Aqueous pharmaceutical composition containing an SGLT-2 inhibitor

Abstract

The present invention relates to a novel aqueous pharmaceutical composition comprising at least one SGLT-2 inhibitor and one or more solubilizing agents, as well as the corresponding processes for manufacturing the aqueous pharmaceutical composition and their medical use.

Description

Technical Field

[0001] Incorporation by reference All references cited in this specification are hereby incorporated by reference in their entirety into this specification. The present invention relates to the field of medicine, and more particularly to veterinary medicine. Specifically, the present invention relates to a novel aqueous pharmaceutical composition comprising at least one SGLT-2 inhibitor and one or more solubilizing agents.

Background Art

[0002] The treatment of diabetes and other metabolic disorders involves inhibition of the renal sodium-dependent glucose cotransporter SGLT-2. SGLT-2 regulates glucose levels in the kidney by mediating the reabsorption of glucose from the filtrate back into the plasma. Thus, SGLT-2 inhibition can induce glucosuria and lower blood glucose levels. A wide variety of SGLT-2 inhibitors are known. Pharmaceutical formulations of SGLT-2 inhibitors are essential for administering such compounds to patients in a suitable manner. EP1 609 785 discloses C-glycoside derivatives and salts thereof in which the B ring is linked to the A ring via -X- and the A ring is directly linked to a glucose residue, which are useful as Na + -glucose cotransporter inhibitors, in particular for the treatment and / or prevention of diabetes such as insulin-dependent diabetes (type 1 diabetes) and insulin-independent diabetes (type 2 diabetes), and diabetes-related diseases such as insulin resistance disorders and obesity. WO 2006 / 064033 discloses glucopyranosyl-substituted benzene derivatives including tautomers, their stereoisomers, mixtures thereof and salts thereof, which are suitable for treating metabolic disorders.

[0003] SGLT-2 inhibitors are described, for example, in WO 2007 / 028814, which relates to the crystalline forms of 1-chloro-4-([beta]-D-glucopyranos-1-yl)-2-(4-ethynyl-benzyl)-benzene, methods for preparing the same, and their use for preparing medicaments. It discloses a solution of 1-chloro-4-([beta]-D-glucopyranos-1-yl)-2-(4-ethynyl-benzyl)-benzene in a solvent or a mixture of solvents, and further specifies suitable organic solvents such as ethanol or ethanol / water mixtures. WO 2007 / 080170 describes the crystalline forms of 1'-(1-methylethyl)-4'-[(2-fluoro-4-methoxyphenyl)methyl]-5'-methyl-1H-pyrazole-3'-O-[beta]-D-glucopyranoside, methods for preparing the same, and their use for preparing medicaments. It discloses a solution of 1'-(1-methylethyl)-4'-[(2-fluoro-4-methoxyphenyl)methyl]-5'-methyl-1H-pyrazole-3'-O-[beta]-D-glucopyranoside in a solvent or a mixture of solvents, and further specifies suitable organic solvents such as ethanol or ethanol / water mixtures.

[0004] In addition, WO 2007 / 093610 describes glucopyranosyl-substituted benzonitrile derivatives, pharmaceutical compositions containing such compounds, their medical uses, and processes for manufacturing them. It states that such glucopyranosyl-substituted benzonitrile derivatives can be formulated, inter alia, with one or more inert carriers and / or diluents such as water / ethanol, water / glycerol, propylene glycol and the like. It further discloses, among many other compounds, 1-cyano-2-(4-cyclopropyl-benzyl)-4-(β-D-glucopyranos-1-yl)-benzene (velaglucerase).

[0005] Furthermore, SGLT-2 inhibitors are described in WO 2007 / 128749, which relates to glucopyranosyl-substituted benzonitrile derivatives, pharmaceutical compositions containing such compounds, their medical use, and processes for their manufacture. It states that such glucopyranosyl-substituted benzonitrile derivatives can be formulated, inter alia, with one or more inert carriers and / or diluents such as water / ethanol, water / glycerol, propylene glycol and the like. It further discloses, among many other compounds, 1-cyano-2-(4-cyclopropyl-benzyl)-4-(β-D-glucopyranos-1-yl)-benzene (veragliflozin).

[0006] US 2011 / 077213 discloses a method for treating and / or preventing kidney stones by using an SGLT-2 inhibitor alone, or in combination with a carbohydrate supply and / or in combination with a diuretic. WO 2013 / 079501 is directed to crystalline dapagliflozin hydrate and a method for preparing the same. It discloses a solution of dapagliflozin in a solvent or a mixture of solvents, and further specifies suitable solvents by way of example, such as water and C1-C4 alcohols or a mixture thereof. WO 2014 / 016381 (US2014 / 031540) describes a crystalline complex of 1-cyano-2-(4-cyclopropyl-benzyl)-4-(β-D-glucopyranos-1-yl)-benzene with a natural amino acid, a method for preparing the same, and its use for preparing a medicament. It discloses a solution of 1-cyano-2-(4-cyclopropyl-benzyl)-4-(β-D-glucopyranos-1-yl)-benzene in a solvent or a mixture of solvents, and further specifies suitable organic solvents by way of example, such as C1-C4 alkanols, ethanol and mixtures thereof, in particular mixtures with water. Furthermore, WO 2014 / 195966 describes an amorphous form of canagliflozin, a process for producing the same, and corresponding pharmaceutical compositions and their pharmaceutical uses. It discloses a solution of canagliflozin in one or more organic solvents, and further specifies organic solvents suitable as examples, such as ethanol.

[0007] WO 2015 / 110402 relates to SGLT-2 inhibitors for use in the treatment and / or prevention of metabolic disorders in canines. WO 2015 / 173584 discloses a method for avoiding an increase in glucagon secretion associated with the administration of a sodium glucose cotransporter 2 (SGLT-2) inhibitor via co-administration of a dipeptidyl peptidase IV (DPP IV) inhibitor. In addition, it discloses a method for normalizing glucagon secretion associated with the administration of a sodium glucose cotransporter 2 (SGLT-2) inhibitor via co-administration of a dipeptidyl peptidase IV (DPP IV) inhibitor. This WO publication also relates to methods for treating diabetes, particularly type 2 diabetes, as well as hyperglycemia, hyperinsulinemia, obesity, hypertriglyceridemia, syndrome X, diabetic complications, atherosclerosis and related diseases, which include administering an SGLT-2 inhibitor and a dipeptidyl peptidase IV (DPP IV) inhibitor. WO 2017 / 032799 relates to a liquid pharmaceutical composition comprising at least one SGLT-2 inhibitor and one or more polar organic solvents, wherein the one or more polar organic solvents preferably always include propan-1,2-diol (propylene glycol).

[0008] US 2017 / 145000 discloses canagliflozin monohydrate and its crystalline forms. US 2020 / 237794 discloses one or more SGLT-2 inhibitors or pharmaceutically acceptable forms thereof for use in the treatment and / or prevention of metabolic disorders in equines, such as laminitis, vascular insufficiency, hypertension, hepatic lipidosis, atherosclerosis, hyperadrenocorticism, pituitary pars intermedia dysfunction and / or equine metabolic syndrome.

[0009] WO 2020 / 219645 discloses a method for reducing the weight loss of cats in need thereof and / or increasing their weight, and / or managing diseases in cats having diabetes and elevated IGF-1 concentrations, the method comprising administering to a cat in need thereof about 2 to 50 mg of total daily dosage of empagliflozin or a pharmaceutically acceptable form thereof. WO 2021 / 105152 discloses the use of at least one SGLT-2 inhibitor in non-human mammals, preferably ruminants, preferably for drying off non-human mammals, preferably ruminants, and corresponding methods, such as methods for improving and / or facilitating the drying off of non-human mammals, preferably ruminants, the method comprising administering to such non-human mammals, preferably ruminants, at least one SGLT-2 inhibitor.

[0010] WO 2021 / 165177 discloses the use of one or more SGLT-2 inhibitors or pharmaceutically acceptable forms thereof for preventing and / or treating one or more heart diseases in felines. US 2022 / 016078 discloses a method for treating or preventing kidney stones in a patient: a therapeutically effective amount of a compound that induces glycosuria or a pharmaceutically acceptable salt, solvate or hydrate thereof or a pharmaceutical composition thereof is administered to a patient in need thereof. WO 2023 / 006718 discloses the use of one or more SGLT-2 inhibitors or pharmaceutically acceptable forms thereof for preventing and / or treating one or more heart diseases in non-human mammals other than cats / non-human mammalian patients, particularly dogs / dog patients. WO 2023 / 006745 discloses the use of one or more SGLT-2 inhibitors or pharmaceutically acceptable forms thereof for preventing and / or treating hypertension in non-human mammals, preferably carnivores, particularly cats or dogs. WO 2023 / 006747 discloses the use of one or more SGLT-2 inhibitors or pharmaceutically acceptable forms thereof for preventing and / or treating one or more kidney diseases in non-human mammals, such as carnivores, particularly cats or dogs.

[0011] Xu G et al. (Journal of Medical Chemistry 2014, 57: 1236-1251) are directed to the design, synthesis, and biological evaluation of deuterated C-aryl glycosides as potent and long-acting renal SGLT-2 inhibitors for treating type 2 diabetes. A further problem known in the prior art is their positive log 10 P value, the limited solubility of SGLT-2 inhibitors in water, which typically affects the bioavailability in the patient's body or makes it difficult to find a suitable solvent to dissolve the substance in a liquid formulation before administration to the patient's body.

Summary of the Invention

[0012] The present invention relates to an aqueous pharmaceutical composition comprising at least one SGLT-2 inhibitor and one or more solubilizing agents. In the process of the present invention, the term "aqueous" with respect to the term "pharmaceutical composition" refers to a water-containing pharmaceutical composition, preferably such water is present in the form of an aqueous buffer such as a citrate buffer. However, according to the knowledge and skills of those skilled in the art, any suitable aqueous buffer (system) can be used. The water content / aqueous buffer content of such a water-containing pharmaceutical composition is 30-100 g / 100 mL (30-100 mass / volume %), preferably 30-95 g / 100 mL (30-95 mass / volume %), more preferably 30-90 g / 100 mL (30-90 mass / volume %), more preferably 30-85 g / 100 mL (30-85 mass / volume %), even more preferably 30-80 g / 100 mL (30-80 mass / volume %), and most preferably 50-80 g / 100 mL (50-80 mass / volume %). The present invention also provides that at least one SGLT-2 inhibitor is (1) Glucopyranosyl-substituted benzene derivative of formula (1)

[0013] [Chemical formula] (In the formula, R 1 represents cyano, Cl or methyl (most preferably cyano); R 2 represents H, methyl, methoxy or hydroxy (most preferably H), R 3 represents cyclopropyl, hydrogen, fluorine, chlorine, bromine, iodine, methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, tert-butyl, 3-methyl-but-1-yl, cyclobutyl, cyclopentyl, cyclohexyl, 1-hydroxy-cyclopropyl, 1-hydroxy-cyclobutyl, 1-hydroxy-cyclopentyl, 1-hydroxy-cyclohexyl, ethynyl, ethoxy, difluoromethyl, trifluoromethyl, pentafluoroethyl, 2-hydroxyl-ethyl, hydroxymethyl, 3-hydroxy-propyl, 2-hydroxy-2-methyl-prop-1-yl, 3-hydroxy-3-methyl-but-1-yl, 1-hydroxy-1-methyl-ethyl, 2,2,2-trifluoro-1-hydroxy-1-methyl-ethyl, 2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl, 2-methoxy-ethyl, 2-ethoxy-ethyl, hydroxy, difluoromethyloxy, trifluoromethyloxy, 2-methyloxy-ethyloxy, methylsulfanyl, methylsulfinyl, methylsulfonyl (methlysulfonyl), ethylsulfinyl, ethylsulfonyl, trimethylsilyl, (R)-tetrahydrofuran-3-yloxy or (S)-tetrahydrofuran-3-yloxy or cyano; R 3 is preferably selected from cyclopropyl, ethyl, ethynyl, ethoxy, (R)-tetrahydrofuran-3-yloxy or (S)-tetrahydrofuran-3-yloxy; most preferably R 3 is cyclopropyl), or one or more hydroxyl groups of the β-D-glucopyranosyl group are acylated with a group selected from (C 1-18 -alkyl)carbonyl, (C 1-18 -alkyl)oxycarbonyl, phenylcarbonyl and phenyl-(C 1-3 -alkyl)-carbonyl, derivatives thereof; (2) Veragliflozin represented by formula (2);

[0014]

Chemical formula

[0015]

Chemical formula

Chemical formula

[0016]

Chemical formula

Chemical formula

[0017]

Chemical formula

[0018]

Chemical formula

[0019] [Chemistry] (10) Acigliflozin represented by formula (10);

[0020] [Chemistry] (11) Remogliflozin represented by formula (11);

[0021] [Chemistry] (11A) Remogliflozin etabonate represented by formula (11A);

[0022] [Chemistry] (12) Thiophene derivative of formula (12)

[0023] [Chemistry] (wherein R represents methoxy or trifluoromethoxy) (13) 1-(β-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienylmethyl]benzene represented by formula (13);

[0024] [Chemistry] (14) Spiroketal derivative of formula (14);

[0025] [Chemistry] (wherein R represents methoxy, trifluoromethoxy, ethoxy, ethyl, isopropyl or tert-butyl) (15) Pyrazole-O-glucoside derivative of formula (15)

[0026]

Chem.

[0027]

Chem.

[0028]

Chem.

[0029]

Chem.

[0030]

Chemical formula

[0031] [Chemical formula] (21) Longagliflozin represented by formula (21);

[0032] [Chemical formula] (22) Wanpagliflozin; (23) Empagliflozin represented by formula (23);

[0033] [Chemical formula] (24) TFC-039 represented by formula (24);

[0034] [Chemical formula] Relates to an aqueous pharmaceutical composition selected from the group consisting of, as described and / or claimed herein. The present invention also relates to an aqueous pharmaceutical composition as described and / or claimed herein, which contains only one SGLT-2 inhibitor, preferably only velagliflozin, as a single SGLT-2 inhibitor.

[0035] The present invention also relates to an aqueous pharmaceutical composition as described and / or claimed herein, wherein at least one SGLT-2 inhibitor is velagliflozin, which is preferably the only SGLT-2 inhibitor contained in the aqueous pharmaceutical composition, and / or the aqueous pharmaceutical composition is preferably for administration to a subject, more preferably an animal, even more preferably a mammal, particularly a horse, a cat, a dog or a cow, preferably directly, without further necessary processing and / or purification steps; preferably it is sterile.

[0036] The present invention also relates to the following pharmaceutical indications: (i) A metabolic disorder in equine animals, preferably one or more disorders selected from insulin resistance, hyperinsulinemia, impaired glucose tolerance, dyslipidemia, dysadipokinemia, asymptomatic inflammation, systemic inflammation, mild systemic inflammation, obesity, and / or local obesity, preferably a clinical condition associated with insulin resistance, hyperinsulinemia, and / or insulin resistance and / or hyperinsulinemia; preferably, the clinical condition is one or more conditions selected from impaired glucose tolerance, dyslipidemia, dysadipokinemia, asymptomatic inflammation, systemic inflammation, mild systemic inflammation, obesity, and / or local obesity, a metabolic disorder; (ii) A metabolic disorder in equine animals, preferably one or more disorders selected from laminitis, vascular insufficiency, hypertension, hepatic lipidosis, atherosclerosis, hyperadrenocorticism, pituitary pars intermedia dysfunction, and / or equine metabolic syndrome, preferably a clinical condition / symptom associated with insulin resistance and / or hyperinsulinemia, and the clinical condition / symptom is preferably one or more conditions selected from laminitis, vascular insufficiency, hypertension, hepatic lipidosis, atherosclerosis, hyperadrenocorticism, pituitary pars intermedia dysfunction, and / or equine metabolic syndrome, a metabolic disorder; (iii) A metabolic disorder in feline animals, preferably one or more selected from the group consisting of ketoacidosis, prediabetes, type 1 or type 2 diabetes, insulin resistance, acromegaly, diabetes with high IGF-1 concentration, obesity, hyperglycemia, impaired glucose tolerance, hyperinsulinemia, dyslipidemia, dysadipokinemia, asymptomatic inflammation, systemic inflammation, mild systemic inflammation, hepatic lipidosis, atherosclerosis, pancreatitis, neuropathy, and / or syndrome X (metabolic syndrome) and / or loss of pancreatic beta cell function, and / or remission of the metabolic disorder, preferably diabetes remission is achieved and / or maintained, a metabolic disorder; (iv) A metabolic disorder of a canine, preferably one or more selected from the group consisting of ketoacidosis, prediabetes, insulin-dependent diabetes, insulin-resistant diabetes, insulin resistance, obesity, hyperglycemia, hyperglycemia-induced cataract formation, impaired glucose tolerance, hyperinsulinemia, dyslipidemia, abnormal lipid dynamics, asymptomatic inflammation, systemic inflammation, mild systemic inflammation, hepatic lipidosis, pancreatitis, and as a result of metabolic disorders, for example, hypertension, renal insufficiency and / or musculoskeletal disorders, and / or syndrome X (metabolic syndrome), preferably prediabetes, insulin-dependent diabetes, insulin-resistant diabetes, insulin resistance; preferably, the occurrence of hyperglycemia-induced cataract formation is prevented or remission is achieved, and / or preferably, as a result of metabolic disorders, for example, the occurrence of hypertension, renal dysfunction and / or musculoskeletal disorders is prevented, or the progression is decelerated, or remission is achieved, metabolic disorder; (v) A heart disease of a feline, preferably the heart disease is selected from the group consisting of heart failure, heart failure due to one or more cardiomyopathies, heart failure due to hypertrophic cardiomyopathy (HCM), heart failure due to restrictive cardiomyopathy (RCM), heart failure due to dilated cardiomyopathy (DCM), heart failure due to unclassified cardiomyopathy (UCM), heart failure due to arrhythmogenic right ventricular cardiomyopathy (ARVC), hypertrophic cardiomyopathy (HCM), restrictive cardiomyopathy (RCM), dilated cardiomyopathy (DCM), unclassified cardiomyopathy (UCM), and / or arrhythmogenic right ventricular cardiomyopathy (ARVC); preferably one or more selected from the group consisting of heart failure due to one or more cardiomyopathies, heart failure due to hypertrophic cardiomyopathy (HCM), hypertrophic cardiomyopathy (HCM), heart disease; (vi) A dry-off of a non-human mammal, preferably a ruminant, which improves and / or promotes the dry-off of the non-human mammal, preferably a ruminant, reduces milk production, preferably milk production and / or secretion, in a non-human mammal, preferably a ruminant, during pregnancy and / or lactation, reduces milk accumulation and / or engorgement in the mammary gland, preferably the mammary gland and / or mammary gland, of a non-human mammal, preferably a ruminant, reduces the discomfort associated with mammary engorgement, for example, increases the daytime lying time of a non-human mammal, preferably a ruminant, and / or reduces stress, reduces milk leakage after dry-off of a non-human mammal, preferably a ruminant, and reduces the incidence of intramammary infections (IMI), preferably mastitis and / or metritis, in a non-human mammal, preferably a ruminant; dry-off; (vii) A heart disease of a non-human mammal other than a cat, particularly a dog, preferably heart failure; congestive heart failure; asymptomatic / preclinical / potential heart failure; heart failure due to (mucoid) mitral valve disease [(M)MVD]; congestive heart failure due to (mucoid) mitral valve disease [(M)MVD]; asymptomatic / preclinical / potential heart failure due to (mucoid) mitral valve disease [(M)MVD]; (mucoid) mitral valve disease [(M)MVD]; clinically apparent (mucoid) mitral valve disease [(M)MVD]; asymptomatic / preclinical / potential (mucoid) mitral valve disease [(M)MVD]; heart failure due to dilated cardiomyopathy (DCM); congestive heart failure due to dilated cardiomyopathy (DCM); asymptomatic / preclinical / potential heart failure due to dilated cardiomyopathy (DCM); dilated cardiomyopathy (DCM); clinically apparent dilated cardiomyopathy (DCM); asymptomatic / preclinical / potential dilated cardiomyopathy (DCM); aortic valve stenosis (valvular, supravalvular and / or subvalvular), which is one or more selected from the group consisting of; heart disease; (viii) Hypertension in non-human mammals, preferably carnivores, more preferably cats or dogs, preferably one or more selected from the group consisting of situational hypertension, secondary hypertension, and idiopathic hypertension, preferably secondary hypertension being associated with chronic kidney disease (CKD), diabetes, obesity, heart disease, endocrine diseases such as Cushing's disease, hyperthyroidism, acromegaly, and hypertension induced by medications, preferably glucocorticoids, mineralocorticoids, erythropoietin, ephedrine, and / or high-dose sodium chloride; (ix) Kidney diseases in non-human mammals, preferably carnivores, more preferably cats or dogs, preferably one or more selected from the group consisting of renal dysplasia, glomerulopathy, polycystic kidney disease, amyloidosis, tubulointerstitial nephritis (TIN), acute kidney disease, and chronic kidney disease; A subject, preferably an animal, more preferably a mammal, particularly a horse, cat, dog, or cow, in need of such treatment and / or prevention, selected from among those in need of such treatment and / or prevention, for use in a method of treating and / or preventing one or more pharmaceutical indications as described and / or claimed herein, relates to an aqueous pharmaceutical composition as described and / or claimed herein.

[0037] The present invention further relates to a process for producing an aqueous pharmaceutical composition as described and / or claimed herein, comprising: (i) mixing one or more organic solvents (if any), such as ethanol, with water (if no organic solvent is present, using only water as the starting material); (ii) adding one or more solubilizing agents to the mixture obtained from step (i) (or water if no organic solvent is present); (iii) dissolving at least one SGLT-2 inhibitor, preferably empagliflozin, in the mixture obtained from step (ii); (iv) optionally, dissolving one or more preservatives in the mixture obtained from step (iii). (v) Optionally, further dissolving in the mixture obtained from step (iii) or optionally (iv) further excipients such as pH adjusters, flavoring agents, sweetening agents, antioxidants, thickening agents and the like; (vi) Optionally, filtering the mixture obtained from step (iii), optionally step (iv) or optionally step (v); comprising; Thereby, optionally, independently of each other, after any of the individual process steps, whether essential or optional, an additional mixing step is carried out, relating to a process.

[0038] In the process of the present invention, such process steps (i) to (vi) do not need to be carried out in a given order, but can also be carried out in any other significant order, for example (i), (v), (ii), (iii), (iv), (vi). Changing the order of the process steps in order to obtain the desired process result, namely the aqueous pharmaceutical composition according to the present invention, is within the knowledge of a person skilled in the art. For example, when adding one or more thickening agents, it is preferred to heat the mixture in order to completely dissolve the one or more thickening agents. Then, in order to avoid the decomposition of unnecessary and undesired substances through such a heating step, it is necessary to cool the mixture thus obtained before adding at least one SGLT-2 inhibitor, preferably empagliflozin (for example, in the form of its L-proline-water co-crystal).

[0039] The present invention further relates to a kit-of-parts comprising: (a) the aqueous pharmaceutical composition described herein and / or the aqueous pharmaceutical composition described in the claims; and (b) an accompanying document containing information that the aqueous pharmaceutical composition is used for preventing and / or treating one or more pharmaceutical indications in a subject in need of such prevention and / or treatment, wherein the one or more indications are the following pharmaceutical indications: (i) A metabolic disorder in equine animals, preferably one or more disorders selected from insulin resistance, hyperinsulinemia, impaired glucose tolerance, dyslipidemia, abnormal lipid kinetics, asymptomatic inflammation, systemic inflammation, mild systemic inflammation, obesity, and / or local obesity. Preferably, the metabolic disorder is insulin resistance, hyperinsulinemia, and / or a clinical condition associated with insulin resistance and / or hyperinsulinemia. Preferably, the clinical condition is one or more conditions selected from impaired glucose tolerance, dyslipidemia, abnormal lipid kinetics, asymptomatic inflammation, systemic inflammation, mild systemic inflammation, obesity, and / or local obesity. (ii) A metabolic disorder in equine animals, preferably one or more disorders selected from laminitis, vascular insufficiency, hypertension, hepatic lipidosis, atherosclerosis, hyperadrenocorticism, pituitary pars intermedia dysfunction, and / or equine metabolic syndrome. Preferably, it is a clinical condition / symptom associated with insulin resistance and / or hyperinsulinemia, and the clinical condition / symptom is preferably one or more conditions selected from laminitis, vascular insufficiency, hypertension, hepatic lipidosis, atherosclerosis, hyperadrenocorticism, pituitary pars intermedia dysfunction, and / or equine metabolic syndrome. (iii) A metabolic disorder in feline animals, preferably one or more selected from the group consisting of ketoacidosis, prediabetes, type 1 or type 2 diabetes, insulin resistance, acromegaly, diabetes with high IGF-1 concentration, obesity, hyperglycemia, impaired glucose tolerance, hyperinsulinemia, dyslipidemia, abnormal lipid kinetics, asymptomatic inflammation, systemic inflammation, mild systemic inflammation, hepatic lipidosis, atherosclerosis, pancreatitis, neuropathy, and / or syndrome X (metabolic syndrome) and / or loss of pancreatic beta cell function, and / or remission of the metabolic disorder, preferably achievement and / or maintenance of diabetes remission. (iv) A metabolic disorder in canids, preferably ketosis, prediabetes, insulin-dependent diabetes, insulin-resistant diabetes, insulin resistance, obesity, hyperglycemia, hyperglycemia-induced cataract formation, impaired glucose tolerance, hyperinsulinemia, dyslipidemia, abnormal lipid metabolism, asymptomatic inflammation, systemic inflammation, mild systemic inflammation, hepatic lipidosis, pancreatitis, as a result of metabolic disorders, such as hypertension, renal insufficiency and / or musculoskeletal disorders, and / or Syndrome X (metabolic syndrome), preferably selected from the group consisting of prediabetes, insulin-dependent diabetes, insulin-resistant diabetes, insulin resistance, and preferably, the occurrence of hyperglycemia-induced cataract formation is prevented or remission is achieved, and / or preferably, as a result of metabolic disorders, such as hypertension, renal insufficiency and / or musculoskeletal disorders, the occurrence is prevented, or the progression is decelerated, or remission is achieved, metabolic disorder; (v) A heart disease in felids, preferably heart failure, heart failure due to one or more cardiomyopathies, heart failure due to hypertrophic cardiomyopathy (HCM), heart failure due to restrictive cardiomyopathy (RCM), heart failure due to dilated cardiomyopathy (DCM), heart failure due to unclassified cardiomyopathy (UCM), arrhythmogenic right ventricular cardiomyopathy (ARVC), hypertrophic cardiomyopathy (HCM), restrictive cardiomyopathy (RCM), dilated cardiomyopathy (DCM), unclassified cardiomyopathy (UCM), and / or arrhythmogenic right ventricular cardiomyopathy (ARVC); preferably selected from the group consisting of heart failure due to one or more cardiomyopathies, heart failure due to hypertrophic cardiomyopathy (HCM), and one or more selected from the group consisting of hypertrophic cardiomyopathy (HCM), heart disease; (vi) Dry-off of non-human mammals, preferably ruminants, which improves and / or promotes dry-off of non-human mammals, preferably ruminants, reduces milk production, preferably milk production and / or secretion, in non-human mammals, preferably ruminants, during pregnancy and / or lactation, reduces milk accumulation and / or engorgement in the mammary glands, preferably mammary glands and / or mammary tissue, of non-human mammals, preferably ruminants, reduces the discomfort associated with mammary engorgement, for example, increases the daytime lying time of non-human mammals, preferably ruminants, and / or reduces stress, reduces milk leakage after dry-off of non-human mammals, preferably ruminants, and reduces the incidence of intramammary infections (IMI), preferably mastitis and / or metritis, in non-human mammals, preferably ruminants; dry-off; (vii) Heart disease in non-human mammals other than cats, particularly dogs, preferably heart failure; congestive heart failure; asymptomatic / preclinical / potential heart failure; heart failure due to (myxomatous) mitral valve disease [(M)MVD]; congestive heart failure due to (myxomatous) mitral valve disease [(M)MVD]; asymptomatic / preclinical / potential heart failure due to (myxomatous) mitral valve disease [(M)MVD]; (myxomatous) mitral valve disease [(M)MVD]; clinically evident (myxomatous) mitral valve disease [(M)MVD]; asymptomatic / preclinical / potential (myxomatous) mitral valve disease [(M)MVD]; heart failure due to dilated cardiomyopathy (DCM); congestive heart failure due to dilated cardiomyopathy (DCM); asymptomatic / preclinical / potential heart failure due to dilated cardiomyopathy (DCM); dilated cardiomyopathy (DCM); clinically evident dilated cardiomyopathy (DCM); asymptomatic / preclinical / potential dilated cardiomyopathy (DCM); aortic stenosis (valvular, supravalvular and / or subvalvular), which is one or more selected from the group consisting of; heart disease; (viii) Hypertension in non-human mammals, preferably carnivores, more preferably cats or dogs, preferably one or more selected from the group consisting of situational hypertension, secondary hypertension, and idiopathic hypertension, preferably secondary hypertension being associated with chronic kidney disease (CKD), diabetes, obesity, heart disease, endocrine diseases such as Cushing's disease, hyperthyroidism, acromegaly, and hypertension induced by medications, preferably glucocorticoids, mineralocorticoids, erythropoietin, ephedrine, and / or high-dose sodium chloride; (ix) Kidney diseases in non-human mammals, preferably carnivores, more preferably cats or dogs, preferably one or more selected from the group consisting of renal dysplasia, glomerulopathy, polycystic kidney disease, amyloidosis, tubulointerstitial nephritis (TIN), acute kidney disease, and chronic kidney disease; Selected from among the attached documents and A kit of parts comprising.

[0040] The advantages of the aqueous pharmaceutical composition according to the present invention are as follows: - Suitable for administration to a subject, preferably without further essential processing and / or purification steps, preferably for direct administration. Thus, preferably, it is sterile and compliant with GMP manufacturing conditions and GCP-compliant clinical protocols; - Stable against unwanted contamination by microorganisms / their growth; - Preferably, a true solution, emulsion, or suspension in a water-based system containing a minimal amount of organic solvent (if any), more preferably a true solution, which preferably ensures biocompatibility and cost reduction.

Mode for Carrying Out the Invention

[0041] Before describing embodiments of the present invention in further detail, as used herein and in the appended claims, the singular forms "a", "an", and "the" are to be construed to include the plural referents unless the context clearly dictates otherwise.

[0042] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. All given ranges and values may vary by 1 to 5% unless otherwise indicated or known to one of ordinary skill in the art, and thus the term "about" is usually omitted herein and in the claims. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, preferred methods, devices, and materials are described herein. All publications described herein are hereby incorporated by reference for the purpose of describing and disclosing the substances, excipients, carriers, and methods reported in the publications that can be used in connection with the present invention. It is not to be construed in this specification that there is any admission that the present invention is prior to such disclosure due to prior invention.

[0043] The at least one SGLT-2 inhibitor according to the present invention includes, but is not limited to, glucopyranosyl-substituted benzene derivatives, for example, glucopyranosyl-substituted benzene derivatives as described in WO01 / 27128, WO03 / 099836, WO2005 / 092877, WO2006 / 034489, WO2006 / 064033, WO2006 / 117359, WO2006 / 117360, WO2007 / 025943, WO2007 / 028814, WO2007 / 031548, WO2007 / 093610, WO2007 / 128749, WO2008 / 049923, WO2008 / 055870, WO2008 / 055940, WO2009 / 022020 or WO2009 / 022008.

[0044] Furthermore, at least one SGLT-2 inhibitor according to the present invention may be selected from the group consisting of the following compounds or their pharmaceutically acceptable (crystalline) forms: (1) Glucopyranosyl-substituted benzene derivatives of formula (1)

[0045] [Chemical formula] (wherein R 1 represents cyano, Cl or methyl (most preferably cyano); R 2 represents H, methyl, methoxy or hydroxy (most preferably H), R 3 represents cyclopropyl, hydrogen, fluorine, chlorine, bromine, iodine, methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, tert-butyl, 3-methyl-but-1-yl, cyclobutyl, cyclopentyl, cyclohexyl, 1-hydroxy-cyclopropyl, 1-hydroxy-cyclobutyl, 1-hydroxy-cyclopentyl, 1-hydroxy-cyclohexyl, ethynyl, ethoxy, difluoromethyl, trifluoromethyl, pentafluoroethyl, 2-hydroxyl-ethyl, hydroxymethyl, 3-hydroxy-propyl, 2-hydroxy-2-methyl-prop-1-yl, 3-hydroxy-3-methyl-but-1-yl, 1-hydroxy-1-methyl-ethyl, 2,2,2-trifluoro-1-hydroxy-1-methyl-ethyl, 2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl, 2-methoxy-ethyl, 2-ethoxy-ethyl, hydroxy, difluoromethyloxy, trifluoromethyloxy, 2-methyloxy-ethyloxy, methylsulfanyl, methylsulfinyl, methylsulfonyl, ethylsulfinyl, ethylsulfonyl, trimethylsilyl, (R)-tetrahydrofuran-3-yloxy or (S)-tetrahydrofuran-3-yloxy or cyano; R 3is preferably selected from cyclopropyl, ethyl, ethynyl, ethoxy, (R)-tetrahydrofuran-3-yloxy or (S)-tetrahydrofuran-3-yloxy; most preferably R 3 is cyclopropyl), or one or more hydroxyl groups of the β-D-glucopyranosyl group are (C 1-18 -alkyl)carbonyl, (C 1-18 -alkyl)oxycarbonyl, phenylcarbonyl and phenyl-(C 1-3 -alkyl)-carbonyl acylated with a group selected from, its derivatives; (2) Veragliflozin represented by formula (2);

[0046]

Chemical formula

Chemical formula

[0047]

Chemical formula

Chemical formula

[0048]

Chemical formula

[0049]

Chemical formula

[0050] [Chemical formula] (9) Ertugliflozin represented by formula (9);

[0051] [Chemical formula] (10) Axicugliflozin represented by formula (10);

[0052] [Chemical formula] (11) Remogliflozin represented by formula (11);

[0053] [Chemical formula] (11A) Remogliflozin etabonate represented by formula (11A);

[0054] [Chemical formula] (12) Thiophene derivative of formula (12);

[0055] [Chemical formula] (wherein R represents methoxy or trifluoromethoxy) (13) 1-(β-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienylmethyl]benzene represented by formula (13);

[0056] [Chemical formula] (14) Spiroketal derivative of formula (14);

[0057] [Chemical formula] (In the formula, R represents methoxy, trifluoromethoxy, ethoxy, ethyl, isopropyl or tert-butyl) (15) Pyrazole-O-glucoside derivative of formula (15)

[0058]

Chemical formula

[0059]

Chemical formula

[0060]

Chemical formula

[0061]

Chemical formula

[0062]

Chemical formula

[0063] [Chemical formula] (21) Longgliflozin represented by formula (21);

[0064] [Chemical formula] (22) Onepagliflozin (23) Enagliflozin represented by formula (23);

[0065] [Chemical formula] (24) TFC-039 represented by formula (24);

[0066] [Chemical formula]

[0067] As used herein, the term "velagliflozin" refers to the pharmaceutically acceptable forms of velagliflozin of the above structure, as well as its hydrates and solvates, and their crystalline forms. The compound, its synthesis method and its cocrystals are described, for example, in WO2007 / 128749, WO2014 / 016381 and WO2019 / 121509.

[0068] As used herein, the term "dapagliflozin" refers to the pharmaceutically acceptable forms of dapagliflozin of the above structure, as well as its hydrates and solvates, and their crystalline forms. The compound, its synthesis method and its cocrystals are described, for example, in WO03 / 099836. Preferred hydrates, solvates and crystalline forms are described, for example, in patent applications WO2008 / 116179 and WO2008 / 002824. As used herein, the term "canagliflozin" refers to its pharmaceutically acceptable forms, including canagliflozin of the above structure, as well as its hydrates and solvates, and their crystalline forms. The compound and its synthesis method are described, for example, in WO2005 / 012326 and WO2009 / 035969. Preferred hydrates, solvates and crystalline forms are described, for example, in patent application WO2008 / 069327.

[0069] As used herein, the term "empagliflozin" refers to its pharmaceutically acceptable forms, including empagliflozin of the above structure, as well as its hydrates and solvates, and their crystalline forms. The compound and its synthesis method are described, for example, in WO2005 / 092877, WO2006 / 120208 and WO2011 / 039108. Preferred crystalline forms are described, for example, in patent applications WO2006 / 117359 and WO2011 / 039107. As used herein, the term "alogliptin" refers to its pharmaceutically acceptable forms, including alogliptin of the above structure, as well as its hydrates and solvates, and their crystalline forms. The compound and its synthesis method are described, for example, in WO2004 / 007517.

[0070] As used herein, the term "ipragliflozin" refers to its pharmaceutically acceptable forms, including ipragliflozin of the above structure, as well as its hydrates and solvates, and their crystalline forms. The compound and its synthesis method are described, for example, in WO2004 / 080990, WO2005 / 012326 and WO2007 / 114475. As used herein, the term "tofogliflozin" refers to its pharmaceutically acceptable forms, including tofogliflozin of the above structure, as well as its hydrates and solvates, and their crystalline forms. The compound and its synthesis method are described, for example, in WO2007 / 140191 and WO2008 / 013280.

[0071] As used herein, the term "luseogliflozin" refers to its pharmaceutically acceptable forms, including luseogliflozin of the above structure, as well as its hydrates and solvates, and their crystalline forms. As used herein, the term "ertugliflozin" refers to its pharmaceutically acceptable forms, including ertugliflozin of the above structure, as well as its hydrates and solvates, and their crystalline forms. The compound is described, for example, in WO2010 / 023594. As used herein, the term "remogliflozin" refers to its pharmaceutically acceptable forms, including remogliflozin of the above structure, as well as prodrugs of remogliflozin, particularly remogliflozin etabonate, and its hydrates and solvates, and their crystalline forms. The method for its synthesis is described, for example, in patent applications EP1 213296 and EP1354888.

[0072] As used herein, the term "sergliflozin" refers to its pharmaceutically acceptable forms, including sergliflozin of the above structure, as well as prodrugs of sergliflozin, particularly sergliflozin etabonate, and its hydrates and solvates, and their crystalline forms. The method for its production is described, for example, in patent applications EP1344780 and EP1489089. The compound of formula (16) above, i.e., sotagliflozin, and its production are described, for example, in WO2008 / 042688 or WO2009 / 014970.

[0073] As used herein, the term "bexagliflozin" refers to its pharmaceutically acceptable forms, including bexagliflozin of the above structure, as well as its hydrates and solvates, and their crystalline forms. The compound and its synthesis method are described, for example, in WO2009 / 026537. As used herein, the term "TFC-039" refers to its pharmaceutically acceptable forms, including the above structure, as well as its hydrates and solvates, and their crystalline forms. The compound and its synthesis method are described, for example, in WO2012 / 160218.

[0074] Preferred SGLT-2 inhibitors are glucopyranosyl-substituted benzene derivatives. Optionally, one or more hydroxyl groups of the glucopyranosyl group in such one or more SGLT-2 inhibitors may be acylated with a group selected from (C 1-18 -alkyl)carbonyl, (C 1-18 -alkyloxycarbonyl, phenylcarbonyl and phenyl-(C 1-3 -alkyl)-carbonyl. More preferred are the glucopyranosyl-substituted benzonitrile derivatives of formula (1) as disclosed above herein. The glucopyranosyl-substituted benzonitrile derivative of formula (18):

[0075]

Chemical formula

[0076] Preferably, such an SGLT-2 inhibitor is empagliflozin as shown in formula (2). Optionally, one or more hydroxyl groups of the β-D-glucopyranosyl group of empagliflozin may be acylated with a group selected from (C 1-18 -alkyl)carbonyl, (C 1-18 -alkyl)oxycarbonyl, phenylcarbonyl and phenyl-(C 1-3 -alkyl)-carbonyl. Thus, in a preferred embodiment, at least one SGLT-2 inhibitor according to the invention is a glucopyranosyl-substituted benzene derivative SGLT-2 inhibitor, preferably in each case an SGLT-2 inhibitor of formula (1) as defined above herein, more preferably an SGLT-2 inhibitor of formula (18), or even more preferably an SGLT-2 inhibitor of formula (2), i.e., empagliflozin.

[0077] In the process of the present invention, 1-cyano-2-(4-cyclopropyl-benzyl)-4-(β-D-glucopyranos-1-yl)-benzene (empagliflozin) is also referred to as the "substance", and together with it, the co-crystal 1-cyano-2-(4-cyclopropyl-benzyl)-4-(β-D-glucopyranos-1-yl)-benzene - L-proline, and the 1:1:1 co-crystal 1-cyano-2-(4-cyclopropyl-benzyl)-4-(β-D-glucopyranos-1-yl)-benzene - L-proline - water (as disclosed in WO2014 / 016381) are also understood to be included. Generally, in the case of the concentrations (mass / volume %) and amounts (g, mg) disclosed and claimed, the concentration or amount always refers to 1-cyano-2-(4-cyclopropyl-benzyl)-4-(β-D-glucopyranos-1-yl)-benzene itself, i.e., in practice (and in the Examples section), even if the 1:1:1 co-crystal 1-cyano-2-(4-cyclopropyl-benzyl)-4-(β-D-glucopyranos-1-yl)-benzene - L-proline - water is actually added / used, the L-proline and water of crystallization are excluded unless otherwise explicitly stated.

[0078] In the process of the present invention, the term "for administration to a subject, preferably for direct administration" in relation to an "aqueous pharmaceutical composition" means that the aqueous pharmaceutical composition can be directly administered to the subject, preferably without further essential processing and / or purification steps, and specifically excludes organic solvents (mixtures) that are only described in the context of producing a crystalline complex of an SGLT-2 inhibitor. Thus, preferably, such an "aqueous pharmaceutical composition" that is "for direct administration to a subject" is sterile and / or compliant with GMP manufacturing conditions and GCP-compliant clinical protocols. In one aspect, the present invention relates to an aqueous pharmaceutical composition as described and / or claimed herein, which is preferably for administration to a subject, more preferably an animal, even more preferably a mammal, particularly a horse, cat, dog or cow, preferably directly, without further essential processing and / or purification steps; preferably, it relates to an aqueous pharmaceutical composition that is sterile.

[0079] In yet another aspect, the present invention relates to an aqueous pharmaceutical composition as described and / or claimed herein, wherein at least one SGLT-2 inhibitor is empagliflozin, which is preferably the only SGLT-2 inhibitor contained in the aqueous pharmaceutical composition.

[0080] In another aspect, the present invention relates to an aqueous pharmaceutical composition as described and / or claimed herein, which is a solution, emulsion or suspension, preferably a solution, emulsion or suspension having an NTU value equal to or less than 10.0, more preferably equal to or less than 7.0, even more preferably equal to or less than 3.0, most preferably a solution, particularly a solution having an NTU value equal to or less than 3.0. In the process of the present invention, the term "NTU" refers to nephelometric turbidity units and the opalescent value as defined and described in the European Pharmacopoeia, 8th Edition (Ph. Eur. 8, Chapter 2.2.1. "Clarity and degree of opalescence of liquids").

[0081] In another aspect, the present invention relates to an aqueous pharmaceutical composition as described and / or claimed herein, containing one or more organic solvents characterized by a negative log 10 P value, preferably a negative logarithm partition coefficient (P) with base 10, in the n-octanol / water system. log 10 P n-オクタノール / 水 = concentration of non-ionized compound in n-octanol / concentration of non-ionized compound in water (II) In a further aspect, the present invention relates to an aqueous pharmaceutical composition as described and / or claimed herein, characterized as a whole by a negative LogP-parameter, preferably a negative LogP-parameter equal to or higher than -2.0 (i.e., -2.0 ≤ LogP-parameter < 0). To avoid doubt, the LogP-parameter is defined as in Equation 4 of Example 1 and is not the same as and should not be confused with the (negative) log 10 P value as shown for the organic solvents.

[0082] In yet another aspect, the present invention relates to an aqueous pharmaceutical composition as described and / or claimed herein, wherein one or more organic solvents are ethanol (log 10 P: -0.16), propane-1,2,3-triol (glycerol; log 10 P: -1.84), pyrrolidone (log 10 P: -0.58), methylpyrrolidone (log 10 P: -0.356), N,N-dimethylacetamide (log10 P: -0.583) and / or N,N-dimethylformamide (log 10 P: -0.632) selected from the group consisting of. log 10 The P value was obtained from http: / / www.chemicalize.org / . In yet another aspect, the present invention relates to an aqueous pharmaceutical composition as described and / or claimed herein, comprising at least two different organic solvents, preferably propan-1,2,3-triol (glycerol) and ethanol. In yet another aspect, the present invention relates to an aqueous pharmaceutical composition as described and / or claimed herein, containing an organic solvent of 20 g / 100 mL (20 mass / volume%) or less, preferably 15 g / 100 mL (15 mass / volume%) or less, more preferably 10 g / 100 mL (10 mass / volume%) or less.

[0083] In yet another aspect, the present invention relates to an aqueous pharmaceutical composition as described and / or claimed herein, which does not contain propan-1,2-diol (propylene glycol). In yet another aspect, the present invention relates to an aqueous pharmaceutical composition as described and / or claimed herein, containing ethanol as the only organic solvent in the aqueous pharmaceutical composition. Preferably, ethanol is present in the aqueous pharmaceutical composition at 20 g / 100 mL (20 mass / volume%) or less, more preferably 15 g / 100 mL (15 mass / volume%) or less, even more preferably 10 g / 100 mL (10 mass / volume%) or less, and most preferably 8 g / 100 mL (8 mass / volume%).

[0084] In yet another aspect, the present invention relates to an aqueous pharmaceutical composition as described and / or claimed herein, which substantially does not contain an organic solvent and preferably contains no organic solvent at all. When no organic solvent is present, the solvent of the aqueous pharmaceutical composition is 100% water and is preferably in the form of an aqueous buffer solution. In yet another aspect, the present invention relates to an aqueous pharmaceutical composition as described and / or claimed herein, which contains water in the form of an aqueous buffer solution, such as a citrate buffer solution, a phosphate buffer solution, an ammonium sulfate buffer solution, an ammonium acetate buffer solution, a sodium acetate buffer solution, and the like, preferably an aqueous buffer solution having a pH of 4.5, more preferably a citrate buffer solution having a pH of 4.5.

[0085] In yet another aspect, the present invention relates to an aqueous pharmaceutical composition as described and / or claimed herein, which contains 30 to 100 g / 100 mL (30 to 100 mass / volume %), preferably 30 to 95 g / 100 mL (30 to 95 mass / volume %), more preferably 30 to 90 g / 100 mL (30 to 90 mass / volume %), more preferably 30 to 85 g / 100 mL (30 to 85 mass / volume %), even more preferably 30 to 80 g / 100 mL (30 to 80 mass / volume %), and most preferably 50 to 80 g / 100 mL (50 to 80 mass / volume %) of water, more preferably in the form of an aqueous buffer solution, such as a citrate buffer solution, even more preferably an aqueous buffer solution having a pH of 4.5, and most preferably a citrate buffer solution having a pH of 4.5. In yet another aspect, the present invention relates to an aqueous pharmaceutical composition as described and / or claimed herein, which has a (measured) pH value of 2 to 7, preferably 3 to 7, more preferably 3.0 to 6.5, even more preferably 4.0 to 6.5, even more preferably 4.0 to 5.0, and most preferably 4.5. To avoid doubt, the term "measured pH value" refers to the pH value actually measured for the entire aqueous pharmaceutical composition according to the present invention, i.e., including both the organic solvent phase and the aqueous phase if any.

[0086] In yet another aspect, the present invention relates to an aqueous pharmaceutical composition as described and / or claimed herein, additionally comprising one or more preservatives, preferably sorbic acid or a salt thereof, preferably sodium sorbate, potassium sorbate, calcium sorbate; benzoic acid or a salt thereof, preferably sodium benzoate; benzalkonium chloride; benzethonium chloride; benzyl alcohol, cetylpyridinium chloride; sodium metabisulfite; sodium acetate; parabens and salts thereof, preferably methylparaben, ethylparaben, propylparaben, butylparaben, sodium butylparaben; most preferably one or more preservatives selected from the group consisting of benzoic acid and / or a salt thereof, such as sodium benzoate.

[0087] In yet another aspect, the present invention relates to an aqueous pharmaceutical composition as described and / or claimed herein, additionally comprising one or more antioxidants, preferably ascorbic acid or a pharmaceutically acceptable salt thereof, particularly sodium ascorbate; citric acid (anhydrous and / or monohydrate) or a pharmaceutically acceptable salt thereof, more preferably sodium citrate; erythorbic acid; fumaric acid; malic acid; monothioglycerol; phosphoric acid; sodium metabisulfite; potassium metabisulfite; propionic acid; sodium bisulfite; sodium sulfite; resveratrol; butylated hydroxyanisole; butylated hydroxytoluene; gallate derivatives, particularly propyl gallate, octyl gallate; vitamin E or a pharmaceutically acceptable salt thereof; ascorbyl palmitate; edetic acid or a pharmaceutically acceptable salt thereof; most preferably an antioxidant selected from the group consisting of sodium metabisulfite.

[0088] In yet another aspect, the present invention relates to an aqueous pharmaceutical composition as described and / or claimed herein, wherein one or more solubilizing agents are selected from the group consisting of surfactants, anionic surfactants, nonionic surfactants, hydrogenated castor oil, polyoxyethylene-polyoxypropylene block copolymers, polyethylene glycols, propylene glycol derivatives, and polyvinylpyrrolidone, more preferably selected from the group consisting of sodium dodecyl sulfate (SDS), Cremophor RH 40 (PEG-40 hydrogenated castor oil, Macrogol glycerol hydroxystearate 40), polysorbate 20, Lutrol F68 (Poloxamer 188), PEG 200, PEG 300, PEG 400, propylene glycol monolaurate, Kollidon 12 (povidone), preferably the total amount of one or more solubilizing agents is 1 to 50 g / 100 mL (1 to 50 mass / volume %), more preferably 1 to 45 g / 100 mL (1 to 45 mass / volume %), even more preferably 1 to 40 g / 100 mL (1 to 40 mass / volume %), even more preferably 1 to 35 g / 100 mL (1 to 35 mass / volume %), even more preferably 1 to 30 g / 100 mL (1 to 30 mass / volume %), even more preferably 1 to 25 g / 100 mL (1 to 25 mass / volume %), and most preferably 5 to 25 g / 100 mL (5 to 25 mass / volume %). In yet another aspect, the present invention relates to an aqueous pharmaceutical composition as described and / or claimed herein, wherein two or more solubilizing agents are included in the aqueous pharmaceutical composition.

[0089] In yet another aspect, the present invention is an aqueous pharmaceutical composition as described and / or claimed herein, wherein two solubilizers are contained in the aqueous pharmaceutical composition, preferably, the amount of the first solubilizer and the amount of the second solubilizer are, independently of each other, selected from 1 to 50 g / 100 mL (1 to 50 mass / volume %), more preferably 1 to 45 g / 100 mL (1 to 45 mass / volume %), even more preferably 1 to 40 g / 100 mL (1 to 40 mass / volume %), even more preferably 1 to 35 g / 100 mL (1 to 35 mass / volume %), even more preferably 1 to 30 g / 100 mL (1 to 30 mass / volume %), even more preferably 1 to 25 g / 100 mL (1 to 25 mass / volume %), most preferably 5 to 25 g / 100 mL (5 to 25 mass / volume %), more preferably these two solubilizers are, independently of each other, selected from the group consisting of sodium dodecyl sulfate (SDS), Cremophor RH 40 (PEG-40 hydrogenated castor oil, Macrogol glycerol hydroxystearate 40), polysorbate 20, Lutrol F 68 (Poloxamer 188), PEG 200, PEG 300, PEG 400, propylene glycol monolaurate, Kollidon 12 (povidone), even more preferably, the two solubilizers are Kollidon 12 (povidone), and PEG 200, PEG 300, or PEG 400, most preferably Kollidon 12 (povidone) and PEG 300, and relates to an aqueous pharmaceutical composition.

[0090] In yet another aspect, the present invention is an aqueous pharmaceutical composition as described and / or claimed herein, which additionally contains one or more thickeners, preferably, selected from the group consisting of inorganic gel formers, organic gel formers, cellulose derivatives, more preferably thickeners selected from the group consisting of hydroxyethyl cellulose, hydroxypropyl methyl cellulose, silicon dioxide, and relates to an aqueous pharmaceutical composition. In yet another aspect, the present invention relates to an aqueous pharmaceutical composition as described and / or claimed herein, additionally comprising one or more flavoring agents and / or sweetening agents, preferably a honey flavoring agent, a lime / salvia flavoring agent, a jasmine flavoring agent, a lavender flavoring agent, a peppermint flavoring agent, a raspberry flavoring agent, a lemon flavoring agent, a herb flavoring agent, a meat flavoring agent, a vanilla / vanilla flavoring agent, saccharin, aspartame, sorbitol, xylitol, selected from the group consisting of flavoring agents and / or sweetening agents.

[0091] In yet another aspect, the present invention relates to an aqueous pharmaceutical composition as described and / or claimed herein, preferably and independently of each other, equal to 0 or higher log 10 characterized by a P value and containing no non-polar organic solvent, an aqueous pharmaceutical composition.

[0092] In yet another aspect, the present invention relates to an aqueous pharmaceutical composition as described and / or claimed herein, for oral and / or parenteral administration, preferably for oral administration, an aqueous pharmaceutical composition.

[0093] In yet another aspect, the present invention relates to an aqueous pharmaceutical composition as described and / or claimed herein, (i) at least one SGLT-2 inhibitor, preferably empagliflozin, more preferably the only and single SGLT-2 inhibitor, even more preferably empagliflozin alone as the single SGLT-2 inhibitor; (ii) Optionally, but preferably, one or more preservatives; preferably sorbic acid or its salts, preferably sodium sorbate, potassium sorbate, calcium sorbate; benzoic acid or its salts, preferably sodium benzoate; benzalkonium chloride; benzethonium chloride; benzyl alcohol, cetylpyridinium chloride; sodium metabisulfite; sodium acetate; parabens and their salts, preferably methylparaben, ethylparaben, propylparaben, butylparaben, sodium butylparaben; or a combination thereof; most preferably a preservative selected from the group consisting of benzoic acid and / or its salts, such as sodium benzoate; (iii) Optionally, one or more organic solvents, preferably an organic solvent selected from the group consisting of ethanol, propane-1,2,3-triol (glycerol), pyrrolidone, methylpyrrolidone, N,N-dimethylacetamide and / or N,N-dimethylformamide, more preferably ethanol; (iv) Optionally, one or more flavoring agents and / or sweeteners, preferably a flavoring agent and / or sweetener selected from the group consisting of honey flavor, lime / salvia flavor, jasmine flavor, lavender flavor, peppermint flavor, raspberry flavor, lemon flavor, herb flavor, meat flavor, vanilla / vanilla flavor, saccharin, aspartame, sorbitol, xylitol; (v) Water, preferably an aqueous buffer, more preferably a citrate buffer, even more preferably an aqueous buffer having a pH of 4.5, most preferably water in the form of a citrate buffer having a pH of 4.5; (vi) one or more solubilizing agents, preferably selected from the group consisting of surfactants, anionic surfactants, nonionic surfactants, hydrogenated castor oil, polyoxyethylene-polyoxypropylene block copolymers, polyethylene glycols, propylene glycol derivatives, polyvinylpyrrolidone, more preferably a solubilizing agent selected from the group consisting of sodium dodecyl sulfate (SDS), Cremophor RH 40 (PEG-40 hydrogenated castor oil, Macrogol glycerol hydroxystearate 40), polysorbate 20, Lutrol F68 (Poloxamer 188), PEG 200, PEG 300, PEG 400, propylene glycol monolaurate, Kollidon 12 (povidone); (vii) optionally, one or more thickeners, preferably selected from the group consisting of inorganic gel formers, organic gel formers, cellulose derivatives, more preferably a thickener selected from the group consisting of hydroxyethyl cellulose, hydroxypropyl methylcellulose, silicon dioxide; (viii) optionally, one or more antioxidants, preferably ascorbic acid or a pharmaceutically acceptable salt thereof, particularly sodium ascorbate; citric acid (anhydrous and / or monohydrate) or a pharmaceutically acceptable salt thereof, more preferably sodium citrate; erythorbic acid; fumaric acid; malic acid; monothioglycerol; phosphoric acid; sodium metabisulfite; potassium metabisulfite; propionic acid; sodium bisulfite; sodium sulfite; resveratrol; butylhydroxyanisole; butylhydroxytoluene; gallate derivatives, particularly propyl gallate, octyl gallate; vitamin E or a pharmaceutically acceptable salt thereof; ascorbyl palmitate; edetic acid or a pharmaceutically acceptable salt thereof; most preferably an antioxidant selected from the group consisting of sodium metabisulfite relates to an aqueous pharmaceutical composition comprising, preferably consisting of, these.

[0094] In yet another aspect, the present invention is an aqueous pharmaceutical composition as described and / or claimed herein, (i) At least one SGLT-2 inhibitor at 0.5 to 20.0 g / 100 mL (0.5 to 20.0 mass / volume %), preferably 0.5 to 15.0 g / 100 mL (0.5 to 15.0 mass / volume %), more preferably 1.0 to 1.5 g / 100 mL (1.0 to 1.5 mass / volume %), preferably empagliflozin, more preferably the sole and single SGLT-2 inhibitor, and even more preferably only empagliflozin as the single SGLT-2 inhibitor; (ii) One or more preservatives at 0 to 3.0 g / 100 mL (0 to 3.0 mass / volume %), preferably 0.05 to 3.0 g / 100 mL (0.05 to 3.0 mass / volume %), more preferably 0.05 to 2.0 g / 100 mL (0.05 to 2.0 mass / volume %); even more preferably sorbic acid or its salts, preferably sodium sorbate, potassium sorbate, calcium sorbate; benzoic acid or its salts, preferably sodium benzoate; benzalkonium chloride; benzethonium chloride; benzyl alcohol, cetylpyridinium chloride; sodium metabisulfite; sodium acetate; parabens and their salts, preferably methylparaben, ethylparaben, propylparaben, butylparaben, sodium butylparaben; or a combination thereof; most preferably a preservative selected from the group consisting of benzoic acid and / or its salts, such as sodium benzoate; (iii) One or more organic solvents at 0 to 20 g / 100 mL (0 to 20 mass / volume %), preferably 0 to 15 g / 100 mL (0 to 15 mass / volume %), more preferably 0 to 12 g / 100 mL (0 to 12 mass / volume %), even more preferably 0 to 10 g / 100 mL (0 to 10 mass / volume %), preferably an organic solvent selected from the group consisting of ethanol, propane-1,2,3-triol (glycerol), pyrrolidone, methylpyrrolidone, N,N-dimethylacetamide and / or N,N-dimethylformamide, more preferably ethanol; (iv) One or more flavoring agents and / or sweeteners in an amount of 0 to 40 g / 100 mL (0 to 40 mass / volume %), preferably 0 to 30 g / 100 mL (0 to 30 mass / volume %), more preferably 0 to 2 g / 100 mL (0 to 2 mass / volume %), more preferably a honey flavoring agent, a lime / salvia flavoring agent, a jasmine flavoring agent, a lavender flavoring agent, a peppermint flavoring agent, a raspberry flavoring agent, a lemon flavoring agent, a herb flavoring agent, a meat flavoring agent, a vanilla / vanilla flavoring agent, saccharin, aspartame, sorbitol, xylitol; (v) Water in an amount of 30 to 100 g / 100 mL (30 to 100 mass / volume %), preferably 30 to 95 g / 100 mL (30 to 95 mass / volume %), more preferably 30 to 90 g / 100 mL (30 to 90 mass / volume %), more preferably 30 to 85 g / 100 mL (30 to 85 mass / volume %), even more preferably 30 to 80 g / 100 mL (30 to 80 mass / volume %), most preferably 50 to 80 g / 100 mL (50 to 80 mass / volume %), preferably in the form of an aqueous buffer, more preferably a citrate buffer, even more preferably an aqueous buffer having a pH of 4.5, most preferably a citrate buffer having a pH of 4.5; (vi) One or more solubilizing agents at 1 to 50 g / 100 mL (1 to 50 mass / volume %), preferably 1 to 45 g / 100 mL (1 to 45 mass / volume %), more preferably 1 to 40 g / 100 mL (1 to 40 mass / volume %), even more preferably 1 to 35 g / 100 mL (1 to 35 mass / volume %), even more preferably 1 to 30 g / 100 mL (1 to 30 mass / volume %), even more preferably 1 to 25 g / 100 mL (1 to 25 mass / volume %), and most preferably 5 to 25 g / 100 mL (5 to 25 mass / volume %), preferably selected from the group consisting of surfactants, anionic surfactants, nonionic surfactants, hydrogenated castor oil, polyoxyethylene-polyoxypropylene block copolymers, polyethylene glycols, propylene glycol derivatives, and polyvinylpyrrolidone, more preferably selected from the group consisting of sodium dodecyl sulfate (SDS), Cremophor RH 40 (PEG-40 hydrogenated castor oil, Macrogol glycerol hydroxystearate 40), polysorbate 20, Lutrol F68 (Poloxamer 188), PEG 200, PEG 300, PEG 400, propylene glycol monolaurate, and Kollidon 12 (povidone); (vii) One or more thickeners at 0 to 40 g / 100 mL (0 to 40 mass / volume %), preferably 10 to 30 g / 100 mL (10 to 30 mass / volume %), preferably selected from the group consisting of inorganic gel formers, organic gel formers, and cellulose derivatives, more preferably selected from the group consisting of hydroxyethyl cellulose, hydroxypropyl methylcellulose, and silicon dioxide; (viii) One or more antioxidants in an amount of 0 to 1.0 g / 100 mL (0 to 1.0 mass / volume %), preferably 0 to 0.5 g / 100 mL (0 to 0.5 mass / volume %), more preferably 0.1 to 0.3 g / 100 mL (0.1 to 0.3 mass / volume %), preferably ascorbic acid or a pharmaceutically acceptable salt thereof, particularly sodium ascorbate; citric acid (anhydrous and / or monohydrate) or a pharmaceutically acceptable salt thereof, more preferably sodium citrate; erythorbic acid; fumaric acid; malic acid; monothioglycerol; phosphoric acid; sodium metabisulfite; potassium metabisulfite; propionic acid; sodium bisulfite; sodium sulfite; resveratrol; butylated hydroxyanisole; butylated hydroxytoluene; gallate derivatives, particularly propyl gallate, octyl gallate; vitamin E or a pharmaceutically acceptable salt thereof; ascorbyl palmitate; edetic acid or a pharmaceutically acceptable salt thereof; most preferably an antioxidant selected from the group consisting of sodium metabisulfite relates to an aqueous pharmaceutical composition comprising, preferably consisting of, the same.

[0095] In yet another aspect, the present invention relates to an aqueous pharmaceutical composition as described and / or claimed herein, comprising velagliflozin; sodium dodecyl sulfate (SDS), Cremophor RH 40 (PEG-40 hydrogenated castor oil, Macrogol glycerol hydroxystearate 40), polysorbate 20, Lutrol F 68 (Poloxamer 188), PEG 200, PEG 300, PEG 400, propylene glycol monolaurate and / or Kollidon 12 (povidone); sodium benzoate; optionally, Na metabisulfite; optionally, ethanol; water, preferably consisting of the same.

[0096] In yet another aspect, the present invention relates to an aqueous pharmaceutical composition as described and / or claimed herein, comprising velagliflozin; citric acid monohydrate; NaOH; sodium dodecyl sulfate (SDS), Cremophor RH 40 (PEG-40 hydrogenated castor oil, Macrogol glycerol hydroxystearate 40), polysorbate 20, Lutrol F 68 (Poloxamer 188), PEG 200, PEG 300, PEG 400, propylene glycol monolaurate and / or Kollidon 12 (povidone); sodium benzoate; optionally, sodium metabisulfite; optionally, ethanol; water, preferably consisting of these, an aqueous pharmaceutical composition.

[0097] In yet another aspect, the present invention relates to an aqueous pharmaceutical composition as described and / or claimed herein, comprising velagliflozin; citric acid monohydrate; NaOH; sodium dodecyl sulfate (SDS), Cremophor RH 40 (PEG-40 hydrogenated castor oil, Macrogol glycerol hydroxystearate 40), polysorbate 20, Lutrol F 68 (Poloxamer 188), PEG 200, PEG 300, PEG 400, propylene glycol monolaurate and / or Kollidon 12 (povidone); sodium benzoate; optionally, sodium metabisulfite; optionally, ethanol; sorbitol and / or xylitol; honey flavoring agent and / or vanillin and / or meat flavoring agent; water, preferably consisting of these, an aqueous pharmaceutical composition. In yet another aspect, the present invention is:

[0098] [Table 1] JPEG2025516857000051.jpg83157 JPEG2025516857000052.jpg73156 relates to an aqueous pharmaceutical composition as described and / or claimed herein, selected from [Examples]

[0099] The following examples are useful for further illustrating the present invention; they should not be construed as limiting or interpreting the scope of the present invention disclosed herein.

[0100] (Example 1) The test criteria applied are for evaluating the clarity of a liquid (formulation) containing 1-cyano-2-(4-cyclopropyl-benzyl)-4-(β-D-glucopyranos-1-yl)-benzene (veragliflozin) according to the 8th edition of the European Pharmacopoeia. Regarding Chapter 2.2.1. "Clarity and degree of opalescence of liquids" in the 8th edition of the European Pharmacopoeia, a liquid is judged to be clear if its opalescence is not more pronounced than that of reference suspension I with an opalescent value of 3 NTU (Table 1).

[0101] [Table 2] Next, exemplary pharmaceutical compositions of solvents mixed with 1-cyano-2-(4-cyclopropyl-benzyl)-4-(β-D-glucopyranos-1-yl)-benzene (veragliflozin; substance) according to the present invention are shown in detail. The turbidity was measured by using a Hach Lange 2100 N IS device. In order to quantify the solvent properties with respect to their suitability to form a physically stable solution with the substance, the LogP-parameter was introduced (Equation 4). The LogP-parameter indicates the hydrophilicity / hydrophobicity of a solvent mixture containing an organic solvent and an aqueous solvent and is calculated as follows:

[0102] [Equation]

[0103] mo i[mol / g]: Molecular weight of the organic solvent in the organic phase of the solvent mixture Mo i [-]: Organic solvent mo in the organic phase of the solvent mixture i Mole fraction of LogP i [-]: log 10 P n-オクタノール / 水 = Concentration of non-ionized compound in n-octanol / Concentration of non-ionized compound in water of the organic solvent LogPo[-]: Auxiliary parameter of the organic phase of the solvent mixture a w [g]: Mass of water or aqueous buffer in the solvent mixture a sol [g]: Mass of the solvent mixture X o [-]: Mass fraction of the organic phase in the solvent mixture As described in WO2017 / 032799, when the LogP-parameter < -2.0, an unstable phenomenon is predicted.

[0104] Exemplary calculation For ethanol, log 10 P value (= LogP i ) is -0.16 and the molecular weight is shown as 46.07 g / mol. The solvent mixture of Composition 1 consists of 80.0 mg / mL of ethanol and 644.3 mg / mL of H 2 O (total of purified water and aqueous buffer), which corresponds to 11.0% (m / m) of the organic phase. Since ethanol is the only organic solvent, the amount of ethanol in the organic phase is 100% (m / m) or 100 g / 100 g, which corresponds to 0.0217 mol / g (= mo エタノール ). Therefore, Mo エタノール is 1 (Equation 1) and LogPo is calculated as -0.16 (Equation 2). The mass fraction of the organic phase is 11.0% (m / m), or according to Equation 3, X o = 0.11. According to Equation 4, a LogP parameter of -1.45 is calculated for the solvent mixture of Composition 1.

[0105] (Example 2) In Table 2 below, exemplary pharmaceutical compositions according to the present invention are shown in detail (API: active pharmaceutical ingredient).

[0106] [Table 3]

[0107] For a single small-scale batch (1000 mL), the production procedure of an exemplary pharmaceutical composition according to the present invention is as follows in the form of general instructions: Prepare the buffer solution. Weigh the aqueous buffer solution in a container. Weigh the solubilizer component and add it to the buffer solution with stirring. Weigh the preservative (if any) and add it to the solution with stirring. Weigh the antioxidant and add it to the solution with stirring. Weigh the organic solvent (if any) and add it to the solution with stirring. Weigh the sweetening agent and / or thickening agent and add it to the solution with stirring. Weigh at least one SGLT-2 inhibitor, preferably empagliflozin, and add it little by little to the solution. Weigh the flavoring agent and add it to the solution with stirring. Stir until completely dissolved. Filter the solution.

[0108] (Example 3) The formulation was produced using the compositions listed in Table 3 below (API: active pharmaceutical ingredient). [Table 4]

[0109] The following procedure was used to prepare the samples: 1. Weigh the total amount of the aqueous buffer solution into a container. 2. Weigh the total amount of PEG into a beaker and slowly add it to the stirring solution. 3. Weigh the total amount of absolute ethanol and add it to the stirring solution (if any). Stir until completely mixed. 4. Weigh the preservative and add it to the solution with stirring (if any). 5. Weigh the total amount of at least one SGLT-2 inhibitor, preferably empagliflozin, into a beaker and add it little by little to the stirring solution. Stir until completely dissolved. 6. Weigh the total amount of the flavoring agent into a beaker and add it to the stirring solution. Stir until completely dissolved. 7. Weigh the total amount of the sweetening agent and / or thickening agent and add it to the solution with stirring. 8. Stir until completely dissolved. 9. Filter the solution using an 8 μm filter.

[0110] (Example 4) Formulation samples were produced using the compositions listed in Table 4 below.

Table 5

[0111] The following procedure was used to prepare the samples: Weigh the total amount of water into a container. Weigh the total amounts of 1N NaOH and citric acid monohydrate into a beaker and add them to the stirring water. Stir until completely dissolved. Weigh the total amount of the solubilizer (Kollidon 12 or PEG 300) into a beaker and slowly add it to the stirring solution. Weigh the total amount of absolute ethanol into a beaker and add it to the stirring solution. Stir until completely mixed. Weigh the antioxidant (if necessary) and the preservative and add them to the solution with stirring. Weigh the total amount of the sweetening agent and / or thickening agent and add it to the solution with stirring. Weigh the total amount of the flavoring agent into a beaker and add it to the stirring solution. Stir until completely dissolved. Weigh the total amount of empagliflozin into a beaker and add it little by little to the stirring solution. Stir until completely dissolved. Filter the solution using an 8 μm filter. The solution was found to have the following characteristics (Table 5).

[0112] [Table 6]

[0113] Furthermore, the effectiveness of antimicrobial preservation of Compositions 1 - 4 was investigated. The test criteria applied are for evaluating the antimicrobial activity of oral preparations according to the European Pharmacopoeia 7 (tested on days 14 and 28). The acceptance criteria of the European Pharmacopoeia, 7th Edition, Method 5.1.3, "Efficacy of Antimicrobial Preservation", and the United States Pharmacopoeia 34, Method <51>, "Antimicrobial Effectiveness Testing" are listed in Table 6 below.

[0114] [Table 7]

[0115] The following microorganisms were tested: Pseudomonas aeruginosa, Staphylococcus aureus, Escherichia coli, Candida albicans, Aspergillus brasiliensis, Burkholderia cepacia. In the tests conducted, it was found that for all microorganisms, all the formulations met the United States Pharmacopoeia 34 Method <51> Criteria as listed in Table 6.

[0116] (Example 5) After sample preparation, for the investigation of chemical stability, the solution was filled into polyethylene bottles and closed with polypropylene caps. For Compositions 1, 2, 3, and 4, according to HPLC analysis, after 6 months at 25°C / 60% relative humidity and 40°C / 75% relative humidity, the API content remained constant at 15.0 ± 0.1 mg / mL, and no additional degradation of ≥ 1.0% was measured (Table 7).

[0117] [Table 8]

[0118] (Example 6) Formulation samples were produced using the compositions listed in Tables 8 and 9 below. [Table 9]

[0119] [Table 10]

[0120] The following procedure was used to prepare the samples: Weigh approximately 80% of the predicted amount of water into a container. Weigh the total amount of 1N NaOH and citric acid monohydrate into a beaker and add to the stirring water. Stir until completely dissolved. Weigh the total amount of each solubilizer (Kollidon 12, PEG 300, sodium lauryl sulfate, Cremophor RH40, polysorbate 80, Poloxamer 188, and / or PEG 400) into a beaker and slowly add to the stirring solution. Weigh the antioxidant (if required) and preservative and add to the solution with stirring. Weigh the total amount of sweetener and / or thickener and add to the solution with stirring. Weigh the total amount of the flavoring agent into a beaker and add to the stirring solution. Stir until completely dissolved. Weigh the total amount of velagliflozin into a beaker and add it little by little to the stirring solution. Stir until completely dissolved. Fill with water until it reaches 1100 ml. Stir until a uniform and clear solution is obtained. The temperature test (alternate storage between 4 °C and 23 °C for 3 weeks) showed no visual changes for all samples (Table 10).

[0121]

Table 11

[0122] JPEG2025516857000064.jpg172113

[0123] The following clauses are also part of the present disclosure and are included within the spirit and scope of the present invention: 1. An aqueous pharmaceutical composition comprising at least one SGLT-2 inhibitor and one or more solubilizing agents. 2. The at least one SGLT-2 inhibitor is: (1) A glucopyranosyl-substituted benzene derivative of formula (1)

[0124]

Chemical formula

[0125]

Chemical formula

[0126]

Chem.

[0127]

Chem.

Chem.

[0128]

Chem.

[0129]

Chem.

[0130]

Chem.

[0131]

Chem.

[0132]

Chem.

[0133]

Chem.

[0134]

Chem.

[0135]

Chem.

[0136]

Chem.

[0137]

Chem.

[0138]

Chem.

[0139]

Chemical formula

[0140]

Chemical formula

[0141]

Chemical formula

[0142]

Chemical formula

[0143] [Chemical formula] (21) Longiflozin,

[0144] [Chemical formula] (22) Onepagliflozin The aqueous pharmaceutical composition according to clause 1, selected from the group consisting of

[0145] 3. At least one SGLT-2 inhibitor is velagliflozin, which is preferably the only SGLT-2 inhibitor contained in the aqueous pharmaceutical composition, and / or the aqueous pharmaceutical composition is for administration to a subject, preferably an animal, more preferably a mammal, particularly a horse, a cat, a dog or a cow; preferably sterile, the aqueous pharmaceutical composition according to any one of clauses 1 to 2. 4. The aqueous pharmaceutical composition according to any one of clauses 1 to 3, substantially free of organic solvents, preferably containing no organic solvents. 5. The aqueous pharmaceutical composition according to any one of clauses 1 to 3, containing 20 g / 100 mL (20 mass / volume%) or less of an organic solvent, preferably 15 g / 100 mL (15 mass / volume%) or less of an organic solvent, more preferably 10 g / 100 mL (10 mass / volume%) or less of an organic solvent, preferably the organic solvent contains ethanol, and more preferably ethanol is the only organic solvent contained in the aqueous pharmaceutical composition.

[0146] 6. The aqueous pharmaceutical composition according to clause 5, not containing propane-1,2-diol (propylene glycol). 7. One or more solubilizing agents are selected from the group consisting of "surfactants, anionic surfactants, nonionic surfactants, hydrogenated castor oil, polyoxyethylene-polyoxypropylene block copolymers, polyethylene glycols, propylene glycol derivatives, polyvinylpyrrolidone", preferably selected from the group consisting of "sodium dodecyl sulfate (SDS), Cremophor RH 40 (PEG-40 hydrogenated castor oil, Macrogol glycerol hydroxystearate 40), polysorbate 20, Lutrol F68 (Poloxamer 188), PEG 200, PEG 300, PEG 400, propylene glycol monolaurate, Kollidon 12 (povidone)", preferably the total amount of one or more solubilizing agents is 1 to 50 g / 100 mL (1 to 50 mass / volume %), more preferably 1 to 45 g / 100 mL (1 to 45 mass / volume %), even more preferably 1 to 40 g / 100 mL (1 to 40 mass / volume %), even more preferably 1 to 35 g / 100 mL (1 to 35 mass / volume %), even more preferably 1 to 30 g / 100 mL (1 to 30 mass / volume %), even more preferably 1 to 25 g / 100 mL (1 to 25 mass / volume %), and most preferably 5 to 25 g / 100 mL (5 to 25 mass / volume %), the aqueous pharmaceutical composition according to any one of clauses 1 to 6.

[0147] 8. The aqueous pharmaceutical composition according to any one of clauses 1 to 6, wherein two or more solubilizing agents are contained in the aqueous pharmaceutical composition. 9. Two solubilizers are contained in the aqueous pharmaceutical composition. Preferably, the amount of the first solubilizer and the amount of the second solubilizer are, independently of each other, selected from 1 to 50 g / 100 mL (1 to 50 mass / volume %), more preferably 1 to 45 g / 100 mL (1 to 45 mass / volume %), even more preferably 1 to 40 g / 100 mL (1 to 40 mass / volume %), even more preferably 1 to 35 g / 100 mL (1 to 35 mass / volume %), even more preferably 1 to 30 g / 100 mL (1 to 30 mass / volume %), even more preferably 1 to 25 g / 100 mL (1 to 25 mass / volume %), and most preferably 5 to 25 g / 100 mL (5 to 25 mass / volume %). More preferably, these two solubilizers are, independently of each other, selected from the group consisting of "sodium dodecyl sulfate (SDS), Cremophor RH 40 (PEG-40 hydrogenated castor oil, Macrogol glycerol hydroxystearate 40), polysorbate 20, Lutrol F 68 (Poloxamer 188), PEG 200, PEG 300, PEG 400, propylene glycol monolaurate, Kollidon 12 (povidone)". Even more preferably, the two solubilizers are Kollidon 12 (povidone) and PEG 200, PEG 300, or PEG 400, and most preferably Kollidon 12 (povidone) and PEG 300. The aqueous pharmaceutical composition according to clause 8.

[0148] 10. A solution, emulsion or suspension, preferably having an NTU value equal to or less than 10.0, more preferably equal to or less than 7.0, even more preferably equal to or less than 3.0. Most preferably, it is a solution, especially a solution having an NTU value equal to or less than 3.0. The aqueous pharmaceutical composition according to any one of clauses 1 to 9. 11. The aqueous pharmaceutical composition according to any one of clauses 1 to 10, containing water in an amount of 30 to 100 g / 100 mL (30 to 100 mass / volume %), preferably 30 to 95 g / 100 mL (30 to 95 mass / volume %), more preferably 30 to 90 g / 100 mL (30 to 90 mass / volume %), still more preferably 30 to 85 g / 100 mL (30 to 85 mass / volume %), even more preferably 30 to 80 g / 100 mL (30 to 80 mass / volume %), and most preferably 50 to 80 g / 100 mL (50 to 80 mass / volume %), preferably in the form of an aqueous buffer, such as a citrate buffer.

[0149] 12. The aqueous pharmaceutical composition according to clause 11, having a measured pH value of 2 to 7, preferably 3 to 7, more preferably 3.0 to 6.5, still more preferably 4.0 to 6.5, even more preferably 4.0 to 5.0, and most preferably 4.5.

[0150] 13. Additionally, it contains one or more preservatives, preferably sorbic acid or its salts, more preferably sodium sorbate, potassium sorbate, calcium sorbate; benzoic acid or its salts, more preferably sodium benzoate; benzalkonium chloride; benzethonium chloride; benzyl alcohol, cetylpyridinium chloride; sodium metabisulfite; sodium acetate; parabens and their salts, more preferably methylparaben, ethylparaben, propylparaben, butylparaben, sodium butylparaben; most preferably a preservative selected from the group consisting of benzoic acid and / or its salts, such as sodium benzoate; and / or additionally, it contains one or more antioxidants, preferably ascorbic acid or its pharmaceutically acceptable salts, particularly sodium ascorbate; citric acid (anhydrous and / or monohydrate) or its pharmaceutically acceptable salts, more preferably sodium citrate; erythorbic acid; fumaric acid; malic acid; monothioglycerol; phosphoric acid; sodium metabisulfite; potassium metabisulfite; propionic acid; sodium bisulfite; sodium sulfite; resveratrol; butylated hydroxyanisole; butylated hydroxytoluene; gallate derivatives, particularly propyl gallate, octyl gallate; vitamin E or its pharmaceutically acceptable salts; ascorbyl palmitate; edetic acid or its pharmaceutically acceptable salts; most preferably an antioxidant selected from the group consisting of sodium metabisulfite; and / or additionally, it contains one or more thickeners, preferably selected from the group consisting of "inorganic gel formers, organic gel formers, cellulose derivatives", more preferably a thickener selected from the group consisting of "hydroxyethyl cellulose, hydroxypropyl methyl cellulose, silicon dioxide"; and / or additionally, it contains one or more flavoring agents and / or sweetening agents, preferably a flavoring agent and / or sweetening agent selected from the group consisting of "honey flavoring agent, lime / salvia flavoring agent, jasmine flavoring agent, lavender flavoring agent, peppermint flavoring agent, raspberry flavoring agent, lemon flavoring agent, herb flavoring agent, meat flavoring agent, vanilla / vanilla flavoring agent, saccharin, aspartame, sorbitol, xylitol", the aqueous pharmaceutical composition according to any one of clauses 1 to 12.

[0151] 14. (i) At least one SGLT-2 inhibitor, preferably empagliflozin, more preferably the only and single SGLT-2 inhibitor, even more preferably only empagliflozin as the single SGLT-2 inhibitor; (ii) Optionally, but preferably, one or more preservatives; preferably sorbic acid or its salts, preferably sodium sorbate, potassium sorbate, calcium sorbate; benzoic acid or its salts, preferably sodium benzoate; benzalkonium chloride; benzethonium chloride; benzyl alcohol, cetylpyridinium chloride; sodium metabisulfite; sodium acetate; parabens and their salts, preferably methylparaben, ethylparaben, propylparaben, butylparaben, sodium butylparaben; or a combination thereof; most preferably a preservative selected from the group consisting of benzoic acid and / or its salts, such as sodium benzoate; (iii) Optionally, one or more organic solvents, preferably an organic solvent selected from the group consisting of "ethanol, propane-1,2,3-triol (glycerol), pyrrolidone, methylpyrrolidone, N,N-dimethylacetamide and / or N,N-dimethylformamide", more preferably ethanol; (iv) Optionally, one or more flavoring agents and / or sweeteners, preferably a flavoring agent and / or sweetener selected from the group consisting of "honey flavoring agent, lime / salvia flavoring agent, jasmine flavoring agent, lavender flavoring agent, peppermint flavoring agent, raspberry flavoring agent, lemon flavoring agent, herb flavoring agent, meat flavoring agent, vanilla / vanilla flavoring agent, saccharin, aspartame, sorbitol, xylitol"; (v) Water, preferably an aqueous buffer, more preferably a citrate buffer, even more preferably water in the form of an aqueous buffer having a pH of 4.5, most preferably a citrate buffer having a pH of 4.5; (vi) one or more solubilizing agents, preferably selected from the group consisting of "surfactants, anionic surfactants, nonionic surfactants, hydrogenated castor oil, polyoxyethylene-polyoxypropylene block copolymers, polyethylene glycols, propylene glycol derivatives, polyvinylpyrrolidone", more preferably selected from the group consisting of "sodium dodecyl sulfate (SDS), Cremophor RH 40 (PEG-40 hydrogenated castor oil, Macrogol glycerol hydroxystearate 40), polysorbate 20, Lutrol F68 (Poloxamer 188), PEG 200, PEG 300, PEG 400, propylene glycol monolaurate, Kollidon 12 (povidone)"; (vii) optionally, one or more thickeners, preferably selected from the group consisting of "inorganic gel formers, organic gel formers, cellulose derivatives", more preferably selected from the group consisting of "hydroxyethyl cellulose, hydroxypropyl methylcellulose, silicon dioxide"; (viii) optionally, one or more antioxidants, preferably ascorbic acid or a pharmaceutically acceptable salt thereof, particularly sodium ascorbate; citric acid (anhydrous and / or monohydrate) or a pharmaceutically acceptable salt thereof, more preferably sodium citrate; erythorbic acid; fumaric acid; malic acid; monothioglycerol; phosphoric acid; sodium metabisulfite; potassium metabisulfite; propionic acid; sodium bisulfite; sodium sulfite; resveratrol; butylhydroxyanisole; butylhydroxytoluene; gallate derivatives, particularly propyl gallate, octyl gallate; vitamin E or a pharmaceutically acceptable salt thereof; ascorbyl palmitate; edetic acid or a pharmaceutically acceptable salt thereof; most preferably an antioxidant selected from the group consisting of sodium metabisulfite An aqueous pharmaceutical composition according to any one of clauses 1 to 13, preferably consisting of them.

[0152] 15. (i) At least one SGLT-2 inhibitor at 0.5 to 20.0 g / 100 mL (0.5 to 20.0 mass / volume %), preferably 0.5 to 15.0 g / 100 mL (0.5 to 15.0 mass / volume %), more preferably 1.0 to 1.5 g / 100 mL (1.0 to 1.5 mass / volume %), preferably empagliflozin, more preferably the sole and single SGLT-2 inhibitor, and even more preferably only empagliflozin as the single SGLT-2 inhibitor; (ii) One or more preservatives at 0 to 3.0 g / 100 mL (0 to 3.0 mass / volume %), preferably 0.05 to 3.0 g / 100 mL (0.05 to 3.0 mass / volume %), more preferably 0.05 to 2.0 g / 100 mL (0.05 to 2.0 mass / volume %); more preferably sorbic acid or its salts, preferably sodium sorbate, potassium sorbate, calcium sorbate; benzoic acid or its salts, preferably sodium benzoate; benzalkonium chloride; benzethonium chloride; benzyl alcohol, cetylpyridinium chloride; sodium metabisulfite; sodium acetate; parabens and their salts, preferably methylparaben, ethylparaben, propylparaben, butylparaben, sodium butylparaben; or a combination thereof; most preferably a preservative selected from the group consisting of benzoic acid and / or its salts, such as sodium benzoate; (iii) One or more organic solvents at 0 to 20 g / 100 mL (0 to 20 mass / volume %), preferably 0 to 15 g / 100 mL (0 to 15 mass / volume %), more preferably 0 to 12 g / 100 mL (0 to 12 mass / volume %), and even more preferably 0 to 10 g / 100 mL (0 to 10 mass / volume %), preferably an organic solvent selected from the group consisting of "ethanol, propane-1,2,3-triol (glycerol), pyrrolidone, methylpyrrolidone, N,N-dimethylacetamide and / or N,N-dimethylformamide", more preferably ethanol; (iv) One or more flavoring agents and / or sweeteners in an amount of 0 to 40 g / 100 mL (0 to 40 mass / volume %), preferably 0 to 30 g / 100 mL (0 to 30 mass / volume %), more preferably 0 to 2 g / 100 mL (0 to 2 mass / volume %), and more preferably flavoring agents and / or sweeteners selected from the group consisting of "honey flavoring agent, lime / salvia flavoring agent, jasmine flavoring agent, lavender flavoring agent, peppermint flavoring agent, raspberry flavoring agent, lemon flavoring agent, herb flavoring agent, meat flavoring agent, vanilla / vanilla flavoring agent, saccharin, aspartame, sorbitol, xylitol"; (v) Water in an amount of 30 to 100 g / 100 mL (30 to 100 mass / volume %), preferably 30 to 95 g / 100 mL (30 to 95 mass / volume %), more preferably 30 to 90 g / 100 mL (30 to 90 mass / volume %), more preferably 30 to 85 g / 100 mL (30 to 85 mass / volume %), even more preferably 30 to 80 g / 100 mL (30 to 80 mass / volume %), and most preferably 50 to 80 g / 100 mL (50 to 80 mass / volume %), preferably in the form of an aqueous buffer, more preferably a citrate buffer, even more preferably an aqueous buffer having a pH of 4.5, and most preferably a citrate buffer having a pH of 4.5; (vi) One or more solubilizing agents at 1 to 50 g / 100 mL (1 to 50 mass / volume %), preferably 1 to 45 g / 100 mL (1 to 45 mass / volume %), more preferably 1 to 40 g / 100 mL (1 to 40 mass / volume %), still more preferably 1 to 35 g / 100 mL (1 to 35 mass / volume %), still more preferably 1 to 30 g / 100 mL (1 to 30 mass / volume %), still more preferably 1 to 25 g / 100 mL (1 to 25 mass / volume %), and most preferably 5 to 25 g / 100 mL (5 to 25 mass / volume %), preferably selected from the group consisting of "surfactants, anionic surfactants, nonionic surfactants, hydrogenated castor oil, polyoxyethylene-polyoxypropylene block copolymer, polyethylene glycol, propylene glycol derivative, polyvinylpyrrolidone", more preferably selected from the group consisting of "sodium dodecyl sulfate (SDS), Cremophor RH 40 (PEG-40 hydrogenated castor oil, Macrogol glycerol hydroxystearate 40), polysorbate 20, Lutrol F68 (Poloxamer 188), PEG 200, PEG 300, PEG 400, propylene glycol monolaurate, Kollidon 12 (povidone)"; (vii) One or more thickeners at 0 to 40 g / 100 mL (0 to 40 mass / volume %), preferably 10 to 30 g / 100 mL (10 to 30 mass / volume %), preferably selected from the group consisting of "inorganic gel formers, organic gel formers, cellulose derivatives", more preferably selected from the group consisting of "hydroxyethyl cellulose, hydroxypropyl methyl cellulose, silicon dioxide"; (viii) One or more antioxidants in an amount of 0 to 1.0 g / 100 mL (0 to 1.0 mass / volume %), preferably 0 to 0.5 g / 100 mL (0 to 0.5 mass / volume %), more preferably 0.1 to 0.3 g / 100 mL (0.1 to 0.3 mass / volume %), preferably ascorbic acid or a pharmaceutically acceptable salt thereof, particularly sodium ascorbate; citric acid (anhydrous and / or monohydrate) or a pharmaceutically acceptable salt thereof, more preferably sodium citrate; erythorbic acid; fumaric acid; malic acid; monothioglycerol; phosphoric acid; sodium metabisulfite; potassium metabisulfite; propionic acid; sodium bisulfite; sodium sulfite; resveratrol; butylhydroxyanisole; butylhydroxytoluene; gallate derivatives, particularly propyl gallate, octyl gallate; vitamin E or a pharmaceutically acceptable salt thereof; ascorbyl palmitate; edetic acid or a pharmaceutically acceptable salt thereof; most preferably an antioxidant selected from the group consisting of sodium metabisulfite The aqueous pharmaceutical composition according to any one of clauses 1 to 14, comprising, preferably consisting of, the same

[0153] 16. Beragliflozin; sodium dodecyl sulfate (SDS), Cremophor RH 40 (PEG-40 hydrogenated castor oil, Macrogol glycerol hydroxystearate 40), polysorbate 20, Lutrol F 68 (Poloxamer 188), PEG 200, PEG 300, PEG 400, propylene glycol monolaurate and / or Kollidon 12 (povidone); sodium benzoate; optionally, sodium metabisulfite; optionally, ethanol; water, the aqueous pharmaceutical composition according to any one of clauses 1 to 15 17. The aqueous pharmaceutical composition according to any one of clauses 1 to 16, selected from the group consisting of the following compositions 1 to 12

[0154]

Table 12

[0155] 18. An aqueous pharmaceutical composition according to any one of clauses 1 to 17, for oral and / or parenteral administration, preferably for oral administration.

[0156] 19. The following pharmaceutical indications: (i) A metabolic disorder in equine animals, preferably one or more disorders selected from insulin resistance, hyperinsulinemia, impaired glucose tolerance, dyslipidemia, abnormal lipid dynamics, asymptomatic inflammation, systemic inflammation, mild systemic inflammation, obesity, and / or local obesity, preferably a clinical condition associated with insulin resistance, hyperinsulinemia, and / or insulin resistance and / or hyperinsulinemia; preferably, the clinical condition is one or more conditions selected from impaired glucose tolerance, dyslipidemia, abnormal lipid dynamics, asymptomatic inflammation, systemic inflammation, mild systemic inflammation, obesity, and / or local obesity. (ii) A metabolic disorder in equine animals, which is one or more disorders selected from laminitis, vascular insufficiency, hypertension, hepatic lipidosis, atherosclerosis, hyperadrenocorticism, pituitary mid-lobe insufficiency, and / or equine metabolic syndrome, preferably a clinical condition / symptom associated with insulin resistance and / or hyperinsulinemia, and the clinical condition / symptom is preferably one or more conditions selected from laminitis, vascular insufficiency, hypertension, hepatic lipidosis, atherosclerosis, hyperadrenocorticism, pituitary mid-lobe insufficiency, and / or equine metabolic syndrome. (iii) A metabolic disorder in felines, preferably one or more selected from the group consisting of ketoacidosis, prediabetes, type 1 or type 2 diabetes, insulin resistance, obesity, hyperglycemia, impaired glucose tolerance, hyperinsulinemia, dyslipidemia, abnormal lipid dynamics, asymptomatic inflammation, systemic inflammation, mild systemic inflammation, hepatic lipidosis, atherosclerosis, pancreatitis, neuropathy and / or syndrome X (metabolic syndrome) and / or loss of pancreatic beta cell function; and / or a metabolic disorder in which remission of the metabolic disorder, preferably remission of diabetes, is achieved and / or maintained; (iv) A metabolic disorder in canines, preferably one or more selected from the group consisting of ketoacidosis, prediabetes, insulin-dependent diabetes, insulin-resistant diabetes, insulin resistance, obesity, hyperglycemia, hyperglycemia-induced cataract formation, impaired glucose tolerance, hyperinsulinemia, dyslipidemia, abnormal lipid dynamics, asymptomatic inflammation, systemic inflammation, mild systemic inflammation, hepatic lipidosis, pancreatitis, and as a result of the metabolic disorder, for example, hypertension, renal insufficiency and / or musculoskeletal disorders, and / or syndrome X (metabolic syndrome), preferably one or more selected from the group consisting of prediabetes, insulin-dependent diabetes, insulin-resistant diabetes, insulin resistance; preferably, the occurrence of hyperglycemia-induced cataract formation is prevented or remission is achieved, and / or preferably, as a result of the metabolic disorder, for example, the occurrence of hypertension, renal insufficiency and / or musculoskeletal disorders is prevented, or the progression is decelerated, or remission is achieved; a metabolic disorder; (v) A heart disease in felines, preferably heart failure, heart failure due to one or more cardiomyopathies, heart failure due to hypertrophic cardiomyopathy (HCM), heart failure due to restrictive cardiomyopathy (RCM), heart failure due to dilated cardiomyopathy (DCM), heart failure due to unclassified cardiomyopathy (UCM), heart failure due to arrhythmogenic right ventricular cardiomyopathy (ARVC), hypertrophic cardiomyopathy (HCM), restrictive cardiomyopathy (RCM), dilated cardiomyopathy (DCM), unclassified cardiomyopathy (UCM), and / or arrhythmogenic right ventricular cardiomyopathy (ARVC); preferably one or more selected from the group consisting of heart failure due to one or more cardiomyopathies, heart failure due to hypertrophic cardiomyopathy (HCM), hypertrophic cardiomyopathy (HCM); a heart disease; (vi) A dry-off of a non-human mammal, preferably a ruminant, which improves and / or promotes the dry-off of a non-human mammal, preferably a ruminant, reduces milk production, preferably milk production and / or secretion, in a non-human mammal, preferably a ruminant, during pregnancy and / or lactation, reduces milk accumulation and / or engorgement in the mammary gland, preferably the mammary gland and / or mammary gland, of a non-human mammal, preferably a ruminant, reduces the discomfort associated with mammary engorgement, for example, increases the daytime lying time of a non-human mammal, preferably a ruminant, and / or reduces stress, reduces milk leakage after dry-off of a non-human mammal, preferably a ruminant, reduces the incidence of intramammary infections (IMI), preferably mastitis and / or metritis, in a non-human mammal, preferably a ruminant, the dry-off of a non-human mammal, preferably a ruminant An aqueous pharmaceutical composition according to any one of clauses 1 to 18 for use in a method of treating and / or preventing one or more pharmaceutical indications in a subject, preferably an animal, more preferably a mammal, particularly a horse, cat, dog or cow, selected from among those in need of such treatment and / or prevention.

[0157] 20. A process for producing an aqueous pharmaceutical composition according to any one of clauses 1 to 18, (i) mixing one or more organic solvents (if any), such as ethanol, with water (if no organic solvent is present, only water is used as the starting material); (ii) adding one or more solubilizing agents to the mixture (or water) obtained from step (i); (iii) dissolving at least one SGLT-2 inhibitor, preferably empagliflozin, in the mixture obtained from step (ii); (iv) optionally, dissolving one or more preservatives in the mixture obtained from step (iii), (v) Optionally, further dissolving additional excipients, such as pH adjusters, flavoring agents, sweetening agents, antioxidants, thickening agents, and the like, in the mixture obtained from step (iii) or optionally (iv); (vi) Optionally, filtering the mixture obtained from step (iii), optionally step (iv), or optionally step (v); comprising (in any significant order), thereby, optionally, independently of each other, performing an additional mixing step, whether essential or optional, after any of the individual process steps, a process.

[0158] 21. A kit of parts comprising: (a) an aqueous pharmaceutical composition according to any one of clauses 1 to 18; (b) a package insert containing information that the aqueous pharmaceutical composition is used to prevent and / or treat one or more pharmaceutical indications in a subject in need of such prevention and / or treatment, wherein the one or more indications are the following pharmaceutical indications: (i) a metabolic disorder in equine animals, preferably one or more disorders selected from insulin resistance, hyperinsulinemia, impaired glucose tolerance, dyslipidemia, abnormal lipid metabolism, asymptomatic inflammation, systemic inflammation, mild systemic inflammation, obesity, and / or local obesity, preferably a clinical condition associated with insulin resistance, hyperinsulinemia, and / or insulin resistance and / or hyperinsulinemia; preferably the clinical condition is one or more conditions selected from impaired glucose tolerance, dyslipidemia, abnormal lipid metabolism, asymptomatic inflammation, systemic inflammation, mild systemic inflammation, obesity, and / or local obesity, a metabolic disorder; (ii) A metabolic disorder of equine animals, which is one or more disorders selected from laminitis, vascular insufficiency, hypertension, hepatic lipidosis, atherosclerosis, hyperadrenocorticism, pituitary mid-lobe insufficiency and / or equine metabolic syndrome, preferably a clinical condition / symptom associated with insulin resistance and / or hyperinsulinemia, and the clinical condition / symptom is preferably one or more conditions selected from laminitis, vascular insufficiency, hypertension, hepatic lipidosis, atherosclerosis, hyperadrenocorticism, pituitary mid-lobe insufficiency and / or equine metabolic syndrome; a metabolic disorder; (iii) A metabolic disorder of feline animals, preferably one or more selected from the group consisting of ketoacidosis, prediabetes, type 1 or type 2 diabetes, insulin resistance, obesity, hyperglycemia, glucose intolerance, hyperinsulinemia, dyslipidemia, abnormal lipid kinetics, asymptomatic inflammation, systemic inflammation, mild systemic inflammation, hepatic lipidosis, atherosclerosis, pancreatitis, neuropathy and / or syndrome X (metabolic syndrome) and / or loss of pancreatic beta cell function, and / or remission of the metabolic disorder, preferably diabetes remission, is achieved and / or maintained; a metabolic disorder; (iv) A metabolic disorder of canine animals, preferably one or more selected from the group consisting of ketoacidosis, prediabetes, insulin-dependent diabetes, insulin-resistant diabetes, insulin resistance, obesity, hyperglycemia, hyperglycemia-induced cataract formation, glucose intolerance, hyperinsulinemia, dyslipidemia, abnormal lipid kinetics, asymptomatic inflammation, systemic inflammation, mild systemic inflammation, hepatic lipidosis, pancreatitis, and as a result of the metabolic disorder, for example, hypertension, renal insufficiency and / or musculoskeletal disorders, and / or syndrome X (metabolic syndrome), preferably one or more selected from the group consisting of prediabetes, insulin-dependent diabetes, insulin-resistant diabetes, insulin resistance, and preferably the occurrence of hyperglycemia-induced cataract formation is prevented or remission is achieved, and / or preferably as a result of the metabolic disorder, for example, the occurrence of hypertension, renal insufficiency and / or musculoskeletal disorders is prevented, or the progression is decelerated, or remission is achieved; a metabolic disorder; (v) A heart disease of felines, preferably heart failure, heart failure due to one or more cardiomyopathies, heart failure due to hypertrophic cardiomyopathy (HCM), heart failure due to restrictive cardiomyopathy (RCM), heart failure due to dilated cardiomyopathy (DCM), heart failure due to unclassified cardiomyopathy (UCM), heart failure due to arrhythmogenic right ventricular cardiomyopathy (ARVC), hypertrophic cardiomyopathy (HCM), restrictive cardiomyopathy (RCM), dilated cardiomyopathy (DCM), unclassified cardiomyopathy (UCM), and / or arrhythmogenic right ventricular cardiomyopathy (ARVC); preferably one or more selected from the group consisting of heart failure due to one or more cardiomyopathies, heart failure due to hypertrophic cardiomyopathy (HCM), and hypertrophic cardiomyopathy (HCM); a heart disease that is one or more selected from the group consisting of. (vi) Dry-off of non-human mammals, preferably of ruminants, which improves and / or promotes dry-off of non-human mammals, preferably ruminants, milk production, preferably reduces milk production and / or secretion, in pregnant and / or lactating non-human mammals, preferably ruminants, reduces milk accumulation and / or engorgement, preferably in the udder and / or mammary gland of non-human mammals, preferably ruminants, reduces the discomfort associated with udder engorgement, for example, increases the daytime lying time of non-human mammals, preferably ruminants, and / or reduces stress, reduces milk leakage after dry-off of non-human mammals, preferably ruminants, and reduces the incidence of intramammary infections (IMI), preferably mastitis and / or metritis, in non-human mammals, preferably ruminants; dry-off of non-human mammals, preferably ruminants selected from among; an attachment document and a kit of parts containing the same.

Claims

1. An aqueous pharmaceutical composition comprising at least one SGLT-2 inhibitor and one or more solubilizing agents.

2. The at least one SGLT-2 inhibitor is (1) a glucopyranosyl-substituted benzene derivative of formula (1) 【Chemical 1】 (wherein R 1 represents cyano, Cl or methyl (most preferably cyano); R 2 represents H, methyl, methoxy or hydroxy (most preferably H), and R 3 represents cyclopropyl, hydrogen, fluorine, chlorine, bromine, iodine, methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, tert-butyl, 3-methyl-but-1-yl, cyclobutyl, cyclopentyl, cyclohexyl, 1-hydroxy-cyclopropyl, 1-hydroxy-cyclobutyl, 1-hydroxy-cyclopentyl, 1-hydroxy-cyclohexyl, ethynyl, ethoxy, difluoromethyl, trifluoromethyl, pentafluoroethyl, 2-hydroxyl-ethyl, hydroxymethyl, 3-hydroxy-propyl, 2-hydroxy-2-methyl-prop-1-yl, 3-hydroxy-3-methyl-but-1-yl, 1-hydroxy-1-methyl-ethyl, 2,2,2-trifluoro-1-hydroxy-1-methyl-ethyl, 2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl, 2-methoxy-ethyl, 2-ethoxy-ethyl, hydroxy, difluoromethyloxy, trifluoromethyloxy, 2-methyloxy-ethyloxy, methylsulfanyl, methylsulfinyl, methylsulfonyl, ethylsulfinyl, ethylsulfonyl, trimethylsilyl, (R)-tetrahydrofuran-3-yloxy or (S)-tetrahydrofuran-3-yloxy or cyano; R 3 is preferably selected from cyclopropyl, ethyl, ethynyl, ethoxy, (R)-tetrahydrofuran-3-yloxy or (S)-tetrahydrofuran-3-yloxy; most preferably R 3 is cyclopropyl), or one or more hydroxyl groups of the β-D-glucopyranosyl group are acylated with a group selected from (C 1-18 -alkyl)carbonyl, (C 1-18 -alkyl)oxycarbonyl, phenylcarbonyl and phenyl-(C 1-3 -alkyl)-carbonyl; a derivative thereof (2) empagliflozin represented by formula (2); 【Chemical 2】 (3) dapagliflozin represented by formula (3); 【Chemical 3】 (4) canagliflozin represented by formula (4); [Chemical Formula 4] (5) empagliflozin represented by formula (5); 【Chemical Formula 5】 (6) luseogliflozin represented by formula (6); 【Chemical Formula 6】 (7) tofogliflozin represented by formula (7); [Chemical Formula 7] (8) ipragliflozin represented by formula (8); 【Chemical Formula 8】 (9) ertugliflozin represented by formula (9); 【Chemical Formula 9】 (10) acigliflozin represented by formula (10); 【Chemical Formula 10】 (11) remogliflozin represented by formula (11); 【Chemical 11】 (11A) remogliflozin etabonate represented by formula (11A); 【Chemical 12】 (12) a thiophene derivative of formula (12) 【Chemical 13】 (wherein R represents methoxy or trifluoromethoxy) (13) 1-(β-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienylmethyl]benzene represented by formula (13); 【Chemical Formula 14】 (14) a spiroketal derivative of formula (14); 【Chemical Formula 15】 (wherein R represents methoxy, trifluoromethoxy, ethoxy, ethyl, isopropyl or tert-butyl) (15) a pyrazole-O-glucoside derivative of formula (15); 【Chemical 16】 (wherein R 1 represents C 1-3 -alkoxy, and L 1 and L 2 each independently represents H or F, R 6 represents H, (C 1-3 -alkyl)carbonyl, (C 1-6 -alkyl)oxycarbonyl, phenyloxycarbonyl, benzyloxycarbonyl or benzylcarbonyl) (16) sotagliflozin represented by formula (16) 【Chemical 17】 (17) sergliflozin represented by formula (17); 【Chemical 18】 （１８） a compound represented by formula (18) 【Chemical Formula 19】 (wherein R 3 is cyclopropyl, hydrogen, fluorine, chlorine, bromine, iodine, methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, tert-butyl, 3-methyl-but-1-yl, cyclobutyl, cyclopentyl, cyclohexyl, 1-hydroxy-cyclopropyl, 1-hydroxy-cyclobutyl, 1-hydroxy-cyclopentyl, 1-hydroxy-cyclohexyl, ethynyl, ethoxy, difluoromethyl, trifluoromethyl, pentafluoroethyl, 2-hydroxyl-ethyl, hydroxymethyl, 3-hydroxy-propyl, 2-hydroxy-2-methyl-prop-1-yl, 3-hydroxy-3-methyl-but-1-yl, 1-hydroxy-1-methyl-ethyl, 2,2,2-trifluoro-1-hydroxy-1-methyl-ethyl, 2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl, 2-methoxy-ethyl, 2-ethoxy-ethyl, hydroxy, difluoromethyloxy, trifluoromethyloxy, 2-methyloxy-ethyloxy, methylsulfanyl, methylsulfinyl, methylsulfonyl (, ethylsulfinyl, ethylsulfonyl, trimethylsilyl, (R)-tetrahydrofuran-3-yloxy or (S)-tetrahydrofuran-3-yloxy or cyano, and R 3 is preferably selected from cyclopropyl, ethyl, ethynyl, ethoxy, (R)-tetrahydrofuran-3-yloxy or (S)-tetrahydrofuran-3-yloxy; R 3 is most preferably cyclopropyl), or a derivative thereof in which one or more hydroxyl groups of the β-D-glucopyranosyl group are acylated with a group selected from (C 1-18 -alkyl)carbonyl, (C 1-18 -alkyl)oxycarbonyl, phenylcarbonyl and phenyl-(C 1-3 -alkyl)-carbonyl; (19) bexagliflozin represented by formula (19); 【Chemical 20】 (20) janagliflozin represented by formula (20); 【Chemical 21】 (21) longagliflozin represented by formula (21); 【Chemical 22】 (22) onepagliflozin; (23) enabogliflozin represented by formula (23); 【Chemical 23】 (24) TFC-039 represented by formula (24); 【Chemical 24】 The aqueous pharmaceutical composition according to claim 1, selected from the group consisting of.

3. The aqueous pharmaceutical composition according to claim 1 or 2, wherein the at least one SGLT-2 inhibitor is empagliflozin.

4. The aqueous pharmaceutical composition according to claim 3, wherein empagliflozin is the only SGLT-2 inhibitor contained in the aqueous pharmaceutical composition.

5. For administration to a subject, preferably for direct administration, more preferably without further essential processing and / or purification steps, even more preferably for administration to an animal, still more preferably to a mammal, particularly a horse, cat, dog or cow, the aqueous pharmaceutical composition according to any one of claims 1 to 4.

6. The aqueous pharmaceutical composition according to claim 5, which is sterile.

7. The aqueous pharmaceutical composition according to any one of claims 1 to 6, which substantially does not contain an organic solvent, preferably does not contain any organic solvent.

8. The aqueous pharmaceutical composition according to any one of claims 1 to 6, which contains an organic solvent of 20 g / 100 mL (20 mass / volume%) or less, preferably 15 g / 100 mL (15 mass / volume%) or less, more preferably 10 g / 100 mL (10 mass / volume%) or less.

9. The aqueous pharmaceutical composition according to claim 8, wherein the organic solvent contains ethanol.

10. The aqueous pharmaceutical composition according to claim 9, wherein the organic solvent contains propane-1,2,3-triol (glycerol) and ethanol, preferably consists of propane-1,2,3-triol (glycerol) and ethanol.

11. The aqueous pharmaceutical composition according to claim 9, wherein ethanol is the only organic solvent contained in the aqueous pharmaceutical composition.

12. The aqueous pharmaceutical composition according to any one of claims 9 to 11, which contains ethanol of 20 g / 100 mL (20 mass / volume%) or less, preferably 15 g / 100 mL (15 mass / volume%) or less, more preferably 10 g / 100 mL (10 mass / volume%) or less; most preferably contains 8 g / 100 mL (8 mass / volume%) of ethanol.

13. The aqueous pharmaceutical composition according to claims 1 to 6, 8 to 10 and 12, which does not contain propane-1,2-diol (propylene glycol).

14. One or more solubilizing agents are selected from the group consisting of surfactants, anionic surfactants, nonionic surfactants, hydrogenated castor oil, polyoxyethylene-polyoxypropylene block copolymers, polyethylene glycols, propylene glycol derivatives, and polyvinylpyrrolidone, preferably selected from the group consisting of sodium dodecyl sulfate (SDS), Cremophor RH 40 (PEG-40 hydrogenated castor oil, Macrogol glycerol hydroxystearate 40), polysorbate 20, Lutrol F68 (Poloxamer 188), PEG 200, PEG 300, PEG 400, propylene glycol monolaurate, Kollidon 12 (povidone), preferably the total amount of one or more solubilizing agents is 1 to 50 g / 100 mL (1 to 50 mass / volume %), more preferably 1 to 45 g / 100 mL (1 to 45 mass / volume %), even more preferably 1 to 40 g / 100 mL (1 to 40 mass / volume %), even more preferably 1 to 35 g / 100 mL (1 to 35 mass / volume %), even more preferably 1 to 30 g / 100 mL (1 to 30 mass / volume %), even more preferably 1 to 25 g / 100 mL (1 to 25 mass / volume %), most preferably 5 to 25 g / 100 mL (5 to 25 mass / volume %), the aqueous pharmaceutical composition according to any one of claims 1 to 13.

15. The aqueous pharmaceutical composition according to any one of claims 1 to 14, wherein two or more solubilizing agents are included in the aqueous pharmaceutical composition.

16. Two solubilizing agents are contained in the aqueous pharmaceutical composition, preferably the amount of the first solubilizing agent and the amount of the second solubilizing agent are, independently of each other, 1 to 50 g / 100 mL (1 to 50 mass / volume %), more preferably 1 to 45 g / 100 mL (1 to 45 mass / volume %), even more preferably 1 to 40 g / 100 mL (1 to 40 mass / volume %), even more preferably 1 to 35 g / 100 mL (1 to 35 mass / volume %), even more preferably 1 to 30 g / 100 mL (1 to 30 mass / volume %), even more preferably 1 to 25 g / 100 mL (1 to 25 mass / volume %), most preferably selected from 5 to 25 g / 100 mL (5 to 25 mass / volume %), the aqueous pharmaceutical composition according to claim 15.

17. The aqueous pharmaceutical composition according to claim 16, wherein two solubilizing agents are independently selected from the group consisting of sodium dodecyl sulfate (SDS), Cremophor RH 40 (PEG-40 hydrogenated castor oil, Macrogol glycerol hydroxystearate 40), polysorbate 20, Lutrol F 68 (Poloxamer 188), PEG 200, PEG 300, PEG 400, propylene glycol monolaurate, and Kollidon 12 (povidone).

18. The aqueous pharmaceutical composition according to claim 17, wherein the two solubilizing agents are Kollidon 12 (povidone) and PEG 200, PEG 300, or PEG 400.

19. The aqueous pharmaceutical composition according to claim 18, wherein the two solubilizing agents are Kollidon 12 (povidone) and PEG 300.

20. A solution, emulsion or suspension, preferably having an NTU value equal to or less than 10.0, more preferably equal to or less than 7.0, even more preferably equal to or less than 3.0, the aqueous pharmaceutical composition according to any one of claims 1 to 19.

21. The aqueous pharmaceutical composition according to claim 20, which is a solution having an NTU value equal to or less than 3.

0.

22. The aqueous pharmaceutical composition according to any one of claims 1 to 21, containing 30 to 100 g / 100 mL (30 to 100 mass / volume %), preferably 30 to 95 g / 100 mL (30 to 95 mass / volume %), more preferably 30 to 90 g / 100 mL (30 to 90 mass / volume %), more preferably 30 to 85 g / 100 mL (30 to 85 mass / volume %), even more preferably 30 to 80 g / 100 mL (30 to 80 mass / volume %), most preferably 50 to 80 g / 100 mL (50 to 80 mass / volume %) of water, more preferably in the form of an aqueous buffer, such as a citrate buffer.

23. The aqueous pharmaceutical composition according to claim 22, having a pH value of 2 to 7, preferably 3 to 7, more preferably 3.0 to 6.5, even more preferably 4.0 to 6.5, even more preferably 4.0 to 5.0, most preferably 4.

5.

24. Additionally, one or more preservatives, preferably sorbic acid or a salt thereof, more preferably sodium sorbate, potassium sorbate, calcium sorbate; benzoic acid or a salt thereof, more preferably sodium benzoate; benzalkonium chloride; benzethonium chloride; benzyl alcohol, cetylpyridinium chloride; sodium metabisulfite; sodium acetate; parabens and salts thereof, more preferably methylparaben, ethylparaben, propylparaben, butylparaben, sodium butylparaben; most preferably a preservative selected from the group consisting of benzoic acid and / or a salt thereof, such as sodium benzoate, is included in the aqueous pharmaceutical composition according to any one of claims 1 to 23.

25. Additionally, one or more antioxidants, preferably ascorbic acid or a pharmaceutically acceptable salt thereof, particularly sodium ascorbate; citric acid (anhydrous and / or monohydrate) or a pharmaceutically acceptable salt thereof, more preferably sodium citrate; erythorbic acid; fumaric acid; malic acid; monothioglycerol; phosphoric acid; sodium metabisulfite; potassium metabisulfite; propionic acid; sodium bisulfite; sodium sulfite; resveratrol; butylated hydroxyanisole; butylated hydroxytoluene; gallate derivatives, particularly propyl gallate, octyl gallate; vitamin E or a pharmaceutically acceptable salt thereof; ascorbyl palmitate; edetic acid or a pharmaceutically acceptable salt thereof; most preferably an antioxidant selected from the group consisting of sodium metabisulfite, is included in the aqueous pharmaceutical composition according to any one of claims 1 to 24.

26. Additionally, one or more thickeners, preferably a thickener selected from the group consisting of inorganic gel formers, organic gel formers, cellulose derivatives, more preferably selected from the group consisting of hydroxyethyl cellulose, hydroxypropyl methyl cellulose, silicon dioxide, is included in the aqueous pharmaceutical composition according to any one of claims 1 to 25.

27. Additionally, an aqueous pharmaceutical composition according to any one of claims 1 to 26, comprising one or more flavoring agents and / or sweetening agents, preferably a honey flavoring agent, a lime / salvia flavoring agent, a jasmine flavoring agent, a lavender flavoring agent, a peppermint flavoring agent, a raspberry flavoring agent, a lemon flavoring agent, a herb flavoring agent, a meat flavoring agent, a vanilla / vanilla flavoring agent, saccharin, aspartame, sorbitol, xylitol, selected from the group consisting of flavoring agents and / or sweetening agents. **Claim 28** (i) at least one SGLT-2 inhibitor, preferably empagliflozin, more preferably the sole and single SGLT-2 inhibitor, even more preferably empagliflozin only as the single SGLT-2 inhibitor; (ii) optionally, but preferably, one or more preservatives; preferably sorbic acid or its salts, preferably sodium sorbate, potassium sorbate, calcium sorbate; benzoic acid or its salts, preferably sodium benzoate; benzalkonium chloride; benzethonium chloride; benzyl alcohol, cetylpyridinium chloride; sodium metabisulfite; sodium acetate; parabens and their salts, preferably methylparaben, ethylparaben, propylparaben, butylparaben, sodium butylparaben; or a combination thereof; most preferably a preservative selected from the group consisting of benzoic acid and / or its salts, such as sodium benzoate; (iii) optionally, one or more organic solvents, preferably an organic solvent selected from the group consisting of ethanol, propane-1,2,3-triol (glycerol), pyrrolidone, methylpyrrolidone, N,N-dimethylacetamide and / or N,N-dimethylformamide, more preferably ethanol; (iv) optionally, one or more flavoring agents and / or sweetening agents, preferably a flavoring agent and / or sweetening agent selected from the group consisting of a honey flavoring agent, a lime / salvia flavoring agent, a jasmine flavoring agent, a lavender flavoring agent, a peppermint flavoring agent, a raspberry flavoring agent, a lemon flavoring agent, a herb flavoring agent, a meat flavoring agent, a vanilla / vanilla flavoring agent, saccharin, aspartame, sorbitol, xylitol; (v) water, preferably an aqueous buffer, more preferably a citrate buffer, even more preferably an aqueous buffer having a pH of 4.5, most preferably water in the form of a citrate buffer having a pH of 4.5; (vi) one or more solubilizing agents, preferably selected from the group consisting of surfactants, anionic surfactants, nonionic surfactants, hydrogenated castor oil, polyoxyethylene-polyoxypropylene block copolymers, polyethylene glycols, propylene glycol derivatives, polyvinylpyrrolidone, more preferably selected from the group consisting of sodium dodecyl sulfate (SDS), Cremophor RH 40 (PEG-40 hydrogenated castor oil, Macrogol glycerol hydroxystearate 40), polysorbate 20, Lutrol F68 (Poloxamer 188), PEG 200, PEG 300, PEG 400, propylene glycol monolaurate, Kollidon 12 (povidone); (vii) optionally, one or more thickening agents, preferably selected from the group consisting of inorganic gel formers, organic gel formers, cellulose derivatives, more preferably selected from the group consisting of hydroxyethyl cellulose, hydroxypropyl methyl cellulose, silicon dioxide; (viii) optionally, one or more antioxidants, preferably ascorbic acid or a pharmaceutically acceptable salt thereof, especially sodium ascorbate; citric acid (anhydrous and / or monohydrate) or a pharmaceutically acceptable salt thereof, more preferably sodium citrate; erythorbic acid; fumaric acid; malic acid; monothioglycerol; phosphoric acid; sodium metabisulfite; potassium metabisulfite; propionic acid; sodium bisulfite; sodium sulfite; resveratrol; butylhydroxyanisole; butylhydroxytoluene; gallate derivatives, especially propyl gallate, octyl gallate; vitamin E or a pharmaceutically acceptable salt thereof; ascorbyl palmitate; edetic acid or a pharmaceutically acceptable salt thereof; most preferably an antioxidant selected from the group consisting of sodium metabisulfite The aqueous pharmaceutical composition according to any one of claims 1 to 27, comprising, preferably consisting of, the above.

29. (i) At least one SGLT-2 inhibitor at 0.5 to 20.0 g / 100 mL (0.5 to 20.0 mass / volume %), preferably 0.5 to 15.0 g / 100 mL (0.5 to 15.0 mass / volume %), more preferably 1.0 to 1.5 g / 100 mL (1.0 to 1.5 mass / volume %), preferably empagliflozin, more preferably the sole and single SGLT-2 inhibitor, even more preferably only empagliflozin as the single SGLT-2 inhibitor; (ii) One or more preservatives at 0 to 3.0 g / 100 mL (0 to 3.0 mass / volume %), preferably 0.05 to 3.0 g / 100 mL (0.05 to 3.0 mass / volume %), more preferably 0.05 to 2.0 g / 100 mL (0.05 to 2.0 mass / volume %); more preferably sorbic acid or its salts, preferably sodium sorbate, potassium sorbate, calcium sorbate; benzoic acid or its salts, preferably sodium benzoate; benzalkonium chloride; benzethonium chloride; benzyl alcohol, cetylpyridinium chloride; sodium metabisulfite; sodium acetate; parabens and their salts, preferably methylparaben, ethylparaben, propylparaben, butylparaben, sodium butylparaben; or a combination thereof; most preferably a preservative selected from the group consisting of preservatives selected from the group consisting of benzoic acid and / or its salts, such as sodium benzoate; (iii) One or more organic solvents at 0 to 20 g / 100 mL (0 to 20 mass / volume %), preferably 0 to 15 g / 100 mL (0 to 15 mass / volume %), more preferably 0 to 12 g / 100 mL (0 to 12 mass / volume %), even more preferably 0 to 10 g / 100 mL (0 to 10 mass / volume %), preferably an organic solvent selected from the group consisting of ethanol, propane-1,2,3-triol (glycerol), pyrrolidone, methylpyrrolidone, N,N-dimethylacetamide and / or N,N-dimethylformamide, more preferably ethanol; (iv) One or more flavoring agents and / or sweeteners in an amount of 0 to 40 g / 100 mL (0 to 40 mass / volume %), preferably 0 to 30 g / 100 mL (0 to 30 mass / volume %), more preferably 0 to 2 g / 100 mL (0 to 2 mass / volume %), more preferably a honey flavoring agent, a lime / salvia flavoring agent, a jasmine flavoring agent, a lavender flavoring agent, a peppermint flavoring agent, a raspberry flavoring agent, a lemon flavoring agent, a herb flavoring agent, a meat flavoring agent, a vanilla / vanilla flavoring agent, saccharin, aspartame, sorbitol, xylitol; (v) Water in an amount of 30 to 100 g / 100 mL (30 to 100 mass / volume %), preferably 30 to 95 g / 100 mL (30 to 95 mass / volume %), more preferably 30 to 90 g / 100 mL (30 to 90 mass / volume %), more preferably 30 to 85 g / 100 mL (30 to 85 mass / volume %), even more preferably 30 to 80 g / 100 mL (30 to 80 mass / volume %), most preferably 50 to 80 g / 100 mL (50 to 80 mass / volume %), preferably in the form of an aqueous buffer solution, more preferably a citrate buffer solution, even more preferably an aqueous buffer solution having a pH of 4.5, most preferably an aqueous citrate buffer solution having a pH of 4.5; (vi) One or more solubilizing agents in an amount of 1 to 50 g / 100 mL (1 to 50 mass / volume %), preferably 1 to 45 g / 100 mL (1 to 45 mass / volume %), more preferably 1 to 40 g / 100 mL (1 to 40 mass / volume %), still more preferably 1 to 35 g / 100 mL (1 to 35 mass / volume %), still more preferably 1 to 30 g / 100 mL (1 to 30 mass / volume %), still more preferably 1 to 25 g / 100 mL (1 to 25 mass / volume %), and most preferably 5 to 25 g / 100 mL (5 to 25 mass / volume %), preferably selected from the group consisting of surfactants, anionic surfactants, nonionic surfactants, hydrogenated castor oil, polyoxyethylene-polyoxypropylene block copolymers, polyethylene glycols, propylene glycol derivatives, and polyvinylpyrrolidone, more preferably selected from the group consisting of sodium dodecyl sulfate (SDS), Cremophor RH 40 (PEG-40 hydrogenated castor oil, Macrogol glycerol hydroxystearate 40), polysorbate 20, Lutrol F68 (Poloxamer 188), PEG 200, PEG 300, PEG 400, propylene glycol monolaurate, and Kollidon 12 (povidone); (vii) One or more thickeners in an amount of 0 to 40 g / 100 mL (0 to 40 mass / volume %), preferably 10 to 30 g / 100 mL (10 to 30 mass / volume %), preferably selected from the group consisting of inorganic gel formers, organic gel formers, and cellulose derivatives, more preferably selected from the group consisting of hydroxyethyl cellulose, hydroxypropyl methylcellulose, and silicon dioxide; (viii) One or more antioxidants in an amount of 0 to 1.0 g / 100 mL (0 to 1.0 mass / volume %), preferably 0 to 0.5 g / 100 mL (0 to 0.5 mass / volume %), more preferably 0.1 to 0.3 g / 100 mL (0.1 to 0.3 mass / volume %), preferably ascorbic acid or a pharmaceutically acceptable salt thereof, particularly sodium ascorbate; citric acid (anhydrous and / or monohydrate) or a pharmaceutically acceptable salt thereof, more preferably sodium citrate; erythorbic acid; fumaric acid; malic acid; monothioglycerol; phosphoric acid; sodium metabisulfite; potassium metabisulfite; propionic acid; sodium bisulfite; sodium sulfite; resveratrol; butylhydroxyanisole; butylhydroxytoluene; gallate derivatives, particularly propyl gallate, octyl gallate; vitamin E or a pharmaceutically acceptable salt thereof; ascorbyl palmitate; edetic acid or a pharmaceutically acceptable salt thereof; most preferably an antioxidant selected from the group consisting of sodium metabisulfite The aqueous pharmaceutical composition according to any one of claims 1 to 28, comprising, preferably consisting of, the above.

30. Beragliflozin; sodium dodecyl sulfate (SDS), Cremophor RH 40 (PEG-40 hydrogenated castor oil, Macrogol glycerol hydroxystearate 40), polysorbate 20, Lutrol F 68 (Poloxamer 188), PEG 200, PEG 300, PEG 400, propylene glycol monolaurate and / or Kollidon 12 (povidone); sodium benzoate; optionally, Na metabisulfite; optionally, ethanol; water, the aqueous pharmaceutical composition according to any one of claims 1 to 29, comprising, preferably consisting of, the above.

31. Veragliflozin; citric acid monohydrate; NaOH; sodium dodecyl sulfate (SDS), Cremophor RH 40 (PEG-40 hydrogenated castor oil, Macrogol glycerol hydroxystearate 40), polysorbate 20, Lutrol F 68 (Poloxamer 188), PEG 200, PEG 300, PEG 400, propylene glycol monolaurate and / or Kollidon 12 (povidone); sodium benzoate; optionally, Na metabisulfite; optionally, ethanol; water, preferably consisting of, the aqueous pharmaceutical composition according to any one of claims 1 to 29.

32. Veragliflozin; citric acid monohydrate; NaOH; sodium dodecyl sulfate (SDS), Cremophor RH 40 (PEG-40 hydrogenated castor oil, Macrogol glycerol hydroxystearate 40), polysorbate 20, Lutrol F 68 (Poloxamer 188), PEG 200, PEG 300, PEG 400, propylene glycol monolaurate and / or Kollidon 12 (povidone); sodium benzoate; optionally, Na metabisulfite; optionally, ethanol; sorbitol and / or xylitol; honey flavoring agent and / or vanillin and / or meat flavoring agent; water, preferably consisting of, the aqueous pharmaceutical composition according to any one of claims 1 to 29.

33. The aqueous pharmaceutical composition according to any one of claims 1 to 32, selected from the group consisting of the following compositions 1 to 12. 【Table 1】

34. The aqueous pharmaceutical composition according to any one of claims 1 to 33, for oral and / or parenteral administration, preferably for oral administration.

35. The following pharmaceutical indications: (i)A metabolic disorder in equine animals, preferably one or more disorders selected from insulin resistance, hyperinsulinemia, impaired glucose tolerance, dyslipidemia, abnormal lipid kinetics, asymptomatic inflammation, systemic inflammation, mild systemic inflammation, obesity, and / or local obesity, preferably a clinical condition associated with insulin resistance, hyperinsulinemia, and / or insulin resistance and / or hyperinsulinemia; preferably, the clinical condition is one or more conditions selected from impaired glucose tolerance, dyslipidemia, abnormal lipid kinetics, asymptomatic inflammation, systemic inflammation, mild systemic inflammation, obesity, and / or local obesity, a metabolic disorder; (ii)A metabolic disorder in equine animals, preferably one or more disorders selected from laminitis, vascular insufficiency, hypertension, hepatic lipidosis, atherosclerosis, hyperadrenocorticism, pituitary pars intermedia dysfunction, and / or equine metabolic syndrome, preferably a clinical condition / symptom associated with insulin resistance and / or hyperinsulinemia, and the clinical condition / symptom is preferably one or more conditions selected from laminitis, vascular insufficiency, hypertension, hepatic lipidosis, atherosclerosis, hyperadrenocorticism, pituitary pars intermedia dysfunction, and / or equine metabolic syndrome, a metabolic disorder; (iii)A metabolic disorder in feline animals, preferably one or more selected from the group consisting of ketoacidosis, prediabetes, type 1 or type 2 diabetes, insulin resistance, acromegaly, diabetes with high IGF-1 concentration, obesity, hyperglycemia, impaired glucose tolerance, hyperinsulinemia, dyslipidemia, abnormal lipid kinetics, asymptomatic inflammation, systemic inflammation, mild systemic inflammation, hepatic lipidosis, atherosclerosis, pancreatitis, neuropathy, and / or syndrome X (metabolic syndrome) and / or loss of pancreatic beta cell function and / or remission of the metabolic disorder, preferably diabetes remission is achieved and / or maintained, a metabolic disorder; (iv) A metabolic disorder in canids, preferably ketosis, prediabetes, insulin-dependent diabetes, insulin-resistant diabetes, insulin resistance, obesity, hyperglycemia, hyperglycemia-induced cataract formation, impaired glucose tolerance, hyperinsulinemia, dyslipidemia, abnormal lipid metabolism, asymptomatic inflammation, systemic inflammation, mild systemic inflammation, hepatic lipidosis, pancreatitis, and as a result of metabolic disorders, for example, hypertension, renal insufficiency and / or musculoskeletal disorders, and / or syndrome X (metabolic syndrome), preferably selected from the group consisting of prediabetes, insulin-dependent diabetes, insulin-resistant diabetes, insulin resistance, and preferably, the occurrence of hyperglycemia-induced cataract formation is prevented or remission is achieved, and / or preferably, as a result of metabolic disorders, for example, the occurrence of hypertension, renal dysfunction and / or musculoskeletal disorders is prevented, or the progression is decelerated, or remission is achieved, metabolic disorder; (v) A heart disease in felids, preferably heart failure, heart failure due to one or more cardiomyopathies, heart failure due to hypertrophic cardiomyopathy (HCM), heart failure due to restrictive cardiomyopathy (RCM), heart failure due to dilated cardiomyopathy (DCM), heart failure due to unclassified cardiomyopathy (UCM), heart failure due to arrhythmogenic right ventricular cardiomyopathy (ARVC), hypertrophic cardiomyopathy (HCM), restrictive cardiomyopathy (RCM), dilated cardiomyopathy (DCM), unclassified cardiomyopathy (UCM), and / or arrhythmogenic right ventricular cardiomyopathy (ARVC); preferably selected from the group consisting of heart failure due to one or more cardiomyopathies, heart failure due to hypertrophic cardiomyopathy (HCM), and one or more selected from the group consisting of hypertrophic cardiomyopathy (HCM), heart disease; (vi) A dry-off of a non-human mammal, preferably a ruminant, which improves and / or promotes the dry-off of the non-human mammal, preferably a ruminant, reduces milk production, preferably milk production and / or secretion, in a non-human mammal, preferably a ruminant, during pregnancy and / or lactation, reduces milk accumulation and / or congestion in the mammary gland, preferably the mammary gland and / or mammary tissue, of the non-human mammal, preferably a ruminant, reduces the discomfort associated with mammary congestion, for example, increases the daily lying time of the non-human mammal, preferably a ruminant, and / or reduces stress, reduces milk leakage after dry-off in the non-human mammal, preferably a ruminant, and reduces the incidence of intramammary infections (IMI), preferably mastitis and / or metritis, in the non-human mammal, preferably a ruminant; dry-off; (vii) A heart disease of non-human mammals other than cats, particularly dogs, preferably heart failure; congestive heart failure; asymptomatic / preclinical / potential heart failure; heart failure due to (mucoid) mitral valve disease [(M)MVD]; congestive heart failure due to (mucoid) mitral valve disease [(M)MVD]; asymptomatic / preclinical / potential heart failure due to (mucoid) mitral valve disease [(M)MVD]; (mucoid) mitral valve disease [(M)MVD]; clinically apparent (mucoid) mitral valve disease [(M)MVD]; asymptomatic / preclinical / potential (mucoid) mitral valve disease [(M)MVD]; heart failure due to dilated cardiomyopathy (DCM); congestive heart failure due to dilated cardiomyopathy (DCM); asymptomatic / preclinical / potential heart failure due to dilated cardiomyopathy (DCM); dilated cardiomyopathy (DCM); clinically apparent dilated cardiomyopathy (DCM); asymptomatic / preclinical / potential dilated cardiomyopathy (DCM); aortic valve stenosis (valvular, supravalvular and / or subvalvular), which is one or more selected from the group consisting of; heart disease; (viii) Hypertension in non-human mammals, preferably carnivores, more preferably cats or dogs, preferably one or more selected from the group consisting of situational hypertension, secondary hypertension, and essential hypertension, preferably secondary hypertension being associated with chronic kidney disease (CKD), diabetes, obesity, heart disease, endocrine diseases such as Cushing's disease, hyperthyroidism, acromegaly, and hypertension induced by medications, preferably glucocorticoids, mineralocorticoids, erythropoietin-stimulating factors, ephedrine, and / or high-dose sodium chloride; (ix) Kidney diseases in non-human mammals, preferably carnivores, more preferably cats or dogs, preferably one or more selected from the group consisting of renal dysplasia, glomerulopathy, polycystic kidney disease, amyloidosis, tubulointerstitial nephritis (TIN), acute kidney disease, and chronic kidney disease Such a subject, preferably an animal, more preferably a mammal, particularly a horse, cat, dog, or cow, selected from among those in need of such treatment and / or prevention, for use in a method of treating and / or preventing one or more pharmaceutical indications in a method of treating and / or preventing one or more pharmaceutical indications. An aqueous pharmaceutical composition according to any one of claims 1 to 34.

36. A process for producing an aqueous pharmaceutical composition according to any one of claims 1 to 34, comprising: (i) mixing one or more organic solvents (if any), such as ethanol, with water (if no organic solvent is present, only water is used as the starting material); (ii) adding one or more solubilizing aids to the mixture obtained from step (i) (or water if no organic solvent is present); (iii) dissolving at least one SGLT-2 inhibitor, preferably empagliflozin, in the mixture obtained from step (ii); (iv) optionally, dissolving one or more preservatives in the mixture obtained from step (iii); (v) optionally, further dissolving additional excipients such as pH adjusters, flavoring agents, sweetening agents, antioxidants, thickening agents, and the like in the mixture obtained from step (iii) or optionally (iv); (vi)optionally, filtering the mixture obtained from step (iii), optionally step (iv) or optionally step (v); comprising (in any significant order), thereby, optionally, independently of each other, performing an additional mixing step, either mandatory or optional, after any of the individual process steps, a process.

37. A kit of parts comprising: (a) an aqueous pharmaceutical composition according to any one of claims 1 to 34; (b) a package insert containing information that the aqueous pharmaceutical composition is used for preventing and / or treating one or more pharmaceutical indications in a subject in need of such prevention and / or treatment, wherein the one or more indications are the following pharmaceutical indications: (i) a metabolic disorder in equine animals, preferably one or more disorders selected from insulin resistance, hyperinsulinemia, impaired glucose tolerance, dyslipidemia, abnormal lipid dynamics, asymptomatic inflammation, systemic inflammation, mild systemic inflammation, obesity, and / or local obesity, preferably a clinical condition associated with insulin resistance, hyperinsulinemia, and / or insulin resistance and / or hyperinsulinemia; preferably the clinical condition is one or more conditions selected from impaired glucose tolerance, dyslipidemia, abnormal lipid dynamics, asymptomatic inflammation, systemic inflammation, mild systemic inflammation, obesity, and / or local obesity, a metabolic disorder; (ii) a metabolic disorder in equine animals, preferably one or more disorders selected from laminitis, vascular insufficiency, hypertension, hepatic lipidosis, atherosclerosis, hyperadrenocorticism, pituitary pars intermedia dysfunction, and / or equine metabolic syndrome, preferably a clinical condition / symptom associated with insulin resistance and / or hyperinsulinemia, said clinical condition / symptom preferably being one or more conditions selected from laminitis, vascular insufficiency, hypertension, hepatic lipidosis, atherosclerosis, hyperadrenocorticism, pituitary pars intermedia dysfunction, and / or equine metabolic syndrome, a metabolic disorder; (iii) A metabolic disorder in a feline, preferably one or more selected from the group consisting of ketoacidosis, prediabetes, type 1 or type 2 diabetes, insulin resistance, acromegaly, diabetes with high IGF-1 concentration, obesity, hyperglycemia, impaired glucose tolerance, hyperinsulinemia, dyslipidemia, abnormal lipid dynamics, asymptomatic inflammation, systemic inflammation, mild systemic inflammation, hepatic lipidosis, atherosclerosis, pancreatitis, neuropathy and / or syndrome X (metabolic syndrome) and / or loss of pancreatic beta cell function; and / or a metabolic disorder in which remission of the metabolic disorder, preferably remission of diabetes, is achieved and / or maintained; (iv) A metabolic disorder in a canine, preferably one or more selected from the group consisting of ketoacidosis, prediabetes, insulin-dependent diabetes, insulin-resistant diabetes, insulin resistance, obesity, hyperglycemia, hyperglycemia-induced cataract formation, impaired glucose tolerance, hyperinsulinemia, dyslipidemia, abnormal lipid dynamics, asymptomatic inflammation, systemic inflammation, mild systemic inflammation, hepatic lipidosis, pancreatitis, and as a result of the metabolic disorder, for example, hypertension, renal insufficiency and / or musculoskeletal disorders, and / or syndrome X (metabolic syndrome), preferably one or more selected from the group consisting of prediabetes, insulin-dependent diabetes, insulin-resistant diabetes, insulin resistance; preferably, the occurrence of hyperglycemia-induced cataract formation is prevented or remission is achieved, and / or preferably, as a result of the metabolic disorder, for example, the occurrence of hypertension, renal insufficiency and / or musculoskeletal disorders is prevented, or the progression is decelerated, or remission is achieved; a metabolic disorder; (v) A heart disease in a feline, preferably heart failure, heart failure due to one or more cardiomyopathies, heart failure due to hypertrophic cardiomyopathy (HCM), heart failure due to restrictive cardiomyopathy (RCM), heart failure due to dilated cardiomyopathy (DCM), heart failure due to unclassified cardiomyopathy (UCM), heart failure due to arrhythmogenic right ventricular cardiomyopathy (ARVC), hypertrophic cardiomyopathy (HCM), restrictive cardiomyopathy (RCM), dilated cardiomyopathy (DCM), unclassified cardiomyopathy (UCM), and / or arrhythmogenic right ventricular cardiomyopathy (ARVC); preferably one or more selected from the group consisting of heart failure due to one or more cardiomyopathies, heart failure due to hypertrophic cardiomyopathy (HCM), heart failure due to hypertrophic cardiomyopathy (HCM); a heart disease; (vi) A dry-off of a non-human mammal, preferably a ruminant, which improves and / or promotes the dry-off of a non-human mammal, preferably a ruminant, reduces milk production, preferably milk production and / or secretion, in a non-human mammal, preferably a ruminant, during pregnancy and / or lactation, reduces milk accumulation and / or congestion in the mammary gland, preferably the mammary gland and / or mammary gland, of a non-human mammal, preferably a ruminant, reduces the discomfort associated with mammary congestion, for example, increases the daytime lying time of a non-human mammal, preferably a ruminant, and / or reduces stress, reduces milk leakage after dry-off of a non-human mammal, preferably a ruminant, and reduces the incidence of intramammary infections (IMI), preferably mastitis and / or metritis, in a non-human mammal, preferably a ruminant; dry-off; (vii) A heart disease of a non-human mammal other than a cat, particularly a dog, preferably heart failure; congestive heart failure; asymptomatic / preclinical / potential heart failure; heart failure due to (myxomatous) mitral valve disease [(M)MVD]; congestive heart failure due to (myxomatous) mitral valve disease [(M)MVD]; asymptomatic / preclinical / potential heart failure due to (myxomatous) mitral valve disease [(M)MVD]; (myxomatous) mitral valve disease [(M)MVD]; clinically apparent (myxomatous) mitral valve disease [(M)MVD]; asymptomatic / preclinical / potential (myxomatous) mitral valve disease [(M)MVD]; heart failure due to dilated cardiomyopathy (DCM); congestive heart failure due to dilated cardiomyopathy (DCM); asymptomatic / preclinical / potential heart failure due to dilated cardiomyopathy (DCM); dilated cardiomyopathy (DCM); clinically apparent dilated cardiomyopathy (DCM); asymptomatic / preclinical / potential dilated cardiomyopathy (DCM); aortic valve stenosis (valvular, supravalvular and / or subvalvular), which is one or more selected from the group consisting of; heart disease; (viii) Hypertension in a non-human mammal, preferably a carnivore, more preferably a cat or a dog, preferably one or more selected from the group consisting of situational hypertension, secondary hypertension, and idiopathic hypertension, preferably secondary hypertension being associated with chronic kidney disease (CKD), diabetes, obesity, heart disease, endocrine diseases, such as Cushing's disease, hyperthyroidism, acromegaly, and hypertension induced by a medicament, preferably a glucocorticoid, a mineralocorticoid, an erythropoietin, ephedrine, and / or a high dose of sodium chloride (BP); (ix) A kidney disease in a non-human mammal, preferably a carnivore, more preferably a cat or a dog, preferably one or more selected from the group consisting of renal dysplasia, glomerulopathy, polycystic kidney disease, amyloidosis, tubulointerstitial nephritis (TIN), acute kidney disease, chronic kidney disease selected from among, and the accompanying document A kit of parts comprising.

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