.

Description

[0001] COMPLEXED LANDIOLOL ENCAPSULATED OR DISSOLVED IN LIPOPHILIC

[0002] MATRIX

[0003] FIELD OF THE INVENTION

[0004] The present invention relates to the field of complexes and compositions comprising landiolol. Specifically, the present invention relates to a composition comprising a complex of landiolol and an oppositely charged excipient, wherein said composition comprises a lipophilic or amphiphilic excipient. Further, the present invention relates also to the medical use of a pharmaceutical composition comprising said complex and for manufacturing of a medicament.

[0005] BACKGROUND OF THE INVENTION

[0006] Landiolol is an ultrashort-acting, P1 -superselective intravenous adrenergic antagonist, which decreases the heart rate effectively with less negative effect on blood pressure or myocardial contractility. W02005 / 014042A1 discloses a pharmaceutical composition comprising Landiolol, which decreases a patient’s heart rate.

[0007] In comparison to other betablockers, landiolol has the shortest elimination halflife (3 to 4 minutes), ultra-rapid onset of effect (heart rate begins to decrease immediately after completion of administration), and predictable effectiveness with inactive metabolites (heart rate returns to baseline levels at 30 min after completion of landiolol hydrochloride administration). Therefore, landiolol is used in a hospital setting as an intravenous injection, e.g., landiolol hydrochloride is administered as an aqueous saline solution in patients with cardiac arrhythmias (Atarashi H. et al. (2000). Clinical Pharmacology and Therapeutics, vol. 68(2), 2000, pp. 143-150). WO2022 / 071481A1 discloses a pharmaceutical complex containing a water-soluble beta blocker and lecithin. However, landiolol is chemically unstable when in contact with water. So far, a landiolol formulation was developed as a lyophilizate which needs to be reconstituted before administration. While the lyophilizate formulation addresses the chemical instability of landiolol and provides a stable product, significant limitations remain. The lyophilization is a costly process and requires reconstitution of the formulation before use even in an emergency situation, which could potentially restrict its use in emergency and ambulatory case situations.

[0008] Accordingly, there exists a need for an aqueous formulation of landiolol which is ready to use and has a long stability at ambient conditions while preserving pharmacokinetics of landiolol in terms of ultra-rapid onset of action. Designing such a formulation is challenging considering the high solubility in water of landiolol and the need to minimize the contact of the landiolol molecule with water to ensure the chemical stability and at the same time keeping the pharmacokinetic and pharmacodynamic properties of landiolol. Such a formulation would provide greater ease of handling and result in cost savings to health care providers and patients by decreasing landiolol waste and reducing the time-consuming efforts involved with reconstitution of lyophilized formulation. Additionally, such a formulation would enable easier access to patients requiring ambulatory care.

[0009] SUMMARY OF THE INVENTION

[0010] It is the objective of the present invention to provide a composition comprising landiolol with improved storage-stability while preserving pharmacokinetics of landiolol and which does not need reconstitution before use.

[0011] The objective is solved by the subject matter of the present invention.

[0012] According to the invention, it has been surprisingly found that landiolol is stable as a ready to use formulation if a composition comprises landiolol complexed with an oppositely charged excipient and comprises at least one lipophilic or amphiphilic excipient. Specifically, it is stable as a ready to use formulation if this composition is further dissolved or encapsulated into at least one lipophilic or amphiphilic excipient.

[0013] According to the present invention there is provided a composition comprising i. landiolol complexed with an oppositely charged excipient; and ii. at least one lipophilic or amphiphilic excipient.

[0014] Specifically, the oppositely charged excipient comprises a lipophilic moiety.

[0015] Specifically, the oppositely charged excipient is negatively charged, preferably the oppositely charged excipient is selected from the group consisting of a salt, specifically sodium salt, a bile acid salt, and a fatty acid salt, more specifically sodium deoxycholate, and sodium oleate; an acid, specifically a fatty acid, more specifically an oleic acid, a stearic acid; and any combination thereof.

[0016] Specifically, the lipophilic or amphiphilic excipient is a lipid, a surfactant, or a combination thereof.

[0017] Specifically, the lipid is selected from the group consisting of oils; fatty acids; glycerolipids; glycerophospholipids; sphingolipids; sterols, specifically cholesterol; prenols, specifically vitamin E; saccharolipids; and polyketides. Specifically, the glycerophospholipids is phosphatidylcholine (PC), specifically hydrogenated PC from soybean, PC from egg yolk, or a combination thereof; or phosphatidylglycerol (PG), specifically sodium 1 ,2-Dimyristoyl-sn-glycero-3-phospho- rac-glycerol, sodium 1 ,2-Distearoyl-sn-glycero-3-phospho-rac-glycerol, sodium 1 ,2- Dioleolyl-sn-glycero-3-phospho-rac-glycerol, or a combination thereof; and any combination thereof.

[0018] Specifically, the oil is selected from the group consisting of castor oil, corn oil, cottonseed oil, olive oil, peanut oil, peppermint oil, safflower oil, sesame oil, soybean oil, hydrogenated vegetable oil, hydrogenated soybean oil, palm oil, palm kernel oil, medium chain triglycerides, and any combination thereof.

[0019] Specifically, the surfactant is sorbitan, preferably PEGylated sorbitan; or polysorbate, preferably polysorbate 80.

[0020] Specifically, the landiolol complexed with an oppositely charged excipient is dissolved in, coated or encapsulated by the lipophilic or amphiphilic excipient.

[0021] Specifically, the lipophilic or amphiphilic excipient forms a lipid particle, specifically the lipid particle is a lipid membrane, a liposome, an emulsion, a solid lipid particle, or a nanoparticle, specifically wherein the lipid particle has a diameter of less than 900 nm.

[0022] Specifically, the composition is an aqueous colloidal suspension or an emulsion.

[0023] Specifically, the composition is a pharmaceutical composition.

[0024] Specifically, further comprising an antioxidant.

[0025] According to the present invention there is further provided a composition as described herein for use as a medicament.

[0026] According to the present invention there is further provided a composition as described herein for use in reducing the ventricular rate of patients with atrial fibrillation, the treatment of atrial flutter and sinus tachycardia, atrio-ventricular and AV node tachycardia, tachycardiac supra- and ventricular arrhythmias, tachycardia and / or hypertension before, during, and after operations and in other emergencies; unstable angina pectoris, acute myocardial infarction, and the prophylaxis and treatment of perioperative ischemia.

[0027] FIGURES

[0028] Figure 1. LDL-deoxycholate complex: after filtration (left), after drying (right)

[0029] Figure 2. Release profile of liposomal formulation DETAILED DESCRIPTION

[0030] Unless indicated or defined otherwise, all terms used herein have their usual meaning in the art, which will be clear to the skilled person.

[0031] 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.

[0032] The term “about” as used herein refers to the same value or a value differing by + / -5 % of the given value.

[0033] 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.

[0034] The term “landiolol” (abbreviated as “LDL”) 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, having the molecular formula C25H39N3O8, molecular weight 509.59. The term “landiolol” as used herein also refers to a pharmaceutically acceptable salt thereof.

[0035] According to one embodiment, a pharmaceutically acceptable salt of landiolol is landiolol hydrochloride (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, empirical formula C25H39N3O8HCI (molecular weight 546.05) or any other pharmaceutically acceptable salt thereof.

[0036] According to one embodiment of the invention, a complex of landiolol and an oppositely charged excipient is described herein. In other words, a complex comprising landiolol and an oppositely charged excipient is described herein. In other words, landiolol complexed with an oppositely charged excipient is described herein.

[0037] The term “complex” or “complexed” as used herein refers to a molecular entity formed by an interaction or association of two or more molecular entities.

[0038] The terms “complexed landiolol” or “landiolol complex” as used herein refer to the complex of landiolol and an oppositely charged excipient as described herein.

[0039] According to one embodiment of the invention, provided is a complex formation of landiolol or a pharmaceutically acceptable salt thereof, and an oppositely charged excipient where there is a physical interaction of landiolol with the excipient resulting in the decrease of aqueous solubility of landiolol in the complex form. The term “oppositely charged excipient” as used herein refers to an excipient having a charge opposite to the complexed molecule. The term “charged” or “charge” as used herein refers to a charge as present in an anion, in a cation, or in a partial charge. A partial charge is present due to asymmetric distribution of electrons in chemical bonds. For example, in the case of sodium deoxycholate, deoxycholate is an anion and has a negative charge and sodium is a cation and has a positive charge. In another example, in the case of stearic acid, stearic acid is negatively charged in water due to dissociation of the hydrogen / proton present in the carboxylic acid.

[0040] According to one embodiment, the oppositely charged excipient has a charge oppositely to the charge of landiolol.

[0041] According to a specific embodiment, complex formation is facilitated by addition of an acid such as citric acid, formic acid, tartaric acid, or hydrochloric acid.

[0042] According to one embodiment, the formation of the herein described complexed landiolol is pH dependent.

[0043] According to a specific embodiment, landiolol is positively charged at low pH so that a complex can be formed with a negatively charged excipient. Specifically, if the pH is increased, the complex is reversed and landiolol is released.

[0044] According to one embodiment, the oppositely charged excipient is an anion.

[0045] According to one embodiment, the oppositely charged excipient is an anionic amphiphilic molecule or an amphiphilic molecule having a partial negative charge.

[0046] According to one embodiment, the oppositely charged excipient is amphiphilic.

[0047] According to a specific embodiment, the oppositely charged excipient comprises a lipophilic moiety.

[0048] According to a specific embodiment, the oppositely charged excipient comprises a hydrophobic moiety.

[0049] The term “hydrophobic” as used herein refers to the physical property of a molecule that is seemingly repelled from a mass of water. In contrast, hydrophiles are attracted to water. Hydrophobic molecules tend to be nonpolar and, thus, prefer other neutral molecules and nonpolar solvents. Because water molecules are polar, hydrophobic molecules or moieties do not dissolve well among them. Hydrophobic molecules in water often cluster together, forming micelles. Non-limiting examples of hydrophobic molecules include alkanes, oils, and lipids.

[0050] The term “amphiphilic” as used herein refers to a chemical compound possessing both hydrophilic (water-loving, polar) and lipophilic (fat-loving) properties. Such a compound is called amphiphilic or amphipathic. An example of such an amphiphilic compound is a surfactant or a phospholipid.

[0051] The term “lipophilic” as used herein refers to the ability of a chemical compound to dissolve in fats, oils, lipids, and non-polar solvents such as e.g., hexane or toluene.

[0052] The term “moiety” as used herein refers to a part of a molecule having a specific property. For example, a lipophilic moiety is a part of a molecule having lipophilic properties. Amphiphilic molecules may have for example a lipophilic moiety and a hydrophilic moiety.

[0053] According to one embodiment, a negatively charged excipient is a salt or an acid.

[0054] According to one embodiment, a negatively charged excipient has a partial negative charge.

[0055] According to a specific embodiment, the oppositely charged excipient is negatively charged, preferably the oppositely charged excipient is selected from the group consisting of a salt, specifically a sodium salt, a bile acid salt, and a fatty acid salt, more specifically a sodium deoxycholate and a sodium oleate; an acid, specifically a fatty acid, more specifically a stearic acid; and any combination thereof.

[0056] 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.

[0057] The term “sodium salt” is commonly known in the field and as used herein refers to salts composed of a sodium cation and the conjugate base anion of inorganic or organic acids.

[0058] The term “bile acid” is commonly known in the field and as used herein refers to a family of molecules that have a steroidal structure. In nature, bile acids are synthesized from cholesterol in the liver and actively secreted along with cholesterol and phospholipids into the bile. Non-limiting examples of bile acids are cholic acid, glycocholic acid, taurocholic acid, deoxycholic acid, chenodeoxycholic acid, glycochenodeoxycholic acid, taurochenodeoxycholic acid, and lithocholic acid.

[0059] The term “bile acid salt” is commonly known in the field and as used herein refers to a salt of a bile acid.

[0060] The term “faty acid” is commonly known in the field and as used herein refers to a carboxylic acid with an aliphatic chain, which is either saturated or unsaturated. Non- limiting examples of fatty acids are caprylic acid, capric acid, lauric acid, myristic acid, palmitic acid, stearic acid, arachidic acid, behenic acid, lignoceric acid, cerotic acid, myristoleic acid, palmitoleic acid, sapienic acid, oleic acid, elaidic acid, vaccenic acid, linoleic acid, alpha-linoleic acid, arachidonic acid, eicosapentaenoic acid, erucic acid, and docosahexaenoic acid.

[0061] The term “faty acid salt” as used herein refers to a salt of a fatty acid.

[0062] The term “stearic acid” as used herein refers to a saturated fatty acid with an 18 carbon-chain.

[0063] According to a specific embodiment, the oppositely charged excipient is selected from the group consisting of sodium deoxycholate, sodium oleate, stearic acid, and any combination thereof.

[0064] In another embodiment of the invention, the excipient for complex formation is vitamin E TPGS, lauryl glucoside, oleyl alcohol, stearyl alcohol, plutonic acid, sodium dodecyl sulfate (SDS), bile acid salts, phospholipid derivatives, lecithin, lysolecithin, phosphatidylserine, glycerophosphocholine, oleic acid and oleic acid salts, diethylenetriaminepentaacetic acid, or combinations thereof.

[0065] According to one embodiment, in the complexed landiolol described herein, the ratio of landiolol: oppositely charged excipient is 1 :1 , 1 :2, 2:1 , or any other suitable ratio.

[0066] According to one embodiment, the complexed landiolol described herein is lipophilic. Specifically, the complexed landiolol is lipophilic and may dissolve in the further water-insoluble excipient described herein.

[0067] According to one embodiment, described herein is a composition comprising i. landiolol complexed with an oppositely charged excipient; and ii. at least one lipophilic or amphiphilic excipient.

[0068] In general, in the composition described herein, the oppositely charged excipient and the lipophilic or amphiphilic excipient may be the same or different molecules. The oppositely charged excipient comprises a charge but may also comprise a lipophilic moiety and thus, the oppositely charged excipient may be amphiphilic. Thereby, the oppositely charged excipient may form a complex with landiolol via the charge, and interact with the lipophilic or amphiphilic excipient via the lipophilic moiety.

[0069] According to one embodiment, the composition described herein comprises i. landiolol complexed with an oppositely charged excipient; and ii. at least one, two, three, four, five, six, seven, eight, nine, ten, or more lipophilic or amphiphilic excipient(s). According to one embodiment, the lipophilic or amphiphilic excipient is waterinsoluble.

[0070] According to one embodiment, the lipophilic or amphiphilic excipient is a waterinsoluble excipient.

[0071] According to one embodiment, the lipophilic or amphiphilic excipient is selected from the group consisting of oils, fatty acids, glycerolipids, glycerophospholipids, sphingolipids, sterols, prenols, saccharolipids, and polyketides.

[0072] The term “lipid” as used herein refers to organic compounds which are hydrophobic or amphiphilic molecules. In general, lipids can be classified into the following categories: oil, fatty acids, glycerolipids, glycerophospholipids, sphingolipids, sterols, prenols, saccharolipids, and polyketides.

[0073] According to a specific embodiment, the sterol is cholesterol.

[0074] According to a specific embodiment, the prenol is vitamin E.

[0075] According to a specific embodiment, the glycerophospholipid is phosphatidylcholine (PC), or phosphatidylglycerol (PG).

[0076] According to a specific embodiment, the phosphatidylcholine (PC) is hydrogenated PC from soybean, or PC from egg yolk, or a combination thereof.

[0077] According to a specific embodiment, the phosphatidylglycerol (PG) is 1 ,2- Dimyristoyl-sn-glycero-3-phospho-rac-glycerol, 1 ,2-Distearoyl-sn-glycero-3-phospho- rac-glycerol, 1 ,2-Dioleolyl-sn-glycero-3-phospho-rac-glycerol, or a salt thereof. According to a specific embodiment, the phosphatidylglycerol (PG) is sodium 1 ,2- Dimyristoyl-sn-glycero-3-phospho-rac-glycerol, sodium 1 ,2-Distearoyl-sn-glycero-3- phospho-rac-glycerol, or sodium 1 ,2-Dioleolyl-sn-glycero-3-phospho-rac-glycerol.

[0078] The term “surfactant” as used herein refers to chemical compounds that decrease the surface tension or interfacial tension between two liquids, a liquid and a gas, or a liquid and a solid. Surfactants may function as emulsifiers, wetting agents, detergents, foaming agents, or dispersants. Most surfactants are organic compounds with hydrophilic “heads" (a hydrophilic moiety) and hydrophobic "tails” (a hydrophobic moiety).

[0079] According to one embodiment, the surfactant is sorbitan, preferably PEGylated sorbitan; or polysorbate, preferably polysorbate 80.

[0080] According to one embodiment, the oil is selected from the group consisting of castor oil, corn oil, cottonseed oil, olive oil, peanut oil, peppermint oil, safflower oil, sesame oil, soybean oil, hydrogenated vegetable oil, hydrogenated soybean oil, palm oil, palm kernel oil, medium chain triglycerides, and any combination thereof.

[0081] According to another embodiment, the lipophilic or amphiphilic excipient is selected from the group consisting of vitamin E, vitamin E derivatives, bile acid, bile acid derivatives, phospholipids, phospholipid derivatives, lecithin, lysolecithin, phosphotidylserine, glycerophosphocholine, oleic acid, diethylenetriamine- pentaaceticacid, polyoxyethylene castor, polyoxyethylenehydrogenated castor oil base, polyoxyethylene sorbitan monolaurate, and combinations thereof. Specifically, phospholipid derivatives are selected from the group consisting of natural phospholipids such as the phospholipid isolated from egg yolk or soya beans, synthetic phospholipids, phosphotadylcholine, hydrogenated phospholipids, and combinations thereof. Specifically, bile acid derivatives are selected from the group consisting of cholic acid, chenodeoxycholic acid, deoxycholic acid, urodeoxycholic acid, and combinations thereof.

[0082] According to one embodiment, the landiolol complexed with an oppositely charged excipient is dissolved in, coated, or encapsulated by the lipophilic or amphiphilic excipient.

[0083] According to a specific embodiment, the landiolol complexed with an oppositely charged excipient described herein is dissolved in the lipophilic or amphiphilic excipient.

[0084] The term “dissolved” as used herein refers to the dissolution or solution of landiolol complexed with an oppositely charged excipient described herein in or with a lipophilic or amphiphilic excipient.

[0085] According to a specific embodiment, the landiolol complexed with an oppositely charged excipient described herein is coated by the lipophilic or amphiphilic excipient.

[0086] The term “coated” as used herein refers to the coating of the complexed landiolol with a matrix. Specifically, the matrix comprises the lipophilic or amphiphilic excipient as described herein.

[0087] According to a specific embodiment, the landiolol complexed with an oppositely charged excipient described herein is encapsulated by the lipophilic or amphiphilic excipient.

[0088] The term “encapsulated” as used herein refers to the coating of the complexed landiolol with a continuous matrix. Specifically, the continuous matrix comprises the lipophilic or amphiphilic excipient as described herein. According to a specific embodiment, the composition described herein comprises landiolol complexed with sodium deoxycholate, wherein said composition further comprises sodium oleate.

[0089] In a further specific embodiment, the composition described herein comprises about 20 to 100 mg / ml, specifically about 25 to 82 mg / ml, more specifically about 27, 76.6, 78.6, or 80.7 mg / ml landiolol HCI complexed with about 10 to 100 mg / ml, more specifically about 50 to 75 mg / ml, more specifically about 70.6, 72,5, or 74,3 mg / ml sodium deoxycholate and about 10 to 30 mg / ml, more specifically about 20 to 28 mg / ml, more specifically about 27.2 mg / ml sodium oleate.

[0090] In a further specific embodiment, the composition described herein comprises about 20 to 100 mg / ml, specifically about 25 to 82 mg / ml, more specifically about 27, 76.6, 78.6, or 80.7 mg / ml landiolol HCI complexed with about 10 to 100 mg / ml, more specifically about 50 to 75 mg / ml, more specifically about 70.6, 72,5, or 74,3 mg / ml sodium deoxycholate, or about 10 to 30 mg / ml, more specifically about 20 to 28 mg / ml, more specifically about 27.2 mg / ml sodium oleate.

[0091] According to a specific embodiment, the composition described herein comprises landiolol complexed with sodium deoxycholate, wherein said composition further comprises cholesterol and phosphatidylcholine. Specifically, said phosphatidylcholine is hydrogenated phosphatidylcholine from soybean (Lipoid SPC3).

[0092] In a further specific embodiment, the composition described herein comprises about 1 to 20 mg / ml, specifically about 1.5 to 11 mg / ml, more specifically about 2, 3, 4, 5, 6, 7, 8, 9, or 10 mg / ml landiolol HCI complexed with about 0.8 to 20 mg / ml, specifically about 0.9 to 11 mg / ml, more specifically about 1 , 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 7, 8, 9, or 10 mg / ml sodium deoxycholate and about 0.1 to 5 mg / ml, specifically about 0.5 to 2.1 mg / ml, more specifically about 0.6, 0.7, 0.8, 0.9, 1.0, 1.1 , 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2 mg / ml cholesterol and about 0.5 to 5 mg / ml, specifically about 1 to 4.5 mg / ml, more specifically about 1.5, 2, 2.5, 3, 3.5, 4 mg / ml hydrogenated phosphatidylcholine .

[0093] According to a specific embodiment, the composition described herein comprises landiolol complexed with sodium deoxycholate, wherein said composition further comprises cholesterol, phosphatidylcholine, and vitamin E (dL-alpha tocopherol). Specifically, said phosphatidylcholine is hydrogenated phosphatidylcholine from soybean.

[0094] In a further specific embodiment, the composition described herein comprises about 1 to 20 mg / ml, specifically about 1.5 to 11 mg / ml, more specifically about 2, 3, 4, 5, 6, 7, 8, 9, or 10 mg / ml landiolol HCI complexed with about 0.8 to 20 mg / ml, specifically about 0.9 to 11 mg / ml, more specifically about 1 , 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 7, 8, 9, or 10 mg / ml sodium deoxycholate and about 0.1 to 5 mg / ml, specifically about 0.5 to 2.1 mg / ml, more specifically about 0.6, 0.7, 0.8, 0.9, 1.0, 1.1 , 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2 mg / ml cholesterol and about 0.5 to 5 mg / ml, specifically about 1 to 4.5 mg / ml, more specifically about 2, 2.5, 3, 3.5, 4 mg / ml hydrogenated phosphatidylcholine (Lipoid SPC3) and about 0.01 to 0.1 mg / ml, specifically about 0.04 to 0.09 mg / ml, more specifically about 0.05, 0.06, 0.07, 0.08 mg / ml Vitamin E. According to a specific embodiment, the composition described herein comprises landiolol complexed with sodium deoxycholate, wherein said composition further comprises cholesterol, phosphatidylcholine, and polysorbate. Specifically, said phosphatidylcholine is hydrogenated phosphatidylcholine from soybean. Specifically, said polysorbate is polysorbate 80.

[0095] In a further specific embodiment, the composition described herein comprises about 1 to 20 mg / ml, specifically about 1.1 to 11 mg / ml, more specifically about 1.2, 2, 3, 4, 5, 6, 7, 8, 9, or 10 mg / ml landiolol HCI complexed with about 0.8 to 20 mg / ml, specifically about 0.9 to 11 mg / ml, more specifically about 1 , 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 7, 8, 9, or 10 mg / ml sodium deoxycholate and about 0.1 to 5 mg / ml, specifically about 0.5 to 2.1 mg / ml, more specifically about 0.6, 0.7, 0.8, 0.9, 1.0, 1.1 , 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2 mg / ml cholesterol and about 0.8 to 20 mg / ml, specifically about 0.9 to 11 mg / ml, more specifically about 1 , 2, 3, 4, 5, 6, 7, 8, 9, or 10 mg / ml hydrogenated phosphatidylcholine (Lipoid SPC3) and about 0.8 to 20 mg / ml, specifically about 0.9 to 11 mg / ml, more specifically about 1 , 2, 3, 4, 5, 6, 7, 8, 9, or 10 mg / ml Polysorbate (Tween) 80.

[0096] According to a specific embodiment, the composition described herein comprises landiolol complexed with sodium deoxycholate, wherein said composition further comprises cholesterol, phosphatidylcholine, vitamin E and phosphatidylglycerol. Specifically, said phosphatidylcholine is hydrogenated phosphatidylcholine from soybean. Specifically, said phosphatidylglycerol is sodium 1 ,2-Distearoyl-sn-glycero-3- phospho-rac-glycerol.ln a further specific embodiment, the composition described herein comprises about 0.8 to 20 mg / ml, specifically about 0.9 to 11 mg / ml, more specifically about 1 , 2, 3, 4, 5, 6, 7, 8, 9, or 10 mg / ml landiolol HCI complexed with about 0.8 to 20 mg / ml, specifically about 0.9 to 11 mg / ml, more specifically about 1 , 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 7, 8, 9, or 10 mg / ml sodium deoxycholate and about 1 to 30 mg / ml, specifically about 5 to 25 mg / ml, more specifically about 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 mg / ml hydrogenated phosphatidylcholine (Lipoid SPC3) and about 0.8 to 20 mg / ml, specifically about 0.9 to 11 mg / ml, more specifically about 1 , 2, 3, 4, 5, 6, 7, 8, 9, or 10 mg / ml cholesterol and about 0.8 to 20 mg / ml, specifically about 0.9 to 11 mg / ml, more specifically about 1 , 2, 3, 4, 5, 6, 7, 8, 9, or 10 mg / ml phosphatidylglycerol (sodium 1 ,2-Distearoyl-sn-glycero-3-phospho-rac-glycerol; DSPG Na) and about 0.1 to 1 mg / ml, specifically 0.2 to 0.9 mg / ml, more specifically 0.3, 0.4, 0.5, 0.6, 0.7, 0.8 mg / ml Vitamin E.

[0097] According to one embodiment, the lipophilic or amphiphilic excipient forms a lipid particle. Specifically, the lipophilic or amphiphilic excipient is a lipid and the lipid forms a lipid particle. More specifically, the lipid forms a lipid particle which coats or encapsulates the complexed landiolol.

[0098] According to a specific embodiment, the lipophilic or amphiphilic excipient forms a lipid particle. Specifically, the lipid particle forms a lipid membrane, a liposome, a solid lipid particle, an emulsion, or a nanoparticle.

[0099] In another embodiment, the complexed landiolol is dissolved in a lipid and the lipid is dispersed in an aqueous phase resulting in solid lipid nanoparticles or lipid particles. Specifically, the aqueous phase is a water phase.

[0100] In another embodiment, the complexed landiolol is dissolved in a lipid phase and the lipid form a liposome structure in an aqueous phase where the complexed landiolol is entrapped in a bilayer structure. Specifically, the aqueous phase is a water phase.

[0101] In another embodiment, the concentration of the complexed landiolol can vary within the particle where different landiolol complex concentrations are observed in the core of the particle or at the outer parts of the particles.

[0102] The term “lipid membrane” as used herein refers to a lipid bilayer.

[0103] The term “liposome” as used herein refers to a vesicle which is spherical in shape and has at least one lipid bilayer.

[0104] The term “solid lipid particle” as used herein refers to a lipid particle which is solid.

[0105] The term “emulsion” as used herein refers to a mixture of two or more liquids that are normally immiscible due to liquid-liquid phase separation.

[0106] According to a specific embodiment, the complexed landiolol described herein is coated with a lipophilic or amphiphilic excipient such as an oil. Thereby, emulsifying the complexed landiolol coated by a lipophilic or amphiphilic excipient results in an emulsion. Specifically, the emulsion comprises the complexed landiolol coated by a lipophilic or amphiphilic excipient such as by an oil, wherein the lipophilic or amphiphilic excipient forms a lipid particle coating the complexed landiolol, and wherein this lipid particle is emulsified in a water phase resulting in an emulsion.

[0107] In one embodiment, the complexed landiolol is dissolved in oil and emulsified in an aqueous phase resulting in an emulsion. Specifically, the aqueous solution is a water phase.

[0108] According to one embodiment, the complexed landiolol described herein is mixed with a lipid phase and is dispersed in water phase to form lipid particles such as solid lipid particles or liposomes.

[0109] According to one embodiment, a liposome described herein has a diameter of less than 900 nm. Specifically, the liposome has a diameter in the range of 50-800, 50- 700, 50-600, 50-500, 50-400, 50-300, 50-250, 50-200, 50-150, 100-800, 100-700, 100- 600, 100-500, 100-400, 100-300, 100-250, 100-240, 100-230, or 100-220 nm.

[0110] According to a specific embodiment, the liposome has a diameter in the range of 50-250 nm.

[0111] According to a specific embodiment, the liposome described herein has a polydispersity of a less than 0.6, 0.5, 0.4, 0.3, or 0.2.

[0112] The diameter of a particle can be determined e.g., by dynamic light scattering (DLS).

[0113] The term "polydispersity", "polydispersity index", or "PDI" gives the width of the particle size distribution in suspension and is defined as the relative variance in the correlation decay rate distribution. PDI can be determined e.g., by dynamic light scattering.

[0114] According to a specific embodiment, the complexed landiolol described herein is dissolved in a lipid phase and the lipids are dispersed in a water phase resulting in solid lipid nanoparticles or lipid particles.

[0115] According to a specific embodiment, the complexed landiolol described herein is dissolved in a lipid phase and the lipids form a liposome structure in a water phase where the complex is entrapped in a lipid membrane.

[0116] According to one embodiment, the complexed landiolol dissolved in, coated or encapsulated by a lipophilic or amphiphilic excipient as described herein is a nanoparticle. Specifically, the nanoparticle has a diameter of less than 900 nm. Specifically, the nanoparticle has a diameter in the range of 50-800, 50-700, 50-600, 50- 500, 50-400, 50-300, 100-800, 100-700, 100-600, 100-500, 100-400, 100-300, 200-300, 210-290, 220-280, 230-270, or 240-260 nm.

[0117] According to a specific embodiment, the nanoparticle described herein has a polydispersity of a less than 0.6, 0.5, 0.4, 0.3, or 0.2.

[0118] According to one embodiment, the particles size is 100 - 200 nm.

[0119] According to one embodiment, the lipid particles size is 100 - 200 nm.

[0120] In another embodiment of the invention, the nanoparticle described herein is a therapeutic nanoparticle. Specifically, the size of the nanoparticle is less than 900nm, preferably 50-600 nm, more preferably 50-150 nm. Specifically, the polydispersibility of the nanoparticle formulation is less than 0.6, preferably less than 0.4 more preferably less than 0.2.

[0121] According to one embodiment, the complexed landiolol described herein is in the core or within layers of the lipophilic or amphiphilic excipient.

[0122] According to one embodiment, the complexed landiolol described herein dissolved in, coated or encapsulated by the lipophilic or amphiphilic excipient may have or may not have immediate release characteristics.

[0123] According to one embodiment, the composition comprising i. landiolol complexed with an oppositely charged excipient; and ii. at least one lipophilic or amphiphilic excipient may have or may not have immediate release characteristics.

[0124] According to one embodiment, the composition described herein is an aqueous colloidal suspension or an emulsion.

[0125] The term “colloid” or “colloidal suspension” as used herein refers to a mixture in which one substance comprising microscopically dispersed insoluble particles is suspended throughout another substance. In general, it is commonly known in the field how to prepare a colloidal suspension such as e.g., a liposome preparation.

[0126] According to one embodiment, the composition described herein further comprises an antioxidant.

[0127] According to one embodiment, the nanoparticles described herein comprise an antioxidant.

[0128] According to a specific embodiment, the antioxidant is selected from the group consisting of acetylcysteine; ascorbyl palmitate; butylated hydroxyanisole (BHA); butylated hydroxytoluene (BHT); monothioglycerol; ascorbic acid; sodium ascorbate; sodium formaldehyde sulfoxylate; sodium metabisulfite; sodium bisulfite; propyl gallate; edetate (EDTA), specifically disodium edetate; diethylenetriaminepentaacetic acid (DTP A); and any combination thereof.

[0129] According to one embodiment, the complexed landiolol described herein or a composition comprising the complexed landiolol described herein is storage-stable.

[0130] The term “storage-stable” as used herein refers to a e.g., a complex or a composition, which can be stored at ambient temperature for commercially relevant periods of time (e.g., one month, two months, three months, or longer) without any clinically significant degradation of the contained active substance taking place. That is, compositions of the disclosure are safe and effective for human use, even after commercially relevant storage periods. Storage stability can be measured using techniques known to those in the art, for example, by Rp-HPLC with UV detection and gradient elution using the following protocol:

[0131] HPLC column: Waters Nova-Pak C18, 3.9 x 150 mm, 4 pm

[0132] Column Temp: 30°C

[0133] Flow rate: 0.250 mL / min

[0134] Mobile Phase A: Buffer Solution, pH 2.35

[0135] Mobile Phase B: Acetonitrile

[0136] Gradient: 0 min: 87%A, 13%B;

[0137] 5 min: 87%A, 13%B;

[0138] 22 min: 80%A, 20%B;

[0139] 33 min 60%A, 40%B;

[0140] 40 min: 60%A, 40%B

[0141] 43 min 87%A, 13%B;

[0142] 50 min: 87%A, 13%B

[0143] UV detection: 220 nm.

[0144] According to one embodiment, the complexed landiolol described herein or a composition comprising the complexed landiolol described herein exhibits an increase in concentration of total impurities (%) that is less than 4%, for example, less than 3.9, 3.8, 3.7, 3.6, 3.5, 3.4, 3.3, 3.2, 3.1 , 3, 2.9, 2.8, 2.7, 2.6, 2.5, 2.4, 2.3, 2.2, 2.1 , 2, 1.9, 1.8, 1 .7, 1 .6, 1 .5, 1 .4, 1 .3, 1.2, 1 , 0.9, 0.8, 0.7, 0.6, 0.5, 0.4, 0.3, 0.2, or 0.1 % after one month (or four weeks) of storage at 25 °C. Specifically, the complexed landiolol described herein or a composition comprising the complexed landiolol described herein exhibits an increase in concentration of total impurities (%) that is less than 10%, for example, less than 9.5, 9, 8.5, 8, 7.5, 7, 6.5, 6, 5.5, 5, 4.9, 4.8, 4.7, 4.6, 4.5, 4.4, 4.3, 4.2, 4.1 , 4, 3.9, 3.8, 3.7, 3.6, 3.5, 3.4, 3.3, 3.2, 3.1 , 3, 2.9, 2.8, 2.7, 2.6, 2.5, 2.4, 2.3, 2.2, 2.1 , 2, 1.9, 1.8,

[0145] 1.7, 1.6, 1.5, 1.4, 1.3, 1.2, 1 , 0.9, 0.8, 0.7, 0.6, 0.5, 0.4, 0.3, 0.2, or 0.1% after eight weeks of storage at 25 °C. Specifically, the complexed landiolol described herein or a composition comprising the complexed landiolol described herein exhibits an increase in concentration of total impurities (%) that is less than 15%, for example, less than 14.5, 14, 13.5, 13, 12.5, 12, 11.5, 11 , 10.5, 10, 9.5, 9, 8.5, 8, 7.5, 7, 6.5, 6, 5.5, 5, 4.9, 4.8,

[0146] 4.7, 4.6, 4.5, 4.4, 4.3, 4.2, 4.1 , 4, 3.9, 3.8, 3.7, 3.6, 3.5, 3.4, 3.3, 3.2, 3.1 , 3, 2.9, 2.8, 2.7, 2.6, 2.5, 2.4, 2.3, 2.2, 2.1 , 2, 1.9, 1.8, 1.7, 1.6, 1.5, 1.4, 1.3, 1.2, 1 , 0.9, 0.8, 0.7, 0.6, 0.5, 0.4, 0.3, 0.2, or 0.1 % after twenty weeks of storage at 25 °C.

[0147] Understood as “storage-stable” in particular are complexed landiolol described herein or compositions comprising the complexed landiolol described herein, in which after one month at room temperature less than 3.5% of the starting concentration of active substance, i.e. any one of landiolol or their pharmaceutically acceptable salts, has degraded. Specifically, after one month at room temperature less than 3, 2.5, 2, 1.5, or 1 % of the starting concentration of the active substance has degraded.

[0148] According to one embodiment, the composition described herein is a pharmaceutical composition.

[0149] According to a specific embodiment, the pharmaceutical composition described herein comprises a pharmaceutically acceptable carrier.

[0150] The term "carrier" refers to a diluent, adjuvant, excipient, or vehicle with which the pharmaceutical solution is administered. Saline solutions and aqueous dextrose and glycerol solutions can also be employed as liquid carriers, particularly for injectable solutions. Examples of suitable pharmaceutical carriers are described in "Remington's Pharmaceutical Sciences" by E.W. Martin.

[0151] The term “pharmaceutically acceptable” or “pharmacologically acceptable” means compatible with the treatment of humans. The term “pharmacologically acceptable salt” includes both pharmacologically acceptable acid addition salts and pharmacologically acceptable basic addition salts.

[0152] According to one embodiment, the pharmaceutical composition described herein can be administered or mixed with any pharmaceutically acceptable substances or carriers or excipients as known in the art. These can be for example, but are not restricted to water; parenteral solutions; neutralizing agents like NaOH, KOH; stabilizers; buffers, e.g. acetate buffer, phosphate buffer, citrate buffer; solvents; DMSO; or saline. According to one embodiment, the pharmaceutical composition described herein may further comprise stabilizers, preservatives, buffers, tonicity agents, and / or other excipients.

[0153] According to one embodiment, the pharmaceutical composition described herein may comprise further excipients selected from the group consisting of buffer, preservative, solvents mixable with water, salts, sugar alcohols (e.g., mannitol), and sugars.

[0154] According to a specific embodiment, examples of such suitable excipients for the pharmaceutical composition are starch, glucose, lactose, sucrose, gelatine, microcrystalline cellulose, sodium stearate, glycerol monostearate, talc, sodium chloride, glycerol, propylene, glycol, propylene glycol, polyethylene glycol, polyvinylpyrrolidone, water, and ethanol.

[0155] According to a specific embodiment, the pharmaceutical composition described herein may comprise a buffer. Non-limiting examples of such a buffer are citrate, sodium / potassium phosphate, 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.

[0156] According to one embodiment, the pharmaceutical composition described herein has a pH value in the range of 3.0 to 7.5.

[0157] According to a specific embodiment, the pharmaceutical composition described herein has a pH value in the range of 5.0 to 7.0.

[0158] According to a specific embodiment, the pharmaceutical composition described herein have a pH value of 3.0, 3.1 , 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1 , 4.2, 4.3,

[0159] 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1 , 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1 , 6.2, 6.3,

[0160] 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1 , 7.2, 7.3, 7.4, or 7.5.

[0161] According to a specific embodiment, the pharmaceutical composition described herein has a pH value of 5.0, 5.1 , 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1 , 6.2, 6.3,

[0162] 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, or 7.0.

[0163] According to a specific embodiment, the pharmaceutical composition described herein have a pH value in the range of 6 and 7, for example, 6.1 , 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, or 7, specifically about 6.5.

[0164] According to one embodiment, the pharmaceutical composition described herein comprises water, for example, water for injection (WFI). According to one embodiment, the pharmaceutical composition described herein is storage-stable.

[0165] According to one embodiment, the pharmaceutical composition described herein is used as a medicament.

[0166] According to a specific embodiment, the pharmaceutical composition described herein is administered parenterally or intravenously.

[0167] In another embodiment of the invention, the nanoparticle described herein is administered parenterally.

[0168] In another embodiment of the invention, the nanoparticle described herein is administered intravenously.

[0169] In another embodiment of the invention, a nanoparticle colloidal suspension is described herein for use in treating hypertension.

[0170] The term “parenterally” as used herein refers to subcutaneous, intracutaneous, intravenous, intramuscular, intraarticular, intraarterial, intrasynovial, intrasternal, intrathecal, intralesional, intraperitoneal, intratracheal, intracranial, or intracoronary.

[0171] According to a specific embodiment, the pharmaceutical composition described herein is administered intravenously.

[0172] According to a specific embodiment, the pharmaceutical composition described herein is ready-to-use.

[0173] According to a specific embodiment, the pharmaceutical composition described herein is a solution.

[0174] According to a specific embodiment, the pharmaceutical composition described herein is a ready-to-use solution.

[0175] The term “ready-to-use” with reference to the pharmaceutical composition as described herein shall mean the preparation not requiring dissolution of any solids by the health practitioner, with standardized concentration and quality, prefilled in the single-use or multi-use container, such as glass vials, ampoules, infusion bags or syringes, ready for direct administration to the patient. The term “direct administration” with reference to the pharmaceutical composition as described herein shall mean the immediate administration, i.e. without further dilution, premixing with other substances or otherwise changing the composition or formulation of the pharmaceutical solution. Such pharmaceutical solution is typically directly discharged from an infusion device and administered via a vascular access port or through a central line. According to one embodiment, the pharmaceutical composition described herein comprises a therapeutically effective amount of landiolol or a pharmaceutically acceptable salt thereof.

[0176] The term “therapeutically effective amount”, “effective amount”, or “sufficient amount” of a compound of the present invention is a quantity sufficient to, when administered to a human, effect beneficial or desired results, including clinical results, and, as such, an effective amount or synonym thereof depends upon the context in which it is being applied.

[0177] According to one embodiment, in the pharmaceutical composition described herein the concentration of landiolol or the pharmaceutically acceptable salt thereof (e.g., landiolol hydrochloride) is in the range of 0.1 to 20 mg / ml (based on the free base). Specifically, in the concentration range of 1 to 15 mg / ml (based on the free base). More specifically, in the range of 1 to 12 mg / ml, or 1 to 10 mg / ml. Even more specifically, at a concentration of 1 , 2, 3, 4, 5, 6, 7, 8, 9,10, 11 , 12, 13, 14, 15 mg / ml, or more than 15 mg / ml (based on the free base).

[0178] According to a specific embodiment, the pharmaceutical composition described herein comprises 6 mg / ml landiolol hydrochloride.

[0179] According to one embodiment, the pharmaceutical composition can be used in particular for the manufacture of a medicament for reducing the ventricular rate of patients with atrial fibrillation, atrial flutter and sinus tachycardia, in atrio-ventricular and AV node tachycardia, in tachycardiac supra- and ventricular arrhythmias, in tachycardia and / or hypertension, before, during, and after operations and in other emergencies, for the prophylaxis and treatment of perioperative ischemia, for the treatment of unstable angina pectoris and acute myocardial infarction.

[0180] According to one embodiment, the pharmaceutical composition described herein is for use in the treatment for reducing the ventricular rate of patients with atrial fibrillation, atrial flutter and sinus tachycardia, in atrio-ventricular and AV node tachycardia, in tachycardiac supra- and ventricular arrhythmias, in tachycardia and / or hypertension, before, during, and after operations and in other emergencies, for the prophylaxis and treatment of perioperative ischemia, for the treatment of unstable angina pectoris and acute myocardial infarction.

[0181] According to one embodiment, the pharmaceutical composition can be used for reducing the ventricular rate in patients with atrial fibrillation, atrial flutter and sinus tachycardia, in atrioventricular and AV node tachycardia, in tachycardia supra- and ventricular arrhythmias, in tachycardia and / or hypertension before, during, and after surgery as well in other emergencies, for the prophylaxis and treatment of perioperative ischemia, for the treatment of unstable angina pectoris and acute myocardial infarction.

[0182] According to a further embodiment, the pharmaceutical composition described herein is for use to control or treat supraventricular tachycardia including inappropriate sinus tachycardia, junctional ectopic tachycardia, atrial flutter, atrial fibrillation, focal atrial tachycardia; and atrioventricular nodal re-entry tachycardia and atrioventricular reciprocating (re-entry) tachycardia refractory to treatment with adenosine in surgical (peri- and postoperative, cardiac and non-cardiac surgery) and non- surgical patients, including pediatric patients.

[0183] According to a further embodiment, the pharmaceutical composition described herein can be used in particular to produce a medicinal product to control or treat supraventricular tachycardia including inappropriate sinus tachycardia, junctional ectopic tachycardia, atrial flutter, atrial fibrillation, focal atrial tachycardia; and atrioventricular nodal re-entry tachycardia and atrioventricular reciprocating (re-entry) tachycardia refractory to treatment with adenosine in surgical (peri- and postoperative, cardiac and non-cardiac surgery) and non- surgical patients, including pediatric patients.

[0184] The term “treatment” and its cognates as used herein refers to slowing or stopping disease progression. “Treatment” includes, but is not limited to the following: complete or partial remission, lower risk of disease development, and disease-related complications. Improvements in or lessening the severity of any one of these symptoms can be readily assessed according to methods and techniques known in the art or subsequently developed. Desirable effects of treatment include preventing the occurrence or recurrence of a disease, condition, or symptom as described herein, diminishing any direct or indirect pathological consequences of such a disease, condition, or symptom as described herein, decreasing the rate of progression or severity, and / or ameliorating or palliating. In some embodiment, methods and composition of the invention are used on patient sub-populations identified to be at risk of developing a disease, condition, or symptom as described herein.

[0185] According to a specific embodiment, the pharmaceutical composition described herein is for use in treatment of tachycardic arrythmias.

[0186] According to one embodiment, the invention described herein provides for an improved parenteral formulation for used in the treatment of patients. Herein the terms “subject”, “individual” and “patient” are used interchangeably and refer to human beings in need of such treatment.

[0187] The terms “tachycardic arrythmias”, “tachycardia”, and “tachyarrhythmia” may be used interchangeable herein and are understood in the broadest sense, including all disease conditions associated with fast or irregular heart rate, in particular a condition in which the heart contracts at a rate greater than 90-100 / min in adults. In some cases, specifically in case of severe coronary stenosis or other severe cardiac diseases, heart rates above 80 bpm may be considered too high (relative tachycardia).

[0188] According to a specific embodiment, herein tachycardia specifically refers to pathologic tachycardia accompanying anoxia, such as that caused by anemia; congestive heart failure; hemorrhage; or shock. Tachycardia acts to increase the amount of oxygen delivered to the cells of the body by increasing the rate at which blood circulates through the vessels.

[0189] The term “heart rate” means the heart beats per minute.

[0190] According to a specific embodiment, the pharmaceutical solution described herein is for use in treatment of supraventricular tachycardia.

[0191] Herein, the term “supraventricular tachycardia” (SVT) defines a condition presenting as a rapid heart rhythm originating at or above the atrioventricular node. Although SVT can be due to any supraventricular cause, the term is most often used to refer to a specific example, paroxysmal supraventricular tachycardia (PSVT), two common types being atrioventricular reciprocating tachycardia and AV nodal reentrant tachycardia.

[0192] In general, SVT is caused by one of two mechanisms: The first is re-entry; the second is automaticity. Re-entry (such as AV nodal reentrant tachycardia and atrioventricular reciprocating tachycardia) often presents with an almost immediate onset with sudden increase in heart rate. A person experiencing this type of PSVT may feel the heart rate accelerate from 60 to 200 beats per minute or more. Typically, when it reverts to normal rhythm, this is also sudden.

[0193] The main pumping chamber, the ventricle, is protected (to a certain extent) against excessively high rates arising from the supraventricular areas by a 'gating mechanism' at the atrioventricular node, which allows only a proportion of the fast impulses to pass through to the ventricles. In a condition called Wolff-Parkinson-White Syndrome, a 'bypass tract' avoids this node and its protection and the fast rate may be directly transmitted to the ventricles. This situation has characteristic findings on ECG. In automatic types of SVT (atrial tachycardia, junctional ectopic tachycardia), there is more typically a gradual increase and decrease in the heart rate. These are due to an area in the heart that generates its own electrical signal.

[0194] Supraventricular tachycardias can be contrasted with the potentially more dangerous ventricular tachycardias rapid rhythms that originate within the ventricular tissue.

[0195] According to one embodiment, the pharmaceutical composition described herein is for use in the treatment of subjects suffering from tachycardia selected from supraventricular tachycardia, ventricular tachycardia or hypertension and noncompensatory sinus tachycardia, atrial fibrillation, atrial flutter in perioperative, postoperative, or other circumstances where persistent control of the ventricular rate is indicated or desirable, or subjects who are in need of blood pressure lowering, for example perioperatively or in other acute situations, or during aortic dissection, or for controlled hypotension, e.g. to avoid blood loss in ear, nose, or throat surgery, or for diagnostic purposes.

[0196] According to one embodiment, the pharmaceutical composition described herein is also for use for subjects having cardiac decompensation, hyperhydration, renal decompensation, hypernatremia, hyperchloremic acidosis, and / or hyperhydration.

[0197] According to a further embodiment, the pharmaceutical composition are used for a subject receiving a positive inotropic drug or is suffering from intoxication due to the administration of an inotropic drug, specifically selected from the group of Berberine, calcium, calcium sensitizers like Levosimendan, cardiac myosin activators like Omecamtiv, catecholamines selected from the group of Dopamine, Dobutamine, Dopexamine, Epinephrine (adrenaline), Isoprenaline (isoproterenol), Norepinephrine (noradrenaline), ephedrine, Digoxin Digitalis; Eicosanoids like prostaglandins; phosphodiesterase inhibitors selected from the group of Enoximone Milrinone, Amrinone, Theophylline; Glucagon or Insulin or a sympathomimetic drug, specifically selected from the group of Bi and or B2 agonists.

[0198] According to a further embodiment, the pharmaceutical composition described herein is used for persistent reduction of the heart rate and / or blood pressure during the administration period of ultrashort-effective-adrenoreceptor antagonist for producing a medicament for the treatment of a human suffering from tachycardia, tachyarrhythmia and / or hypertension, wherein ultrashort-effective-adrenoreceptor antagonist, specifically landiolol hydrochloride, is administered at a constant dose in the range of 5 to 40 pg / kg / min, specifically of at least 5 pg / kg / min, at least 10 pg / kg / min, at least 20 pg / kg / min, specifically for a period of at least 2 hours.

[0199] According to a further embodiment, described herein is a method of treating a patient with tachycardia or tachyarrhythmia, specifically with supraventricular tachycardia, and / or hypertension, wherein said patient is administered a constant dose of more than 5 pg / kg / min, specifically 10 pg / kg / min, 20 pg / kg / min, 40 pg / kg / min landiolol hydrochloride for a period of at least 1.5 hours, specifically of at least or more than 2 hours and wherein the heart rate of said patient is thereby persistently reduced during the administration period compared to the patient's heart rate before treatment.

[0200] According to one embodiment, the pharmaceutical composition described herein is for use in treatment before electrical shock.

[0201] According to one embodiment, the pharmaceutical composition described herein is for use in treatment of dobutamine stress echo.

[0202] According to one embodiment, the pharmaceutical composition described herein is for use in treatment of controlled hypertension, specifically during surgery.

[0203] The term “hypertension” or, as equivalent “high blood pressure” or “arterial hypertension”, is a medical condition in which the blood pressure in the arteries is elevated. Blood pressure is summarized by two measurements, systolic and diastolic, which depend on whether the heart muscle is contracting (systole) or relaxed between beats (diastole). This equals the maximum and minimum pressure, respectively. Normal blood pressure at rest is within the range of 100-140 mmHg systolic (top reading) and 60-90 mmHg diastolic (bottom reading). High blood pressure is said to be present if it is at or above 140 / 90 mmHg. Severely elevated blood pressure, i.e. equal to or greater than a systolic 180 or diastolic of 110, sometimes termed malignant or accelerated hypertension, is referred to as a "hypertensive crisis", as blood pressure at this level confers a high risk of complications.

[0204] The term “blood pressure” means systolic and diastolic blood pressure expressed in mmHg or kPa.

[0205] The term “controlled hypertension” or “CHTN” as used herein refers to a systolic blood pressure (SBP) of <140 mmHg and a diastolic blood pressure (DBP) of <90 mmHg among persons with hypertension. According to ACC / AHA 2017 guideline, CHTN is defined if individuals have systolic BP < 130 mmHg and diastolic BP < 80 mmHg among those with HTN. As patients with hypertension display greater cardiovascular ability during surgery the control during surgery and stabilization of blood pressure parameters is necessary.

[0206] According to one embodiment, the pharmaceutical composition described herein is for use in treatment of tachycardic arrythmias, treatment before electrical shock, dobutamine stress echo, and / or controlled hypertension, specifically during surgery.

[0207] According to a specific embodiment, the heart rate and / or blood pressure are reduced at least 1 %, preferably at least 2%, preferably at least 3%, preferably at least 4%, preferably at least 5%, preferably between 10% and 50% compared to the heart rate and / or blood pressure before treatment.

[0208] According to one embodiment, for long term treatment, continuous infusion the pharmaceutical composition described herein is the preferred administration form. Specifically, the pharmaceutical composition described herein may be administered as maintenance infusion at a dose of between 0.1 to 100 pg / kg / min, specifically between 5 to 50 pg / kg / min, more specifically between 10 to 50 pg / kg / min.

[0209] According to a specific embodiment, the pharmaceutical composition described herein may be administered using peripheral veins.

[0210] According to one embodiment, the administration of the pharmaceutical composition after at least two hours at constant dose can be terminated immediately or the dose can also be stepwise reduced, either within a short period of several minutes or hours. As an alternative, the dose can also be increased after the minimum period of two hours, i.e. it may be increased to a dose of ultrashort-effective-adrenoreceptor antagonist up to 40 pg / kg / min or even more than 40 pg / kg / min, depending on the need of the patient and the condition. Said increase of dosage can be gradually or stepwise.

[0211] The term “long-term administration” means an administration which takes at least 30 minutes.

[0212] According to one embodiment, the pharmaceutical composition described herein may be administrated at a high dose of landiolol.

[0213] The term “high dose” means a dose of more than 20 pg / kg / min, specifically more than 25 pg / kg / min, more than 30 pg / kg / min, more than 35 pg / kg / min, more preferably more than 40 pg / kg / min.

[0214] According to one embodiment, the pharmaceutical composition described herein can be combined with any B adrenergic agonist treatment, for example, it can be combined with positive inotropic substances like dobutamine or amrinone, or with any other known Bi and B2 stimulating agents. The examples described herein are illustrative of the present invention and are not intended to be limitations thereon. Many modifications and variations may be made to the techniques described and illustrated herein without departing from scope of the invention. EXAMPLES

[0215] Example 1 : Complexation of Landiolol and anionic amphiphilic molecules The following Table 1 shows the tested experimental mixtures.

[0216] Table 1 : Tested experimental mixtures

[0217] _OQ: Limit of quantification; N / A not available

[0218] The following chemicals were used in the example:

[0219] • Landiolol HCI; chemical ID: C-05175

[0220] ® Na-deoxycholate; chemical ID: C-05439; supplier: PanReac AppliChem; supplier number: A1531.0100

[0221] ® Na-Oleate; chemical ID: C-05237; supplier: LIPOID; supplier number: 520400

[0222] Respective amount of landiolol HCI (see Table 1) was dissolved in deionized water. 8.4 g of Na deoxycholate, resp. 4.870 g Na Oleate was dissolved in 100 mL, resp. 200 mL deionized water. Both solutions were mixed using a magnetic stirrer at 1200 rpm and 3, 6 resp. 9 mL 2 M HCI was added to facilitate the complex formation. After the formation of the complex, it was filtered (3-5 pm paper filter) and dried at 40 °C.

[0223] The LDL recovery in achieved complex was analysed by HPLC-UV as follows: 20 mg complex was weighted in 25 mL volumetric flask. Approximately 20 mL isopropyl alcohol was added to dissolve on a magnetic stirrer. The volumetric flask was filled up to volume with isopropyl alcohol. 1 mL of this solution was transferred into 5 mL volumetric flask and filled up to volume with ACN / Phosphate Buffer pH 6,0 (15:85 v / v). The sample was filled into HPLC vial, and analysed with following analytical method (see following Table 2).

[0224] Table 2 Figure 1 shows LDL-deoxycholate complex: after filtration (left), after drying (right). The figure shows a white paste-like complex after filtration (left) and a transparent solid complex after drying (right).

[0225] The following Table 3 shows the stability of LDL-deoxycholate complex after 2 months of storage.

[0226] Table 3: Stability of LDL-deoxycholate complex after 2 months of storage

[0227] (relative humidity); LOQ Limit of quantification; LOD: limit of detection (0.01 %)

[0228] Example 2: Liposomal formulations

[0229] The following Table 4 shows the composition of the tested formulation.

[0230] Table 4

[0231] The following chemicals were used in the example:

[0232] • Landiolol HCI; chemical ID: C-05175

[0233] ® Na-deoxycholate; chemical ID: C-05439; supplier: PanReac AppliChem; supplier number: A1531.0100

[0234] • Lipoid SPC3; chemical ID: C-05363; supplier: LIPOID; supplier number: 556500

[0235] ® Cholesterol; chemical ID: C-04236; supplier: Sigma Aldrich; supplier number: C8667-5G

[0236] Landiolol HCI and Na deoxycholate complex was produced by the procedure outlined in example 1. Complex, together with cholesterol and hydrogenated phosphatidylcholine from soybean (CAS-No. 97281-48-6; phosphatidylcholine, hydrogenated; Lipoid SPC3) were dissolved in 10 mL ethanol and rapidly introduced into 50 mL water phase. A mixing ratio 1 :5 is used to produce liposome formulations. Each formulation was produced either using water, pH 5.5 sodium citrate buffer 0.1 M or pH 6.5 sodium phosphate buffer 0.1 M.

[0237] The samples were filled into Type I amber injection vials, and closed with elastomeric stopper and aluminum overseal. The samples were stored for 1 month at 40°C alongside with control sample (Landiolol lyophilizate, reconstituted with 50 mL to nominal concentration 6 mg / mL, filled in the same way into the same container). The samples were analysed by HPLC-UV method as outlined above (see example 1), with sample preparation as follows: 1mL of sample was transferred to 5mL volumetric flask and dissolved with 3mL isopropylalcohol. The volumetric flask was made up to volume IPA. 1mL of this solution was transferred to 20mL volumetric flask and made up to volume with ACN / phosphate buffer pH 6.0 (15:85 v / v) the samples were filtered via 0.2pm cellulose filter and prepared for HPLC.

[0238] In addition, particle size of liposomes was analysed by DLS (dynamic light scattering).

[0239] The results indicate significant improvement in stability in comparison to control sample. DLS results indicate stable particles size ca 100 - 200nm, with acceptable polydispersity. The results are summarized in Table 7 and 8 below.

[0240] LDL is short acting 0-blocker, used in clinical situation where immediate onset of action is of utmost importance. It is well-known that nanoparticles or liposomal formulation may impact the release of drug into the bloodstream, followed by slow or insufficient clinical effect. Release profile of selected formulation (Example 1) was investigated using a Nanodis device. 0.05M sodium phosphate buffer pH 7.4 was used with a rotation speed of 100rpm at 37 °C. 900 mL was used as dissolution volume and 6 mg API / vessel was introduced in the form of particle suspension. The samples were taken at 5, 10, 15 and 20 minutes and assayed with HPLC-UV for drug content after separation of the particles from the samples. Each formulation was tested as triplicates. The results indicate complete release of the formulations within 15 minutes under in- vitro conditions. This translates as an immediate release once the formulations are injected into the blood stream, where dilution rate is higher compared to the in-vitro conditions, resulting in an immediate release of the API.

[0241] Figure 2 shows the release profile of liposomal formulation. Example 3: Liposomal formulation

[0242] The following Table 5 shows the composition of the tested formulation.

[0243] Table 5

[0244] The following chemicals were used in the example:

[0245] • Landiolol HCI; chemical ID: C-05175

[0246] ® Na-deoxycholate; chemical ID: C-05439; supplier: PanReac AppliChem; supplier number: A1531.0100

[0247] • Lipoid SPC3; chemical ID: C-05363; supplier: LIPOID; supplier number: 556500

[0248] ® Cholesterol; chemical ID: C-04236; supplier: Sigma Aldrich; supplier number: C8667-5G

[0249] ® Vitamin E (dL-alpha tocopherol); chemical ID: C-04967; supplier: BTC Chemical; supplier number: 50033453

[0250] Landiolol HCI and Na deoxycholate complex were produced by procedure outlined in example 1. Complex, together with cholesterol and hydrogenated phosphatidylcholine from soybean (CAS-No. 97281-48-6; phosphatidylcholine, hydrogenated; Lipoid SPC 3) were dissolved in 10 mL Ethanol and rapidly introduced into 50 mL water phase. A mixing ratio 1 :5 is used to produce liposome formulations. Each formulation was produced either using water, pH 5.5 sodium citrate buffer 0.1 M or pH 6.5 sodium phosphate buffer 0.1 M.

[0251] The samples were filled into Type I amber injection vials, and closed with elastomeric stopper and aluminum overseal. The samples were stored for 1 month at 40°C alongside with control sample (Landiolol lyophilizate, reconstituted with 50 mL to nominal concentration 6 mg / mL, filled in the same way into the same container). The samples were analysed by HPLC-UV method as outlined above (see example 1), with sample preparation as follows: 1mL of sample was transferred to 5mL volumetric flask and dissolved with 3mL IPA. The volumetric flask was made up to volume IPA. 1mL of this solution was transferred to 20mL volumetric flask and made up to volume with ACN / phosphate buffer pH 6.0 (15:85 v / v). The samples were filtered via 0.2pm cellulose filter and prepared for HPLC.

[0252] In addition, particle size of liposomes was analysed by DLS (dynamic light scattering).

[0253] The results indicate significant improvement in stability in comparison to control sample. DLS results indicate stable particles size ca 100 - 200nm, with acceptable polydispersity. The results are summarized in Table 7 and 8 below.

[0254] Example 4: Liposomal formulation

[0255] The following Table 6 shows the composition of the tested formulation.

[0256] Table 6

[0257] The following chemicals were used in the example:

[0258] • Landiolol HCI; chemical ID: C-05175

[0259] ® Na-deoxycholate; chemical ID: C-05439; supplier: PanReac AppliChem; supplier number: A1531.0100

[0260] • Lipoid SPC3; chemical ID: C-05363; supplier: LIPOID; supplier number: 556500

[0261] ® Cholesterol; chemical ID: C-04236; supplier: Sigma Aldrich; supplier number: C8667-5G

[0262] • Tween 80 (Polysorbate 80), EMPROVE® ESSENTIAL Ph. Eur., JP, NF, SAFC® from Merck

[0263] Landiolol HCI and Na deoxycholate complex were produced by the procedure outlined in example 1. Complex, together with cholesterol and hydrogenated phosphatidylcholine from soybean (CAS-No. 97281-48-6; phosphatidylcholine, hydrogenated; Lipoid SPC 3) were dissolved in 10 mL Ethanol and rapidly introduced into 50 mL water phase (WFI, sodium phosphate or sodium citrate) with dissolved Tween 80 (polysorbate 80). A mixing ratio 1 :5 is used to produce liposome formulations. Each formulation was produced either using water, pH 5.5 sodium citrate buffer 0.1 M or pH 6.5 sodium phosphate buffer 0.1 M.

[0264] The sample were filled into Type I amber injection vials, and closed with elastomeric stopper and aluminum overseal. The samples were stored for 1 month at 40°C alongside with control sample (Landiolol lyophilizate, reconstituted with 50 mL to nominal concentration 6 mg / mL, filled in the same way into the same container). The samples were analysed by HPLC-UV method as outlined above (see example 1), with sample preparation as follows: 1 mL of sample was transferred to 5mL volumetric flask and dissolved with 3mL IPA. The volumetric flask was made up to volume IPA. 1 mL of this solution was transferred to 20mL volumetric flask and made up to volume with ACN / phosphate buffer pH 6.0 (15:85 v / v). The samples were filtered via 0.2pm cellulose filter and prepared for HPLC.

[0265] The results indicate significant improvement in stability in comparison to control sample. Amount of total impurities was significantly reduced in samples described in examples in comparison to control sample (Table 7). The landiolol-peak has also a significantly higher %Area in the compositions of the examples. The herein provided results show that the stability is significantly improved in the herein described compositions in comparison to the control sample. DLS results indicate stable particles size ca 100 - 200nm, with acceptable polydispersity. The results are summarized in Table 7 and 8 below.

[0266] Table 7: Stability of prepared liposomes measured by HPLC-UV

[0267] Table 8: Particle size and polydispersity of liposomal formulations stored 1M at 40°C

[0268] PDI: polydispersity index

[0269] Example 5: Solid lipid nanoparticle The following Table 9 shows the composition of the tested formulation.

[0270] Table 9

[0271] The following chemicals were used in the example:

[0272] • Landiolol HCI; chemical ID: C-05175 ® Na-deoxycholate; chemical ID: C-05439; supplier: PanReac AppliChem; supplier number: A1531.0100

[0273] • Lipoid SPC3; chemical ID: C-05363; supplier: LIPOID; supplier number: 556500

[0274] ® Cholesterol; chemical ID: C-04236; supplier: Sigma Aldrich; supplier number: C8667-5G

[0275] ® Vitamin E (dL-alpha tocopherol); chemical ID: C-04967; supplier: BTC Chemical; supplier number: 50033453 • DSPG Na, LIPOID PG 18:0 / 18:0 (DSPG-Na), 1 ,2-Distearoyl-sn-glycero-3- phospho-rac-glycerol, sodium salt, CAS-No. 200880-42-8

[0276] Landiolol HCI and Na deoxycholate complex were produced by the procedure outlined in example 1. Complex, together with all other excipients were dissolved in 10 mL Chloroform: Methanol 1 :1 , evaporated until complete dryness and the resulting film was redispersed either in water, pH 5.5 sodium citrate buffer 0.1 M or pH 6.5 sodium phosphate buffer 0.1 M.

[0277] The sample were filled into Type I amber injection vials, and closed with elastomeric stopper and aluminum overseal. The samples were stored for 1 month at 40°C alongside with control sample (Landiolol lyophilizate, reconstituted with 50 mL to nominal concentration 6 mg / mL, filled in the same way into the same container). The samples were analysed by HPLC-UV method as outlined above (see example 1), with sample preparation as follows: 1 mL of sample was transferred to 5mL volumetric flask and dissolved with 3 mL IPA. The volumetric flask was made up to volume IPA. 1 mL of this solution was transferred to 20mL volumetric flask and made up to volume with ACN / phosphate buffer pH 6.0 (15:85 v / v) the samples were filtered via 0.2pm cellulose filter and prepared for HPLC.

[0278] The results indicate significant improvement in stability in comparison to control sample. The results indicate significantly lower amounts of total impurities of lipid particles presentations in comparison to control samples. The landiolol-peak has a significantly higher %Area in the compositions of the examples in comparison to the control sample. The herein provided results show that the stability is significantly improved in the herein described compositions in comparison to the control sample. DLS results indicate stable particles size ca 250nm, with acceptable polydispersity. The results are summarized in Table 10 and 11 below.

[0279] Table 10: Stability of prepared lipid particles measured by HPLC-UV Table 11 : Particle size and polydispersity of lipid nanoparticle formulations stored 1 M at 40°C

[0280] PDI: polydispersity index

[0281] Example 6: Liposomal formulation

[0282] The following Table 12 shows the composition of the tested formulation.

[0283] Table 12

[0284] The following chemicals were used in the example:

[0285] • Landiolol HCI; chemical ID: C-05175

[0286] ® Na-deoxycholate; chemical ID: C-05439; supplier: PanReac AppliChem; supplier number: A1531.0100

[0287] ® Lipoid SPC3; hydrogenated phosphatidylcholine from soybean; chemical ID: C-05363; supplier: LIPOID; supplier number: 556500

[0288] ® Cholesterol; chemical ID: C-04236; supplier: Sigma Aldrich; supplier number: C8667-5G

[0289] Landiolol HCI and Na deoxycholate complex was produced by precipitation with HCI, using procedure outlined in example 1. Lipoid SPC3 was dissolved in 5 mL ethanol at final concentration 2 mg / mL together with cholesterol at concentration 1 mg / mL and LDL-deoxycholate complex (3.5 mg / mL) and precipitated against water. This solution was rapidly mixed with 0.5M acetate buffer pH 5.5 on a magnetic stirrer (750 RPM, 60 seconds) to facilitate the formation of liposomes. Liposome formulations were subjected to cross flow filtration with following parameters:

[0290] • Membrane chemistry: mPES, • Membrane pore size: 100 kDa

[0291] • Pressure: 1 bar TMP

[0292] • Exchange medium: 0,5 M acetate buffer pH 4.5 The formulation was characterized by HPLC-UV for drug content and purity before / after cross flow filtration and after storage at 25°C for 2 months, as well as by DLS. The results, summarized in Table 13, indicate acceptable API loss during production process and stable particle size. Total impurities data also indicate much slower degradation in comparison to LDL formulated in water only.

[0293] Table 13: Assay, purity, and particle size of liposomal formulation (Example 6)

[0294] PDI: polydispersity index; N / A not available

Claims

CLAIMS1 . A composition comprising1. landiolol complexed with an oppositely charged excipient; and ii. at least one lipophilic or amphiphilic excipient.

2. The composition of claim 1 , wherein the oppositely charged excipient comprises a lipophilic moiety.

3. The composition of claim 1 or 2, wherein the oppositely charged excipient is negatively charged, preferably the oppositely charged excipient is selected from the group consisting of a salt, specifically sodium salt, a bile acid salt, and a fatty acid salt, more specifically sodium deoxycholate, and sodium oleate; an acid, specifically a fatty acid, more specifically an oleic acid, a stearic acid; and any combination thereof.

4. The composition of any one of claims 1 to 3, wherein the lipophilic or amphiphilic excipient is a lipid, a surfactant, or a combination thereof.

5. The composition of claim 4, wherein the lipid is selected from the group consisting of oils; fatty acids; glycerolipids; glycerophospholipids; sphingolipids; sterols, specifically cholesterol; prenols, specifically vitamin E; saccharolipids; and polyketides.

6. The composition of claim 5, wherein the glycerophospholipid is phosphatidylcholine (PC), specifically hydrogenated PC from soybean, PC from egg yolk, or a combination thereof; or phosphatidylglycerol (PG), specifically sodium 1 ,2- Dimyristoyl-sn-glycero-3-phospho-rac-glycerol, sodium 1 ,2-Distearoyl-sn-glycero-3- phospho-rac-glycerol, sodium 1 ,2-Dioleolyl-sn-glycero-3-phospho-rac-glycerol, or a combination thereof; and any combination thereof.

7. The composition of claim 5, wherein the oil is selected from the group consisting of castor oil, corn oil, cottonseed oil, olive oil, peanut oil, peppermint oil, safflower oil, sesame oil, soybean oil, hydrogenated vegetable oil, hydrogenated soybean oil, palm oil, palm kernel oil, medium chain triglycerides, and any combination thereof.

8. The composition of claim 4, wherein the surfactant is sorbitan, preferably PEGylated sorbitan; or polysorbate, preferably polysorbate 80.

9. The composition of any one of claims 1 to 8, wherein the landiolol complexed with an oppositely charged excipient is dissolved in, coated or encapsulated by the lipophilic or amphiphilic excipient.

10. The composition of any one of claims 1 to 9, wherein the lipophilic or amphiphilic excipient forms a lipid particle specifically the lipid particle is a lipidmembrane, a liposome, an emulsion, a solid lipid particle, or a nanoparticle, specifically wherein the lipid particle has a diameter of less than 900 nm, wherein the lipid particle diameter is determined by dynamic light scattering.

11. The composition of any one of claims 1 to 10, wherein the composition is an aqueous colloidal suspension or an emulsion.

12. The composition of any one of claims 1 to 11 , wherein the composition is a pharmaceutical composition.

13. The composition of any one of claims 1 to 12, further comprising an antioxidant.

14. The composition of any one of claims 1 to 13 for use as a medicament.

15. The composition of any one of claims 1 to 13 for use in reducing the ventricular rate of patients with atrial fibrillation, the treatment of atrial flutter and sinus tachycardia, atrio-ventricular and AV node tachycardia, tachycardiac supra- and ventricular arrhythmias, tachycardia and / or hypertension before, during, and after operations and in other emergencies; unstable angina pectoris, acute myocardial infarction, and the prophylaxis and treatment of perioperative ischemia.

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