Combinations of SGLT2 inhibitors and antioxidants and their uses

Abstract

Disclosed herein are combinations comprising: an SGLT2 inhibitor and an antioxidant; or TUDCA and an antioxidant. The combinations are useful in treating a number of diseases, including metabolic dysfunction-associated steatotic liver disease (MASLD), metabolic dysfunction-associated steatohepatitis (MASH), fatty liver disease (FLD), irritable bowel disease (IBD), Crohn's disease, ulcerative colitis (UC), and macular degeneration (MD).

Description

1960197.00021COMBINATIONS OF SGLT2 INHIBITORS AND ANTIOXIDANTS AND THEIR USES RELATED APPLICATIONS

[0001] This application claims priority of U.S. Provisional Patent Application Serial No.63 / 749,939, filed on January 27, 2025, U.S. Provisional Patent Application Serial No. 63 / 749,937, filed on January 27, 2025, and U.S. Provisional Patent Application Serial No. 63 / 749,957, filed on January 27, 2025, the entire content of each of which are hereby incorporated by reference.BACKGROUND

[0002] One driving force behind acute inflammation is the body’s immune system. When the body detects damaged tissue, cells called phagocytes rush to the site, ingesting disease-causing microorganisms or damaged cells as well as other foreign materials. This process is usually accompanied by the four cardinal signs of inflammation: redness, heat, swelling and pain.

[0003] With many infections, the disease-causing microorganism itself or a measured immune reaction to it triggers most symptoms. For example, some symptoms include fevers that alert the body to an attack or coughs and loose stools that expel microscopic infectious particles. But if the immune system fails in managing the organism or other source of cell trauma, it can resort to a “flood” of inflammation wherein immune cells produce high volumes of cytokines, small proteins that act as messengers, in an attempt to fight the infection.

[0004] Inflammation can persist with or without a known trigger, destroying healthy tissue. Autoimmune diseases such as arthritis or lupus, which turn inflammation against the body, can be devastating and sometimes fatal. Some patients can suffer from inflammatory bowel disease (IBD), an autoimmune condition in which severe intestinal inflammation can require surgical intervention to remove most or all of the intestines. Additionally, many others endure inflammation from acid reflux, food sensitivities, celiac disease, or irritable bowel syndrome (IBS), among other inflammatory outcomes. Crohn's Disease (CD) and Ulcerative Colitis (UC), the most common types of IBD, cause swelling of the tissues (inflammation) in the digestive tract, which can lead to abdominal pain, severe diarrhea, fatigue, weight loss, and malnutrition. In addition, conditions like Metabolic Dysfunction-associated Steatotic Liver Disease (MASLD) are also associated with inflammation. In addition, macular degeneration is also associated with inflammation.

[0005] However, effective treatment options are limited, and improved compositions and methods for treating inflammation-related conditions are desirable.1960197.00021SUMMARY

[0006] Disclosed herein are combinations comprising: an SGLT2 inhibitor and an antioxidant; or TUDCA and an antioxidant. The combinations are useful in treating a number of diseases, including metabolic dysfunction-associated steatotic liver disease (MASLD), metabolic dysfunction-associated steatohepatitis (MASH), fatty liver disease (FLD), irritable bowel disease (IBD), Crohn's disease, ulcerative colitis (UC), and macular degeneration (MD).

[0007] Thus, provided herein are combinations, comprising: a first compound, which is an SGLT2 inhibitor; and a second compound, which is an antioxidant.

[0008] Also provided herein are combinations, comprising: a first compound, which is TUDCA; and a second compound, which is an antioxidant.

[0009] Also provided herein are methods of treating metabolic dysfunction-associated steatotic liver disease in a subject in need thereof, comprising administration of a combination herein to the subject.

[0010] Also provided herein are methods of treating metabolic dysfunction-associated steatohepatitis in a subject in need thereof, comprising administration of a combination herein to the subject.

[0011] Also provided herein are methods of treating fatty liver disease in a subject in need thereof, comprising administration of a combination herein to the subject.

[0012] Also provided herein are methods of treating inflammatory bowel disease in a subject in need thereof, comprising administration of a combination herein to the subject.

[0013] Also provided herein are methods of treating ulcerative colitis in a subject in need thereof, comprising administration of a combination herein to the subject.

[0014] Also provided herein are methods of treating Crohn’s disease in a subject in need thereof, comprising administration of a combination herein to the subject.

[0015] Also provided herein are methods of treating macular degeneration in a subject in need thereof, comprising administration of a combination herein to the subject.BRIEF DESCRIPTION OF THE DRAWINGS

[0016] FIG. 1 depicts the physical appearance of a “fatty” liver.

[0017] FIG. 2 depicts the back of the eye with macular degeneration visible.1960197.00021

[0018] FIG. 3 depicts an Amsler grid test which can help identify the distorted vision typical of macular degeneration.DETAILED DESCRIPTIONDefinitions

[0019] Certain terms, whether used alone or as part of a phrase or another term, are defined below.

[0020] The articles “a” and “an” refer to one or to more than one of the grammatical object of the article.

[0021] Numerical values relating to measurements are subject to measurement errors that place limits on their accuracy. For this reason, the term “about” may explicitly or implicitly modify all numerical values provided herein, unless otherwise indicated.

[0022] The term “about” generally indicates a possible variation of a numerical value. In some embodiments, the possible variation (±) may be no more than 10%, 5%, or 1% of the numerical value. In some embodiments, the last decimal place of a numerical value provided herein indicates its degree of accuracy. In some embodiments, where no other error margins are given, the maximum margin is ascertained by applying the rounding-off convention to the last decimal place or last significant digit when a decimal is not present in the given numerical value.

[0023] The term “amelioration” means a lessening of severity of at least one indicator of a condition or disease, such as a delay or slowing in the progression of one or more indicators of a condition or disease. The severity of indicators may be determined by subjective or objective measures which are known to those skilled in the art.

[0024] The terms “composition” and “pharmaceutical composition” refer to a mixture of at least one compound described herein with another component, such as a carrier or a pharmaceutically acceptable carrier, respectively, and / or optionally another pharmaceutically active compound. The pharmaceutical composition facilitates administration of the compound to a patient or subject. Multiple techniques of administering a composition exist including, but not limited to, ocular instillation, or intravenous, oral, nasal, rectal, intravaginal, aerosol, parenteral, buccal, sublingual, ophthalmic, pulmonary, transdermal, and topical administration.

[0025] The terms “effective amount” and “therapeutically effective amount” refer to an amount of therapeutic compound, such as a compound described herein, administered to a1960197.00021subject, either as a single dose or as part of a series of doses, which is effective to produce a desired therapeutic effect.

[0026] The term “pharmaceutically acceptable carrier” means a pharmaceutically acceptable material, composition, or carrier, such as a liquid filler, solid filler, stabilizer, dispersing agent, suspending agent, diluent, excipient, thickening agent, solvent, or encapsulating material, involved in carrying or transporting at least one compound described herein within or to the patient such that the compound may perform its intended function. A given carrier must be “acceptable” in the sense of being compatible with the other ingredients of a particular formulation, including the compounds described herein, and not injurious to the patient. Other ingredients that may be included in the pharmaceutical compositions or dosage forms described herein are known in the art and described, for example, in “Remington’s Pharmaceutical Sciences” (Genaro (Ed.), Mack Publishing Co., 1985), the entire content of which is incorporated herein by reference.

[0027] The term “pharmaceutically acceptable salt” refers to derivatives of the disclosed compounds wherein the parent compound is modified by converting an existing acid or base moiety to its salt form. Lists of salts are found in “Handbook of Pharmaceutical Salts: Properties, Selection, and Use” (P. Henrich Stahl & Camille G. Wermuth (Eds.), VHCA & Wiley-VCH, 2002), the entire content of which is incorporated herein by reference.

[0028] The terms “treatment” or “treating” refer to the application of one or more specific procedures used for the amelioration of a disease. The term “treatment” can include “therapeutic treatment”. A “prophylactic” treatment, refers to reducing the rate of progression of the disease or condition being treated, delaying the onset of that disease or condition, or reducing the severity of its onset.

[0029] Recitation of ranges of values herein is merely intended to serve as a shorthand method of referring individually to each separate value falling within the range. Unless otherwise indicated herein, each individual value is incorporated into the specification as if it were individually recited herein. All methods described herein may be performed in any suitable order, and may include a combination of one or more embodiments herein, unless otherwise indicated herein or otherwise clearly contradicted by context. The use of examples, or exemplary language (“for example,” “such as,” etc.) provided herein is intended merely to better illuminate the described subject matter and does not pose a limitation on the scope of the subject matter otherwise claimed. No language in the specification should be construed as indicating any nonclaimed element essential to practicing the described subject matter.1960197.00021

[0030] Each group member of a grouping of alternative elements or embodiments of this disclosure may be referred to and claimed individually or in any combination with other members of the group or other elements found herein. Furthermore, a recited member of a group may be included in, or excluded from, another recited group for reasons of convenience or patentability.

[0031] Reference made to a patent or printed publication document throughout this specification incorporate herein by reference the document’s entire content.

[0032] Embodiments of this disclosure are illustrative. Accordingly, the present disclosure is not limited to that precisely as shown and described.Compositions

[0033] Disclosed herein are combinations comprising: an SGLT2 inhibitor and an antioxidant; or TUDCA and an antioxidant. The combinations are useful in treating a number of diseases, including metabolic dysfunction-associated steatotic liver disease (MASLD), metabolic dysfunction-associated steatohepatitis (MASH), fatty liver disease (FLD), irritable bowel disease (IBD), Crohn’s disease, ulcerative colitis (UC), and macular degeneration (MD).

[0034] Thus, in some embodiments, provided herein are combinations, comprising: a first compound, which is an SGLT2 inhibitor; and a second compound, which is an antioxidant.

[0035] In some embodiments of the combinations herein, the second compound is N-acetyl-L-cysteine, 4-hydroxy-2,2,6,6-tetramethylpiperidin-1-oxyl (TEMPOL), a TEMPOL hybrid, or a pharmaceutically acceptable salt thereof.

[0036] In some embodiments of the combinations herein, the SGLT2 inhibitor is dapagliflozin, remogliflozin etabonate, bexagliflozin, canagliflozin, empagliflozin, enavogliflozin ertugliflozin, henagliflozin, ipragliflozin, luseogliflozin, rongliflozin, sotagliflozin, or tofogliflozin, or a pharmaceutically acceptable salt thereof. In some embodiments of the combinations herein, the SGLT2 inhibitor is dapagliflozin or remogliflozin etabonate.

[0037] In other embodiments, provided herein are combinations, comprising: a first compound, which is Tauroursodeoxycholic acid (TUDCA) or a pharmaceutically acceptable salt thereof; and a second compound, which is an antioxidant.1960197.00021

[0038] In other embodiments, provided herein are combinations, comprising: a firstcompound, whichor a pharmaceutically acceptable salt thereof; anda second compound, which is an antioxidant.

[0039] In some embodiments of the combinations herein, the combination comprises one of dapagliflozin and NAC, dapagliflozin and TEMPOL, dapagliflozin and a TEMPOL hybrid, remogliflozin etabonate and NAC, remogliflozin etabonate and TEMPOL, remogliflozin etabonate and a TEMPOL hybrid, TEMPOL and TUDCA, or a TEMPOL hybrid and TUDCA, and wherein the dapagliflozin, when present, is present in the combination at from about 5 mg to about 10 mg (e.g., about 5 mg or about 10 mg), the remogliflozin etabonate, when present, is present in the combination at from about 100 mg to about 250 mg (e.g., about 100 mg or about 250 mg), the NAC, when present, is present in the combination at from about 300 mg to about 600 mg, from about 600 mg to about 900 mg, from about 900 mg to about 1200 mg, or from about 1200 mg to about 1800 mg (e.g., about 300 mg, about 600 mg, about 900 mg, about 1200 mg, or about 1800 mg), the TEMPOL, when present, is present in the combination at from about 400 mg to about 600 mg, from about 600 mg to about 800 mg, from about 800 mg to about 900 mg, from about 900 mg to about 1200 mg, from about 1200 mg to about 1600 mg, or from about 1600 mg to about 1800 mg (e.g., about 400 mg, about 600 mg, about 800 mg, about 900 mg, about 1200 mg, about 1600 mg, or about 1800 mg), the TEMPOL hybrid, when present, is present in the combination at from about 10 mg to about 100 mg, from about 100 mg to about 400 mg, from about 400 mg to about 600 mg, from about 600 mg to about 800 mg, from about 800 mg to about 900 mg, from about 900 mg to about 1200 mg, from about 1200 mg to about 1600 mg, or from about 1600 mg to about 1800 mg (e.g., about 10 mg, about 20 mg, about 100 mg, about 200 mg, about 400 mg, about 600 mg, about 800 mg, about 900 mg, about 1200 mg, about 1600 mg, or about 1800 mg), and the TUDCA, when present, is present in the combination at from about 300 mg to about 600 mg, from about 600 mg to about 900 mg, from about 900 mg to about 1200 mg, or from about 1200 mg to about 1800 mg (e.g., about 300 mg, about 600 mg, about 900 mg, about 1200 mg, or about 1800 mg).1960197.00021

[0040] Disclosed combinations can comprise at least one antioxidant, which are compounds that inhibit oxidation, a chemical reaction that can produce free radicals and chain reactions that may cause cellular damage and inflammation. Specifically, antioxidants can break down dangerous oxidative products, such as free radicals and reactive oxygen species (ROS). Dangerous oxidative products can be converted to H2O2 and then to water by enzymatic antioxidants that are able to break down free radicals in a multistep process in the presence of cofactors such as copper (Cu), zinc (Zn), manganese (Mn), selenium (Se), and iron (Fe). In contrast, non-enzymatic antioxidants, such as vitamin C, vitamin E, plant polyphenol, carotenoids, and glutathione (GSH), act by interrupting free radical chain reactions and neutralizing the reactive oxygen species (ROS) in a process called radicals scavenging.

[0041] Disclosed combinations can comprise antioxidants of a number of classes. According to size, antioxidants can be categorized as small or large-molecule antioxidants. The small molecule antioxidants C, vitamin E, carotenoids, and glutathione (GSH) are the main antioxidants in this category. Large molecule antioxidants include enzymes (SOD, CAT, and GPx) and sacrificial proteins (albumin) that absorb ROS and prevent them from attacking other essential proteins.

[0042] In some embodiments, disclosed combinations can comprise any of enzymatic, non-enzymatic antioxidants, small molecule, or large molecule antioxidants.

[0043] Remogliflozin etabonate is a commercially available oral prodrug of remogliflozin, a benzyl pyrazole glucoside-based inhibitor of renal sodium-glucose co-transporter subtype 2 (SGLT2) with antihyperglycemic activity. Upon administration and absorption, the prodrug remogliflozin etabonate is converted to remogliflozin, which acts selectively on the sodiumglucose co-transporter subtype 2 (SGLT2).

[0044] In some embodiments of the combinations herein, the SGLT2 inhibitor is1960197.00021. In some embodiments, the SGLT2 inhibitor is Remogliflozin etabonate or ethyl [(2R,3S,4S,5R,6S)-3,4,5-trihydroxy-6-[5-methyl-1-propan-2-yl-4-[(4-propan-2-yloxyphenyl)methyl]pyrazol-3-yl]oxyoxan-2-yl]methyl carbonate. In some embodiments of the combinations herein, the SGLT2 inhibitor is about 100 mg of the total combination mass. In some embodiments of the combinations herein, the SGLT2 inhibitor is about 1-250 mg of the total combination mass.

[0045] Dapagliflozin, also marketed as FARXIGA®, is a commercially available SGLT2 inhibitor which is approved by the Food and Drug Administration (FDA) as an adjunct therapy to improve glycemic control and reduce the risk of hospitalization for heart failure in adults with type 2 diabetes. It can also be used to lower the risks of hospitalization and death associated with cardiovascular disease and kidney disease.

[0046] Further disclosure relating to Dapagliflozin can be found in U.S. Patent Nos.6515117, 8501698, 8221786, 8361972, 8716251, 7851502, 7919598, 8685934, and 11903955, which are incorporated by reference herein in their entirety.

[0047] In some embodiments of the combinations herein, the SGLT2 inhibitor is. In some embodiments, the SGLT2 inhibitor is dapagliflozin, dapagliflozin propanediol monohydrate, or (2S,3R,4R,5S,6R)-2-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-6-(hydroxymethyl)oxane-3,4,5-triol;(2S)-propane-1,2-diol;hydrate. In some embodiments of the combinations herein, the SGLT2 inhibitor is about 1-20 mg of the total combination mass. In some embodiments of the combinations herein, the SGLT2 inhibitor is about6 (e.g., 6.14) mg or about 12 (e.g., 12.28) mg of the total combination mass.

[0048] In some embodiments of the combinations herein, the SGLT2 inhibitor is1960197.00021. in some embodiments, the SGLT2 inhibitor is dapagliflozin or (2S,3R,4R,5S,6R)-2-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-6-(hydroxymethyl)oxane-3,4,5-triol. In some embodiments of the combinations herein, the SGLT2 inhibitor is about 1-20 mg of the total combination mass. In some embodiments of the combinations herein, the SGLT2 inhibitor is about 5 mg or about 10 mg of the total combination mass. In some embodiments of the combinations herein, the SGLT2 inhibitor is about 1-20 mg of the total combination mass.

[0049] Empagliflozin, also marketed as JARDIANCE®, is a commercially available SGLT2 inhibitor which is approved by the Food and Drug Administration (FDA) as an adjunct therapy to improve glycemic control and reduce the risk of hospitalization for heart failure in adults with type 2 diabetes. It can also be used to lower the risks of hospitalization and death associated with cardiovascular disease and kidney disease.

[0050] In some embodiments of the combinations herein, the SGLT2 inhibitor is. In some embodiments, the SGLT2 inhibitor is empagliflozin or (2S,3R,4R,5S,6R)-2-[4-chloro-3-[[4-[(3S)-oxolan-3-yl]oxyphenyl]methyl]phenyl]-6-(hydroxymethyl)oxane-3,4,5-triol. In some embodiments of the combinations herein, the SGLT2 inhibitor is about 10 mg or about 25 mg of the total combination mass. In some embodiments of the combinations herein, the SGLT2 inhibitor is about 1-30 mg of the total combination mass.

[0051] Ertugliflozin also marketed as STEGLATRO®, is a commercially available SGLT2 inhibitor which is approved by the Food and Drug Administration (FDA) as an adjunct therapy to improve glycemic control and reduce the risk of hospitalization for heart failure in adults with type 2 diabetes. It can also be used to lower the risks of hospitalization and death associated with cardiovascular disease and kidney disease.

[0052] In some embodiments of the combinations herein, the SGLT2 inhibitor is1960197.00021In some embodiments, the SGLT2 inhibitor is ertugliflozin, (1S,2S,3S,4R,5S)-5-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-1- (hydroxymethyl)-6,8-dioxabicyclo[3.2.1]octane-2,3,4-triol, ertugliflozin L-pyroglutamic acid, or (S)- 5-oxopyrrolidine-2-carboxylic acid-(1S,2S,3S,4R,5S)-5-(4-chloro-3-(4-ethoxybenzyl)phenyl)-1- (hydroxymethyl)-6,8-dioxabicyclo[3.2.1]octane-2,3,4-triol. In some embodiments, the SGLT2 inhibitor is about 6.5 (e.g., 6.48) mg or about 19.4 (e.g., 19.43) mg of the total combination mass. In some embodiments, the SGLT2 inhibitor is about 1-20 mg of the total combination mass.

[0053] In some embodiments of the combinations herein, the SGLT2 inhibitor is<<>"In some embodiments, the SGLT2 inhibitor is ertugliflozin, or (1S,2S,3S,4R,5S)-5-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-1-(hydroxymethyl)-6,8-dioxabicyclo[3.2.1]octane-2,3,4-triol. In some embodiments of the combinations herein, the SGLT2 inhibitor is about 5 mg or about 15 mg of the total combination mass. In some embodiments, theSGLT2 inhibitor is about 1-20 mg of the total combination mass.

[0054] Canagliflozin, also marketed as INVOKANA®, is a commercially available SGLT2 inhibitor which is approved by the Food and Drug Administration (FDA) as an adjunct therapy to improve glycemic control and reduce the risk of hospitalization for heart failure in adults with type 2 diabetes. It can also be used to lower the risks of hospitalization and death associated with cardiovascular disease and kidney disease.

[0055] In some embodiments of the combinations herein, the SGLT2 inhibitor is1960197.00021. In some embodiments, the SGLT2 inhibitor is canagliflozin, canagliflozin hydrate, or (2S,3R,4R,5S,6R)-2-[3-[[5-(4-fluorophenyl)thiophen-2-yl]methyl]-4-methylphenyl]-6-(hydroxymethyl)oxane-3,4,5-triol. In some embodiments of the combinations herein, the SGLT2 inhibitor is about 102 mg or about 306 mg of the total combination mass. In some embodiments, the SGLT2 inhibitor is about 1-400 mg of the total combination mass.

[0056] In some embodiments of the combinations herein, the SGLT2 inhibitor is" ". In some embodiments, the SGLT2 inhibitor is canagliflozin or (2S,3R,4R,5S,6R)-2-[3-[[5-(4-fluorophenyl)thiophen-2-yl]methyl]-4-methylphenyl]-6-(hydroxymethyl)oxane-3,4,5-triol. In some embodiments of the combinations herein, the SGLT2 inhibitor is about 100 mg or about 300 mg of the total combination mass. In some embodiments, the SGLT2 inhibitor is about 1-400 mg of the total combination mass.

[0057] TUDCA is the taurine conjugate of ursodeoxycholic acid (UDCA), the latter of which is Food and Drug Administration (FDA) approved for primary biliary cholangitis. TUDCA is also available over the counter as a supplement. UDCA has been approved for the treatment of certain cholestatic liver diseases.

[0058] In some embodiments of the combinations herein, the antioxidant isIn some embodiments, the antioxidant is TUDCA, tauroursodeoxycholic acid, 2-[[(4R)-4-[(3R,5S,7S,8R,9S,10S,13R,14S,17R)-3,7-1960197.00021dihydroxy-10, 13-dimethyl-2,3,4,5,6,7,8,9, 11 , 12,14, 15, 16, 17-tetradecahydro-1 H-cyclopenta[a]phenanthren-17-yl]pentanoyl]amino]ethanesulfonic acid, or a pharmaceutically acceptable salt thereof. In some embodiments of the combinations herein, the antioxidant is about 600 mg, about 1200 mg, or about 1800 mg of the total combination mass. In some embodiments, the antioxidant is 1-2000 mg of the total combination mass.

[0059] TEMPOL / TEMPOL hybrids or derivatives. In some embodiments of the combinations herein, the antioxidant is 4-Hydroxy-TEMPO or 4-hydroxy-2,2,6,6-tetramethylpiperidin-1-oxyl (TEMPOL),

[0060] In some embodiments of the combinations herein, the antioxidant is a 4-hydroxy-2,2,6,6-tetramethylpiperidin-1-oxyl (TEMPOL) derivative or hybrid.

[0061] In some embodiments, the TEMPOL derivative or hybrid is SA-2, SA-9, SA-10, SA-21, SA-23, and SA-24, or a pharmaceutically acceptable salt thereof. Further disclosure relating to SA-2, SA-9, SA-10, SA-21, SA-23, and SA-24 can be found in U.S. patent publication 20220073503, which is incorporated by reference herein in its entirety.

[0062] TEMPOL / TEMPOL hybrids are synthetic antioxidants, safe and well tolerated for acute or chronic dosing.. They can be administered as an oral liquid, solid, topical, or intravenous1960197.00021dose form. TEMPOL is also blood-brain barrier permeable. Additionally, they can prevent and reverse the production of free radicals, thereby preventing or reducing oxidative stress created by, for example, infection, inflammation, tissue injury, chemotherapy, and radiation. TEMPOL is commercially available.

[0063] In some embodiments of the combinations herein, the antioxidant is. In some embodiments, the antioxidant is TEMPOL, 4-Hydroxy-TEMPO or 4-hydroxy-2,2,6,6-tetramethylpiperidin-1-oxyl. In some embodiments of the combinations herein, the antioxidant is about 800 mg, about 1200 mg, or about 1800 mg of the total combination mass. In some embodiments, the antioxidant is about 1-2000 mg of the total combination mass.

[0064] N-acetyl-L-Cysteine (NAC) is a non-enzymatic antioxidant and a drug approved by the Food and Drug Administration (FDA) and used widely for the treatment of acetaminophen (paracetamol) overdose. It is also approved for use in conditions with abnormal viscid or thickened mucous secretions such as pneumonia, bronchitis, tracheobronchitis, cystic fibrosis, post-traumatic chest conditions and before diagnostic bronchoscopy to help with mucus plugging. NAC is also available over the counter as a supplement.

[0065] In some embodiments of the combinations herein, the antioxidant is> "pharmaceutically acceptable salt thereof. In some embodiments, the antioxidant is N-acetyl-L-Cysteine (NAC) or (2R)-2-acetamido-3-sulfanylpropanoic acid. In some embodiments of the combinations herein, the antioxidant is about 600 mg, about 1200 mg, or about 1800 mg of the total combination mass. In some embodiments, the antioxidant is about 1-2000 mg of the total combination mass.

[0066] In some embodiments of the combinations herein, the combinations comprise: canagliflozin and N-acetyl-L-Cysteine; canagliflozin and 4-hydroxy-2,2,6,6-tetramethylpiperidin-1-oxyl; canagliflozin and one of SA-2, SA-9, SA-10, SA-21, SA-23, or SA-24, or a pharmaceutically acceptable salt thereof; dapagliflozin and N-acetyl-L-Cysteine; dapagliflozin and1960197.000214-hydroxy-2,2,6,6-tetramethylpiperidin- 1-oxyl; dapagliflozin and one of SA-2, SA-9, SA-10, SA-21, SA-23, or SA-24, or a pharmaceutically acceptable salt thereof; empagliflozin and N-acetyl-L-Cysteine; empagliflozin and 4-hydroxy-2,2,6,6-tetramethylpiperidin-1-oxyl; empagliflozin and one of SA-2, SA-9, SA-10, SA-21, SA-23, or SA-24, or a pharmaceutically acceptable salt thereof; ertugliflozin and N-acetyl-L-Cysteine; ertugliflozin and 4-hydroxy-2,2,6,6-tetramethylpiperidin-1-oxyl; ertugliflozin and one of SA-2, SA-9, SA-10, SA-21, SA-23, or SA-24, or a pharmaceutically acceptable salt thereof; remogliflozin etabonate and N-acetyl-L-Cysteine; remogliflozin etabonate and 4-hydroxy-2,2,6,6-tetramethylpiperidin-1-oxyl; or remogliflozin etabonate and one of SA-2, SA-9, SA-10, SA-21, SA-23, or SA-24, or a pharmaceutically acceptable salt thereof.

[0067] In some embodiments of the combinations herein, the combinations comprise: Canagliflozin and NAC; Canagliflozin and TEMPOL; Canagliflozin and TUDCA; Dapagliflozin and NAC; Dapagliflozin and TEMPOL; Dapagliflozin and TUDCA; Empagliflozin and NAC; Empagliflozin and TEMPOL; Empagliflozin and TUDCA; Ertugliflozin and NAC; Ertugliflozin and TEMPOL; Ertugliflozin and TUDCA; Remogliflozin etabonate and NAC; Remogliflozin etabonate and TEMPOL; or Remogliflozin etabonate and TUDCA.

[0068] In some embodiments of the combinations herein, the combinations comprise: Canagliflozin and N-acetyl-L-Cysteine; Canagliflozin and 4-hydroxy-2,2,6,6-tetramethylpiperidin-1-oxyl; Canagliflozin and or Tauroursodeoxycholic acid; Dapagliflozin and N-acetyl-L-Cysteine; Dapagliflozin and 4-hydroxy-2,2,6,6-tetramethylpiperidin-1-oxyl; Dapagliflozin and or Tauroursodeoxycholic acid; Empagliflozin and N-acetyl-L-Cysteine; Empagliflozin and 4-hydroxy-2,2,6,6-tetramethylpiperidin-1-oxyl; Empagliflozin and or Tauroursodeoxycholic acid; Ertugliflozin and N-acetyl-L-Cysteine; Ertugliflozin and 4-hydroxy-2,2,6,6-tetramethylpiperidin-1-oxyl; Ertugliflozin and or Tauroursodeoxycholic acid; Remogliflozin etabonate and N-acetyl-L-Cysteine; Remogliflozin etabonate and 4-hydroxy-2,2,6,6-tetramethylpiperidin-1-oxyl; or Remogliflozin etabonate and or Tauroursodeoxycholic acid.

[0069] In some embodiments of the combinations herein, the combinations further comprise 4-hydroxy-2,2,6,6-tetramethylpiperidin-1-oxyl (TEMPOL).

[0070] In some embodiments of the combinations herein, the combinations comprise: Canagliflozin, NAC, and TEMPOL; Canagliflozin, TUDCA, and TEMPOL; Dapagliflozin, NAC, and TEMPOL; Dapagliflozin, TUDCA, and TEMPOL; Empagliflozin, NAC, and TEMPOL; Empagliflozin, TUDCA, and TEMPOL; Ertugliflozin, NAC, and TEMPOL; Ertugliflozin, TUDCA, and TEMPOL; Remogliflozin etabonate, NAC, and TEMPOL; or Remogliflozin etabonate, TUDCA, and TEMPOL.1960197.00021

[0071] In some embodiments of the combinations herein, the combinations comprise: Canagliflozin, N-acetyl-L-Cysteine, and 4-hydroxy-2,2,6,6-tetramethylpiperidin-1-oxyl; Canagliflozin, Tauroursodeoxycholic acid, and 4-hydroxy-2,2,6,6-tetramethylpiperidin-1-oxyl; Dapagliflozin, N-acetyl-L-Cysteine, and 4-hydroxy-2,2,6,6-tetramethylpiperidin-1-oxyl; Dapagliflozin, Tauroursodeoxycholic acid, and 4-hydroxy-2,2,6,6-tetramethylpiperidin-1-oxyl; Empagliflozin, N-acetyl-L-Cysteine, and 4-hydroxy-2,2,6,6-tetramethylpiperidin-1-oxyl; Empagliflozin, Tauroursodeoxycholic acid, and 4-hydroxy-2,2,6,6-tetramethylpiperidin-1-oxyl; Ertugliflozin, N-acetyl-L-Cysteine, and 4-hydroxy-2,2,6,6-tetramethylpiperidin-1-oxyl; Ertugliflozin, Tauroursodeoxycholic acid, and 4-hydroxy-2,2,6,6-tetramethylpiperidin-1-oxyl; Remogliflozin etabonate, N-acetyl-L-Cysteine, and 4-hydroxy-2,2,6,6-tetramethylpiperidin-1-oxyl; or Remogliflozin etabonate, Tauroursodeoxycholic acid, and 4- hydroxy-2, 2,6,6-tetramethylpiperidin-1-oxyl.

[0072] In some embodiments of the combinations herein, the combinations comprise: TEMPOL and NAC; TEMPOL and TUDCA; or TUDCA and NAC.

[0073] In some embodiments of the combinations herein, the combinations comprise dapagliflozin and TEMPOL.

[0074] In some embodiments of the combinations herein, the combinations comprise dapagliflozin and NAC.

[0075] In some embodiments of the combinations herein, the combinations comprise remogliflozin etabonate and TEMPOL.

[0076] In some embodiments of the combinations herein, the combinations comprise: remogliflozin etabonate and NAC.

[0077] In some embodiments of the combinations herein, the combinations comprise: empagliflozin and TEMPOL.

[0078] In some embodiments of the combinations herein, the combinations comprise: empagliflozin and NAC.

[0079] In some embodiments of the combinations herein, the combinations comprise: ertugliflozin and TEMPOL.

[0080] In some embodiments of the combinations herein, the combinations comprise: ertugliflozin and NAC.1960197.00021

[0081] In some embodiments of the combinations herein, the combinations comprise: canagliflozin and TEMPOL.

[0082] In some embodiments of the combinations herein, the combinations comprise: canagliflozin and NAC.

[0083] In some embodiments of the combinations herein, the combinations comprise: at least two of TEMPOL and a TEMPOL hybrid.

[0084] In some embodiments of the combinations herein, the combinations comprise: 4-hydroxy-2,2,6,6-tetramethylpiperidin-1-oxyl and N-acetyl-L-Cysteine; 4-hydroxy-2, 2,6,6-tetramethylpiperidin-1-oxyl and Tauroursodeoxycholic acid; orTauroursodeoxycholic acid and N-acetyl-L-Cysteine.

[0085] In some embodiments of the combinations herein, the combination is a mixture composition, such as an admixture composition, the active pharmaceutical ingredients, such as the SGLT2 inhibitor and the antioxidant, being formulated in the same mixture. In some embodiments of the combinations herein, the active pharmaceutical ingredients, such as the SGLT2 inhibitor and the antioxidant, are formulated in separate compositions, for example is a kit which may include instructions for therapeutic use or administration of the combination.

[0086] In some embodiments of the combinations herein, the combination is a solid dosage form.

[0087] In some embodiments of the combinations herein, the combination is a liquid dosage form.

[0088] In some embodiments of the combinations herein, the combination is a pharmaceutical composition further comprising a pharmaceutically acceptable carrier. In some embodiments of the combinations herein, the combination is a set of pharmaceutical compositions, one (e.g., a first) pharmaceutical composition comprising an SGLT2 inhibitor and further comprising a (e.g., a first) pharmaceutically acceptable carrier, and another (e.g., a second) pharmaceutical composition comprising an antioxidant inhibitor and further comprising a (e.g., a second) pharmaceutically acceptable carrier. In some embodiments of the combinations herein, the combination is a set of pharmaceutical compositions, one (e.g., a first) pharmaceutical composition comprising a first antioxidant and further comprising a (e.g., a first) pharmaceutically acceptable carrier, and another (e.g., a second) pharmaceutical composition comprising a second antioxidant inhibitor and further comprising a (e.g., a second) pharmaceutically acceptable carrier,1960197.00021optionally including a third pharmaceutical composition comprising a third antioxidant and further comprising a (e.g., a third) pharmaceutically acceptable carrier.Kits

[0089] In some embodiments, provided herein are packaged combinations, compositions, or dosage forms, comprising a container holding a therapeutically effective amount of a combination herein, and instructions for their use in accordance with one or more of the methods provided herein.

[0090] Such combinations and associated materials can be finished as a commercial product by the usual steps performed in the present field, for example by appropriate sterilization and packaging steps. For example, the material can be treated by UV / vis irradiation (200-500 nm), for example using photo-initiators with different absorption wavelengths (for example, Irgacure 184, 2959), preferably water-soluble initiators (for example, Irgacure 2959). Such irradiation is usually performed for an irradiation time of 1-60 min, but longer irradiation times may be applied, depending on the specific method. The material according to the present disclosure can be finally sterile wrapped so as to retain sterility until use and packaged (for example, by the addition of specific product information leaflets) into suitable containers (boxes, etc.).

[0091] According to further embodiments, the compositions can also be provided in kit form combined with other components necessary for administration of the material to the patient. For example, combinations may be provided in the form of a kit where two or three components are to be administered using different routes of administration, where, for instance, one component is administered using one route of administration and the other component(s) is / are administered using (a) different route(s) of administration. In some embodiments, disclosed compositions are administered via oral, topical, or intravenous routes.

[0092] The kits may be designed in various forms based on the specific deficiencies they are designed to treat.Effects of Combinations

[0093] Combinations as disclosed herein can provide a treatment of inflammation-associated conditions, including metabolic dysfunction-associated steatotic liver disease (MASLD), metabolic dysfunction-associated steatohepatitis (MASH), inflammatory bowel disease (IBD), Crohn’s disease (CD), Ulcerative Colitis (UC), glaucoma, macular degeneration (MD), and diabetic retinopathy, which can be synergistic.1960197.00021

[0094] Metabolic dysfunction-associated steatotic liver disease (MASLD)

[0095] The liver is the largest organ in the body. It helps the body digest food, store energy, and remove poisons. Fatty liver disease (FLD) is a condition in which fat builds up in the liver. There are two main types differentiated by cause:Alcoholic fatty liver disease (ALD), also called alcoholic steatohepatitis (AS); and Metabolic dysfunction-associated steatotic liver disease (MASLD), also known as Nonalcoholic fatty liver disease (NAFLD).

[0096] These two types can progress through subsequent stages of increasing severity to cirrhosis.

[0097] While Alcoholic fatty liver disease (ALD) is associated with heavy alcohol use, Metabolic dysfunction-associated steatotic liver disease (MASLD) is a chronic liver disease associated with metabolic problems (e.g., diabetes, obesity). Both forms are inflammatory. Metabolic dysfunction-associated steatotic liver disease (MASLD) can vary in severity, and ranges from the hepatic steatosis (or fatty liver) to Metabolic Dysfunction-Associated Steatohepatitis (MASH: formerly known as Nonalcoholic steatohepatitis (NASH). MASH is a severe liver condition resulting from liver fat buildup triggering chronic inflammation which damages the liver, which can progress to cirrhosis and liver cancer.

[0098] In addition to alcohol and metabolic risk factors, chemotherapy can also promote the development of FLD. Numerous cancer drugs can cause blockage of the central and sublobular veins in the liver resulting in sinusoidal obstruction syndrome (SOS) and other liver complications, such as higher than normal liver enzymes and increased bilirubin levels. This can lead to toxicity and liver dysfunction. During chemotherapy, up to 85% of patients develop liver steatosis and this becomes more serious if accompanied by increased bilirubin levels. Together, all of this can be a sign of liver inflammation, which creates a significant risk of developing FLD and increases apoptosis.

[0099] Because the liver is the central organ of intermediate metabolism, metabolic detoxification, and excretion of waste products, it becomes essential to have, as close to possible, normally functioning hepatocytes in order to properly administer chemotherapy.

[0100] To this end, TUDCA and UDCA have been shown to exert protective effects on the liver by decreasing apoptosis and interfering with the mitochondrial pathway of cell death, protecting liver enzymes and bilirubin, and significantly inhibiting reactive oxygen species.1960197.00021

[0101] Liver antioxidant capacity is dependent on glutathione production to prevent free radical formation, and it is known that N-acetyl-L-Cysteine (NAC) produces healthy glutathione levels, promoting normal liver function. Additionally, NAC is a powerful antioxidant that protects cells from oxidative stress. Because chemotherapy can have long term effects (cognition, hearing, heart, lung, blood, nerve, and reproductive damage), dual therapy may allow the appropriate management to reduce morbidity and mortality. In addition to TUDCA, NAC has been shown to help with detoxification of kidney and liver damage, may improve cognitive health, may help relieve symptoms of respiratory conditions, may improve fertility in men and women, and may stabilize blood sugar.

[0102] As to FLD, interest in bile acids (BA) arose from the discovery of their signaling properties and ability to regulate the activity of many genes through the orphan nuclear receptor (Farnesoid X Receptor, RXR). FXR agonists have shown potential as treatment for primary biliary cirrhosis and nonalcoholic steatohepatitis.

[0103] The gut-liver axis is associated with progression of NAFLD. Therefore, targeting the gut-liver axis with bile acid-based combination drug should prove beneficial in the treatment of NAFLD. Studies have shown that TUDCA fulfills the criteria. TUDCA treatment markedly reduces high fat diet-induced NAFLD in mice. In addition, to its commonly accepted protective effect of ER stress, TUDCA attenuates gut inflammation, improves the intestinal barrier function, decreases intestinal fat transport, and modulates the intestinal microbiota composition.

[0104] There are indications that TUDCA could reduce the severity of NAFLD and MASH by reduction of liver inflammation. TUDCA would be used to protect the liver cells by downregulating the inflammatory cascade, reducing the ROS, inhibiting apoptosis, reducing ER stress, and stabilizing the UPR.

[0105] TUDCA alone has been shown to attenuate progression of HFD induced NAFLD in mice by ameliorating gut inflammation, improving intestinal barrier protection, decreasing intestinal fat transport, and modulating intestinal flora. A combination drug to treat MASH will also play a significant role in reducing cardiovascular disease, chronic kidney disease and intra-hepatic and extra-hepatic malignancy, all of which have been associated with NAFLD.

[0106] Combinations of TUDCA and NAC and remogliflozin etabonate produce a broader spectrum of disease-fighting mechanisms than one would have alone. This should enable the combination to have a more positive impact in treatment of complex diseases than any single1960197.00021drug. MASH is an example. The disease mechanisms that lead to MASH and fibrosis are complex, involving both metabolic and inflammatory pathways, including:Insulin resistance and lipid metabolism;Lipid toxicity and immune activation;Cell death;Fibrogenesis, collagen turnover, and Endoplasmic reticulum (ER) stress.

[0107] Combinations of TUDCA and NAC and remogliflozin etabonate target both dysfunction and cell damage. Based on published literature, TUDCA and NAC and remogliflozin etabonate have complementary effects on many of the known biological mechanisms that are active in MASH.

[0108] Antioxidant activity plays a key role in protecting the liver, and NAC is a powerful antioxidant. NAC can confer benefits in disorders caused by oxidative stress (OS). For example, in mice fed high fat diets (HFD), NAC significantly reduced hepatic steatosis and metabolic disturbances as compared to normally fed mice. NAC totally restored normal morphology of hepatic tissue. Large lipid droplets and large adipocytes were shown to be higher in the HFD mice. Additionally, NAC treated mice showed improved glucose tolerance demonstrating that NAC could attenuate HFD-induced metabolic disturbance.

[0109] Combination treatments of TUDCA and NAC can be used to treat MASH, in cases with synergistic effects:1960197.000211960197.00021

[0110] Similarly, combination treatments of TUDCA and remogliflozin etabonate can be used to treat MASH, in cases with synergistic effects:1960197.00021

[0111] Further, combination treatments of NAC and remogliflozin etabonate can be used to treat MASH, in cases with synergistic effects:1960197.00021

[0112] Inflammatory Bowel Diseases

[0113] IBD is a global healthcare problem with an increasing incidence. IBD is a chronic inflammation of the gastrointestinal tract (Gl). IBDs are multifactorial disorders characterized by genetic susceptibility, immune cell overactivation, microbial gut dysbiosis and changes in intestinal barrier permeability. IBDs normally further classified as CD or UC which are differentiated by their location and by depth of involvement in the bowel wall. Both inflammatory conditions increase the risk of colon cancer.

[0114] In embodiments, the combination of TUDCA and NAC can provide synergistic effects in the treatment of IBD:1960197.000211960197.00021

[0115] CD is chronic inflammation in the gastrointestinal tract that spreads through the bowel wall. It may involve any part of the digestive tract although the small intestine, particularly the ileum, is the most commonly involved organ with the colon the next most commonly involved organ. CD is an autoimmune disease. With CD, once the inflammatory response is triggered by the immune system, it does not subside. Regarding CD treatments, decreased blood and mucosal levels of antioxidant vitamins A, C, E, and p-carotene have been reported in CD patients. It has been shown that antioxidants inhibit the production of inflammatory cytokines, such as IL-1 and TNFa, in the colonic mucosa of inflammatory bowel disease patients including those with CD. Further, TUDCA decreases inflammatory cytokines, including TNF-alpha, induces resolution of ER stress in intestinal epithelial cells and improves the function of the tight junction, lipid transport, and gut microbiota.

[0116] UC is a type of inflammatory bowel disease along with CD and microscopic colitis. It is a long-term condition that results in inflammation and ulcers of the colon and rectum. The primary symptoms of active disease are abdominal pain and diarrhea mixed with blood. Weight loss, fever, and anemia may also occur. Often, symptoms come on slowly and can range from mild to severe. Symptoms typically occur intermittently with periods of no symptoms between flares. Complications may include abnormal dilation of the colon, inflammation of the eye, joints, or liver, and colon cancer.

[0117] Combinations as disclosed herein can provide a synergistic treatment effect by combining the following effects, including synergistic effects, for example in the treatment of UC and CD:1960197.000211960197.00021

[0118] Glaucoma / Macular Degeneration I Diabetic Retinopathy

[0119] Glaucoma is a group of eye diseases that result in damage to the optic nerve (or retina) and cause vision loss. The most common type is open-angle (wide angle, chronic simple) glaucoma, in which the drainage angle for fluid within the eye remains open, with less common types including closed-angle (narrow angle, acute congestive) glaucoma and normal-tension glaucoma. Open-angle glaucoma develops slowly over time and there is no pain. Peripheral vision may begin to decrease, followed by central vision, resulting in blindness if not treated.

[0120] Glaucoma is characterized by damage of the optic nerve and progressive degeneration of retinal ganglion cells (RGCs) which are critical elements for vision loss. Current glaucoma therapies target reduction in intraocular pressure (IOP), but since RGC death is the cause of irreversible vision loss, neuroprotection may be a good strategy for glaucoma treatment. Oxidative stress is an important risk factor in human glaucoma and consistently, the plasma levels of glutathione (GSH), an antioxidant, is decreased in glaucoma patients.

[0121] Oxidative stress induced signaling for neuroinflammation in glaucoma includes the stimulation of a transcriptional program for inflammatory mediators, such as IL-1, IL-2, IFN-y and TNFa. The ROS master transcriptional regulator of cytokine production, namely nuclear factorkappa beta (NFKP) is upregulated in human glaucoma and animal models. Results in C57BL / 6J mice with experimentally induced glaucoma showed that tempol treatment decreased neuroinflammation in the ocular hypertensive retina and optic nerve. It should be noted that TEMPOL is blood-brain barrier permeable and can readily access the intracellular compartment.1960197.00021

[0122] N-acetyl cysteine (NAC) has been shown to have a positive (protective) effect on primary cultures of human retinal pigment epithelium (RPE) from patients with AMD. NAC protects against oxidative stress by blocking excessive ROS accumulation and preventing both H2O2 induced cell death and GSH depletion in RPE from both positive and negative AMD donors. NAC also improved basal mitochondrial function (ATP) in both groups of cells. Strong experimental evidence supports the idea that mitochondrial damage is one of the key events driving AMD pathology.

[0123] Several beneficial effects specific for AMD RPE include reduction in basal ROS, an increase in basal GSH content and greater NAC protection after oxidation. It should be noted that RPE are adjacent to the choriocapillaris, the main source of oxygen for the outer retina, placing them in a highly oxidative environment. Also, the oxidizing environment within the RPE are the ROS generated as a product of the reaction of light with abundant photosensitizers (lipofuscin and melanin). The results support the relevance of NAC as a possible therapeutic for AMD taking into consideration the importance of maintaining RPE mitochondrial function for overall retinal health.

[0124] It should also be noted that in a mouse model of photo-induced retinal degeneration, intraperitoneal injection of NAC suppressed oxidation and ER stresses, while inhibiting ROS accumulation in the Balb / c mouse retina. Additionally, in a murine dry eye study, eye drop administration of NAC diminished the levels of ROS and inflammasome signaling. These studies also support the fact that NAC treatment reduces ROS and improves cell viability. In another mouse study, NAC was effective in protecting the retina from oxidative damage when applied topically to the eye. This was shown in rd 10 + / + mice, a model of retinitis pigmentosa. This has important implications in that when NAC is applied to the cornea, it is able to penetrate to the posterior segment and protect the retina.

[0125] NAC has a long history of successful use in multiple conditions where elevated ROS induces pathology. NAC has also been shown to have a protective effect on retinal degeneration in a mouse model of normal tension glaucoma (NTG). In EAAC1 KO mice (excitatory amino-acid carrier 1) oxidative stress and autophagy were suppressed with increased glutathione levels by NAC treatment. NAC prevented the decline of retinal function and was shown to be neuroprotective. NAC treatment also protected retinal ganglion cells (RGC) from NTG-like neurodegeneration. EAAC1 is expressed in retinal neurons including RGC. EAAC1 transports not only extracellular glutamate, but also cysteine, which is an important substrate for glutathione (GSH) synthesis, into neural cells. GSH has a strong protective role against oxidative stress as1960197.00021an antioxidant in the retina. Oxidative stress is one of the pathogenic factors for glaucoma. The plasma level of GSH is decreased in primary open angle glaucoma including NTG patients, supporting the fact that the mouse model is suitable for basic research of NTG. Therefore, targeting oxidative stress in the retina, combined with the treatment of IOP reduction, may be a therapeutic strategy to treat glaucoma.

[0126] Another bile acid receptor is transmembrane G-protein coupled receptor 5 (TGR5), which is widely distributed throughout the body. It has brought on new explorations of Bile Acid (BA)-based therapies and their extra-hepatic-homeostatic functions on lipid, glucose, and energy metabolism. This includes a number of ocular afflictions, including Macular degeneration (MD).

[0127] Macular degeneration damages the macula, which provides sharp, central vision. The macula is the most sensitive part of the retina. It is located at the back of the eye. The retina turns light into electrical signals and then sends them through the optic nerve to the brain, where they are translated into the images we see. There are two forms of macular degeneration:Dry macular degeneration. Most people with macular degeneration have this type. The cells of the macula slowly break down. This produces blurring at first, then blank spots in the eye's central vision. In the beginning, the symptoms are subtle, then become more noticeable. Some cases of dry macular degeneration progress to the more serious wet macular degeneration; andWet macular degeneration. Everyone with wet macular degeneration starts out with the dry form. At some point, new blood vessels begin to grow beneath the retina. The new vessels leak blood and fluid into the macula, causing scarring. Wet macular degeneration can cause rapid loss of vision over days to weeks and continued loss of vision over time.

[0128] TUDCA has recently been shown to block apoptosis following cellular injury in several models of neurodegeneration and damage, including models of retinal degeneration. The mechanism of action includes stabilizing the mitochondrial membrane, inhibiting apoptosis, and the prevention of endoplasmic reticulum (ER) stress.

[0129] Both mouse and rat optic crush models have been used to induce retinal ganglion cell (RCG) death. The loss of RGCs occurs in a way that is comparable to glaucoma (highly acute glaucoma model). TUDCA treatment has been used in these models with similar positive results. Systemic treatment with TUDCA significantly enhanced RCGs survival and suppressed apoptosis following optic nerve crush. In glaucoma, RCGs die in at least three ways: mechanical damage to the axon, vascular insufficiency and exocytotoxic damage. The surgical crush mimics the1960197.00021mechanical injury to the RCG axons exiting the eye and the indirect partial occlusion of the central retinal vein (which travels the optic nerve bundle) mimics glaucomatous vascular insufficiency. The exocytotoxic injury found in glaucoma is also mimicked in the optic nerve crush model, as the crush elevates both intraocular glutamate and aspartate levels.

[0130] Another model that causes corneal and retinal damage is the ocular alkali burn model (OAB). It is one of the most severe ophthalmic emergencies and is responsible for 6.9% to 13.2% of ocular injuries. In the OAB model, treatment with TUDCA was shown to inhibit ocular inflammation and protect the cornea and retina from injury. The healing and preservative action of TUDCA is even more effective in combination with TEMPOL.

[0131] Diabetic retinopathy is a chronic condition that occurs when high blood sugar levels damage the blood vessels in the retina, the light-sensitive tissue at the back of the eye. At first, diabetic retinopathy might cause no symptoms or only mild vision problems. But it can lead to blindness.

[0132] The condition can develop in anyone who has type 1 or type 2 diabetes. The longer one has diabetes and the less controlled their blood sugar is, the more likely they are to develop this eye complication.

[0133] Considering the mechanism of action and the current experimental evidence, the combination of TUDCA and NAC may very well play an important role in the treatment of glaucoma, MD, and diabetic retinopathy; for example, by combining the following effects, which can be synergistic:1960197.00021

[0134] Similarly, combination treatments of TUDCA and TEMPOL / TEMPOL hybrids can be used to treat glaucoma, MD, and diabetic retinopathy, and in cases provide synergistic effects:1960197.00021

[0135] Similarly, combination treatments of NAC and TEMPOL / TEMPOL hybrids can be used to treat glaucoma, MD, and diabetic retinopathy, and in cases provide synergistic effects:1960197.00021I Blood / brain barrier permeable

[0136] Further embodiments can comprise treatments of the conditions in the following Table using disclosed combinations, in some cases with synergistic effects:Methods

[0137] The combinations disclosed herein are useful in treating a number of diseases, including metabolic dysfunction-associated steatotic liver disease (MASLD), metabolic dysfunction-associated steatohepatitis (MASH), inflammatory bowel disease (IBD; including Crohn’s Disease (CD) and ulcerative colitis (UC)) macular degeneration (MD), glaucoma, and diabetic retinopathy.1960197.00021

[0138] Thus, in some embodiments provided herein are methods of treating metabolic dysfunction-associated steatotic liver disease (MASLD) in a subject in need thereof, comprising administration of a combination herein to the subject.

[0139] In some embodiments provided herein are methods of treating metabolic dysfunction-associated steatotic liver disease (MASLD) in a subject in need thereof, comprising administration of a combination comprising: a first compound, which is an SGLT2 inhibitor; and a second compound, which is an antioxidant, herein to the subject.

[0140] In some embodiments provided herein are methods of treating metabolic dysfunction-associated steatohepatitis (MASH) in a subject in need thereof, comprising administration of a combination herein to the subject.

[0141] In some embodiments provided herein are methods of treating metabolic dysfunction-associated steatohepatitis (MASH) in a subject in need thereof, comprising administration of a combination comprising: a first compound, which is an SGLT2 inhibitor; and a second compound, which is an antioxidant, herein to the subject.

[0142] In some embodiments provided herein are methods of treating fatty liver disease (FLD) in a subject in need thereof, comprising administration of a combination herein to the subject.

[0143] In some embodiments provided herein are methods of treating fatty liver disease (FLD) in a subject in need thereof, comprising administration of a combination comprising: a first compound, which is an SGLT2 inhibitor; and a second compound, which is an antioxidant, herein to the subject.

[0144] In some embodiments provided herein are methods of treating inflammatory bowel disease (IBD) in a subject in need thereof, comprising administration of a combination herein to the subject. In some embodiments, the inflammatory bowel disease is Crohn’s disease (CD) or Ulcerative Colitis (UC). In some embodiments provided herein are methods of Crohn’s disease in a subject in need thereof, comprising administration of a combination herein to the subject.

[0145] In some embodiments provided herein are methods of treating inflammatory bowel disease (IBD) in a subject in need thereof, comprising administration of a combination comprising: a first compound, which is TUDCA; and a second compound, which is an antioxidant, herein to the subject.1960197.00021

[0146] In some embodiments provided herein are methods of treating Ulcerative Colitis in a subject in need thereof, comprising administration of a combination herein to the subject.

[0147] In some embodiments provided herein are methods of treating Ulcerative Colitis in a subject in need thereof, comprising administration of a combination comprising: a first compound, which is TUDCA; and a second compound, which is an antioxidant, herein to the subject.

[0148] In some embodiments provided herein are methods of treating Crohn’s disease in a subject in need thereof, comprising administration of a combination herein to the subject.

[0149] In some embodiments provided herein are methods of treating Crohn’s disease in a subject in need thereof, comprising administration of a combination comprising: a first compound, which is TUDCA; and a second compound, which is an antioxidant, herein to the subject.

[0150] In some embodiments provided herein are methods of treating macular degeneration in a subject in need thereof, comprising administration of a combination herein to the subject.

[0151] In some embodiments provided herein are methods of treating macular degeneration in a subject in need thereof, comprising administration of a combination comprising: a first compound, which is TUDCA; and a second compound, which is an antioxidant, herein to the subject.

[0152] In some embodiments provided herein are methods of treating glaucoma in a subject in need thereof, comprising administration of a combination herein to the subject.

[0153] In some embodiments provided herein are methods of treating diabetic retinopathy in a subject in need thereof, comprising administration of a combination herein to the subject.

[0154] In some embodiments of the methods provided herein, a therapeutically effective amount of the combination is administered to the subject.

[0155] In some embodiments provided herein are methods of administering a combination to a subject, wherein the combination is a combination provided herein.

[0156] In some embodiments of the methods provided herein are methods of administering a therapeutically effective amount of the combination as provided herein.

[0157] In some embodiments of the methods provided herein are methods of orally administering a combination to a subject, wherein the combination is a combination provided herein.1960197.00021

[0158] In some embodiments provided herein are methods of treating metabolic dysfunction-associated steatotic liver disease (MASLD) in a subject in need thereof, comprising administration of an SGLT2 inhibitor to the subject.

[0159] In some embodiments provided herein are methods of treating metabolic dysfunction-associated steatohepatitis (MASH), in a subject in need thereof, comprising administration of an SGLT2 inhibitor to the subject.

[0160] In some embodiments of the methods provided herein, the SGLT2 inhibitor is dapagliflozin, remogliflozin etabonate, bexagliflozin, canagliflozin, empagliflozin, enavogliflozin ertugliflozin, henagliflozin, ipragliflozin, luseogliflozin, rongliflozin, sotagliflozin, or tofogliflozin, or a pharmaceutically acceptable salt thereof. In some embodiments of the methods provided herein, the SGLT2 inhibitor is dapagliflozin or remogliflozin etabonate.

[0161] In some embodiments provided herein are methods of treating metabolic dysfunction-associated steatotic liver disease (MASLD) in a subject in need thereof, comprising administration of TEMPOL or a TEMPOL hybrid to the subject.

[0162] In some embodiments provided herein are methods of treating metabolic dysfunction-associated steatohepatitis (MASH), in a subject in need thereof, comprising administration of TEMPOL or a TEMPOL hybrid.to the subject.

[0163] In some embodiments provided herein TUDCA can be used in combination with NAC for treating UC.

[0164] In some embodiments provided herein are methods of using the combinations provided herein for the manufacture of a medicament for the treatment of metabolic dysfunction-associated steatotic liver disease (MASLD).

[0165] In some embodiments provided herein are methods of using the combinations provided herein for the manufacture of a medicament for the treatment of metabolic dysfunction-associated steatohepatitis (MASH).

[0166] In some embodiments provided herein are methods of using the combinations provided herein for the manufacture of a medicament for the treatment of inflammatory bowel disease.

[0167] In some embodiments provided herein are methods of using the combinations provided herein for the manufacture of a medicament for the treatment of Crohn’s disease.1960197.00021

[0168] In some embodiments provided herein are methods of using the combinations provided herein for the manufacture of a medicament for the treatment of Ulcerative Colitis.

[0169] In some embodiments provided herein are methods of using the combinations provided herein for the manufacture of a medicament for the treatment of diabetic retinopathy.

[0170] In some embodiments provided herein are methods of using the combinations provided herein for the manufacture of a medicament for the treatment of glaucoma.

[0171] In some embodiments provided herein are methods of using the combinations provided herein for the manufacture of a medicament for the treatment of macular degeneration.

[0172] In some embodiments provided herein are methods of treating metabolic dysfunction-associated steatotic liver disease (MASLD) in a subject in need thereof, comprising administration of a combination to the subject, wherein the combination comprises one of dapagliflozin and NAC, dapagliflozin and TEMPOL, dapagliflozin and a TEMPOL hybrid, remogliflozin etabonate and NAC, remogliflozin etabonate and TEMPOL, remogliflozin etabonate and a TEMPOL hybrid, TEMPOL and TUDCA, or a TEMPOL hybrid and TUDCA, and wherein the dapagliflozin, when present, is present in the combination at from about 5 mg to about 10 mg (e.g., about 5 mg or about 10 mg), the remogliflozin etabonate, when present, is present in the combination at from about 100 mg to about 250 mg (e.g., about 100 mg or about 250 mg), the NAC, when present, is present in the combination at from about 300 mg to about 600 mg, from about 600 mg to about 900 mg, from about 900 mg to about 1200 mg, or from about 1200 mg to about 1800 mg (e.g., about 300 mg, about 600 mg, about 900 mg, about 1200 mg, or about 1800 mg), the TEMPOL, when present, is present in the combination at from about 400 mg to about 600 mg, from about 600 mg to about 800 mg, from about 800 mg to about 900 mg, from about 900 mg to about 1200 mg, from about 1200 mg to about 1600 mg, or from about 1600 mg to about 1800 mg (e.g., about 400 mg, about 600 mg, about 800 mg, about 900 mg, about 1200 mg, about 1600 mg, or about 1800 mg), the TEMPOL hybrid, when present, is present in the combination at from about 10 mg to about 100 mg, from about 100 mg to about 400 mg, from about 400 mg to about 600 mg, from about 600 mg to about 800 mg, from about 800 mg to about 900 mg, from about 900 mg to about 1200 mg, from about 1200 mg to about 1600 mg, or from about 1600 mg to about 1800 mg (e.g., about 10 mg, about 20 mg, about 100 mg, about 200 mg, about 400 mg, about 600 mg, about 800 mg, about 900 mg, about 1200 mg, about 1600 mg, or about 1800 mg), and the TUDCA, when present, is present in the combination at from about 300 mg to about 600 mg, from about 600 mg to about 900 mg, from about 900 mg to about 1200 mg, or from about 1200 mg to about 1800 mg (e.g., about 300 mg, about 600 mg, about 900 mg, about 1200 mg, or about 1800 mg).1960197.00021wherein the NAC, when administered, is administered orally twice a day, the TUDCA, when administered, is administered orally twice a day, the dapagliflozin, when administered, is administered orally once a day, the remogliflozin etabonate, when administered, is administered orally twice a day, the TEMPOL, when administered, is administered once or twice a day, and the TEMPOL hybrid, when administered, is administered once or twice a day.

[0173] In some embodiments provided herein are methods of treating MASH in a subject in need thereof, comprising administration of a combination to the subject, wherein the combination comprises one of dapagliflozin and NAC, dapagliflozin and TEMPOL, dapagliflozin and a TEMPOL hybrid, remogliflozin etabonate and NAC, remogliflozin etabonate and TEMPOL, remogliflozin etabonate and a TEMPOL hybrid, TEMPOL and TUDCA, or a TEMPOL hybrid and TUDCA,wherein the dapagliflozin, when present, is present in the combination at about 5 mg or about 10 mg, the remogliflozin etabonate, when present, is present in the combination at about 100 mg or about 250 mg, the NAC, when present, is present in the combination at about 300 mg, about 600 mg, about 900 mg, about 1200 mg, or about 1800 mg, the TEMPOL, when present, is present in the combination at about 400 mg, about 600 mg, about 800 mg, about 900 mg, about 1200 mg, about 1600 mg, or about 1800 mg, the TEMPOL hybrid, when present, is present in the combination at about 400 mg, about 600 mg, about 800 mg, about 900 mg, about 1200 mg, about 1600 mg, or about 1800 mg, and the TUDCA, when present, is present in the combination at about 300 mg, about 600 mg, about 900 mg, about 1200 mg, or about 1800 mg, and wherein the NAC, when administered, is administered orally twice a day, the TUDCA, when administered, is administered orally twice a day, the dapagliflozin, when administered, is administered orally once a day, the remogliflozin etabonate, when administered, is administered orally twice a day, the TEMPOL, when administered, is administered once or twice a day, and the TEMPOL hybrid, when administered, is administered once or twice a day.

[0174] In some embodiments provided herein are methods of treating fatty liver disease (FLD) in a subject in need thereof, comprising administration of a combination to the subject, wherein the combination comprises one of dapagliflozin and NAC, dapagliflozin and TEMPOL, dapagliflozin and a TEMPOL hybrid, remogliflozin etabonate and NAC, remogliflozin etabonate and TEMPOL, remogliflozin etabonate and a TEMPOL hybrid, TEMPOL and TUDCA, or a TEMPOL hybrid and TUDCA,1960197.00021wherein the dapagliflozin, when present, is present in the combination at from about 5 mg to about 10 mg (e g., about 5 mg or about 10 mg), the remogliflozin etabonate, when present, is present in the combination at from about 100 mg to about 250 mg (e.g., about 100 mg or about 250 mg), the NAC, when present, is present in the combination at from about 300 mg to about 600 mg, from about 600 mg to about 900 mg, from about 900 mg to about 1200 mg, or from about 1200 mg to about 1800 mg (e.g., about 300 mg, about 600 mg, about 900 mg, about 1200 mg, or about 1800 mg), the TEMPOL, when present, is present in the combination at from about 400 mg to about 600 mg, from about 600 mg to about 800 mg, from about 800 mg to about 900 mg, from about 900 mg to about 1200 mg, from about 1200 mg to about 1600 mg, or from about 1600 mg to about 1800 mg (e.g., about 400 mg, about 600 mg, about 800 mg, about 900 mg, about 1200 mg, about 1600 mg, or about 1800 mg), the TEMPOL hybrid, when present, is present in the combination at from about 10 mg to about 100 mg, from about 100 mg to about 400 mg, from about 400 mg to about 600 mg, from about 600 mg to about 800 mg, from about 800 mg to about 900 mg, from about 900 mg to about 1200 mg, from about 1200 mg to about 1600 mg, or from about 1600 mg to about 1800 mg (e.g., about 10 mg, about 20 mg, about 100 mg, about 200 mg, about 400 mg, about 600 mg, about 800 mg, about 900 mg, about 1200 mg, about 1600 mg, or about 1800 mg), and the TUDCA, when present, is present in the combination at from about 300 mg to about 600 mg, from about 600 mg to about 900 mg, from about 900 mg to about 1200 mg, or from about 1200 mg to about 1800 mg (e.g., about 300 mg, about 600 mg, about 900 mg, about 1200 mg, or about 1800 mg), andwherein the NAC, when administered, is administered orally twice a day, the TUDCA, when administered, is administered orally twice a day, the dapagliflozin, when administered, is administered orally once a day, the remogliflozin etabonate, when administered, is administered orally twice a day, the TEMPOL, when administered, is administered once or twice a day, and the TEMPOL hybrid, when administered, is administered once or twice a day.

[0175] In some embodiments provided herein are methods of treating IBD in a subject in need thereof, comprising administration of a combination to the subject, wherein the combination comprises one of TUDCA and TEMPOL, TUDCA and a TEMPOL hybrid, or NAC and TUDCA, wherein the NAC, when present, is present in the combination at about 300 mg, about 600 mg, or about 900 mg, the TEMPOL, when present, is present in the combination at about 400 mg, about 600 mg, about 800 mg, about 900 mg, about 1200 mg, about 1600 mg, or about 1800 mg, the TEMPOL hybrid, when present, is present in the combination at about 400 mg, about 600 mg, about 800 mg, about 900 mg, about 1200 mg, about 1600 mg, or about 1800 mg, and the TUDCA,1960197.00021when present, is present in the combination at about 300 mg, about 600 mg, or about 900 mg, or about 1200 mg, or about 1800 mg,wherein the NAC, when administered, is administered orally twice a day, the TUDCA, when administered, is administered orally twice a day, and the TEMPOL, when administered, is administered once or twice a day.

[0176] In some embodiments provided herein are methods of treating UC in a subject in need thereof, comprising administration of a combination to the subject, wherein the combination comprises one of TUDCA and TEMPOL, TUDCA and a TEMPOL hybrid, or NAC and TUDCA, wherein the NAC, when present, is present in the combination at about 300 mg, about 600 mg, or about 900 mg, the TEMPOL, when present, is present in the combination at about 400 mg, about 600 mg, about 800 mg, about 900 mg, about 1200 mg, about 1600 mg, or about 1800 mg, the TEMPOL hybrid, when present, is present in the combination at about 400 mg, about 600 mg, about 800 mg, about 900 mg, about 1200 mg, about 1600 mg, or about 1800 mg, and the TUDCA, when present, is present in the combination at about 300 mg, about 600 mg, or about 900 mg, or about 1200 mg, or about 1800 mg,wherein the NAC, when administered, is administered orally twice a day, the TUDCA, when administered, is administered orally twice a day, and the TEMPOL, when administered, is administered once or twice a day.

[0177] In some embodiments provided herein are methods of treating Crohn’s disease in a subject in need thereof, comprising administration of a combination to the subject, wherein the combination comprises one of TUDCA and TEMPOL, TUDCA and a TEMPOL hybrid, or NAC and TUDCA,wherein the NAC, when present, is present in the combination at about 300 mg, about 600 mg, or about 900 mg, the TEMPOL, when present, is present in the combination at about 400 mg, about 600 mg, about 800 mg, about 900 mg, about 1200 mg, about 1600 mg, or about 1800 mg, the TEMPOL hybrid, when present, is present in the combination at about 400 mg, about 600 mg, about 800 mg, about 900 mg, about 1200 mg, about 1600 mg, or about 1800 mg, and the TUDCA, when present, is present in the combination at about 300 mg, about 600 mg, or about 900 mg, or about 1200 mg, or about 1800 mg,wherein the NAC, when administered, is administered orally twice a day, the TUDCA, when administered, is administered orally twice a day, and the TEMPOL, when administered, is administered once or twice a day.1960197.00021

[0178] In some embodiments provided herein are methods of treating macular degeneration in a subject in need thereof, comprising administration of a combination to the subject, wherein the combination comprises one of TUDCA and TEMPOL, TUDCA and a TEMPOL hybrid, or NAC and TUDCA,wherein the NAC, when present, is present in the combination at about 300 mg, about 600 mg, or about 900 mg, the TEMPOL, when present, is present in the combination at about 400 mg, about 600 mg, about 800 mg, about 900 mg, about 1200 mg, about 1600 mg, or about 1800 mg, the TEMPOL hybrid, when present, is present in the combination at about 400 mg, about 600 mg, about 800 mg, about 900 mg, about 1200 mg, about 1600 mg, or about 1800 mg, and the TUDCA, when present, is present in the combination at about 300 mg, about 600 mg, or about 900 mg, or about 1200 mg, or about 1800 mg,wherein the NAC, when administered, is administered orally twice a day, the TUDCA, when administered, is administered orally twice a day, and the TEMPOL, when administered, is administered once or twice a day.

[0179] In some embodiments of the methods herein, when the TEMPOL is administered with dapagliflozin, the TEMPOL is administered once a day. In some embodiment, when the TEMPOL is administered with remogliflozin etabonate, the TEMPOL is administered twice a day.

[0180] In some embodiments of the methods herein, the combination is administrated for a duration of about 2 weeks, about 4 weeks, about 8 weeks, about 12 weeks, about 16 weeks, about 2 weeks, or about 50 weeks. In some embodiments of the methods herein, the combination is administrated for a duration of up to about 50 weeks.

[0181] In some embodiments of the methods herein, the active pharmaceutical ingredients (e g., the SGLT2 inhibitors or the antioxidants) of the combinations are administered simultaneously, whether in a single composition or administered concurrently (e.g., within 60 minutes of one another) in separate compositions.

[0182] In some embodiments of the methods herein, the first compound and second compound are administered within 60 minutes of one another.Administration and dosage

[0183] Disclosed methods can comprise administration of combinations. Combinations can include administration of a single composition comprising combinations of antioxidants, or administration of multiple compositions, each comprising a single antioxidant. Disclosed methods1960197.00021can comprise administration of compositions in different forms. For example, in some embodiments, a liquid antioxidant composition can be administered with a solid composition, or a capsule can be administered with a powder or spray, etc.

[0184] The components of the combinations disclosed herein may be administered individually, i.e., sequentially in any order, or simultaneously. Simultaneous administration may be via any acceptable dosage form and route of administration. Sequential administration may be performed using individually packaged preparations. In one embodiment, oral dosage forms may be provided to the patent is a blister back having multiple individual composition in the same package.

[0185] In some embodiments of the methods herein, the combination is administered as a single composition, e.g., an admixture, such as an encapsulated powder or a pressed tablet (e.g., a solid tablet). In some embodiments of the methods herein, the combination is administered as an admixture composition.

[0186] In some embodiments of the methods herein, the combination is administered as multiple compositions, e.g., a dosage form comprising a first active pharmaceutical ingredient (e.g., an SGLT2 inhibitor) and a second dosage form comprising a second active ingredient (e.g., an antioxidant).

[0187] Disclosed combinations can be administered in any frequency that results in a therapeutic response. Disclosed methods can comprise use of a loading dose, an initial higher dose of a drug that can be given at the beginning of a course of treatment before dropping down to a lower maintenance dose.

[0188] In some embodiments, administration can be one, two, three, four, five, or more times a day. In some embodiments, the administration is once or twice daily. In some embodiments, the administration includes once daily administration (QD) of a combination herein. In some embodiments, the administration includes once daily administration (QD) of a combination herein and a separate once daily administration of an antioxidant herein. In some embodiments, the administration includes twice daily administration (BID) of a combination herein. In some embodiments, administration can be every other day, every third day, every fourth day, every fifth day, every sixth day, once per week, twice per month, monthly, and the like. In some embodiments of the methods herein, the administration comprises once or twice daily administration of a dosage form comprising the combination. In some embodiments, the administration is oral administration.

[0189] Disclosed combinations can further comprise a pharmaceutically acceptable carrier.1960197.00021

[0190] Disclosed combinations can comprise any pharmaceutically acceptable form, such as liquids as well as solid dosage forms including pills and tablets. In some embodiments, the solid dosage form can dissolve at or above a particular pH value, such as, for example, 7.0. In some embodiments, the combinations as described herein can comprise any appropriate form, for example liquids such as aqueous liquids, capsules, solids, nanoparticles, semi-solids, gels, extended-release forms such as implants, and the like.

[0191] As described above, administration of disclosed embodiments can be via a number of appropriate routes, such as:

[0192] Disclosed methods of treatment can comprise administration of a disclosed combination in the appropriate proportion.

[0193] In some embodiments comprising an SGLT2 inhibitor and an antioxidant, the relative proportion by weight of the two can be, for example, 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, 1:10, 1:11, 1:12, or the like. Further, the relative proportion by weight of the two can be expressed as A : B, wherein A and B can have values between 1 and 99% and the total percentage is equal to 100.

[0194] In some embodiments comprising two antioxidants, the relative proportion by weight of the two can be, for example, 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, 1:10, 1:11, 1:12, or the like. Further, the relative proportion by weight of the two can be expressed as A : B, wherein A and B can have values between 1 and 99% and the total percentage is equal to 100.

[0195] In some embodiments comprising remogliflozin etabonate and a single TEMPOL or TEMPOL hybrid, the relative proportion by weight between the remogliflozin etabonate and the TEMPOL / TEMPOL hybrid can be, for example, 1:1, 1:1.5, 1:2, 1:2.5, 1:3, 1:3.5, 1:4, 1:4.5, 1:5, 1:5.5, 1:6, 1:6.5, 1:7, 1:7.5, 1:8, 1:8.5, 1:9, 1:8.5, 1:10, 1:11, 1:12, orthe like.1960197.00021

[0196] In some embodiments, the ratio of remogliflozin etabonate to NAC is 1:9. In an embodiment, the ratio of remogliflozin etabonate to TUDCA is 1:9.

[0197] In some embodiments, the dose of the TEMPOL / TEMPOL hybrid is lower than that of TUDCA or NAC. For example, in some embodiments comprising a TEMPOL / TEMPOL hybrid and TUDCA or NAC, the relative proportion by weight of the two can be, for example, 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, 1:10, 1:11, 1:12, or the like. Further, the relative proportion by weight of the two can be expressed as A:B, wherein A and B can have values between 1 and 99% and the total percentage is equal to 100.

[0198] In some embodiments comprising three antioxidants, the relative proportion by weight of the three can be, for example, 1:1:1, 1:2:1, 1:3:1, or the like. Further, the relative proportion by weight of the two can be expressed as A:B:C, wherein A, B, and C can have values between 1 and 99% and the total percentage is equal to 100.

[0199] Disclosed methods of treatment can comprise administration of a disclosed combination in an appropriate dosage. For example, in disclosed embodiments, the dosage can comprise daily remogliflozin etabonate administration of a positive amount of remogliflozin etabonate, for example, less than about 2000 mg, less than about 1900 mg, less than about 1800 mg, less than about 1700 mg, less than about 1600 mg, less than about 1500 mg, less than about 1400 mg, less than about 1300 mg, less than about 1200 mg, less than about 1100 mg, less than about 1000 mg, less than about 900 mg, less than about 800 mg, less than about 700 mg, less than about 600 mg, less than about 500 mg, less than about 400 mg, less than about 300 mg, less than about 200 mg, less than about 100 mg, less than about 50 mg, or the like.

[0200] In some embodiments, the daily dose of remogliflozin etabonate can comprise between about 250 mg and 3000 mg, between about 500 mg and 2500 mg, between about 1000 mg and 2000 mg, or the like.

[0201] In some embodiments, the daily dose of remogliflozin etabonate can comprise about 5-35 mg / kg body weight, about 10-30 mg / kg body weight, about 15-25 mg / kg body weight, or the like.

[0202] In some embodiments, the daily dose of remogliflozin etabonate can comprise about 25 mg, 50 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg, 850 mg, 900 mg, 950 mg, 1000 mg, 1050 mg, 1100 mg, 1150 mg, 1200 mg, 1250 mg, 1300 mg, 1350 mg, 1400 mg, 1450 mg, 1500 mg,1960197.000211550 mg, 1600 mg, 1650 mg, 1700 mg, 1750 mg, 1800 mg, 1850 mg, 1900 mg, 1950 mg, 2000 mg, 2050 mg, 2100 mg, 2150 mg, 2200 mg, or the like.

[0203] In some embodiments, about 100 mg remogliflozin etabonate is administered twice a day.

[0204] In some disclosed, the dosage can comprise daily N-acetyl-L-Cysteine administration of a positive amount of N-acetyl-L-Cysteine, for example, less than about 3000 mg, less than about 2900 mg, less than about 2800 mg, less than about 2700 mg, less than about 2600 mg, less than about 2500 mg, less than about 2400 mg, less than about 2300 mg, less than about 2200 mg, less than about 2100 mg, less than about 2000 mg, less than about 1900 mg, less than about 1800 mg, less than about 1700 mg, less than about 1600 mg, less than about 1500 mg, less than about 1400 mg, less than about 1300 mg, less than about 1200 mg, less than about 1100 mg, less than about 1000 mg, less than about 900 mg, less than about 800 mg, less than about 700 mg, less than about 600 mg, less than about 500 mg, less than about 400 mg, less than about 300 mg, less than about 200 mg, less than about 100 mg, less than about 50 mg, or the like.

[0205] In some embodiments, the daily dose of N-acetyl-L-Cysteine can comprise between about 250 mg and 3000 mg, between about 500 mg and 2500 mg, between about 1000 mg and 2000 mg, or the like.

[0206] In some embodiments, the daily dose of N-acetyl-L-Cysteine can comprise about 5-35 mg / kg body weight, 10-30 mg / kg body weight, 15-25 mg / kg body weight, or the like.

[0207] In some embodiments, the daily dose of N-acetyl-L-Cysteine can comprise about 25 mg, 50 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg, 850 mg, 900 mg, 950 mg, 1000 mg, 1050 mg, 1100 mg, 1150 mg, 1200 mg, 1250 mg, 1300 mg, 1350 mg, 1400 mg, 1450 mg, 1500 mg, 1550 mg, 1600 mg, 1650 mg, 1700 mg, 1750 mg, 1800 mg, 1850 mg, 1900 mg, 1950 mg, 2000 mg, 2050 mg, 2100 mg, 2150 mg, 2200 mg, 2250 mg, 2300 mg, 2350 mg, 2400 mg, 2450 mg, 2500 mg, 2550 mg, 2600 mg, 2650 mg, 2700 mg, 2750 mg, 2800 mg, 2850 mg, 2900 mg, 2950 mg, 3000 mg, or the like.

[0208] In some embodiments, about 900 mg N-acetyl-L-Cysteine is administered twice a day.

[0209] In some embodiments, the dosage can comprise daily TEMPOL / TEMPOL hybrid administration of a positive amount of TEMPOL / TEMPOL hybrid, for example, less than about1960197.000213000 mg, less than about 2900 mg, less than about 2800 mg, less than about 2700 mg, less than about 2600 mg, less than about 2500 mg, less than about 2400 mg, less than about 2300 mg, less than about 2200 mg, less than about 2100 mg, less than about 2000 mg, less than about 1900 mg, less than about 1800 mg, less than about 1700 mg, less than about 1600 mg, less than about 1500 mg, less than about 1400 mg, less than about 1300 mg, less than about 1200 mg, less than about 1100 mg, less than about 1000 mg, less than about 900 mg, less than about 800 mg, less than about 700 mg, less than about 600 mg, less than about 500 mg, less than about 400 mg, less than about 300 mg, less than about 200 mg, less than about 100 mg, less than about 50 mg, or the like.

[0210] In some embodiments, the daily dose of TEMPOL / TEMPOL hybrid can comprise between about 250 mg and 3000 mg, between about 500 mg and 2500 mg, between about 1000 mg and 2000 mg, or the like.

[0211] In some embodiments, the daily dose of TEMPOL / TEMPOL hybrid can comprise about 5-35 mg / kg body weight, about 10-30 mg / kg body weight, about 15-25 mg / kg body weight, or the like.

[0212] In some embodiments, the daily dose of TEMPOL / TEMPOL hybrid can comprise about 25 mg, 50 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg, 850 mg, 900 mg, 950 mg, 1000 mg, 1050 mg, 1100 mg, 1150 mg, 1200 mg, 1250 mg, 1300 mg, 1350 mg, 1400 mg, 1450 mg, 1500 mg, 1550 mg, 1600 mg, 1650 mg, 1700 mg, 1750 mg, 1800 mg, 1850 mg, 1900 mg, 1950 mg, 2000 mg, 2050 mg, 2100 mg, 2150 mg, 2200 mg, 2250 mg, 2300 mg, 2350 mg, 2400 mg, 2450 mg, 2500 mg, 2550 mg, 2600 mg, 2650 mg, 2700 mg, 2750 mg, 2800 mg, 2850 mg, 2900 mg, 2950 mg, 3000 mg, or the like.

[0213] In some embodiments, about 900 mg TEMPOL / TEMPOL hybrid is administered twice a day, for example in a capsule. In some embodiments, the combination is formulated as a nanoparticle, such as nanoparticles comprising PLGA.

[0214] In some embodiments, the dosage can comprise daily Tauroursodeoxycholic acid administration of a positive amount of Tauroursodeoxycholic acid, for example, less than about 3000 mg, less than about 2900 mg, less than about 2800 mg, less than about 2700 mg, less than about 2600 mg, less than about 2500 mg, less than about 2400 mg, less than about 2300 mg, less than about 2200 mg, less than about 2100 mg, less than about 2000 mg, less than about 1900 mg, less than about 1800 mg, less than about 1700 mg, less than about 1600 mg, less than1960197.00021about 1500 mg, less than about 1400 mg, less than about 1300 mg, less than about 1200 mg, less than about 1100 mg, less than about 1000 mg, less than about 900 mg, less than about 800 mg, less than about 700 mg, less than about 600 mg, less than about 500 mg, less than about 400 mg, less than about 300 mg, less than about 200 mg, less than about 100 mg, less than about 50 mg, or the like.

[0215] In some embodiments, the daily dose of Tauroursodeoxycholic acid can comprise between about 250 mg and 3000 mg, between about 500 mg and 2500 mg, between about 1000 mg and 2000 mg, or the like.

[0216] In some embodiments, the daily dose of Tauroursodeoxycholic acid can comprise about 5-35 mg / kg body weight, about 10-30 mg / kg body weight, about 15-25 mg / kg body weight, or the like.

[0217] In some embodiments, the daily dose of Tauroursodeoxycholic acid can comprise 25 mg, 50 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg, 850 mg, 900 mg, 950 mg, 1000 mg, 1050 mg, 1100 mg, 1150 mg, 1200 mg, 1250 mg, 1300 mg, 1350 mg, 1400 mg, 1450 mg, 1500 mg, 1550 mg, 1600 mg, 1650 mg, 1700 mg, 1750 mg, 1800 mg, 1850 mg, 1900 mg, 1950 mg, 2000 mg, 2050 mg, 2100 mg, 2150 mg, 2200 mg, 2250 mg, 2300 mg, 2350 mg, 2400 mg, 2450 mg, 2500 mg, 2550 mg, 2600 mg, 2650 mg, 2700 mg, 2750 mg, 2800 mg, 2850 mg, 2900 mg, 2950 mg, 3000 mg, or the like.

[0218] In some embodiments, the administration can comprise twice daily administration. In other embodiments, each of the twice daily administration can comprise about 100 mg remogliflozin etabonate, about 900 mg NAC, and about 900 mg TUDCA. In some embodiments, the twice daily administration can comprise about 100 mg remogliflozin etabonate and about 900 mg TUDCA. In other embodiments, the twice daily administration can comprise about 100 mg remogliflozin etabonate and about 900 mg NAC.EXAMPLES1960197.00021

[0219] The following non-limiting Examples are provided for illustrative purposes only in order to facilitate a more complete understanding of representative embodiments. This example should not be construed to limit any of the embodiments described in the present Specification.Example 1

[0220] A disclosed combination comprising TUDCA and SA-2 in a 1:1 w / w ratio is administered to a patient with macular degeneration. The combination of antioxidants produces a synergistic treatment effect.Example 2

[0221] A disclosed combination comprising TUDCA and SA-9 in a 1:1 w / w ratio is administered to a patient with macular degeneration. The combination of antioxidants produces a synergistic treatment effect.Example 3

[0222] A disclosed combination comprising TUDCA and SA-10 in a 1:1 w / w ratio is administered to a patient with macular degeneration. The combination of antioxidants produces a synergistic treatment effect.Example 4

[0223] A disclosed combination comprising TUDCA and SA-21 in a 1:1 w / w ratio is administered to a patient with macular degeneration. The combination of antioxidants produces a synergistic treatment effect.Example 5

[0224] A disclosed combination comprising TUDCA and SA-23 in a 1:1 w / w ratio is administered to a patient with macular degeneration. The combination of antioxidants produces a synergistic treatment effect.Example 6

[0225] A disclosed combination comprising TUDCA and SA-24 in a 1:1 w / w ratio is administered to a patient with macular degeneration. The combination of antioxidants produces a synergistic treatment effect.Example 7

[0226] A disclosed combination comprising TUDCA and SA-2 in a 1:2 w / w ratio is administered to a patient with macular degeneration. The combination of antioxidants produces a synergistic treatment effect.1960197.00021Example 8

[0227] A disclosed combination comprising TUDCA and SA-9 in a 1:2 w / w ratio is administered to a patient with macular degeneration. The combination of antioxidants produces a synergistic treatment effect.Example 9

[0228] A disclosed combination comprising TUDCA and SA-10 in a 1:2 w / w ratio is administered to a patient with macular degeneration. The combination of antioxidants produces a synergistic treatment effect.Example 10

[0229] A disclosed combination comprising TUDCA and SA-21 in a 1:2 w / w ratio is administered to a patient with macular degeneration. The combination of antioxidants produces a synergistic treatment effect.Example 11

[0230] A disclosed combination comprising TUDCA and SA-23 in a 1:2 w / w ratio is administered to a patient with macular degeneration. The combination of antioxidants produces a synergistic treatment effect.Example 12

[0231] A disclosed combination comprising TUDCA and SA-24 in a 1:2 w / w ratio is administered to a patient with macular degeneration. The combination of antioxidants produces a synergistic treatment effect.Example 13

[0232] A disclosed combination comprising TUDCA and SA-2 in a 2:1 w / w ratio is administered to a patient with macular degeneration. The combination of antioxidants produces a synergistic treatment effect.Example 14

[0233] A disclosed combination comprising TUDCA and SA-9 in a 2:1 w / w ratio is administered to a patient with macular degeneration. The combination of antioxidants produces a synergistic treatment effect.Example 15

[0234] A disclosed combination comprising TUDCA and SA-10 in a 2:1 w / w ratio is administered to a patient with macular degeneration. The combination of antioxidants produces a synergistic treatment effect.1960197.00021Example 16

[0235] A disclosed combination comprising TUDCA and SA-21 in a 2:1 w / w ratio is administered to a patient with macular degeneration. The combination of antioxidants produces a synergistic treatment effect.Example 17

[0236] A disclosed combination comprising TUDCA and SA-23 in a 2:1 w / w ratio is administered to a patient with macular degeneration. The combination of antioxidants produces a synergistic treatment effect.Example 18

[0237] A disclosed combination comprising TUDCA and SA-24 in a 2:1 w / w ratio is administered to a patient with macular degeneration. The combination of antioxidants produces a synergistic treatment effect.Example 19

[0238] A disclosed combination comprising TUDCA and SA-2 in a 1:1 w / w ratio is administered to a patient with diabetic retinopathy. The combination of antioxidants produces a synergistic treatment effect.Example 20

[0239] A disclosed combination comprising TUDCA and SA-9 in a 1:1 w / w ratio is administered to a patient with diabetic retinopathy. The combination of antioxidants produces a synergistic treatment effect.Example 21

[0240] A disclosed combination comprising TUDCA and SA-10 in a 1:1 w / w ratio is administered to a patient with diabetic retinopathy. The combination of antioxidants produces a synergistic treatment effect.Example 22

[0241] A disclosed combination comprising TUDCA and SA-21 in a 1:1 w / w ratio is administered to a patient with diabetic retinopathy. The combination of antioxidants produces a synergistic treatment effect.Example 23

[0242] A disclosed combination comprising TUDCA and SA-23 in a 1:1 w / w ratio is administered to a patient with diabetic retinopathy. The combination of antioxidants produces a synergistic treatment effect.1960197.00021Example 24

[0243] A disclosed combination comprising TUDCA and SA-24 in a 1:1 w / w ratio is administered to a patient with diabetic retinopathy. The combination of antioxidants produces a synergistic treatment effect.Example 25

[0244] A disclosed combination comprising TUDCA and SA-2 in a 1:2 w / w ratio is administered to a patient with diabetic retinopathy. The combination of antioxidants produces a synergistic treatment effect.Example 26

[0245] A disclosed combination comprising TUDCA and SA-9 in a 1:2 w / w ratio is administered to a patient with diabetic retinopathy. The combination of antioxidants produces a synergistic treatment effect.Example 27

[0246] A disclosed combination comprising TUDCA and SA-10 in a 1:2 w / w ratio is administered to a patient with diabetic retinopathy. The combination of antioxidants produces a synergistic treatment effect.Example 28

[0247] A disclosed combination comprising TUDCA and SA-21 in a 1:2 w / w ratio is administered to a patient with diabetic retinopathy. The combination of antioxidants produces a synergistic treatment effect.Example 29

[0248] A disclosed combination comprising TUDCA and SA-23 in a 1:2 w / w ratio is administered to a patient with diabetic retinopathy. The combination of antioxidants produces a synergistic treatment effect.Example 30

[0249] A disclosed combination comprising TUDCA and SA-24 in a 1:2 w / w ratio is administered to a patient with diabetic retinopathy. The combination of antioxidants produces a synergistic treatment effect.Example 31

[0250] A disclosed combination comprising TUDCA and SA-2 in a 2:1 w / w ratio is administered to a patient with diabetic retinopathy. The combination of antioxidants produces a synergistic treatment effect.1960197.00021Example 32

[0251] A disclosed combination comprising TUDCA and SA-9 in a 2:1 w / w ratio is administered to a patient with diabetic retinopathy. The combination of antioxidants produces a synergistic treatment effect.Example 33

[0252] A disclosed combination comprising TUDCA and SA-10 in a 2:1 w / w ratio is administered to a patient with diabetic retinopathy. The combination of antioxidants produces a synergistic treatment effect.Example 34

[0253] A disclosed combination comprising TUDCA and SA-21 in a 2:1 w / w ratio is administered to a patient with diabetic retinopathy. The combination of antioxidants produces a synergistic treatment effect.Example 35

[0254] A disclosed combination comprising TUDCA and SA-23 in a 2:1 w / w ratio is administered to a patient with diabetic retinopathy. The combination of antioxidants produces a synergistic treatment effect.Example 36

[0255] A disclosed combination comprising TUDCA and SA-24 in a 2:1 w / w ratio is administered to a patient with diabetic retinopathy. The combination of antioxidants produces a synergistic treatment effect.Example 37

[0256] A disclosed combination comprising TUDCA and SA-2 in a 1:1 w / w ratio is administered to a patient with glaucoma. The combination of antioxidants produces a synergistic treatment effect.Example 38

[0257] A disclosed combination comprising TUDCA and SA-9 in a 1:1 w / w ratio is administered to a patient with glaucoma. The combination of antioxidants produces a synergistic treatment effect.Example 39

[0258] A disclosed combination comprising TUDCA and SA-10 in a 1:1 w / w ratio is administered to a patient with glaucoma. The combination of antioxidants produces a synergistic treatment effect.1960197.00021Example 40

[0259] A disclosed combination comprising TUDCA and SA-21 in a 1:1 w / w ratio is administered to a patient with glaucoma. The combination of antioxidants produces a synergistic treatment effect.Example 41

[0260] A disclosed combination comprising TUDCA and SA-23 in a 1:1 w / w ratio is administered to a patient with glaucoma. The combination of antioxidants produces a synergistic treatment effect.Example 42

[0261] A disclosed combination comprising TUDCA and SA-24 in a 1:1 w / w ratio is administered to a patient with glaucoma. The combination of antioxidants produces a synergistic treatment effect.Example 43

[0262] A disclosed combination comprising TUDCA and SA-2 in a 1:2 w / w ratio is administered to a patient with glaucoma. The combination of antioxidants produces a synergistic treatment effect.Example 44

[0263] A disclosed combination comprising TUDCA and SA-9 in a 1:2 w / w ratio is administered to a patient with glaucoma. The combination of antioxidants produces a synergistic treatment effect.Example 45

[0264] A disclosed combination comprising TUDCA and SA-10 in a 1:2 w / w ratio is administered to a patient with glaucoma. The combination of antioxidants produces a synergistic treatment effect.Example 46

[0265] A disclosed combination comprising TUDCA and SA-21 in a 1:2 w / w ratio is administered to a patient with glaucoma. The combination of antioxidants produces a synergistic treatment effect.Example 47

[0266] A disclosed combination comprising TUDCA and SA-23 in a 1:2 w / w ratio is administered to a patient with glaucoma. The combination of antioxidants produces a synergistic treatment effect.1960197.00021Example 48

[0267] A disclosed combination comprising TUDCA and SA-24 in a 1:2 w / w ratio is administered to a patient with glaucoma. The combination of antioxidants produces a synergistic treatment effect.Example 49

[0268] A disclosed combination comprising TUDCA and SA-2 in a 2:1 w / w ratio is administered to a patient with glaucoma. The combination of antioxidants produces a synergistic treatment effect.Example 50

[0269] A disclosed combination comprising TUDCA and SA-9 in a 2:1 w / w ratio is administered to a patient with glaucoma. The combination of antioxidants produces a synergistic treatment effect.Example 51

[0270] A disclosed combination comprising TUDCA and SA-10 in a 2:1 w / w ratio is administered to a patient with glaucoma. The combination of antioxidants produces a synergistic treatment effect.Example 52

[0271] A disclosed combination comprising TUDCA and SA-21 in a 2:1 w / w ratio is administered to a patient with glaucoma. The combination of antioxidants produces a synergistic treatment effect.Example 53

[0272] A disclosed combination comprising TUDCA and SA-23 in a 2:1 w / w ratio is administered to a patient with glaucoma. The combination of antioxidants produces a synergistic treatment effect.Example 54

[0273] A disclosed combination comprising TUDCA and SA-24 in a 2:1 w / w ratio is administered to a patient with glaucoma. The combination of antioxidants produces a synergistic treatment effect.1960197.00021Example 55

[0274] A disclosed combination comprising TUDCA and SA-2 in a 1:1 w / w ratio is administered to a patient with CD. The combination of antioxidants produces a synergistic treatment effect.Example 56

[0275] A disclosed combination comprising TUDCA and SA-9 in a 1:1 w / w ratio is administered to a patient with CD. The combination of antioxidants produces a synergistic treatment effect.Example 57

[0276] A disclosed combination comprising TUDCA and SA-10 in a 1:1 w / w ratio is administered to a patient with CD. The combination of antioxidants produces a synergistic treatment effect.Example 58

[0277] A disclosed combination comprising TUDCA and SA-21 in a 1:1 w / w ratio is administered to a patient with CD. The combination of antioxidants produces a synergistic treatment effect.Example 59

[0278] A disclosed combination comprising TUDCA and SA-23 in a 1:1 w / w ratio is administered to a patient with CD. The combination of antioxidants produces a synergistic treatment effect.Example 60

[0279] A disclosed combination comprising TUDCA and SA-24 in a 1:1 w / w ratio is administered to a patient with CD. The combination of antioxidants produces a synergistic treatment effect.Example 61

[0280] A disclosed combination comprising TUDCA and SA-2 in a 1:2 w / w ratio is administered to a patient with CD. The combination of antioxidants produces a synergistic treatment effect.Example 62

[0281] A disclosed combination comprising TUDCA and SA-9 in a 1:2 w / w ratio is administered to a patient with CD. The combination of antioxidants produces a synergistic treatment effect.1960197.00021Example 63

[0282] A disclosed combination comprising TUDCA and SA-10 in a 1:2 w / w ratio is administered to a patient with CD. The combination of antioxidants produces a synergistic treatment effect.Example 64

[0283] A disclosed combination comprising TUDCA and SA-21 in a 1:2 w / w ratio is administered to a patient with CD. The combination of antioxidants produces a synergistic treatment effect.Example 65

[0284] A disclosed combination comprising TUDCA and SA-23 in a 1:2 w / w ratio is administered to a patient with CD. The combination of antioxidants produces a synergistic treatment effect.Example 66

[0285] A disclosed combination comprising TUDCA and SA-24 in a 1:2 w / w ratio is administered to a patient with CD. The combination of antioxidants produces a synergistic treatment effect.Example 67

[0286] A disclosed combination comprising TUDCA and SA-2 in a 2:1 w / w ratio is administered to a patient with CD. The combination of antioxidants produces a synergistic treatment effect.Example 68

[0287] A disclosed combination comprising TUDCA and SA-9 in a 2:1 w / w ratio is administered to a patient with CD. The combination of antioxidants produces a synergistic treatment effect.Example 69

[0288] A disclosed combination comprising TUDCA and SA-10 in a 2:1 w / w ratio is administered to a patient with CD. The combination of antioxidants produces a synergistic treatment effect.Example 70

[0289] A disclosed combination comprising TUDCA and SA-21 in a 2:1 w / w ratio is administered to a patient with CD. The combination of antioxidants produces a synergistic treatment effect.1960197.00021Example 71

[0290] A disclosed combination comprising TUDCA and SA-23 in a 2:1 w / w ratio is administered to a patient with CD. The combination of antioxidants produces a synergistic treatment effect.Example 72

[0291] A disclosed combination comprising TUDCA and SA-24 in a 2:1 w / w ratio is administered to a patient with CD. The combination of antioxidants produces a synergistic treatment effect.Example 73

[0292] A disclosed combination comprising TUDCA and SA-2 in a 1:1 w / w ratio is administered to a patient with UC. The combination of antioxidants produces a synergistic treatment effect.Example 74

[0293] A disclosed combination comprising TUDCA and SA-9 in a 1:1 w / w ratio is administered to a patient with UC. The combination of antioxidants produces a synergistic treatment effect.Example 75

[0294] A disclosed combination comprising TUDCA and SA-10 in a 1:1 w / w ratio is administered to a patient with UC. The combination of antioxidants produces a synergistic treatment effect.Example 76

[0295] A disclosed combination comprising TUDCA and SA-21 in a 1:1 w / w ratio is administered to a patient with UC. The combination of antioxidants produces a synergistic treatment effect.Example 77

[0296] A disclosed combination comprising TUDCA and SA-23 in a 1:1 w / w ratio is administered to a patient with UC. The combination of antioxidants produces a synergistic treatment effect.Example 78

[0297] A disclosed combination comprising TUDCA and SA-24 in a 1:1 w / w ratio is administered to a patient with UC. The combination of antioxidants produces a synergistic treatment effect.1960197.00021Example 79

[0298] A disclosed combination comprising TUDCA and SA-2 in a 1:2 w / w ratio is administered to a patient with UC. The combination of antioxidants produces a synergistic treatment effect.Example 80

[0299] A disclosed combination comprising TUDCA and SA-9 in a 1:2 w / w ratio is administered to a patient with UC. The combination of antioxidants produces a synergistic treatment effect.Example 81

[0300] A disclosed combination comprising TUDCA and SA-10 in a 1:2 w / w ratio is administered to a patient with UC. The combination of antioxidants produces a synergistic treatment effect.Example 82

[0301] A disclosed combination comprising TUDCA and SA-21 in a 1:2 w / w ratio is administered to a patient with UC. The combination of antioxidants produces a synergistic treatment effect.Example 83

[0302] A disclosed combination comprising TUDCA and SA-23 in a 1:2 w / w ratio is administered to a patient with UC. The combination of antioxidants produces a synergistic treatment effect.Example 84

[0303] A disclosed combination comprising TUDCA and SA-24 in a 1:2 w / w ratio is administered to a patient with UC. The combination of antioxidants produces a synergistic treatment effect.Example 85

[0304] A disclosed combination comprising TUDCA and SA-2 in a 2:1 w / w ratio is administered to a patient with UC. The combination of antioxidants produces a synergistic treatment effect.Example 86

[0305] A disclosed combination comprising TUDCA and SA-9 in a 2:1 w / w ratio is administered to a patient with UC. The combination of antioxidants produces a synergistic treatment effect.1960197.00021Example 87

[0306] A disclosed combination comprising TUDCA and SA-10 in a 2:1 w / w ratio is administered to a patient with UC. The combination of antioxidants produces a synergistic treatment effect.Example 88

[0307] A disclosed combination comprising TUDCA and SA-21 in a 2:1 w / w ratio is administered to a patient with UC. The combination of antioxidants produces a synergistic treatment effect.Example 89

[0308] A disclosed combination comprising TUDCA and SA-23 in a 2:1 w / w ratio is administered to a patient with UC. The combination of antioxidants produces a synergistic treatment effect.Example 90

[0309] A disclosed combination comprising TUDCA and SA-24 in a 2:1 w / w ratio is administered to a patient with UC. The combination of antioxidants produces a synergistic treatment effect.Example 91

[0310] A disclosed combination comprising SA-2 and remogliflozin etabonate in a 9:1 w / w ratio is administered to a patient with MASH. The combination of antioxidants produces a synergistic treatment effect.Example 92

[0311] Two disclosed liquid compositions comprising remogliflozin etabonate and SA-10 (in a 1:9 w / w active ingredient ratio) are administered to a patient with FLD. The combination of antioxidants produces a synergistic treatment effect.Example 93

[0312] A disclosed composition comprising oral TUDCA and NAC is administered to a patient with UC. Within 3 months, the patient shows signs of clinical remission.Example 94

[0313] A disclosed combination comprising NAC and remogliflozin etabonate in an 8:1 w / w ratio is administered to a patient with MASH. Symptoms of MASH improve within 2 months, and the combination produces a synergistic treatment effect.1960197.00021Example 95

[0314] A 36 year old male patient is diagnosed with FLD. He is treated with 900 mg NAC and 100 mg of Remogliflozin etabonate twice daily for 12 weeks. He is tested for AST and ALT (and other liver enzymes) at 12 day intervals. After 12 weeks, his liver enzymes reduce and return to normal levels.Example 96

[0315] A cell-based fluorescent glucose transport assay is performed according to a published protocol (Lu, Yan-Ting, et al. "A fluorescent glucose transport assay for screening SGLT2 inhibitors in endogenous SGLT2-expressing HK-2 cells." Natural Products and Bioprospecting 9.1 (2019): 13-21.) to measure SGLT2 inhibition of SGLT2 inhibitor and antioxidant combinations. SGLT2-expressing cells are incubated with a fluorescent glucose derivative and uptake is measured by measuring the fluorescence intensity of the fluorescent glucose derivative in the cells. Treatment of cells with dapagliflozin reduces the fluorescence intensity of the cells relative to the controls, indicating inhibition of glucose transport. The addition of TEMPOL further increases the SGLT2 inhibitory effect by an amount greater than the additive effect of TEMPOL and dapagliflozin individually. Furthermore, addition of TEMPOL reduce the concentration of dapagliflozin needed to achieve the same level of inhibition. Dapagliflozin and TEMPOL show a synergistic effect.Example 97

[0316] A disclosed combination comprising NAC and remogliflozin etabonate in a 9:1 w / w ratio is administered to a patient with MASH. The combination of antioxidants produces a synergistic treatment effect.Example 98

[0317] A disclosed powder composition comprising NAC and remogliflozin etabonate in a 9:1 w / w ratio are administered to a patient with FLD. The combination of antioxidants produces a synergistic treatment effect.Example 99

[0318] A disclosed powder composition comprising NAC and remogliflozin etabonate in an 8:1 w / w ratio are administered to a patient with FLD. The combination of antioxidants produces a synergistic treatment effect.1960197.00021Example 100

[0319] A disclosed powder composition comprising NAC and remogliflozin etabonate in a 10:1 w / w ratio are administered to a patient with FLD. The combination of antioxidants produces a synergistic treatment effect.Example 101

[0320] A disclosed powder composition comprising remogliflozin etabonate and a disclosed liquid NAC (in a 1:9 w / w active ingredient ratio) are administered to a patient with FLD. The combination of antioxidants produces a synergistic treatment effect.Example 102

[0321] Two disclosed liquid compositions comprising remogliflozin etabonate and NAC (in a 1:9 w / w active ingredient ratio) are administered to a patient with FLD. The combination of antioxidants produces a synergistic treatment effect.Example 103

[0322] A disclosed combination comprising NAC and remogliflozin etabonate in an 8:1 w / w ratio is administered to a patient with MASH. The combination of antioxidants produces a synergistic treatment effect.Example 104

[0323] A disclosed combination comprising NAC and remogliflozin etabonate in a 10:1 w / w ratio is administered to a patient with MASH. The combination of antioxidants produces a synergistic treatment effect.Example 105

[0324] A disclosed powder composition comprising remogliflozin etabonate and SA-10 (in a 1:9 w / w active ingredient ratio) are administered to a patient with FLD. The combination of antioxidants produces a synergistic treatment effect.Example 106

[0325] A disclosed powder composition comprising remogliflozin etabonate and SA-21 composition (in a 1:9 w / w active ingredient ratio) are administered to a patient with FLD. The combination of antioxidants produces a synergistic treatment effect.Example 107

[0326] A disclosed powder composition comprising remogliflozin etabonate and SA-23 (in a 1:9 w / w active ingredient ratio) are administered to a patient with FLD. The combination of antioxidants produces a synergistic treatment effect.1960197.00021Example 108

[0327] A disclosed powder composition comprising remogliflozin etabonate and SA-24 (in a 1:9 w / w active ingredient ratio) are administered to a patient with FLD. The combination of antioxidants produces a synergistic treatment effect.Example 109

[0328] A disclosed powder composition comprising remogliflozin etabonate and SA-2 (in a 1:8 w / w active ingredient ratio) are administered to a patient with FLD. The combination of antioxidants produces a synergistic treatment effect.Example 110

[0329] A disclosed powder composition comprising remogliflozin etabonate and SA-9 (in a 1:8 w / w active ingredient ratio) are administered to a patient with FLD. The combination of antioxidants produces a synergistic treatment effect.Example 111

[0330] A disclosed powder composition comprising remogliflozin etabonate and SA-10 (in a 1:8 w / w active ingredient ratio) are administered to a patient with FLD. The combination of antioxidants produces a synergistic treatment effect.Example 112

[0331] A disclosed powder composition comprising remogliflozin etabonate and SA-21 composition (in a 1:8 w / w active ingredient ratio) are administered to a patient with FLD. The combination of antioxidants produces a synergistic treatment effect.Example 113

[0332] A disclosed powder composition comprising remogliflozin etabonate and SA-23 (in a 1:8 w / w active ingredient ratio) are administered to a patient with FLD. The combination of antioxidants produces a synergistic treatment effect.Example 114

[0333] A disclosed powder composition comprising remogliflozin etabonate and SA-24 (in a 1:8 w / w active ingredient ratio) are administered to a patient with FLD. The combination of antioxidants produces a synergistic treatment effect.Example 115

[0334] A disclosed powder composition comprising remogliflozin etabonate and SA-2 (in a 1:10 w / w active ingredient ratio) are administered to a patient with FLD. The combination of antioxidants produces a synergistic treatment effect.1960197.00021Example 116

[0335] A disclosed powder composition comprising remogliflozin etabonate and SA-9 (in a 1:10 w / w active ingredient ratio) are administered to a patient with FLD. The combination of antioxidants produces a synergistic treatment effect.Example 117

[0336] A disclosed powder composition comprising remogliflozin etabonate and SA-10 (in a 1:10 w / w active ingredient ratio) is administered to a patient with FLD. The combination of antioxidants produces a synergistic treatment effect.Example 118

[0337] A disclosed powder composition comprising remogliflozin etabonate and SA-21 composition (in a 1:10 w / w active ingredient ratio) are administered to a patient with FLD. The combination of antioxidants produces a synergistic treatment effect.Example 119

[0338] A disclosed powder composition comprising remogliflozin etabonate and SA-23 (in a 1:10 w / w active ingredient ratio) are administered to a patient with FLD. The combination of antioxidants produces a synergistic treatment effect.Example 120

[0339] A disclosed powder composition comprising remogliflozin etabonate and SA-24 (in a 1:10 w / w active ingredient ratio) are administered to a patient with FLD. The combination of antioxidants produces a synergistic treatment effect.Example 121

[0340] Two disclosed liquid compositions comprising remogliflozin etabonate and SA-10 (in a 1:9 w / w active ingredient ratio) are administered to a patient with FLD. The combination of antioxidants produces a synergistic treatment effect.Example 122 — Carbon Tetrachloride Model

[0341] TEMPOL protects rats in the Carbon Tetrachloride Model; increased plasma activities of ALT, AST, and ALP (liver enzymes) compared to controls. TEMPOL significantly lowered levels of oxidative stress (MDA, NO, and APOP) markers.

[0342] TEMPOL increased Nrf-2-H0-1 mediated gene expression and enhanced related antioxidant enzyme gene expression and decreased anti-inflammatory gene expression in the liver.1960197.00021

[0343] Histologically, TEMPOL decreased inflammatory cell infiltration, collagen deposition, and iron deposition. Treatment ameliorated the gene expression of cytokines and TGF-b, thus preventing inflammation-mediated tissue fibrosis.

[0344] TEMPOL can protect against liver and kidney damage in CCL4administered rats by modulating antioxidant gene expression and restoring antioxidant defense mechanisms.Example 123

[0345] A disclosed combination comprising SA-2 and remogliflozin etabonate in a 9:1 w / w ratio is administered to a patient with MASH. The combination of antioxidants produces a synergistic treatment effect.Example 124

[0346] A disclosed powder composition comprising remogliflozin etabonate and SA-9 (in a 1:9 w / w active ingredient ratio) are administered to a patient with FLD. The combination of antioxidants produces a synergistic treatment effect.Example 125

[0347] A disclosed combination comprising SA-9 and remogliflozin etabonate in a 9:1 w / w ratio is administered to a patient with MASH. The combination of antioxidants produces a synergistic treatment effect.Example 126

[0348] A disclosed combination comprising SA-10 and remogliflozin etabonate in a 9:1 w / w ratio is administered to a patient with MASH. The combination of antioxidants produces a synergistic treatment effect.Example 127

[0349] A disclosed combination comprising SA-2 and remogliflozin etabonate in an 8:1 w / w ratio is administered to a patient with MASH. The combination of antioxidants produces a synergistic treatment effect.Example 128

[0350] A disclosed combination comprising SA-9 and remogliflozin etabonate in an 8:1 w / w ratio is administered to a patient with MASH. The combination of antioxidants produces a synergistic treatment effect.1960197.00021Example 129

[0351] A disclosed combination comprising SA-10 and remogliflozin etabonate in an 8:1 w / w ratio is administered to a patient with MASH. The combination of antioxidants produces a synergistic treatment effect.Example 130

[0352] A disclosed combination comprising SA-2 and remogliflozin etabonate in a 10:1 w / w ratio is administered to a patient with MASH. The combination of antioxidants produces a synergistic treatment effect.Example 131

[0353] A disclosed combination comprising SA-9 and remogliflozin etabonate in a 10:1 w / w ratio is administered to a patient with MASH. The combination of antioxidants produces a synergistic treatment effect.Example 132

[0354] A disclosed combination comprising SA-10 and remogliflozin etabonate in a 10:1 w / w ratio is administered to a patient with MASH. The combination of antioxidants produces a synergistic treatment effect.Example 133

[0355] A disclosed combination comprising SA-2 and remogliflozin etabonate in a 7:1 w / w ratio is administered to a patient with MASH. The combination of antioxidants produces a synergistic treatment effect.Example 134

[0356] A disclosed combination comprising SA-9 and remogliflozin etabonate in a 7:1 w / w ratio is administered to a patient with MASH. The combination of antioxidants produces a synergistic treatment effect.Example 135

[0357] A disclosed combination comprising SA-10 and remogliflozin etabonate in a 7:1 w / w ratio is administered to a patient with MASH. The combination of antioxidants produces a synergistic treatment effect.Example 136

[0358] A disclosed combination comprising SA-21 and remogliflozin etabonate in a 9:1 w / w ratio is administered to a patient with MASH. The combination of antioxidants produces a synergistic treatment effect.1960197.00021Example 137

[0359] A disclosed combination comprising SA-23 and remogliflozin etabonate in a 9:1 w / w ratio is administered to a patient with MASH. The combination of antioxidants produces a synergistic treatment effect.Example 138

[0360] A disclosed combination comprising SA-24 and remogliflozin etabonate in a 9:1 w / w ratio is administered to a patient with MASH. The combination of antioxidants produces a synergistic treatment effect.Example 139

[0361] A disclosed combination comprising SA-21 and remogliflozin etabonate in an 8:1 w / w ratio is administered to a patient with MASH. The combination of antioxidants produces a synergistic treatment effect.Example 140

[0362] A disclosed combination comprising SA-23 and remogliflozin etabonate in an 8:1 w / w ratio is administered to a patient with MASH. The combination of antioxidants produces a synergistic treatment effect.Example 141

[0363] A disclosed combination comprising SA-24 and remogliflozin etabonate in an 8:1 w / w ratio is administered to a patient with MASH. The combination of antioxidants produces a synergistic treatment effect.Example 142

[0364] A disclosed combination comprising SA-21 and remogliflozin etabonate in a 10:1 w / w ratio is administered to a patient with MASH. The combination of antioxidants produces a synergistic treatment effect.Example 143

[0365] A disclosed combination comprising SA-23 and remogliflozin etabonate in a 10:1 w / w ratio is administered to a patient with MASH. The combination of antioxidants produces a synergistic treatment effect.Example 144

[0366] A disclosed combination comprising SA-24 and remogliflozin etabonate in a 10:1 w / w ratio is administered to a patient with MASH. The combination of antioxidants produces a synergistic treatment effect.1960197.00021Example 145

[0367] A disclosed combination comprising SA-21 and remogliflozin etabonate in a 7:1 w / w ratio is administered to a patient with MASH. The combination of antioxidants produces a synergistic treatment effect.Example 146

[0368] A disclosed combination comprising SA-23 and remogliflozin etabonate in a 7:1 w / w ratio is administered to a patient with MASH. The combination of antioxidants produces a synergistic treatment effect.Example 147

[0369] A disclosed combination comprising SA-24 and remogliflozin etabonate in a 7:1 w / w ratio is administered to a patient with MASH. The combination of antioxidants produces a synergistic treatment effect.Example 148

[0370] A disclosed powder composition comprising remogliflozin etabonate and SA-2 (in a 1:9 w / w active ingredient ratio) are administered to a patient with FLD. The combination of antioxidants produces a synergistic treatment effect.Example 149

[0371] A combination comprising 300 mg NAC and 5 mg dapagliflozin is orally administered once a day to a patient with MASH for a duration of 2-50 weeks. The patient also is administered 300 mg NAC once daily about 12 hours after administration of the combination. After the treatment duration, the patient is observed to have experienced an improvement of one or more symptoms of the MASH as compared to day 0 prior to treatment.Example 150

[0372] A combination comprising 600 mg NAC and 5 mg dapagliflozin is orally administered once a day to a patient with MASH for a duration of 2-50 weeks. The patient also is administered 600 mg NAC once daily about 12 hours after administration of the combination. After the treatment duration, the patient is observed to have experienced an improvement of one or more symptoms of the MASH as compared to day 0 prior to treatment.Example 151

[0373] A combination comprising 900 mg NAC and 5 mg dapagliflozin is orally administered once a day to a patient with MASH for a duration of 2-50 weeks. The patient also is administered 900 mg NAC once daily about 12 hours after administration of the combination. After the treatment1960197.00021duration, the patient is observed to have experienced an improvement of one or more symptoms of the MASH as compared to day 0 prior to treatment.Example 152

[0374] A combination comprising 300 mg NAC and 10 mg dapagliflozin is orally administered once a day to a patient with MASH for a duration of 2-50 weeks. The patient also is administered 300 mg NAC once daily about 12 hours after administration of the combination. After the treatment duration, the patient is observed to have experienced an improvement of one or more symptoms of the MASH as compared to day 0 prior to treatment.Example 153

[0375] A combination comprising 600 mg NAC and 10 mg dapagliflozin is orally administered once a day to a patient with MASH for a duration of 2-50 weeks. The patient also is administered 600 mg NAC once daily about 12 hours after administration of the combination. After the treatment duration, the patient is observed to have experienced an improvement of one or more symptoms of the MASH as compared to day 0 prior to treatment.Example 154

[0376] A combination comprising 900 mg NAC and 10 mg dapagliflozin is orally administered once a day to a patient with MASH for a duration of 2-50 weeks. The patient also is administered 900 mg NAC once daily about 12 hours after administration of the combination. After the treatment duration, the patient is observed to have experienced an improvement of one or more symptoms of the MASH as compared to day 0 prior to treatment.Example 155

[0377] A combination comprising 400 mg TEMPOL and 5 mg dapagliflozin is orally administered once a day to a patient with MASH for a duration of 2-50 weeks. After the treatment duration, the patient is observed to have experienced an improvement of one or more symptoms of the MASH as compared to day 0 prior to treatment.Example 156

[0378] A combination comprising 600 mg TEMPOL and 5 mg dapagliflozin is orally administered once a day to a patient with MASH for a duration of 2-50 weeks. After the treatment duration, the patient is observed to have experienced an improvement of one or more symptoms of the MASH as compared to day 0 prior to treatment.1960197.00021Example 157

[0379] A combination comprising 900 mg TEMPOL and 5 mg dapagliflozin is orally administered once a day to a patient with MASH for a duration of 2-50 weeks. After the treatment duration, the patient is observed to have experienced an improvement of one or more symptoms of the MASH as compared to day 0 prior to treatment.Example 158

[0380] A combination comprising 400 mg TEMPOL and 10 mg dapagliflozin is orally administered once a day to a patient with MASH for a duration of 2-50 weeks. After the treatment duration, the patient is observed to have experienced an improvement of one or more symptoms of the MASH as compared to day 0 prior to treatment.Example 159

[0381] A combination comprising 600 mg TEMPOL and 10 mg dapagliflozin is orally administered once a day to a patient with MASH for a duration of 2-50 weeks. After the treatment duration, the patient is observed to have experienced an improvement of one or more symptoms of the MASH as compared to day 0 prior to treatment.Example 160

[0382] A combination comprising 900 mg TEMPOL and 10 mg dapagliflozin is orally administered once a day to a patient with MASH for a duration of 2-50 weeks. After the treatment duration, the patient is observed to have experienced an improvement of one or more symptoms of the MASH as compared to day 0 prior to treatment.Example 161

[0383] A combination comprising 300 mg NAC and 100 mg remogliflozin etabonate is orally administered twice daily to a patient with MASH for a duration of 2-50 weeks. After the treatment duration, the patient is observed to have experienced an improvement of one or more symptoms of the MASH as compared to day 0 prior to treatment.Example 162

[0384] A combination comprising 600 mg NAC and 100 mg remogliflozin etabonate is orally administered twice daily to a patient with MASH for a duration of 2-50 weeks. After the treatment duration, the patient is observed to have experienced an improvement of one or more symptoms of the MASH as compared to day 0 prior to treatment.1960197.00021Example 163

[0385] A combination comprising 900 mg NAC and 100 mg remogliflozin etabonate is orally administered twice daily to a patient with MASH for a duration of 2-50 weeks. After the treatment duration, the patient is observed to have experienced an improvement of one or more symptoms of the MASH as compared to day 0 prior to treatment.Example 164

[0386] A combination comprising 300 mg NAC and 250 mg remogliflozin etabonate is orally administered twice daily to a patient with MASH for a duration of 2-50 weeks. After the treatment duration, the patient is observed to have experienced an improvement of one or more symptoms of the MASH as compared to day 0 prior to treatment.Example 165

[0387] A combination comprising 600 mg NAC and 250 mg remogliflozin etabonate is orally administered twice daily to a patient with MASH for a duration of 2-50 weeks. After the treatment duration, the patient is observed to have experienced an improvement of one or more symptoms of the MASH as compared to day 0 prior to treatment.Example 166

[0388] A combination comprising 900 mg NAC and 250 mg remogliflozin etabonate is orally administered twice daily to a patient with MASH for a duration of 2-50 weeks. After the treatment duration, the patient is observed to have experienced an improvement of one or more symptoms of the MASH as compared to day 0 prior to treatment.Example 167

[0389] A combination comprising 400 mg TEMPOL and 100 mg remogliflozin etabonate is orally administered twice daily to a patient with MASH for a duration of 2-50 weeks. After the treatment duration, the patient is observed to have experienced an improvement of one or more symptoms of the MASH as compared to day 0 prior to treatment.Example 168

[0390] A combination comprising 600 mg TEMPOL and 100 mg remogliflozin etabonate is orally administered twice daily to a patient with MASH for a duration of 2-50 weeks. After the treatment duration, the patient is observed to have experienced an improvement of one or more symptoms of the MASH as compared to day 0 prior to treatment.1960197.00021Example 169

[0391] A combination comprising 900 mg TEMPOL and 100 mg remogliflozin etabonate is orally administered twice daily to a patient with MASH for a duration of 2-50 weeks. After the treatment duration, the patient is observed to have experienced an improvement of one or more symptoms of the MASH as compared to day 0 prior to treatment.Example 170

[0392] A combination comprising 400 mg TEMPOL and 250 mg remogliflozin etabonate is orally administered twice daily to a patient with MASH for a duration of 2-50 weeks. After the treatment duration, the patient is observed to have experienced an improvement of one or more symptoms of the MASH as compared to day 0 prior to treatment.Example 171

[0393] A combination comprising 600 mg TEMPOL and 250 mg remogliflozin etabonate is orally administered twice daily to a patient with MASH for a duration of 2-50 weeks. After the treatment duration, the patient is observed to have experienced an improvement of one or more symptoms of the MASH as compared to day 0 prior to treatment.Example 172

[0394] A combination comprising 900 mg TEMPOL and 250 mg remogliflozin etabonate is orally administered twice daily to a patient with MASH for a duration of 2-50 weeks. After the treatment duration, the patient is observed to have experienced an improvement of one or more symptoms of the MASH as compared to day 0 prior to treatment.Example 173

[0395] A combination comprising 400 mg TEMPOL and 300 mg TUDCA is orally administered twice daily to a patient with ulcerative colitis for a duration of 2-50 weeks. After the treatment duration, the patient is observed to have experienced an improvement of one or more symptoms of the ulcerative colitis as compared to day 0 prior to treatment.Example 174

[0396] A combination comprising 400 mg TEMPOL and 600 mg TUDCA is orally administered twice daily to a patient with ulcerative colitis for a duration of 2-50 weeks. After the treatment duration, the patient is observed to have experienced an improvement of one or more symptoms of the ulcerative colitis as compared to day 0 prior to treatment.1960197.00021Example 175

[0397] A combination comprising 400 mg TEMPOL and 900 mg TUDCA is orally administered twice daily to a patient with ulcerative colitis for a duration of 2-50 weeks. After the treatment duration, the patient is observed to have experienced an improvement of one or more symptoms of the ulcerative colitis as compared to day 0 prior to treatment.Example 176

[0398] A combination comprising 600 mg TEMPOL and 300 mg TUDCA is orally administered twice daily to a patient with ulcerative colitis for a duration of 2-50 weeks. After the treatment duration, the patient is observed to have experienced an improvement of one or more symptoms of the ulcerative colitis as compared to day 0 prior to treatment.Example 177

[0399] A combination comprising 600 mg TEMPOL and 600 mg TUDCA is orally administered twice daily to a patient with ulcerative colitis for a duration of 2-50 weeks. After the treatment duration, the patient is observed to have experienced an improvement of one or more symptoms of the ulcerative colitis as compared to day 0 prior to treatment.Example 178

[0400] A combination comprising 600 mg TEMPOL and 900 mg TUDCA is orally administered twice daily to a patient with ulcerative colitis for a duration of 2-50 weeks. After the treatment duration, the patient is observed to have experienced an improvement of one or more symptoms of the ulcerative colitis as compared to day 0 prior to treatment.Example 179

[0401] A combination comprising 900 mg TEMPOL and 300 mg TUDCA is orally administered twice daily to a patient with ulcerative colitis for a duration of 2-50 weeks. After the treatment duration, the patient is observed to have experienced an improvement of one or more symptoms of the ulcerative colitis as compared to day 0 prior to treatment.Example 180

[0402] A combination comprising 900 mg TEMPOL and 600 mg TUDCA is orally administered twice daily to a patient with ulcerative colitis for a duration of 2-50 weeks. After the treatment duration, the patient is observed to have experienced an improvement of one or more symptoms of the ulcerative colitis as compared to day 0 prior to treatment.1960197.00021Example 181

[0403] A combination comprising 900 mg TEMPOL and 900 mg TUDCA is orally administered twice daily to a patient with ulcerative colitis for a duration of 2-50 weeks. After the treatment duration, the patient is observed to have experienced an improvement of one or more symptoms of the ulcerative colitis as compared to day 0 prior to treatment.Example 182

[0404] A combination comprising 400 mg TEMPOL and 300 mg TUDCA is orally administered twice daily to a patient with IBD for a duration of 2-50 weeks. After the treatment duration, the patient is observed to have experienced an improvement of one or more symptoms of the IBD as compared to day 0 prior to treatment.Example 183

[0405] A combination comprising 400 mg TEMPOL and 600 mg TUDCA is orally administered twice daily to a patient with IBD for a duration of 2-50 weeks. After the treatment duration, the patient is observed to have experienced an improvement of one or more symptoms of the IBD as compared to day 0 prior to treatment.Example 184

[0406] A combination comprising 400 mg TEMPOL and 900 mg TUDCA is orally administered twice daily to a patient with IBD for a duration of 2-50 weeks. After the treatment duration, the patient is observed to have experienced an improvement of one or more symptoms of the IBD as compared to day 0 prior to treatment.Example 185

[0407] A combination comprising 600 mg TEMPOL and 300 mg TUDCA is orally administered twice daily to a patient with IBD for a duration of 2-50 weeks. After the treatment duration, the patient is observed to have experienced an improvement of one or more symptoms of the IBD as compared to day 0 prior to treatment.Example 186

[0408] A combination comprising 600 mg TEMPOL and 600 mg TUDCA is orally administered twice daily to a patient with IBD for a duration of 2-50 weeks. After the treatment duration, the patient is observed to have experienced an improvement of one or more symptoms of the IBD as compared to day 0 prior to treatment.1960197.00021Example 187

[0409] A combination comprising 600 mg TEMPOL and 900 mg TUDCA is orally administered twice daily to a patient with ulcerative colitis for a duration of 2-50 weeks. After the treatment duration, the patient is observed to have experienced an improvement of one or more symptoms of the ulcerative colitis as compared to day 0 prior to treatment.Example 188

[0410] A combination comprising 900 mg TEMPOL and 300 mg TUDCA is orally administered twice daily to a patient with ulcerative colitis for a duration of 2-50 weeks. After the treatment duration, the patient is observed to have experienced an improvement of one or more symptoms of the ulcerative colitis as compared to day 0 prior to treatment.Example 189

[0411] A combination comprising 900 mg TEMPOL and 600 mg TUDCA is orally administered twice daily to a patient with ulcerative colitis for a duration of 2-50 weeks. After the treatment duration, the patient is observed to have experienced an improvement of one or more symptoms of the ulcerative colitis as compared to day 0 prior to treatment.Example 190

[0412] A combination comprising 900 mg TEMPOL and 900 mg TUDCA is orally administered twice daily to a patient with ulcerative colitis for a duration of 2-50 weeks. After the treatment duration, the patient is observed to have experienced an improvement of one or more symptoms of the ulcerative colitis as compared to day 0 prior to treatment.

[0413] Recitation of ranges of values herein is merely intended to serve as a shorthand method of referring individually to each separate value falling within the range. Unless otherwise indicated herein, each individual value is incorporated into the specification as if it were individually recited herein. All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g., “such as”) provided herein is intended merely to better illuminate the combinations and methods herein and does not pose a limitation on the scope of the disclosure otherwise claimed. No language in the specification should be construed as indicating any non-claimed element essential to the practice of the disclosed combinations or methods.

[0414] Groupings of alternative elements or embodiments of the combinations and methods disclosed herein are not to be construed as limitations. Each group member may be referred to1960197.00021and claimed individually or in any combination with other members of the group or other elements found herein. Further, one or more members of a group may be included in, or deleted from, a group for reasons of convenience or patentability.

[0415] Specific embodiments disclosed herein may be further limited in the claims using consisting of or consisting essentially of language.

[0416] Furthermore, references have been made to patents and printed publications throughout this specification. Each of the above cited references and printed publications are herein individually incorporated by reference in their entirety.

Claims

1960197.00021CLAIMSWhat is claimed is:

1. A combination, comprising:a first compound, which is an SGLT2 inhibitor; anda second compound, which is an antioxidant.

2. The combination of claim 1, wherein the SGLT2 inhibitor is dapagliflozin, remogliflozin etabonate, bexagliflozin, canagliflozin, empagliflozin, enavogliflozin ertugliflozin, henagliflozin, ipragliflozin, luseogliflozin, rongliflozin, sotagliflozin, or tofogliflozin, or a pharmaceutically acceptable salt thereof.

3. A combination, comprising:a first compound, which isor a pharmaceutically acceptable salt thereof; anda second compound, which is an antioxidant.

4. The combination of one of claims 1-3, wherein the second compound is N-acetyl-L-cysteine, 4-hydroxy-2,2,6,6-tetramethylpiperidin-1-oxyl (TEMPOL), a TEMPOL hybrid, or a pharmaceutically acceptable salt thereof.

5. The combination of claim 4, wherein the TEMPOL hybrid or a pharmaceutically acceptable salt thereof is selected from SA-2, SA-9, SA-10, SA-21, SA-23, or SA-24, or a pharmaceutically acceptable salt thereof.

6. The combination of one of compounds 3-5, wherein the first compound is about 300 mg, about 600 mg, about 900 mg, about 1200 mg, or about 1800 mg of the total combination mass.

7. The combination of one of claims 1-6, wherein the second compound is1960197.000218. The combination of one of claims 1-6, wherein the second compound is selected from SA-2, SA-9, SA-10, SA-21 , SA-23, or SA-24, or a pharmaceutically acceptable salt thereof.

9. The combination of one of claims 1-8, wherein the second compound is about 400 mg, about 600 mg, about 800 mg, about 900 mg, about 1200 mg, or about 1800 mg of the total combination mass.

10. The combination of one of claims 1-6, wherein the second compound is"pharmaceutically acceptable salt thereof.

11. The combination of any one of claims 1-6 or 10 inclusive, wherein the second compound is about 300 mg, about 600 mg, about 900 mg, about 1200 mg, or about 1800 mg of the total combination mass.

12. The combination of any one of claims 1 , 2, or 4-11 inclusive, wherein the SGLT2 inhibitor is13. The combination of any one of claims 1, 2, or 4-12 inclusive, wherein the SGLT2 inhibitor is about 6 (e.g., 6.14) mg or about 12 (e.g., 12.28) mg of the total combination mass.

14. The combination of any one of claims 1 , 2, or 4-11 inclusive, wherein the SGLT2 inhibitor is1960197.0002115. The combination of any one of claims 1, 2, 4-12, or 14 inclusive, wherein the SGLT2 inhibitor is about 5 mg or about 10 mg of the total combination mass.

16. The combination of any one of claims 1 , 2, or 4-11 inclusive, wherein the SGLT2 inhibitor17. The combination of any one of claims 1, 2, 4-11, or 16 inclusive, wherein the SGLT2 inhibitor is about 10 mg or about 25 mg of the total combination mass.

18. The combination of any one of claims 1, 2, or 4-11 inclusive, wherein the SGLT2 inhibitor19. The combination of any one of claims 1, 2, 4-11, or 18 inclusive, wherein the SGLT2 inhibitor is about 100 mg or about 250 mg of the total combination mass.

20. The combination of any one of claims 1 , 2, or 4-11 inclusive, wherein the SGLT2 inhibitor is1960197.0002121. The combination of any one of claims 1, 2, 4-11, or 20 inclusive, wherein the SGLT2 inhibitor is about 6.5 (e.g., 6.48) mg or about 19.4 (e.g., 19.43) mg of the total combination mass.

22. The combination of any one of claims 1, 2, 4-11 or 21 inclusive, wherein the SGLT2 inhibitor is23. The combination of any one of claims 1, 2, 4-11, or 22 inclusive, wherein the SGLT2 inhibitor is about 5 mg or about 15 mg of the total combination mass.

24. The combination of any one of claims 1 , 2, or 4-11 inclusive, wherein the SGLT2 inhibitor is25. The combination of any one of claims 1, 2, 4-11, or 24 inclusive, wherein the SGLT2 inhibitor is about 102 mg or about 306 mg of the total combination mass.

26. The combination of any one of claims 1, 2, 4-11 or 25 inclusive, wherein the SGLT2 inhibitor is1960197.0002127. The combination of any one of claims 1, 2, 4-11, or 26 inclusive, wherein the SGLT2 inhibitor is about 100 mg or about 300 mg of the total combination mass.

28. The combination of claim 1, comprising:canagliflozin and N-acetyl-L-Cysteine;canagliflozin and 4-hydroxy-2,2,6,6-tetramethylpiperidin-1-oxyl;canagliflozin and one of SA-2, SA-9, SA-10, SA-21, SA-23, or SA-24, or a pharmaceutically acceptable salt thereof;dapagliflozin and N-acetyl-L-Cysteine;dapagliflozin and 4-hydroxy-2,2,6,6-tetramethylpiperidin-1-oxyl;dapagliflozin and one of SA-2, SA-9, SA-10, SA-21, SA-23, or SA-24, or a pharmaceutically acceptable salt thereof;empagliflozin and N-acetyl-L-Cysteine;empagliflozin and 4-hydroxy-2,2,6,6-tetramethylpiperidin-1-oxyl;empagliflozin and one of SA-2, SA-9, SA-10, SA-21, SA-23, or SA-24, or a pharmaceutically acceptable salt thereof;ertugliflozin and N-acetyl-L-Cysteine;ertugliflozin and 4-hydroxy-2,2,6,6-tetramethylpiperidin-1-oxyl;ertugliflozin and one of SA-2, SA-9, SA-10, SA-21, SA-23, or SA-24, or a pharmaceutically acceptable salt thereof;1960197.00021remogliflozin etabonate and N-acetyl-L-Cysteine;remogliflozin etabonate and 4-hydroxy-2,2,6,6-tetramethylpiperidin-1-oxyl; orremogliflozin etabonate and one of SA-2, SA-9, SA-10, SA-21, SA-23, or SA-24, or a pharmaceutically acceptable salt thereof.

29. The combination of one of claims 1-28, which is an admixture composition.

30. The combination of one of claims 1-29, which is a solid dosage form.

31. The combination of one of claims 1-30, which is a pharmaceutical composition further comprising a pharmaceutically acceptable carrier.

32. A method of treating metabolic dysfunction-associated steatotic liver disease (MASLD) in a subject in need thereof, comprising administration of the combination of any one of claims 1, 2, or 4-31 inclusive to the subject.

33. A method of treating metabolic dysfunction-associated steatohepatitis (MASH) in a subject in need thereof, comprising administration of the combination ofany one of claims 1, 2, or 4-31 inclusive to the subject.

34. A method of treating fatty liver disease (FLD) in a subject in need thereof, comprising administration of the combination of any one of claims 1 , 2, or 4-31 inclusive to the subject.

35. A method of treating inflammatory bowel disease (IBD) in a subject in need thereof, comprising administration of the combination of any of claims 3-11 or 29-30 to the subject.

36. A method of treating ulcerative colitis (UC) in a subject in need thereof, comprising administration of the combination of any of claims 3-11 or 29-30 to the subject.

37. A method of treating Crohn’s disease in a subject in need thereof, comprising administration of the combination of any of claims 3-11 or 29-30 to the subject.

38. A method of treating macular degeneration (MD) in a subject in need thereof, comprising administration of the combination of any of claims 3-11 or 29-30 to the subject.

39. A method of orally administering a combination to a subject, wherein the combination is the combination of one of claims 1-31.1960197.0002140. The method of one of claims 32-39, wherein the administration comprises oral administration of the combination.

41. The method of one of claims 32-40, wherein the administration comprises administration of the first compound and second compound within 60 minutes of one another.

42. The method of one of claims 32-41, wherein the administration comprises coadministration of a single dosage form comprising the combination.

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