Aqueous pharmaceutical compositions comprising SGLT-2 inhibitors
The invention relates to novel aqueous pharmaceutical compositions comprising at least one SGLT-2 inhibitor and one or more solubilizing agents as well as corresponding processes of manufacturing such aqueous pharmaceutical compositions and their medical uses.
1 . An aqueous pharmaceutical composition comprising at least one SGLT-2 inhibitor and one or more solubilizing agents, wherein:
the aqueous pharmaceutical composition is free of ethanol, propane-1,2-diol (propylene glycol), and glycerol; and
the at least one SGLT-2 inhibitor comprises Velagliflozin, represented by the following formula:
2 . The aqueous pharmaceutical composition according to claim 1 , wherein the at least one SGLT-2 inhibitor further includes one or more SGLT-2 inhibitors selected from the group consisting of:
(1) a glucopyranosyl-substituted benzene derivative of the formula (1) other than Velagliflozin
wherein R 1 denotes cyano, or methyl;
R 2 denotes H, methyl, methoxy or hydroxy; and
R 3 denotes cyclopropyl, hydrogen, fluorine, chlorine, bromine, iodine, methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, iso-butyl, tert-butyl, 3-methyl-but-1-yl, cyclobutyl, cyclopentyl, cyclohexyl, 1-hydroxy-cyclopropyl, 1-hydroxy-cyclobutyl, 1-hydroxy-cyclopentyl, 1-hydroxy-cyclohexyl, ethinyl, 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, methlysulfonyl, ethylsulfinyl, ethylsulfonyl, trimethylsilyl, (R)-tetrahydrofuran-3-yloxy or (S)-tetrahydrofuran-3-yloxy or cyano;
wherein R 3 is selected from cyclopropyl, ethyl, ethinyl, ethoxy, (R)-tetrahydrofuran-3-yloxy or (S)-tetrahydrofuran-3-yloxy;
or a derivative thereof wherein one or more hydroxyl groups of the β-D-glucopyranosyl group are acylated with groups selected from (C 1-18 -alkyl)carbonyl, (C 1-18 -alkyl)oxycarbonyl, phenylcarbonyl and phenyl-(C 1-3 -alkyl)-carbonyl;
(3) Dapagliflozin, represented by formula (3):
(4) Canagliflozin, represented by formula (4):
(5) Empagliflozin, represented by formula (5):
(6) Luseogliflozin, represented by formula (6):
(7) Tofogliflozin, represented by formula (7):
(8) Ipragliflozin, represented by formula (8):
(9) Ertugliflozin, represented by formula (9):
(10) Atigliflozin, represented by formula (10):
(11) Remogliflozin, represented by formula (11):
(11A) Remogliflozin etabonate, represented by formula (11A):
(12) a thiophene derivative of the formula (12)
wherein R denotes methoxy or trifluoromethoxy;
(13) 1-(β-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienylmethyl]benzene, represented by formula (13);
(14) a spiroketal derivative of the formula (14):
wherein R denotes methoxy, trifluoromethoxy, ethoxy, ethyl, isopropyl or tert butyl;
(15) a pyrazole-O-glucoside derivative of the formula (15)
wherein
R 1 denotes C 1-3 -alkoxy,
L 1 , L 2 independently of each other denote H or F,
R 6 denotes H, (C 1-3 -alkyl)carbonyl, (C 1-6 -alkyl)oxycarbonyl, phenyloxycarbonyl, benzyloxycarbonyl or benzylcarbonyl;
(16) Sotagliflozin, represented by formula (16):
(17) Sergliflozin, represented by formula (17):
(18) a compound represented by formula (18):
wherein
R 3 denotes cyclopropyl, hydrogen, fluorine, chlorine, bromine, iodine, methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, iso-butyl, tert-butyl, 3-methyl-but-1-yl, cyclobutyl, cyclopentyl, cyclohexyl, 1-hydroxy-cyclopropyl, 1-hydroxy-cyclobutyl, 1-hydroxy-cyclopentyl, 1-hydroxy-cyclohexyl, ethinyl, 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, methlysulfonyl, ethylsulfinyl, ethylsulfonyl, trimethylsilyl, (R)-tetrahydrofuran-3-yloxy or (S)-tetrahydrofuran-3-yloxy or cyano, and wherein R 3 is selected from cyclopropyl, ethyl, ethinyl, ethoxy, (R)-tetrahydrofuran-3-yloxy or (S)-tetrahydrofuran-3-yloxy;
or a derivative thereof wherein one or more hydroxyl groups of the β-D-glucopyranosyl group are acylated with groups 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):
(20) Janagliflozin, represented by formula (20):
(21) Rongliflozin, represented by formula (21):
(22) Wanpagliflozin;
(23) Enavogliflozin, represented by formula (23):
(24) TFC-039, represented by formula (24):
3 . The aqueous pharmaceutical composition according to claim 1 , wherein velagliflozin is the only SGLT-2 inhibitor contained in the aqueous pharmaceutical composition.
4 . The aqueous pharmaceutical composition according to claim 1 , wherein the aqueous pharmaceutical composition is for direct, administration to a subject, without further mandatory processing and/or purification steps, or to an animal, or to a mammal, or to a horse, cat, dog or cow.
5 . The aqueous pharmaceutical composition according to claim 4 , wherein the aqueous pharmaceutical composition is sterile.
6 . The aqueous pharmaceutical composition according to claim 1 , wherein the one or more solubilizing agents are selected from the group consisting of: surfactants, anionic surfactants, non-ionic surfactants, hydrogenated castor oils, polyoxyethylene-polyoxypropylene block copolymers, polyethylene glycols, propylene glycol derivatives, and polyvinylpyrrolidones, and the total amount of the one or more solubilizing agents is from 1 to 50 g/100 mL (1-50% w/v).
7 . The aqueous pharmaceutical composition according to claim 1 , wherein two or more solubilizing agents are contained in the aqueous pharmaceutical composition.
8 . The aqueous pharmaceutical composition according to claim 7 , wherein two solubilizing agents are contained in the aqueous pharmaceutical composition, wherein the amount of the first solubilizing agent and the amount of the second solubilizing agent are independently from each other selected from 1 to 50 g/100 mL (1-50% w/v), or from 1 to 45 g/100 mL (1-45% w/v), or from 1 to 40 g/100 mL (1-40% w/v), or from 1 to 35 g/100 mL (1-35% w/v), or from 1 to 30 g/100 mL (1-30% w/v), or from 1 to 25 g/100 mL (1-25% w/v), or from 5 to 25 g/100 mL (5-25% w/v).
9 . The aqueous pharmaceutical composition according to claim 8 , wherein the two solubilizing agents are independently from each other selected from the group consisting of: sodium dodecyl sulphate (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).
10 . The aqueous pharmaceutical composition according to claim 9 , wherein the two solubilizing agents are Kollidon 12 (povidone) as well as PEG 200, PEG 300 or PEG 400.
11 . The aqueous pharmaceutical composition according to claim 10 , wherein the two solubilizing agents are Kollidon 12 (povidone) and PEG 300.
12 . The aqueous pharmaceutical composition according to claim 1 , wherein the aqueous pharmaceutical composition is a solution, an emulsion or a suspension, or a solution, an emulsion or a suspension with an NTU value of equal to or less than 10.0, or equal to or less than 7.0, or equal to or less than 3.0.
13 . The aqueous pharmaceutical composition according to claim 12 , wherein the aqueous pharmaceutical composition is a solution with an NTU value of equal to or less than 3.0.
14 . The aqueous pharmaceutical composition according to claim 1 , wherein the aqueous pharmaceutical composition contains from 30 to 100 g/100 mL (30 to 100% w/v), or from 30 to 95 g/100 mL (30 to 95% w/v), or from 30 to 90 g/100 mL (30 to 90% w/v), or from 30 to 85 g/100 mL (30 to 85% w/v), or from 30 to 80 g/100 mL (30 to 80% w/v), or from 50 to 80 g/100 mL (50 to 80% w/v) water, or in the form of aqueous buffer.
15 . The aqueous pharmaceutical composition according to claim 14 , wherein the aqueous pharmaceutical composition has a pH value of from 2 to 7, or from 3 to 7, or from 3.0 to 6.5, or from 4.0 to 6.5, or from 4.0 to 5.0, or of 4.5.
16 . The aqueous pharmaceutical composition according to claim 1 , wherein the aqueous pharmaceutical composition additionally comprises one or more preservatives selected from the group consisting of: sorbic acid or salts thereof, benzoic acid or salts thereof, benzalkonium chloride; benzethonium chloride; benzyl alcohol, cetylpyridinium chloride; sodium metabisulfite; sodium acetate; and parabens and salts thereof.
17 . The aqueous pharmaceutical composition according to claim 1 , wherein the aqueous pharmaceutical composition additionally comprises one or more antioxidation agents selected from the group consisting of: ascorbic acid or pharmaceutically acceptable salts thereof, citric acid (anhydrous and/or monohydrate) or pharmaceutically acceptable salts thereof; erythorbic acid; fumaric acid; malic acid; monothioglycerol; phosphoric acid; sodium metabisulfite; potassium metabisulfite; propionic acid; sodium bisulfite; sodium sulfite; resveratrol; butylhydroxyanisol; butylhydroxytoluene; gallate derivatives; Vitamin E or pharmaceutically acceptable salts thereof; ascorbyl palmitate; and edetic acid or pharmaceutically acceptable salts thereof.
18 . The aqueous pharmaceutical composition according to claim 1 , wherein the aqueous pharmaceutical composition additionally comprises one or more viscosity-enhancing agents selected from the group consisting of: inorganic gel forming agents, organic gel forming agents, and cellulose derivatives.
19 . The aqueous pharmaceutical composition according to claim 1 , wherein the aqueous pharmaceutical composition additionally comprises one or more flavours and/or sweeteners selected from the group consisting of: honey flavor, lime/salvia flavor, jasmine flavor, lavender flavor, peppermint flavor, raspberry flavor, lemon flavor, herbs flavor, meat flavor, vanillin/vanilla flavor, saccharine, aspartame, sorbitol, and xylitol.
20 . The aqueous pharmaceutical composition according to claim 1 , comprising:
one or more preservatives selected from the group consisting of: sorbic acid or salts thereof; benzoic acid or salts thereof, benzethonium chloride; benzyl alcohol, cetylpyridinium chloride; sodium metabisulfite; sodium acetate; and parabens and salts thereof;
one or more flavors and/or sweeteners selected from the group consisting of: honey flavor, lime/salvia flavor, jasmine flavor, lavender flavor, peppermint flavor, raspberry flavor, lemon flavor, herbs flavor, meat flavor, vanillin/vanilla flavor, saccharine, aspartame, sorbitol, xylitol;
water in the form of aqueous buffer with pH 4.5;
one or more solubilizing agents selected from the group consisting of: surfactants, anionic surfactants, non-ionic surfactants, hydrogenated castor oils, polyoxyethylene-polyoxypropylene block copolymers, polyethylene glycols, propylene glycol derivatives, and polyvinylpyrrolidones;
one or more viscosity-enhancing agents selected from the group consisting of: inorganic gel forming agents, organic gel forming agents, and cellulose derivatives; and
one or more antioxidation agents selected from the group consisting of: ascorbic acid or pharmaceutically acceptable salts thereof; citric acid (anhydrous and/or monohydrate) or pharmaceutically acceptable salts thereof; erythorbic acid; fumaric acid; malic acid; monothioglycerol; phosphoric acid; sodium metabisulfite; potassium metabisulfite; propionic acid; sodium bisulfite; sodium sulfite; resveratrol; butylhydroxyanisol; butylhydroxytoluene; gallate derivatives; Vitamin E or pharmaceutically acceptable salts thereof; ascorbyl palmitate; and edetic acid or pharmaceutically acceptable salts thereof.
21 . The aqueous pharmaceutical composition according to claim 1 , comprising:
0.5-20.0 g/100 mL (0.5-20.0% w/v), or 0.5-15.0 g/100 mL (0.5-15.0% w/v), or 1.0-1.5 g/100 mL (1.0-1.5% w/v) of velagliflozin as a single SGLT-2 inhibitor;
0-3.0 g/100 mL (0-3.0% w/v), or 0.05-3.0 g/100 mL (0.05-3.0% w/v), or 0.05-2.0 g/100 mL (0.05-2.0% w/v) of one or more preservatives selected from the group consisting of: sorbic acid or salts thereof; benzoic acid or salts thereof; benzalkonium chloride; benzethonium chloride; benzyl alcohol; cetylpyridinium chloride; sodium metabisulfite; sodium acetate; and parabens and salts thereof;
0-40 g/100 mL (0-40% w/v), or 0-30 g/100 mL (0-30% w/v), or 0-2 g/100 mL (0-2% w/v) of one or more flavors and/or sweeteners selected from the group consisting of: honey flavor, lime/salvia flavor, jasmine flavor, lavender flavor, peppermint flavor, raspberry flavor, lemon flavor, herbs flavor, meat flavor, vanillin/vanilla flavor, saccharine, aspartame, sorbitol, and xylitol;
30 to 100 g/100 mL (30 to 100% w/v), or from 30 to 95 g/100 mL (30 to 95% w/v), or from 30 to 90 g/100 mL (30 to 90% w/v), or from 30 to 85 g/100 mL (30 to 85% w/v), or from 30 to 80 g/100 mL (30 to 80% w/v), or from 50 to 80 g/100 mL (50 to 80% w/v) water in the form of aqueous buffer with pH 4.5;
1 to 50 g/100 mL (1-50% w/v), or from 1 to 45 g/100 mL (1-45% w/v), or from 1 to 40 g/100 mL (1-40% w/v), or from 1 to 35 g/100 mL (1-35% w/v), or from 1 to 30 g/100 mL (1-30% w/v), or from 1 to 25 g/100 mL (1-25% w/v), or from 5 to 25 g/100 mL (5-25% w/v) of one or more solubilizing agents selected from the group consisting of: surfactants, anionic surfactants, non-ionic surfactants, hydrogenated castor oils, polyoxyethylene-polyoxypropylene block copolymers, polyethylene glycols, propylene glycol derivatives, and polyvinylpyrrolidones;
0-40 g/100 mL (0-40% w/v), or 10-30 g/100 mL (10-30% w/v) of one or more viscosity-enhancing agents selected from the group consisting of: inorganic gel forming agents, organic gel forming agents, cellulose derivatives; and
0-1.0 g/100 mL (0-1.0% w/v), or 0-0.5 g/100 mL (0-0.5% w/v), or 0.1-0.3 g/100 mL (0.1-0.3% w/v) of one or more antioxidation agents selected from the group consisting of: ascorbic acid or pharmaceutically acceptable salts thereof, citric acid (anhydrous and/or monohydrate) or pharmaceutically acceptable salts thereof; erythorbic acid; fumaric acid; malic acid; monothioglycerol; phosphoric acid; sodium metabisulfite; potassium metabisulfite; propionic acid; sodium bisulfite; sodium sulfite; resveratrol; butylhydroxyanisol; butylhydroxytoluene; gallate derivatives; Vitamin E or pharmaceutically acceptable salts thereof; ascorbyl palmitate; and edetic acid or pharmaceutically acceptable salts thereof.
22 . The aqueous pharmaceutical composition according to claim 1 , consisting of: velagliflozin; sodium dodecyl sulphate (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; and water.
23 . The aqueous pharmaceutical composition according to claim 1 , consisting of: velagliflozin; citric acid monohydrate; NaOH; sodium dodecyl sulphate (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; and water.
24 . The aqueous pharmaceutical composition according to claim 1 , consisting of: velagliflozin; citric acid monohydrate; NaOH; sodium dodecyl sulphate (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; sorbitol and/or xylitol; honey flavor and/or vanillin and/or meat flavor; and water.
25 . The aqueous pharmaceutical composition according to claim 1 , wherein the aqueous pharmaceutical composition is for oral and/or parenteral administration.
26 . A method of treating and/or preventing one or more medicinal indications in a subject in need of such treatment and/or prevention by administering the aqueous pharmaceutical composition according to claim 1 , to the subject, wherein the subject is a mammal, or a horse, or a cat, or a dog, or a cow, and the one or more medicinal indications is selected from the group consisting of:
(i) a metabolic disorder and/or a clinical condition of an equine animal, wherein the metabolic disorder is one or more disorders selected from insulin resistance, hyperinsulinemia, impaired glucose tolerance, dyslipidemia, dysadipokinemia, subclinical inflammation, systemic inflammation, low grade systemic inflammation, obesity, and/or regional adiposity, and the clinical condition is one or more conditions selected from impaired glucose tolerance, dyslipidemia, dysadipokinemia, subclinical inflammation, systemic inflammation, low grade systemic inflammation, obesity, and/or regional adiposity;
(ii) a metabolic disorder of an equine animal, wherein the metabolic disorder is one or more disorders selected from laminitis, vascular dysfunction, hypertension, hepatic lipidosis, atherosclerosis, hyperadrenocorticism, Pituitary Pars Intermedia Dysfunction and/or Equine Metabolic Syndrome, or wherein the metabolic disorder is a clinical condition/sign associated with insulin resistance and/or hyperinsulinemia, wherein said clinical condition/sign is one or more conditions selected from laminitis, vascular dysfunction, hypertension, hepatic lipidosis, atherosclerosis, hyperadrenocorticism, Pituitary Pars Intermedia Dysfunction and/or Equine Metabolic Syndrome;
(iii) a metabolic disorder of a feline animal, wherein the metabolic disorder is one or more selected from the group consisting of: ketoacidosis, pre-diabetes, diabetes mellitus type 1 or type 2, insulin resistance, acromegaly, diabetes with elevated IGF-1 concentration, obesity, hyperglycemia, impaired glucose tolerance, hyperinsulinemia, dyslipidemia, dysadipokinemia, subclinical inflammation, systemic inflammation, low grade systemic inflammation, hepatic lipidosis, atherosclerosis, inflammation of the pancreas, neuropathy and/or Syndrome X (metabolic syndrome) and/or loss of pancreatic beta cell function and/or wherein the remission of the metabolic disorder is achieved and/or maintained;
(iv) a metabolic disorder of a canine animal, wherein the metabolic disorder is one or more selected from the group consisting of: ketoacidosis, pre-diabetes, insulin dependent diabetes mellitus, insulin resistance diabetes, insulin resistance, obesity, hyperglycemia, hyperglycemia induced cataract formation, impaired glucose tolerance, hyperinsulinemia, dyslipidemia, dysadipokinemia, subclinical inflammation, systemic inflammation, low grade systemic inflammation, hepatic lipidosis, inflammation of the pancreas, and metabolic disorder consequences selected from the group consisting of hypertension, renal dysfunction, and musculoskeletal disorders, and Syndrome X (metabolic syndrome), wherein the development of hyperglycemia induced cataract formation is prevented or remission is achieved and/or wherein the development of metabolic disorder consequences is prevented or progression is slowed or remission is achieved;
(v) a cardiac disease of a feline animal, wherein the cardiac disease is one or more 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 and arrhythmogenic right ventricular cardiomyopathy (ARVC);
(vi) drying-off of a non-human mammal, improving and/or facilitating the drying-off of a non-human mammal, reducing the milk production and/or secretion, in a pregnant and/or lactating non-human mammal, decreasing milk accumulation and/or engorgement in the udder and/or mammary gland, of a non-human mammal, decreasing the discomfort associated with udder engorgement of a non-human mammal, decreasing milk leakage after drying-off of a non-human mammal, and decreasing the incidence of intra-mammary infections (IMI) in a non-human mammal;
(vii) a cardiac disease of a canine, wherein the cardiac disease is one or more selected from the group consisting of: heart failure; congestive heart failure; asymptomatic/preclinical/occult 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/occult heart failure due to (myxomatous) mitral valve disease [(M)MVD]; (myxomatous) mitral valve disease [(M)MVD]; clinically overt (myxomatous) mitral valve disease [(M)MVD]; asymptomatic/preclinical/occult (myxomatous) mitral valve disease [(M)MVD]; heart failure due to dilated cardiomyopathy (DCM); congestive heart failure due to dilated cardiomyopathy (DCM); asymptomatic/preclinical/occult heart failure due to dilated cardiomyopathy (DCM); dilated cardiomyopathy (DCM); clinically overt dilated cardiomyopathy (DCM); asymptomatic/preclinical/occult dilated cardiomyopathy (DCM); and aortic stenosis (valvular, supravalvular and/or subvalvular);
(viii) hypertension in a cat or a dog, wherein the hypertension is one or more selected from the group consisting of: situational hypertension, secondary hypertension and idiopathic hypertension, wherein the secondary hypertension is selected from the group consisting of hypertension associated with chronic kidney disease (CKD), diabetes, obesity, heart disease, endocrine disease, hyperthyroidism, acromegaly, and elevated blood pressure (BP) induced by medicaments; and
(ix) a renal disease of a cat or a dog, wherein the renal disease is one or more selected from the group consisting of: renal dysplasia, glomerulopathy, polycystic kidney disease, amyloidosis, tubulo-nephritis/tubulointerstitial nephritis (TIN), acute kidney disease, chronic kidney disease.
27 . A process for producing the aqueous pharmaceutical composition according to claim 1 , comprising the steps (in any meaningful order):
(i) providing water as starting material;
(ii) adding one or more solubilizing agents to the water from step (i) to form a mixture;
(iii) dissolving the at least one SGLT-2 inhibitor comprising velagliflozin, in the mixture resulting from step (ii);
(iv) optionally, dissolving one or more preservatives in the mixture resulting from step (iii),
(v) optionally, further dissolving one or more further excipients selected from the group consisting of pH modifier(s), flavor(s), sweeteners, antioxidation agents, and viscosity-enhancing agents, and in the mixture resulting from step (iii) or optionally (iv);
(vi) optionally, filtrating the mixture resulting from step (iii), optionally step (iv) or optionally step (v);
whereby, optionally, independently from each other after any of the individual process steps—be they mandatory or optional—an additional mixing step is performed.
28 . A kit-of-parts comprising:
(a) an aqueous pharmaceutical composition according to claim 1 ; and
(b) a package leaflet including the information that the aqueous pharmaceutical composition is to be used for the prevention and/or treatment of one or more medicinal indications in a subject in need of such prevention and/or treatment, which are selected from among the medicinal indications:
(i) a metabolic disorder and/or a clinical condition of an equine animal, wherein the metabolic disorder is one or more disorders selected from insulin resistance, hyperinsulinemia, impaired glucose tolerance, dyslipidemia, dysadipokinemia, subclinical inflammation, systemic inflammation, low grade systemic inflammation, obesity, and/or regional adiposity; wherein said clinical condition is one or more conditions selected from impaired glucose tolerance, dyslipidemia, dysadipokinemia, subclinical inflammation, systemic inflammation, low grade systemic inflammation, obesity, and regional adiposity;
(ii) a metabolic disorder of an equine animal, wherein the metabolic disorder is one or more disorders selected from laminitis, vascular dysfunction, hypertension, hepatic lipidosis, atherosclerosis, hyperadrenocorticism, Pituitary Pars Intermedia Dysfunction and/or Equine Metabolic Syndrome, or the metabolic disorder is a clinical condition/sign associated with insulin resistance and/or hyperinsulinaemia, wherein said clinical condition/sign is one or more conditions selected from laminitis, vascular dysfunction, hypertension, hepatic lipidosis, atherosclerosis, hyperadrenocorticism, Pituitary Pars Intermedia Dysfunction and/or Equine Metabolic Syndrome;
(iii) a metabolic disorder of a feline animal, wherein the metabolic disorder is one or more selected from the group consisting of: ketoacidosis, pre-diabetes, diabetes mellitus type 1 or type 2, insulin resistance, acromegaly, diabetes with elevated IGF-1 concentration, obesity, hyperglycemia, impaired glucose tolerance, hyperinsulinemia, dyslipidemia, dysadipokinemia, subclinical inflammation, systemic inflammation, low grade systemic inflammation, hepatic lipidosis, atherosclerosis, inflammation of the pancreas, neuropathy and/or Syndrome X (metabolic syndrome), and loss of pancreatic beta cell function, wherein the remission of the metabolic disorder is achieved and/or maintained;
(iv) a metabolic disorder of a canine animal, wherein the metabolic disorder is one or more selected from the group consisting of: ketoacidosis, pre-diabetes, insulin dependent diabetes mellitus, insulin resistance diabetes, insulin resistance, obesity, hyperglycemia, hyperglycemia induced cataract formation, impaired glucose tolerance, hyperinsulinemia, dyslipidemia, dysadipokinemia, subclinical inflammation, systemic inflammation, low grade systemic inflammation, hepatic lipidosis, inflammation of the pancreas, metabolic disorder consequences selected from the group consisting of hypertension, renal dysfunction, and musculoskeletal disorders, and Syndrome X (metabolic syndrome), wherein the development of hyperglycemia induced cataract formation is prevented or remission is achieved and/or wherein the development of metabolic disorder consequences is prevented or progression is slowed or remission is achieved;
(v) a cardiac disease of a feline animal, wherein the cardiac disease is one or more 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);
(vi) drying-off of a non-human mammal, improving and/or facilitating the drying-off of a non-human mammal, reducing the milk production and/or secretion in a pregnant and/or lactating non-human mammal, decreasing milk accumulation and/or engorgement in the udder and/or mammary gland of a non-human mammal, decreasing the discomfort associated with udder engorgement of a non-human mammal, decreasing milk leakage after drying-off of a non-human mammal, and decreasing the incidence of intra-mammary infections (IMI) in a non-human mammal;
(vii) a cardiac disease of a canine, wherein the cardiac disease is one or more selected from the group consisting of: heart failure; congestive heart failure; asymptomatic/preclinical/occult 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/occult heart failure due to (myxomatous) mitral valve disease [(M)MVD]; (myxomatous) mitral valve disease [(M)MVD]; clinically overt (myxomatous) mitral valve disease [(M)MVD]; asymptomatic/preclinical/occult (myxomatous) mitral valve disease [(M)MVD]; heart failure due to dilated cardiomyopathy (DCM); congestive heart failure due to dilated cardiomyopathy (DCM); asymptomatic/preclinical/occult heart failure due to dilated cardiomyopathy (DCM); dilated cardiomyopathy (DCM); clinically overt dilated cardiomyopathy (DCM); asymptomatic/preclinical/occult dilated cardiomyopathy (DCM); and aortic stenosis (valvular, supravalvular and/or subvalvular);
(viii) hypertension in a cat or a dog, wherein the hypertension is one or more selected from the group consisting of: situational hypertension, secondary hypertension and idiopathic hypertension, wherein the secondary hypertension is selected from the group consisting of hypertension associated with chronic kidney disease (CKD), diabetes, obesity, heart disease, endocrine disease, hyperthyroidism, acromegaly, and elevated blood pressure (BP) induced by medicaments;
(ix) a renal disease of a cat or a dog, wherein the renal disease is one or more selected from the group consisting of: renal dysplasia, glomerulopathy, polycystic kidney disease, amyloidosis, tubulo-nephritis/tubulointerstitial nephritis (TIN), acute kidney disease, and chronic kidney disease.