Antioxidant Compositions and Methods of Use

Abstract

Disclosed herein are compositions comprising antioxidants, and methods of using the same.

Description

[Technical Field]

[0001] (CROSS-REFERENCE TO RELATED APPLICATIONS) This application claims priority to U.S. Provisional Patent Application No. 63 / 420,221, filed October 28, 2022, and U.S. Provisional Patent Application No. 63 / 429,672, filed December 2, 2022, the entire contents of all of which are incorporated by reference.

[0002] (Field) This specification relates to the use of antioxidants to treat a variety of conditions, including conditions associated with inflammation. [Background technology]

[0003] The main driver of acute inflammation is the body's immune system. When the body detects damaged tissue, cells called phagocytes rush to the site and ingest disease-causing microorganisms, damaged cells, and other foreign particles. This process is usually accompanied by the four "cardinal" signs of inflammation, first noted by the Greek physician Celsus in the 2nd century BC: redness, heat, swelling, and pain.

[0004] In injured tissue, blood vessels dilate, causing a surge in blood flow, resulting in redness and heat. Inflamed blood vessel walls become porous, allowing inflammatory cells, proteins, and fluid to leak into the tissue, causing swelling and compressing nerve endings.

[0005] In many infectious diseases, the disease-causing microorganism itself, or the immune response to it, triggers most of the symptoms—fever that alerts the body to an attack, or coughing and loose stools that expel tiny infectious particles. But when the immune system can't effectively control the organism or other source of cellular trauma, a "flood" of inflammation occurs, and immune cells try to fight the infection by producing large amounts of cytokines, small proteins that act as messengers.

[0006] Many people in intensive care units die from this inflammatory outburst rather than from the infection itself. An overactive immune response helps explain why young, seemingly healthy people become seriously ill or die during pandemics such as SARS-CoV-2.

[0007] Inflammation can persist with or without a known trigger and destroy healthy tissue. Autoimmune diseases such as arthritis or lupus can direct inflammation at the body, wreaking devastating havoc and sometimes becoming fatal. Patients can suffer from inflammatory bowel disease (IBD), an autoimmune condition involving severe intestinal inflammation that can require surgical intervention to remove most or all of the intestine. Additionally, many patients deal with inflammation due to conditions such as acid reflux, food sensitivities, celiac disease, and irritable bowel syndrome (IBS).

[0008] Antioxidants are known to offer therapeutic benefits in several treatment scenarios, such as inflammation-related conditions. However, to date, their potential has not been realized in many areas. For example, Crohn's disease (CD), a type of IBD that causes swelling (inflammation) of tissues in the digestive tract, can lead to abdominal pain, severe diarrhea, fatigue, weight loss, and malnutrition. "Fatty" liver and macular degeneration are also associated with inflammation.

[0009] Furthermore, chemotherapy is known to destroy both cancer cells and healthy cells. Inflammation-related consequences of chemotherapy can include conditions such as sinusoidal obstruction syndrome (SOS), fatty liver, pseudocirrhosis, and even liver necrosis. Because drugs are primarily broken down in the liver, liver damage can be a major side effect of chemotherapy. Many drugs require adequate liver function for metabolism, and these same drugs can cause significant liver damage. In some cases, patients are managed with supportive care, and thus liver toxicity can resolve once chemotherapy is discontinued.

[0010] Chemotherapy-induced hepatotoxicity manifests in various ways. Free radicals resulting from alterations in liver cells can impair liver function. Also, the combination of low-dose radiation therapy with systemic administration of non-hepatotoxic chemotherapy drugs can cause liver damage. Even treatment with agents such as cytokines (e.g., IL-2) can induce a cholestatic pattern that elevates many liver enzymes. This problem has not yet been fully resolved.

[0011] Therefore, improved compositions and methods for treating inflammation-related conditions are desirable. Summary of the Invention [Means for solving the problem]

[0012] The present disclosure provides compositions comprising antioxidants and methods for their use in several areas, such as the treatment and prevention of inflammation-related conditions. The disclosed compositions may include multiple antioxidants, which may exert synergistic effects.

[0013] For example, the disclosed compositions include tauroursodeoxycholic acid (TUDCA): [ka] The composition may contain at least one antioxidant such as

[0014] The disclosed compositions include N-acetyl-cysteine ​​(NAC:C5H9NO3S): [ka] may include:

[0015] NAC is a Food and Drug Administration-approved medication widely used to treat acetaminophen (paracetamol) overdose. It is also approved for use in conditions associated with abnormally viscous or thick mucus secretions that contribute to mucus plugging, such as pneumonia, bronchitis, tracheobronchitis, cystic fibrosis, post-traumatic chest disease, and prediagnostic bronchoscopy. Off-label uses include acute liver failure, prevention of contrast nephropathy, and topical treatment of keratoconjunctivitis sicca.

[0016] The disclosed compositions comprise 4-hydroxy-TEMPO or TEMPOL, formally 4-hydroxy-2,2,6,6-tetramethylpiperidine-1-oxyl: [ka] may include:

[0017] The disclosed compositions can include at least one of TUDCA, NAC, and TEMPOL.

[0018] The disclosed compositions can include at least two of TUDCA, NAC, and TEMPOL.

[0019] The disclosed compositions can include TUDCA, NAC, and TEMPOL.

[0020] The disclosed compositions can consist of at least one of TUDCA, NAC, and TEMPOL.

[0021] The disclosed compositions can consist of at least two of TUDCA, NAC, and TEMPOL.

[0022] The disclosed compositions can consist of TUDCA, NAC, and TEMPOL.

[0023] The disclosed compositions can include a pharmaceutically acceptable carrier.

[0024] The disclosed compositions may be in any pharmaceutically acceptable form, such as solid dosage forms, including pills and tablets. In embodiments, the solid dosage form may dissolve at or above a specific pH value. For example, in embodiments involving the treatment of CD, the solid dosage form may be formulated to dissolve at, for example, 7.0 or above. By providing a composition that dissolves at a specific pH value, the composition may be more precisely targeted to tissues and organs beyond the stomach.

[0025] The disclosed compositions can include, for example, liquid solutions for topical use or for use via injection, such as intravenous injection.

[0026] The disclosed compositions can be administered via any suitable route, such as topically, orally, or parenterally. In some embodiments, TEMPOL / TUDCA / NAC and / or combinations thereof are administered topically (cutaneously and / or transdermally), orally, sublingually, rectally, ocularly, intramuscularly, subcutaneously, or intravenously.

[0027] The compositions disclosed herein can be administered individually, i.e., sequentially in any order, or simultaneously. Simultaneous administration can be via any acceptable dosage form and administration route. Sequential administration can be carried out using individually packaged formulations. In some embodiments, the oral dosage form that can be provided to patients is a blister bag containing multiple individual compositions in the same package.

[0028] The disclosed methods include, but are not limited to, methods of treating several inflammation-related conditions, such as IBD (including CD and ulcerative colitis (UC)), nonalcoholic steatohepatitis (NASH), fatty liver disease (FLD), macular degeneration, and glaucoma. Further embodiments include limiting or preventing chemotherapy-induced liver toxicity. In embodiments, the disclosed methods may include administration before, concurrently with, or after chemotherapy.

[0029] The disclosed methods may include administering a composition containing a combination of antioxidants, or administering multiple compositions each containing a single antioxidant. The disclosed methods may include administering compositions in different forms. For example, in embodiments, a liquid antioxidant composition may be administered with a solid composition, or a capsule may be administered with a powder or spray, etc. [Brief explanation of the drawings]

[0030] [Figure 1] Shows the physical appearance of a "fatty" liver. [Figure 2] Shows the back of the eye showing macular degeneration. [Figure 3] Shown is the Amsler grid test, which helps identify distorted vision typical of macular degeneration. DETAILED DESCRIPTION OF THE INVENTION

[0031] TUDCA and UDCA are pleiotropic drugs with multiple cellular targets, capable of inhibiting apoptosis and upregulating survival pathways. The unfolded protein response (UPR), endoplasmic reticulum stress, and apoptosis are all important factors involved in many diseases, and inhibition of these events is known to be able to alter the course or manifestation of the disease. It is not surprising that the Chinese have used bear bile for hundreds of years to treat many ailments, as TUDCA and UDCA constitute over 50% of the "bile pool" in bear bile, compared with only 2% in humans.

[0032] (definition) "Administration" or "administering" means the step of giving (i.e., administering) a medical device, material, or agent to a subject. The materials disclosed herein can be administered by several suitable routes.

[0033] "Chemotherapy-related" means a condition (such as toxicity) that occurs as a result of chemotherapy.

[0034] "Patient" means a human or non-human subject receiving medical or veterinary treatment.

[0035] "Parenteral administration" and "administered parenterally" are art-recognized terms and include modes of administration other than enteral and topical administration, such as injection, including, but not limited to, retroorbital, intraocular, intravenous, intramuscular, intrapleural, intravascular, intrapericardial, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, intracutaneous, intra-articular, subcapsular, intrathecal, intraspinal and intrasternal injection and infusion.

[0036] "Pharmaceutically acceptable" or "therapeutically acceptable" refers to a material that does not interfere with the efficacy or biological activity of the active ingredients and that is not toxic to the patient.

[0037] A "pharmaceutically acceptable carrier" is art-recognized and includes, for example, a liquid or solid filler, diluent, excipient, solvent, encapsulating material, or other pharmaceutically acceptable material, composition, or vehicle that is involved in carrying or transporting a subject composition from one organ or body part to another. Each carrier must be "acceptable" in the sense of being compatible with (being able to dissolve or carry) the other ingredients of the subject composition and not harmful to the patient. In certain embodiments, a pharmaceutically acceptable carrier is non-pyrogenic. Exemplary materials that can serve as pharmaceutically acceptable carriers include sugars such as lactose, glucose, and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethylcellulose, ethyl cellulose, and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, and soybean oil; glycols such as propylene glycol; polyols such as glycerin, sorbitol, mannitol, and polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffers such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol; phosphate buffer; and other non-toxic compatible substances used in pharmaceutical formulations.

[0038] A "pharmaceutical composition" refers to a formulation containing an active ingredient. The term "formulation" refers to the presence of at least one additional component in addition to the active ingredient in the pharmaceutical composition (e.g., but not limited to, albumin (such as human serum albumin or recombinant human albumin) and / or sodium chloride). Thus, a pharmaceutical composition is a formulation suitable for diagnostic, therapeutic, or cosmetic administration to a subject, such as a human patient. A pharmaceutical composition can be in a lyophilized or vacuum-dried state, a solution formed after reconstitution of a lyophilized or vacuum-dried pharmaceutical composition with saline or water, or a solution that does not require reconstitution. As noted above, a pharmaceutical composition can be liquid, semi-liquid, or solid. A pharmaceutical composition can be animal protein-free. The pharmaceutical compositions disclosed herein can optionally contain other pharmaceutically acceptable ingredients (or medicinal ingredients), including, but not limited to, buffers, preservatives, tonicity adjusters, salts, osmotic pressure adjusters, physiological substances, pharmacological substances, bulking agents, emulsifiers, wetting agents, flavorings, coloring agents, suspending agents, etc.

[0039] "Reduce," "suppress," and "inhibit" have the commonly understood meaning of "to lessen" or "to decrease."

[0040] "Therapeutic formulation" means a formulation that can be used to treat and thereby alleviate a disorder or disease and / or symptoms associated therewith.

[0041] "Therapeutically effective amount" refers to the level, amount, or concentration of a drug, material, or composition needed to achieve a therapeutic goal.

[0042] "Treat," "treating," or "treatment" means the alleviation or relief (some relief, significant relief, and nearly complete relief), elimination, or prevention (temporary or permanent) of symptoms, disease, disorder, or condition, such as by healing injured or damaged tissue, or by altering, altering, strengthening, ameliorating, improving, and / or beautifying an existing or known disease, disorder, or condition, to achieve a desired therapeutic or cosmetic result.

[0043] (Antioxidant composition) Disclosed embodiments include pharmaceutical compositions, which in embodiments may be in any suitable form, such as a liquid, such as an aqueous liquid, a solid, a semi-solid, a gel, a sustained release form, such as an implant, etc.

[0044] The disclosed compositions can include at least one antioxidant, a compound that inhibits oxidation, a chemical reaction that can cause free radicals and chain reactions that can damage cells. For example, the disclosed compositions can include several classes of antioxidants. For example, antioxidants suitable for use in the disclosed embodiments can be classified as enzymatic or non-enzymatic antioxidants. a. Hazardous oxidation products are converted to H2O2 and then to water by enzymatic antioxidants that can decompose free radicals in a multi-step process in the presence of cofactors such as copper (Cu), zinc (Zn), manganese (Mn), selenium (Se), and iron (Fe). b. In contrast, vitamin C, vitamin E, plant polyphenols, carotenoids, and glutathione are nonenzymatic antioxidants that function by interfering with free radical chain reactions. c. Antioxidants can be categorized based on their size as small molecule or large molecule antioxidants. Small molecule antioxidants neutralize reactive oxygen species (ROS) in a process termed radical scavenging. Vitamin C, vitamin E, carotenoids, and glutathione (GSH) are the primary antioxidants in this category. d. Large molecule antioxidants include enzymes (SOD, CAT, and GPx) and sacrificial proteins (albumin) that absorb ROS and prevent them from attacking other essential proteins.

[0045] The disclosed compositions can include either enzymatic, non-enzymatic antioxidants, small molecule, or large molecule oxidants. For example, the disclosed compositions can include the non-enzymatic antioxidant TUDCA: [ka] may include:

[0046] TUDCA, a taurine conjugate of ursodeoxycholic acid (UDCA), is approved by the Food and Drug Administration (FDA) for primary biliary cholangitis (PBC). UDCA is approved for the treatment of certain cholestatic liver diseases due to its hepatocellular protective properties. TUDCA and UDCA function by interfering with the mitochondrial pathway of cell death and have been shown to act as potent inhibitors of apoptosis. Additionally, they have been shown to inhibit ROS, reduce endoplasmic reticulum (ER) stress, and stabilize the unfolded protein response (UPR).

[0047] TUDCA has been shown to be protective and downregulate the inflammatory cascade. a.Inhibits epithelial cytokine release b. Inhibits the recruitment of immune cells c. inhibits immune cell activation d. Inhibits apoptosis (cell death) caused by inflammation and impaired barrier function e. Promotes epithelial cell recovery f. Repair the mucus layer g. Repairing the microbiome h.Inhibits ROS production i. Prevent Bax-induced mitochondrial membrane perturbation j. Downregulating the unfolded protein response (UPR) k. Inhibits endoplasmic reticulum (ER) stress l. Regulates the expression of cell cycle proteins m. Activates the bile acid receptor farnesoid X

[0048] Similarly, N-acetyl-L-cysteine ​​(NAC) is a non-enzymatic antioxidant that can be used in the disclosed compositions. [ka]

[0049] NAC is an FDA-approved drug widely used to treat acetaminophen (paracetamol) overdose. It is also approved for use in conditions associated with abnormally viscous or flatulent mucus secretions that promote mucus plugging, such as pneumonia, bronchitis, tracheobronchitis, cystic fibrosis, post-traumatic chest disease, and before diagnostic bronchoscopy. Off-label uses include acute liver failure, prevention of contrast nephropathy, and topical treatment of keratoconjunctivitis sicca. Animal and human studies have shown that its use reduces cisplatin-induced nephrotoxicity.

[0050] NAC has been shown to protect against an acetic acid-induced experimental colitis model in rats. Acetic acid-induced colitis is characterized by increased myeloperoxidase (MPO) activity, an indicator of colonic accumulation or infiltration of polymorphonuclear neutrophils. Treatment with NAC (100 mg / kg) for 7 days significantly reduced MPO activity and restored GSH and NO concentrations in colonic tissue compared with vehicle controls. Macroscopic and histological findings also suggested a protective role for NAC. Some of the effects of NAC are shown in the table below.

[0051] [Table 1]

[0052] Similarly, 4-hydroxy-TEMPO or TEMPOL, formally 4-hydroxy-2,2,6,6-tetramethylpiperidine-1-oxyl, is a non-enzymatic antioxidant that can be used in the disclosed compositions. [ka]

[0053] TEMPOL is a synthetic antioxidant with an excellent profile, demonstrating safety and well-tolerated efficacy with acute or chronic administration. Its half-life is consistent with once- or twice-daily dosing. It has been shown to be effective in numerous published studies, with over 2,000 published articles, including many from the National Cancer Institute and the FDA. It can be administered as an oral liquid, solid, topical, or intravenous route. Furthermore, it prevents and reverses the production of free radicals, thereby preventing or reducing oxidative stress resulting from infection, inflammation, tissue injury, chemotherapy, and radiation.

[0054] TEMPOL promotes the metabolism of reactive oxygen and nitrogen species in a variety of cells, reducing oxidative stress. TEMPOL is uncharged and is transported into cells across membranes. It is non-toxic and non-immunogenic to normal cells. It does not react with biomolecules or dimerize. Its steric hindrance in structure allows it to react only with small reactive oxygen species. More specifically, TEMPOL: a. It is a redox-cycling nitroxide that promotes the metabolism of many reactive oxygen species (ROS) and improves the bioavailability of nitric oxide. b. Neutralizes reactive oxygen species (ROS) generated by infection, tissue injury, inflammation, radiation, and / or chemotherapy and acts as an SOD mimetic. c. Acts as an antioxidant and anti-inflammatory substance. d. Reduce oxidative stress by repairing damaged mitochondria and preventing increased free radical production. Restore mitochondrial stability and viability. e. It has been shown to downregulate pro-inflammatory cytokines such as IL-6, IL-8, IL-1 beta, TNF-alpha, and interferon-gamma. f.Inhibits NF-κB, a key regulator of inflammation. g. Reduces cytokine production in the retina and optic nerve. Has the following gene regulatory effects:

[0055] Gene regulation studies on TEMPOL have shown its ability to regulate a variety of genes, including: a. Statistically increased ADIPOQ gene expression. Increased ADIPOQ reduces inflammatory responses. b. It is also a key regulator of pro-inflammatory TNFα and downregulates TNFα. c. TEMPOL has a positive effect on genes that control the cell cycle and programmed cell death (apoptosis). TEMPOL significantly increases UNC5b and promotes cell death in cancer cells. d. Significantly increases the expression of glutathione S-transferase (GST) genes, which are essential for cellular defense in response to destructive free radicals. e. Significantly increase the expression level of keratinocyte growth factor (KGF) gene. KGF stimulates the proliferation and differentiation of epithelial cells. It significantly reduces the expression of genes encoding the f.26s proteasome complex. Abnormal cells naturally increase the expression of these genes, leading to an increase in misfolded proteins. g. Statistically reduces the expression of HIF-1α and HIF-2α. Elevated levels are strongly correlated with metastasis, tumor resistance, and progression of ocular disease.

[0056] The beneficial biological effects of TEMPOL range from protection against cancer, radiation, chemotherapy, metabolic syndrome, and shock to protection of inflammatory bowel disease, the eyes, liver, heart, kidneys, and central nervous system. TEMPOL has also been shown to reduce platelet activation, reduce pneumonia, protect non-cancerous cells from various toxic substances, including chemotherapeutic drugs such as paclitaxel, doxorubicin, and cisplatin, and alleviate and prevent chemotherapy-induced neuropathic pain by reducing levels of inflammatory cytokines and free radicals in the dorsal root ganglion.

[0057] Tempol has been studied in hundreds of animal models of oxidative stress and inflammation. No safety concerns have been identified. Topical Tempol has been shown to reduce eye damage in rat and rhesus monkey models.

[0058] Because of its broad spectrum of action, TEMPOL may be more effective than a single anti-cytokine agent. TEMPOL has been used topically in multiple human studies of radiation dermatitis and has been shown to prevent radiation-induced alopecia in human clinical trials. These alopecia studies were conducted by a former head of the FDA. TEMPOL (oral formulation) is currently being tested in a Phase 2 trial for radiation-induced mucositis in head and neck cancer.

[0059] The disclosed compositions can include at least one of TUDCA, NAC, and TEMPOL.

[0060] The disclosed compositions can include at least two of TUDCA, NAC, and TEMPOL.

[0061] The disclosed compositions can include TUDCA, NAC, and TEMPOL.

[0062] The disclosed compositions can consist of at least one of TUDCA, NAC, and TEMPOL.

[0063] The disclosed compositions can consist of at least two of TUDCA, NAC, and TEMPOL.

[0064] The disclosed compositions can consist of TUDCA, NAC, and TEMPOL.

[0065] (Treatment method) Disclosed embodiments include methods of treatment, e.g., methods comprising the administration of at least one composition described herein. Disclosed methods include, for example, treatment of:

[0066] (inflammatory bowel disease) IBD is a global medical problem with a continuously increasing incidence. IBD is a chronic inflammation of the intestinal (GI) tract. IBD is a multifactorial disorder characterized by genetic susceptibility, immune cell hyperactivation, microbial dysbiosis, and altered intestinal barrier permeability. IBD is usually further classified as CD or UC, which are differentiated by the location and depth of the lesion in the intestinal wall. Both inflammatory conditions increase the risk of colorectal cancer. In embodiments, the combination of TUDCA and NAC may provide a synergistic effect in the treatment of IBD.

[0067] [Table 2-1] [Table 2-2]

[0068] (Crohn's disease / ulcerative colitis) CD is a chronic inflammation of the gastrointestinal tract that spreads through the intestinal wall. While it can occur in any part of the gastrointestinal tract, the small intestine, particularly the ileum, is the most commonly affected organ, followed by the large intestine. Crohn's disease is an autoimmune disease. In CD, once the immune system triggers an inflammatory response, it persists. For the treatment of CD, reductions in serum and mucosal levels of antioxidant vitamins A, C, E, and beta-carotene have been reported in Crohn's disease patients. Antioxidants have been shown to inhibit the production of inflammatory cytokines, such as IL-1 and TNFα, in the colonic mucosa of patients with inflammatory bowel diseases, including CD. Furthermore, TUDCA reduces inflammatory cytokines, including TNFα, induces the resolution of ER stress in intestinal epithelial cells, and improves tight junction function, lipid transport, and the intestinal microbiota.

[0069] UC, along with Crohn's disease and microscopic colitis, is a type of inflammatory bowel disease. It is a long-term condition that results in inflammation and ulcers of the colon and rectum. The main symptoms of active disease are abdominal pain and bloody diarrhea. Weight loss, fever, and anemia may also occur. Symptoms often develop slowly and can range from mild to severe. Symptoms typically occur intermittently, with symptom-free periods between attacks. Complications can include abnormal dilation of the colon, inflammation of the eyes, joints, or liver, and colon cancer.

[0070] The combinations as disclosed herein may provide synergistic therapeutic effects, for example, in the treatment of UC and CD, due to the combination of the following effects, including synergistic effects:

[0071] [Table 3-1] [Table 3-2]

[0072] (Glaucoma / Macular degeneration) Glaucoma is a group of eye diseases that damage the optic nerve and cause vision loss. The most common type is open-angle (wide-angle, chronic simple) glaucoma, in which the angle for drainage of fluid within the eye remains open; less common types include angle-closure (narrow-angle, acute congestive) glaucoma and normal-tension glaucoma. Open-angle glaucoma progresses slowly over time and is painless. Peripheral vision begins to deteriorate, followed by central vision, and, if untreated, can lead to blindness.

[0073] Glaucoma is characterized by optic nerve damage and progressive degeneration of retinal ganglion cells (RCGs), which are key components of vision loss. Current glaucoma treatments target lowering intraocular pressure (IOP), but because RCG death is the cause of irreversible vision loss, neuroprotection may be a viable strategy for glaucoma treatment. Oxidative stress is consistently identified as a significant risk factor for human glaucoma, and plasma levels of the antioxidant glutathione (GSH) are reduced in glaucoma patients.

[0074] Oxidative stress-induced signaling of neuroinflammation in glaucoma involves the stimulation of transcriptional programs of inflammatory mediators such as IL-1, IL-2, IFN-α, and TNFα. The ROS master transcriptional regulator of cytokine production, nuclear factor kappa beta (NF-κβ), is upregulated in human glaucoma and animal models. Results from experimentally induced glaucoma in C57BL / 6J mice showed that treatment with tempol reduced neuroinflammation in the retina and optic nerve of hypertensive mice. Notably, tempol is blood-brain barrier permeable and readily accessible to intracellular compartments.

[0075] N-acetylcysteine ​​(NAC) has been shown to have a beneficial (protective) effect in primary cultures of human retinal pigment epithelium (PRE) from patients with AMD. NAC protects against oxidative stress by inhibiting the accumulation of excessive ROS in the RPE of both AMD-positive and AMD-negative donors and by preventing both H2O2-induced cell death and GSH depletion in PRE. NAC also improved basal mitochondrial function (ATP) in both groups of cells. Strong experimental evidence supports the view that mitochondrial damage is a key event in the progression of AMD pathology.

[0076] Several beneficial effects specific to the PRE in AMD include a reduction in basal ROS, an increase in basal GSH content, and increased post-oxidative NAC protection. Notably, the PRE is adjacent to the choriocapillaris, the primary source of oxygen to the outer retina, placing it in a highly oxidative environment. Furthermore, the oxidative environment within the RPE is dominated by reactive oxygen species (ROS), which are generated as a product of the reaction between light and abundant photosensitizers (lipofuscin and melanin). These results support the validity of NAC as a potential treatment for AMD, given the importance of maintaining RPE mitochondrial function for overall retinal health.

[0077] Notably, intraperitoneal injection of NAC suppressed oxidative and ER stress in a mouse model of light-induced retinal degeneration, while inhibiting ROS accumulation in the retina of Balb / c mice. Furthermore, in a study of mouse dry eye, topical administration of NAC reduced ROS levels and inflammasome signaling. These studies 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 demonstrated in rd10+ / + mice, a model of retinitis pigmentosa. This is significant because NAC, when applied to the cornea, can penetrate to the posterior segment of the eye and protect the retina.

[0078] NAC has a long history of successful use in multiple diseases in which elevated ROS induces pathology. NAC has also been shown to have protective effects against 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 along with elevated glutathione levels following NAC treatment. NAC has been shown to prevent the decline of retinal function and to be neuroprotective. NAC treatment also protects retinal ganglion cells (RCGs) from NTG-like neurodegeneration. EAAC1 is expressed in retinal neurons, including RCGs. EAAC1 transports not only extracellular glutamate but also cysteine, an important substrate for glutathione (GST) synthesis, to neurons. GSH, as a retinal antioxidant, plays a potent protective role against oxidative stress. Oxidative stress is one of the causes of glaucoma. The reduced plasma levels of GST in primary open-angle glaucoma, including NTG patients, support the suitability of this mouse model for basic research in NTG. Therefore, targeting oxidative stress in the retina in conjunction with IOP-lowering treatments may be a therapeutic strategy for treating glaucoma.

[0079] Another bile acid receptor is the transmembrane G protein-coupled receptor 5 (TGR5), which is widely distributed throughout the body. This has led to new explorations of bile acid (BA)-based therapeutics and the extrahepatic homeostatic functions of bile acids in lipid, glucose, and energy metabolism, including several ophthalmic diseases, including MD.

[0080] Macular degeneration damages the macula, which provides sharp central vision. The macula is the most sensitive part of the retina. It's located at the back of the eye. The retina converts light into electrical signals that are sent through the optic nerve to the brain, where they are converted into the images we see. There are two types of macular degeneration: a. Dry macular degeneration. This is the most common form of macular degeneration. The cells in the macula slowly break down. This causes first blurring and then blank spaces in the eye's central vision. The symptoms are subtle at first and then become more noticeable. Some cases of dry macular degeneration progress to the more serious wet macular degeneration. b. Wet Macular Degeneration. All wet macular degeneration begins as the dry form. At some point, new blood vessels begin to grow in the retina. The new vessels leak blood and fluid into the macula, causing scarring. Wet macular degeneration can cause rapid vision loss within days to weeks, with continued vision loss over time.

[0081] TUDCA has recently been shown to inhibit apoptosis following cell injury in several models of neurodegeneration and injury, including retinal degeneration. The mechanisms of action include mitochondrial membrane stabilization, inhibition of apoptosis, and prevention of endoplasmic reticulum (ER) stress.

[0082] Optic nerve crush models in both mice and rats have been used to induce retinal ganglion cell (RCG) death. RCG loss occurs in a manner comparable to glaucoma (severe acute glaucoma model). TUDCA treatment has been used in these models with similarly favorable results. Systemic treatment with TUDCA significantly enhanced RCG survival and inhibited apoptosis after optic nerve crush. In glaucoma, RCGs die in at least three ways: mechanical injury to axons, vascular insufficiency, and extracellular toxic injury. Surgical crushing mimics mechanical injury to RCG axons exiting the eye, while indirect partial occlusion of the central retinal vein (through which the optic nerve bundle passes) mimics the vascular insufficiency of glaucoma. The extracellular toxic injury seen in glaucoma is mimicked in the optic nerve crush model, and crushing increases both intraocular glutamate and aspartate levels.

[0083] Another model that causes corneal and retinal damage is the ocular alkali burn (OAB) model. It is one of the most severe ocular emergencies, accounting for 6.9% to 13.2% of ocular injuries. In the OAB model, treatment with TUDCA has been shown to inhibit ocular inflammation and protect the cornea and retina from injury. The healing and preventive effects of TUDCA are more effective in combination with TEMPOL.

[0084] Considering the mechanism of action and current experimental evidence, the combination of TUDCA and NAC may play an important role in the treatment of glaucoma and MD. For example, the following effects can be combined to produce a synergistic effect:

[0085] [Table 4]

[0086] Similarly, a combination of TUDCA and NAC can be used to treat glaucoma and MD, possibly resulting in a synergistic effect.

[0087] [Table 5]

[0088] (non-alcoholic steatohepatitis) The FDA has approved TUDCA for the treatment of certain cholestatic liver diseases. TUDCA was recently approved in Canada and the United States for amyotrophic lateral sclerosis (ALS) (or Lou Gehrig's disease). TUDCA is also available over the counter as a dietary supplement.

[0089] Many anticancer drugs can cause blockage of the central and sublobular veins of the liver, leading to SOS and other liver problems such as elevated liver enzymes and bilirubin levels above normal. This can lead to toxicity and liver dysfunction. Up to 85% of patients develop fatty liver during chemotherapy, which is more severe when accompanied by elevated bilirubin levels. All of these are signs of hepatitis, which increases the risk of developing FLD and increases apoptosis.

[0090] Because the liver is the central organ for intermediary metabolism, metabolic detoxification, and waste excretion, having as many functioning hepatocytes as possible is essential for the proper delivery of chemotherapy.

[0091] To this end, TUDCA and UDCA have been shown to exert protective effects in the liver by reducing apoptosis, interfering with the mitochondrial pathway of cell death, protecting enzymes and bile acids, and inhibiting reactive oxygen species. Given these attributes, TUDCA is an excellent candidate for liver protection during chemotherapy. Indeed, TUDCA may allow for higher doses of chemotherapy, potentially resulting in better clinical outcomes.

[0092] The liver's antioxidant capacity depends on the production of glutathione, which prevents free radical production. N-acetyl-L-cysteine ​​(NAC) is known to create healthy glutathione levels and promote normal liver function. Furthermore, NAC is known to be a powerful antioxidant that protects cells from oxidative stress. Because chemotherapy can have long-term effects (damage to cognition, hearing, heart, lungs, blood, nerves, and reproductive function), dual therapy may enable appropriate management to reduce morbidity and mortality. In addition to TUDCA, NAC has been shown to aid in detoxification of kidney and liver damage, potentially improving cognitive function, potentially helping to alleviate symptoms of respiratory disease, potentially improving male and female reproductive function, and potentially stabilizing blood sugar.

[0093] Regarding FLD, interest in bile acids (BAs) arose from the discovery of their signaling properties and ability to regulate the activity of many genes through an orphan nuclear receptor (farnesoid X receptor, RXR). FXR agonists have shown potential as therapeutic agents for primary biliary cirrhosis and nonalcoholic steatohepatitis.

[0094] The liver is the body's largest organ. It helps the body digest food, stores energy, and removes toxins. Fatty liver disease is a condition in which fat accumulates in the liver. There are two main types depending on the cause: a. Alcoholic fatty liver disease, also known as alcoholic steatohepatitis (AS) b. Nonalcoholic fatty liver disease (NAFLD)

[0095] These two forms then progress to increasingly severe cirrhosis.

[0096] The gut-liver axis is associated with the progression of NAFLD. Therefore, targeting the gut-liver axis with bile acid-based combination drugs should prove beneficial in the treatment of NAFLD. Studies have shown that TUDCA meets this criteria. In mice, TUDCA treatment significantly reduced high-fat diet-induced NAFLD. In addition to the generally accepted protective effects of ER stress, TUDCA also attenuates intestinal inflammation, improves intestinal barrier function, reduces intestinal fat transport, and modulates gut microbiota composition.

[0097] There are indications that TUDCA may reduce the severity of NAFLD and NASH by reducing liver inflammation. TUDCA may be used to protect stem cells by downregulating the inflammatory cascade, reducing ROS, inhibiting apoptosis, reducing ER stress, and stabilizing the UPR.

[0098] TUDCA alone has been shown to attenuate the progression of HFD-induced NAFLD in mice by improving intestinal inflammation, improving intestinal barrier protection, reducing intestinal fat transport, and modulating the gut microbiota. Furthermore, a combination drug for treating NASH may play a significant role in reducing cardiovascular disease, chronic kidney disease, and intrahepatic and extrahepatic malignancies, all of which are associated with NAFLD.

[0099] The combination of TUDCA and NAC creates a broader range of disease-fighting mechanisms than either agent alone. This should enable the combination to be more effective than a single agent in treating complex diseases. NASH is one example. Currently, there are no approved drugs for the treatment of NASH, but several are in clinical trials. The disease mechanisms that cause NASH and fibrosis are complex and involve both metabolic and inflammatory pathways, including: a. Insulin resistance and lipid metabolism b. Lipotoxicity and immune activation c.Cell death d. Fibrogenesis and collagen turnover

[0100] The combination of TUDCA and NAC targets both metabolic dysfunction and cellular injury. Based on published literature, TUDCA and NAC have complementary effects on many of the known biological mechanisms that are active in NASH.

[0101] Antioxidant activity plays an important role in liver protection, and NAC is a potent antioxidant. NAC may be beneficial in disorders caused by oxidative stress (OS). For example, in mice fed a high-fat diet (HFD), NAC significantly reduced hepatic steatosis and metabolic disorders compared with normal-fed mice. NAC completely restored normal liver tissue morphology. Larger lipid droplets and larger adipocytes were found to be more abundant in HFD mice. Furthermore, NAC-treated mice were shown to improve glucose tolerance, demonstrating that NAC can suppress HFD-induced metabolic disorders. Based on published literature, TUDCA and NAC have complementary effects on the known biological mechanisms of NASH. TUDCA alone has been shown to attenuate the progression of HFD-induced NAFLD in mice by improving intestinal inflammation, improving intestinal barrier protection, reducing intestinal fat transport, and modulating the gut microbiota.

[0102] The combinations as disclosed herein may provide a synergistic treatment in NASH.

[0103] [Table 6-1] [Table 6-2]

[0104] Similarly, combined treatment with TUDCA and NAC, if synergistic, can be used to treat NASH.

[0105] [Table 7-1] [Table 7-2]

[0106] (Treatment of chemotherapy-related liver toxicity) The disclosed compositions can be used to prevent, limit, or reduce chemotherapy-related liver toxicity. The disclosed compositions can be administered before, simultaneously with, or after cancer treatment to prevent, limit, or reduce chemotherapy-related liver toxicity. For example, in embodiments, the disclosed compositions can be administered before, simultaneously, or after a chemotherapy regimen including alkylating agents, antimetabolites, antitumor antibiotics, topoisomerase inhibitors, mitotic inhibitors, plant alkaloids, combinations thereof, and the like.

[0107] For example, in embodiments, the disclosed compositions may be administered before, concurrently with, or after a chemotherapy regimen including any of the following:

[0108] Alkylating agents, including: a. Altretamine b. Bendamustine C. Busulfan d. Carboplatin e. Carmustine f. Chlorambucil g. Cisplatin h. Cyclophosphamide i. Dacarbazine j. Ifosfamide K. Lomustine l. Mechlorethamine m.melphalan n. Oxaliplatin o. Temozolomide P. thiotepa q.Trabectedin

[0109] Nitrosoureas, including Carmustine b. Lomustine C. streptozocin

[0110] Antimetabolites, including: Azacitidine b. 5-fluorouracil (5-FU) c. 6-mercaptopurine (6-MP) d. Capecitabine (Xeloda) Cladribine f. Clofarabine g. Cytarabine (Ara-C) h. Decitabine i.Floxuridine j. Fludarabine k. Gemcitabine (Gemzar) l. Hydroxyurea m. methotrexate n.Nelarabbin Pemetrexed (Alimta) P. Pentostatin Q. Pralatrexate r. thioguanine s. Trifluridine / tipiracil combination

[0111] Antitumor antibiotics, including: Daunorubicin b. Doxorubicin (Adriamycin) c. Doxorubicin liposome d. epirubicin e. Idarubicin f. Barbicin G. Bleomycin h. Dactinomycin i. Mitomycin C j. Mitoxantrone (also acts as a topoisomerase II inhibitor)

[0112] Topoisomerase I inhibitors (also called camptothecins), including: Irinotecan b. Irinotecan liposome c. Topotecan

[0113] Topoisomerase II inhibitors (also called epipodophyllotoxins), including: Etoposide (VP-16) b. Mitoxantrone (also acts as an antitumor antibiotic) c. Teniposide

[0114] Mitotic inhibitors, including taxanes and vinca alkaloids: a. Taxanes, including: i. Cabazitaxel ii. Docetaxel iii. Nab-paclitaxel iv. Paclitaxel b. Vinca alkaloids, including: i. Vinblastine ii. Vincristine iii. Vincristine liposomes iv. Vinorelbine

[0115] Corticosteroids, including: Prednisone b. Methylprednisolone c. Dexamethasone

[0116] Other chemotherapy drugs, including: all-trans retinoic acid b. Arsenic trioxide C. asparaginase d.Eribulin e. Hydroxyurea f. Ixabepilone g. Mitotane h. Omacetaxine i. Pegaspagase j. Procarbazine K. Romidepsin l. Vorinostat

[0117] The disclosed methods can further include radiation therapy.

[0118] Thus, the disclosed embodiments include the treatment of chemotherapy-related hepatotoxicity with the administration of the disclosed antioxidant compositions.

[0119] Further embodiments may include treatment of the conditions in the table below with the disclosed compositions, optionally with a synergistic effect.

[0120] [Table 8]

[0121] The disclosed methods can include administering a composition comprising multiple antioxidants, e.g., NAC, TEMPOL, and TUDCA. In embodiments comprising two antioxidants, the relative weight ratio of the two can be, for example, 1:1, 1:2, 1:3, 1:4, 1:5, etc. Furthermore, the relative weight ratio can be expressed as A:B, where A and B are values ​​between 1 and 99%, and the total percentage equals 100.

[0122] In embodiments including three antioxidants, the relative weight ratio of the three can be, for example, 1:1:1, 1:2:1, 1:3:1, etc. Furthermore, the relative weight ratio of the two can be expressed as A:B:C, where A, B, and C are values ​​between 1 and 99%, and the total percentage equals 100.

[0123] The disclosed compositions can further comprise a pharmaceutically acceptable carrier.

[0124] The disclosed compositions can include any pharmaceutically acceptable form, such as liquids and solids, including pills and tablets. In embodiments, the solid dosage forms can dissolve above a certain pH value, such as 7.0.

[0125] The disclosed methods of treatment can include administration of the disclosed compositions in appropriate doses. For example, in disclosed embodiments, dosages may include, for example, administration of less than 3000 mg, less than 2900 mg, less than 2800 mg, less than 2700 mg, less than 2600 mg, less than 2500 mg, less than 2400 mg, less than 2300 mg, less than 2200 mg, less than 2100 mg, less than 2000 mg, less than 1900 mg, less than 1800 mg, less than 1700 mg, less than 1600 mg, less than 1500 mg, less than 1400 mg, less than 1300 mg, less than 1200 mg, less than 1100 mg, less than 1000 mg, less than 900 mg, less than 800 mg, less than 700 mg, less than 600 mg, less than 500 mg, less than 400 mg, less than 300 mg, less than 200 mg, less than 100 mg, less than 50 mg, etc. of TUDCA once daily.

[0126] In embodiments, daily doses of TUDCA may include between 250 mg and 3000 mg, between 500 mg and 2500 mg, between 1000 mg and 2000 mg, and the like.

[0127] In embodiments, the daily dose of TUDCA may include 5-35 mg / kg body weight, 10-30 mg / kg body weight, 15-25 mg / kg body weight, etc.

[0128] In embodiments, the daily dose of TUDCA is 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, 1600 mg, 1700 mg, 1800 mg, 1900 mg, 2000 mg, 2100 mg, 2200 mg, 2300 mg, 2400 mg, 2500 mg, 2600 mg, 2700 mg, 2800 mg, 2900 mg, 3000 mg, 3100 mg, 3200 mg, 3300 mg, 3400 mg, 3500 mg, 3600 mg, 3700 mg, 3800 mg, 3900 mg, 4000 mg, 4100 mg, 4200 mg, 4300 mg, 4400 mg, 4500 mg, 4600 mg, 4700 mg, 4800 mg, 4900 mg, 5000 mg, 5100 mg, 5200 mg, 5300 mg, 5400 mg, 5500 mg, 5600 mg, 5700 mg, 5800 mg, 590 may include 550mg, 1600mg, 1650mg, 1700mg, 1750mg, 1800mg, 1850mg, 1900mg, 1950mg, 2000mg, 2050mg, 2100mg, 2150mg, 2200mg, 2250mg, 2300mg, 2350mg, 2400mg, 2450mg, 2500mg, 2550mg, 2600mg, 2650mg, 2700mg, 2750mg, 2800mg, 2850mg, 2900mg, 2950mg, 3000mg, etc.

[0129] The disclosed methods of treatment can include administration of the disclosed compositions in appropriate doses. For example, in disclosed embodiments, dosages can include, for example, administration of less than 3000 mg, less than 2900 mg, less than 2800 mg, less than 2700 mg, less than 2600 mg, less than 2500 mg, less than 2400 mg, less than 2300 mg, less than 2200 mg, less than 2100 mg, less than 2000 mg, less than 1900 mg, less than 1800 mg, less than 1700 mg, less than 1600 mg, less than 1500 mg, less than 1400 mg, less than 1300 mg, less than 1200 mg, less than 1100 mg, less than 1000 mg, less than 900 mg, less than 800 mg, less than 700 mg, less than 600 mg, less than 500 mg, less than 400 mg, less than 300 mg, less than 200 mg, less than 100 mg, less than 50 mg, etc. of TEMPOL once a day.

[0130] In embodiments, the daily dose of TEMPOL may include between 250 mg and 3000 mg, between 500 mg and 2500 mg, between 1000 mg and 2000 mg, and the like.

[0131] In embodiments, the daily dose of TEMPOL may include 5-35 mg / kg body weight, 10-30 mg / kg body weight, 15-25 mg / kg body weight, and the like.

[0132] In embodiments, the daily dose of TEMPOL is 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, may include 1550mg, 1600mg, 1650mg, 1700mg, 1750mg, 1800mg, 1850mg, 1900mg, 1950mg, 2000mg, 2050mg, 2100mg, 2150mg, 2200mg, 2250mg, 2300mg, 2350mg, 2400mg, 2450mg, 2500mg, 2550mg, 2600mg, 2650mg, 2700mg, 2750mg, 2800mg, 2850mg, 2900mg, 2950mg, 3000mg, etc.

[0133] The disclosed treatment methods can include administering the disclosed compositions at an appropriate dose. For example, in disclosed embodiments, the dose can include, for example, administration of less than 3000 mg, less than 2900 mg, less than 2800 mg, less than 2700 mg, less than 2600 mg, less than 2500 mg, less than 2400 mg, less than 2300 mg, less than 2200 mg, less than 2100 mg, less than 2000 mg, less than 1900 mg, less than 1800 mg, less than 1700 mg, less than 1600 mg, less than 1500 mg, less than 1400 mg, less than 1300 mg, less than 1200 mg, less than 1100 mg, less than 1000 mg, less than 900 mg, less than 800 mg, less than 700 mg, less than 600 mg, less than 500 mg, less than 400 mg, less than 300 mg, less than 200 mg, less than 100 mg, less than 50 mg, etc. of NAC once a day.

[0134] In embodiments, the daily dose of NAC may include between 250 mg and 3000 mg, between 500 mg and 2500 mg, between 1000 mg and 2000 mg, etc.

[0135] In embodiments, the daily dose of NAC may include 5-35 mg / kg body weight, 10-30 mg / kg body weight, 15-25 mg / kg body weight, etc.

[0136] In embodiments, the daily dose of NAC is 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, 1500 mg, 1600 mg, 1650 mg, 1700 mg, 1750 mg, 1800 mg, 1850 mg, 1900 mg, 2000 mg, 2100 mg, 2200 mg, 2300 mg, 2400 mg, 2500 mg, 2600 mg, 2700 mg, 2800 mg, 2900 mg, 3000 mg, 3100 mg, 3200 mg, 3300 mg, 3400 mg, 3500 mg, 3600 mg, 3700 mg, 3800 mg, 3900 mg, 4000 mg, 4100 mg, 4200 mg, 4300 mg, 4400 mg, 4500 mg, 4600 mg, 4700 mg, 4800 mg, 4900 mg, 5000 mg, 5100 mg, 5200 mg, 5300 mg, 5400 mg, 5500 It may contain 50mg, 1600mg, 1650mg, 1700mg, 1750mg, 1800mg, 1850mg, 1900mg, 1950mg, 2000mg, 2050mg, 2100mg, 2150mg, 2200mg, 2250mg, 2300mg, 2350mg, 2400mg, 2450mg, 2500mg, 2550mg, 2600mg, 2650mg, 2700mg, 2750mg, 2800mg, 2850mg, 2900mg, 2950mg, 3000mg, etc.

[0137] As mentioned above, administration of the disclosed embodiments may be via several suitable routes, such as:

[0138] [Table 9]

[0139] The disclosed compositions can be administered at any frequency that results in a therapeutic response. The disclosed methods can include the use of a loading dose, i.e., an initial high dose of an agent that is administered at the beginning of a course of treatment, which can then be tapered to a lower maintenance dose.

[0140] In embodiments, administration may be once, twice, three times, four times, five times, or more per day. In embodiments, administration may be every two days, every three days, every four days, every five days, every six days, once per week, twice per month, monthly, etc. In embodiments, administration is once per day.

[0141] (Commercially available / kit) The compositions and related materials can be commercialized by following standard procedures, such as appropriate sterilization and packaging. For example, the materials can be treated with UV / visible radiation (200-500 nm) using photoinitiators with different absorption wavelengths (e.g., Irgacure 184, 2959), preferably a water-soluble initiator (Irgacure 2959). Such irradiation is typically performed for 1-60 minutes, although longer irradiation times may be used depending on the method. Sterile filtration can also be used for sterilization.

[0142] Materials according to the present disclosure may be terminally sterile packaged and packaged in a suitable container (such as a box) (eg, with a specific product information leaflet) so as to remain sterile until use.

[0143] According to further embodiments, the composition may also be provided in kit form in combination with other components necessary for administration of the material to a patient, for example, a combination may be provided in kit form in which two or three components are administered by different routes of administration, e.g., one component is administered by one route of administration and the other component(s) are administered by a different route of administration.

[0144] Kits are designed in a variety of forms based on the particular deficiency they are designed to treat.

[0145] (Example) The following non-limiting examples are provided for illustrative purposes only to facilitate a more complete understanding of representative embodiments, and should not be construed as limiting any of the embodiments described herein.

[0146] Example 1 (Use in the treatment of CD) The disclosed composition, comprising NAC and TUDCA in a 1:1 w / w ratio, is administered to patients with CD. The solid composition dissolves at a pH value of 7 or higher.

[0147] Example 2 (Use in the treatment of CD) The disclosed composition, comprising NAC and TEMPOL in a 1:1 w / w ratio, is administered to patients with CD. The solid composition dissolves at pH values ​​of 7 or higher.

[0148] Example 3 (Use in the treatment of CD) The disclosed composition, comprising TEMPOL and TUDCA in a 1:2 w / w ratio, is administered to patients with CD. The solid composition dissolves at pH values ​​of 7 or higher.

[0149] Example 4 (Use in the treatment of UC) The disclosed composition, comprising NAC and TUDCA in a 1:1 w / w ratio, is administered to patients with UC. The solid composition dissolves at a pH value of 7 or higher.

[0150] Example 5 (Use in the treatment of UC) The disclosed composition, comprising NAC and TEMPOL in a 1:1 w / w ratio, is administered to patients with UC. The solid composition dissolves at pH values ​​of 7 or higher.

[0151] Example 6 (Use in the treatment of UC) The disclosed composition, comprising TEMPOL and TUDCA in a 1:2 w / w ratio, is administered to patients with UC. The solid composition dissolves at pH values ​​of 7 or greater.

[0152] Example 7 (Use in the treatment of macular degeneration) The disclosed composition, comprising NAC and TUDCA in a 1:1 w / w ratio, is administered to a patient with macular degeneration.

[0153] Example 8 (Use in the treatment of macular degeneration) The disclosed composition, comprising NAC and TEMPOL in a 1:1 w / w ratio, is administered to a patient with macular degeneration.

[0154] Example 9 (Use in the treatment of glaucoma) The disclosed composition, comprising TEMPOL and TUDCA in a 1:2 w / w ratio, is administered to patients with glaucoma.

[0155] Example 10 (Use in the treatment of glaucoma) The disclosed composition, comprising NAC and TUDCA in a 1:1 w / w ratio, is administered to a patient with glaucoma.

[0156] Example 11 (Use in the treatment of glaucoma) The disclosed composition, comprising NAC and TEMPOL in a 1:1 w / w ratio, is administered to a patient with glaucoma.

[0157] Example 12 (Use in the treatment of glaucoma) The disclosed composition, comprising TEMPOL and TUDCA in a 1:2 w / w ratio, is administered to patients with glaucoma.

[0158] Example 13 (Use in the treatment of FLD) The disclosed composition, comprising NAC and TUDCA in a 1:1 w / w ratio, is administered to patients with FLD.

[0159] Example 14 (Use in the treatment of FLD) The disclosed composition, comprising NAC and TEMPOL in a 1:1 w / w ratio, is administered to patients with FLD.

[0160] Example 15 (Use in the treatment of FLD) The disclosed composition, comprising TEMPOL and TUDCA in a 1:2 w / w ratio, is administered to patients with FLD.

[0161] Example 16 (Use in the treatment of NASH) The disclosed composition, comprising NAC and TUDCA in a 1:1 w / w ratio, is administered to patients with NASH.

[0162] Example 17 (Use in the treatment of NASH) The disclosed composition, comprising NAC and TEMPOL in a 1:1 w / w ratio, is administered to patients with NASH.

[0163] Example 18 (Use in the treatment of NASH) The disclosed composition, comprising TEMPOL and TUDCA in a 1:2 w / w ratio, is administered to patients with NASH.

[0164] Example 19 (Use in the treatment of cancer) The disclosed composition, comprising NAC, TUDCA, and TEMPOL in a 1:1:1 w / w ratio, is administered to a patient prior to chemotherapy.

[0165] Example 20 (Use in the treatment of cancer) The disclosed composition, comprising NAC and TUDCA in a 1:1 w / w ratio, is administered to a patient after chemotherapy.

[0166] Example 21 (Use in the treatment of cancer) The disclosed composition, comprising NAC and TEMPOL in a 1:1 w / w ratio, is administered to a patient concurrently with chemotherapy.

[0167] Example 22 (Use in the treatment of cancer) The disclosed composition, comprising NAC and TUDCA in a 2:1 w / w ratio, is administered to a patient prior to chemotherapy.

[0168] Example 23 (Use in the treatment of cancer) The disclosed composition, comprising NAC and TEMPOL in a 2:1 w / w ratio, is administered to patients after chemotherapy.

[0169] Example 24 (Use in the treatment of cancer) The disclosed composition, comprising TEMPOL and TUDCA in a 2:1 w / w ratio, is administered to patients concurrently with chemotherapy.

[0170] Example 25 (Use in the treatment of cancer) The disclosed composition, comprising NAC and TUDCA in a 1:2 w / w ratio, is administered to a patient prior to chemotherapy.

[0171] Example 26 (Use in the treatment of cancer) The disclosed composition, comprising NAC and TUDCA in a 1:2 w / w ratio, is administered to a patient after chemotherapy.

[0172] Example 27 (Use in the treatment of cancer) The disclosed composition, comprising NAC and TUDCA in a 1:2 w / w ratio, is administered to a patient concurrently with chemotherapy.

[0173] Example 28 (Use in the treatment of glaucoma) The disclosed composition, comprising NAC, TUDCA and TEMPOL in a 1:2:1 w / w ratio, is administered to a patient concomitantly with glaucoma.

[0174] Example 29 (Use in the treatment of CD) Two disclosed liquid compositions containing NAC and TUDCA (1:1 w / w active ingredient ratio) are administered to patients with CD.

[0175] Example 30 (Use in the treatment of CD) The disclosed solid composition containing NAC and a liquid composition containing TEMPOL (1:1 w / w active ingredient ratio) are administered to patients with CD.

[0176] Example 31 (Use in the treatment of CD) The disclosed solid composition containing TEMPOL and a liquid composition containing TUDCA (active ingredient ratio of 1:2 w / w) are administered to patients with CD.

[0177] Example 32 (Use in the treatment of UC) Two solid compositions in a 1:1 w / w ratio, one containing NAC and the other containing TUDCA, are administered to patients with UC.

[0178] Example 33 (Use in the treatment of UC) Two disclosed liquid compositions containing NAC and TEMPOL in a 1:1 w / w ratio are administered to patients with UC.

[0179] Example 34 (Use in the treatment of UC) A disclosed liquid composition containing TEMPOL and a disclosed solid composition containing TUDCA (1:2 w / w active ingredient ratio) are administered to patients with UC.

[0180] Example 35 (Use in the treatment of macular degeneration) The disclosed liquid composition containing NAC and TUDCA in a 1:1 w / w ratio is administered to a patient with macular degeneration.

[0181] Example 36 (Use in the treatment of macular degeneration) The disclosed liquid composition containing NAC and a solid composition containing TEMPOL (1:1 w / w active ingredient ratio) are administered to patients with macular degeneration.

[0182] Example 37 (Use in the treatment of glaucoma) The disclosed liquid composition containing TEMPOL and a solid composition containing TUDCA (1:2 w / w active ingredient ratio) are administered to patients with glaucoma.

[0183] Example 38 (Use in the treatment of glaucoma) The disclosed liquid composition containing NAC and TUDCA (1:1 w / w active ingredient ratio) is administered to patients with glaucoma.

[0184] Example 39 (Use in the treatment of glaucoma) The disclosed liquid composition containing NAC and TEMPOL (1:1 w / w active ingredient ratio) is administered to patients with glaucoma.

[0185] Example 40 (Use in the treatment of glaucoma) The disclosed liquid composition containing TEMPOL and TUDCA (1:1 w / w active ingredient ratio) is administered to patients with glaucoma.

[0186] Example 41 (Use in the treatment of FLD) The disclosed powder composition containing NAC and the disclosed liquid TUDCA (1:1 w / w active ingredient ratio) are administered to patients with FLD.

[0187] Example 42 (Use in the treatment of FLD) Two disclosed liquid compositions containing NAC and TEMPOL (1:1 w / w active ingredient ratio) are administered to patients with FLD.

[0188] Example 43 (Use in the treatment of CD) The disclosed composition, comprising NAC and TUDCA in a 1:1 w / w ratio, is administered to patients with CD. The solid composition dissolves at a pH value of 7 or higher. The combination of antioxidants provides a synergistic therapeutic effect.

[0189] Example 44 (Use in the treatment of CD) The disclosed composition, containing NAC and TEMPOL in a 1:1 w / w ratio, is administered to patients with CD. The solid composition dissolves at a pH value of 7 or higher. The combination of antioxidants provides a synergistic therapeutic effect.

[0190] Example 45 (Use in the treatment of CD) The disclosed composition, comprising TEMPOL and TEMPOL in a 1:2 w / w ratio, is administered to patients with CD. The solid composition dissolves at a pH value of 7 or greater. The combination of antioxidants provides a synergistic therapeutic effect.

[0191] Example 46 (Use in the treatment of UC) The disclosed composition, comprising NAC and TUDCA in a 1:1 w / w ratio, is administered to patients with UC. The solid composition dissolves at a pH value of 7 or higher. The combination of antioxidants provides a synergistic therapeutic effect.

[0192] Example 47 (Use in the treatment of UC) The disclosed composition, comprising NAC and TEMPOL in a 1:1 w / w ratio, is administered to patients with UC. The solid composition dissolves at a pH value of 7 or higher. The combination of antioxidants provides a synergistic therapeutic effect.

[0193] Example 48 (Use in the treatment of UC) The disclosed composition, comprising TEMPOL and TUDCA in a 1:2 w / w ratio, is administered to patients with UC. The solid composition dissolves at a pH value of 7 or higher. The combination of antioxidants provides a synergistic therapeutic effect.

[0194] Example 49 (Use in the treatment of macular degeneration) The disclosed composition, comprising NAC and TUDCA in a 1:1 w / w ratio, is administered to patients with macular degeneration. The combination of antioxidants provides a synergistic therapeutic effect.

[0195] Example 50 (Use in the treatment of macular degeneration) The disclosed composition, comprising NAC and TEMPOL in a 1:1 w / w ratio, is administered to patients with macular degeneration. The combination of antioxidants provides a synergistic therapeutic effect.

[0196] Example 51 (Use in the treatment of glaucoma) The disclosed composition, comprising TEMPOL and TUDCA in a 1:2 w / w ratio, is administered to patients with glaucoma. The combination of antioxidants provides a synergistic therapeutic effect.

[0197] Example 52 (Use in the treatment of glaucoma) The disclosed composition, comprising NAC and TUDCA in a 1:1 w / w ratio, is administered to patients with glaucoma. The combination of antioxidants provides a synergistic therapeutic effect.

[0198] Example 53 (Use in the treatment of glaucoma) The disclosed composition, comprising NAC and TEMPOL in a 1:1 w / w ratio, is administered to patients with glaucoma. The combination of antioxidants provides a synergistic therapeutic effect.

[0199] Example 54 (Use in the treatment of glaucoma) The disclosed composition, comprising TEMPOL and TUDCA in a 1:2 w / w ratio, is administered to patients with glaucoma. The combination of antioxidants provides a synergistic therapeutic effect.

[0200] Example 55 (Use in the treatment of FLD) The disclosed composition, comprising NAC and TUDCA in a 1:1 w / w ratio, is administered to patients with FLD. The combination of antioxidants provides a synergistic therapeutic effect.

[0201] Example 56 (Use in the treatment of FLD) The disclosed composition, comprising NAC and TEMPOL in a 1:1 w / w ratio, is administered to patients with FLD. The combination of antioxidants provides a synergistic therapeutic effect.

[0202] Example 57 (Use in the treatment of FLD) The disclosed composition, comprising TEMPOL and TUDCA in a 1:2 w / w ratio, is administered to patients with FLD. The combination of antioxidants provides a synergistic therapeutic effect.

[0203] Example 58 (Use in the treatment of NASH) The disclosed composition, comprising NAC and TUDCA in a 1:1 w / w ratio, is administered to patients with NASH. The combination of antioxidants provides a synergistic therapeutic effect.

[0204] Example 59 (Use in the treatment of NASH) The disclosed composition, comprising NAC and TEMPOL in a 1:1 w / w ratio, is administered to patients with NASH. The combination of antioxidants provides a synergistic therapeutic effect.

[0205] Example 60 (Use in the treatment of NASH) The disclosed composition, comprising TEMPOL and TUDCA in a 1:2 w / w ratio, is administered to patients with NASH. The combination of antioxidants provides a synergistic therapeutic effect.

[0206] Example 61 (Use in the treatment of cancer) The disclosed composition, comprising NAC, TUDCA, and TEMPOL in a 1:1:1 w / w ratio, is administered to patients prior to chemotherapy. The combination of antioxidants provides a synergistic therapeutic effect.

[0207] Example 62 (Use in the treatment of cancer) The disclosed composition, comprising NAC and TUDCA in a 1:1 w / w ratio, is administered to patients after chemotherapy. The combination of antioxidants provides a synergistic therapeutic effect.

[0208] Example 63 (Use in the treatment of cancer) The disclosed composition, comprising NAC and TEMPOL in a 1:1 w / w ratio, is administered to patients concurrently with chemotherapy. The combination of antioxidants provides a synergistic therapeutic effect.

[0209] Example 64 (Use in the treatment of cancer) The disclosed composition, comprising NAC and TUDCA in a 2:1 w / w ratio, is administered to patients prior to chemotherapy. The combination of antioxidants provides a synergistic therapeutic effect.

[0210] Example 65 (Use in the treatment of cancer) The disclosed composition, comprising NAC and TEMPOL in a 2:1 w / w ratio, is administered to patients after chemotherapy. The combination of antioxidants provides a synergistic therapeutic effect.

[0211] Example 66 (Use in the treatment of cancer) The disclosed composition, comprising TEMPOL and TUDCA in a 2:1 w / w ratio, is administered to patients concurrently with chemotherapy. The combination of antioxidants provides a synergistic therapeutic effect.

[0212] Example 67 (Use in the treatment of cancer) The disclosed composition, comprising NAC and TUDCA in a 1:2 w / w ratio, is administered to patients prior to chemotherapy. The combination of antioxidants provides a synergistic therapeutic effect.

[0213] Example 68 (Use in the treatment of cancer) The disclosed composition, comprising NAC and TUDCA in a 1:2 w / w ratio, is administered to patients after chemotherapy. The combination of antioxidants provides a synergistic therapeutic effect.

[0214] Example 69 (Use in the treatment of cancer) The disclosed composition, comprising NAC and TUDCA in a 1:2 w / w ratio, is administered to patients concurrently with chemotherapy. The combination of antioxidants provides a synergistic therapeutic effect.

[0215] Example 70 (Use in the treatment of glaucoma) The disclosed composition, comprising NAC, TUDCA, and TEMPOL in a 1:2:1 w / w ratio, is administered to a patient simultaneously with glaucoma. The combination of antioxidants provides a synergistic therapeutic effect.

[0216] Example 71 (Use in the treatment of CD) Two disclosed liquid compositions containing NAC and TUDCA (1:1 w / w active ingredient ratio) are administered to patients with CD. The combination of antioxidants provides a synergistic therapeutic effect.

[0217] Example 72 (Use in the treatment of CD) The disclosed solid composition containing NAC and liquid composition containing TEMPOL (1:1 w / w active ingredient ratio) were administered to patients with CD. The combination of antioxidants provides a synergistic therapeutic effect.

[0218] Example 73 (Use in the treatment of CD) The disclosed solid composition containing TEMPOL and a liquid composition containing TUDCA (active ingredient ratio of 1:2 w / w) are administered to patients with CD. The combination of antioxidants provides a synergistic therapeutic effect.

[0219] Example 74 (Use in the treatment of UC) Two solid compositions (one containing NAC and the other containing TUDCA) in a 1:1 w / w ratio are administered to patients with UC. The combination of antioxidants provides a synergistic therapeutic effect.

[0220] Example 75 (Use in the treatment of UC) Two disclosed liquid compositions containing NAC and TEMPOL in a 1:1 w / w ratio are administered to patients with UC. The combination of antioxidants provides a synergistic therapeutic effect.

[0221] Example 76 (Use in the treatment of UC) The disclosed liquid composition containing TEMPOL and the disclosed solid composition containing TUDCA (active ingredient ratio of 1:2 w / w) are administered to patients with UC. The combination of antioxidants provides a synergistic therapeutic effect.

[0222] Example 77 (Use in the treatment of macular degeneration) The disclosed liquid composition containing NAC and TUDCA in a 1:1 w / w ratio is administered to patients with macular degeneration. The combination of antioxidants provides a synergistic therapeutic effect.

[0223] Example 78 (Use in the treatment of macular degeneration) The disclosed liquid composition containing NAC and solid composition containing TEMPOL (1:1 w / w active ingredient ratio) are administered to patients with macular degeneration. The combination of antioxidants provides a synergistic therapeutic effect.

[0224] Example 79 (Use in the treatment of glaucoma) The disclosed liquid composition containing TEMPOL and the solid composition containing TUDCA (active ingredient ratio of 1:2 w / w) are administered to patients with glaucoma. The combination of antioxidants provides a synergistic therapeutic effect.

[0225] (Example 80) (Use in the treatment of glaucoma) The disclosed liquid composition containing NAC and TUDCA (1:1 w / w active ingredient ratio) is administered to patients with glaucoma. The combination of antioxidants provides a synergistic therapeutic effect.

[0226] Example 81 (Use in the treatment of glaucoma) The disclosed liquid composition containing NAC and TEMPOL (1:1 w / w active ingredient ratio) is administered to patients with glaucoma. The combination of antioxidants provides a synergistic therapeutic effect.

[0227] Example 82 (Use in the treatment of glaucoma) The disclosed liquid composition containing TEMPOL and TUDCA (active ingredient ratio 1:1 w / w) is administered to patients with glaucoma. The combination of antioxidants provides a synergistic therapeutic effect.

[0228] Example 83 (Use in the treatment of FLD) The disclosed powder composition containing NAC and the disclosed liquid TUDCA (1:1 w / w active ingredient ratio) are administered to patients with FLD. The combination of antioxidants provides a synergistic therapeutic effect.

[0229] Example 84 (Use in the treatment of FLD) Two liquid compositions containing NAC and TEMPOL (1:1 w / w active ingredient ratio) were administered to patients with FLD. The combination of antioxidants provided a synergistic therapeutic effect.

[0230] Finally, while aspects of this specification are emphasized by reference to particular embodiments, those skilled in the art will readily appreciate that these disclosed embodiments are merely illustrative of the principles of the subject matter disclosed herein. Accordingly, it should be understood that the disclosed subject matter is in no way limited to the particular methodology, protocols, and / or reagents, etc., described herein. As such, various modifications or variations of the disclosed subject matter, or alternative configurations, may be made in accordance with the teachings herein without departing from the spirit of the specification. Finally, the terminology used herein is for the purpose of describing particular embodiments only and is not intended to limit the scope of the present disclosure, which is defined solely by the claims. Therefore, the embodiments of the present disclosure are not limited to those precisely as shown and described.

[0231] Certain embodiments are described herein, including the best modes known to the inventors for carrying out the methods and apparatus described herein. Of course, variations on these described embodiments will be apparent to those skilled in the art upon reading the foregoing description. Accordingly, this disclosure includes all modifications and equivalents of the subject matter recited in the claims appended hereto as permitted by applicable law. Furthermore, combinations of the above-described embodiments in all possible variations are included in this disclosure unless otherwise indicated herein or clearly contradicted by context.

[0232] Groupings of alternative embodiments, elements, or steps in the present disclosure should not be construed as limiting. The members of each group may be referenced and claimed individually or in any combination with other group members disclosed herein. It is anticipated that for reasons of convenience and / or patentability, one or more members of a group may be included in, or deleted from, a group. When such inclusion or deletion occurs, the specification is deemed to include the modified group, and satisfies all recitations of a Markush group as used in the appended claims.

[0233] Unless otherwise specified, all numerical values ​​expressing properties, items, quantities, parameters, characteristics, terms, etc. used in the specification and claims are understood to be modified in all instances by the term "about." As used herein, the term "about" means that the property, item, quantity, parameter, characteristic, or term encompasses a range of plus or minus 10% above and below the value of the stated property, item, quantity, parameter, characteristic, or term. Thus, unless indicated to the contrary, the numerical parameters set forth in this specification and the appended claims are approximations that may vary. At the very least, no attempt is made to limit the scope of the claims to equivalents, and each numerical designation should at least be construed in light of the number of reported significant digits and by applying ordinary rounding techniques. Notwithstanding that the numerical ranges and values ​​setting forth the broad scope of the present disclosure are approximations, the numerical ranges and values ​​set forth in the specific examples are reported as precisely as possible. However, any numerical range or value inherently contains errors necessarily resulting from the standard deviation found in their respective testing measurements. The 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, and unless expressly stated otherwise herein, each separate value of a range of values ​​is incorporated herein as if it were individually set forth herein.

[0234] As used in the context of describing this disclosure (particularly in the context of the claims below), the terms "a," "an," "the," and similar references should be construed to cover both the singular and the plural unless otherwise stated or clearly contradicted by context. All methods described herein can be performed in any suitable order unless otherwise stated herein or clearly contradicted by context. The use of any and all examples or exemplary language (e.g., "such as") provided herein is intended to better clarify the disclosure and does not limit the scope, as otherwise claimed. No statement in the specification should be construed as indicating any non-claimed element essential to the practice of the embodiments disclosed herein.

[0235] Some of the embodiments disclosed herein may be further limited in the claims by the use of the phrases "consisting of" or "consisting essentially of." When used in a claim, whether originally filed or added by amendment, the transitional phrase "consisting of" excludes any element, step, or ingredient not specified in the claim. The transitional phrase "consisting essentially of" limits the scope of the claim to particular materials or steps and those that do not materially affect the basic and novel characteristic(s). Embodiments of the present disclosure so claimed are essentially or expressly described and enabled herein.

[0236] (Addendum) (Appendix 1) A method of treating inflammatory bowel disease (IBD) comprising administering at least two antioxidants to a patient in need of treatment.

[0237] (Appendix 2) The method of claim 1, wherein the IBD is Crohn's disease (CD).

[0238] (Appendix 3) 2. The method of claim 1, wherein the IBD is ulcerative colitis (UC).

[0239] (Appendix 4) A method of treating glaucoma comprising administering at least two antioxidants to a patient in need of treatment.

[0240] (Appendix 5) A method of treating macular degeneration comprising administering at least two antioxidants to a patient in need of treatment.

[0241] (Appendix 6) A method for treating fatty liver disease (FLD) comprising administering at least two antioxidants to a patient in need of treatment.

[0242] (Appendix 7) A method for reducing chemotherapy-associated liver toxicity comprising administering at least two antioxidants to a patient in need of treatment.

[0243] (Appendix 8) 8. The method of claim 7, wherein the administration occurs prior to chemotherapy.

[0244] (Appendix 9) 8. The method of claim 7, wherein the administration is concurrent with chemotherapy.

[0245] (Appendix 10) 8. The method of claim 7, wherein the administration occurs after chemotherapy.

[0246] (Appendix 11) The chemotherapy may be altretamine, bendamustine, busulfan, carboplatin, carmustine, chlorambucil, cisplatin, cyclophosphamide, dacarbazine, ifosfamide, lomustine, mechlorethamine, melphalan, oxaliplatin, temozolomide, thiotepa, trabectedin, carmustine, lomustine, streptozocin, azacitidine, 5-fluorouracil (5-FU), 6- Mercaptopurine (6-MP), capecitabine (Xeloda), cladribine, clofarabine, cytarabine (Ara-C), decitabine, floxuridine, fludarabine, gemcitabine (Gemzar), hydroxyurea, methotrexate, nelarabine, pemetrexed (Alimta), pentostatin, pralatrexate, thioguanine, trifluridine / tipiracil combination, daunorubicin, doxorubicin Sorubicin (Adriamycin), doxorubicin liposome, epirubicin, idarubicin, valrubicin, bleomycin, dactinomycin, mitomycin-C, mitoxantrone, irinotecan, irinotecan liposome, topotecan, etoposide (VP-16), mitoxantrone, teniposide, cabazitaxel, docetaxel, nab-paclitaxel, paclitaxel, vinblastine, vincristine 11. The method of any one of claims 7-10, comprising administering at least one of: vincristine, vincristine liposome, vinorelbine, prednisone, methylprednisolone, dexamethasone, all-trans retinoic acid, arsenic trioxide, asparaginase, eribulin, hydroxyurea, ixabepilone, mitotane, omacetaxine, pegaspargase, procarbazine, romidepsin, and vorinostat.

[0247] (Appendix 12) 12. The method according to any one of appendices 7 to 11, wherein the chemotherapy is performed in combination with radiation therapy.

[0248] (Appendix 13) 13. The method of any one of appendices 1-12, wherein the administering comprises daily administration.

[0249] (Appendix 14) 13. The method of any one of claims 1 to 12, wherein the administration comprises once a week.

[0250] (Appendix 15) 13. The method of any one of appendices 1-12, wherein said administering comprises administering once a month.

[0251] (Appendix 16) 16. The method of any one of appendixes 1 to 15, wherein one of the at least two antioxidants comprises NAC.

[0252] (Appendix 17) 17. The method of any one of appendixes 1 to 16, wherein one of the at least two antioxidants comprises TUDCA.

[0253] (Appendix 18) 18. The method of any one of appendixes 1 to 17, wherein one of the at least two antioxidants comprises TEMPOL.

[0254] (Appendix 19) 19. The method of any one of claims 1 to 18, wherein the at least two antioxidants comprise a single composition.

[0255] (Appendix 20) 20. The method of claim 19, wherein the single composition comprises a solid composition.

[0256] (Appendix 21) 20. The method of claim 19, wherein the single composition comprises a liquid composition.

[0257] (Appendix 22) 19. The method of any one of claims 1 to 18, wherein the at least two antioxidants comprise a plurality of compositions.

[0258] (Appendix 23) 23. The method of claim 22, wherein the plurality of compositions comprises a solid composition.

[0259] (Appendix 24) 23. The method of claim 22, wherein the plurality of compositions comprises a liquid composition.

[0260] (Appendix 25) 1. Use of at least two antioxidants for the manufacture of a medicament for the treatment of inflammatory bowel disease (IBD) for medical use.

[0261] (Appendix 26) The use of claim 25, wherein the IBD is Crohn's disease (CD).

[0262] (Appendix 27) The use of claim 25, wherein the IBD is ulcerative colitis (UC).

[0263] (Appendix 28) 1. Use of at least two antioxidants for the manufacture of a medicament for the treatment of glaucoma.

[0264] (Appendix 29) 1. Use of at least two antioxidants for the manufacture of a medicament for the treatment of degenerative diseases.

[0265] (Appendix 30) 1. Use of at least two antioxidants for the manufacture of a medicament for the treatment of fatty liver disease (FLD).

[0266] (Appendix 31) 1. Use of at least two antioxidants for the manufacture of a medicament for the treatment of chemotherapy-related liver toxicity.

[0267] (Appendix 32) 32. The use of claim 31, wherein the use comprises administration prior to chemotherapy.

[0268] (Appendix 33) 32. The use of claim 31, wherein the use comprises administration concomitantly with chemotherapy.

[0269] (Appendix 34) 32. The use of claim 31, wherein the use comprises administration after chemotherapy.

[0270] (Appendix 35) The chemotherapy may be altretamine, bendamustine, busulfan, carboplatin, carmustine, chlorambucil, cisplatin, cyclophosphamide, dacarbazine, ifosfamide, lomustine, mechlorethamine, melphalan, oxaliplatin, temozolomide, thiotepa, trabectedin, carmustine, lomustine, streptozocin, azacitidine, 5-fluorouracil (5-FU), 6- Mercaptopurine (6-MP), capecitabine (Xeloda), cladribine, clofarabine, cytarabine (Ara-C), decitabine, floxuridine, fludarabine, gemcitabine (Gemzar), hydroxyurea, methotrexate, nelarabine, pemetrexed (Alimta), pentostatin, pralatrexate, thioguanine, trifluridine / tipiracil combination, daunorubicin, doxorubicin Rubicin (Adriamycin), Doxorubicin liposome, Epirubicin, Idarubicin, Valrubicin, Bleomycin, Dactinomycin, Mitomycin-C, Mitoxantrone, Irinotecan, Irinotecan liposome, Topotecan, Etoposide (VP-16), Mitoxantrone, Teniposide, Cabazitaxel, Docetaxel, Nab-paclitaxel, Paclitaxel, Vinblastine, Vincris 35. The use of any one of claims 31-34, comprising administering at least one of vincristine, vincristine liposome, vinorelbine, prednisone, methylprednisolone, dexamethasone, all-trans retinoic acid, arsenic trioxide, asparaginase, eribulin, hydroxyurea, ixabepilone, mitotane, omacetaxine, pegaspargase, procarbazine, romidepsin, and vorinostat.

[0271] (Appendix 36) 36. The use according to any one of appendices 31 to 35, wherein the chemotherapy is performed in combination with radiation therapy.

[0272] (Appendix 37) 37. The use of any one of appendices 25 to 36, wherein the use comprises daily administration.

[0273] (Appendix 38) 37. The use of any one of appendices 25 to 36, wherein the use comprises once-weekly administration.

[0274] (Appendix 39) 37. The use of any one of appendices 25 to 36, wherein the use comprises once-monthly administration.

[0275] (Appendix 40) 40. The use of any one of claims 25 to 39, wherein one of the at least two antioxidants comprises NAC.

[0276] (Appendix 41) 41. The use of any one of claims 25 to 40, wherein one of the at least two antioxidants comprises TUDCA.

[0277] (Appendix 42) 42. The use of any one of Appendices 25 to 41, wherein one of the at least two antioxidants comprises TEMPOL.

[0278] (Appendix 43) 43. The use of any one of claims 25 to 42, wherein the at least two antioxidants comprise a single composition.

[0279] (Appendix 44) 44. The use of claim 43, wherein the single composition comprises a solid composition.

[0280] (Appendix 45) 44. The use of claim 43, wherein the single composition comprises a liquid composition.

[0281] (Appendix 46) 43. The use of any one of claims 25 to 42, wherein the at least two antioxidants comprise a plurality of compositions.

[0282] (Appendix 47) 47. The use of claim 46, wherein the plurality of compositions comprises a solid composition.

[0283] (Appendix 48) 47. The use of claim 46, wherein the plurality of compositions comprises a liquid composition.

[0284] (Appendix 49) A composition comprising at least two antioxidants.

[0285] (Appendix 50) 50. The composition of claim 49, wherein one of the at least two antioxidants comprises NAC.

[0286] (Appendix 51) 51. The composition of claim 49 or 50, wherein one of the at least two antioxidants comprises TUDCA.

[0287] (Appendix 52) 52. The composition of any one of claims 49 to 51, wherein one of the at least two antioxidants comprises TEMPOL.

[0288] (Appendix 53) 53. The composition of any one of appendices 49 to 52, wherein the composition is a solid.

[0289] (Appendix 54) 53. The composition according to any one of claims 49 to 52, wherein the composition is a liquid.

[0290] (Appendix 55) A kit comprising a composition according to any one of Appendices 49 to 54 for use in a method according to any one of Appendices 1 to 24, or for use according to any one of Appendices 25 to 48.

Claims

1. A method of treating inflammatory bowel disease (IBD) comprising administering at least two antioxidants to a patient in need of treatment.

2. 10. The method of claim 1, wherein the IBD is Crohn's disease (CD).

3. 2. The method of claim 1, wherein the IBD is ulcerative colitis (UC).

4. A method of treating glaucoma comprising administering at least two antioxidants to a patient in need of treatment.

5. A method of treating macular degeneration comprising administering at least two antioxidants to a patient in need of treatment.

6. A method of treating fatty liver disease (FLD) comprising administering at least two antioxidants to a patient in need of treatment.

7. A method for reducing chemotherapy-associated liver toxicity comprising administering at least two antioxidants to a patient in need of treatment.

8. 8. The method of claim 7, wherein the administration occurs prior to chemotherapy.

9. The method of claim 7, wherein the administration is concurrent with chemotherapy.

10. 8. The method of claim 7, wherein the administration occurs after chemotherapy.

11. The chemotherapy may be altretamine, bendamustine, busulfan, carboplatin, carmustine, chlorambucil, cisplatin, cyclophosphamide, dacarbazine, ifosfamide, lomustine, mechlorethamine, melphalan, oxaliplatin, temozolomide, thiotepa, trabectedin, carmustine, lomustine, streptozocin, azacitidine, 5-fluorouracil (5-FU), 6- Mercaptopurine (6-MP), capecitabine (Xeloda), cladribine, clofarabine, cytarabine (Ara-C), decitabine, floxuridine, fludarabine, gemcitabine (Gemzar), hydroxyurea, methotrexate, nelarabine, pemetrexed (Alimta), pentostatin, pralatrexate, thioguanine, trifluridine / tipiracil combination, daunorubicin, doxorubicin Rubicin (Adriamycin), doxorubicin liposome, epirubicin, idarubicin, valrubicin, bleomycin, dactinomycin, mitomycin-C, mitoxantrone, irinotecan, irinotecan liposome, topotecan, etoposide (VP-16), mitoxantrone, teniposide, cabazitaxel, docetaxel, nab-paclitaxel, paclitaxel, vinblastine, vincristine 11. The method of any one of claims 7 to 10, comprising administering at least one of vincristine, vincristine liposome, vinorelbine, prednisone, methylprednisolone, dexamethasone, all-trans retinoic acid, arsenic trioxide, asparaginase, eribulin, hydroxyurea, ixabepilone, mitotane, omacetaxine, pegaspargase, procarbazine, romidepsin, and vorinostat.

12. The method according to any one of claims 7 to 11, wherein the chemotherapy is performed in combination with radiation therapy.

13. The method of any one of claims 1 to 12, wherein said administering comprises daily administration.

14. The method of any one of claims 1 to 12, wherein the administration comprises a once-weekly administration.

15. 13. The method of any one of claims 1 to 12, wherein said administering comprises a monthly administration.

16. The method of any one of claims 1 to 15, wherein one of the at least two antioxidants comprises NAC.

17. 17. The method of any one of claims 1 to 16, wherein one of the at least two antioxidants comprises TUDCA.

18. 18. The method of any one of claims 1 to 17, wherein one of the at least two antioxidants comprises TEMPOL.

19. The method of any one of claims 1 to 18, wherein the at least two antioxidants comprise a single composition.

20. 20. The method of claim 19, wherein the single composition comprises a solid composition.

21. 20. The method of claim 19, wherein the single composition comprises a liquid composition.

22. The method of any one of claims 1 to 18, wherein the at least two antioxidants comprise a plurality of compositions.

23. 23. The method of claim 22, wherein the plurality of compositions comprises a solid composition.

24. The method of claim 22 , wherein the plurality of compositions comprises a liquid composition.

25. 1. Use of at least two antioxidants for the manufacture of a medicament for the treatment of inflammatory bowel disease (IBD) for medical use.

26. 26. The use of claim 25, wherein the IBD is Crohn's disease (CD).

27. 26. The use of claim 25, wherein the IBD is ulcerative colitis (UC).

28. 1. Use of at least two antioxidants for the manufacture of a medicament for the treatment of glaucoma.

29. 1. Use of at least two antioxidants for the manufacture of a medicament for the treatment of degenerative diseases.

30. 1. Use of at least two antioxidants for the manufacture of a medicament for the treatment of fatty liver disease (FLD).

31. 1. Use of at least two antioxidants for the manufacture of a medicament for the treatment of chemotherapy-related liver toxicity.

32. 32. The use of claim 31, wherein the use comprises administration prior to chemotherapy.

33. 32. The use of claim 31 , wherein the use comprises administration concomitantly with chemotherapy.

34. 32. The use of claim 31, wherein the use comprises administration after chemotherapy.

35. The chemotherapy may be altretamine, bendamustine, busulfan, carboplatin, carmustine, chlorambucil, cisplatin, cyclophosphamide, dacarbazine, ifosfamide, lomustine, mechlorethamine, melphalan, oxaliplatin, temozolomide, thiotepa, trabectedin, carmustine, lomustine, streptozocin, azacitidine, 5-fluorouracil (5-FU), 6- Mercaptopurine (6-MP), capecitabine (Xeloda), cladribine, clofarabine, cytarabine (Ara-C), decitabine, floxuridine, fludarabine, gemcitabine (Gemzar), hydroxyurea, methotrexate, nelarabine, pemetrexed (Alimta), pentostatin, pralatrexate, thioguanine, trifluridine / tipiracil combination, daunorubicin, doxorubicin Rubicin (Adriamycin), doxorubicin liposome, epirubicin, idarubicin, valrubicin, bleomycin, dactinomycin, mitomycin-C, mitoxantrone, irinotecan, irinotecan liposome, topotecan, etoposide (VP-16), mitoxantrone, teniposide, cabazitaxel, docetaxel, nab-paclitaxel, paclitaxel, vinblastine, vincristine 35. The use of any one of claims 31 to 34, comprising administering at least one of the following: vincristine liposome, vinorelbine, prednisone, methylprednisolone, dexamethasone, all-trans retinoic acid, arsenic trioxide, asparaginase, eribulin, hydroxyurea, ixabepilone, mitotane, omacetaxine, pegaspargase, procarbazine, romidepsin, and vorinostat.

36. The use according to any one of claims 31 to 35, wherein the chemotherapy is performed in combination with radiotherapy.

37. The use according to any one of claims 25 to 36, wherein the use comprises daily administration.

38. The use according to any one of claims 25 to 36, wherein the use comprises once-weekly administration.

39. The use according to any one of claims 25 to 36, wherein the use comprises once-monthly administration.

40. 40. The use according to any one of claims 25 to 39, wherein one of the at least two antioxidants comprises NAC.

41. 41. The use according to any one of claims 25 to 40, wherein one of the at least two antioxidants comprises TUDCA.

42. 42. The use according to any one of claims 25 to 41, wherein one of the at least two antioxidants comprises TEMPOL.

43. The use according to any one of claims 25 to 42, wherein the at least two antioxidants comprise a single composition.

44. 44. The use of claim 43, wherein the single composition comprises a solid composition.

45. 44. The use of claim 43, wherein the single composition comprises a liquid composition.

46. The use according to any one of claims 25 to 42, wherein the at least two antioxidants comprise a plurality of compositions.

47. 47. The use of claim 46, wherein the plurality of compositions comprises a solid composition.

48. 47. The use of claim 46, wherein the plurality of compositions comprises a liquid composition.

49. A composition comprising at least two antioxidants.

50. 50. The composition of claim 49, wherein one of the at least two antioxidants comprises NAC.

51. 51. The composition of claim 49 or 50, wherein one of the at least two antioxidants comprises TUDCA.

52. 52. The composition of any one of claims 49 to 51, wherein one of the at least two antioxidants comprises TEMPOL.

53. The composition of any one of claims 49 to 52, wherein the composition is a solid.

54. The composition of any one of claims 49 to 52, wherein the composition is a liquid.

55. A kit comprising a composition according to any one of claims 49 to 54 for use in a method according to any one of claims 1 to 24 or for use according to any one of claims 25 to 48.

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