System for delivery of liquid pharmaceutical compositions comprising, inter alia, one or more SGLT-2 inhibitors

Abstract

Systems and methods for treating and / or preventing metabolic disorders and / or other medical conditions in a patient, such as a feline, by administering to the patient a liquid pharmaceutical composition, preferably comprising one or more SGLT-2 inhibitor compounds, via a delivery system comprising a syringe are described. The syringe includes features that facilitate administration of a simple, safe, and effective dose of the liquid pharmaceutical composition in a small volumetric dose to a patient during administration.

Description

[0001] [Included by reference]

[0002] All references cited in this article are incorporated herein by reference.

Technical field

[0003] This invention relates to the field of medicine, and more particularly to the field of veterinary medicine. Specifically, this invention relates to a delivery system including a syringe and a corresponding method for delivering a liquid pharmaceutical composition, particularly comprising one or more SGLT-2 inhibitor compounds, to a patient. [Existing Technology]

[0004] Treatment of metabolic disorders in mammals includes inhibiting the renal sodium-dependent glucose cotransporter SGLT-2. SGLT-2 in the kidneys regulates glucose levels by mediating the reabsorption of glucose back into the plasma after filtration in the blood. Therefore, SGLT-2 inhibition induces glucuria and reduces blood glucose levels.

[0005] For example, companion animals, including felines (e.g., cats) and canines (e.g., dogs), can be affected by a variety of metabolic disorders, including hyperglycemia, insulin resistance, diabetes (such as type 1 or type 2 diabetes, or prediabetes), fatty liver, obesity, hyperinsulinemia, impaired glucose tolerance, ketosis (especially ketoacidosis), dyslipidemia, dysadipokinemia, subclinical or systemic inflammation (especially low-grade systemic inflammation, which also includes adipose tissue), metabolic syndrome X, atherosclerosis, and / or pancreatitis. Various correlations exist among these conditions. Among these conditions, diabetes, especially prediabetes and type 2 diabetes, as well as hyperglycemia, insulin resistance, fatty liver, and obesity are increasingly important. Pharmaceutical compositions comprising one or more SGLT-2 inhibitors for the treatment and / or prevention of metabolic disorders in felines and canines have been described, for example, in WO 2015 / 091313 and WO 2015 / 110402.

[0006] Equines (such as horses) are affected by various metabolic disorders, including insulin resistance and hyperinsulinemia. For example, these insulin-related conditions in equines are rarely associated with diabetes and hyperglycemia as they are in humans or other mammals. However, in equines, insulin also regulates vital metabolic functions; for example, it drives glucose into tissues (such as the liver, fat, and skeletal muscle); induces vasoconstriction and vasodilation pathways; and regulates protein and fat metabolism. Therefore, insulin-related conditions can have serious and life-threatening effects on the health of equines. These conditions are associated with or may be related to a number of other equine conditions, symptoms, or syndromes, including impaired glucose tolerance, dyslipidemia, adipokines abnormalities, obesity and / or regional adiposity, subclinical or systemic inflammation (especially low-grade systemic inflammation, which also includes adipose tissue), equine metabolic syndrome (EMS), and / or equine pituitary pars intermedia dysfunction (PPID), also known as Cushing's syndrome, characterized by, for example, laminitis, vascular dysfunction, hypertension, fatty liver, hyperadrenocorticism, and / or atherosclerosis. Pharmaceutical compositions comprising one or more SGLT-2 inhibitors for the treatment and / or prevention of metabolic disorders in equines have been described, for example, in WO 2014 / 161836 and WO 2015 / 150299.

[0007] Other uses of SGLT-2 inhibitors in animals and / or medical indications and / or conditions for treatment and / or prevention by SGLT-2 inhibitors include, for example, the uses and / or medical indications and / or conditions disclosed in WO 2020 / 219645, WO 2021 / 105152, WO 2021 / 165177, WO2023 / 006718, WO 2023 / 006745 and WO 2023 / 006747.

[0008] Many SGLT-2 inhibitors are known and described in the art. Liquid pharmaceutical formulations of SGLT-2 inhibitors are particularly suitable for ensuring that these compounds are administered to patients in a safe and effective manner. However, ensuring that an accurate dose is administered based on the patient's weight at any given time can be a challenge. This is especially true for smaller (e.g., companion) animals, including felines and canines, because the dose based on the animal's weight may be very small (e.g., 1 mL or less). [Invention Overview]

[0010] According to the embodiments described herein, a drug delivery system includes a system for administering a liquid drug composition to a patient, the system including a syringe. The syringe includes a cylinder comprising a hollow elongated portion having an open front end and an open rear end, the hollow elongated portion including a first portion extending from the open front end to a transition section disposed along the hollow elongated portion, the first portion having a first cross-sectional dimension; and a second portion extending from the transition section to the open rear end of the open cylinder, the second portion having a second cross-sectional dimension larger than the first cross-sectional dimension. The syringe further includes a plunger comprising an elongated portion having a plunger front end and a plunger rear end. The plunger and cylinder are sized such that a portion of the plunger, including the plunger front end, can be inserted into the hollow elongated portion of the cylinder at the open rear end of the cylinder, and the plunger can extend within the cylinder until the plunger front end engages with a portion of the inner surface of the hollow elongated portion at the cylinder front end. The liquid drug composition received into the syringe via the open cylindrical tip is confined to a volume defined within a first portion of the cylinder, which can be adjusted by regulating the displacement of the plunger tip away from the cylinder tip. Furthermore, the surface wall portion of the plunger includes markings comprising a dosage scale that indicates the volume of the liquid drug composition received into the first portion of the cylinder based on the corresponding displacement of the plunger tip away from the cylinder tip.

[0011] According to other embodiments described herein, one or more SGLT-2 inhibitor compounds are disclosed for use in a method of treating a patient with a liquid pharmaceutical composition. The method includes: providing a syringe and a container containing the liquid pharmaceutical composition; drawing a desired dose of the liquid pharmaceutical composition from the container into a first portion of the syringe barrel by moving a plunger tip a selected distance from the front end of a cylinder until a selected mark of a plurality of dose graduations aligns with the outer surface of the cylinder at the rear end; and administering the desired dose of the liquid pharmaceutical composition to a patient from the syringe. The present invention also aims to include a corresponding method of treating a patient with a liquid pharmaceutical composition, and the use of one or more SGLT-2 inhibitor compounds in the preparation of a medicament for treating a patient with a liquid pharmaceutical composition.

[0012] The above and other features and advantages of the invention will become apparent after considering the following detailed description of specific embodiments thereof. [Attached Image Description]

[0013] Figure 1 A front view depicting the components of a delivery system (10) for administering a liquid pharmaceutical composition according to the embodiments described herein.

[0014] Figure 2 Depicting Figure 1A partial cross-sectional view of a portion (cap) of the container of the delivery system.

[0015] Figure 3A Depicting Figure 1 A perspective view of the container adapter of the delivery system.

[0016] Figure 3B Depicting Figure 3A A front view of the cross-section of the adapter.

[0017] Figure 4 Depicting Figure 1 A front view of the syringe cylinder of the delivery system.

[0018] Figure 5 Depicting Figure 1 A front view of the plunger of the syringe in the delivery system.

[0019] Figure 6 Depicting Figure 1 A partial cross-sectional front view of a syringe comprising a plunger engaging with a cylinder in its delivery system.

[0020] Figure 7 Depicting Figure 1 An exemplary implementation of a dosage scale provided on the plunger of a syringe in a delivery system.

[0021] Throughout this disclosure, the same reference numerals are used to identify the same components. [Detailed Description of the Invention]

[0023] Before describing embodiments of the invention in further detail, it should be noted that, as used herein and in the appended claims, the singular forms “a,” “an,” and “the” include a plurality of indicators unless the context clearly specifies otherwise.

[0024] 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 invention pertains. Unless otherwise specified or otherwise known to those skilled in the art, all given ranges and values ​​may vary by 1 to 5%, therefore the term "about" is omitted in the specification and claims. Although any methods and materials similar to or equivalent to those described herein may be used in the practice or testing of this invention, preferred methods, apparatus, and materials are described hereafter. All publications mentioned herein are incorporated herein by reference for the purpose of describing and disclosing substances, excipients, carriers, and methods reported in those publications that may be used in conjunction with this invention. Nothing herein should be construed as a prior art claim of priority over such disclosures.

[0025] The system described herein includes a liquid pharmaceutical composition and a drug delivery device or apparatus including a syringe capable of efficiently delivering small and precise doses of the liquid pharmaceutical composition to a patient. As described herein, liquid pharmaceutical compositions, particularly those containing one or more SGLT-2 inhibitor compounds, are effective in preventing and / or treating metabolic disorders and / or any other medical condition when administered to a patient. The liquid pharmaceutical composition may be provided in a tamper-proof container as described herein, wherein the cooperative arrangement of the syringe and container efficiently facilitates the transfer of a precise volume of the liquid pharmaceutical composition from the container to the syringe during use. The system may also be provided in a cartridge form, wherein the container containing the liquid pharmaceutical composition and the syringe are provided together (e.g., combined in a single package structure) for commercial sale / end use. Alternatively, the liquid pharmaceutical composition may be provided separately from the delivery device.

[0026] Pharmaceutical Composition

[0027] The liquid pharmaceutical composition used in the system described herein preferably comprises one or more SGLT-2 inhibitor compounds suitable for treating and / or preventing metabolic disorders and / or any other medical condition in a patient. For example, the pharmaceutical composition may comprise a single SGLT-2 inhibitor compound, or two or more SGLT-2 inhibitor compounds.

[0028] SGLT-2 inhibitors that can be used in liquid pharmaceutical compositions of the systems described herein include, but are not limited to, glucopyranosyl-substituted benzene derivatives, such as WO 01 / 27128, WO 03 / 099836, WO2005 / 092877, WO 2006 / 034489, WO 2006 / 064033, WO 2006 / 117359, WO 2006 / 117360, WO2007 / 025943, WO 2007 / 028814, WO 2007 / 031548, WO 2007 / 093610, WO 2007 / 128749, WO2008 / 049923, WO 2008 / 055870, WO 2008 / 055940, WO As described in 2009 / 02 / 2020 or WO 2009 / 02 / 2008.

[0029] Some non-limiting examples of SGLT-2 inhibitor compounds that may be provided in the liquid pharmaceutical compositions described herein include the following compounds or their pharmaceutically acceptable forms:

[0030] (1) Benzene derivatives substituted with glucopyranosyl groups, represented by the following formula:

[0031]

[0032] Where R 1 It represents cyano, Cl, or methyl (cyano is the most preferred).

[0033] R 2 It represents H, methyl, methoxy, or hydroxyl (most preferably H), and

[0034] R 3 This indicates cyclopropyl, hydrogen, fluorine, chlorine, bromine, iodine, methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, tert-butyl, 3-methyl-butyl-1-yl, cyclobutyl, cyclopentyl, cyclohexyl, 1-hydroxy-cyclopropyl, 1-hydroxy-cyclobutyl, 1-hydroxy-cyclopentyl, 1-hydroxy-cyclohexyl, ethynyl, ethoxy, difluoromethyl, trifluoromethyl, pentafluoroethyl, 2-hydroxy-ethyl, hydroxymethyl, 3-hydroxy-propyl, 2-hydroxy-2-methyl-propyl-1-yl, 3-hydroxy-3-methyl-butyl-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, difluoromethoxy, trifluoromethoxy, 2-methoxy-ethoxy, methylthio, methylsulfinyl, methylsulfonyl, ethylsulfinyl, ethylsulfonyl, trimethylsilyl, (R)-tetrahydrofuran-3-yloxy or (S)-tetrahydrofuran-3-yloxy, or cyano;

[0035] Where R 3 Preferably selected from cyclopropyl, ethyl, ethynyl, ethoxy, (R)-tetrahydrofuran-3-yloxy or (S)-tetrahydrofuran-3-yloxy; and most preferably, R 3 It is cyclopropyl.

[0036] Or its derivatives, wherein one or more hydroxyl groups of the β-D-glucopyranoyl group are selected from (C 1-18 alkyl)carbonyl, (C 1-18 Alkyl)oxycarbonyl, phenylcarbonyl and phenyl-(C) 1-3 Acylation of alkyl-carbonyl groups;

[0037] (2) Velagliflozin as expressed by the following formula:

[0038]

[0039] (3) Dapagliflozin expressed by the following formula:

[0040]

[0041] (4) Canagliflozin as expressed by the following formula:

[0042]

[0043] (5) Empagliflozin as expressed by the following formula:

[0044]

[0045] (6) Luseogliflozin as expressed by the following formula:

[0046]

[0047] (7) Tofogliflozin as expressed by the following formula:

[0048]

[0049] (8) Ipragliflozin as expressed by the following formula:

[0050]

[0051] (9) Ertugliflozin as expressed by the following formula:

[0052]

[0053] (10) Atigliflozin expressed by the following formula:

[0054]

[0055] (11) Remogliflozin as expressed by the following formula:

[0056]

[0057] (11A) Remogliflozin etabonate expressed by the following formula:

[0058]

[0059] (12) Thiophene derivatives represented by the following formula:

[0060]

[0061] Where R represents methoxy or trifluoromethoxy;

[0062] (13) 1-(β-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienylmethyl]benzene represented by the following formula:

[0063]

[0064] (14) Spiroacetal derivatives represented by the following formula:

[0065]

[0066] Where R represents methoxy, trifluoromethoxy, ethoxy, ethyl, isopropyl, or tert-butyl;

[0067] (15) Pyrazole-O-glucoside derivatives represented by the following formula:

[0068]

[0069] in:

[0070] R 1 C represents 1-3 Alkoxy

[0071] L 1 L 2 H or F can be represented independently of each other.

[0072] R 6 Represents H, (C 1-3 alkyl)carbonyl, (C 1-6 Alkyl)oxycarbonyl, phenoxycarbonyl, benzyloxycarbonyl or benzylcarbonyl; (16) Sotagliflozin represented by the following formula:

[0073]

[0074] (17) Sergliflozin as expressed by the following formula:

[0075]

[0076] (18) Compounds represented by the following formula:

[0077]

[0078] in:

[0079] R 3This indicates cyclopropyl, hydrogen, fluorine, chlorine, bromine, iodine, methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, tert-butyl, 3-methyl-butyl-1-yl, cyclobutyl, cyclopentyl, cyclohexyl, 1-hydroxy-cyclopropyl, 1-hydroxy-cyclobutyl, 1-hydroxy-cyclopentyl, 1-hydroxy-cyclohexyl, ethynyl, ethoxy, difluoromethyl, trifluoromethyl, pentafluoroethyl, 2-hydroxy-ethyl, hydroxymethyl, 3-hydroxy-propyl, 2-hydroxy-2-methyl-propyl-1-yl, 3-hydroxy-3-methyl-butyl-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, difluoromethoxy, trifluoromethoxy, 2-methoxy-ethoxy, methylthio, methylsulfinyl, methylsulfonyl, ethylsulfinyl, ethylsulfonyl, trimethylsilyl, (R)-tetrahydrofuran-3-yloxy or (S)-tetrahydrofuran-3-yloxy, or cyano; and wherein R 3 Preferably selected from cyclopropyl, ethyl, ethynyl, ethoxy, (R)-tetrahydrofuran-3-yloxy or (S)-tetrahydrofuran-3-yloxy; and R 3 The most preferred is cyclopropyl.

[0080] Or its derivatives, wherein one or more hydroxyl groups of the β-D-glucopyranoyl group are selected from (C 1-18 alkyl)carbonyl, (C 1-18 Alkyl)oxycarbonyl, phenylcarbonyl and phenyl-(C) 1-3 Acylation of alkyl-carbonyl groups;

[0081] (19) Bexagliflozin expressed by the following formula:

[0082]

[0083] (20) Janagliflozin as expressed by the following formula:

[0084]

[0085] (21) Rongliflozin;

[0086]

[0087] (22) Wanpagliflozin;

[0088] (23) Enavogliflozin as expressed by the following formula:

[0089] and

[0090] (24) TFC-039 is represented by the following formula:

[0091]

[0092] As used herein, the term "vilagliflozin" refers to vilagliflozin having the above structure and its pharmaceutically acceptable forms, including its hydrates and solvates and their crystalline forms. This compound, its synthetic methods, and its cocrystals are described, for example, in WO 2007 / 128749, WO 2014 / 016381, and WO 2019 / 121509.

[0093] As used herein, the term "dapagliflozin" refers to dapagliflozin having the above structure and its pharmaceutically acceptable forms, including its hydrates, solvates, and crystalline forms. This compound and its synthetic methods are described, for example, in WO 03 / 099836. Preferred hydrates, solvates, and crystalline forms are described, for example, in patent applications WO 2008 / 116179 and WO 2008 / 002824.

[0094] As used herein, the term "canagliflozin" refers to canagliflozin having the above structure and its pharmaceutically acceptable forms, including its hydrates, solvates, and crystalline forms. This compound and its synthetic methods are described, for example, in WO 2005 / 012326 and WO 2009 / 035969. Preferred hydrates, solvates, and crystalline forms are described, for example, in patent application WO 2008 / 069327.

[0095] As used herein, the term "empagliflozin" refers to empagliflozin having the above structure and its pharmaceutically acceptable forms, including its hydrates and solvates and their crystalline forms. This compound and its synthetic methods are described, for example, in WO 2005 / 092877, WO 2006 / 120208 and WO 2011 / 039108. Preferred crystalline forms are described, for example, in patent applications WO 2006 / 117359 and WO 2011 / 039107.

[0096] As used herein, the term "aloggliflozin" refers to aloggliflozin having the above structure and its pharmaceutically acceptable forms, including its hydrates and solvates and their crystalline forms. This compound and its synthetic methods are described, for example, in WO 2004 / 007517.

[0097] As used herein, the term "ioggliflozin" refers to ioggliflozin having the above structure and its pharmaceutically acceptable forms, including its hydrates and solvates and their crystalline forms. This compound and its synthetic methods are described, for example, in WO 2004 / 080990, WO 2005 / 012326 and WO 2007 / 114475.

[0098] As used herein, the term "torpagliflozin" refers to topagliflozin having the above structure and its pharmaceutically acceptable forms, including its hydrates and solvates and their crystalline forms. This compound and its synthetic methods are described, for example, in WO 2007 / 140191 and WO 2008 / 013280.

[0099] As used herein, the term "ruggliflozin" refers to ruggliflozin having the above structure and its pharmaceutically acceptable forms, including its hydrates and solvates and their crystalline forms.

[0100] As used herein, the term "eoglitazone" refers to eoglitazone having the above structure and its pharmaceutically acceptable forms, including its hydrates and solvates and their crystalline forms. This compound is described, for example, in WO 2010 / 023594.

[0101] As used herein, the term "regoragliflozin" refers to repagliflozin having the above structure and its pharmaceutically acceptable forms, including repagliflozin prodrugs, particularly repagliflozin decahydrate, including its hydrates and solvates and their crystalline forms. Methods of synthesis are described, for example, in patent applications EP 1 213 296 and EP 1 354 888.

[0102] As used herein, the term "sergagliflozin" refers to sergagliflozin having the above structure and its pharmaceutically acceptable forms, including sergagliflozin prodrugs, particularly sergagliflozin decacarbonate, including its hydrates and solvates and their crystalline forms. Methods of preparation are described, for example, in patent applications EP 1 344 780 and EP 1 489 089.

[0103] The compound of formula (16) above (i.e., soggliflozin) and its preparation are described, for example, in WO 2008 / 042688 or WO2009 / 014970.

[0104] As used herein, the term "besagliflozin" refers to besagliflozin having the above structure and its pharmaceutically acceptable forms, including its hydrates and solvates and their crystalline forms. This compound and its synthetic methods are described, for example, in WO 2009 / 026537.

[0105] As used herein, the term "TFC-039" refers to TFC-039 having the above structure and its pharmaceutically acceptable forms, including its hydrates and solvates and their crystalline forms. This compound and its synthetic methods are described, for example, in WO2012 / 160218.

[0106] Liquid pharmaceutical compositions may be in any suitable form that facilitates simple and efficient administration using the delivery systems described herein. For example, the composition may be in the form of a solution, syrup, or suspension. As described herein with respect to delivery systems, liquid pharmaceutical compositions can be administered at highly precise doses based on patient weight. Depending on the desired characteristics of the liquid pharmaceutical composition for a particular therapeutic form (e.g., viscosity, turbidity, solubility / suspension, number and type of active pharmaceutical ingredient, etc.), many other components may be provided in the composition in addition to one or more SGLT-2 inhibitor compounds.

[0107] According to a preferred embodiment, the liquid pharmaceutical composition is in the form of a solution or suspension. In other words, the pharmaceutical composition comprises one or more SGLT-2 inhibitor compounds in dissolved or suspended form.

[0108] For compositions used as suspensions, it is preferred when the liquid pharmaceutical composition contains one or more SGLT-2 inhibitor compounds in the form of solid particles. In this case, the size of the solid particles can be from 0.01 μm to 150 μm, or from 0.1 μm to 15 μm, or from 0.2 μm to 10.0 μm, or from 0.5 μm to 5 μm, depending on the maximum particle size.

[0109] SGLT-2 inhibitors may be administered to patients as monotherapy for the treatment and / or prevention of metabolic disorders and / or other medical indications and / or symptoms. Alternatively, the treatment may comprise one or more other active agents besides the SGLT-2 inhibitor compound.

[0110] For example, a liquid pharmaceutical composition may also contain a combination of one or more SGLT-2 inhibitors with any one or more other active pharmaceutical ingredients (APIs), allowing for simultaneous administration of both types. Alternatively, a liquid pharmaceutical composition containing one or more SGLT-2 inhibitor compounds may be administered separately from one or more other APIs. Some non-limiting examples of APIs that can be administered in combination with one or more SGLT-2 inhibitors (either within the same liquid pharmaceutical composition or separately) include: diuretics, such as furosemide, torasemide, or spironolactone; beta-blockers, such as atenolol or propranolol; and calcium channel blockers, such as diltiazem. (diltiazem); ACE inhibitors, such as benazepril, ramipril, or enalapril; angiotensin receptor blockers, such as telmisartan; antiarrhythmic agents, such as flecainide; platelet aggregation inhibitors, such as clopidogrel; nonsteroidal anti-inflammatory drugs (NSAIDs), such as aspirin; anticoagulants, such as coumarin (vitamin K antagonist), (low molecular weight) heparin, synthetic pentasaccharide inhibitors of factor Xa, and direct factor Xa inhibitors and / or direct thrombin inhibitors; DPP-IV inhibitors; and / or calcium channel sensitizers and / or inotropes, such as pimobendan and / or digitalis alkaloids;

[0111] Other solvents, excipients, buffers, flavoring agents, and / or other additives (such as preservatives and / or solubilizers) may also be provided in the liquid pharmaceutical composition, as disclosed in WO 2017 / 032799 and WO 2023 / 227492 / EP 22175413.8. For example, one or more polar organic solvents may be provided in the liquid pharmaceutical composition, such as ethanol (e.g., at an amount of 0-20 g / 100 mL), propylene glycol (propane-1,2-diol) (e.g., at an amount of 0-60 g / 100 mL), and / or glycerol (propane-1,2,3-triol) (e.g., at an amount of 0-60 g / mL). In another embodiment, the liquid pharmaceutical composition may be substantially free of organic solvents, i.e., it is completely free of any organic solvents. Water or an aqueous buffer solution including, for example, citric acid or phosphate may also be provided in the liquid pharmaceutical composition to achieve any desired pH of the composition (e.g., in amounts of 0-100 g / 100 mL, preferably 30-100 g / 100 mL). For example, the liquid pharmaceutical composition may be prepared with a pH range of 3 to 9.

[0112] Surprisingly, it was found that solvents affect the dosability and suitability of liquid pharmaceutical compositions, and that certain solvents or combinations of solvents make it easier and more precise to administer very small volumes.

[0113] Particularly good results can be achieved when the liquid pharmaceutical composition contains at least two or three organic polar solvents, and propylene glycol (propane-1,2-diol) is one of the at least two or three organic polar solvents. These compositions are disclosed in WO 2017 / 032799. Compositions 1 to 6 disclosed in WO 2017 / 032799 are incorporated herein by reference.

[0114] Preferably, the liquid pharmaceutical composition comprises 10 to 60 g / 100 mL, particularly 35 to 60 g / 100 mL, and preferably 50 to 60 g / 100 mL of propylene glycol, and at least one or two other polar organic solvents selected from ethanol and / or glycerol (propane-1,2,3-triol). Regarding other polar organic solvents, it is more preferred when the liquid pharmaceutical composition comprises 1 to 20 g / 100 mL, particularly 1 to 15 g / 100 mL, preferably 1 to 10 g / 100 mL, and more preferably 1 to 8 g / 100 mL of ethanol, and / or 1 to 60 g / 100 mL, particularly 1 to 52 g / 100 mL of glycerol.

[0115] According to a particularly preferred embodiment, the liquid pharmaceutical composition comprises 10 to 60 g / 100 mL, particularly 35 to 60 g / 100 mL, preferably 50 to 60 g / 100 mL of propylene glycol, and 1 to 20 g / 100 mL, particularly 2 to 15 g / 100 mL, preferably 3 to 10 g / 100 mL, particularly preferably 5 to 8 g / 100 mL of ethanol. According to composition 5 of WO 2017 / 032799, the composition comprising 60 g / 100 mL of propylene glycol and 8 g / 100 mL of ethanol exhibits particularly precise dosability in the delivery system described in paragraphs

[0078] to

[00107] of this specification.

[0116] In another aspect, the liquid pharmaceutical composition may contain ethanol as the sole organic polar solvent. According to this embodiment, the liquid pharmaceutical composition contains no more than 20 g / 100 mL of ethanol, preferably no more than 15 g / 100 mL of ethanol, more preferably no more than 10 g / 100 mL of ethanol. Preferably, ethanol is present in the liquid pharmaceutical composition in an amount of 1 to 20 g / 100 mL, preferably 2 to 15 g / 100 mL, more preferably 5 to 10 g / 100 mL. According to a particularly preferred embodiment, ethanol is present in the liquid pharmaceutical composition in an amount of 8 g / 100 mL. Examples of these compositions are disclosed in EP 22175413.8 and WO 2023 / 227492 as compositions 1 to 4. Compositions 1 to 4 disclosed in EP 22175413.8 and WO 2023 / 227492 are incorporated herein by reference.

[0117] In another aspect, the liquid pharmaceutical composition is free of any organic solvents, especially the organic solvents described in paragraphs

[0046] to

[0051] (the first six paragraphs from this paragraph). If no organic solvent is present, the solvent of the liquid pharmaceutical composition is 100% water, preferably in the form of an aqueous buffer solution. Examples of suitable compositions free of organic solvents are described in EP22175413.8 and WO 2023 / 227492 as compositions 5 to 12. Compositions 5 to 12 disclosed in EP 22175413.8 and WO 2023 / 227492 are incorporated herein by reference.

[0118] Liquid pharmaceutical compositions may also contain one or more solubilizers, including but not limited to surfactants, anionic surfactants, nonionic surfactants, hydrogenated castor oil, polyoxyethylene-polyoxypropylene block copolymers, polyethylene glycol, and propylene glycol derivatives. Some specific non-limiting examples of suitable solubilizers include sodium dodecyl sulfate (SDS), Cremophor RH 40 (PEG-40 hydrogenated castor oil, polyethylene glycol glycerol hydroxystearate 40), polysorbate 20, Lutrol F 68 (poloxamer 188), PEG 200, PEG 300, PEG 400, propylene glycol monolaurate, and Kollidon 12 (povidone) (e.g., in amounts of 0-50 g / 100 mL, preferably 1-50 g / 100 mL).

[0119] According to a preferred embodiment of this aspect, the liquid pharmaceutical composition contains one or more solubilizers, particularly wherein the solubilizers are selected from sodium dodecyl sulfate (SDS), Cremophor RH 40 (PEG-40 hydrogenated castor oil, polyethylene glycol glycerol hydroxystearate 40), polysorbate 20, Lutrol F 68 (poloxam 188), PEG 200, PEG 300, PEG 400, propylene glycol monolaurate, and Kollidon 12 (povidone) and combinations thereof.

[0120] Preferably, the total amount of solubilizer in the liquid pharmaceutical composition is 1 to 50 g / 100 mL, especially 1 to 45 g / 100 mL, preferably 1 to 40 g / 100 mL, more preferably 1 to 35 g / 100 mL, even more preferably 1 to 30 g / mL, even more preferably 1 to 25 g / 100 mL, and most preferably 5 to 25 g / 100 mL.

[0121] In another aspect, the liquid pharmaceutical composition described herein contains two or more, preferably two, solubilizers. In this case, it is preferred when the solubilizer is Kollidon 12 (povidone) and PEG 200, PEG 300 or PEG 400, more preferably Kollidon 12 (povidone) and PEG 300.

[0122] According to another embodiment, particularly when the composition is a suspension, the liquid pharmaceutical composition contains a liquid carrier to carry solid particles comprising one or more SGLT-2 inhibitor compounds. The liquid carrier may be aqueous or organic, preferably aqueous. According to a particularly preferred embodiment, the liquid carrier is water or an aqueous buffer solution.

[0123] In another aspect, one or more suspending agents may be provided in the liquid pharmaceutical composition. Examples of suitable suspending agents are thickeners, such as cellulose derivatives, or gel-forming agents and / or thixotropic agents, such as gel-forming polysaccharides or natural gums.

[0124] One or more thickeners may also be provided in liquid pharmaceutical compositions, including but not limited to inorganic gel-forming agents, organic gel-forming agents, and cellulose derivatives. Some specific non-limiting examples of suitable thickeners include hydroxyethyl cellulose, hydroxypropyl methylcellulose, methylcellulose, carboxymethyl cellulose, and silica.

[0125] One or more thixotropic agents may be provided in liquid pharmaceutical compositions, including but not limited to synthetic or natural gums and mucilages. Some specific non-limiting examples of suitable thixotropic agents include tragacanth gum, xanthan gum, or alginate.

[0126] One or more flavoring agents (including flavorings and / or sweeteners) may be provided in liquid pharmaceutical compositions (particularly compositions for oral administration). Non-limiting examples of flavoring agents that may be provided in the composition include honey flavoring, lime / sage flavoring, jasmine flavoring, lavender flavoring, peppermint flavoring, raspberry flavoring, lemon flavoring, vanilla flavoring, meat flavoring, margarine flavoring, saccharin, stevia, and aspartame.

[0127] The concentration of the API including an SGLT-2 inhibitor in the liquid pharmaceutical composition can vary depending on a variety of factors, including but not limited to the required daily dose for a particular type of patient, the solubility characteristics of the API in combination with other components in the solution, etc. The concentration of one or more SGLT-2 inhibitor compounds in the liquid pharmaceutical composition can be from 0.1 mg / mL to 20 mg / mL or greater, for example, 1.2 mg / mL to 15 mg / mL, or 1 mg / mL to 5 mg / mL, or 5 mg / mL to 20 mg / mL, or 10 mg / mL to 20 mg / mL, or 12 mg / mL to 18 mg / mL. In an exemplary embodiment (e.g., for treating felines), the concentration of the SGLT-2 inhibitor compound in the liquid pharmaceutical composition can be 15 mg / mL. In another exemplary embodiment (e.g., for treating canines), the concentration of the SGLT-2 inhibitor compound in the liquid pharmaceutical composition can be 1.2 mg / mL. In another exemplary embodiment (e.g., for treating equines), the concentration of the SGLT-2 inhibitor compound in the liquid pharmaceutical composition can be 15 mg / mL.

[0128] Dosage and administration

[0129] The dosage of one or more SGLT-2 inhibitors to be administered to a patient may be determined based on a variety of factors, including patient / mammal type, patient body size / weight, metabolic disorder and / or the specific type of other medical condition to be prevented and / or treated.

[0130] Liquid pharmaceutical compositions and delivery systems for administering such compositions described herein are suitable for the treatment and / or prevention of one or more metabolic disorders and / or other medical indications in any suitable patient. Patients are preferably animals, more preferably non-human mammals, such as equines (e.g., horses), canines (e.g., dogs), felines (e.g., cats), or ruminants (e.g., cattle). The embodiments described herein are particularly suitable for treatments involving smaller companion animals, such as felines and (small) canines.

[0131] Generally, the dose of one or more SGLT-2 inhibitors to be administered to a patient is 0.01 to 10 mg / kg BW (patient body weight) per day. This dose can be administered once daily or multiple times daily, such as twice daily (e.g., every 12 hours), three times daily, etc. Depending on the patient's weight and the concentration of one or more SGLT-2 inhibitor compounds in the liquid pharmaceutical composition, the dose can be extremely small (e.g., about 1 mL or less). Therefore, having an efficient delivery system that can provide precise dosing is important.

[0132] For example, one or more SGLT-2 inhibitor compounds may be administered at doses of 0.01-10 mg / kg BW, or 0.01-5 mg / kg BW, or 0.01-4 mg / kg BW, or 0.01-3 mg / kg BW, or 0.01-2 mg / kg BW, or 0.01-1.5 mg / kg BW, or 0.01-1 mg / kg BW, or 0.01-0.75 mg / kg BW, or 0.01-0.5 mg / kg BW, or 0.01-0.4 mg / kg BW, or 0.01-0.3 mg / kg BW; or 0.1-5.0 mg / kg BW, or 0.1-3.0 mg / kg BW, or 0.2-2.0 mg / kg BW, or 0.1-1 mg / kg BW. Administer at a daily dose of BW, or 0.02-0.5 mg / kg BW, or 0.03-0.4 mg / kg BW, or 0.03-0.3 mg / kg BW.

[0133] An SGLT-2 inhibitor can be administered to achieve an appropriate plasma concentration of the SGLT-2 inhibitor (e.g., a maximum plasma concentration, or a plasma concentration after a given time, such as 4, 8, 12, or 24 hours after oral administration, preferably about 8 hours after oral administration). For example, for veragliflozin, the plasma concentration (e.g., the maximum plasma concentration or plasma concentration after the given time following oral administration) can be 2 to 4000 nM, for example 20 to 3000 nM, or for example 40 to 2000 nM. Preferably, such levels are maintained in the blood for at least 12 hours, more preferably at least 18 hours, and most preferably at least 24 hours after administration and the time required for the SGLT-2 inhibitor to reach blood flow.

[0134] Preferably, according to the embodiments described herein, the liquid pharmaceutical composition is administered orally. Using the delivery system described herein, the liquid pharmaceutical composition containing an SGLT-2 inhibitor compound can be administered directly to a patient's mouth or together with animal feed or beverages (e.g., its drinking water). Alternatively, the liquid pharmaceutical composition can also be administered parenterally or via any other suitable route of administration (e.g., rectally) through the delivery system described herein.

[0135] Metabolic disorders / other medical conditions

[0136] The liquid pharmaceutical compositions comprising one or more SGLT-2 inhibitors described herein may be used in combination with the delivery systems described herein to treat and / or prevent various metabolic disorders and / or other medical indications in various types of patients.

[0137] For example, the liquid pharmaceutical compositions described herein, comprising one or more SGLT-2 inhibitor compounds, may be used to treat and / or prevent one or more metabolic disorders (or symptoms associated with these metabolic disorders) in equine patients (e.g., horses), including but not limited to insulin resistance, hyperinsulinemia, impaired glucose tolerance, dyslipidemia, adipokines abnormalities, subclinical inflammation, systemic inflammation, low-grade systemic inflammation (including adipose tissue), obesity, regional fat accumulation, laminitis, vascular dysfunction, hypertension, fatty liver, atherosclerosis, hyperadrenocorticism, middle pituitary dysfunction, and / or equine metabolic syndrome.

[0138] The liquid pharmaceutical compositions described herein, comprising one or more SGLT-2 inhibitor compounds, may also be used to treat and / or prevent one or more metabolic disorders (or symptoms associated with these metabolic disorders) in canine patients (e.g., dogs), including, but not limited to, diabetes, prediabetes, obesity, and / or any condition, disease, symptom, or illness associated with one or more of those conditions. Specifically, metabolic disorders may include hyperglycemia, impaired glucose tolerance, insulin resistance, insulin-dependent diabetes mellitus, and / or fatty liver. Other associated metabolic disorders include hyperinsulinemia, impaired glucose tolerance, ketosis (especially ketoacidosis), hyperlipidemia, dyslipidemia, elevated blood levels of fatty acids and / or glycerol, syndrome X (metabolic syndrome), and / or pancreatitis, low-grade systemic inflammation, and adipose tissue inflammation. The liquid pharmaceutical compositions described herein, comprising one or more SGLT-2 inhibitor compounds, may further be used to treat and / or prevent one or more other medical conditions in canine patients (e.g., dogs), including, but not limited to, one or more heart diseases. Specifically, the one or more heart diseases may include, but are not limited to, heart failure; congestive heart failure; asymptomatic / preclinical / silent heart failure; heart failure caused by (mica) mitral valve disease [(M)MVD]; congestive heart failure caused by (mica) mitral valve disease [(M)MVD]; asymptomatic / preclinical / silent heart failure caused by (mica) mitral valve disease [(M)MVD]; (mica) mitral valve disease [(M)MVD]; clinically overt (mica) mitral valve disease [(M)MVD] [(M)MVD]; asymptomatic / preclinical / occult (mixic) mitral valve disease; 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); aortic stenosis (valvular, supravalvular and / or subvalvular).

[0139] Furthermore, the liquid pharmaceutical compositions described herein, comprising one or more SGLT-2 inhibitor compounds, may be used to treat and / or prevent one or more metabolic disorders (or symptoms associated with these metabolic disorders) in feline patients (e.g., cats), including but not limited to diabetes, prediabetes, type 2 diabetes, acromegaly, diabetes with elevated IGF-1 levels, obesity, and / or any condition, disease, symptom, or illness associated with one or more of these disorders, hyperglycemia, insulin resistance, diabetes and / or fatty liver, hyperinsulinemia, impaired glucose tolerance, ketosis (especially ketoacidosis), hyperlipidemia, elevated blood levels of fatty acids and / or glycerol, syndrome X (metabolic syndrome), atherosclerosis, pancreatitis, adipose tissue inflammation, and / or pancreatic β-cell dysfunction. The liquid pharmaceutical compositions described herein, comprising one or more SGLT-2 inhibitor compounds, may be used to treat and / or prevent one or more other medical conditions in feline patients (e.g., cats), including but not limited to one or more heart diseases. Specifically, the one or more heart diseases may include, but are not limited to, heart failure, heart failure caused by one or more cardiomyopathy, heart failure caused by hypertrophic cardiomyopathy (HCM), heart failure caused by restrictive cardiomyopathy (RCM), heart failure caused by dilated cardiomyopathy (DCM), heart failure caused by unclassified cardiomyopathy (UCM), heart failure caused by 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: heart failure caused by one or more cardiomyopathy, heart failure caused by hypertrophic cardiomyopathy (HCM), and hypertrophic cardiomyopathy (HCM).

[0140] Furthermore, the liquid pharmaceutical compositions described herein, comprising one or more SGLT-2 inhibitor compounds, may be used to treat and / or prevent one or more kidney diseases in non-human mammals, such as felines and / or canines (e.g., cats and / or dogs), including but not limited to renal dysplasia, glomerulonephropathy, polycystic kidney disease, amyloidosis, tubulonephritis / tubulointerstitial nephritis (TIN), acute kidney disease, and chronic kidney disease.

[0141] Additionally, the liquid pharmaceutical compositions described herein comprising one or more SGLT-2 inhibitor compounds may be used to treat and / or prevent hypertension in non-human mammals, such as felines and / or canines (e.g., cats and / or dogs), including but not limited to situational hypertension, secondary hypertension, and idiopathic hypertension, wherein secondary hypertension may be selected from: hypertension associated with chronic kidney disease (CKD), diabetes, obesity, heart disease, endocrine disorders such as Cushing's disease, hyperthyroidism, acromegaly; and hypertension induced by drugs, preferably glucocorticoids, mineralocorticoids, erythropoietin, ephedrine, and / or high-dose sodium chloride.

[0142] Furthermore, the liquid pharmaceutical compositions described herein, comprising one or more SGLT-2 inhibitor compounds, may be used for drying-off in non-human mammals, such as ruminants, including but not limited to improving and / or promoting drying-off; reducing milk production; reducing milk accumulation and / or engorgement in the mammary glands and / or breasts; reducing discomfort associated with breast swelling, such as increasing daily lying time and / or reducing stress; reducing milk leakage after drying-off; and / or reducing the incidence of intramammary infections (IMI), such as mastitis and / or endometritis.

[0143] Delivery system

[0144] The delivery system for the liquid pharmaceutical composition described herein facilitates administration to patients and includes a storage container for receiving and storing the composition, and a syringe for efficiently drawing a precise dose volume of the composition from the container and delivering that dose volume (directly or indirectly) to the patient.

[0145] See Figures 1 to 7 The delivery system 10 for a liquid pharmaceutical composition includes a container 20 and a syringe 50. The container 20 includes a vessel 25 having a hollow interior, an open upper end 26, and an opposite closed lower end 27. The vessel 25 has suitable geometry and sufficient internal volume to store a suitable dose of the liquid pharmaceutical composition prior to use. For example, the volume of the vessel may be from 10 mL to 60 mL, preferably from 15 mL to 45 mL, so that the liquid pharmaceutical composition provides a sufficient daily dose for at least 14 days, preferably at least 28 or 30 days, wherein the SGLT-2 concentration in the liquid pharmaceutical composition may be from 1.2 mg / mL to 15 mg / mL (1.2 mg / mL for canines; 15 mg / mL for felines; 15 mg / mL for equines).

[0146] Container 20 further includes a lid or cap 30, which is detachably secured to the upper 26 of the opening of the vessel 25 (e.g., via threaded engagement between the cap and the opening of the vessel, such as...). Figure 2 (A partial cross-sectional view of the cap is shown). The storage container 25 and the cap 30 are each made of one or more polymers and / or other suitable materials that are relatively inert and non-reactive to any component of the liquid pharmaceutical composition stored in the container 20. For example, the storage container and the cap may each be made of one or more polyolefin materials. In an exemplary embodiment, the storage container is made of a polymer material comprising polyethylene (e.g., high-density polyethylene or HDPE), preferably polyethylene (e.g., high-density polyethylene or HDPE), while the cap is made of a polymer material comprising polypropylene and polyethylene (particularly preferred polypropylene), preferably polypropylene and polyethylene (particularly preferred polypropylene). As is known, high-density polyethylene (HDPE) has a linear polymer chain structure and is opaque, while low-density polyethylene (LDPE) has a branched polymer chain structure and is transparent or translucent. Although HDPE and LDPE have similar properties, HDPE has greater hardness or rigidity and is more tear / abrasion resistant than LDPE, while LDPE is a softer and more flexible material than HDPE.

[0147] The cap 30 includes an outer portion 33 comprising polypropylene, preferably polypropylene, and an inner portion 31 comprising polyethylene (e.g., high-density polyethylene or HDPE), preferably polyethylene. The inner portion 31 includes internal threads that engage threadedly with corresponding external threads at the upper opening 26 of the vessel 25. The inner portion 31 can be secured or welded to the outer portion 33 by any suitable means (e.g., via bonding, welding, co-injection molding, etc.). A gasket (e.g., comprising polyethylene, preferably polyethylene) may be disposed on the upper inner surface of the inner portion 31 to engage with the vessel at the upper opening 26 of the vessel 25 and form an effective fluid seal at the interface. The cap may further include a tamper-evident component indicating whether the container has been opened (i.e., the cap has been partially or completely detached from the storage vessel) before initial use of the delivery system. Specifically, the inner portion 31 of the cap 30 includes a removable ring 32, which is removably connected to the open end of the cap 30 located directly below the internal threads of the cap 30 (wherein the internal threads of the cap engage with the corresponding external threads at the upper end 26 of the opening of the vessel 25). The removable ring 32 may be connected to the inner portion 31 of the cap 30 at the lower end of the cap 30, for example, via a break-away tab 34.

[0148] During the initial installation or connection of the cap 30 to the upper 26 of the opening of the vessel 25, the cap 30 is connected to the upper end of the vessel via corresponding threads, wherein the cap rotates (e.g., clockwise) and moves downward to the upper end of the vessel to close the container 20. The removable ring 32 also moves downward along the upper end of the vessel and moves to or rides over the flange 28 at the upper 26 of the vessel's opening. The removable ring 32 further includes one or more inwardly extending and upwardly inclined (i.e., inclined towards the closed end of the cap) stopper members 36. The design of the ring 32 and the one or more stopper members 36 allows the ring 32 and the stopper members 36 to slide over or over the flange 28 when rotating downward (e.g., clockwise) onto the vessel 25. However, when the ring 32 is below the flange 28 (i.e., between the flange and the lower closed end 27 of the vessel 25), the stop 36 prevents the ring 32 from moving upward beyond the flange 28. The cap 30 can still be rotated upward (e.g., counterclockwise) and removed from the open upper end 26 of the vessel 25 because after the cap has been rotated a selected distance, the breakable pull tab 34 disengages the ring 32 from the inner portion 31 of the cap 30, thereby removing it from the vessel 25 (e.g., partially or completely disengaged / removed). The separation of the ring 32 from the cap 30 provides an indication that the container 20 has been at least partially opened and therefore used (at least once) before initial use or has been tampered with in some way (potentially damaging the liquid pharmaceutical composition within the container).

[0149] Container 20 may further include an adapter 40, which is secured to the top or upper open end of vessel 25. The adapter may be made of a polymer or other suitable material, such as a polyolefin. In an exemplary embodiment, adapter 40 is made of a polymer material comprising polyethylene (e.g., low-density polyethylene or LDPE), preferably polyethylene (e.g., low-density polyethylene or LDPE). See also Figure 3A and Figure 3BThe adapter 40 includes a hollow, elongated (e.g., generally cylindrical) main component 42, appropriately sized to fit substantially within the open upper end 26 of the vessel 25. At least a portion of the outer diameter of the main component 42 of the adapter 40 is substantially similar to, and may be slightly larger than, the inner diameter (ID) at the open upper end 26 of the vessel 25. The combination of the dimensions of the adapter and the open upper end of the vessel, as well as the materials constituting these two components (e.g., the adapter made of LDPE; the vessel made of HDPE), ensures a frictionally and fluidly sealed fit between the two components when the adapter 40 is installed in the open upper end 26 of the vessel and the outer wall portion of the main component 42 engages with the inner wall portion of the vessel at the open upper end of the vessel 25. The main component 42 includes an open upper end 44 and an end wall located at an opposite lower end 45. An annular flange 46 is disposed at the upper end 44 of the opening of the main component 42, wherein the cross-sectional dimension of the flange 46 is larger than that of the main component 42. The flange 46 extends outward at the upper end 44 of the main component and its diameter is substantially the same as the outer diameter at the upper end 26 of the opening of the vessel 25. Therefore, when the adapter 40 is connected to the vessel 25, the flange 46 is fixed to and rests on the upper end 26 of the opening of the vessel 25. The adapter 40 is further connected to the vessel 25 in a suitable manner to form a fluid seal between the two components at the opening end of the vessel.

[0150] The end wall at the lower end 45 of the main component 42 includes a central opening 47, which is smaller than the opening at the upper end 44. Within the hollow main component 42, an elongated, hollow (e.g., cylindrical) internal connecting member 48 extends longitudinally from the end wall at the lower end 45, wherein the internal connecting member 48 is fluid-tightly connected (i.e., aligned) with the central opening at the lower end wall of the lower end 45, and further extends within the outer hollow main component 42 to the open upper end 44. The internal connecting member 48 is open at its upper end, and the upper end of the internal connecting member is generally coplanar with or flush with the flange 46, or extends slightly beyond the flange 46. Therefore, when the adapter 40 is secured to the vessel 25 at the open upper end 26 of the vessel, the adapter provides an outlet through the elongated internal connecting member 48 to allow the liquid pharmaceutical composition to be drawn from the interior of the vessel. As described herein with respect to syringe 50, the cross-section (e.g., diameter) of the hollow internal connecting member 48 is appropriately sized to engage with the corresponding end of the syringe in a releasable, friction-sealed, and fluid-sealed manner.

[0151] See Figure 4 and Figure 5The syringe 50 of the delivery system 10 includes a cylinder 60 and a plunger 80, wherein the plunger 80 is appropriately sized such that a portion of the plunger is slidably housed within the cylinder and can retractably move within the cylinder to facilitate the drawing of fluid from a container into the cylinder and the forced flow of fluid out of the cylinder via the plunger during use. The syringe cylinder and plunger can each be made of any suitable polymer and / or other materials that are relatively inert and non-reactive to any component of the liquid pharmaceutical composition that the syringe comes into contact with during use. For example, the syringe cylinder and plunger can each be made of the same or different polyolefin materials. In a preferred embodiment, the syringe cylinder is made of a polymer material comprising polyethylene (e.g., low-density polyethylene or LDPE), preferably polyethylene, while the syringe plunger is made of a polymer material comprising polystyrene, preferably polystyrene. The choice of plunger and cylinder materials has an unexpected impact on the drug delivery characteristics of the syringe. The combination of a syringe barrel made of LDPE and a plunger made of polystyrene enables improved, and especially more precise, administration or delivery of liquid drug compositions in very small volumes.

[0152] The syringe cylinder 60 is hollow and has an elongated, generally cylindrical structure, including a lower or front end 62 through which solution is drawn from the vessel 25 of the container 20 (via the plunger 80). The cylinder 60 further has an open upper or rear end 64, appropriately sized to accommodate a portion of the plunger 80. The cross-sectional dimension or diameter of the cylinder 60 varies along its length, including a first portion 66 extending from the front end 62 to a transition section 68, where the cross-sectional dimension or diameter increases. A second portion 70 of the cylinder 60 extends from the transition section 68 to the open rear end 64. The cross-sectional dimension or diameter of the second portion 70 (i.e., the second cross-sectional dimension) is larger than that of the first portion 66 (i.e., the first cross-sectional dimension). A finger gripping flange 72 is located at the open rear end 64, and its cross-sectional dimension is larger than that of the open rear end 64.

[0153] The front end 62 of the cylinder includes an end wall 74 through which a smaller central opening passes. The opening through the end wall 74 at the front end 62 is smaller than the opening at the rear end 64 of the cylinder. The suitable outer diameter (OD) of the first portion 66 of the cylinder is also substantially similar to, and may be slightly larger than, the inner diameter (OD) of the elongated inner connecting member 48 of the adapter 40 at the upper end of the adapter. This facilitates the formation of a frictional and fluid-tight connection between the first portion 66 of the cylinder and the inner connecting member 48 of the adapter when the front end 62 of the cylinder is inserted into the inner connecting member 48. This facilitates the efficient transfer of liquid pharmaceutical compositions from the container 20 into the hollow interior of the cylinder 60 while preventing fluid leakage between the two components. In some embodiments, the first portion of the cylinder at the front end may have a unique external cross-sectional geometry (e.g., conical, polygonal, etc.) that matches the internal cross-sectional geometry of the elongated inner connecting member of the adapter.

[0154] A closed dimensional correspondence is formed between the OD of the first portion of the cylinder at the front end of the cylinder and the ID of the internal connecting part of the adapter. Optionally, a corresponding or matching geometry is formed at the meshing surface between the front end of the cylinder and the internal connecting part of the adapter, providing a key-like connection. This connection requires the syringe 50 to be used with the container 20 to ensure a secure and fluid-tight connection between their interfaces, and to effectively transfer the liquid drug composition into the syringe cylinder. In other words, the key-like connection between the syringe cylinder and the container formed via the adapter ensures that only a specific syringe can be effectively used with a container containing a specific liquid drug composition, the syringe being configured for use with the drug provided in the corresponding container, and cannot be replaced by other syringes. Such a key-like feature can be unique for this specific syringe and its paired container containing the specific liquid drug composition. This limits or prevents the use of a specific syringe of the delivery system with another container that may contain a different liquid drug composition (the other container is not designed for use with the specific syringe).

[0155] The plunger 80 includes an elongated portion appropriately sized to be substantially received within the cylinder 60 via an open rear end 64, facilitating retractable sliding within the cylinder during use. The plunger 80 includes an upper or rear end 84 and a lower or front end 82, wherein the plunger front end 82 is disposed within the cylinder and extends within the hollow interior of the cylinder within a first portion 66 and a second portion 70. The plunger includes a first portion 86 extending from the plunger front end 82 to a transition section 88, and a second portion 90 extending from the transition section 88 to the plunger rear end 84. Similar to the cylinder 60, the transverse cross-section (e.g., diameter) of the plunger second portion 90 is larger than that of the plunger first portion 86. A finger-gripping flange 92 is disposed at the plunger rear end 84, wherein the flange 92 extends laterally beyond the cross-sectional dimension of the plunger rear end 84 to provide a gripping surface during use of the syringe 50 (e.g., as the plunger moves within the cylinder).

[0156] The longitudinal or length dimension of the plunger 80 is at least substantially the same as, and preferably larger than, the longitudinal or length dimension of the cylinder 60. This facilitates complete retraction of the plunger within the cylinder, where the plunger tip can engage with the front wall of the cylinder. Additionally, when the plunger is longer than the cylinder, a small portion of the plunger at its rear end extends beyond the rear end of the cylinder when the plunger is fully retracted (i.e., the plunger tip contacts the front end of the cylinder). In this embodiment, the plunger flange always extends beyond the cylinder flange by a suitable distance (thus allowing easy gripping of the plunger flange to withdraw a portion of the plunger from the cylinder).

[0157] The plunger and cylinder are each appropriately sized to facilitate the extraction of a sufficient amount of liquid within the cylinder, thereby ensuring adequate dosage of the liquid pharmaceutical composition is administered to the patient. The tip 82 of the plunger 80 includes a stop 94, sized to provide a friction-sealed and fluid-sealed engagement along the inner wall of the first portion 66 of the cylinder. The stop 94 may be formed of the same material (e.g., polystyrene) as the rest of the plunger 80 (including the first portion 86, the transition section 88, and the second portion 90). The lateral cross-section of the stop 94 is larger than the internal lateral cross-section (e.g., inner diameter) of the cylinder transition section 68. During insertion of the plunger into the cylinder, the plunger 80 is inserted into the cylinder 60, forcing the plunger tip 82 with the stop 94 downward through the cylinder transition section 68 and toward the cylinder tip 62. During the withdrawal of the plunger from the cylinder, the cylinder transition section 68 forms a slight abutment on the plunger tip 82 with the stop 94 to provide the user with a stop point indication where the plunger should not be withdrawn further from the cylinder. Therefore, the maximum fluid volume within the cylinder 60 is limited by the volume defined by the first section 66 of the cylinder.

[0158] The syringe 50 is structurally designed to provide certain advantageous features, allowing for the dispensing of extremely small, discrete, and precise doses of a liquid drug composition from the container 20 according to the patient's required dosage. For example, when the patient's weight is relatively low (e.g., a feline or small canine), the volume of the liquid drug composition to be administered may need to be extremely small. The volume of the liquid drug composition depends on the required therapeutic dose (in mg active ingredient / kg patient BW), the concentration of the active ingredient in the liquid drug composition (e.g., an SGLT-2 inhibitor), and the patient's weight. For example, in treating a metabolic disorder in a feline (where the feline weighs approximately 2 kg), a single dose of 1.0 mg / kg BW is required, and the concentration of the liquid drug composition is 15 mg / mL. In this scenario, a single dose (e.g., oral administration) for the feline would be approximately 0.133 mL. Providing such a small volume of dose within the cylinder of a conventional syringe is extremely difficult.

[0159] The syringe 50 can be designed such that the cylindrical volume defined at the first portion 66 is limited to no more than 3 mL, preferably no more than 2 mL, more preferably no more than 1 mL, for example, no more than 0.9 mL, or no more than 0.8 mL, or no more than 0.7 mL, or no more than 0.6 mL, or no more than 0.5 mL, or preferably no more than 0.4 mL. Specifically, the syringe 50 can be designed such that the cylindrical volume defined at the first portion 66 is 0.01 mL to 3 mL, preferably 0.01 mL to 2 mL, more preferably 0.01 mL to 1 mL, especially 0.02 mL to 0.9 mL, more preferably 0.03 mL to 0.8 mL, more preferably 0.04 mL to 0.7 mL, and most preferably 0.05 mL to 0.6 mL. The syringe dose increment is based on the patient's weight, and its scale can be divided into up to 10 or more increment levels. Therefore, the dose volume can be as small as 0.05 mL or even smaller. According to a preferred embodiment, the dosage volume is 0.01 mL to 3 mL, preferably 0.01 mL to 2 mL, more preferably 0.01 mL to 1 mL, particularly 0.02 mL to 0.9 mL, more preferably 0.03 mL to 0.8 mL, more preferably 0.04 mL to 0.7 mL, and most preferably 0.05 mL to 0.6 mL. In an exemplary embodiment, the dosage volume of the syringe is 0.05 mL to 0.6 mL. The syringe 50 is designed so that each dosage increment can be easily selected according to the specific treatment situation of the patient.

[0160] Nevertheless, the cylindrical volume defined at the first portion 66 can be selected according to the patient's weight, body size, and required dosage. Therefore, in another aspect, the syringe 50 can be designed such that the cylindrical volume defined at the first portion 66 is 5 mL to 40 mL, preferably 10 mL to 30 mL, more preferably 15 mL to 25 mL. According to this embodiment, the dosage volume is 5 mL to 40 mL, preferably 10 mL to 30 mL, more preferably 15 mL to 25 mL. These dosage volumes and structures of the syringe 50 are particularly suitable for treating equines.

[0161] Specifically, the first cylindrical portion 66 defines the maximum volume that can be drawn into the syringe 50 from the container 20, and the length of the first cylindrical portion 66 is much larger than its inner diameter (ID) or internal cross-section. By increasing the length of its internal volume relative to the inner diameter of the cylindrical portion receiving the fluid, the plunger can draw fluid in very small volume increments within the cylinder with high precision and high particle size, because the amount of fluid drawn from the cylinder into the syringe's internal volume is minimized with each incremental displacement of the plunger from the cylinder, while allowing the plunger to be drawn a longer distance from the cylinder. Preferably, the ratio of the length of the first cylindrical portion 66 to its inner diameter (or internal cross-section) (referred to as L / D) is at least 5. For example, the L / D ratio of the first cylindrical portion 66 can be 5 to 20, or 7 to 15, or 9 to 14. In a specific exemplary embodiment, the L / D ratio of the first cylindrical portion is about 12.2 (L / D = 12.2). This also provides the following effect: increasing the distance between the graduation scales on the syringe that define the volume increment (i.e., making it easier for the user to intuitively understand the correct amount of fluid being drawn from the syringe barrel).

[0162] The constituent materials of both the plunger and the cylinder also facilitate the extraction of extremely small increments of the liquid pharmaceutical composition into the cylinder in a highly discrete and small volume manner. For example, a plunger formed from a polymer material comprising polystyrene, preferably polystyrene, and a cylinder formed from a polymer material comprising polyethylene (e.g., LDPE), preferably polyethylene (e.g., LDPE), provides a very smooth and seamless interaction at the friction-sealed and fluid-sealed interface of the two components (e.g., between the plunger stop 94 and the inner wall surface area of ​​the first portion 66 of the cylinder). This helps the plunger smoothly and easily extract extremely precise small volume increments (e.g., less than 0.05 mL) from the cylinder when fluid is drawn from the fluid chamber of the cylinder (defined by the first portion of the cylinder). Furthermore, the structure of the adapter and the cylinder facilitates the extraction of even the smallest remaining portion of the container during use.

[0163] Further improvements to the syringe 50 include: providing markings (e.g., printed and / or etched markings) along the exposed surface wall section of the plunger 80, preferably at the second portion 90 of the plunger, wherein the markings include dose graduations 100 of a gradation mark comprising lines and / or corresponding numbers aligned with (e.g., substantially parallel to) the longitudinal dimension of the plunger (see, for example...). Figure 7 The markings and / or corresponding numbers indicate the specific dose that has been drawn into the front end 62 of the cylinder (when the cylinder 60 is connected to the container 20 in the manner described herein). Typically, the volume or dose graduations of a conventional syringe are set along the cylinder rather than the plunger, where the front end of the plunger aligns with a graduation on the cylinder when fluid is drawn into the cylinder (where the cylinder is transparent or at least partially translucent), thereby obtaining the desired volume of fluid within the cylinder. The syringe 50 described herein can be operated to obtain a precise volume (and therefore a precise dose) of a liquid pharmaceutical composition within the cylinder 60 by withdrawing the plunger 80 from the cylinder 60 until the desired dose graduation 100 on the plunger is visible at a designated location along the second portion 70 of the cylinder or on the exposed portion of the second portion 90 of the plunger (i.e., outside the cylinder). See also Figure 6 The precise indication of the fluid volume (i.e., the precise dose) within the first portion 66 of the cylinder is determined based on the scale lines of the scale 100 along the exposed second portion 90 of the plunger and the outside of the cylinder 60. Specifically, during the extraction of a liquid drug composition from the container 20, the plunger 80 may be moved out of the cylinder 60 until a specific scale line of the scale 100 is aligned (e.g., substantially coplanar) with the rear surface 73 (as part of the cylinder flange 72) defining the rear end 64 of the cylinder. Alternatively, the plunger may also be aligned with the cylinder in any other manner that aligns a specific scale line of the dose scale with any other part of the syringe. In another exemplary embodiment, the cylinder may include a window or other indicator (e.g., a cutout portion along the second portion of the cylinder and / or a printed mark along the second portion of the cylinder) that provides a location where a specific scale line of the dose scale, provided on a surface wall section of the second portion of the plunger, is aligned to indicate the precise volume / dose that has been drawn into the cylinder at the first portion of the cylinder. The dosage scale is set at a precise position along the second part of the plunger so that the displacement of the plunger from the cylinder can be aligned with a specific scale line along the indicator position of the cylinder, thereby determining the precise volume of fluid pumped into the first part of the cylinder.

[0164] The graduations on the dose scale 100 of the plunger 80 may be provided in volumetric quantities (e.g., milliliters or mL), or in any other digital marking that facilitates the administration of a precise dose to a patient using a syringe. In one exemplary embodiment (e.g.) Figure 7As shown, the dosage scale 100 of the plunger 80 may include graduations numerically ordered based on the patient's (e.g., feline) weight or gravimetrics, where weight or gravimetrics can be provided in any suitable type of unit, such as SI units or in kg (kilograms) or imperial units or lb (pounds). This improves the simplicity or ease of use of the delivery system, allowing for the delivery of an appropriate dose to the patient based on their weight and the concentration of the SGLT-2 inhibitor (and / or other API) in the liquid drug composition used. Specifically, this minimizes the possibility of user errors in dosing by converting the dosage scale to the patient's weight, which is particularly convenient for end-users who may not be healthcare or medical professionals (e.g., veterinarians) but rather patient owners (e.g., pet owners of feline or other animal patients).

[0165] For example, when the required dose of SGLT-2 inhibitor for treating a specific metabolic disorder in a feline patient is 0.1 mg / kg BW, the dosage scale 100 provides an easy conversion for the user to administer the correct volume from syringe 50. The user simply removes the plunger 80 from the cylinder 60 until the graduation line on scale 100 representing the feline patient's weight in kilograms (kg) aligns with the corresponding indicator on the syringe (e.g., the graduation line on the plunger aligns with or is substantially coplanar with the rear surface 73 of the cylinder flange 72), thus easily drawing the liquid drug composition from container 20 into syringe cylinder 60. It should be noted that such markings in patient weight need to be consistent with the concentration of the SGLT-2 inhibitor (and / or other APIs) in the administered liquid drug composition (e.g., 15 mg / mL, such as...). Figure 7 The dosage scale is consistent with that shown in the diagram. The key-like connection between the syringe and the container (achieved via an adapter to the container) ensures that the appropriate syringe with the dosage scale corresponds to the correct liquid drug composition drawn from the container.

[0166] As previously described, in particular, liquid pharmaceutical compositions and delivery systems (containers with syringes) containing one or more SGLT-2 inhibitor compounds can be combined into a cartridge for commercial or other end-use purposes by being provided together in a single package as a cartridge. The cartridge may include a single package structure comprising a container containing the liquid pharmaceutical composition and a syringe. Each of these components may be dispensed within the single cartridge package (i.e., provided separately). The cartridge may further include suitable instructions, for example, in the form of an insert or booklet, containing information on the use of the administration and delivery system of the liquid pharmaceutical composition described herein for the treatment and / or prevention of metabolic disorders and / or other medical indications in designated patients.

[0167] The delivery system can be designed to administer liquid pharmaceutical compositions to animal patients, such as equines, ruminants, canines, and felines. The route of administration can be oral or parenteral, but oral administration is preferred. The delivery system 10 described herein includes a needleless injector, wherein the liquid pharmaceutical composition is drawn into the injector cylinder 60 via engagement of the cylindrical tip 62 with an adapter 40 of the container 20. However, it should be noted that, in some embodiments, the delivery system may also include a needle for parenteral administration.

[0168] An exemplary embodiment will now be described to illustrate the operation of a delivery system 10 that treats and / or prevents metabolic disorders or other medical indications in a patient by administering a liquid pharmaceutical composition, specifically comprising one or more SGLT-2 inhibitors, to the patient. In this exemplary embodiment, the patient is a feline, and the dosage scale 100 of the syringe 80 is as follows: Figure 7 As shown (the 100 mark is related to the weight of a feline in kg).

[0169] Before the syringe 50 engages with the container 20, the plunger 80 is fully inserted into the cylinder 60 such that the plunger tip 82, including the stop 94, contacts the inner surface of the cylinder tip 62. After removing the cap 30 from the container 20, the syringe 50 (including, for example, the plunger 80) is fully inserted into the internal connecting part 48 of the adapter 40 to ensure a friction-sealed and fluid-sealed engagement by fully inserting the cylinder tip 62 into the internal connecting part 48 of the adapter 40. Figure 1 and Figure 6 The plunger 80 shown, installed within the cylinder 60, is connected to the container 20. The container 20, which engages with the syringe 50, can then be inverted (e.g., vertically oriented so that the upper end 26 of the container is below the lower end 27 and the syringe 50 is below the container 20). This places the liquid drug composition within the upper end 26 of the container 20, and there is substantially no air gap or void between the inner surface portion of the adapter 40 within the container 20 and the liquid drug composition contacting that inner surface portion. Additionally, and for example in… Figure 5 and Figure 6 As can be seen, the graduations of the dosage scale 100 can be inverted (e.g., upside down) relative to the front end 82 of the plunger 80. This makes it easy to read the dosage scale 100 when the syringe 50 is inverted and the liquid drug composition is drawn into the cylinder 60 (e.g., the graduations will be facing upwards).

[0170] The plunger rear end 92 and plunger front end 82 are moved a selected distance from their respective cylindrical rear end 72 and cylindrical front end 62 until the designated graduation line on the second part 90 of the plunger along the dose scale 100 corresponding to the feline patient's weight (kg) is properly aligned (e.g., coplanar) with the rear surface 73 of the cylindrical flange 72. For example, if the feline weighs 4 kg, the plunger 80 is moved from the cylinder until the graduation line for the number 4 on the dose scale 100 is aligned (e.g., coplanar) with the cylindrical flange surface 73. Figure 6 (As depicted in the illustration). This displacement of the plunger 80 from the cylinder 60 allows the liquid drug composition to be drawn from the container 20 into the first cylindrical portion 66 through the internal connecting part 48 of the adapter 40 and through the opening in the end wall 74 of the cylinder front end 62. The displacement of the plunger 80 from the cylinder 60 aligns the designated graduation line of scale 100 with the rear surface 73 of the cylinder flange, ensuring that a precise dose of the liquid drug composition has been drawn from the container 20 into the first cylindrical portion 66. The structural design of the plunger and cylinder, and the frictional and fluid-tight fit between the cylinder front end 66 and the internal connecting part 48 of the adapter 40, ensure that when the plunger rear end 84 moves a selected distance from the cylinder rear end 64, a sufficient vacuum force is generated within the first cylindrical portion 66, such that the total volume defined by the interior of the first cylindrical portion 66 between the cylinder front end 62 and the stop 94 of the syringe 80 is substantially the same as the volume of the liquid drug composition drawn into the cylinder.

[0171] The specified dose of the liquid drug composition drawn into the syringe cylinder of the delivery system can be administered orally to the feline patient directly by injecting the composition from the cylinder 60 into the feline patient's mouth (i.e., by moving the plunger 80 back into the cylinder 60 to force the composition through the opening in the end wall 74 of the cylinder tip 62). Alternatively, the dose can be administered orally indirectly by providing the liquid drug composition from the syringe 50 into a liquid (e.g., water) or food consumed by the feline patient. An insert or brochure within the packaging provides the end user with information on the daily dose (e.g., number of doses per day) to be administered to the treated feline patient, depending on the individual's metabolic disorder or other medical indications.

[0172] Therefore, the embodiments described herein facilitate the administration of liquid pharmaceutical compositions, specifically comprising one or more SGLT-2 inhibitor compounds, in very small, discrete doses for the treatment and / or prevention of one or more metabolic disorders and / or one or more other medical indications. Delivery systems with key-like features ensure that a suitable syringe (with dosage indications for a specific composition, a specific patient type, and / or a specific medical treatment) matches a suitable container containing the specific composition for administration to the patient.

[0173] Specifically, exemplary embodiments of the present invention have been described herein by the following items, which are also part of this disclosure and included within the spirit and scope of the invention:

[0174] 1. A system for administering a liquid pharmaceutical composition to a patient, the system comprising a syringe, wherein the syringe comprises:

[0175] A cylinder including a hollow, elongated component, the hollow, elongated component comprising an open front end and an open rear end, the hollow, elongated component comprising:

[0176] A first portion, extending from the front end of the open cylinder to a transition section along the hollow elongated member, the first portion having a first cross-sectional dimension; and

[0177] The second portion extends from the transition section to the rear end of the open cylinder, and the second portion has a second cross-sectional dimension larger than the first cross-sectional dimension; and

[0178] A plunger including an elongated component, the elongated component including a plunger front end and a plunger rear end;

[0179] in:

[0180] The dimensions of the plunger and the cylinder are such that a portion of the plunger, including the front end of the plunger, can be inserted into the hollow elongated part of the cylinder at the rear end of the open cylinder, and the plunger can extend within the cylinder until the front end of the plunger engages with a portion of the inner surface of the hollow elongated part at the front end of the cylinder.

[0181] The liquid drug composition received into the syringe via the front end of the open cylinder is confined to a volume defined within the first portion of the cylinder, wherein the volume can be adjusted by displacing the plunger tip away from the front end of the cylinder; and

[0182] The surface wall portion of the plunger includes markings, the markings including a dosage scale, the dosage scale indicating the volume of the liquid drug composition received into the first portion of the cylinder based on a corresponding displacement of the plunger tip away from the cylinder tip.

[0183] 2. The system as described in claim 1, wherein the cylinder is formed of a polymer material comprising polyethylene, preferably composed of polyethylene, and most preferably composed of low-density polyethylene, and the plunger is formed of a polymer material comprising polystyrene, preferably composed of polystyrene.

[0184] 3. The system of any one of claims 1 to 2, wherein the length / diameter (L / D) ratio of the second portion of the cylinder is 5 to 20, or 7 to 15, or 9 to 14.

[0185] 4. The system of any one of claims 1 to 3, wherein the second portion of the cylinder defines a volume within the hollow elongated member of not more than 1 mL, or not more than 0.9 mL, or not more than 0.8 mL, or not more than 0.7 mL, or not more than 0.6 mL, or not more than 0.5 mL, or not more than 0.4 mL.

[0186] 5. The system as described in any one of items 1 to 4, wherein:

[0187] The dose scale on the surface wall portion of the plunger includes a plurality of markings, the markings being arranged in the same direction as the longitudinal dimension of the plunger; and

[0188] In operation, the volume of the liquid drug composition received within the first portion of the cylinder in response to displacement of the plunger tip away from the cylinder tip is indicated by aligning the corresponding mark of the dosage scale with the outer surface of the cylinder at the rear end of the cylinder.

[0189] 6. The system as described in any one of claims 1 to 5, further comprising:

[0190] Containers containing liquid pharmaceutical compositions.

[0191] 7. The system as described in item 6, wherein the liquid pharmaceutical composition comprises one or more SGLT-2 inhibitor compounds selected from:

[0192] (1) Benzene derivatives substituted with glucopyranosyl groups, represented by the following formula:

[0193]

[0194] Where R 1 It represents cyano, Cl, or methyl (cyano is the most preferred).

[0195] R 2 It represents H, methyl, methoxy, or hydroxyl (most preferably H), and

[0196] R 3This indicates cyclopropyl, hydrogen, fluorine, chlorine, bromine, iodine, methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, tert-butyl, 3-methyl-butyl-1-yl, cyclobutyl, cyclopentyl, cyclohexyl, 1-hydroxy-cyclopropyl, 1-hydroxy-cyclobutyl, 1-hydroxy-cyclopentyl, 1-hydroxy-cyclohexyl, ethynyl, ethoxy, difluoromethyl, trifluoromethyl, pentafluoroethyl, 2-hydroxy-ethyl, hydroxymethyl, 3-hydroxy-propyl, 2-hydroxy-2-methyl-propyl-1-yl, 3-hydroxy-3-methyl-butyl-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, difluoromethoxy, trifluoromethoxy, 2-methoxy-ethoxy, methylthio, methylsulfinyl, methylsulfonyl, ethylsulfinyl, ethylsulfonyl, trimethylsilyl, (R)-tetrahydrofuran-3-yloxy or (S)-tetrahydrofuran-3-yloxy, or cyano;

[0197] Where R 3 Preferably selected from cyclopropyl, ethyl, ethynyl, ethoxy, (R)-tetrahydrofuran-3-yloxy or (S)-tetrahydrofuran-3-yloxy; and most preferably, R 3 It is cyclopropyl.

[0198] Or its derivatives, wherein one or more hydroxyl groups of the β-D-glucopyranoyl group are selected from (C 1-18 alkyl)carbonyl, (C 1-18 Alkyl)oxycarbonyl, phenylcarbonyl and phenyl-(C) 1-3 Acylation of alkyl)-carbonyl groups;

[0199] (2) Veragranin expressed by the following formula:

[0200]

[0201] (3) Dapagliflozin expressed by the following formula:

[0202]

[0203] (4) Canagliflozin as expressed by the following formula:

[0204]

[0205] (5) Engagliflozin as expressed by the following formula:

[0206]

[0207] (6) Luglevin as expressed by the following formula:

[0208]

[0209] (7) Togliflozin expressed by the following formula:

[0210]

[0211] (8) Iglevin as expressed by the following formula:

[0212]

[0213] (9) Eggliflozin as expressed by the following formula:

[0214]

[0215] (10) Aggliflozin expressed by the following formula:

[0216]

[0217] (11) Repaglinide expressed by the following formula:

[0218]

[0219] (11A) Repaglinide carbonate, expressed by the following formula:

[0220]

[0221] (12) Thiophene derivatives represented by the following formula:

[0222]

[0223] Where R represents methoxy or trifluoromethoxy;

[0224] (13) 1-(β-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienylmethyl]benzene represented by the following formula:

[0225] (14) Spiroacetal derivatives represented by the following formula:

[0226]

[0227] Where R represents methoxy, trifluoromethoxy, ethoxy, ethyl, isopropyl, or tert-butyl;

[0228] (15) Pyrazole-O-glucoside derivatives represented by the following formula:

[0229]

[0230] in:

[0231] R 1 C represents 1-3Alkoxy

[0232] L 1 L 2 H or F can be represented independently of each other.

[0233] R 6 Represents H, (C 1-3 alkyl)carbonyl, (C 1-6 (16) Sorafenib, represented by the following formula: alkyl)oxycarbonyl, phenoxycarbonyl, benzyloxycarbonyl or benzylcarbonyl;

[0234]

[0235] (17) Seglecrine expressed by the following formula:

[0236]

[0237] (18) Compounds represented by the following formula:

[0238]

[0239] in:

[0240] R 3 This indicates cyclopropyl, hydrogen, fluorine, chlorine, bromine, iodine, methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, tert-butyl, 3-methyl-butyl-1-yl, cyclobutyl, cyclopentyl, cyclohexyl, 1-hydroxy-cyclopropyl, 1-hydroxy-cyclobutyl, 1-hydroxy-cyclopentyl, 1-hydroxy-cyclohexyl, ethynyl, ethoxy, difluoromethyl, trifluoromethyl, pentafluoroethyl, 2-hydroxy-ethyl, hydroxymethyl, 3-hydroxy-propyl, 2-hydroxy-2-methyl-propyl-1-yl, 3-hydroxy-3-methyl-butyl-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, difluoromethoxy, trifluoromethoxy, 2-methoxy-ethoxy, methylthio, methylsulfinyl, methylsulfonyl, ethylsulfinyl, ethylsulfonyl, trimethylsilyl, (R)-tetrahydrofuran-3-yloxy or (S)-tetrahydrofuran-3-yloxy, or cyano; and wherein R 3 Preferably selected from cyclopropyl, ethyl, ethynyl, ethoxy, (R)-tetrahydrofuran-3-yloxy or (S)-tetrahydrofuran-3-yloxy; and R 3 The most preferred is cyclopropyl.

[0241] Or its derivatives, wherein one or more hydroxyl groups of the β-D-glucopyranoyl group are selected from (C 1-18 alkyl)carbonyl, (C 1-18Alkyl)oxycarbonyl, phenylcarbonyl and phenyl-(C) 1-3 Acylation of alkyl-carbonyl groups;

[0242] (19) Bexagliflozin expressed by the following formula:

[0243]

[0244] (20) Gaglequin, expressed as follows:

[0245]

[0246] (21) Junglexin;

[0247]

[0248] (22) Vapagliflozin;

[0249] (23) Inagrejacin expressed by the following formula:

[0250] and

[0251] (24) TFC-039 is represented by the following formula:

[0252]

[0253] 8. The system as described in item 7, wherein the concentration of the one or more SGLT-2 inhibitor compounds in the liquid pharmaceutical composition is from 0.1 mg / mL to 20 mg / mL.

[0254] 9. The system as described in item 8, wherein the one or more SGLT-2 inhibitor compounds include vilaggliflozin, wherein preferably, vilaggliflozin is the only SGLT-2 inhibitor contained in the liquid pharmaceutical composition.

[0255] 10. The system as described in item 9, wherein the concentration of vilaggliflozin in the liquid pharmaceutical composition is 1.2 mg / mL or 15 mg / mL.

[0256] 11. The system as described in any one of claims 1 to 10, further comprising:

[0257] An adapter connected to an opening in the container, the adapter including a hollow connecting member that facilitates engagement of the front end of the cylinder with the connecting member to facilitate the transfer of the liquid pharmaceutical composition to the first portion of the cylinder, wherein the outer diameter of a portion of the hollow connecting member of the adapter is substantially similar to the inner diameter of the opening in the container to create a frictional and fluid-tight connection between the adapter and the container, and the inner diameter of the hollow connecting member of the adapter is substantially similar to the outer diameter of the front end of the cylinder to create a frictional and fluid-tight connection between the adapter and the cylinder in response to insertion of the front end of the cylinder into the hollow connecting member.

[0258] 12. The system of any one of claims 1 to 11, wherein the adapter is formed of a polymer material comprising low-density polyethylene, preferably low-density polyethylene, and the container is formed of a polymer material comprising high-density polyethylene, preferably high-density polyethylene.

[0259] 13. A method for treating and / or preventing metabolic disorders and / or other medical conditions in a patient by administering to a patient a dose of a liquid pharmaceutical composition comprising the one or more SGLT-2 inhibitor compounds, the method comprising:

[0260] A syringe and a container containing the liquid drug composition are provided, the syringe comprising a cylinder and a plunger, wherein:

[0261] The cylinder includes a hollow, elongated component having an open front end and an open rear end; a first portion extending from the open front end to a transition section along the hollow, elongated component, the first portion having a first cross-sectional dimension; and a second portion extending from the transition section to the open rear end, the second portion having a second cross-sectional dimension larger than the first cross-sectional dimension.

[0262] The plunger includes an elongated component and a dosage scale. The elongated component includes a plunger front end and a plunger rear end, and the dosage scale includes a plurality of marks disposed on the surface wall portion of the plunger and arranged in the same direction as the longitudinal dimension of the plunger; and

[0263] The dimensions of the plunger and the cylinder are such that a portion of the plunger's front end can be inserted into the hollow, elongated portion of the cylinder at the rear end of the open cylinder, and the plunger can extend within the cylinder until the plunger's front end engages with a portion of the inner surface of the hollow, elongated portion at the front end of the cylinder; and

[0264] By moving the plunger tip a selected distance from the front end of the cylinder until a selected mark among the plurality of marks on the dosage scale aligns with the outer surface of the cylinder at the rear end, the desired dose of the liquid drug composition is drawn from the container into the first portion of the cylinder of the syringe; and

[0265] The liquid pharmaceutical composition is administered to the patient in the required dose via the syringe.

[0266] (This invention also aims to include a corresponding method for treating and / or preventing metabolic disorders and / or other medical conditions in a patient by administering a dose of a liquid pharmaceutical composition comprising one or more SGLT-2 inhibitor compounds to the patient, and the use of one or more SGLT-2 inhibitor compounds in the preparation of a medicament for treating and / or preventing metabolic disorders and / or other medical conditions in a patient.)

[0267] 14. One or more SGLT-2 inhibitor compounds for the method as described in claim 13, wherein the liquid pharmaceutical composition for administering the required dose to the patient from the syringe comprises oral or parenteral administration to the patient, preferably oral administration.

[0268] 15. One or more SGLT-2 inhibitor compounds for the method as described in any one of claims 13 to 14, wherein the liquid pharmaceutical composition for administering the required dose to the patient from the syringe comprises oral administration to the patient by directly delivering the liquid pharmaceutical composition from the syringe to the patient or by indirectly delivering the liquid pharmaceutical composition from the syringe to a food or liquid for the patient to consume.

[0269] 16. One or more SGLT-2 inhibitor compounds for use in the method as described in any one of items 13 to 15, wherein the desired dose is no more than 1 mL, or no more than 0.9 mL, or no more than 0.8 mL, or no more than 0.7 mL, or no more than 0.6 mL, or no more than 0.5 mL, or no more than 0.4 mL.

[0270] 17. One or more SGLT-2 inhibitor compounds as described in any one of claims 13 to 16 for use in the method, wherein the desired dose is from 0.05 mL to 0.6 mL.

[0271] 18. One or more SGLT-2 inhibitor compounds for use in the method as described in any one of claims 13 to 17, wherein the one or more SGLT-2 inhibitor compounds are selected from:

[0272] (1) Benzene derivatives substituted with glucopyranosyl groups, represented by the following formula:

[0273]

[0274] Where R 1 It represents cyano, Cl, or methyl (cyano is the most preferred).

[0275] R 2 It represents H, methyl, methoxy, or hydroxyl (most preferably H), and

[0276] R 3 This indicates cyclopropyl, hydrogen, fluorine, chlorine, bromine, iodine, methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, tert-butyl, 3-methyl-butyl-1-yl, cyclobutyl, cyclopentyl, cyclohexyl, 1-hydroxy-cyclopropyl, 1-hydroxy-cyclobutyl, 1-hydroxy-cyclopentyl, 1-hydroxy-cyclohexyl, ethynyl, ethoxy, difluoromethyl, trifluoromethyl, pentafluoroethyl, 2-hydroxy-ethyl, hydroxymethyl, 3-hydroxy-propyl, 2-hydroxy-2-methyl-propyl-1-yl, 3-hydroxy-3-methyl-butyl-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, difluoromethoxy, trifluoromethoxy, 2-methoxy-ethoxy, methylthio, methylsulfinyl, methylsulfonyl, ethylsulfinyl, ethylsulfonyl, trimethylsilyl, (R)-tetrahydrofuran-3-yloxy or (S)-tetrahydrofuran-3-yloxy or cyano;

[0277] Where R 3 Preferably selected from cyclopropyl, ethyl, ethynyl, ethoxy, (R)-tetrahydrofuran-3-yloxy or (S)-tetrahydrofuran-3-yloxy; and most preferably, R 3 It is cyclopropyl.

[0278] Or its derivatives, wherein one or more hydroxyl groups of the β-D-glucopyranoyl group are selected from (C 1-18 alkyl)carbonyl, (C 1-18 Alkyl)oxycarbonyl, phenylcarbonyl and phenyl-(C) 1-3 Acylation of alkyl-carbonyl groups;

[0279] (2) Veragranin expressed by the following formula:

[0280]

[0281] (3) Dapagliflozin expressed by the following formula:

[0282]

[0283] (4) Canagliflozin as expressed by the following formula:

[0284]

[0285] (5) Engagliflozin as expressed by the following formula:

[0286]

[0287] (6) Luglevin as expressed by the following formula:

[0288]

[0289] (7) Togliflozin expressed by the following formula:

[0290]

[0291] (8) Iglevin as expressed by the following formula:

[0292]

[0293] (9) Eggliflozin as expressed by the following formula:

[0294]

[0295] (10) Aggliflozin expressed by the following formula:

[0296]

[0297] (11) Repaglinide expressed by the following formula:

[0298]

[0299] (11A) Repaglinide carbonate, expressed by the following formula:

[0300] (12) Thiophene derivatives represented by the following formula:

[0301]

[0302] Where R represents methoxy or trifluoromethoxy;

[0303] (13) 1-(β-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienylmethyl]benzene represented by the following formula:

[0304] (14) Spiroacetal derivatives represented by the following formula:

[0305]

[0306] Where R represents methoxy, trifluoromethoxy, ethoxy, ethyl, isopropyl, or tert-butyl;

[0307] (15) Pyrazole-O-glucoside derivatives represented by the following formula:

[0308]

[0309] in:

[0310] R 1 C represents 1-3 Alkoxy

[0311] L 1 L 2 H or F can be represented independently of each other.

[0312] R 6 Represents H, (C 1-3 alkyl)carbonyl, (C 1-6 (16) Sorafenib, represented by the following formula: alkyl)oxycarbonyl, phenoxycarbonyl, benzyloxycarbonyl or benzylcarbonyl;

[0313]

[0314] (17) Seglecrine expressed by the following formula:

[0315]

[0316] (18) Compounds represented by the following formula:

[0317]

[0318] in:

[0319] R 3 This indicates cyclopropyl, hydrogen, fluorine, chlorine, bromine, iodine, methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, tert-butyl, 3-methyl-butyl-1-yl, cyclobutyl, cyclopentyl, cyclohexyl, 1-hydroxy-cyclopropyl, 1-hydroxy-cyclobutyl, 1-hydroxy-cyclopentyl, 1-hydroxy-cyclohexyl, ethynyl, ethoxy, difluoromethyl, trifluoromethyl, pentafluoroethyl, 2-hydroxy-ethyl, hydroxymethyl, 3-hydroxy-propyl, 2-hydroxy-2-methyl-propyl-1-yl, 3-hydroxy-3-methyl-butyl-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, difluoromethoxy, trifluoromethoxy, 2-methoxy-ethoxy, methylthio, methylsulfinyl, methylsulfonyl, ethylsulfinyl, ethylsulfonyl, trimethylsilyl, (R)-tetrahydrofuran-3-yloxy or (S)-tetrahydrofuran-3-yloxy or cyano; and wherein R 3Preferably selected from cyclopropyl, ethyl, ethynyl, ethoxy, (R)-tetrahydrofuran-3-yloxy or (S)-tetrahydrofuran-3-yloxy; and R 3 The most preferred is cyclopropyl.

[0320] Or its derivatives, wherein one or more hydroxyl groups of the β-D-glucopyranoyl group are selected from (C 1-18 alkyl)carbonyl, (C 1-18 Alkyl)oxycarbonyl, phenylcarbonyl and phenyl-(C) 1-3 Acylation of alkyl-carbonyl groups;

[0321] (19) Bexagliflozin expressed by the following formula:

[0322]

[0323] (20) Gaglequin, expressed as follows:

[0324]

[0325] (21) Junglexin;

[0326]

[0327] (22) Vapagliflozin;

[0328] (23) Inagrejacin expressed by the following formula:

[0329] and

[0330] (24) TFC-039 is represented by the following formula:

[0331]

[0332] 19. One or more SGLT-2 inhibitor compounds for the method as described in claim 18, wherein the one or more SGLT-2 inhibitor compounds include vilaggliflozin, preferably wherein vilaggliflozin is the only SGLT-2 inhibitor compound administered.

[0333] 20. One or more SGLT-2 inhibitor compounds as described in any one of claims 13 to 19 for use in the method, wherein the dose is 0.01 to 10 mg / kg patient body weight.

[0334] 21. One or more SGLT-2 inhibitor compounds for use in the method as described in any one of claims 13 to 20, wherein the patient is a non-human mammal selected from equines, ruminants, felines, and canines, preferably felines or (small) canines.

[0335] 22. One or more SGLT-2 inhibitor compounds as described in any one of claims 13 to 21 for use in the method, wherein the metabolic disorder and / or other medical condition is selected from:

[0336] (i) Metabolic disorders in equines, preferably, the metabolic disorder being one or more conditions selected from the following: insulin resistance, hyperinsulinemia, impaired glucose tolerance, dyslipidemia, adipokines abnormalities, subclinical inflammation, systemic inflammation, low-grade systemic inflammation, obesity, and / or regional fat accumulation; preferably, the metabolic disorder is insulin resistance, hyperinsulinemia, and / or clinical symptoms associated with insulin resistance and / or hyperinsulinemia; preferably, the clinical symptoms are one or more conditions selected from the following: impaired glucose tolerance, dyslipidemia, adipokines abnormalities, subclinical inflammation, systemic inflammation, low-grade systemic inflammation, obesity, and / or regional fat accumulation;

[0337] (ii) Metabolic disorders in equines, wherein the metabolic disorder is one or more conditions selected from the following: laminitis, vascular dysfunction, hypertension, fatty liver, atherosclerosis, hyperadrenocorticism, middle pituitary dysfunction and / or equine metabolic syndrome, wherein preferably, the metabolic disorder is a clinical symptom / sign associated with insulin resistance and / or hyperinsulinemia, wherein the clinical symptom / sign is preferably one or more conditions selected from the following: laminitis, vascular dysfunction, hypertension, fatty liver, atherosclerosis, hyperadrenocorticism, middle pituitary dysfunction and / or equine metabolic syndrome;

[0338] (iii) Metabolic disorders in felines, wherein preferably, the metabolic disorder is selected from one or more of the following: ketoacidosis, prediabetes, type 1 or type 2 diabetes, insulin resistance, acromegaly, diabetes with elevated IGF-1 concentration, obesity, hyperglycemia, impaired glucose tolerance, hyperinsulinemia, dyslipidemia, adipokines abnormality, subclinical inflammation, systemic inflammation, low-grade systemic inflammation, fatty liver, atherosclerosis, pancreatitis, neuropathy and / or syndrome X (metabolic syndrome) and / or loss of pancreatic β-cell function, and / or wherein relief of the metabolic disorder is achieved and / or maintained, preferably relief of diabetes;

[0339] (iv) Metabolic disorders in canines, preferably, the metabolic disorder being selected from one or more of the following: ketoacidosis, prediabetes, insulin-dependent diabetes, insulin-resistant diabetes, insulin resistance, obesity, hyperglycemia, hyperglycemia-induced cataracts, impaired glucose tolerance, hyperinsulinemia, dyslipidemia, adipokines abnormalities, subclinical inflammation, systemic inflammation, low-grade systemic inflammation, fatty liver, pancreatitis, metabolic disorder consequences such as hypertension, renal dysfunction and / or musculoskeletal disorders, and / or Syndrome X (metabolic syndrome), preferably prediabetes, insulin-dependent diabetes, insulin-resistant diabetes, insulin resistance, preferably, preventing the development of hyperglycemia-induced cataracts or achieving its remission, and / or preferably, preventing the development of metabolic disorder consequences such as hypertension, renal dysfunction and / or musculoskeletal disorders, slowing their progression, or achieving their remission;

[0340] (v) Heart disease in felines, wherein preferably, the heart disease is selected from one or more of the following: heart failure, heart failure caused by one or more cardiomyopathy, heart failure caused by hypertrophic cardiomyopathy (HCM), heart failure caused by restrictive cardiomyopathy (RCM), heart failure caused by dilated cardiomyopathy (DCM), heart failure caused by unclassified cardiomyopathy (UCM), heart failure caused by 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 one or more of the following: heart failure caused by one or more cardiomyopathy, heart failure caused by hypertrophic cardiomyopathy (HCM), hypertrophic cardiomyopathy (HCM);

[0341] (vi) Drying of non-human mammals, preferably ruminants, wherein preferably, the medical condition is selected from one or more of the following: improving and / or promoting drying of non-human mammals, preferably ruminants; reducing milk production in gestation and / or lactation of non-human mammals, preferably ruminants, preferably milk production and / or lactation; reducing milk accumulation and / or engorgement in the udder of non-human mammals, preferably ruminants, preferably milk accumulation and / or engorgement in the udder and / or mammary glands; reducing discomfort related to udder swelling in non-human mammals, preferably ruminants, such as increasing daily lying time and / or reducing stress; reducing milk leakage in non-human mammals, preferably ruminants, after drying; reducing the incidence of intramammary infection (IMI) in non-human mammals, preferably ruminants, preferably mastitis and / or endometritis;

[0342] (vii) Heart disease in non-human mammals other than felines, particularly canines, wherein preferably, the heart disease is selected from one or more of the following: heart failure; congestive heart failure; asymptomatic / preclinical / silent heart failure; heart failure caused by (mica) mitral valve disease [(M)MVD]; congestive heart failure caused by (mica) mitral valve disease [(M)MVD]; asymptomatic / preclinical / silent heart failure caused by (mica) mitral valve disease [(M)MVD]; (mica) mitral valve disease [(M)MVD]; Clinically overt (mixic) mitral valve disease [(M)MVD]; asymptomatic / preclinical / occult (mixic) 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); aortic stenosis (valvular, supravalvular, and / or subvalvular);

[0343] (viii) Hypertension in non-human mammals, preferably carnivores, more preferably cats or dogs, wherein preferably, the hypertension is selected from one or more of the following: situational hypertension, secondary hypertension, and idiopathic hypertension, wherein preferably, the secondary hypertension is selected from: hypertension associated with chronic kidney disease (CKD), diabetes, obesity, heart disease, endocrine disorders such as Cushing's disease, hyperthyroidism, acromegaly; and hypertension induced by drugs, preferably glucocorticoids, mineralocorticoids, erythropoietin, ephedrine, and / or high doses of sodium chloride;

[0344] (ix) Kidney disease in non-human mammals, preferably carnivores, more preferably cats or dogs, wherein preferably, the kidney disease is selected from one or more of the following: renal dysplasia, glomerulonephropathy, polycystic kidney disease, amyloidosis, tubulonephritis / tubulointerstitial nephritis (TIN), acute kidney disease, chronic kidney disease.

[0345] This invention is intended to cover modifications and variations thereof, provided that such modifications and variations fall within the scope of the appended claims and their equivalents. It should be understood that relative terms that may be used herein, such as “top,” “bottom,” “front,” “rear,” “side,” “height,” “length,” “width,” “upper,” “lower,” “inner,” “outer,” etc., describe reference points only and are not intended to limit the invention to any particular orientation or configuration.

Claims

1. A system for administering a liquid pharmaceutical composition to a patient, the system comprising a syringe, wherein the syringe comprises: A cylinder including a hollow, elongated component, the hollow, elongated component comprising an open front end and an open rear end, the hollow, elongated component comprising: A first portion, extending from the front end of the open cylinder to a transition section along the hollow elongated member, the first portion having a first cross-sectional dimension; and The second portion extends from the transition section to the rear end of the open cylinder, and the second portion has a second cross-sectional dimension larger than the first cross-sectional dimension; and A plunger including an elongated component, the elongated component including a plunger front end and a plunger rear end; in: The dimensions of the plunger and the cylinder are such that a portion of the plunger, including the front end of the plunger, can be inserted into the hollow elongated part of the cylinder at the rear end of the open cylinder, and the plunger can extend within the cylinder until the front end of the plunger engages with a portion of the inner surface of the hollow elongated part at the front end of the cylinder. The liquid drug composition received into the syringe via the front end of the open cylinder is confined to a volume defined within the first portion of the cylinder, wherein the volume can be adjusted by displacing the plunger tip away from the front end of the cylinder; and The surface wall portion of the plunger includes markings, the markings including a dosage scale, the dosage scale indicating the volume of the liquid drug composition received into the first portion of the cylinder based on a corresponding displacement of the plunger tip away from the cylinder tip.

2. The system of claim 1, wherein the cylinder is formed of a polymer material comprising polyethylene, preferably composed of polyethylene, and most preferably composed of low-density polyethylene, and the plunger is formed of a polymer material comprising polystyrene, preferably composed of polystyrene.

3. The system of any one of claims 1 to 2, wherein the length / diameter (L / D) ratio of the first portion of the cylinder is 5 to 20, or 7 to 15, or 9 to 14.

4. The system of any one of claims 1 to 3, wherein the first portion of the cylinder defines a volume within the hollow elongated component of not more than 3 mL, or not more than 2 mL, or not more than 1 mL, or not more than 0.9 mL, or not more than 0.8 mL, or not more than 0.7 mL, or not more than 0.6 mL, or not more than 0.5 mL, or not more than 0.4 mL; and / or The first portion of the cylinder defines a volume within the hollow elongated component of 0.01 mL to 3 mL, preferably 0.01 mL to 2 mL, more preferably 0.01 mL to 1 mL, particularly 0.02 mL to 0.9 mL, more preferably 0.03 mL to 0.8 mL, more preferably 0.04 mL to 0.7 mL, and most preferably 0.05 mL to 0.6 mL.

5. The system as described in any one of claims 1 to 4, wherein: The dose scale on the surface wall portion of the plunger includes a plurality of marks, the arrangement of which is consistent with the longitudinal dimension of the plunger; and In operation, the volume of the liquid drug composition received within the first portion of the cylinder in response to displacement of the plunger tip away from the cylinder tip is indicated by aligning the corresponding mark of the dosage scale with the outer surface of the cylinder at the rear end of the cylinder.

6. The system as claimed in any one of claims 1 to 5, further comprising: A container containing the liquid pharmaceutical composition.

7. The system of claim 6, wherein the liquid pharmaceutical composition comprises one or more SGLT-2 inhibitor compounds selected from: (1) Benzene derivatives substituted with glucopyranosyl groups, represented by the following formula: Where R 1 It represents cyano, Cl, or methyl (cyano is the most preferred). R 2 It represents H, methyl, methoxy, or hydroxyl (most preferably H), and R 3 This indicates cyclopropyl, hydrogen, fluorine, chlorine, bromine, iodine, methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, tert-butyl, 3-methyl-butyl-1-yl, cyclobutyl, cyclopentyl, cyclohexyl, 1-hydroxy-cyclopropyl, 1-hydroxy-cyclobutyl, 1-hydroxy-cyclopentyl, 1-hydroxy-cyclohexyl, ethynyl, ethoxy, difluoromethyl, trifluoromethyl, pentafluoroethyl, 2-hydroxy-ethyl, hydroxymethyl, 3-hydroxy-propyl, 2-hydroxy-2-methyl-propyl-1-yl, 3-hydroxy-3-methyl-butyl-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, difluoromethoxy, trifluoromethoxy, 2-methoxy-ethoxy, methylthio, methylsulfinyl, methylsulfonyl, ethylsulfinyl, ethylsulfonyl, trimethylsilyl, (R)-tetrahydrofuran-3-yloxy or (S)-tetrahydrofuran-3-yloxy, or cyano; Where R 3 Preferably selected from cyclopropyl, ethyl, ethynyl, ethoxy, (R)-tetrahydrofuran-3-yloxy or (S)-tetrahydrofuran-3-yloxy; and most preferably, R 3 It is cyclopropyl. Or its derivatives, wherein one or more hydroxyl groups of the β-D-glucopyranoyl group are selected from (C 1-18 alkyl)carbonyl, (C 1-18 Alkyl)oxycarbonyl, phenylcarbonyl and phenyl-(C) 1-3 Acylation of alkyl-carbonyl groups; (2) Veragranin expressed by the following formula: (3) Dapagliflozin expressed by the following formula: (4) Canagliflozin as expressed by the following formula: (5) Empaleline as expressed by the following formula: (6) Luglevin as expressed by the following formula: (7) Togliflozin expressed by the following formula: (8) Iglevin as expressed by the following formula: (9) Eggliflozin as expressed by the following formula: (10) Aggliflozin expressed by the following formula: (11) Repaglinide expressed by the following formula: (11A) Repaglinide carbonate, expressed by the following formula: (12) Thiophene derivatives represented by the following formula: Where R represents methoxy or trifluoromethoxy; (13) 1-(β-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienylmethyl]benzene represented by the following formula: (14) Spiroacetal derivatives represented by the following formula: Where R represents methoxy, trifluoromethoxy, ethoxy, ethyl, isopropyl, or tert-butyl; (15) Pyrazole-O-glucoside derivatives represented by the following formula: in: R 1 C represents 1-3 Alkoxy L 1 L 2 H or F can be represented independently of each other. R 6 Represents H, (C 1-3 alkyl)carbonyl, (C 1-6 Alkyl)oxycarbonyl, phenoxycarbonyl, benzyloxycarbonyl or benzylcarbonyl; (16) Soggliflozin as expressed by the following formula: (17) Seglecrine expressed by the following formula: (18) Compounds represented by the following formula: in: R 3 This indicates cyclopropyl, hydrogen, fluorine, chlorine, bromine, iodine, methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, tert-butyl, 3-methyl-butyl-1-yl, cyclobutyl, cyclopentyl, cyclohexyl, 1-hydroxy-cyclopropyl, 1-hydroxy-cyclobutyl, 1-hydroxy-cyclopentyl, 1-hydroxy-cyclohexyl, ethynyl, ethoxy, difluoromethyl, trifluoromethyl, pentafluoroethyl, 2-hydroxy-ethyl, hydroxymethyl, 3-hydroxy-propyl, 2-hydroxy-2-methyl-propyl-1-yl, 3-hydroxy-3-methyl-butyl-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, difluoromethoxy, trifluoromethoxy, 2-methoxy-ethoxy, methylthio, methylsulfinyl, methylsulfonyl, ethylsulfinyl, ethylsulfonyl, trimethylsilyl, (R)-tetrahydrofuran-3-yloxy or (S)-tetrahydrofuran-3-yloxy, or cyano; and wherein R 3 Preferably selected from cyclopropyl, ethyl, ethynyl, ethoxy, (R)-tetrahydrofuran-3-yloxy or (S)-tetrahydrofuran-3-yloxy; and R 3 The most preferred is cyclopropyl. Or its derivatives, wherein one or more hydroxyl groups of the β-D-glucopyranoyl group are selected from (C 1-18 alkyl)carbonyl, (C 1-18 Alkyl)oxycarbonyl, phenylcarbonyl and phenyl-(C) 1-3 Acylation of alkyl-carbonyl groups; (19) Bexagliflozin expressed by the following formula: (20) Gaglequin, expressed as follows: (21) Junglexin; (22) Vapagliflozin; (23) Inagrejacin expressed by the following formula: And (24) TFC-039 expressed by the following formula:

8. The system of claim 7, wherein the concentration of the one or more SGLT-2 inhibitor compounds in the liquid pharmaceutical composition is from 0.1 mg / mL to 20 mg / mL.

9. The system of claim 7 or 8, wherein the one or more SGLT-2 inhibitor compounds include vilaggliflozin, wherein preferably, vilaggliflozin is the only SGLT-2 inhibitor contained in the liquid pharmaceutical composition, and more preferably, the concentration of vilaggliflozin in the liquid pharmaceutical composition is 1.2 mg / mL or 15 mg / mL.

10. The system of any one of claims 6 to 9, wherein the liquid pharmaceutical composition comprises one or more SGLT-2 inhibitor compounds in a dissolved or suspended form, preferably in a dissolved form, and / or wherein the liquid pharmaceutical composition is in a solution or suspension form, preferably in a solution form.

11. The system of any one of claims 6 to 10, wherein the liquid pharmaceutical composition comprises one or more organic polar solvents, the organic polar solvents preferably selected from ethanol and / or propylene glycol and / or glycerol, and particularly wherein the liquid pharmaceutical composition comprises propylene glycol as an organic polar solvent and at least one other organic polar solvent selected from ethanol and / or glycerol.

12. The system as claimed in any one of claims 1 to 11, further comprising: An adapter connected to an opening in the container, the adapter including a hollow connecting member that facilitates engagement of the front end of the cylinder with the connecting member to facilitate the transfer of the liquid pharmaceutical composition to the first portion of the cylinder, wherein the outer diameter of a portion of the hollow connecting member of the adapter is substantially similar to the inner diameter of the opening in the container to create a frictional and fluid-tight connection between the adapter and the container, and the inner diameter of the hollow connecting member of the adapter is substantially similar to the outer diameter of the front end of the cylinder to create a frictional and fluid-tight connection between the adapter and the cylinder in response to insertion of the front end of the cylinder into the hollow connecting member.

13. The system of claim 12, wherein the adapter is formed of a polymer material comprising low-density polyethylene, preferably low-density polyethylene, and the container is formed of a polymer material comprising high-density polyethylene, preferably high-density polyethylene.

14. A method for treating and / or preventing metabolic disorders and / or other medical conditions in a patient by administering to a patient a dose of a liquid pharmaceutical composition comprising the one or more SGLT-2 inhibitor compounds, the method comprising: A syringe and a container containing the liquid drug composition are provided, the syringe comprising a cylinder and a plunger, wherein: The cylinder includes a hollow, elongated component having an open front end and an open rear end; a first portion extending from the open front end to a transition section along the hollow, elongated component, the first portion having a first cross-sectional dimension; and a second portion extending from the transition section to the open rear end, the second portion having a second cross-sectional dimension larger than the first cross-sectional dimension. The plunger includes an elongated component and a dosage scale. The elongated component includes a plunger front end and a plunger rear end, and the dosage scale includes a plurality of marks disposed on the surface wall portion of the plunger and arranged in the same direction as the longitudinal dimension of the plunger; and The dimensions of the plunger and the cylinder are such that a portion of the plunger's front end can be inserted into the hollow, elongated portion of the cylinder at the rear end of the open cylinder, and the plunger can extend within the cylinder until the plunger's front end engages with a portion of the inner surface of the hollow, elongated portion at the front end of the cylinder; and The desired dose of the liquid drug composition is drawn from the container into the first portion of the syringe cylinder by moving the plunger tip a selected distance from the front end of the cylinder until a selected mark among a plurality of marks on the dosage scale aligns with the outer surface of the cylinder at the rear end of the cylinder.

15. One or more SGLT-2 inhibitor compounds for use in the method of claim 14, wherein administering the required dose of the liquid pharmaceutical composition to the patient from the syringe comprises oral or parenteral administration to the patient, preferably oral administration, wherein more preferably, administering the required dose of the liquid pharmaceutical composition to the patient from the syringe comprises oral administration to the patient by directly delivering the liquid pharmaceutical composition from the syringe to the patient or by indirectly delivering the liquid pharmaceutical composition from the syringe to a food or liquid for the patient to consume.

16. One or more SGLT-2 inhibitor compounds used in the method of any one of claims 14 to 15, wherein the required dose is no more than 3 mL, or no more than 2 mL, or no more than 1 mL, or no more than 0.9 mL, or no more than 0.8 mL, or no more than 0.7 mL, or no more than 0.6 mL, or no more than 0.5 mL, or no more than 0.4 mL, or wherein the required dose is from 0.05 mL to 0.6 mL; and / or wherein the required dose is from 0.01 mL to 3 mL, or 0.01 mL to 2 mL, or 0.01 mL to 1 mL, or 0.02 mL to 0.9 mL, or 0.03 mL to 0.8 mL, or 0.04 mL to 0.7 mL, or 0.05 mL to 0.6 mL.

17. One or more SGLT-2 inhibitor compounds for the method as described in any one of claims 14 to 16, wherein at least one SGLT-2 inhibitor compound is selected from: (1) Benzene derivatives substituted with glucopyranosyl groups, represented by the following formula: Where R 1 It represents cyano, Cl, or methyl (cyano is the most preferred). R 2 It represents H, methyl, methoxy, or hydroxyl (most preferably H), and R 3 This indicates cyclopropyl, hydrogen, fluorine, chlorine, bromine, iodine, methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, tert-butyl, 3-methyl-butyl-1-yl, cyclobutyl, cyclopentyl, cyclohexyl, 1-hydroxy-cyclopropyl, 1-hydroxy-cyclobutyl, 1-hydroxy-cyclopentyl, 1-hydroxy-cyclohexyl, ethynyl, ethoxy, difluoromethyl, trifluoromethyl, pentafluoroethyl, 2-hydroxy-ethyl, hydroxymethyl, 3-hydroxy-propyl, 2-hydroxy-2-methyl-propyl-1-yl, 3-hydroxy-3-methyl-butyl-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, difluoromethoxy, trifluoromethoxy, 2-methoxy-ethoxy, methylthio, methylsulfinyl, methylsulfonyl, ethylsulfinyl, ethylsulfonyl, trimethylsilyl, (R)-tetrahydrofuran-3-yloxy or (S)-tetrahydrofuran-3-yloxy or cyano; Where R 3 Preferably selected from cyclopropyl, ethyl, ethynyl, ethoxy, (R)-tetrahydrofuran-3-yloxy or (S)-tetrahydrofuran-3-yloxy; and most preferably, R 3 It is cyclopropyl. Or its derivatives, wherein one or more hydroxyl groups of the β-D-glucopyranoyl group are selected from (C 1-18 alkyl)carbonyl, (C 1-18 Alkyl)oxycarbonyl, phenylcarbonyl and phenyl-(C) 1-3 Acylation of alkyl-carbonyl groups; (2) Veragranin expressed by the following formula: (3) Dapagliflozin expressed by the following formula: (4) Canagliflozin as expressed by the following formula: (5) Engagliflozin as expressed by the following formula: (6) Luglevin as expressed by the following formula: (7) Togliflozin expressed by the following formula: (8) Iglevin as expressed by the following formula: (9) Eggliflozin as expressed by the following formula: (10) Aggliflozin expressed by the following formula: (11) Repaglinide expressed by the following formula: (11A) Repaglinide carbonate, expressed by the following formula: (12) Thiophene derivatives represented by the following formula: Where R represents methoxy or trifluoromethoxy; (13) 1-(β-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienylmethyl]benzene represented by the following formula: (14) Spiroacetal derivatives represented by the following formula: Where R represents methoxy, trifluoromethoxy, ethoxy, ethyl, isopropyl, or tert-butyl; (15) Pyrazole-O-glucoside derivatives represented by the following formula: in: R 1 C represents 1-3 Alkoxy L 1 L 2 H or F can be represented independently of each other. R 6 Represents H, (C 1-3 alkyl)carbonyl, (C 1-6 Alkyl)oxycarbonyl, phenoxycarbonyl, benzyloxycarbonyl or benzylcarbonyl; (16) Soggliflozin as expressed by the following formula: (17) Seglecrine expressed by the following formula: (18) Compounds represented by the following formula: in: R 3 This indicates cyclopropyl, hydrogen, fluorine, chlorine, bromine, iodine, methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, tert-butyl, 3-methyl-butyl-1-yl, cyclobutyl, cyclopentyl, cyclohexyl, 1-hydroxy-cyclopropyl, 1-hydroxy-cyclobutyl, 1-hydroxy-cyclopentyl, 1-hydroxy-cyclohexyl, ethynyl, ethoxy, difluoromethyl, trifluoromethyl, pentafluoroethyl, 2-hydroxy-ethyl, hydroxymethyl, 3-hydroxy-propyl, 2-hydroxy-2-methyl-propyl-1-yl, 3-hydroxy-3-methyl-butyl-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, difluoromethoxy, trifluoromethoxy, 2-methoxy-ethoxy, methylthio, methylsulfinyl, methylsulfonyl, ethylsulfinyl, ethylsulfonyl, trimethylsilyl, (R)-tetrahydrofuran-3-yloxy or (S)-tetrahydrofuran-3-yloxy or cyano; and wherein R 3 Preferably selected from cyclopropyl, ethyl, ethynyl, ethoxy, (R)-tetrahydrofuran-3-yloxy or (S)-tetrahydrofuran-3-yloxy; and R 3 The most preferred is cyclopropyl. Or its derivatives, wherein one or more hydroxyl groups of the β-D-glucopyranoyl group are selected from (C 1-18 alkyl)carbonyl, (C 1-18 Alkyl)oxycarbonyl, phenylcarbonyl and phenyl-(C) 1-3 Acylation of alkyl-carbonyl groups; (19) Bexagliflozin expressed by the following formula: (20) Gaglequin, expressed as follows: (21) Junglexin; (22) Vapagliflozin; (23) Inagrejacin expressed by the following formula: and (24) TFC-039 is represented by the following formula: Preferably, the one or more SGLT-2 inhibitor compounds include vilaggliflozin, more preferably, wherein vilaggliflozin is the only SGLT-2 inhibitor compound administered.

18. One or more SGLT-2 inhibitor compounds for use in the method according to any one of claims 14 to 17, wherein the metabolic disorder and / or other medical condition is selected from: (i) Metabolic disorders in equines, preferably, the metabolic disorder being one or more conditions selected from the following: insulin resistance, hyperinsulinemia, impaired glucose tolerance, dyslipidemia, adipokines abnormalities, subclinical inflammation, systemic inflammation, low-grade systemic inflammation, obesity, and / or regional fat accumulation; preferably, the metabolic disorder is insulin resistance, hyperinsulinemia, and / or clinical symptoms associated with insulin resistance and / or hyperinsulinemia; preferably, the clinical symptoms are one or more conditions selected from the following: impaired glucose tolerance, dyslipidemia, adipokines abnormalities, subclinical inflammation, systemic inflammation, low-grade systemic inflammation, obesity, and / or regional fat accumulation; (ii) Metabolic disorders in equines, wherein the metabolic disorder is one or more conditions selected from the following: laminitis, vascular dysfunction, hypertension, fatty liver, atherosclerosis, hyperadrenocorticism, middle pituitary dysfunction and / or equine metabolic syndrome, wherein preferably, the metabolic disorder is a clinical symptom / sign associated with insulin resistance and / or hyperinsulinemia, wherein the clinical symptom / sign is preferably one or more conditions selected from the following: laminitis, vascular dysfunction, hypertension, fatty liver, atherosclerosis, hyperadrenocorticism, middle pituitary dysfunction and / or equine metabolic syndrome; (iii) Metabolic disorders in felines, wherein preferably, the metabolic disorder is selected from one or more of the following: ketoacidosis, prediabetes, type 1 or type 2 diabetes, insulin resistance, acromegaly, diabetes with elevated IGF-1 concentration, obesity, hyperglycemia, impaired glucose tolerance, hyperinsulinemia, dyslipidemia, adipokines abnormality, subclinical inflammation, systemic inflammation, low-grade systemic inflammation, fatty liver, atherosclerosis, pancreatitis, neuropathy and / or syndrome X (metabolic syndrome) and / or loss of pancreatic β-cell function, and / or wherein relief of the metabolic disorder is achieved and / or maintained, preferably relief of diabetes; (iv) Metabolic disorders in canines, preferably, the metabolic disorder being selected from one or more of the following: ketoacidosis, prediabetes, insulin-dependent diabetes, insulin-resistant diabetes, insulin resistance, obesity, hyperglycemia, hyperglycemia-induced cataracts, impaired glucose tolerance, hyperinsulinemia, dyslipidemia, adipokines abnormalities, subclinical inflammation, systemic inflammation, low-grade systemic inflammation, fatty liver, pancreatitis, metabolic disorder consequences such as hypertension, renal dysfunction and / or musculoskeletal disorders, and / or Syndrome X (metabolic syndrome), preferably prediabetes, insulin-dependent diabetes, insulin-resistant diabetes, insulin resistance, preferably, preventing the development of hyperglycemia-induced cataracts or achieving its remission, and / or preferably, preventing the development of metabolic disorder consequences such as hypertension, renal dysfunction and / or musculoskeletal disorders, slowing their progression, or achieving their remission; (v) Heart disease in felines, wherein preferably, the heart disease is selected from one or more of the following: heart failure, heart failure caused by one or more cardiomyopathy, heart failure caused by hypertrophic cardiomyopathy (HCM), heart failure caused by restrictive cardiomyopathy (RCM), heart failure caused by dilated cardiomyopathy (DCM), heart failure caused by unclassified cardiomyopathy (UCM), heart failure caused by 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 one or more of the following: heart failure caused by one or more cardiomyopathy, heart failure caused by hypertrophic cardiomyopathy (HCM), hypertrophic cardiomyopathy (HCM); (vi) Drying of non-human mammals, preferably ruminants, wherein preferably, the medical condition is selected from one or more of the following: improving and / or promoting drying of non-human mammals, preferably ruminants; reducing milk production in gestation and / or lactation of non-human mammals, preferably ruminants, preferably milk production and / or lactation; reducing milk accumulation and / or engorgement in the udder of non-human mammals, preferably ruminants, preferably milk accumulation and / or engorgement in the udder and / or mammary glands; reducing discomfort related to udder swelling in non-human mammals, preferably ruminants, such as increasing daily lying time and / or reducing stress; reducing milk leakage in non-human mammals, preferably ruminants, after drying; reducing the incidence of intramammary infection (IMI) in non-human mammals, preferably ruminants, preferably mastitis and / or endometritis; (vii) Heart disease in non-human mammals other than felines, particularly canines, wherein preferably, the heart disease is selected from one or more of the following: heart failure; congestive heart failure; asymptomatic / preclinical / occult heart failure; heart failure caused by (mica) mitral valve disease [(M)MVD]; congestive heart failure caused by (mica) mitral valve disease [(M)MVD]; asymptomatic / preclinical / occult heart failure caused by (mica) mitral valve disease [(M)MVD]; (mica) mitral valve disease [(M)MVD]; clinically overt (mica) mitral valve disease [(M)MVD]; asymptomatic / preclinical / occult (mica) mitral valve disease [(M)MVD]; Heart failure caused by dilated cardiomyopathy (DCM); Congestive heart failure caused by dilated cardiomyopathy (DCM); asymptomatic / preclinical / silent heart failure caused by dilated cardiomyopathy (DCM); dilated cardiomyopathy (DCM); clinically overt dilated cardiomyopathy (DCM); asymptomatic / preclinical / silent dilated cardiomyopathy (DCM); aortic stenosis (valvular, supravalvular and / or subvalvular); (viii) Hypertension in non-human mammals, preferably carnivores, more preferably cats or dogs, wherein preferably, the hypertension is selected from one or more of the following: situational hypertension, secondary hypertension, and idiopathic hypertension, wherein preferably, the secondary hypertension is selected from: hypertension associated with chronic kidney disease (CKD), diabetes, obesity, heart disease, endocrine disorders such as Cushing's disease, hyperthyroidism, acromegaly; and hypertension induced by drugs, preferably glucocorticoids, mineralocorticoids, erythropoietin, ephedrine, and / or high doses of sodium chloride; (ix) Kidney disease in non-human mammals, preferably carnivores, more preferably cats or dogs, wherein preferably, the kidney disease is selected from one or more of the following: renal dysplasia, glomerulonephropathy, polycystic kidney disease, amyloidosis, tubulonephritis / tubulointerstitial nephritis (TIN), acute kidney disease, chronic kidney disease; Preferably, the dose is 0.01 to 10 mg / kg of patient body weight.

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