Methods for treating or preventing liver disease or disorders

Abstract

The present invention relates to compositions and methods comprising various short chain fatty acids (SCFAs), such as butyrate and acetate, in combination with antioxidants, such as vitamin E, for the treatment or prevention of liver diseases or disorders, such as non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), fibrosis, and other similar diseases or disorders.

Description

[Technical Field]

[0001] (CROSS-REFERENCE TO RELATED APPLICATIONS) This application claims the benefit of U.S. Provisional Patent Application No. 63 / 383,175, filed November 10, 2022, which is incorporated herein by reference in its entirety. [Background technology]

[0002] Nonalcoholic steatohepatitis (NASH) is an advanced form of nonalcoholic fatty liver disease (NAFLD) characterized by fat accumulation, inflammation, hepatocellular injury, and varying degrees of fibrosis, which can progress to nonalcoholic steatohepatitis (NASH), cirrhosis, and / or hepatocellular carcinoma (HCC).

[0003] Many drug candidates have failed to demonstrate clear benefit. Perhaps none of the molecules currently under investigation are expected to significantly improve NASH in more than a small number of patients. Given the complex pathogenesis of NASH, this appears unlikely to succeed, as existing drug candidates are intended for monotherapy and compensatory mechanisms may attenuate the drug's effectiveness.

[0004] Thus, there is a need in the art for effective compositions and methods for treating or preventing liver diseases or disorders, such as NAFLD, NASH, fibrosis, and other similar diseases or disorders. The present disclosure addresses this unmet need.

[0005] Incorporation by Reference All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. Summary of the Invention

[0006] Disclosed herein are methods for alleviating a condition in a subject in need thereof, the method comprising administering to the subject a composition comprising: (a) at least two short chain fatty acids (SCFAs) or pharmaceutically acceptable salts thereof; and (b) a reduced amount of tocopherol, wherein the reduced amount of tocopherol is therapeutically effective in combination with the at least two SCFAs or pharmaceutically acceptable salts thereof for alleviating the condition, and wherein the reduced amount of tocopherol is less than the amount of tocopherol that is therapeutically effective for the condition in the absence of the at least two SCFAs or pharmaceutically acceptable salts thereof.

[0007] Disclosed herein are methods for providing prevention against the progression of a condition to fibrosis in a subject in need thereof, the method comprising administering to the subject a composition comprising: (a) at least one SCFA or a pharmaceutically acceptable salt thereof, and (b) tocopherol.

[0008] Disclosed herein are methods for providing prevention against the progression of NASH to fibrosis in a subject in need thereof, the method comprising administering to the subject a composition comprising (a) at least one SCFA or a pharmaceutically acceptable salt thereof, and (b) tocopherol.

[0009] Disclosed herein is a pharmaceutical composition comprising active ingredients in a unit dosage form, the active ingredients comprising: (a) a therapeutically effective amount of at least one SCFA or a pharmaceutically acceptable salt thereof, and (b) tocopherol. [Brief explanation of the drawings]

[0010] [Figure 1] Mouse weights from the start of treatment on day 0 until euthanasia on day 81 are shown.

[0011] [Figure 2] The mean histopathological scores of mice fed high dose SCFAs, mice fed low dose SCFAs, or mice given no drug are shown.

[0012] [Figure 3] The mean histopathological scores of mice fed high dose SCFAs, mice fed low dose SCFAs, or mice given no drug are shown.

[0013] [Figure 4] Representative H&E staining for inflammatory infiltrates characteristic of NASH in liver samples from control mice fed a high-fat diet and euthanized at 76 weeks of age (Group 5).

[0014] [Figure 5] Representative H&E staining for inflammatory infiltrates characteristic of NASH in liver samples from control mice fed a high-fat diet and euthanized at 84 weeks of age is shown (Group 6).

[0015] [Figure 6] Representative H&E staining for inflammatory infiltrates characteristic of NASH in liver samples from mice fed high-dose SCFA and euthanized at 76 weeks of age (Group 1) is shown.

[0016] [Figure 7] Representative H&E staining for inflammatory infiltrates characteristic of NASH in liver samples from mice fed high-dose SCFA and euthanized at 84 weeks of age (Group 3).

[0017] [Figure 8] Representative Masson's trichrome staining for fibrosis in liver samples from control mice fed a high-fat diet and euthanized at 76 weeks of age (group 5).

[0018] [Figure 9] Representative Masson's trichrome staining for fibrosis in liver samples from mice fed high dose SCFA and euthanized at 76 weeks of age (Group 1). DETAILED DESCRIPTION OF THE INVENTION

[0019] The present disclosure is based on the unexpected finding that a combination of a Ca / Mg salt of butyric acid and tocopherol acetate provides an effective treatment for NASH with or without fibrosis. Accordingly, in some aspects, the present disclosure provides methods for preventing or treating liver disease, fibrosis, or inflammation using a composition comprising at least one compound selected from short-chain fatty acids (SCFAs), salts of SCFAs, SCFA precursors, SCFA biosynthetic precursors, compounds containing an SFCA moiety, derivatives of SCFAs, and any combination thereof. In some embodiments, the salt of SCFA comprises a Ca salt of SCFA (e.g., a Ca salt of butyric acid, a Ca salt of acetic acid, etc.), a Mg salt of SCFA (e.g., a Mg salt of butyric acid, a Mg salt of acetic acid, etc.), or any combination thereof. In some embodiments, the composition further comprises at least one antioxidant (e.g., vitamin E, tocopherol acetate, etc.).

[0020] In one embodiment, the subject is a human. In one embodiment, the subject is a non-human animal.

[0021] Provided herein are compositions and methods for treating a condition (e.g., liver disease, fibrosis, or inflammation), comprising administering to a subject in need thereof a composition comprising at least one short-chain fatty acid (SCFA), a salt of an SCFA, a SCFA precursor, a SCFA biosynthetic precursor, a composition comprising an SFCA moiety, a derivative of an SCFA, or any combination thereof. In some embodiments, the compositions disclosed herein are in salt form. In some embodiments, the methods disclosed herein further comprise, for example, administering a second pharmaceutical composition.

[0022] definition It should be understood that the figures and descriptions of the present disclosure have been simplified to illustrate elements relevant to a clear understanding of the present disclosure, but for clarity have excluded many other elements found in the present disclosure. One skilled in the art may recognize that other elements and / or steps are desirable and / or required in implementing the present disclosure. However, because such elements and steps are well known in the art and because they do not facilitate a better understanding of the present disclosure, descriptions of such elements and steps are not provided herein. The disclosure herein covers all such variations and modifications to such elements and methods known to those skilled in the art.

[0023] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of this disclosure, exemplary methods and materials are described.

[0024] As used herein, each of the following terms has the meaning associated with it in this section.

[0025] The articles "a" and "an" are used herein to refer to one or to more than one (i.e., to at least one) of the grammatical object of the article. By way of example, "an element" means one element or more than one element.

[0026] As used herein, when referring to a measurable value, e.g., amount, duration, etc., "about" is meant to encompass a variation of ±20%, ±10%, ±5%, ±1%, or ±0.1% from the specified value, where such variation is appropriate.

[0027] The term "abnormal," when used in the context of an organism, tissue, cell, or component thereof, refers to an organism, tissue, cell, or component thereof that differs in at least one observable or detectable characteristic (e.g., age, treatment, time, etc.) from an organism, tissue, cell, or component thereof that exhibits the "normal" (expected) respective characteristic. A characteristic that is normal or expected in one cell or tissue type may be abnormal in a different cell or tissue type.

[0028] As used herein, "combination," as in the phrase "a first agent in combination with a second agent," includes co-administration of the first agent and the second agent, or administration of the first agent followed by administration of the second agent, or administration of the second agent followed by administration of the first agent, which may, for example, be dissolved or mixed in the same pharmaceutically acceptable carrier.

[0029] The term "combined" in the phrase "combined therapeutic treatment" includes administering an agent in the presence of a second agent. Combination therapeutic treatment methods include methods in which a first, second, third, or additional agent is co-administered. Combination therapeutic treatment methods also include methods in which a first agent or additional agent is administered in the presence of a second agent or additional agent, which may, for example, have been previously administered. Combination therapeutic treatment methods may be performed in stages by different actors. For example, one actor may administer a first agent to a subject, and a second actor may administer a second agent to the subject, and the administering steps may be performed simultaneously, nearly simultaneously, or separated in time, as long as the first agent (and additional agent) is administered after the administration of the second agent (and additional agent) in the presence of the second agent (and additional agent). The actor and subject may be the same entity (e.g., a human).

[0030] As used herein, the term "combination therapy" refers to the administration of two or more therapies, two or more therapeutic agents, or at least one therapeutic agent in combination with at least one therapeutic method, e.g., a combination of radiation, immunotherapy, and chemotherapy.

[0031] A "disease" is a condition in an animal's health in which the animal is unable to maintain homeostasis, and if the disease is not ameliorated, the animal's health continues to deteriorate.

[0032] In contrast, a "disorder" in an animal is a state of health in which the animal is able to maintain homeostasis, but the animal's health is less favorable than it would be in the absence of the disorder. If left untreated, the disorder does not necessarily further deteriorate the animal's health.

[0033] A subject is "at risk" of developing a condition if the individual has an increased probability of developing the condition compared to a population (e.g., the overall population, an age-matched population, a population of the same sex). The increased probability can be due to one or a combination of factors, including the presence of particular alleles / mutations of a gene or exposure to a particular environment.

[0034] As used herein, the term "cancer" is defined as a disease characterized by the rapid and uncontrolled growth of aberrant cells. Cancer cells can spread locally or to other parts of the body via the bloodstream and lymphatic system. Examples of various cancers include, but are not limited to, breast cancer, prostate cancer, ovarian cancer, cervical cancer, skin cancer, pancreatic cancer, colon cancer, bladder cancer, kidney cancer, brain cancer, lymphoma, leukemia, lung cancer, etc.

[0035] A disease or disorder is "alleviated" if the severity of a sign or symptom of the disease or disorder, the frequency with which the patient experiences such sign or symptom, or both, is reduced.

[0036] As used herein, the term "inhibit" means to reduce or block an activity or function by at least about 10 percent compared to a control value. Illustratively, the activity is reduced or blocked by 50%, 75%, or 95% or more compared to a control value.

[0037] The terms "treatment," "treating," and the like are used herein generally to mean obtaining a desired pharmacological and / or physiological effect. The effect may be preventative, in that a disease or disorder or its symptoms are completely or partially prevented, and / or may be therapeutic, in that the disease or disorder and / or adverse effects resulting from the disease or disorder are partially or completely cured. As used herein, the term "treatment" includes any treatment of a disease or disorder in a subject, including (a) preventing the disease or disorder from occurring in a subject who may be predisposed to the disease or disorder, (b) inhibiting the disease or disorder, i.e., arresting its development, or (c) alleviating the disease or disorder, i.e., causing regression of the disease or disorder.

[0038] The terms "effective amount" and "pharmaceutically effective amount" refer to an amount of an agent sufficient to produce a desired biological result, which may be reduction and / or alleviation of the signs, symptoms, or causes of a disease or disorder, or any other desired alteration of a biological system.

[0039] A "therapeutically effective amount" refers to an amount that provides a therapeutic effect for a given condition and administration regimen. In particular, a "therapeutically effective amount" means an amount that is effective to prevent, alleviate or ameliorate symptoms of a disease or disorder or prolong the survival of the subject being treated, which can be a human or non-human animal.

[0040] As used herein, the term "pharmaceutical composition" refers to a mixture of at least one compound of the present disclosure with other chemical components and entities, such as carriers, stabilizers, diluents, dispersants, suspending agents, thickeners, and / or excipients. Pharmaceutical compositions facilitate the administration of a compound to an organism. Multiple techniques for administering a compound exist in the art, including, but not limited to, intravenous, oral, aerosol, parenteral, ocular, pulmonary, and topical administration.

[0041] "Pharmaceutically acceptable" refers to properties and / or substances that are acceptable to a patient from a pharmacological / toxicological standpoint and to a manufacturing pharmaceutical chemist from a physical / chemical standpoint with regard to composition, formulation, stability, patient acceptability, and bioavailability.

[0042] As used herein, the term "pharmaceutically acceptable carrier" refers to a pharmaceutically acceptable material, composition, or carrier, such as a liquid or solid filler, stabilizer, dispersant, suspending agent, diluent, excipient, thickener, solvent, or encapsulating material, that is involved in carrying or transporting a compound useful within the compositions disclosed herein within or to a patient so that it can perform its intended function. Typically, such constructs are carried or transported from one organ or part of the body to another. Each carrier is intended to be "acceptable" in the sense of being compatible with the other ingredients of the formulation, including the compound useful within the compositions disclosed herein, and not harmful to the patient. Some examples of 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, ethylcellulose, and cellulose acetate; excipients such as tragacanth powder, malt, gelatin, talc, cocoa butter, and suppository wax; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; glycols such as propylene glycol, polyols such as glycerin, sorbitol, mannitol, polyethylene glycol, and glycerol; esters such as ethyl oleate and ethyl laurate, agar, buffers such as magnesium hydroxide and aluminum hydroxide, surfactants, alginic acid, pyrogen-free water, isotonic saline, Ringer's solution, ethyl alcohol, phosphate buffer, and other non-toxic, compatible substances used in pharmaceutical formulations. As used herein, "pharmaceutically acceptable carriers" also includes any and all coatings, antibacterial and antifungal agents, absorption delaying agents, and the like, that are compatible with the activity of the compounds useful within the compositions disclosed herein and are physiologically acceptable to the patient. Supplementary active compounds can also be incorporated into the compositions. "Pharmaceutically acceptable carriers" can further include pharmaceutically acceptable salts of the compounds useful within the compositions disclosed herein.Other additional ingredients that may be included in pharmaceutical compositions used to practice the present disclosure are known in the art and are described, for example, in Remington's Pharmaceutical Sciences (Genaro, Ed., Mack Publishing Co., 1985, Easton, PA), which is incorporated herein by reference.

[0043] The term "nutritional composition" may refer to a food product intended for human consumption, such as a beverage, drink, bar, snack, ice cream, dairy product, such as a refrigerated or shelf stable dairy product, fermented dairy product, beverage, such as a milk-based beverage, infant formula, growing-up milk, confectionery product, chocolate, cereal product, such as a breakfast cereal, sauce, soup, instant drink, frozen product intended to be consumed after heating in a microwave or conventional oven, ready-to-eat product, fast food or nutritional formulation.

[0044] The terms "patient," "subject," "individual," and the like are used interchangeably herein and refer to any animal or cells thereof, whether in vitro or in situ, suitable for the methods described herein. A patient, subject, or individual can be a human or non-human animal.

[0045] As used herein, the term "container" includes any receptacle for holding a pharmaceutical composition. For example, in one embodiment, the container is a package that holds the pharmaceutical composition. In other embodiments, the container is not a package that holds the pharmaceutical composition; i.e., the container is a receptacle, such as a box or vial, that holds a packaged or unpackaged pharmaceutical composition and instructions for use of the pharmaceutical composition. Furthermore, packaging technology is well known in the art. It should be understood that instructions for use of the pharmaceutical composition may be included in the package that holds the pharmaceutical composition, and as such, the instructions form an incremental functional relationship with the packaged product. However, it should be understood that the instructions may also include information regarding the ability of the compound to perform its intended function, e.g., treating or preventing a disease in a subject.

[0046] As used herein, the term "instructional material" includes publications, records, diagrams, or any other medium of expression that can be used to communicate the usefulness of components of the present disclosure in kits for identifying, alleviating, or treating various diseases or disorders described herein. Optionally, or alternatively, the instructional material may describe one or more methods of identifying or alleviating a disease or disorder in a cell or tissue of a subject. Kit instructional material may, for example, be affixed to a container holding the composition or shipped together with a container holding the composition.

[0047] Alternatively, the instructional material may be shipped separately from the container with the intention that the recipient use the instructional material and the composition cooperatively.

[0048] Ranges: Throughout this disclosure, various aspects of the present disclosure may be presented in a range format. It should be understood that the description in range format is merely for convenience and brevity and should not be construed as a fixed limitation on the scope of the present disclosure. Accordingly, the description of a range should be considered to have specifically disclosed all possible subranges as well as individual numerical values ​​within that range. For example, the description of a range such as 1 to 6 should be considered to have specifically disclosed subranges such as 1 to 3, 1 to 4, 1 to 5, 2 to 4, 2 to 6, 3 to 6, etc., as well as individual numbers within that range, e.g., 1, 2, 2.7, 3, 4, 5, 5.3, and 6. This is true regardless of the breadth of the range.

[0049] explanation

[0050] The present disclosure is based on the unexpected finding that a combination of a Ca / Mg salt of butyric acid and tocopherol acetate provides an effective treatment for NASH with or without fibrosis. Accordingly, in some aspects, the present disclosure provides methods for preventing or treating liver disease, fibrosis, or inflammation using a composition comprising at least one compound selected from short-chain fatty acids (SCFAs), salts of SCFAs, SCFA precursors, SCFA biosynthetic precursors, compounds containing an SFCA moiety, derivatives of SCFAs, and any combination thereof. In some embodiments, the salt of SCFA comprises a Ca salt of SCFA (e.g., a Ca salt of butyric acid, a Ca salt of acetic acid, etc.), a Mg salt of SCFA (e.g., a Mg salt of butyric acid, a Mg salt of acetic acid, etc.), or any combination thereof. In some embodiments, the composition further comprises at least one antioxidant (e.g., vitamin E, tocopherol acetate, etc.).

[0051] In one embodiment, the subject is a human. In one embodiment, the subject is a non-human animal.

[0052] The present disclosure provides a method of treating or preventing liver disease, fibrosis, and / or inflammation in a subject in need thereof by administering to said subject a therapeutically effective amount of a composition comprising at least one compound selected from short chain fatty acids (SCFAs), salts of SCFAs, SCFA precursors, SCFA biosynthetic precursors, compounds containing an SFCA moiety, derivatives of SCFAs, and any combination thereof.

[0053] Liver disease

[0054] Liver disease and disorders include, for example, non-alcoholic steatohepatitis (NASH).NASH can progress to fibrosis, cirrhosis and hepatocellular carcinoma (HCC), and therefore is a growing public health threat worldwide.NASH is associated with chronic inflammatory conditions such as type 2 diabetes and obesity.

[0055] NAFLD / NASH currently afflict hundreds of millions of people. NAFLD / NASH is on the rise worldwide, and current treatment approaches include lifestyle adjustments, physical activity, smoking / alcohol cessation, high-dose vitamin E (800 IU as an antioxidant), and pioglitazone (as an insulin sensitizer). Despite urgent clinical need and attractive commercial opportunity, there are no FDA-approved treatments for NASH. Many pharmaceutical companies have attempted, but unfortunately failed, to develop drugs that could unravel the complexities of this disease.

[0056] The present disclosure provides methods and compositions with significantly higher therapeutic success than current treatment approaches. More specifically, the present disclosure provides compositions containing a combination of butyrate and acetate (which simultaneously target multiple mechanisms related to the pathogenesis of NASH) in addition to an antioxidant (e.g., vitamin E), providing effective and safe therapeutic outcomes. Thus, the present disclosure provides compositions for treating NASH with or without fibrosis.

[0057] In some embodiments, the compositions disclosed herein are administered to a subject to prevent disease progression of a liver disease or disorder, hi some embodiments, the compositions disclosed herein are administered to a subject to delay disease progression of a liver disease or disorder.

[0058] In some embodiments, the compositions disclosed herein are administered to a subject for the treatment of a liver disease or disorder, hi some embodiments, the compositions disclosed herein are administered to a subject for the prevention of a liver disease or disorder.

[0059] In some embodiments, the compositions disclosed herein are administered to a subject determined to be at risk for developing a liver disease or disorder.

[0060] Non-limiting examples of liver diseases or disorders include fatty liver disease, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), liver fibrosis, alcoholic liver disease, autoimmune diseases or disorders, cirrhosis, liver cancer, hepatocellular carcinoma (HCC), hepatitis B-related chronic liver disease, dysplasia, autoimmune hepatitis, primary biliary cirrhosis (PBC), primary sclerosing cholangitis, hemochromatosis, Wilson's disease, liver failure, or any combination thereof.

[0061] In some embodiments, the compositions disclosed herein are administered to a subject to treat or prevent an inflammatory condition. In some embodiments, the compositions disclosed herein are administered to a subject to treat or prevent a chronic inflammatory condition. Non-limiting examples of chronic inflammatory conditions include type 2 diabetes and obesity.

[0062] Short-chain fatty acids (SCFAs)

[0063] "Short-chain fatty acids" (SCFAs) are fatty acids that typically have aliphatic tails that are shorter than those of long-chain fatty acids. Short-chain fats can be derivatized to provide salts or esters thereof, such as pharmaceutically acceptable salts and esters of fatty acids (e.g., sodium butyrate, arginine butyrate).

[0064] In some embodiments, the composition comprises about 100 milligrams (mg) to about 100 grams (g) of at least one SCFA. In some embodiments, the composition comprises about 100 milligrams (mg) to about 6 grams (g) of at least one SCFA. In some embodiments, the composition comprises about 1 gram (g) to about 6 grams (g) of at least one SCFA. In some embodiments, the composition comprises about 1 gram (g) to about 4 grams (g) of at least one SCFA. In some embodiments, the composition comprises about 2 grams (g) to about 4 grams (g) of at least one SCFA. In some embodiments, the composition comprises about 2 grams (g) to about 3 grams (g) of at least one SCFA. For example, in one embodiment, the composition comprises about 2.4 grams (g) of at least one SCFA.

[0065] In some embodiments, the compositions disclosed herein comprise about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 110 mg, about 115 mg, about 120 mg, about 125 mg, about 130 mg, about 135 mg, about 140 mg, about 145 mg, or about 150 mg of SCFAs.

[0066] In some embodiments, the compositions disclosed herein comprise about 500 mg, about 550 mg, about 600 mg, about 650 mg, about 700 mg, about 750 mg, about 800 mg, about 850 mg, about 900 mg, about 950 mg, about 1000 mg, about 1050 mg, about 1100 mg, about 1150 mg, about 1200 mg, about 1250 mg, about 1300 mg, about 1350 mg, about 1400 mg, about 1450 mg, about 1500 mg, about 1550 mg, about 1600 mg, about 1650 mg, about 1700 mg, about 1750 mg, about 1800 mg, about 1850 mg, about 1900 mg, or about 2000 mg of SCFAs.

[0067] In one embodiment, the composition comprises at least one SCFA, a salt thereof, or a compound comprising an SCFA moiety. In some embodiments, the compositions disclosed herein comprise at least one SCFA. In some embodiments, the compositions disclosed herein comprise at least one short-chain fatty acid (SCFA), SCFA precursor, SCFA biosynthetic precursor, derivative thereof, SCFA moiety, or combination thereof.

[0068] In some embodiments, the compositions disclosed herein comprise at least one SCFA or a compound comprising an SCFA moiety. In some embodiments, the compositions disclosed herein comprise at least two SCFAs. In some embodiments, the compositions disclosed herein comprise at least three SCFAs.

[0069] Non-limiting examples of SCFAs, salts thereof, or SCFA moieties include acetic acid, butyric acid (BA), C3-C12 fatty acids, C3-C10 fatty acids, C3-C8 fatty acids, methoxyacetic acid, valproic acid (VPA), propionic acid, 3-methoxypropionic acid, ethoxyacetic acid, formic acid, isobutyric acid, tributyrin, N-acetylbutyrate (as well as other forms of butyrate, e.g., phenylbutyrate, isobutyrate, pivaloyloxymethylbutyrate, monoacetone glucose 3-butyrate), isovaleric acid, isobutyric acid, valer ... Caproic acid, caproic acid, lactic acid, succinic acid, pyruvic acid, octanoic acid, dodecanoic acid, (4R)-4-hydroxypentanoic acid, 2-ethylhydracrylic acid, 2-hydroxy-3-methylpentanoate, 2-hydroxy-3-methylpentanoic acid, 2-methylbut-2-enoic acid, 2-oxobutanoic acid, 3-hydroxypentanoic acid, 3-methylbut-2-enoic acid, butenoic acid, methylbutyric acid, dimethylbutyric acid, pentadienoic acid, pentenoic acid, pivalic acid, propynoic acid, or any combination thereof.

[0070] In one embodiment, the composition includes a salt of SCFA or a derivative thereof. For example, in one embodiment, the salt of SCFA includes at least one of butyrate, propionate, and / or acetate. The salt of butyric acid can be one or more of sodium butyrate, magnesium butyrate, or calcium butyrate. In one embodiment, the composition includes one or more of magnesium butyrate and calcium butyrate.

[0071] In some embodiments, butyrate can (1) enhance peroxisome proliferator-activated receptor (PPAR) signaling (PPARs regulate the expression of genes involved in fatty acid beta-oxidation, glucose metabolism, and inflammatory responses and are key regulators of energy homeostasis), (2) suppress pro-inflammatory cytokines such as tumor necrosis factor (TNF)-α, CCL2 / CCR2, and CCL5 / CCR5 (key cytokines involved in adipocyte-associated inflammation, hepatic stellate cell activation, and initiating fibrogenic responses), (3) improve insulin sensitivity, (4) promote GLP-1R expression (GLP-1 regulates glucose homeostasis, gastric motility, and food intake), and / or (5) inhibit the development of fibrosis (as indicated by a decrease in hepatic collagen content). In some embodiments, acetate can inhibit lipid accumulation by promoting lipolysis and fatty acid oxidation and inhibiting fatty acid synthesis. In some embodiments, vitamin E prevents liver injury by protecting against mitochondrial toxicity and blocking the intrinsic apoptotic pathway. Unlike other treatments that are largely based on single-channel drugs, the present disclosure provides broad multi-channel protection.

[0072] Mechanisms of action of butyrate, acetate, and vitamin E in the context of NAFLD / NASH / fibrosis: SCFAs (including butyrate and acetate) are derived from bacterial fermentation of fiber and play an important role in maintaining nutritional and immune homeostasis of the intestinal epithelium (Sanna et al., 2019; Van der Hee et al., 2021). SCFAs enter the liver directly through the portal vein, and there are several possible mechanisms by which SCFAs reduce the development of NASH / NAFLD. For example, in the liver, SCFAs (including butyrate and acetate) induce AMP-activated protein kinase (AMPK) activation and suppress macrophage pro-inflammatory activation, thereby alleviating hepatic steatosis.

[0073] Mice fed SCFAs showed a two-fold increase in hepatic lipid oxidation and a shift in hepatic lipid metabolism toward a more oxidative state, which was associated with increased phosphorylation and activation of AMPK (a central regulator of energy homeostasis) and its downstream target, acetyl-CoA carboxylase (ACC) (den Besten et al., 2015; Kim et al., 2016).

[0074] Butyrate and acetate also increase the transcriptional expression of adiponectin and resistin (both adipose tissue-derived hormones that play important roles in protecting against insulin resistance, diabetes, and obesity) through epigenetic modulation (DNA methylation) in obese mice (Dai et al., 2020) and decrease the expression of lipogenic genes (through histone deacetylase [HDAC] inhibition) such as those encoding ACC, Fasn, and Srebp1c (Kim et al., 2018), all of which are associated with NASH progression. Butyrate is the most potent natural HDAC inhibitor (Waldecker et al., 2008). In mouse models, oral administration of butyrate significantly reduced hepatic steatosis and inflammation in Western-diet-induced NASH (Jin et al., 2015) and fat-fructose-cholesterol-rich diet-induced NASH mice (Baumann et al., 2020). (2012) reported that mice treated with the butyrate prodrug tributyrin were protected from diet-induced obesity, insulin resistance, and hepatic steatosis. Butyrate is a PPAR agonist (Nepelska et al., 2017).

[0075] PPARs are nuclear receptors that regulate the expression of genes involved in fatty acid beta-oxidation, glucose metabolism, and inflammatory responses (by acting on NF-kB and AP1 transcription factors) and are key regulators of energy homeostasis. In animal models of steatosis and steatohepatitis, the use of PPAR activators improved disease outcomes (Caligiuri et al., 2016). Butyrate protected against high-fat diet-induced obesity via a PPARγ-dependent switch from lipogenesis to fat oxidation (den Besten, et al., 2015). Inflammation represents a key aspect in the pathogenesis of NASH. Overload of toxic lipids, primarily free fatty acids (FFAs), causes cellular stress and induces specific signals that trigger hepatocyte apoptosis. Strong evidence supports the crucial role of the pro-inflammatory cytokine TNF-ct in the pathogenesis of NASH (Day et al., 1998). In the liver, TNF-ct is secreted directly by hepatocytes and Kupffer cells or indirectly by abdominal fat. Data from animal and clinical studies indicate that TNF-α mediates not only the early stages of liver injury but also the transition to more advanced stages (Crespo et al., 2001; Hotamisligil et al., 1993). Butyrate suppresses TNF-α (and thus inflammation), one of the mechanisms by which it does so is by promoting its mRNA degradation (Fukae et al., 2005).

[0076] Other upregulated pro-inflammatory cytokines involved in the pathogenesis of NASH include IL-1β, IL-12, CCL2, and CCL5. The latter two recruit macrophages (and other inflammatory cells), induce hepatic stellate cell activation, and initiate a fibrogenic response (Marra et al., 2014). Expression of CCR2 and CCR5 has been shown to be upregulated in vivo and in the livers of obese patients with severe steatosis and NASH. Human data show that patients with NAFLD have higher serum CCL2 levels, which positively correlate with their liver fat content (Braunersreuther et al., 2012).

[0077] In NASH patients, increased hepatic CCL5 mRNA levels were associated with more severe fibrosis (Berres et al., 2010). In a HFD-induced NASH mouse model, high hepatic CCL5 levels were significantly reduced by butyrate (Gart et al., 2021). Clinical trials in NAFLD patients showed that glucagon-like peptide 1 receptor (GLP-1R) agonists reduced hepatic fat content. GLP-1R agonists enhance the inhibition of glucose-stimulated insulin and glucagon secretion, leading to weight loss and ultimately to the improvement of hepatic steatosis. In obese mice fed a high-fat diet (HFD), butyrate stimulated the expression of GLP-1R (Chen et al., 2020) and GLP-1 (Yadav et al., 2019; Zhao et al., 2021). Interestingly, Gart et al. (2021) showed that butyrate inhibits the development of fibrosis, as demonstrated by a reduction in hepatic collagen content in liver histopathology.

[0078] One of the mechanisms by which SCFAs affect fat accumulation in both the liver and adipose tissue is through the regulation of insulin sensitivity via G protein-coupled receptor 43 (GPR43), also known as free fatty acid receptor 2 (FFAR2). Acetate is the most selective ligand for GPR43 (Kolodziejczyk et al., 2019). Activation of GPR43 signaling promotes energy expenditure and inhibits fat accumulation (through lipolysis and fatty acid oxidation) (Kimura et al., 2013; Dai et al., 2020), and liver-specific silencing of FFAR2 exacerbates local insulin resistance and lipid metabolism dysregulation (Aoki et al., 2021).

[0079] Few animal studies have shown that acetate supplementation reduces hepatic lipogenesis and fatty acid uptake and protects mice from HFD-induced weight gain, steatosis, and insulin resistance (Weitkunat et al., 2017; Hernandez et al., 2019). Furthermore, activation of hepatic FFAR2 by acetate may represent a promising therapeutic strategy for NAFLD / NASH (Aoki et al., 2021). A well-defined mouse study using PET-CT showed that intravenously and intracolonically administered 11C-acetate could cross the blood-brain barrier and be taken up into the hypothalamus. This uptake resulted in a decrease in food intake via appetite suppression accompanied by increased production of lactate and γ-aminobutyric acid (Frost et al., 2014).

[0080] Furthermore, in humans, acetate can cross the blood-brain barrier and be metabolized in the brain (subjects were given [2-13C] acetate for 2 hours and their brains were scanned by magnetic resonance spectroscopy) (Jiang et al., 2013). There are data from small human clinical trials showing beneficial effects of acetate (Kondo et al., 2009).

[0081] In some embodiments, the salt of the SCFA comprises at least one Ca salt of the SCFA, Mg salt of the SCFA, Na salt of the SCFA, or any combination thereof. For example, in some embodiments, the salt of the SCFA comprises at least one Ca salt of butyric acid, Mg salt of butyric acid, Na salt of butyric acid, Ca salt of acetic acid, Mg salt of acetic acid, Na salt of acetic acid, or any combination thereof.

[0082] Non-limiting examples of SCFAs or SCFA moieties include compounds or structures having at least 12 carbon atoms, at least 11 carbon atoms, at least 10 carbon atoms, at least 9 carbon atoms, at least 8 carbon atoms, at least 7 carbon atoms, at least 6 carbon atoms, at least 5 carbon atoms, at least 4 carbon atoms, at least 3 carbon atoms, and at least 2 carbon atoms. In one embodiment, the SCFA or SCFA moiety includes compounds or structures having fewer than 13 carbon atoms, fewer than 12 carbon atoms, fewer than 11 carbon atoms, fewer than 10 carbon atoms, fewer than 9 carbon atoms, fewer than 8 carbon atoms, or fewer than 7 carbon atoms. In one embodiment, the SCFA or SCFA moiety is not a branched fatty acid. In one embodiment, the SCFA or SCFA moiety is a branched fatty acid.

[0083] In one embodiment, the composition comprises at least one compound comprising a precursor or portion thereof of an SCFA, hi one embodiment, the precursor or portion thereof is selected from the group including, but not limited to, plant cell wall polysaccharides, dietary non-starch polysaccharides (NSPs), salts of lactate, salts of succinate, salts of formate, 1,2-propendol, trypamine, indole, indole-3-acetate, and combinations thereof.

[0084] In one embodiment, the composition comprises at least one compound comprising a biosynthetic precursor of an SCFA or a portion thereof, in one embodiment, the biosynthetic precursor or portion thereof is selected from the group including, but not limited to, an acetyl-CoA carboxylase inhibitor, an adenosine monophosphate kinase (AMPK) activator, vitamin D, and combinations thereof.

[0085] antioxidants

[0086] Vitamin E is a fat-soluble antioxidant that stops the production of ROS formed when fats undergo oxidation. There are eight forms of vitamin E, including four tocopherols (alpha-, beta-, gamma-, and delta-tocopherol) and four tocotrienols (alpha-, beta-, gamma-, and delta-tocotrienol), which have varying levels of biological activity.

[0087] Tocopherols are organic compounds containing various methylated phenols, many of which have vitamin E activity. Non-limiting examples of tocopherols include alpha-tocopherol or α-tocopherol, RRR-α-tocopherol, d-α-tocopherol, ddd-α-tocopherol, RSR-α-tocopherol, all-rac-α-tocopherol, dl-tocopherol, dl-α-tocopherol, dl-tocopheryl acetate, tocopherol acetate, tocopheryl acetate, α-tocopheryl acetate, and alpha-tocopheryl acetate. Tocopheryl acetate, dl-α-tocopheryl acetate, d-α-tocopheryl acetate, α-tocopheryl succinate, α-tocopheryl nicotinate, α-tocopheryl phosphate, tocopheryl esters, tocopheryl nicotinate, tocopheryl linoleate, and tocopheryl palmitate, gamma-tocopherol, tocopheryl linoleate, beta-tocopherol, gamma-tocopherol, d-γ-tocopherol, or mixed tocopherols.

[0088] In some embodiments, vitamin E is alpha-tocopherol or α-tocopherol. In some embodiments, the tocopherol is alpha-tocopherol or α-tocopherol. In some embodiments, vitamin E is d-α-tocopherol acetate. In some embodiments, the tocopherol is d-α-tocopherol acetate. In some embodiments, vitamin E is dl-α-tocopherol. In some embodiments, the tocopherol is dl-α-tocopherol.

[0089] In some embodiments, the tocopherols disclosed herein are hydrolyzed, for example, α-tocopherol acetate is hydrolyzed to α-tocopherol and acetic acid.

[0090] In some embodiments, the tocopherol is synthetic. In some embodiments, the tocopherol is fully synthetic. In some embodiments, the tocopherol is semi-synthetic. In some embodiments, the tocopherol is natural. In some embodiments, the tocopherol is fractionated. In some embodiments, the tocopherol is highly fractionated. In some embodiments, the tocopherol is less fractionated.

[0091] Antioxidants, such as tocopherol or vitamin E, can prevent liver injury by protecting against mitochondrial toxicity and blocking the intrinsic apoptotic pathway. Vitamin E can also downregulate the NF-kB-dependent inflammatory pathway (Ratziu et al., 2015). However, antioxidant therapy is not always beneficial and has been shown to be associated with worsening disease. Administration of high-dose vitamin E improved NAS within two years but often increased insulin resistance and plasma triglyceride levels (Hackam, 2007; Chalasani et al., 2012). Indeed, concerns exist about the long-term safety of high-dose vitamin E, including increased all-cause mortality, hemorrhagic stroke, and even prostate cancer in men over the age of 50 (Miller et al., 2005; Ratziu et al., 2015; Hackam, 2007). In some embodiments, the high-dose vitamin E is approximately 800 IU.

[0092] In some embodiments, the compositions disclosed herein comprise a reduced amount of tocopherol or vitamin E. In some embodiments, the reduced amount of tocopherol or vitamin E alleviates or reduces adverse events associated with high-dose vitamin E. Non-limiting examples of adverse events associated with high-dose vitamin E include increased insulin resistance, increased plasma triglyceride levels, increased mortality, increased incidence of hemorrhagic stroke, and increased incidence of prostate cancer.

[0093] In some embodiments, a reduced amount of tocopherol, in combination with at least one SCFA or a pharmaceutically acceptable salt thereof, is therapeutically effective to alleviate a condition in a subject in need thereof, hi some embodiments, a reduced amount of vitamin E, in combination with at least one SCFA or a pharmaceutically acceptable salt thereof, is therapeutically effective to alleviate a condition in a subject in need thereof.

[0094] In some embodiments, a reduced amount of tocopherol, in combination with at least two SCFAs or pharmaceutically acceptable salts thereof, is therapeutically effective to alleviate a condition in a subject in need thereof, hi some embodiments, a reduced amount of vitamin E, in combination with at least two SCFAs or pharmaceutically acceptable salts thereof, is therapeutically effective to alleviate a condition in a subject in need thereof.

[0095] In some embodiments, the reduced amount of tocopherol is less than the amount of tocopherol that would be therapeutically effective for the condition in the absence of the at least one SCFA or pharmaceutically acceptable salt thereof, hi some embodiments, the reduced amount of vitamin E is less than the amount of tocopherol that would be therapeutically effective for the condition in the absence of the at least one SCFA or pharmaceutically acceptable salt thereof.

[0096] In some embodiments, the reduced amount of tocopherol is less than the amount of tocopherol that would be therapeutically effective for the condition in the absence of the at least two SCFAs or pharmaceutically acceptable salts thereof, hi some embodiments, the reduced amount of vitamin E is less than the amount of tocopherol that would be therapeutically effective for the condition in the absence of the at least two SCFAs or pharmaceutically acceptable salts thereof.

[0097] In some embodiments, tocopherol exhibits a synergistic effect with at least one SCFA or a pharmaceutically acceptable salt thereof. In some embodiments, vitamin E exhibits a synergistic effect with at least one SCFA or a pharmaceutically acceptable salt thereof.

[0098] In some embodiments, the compositions disclosed herein provide about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, about 21%, about 22%, about 23%, about 24%, about 25%, about 26%, about 27%, about 28%, about 29%, about 30%, about 31%, about 32%, about 33%, about 34%, about 35%, about 36%, about 37%, about 38%, about 39%, about 40%, about 41%, about 42%, about 43%, about 44%, about 45%, about 46%, about 47%, about 48%, about 49%, about 50%, about 51%, about 52%, about 53%, about 54%, about 55%, about 56%, about 57%, about 58%, about 59%, about 60%, about 61%, about 62%, about 63%, about 64%, about 65%, about 66%, about 67%, about 68%, about 69%, about 70%, about 71%, about 72%, about 73%, about 74%, about 75%, about 76%, about 77%, about 78%, about 79%, about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94% of the amount of tocopherol or vitamin E that is therapeutically effective for a condition in the absence of at least one SCFA or a pharmaceutically acceptable salt thereof. 7%, approximately 48%, approximately 49%, approximately 50%, approximately 51%, approximately 52%, approximately 53%, approximately 54%, approximately 55%, approximately 56%, approximately 57%, approximately 58%, approximately 59%, approximately 60%, approximately 61%, approximately 62%, approximately 63%, approximately 64%, approximately 65%, approximately 66%, approximately 67%, approximately 68%, approximately 69%, approximately 70%, approximately 71%, approximately 72%, approximately 73%, approximately 74%, approximately 75% , about 76%, about 77%, about 78%, about 79%, about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% tocopherol or vitamin E.

[0099] In some embodiments, the compositions disclosed herein comprise less than about 600 IU, less than about 550 IU, less than about 500 IU, less than about 450 IU, less than about 400 IU, less than about 350 IU, less than about 300 IU, less than about 250 IU, less than about 200 IU, less than about 150 IU, less than about 100 IU, less than about 50 IU, less than about 40 IU, less than about 30 IU, less than about 20 IU, or less than about 10 IU of tocopherol or vitamin E.

[0100] In some embodiments, the compositions disclosed herein comprise more than about 100 IU, more than about 150 IU, more than about 200 IU, more than about 250 IU, more than about 300 IU, more than about 350 IU, more than about 400 IU, more than about 450 IU, more than about 500 IU, more than about 550 IU, or more than about 600 IU of tocopherol or vitamin E.

[0101] In some embodiments, the compositions disclosed herein comprise from about 100.1 to about 600 IU of tocopherol or vitamin E. In some embodiments, the compositions disclosed herein comprise from about 101 to about 600 IU of tocopherol or vitamin E. In some embodiments, the compositions disclosed herein comprise from about 200.1 to about 600 IU of tocopherol or vitamin E. In some embodiments, the compositions disclosed herein comprise from about 201 to about 600 IU of tocopherol or vitamin E. In some embodiments, the compositions disclosed herein comprise from about 300 to about 600 IU of tocopherol or vitamin E. In some embodiments, the compositions disclosed herein comprise from about 400 to about 600 IU of tocopherol or vitamin E. In some embodiments, the compositions disclosed herein comprise from about 500 to about 600 IU of tocopherol or vitamin E.

[0102] In some embodiments, the compositions disclosed herein include from about 1 to about 49.9 IU of tocopherol or vitamin E. In some embodiments, the compositions disclosed herein include from about 1 to about 49 IU of tocopherol or vitamin E. In some embodiments, the compositions disclosed herein include from about 1 to about 40 IU of tocopherol or vitamin E. In some embodiments, the compositions disclosed herein include from about 1 to about 30 IU of tocopherol or vitamin E. In some embodiments, the compositions disclosed herein include from about 1 to about 20 IU of tocopherol or vitamin E. In some embodiments, the compositions disclosed herein include from about 1 to about 10 IU of tocopherol or vitamin E.

[0103] In some embodiments, the compositions disclosed herein comprise about 100.1 IU, about 100.2 IU, about 100.3 IU, about 100.4 IU, about 100.5 IU, about 100.6 IU, about 100.7 IU, about 100.8 IU, about 100.9 IU, about 101.0 IU, about 101.1 IU, about 101.2 IU, about 101.3 IU, about 101.4 IU, about 101.5 IU, about 101.6 IU, about 101.7, about 101.8 IU, about 101.9 IU, or about 102.0 IU of tocopherol or vitamin E.

[0104] In some embodiments, the compositions disclosed herein comprise about 200.1 IU, about 200.2 IU, about 200.3 IU, about 200.4 IU, about 200.5 IU, about 200.6 IU, about 200.7 IU, about 200.8 IU, about 200.9 IU, about 201.0 IU, about 201.1 IU, about 201.2 IU, about 201.3 IU, about 201.4 IU, about 201.5 IU, about 201.6 IU, about 201.7, about 201.8 IU, about 201.9 IU, or about 202.0 IU of tocopherol or vitamin E.

[0105] In some embodiments, the compositions disclosed herein comprise about 49.9 IU, about 49.8 IU, about 49.7 IU, about 49.6 IU, about 49.5 IU, about 49.4 IU, about 49.3 IU, about 49.2 IU, about 49.1 IU, about 49.0 IU, about 48.9 IU, about 48.8 IU, about 48.7 IU, about 48.6 IU, about 48.5 IU, about 48.4 IU, about 48.3 IU, about 48.2 IU, about 48.1 IU, or about 48.0 IU of tocopherol or vitamin E.

[0106] In some embodiments, the composition contains about 20 IU, about 25 IU, about 30 IU, about 35 IU, about 40 IU, about 45 IU, about 50 IU, about 55 IU, about 60 IU, about 65 IU, about 70 IU, about 75 IU, about 80 IU, about 85 IU, about 90 IU, about 95 IU, about 100 IU, about 10 ... about 120 IU, about 130 IU, about 140 IU, about 150 IU, about 160 IU, about 170 IU, about 180 IU, about 190 IU, about 200 IU, about 210 IU, about 220 IU, about 230 IU, about 240 IU, about 250 IU, about 260 IU, about 270 IU, about 280 IU, about 290 IU, about 300 IU, about 320 IU, about 330 IU, about 340 IU, about 350 IU, about 360 IU, about 370 IU, about 380 IU, about 390 IU, and about 400 IU.

[0107] In various embodiments, the methods of the present disclosure comprise administering to a subject in need thereof a composition disclosed herein further comprising at least one antioxidant.

[0108] In some embodiments, the composition comprises between about 1 milligram (mg) and about 100,000 milligrams (mg) of at least one antioxidant. In some embodiments, the composition comprises between about 1 milligram (mg) and about 100 milligrams (mg) of at least one antioxidant. In some embodiments, the composition comprises between about 1 milligram (mg) and about 90 milligrams (mg) of at least one antioxidant. In some embodiments, the composition comprises between about 1 milligram (mg) and about 80 milligrams (mg) of at least one antioxidant. In some embodiments, the composition comprises between about 1 milligram (mg) and about 70 milligrams (mg) of at least one antioxidant. In some embodiments, the composition comprises between about 1 milligram (mg) and about 60 milligrams (mg) of at least one antioxidant. In some embodiments, the composition comprises between about 1 milligram (mg) and about 50 milligrams (mg) of at least one antioxidant. In some embodiments, the composition comprises between about 1 milligram (mg) and about 40 milligrams (mg) of at least one antioxidant. In some embodiments, the composition comprises about 1 milligram (mg) to about 30 milligrams (mg) of at least one antioxidant. In some embodiments, the composition comprises about 1 milligram (mg) to about 20 milligrams (mg) of at least one antioxidant. For example, in some embodiments, the composition comprises about 12 milligrams (mg) of at least one antioxidant.

[0109] In some embodiments, the composition comprises about 20 IU to about 300 IU of at least one antioxidant. In some embodiments, the composition comprises about 20 IU to about 200 IU of at least one antioxidant. In some embodiments, the composition comprises about 50 IU to about 200 IU of at least one antioxidant. In some embodiments, the composition comprises about 200 IU to about 600 IU of at least one antioxidant.

[0110] In some embodiments, the tocopherol is tocopherol acetate. In some embodiments, the tocopherol is d-α-tocopherol acetate.

[0111] In some embodiments, the at least one antioxidant is vitamin E (d-α-tocopherol acetate).

[0112] In some embodiments, the antioxidant comprises at least one of vitamin C, vitamin E (d-α-tocopheryl acetate), beta-carotene, carotenoids, selenium, manganese, glutathione, coenzyme Q10, lipoic acid, flavonoids, phenols, polyphenols, phytoestrogens, vitamin D3, or any combination thereof. Magnesium is a cofactor for over 300 enzymes that regulate a variety of biochemical reactions, including regulation of blood glucose levels, detoxification, etc. Vitamin D3 deficiency frequently occurs in patients with immune disorders. Vitamin E has unique antioxidant activity. In one embodiment, the method comprises administering to a subject in need thereof a composition comprising at least one SCFA, a salt thereof, or a biologically active derivative or precursor thereof, and further comprising one or more of magnesium, vitamin D3, and vitamin E. In one embodiment, the method comprises administering to a subject in need thereof a composition comprising at least one SCFA, a salt thereof, or a biologically active derivative or precursor thereof, in combination with a composition comprising one or more of magnesium, vitamin D3, and vitamin E.

[0113] situation

[0114] In some embodiments, diseases and disorders that may be treated, prevented, or ameliorated by the methods of the present disclosure include, but are not limited to, inflammatory diseases and various cancer diseases. In some embodiments, inflammatory diseases and disorders that may be treated or ameliorated include, but are not limited to, asthma, arthritis, allergic rhinitis, psoriasis, atopic dermatitis, inflammatory bowel disease, Crohn's disease, allergic or autoimmune diseases or disorders associated with cesarean section in newborns, uveitis, and vasculitis. In some embodiments, cancer diseases and disorders that may be treated or ameliorated include, but are not limited to, leukemia and lymphoma.

[0115] In one embodiment, the autoimmune disease or disorder is Addison's disease, agammaglobulinemia, allergic rhinitis, alopecia areata, amyloidosis, ankylosing spondylitis, anti-GBM / anti-TBM nephritis, antiphospholipid syndrome (APS), asthma, autoimmune inner ear disease (AIED), axonal and neuronal neuropathy (AMAN), Behcet's disease, bullous pemphigoid, Castleman's disease (CD), celiac disease, Chagas' disease, chronic inflammatory demyelinating polyneuropathy (CIDP), chronic relapsing multifocal osteomyelitis (CRMO), Churg-Strauss, cicatricial pemphigoid / benign mucous membrane pemphigus, Cogan's syndrome. , cold agglutinin disease, congenital heart block, Coxsackie myocarditis, CREST syndrome, Crohn's disease, dermatitis herpetiformis, dermatomyositis, Devic's disease (neuromyelitis optica), discoid lupus, Dressler syndrome, eosinophilic esophagitis (EoE), eosinophilic fasciitis, erythema nodosum, essential mixed cryoglobulinemia, Evans syndrome, fibromyalgia, fibrosing alveolitis, food allergy, gastroenteritis, giant cell arteritis (temporal arteritis), giant cell myocarditis, glomerulonephritis, Goodpasture's syndrome, granulomatosis with polyangiitis, Graves' disease, Guillain-Barré syndrome, Hashimoto's thyroiditis, hemolytic anemia, Henoch- Herpes gestationis or pemphigoid of gestationis (PG), hypogammaglobulinemia, IgA nephropathy, IgG4-related sclerosing disease, inclusion body myositis (IBM), inflammatory bowel disease, interstitial cystitis (IC), juvenile arthritis, juvenile rheumatoid arthritis, juvenile diabetes mellitus (type 1 diabetes), juvenile myositis (JM), Kawasaki disease, Lambert-Eaton sign, leukocytoclastic vasculitis, lichen planus, lichen sclerosus, lignified conjunctivitis, linear IgA disease (LAD), lupus, chronic Lyme disease, Meniere's disease, microscopic polyangiitis (MPA), mixed connective tissue disease (MCTD), Mooren's ulcer, Ka-Habermann disease, multiple sclerosis (MS), myasthenia gravis, myositis, narcolepsy, neuromyelitis optica, neutropenia, ocular cicatricial pemphigoid, optic neuritis, relapsing rheumatoid arthritis (PR), PANDAS (pediatric autoimmune neuropsychiatric disorders associated with streptococcus), paraneoplastic neurological syndrome (PCD), paroxysmal nocturnal hemoglobinuria (PNH), Parry-Romberg syndrome, pars planitis (peripheral uveitis), Parsonage-Turner syndrome, pemphigus, peripheral neuropathy, perivenous encephalomyelitis, pernicious anemia (PA), POEMS syndrome (polyneuropathy, organomegaly,Endocrine disorders, monoclonal, gammaglobulin disorders, skin changes), polyarteritis nodosa, polymyalgia rheumatica, polymyositis, post-myocardial infarction syndrome, post-pericardiotomy syndrome, progestational dermatitis, psoriasis, plaque psoriasis, guttate psoriasis, inverse psoriasis, pustular psoriasis, plaque psoriasis, seborrheic psoriasis, erythrodermic psoriasis, nail psoriasis, psoriatic arthritis, pure red cell aplasia (PRCA), pyoderma gangrenosum, Raynaud's phenomenon, reactive arthritis, reflex sympathetic dystrophy, Reiter's syndrome, plaque psoriasis, restless legs syndrome (RLS), retroperitoneal fibrosis, rheumatic fever, rheumatoid arthritis (RA), At least one of the following conditions is present: sarcoidosis, Schmidt syndrome, scleritis, scleroderma, Sjögren's syndrome, sperm and testicular autoimmunity, stiff-person syndrome (SPS), subacute bacterial endocarditis (SBE), Sasac syndrome, sympathetic ophthalmia (SO), Takayasu's arteritis, temporal arteritis / giant cell arteritis, thrombocytopenic purpura (TTP), Tolosa-Hunt syndrome (THS), transverse myelitis, type 1 diabetes, ulcerative colitis (UC), undifferentiated connective tissue disease (UCTD), uveitis, vasculitis, vitiligo, and Wegener's granulomatosis (granulomatosis with polyangiitis (GPA)).

[0116] In other embodiments, diseases and disorders that may be treated, prevented, or ameliorated by the methods of the present disclosure include allergic diseases, infectious diseases, and organ transplant rejection, such as inflammatory bowel disease (IBD), ulcerative colitis, Crohn's disease, sprue, autoimmune arthritis, rheumatoid arthritis, type 1 diabetes, multiple sclerosis, graft-versus-host disease after bone marrow transplantation, osteoarthritis, juvenile chronic arthritis, Lyme arthritis, psoriatic arthritis, reactive arthritis, spondyloarthritis, systemic lupus erythematosus, insulin-dependent diabetes mellitus, thyroiditis, asthma, psoriasis, cutaneous scleroderma, atopic dermatitis, graft-versus-host disease, and thyroiditis. Host disease, acute or chronic immune disorders associated with organ transplantation, sarcoidosis, atherosclerosis, disseminated intravascular coagulation, Kawasaki disease, Graves' disease, nephrotic syndrome, chronic fatigue syndrome, Wegener's granulomatosis, Henoch-Schönlein purpura, microscopic vasculitis of the kidney, uveitis, septic shock, toxic shock syndrome, septic syndrome, cachexia, acquired immune deficiency syndrome, acute transverse myelitis, Huntington's chorea, Parkinson's disease, Alzheimer's disease, stroke, primary biliary cirrhosis, hemolytic anemia, polyglandular deficiency type I syndrome and polyglandular deficiency syndrome Type II syndrome, Schmidt's syndrome, adult (acute) respiratory distress syndrome, alopecia, alopecia areata, seronegative arthropathy, arthropathy, Reiter's disease, psoriatic arthropathy, Chlamydia, Yersinia and Salmonella associated arthropathy, seronegative arthritis, atherosclerosis / arteriosclerosis, allergic colitis, atopic allergies, food allergies such as peanut allergy, tree nut allergy, egg allergy, milk allergy, soy allergy, wheat allergy, seafood allergy, shellfish allergy or sesame seed allergy, autoimmune bullous diseases, pemphigus vulgaris, Pemphigus foliaceus, pemphigoid, linear IgA disease, autoimmune hemolytic anemia, Coombs-positive hemolytic anemia, acquired pernicious anemia, juvenile pernicious anemia, myogenic encephalitis / Royal-Free disease, chronic mucocutaneous candidiasis, giant cell arteritis, acquired immunodeficiency syndrome, acquired immunodeficiency-associated disease, congenital immunodeficiency (congenital variant hypogammaglobulinemia), dilated cardiomyopathy, fibrotic lung disease, fibrosing alveolitis of unknown cause, postinflammatory interstitial lung disease, interstitial pneumonia, connective tissue disease-associated interstitial lung disease, mixed connective tissue disease-associated lung disease, systemic sclerosis-associated interstitial lung disease, rheumatoid arthritis-associated interstitial lung disease,Systemic lupus erythematosus-associated lung disease, dermatomyositis / polymyositis-associated lung disease, Sjögren's syndrome-associated lung disease, ankylosing spondylitis-associated lung disease, vasculitic diffuse lung disease, hemosiderin-associated lung disease, drug-induced interstitial lung disease, radiation fibrosis, bronchiolitis obliterans, chronic eosinophilic acute pneumonia, lymphocytic infiltrative lung disease, dermatomyositis / polymyositis-associated lung disease, Sjögren's disease-associated lung disease, ankylosing spondylitis-associated lung disease, vasculitic diffuse lung disease, hemosiderin-associated lung disease, drug-induced Interstitial lung disease, radiation fibrosis, bronchiolitis obliterans, chronic eosinophilic pneumonia, lymphocytic infiltrative lung disease, post-infectious interstitial lung disease, gouty arthritis, autoimmune-mediated hypoglycemia, type B insulin-resistant acanthosis nigricans, hypoparathyroidism, acute immune disorders associated with organ transplantation, chronic immune disorders associated with organ transplantation, osteoarthritis, primary sclerosing cholangitis, idiopathic leukopenia, autoimmune neutropenia, renal disease NOS, glomerulonephritis, microscopic vasculitis of the kidney, discoid lupus, idiopathic, male infertility Pregnancy or NOS, sperm autoimmunity, multiple sclerosis (all subtypes), insulin-dependent diabetes mellitus, sympathetic ophthalmia, pulmonary hypertension secondary to connective tissue disease, Goodpasture's syndrome, pulmonary manifestations of polyarteritis nodosa, acute rheumatic fever, rheumatoid spondylitis, Still's disease, systemic sclerosis, Takayasu's disease / arteritis, autoimmune thrombocytopenia, idiopathic thrombocytopenia, autoimmune thyroid disease, hyperthyroidism, autoimmune hypothyroidism (Hashimoto's disease), atrophic thyroid disease These include, but are not limited to, autoimmune hypothyroidism, primary myxedema, suppurative uveitis, primary vasculitis, vitiligo, allergic rhinitis (pollen allergy), anaphylaxis, pet allergy, latex allergy, drug allergy, allergic rhinoconjunctivitis, eosinophilic esophagitis, hypereosinophilic syndrome, eosinophilic gastroenteritis, cutaneous lupus erythematosus, eosinophilic esophagitis, hypereosinophilic syndrome, eosinophilic gastroenteritis, and diarrhea.

[0117] Treatment method

[0118] In one embodiment, the present disclosure provides a method for the treatment or prevention of at least one disease or disorder in a subject, comprising administering to the subject at least one composition comprising an SCFA or a compound comprising an SCFA moiety, optionally in combination with at least one additional agent or therapy.

[0119] In some embodiments, the administered compositions of the present disclosure may increase the number of disease-free days, reduce the severity of a disease or disorder, reduce the risk of developing a disease or disorder, reduce the risk of recurrence of a disease or disorder, or a combination thereof in a subject. The administered compositions of the present disclosure may increase the number of disease-free days in a subject by 5 to 60% or more compared to a subject not receiving the treatment. The administered compositions of the present disclosure may reduce the severity of a disease or disorder in a subject by 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60% or more compared to a subject not receiving the treatment. The administered compositions of the disclosure may reduce the risk of developing a disease or disorder in a subject by 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60% or more compared to a subject not receiving treatment. The administered compositions of the disclosure may reduce the risk of recurrence of the disease or disorder in a subject by 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60% or more compared to a subject not receiving treatment.

[0120] In one embodiment, an exemplary method for treating or preventing a disease or disorder comprises administering a daily oral dose of a composition comprising at least 10 mg, at least 20 mg, at least 30 mg, at least 40 mg, at least 50 mg, at least 60 mg, at least 70 mg, at least 80 mg, at least 90 mg, at least 100 mg, at least 200 mg, at least 300 mg, at least 400 mg, at least 500 mg, at least 600 mg, at least 700 mg, at least 800 mg, at least 900 mg, at least 1 g, at least 2 g, at least 3 g, at least 4 g, at least 5 g, at least 6 g, or more than 6 g of at least one SCFA at least once a day, at least twice a day, at least three times a day, or more than three times a day for at least 1 week, at least 2 weeks, at least 3 weeks, at least 1 month, at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, or more than 6 months.

[0121] In one embodiment, the composition comprising at least one SCFA is an enteric coated extended release capsule.

[0122] In one embodiment, the composition comprises a derivative of an SCFA. In one embodiment, the derivative comprises at least one SCFA moiety linked to at least one additional moiety. In one embodiment, the derivative comprises at least one SCFA moiety linked to at least one polyethylene glycol (PEG) moiety. In one embodiment, the at least one SCFA moiety linked to at least one PEG moiety is hydrolyzed under low pH conditions to produce at least one SCFA molecule and at least one PEG molecule.

[0123] In one embodiment, the composition comprises a combination of SCFAs and / or derivatives thereof, hi one embodiment, the composition is prepared in an amount of at least 10 mM, at least 20 mM, at least 30 mM, 40 mM, 50 mM, 60 mM, 70 mM, 80 mM, 90 mM, 100 mM, or more of each or all of the compounds in the composition.

[0124] For example, derivatives of SCFAs having substituents on the carbon chain, such as O, S, N, methyl, ethyl, halogen, and other groups that do not interfere with the therapeutic activity of the compound, can also be used to form the compositions of the present disclosure. In one embodiment, the compounds of the present disclosure include at least one SCFA linked to at least one additional moiety, such as O, S, N, methyl, ethyl, halogen, and other groups that do not interfere with the therapeutic activity of the compound.

[0125] In some examples, the SCFAs of the present disclosure may be pegylated. Polyethylene glycol (PEG) is widely used in biomaterials, biotechnology, and medicine, primarily because PEG is a biocompatible, non-toxic, non-immunogenic, and water-soluble polymer (Zhao and Harris, ACS Symposium Series 680:458-72, 1997). In the field of drug delivery, PEG derivatives are widely used in covalent attachment to proteins (i.e., "PEGylation") to reduce immunogenicity, proteolysis, and renal clearance, as well as to enhance solubility (Zalipsky, Adv. Drug Del. Rev. 16:157-82, 1995). Similarly, PEG has been attached to low-molecular-weight, relatively hydrophobic drugs to increase solubility, reduce toxicity, and alter biodistribution. Typically, PEGylated drugs are injected as a solution; however, they can also be administered orally or by another route.

[0126] A closely related application is the synthesis of crosslinked, degradable PEG networks or formulations for use in drug delivery, since many of the same chemicals used to design degradable, soluble drug carriers can also be used to design degradable gels (Sawhney et al., Macromolecules 26:581-87, 1993). It is also known that interpolymer complexes can be formed by mixing solutions of two complementary polymers. Such complexes are generally stabilized by electrostatic interactions (polyanion-polycation) and / or hydrogen bonds (polyacid-polybase) between the polymers involved, and / or by hydrophobic interactions between the polymers in an aqueous environment (Krupers et al., Eur. Polym J. 32:785-790, 1996). For example, mixing solutions of polyacrylic acid (PAAc) and polyethylene oxide (PEO) under appropriate conditions results in the formation of complexes based mostly on hydrogen bonding. Dissociation of these complexes under physiological conditions allows for the delivery of the free drug (i.e., non-PEGylated). Additionally, complementary polymer conjugates may be formed from both homopolymers and copolymers.

[0127] In one embodiment, the composition comprises a precursor of an SCFA, alone or in combination with one or more SCFAs, including, but not limited to, salts of formate, salts of lactate, salts of succinate, 1,2-propendol, trypamine, indole, and indole-3-acetate.

[0128] In one embodiment, the composition comprises precursors of SCFA biosynthesis, alone or in combination with one or more SCFAs. Precursors of SCFA biosynthesis include, but are not limited to, formate salts, lactate salts, succinate salts, acetyl-CoA carboxylase inhibitors, adenosine monophosphate kinase (AMPK) activators, and vitamin D. SCFAs stimulate T regulatory (Treg) cell function, which is responsible for some of their anti-inflammatory properties. Given that inhibitors of acetyl-CoA carboxylase also promote Treg cell function, in one embodiment, the composition comprises an inhibitor of acetyl-CoA carboxylase, including, but not limited to, biotin or its natural or chemically synthesized analogs (which are acetyl-CoA carboxylase inhibitors), alone or in combination with one or more other SCFAs, to stimulate Treg function.

[0129] In various embodiments, a compound comprising at least one SCFA or a compound comprising an SCFA moiety of the present disclosure can be combined with one or more compounds, such as one or more additional therapeutic agents, for a particular disease or disorder. In one embodiment, one or more SCFAs of the present disclosure can be in the same composition as one or more additional therapeutic agents. In various embodiments, the composition can include at least 1, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, or more than 10 additional therapeutic agents. Exemplary additional therapeutic agents and / or compounds that can be included in the composition are discussed in detail elsewhere herein.

[0130] anti-inflammatory agents

[0131] In one embodiment, the method comprises administering to a subject in need thereof a composition comprising at least one SCFA, or a biologically active derivative or precursor thereof, in combination with one or more anti-inflammatory agents. Exemplary anti-inflammatory agents that may be used in combination with the compositions include nonsteroidal anti-inflammatory drugs (NSAIDs), such as diclofenac (e.g., Arthrotec®), diflunisal (e.g., Dolobid®), etodolac (e.g., Lodine®), fenoprofen (e.g., Nalfon®), ibuprofen (e.g., Advil®, Motrin®, etc.), indomethacin (e.g., Arthrexin®), ketoprofen (e.g., Oruvail®), ketorolac (e.g., Toradol®), fosfomycin tromethamine (e.g., Monural®), meclofenamate (e.g., Meclomen®), nabumetone (e.g., Relafen®), naproxen (e.g., Anaprox®, etc.), oxaprozin (e.g., Daypro®), piroxicam (e.g., For example, Feldene®), sulindac (e.g., Clinoril®), tolmetin (e.g., Tolectin®, etc.), flavonoids (e.g., luteolin, fisetin, and apigenin), steroids, antihistamines, loratadine, theophylline, doxantrazole, quercetin, 8-bromocyclic AMP, disodium cromoglycate, beclomethasone dipropionate, budesonide, budesonide / formoterol, fluticasone, fluoxetine ... In one embodiment, the method comprises administering to a subject in need thereof a composition comprising at least one SCFA, or a biologically active derivative or precursor thereof, and further comprising one or more anti-inflammatory agents.In one embodiment, the method comprises administering to a subject in need thereof a composition comprising at least one SCFA, or a biologically active derivative or precursor thereof, in combination with a composition comprising one or more anti-inflammatory agents.

[0132] chemotherapy drugs

[0133] In one embodiment, the methods of the present disclosure may include administering a composition in combination with one or more chemotherapeutic agents, including, but not limited to, ara-C, daunomycin, cladribine (leustatin, 2-CdA), cytotoxic agents (e.g., 5-fluorouracil, cisplatin, carboplatin, methotrexate, daunorubicin, doxorubicin, vincristine, vinblastine, oxorubicin, carmustine (BCNU), lomustine (CCNU), cytarabine USP, cyclophosphamide, estramucin sodium phosphate, altretamine, hydroxyurea, ifosfamide, procarbazine, mast cell tumor inhibitors, and the like. cyclophosphamide, mitoxantrone, carboplatin, cisplatin, interferon alpha-2a recombinant, paclitaxel, teniposide, and streptozotocin), cytotoxic alkylating agents (e.g., busulfan, chlorambucil, cyclophosphamide, melphalan, or ethylsulfonic acid), alkylating agents (e.g., asarella, AZQ, BCNU, busulfan, bisulfan, carboxyphthalatoplatin, CBDCA, CCNU, CHIP, chlorambucil, chlorozotocin, cisplatin ... Platin, clomesone, cyanomorpholinodoxorubicin, cyclodizone, cyclophosphamide, dianhydrogalactitol, fluorodopan, hepsulfam, hycanthone, ifosfamide, melphalan, methyl CCNU, mitomycin C, mitozolamide, nitrogen mustard, PCNU, piperazine, piperazinedione, pipobroman, porfiromycin, spirohydantoin mustard, streptozotocin, teroxylon, tetraplatin, thiotepa, triethylenemelamine, uracil nitrogen mustard Stard, and Yoshi-864), mitotic inhibitors (e.g., allocolchicine, halichondrin M, colchicine, colchicine derivatives, dolastatin 10, maytansine, rhizoxin, paclitaxel derivatives, paclitaxel, thiocolchicine, trityl cysteine, vinblastine sulfate, and vincristine sulfate), plant alkaloids (e.g., actinomycin D, bleomycin, L-asparaginase, idarubicin, vinblastine sulfate, vincristine sulfate, mithramycin, mitomycin, daunorubicin,VP-16-213, VM-26, navelbine, and taxotere), biologics (e.g., alpha interferon, BCG, G-CSF, GM-CSF, interleukin-2), topoisomerase I inhibitors (e.g., camptothecin, camptothecin derivatives, and morpholinodoxorubicin), topoisomerase II inhibitors (e.g., mitoxantrone, amonafide, m-AMSA, anthrapyrazole derivatives, pyrazoloacridine, bisantrene HCl, daunorubicin, Antiproliferative agents include, but are not limited to, rubicin, deoxydoxorubicin, menogaril, N,N-dibenzyldaunomycin, oxantrazole, rubidazone, VM-26, and VP-16), and synthetic agents (e.g., hydroxyurea, procarbazine, o,p'-DDD, dacarbazine, CCNU, BCNU, cis-diamminedichloroplatinum, mitoxantrone, CBDCA, levamisole, hexamethylmelamine, all-trans retinoic acid, gliadel, and porfimer sodium). In some embodiments, the composition is administered before, during, or after the administration of at least one antiproliferative agent for the treatment of cancer. Antiproliferative agents are compounds that reduce cell proliferation. Antiproliferative agents include, but are not limited to, alkylating agents, antimetabolites, enzymes, biological response modifiers, miscellaneous drugs, hormones and antagonists, androgen inhibitors (e.g., flutamide and leuprolide acetate), antiestrogens (e.g., tamoxifen citrate and its analogs, toremifene, droloxifene, and roloxifene). Additional examples of specific antiproliferative agents include levamisole, gallium nitrate, granisetron, sargramostim strontium-89 chloride, filgrastim, pilocarpine, dexrazoxane, and ondansetron.

[0134] The compositions may be administered alone or in combination with other anti-tumor agents, including cytotoxic / antineoplastic agents and anti-angiogenic agents. Cytotoxic / antineoplastic agents are defined as agents that attack and kill cancer cells. Some cytotoxic / antineoplastic agents are alkylating agents that alkylate genetic material in tumor cells, such as cisplatin, cyclophosphamide, nitrogen mustard, trimethylenethiophosphoramide, carmustine, busulfan, chlorambucil, verstine, uracil mustard, chromafazine, and dacabazine. Other cytotoxic / antineoplastic agents are antimetabolites directed against tumor cells, such as cytosine arabinoside, fluorouracil, methotrexate, mercaptopurine, azathioprine, and procarbazine. Other cytotoxic / antineoplastic agents are antibiotics, such as doxorubicin, bleomycin, dactinomycin, daunorubicin, mithramycin, mitomycin, mitomycin C, and daunomycin. There are numerous liposomal formulations of these compounds commercially available. Still other cytotoxic / antineoplastic agents are the mitotic inhibitors (vinca alkaloids). These include vincristine, vinblastine, and etoposide. Various cytotoxic / antineoplastic agents include taxol and its derivatives, L-asparaginase, antitumor antibodies, dacarbazine, azacitidine, amsacrine, melphalan, VM-26, ifosfamide, mitoxantrone, and vindesine.

[0135] Antiangiogenic agents are known to those skilled in the art. Suitable antiangiogenic agents for combination with the compositions of the present disclosure include anti-VEGF antibodies, including humanized and chimeric antibodies, anti-VEGF aptamers, and antisense oligonucleotides. Other known inhibitors of angiogenesis include angiostatin, endostatin, interferon, interleukin 1 (including alpha and beta), interleukin 12, retinoic acid, and tissue inhibitors of metalloproteinases-1 and -2 (TIMP-1 and -2). Small molecules that inhibit topoisomerase II, such as razoxane, which has antiangiogenic activity, can also be used.

[0136] Other anticancer agents that may be used in combination with the composition include acivicin, aclarubicin, acodazole hydrochloride, acronine, adozelesin, aldesleukin, altretamine, ambomycin, amethanthrone acetate, aminoglutethimide, amsacrine, anastrozole, anthramycin, asparaginase, asperlin, azacytidine, azetepa, azotomycin, batimastat, benzodepa, bicalutamide, bisantrene hydrochloride, bisnafide dimesylate, bizelesin, bleomycin sulfate, brequinar sodium, bropirimine, and busulfan. Cactinomycin, calsterone, caracemide, carbetimer, carboplatin, carmustine, carubicin hydrochloride, carzelesin, cedefingol, chlorambucil, ciloremycin, cisplatin, cladribine, crisnatol mesylate, cyclophosphamide, cytarabine, dacarbazine, dactinomycin, daunorubicin hydrochloride, decitabine, dexorumaplatin, dezaguanine, dezaguanine mesylate, diaziquone, docetaxel, doxorubicin, doxorubicin hydrochloride, droloxifene, droloxifene citrate, droloxifene propionate Mostanolone, duazomycin, edatrexate, eflornithine hydrochloride, elsamitrucin, enloplatin, enpromate, epipropidine, epirubicin hydrochloride, elbrozole, esorubicin hydrochloride, estramustine, estramustine sodium phosphate, etanidazole, etoposide, etoposide phosphate, etopurine, fadrozole hydrochloride, fazarabine, fenretinide, floxuridine, fludarabine phosphate, fluorouracil, fluorocitabine, fosquidone, fostriecin sodium, gemcitabine, gemcitabine hydrochloride, hydrazine Roxiurea, idarubicin hydrochloride, ifosfamide, ilmofosine, interleukin II (including recombinant interleukin II, or rIL2), interferon alpha-2a, interferon alpha-2b, interferon alpha-n1, interferon alpha-n3, interferon beta-Ia, interferon gamma-Ib, iproplatin, irinotecan hydrochloride, lanreotide acetate, letrozole, leuprolide acetate, liarozole hydrochloride, lometrexol sodium, lomustine, losoxantrone hydrochloride, masoprocol,Maytansine, mechlorethamine hydrochloride, megestrol acetate, melengestrol acetate, melphalan, menogaril, mercaptopurine, methotrexate, methotrexate sodium, metoprine, meturedepa, mitindomide, mitocalcin, mitochromine, mitogillin, mitomarcine, mitomycin, mitospel, mitotane, mitoxantrone hydrochloride, mycophenolic acid, nocodazole, nogalamycin, ormaplatin, oxisuran, paclitaxel le, pegaspargase, periomycin, pentamstine, peplomycin sulfate, perfosfamide, pipobroman, piposulfan, piroxantrone hydrochloride, plicamycin, promestane, porfimer sodium, porfiromycin, prednimustine, procarbazine hydrochloride, puromycin, puromycin hydrochloride, pyrazofurin, ribopurin, rogletimide, safingol, safingol hydrochloride, semustine, simtrazene, sparfosa sodium, sparsomycin, spirogermanium hydrochloride, spiromustine, spiroplatin, streptonigrin, streptozocin, sulofenur, tallysomycin, tecogalan sodium, tegafur, teroxantrone hydrochloride, temoporfin, teniposide, teroxylon, testolactone, thiamiprine, thioguanine, thiotepa, tiazofurin, tirapazamine, toremifene citrate, trestrone acetate, triciribine phosphate, trimetrex These include, but are not limited to, vinblastine sulfate, trimetrexate glucuronate, triptorelin, tuburozole hydrochloride, uracil mustard, uredepa, vapreotide, verteporfin, vinblastine sulfate, vincristine sulfate, vindesine, vindesine sulfate, vinepidine sulfate, vinglisinate sulfate, vinleurosine sulfate, vinorelbine tartrate, vinrocidine sulfate, vinzolidine sulfate, vorozole, zeniplatin, zinostatin, and zorubicin hydrochloride. Other anticancer drugs include 20-epi-1,25-dihydroxyvitamin D3, 5-ethynyluracil, abiraterone, aclarubicin, acylfulvene, adecipenol, adzelesin, aldesleukin, ALL-TK antagonists, altretamine, ambamustine, amidox, amifostine, aminolevulinic acid, amrubicin, amsacrine, anagrelide, anastrozole,andrographolide, angiogenesis inhibitor, antagonist D, antagonist G, antarelix, anti-dorsalizing morphogenetic protein-1, antiandrogen, prostate carcinoma, antiestrogenic, antineoplastic, antisense oligonucleotide, aphidicolin glycinate, apoptosis gene modulator, apoptosis regulator, apurinic acid, ara-CDP-DL-PTBA, arginine deaminase, asulaculin, atamestane, atlimustine, axinastatin 1, axinastatin 2, axinastatin 3, azasetron, azatoxin, azatyrosine, baccatin III derivative, balanol, batimastat, BCR / ABL antagonist Nist, benzochlorin, benzoylstaurosporine, beta-lactam derivatives, beta-arretin, betaclamicin B, betulinic acid, bFGF inhibitors, bicalutamide, bisantrene, bisaziridinylspermine, bisnafide, bistratin A, bizelesin, brefulate, bropirimine, budotitanium, buthionine sulfoximine, calcipotriol, calphostin C, camptothecin derivatives, canarypox IL-2, capecitabine, carboxamido-amino-triazole, carboxyamidotriazole, CaRest M3, CARN 700, cartilage-derived inhibitor, carzelesin, casein kinase inhibitor (ICOS), castanospermine, cecropin B, cetrorelix, chlorin, chloroquinoxaline sulfonamide, cicaprost, cis-porphyrin, cladribine, clomiphene analogue, clotrimazole, colismycin A, colismycin B, combretastatin A4, combretastatin analogue, conagenin, clambecidin 816, cristatol, cryptophycin 8, cryptophycin Tofisin A derivatives, curacin A, cyclopentaanthraquinone, cycloplatam, sipemycin, cytarabine ocfosfate, cytolytic factors, cytostatin, dacliximab, decitabine, dehydrodidemnin B, deslorelin, dexamethasone, dexphosphamide, dexrazoxane, dexverapamil, diaziquone, didemnin B, didox, diethylnorspermine, dihydro-5-azacytidine, 9-dihydrotaxol, dioxamycin,Diphenylspiromustine, docetaxel, docosanol, dolasetron, doxifluridine, droloxifene, dronabinol, duocarmycin SA, ebselen, ecomustine, edelfosine, edrecolomab, eflornithine, elemene, emitefur, epirubicin, epristeride, estramustine analogues, estrogen agonists, estrogen antagonists, etanidazole, etoposide phosphate, exemestane, fadrozole, fazarabine, fenretinide, filgrastim, finasteride, flavopiridol, Reselastic, fluasterone, fludarabine, fluorodaunornithine hydrochloride, forfenimex, formestane, fostriecin, fotemustine, gadolinium texaphyrin, gallium nitrate, gallocitabine, ganirelix, gelatinase inhibitors, gemcitabine, glutathione inhibitors, hepsulfam, heregulin, hexamethylene bisacetamide, hypericin, ibandronic acid, idarubicin, idoxifene, idramantone, ilmofosine, ilomastat, imidazoacridone, imiquimod, immunostimulating peptides, insulin-like growth factors -1 receptor inhibitor, interferon agonist, interferon, interleukin, iobenguane, iododoxorubicin, 4-ipomeanol, ilopract, irsogladine, isobengazole, isohomohalichondrin B, itasetron, jasplakinolide, kahalalide F, lamellarin-N triacetate, lanreotide, leinamycin, lenograstim, lentinan sulfate, leptolstatin, letrozole, leukemia inhibitory factor, leukocyte alpha interferon, leuprolide + estrogen + progesterone, leuprorelin, leuprolide Vamisole, liarozole, linear polyamine analogues, lipophilic disaccharide peptides, lipophilic platinum compounds, lisoclinamide 7, lobaplatin, lombricine, lometrexol, lonidamine, losoxantrone, lovastatin, loxoribine, lutetium texaphyrin, lisofylline, cytolytic peptides, maytansine, mannostatin A, marimastat, massoprocol, maspin, matrilysin inhibitors, matrix metalloproteinase inhibitors, menogaril, mervalone, meterelin, methioninase, metoclopramide, MIF inhibitors,Mifepristone, miltefosine, millimostim, mismatched double-stranded RNA, mitoguazone, mitolactol, mitomycin analogues, mitonafide, mitotoxin fibroblast growth factor-saporin, mitoxantrone, mofalotene, molgramostim, monoclonal antibodies, human chorionic gonadotropin, monophosphoryl lipid A + myobacterial cell wall sk, mopidamol, multidrug resistance gene inhibitors, multi-tumor suppressor 1-based therapy, mustard anticancer drugs, mycaperoxide B, mycobacterial cell wall extract, miriaporone, N-acetyldinaline, N-substituted benzamides, nafarelin, nagressip, naloxone + pentazocine, napavine, naphterpine, nartograstim, nedaplatin, nemorubicin, neridronic acid, neutral endopeptidase, nilutamide, nisamycin, nitric oxide modulators, nitroxide antioxidants, nitrulline, O6-benzylguanine, octreotide, oxenone, oligonucleotides, onapristone, ondansetron, ondansetron, oracin, oral cytokine inducers, ormaplatin, osatelon, oxaliplatin, oxaunomycin, Paclitaxel, paclitaxel analogues, paclitaxel derivatives, palauamine, palmitoylrhizoxin, pamidronic acid, panaxytriol, panomifen, parabactin, pazelliptin, pegaspargase, perdecin, pentosan polysulfate sodium, pentostatin, pentorozole, perflubron, perfosfamide, perillyl alcohol, phenazinomycin, phenylacetic acid esters, phosphatase inhibitors, picibanil, pilocarpine hydrochloride, pirarubicin, piritrexim, prasitin A, prasitin B, plasminogen activator factor inhibitors, platinum complexes, platinum compounds, platinum-triamine complexes, porfimer sodium, porfiromycin, prednisone, propyl bis-acridone, prostaglandin J2, proteasome inhibitors, protein A-based immunomodulators, protein kinase C inhibitors, microalgae protein kinase C inhibitors, protein tyrosine phosphatase inhibitors, purine nucleoside phosphorylase inhibitors, purpurins, pyrazoloacridines, pyridoxylated hemoglobin polyoxyethylene conjugates, raf antagonists, raltitrexed,Ramosetron, ras farnesyl protein transferase inhibitor, ras inhibitor, ras-GAP inhibitor, demethylated reteriptin, rhenium Re186 etidronate, rhizoxin, ribozyme, RII retinamide, logretimide, rohitukin, romurtide, roquinimex, rubiginone B1, ruboxil, safingol, Saintopine, SarCNU, Sarcophytol A, Sargramostim, Sdi1 mimic, Semustine, Senescence derived inhibitor 1, sense oligonucleotide, signal transduction inhibitor, signal transduction modulator, single-stranded antigen-binding protein, schizofuran, sobuzoxane, borocaptan sodium, sodium phenylacetate, sorberol, somatomedin-binding protein, sonermin, sparfosic acid, spicamycin D, spiromustine, splenopentin, spongistatin 1, squalamine, stem cell inhibitor, stem cell division inhibitor, stypamide, stromelysin inhibitor, sulfinosine, superactive vasoactive intestinal peptide antagonist, suragist, suramin, swainsonine, synthetic glycosaminoglycan, talimustine, tamoxifen methiodide, tauromustine, tazarotene, tecogalan sodium, tegafur, tellupyrium, telomerase inhibitor, temoporfin, temozolomide, teniposide, tetrachlorodecaoxide, tetrazomine, thaliblastine , thiocoraline, thrombopoietin, thrombopoietin mimic, thymalfasin, thymopoietin receptor agonist, thymotrinan, thyroid stimulating hormone, ethyl etiopurpurin tin, tirapazamine, titanocene dichloride, topsentin, toremifene, totipotent stem cell factor, translation inhibitors, tretinoin, triacetyluridine, triciribine, trimetrexate, triptorelin, tropisetron, turosteride, tyrosine kinase inhibitors, tyrphostins, UBC inhibitors, ubenimex, urogenital sinus-derived growth inhibitory factor, urokinase receptor antagonists, vapreotide, variolin B, erythrocyte gene therapy vector system, veraresol, veramine, verudine, verteporfin, vinorelbine, vinxartin, vitaxin, vorozole, zanoterone, zeniplatin, zilascorub; and zinostatin stimalamer. In one embodiment, the anticancer drug is 5-fluorouracil, taxol, or leucovorin.

[0137] antiviral agents

[0138] The present disclosure contemplates compositions comprising a compound comprising at least one SCFA or SCFA moiety described herein in combination with an antiviral agent, including inhibitors of viral uncoating (e.g., amantadine and rimantidine), reverse transcriptase inhibitors (e.g., acyclovir, zidovudine, and lamivudine), agents that target integrase, agents that block the attachment of transcription factors to viral DNA, agents that affect translation (e.g., antisense molecules) (e.g., fomivirsen), agents that modulate translation / ribozyme function, protease inhibitors, viral assembly modulators (e.g., rifampicin), and the like. ), antiretroviral agents, such as nucleoside analog reverse transcriptase inhibitors (e.g., azidothymidine (AZT), ddl, ddC, 3TC, d4T), non-nucleoside reverse transcriptase inhibitors (e.g., efavirenz, nevirapine), nucleotide analog reverse transcriptase inhibitors, and agents that prevent the release of viral particles (e.g., zanamivir and oseltamivir), abacavir, adefovir, amantadine, amprenavir, ampligen, arbidol, atazanavir, atri Pura, bocepretet, cidofovir, combivir, darunavir, delavirdine, didanosine, docosanol, edoxudine, emtricitabine, enfuvirtide, entecavir, famciclovir, fosamprenavir, foscarnet, fosphonet, ganciclovir, ibacitabine, iminovir, idoxuridine, imiquimod, indinavir, inosine, various interferons (e.g., peginterferon alfa-2a), lopinavir, robiridine, maravir These include, but are not limited to, cyclosporine, morphine, morphine, methicone, methicone, methicone iodine ...

[0139] Biologic agents

[0140] In one embodiment, the method comprises administering to a subject in need thereof a composition comprising at least one SCFA, or a biologically active derivative or precursor thereof, in combination with one or more biologics. Exemplary biologics contemplated by the present disclosure include, but are not limited to, etanercept (Enbrel®), infliximab (Remicade®), apremilast (Otezla®), and adalimumab (Humira®). In one embodiment, the method comprises administering to a subject in need thereof a composition comprising at least one SCFA, or a biologically active derivative or precursor thereof, and further one or more biologics. In one embodiment, the method comprises administering to a subject in need thereof a composition comprising at least one SCFA, or a biologically active derivative or precursor thereof, in combination with a composition comprising one or more biologics.

[0141] Other drugs

[0142] In one embodiment, the method comprises administering to a subject in need thereof a composition comprising at least one SCFA, or a biologically active derivative or precursor thereof, and further comprising one or more additional therapeutic agents. In one embodiment, the method comprises administering to a subject in need thereof a composition comprising at least one SCFA, or a biologically active derivative or precursor thereof, in combination with a composition comprising one or more additional therapeutic agents. Additional therapeutic agents contemplated for administration according to the methods of the present disclosure include rofecoxib, celecoxib, folic acid, sulfasalazine, naproxen, leflunomide, methylprednisolone acetate, parenteral gold, oral gold, indomethacin, hydroxychloroquine, hydroxychloroquine sulfate, sulindac, prednisone, betamethasone dipropionate augmentation, folate, triamcinolone acetonide, diclofenac, dimethyl sulfoxide, piroxicam, diclofenac, cyclosporine ... Fenac sodium, ketoprofen, meloxicam, methylprednisolone, nabumetone, tolmetin sodium, calcipotriene, cyclosporine, diclofenac, sodium / misoprostol, fluocinonide, glucosamine sulfate, gold sodium thiomalate, hydrocodone bitartrate / apap, risedronate sodium, sulfadiazine, thioguanine, valdecoxib, small molecule inhibitor of KDR (ABT-123), Tie-2 Small molecule inhibitors, clobetasol propionate, triamcinolone acetonide, halobetasol propionate, tazarotene, fluocinonide, betamethasone dipropionate augmentation, fluocinolone, acetonide, acitretin, tar shampoo, betamethasone valerate, mometasone furoate, ketoconazole, pramoxine / fluocinolone, hydrocortisone valerate, flurandrenolide, urea, betamethasone, clobetasol propionate / emollient ll), fluticasone propionate, azithromycin, hydrocortisone, moisturizing formulations, folic acid, desonide, coal tar, diflorasone diacetate, folate, lactic acid, methoxysalen, methylprednisolone acetate, prednisone, sunscreen, salicylic acid, halocinonide, anthralin, clocortolone pivalate, coal extract, coal tar / salicylic acid, coal tar / salicylic acid / sulfur, desoximetasone, diazepam, emollients,Pimecrolimus emollient, fluocinonide / emollient, mineral oil / castor oil / nalactone, mineral oil / peanut oil, petroleum / isopropyl myristate, psoralen, salicylic acid, soap / tribromosalan, thimerosal / boric acid, celecoxib, alefacept, efalizumab, tacrolimus, pimecrolimus, PUVA, UVB, sulfasalazine, alemtuzumab, dronabinol, Unimed, daclizumab, mitoxantrone, xaliproden hydrochloride, fampridine, glatiramer acetate, natalizumab, cinnabidiol Lu, α-immunokine NNSO3, ABR-215062, AnergiX.MS, chemokine receptor antagonist, BBR-2778, caragualin, CPI-1189, LEM (liposome-encapsulated mitoxantrone), THC.CBD (cannabinoid agonist), MBP-8298, mesopram (PDE4 inhibitor), MNA-715, anti-IL-6 receptor antibody, neurovax, pirfenidone allotrap 1258 (RDP-1258), sTNF-R1, CDP571 (humanized monoclonal anti-TNF-alpha IgG4 antibody), CDP Examples of antibodies include, but are not limited to, 870 (humanized monoclonal anti-TNF-alpha antibody fragment), anti-TNF dAb (Peptech), CNTO 148 (golimumab, Medarex and Centocor, see WO 02 / 12502), and adalimumab (Humira.RTM. Abbott Laboratories, a human anti-TNF mAb, described as D2E7 in U.S. Pat. No. 6,090,382). Additional TNF antibodies that may be used in the present disclosure include those described in U.S. Patent Nos. 6,593,458, 6,498,237, 6,451,983, and 6,448,380 (each of which is incorporated herein by reference), talampanel, teriflunomide, TGF-beta 2, tiplimotide, VLA-4 antagonists (e.g., TR-14035, VLA4 Ultrahaler, Antegran-ELAN / Biogen), interferon gamma antagonists, IL-4 agonists, the humanized IL-6 antibody tocilizumab, steroids (e.g., dexamethasone, prednisone, prednisolone, triamcinolone acetonide, fluorometholone,and difluprednate), rapamycin, lampalizumab, fluocinolone acetatonide, macuCLEAR eye drops, bone marrow CD34 stem cells, other stem cells, ranibizumab, brimonidine, LFG316, ORACEA®, emixustat hydrochloride, sirolimus, copaxone, other eye drops, AL-78898A, and eculizumab.

[0143] Administration

[0144] Administration of the compositions of the present disclosure to a subject can be carried out using known procedures at dosages and for periods of time effective to treat or prevent a disease or disorder in the subject. The effective amount of therapeutic compound required to achieve a therapeutic effect can vary depending on the actor, e.g., the state of the disease or disorder in the subject, and the age, sex, and weight of the subject.

[0145] The administration regimen may affect what constitutes an effective amount. Furthermore, the dosage of the composition may be proportionally increased or decreased as indicated by the exigencies of the therapeutic or prophylactic situation. A non-limiting example of an effective dose range for the therapeutic compounds of the present disclosure is from about 1 to about 5,000 mg / kg body weight per day. Effective doses may range from 1 mg to 10 mg of active ingredient / kg body weight per dose, and may range from 20 mg to 10 mg of active ingredient / kg body weight per dose. The therapeutic compounds may be administered every 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, or 31 days. The number of doses for effective treatment may be 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more than 10 times.

[0146] One of ordinary skill in the art would be able to examine the relevant factors and make the determination regarding the effective amount of the therapeutic compound without undue experimentation.

[0147] The actual dosage level of the active ingredient in the pharmaceutical compositions of the present disclosure may be varied to obtain an amount of the active ingredient that is not toxic to the subject and is effective to achieve the desired therapeutic response for a particular subject, composition, and mode of administration. In particular, the selected dose level will depend on a variety of factors, including the activity of the particular compound used, the time of administration, the rate of excretion of the compound, the duration of treatment, other drugs, compounds, or substances used in combination with the material, the age, sex, weight, condition, general health, and previous medical history of the subject being treated, and similar factors known in the medical arts.

[0148] A medical practitioner, e.g., a physician or veterinarian, having ordinary skill in the art can readily determine and prescribe the effective amount of the pharmaceutical composition required. For example, the physician or veterinarian may start the dosage of the compound of the present disclosure used in the pharmaceutical composition at a level lower than that required to achieve the desired therapeutic effect, and gradually increase the dosage until the desired effect is achieved.

[0149] The composition for administration may be from about 1 mg to about 10,000 mg, from about 20 mg to about 9,500 mg, from about 40 mg to about 9,000 mg, from about 75 mg to about 8,500 mg, from about 150 mg to about 7,500 mg, from about 200 mg to about 7,000 mg, from about 3,050 mg to about 6,000 mg, from about 500 mg to about 5,000 mg, from about 750 mg to about 4,000 mg, or from about 1 mg to about 3,000 mg. , about 10 mg to about 2,500 mg, about 20 mg to about 2,000 mg, about 25 mg to about 1,500 mg, about 50 mg to about 1,000 mg, about 75 mg to about 900 mg, about 100 mg to about 800 mg, about 250 mg to about 750 mg, about 300 mg to about 600 mg, about 400 mg to about 500 mg, and any and all whole or partial increments therebetween.

[0150] In some embodiments, the dosage of the disclosed compound is from about 1 mg to about 2,500 mg. In some embodiments, the dosage of the disclosed compound used in the compositions described herein is less than about 10,000 mg, or less than about 8,000 mg, or less than about 6,000 mg, or less than about 5,000 mg, or less than about 3,000 mg, or less than about 2,000 mg, or less than about 1,000 mg, or less than about 500 mg, or less than about 200 mg, or less than about 50 mg, or less than about 40 mg, or less than about 30 mg, or less than about 25 mg, or less than about 20 mg, or less than about 15 mg, or less than about 10 mg, or less than about 5 mg, or less than about 2 mg, or less than about 1 mg, or less than about 0.5 mg, and any and all whole or partial increments therebetween.

[0151] In one embodiment, the treatment regimen comprises daily administration of the composition. In one embodiment, the treatment regimen comprises administering short-chain fatty acids at least once daily for at least 1 day, at least 2 days, at least 3 days, at least 4 days, at least 5 days, at least 7 days, at least 10 days, at least 2 weeks, at least 3 weeks, at least 1 month, at least 2 months, at least 3 months, at least 6 months, at least 1 year, or more than 1 year. In one embodiment, the treatment regimen comprises administering short-chain fatty acids three times daily for at least 1 day, at least 2 days, at least 3 days, at least 4 days, at least 5 days, at least 7 days, at least 10 days, at least 2 weeks, at least 3 weeks, at least 1 month, at least 2 months, at least 3 months, at least 6 months, at least 1 year, or more than 1 year. In one embodiment, the treatment regimen comprises administering a composition comprising short-chain fatty acids, short-chain fatty acid precursors, short-chain fatty acid biosynthetic precursors, or a combination thereof, at least once daily upon the onset of a disease or disorder.

[0152] In one embodiment, the treatment regimen comprises daily oral administration of short-chain fatty acids.In one exemplary embodiment, 600 mg of butyrate is administered three times a day (total 1800 mg / day) for at least one week.In one embodiment, the treatment regimen comprises oral administration of two butyrate capsules containing 600 mg of butyrate three times a day (total 3600 mg / day) for at least one week.In one embodiment, the treatment regimen comprises oral administration of two butyrate capsules containing 600 mg of butyrate three times a day (total 3600 mg / day) for at least one week, and then oral administration of a butyrate capsule containing 600 mg of butyrate three times a day (total 1800 mg / day) for at least one week.

[0153] As described herein, administering a composition to an individual can induce tolerance, strengthen the integrity of the intestinal barrier, and reduce inflammation in the individual. The method includes administering a composition described herein to the individual. In some embodiments, the composition includes one or more SCFAs or SCFA derivatives. The composition is administered to the individual in an amount sufficient to produce the desired effects of inducing tolerance, strengthening the intestinal barrier, and reducing inflammation.

[0154] Whether administration of a composition induces tolerance can be determined by using as an indicator an increase or enhancement in at least one of the number of regulatory T cells (Tregs), the proportion of Tregs in colonic T cell populations, Treg function, or the expression of Treg markers. Specific approaches include measuring the count or percentage of Foxp3-expressing Tregs in a patient sample, such as a biopsy or blood sample, and promoting (enhancing) IL-10 expression, promoting (enhancing) CTLA4 expression, promoting (enhancing) IDO expression, or suppressing IL-4 expression as indicators of the induction of regulatory T cell proliferation or accumulation. Whether administration of a composition enhances barrier function can be determined by using as an indicator an increase in the production of active TGF-β and / or tight junction-associated proteins by intestinal epithelial cells. Whether administration of a composition reduces inflammation can be determined by using as an indicator an increase in the production of anti-inflammatory cytokines, such as IL-10 and / or TGF-beta, or a decrease in the production of pro-inflammatory cytokines, such as IL-4.

[0155] In some embodiments, the present disclosure modulates cytokines. In some embodiments, the cytokines are pro-inflammatory cytokines. Non-limiting examples of cytokines include TNFα, IFNγ, IL-17A, IL-21, IL-22, IL-23, IL-27, IL-31, and MIP-3α.

[0156] In some embodiments, short-chain fatty acids (SCFAs) regulate multiple cell signaling proteins, including, but not limited to, IL-18, TLR3, IFN-γ, TNFα, TGF-β, MyD88, PI3K / Akt, JAK / STAT, Smad 2 / 3, Smad 4, IL-10, Notch, Hedgehog, Wnt (beta-catenin), matrix metalloproteinases 9 and 10, tissue inhibitor of metalloproteinases, Nodal, and NF-κB signaling. In some embodiments, signaling proteins regulated by SCFAs regulate biological pathways or processes, including, but not limited to, inflammation, immunity, proliferation, differentiation, apoptosis, oncogenesis, DNA transcription, cytokine production, cell survival, angiogenesis, fibrosis, and cellular responses to stimuli such as stress, cytokines, free radicals, heavy metals, and ultraviolet radiation.

[0157] In some embodiments, the methods disclosed herein include treating or reducing the likelihood of developing a medical disease or disorder characterized by elevated levels or aberrant expression of at least one of IL-18, TLR3, IFN-γ, TNFα, TGF-β, MyD88, PI3K / Akt, JAK / STAT, Smad 2 / 3, Smad 4, or IL-10 signaling. In some embodiments, the methods disclosed herein include treating or reducing the likelihood of developing a medical disease or disorder characterized by decreased levels or aberrant expression of NF-κB signaling.

[0158] Methods for detecting such expression include Northern blotting, RT-PCR, and dot blotting for detecting gene expression at the transcriptional level, and ELISA, radioimmunoassay, immunoblotting, immunoprecipitation, and flow cytometry for detecting gene expression at the translational level. Samples that can be used to measure such indicators include tissues and body fluids obtained from individuals, such as blood, biopsy, or fecal samples.

[0159] Combination with additional drugs

[0160] The present disclosure is also directed to methods of treating or preventing the above diseases or disorders in combination with one or more additional agents.

[0161] The combination may be present in a single formulation, or may be administered separately and sequentially (either first a composition comprising at least one SCFA or molecule comprising an SCFA moiety, then a composition comprising the additional agent, or first a composition comprising the additional agent, then a composition comprising at least one SCFA or molecule comprising an SCFA moiety). In some embodiments, the at least one SCFA or molecule comprising an SCFA moiety is administered within about 30 seconds, 1 minute, 2 minutes, 3 minutes, 4 minutes, 5 minutes, 10 minutes, 15 minutes, 20 minutes, 25 minutes, 30 minutes, 35 minutes, 40 minutes, 45 minutes, 50 minutes, 55 minutes, 60 minutes, 0.25 hours, 0.5 hours, 0.75 hours, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, or 18 hours after the composition comprising the at least one additional agent is administered to the subject. , 18 hours, 19 hours, 20 hours, 21 hours, 22 hours, 23 hours, 24 hours, 36 hours, 48 ​​hours, 60 hours, 72 hours, 84 hours, 96 hours, 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, 29 days, 30 days, 31 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, or 8 weeks prior to administration to the subject.In other embodiments, the composition comprising at least one additional agent is administered within about 30 seconds, 1 minute, 2 minutes, 3 minutes, 4 minutes, 5 minutes, 10 minutes, 15 minutes, 20 minutes, 25 minutes, 30 minutes, 35 minutes, 40 minutes, 45 minutes, 50 minutes, 55 minutes, 60 minutes, 0.25 hours, 0.5 hours, 0.75 hours, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, 18 hours, 19 hours, 20 hours, 21 hours, 22 hours, 23 hours, 24 hours, 25 hours, 26 hours, 27 hours, 28 hours, 29 hours, 30 hours, 31 hours, 32 hours, 33 hours, 34 hours, 35 hours, 36 hours, 37 hours, 38 hours, 39 hours, 40 hours, 41 hours, 42 hours, 43 hours, 44 hours, 45 hours, 46 hours, 47 hours, 48 ​​hours, 49 hours, 50 hours, 51 hours, 52 hours, 53 hours, 54 hours, 55 hours, 56 hours, 57 hours, 58 hours, 59 hours, 60 minutes, 61 hours, 62 hours, 63 hours, 64 hours, 65 hours, 66 hours, 67 hours, 68 hours, 69 hours, 70 hours, 71 hours, 72 hours, 73 hours, 74 hours, 75 hours, 76 hours, 77 hours, 78 hours, 79 hours, 80 hours, 81 hours The subject may be administered the agonist / agonist inhibitor 1 hour, 18 hours, 19 hours, 20 hours, 21 hours, 22 hours, 23 hours, 24 hours, 36 hours, 48 ​​hours, 60 hours, 72 hours, 84 hours, 96 hours, 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 hours, 25 days, 26 days, 27 days, 28 days, 29 days, 30 days, 31 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, or 8 weeks prior to administration of the agonist / agonist inhibitor 1 hour, 18 hours, 19 hours, 20 hours, 21 hours, 22 hours, 23 hours, 24 hours, 36 hours, 48 ​​hours, 60 hours, 72 hours, 84 hours, 96 hours, 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, 29 days, 30 days, 31 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks,

[0162] In one embodiment, the present disclosure provides the general concept of administering at least one of these agents, or a biologically active derivative thereof, in combination with at least one short-chain fatty acid (SCFA), or a biologically active derivative or precursor thereof, as a therapy to treat or prevent a disease or disorder in a subject in need thereof. In one embodiment, a composition comprises at least one of these agents, or a biologically active derivative thereof, and at least one SCFA, or a biologically active derivative or precursor thereof.

[0163] In some embodiments, the immune response can be increased by about 0.5-fold to about 15-fold, about 0.5-fold to about 10-fold, or about 0.5-fold to about 8-fold. Alternatively, the immune response in a subject administered a combination of at least one SCFA, or a molecule comprising an SCFA moiety, and a checkpoint inhibitor can be increased by at least about 0.5-fold, at least about 1.0-fold, at least about 1.5-fold, at least about 2.0-fold, at least about 2.5-fold, at least about 3.0-fold, at least about 3.5-fold, at least about 4.0-fold, at least about 4.5-fold, at least about 5.0-fold, at least about 5.5-fold, at least about 6.0-fold, or at least about 6.5-fold. The increase may be 5-fold, at least about 7.0-fold, at least about 7.5-fold, at least about 8.0-fold, at least about 8.5-fold, at least about 9.0-fold, at least about 9.5-fold, at least about 10.0-fold, at least about 10.5-fold, at least about 11.0-fold, at least about 11.5-fold, at least about 12.0-fold, at least about 12.5-fold, at least about 13.0-fold, at least about 13.5-fold, at least about 14.0-fold, at least about 14.5-fold, or at least about 15.0-fold.

[0164] In yet other alternative embodiments, the immune response in a subject administered a combination of at least one SCFA, or a molecule comprising an SCFA moiety, and a checkpoint inhibitor may be increased by about 50% to about 1500%, about 50% to about 1000%, or about 50% to about 800%. In other embodiments, the immune response in a subject administered a combination of at least one SCFA, or a molecule comprising an SCFA moiety, and a checkpoint inhibitor may be increased by at least about 50%, at least about 100%, at least about 150%, at least about 200%, at least about 250%, at least about 300%, at least about 350%, at least about 400%, at least about 450%, at least about 500%, at least about 550%, at least about 600%, at least about 50%, at least about 700%, at least about 750%, at least about 800%, at least about 850%, at least about 900%, at least about 950%, at least about 1000%, at least about 1050%, at least about 1100%, at least about 1150%, at least about 1200%, at least about 1250%, at least about 1300%, at least about 1350%, at least about 1450%, or at least about 1500%.

[0165] immunotherapy

[0166] In one embodiment, the present disclosure provides a method for stimulating, eliciting, or enhancing an immune response in a subject (individual), comprising administering to the subject an immunotherapeutic agent in combination with a composition comprising an SCFA or a compound comprising an SCFA moiety. In one embodiment, the subject may be at risk for, diagnosed with, previously treated for, or concurrently being treated for a disease using a treatment method (e.g., a treatment method that does not include the use of a composition described herein). The present disclosure is based, in part, on the discovery that administration of at least one short-chain fatty acid (SCFA) can be effective as a therapeutic approach for treating or preventing adverse effects associated with cancer immunotherapy. The therapeutic effect of treatment using a composition comprising at least one SCFA is expected to treat or prevent undesirable adverse effects associated with cancer immunotherapy without significantly interfering with the benefits of the immunotherapy. Thus, in one embodiment, the present disclosure relates to a composition comprising at least one SCFA for use as a therapeutic agent for treating or preventing adverse effects associated with cancer immunotherapy.

[0167] In one embodiment, the present disclosure provides a method for treating, inhibiting, preventing, or reducing adverse effects associated with cancer immunotherapy by administering to a subject in need thereof a composition comprising a compound comprising an SCFA or SCFA moiety disclosed herein, optionally in combination with at least one additional agent or therapy. Adverse effects associated with cancer immunotherapy that can be treated using the methods of the present disclosure include, but are not limited to, cytokine release syndrome (CRS), neurotoxicity, on-target / off-target tumor recognition, anaphylaxis, graft-versus-host disease (GVHD), off-target antigen recognition, and macrophage activation syndrome (MAS). In one embodiment, the present disclosure provides a method for treating, inhibiting, preventing, or reducing a disease associated with adverse effects associated with cancer immunotherapy, comprising administering to a subject in need thereof a composition comprising a compound comprising at least one SCFA or SCFA moiety disclosed herein. In one embodiment, the adverse effects include a combination of adverse effects.

[0168] In one embodiment, the subject experiencing adverse effects associated with cancer immunotherapy is a human. In one embodiment, the subject experiencing adverse effects associated with cancer immunotherapy is a non-human animal.

[0169] In one embodiment, to stimulate an immune response, a subject is administered (i) a compound comprising at least one SCFA or SCFA moiety, and (ii) at least one immunotherapeutic agent. Typically, the compound comprising at least one SCFA or SCFA moiety and the immunotherapeutic agent are administered in the form of a vaccine or vaccine regimen. The compound comprising at least one SCFA or SCFA moiety and the immunotherapeutic agent can be administered to the subject approximately simultaneously, or can be administered separately and / or sequentially.

[0170] Immunotherapeutic agents that may be administered according to the methods of the present disclosure include, but are not limited to, one or more cancer antigens, one or more antigens derived from viruses associated with cancer, and anti-cancer antibodies.

[0171] A cancer antigen can be (a) a cell surface antigen that can be found on a malignant cell, (b) an antigen that can be found within a malignant cell, or (c) a mediator of tumor cell growth. The term "cancer antigen" refers to (i) a tumor-specific antigen, (ii) a tumor-associated antigen, (iii) a cell that expresses a tumor-specific antigen, (iv) a cell that expresses a tumor-associated antigen, (v) an embryonic antigen on a tumor, (vi) an autologous tumor cell, (vii) a tumor-specific membrane antigen, (viii) a tumor-associated membrane antigen, (ix) a growth factor receptor, (x) a growth factor ligand, and (xi) any other type of antigen or antigen-presenting cell or substance associated with cancer.

[0172] The cancer antigen may be a cell, a protein, a peptide, a fusion protein, DNA encoding a peptide or protein, RNA encoding a peptide or protein, a glycoprotein, a lipoprotein, a phosphoprotein, a carbohydrate, a lipopolysaccharide, a lipid, a chemically bonded combination of two or more thereof, a fusion of two or more thereof, or a mixture of two or more thereof. In another embodiment, the cancer antigen is a peptide comprising about 6 to about 24 amino acids, about 8 to about 20 amino acids, about 8 to about 12 amino acids, about 8 to about 10 amino acids, or about 12 to about 20 amino acids. In one embodiment, the cancer antigen is a peptide having an MHC class I-binding motif or an MHC class II-binding motif. In another embodiment, the cancer antigen comprises a peptide corresponding to one or more cytotoxic T lymphocyte (CTL) epitopes.

[0173] In one embodiment, the present disclosure provides a method for treating, inhibiting, preventing, or reducing adverse effects associated with cancer immunotherapy by administering to a subject in need thereof a composition comprising a compound comprising an SCFA or an SCFA moiety disclosed herein, optionally in combination with at least one immunotherapeutic agent.

[0174] In one embodiment, the immunotherapy is chimeric antigen receptor T-cell (CAR-T) therapy. In some embodiments, the composition is administered before, during, or after CAR-T therapy for the treatment of cancer to treat or prevent at least one adverse effect associated with CAR-T therapy. Particular adverse effects treatable and / or preventable by the compositions of the present disclosure include, but are not limited to, cytokine release syndrome (CRS), neurotoxicity, on-target / off-target tumor recognition, anaphylaxis, graft-versus-host disease (GVHD), off-target antigen recognition, and macrophage activation syndrome (MAS). Existing or developing treatments or preventions of these adverse effects include pharmacological immunosuppression (i.e., lymphodepleting chemotherapy using agents such as IL-6R blockade, systemic corticosteroids such as dexamethasone, monoclonal antibodies, and cyclophosphamide), suicide or elimination genes (i.e., killing of CAR-T cells), and targeted activation (i.e., conditional activation of CAR-T cells using a drug or another agent). Thus, in one embodiment, a therapeutic composition of the present disclosure is combined with at least one other strategy to reduce, prevent, treat, or ameliorate one or more adverse effects associated with cancer immunotherapy. In one embodiment, the present disclosure provides a composition for treating or preventing the onset of adverse effects associated with cancer immunotherapy. In one embodiment, the composition comprises at least one SCFA or a compound comprising an SCFA moiety. In one embodiment, the immunotherapy comprises CAR-T therapy. In another embodiment, the immunotherapy comprises treatment with at least one other anti-cancer composition. In some embodiments, the composition is administered before, during, or after chemotherapy for the treatment of cancer.

[0175] In one embodiment, a composition comprising at least one SCFA is administered in parallel with chemotherapy, starting several days before CAR-T cell infusion (SCFAs only) and up to several weeks after CAR-T cell infusion (SCFAs in combination with the chemotherapeutic agent at reduced levels compared to subjects receiving chemotherapy alone).

[0176] Pharmaceutical Composition

[0177] The present disclosure includes pharmaceutical compositions comprising one or more compositions of the present disclosure.The pharmaceutical composition formulations described herein can be prepared by any method known or hereafter developed in the field of pharmacology.In general, such preparation methods include the step of bringing the active ingredient into association with the carrier or one or more other accessory ingredients, and then, if necessary or desired, shaping or packaging the product into a desired single-dose unit or multiple-dose unit.

[0178] The aforementioned compositions may contain additional medicinal agents, pharmaceutical agents, carriers, buffers, adjuvants, dispersants, diluents, etc. depending on the intended use and application.

[0179] Non-limiting examples of suitable pharmaceutical carriers, excipients and / or diluents include gums, starches (e.g., corn starch, pregelatinized starch), sugars (e.g., lactose, mannitol, sucrose, dextrose), cellulosic materials (e.g., microcrystalline cellulose), acrylates (e.g., polymethylacrylate), calcium carbonate, magnesium oxide, talc, or mixtures thereof.

[0180] Pharmaceutically acceptable carriers for liquid formulations are aqueous or non-aqueous solutions, suspensions, emulsions or oils, and examples of non-aqueous solvents are propylene glycol, polyethylene glycol, and injectable organic esters such as ethyl oleate. Examples of oils are those of animal, vegetable, or synthetic origin, such as peanut oil, soybean oil, olive oil, sunflower oil, turmeric oil, fish liver oil, other marine oils, or fats derived from milk or eggs.

[0181] Aqueous carriers include water, alcoholic / aqueous solutions, emulsions or suspensions (including saline and buffered media (e.g., phosphate-buffered saline solution)), water, emulsions, e.g., oil / water emulsions, various types of wetting agents, sterile solutions, and the like. Compositions containing such carriers can be formulated by well-known conventional methods. Suitable carriers can include any material that retains biological activity when combined with the biologically active compounds of the present disclosure. Preparations for parenteral administration can include sterile aqueous or non-aqueous solutions, suspensions, and emulsions. Examples of non-aqueous solvents are propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate. Aqueous carriers include water, alcoholic / aqueous solutions, emulsions or suspensions, including saline and buffered media. Parenteral vehicles can include sodium chloride solution, Ringer's dextrose, dextrose and sodium chloride, lactated Ringer's, or fixed oils. Intravenous vehicles may include fluid and nutrient replenishers, electrolyte replenishers (e.g., those based on Ringer's dextrose), etc. Preservatives and other additives may also be present including, for example, antimicrobial agents, antioxidants, chelating agents, and inert gases and the like; in addition, the pharmaceutical compositions of the present disclosure may include a proteinaceous carrier such as, for example, serum albumin or immunoglobulin.

[0182] The pharmaceutical compositions provided herein can also be administered as controlled-release compositions, i.e., compositions in which the active ingredient is released over a period of time after administration. Controlled-release or sustained-release compositions include formulation in lipophilic depots (e.g., fatty acids, waxes, oils). In another embodiment, the composition is an immediate-release composition, i.e., a composition in which all of the active ingredient is released immediately after administration.

[0183] Additionally, pharmaceutical compositions according to the present disclosure, and in various embodiments described herein, or compositions comprising the aforementioned compounds, may be administered by mixing them into foods, functional foods, beverages, or medicinal foods.

[0184] Although the description of pharmaceutical compositions provided herein primarily relates to pharmaceutical compositions suitable for approved administration to humans, those skilled in the art will understand that such compositions are generally suitable for administration to all types of animals. Modifications of pharmaceutical compositions suitable for administration to humans to make them suitable for administration to a variety of animals are well understood, and an ordinarily skilled veterinary pharmacologist can design and perform such modifications, if any, with no more than routine experimentation. Subjects contemplated for administration of pharmaceutical compositions include, but are not limited to, humans and other primates, mammals (including non-human primates, commercially relevant mammals such as cows, pigs, horses, sheep, cats, and dogs), non-mammals, and other veterinary uses.

[0185] Pharmaceutical compositions useful in the methods of the present disclosure may be prepared, packaged, or sold in formulations suitable for ophthalmic, oral, rectal, vaginal, parenteral, topical, pulmonary, intranasal, buccal, intratumoral, epidural, intracerebral, intracerebroventricular, or another route of administration. Other contemplated formulations include extruded nanoparticles, liposomal preparations, resealed erythrocytes containing the active ingredient, and immunologically-based formulations.

[0186] Pharmaceutical compositions can be prepared, packaged, or sold in bulk, as a single unit dose, or as a plurality of single unit doses. As used herein, a "unit dose" is a discrete amount of pharmaceutical composition containing a predetermined amount of active ingredient. The amount of active ingredient is approximately equal to the dosage of the active ingredient administered to a subject, or a convenient fraction of such a dosage, such as half or one-third of such a dosage.

[0187] The relative amounts of the active ingredient, pharmaceutically acceptable carrier, and any additional ingredients in a pharmaceutical composition will vary depending on the identity, size, and condition of the subject being treated, as well as the route by which the composition is administered. For example, the composition may contain from 0.1% to 100% (w / w) of the active ingredient.

[0188] In addition to the active ingredient, the pharmaceutical composition may further comprise one or more additional pharmaceutically active agents.

[0189] Controlled- or sustained-release formulations of pharmaceutical compositions may be made using conventional techniques.

[0190] Pharmaceutical compositions also include nutritional compositions, such as oral nutritional compositions for oral ingestion and optionally enteral absorption, which nutritional compositions comprise compounds of the present disclosure. Thus, in one embodiment, the present disclosure relates to a nutritional supplement composition.

[0191] When the nutritional composition is formulated for oral administration, the composition can be a liquid oral nutritional supplement (e.g., an incomplete nutritional supplement) or a complete nutritional supplement. Thus, the nutritional composition can be administered in any convenient dosage form, including, for example, tablets, capsules, liquids, chewable tablets, soft gels, sachets, powders, syrups, liquid suspensions, emulsions, infant formulas, and solutions.

[0192] Nutritional formulations encompass any nutritionally complete or supplemental formulation (e.g., nutritional supplements). As used herein, "nutritionally complete" refers to a nutritional product that preferably contains sufficient types and levels of macronutrients (proteins, fats, and carbohydrates) and micronutrients to be the sole source of nutrition for the subject to which it is administered. A patient may obtain 100% of their nutritional requirements from such a complete nutritional composition. According to one embodiment, a nutritional formulation is a supplemental preparation that provides supplemental nutrition. A "supplemental formulation" may not be nutritionally complete, but preferably contains supplemental specific nutrients that further have the beneficial effects of the present disclosure, for example, in combination with physical exercise, and / or address specific or additional needs of the subject.

[0193] The nutritional formulation may be, for example, a generally applicable nutritional formulation adapted for a subject of a particular age, e.g., a pediatric formulation, but it may also be a formulation for elderly patients, intensive care patients, or a formulation specially adapted for, for example, patients suffering from a particular disease. Any nutritional formulation may be reconstitutable, i.e., exist in a substantially dry, e.g., powder form, or may be ready-to-drink, e.g., in the form of a liquid formulation. A pharmaceutical composition suitable for parenteral administration comprises the active ingredient in combination with a pharmaceutically acceptable carrier, such as sterile water or sterile isotonic saline. Such formulations may be prepared, packaged, or sold in a form suitable for bolus administration or continuous administration. Injectable formulations may be prepared, packaged, or sold in unit dosage form, such as in ampoules or multi-dose containers containing a preservative. Formulations for parenteral administration include, but are not limited to, suspensions, solutions, emulsions in oily or aqueous vehicles, pastes, and implantable sustained-release or biodegradable formulations. Such formulations may further comprise one or more additional ingredients including, but not limited to, suspending agents, stabilizing agents, or dispersing agents. In one embodiment of a formulation for parenteral administration, the active ingredient is provided in a dry (i.e., powder or granules) form for reconstitution with a suitable vehicle (e.g., pyrogen-free sterile water) prior to parenteral administration of the reconstituted composition.

[0194] Pharmaceutical compositions may be prepared, packaged, or sold in the form of a sterile injectable aqueous or oily suspension or solution. These suspensions or solutions may be formulated according to known techniques and may contain, in addition to the active ingredient, additional ingredients such as dispersing agents, wetting agents, or suspending agents described herein. Such sterile injectable formulations may be prepared using, for example, a non-toxic, parenterally acceptable diluent or solvent, such as water or 1,3-butanediol. Other acceptable diluents and solvents include, but are not limited to, Ringer's solution, isotonic sodium chloride solution, and fixed oils such as synthetic mono- or diglycerides. Other useful parenterally administrable formulations include formulations comprising the active ingredient in microcrystalline form, in a liposomal preparation, or as a component of a biodegradable polymer system. Compositions for sustained release or implantation may include pharmaceutically acceptable polymeric or hydrophobic materials (e.g., emulsions, ion exchange resins, sparingly soluble polymers, or sparingly soluble salts).

[0195] The compositions of the present disclosure described herein may be used as a complete food, as a food component, as a dietary supplement or part of a dietary supplement, or as a feed additive, and may be in liquid, semi-solid, or solid form. The compositions of the present disclosure described herein may also be in the form of a pharmaceutical composition. The compositions, dietary supplements, foods, baby food products, feed additives, and / or pharmaceutical compositions of the present disclosure may be advantageously utilized in methods for promoting the health of individuals.

[0196] As described above, the compositions may be in liquid, semi-solid, or solid form. For example, the compositions may be administered as tablets, gel packs, capsules, gelatin capsules, flavored beverages, powders that can be reconstituted into such beverages, cooking oils, salad oils or dressings, sauces, syrups, mayonnaise, margarines, and the like. Furthermore, foods, dietary supplements, and the like of the present disclosure may include, but are not limited to, dairy products, baby foods, infant formulas, beverages, bars, powders, food toppings, drinks, cereals, ice cream, candies, snack mixes, baked goods, and fried foods. Beverages of the present disclosure include, but are not limited to, energy drinks, nutritional supplement drinks, smoothies, sports drinks, orange juice, and other fruit drinks. Bars of the present disclosure include, but are not limited to, meal replacements, nutrition bars, snack bars, energy bars, extruded bars, and the like. Dairy products of the present disclosure include, but are not limited to, yogurt, yogurt drinks, cheese, and milk.

[0197] The foods or dietary supplements of the present disclosure may further comprise herbs, herbal extracts, fungal extracts, enzymes, fiber sources, minerals, and vitamins. The microalgae oils and microalgae biomass of the present disclosure may be used in compositions for both therapeutic and non-therapeutic uses. Thus, the compositions, food, and animal feed additives of the present disclosure may be used for therapeutic or non-therapeutic purposes.

[0198] Compositions intended for oral administration can be prepared according to any known method for the manufacture of dietary supplements or pharmaceutical preparations, and such compositions can contain at least one additive selected from the group consisting of taste-improving substances such as sweeteners or flavoring agents, stabilizers, emulsifiers, coloring agents and preservatives in order to provide a nutritionally or pharmaceutically acceptable preparation.Vitamins, minerals and trace elements from any physiologically acceptable source can also be included in the composition.

[0199] The pharmaceutical composition of the present disclosure comprises a therapeutically effective amount of the aforementioned composition of the present disclosure. The composition may further comprise a prescription or non-prescription drug. The combination may advantageously produce one or more of the following effects: (1) additive and / or synergistic benefits, (2) reduced side effects and / or adverse effects associated with the use of the prescription drug in the absence of the aforementioned formulation, and / or (3) the ability to reduce the dosage of the prescription drug compared to the amount of the prescription drug required in the absence of the aforementioned formulation.

[0200] The active agents of the present disclosure can be prepared in the form of their pharmaceutically acceptable salts. As understood by those skilled in the art, a pharmaceutically acceptable salt is a salt that retains the desired biological activity of the parent compound and does not impart undesired toxicological effects. As defined herein, "pharmaceutically acceptable salts" include derivatives of the disclosed SCFAs or compounds containing SCFA moieties, in which the parent compound is modified by making non-toxic salts of its carboxylate group, and also refer to pharmaceutically acceptable hydrates and solvates of such compounds. Examples of pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acid salts of the carboxylic acid group of SCFAs. For example, conventional non-toxic acid salts include salts derived from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, nitric acid, and the like, and organic acids such as acetic acid, propionic acid, succinic acid, glycolic acid, stearic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, pamoic acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, mesylic acid, esylic acid, besylic acid, sulfanilic acid, 2-acetoxybenzoic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethanedisulfonic acid, oxalic acid, isethionic acid, HOOC—(CH2) nExamples of suitable salts include salts derived from --COOH (where n is 0-4). A list of additional suitable salts can be found, for example, in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., p. 1418 (1985). In some embodiments, the SCFA can be present as an ester of the carboxylic acid of the SCFA with a branched or unbranched alkyl alcohol of 1 to 6 carbon atoms. For example, the SCFA can be present as an ethyl ester, propyl ester, butyl ester, isopropyl ester, t-butyl ester, pentyl ester, or hexyl ester. The active agent can be formulated for administration according to known pharmaceutical techniques. See, for example, Remington, *The Science and Practice of Pharmacy* (9th Ed. 1995). In preparing pharmaceutical compositions according to the present disclosure, the active agent (including its physiologically acceptable salt) is typically mixed with, inter alia, an acceptable carrier. The carrier must, of course, be acceptable in the sense of being compatible with any other ingredients in the formulation and not deleterious to the subject. The carrier may be solid or liquid, or both, and may be formulated with the active agent as a unit-dose formulation, for example, a tablet, which may contain 0.01% by weight, or 0.5% by weight to 95% by weight, or 99% by weight, or any value between 0.01% by weight and 99% by weight of the active agent. One or more active agents may be incorporated into a composition, which may be prepared by any of the well-known techniques of pharmacy, including mixing the components, optionally with one or more accessory ingredients. Furthermore, the carrier may be free of preservatives, as described hereinabove.

[0201] In some embodiments, the active agent is present in an amount ranging from about 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10% by weight of the composition at the lower end to about 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99 and up to 100% by weight of the composition. In some embodiments, the active agent is present as about 0.05% to about 99% by weight of the composition.

[0202] Pharmaceutical compositions according to embodiments of the present disclosure are generally formulated for oral or topical (i.e., dermal, ocular, and mucosal surface) administration, with the most suitable route in any given case depending on the nature and severity of the condition being treated and the nature of the particular active agent used.

[0203] Topical preparations

[0204] The compositions of the present disclosure and pharmaceutical compositions containing the aforementioned compounds can be administered topically, and therefore can be formulated in a form suitable for topical administration, i.e., as a pH-balanced cream preparation. An obstacle to the topical administration of pharmaceuticals is the stratum corneum of the epidermis. The stratum corneum is a highly resistant layer composed of proteins, cholesterol, sphingolipids, free fatty acids, and various other lipids, and contains keratinocytes and living cells. One of the factors limiting the penetration rate (flux) of compounds through the stratum corneum is the amount of active substance that can be loaded or applied onto the skin surface. The greater the amount of active substance applied per unit area of ​​skin, the greater the concentration gradient between the skin surface and the underlying layers of the skin, resulting in a greater diffusion force of the active substance through the skin. Therefore, a formulation containing a higher concentration of active substance is more likely to result in a greater and more consistent rate of penetration of the active substance through the skin than a formulation with a lower concentration, all other conditions being equal.

[0205] Formulations suitable for topical administration include, but are not limited to, liquid or semi-liquid preparations, such as liniments, lotions, oil-in-water or water-in-oil emulsions, such as creams, ointments, or pastes, and solutions and suspensions. Furthermore, formulations suitable for topical administration can be in the form of creams and liquids, including, for example, syrups, suspensions or emulsions, inhalants, sprays, mousses, oils, gels, solids, and the like. Topically administrable formulations can contain, for example, about 1% to about 10% (w / w) active ingredient, although the concentration of the active ingredient can be as high as the solubility limit of the active ingredient in the solvent. Formulations for topical administration can further include one or more of the additional ingredients described herein.

[0206] Penetration enhancers may be used. These materials increase the penetration rate of drugs through the skin. Typical enhancers in the art include ethanol, glycerol monolaurate, PGML (polyethylene glycol monolaurate), dimethyl sulfoxide, etc. Other enhancers include oleic acid, oleyl alcohol, ethoxydiglycol, laurocapram, alkanecarboxylic acids, dimethyl sulfoxide, polar lipids, or N-methyl-2-pyrrolidone. One acceptable vehicle for topical delivery of some compositions may contain liposomes. The composition and use of liposomes are known in the art (see, for example, U.S. Pat. No. 6,323,219).

[0207] In alternative embodiments, the topically active pharmaceutical composition may be optionally combined with other ingredients, such as adjuvants, antioxidants, chelating agents, surfactants, foaming agents, humectants, emulsifiers, thickeners, buffers, and preservatives. In another embodiment, a penetration or penetration enhancer is included in the composition and is effective in improving the transdermal penetration of the active ingredient into and through the stratum corneum relative to a composition lacking the penetration enhancer. Various penetration enhancers are known to those skilled in the art, including oleic acid, oleyl alcohol, ethoxydiglycol, laurocapram, alkanecarboxylic acids, dimethyl sulfoxide, polar lipids, or N-methyl-2-pyrrolidone. In another aspect, the composition may further include a hydrotropic agent, which functions to increase the structural disorder of the stratum corneum, thereby allowing for increased transport through the stratum corneum. Various hydrotropic agents, such as isopropyl alcohol, propylene glycol, or sodium xylene sulfonate, are known to those skilled in the art.

[0208] Topically active pharmaceutical compositions should be applied in an amount effective to affect the desired change. As used herein, "effective amount" means an amount sufficient to cover the area of ​​the skin surface where the change is desired. In various embodiments, the active compound may be present in an amount of about 0.0001% to about 15% by weight of the composition, about 0.0005% to about 5% by weight of the composition, or about 0.001% to about 1% by weight of the composition. Such compounds may be synthetically or naturally derived.

[0209] Oral formulation

[0210] The pharmaceutical compositions containing the compositions of the present disclosure and the compounds described above can be administered orally, and therefore can be formulated in a form suitable for oral administration, i.e., as solid or liquid preparations.Suitable solid oral formulations include tablets, capsules, pills, granules, pellets, etc.Suitable liquid oral formulations include solutions, suspensions, dispersions, emulsions, oils, etc.When formulated in the form of a capsule, the compositions of the present disclosure contain a hard gelatin capsule in addition to the active compound and an inert carrier or diluent.In one embodiment, the formulation for oral administration is an enteric-coated, sustained-release capsule.

[0211] Formulations suitable for oral administration may be provided in discrete units such as capsules, cachets, lozenges, or tablets, each containing a predetermined amount of the active compound; as a powder or granules; as a solution or suspension in an aqueous or non-aqueous liquid; or as an oil-in-water liquid or water-in-oil liquid emulsion. Such formulations may be prepared by any suitable method of pharmacy, including bringing into association the active compound and a suitable carrier (which may contain one or more accessory ingredients, as described above). Generally, the formulations of the present disclosure are prepared by uniformly and intimately mixing the active compound with a liquid or finely divided solid carrier, or both, and then, if necessary, shaping the resulting mixture. For example, tablets may be prepared by compressing or molding a powder or granules containing the active compound, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the compound in a free-flowing form, such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, and / or surfactant / dispersant. Molded tablets may be made by molding in a suitable machine the powdered compound moistened with an inert liquid binder.

[0212] Formulations for other routes of administration

[0213] The compositions of the present disclosure and pharmaceutical compositions containing the aforementioned compounds may further be administered intranasally, i.e., by inhalation, and thus may be formulated in a form suitable for intranasal administration, i.e., as an aerosol or liquid preparation.

[0214] The compositions of the present disclosure may also be formulated, for example, for parenteral administration. Pharmaceutical compositions suitable for parenteral administration include the active ingredient combined with a pharmaceutically acceptable carrier, such as sterile water or sterile isotonic saline. Such formulations may be prepared, packaged, or sold in a form suitable for bolus administration or continuous administration. Injectable formulations may be prepared, packaged, or sold in unit dosage form, such as in ampoules or multi-dose containers containing a preservative. Formulations for parenteral administration include, but are not limited to, suspensions, solutions, emulsions in oily or aqueous vehicles, pastes, and implantable sustained-release or biodegradable formulations. Such formulations may further comprise one or more additional ingredients, including, but not limited to, suspending agents, stabilizers, or dispersing agents. In one embodiment of a formulation for parenteral administration, the active ingredient is provided in a dry (i.e., powder or granules) form for reconstitution with a suitable vehicle (e.g., pyrogen-free sterile water) prior to parenteral administration of the reconstituted composition.

[0215] Pharmaceutical compositions may be prepared, packaged, or sold in the form of a sterile injectable aqueous or oily suspension or solution. These suspensions or solutions may be formulated according to known techniques and may contain, in addition to the active ingredient, additional ingredients such as dispersing agents, wetting agents, or suspending agents described herein. Such sterile injectable formulations may be prepared using, for example, a non-toxic, parenterally acceptable diluent or solvent, such as water or 1,3-butanediol. Other acceptable diluents and solvents include, but are not limited to, Ringer's solution, isotonic sodium chloride solution, and fixed oils such as synthetic mono- or diglycerides. Other useful parenterally administrable formulations include formulations comprising the active ingredient in microcrystalline form, in a liposomal preparation, or as a component of a biodegradable polymer system. Compositions for sustained release or implantation may include pharmaceutically acceptable polymeric or hydrophobic materials (e.g., emulsions, ion exchange resins, sparingly soluble polymers, or sparingly soluble salts). Formulations are prepared using pharmaceutically acceptable "carriers" composed of materials deemed safe and effective, and can be administered to individuals without causing undesired biological side effects or unwanted interactions. A "carrier" is any component present in a pharmaceutical formulation other than the active ingredient or ingredients. The term "carrier" includes, but is not limited to, diluents, binders, lubricants, disintegrants, fillers, and coating compositions.

[0216] "Carrier" also includes all components of the coating composition, which may include plasticizers, pigments, colorants, stabilizers, and glidants. Delayed-release dosage formulations can be prepared as described in references such as "Pharmaceutical dosage forms tablets", eds. Liberman et al. (New York, Marcel Dekker, Inc., 1989), "Remington - The science and practice of pharmacy", 20th ed., Lippincott Williams & Wilkins, Baltimore, Md., 2000, and "Pharmaceutical dosage forms and drug delivery systems", 6th Edition, Ansel et al. (Media, Pa.: Williams and Wilkins, 1995), which provide information on tablets and capsules, as well as carriers, materials, equipment, and processes for preparing delayed-release dosage forms of tablets, capsules, and granules.

[0217] Examples of suitable coating materials include, but are not limited to, cellulose polymers such as cellulose acetate phthalate, hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose phthalate, and hydroxypropyl methylcellulose acetate succinate, polyvinyl acetate phthalate, acrylic acid polymers and copolymers, and methacrylic resins commercially available under the trade name Eudragit® (Roth Pharma, Westerstadt, Germany), zein, shellac, and polysaccharides.

[0218] Additionally, the coating material may contain conventional carriers such as plasticizers, pigments, colorants, glidants, stabilizers, pore formers, and surfactants.

[0219] Optional pharmaceutically acceptable excipients present in drug-containing tablets, beads, granules, or particles include, but are not limited to, diluents, binders, lubricants, disintegrants, colorants, stabilizers, and surfactants. Diluents, also known as "fillers," are typically required to increase the bulk of solid dosage forms so that they provide a practical size for tablet compression or bead and granule formation. Suitable diluents include, but are not limited to, dicalcium phosphate dihydrate, calcium sulfate, lactose, sucrose, mannitol, sorbitol, cellulose, microcrystalline cellulose, kaolin, sodium chloride, dry starch, hydrolyzed starch, pregelatinized starch, silicon dioxide, titanium oxide, magnesium aluminum silicate, and powdered sugar.

[0220] Binders are used to impart cohesion to solid dosage formulations, thereby ensuring that tablets or beads or granules remain intact after formation into a dosage form. Suitable binder materials include, but are not limited to, starch, pregelatinized starch, gelatin, sugars (including sucrose, glucose, dextrose, lactose, and sorbitol), polyethylene glycol, waxes, natural and synthetic gums such as acacia, tragacanth, sodium alginate, celluloses including hydroxypropylmethylcellulose, hydroxypropylcellulose, ethylcellulose, and veegum, and synthetic polymers such as acrylic acid and methacrylic acid copolymers, methacrylic acid copolymers, methyl methacrylate copolymers, aminoalkyl methacrylate copolymers, polyacrylic acid / polymethacrylic acid, and polyvinylpyrrolidone.

[0221] Lubricants are used to facilitate tablet manufacture. Examples of suitable lubricants include, but are not limited to, magnesium stearate, calcium stearate, stearic acid, glycerol behenate, polyethylene glycol, talc, and mineral oil.

[0222] Disintegrants are used to facilitate the disintegration or "breakup" of the dosage form after administration and generally include, but are not limited to, starch, sodium starch glycolate, sodium carboxymethyl starch, sodium carboxymethylcellulose, hydroxypropyl cellulose, pregelatinized starch, clay, cellulose, algin, gum, or crosslinked polymers such as crosslinked PVP (Polyplasdone XL from GAF Chemical Corp).

[0223] Stabilizers are used to inhibit or retard drug decomposition reactions that include, by way of example, oxidative reactions.

[0224] The surfactant may be anionic, cationic, amphoteric, or nonionic. Suitable anionic surfactants include, but are not limited to, those containing carboxylate, sulfonate, and sulfate ions. Examples of anionic surfactants include sodium, potassium, and ammonium long-chain alkyl sulfonates and alkylaryl sulfonates, such as sodium dodecylbenzenesulfonate, sodium dialkyl sulfosuccinates, such as sodium dodecylbenzenesulfonate, sodium dialkyl sulfosuccinates, such as sodium bis-(2-ethylthiol)-sulfosuccinate, and alkyl sulfates, such as sodium lauryl sulfate. Cationic surfactants include, but are not limited to, quaternary ammonium compounds, such as benzalkonium chloride, benzethonium chloride, cetrimonium bromide, stearyl dimethyl benzyl ammonium chloride, polyoxyethylene, and coconut amine. Examples of nonionic surfactants include ethylene glycol monostearate, propylene glycol myristate, glyceryl monostearate, glyceryl stearate, polyglyceryl-4-oleate, sorbitan acylate, sucrose acylate, PEG-150 laurate, PEG-400 monolaurate, polyoxyethylene monolaurate, polysorbate, polyoxyethylene octylphenyl ether, PEG-1000 cetyl ether, polyoxyethylene tridecyl ether, polypropylene glycol butyl ether, Poloxamer® 401, stearoyl monoisopropanolamide, and polyoxyethylene hydrogenated tallow amide. Examples of amphoteric surfactants include sodium N-dodecyl beta-alanine, sodium N-lauryl beta-iminodipropionate, myristoamphoacetate, lauryl betaine, and lauryl sulfobetaine.

[0225] If desired, the tablets, beads, granules, or particles may also contain minor amounts of nontoxic auxiliary substances such as wetting or emulsifying agents, dyes, pH buffering agents, and preservatives.

[0226] As will be appreciated by those skilled in the art and as described in the relevant texts and literature, several methods are available for preparing drug-containing tablets, beads, granules, or particles that provide various drug release profiles. Such methods include, but are not limited to, coating the drug or drug-containing composition with a suitable coating material, typically, but not necessarily, incorporating a polymeric material, increasing the particle size of the drug, locating the drug within a matrix, and forming a complex of the drug with a suitable complexing agent.

[0227] The delayed-release dosage units can be coated with a delayed-release polymer coating using conventional techniques, such as conventional coating pans, airless spray techniques, fluidized bed coating equipment (with or without a Wurster insert), etc. For detailed information on materials, equipment, and processes for preparing tablets and delayed-release dosage forms, see Pharmaceutical Dosage Forms: Tablets, eds. Lieberman et al. (New York: Marcel Dekker, Inc., 1989), and Ansel et al., Pharmaceutical Dosage Forms and Drug Delivery Systems, 6 th Ed. (Media, Pa.: Williams & Wilkins, 1995).

[0228] An exemplary method for preparing sustained-release tablets is by compressing a drug-containing blend, such as a blend of granules, prepared using a direct blending, wet granulation, or dry granulation process. Sustained-release tablets can also be molded rather than compressed, starting with a wet material containing a suitable water-soluble lubricant. However, tablets are manufactured using compression rather than molding. A method for forming a sustained-release drug-containing blend is to directly mix drug particles with one or more excipients, such as a diluent (or filler), binder, disintegrant, lubricant, glidant, and colorant. Instead of direct blending, drug-containing blends can be prepared using a wet granulation process or a dry granulation process. Active agent-containing beads can also be prepared by any one of several conventional techniques, typically starting from a fluid dispersion. For example, a typical method for preparing drug-containing beads involves dispersing or dissolving an active agent in a coating suspension or solution containing pharmaceutical excipients such as polyvinylpyrrolidone, methylcellulose, talc, metal stearates, silicon dioxide, plasticizers, etc. The mixture is used to coat bead cores such as sugar spheres (or so-called "non-pareils") having a size of about 60-20 mesh.

[0229] An alternative procedure for preparing drug beads is by blending the drug with one or more pharmaceutically acceptable excipients, such as microcrystalline cellulose, lactose, cellulose, polyvinylpyrrolidone, talc, magnesium stearate, disintegrants, etc., extruding the blend, spheronizing the extrudate, drying, and optionally coating to form immediate release beads.

[0230] Delayed-release formulations are created by coating a solid dosage form with a film of a polymer that is insoluble in the acidic environment of the stomach and soluble in the neutral environment of the small intestine. Delayed-release dosage units can be prepared, for example, by coating a drug or drug-containing composition with a selected coating material. The drug-containing composition can be, for example, a tablet for incorporation into a capsule, a tablet for use as an inner core in a "coated core" dosage form, or a plurality of drug-containing beads, particles, or granules for incorporation into either a tablet or a capsule. Exemplary coating materials include bioerodible, gradually hydrolyzable, gradually water-soluble, and / or enzymatically degradable polymers, and may be conventional "enteric" polymers. As will be understood by those skilled in the art, enteric polymers become soluble in the higher pH environment of the lower gastrointestinal tract or slowly erode as the dosage form passes through the gastrointestinal tract, while enzymatically degradable polymers are degraded by bacterial enzymes present in the lower gastrointestinal tract, particularly the colon.Suitable coating materials for effecting delayed release include, but are not limited to, cellulose polymers such as hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxymethyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl methyl cellulose acetate succinate, hydroxypropyl methyl cellulose phthalate, methyl cellulose, ethyl cellulose, cellulose acetate, cellulose acetate phthalate, cellulose acetate trimellitate, and sodium carboxymethyl cellulose, acrylic acid polymers and copolymers such as those formed from acrylic acid, methacrylic acid, methyl acrylate, ethyl acrylate, methyl methacrylate, and / or ethyl methacrylate, and polymers sold under the tradename Eudragit® (Rohm Pharma; Westerstadt, Germany) (Eudragit® L30D-55 and L100-55 (soluble at pH 5.5 or above), Eudragit® L-100 (soluble at pH 6.0 or above), Eudragit® S (soluble at pH 6.0 or above as a result of a higher degree of esterification), 7.0 or higher), and Eudragits® NE, RL, RS (water-insoluble polymers with different degrees of permeability and swelling), other methacrylic resins, vinyl polymers and copolymers such as polyvinylpyrrolidone, vinyl acetate, vinyl acetate phthalate, vinyl acetate crotonic acid copolymer, and ethylene-vinyl acetate copolymer, enzymatically degradable polymers such as azopolymers, pectin, chitosan, amylose, and guar gum, zein, and shellac. Combinations of different coating materials can also be used. Multi-layer coatings using different polymers can also be applied.

[0231] The coating composition may contain conventional additives such as plasticizers, pigments, colorants, stabilizers, and glidants. Plasticizers are typically present to reduce coating brittleness and generally comprise about 10% to 50% by weight of the dry polymer. Typical examples of plasticizers include polyethylene glycol, propylene glycol, triacetin, dimethyl phthalate, diethyl phthalate, dibutyl phthalate, dibutyl sebacate, triethyl citrate, tributyl citrate, acetyl triethyl citrate, castor oil, and acetylated monoglycerides. Stabilizers are used to stabilize particles in dispersions. Typical stabilizers are nonionic emulsifiers such as sorbitan esters, polysorbates, and polyvinylpyrrolidone. Glidants are recommended to reduce sticking effects during film formation and drying and generally comprise about 25% to 100% by weight of the polymer in the coating solution. One effective glidant is talc. Other glidants such as magnesium stearate and glycerol monostearate can also be used. Pigments such as titanium dioxide can also be used. Small amounts of anti-foaming agents, such as silicones (e.g., simethicone), can also be added to the coating composition.

[0232] Particles can be prepared entirely from the therapeutic agent or from a combination of the agent and a surfactant. Particles can be made from a variety of materials. Both inorganic and organic materials can be used. For example, ceramics can be used. Polymeric materials and non-polymeric materials such as fatty acids can be used to form aerodynamically light particles. Other suitable materials include, but are not limited to, gelatin, polyethylene glycol, trehalose, and dextran. Particles with degradation and release times ranging from seconds to months can be designed and manufactured based on factors such as the particle material.

[0233] In addition to the therapeutic or diagnostic agent (or optionally other desired molecule for delivery), the particles may include excipients, for example, sugars such as lactose, proteins such as albumin, and / or surfactants.

[0234] As used herein, enteric coated capsules: "gastric-resistant natural polymer" refers to a natural polymer or mixture of natural polymers that is insoluble at the acidic pH of the stomach. As used herein, "film-forming natural polymer" refers to a polymer useful for surface coatings applied by spraying, brushing, or various industrial film-forming processes. In most film-forming processes, a relatively low-viscosity liquid coating is applied to a solid substrate and cured into a solid, high-molecular-weight, polymer-based, adhesive film with the properties desired by the user. In most common applications, this film has a thickness in the range of 0.5 to 500 micrometers (0.0005 to 0.5 millimeters, or 0.00002 to 0.02 inches).

[0235] As used herein, "gelling agent" refers to a substance that, when hydrated and dispersed in a dispersion medium or dissolved in a dispersion medium, undergoes a high degree of cross-linking or association. This cross-linking or association of the dispersed phase changes the viscosity of the dispersion medium. The dispersion medium becomes restricted in its movement by the dispersed phase, and its viscosity increases.

[0236] Described herein is a gastro-resistant film-forming composition containing (1) a gastro-resistant natural polymer, (2) a film-forming natural polymer, and, optionally, (3) a gelling agent. Exemplary gastro-resistant natural polymers include, but are not limited to, pectin and pectin-like polymers, which typically consist primarily of galacturonic acid and galacturonic acid methyl ester units forming linear polysaccharide chains. Typically, these polysaccharides are rich in galacturonic acid, rhamnose, arabinose, and galactose, such as polygalacturonan, rhamnogalacturonan, and some arabinans, galactans, and arabinogalactans. They are usually classified according to the degree of esterification. In high (methyl) ester ("HM") pectins, a relatively large proportion of the carboxyl groups occur as methyl esters, with the remaining carboxylic acid groups being in the form of free acids or as their ammonium, potassium, calcium, or sodium salts.

[0237] Useful properties may vary with the degree of esterification and polymerization. Pectin in which less than 50% of the carboxylic acid units occur as methyl esters is commonly referred to as low (methyl) ester or LM-pectin. Generally, low-ester pectin is obtained from high-ester pectin by treatment under mildly acidic or alkaline conditions. Amidated pectin is obtained from high-ester pectin when ammonia is used in an alkaline deesterification process. In this type of pectin, some of the remaining carboxylic acid groups are converted to acid amides. Useful properties of amidated pectin may vary with the proportion of ester and amide units and the degree of polymerization. In one embodiment, the gastro-resistant natural polymer is pectin. The gastro-resistant natural polymer is present in an amount of less than about 5% by weight of the composition, for example, from about 2 to about 4% by weight of the composition.

[0238] Exemplary film-forming natural polymers include, but are not limited to, gelatin and gelatin-like polymers. In an exemplary embodiment, the film-forming natural polymer is gelatin. Many other gelatin-like polymers are commercially available.

[0239] The film-forming natural polymer is present in an amount of from about 20 to about 40% by weight of the composition, for example, from about 25 to about 40% by weight of the composition.

[0240] The composition may optionally contain a gelling agent. Exemplary gelling agents include Ca 2+ and Mg 2+ and divalent cations such as Calcium, Magnesium, and the like. Sources of these ions include inorganic calcium and magnesium salts and calcium gelatin. The gelling agent is present in an amount of less than about 2% by weight of the composition, for example, less than about 1% by weight of the composition.

[0241] One or more plasticizers may be added to the composition to facilitate the film-forming process. Suitable plasticizers include glycerin, sorbitol, sorbitan, maltitol, glycerol, polyethylene glycol, polyhydric alcohols having 3 to 6 carbon atoms, citric acid, citric acid esters, triethyl citrate, and combinations thereof. The concentration of the one or more plasticizers is about 8% to about 30% by weight of the composition. In one embodiment, the plasticizer is glycerin and / or sorbitol.

[0242] The film-forming composition can be used to prepare soft or hard shell gelatin capsules, which can encapsulate a liquid or semisolid fill material or a solid tablet (Softlet®) containing an active agent and one or more pharmaceutically acceptable excipients. Alternatively, the composition can be administered as a liquid, with the active agent dissolved or dispersed in the composition.

[0243] The film-forming compositions can be used to prepare soft or hard capsules using techniques well known in the art. For example, soft capsules are typically produced using a rotary die encapsulation process. The fill formulation is fed into the encapsulation machine by gravity.

[0244] The capsule shell may contain one or more plasticizers selected from the group consisting of glycerin, sorbitol, sorbitan, maltitol, glycerol, polyethylene glycol, polyhydric alcohols having 3 to 6 carbon atoms, citric acid, citrate esters, triethyl citrate, and combinations thereof.

[0245] In addition to plasticizers, the capsule shell may contain opacifiers, colorants, humectants, preservatives, flavoring agents, and other suitable shell additives such as buffer salts and acids.

[0246] Opacifiers are used to render the capsule shell opaque when the encapsulated active agent is light sensitive. Suitable opacifiers include titanium dioxide, zinc oxide, calcium carbonate, and combinations thereof.

[0247] Colorants may be used for marketing and product identification / differentiation purposes. Suitable colorants include synthetic and natural dyes and combinations thereof.

[0248] Humectants can be used to reduce the water activity of the soft gel. Suitable humectants include glycerin and sorbitol, which are often components of plasticizer compositions. Due to the low water activity of dried and properly stored soft gels, the greatest risk from microorganisms comes from mold and yeast. For this reason, preservatives can be incorporated into the capsule shell. Suitable preservatives include alkyl esters of p-hydroxybenzoic acid, such as methyl, ethyl, propyl, butyl, and heptyl (collectively known as "parabens"), or combinations thereof.

[0249] Flavoring agents can be used to mask unpleasant odors and tastes of fill formulations. Suitable flavoring agents include synthetic and natural flavoring agents. The use of flavoring agents can be problematic due to the presence of aldehydes, which can crosslink gelatin. As a result, buffer salts and acids can be used with flavoring agents containing aldehydes to inhibit gelatin crosslinking.

[0250] Soft or hard capsules can be used to deliver a wide variety of pharmaceutically active agents. Suitable agents include small molecules, proteins, nucleic acids, carbohydrates, lipids, and entire organisms.

[0251] The fill formulation can be prepared using a pharmaceutically acceptable carrier, which is made of materials that are considered safe and effective, and can be administered to an individual without causing undesired biological side effects or unwanted interactions.Carriers are all components present in pharmaceutical formulations other than the active ingredient or ingredients.As used generally herein, "carriers" include, but are not limited to, surfactants, humectants, plasticizers, crystallization inhibitors, wetting agents, bulk fillers, solubilizers, bioavailability enhancers, pH adjusters, and combinations thereof.

[0252] Alternatively, the composition may be administered as a liquid, with the active agent dissolved (eg, a solution) or dispersed (eg, a suspension) in the composition.

[0253] Suitable active agents are described above.Solution or suspension can be prepared using one or more pharmaceutically acceptable excipients.Suitable excipients include but are not limited to surfactants, humectants, plasticizers, crystallization inhibitors, wetting agents, bulk fillers, solubilizers, bioavailability enhancers, pH adjusters, flavoring agents, binders, disintegrants, anti-adhesion agents, antistatic agents, surfactants, antioxidants, coating agents, coloring agents, preservatives, suspending agents, emulsifiers, antibacterial agents, spheronizing agents, stabilizers, tonicity enhancers, buffering agents, and any combination thereof.

[0254] Mucoadhesive Particles and Methods of Manufacture: Generally, adhesion of polymers to tissues can be achieved by (i) physical or mechanical bonds, (ii) primary or covalent chemical bonds, and / or (iii) secondary chemical bonds (e.g., ionic). Physical or mechanical bonds can result from deposition and inclusion of adhesive materials in the crevices of mucus or in the folds of mucus. Secondary chemical bonds that contribute to bioadhesive properties consist of dispersive interactions (e.g., van der Waals interactions) and stronger specific interactions, including hydrogen bonds. Hydrophilic functional groups involved in hydrogen bond formation are hydroxyl (--OH) and carboxyl (--COOH) groups.

[0255] The adhesive polymer microspheres have been selected based on their chemical composition and physical properties, such as the physical and chemical bonds formed as a function of surface area, as described in detail below. These microspheres have a viscosity of 11 mN / cm 2 These microspheres are characterized by an adhesive strength to mucosa exceeding 1000 uA. The size of these microspheres ranges from nanoparticles to millimeters in diameter. Adhesion is a function of polymer composition, biological substrate, particle morphology, particle shape (e.g., diameter), and surface modification.

[0256] Classes of polymers useful for forming bioadhesive microspheres: Suitable polymers that can be used to form bioadhesive microspheres include soluble and insoluble, biodegradable and non-biodegradable polymers. These can be natural or synthetic, hydrogels or thermoplastics, homopolymers, copolymers, or blends. However, the key feature is that the polymer will produce a bioadhesive interaction of 110 N / m2 (11 mN / cm2) to 100,000 N / m2 when applied to the mucosal surface of rat intestine.

[0257] In order for the bioadhesive particles to embed themselves or become entrapped in the mucus lining the GI tract, the radius of the individual particles is made to be on the same order of thickness as the natural mucus layer, which has been shown to be typically 5-200 μm in rats and 10-400 μm in humans. However, in humans, it can reach a thickness of approximately 1,000 μm, as described in Spiro, R.G., "Glycoproteins," Annual Review of Biochemistry, 39, 599-638, 1970; Labatt-Robert, J. & Decaeus, C., "Glycoproteins du Mucus Gastrique: Structure, Function, et Pathologie," Pathologie et Biologie (Paris), 24, 241, 1979; Allen, A., Hutton, D.A., Pearson, J.P., & Sellers, L.A., "Mucus Glycoprotein Structure, Gel Formation and Gastrointestinal Mucus Function," in Mucus and Mucosa, Ciba Foundation Symposium 109 (eds. J. Nugent & M. O'Connor), pp. 137 (London: Pitman, 1984). In the past, two classes of polymers appeared to exhibit useful bioadhesive properties: hydrophilic polymers and hydrogels. Within the large class of hydrophilic polymers, those containing carboxyl groups (e.g., poly[acrylic acid]) exhibit the best bioadhesive properties. It can be inferred that polymers with the highest concentrations of carboxyl groups should be the materials of choice for bioadhesion on soft tissue. In other studies, the most promising polymers were sodium alginate, carboxymethylcellulose, hydroxymethylcellulose, and methylcellulose. Some of these materials are water-soluble, while others are hydrogels.

[0258] Rapidly bioerodible polymers, such as poly(lactide-co-glycolide), polyanhydrides, and polyorthoesters, whose carboxyl groups become exposed on their outer surfaces as their smooth surfaces erode, are excellent candidates for bioadhesive drug delivery systems. Furthermore, polymers containing labile bonds, such as polyanhydrides and polyesters, are well known for their hydrolytic reactivity. Their hydrolysis rates can generally be altered by simple changes in the polymer backbone.

[0259] Representative natural polymers include proteins such as zein, modified zein, casein, gelatin, gluten, serum albumin, or collagen, and polysaccharides such as cellulose, dextran, polyhyaluronic acid, polymers of acrylic and methacrylic acid esters, and alginic acid. Representative synthetic polymers include polyphosphazines, poly(vinyl alcohols), polyamides, polycarbonates, polyalkylenes, polyacrylamides, polyalkylene glycols, polyalkylene oxides, polyalkylene terephthalates, polyvinyl ethers, polyvinyl esters, polyvinyl halides, polyvinylpyrrolidone, polyglycolides, polysiloxanes, polyurethanes, and copolymers thereof. Synthetically modified natural polymers include alkylcelluloses, hydroxyalkylcelluloses, cellulose ethers, cellulose esters, and nitrocellulose. Other polymers of interest include, but are not limited to, methyl cellulose, ethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxybutyl methyl cellulose, cellulose acetate, cellulose propionate, cellulose acetate butyrate, cellulose acetate phthalate, carboxymethyl cellulose, cellulose triacetate, cellulose sulfate sodium salt, poly(methyl methacrylate), poly(ethyl methacrylate), poly(butyl methacrylate), poly(isobutyl methacrylate), poly(hexyl methacrylate), poly(isodecyl methacrylate), poly(lauryl methacrylate), poly(phenyl methacrylate), poly(methyl acrylate), poly(isopropyl acrylate), poly(isobutyl acrylate), poly(octadecyl acrylate), polyethylene, polypropylene, poly(ethylene glycol), poly(ethylene oxide), poly(ethylene terephthalate), poly(vinyl acetate), polyvinyl chloride, polystyrene, polyvinylpyrrolidone, and polyvinylphenol.Representative bioerodible polymers include polylactide, polyglycolide and their copolymers, poly(ethylene terephthalate), poly(butyric acid), poly(valeric acid), poly(lactide-co-caprolactone), poly[lactide-co-glycolide], polyanhydrides, polyorthoesters, blends and copolymers thereof.

[0260] The pharmaceutically acceptable compounds of the present disclosure are typically administered to a subject in a daily dosage regimen. For an adult subject, this can be, for example, an oral dose of 0.1 grams to 15 grams of a compound comprising at least one SCFA or SCFA moiety. In further embodiments, the oral dose of a compound comprising at least one SCFA or SCFA moiety can be 0.5 grams to 10 grams. In still further embodiments, the oral dose of a compound comprising at least one SCFA or SCFA moiety can be 0.5 grams to 6 grams.

[0261] Pharmaceutical compositions may be administered 1, 2, 3, 4 or more times per day. Thus, in certain embodiments, compositions formulated for topical administration, for example, may be administered multiple times per day.

[0262] In one embodiment, a composition comprising a 1:1 (w / w) ratio of a first and a second SCFA is contemplated, where 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 grams of the first SCFA may be present. In other embodiments, the ratio of the first SCFA to the second SCFA may be 2:1, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, 9:1, or 10:1 (w / w), where 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 grams of the first SCFA may be present. Of course, the ratio of the first SCFA and the second SCFA administered can vary from that disclosed herein above.For example, any amount of the first SCFA, including 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 grams of the first SCFA, can be administered with any amount of the second SCFA, including 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 grams of the second SCFA.These amounts of any supplements can be mixed in one composition, or can be in separate compositions.

[0263] The pharmaceutical composition can be administered in a local or systemic manner, for example, via direct injection of the compound into an organ, optionally in a depot or sustained release formulation or implant. The pharmaceutical composition can be provided in the form of a rapid release formulation, a sustained release formulation, or an intermediate release formulation. The rapid release formulation can provide immediate release. The sustained release formulation can provide controlled release or sustained delayed release.

[0264] In carrying out the therapeutic methods or uses provided herein, a therapeutically effective amount of a compound described herein is administered in a pharmaceutical composition to a subject having a disease or condition to be treated. In some embodiments, the subject is a mammal, such as a human. The therapeutically effective amount can vary widely depending on the severity of the disease, the age and relative health of the subject, the potency of the compound used, and other factors. The compound can be used alone or in combination with one or more therapeutic agents as components of a mixture.

[0265] Methods for preparing compositions containing the compounds described herein include formulating the compounds with one or more inert pharmaceutically acceptable excipients or carriers to form solid, semi-solid, or liquid compositions. Solid compositions include, for example, powders, tablets, dispersible granules, capsules, and cachets. Liquid compositions include, for example, solutions in which the compounds are dissolved, emulsions containing the compounds, or solutions containing liposomes, micelles, or nanoparticles containing the compounds disclosed herein. Semi-solid compositions include, for example, gels, suspensions, and creams. The compositions can be liquid solutions or suspensions, solid forms suitable for dissolution or suspension in liquid before use, or emulsions. These compositions can also contain minor amounts of non-toxic auxiliary substances, such as wetting or emulsifying agents, pH buffering agents, and other pharmaceutically acceptable additives.

[0266] Non-limiting examples of dosage forms suitable for use in the present disclosure include liquids, powders, gels, nanosuspensions, nanoparticles, microgels, aqueous or oily suspensions, emulsions, and any combination thereof.

[0267] The compositions of the present disclosure may be, for example, immediate-release or controlled-release formulations. Immediate-release formulations can be formulated to rapidly act on the compound. Non-limiting examples of immediate-release formulations include readily dissolvable formulations. Controlled-release formulations can be pharmaceutical formulations formulated to provide an active agent release at a tailored or programmed rate, such that the release rate and release profile of the active agent can be adapted to physiological and chronotherapy requirements. Non-limiting examples of controlled-release formulations include granules, delayed-release granules, hydrogels (e.g., synthetic or natural), other gelling agents (e.g., gel-forming dietary fibers), matrix-based formulations (e.g., formulations comprising a polymeric material in which at least one active ingredient is dispersed), granules in a matrix, polymer mixtures, and granular agglomerates.

[0268] In some embodiments, the controlled release formulation is a delayed release form. The delayed release form can be formulated to delay the action of the compound for a long period of time. The delayed release form can be formulated to delay the release of an effective dose of one or more compounds for, for example, about 4 hours, about 8 hours, about 12 hours, about 16 hours, or about 24 hours.

[0269] The controlled release formulation can be a sustained release form.The sustained release form can be formulated to, for example, sustain the action of the compound for a long period of time.The sustained release form can be formulated to provide an effective dose of any compound described herein (for example, provide a physiologically effective blood profile) for about 4 hours, about 8 hours, about 12 hours, about 16 hours, or about 24 hours.

[0270] Non-limiting examples of pharmaceutically acceptable excipients can be found, for example, in Remington: The Science and Practice of Pharmacy, Nineteenth Ed. (Easton, PA: Mack Publishing Company, 1995); Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, H.A. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, NY, 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkins 1999), each of which is incorporated by reference in its entirety.

[0271] The subject can be, for example, an older adult, an adult, an adolescent, a pre-adolescent, a child, a toddler, an infant, a newborn, and a non-human animal. In some embodiments, the subject is a patient.

[0272] The methods disclosed herein relate to administering a compound disclosed herein as part of a pharmaceutical composition. In some embodiments, the composition of a compound disclosed herein can comprise a liquid containing an active agent in solution, suspension, or both. The liquid composition can comprise a gel. In some embodiments, the liquid composition is aqueous. Alternatively, the composition can be an ointment. In some embodiments, the composition is an aqueous composition capable of in situ gelling. In some embodiments, the composition is an aqueous solution capable of in situ gelling.

[0273] The pharmaceutically acceptable excipient may be present in the pharmaceutical composition in an amount from about 0.1% to about 99% by weight of the composition. For example, a pharmaceutically acceptable excipient may be present in a pharmaceutical composition in an amount by mass of about 0.1% to about 95%, about 0.1% to about 90%, about 0.1% to about 85%, about 0.1% to about 80%, about 0.1% to about 75%, about 0.1% to about 70%, about 0.1% to about 65%, about 0.1% to about 60%, about 0.1% to about 55%, about 0.1% to about 50%, about 0.1% to about 45%, about 0.1% to about 40%, about 0.1% to about 35%, about 0.1% to about 30%, about 0.1% to about 25%, about 0.1% to about 20%, about 0.1% to about 15%, about 0.1% to about 10%, about 0.1% to about 5%, or about 0.1% to about 1% of the formulation.

[0274] Pharmaceutically acceptable excipients may comprise about 0.1%, about 0.2%, about 0.3%, about 0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9%, about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, about 21%, about 22%, about 23%, about 24%, about 25%, about 26%, about 27%, about 28%, about 29%, about 30%, about 31%, about 32%, about 33%, about 34%, about 35%, about 36%, about 37%, about 38%, about 39%, about 40%, about 41%, about 42%, about 43%, about 44%, about 45%, about 46%, about 47%, about 48%, about 49%, about 50%, about 51%, about 52%, about 53%, about 54%, about 55%, about 56%, about 57%, about 58%, about 59%, about 60%, about 61%, about 62%, about 63%, about 64%, about 65%, about 66%, about 67%, about 68%, about 69%, about 70%, about 71%, about 72%, about 73%, about 74%, about 75%, about 76%, about 77%, about 78%, about 79%, about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 9 ,approximately 20%,approximately 21%,approximately 22%,approximately 23%,approximately 24%,approximately 25%,approximately 26%,approximately 27%,approximately 28%,approximately 29%,approximately 30%,approximately 31%,approximately 32%,approximately 33%,approximately 34%,approximately 35%,approximately 36%,approximately 37%,approximately 38%,approximately 39%,approximately 40%,approximately 41%,approximately 42%,approximately 43%,approximately 44%,approximately 45%,approximately 46%,approximately 47%,approximately 48%,approximately 49%,approximately 50%,approximately 51%,approximately 52%,approximately 53%,approximately 54%,approximately 55%,approximately 56%,approximately 57%,approximately 58%,approximately 59%,approximately 60%,approximately 61%,approximately 62%,approximately 63%,approximately 64%,approximately 65%,approximately 66%,approximately 67%,approximately 68%,approximately 69%,approximately 70%,approximately 71%,approximately 72%,approximately 73%,approximately 74%,approximately 75%,approximately 76%,approximately 77%,approximately 78%,approximately 79%,approximately 80%,approximately 81%,approximately 82%,approximately 1%, approximately 52%, approximately 53%, approximately 54%, approximately 55%, approximately 56%, approximately 57%, approximately 58%, approximately 59%, approximately 60%, approximately 61%, approximately 62%, approximately 63%, approximately 64%, approximately 65%, approximately 66%, approximately 67%, approximately 68%, approximately 69%, approximately 70%, approximately 71%, approximately 72%, approximately 73%, approximately 74%, approximately 75%, approximately 76%, approximately 77%, approximately 78%, approximately 79%, approximately 80%, approximately 81%, approximately 82%, It may be present at about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, about 99.1%, about 99.2%, about 99.3%, about 99.4%, about 99.5%, about 99.6%, about 99.7%, about 99.8% or about 99.9% by mass.

[0275] Target / Patient Population The subject may be a human, such as an older adult, adolescent, pre-adolescent, child, infant, baby, newborn, or non-human animal, such as a mouse. In some embodiments, the subject is a patient. In some embodiments, the subject is experiencing and / or exhibiting at least one symptom of a disease or disorder to be treated and / or reduced likelihood of occurrence. In some embodiments, the subject has been identified or diagnosed as having a liver disease or disorder described herein, such as NASH.

[0276] In some embodiments, the treatment methods disclosed herein include identifying a patient population based on one or more selection criteria, e.g., biomarkers, failure to respond to a first-line therapy, and administering a compound disclosed herein, e.g., Compound 1, to treat the patient. Patient population selection criteria may include, but are not limited to, the presence of biomarkers, e.g., markers associated with a particular disease, the presence of markers associated with a poor prognosis of the disease, failure to respond to initial therapy, and the patient's age, sex, and health status. Screening procedures may include, but are not limited to, blood and / or tissue sample analysis, genetic testing, genetic screening, biopsy, and drug susceptibility / resistance testing.

[0277] The methods disclosed herein involve administering a compound disclosed herein as part of a pharmaceutical composition. In some embodiments, the pharmaceutical composition comprises a compound disclosed herein and a pharmaceutically acceptable excipient. In some embodiments, the composition of a compound disclosed herein may comprise a liquid comprising an active agent in solution, suspension, or both. The liquid composition may comprise a gel. In some embodiments, the liquid composition is aqueous. In some embodiments, the composition is an ointment. In some embodiments, the composition is an in situ gellable aqueous composition. In some embodiments, the composition is an in situ gellable aqueous solution.

[0278] Administration The pharmaceutical compositions described herein can be in unit dosage form suitable for single administration of precise dosage amounts.In unit dosage form, the formulation is divided into unit doses containing appropriate amounts of one or more compounds.The unit dosage can be in the form of a package containing discrete amounts of the formulation.Non-limiting examples are packaged injections, vials, or ampoules.Aqueous suspension compositions can be packaged in single-dose non-reclosable containers.Multiple-dose reclosable containers can be used, for example, with or without preservatives.Preparations for parenteral injection can be provided in unit dosage form, for example, in ampoules, or in multi-dose containers containing preservatives.

[0279] The compounds described herein may be administered in an amount of about 1 mg to about 5 mg, about 5 mg to about 10 mg, about 10 mg to about 15 mg, about 15 mg to about 20 mg, about 20 mg to about 25 mg, about 25 mg to about 30 mg, about 30 mg to about 35 mg, about 35 mg to about 40 mg, about 40 mg to about 45 mg, about 45 mg to about 50 mg, about 50 mg to about 55 mg, about 55 mg to about 60 mg, about 60 mg to about 65 mg, about 65 mg to about 70 mg, about 70 mg The amount of hydroxybenzoates may be present in the composition in a range of about 100 mg to about 75 mg, about 75 mg to about 80 mg, about 80 mg to about 85 mg, about 85 mg to about 90 mg, about 90 mg to about 95 mg, about 95 mg to about 100 mg, about 100 mg to about 125 mg, about 125 mg to about 150 mg, about 150 mg to about 175 mg, about 175 mg to about 200 mg, about 200 mg to about 225 mg, about 225 mg to about 250 mg, or about 250 mg to about 300 mg.

[0280] The compounds described herein may be administered in an amount of about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 120 mg, about 140 mg, about 160 mg, about 180 mg, It may be present in the composition in an amount of about 200 mg, about 220 mg, about 240 mg, about 260 mg, about 280 mg, about 300 mg, about 320 mg, about 340 mg, about 360 mg, about 380 mg, about 400 mg, about 420 mg, about 440 mg, about 460 mg, about 480 mg, about 500 mg, about 520 mg, about 540 mg, about 560 mg, about 580 mg, or about 600 mg.

[0281] The compounds described herein can be administered to a subject in an amount of about 0.1 mg / kg to about 500 mg / kg, about 1 mg / kg to about 500 mg / kg, about 0.1 mg / kg to about 300 mg / kg, about 1 mg / kg to about 300 mg / kg, or about 0.1 mg / kg to about 30 mg / kg. In some embodiments, the compounds disclosed herein are administered at a dose of about 1 mg / kg, about 2 mg / kg, about 3 mg / kg, about 4 mg / kg, about 5 mg / kg, about 6 mg / kg, about 7 mg / kg, about 8 mg / kg, about 9 mg / kg, about 10 mg / kg, about 11 mg / kg, about 12 mg / kg, about 13 mg / kg, about 14 mg / kg, about 15 mg / kg, about 16 mg / kg, about 17 mg / kg, about 18 mg / kg, about 19 mg / kg, about 20 mg / kg, about 25 mg / kg, about 30 mg / kg, about 35 mg / kg, about 40 mg / kg, about 45 mg / kg, or about 50 mg / kg. g / kg, about 50 mg / kg, about 55 mg / kg, about 60 mg / kg, about 65 mg / kg, about 70 mg / kg, about 75 mg / kg, about 80 mg / kg, about 85 mg / kg, about 90 mg / kg, about 95 mg / kg, about 100 mg / kg, about 120 mg / kg, about 150 mg / kg, about 160 mg / kg, about 180 mg / kg, about 200 mg / kg, about 250 mg / kg, about 300 mg / kg, about 350 mg / kg, about 400 mg / kg, about 450 mg / kg, about 500 mg / kg, or about 600 mg / kg.

[0282] Dosing regimen The dosing regimens disclosed herein can be, for example, once daily, twice daily, three times daily, once weekly, twice weekly, or three times weekly. In some embodiments, the compounds disclosed herein are administered once daily. In some embodiments, the compounds disclosed herein are administered once daily for 28 days (one cycle). In some embodiments, the compounds disclosed herein are administered once daily for one or more 28-day cycles. In some embodiments, the compounds disclosed herein are administered in a four-week cycle, with three weeks of continuous daily administration followed by one week without administration.

[0283] The compounds described herein can be administered before, during, or after the onset of a disease or condition, and the timing of administering a composition containing the compound can vary. For example, the compounds can be used as prophylactic agents and can be administered continuously to subjects susceptible to a condition or disease to reduce or decrease the likelihood of the disease or condition occurring. The compounds and compositions can be administered to a subject during or as soon as possible after the onset of symptoms. Administration of the compound can begin within the first 48 hours of the onset of symptoms, within the first 24 hours of the onset of symptoms, within the first 6 hours of the onset of symptoms, or within 3 hours of the onset of symptoms. Initial administration can be via any practical route, such as by any route described herein, using any formulation described herein.

[0284] The compound may be administered as soon as practical after the onset of a disease or condition is detected or suspected, for the period of time necessary to treat the disease, for example, from about 1 month to about 3 months. In some embodiments, the length of time the compound may be administered is about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 1 month, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 2 months, about 9 weeks, about 10 weeks, about 11 weeks, about 12 weeks, about 3 months, about 13 weeks, about 14 weeks, about 15 weeks, about 16 weeks, about 4 months, about 17 weeks, about 18 weeks, about 19 weeks, about 20 weeks, about 5 months, about 21 weeks, about 22 weeks, about 23 weeks, about 24 weeks, about 6 months, about 7 months, about 8 months, or about 9 months. The treatment may be for about 1 month, about 9 months, about 10 months, about 11 months, about 1 year, about 13 months, about 14 months, about 15 months, about 16 months, about 17 months, about 18 months, about 19 months, about 20 months, about 21 months, about 22 months, about 23 months, about 2 years, about 2.5 years, about 3 years, about 3.5 years, about 4 years, about 4.5 years, about 5 years, about 6 years, about 7 years, about 8 years, about 9 years, about 10 years, about 11 years, about 12 years, about 13 years, about 14 years, about 15 years, about 16 years, about 17 years, about 18 years, about 19 years, about 20 years, about 21 years, about 22 years, about 23 years, about 24 years, or about 25 years. The length of treatment may vary from subject to subject.

[0285] The dosing schedule for administering the compound described herein can be consistent throughout the duration of the dosing regimen.For example, the compound can be administered every day.Alternatively, or in addition, the dosing schedule for administering the compound described herein can include a period of time during which administration is suspended.For example, the compound can be administered every day for 3 weeks, and then not administered for 1 week.

[0286] The administration schedule for the compounds described herein can include once a day (QD), twice a day (BID), three times a day (TID), four times a day (QID), once a week, twice a week, three times a week, once a month, twice a month, and once every other month.For example, a daily dose can be given in a single dose, or can be divided into multiple doses administered at intervals, for example, twice a day or three times a day.For example, a daily dose of 100 mg can be given, for example, once a day (100 mg), twice a day (50 mg per dose).

[0287] Multiple therapeutic agents can be administered in any order or simultaneously. In some embodiments, the compound of the present disclosure is administered in combination with another therapeutic agent, for example, in combination with a drug such as an aromatase inhibitor, before or after the treatment. In some embodiments, the compound of the present disclosure is administered at regular intervals, for example, once daily, twice daily, or three times daily, and the second therapeutic agent is administered daily or intermittently, or as needed. If administered simultaneously, the multiple therapeutic agents can be provided in a single, unified form or in multiple forms, for example, as multiple separate unit dosage forms. The agents can be packaged together or separately in a single package or multiple packages. One or all of the therapeutic agents can be given in multiple doses. If not administered simultaneously, the timing between the multiple doses can vary by up to about one month.

[0288] kit

[0289] The present disclosure also includes kits comprising compounds useful in the methods of the present disclosure and instructional materials describing how to administer the compositions, e.g., as described elsewhere herein. In one embodiment, the kit comprises the composition.

[0290] Example

[0291] The present invention will be described in further detail by reference to the following experimental examples. These examples are provided for illustrative purposes only and, unless otherwise specified, are not intended to be limiting. Therefore, the present invention should not be construed as being limited to the following examples in any way, but rather as embracing any and all variations that become evident as a result of the teachings provided herein.

[0292] Without further description, it is believed that one of ordinary skill in the art can, using the preceding description and the following illustrative examples, make and utilize the present invention and practice the claimed methods. Thus, the following examples are not to be construed as limiting in any way the remainder of the disclosure.

[0293] Example 1: Combination Therapy for Nonalcoholic Steatohepatitis (NASH) and Fibrosis

[0294] Given the complex pathophysiology of NASH, this study will develop a novel treatment for NASH using a unique combination of short-chain fatty acids (SCFAs), butyrate and acetate, and the antioxidant vitamin E (at a safer dose), both of which target multiple mechanisms related to the pathogenesis of NASH.

[0295] Disclosure A: A unique combination of Ca / Mg butyric acid salt (2.4 g daily) and tocopherol acetate (acetic acid source [12 mg] vitamin E [200 IU]) has been developed that provides an effective treatment for NASH with or without fibrosis.

[0296] Patients diagnosed with NAFLD are also treated with the composition to prevent the progression of NAFLD to NASH and / or fibrosis. Example 2: Treatment with short-chain fatty acids evaluates the prevention of progression of NASH to fibrosis in a preclinical model of aged mice

[0297] Various assays to assess the inhibition of NASH progression to fibrosis were designed and tested, as shown and described in Figures 1-9.

[0298] mouse

[0299] All mice were fed a high-fat diet (HFD) starting at 56 weeks of age until euthanasia at 76 weeks (groups 1, 2, and 5) or 84 weeks (groups 2, 4, and 6) of age (Table 1). Groups 1–4 also received 20.5 mg / kg / mouse / day of tocopherol acetate. Starting at 56 weeks of age, mice were fed a high-fat diet (HFD). At 64 weeks of age, half of the mice were fed either high-dose SCFAs, low-dose SCFAs, or no drug (day 0) for 12 weeks until euthanasia (day 84) (Table 1 and Figure 1). The other half of the colony was divided into identical groups, except that the SCFA diet was started at 72 weeks of age and continued for 12 weeks until euthanasia. [Table 1]

[0300] body weight

[0301] Body weight was determined in all C57 / BL6 male mice throughout the entire study (Figure 1). No effect on weight loss was observed in mice in groups 2 and 4 treated with low doses of SCFA (Figure 1). Mice in groups 1 and 3 given high doses of SCFA lost up to 20% of their body weight within the first few weeks of SCFA feeding (Figure 1), but their food intake, physical appearance, and activity were unchanged, suggesting no overt toxicity.

[0302] H&E staining

[0303] After euthanasia, each liver lobe from each mouse was formalin-fixed and paraffin-embedded. Liver sections were prepared and stained with H&E to assess histopathology (Tables 2-3 and Figures 2-7), while slides from the same blocks were stained with trichrome to assess fibrosis (Figures 8-9).

[0304] Histopathological scores were determined independently for each of the four lobes from individual mice, and data represent the average score from all four lobes of one mouse (Table 2) according to the histopathological evaluation criteria (Table 3).

[0305] [Table 2]

[0306] [Table 3]

[0307] At 64 weeks of age, all mice had NASH. At 72 weeks of age, all mice had NASH and fibrosis.

[0308] The presence, frequency, and distribution of NASH and fibrosis were assessed in SCFA-treated mice compared with control animals at 76 and 84 weeks (Figure 2 and Tables 4-5).

[0309] [Table 4]

[0310] [Table 5]

[0311] When comparing groups 1 and 5 receiving high doses of SCFAs with groups 2 and 5 receiving low doses of SCFAs, NASH was significantly blocked at week 76 (Figure 2 and Table 4). When comparing groups 3 and 6 receiving high doses of SCFAs with groups 4 and 6 receiving low doses of SCFAs, NASH was significantly blocked at week 84 (Figure 2 and Table 5).

[0312] A statistically significant reduction in fibrosis development was observed in mice euthanized at 76 weeks (Figure 3 and Table 4). Comparing mice from groups 1 to 5, these experiments demonstrated that treatment with SCFAs was effective against fibrosis. A similar trend of reduced fibrosis was observed in mice euthanized at 84 weeks (Figure 3 and Table 5).

[0313] SCFAs attenuated the pathogenesis of NASH by blocking the development and / or progression of inflammatory lesions and preventing or delaying the development of liver fibrosis. Example 3: Study evaluating short chain fatty acid treatment and improvement of liver histology in patients with NAFLD / NASH.

[0314] Liver histology in patients with NAFLD / NASH is evaluated after administration of a composition comprising tocopherol butyrate and tocopherol acetate.

[0315] A total of 100 patients with a median age of 60 years will be recruited. Patients will have NAFLD / NASH and associated liver inflammation and / or cirrhosis, and no contraindications to butyrate. Enrolled patients will have a histological diagnosis of NASH.

[0316] Patients receive a formulation containing 600 mg of sodium butyrate and tocopherol acetate (a source of acetate [12 mg] and vitamin E [200 IU]) two to three times daily, or a placebo.

[0317] Evaluation of liver histology

[0318] Baseline and post-treatment (e.g., 96 weeks) liver biopsy specimens are formalin-fixed, paraffin-embedded, and unstained slides are cut from the tissue blocks. Biopsy scoring is assessed according to the NAFLD activity score (NAS) and fibrosis score, or as described, for example, in Example 1.

[0319] Laboratory analysis

[0320] Blood is collected and the sample is processed. Measurements of insulin, glucose, and Adipo-IR index are measured. The Adipo-IR index is calculated, for example, as fasting NEFA [mM] x fasting insulin [pM]. The Adipo-IR index is related to the improvement of steatosis and necroinflammation. A decrease in Adipo-IR may indicate the improvement of NASH through its effect on dysfunctional adipose tissue.

[0321] Exemplary Treatment [Table 6]

[0322] In the study, drug recipients are monitored for the following outcomes: improvement in fibrosis (e.g., a reduction in fibrosis score by liver histology in post-treatment samples compared to baseline samples), improvement in NASH (e.g., a reduction in NASH score by liver histology in post-treatment samples compared to baseline samples), and / or reduction in Adipo-IR.

[0323] Example 4: Treatment of NAFLD / NASH Treatment of NAFLD / NASH is evaluated in subjects administered a composition comprising butyric acid and tocopherol acetate.

[0324] A total of 100 patients will be recruited. Patients will have NAFLD / NASH and / or related liver inflammation and / or cirrhosis, and will have no contraindications to butyrate. Patients will receive either a formulation containing 600 mg of sodium butyrate and tocopherol acetate (12 mg of an acetic acid source and 200 IU of vitamin E) two to three times daily, or a placebo.

[0325] Subjects are followed for a median of 5 years. Immediately prior to treatment, patients are screened for ALT / AST, GGT; liver stiffness by FibroScan; and blood pro- and anti-inflammatory cytokines (e.g., TNFα, IFN-γ, IL-2, IL-4, IL-5-IL-10). Screening is repeated annually until study completion. Patients are analyzed by multivariate analysis for the incidence of chronic liver disease (hepatitis and fibrosis), liver cancer, chronic liver disease-related death (usually due to cirrhosis), or transplantation in treated and untreated cohorts.

[0326] Exemplary Treatment [Table 7]

[0327] In the trial, drug recipients are monitored for the following outcomes: reduced incidence of chronic liver disease (hepatitis and fibrosis), reduced incidence of liver cancer, reduced incidence of chronic, liver disease-related death (usually from cirrhosis), and / or reduced incidence of transplant in the treated cohort compared to the untreated cohort.

[0328] In the studies, drug recipients are monitored for a reduction in the expression of inflammatory cytokines or mediators or a reduction in inflammation.

[0329] The disclosures of each and every patent, patent application, and publication cited herein are incorporated herein by reference in their entirety. Although the present disclosure has been disclosed with reference to particular embodiments, it will be apparent that other embodiments and variations of the present disclosure may be devised by those skilled in the art without departing from the true spirit and scope of the present disclosure. It is intended that the appended claims be construed to include all such embodiments and equivalent variations.

[0330] Embodiment The following non-limiting embodiments provide illustrative examples of the present invention, but do not limit the scope of the invention.

[0331] Embodiment 1. A method of alleviating a condition in a subject in need thereof, comprising administering to the subject a composition comprising: (a) at least one short chain fatty acid (SCFA) or a pharmaceutically acceptable salt thereof; and (b) a reduced amount of tocopherol, wherein the reduced amount of tocopherol, in combination with the at least one SCFA or a pharmaceutically acceptable salt thereof, is therapeutically effective for alleviating the condition, and the reduced amount of tocopherol is less than the amount of tocopherol that is therapeutically effective for the condition in the absence of the at least one SCFA or a pharmaceutically acceptable salt thereof.

[0332] Embodiment 2. The method of embodiment 1, wherein the tocopherol exhibits a synergistic effect with at least one SCFA or a pharmaceutically acceptable salt thereof.

[0333] Embodiment 3. A method of providing prevention against progression of a condition to fibrosis in a subject in need thereof, comprising administering to the subject a composition comprising: (a) at least one SCFA or a pharmaceutically acceptable salt thereof, and (b) tocopherol.

[0334] Embodiment 4. The method of any one of embodiments 1 to 3, wherein the condition is a liver disease.

[0335] Embodiment 5. The method of embodiment 4, wherein the liver disease is selected from the group consisting of fatty liver disease, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), liver fibrosis, alcoholic liver disease, an autoimmune disease or disorder, cirrhosis, liver cancer, hepatocellular carcinoma, autoimmune hepatitis, primary biliary cirrhosis (PBC), primary sclerosing cholangitis, hemochromatosis, Wilson's disease, liver failure, and any combination thereof.

[0336] Embodiment 6 The method of embodiment 4, wherein the liver disease or disorder is fatty liver disease.

[0337] Embodiment 7. The method of embodiment 4, wherein the liver disease or disorder is non-alcoholic fatty liver disease (NAFLD).

[0338] Embodiment 8. The method of embodiment 4, wherein the liver disease or disorder is nonalcoholic steatohepatitis (NASH).

[0339] Embodiment 8 The method of embodiment 4, wherein the liver disease or disorder is liver fibrosis.

[0340] Embodiment 9. The method of embodiment 4, wherein the liver disease or disorder is alcoholic liver disease.

[0341] Embodiment 10. The method of embodiment 4, wherein the liver disease or disorder is cirrhosis.

[0342] Embodiment 11. The method of embodiment 4, wherein the liver disease or disorder is liver cancer.

[0343] Embodiment 12. The method of embodiment 4, wherein the liver disease or disorder is hepatocellular carcinoma.

[0344] Embodiment 13. A method of providing prevention against the progression of NASH to fibrosis in a subject in need thereof, comprising administering to the subject a composition comprising: (a) at least one SCFA or a pharmaceutically acceptable salt thereof, and (b) tocopherol.

[0345] Embodiment 14. The method of any one of embodiments 3 to 13, wherein preventing comprises reducing the likelihood of progression to fibrosis.

[0346] Embodiment 15. The method of embodiment 13 or 14, wherein preventing comprises reducing the likelihood of progression of NASH to fibrosis.

[0347] Embodiment 16. The method of any one of embodiments 3 to 14, wherein preventing comprises delaying or slowing the progression to fibrosis.

[0348] Embodiment 17. The method of any one of embodiments 13-16, wherein preventing comprises delaying or slowing the progression of NASH to fibrosis.

[0349] Embodiment 18. The method of any one of embodiments 1 to 17, wherein the composition comprises from about 100 milligrams (mg) to about 6 grams (g) of one of the SCFAs.

[0350] Embodiment 19. The method of embodiment 18, wherein the composition comprises about 2.4 grams (g) of one of the SCFAs.

[0351] Embodiment 20. The method of claim 20, wherein the at least one SCFA or a pharmaceutically acceptable salt thereof is selected from the group consisting of acetic acid, butyric acid (BA), methoxyacetic acid, valproic acid (VPA), propionic acid, 3-methoxypropionic acid, ethoxyacetic acid, formic acid, isobutyric acid, tributyrin, butyrate, propionate, N-acetylbutyrate, isovaleric acid, valeric acid, isocaproic acid, caproic acid, lactic acid, succinic acid, pyruvic acid, octanoic acid, dodecanoic acid, (4R)-4-hydroxypentanoic acid, 2-ethylhydrazine, benzoic acid ... 20. The method of any one of embodiments 1-19, wherein the hydroxybenzoate is selected from the group consisting of acrylic acid, 2-hydroxy-3-methylpentanoate, 2-hydroxy-3-methylpentanoic acid, 2-methylbut-2-enoic acid, 2-oxobutanoic acid, 3-hydroxypentanoic acid, 3-methylbut-2-enoic acid, butenoic acid, methylbutyric acid, dimethylbutyric acid, pentadienoic acid, pentenoic acid, pivalic acid, propynoic acid, a pharmaceutically acceptable salt of any of these, and any combination thereof.

[0352] Embodiment 21. The method of any one of embodiments 1 to 20, wherein the composition comprises at least one SCFA selected from the group consisting of butyrate, propionate, and acetate, or a pharmaceutically acceptable salt thereof.

[0353] Embodiment 22. The method of any one of embodiments 1 to 21, wherein the composition comprises at least one pharmaceutically acceptable salt selected from the group consisting of a Ca salt, a Mg salt, a Na salt, and any combination thereof.

[0354] Embodiment 23. The method of any one of embodiments 1 to 22, wherein the composition comprises at least two short chain fatty acids (SCFAs) or pharmaceutically acceptable salts thereof.

[0355] Embodiment 24. The method of claim 24, wherein the at least two SCFAs or pharmaceutically acceptable salts thereof are selected from the group consisting of acetic acid, butyric acid (BA), methoxyacetic acid, valproic acid (VPA), propionic acid, 3-methoxypropionic acid, ethoxyacetic acid, formic acid, isobutyric acid, tributyrin, butyrate, propionate, N-acetylbutyrate, isovaleric acid, valeric acid, isocaproic acid, caproic acid, lactic acid, succinic acid, pyruvic acid, octanoic acid, dodecanoic acid, (4R)-4-hydroxypentanoic acid, 2-ethylhexanoic acid, 2-methylbut ... 24. The method of embodiment 23, wherein the hydroxybenzoate is selected from the group consisting of hydroxybenzoate, ...

[0356] Embodiment 25. The method of any one of embodiments 1 to 24, wherein the composition comprises butyrate or a pharmaceutically acceptable salt thereof.

[0357] Embodiment 26. The method of any one of embodiments 1 to 25, wherein the composition comprises a pharmaceutically acceptable salt of butyrate, and the pharmaceutically acceptable salt of butyrate is a Ca salt, a Mg salt, or a Na salt.

[0358] Embodiment 27. The method of any one of embodiments 1 to 26, wherein the composition comprises acetate or a pharmaceutically acceptable salt thereof.

[0359] Embodiment 28. The method of any one of embodiments 1 to 27, wherein the composition comprises a pharmaceutically acceptable salt of acetate, and the pharmaceutically acceptable salt of acetate is a Ca salt, a Mg salt, or a Na salt.

[0360] Embodiment 29. The method of any one of embodiments 1 to 28, wherein the composition comprises from about 100 milligrams (mg) to about 6 grams (g) of SCFAs.

[0361] Embodiment 30. The method of embodiment 29, wherein the composition comprises about 2.4 grams (g) of SCFAs.

[0362] Embodiment 31. The method of any one of embodiments 1 to 30, wherein the composition comprises from about 1 IU to about 600 IU of tocopherol.

[0363] Embodiment 32. The method of any one of embodiments 1 to 31, wherein the composition comprises from about 1 IU to about 49.9 IU tocopherol.

[0364] Embodiment 33. The method of any one of embodiments 1 to 32, wherein the composition comprises less than about 50 IU of tocopherol.

[0365] Embodiment 34. The method of any one of embodiments 1 to 33, wherein the composition comprises from about 100.1 IU to about 600 IU of tocopherol.

[0366] Embodiment 35. The method of any one of embodiments 1 to 34, wherein the composition comprises more than about 100 IU of tocopherol.

[0367] Embodiment 36 The method of any one of embodiments 1 to 35, wherein the tocopherol is tocopherol acetate.

[0368] Embodiment 37. The method of embodiment 36, wherein the composition comprises about 1 milligram (mg) to about 100 milligrams (mg) of tocopherol acetate.

[0369] Embodiment 38. The method of embodiment 37, wherein the composition comprises about 12 milligrams (mg) of tocopherol acetate.

[0370] Embodiment 39. The method of any one of embodiments 1 to 38, wherein the composition is administered orally.

[0371] Embodiment 40. The method of any one of embodiments 1 to 39, wherein the composition is administered with food or drink.

[0372] Embodiment 41 The method of any one of embodiments 1 to 39, wherein the composition is administered with food.

[0373] Embodiment 42. The method of any one of embodiments 1 to 41, wherein the composition is a pharmaceutical composition.

[0374] Embodiment 43. The method of embodiment 42, wherein the pharmaceutical composition further comprises a pharmaceutically acceptable excipient.

[0375] Embodiment 44. The method of any one of embodiments 41-42, wherein the pharmaceutical composition further comprises an enteric coating.

[0376] Embodiment 45. The method of any one of embodiments 41 to 44, wherein the pharmaceutical composition is formulated as a tablet.

[0377] Embodiment 46. The method of any one of embodiments 41 to 45, wherein the pharmaceutical composition is formulated as a capsule.

[0378] Embodiment 47. The method of any one of embodiments 1 to 46, wherein the subject is a human.

[0379] Embodiment 48. A pharmaceutical composition comprising an active ingredient in a unit dosage form, wherein the active ingredient comprises: (a) a therapeutically effective amount of at least one SCFA or a pharmaceutically acceptable salt thereof, and (b) at least one antioxidant.

[0380] Embodiment 49. The pharmaceutical composition of embodiment 49, wherein the amount of the at least one antioxidant is a reduced amount of the at least one antioxidant, and the reduced amount of the at least one antioxidant, in combination with the at least one SCFA or a pharmaceutically acceptable salt thereof, is therapeutically effective for alleviating the condition.

[0381] Embodiment 50. The pharmaceutical composition of embodiment 48 or 49, wherein the amount of the at least one antioxidant is a reduced amount of the at least one antioxidant, wherein the reduced amount of the at least one antioxidant is less than the amount of the at least one antioxidant that is therapeutically effective for the condition in the absence of the at least one SCFA or pharmaceutically acceptable salt thereof.

[0382] Embodiment 51. A pharmaceutical composition comprising an active ingredient in a unit dosage form, wherein the active ingredient comprises: (a) a therapeutically effective amount of at least one SCFA or a pharmaceutically acceptable salt thereof, and (b) tocopherol.

[0383] Embodiment 52. The pharmaceutical composition of embodiment 51, wherein the amount of tocopherol is a reduced amount of tocopherol, which reduced amount of tocopherol, in combination with at least one SCFA or a pharmaceutically acceptable salt thereof, is therapeutically effective for alleviating the condition.

[0384] Embodiment 53. The pharmaceutical composition of embodiment 51 or 52, wherein the amount of tocopherol is a reduced amount of tocopherol, wherein the reduced amount of tocopherol is less than the amount of tocopherol that is therapeutically effective for the condition in the absence of the at least one SCFA or a pharmaceutically acceptable salt thereof.

[0385] Embodiment 54. The pharmaceutical composition of any one of embodiments 48 to 53, comprising from about 100 milligrams (mg) to about 6 grams (g) of at least one SCFA.

[0386] Embodiment 55. The pharmaceutical composition of any one of embodiments 48 to 54, comprising about 2.4 grams (g) of at least one SCFA.

[0387] Embodiment 56. A pharmaceutical composition according to any one of embodiments 48 to 55, comprising at least two SCFAs.

[0388] Embodiment 57. A pharmaceutical composition according to any one of embodiments 48 to 56, comprising butyrate or a pharmaceutically acceptable salt thereof.

[0389] Embodiment 58. A pharmaceutical composition according to any one of embodiments 48 to 57, comprising a Ca salt or butyric acid.

[0390] Embodiment 59. A pharmaceutical composition according to any one of embodiments 48 to 58, comprising a Mg salt or butyric acid.

[0391] Embodiment 60. The pharmaceutical composition of any one of embodiments 48 to 59, comprising from about 1 milligram (mg) to about 100 milligrams (mg) of at least one antioxidant.

[0392] Embodiment 61. The pharmaceutical composition of any one of embodiments 48 to 60, comprising about 12 milligrams (mg) of at least one antioxidant.

[0393] Embodiment 62. The pharmaceutical composition of any one of embodiments 48 to 61, wherein the at least one antioxidant is selected from the group consisting of vitamin C, vitamin E, beta-carotene, carotenoids, selenium, manganese, glutathione, coenzyme Q10, lipoic acid, flavonoids, phenols, polyphenols, phytoestrogens, and any combination thereof.

[0394] Embodiment 63. The pharmaceutical composition of any one of embodiments 48 to 62, wherein the antioxidant is tocopherol.

[0395] Embodiment 64. A pharmaceutical composition according to any one of embodiments 48 to 63, comprising from about 1 IU to about 600 IU of tocopherol.

[0396] Embodiment 65. A pharmaceutical composition according to any one of embodiments 48 to 64, comprising from about 1 IU to about 49.9 IU of tocopherol.

[0397] Embodiment 66. The pharmaceutical composition of any one of embodiments 48 to 65, comprising less than about 50 IU of tocopherol.

[0398] Embodiment 67. The pharmaceutical composition of any one of embodiments 48 to 66, comprising from about 100.1 IU to about 600 IU of tocopherol.

[0399] Embodiment 68. A pharmaceutical composition according to any one of embodiments 48 to 67, comprising more than about 100 IU of tocopherol.

[0400] Embodiment 69. The pharmaceutical composition of any one of embodiments 48 to 68, wherein the antioxidant is tocopherol acetate.

[0401] Embodiment 70. The pharmaceutical composition of any one of embodiments 48 to 69, wherein the antioxidant is d-alpha-tocopherol acetate.

[0402] Embodiment 71. The pharmaceutical composition of any one of embodiments 48 to 70, comprising from about 1 milligram (mg) to about 100 milligrams (mg) of tocopherol acetate.

[0403] Embodiment 72. The pharmaceutical composition of any one of embodiments 48 to 71, comprising about 12 milligrams (mg) of tocopherol acetate.

[0404] Embodiment 73. A pharmaceutical composition according to any one of embodiments 48 to 72, which is administered orally.

[0405] Embodiment 74. A pharmaceutical composition according to any one of embodiments 48 to 73, administered with food or drink.

[0406] Embodiment 75. The pharmaceutical composition of any one of embodiments 48 to 74, which is administered with food.

[0407] Embodiment 76. A pharmaceutical composition according to any one of embodiments 48 to 75, further comprising a pharmaceutically acceptable excipient.

[0408] Embodiment 77. A pharmaceutical composition according to any one of embodiments 48 to 76, further comprising an enteric coating.

[0409] Embodiment 78. The pharmaceutical composition of any one of embodiments 48 to 77, formulated as a tablet.

[0410] Embodiment 79. The pharmaceutical composition of any one of embodiments 48 to 78, formulated as a capsule.

[0411] Embodiment 80. Use of a pharmaceutical composition according to any one of embodiments 48 to 79 in the manufacture of a medicament.

[0412] Embodiment 81 The method of any one of embodiments 1 to 47, wherein administering the composition improves liver histology in a liver biopsy sample from the subject.

[0413] Embodiment 82 The method of embodiment 81, wherein administering the composition improves the NASH score in a liver biopsy sample of the subject.

[0414] Embodiment 83 The method of embodiment 81 or 82, wherein administering the composition improves the fibrosis score in a liver biopsy sample of the subject.

[0415] Embodiment 84 The method of any one of embodiments 81-83, wherein administering the composition reduces the presence of inflammatory foci in a liver biopsy sample from the subject.

[0416] Embodiment 85. The method of any one of embodiments 81-84, wherein administering the composition reduces the distribution of inflammatory foci in a liver biopsy sample from the subject.

[0417] Embodiment 86 The method of any one of embodiments 81-85, wherein administering the composition reduces the frequency of inflammatory foci in a liver biopsy sample from the subject.

[0418] Embodiment 87. The method of any one of embodiments 1-47 and 81-86, wherein administering the composition attenuates the pathogenesis of NASH in the subject.

[0419] Embodiment 88 The method of any one of embodiments 1-47 and 81-87, wherein administering the composition prevents or delays the onset of liver fibrosis in the subject.

[0420] Embodiment 89. The method of any one of embodiments 1-47 and 81-88, wherein administering the composition reduces liver inflammation in the subject.

[0421] Embodiment 90. The method of any one of embodiments 1-47 and 81-89, wherein administering the composition modulates expression of a mediator of inflammation in the subject.

[0422] Embodiment 91 The method of any one of embodiments 1-47 and 81-90, wherein administering the composition reduces expression of a mediator of inflammation in the subject.

[0423] Embodiment 92. A method of preventing or treating a liver disease or disorder in a subject in need thereof, comprising administering to the subject a composition comprising at least one compound selected from the group consisting of short chain fatty acids (SCFAs), salts of SCFAs, SCFA precursors, SCFA biosynthetic precursors, compounds comprising an SFCA moiety, derivatives of SCFAs, and any combination thereof.

[0424] Embodiment 93. The method of embodiment 92, wherein the liver disease or disorder is selected from the group consisting of fatty liver disease, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), liver fibrosis, alcoholic liver disease, an autoimmune disease or disorder, cirrhosis, liver cancer, hepatocellular carcinoma, autoimmune hepatitis, primary biliary cirrhosis (PBC), primary sclerosing cholangitis, hemochromatosis, Wilson's disease, liver failure, and any combination thereof.

[0425] Embodiment 94. A method of preventing or treating fibrosis in a subject, comprising administering to the subject a composition comprising at least one compound selected from the group consisting of short chain fatty acids (SCFAs), salts of SCFAs, SCFA precursors, SCFA biosynthetic precursors, compounds comprising an SFCA moiety, derivatives of SCFAs, and any combination thereof.

[0426] Embodiment 95. A method of preventing or treating inflammation in a subject in need thereof, comprising administering to the subject a composition comprising at least one compound selected from the group consisting of short chain fatty acids (SCFAs), salts of SCFAs, SCFA precursors, SCFA biosynthetic precursors, compounds comprising an SFCA moiety, derivatives of SCFAs, and any combination thereof.

[0427] Embodiment 96. The method of any one of embodiments 92 to 95, wherein the composition comprises from about 100 milligrams (mg) to about 6 grams (g) of at least one SCFA.

[0428] Embodiment 97. The method of embodiment 96, wherein the composition comprises about 2.4 grams (g) of at least one SCFA.

[0429] Embodiment 98. The composition comprises acetic acid, butyric acid (BA), C3-C12 fatty acids, C3-C10 fatty acids, C3-C8 fatty acids, methoxyacetic acid, valproic acid (VPA), propionic acid, 3-methoxypropionic acid, ethoxyacetic acid, formic acid, isobutyric acid, tributyrin, butyrate, propionate, N-acetylbutyrate (as well as other forms of butyrate, e.g., phenylbutyrate, isobutyrate, pivaloyloxymethylbutyrate, monoacetone glucose 3-butyrate), isovaleric acid, valeric acid, isocaproic acid, caproic acid, lactic acid, succinic acid, pyruvic acid, octadecanoic ... 97. The method of any one of embodiments 92-96, comprising at least one SCFA or salt thereof comprising at least one selected from the group consisting of: hydroxybenzoic acid, dodecanoic acid, (4R)-4-hydroxypentanoic acid, 2-ethylhydracrylic acid, 2-hydroxy-3-methylpentanoate, 2-hydroxy-3-methylpentanoic acid, 2-methylbut-2-enoic acid, 2-oxobutanoic acid, 3-hydroxypentanoic acid, 3-methylbut-2-enoic acid, butenoic acid, methylbutyric acid, dimethylbutyric acid, pentadienoic acid, pentenoic acid, pivalic acid, propynoic acid, and any combination thereof.

[0430] Embodiment 99. The method of embodiment 98, wherein the salt of at least one SCFA comprises at least one selected from the group consisting of butyrate, propionate, and acetate.

[0431] Embodiment 100. The method of embodiment 98, wherein the salt of at least one SCFA comprises at least one selected from the group consisting of a Ca salt of an SCFA, a Mg salt of an SCFA, and any combination thereof.

[0432] Embodiment 101. The method of embodiment 98, wherein the salt of the at least one SCFA comprises at least one selected from the group consisting of a Ca salt of butyric acid, a Mg salt of butyric acid, a Ca salt of acetic acid, a Mg salt of acetic acid, and any combination thereof.

[0433] Embodiment 102. The method of any one of embodiments 92 to 101, wherein the composition comprises from about 100 milligrams (mg) to about 6 grams (g) of a calcium salt of butyric acid, a magnesium salt of butyric acid, a calcium salt of acetic acid, a magnesium salt of acetic acid, or any combination thereof.

[0434] Embodiment 103. The method of embodiment 102, wherein the composition comprises about 2.4 grams (g) of a Ca salt of butyric acid, a Mg salt of butyric acid, a Ca salt of acetic acid, a Mg salt of acetic acid, or any combination thereof.

[0435] Embodiment 104. The method of any one of embodiments 92-103, wherein the composition further comprises at least one antioxidant.

[0436] Embodiment 105. The method of embodiment 104, wherein the composition comprises from about 1 milligram (mg) to about 100 milligrams (mg) of at least one antioxidant.

[0437] Embodiment 106. The method of embodiment 105, wherein the composition comprises about 12 milligrams (mg) of at least one antioxidant.

[0438] Embodiment 107. The method of embodiment 106, wherein the antioxidant comprises at least one selected from the group consisting of vitamin C, vitamin E, beta-carotene, carotenoids, selenium, manganese, glutathione, coenzyme Q10, lipoic acid, flavonoids, phenols, polyphenols, phytoestrogens, and any combination thereof.

[0439] Embodiment 108. The method of embodiment 107, wherein the antioxidant is vitamin E.

[0440] Embodiment 109. The method of embodiment 108, wherein the vitamin E comprises tocopherol acetate.

[0441] Embodiment 110. The method of embodiment 109, wherein the composition comprises from about 1 milligram (mg) to about 100 milligrams (mg) of tocopherol acetate.

[0442] Embodiment 111. The method of embodiment 110, wherein the composition comprises about 12 milligrams (mg) of tocopherol acetate.

[0443] Embodiment 112. The method of any one of embodiments 92 to 111, wherein the composition is an enteric-coated sustained-release capsule.

[0444] Embodiment 113. The method of any one of embodiments 92 to 112, wherein the composition is a pharmaceutical composition.

Claims

1. 1. A method of alleviating a condition in a subject in need thereof, comprising administering to said subject: a. at least two short chain fatty acids (SCFAs) or pharmaceutically acceptable salts thereof, and b. a reduced amount of tocopherol; the reduced amount of tocopherol in combination with the at least two SCFAs or pharmaceutically acceptable salts thereof is therapeutically effective to alleviate the condition; The method, wherein the reduced amount of tocopherol is less than the amount of tocopherol that would be therapeutically effective for the condition in the absence of the at least two SCFAs or pharmaceutically acceptable salts thereof.

2. 10. The method of claim 1, wherein the condition is liver disease.

3. 3. The method of claim 2, wherein the liver disease is selected from the group consisting of fatty liver disease, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), liver fibrosis, alcoholic liver disease, autoimmune diseases or disorders, cirrhosis, liver cancer, hepatocellular carcinoma, autoimmune hepatitis, primary biliary cirrhosis (PBC), primary sclerosing cholangitis, hemochromatosis, Wilson's disease, liver failure, and any combination thereof.

4. The method according to any one of claims 1 to 3, wherein the tocopherol exhibits a synergistic effect with the at least two SCFAs or pharmaceutically acceptable salts thereof.

5. 1. A method of providing prevention against progression of NASH to fibrosis in a subject in need thereof, comprising administering to the subject: a. at least one SCFA or a pharmaceutically acceptable salt thereof, and b. tocopherol.

6. 6. The method of claim 5, wherein said prevention comprises reducing the likelihood of NASH progressing to fibrosis.

7. 7. The method of claim 5 or 6, wherein the prevention comprises delaying or slowing the progression of NASH to fibrosis.

8. 8. The method of any one of claims 1 to 7, wherein the composition comprises from about 100 milligrams (mg) to about 6 grams (g) of one of the SCFAs.

9. 9. The method of claim 8, wherein the composition comprises about 2.4 grams (g) of one of the SCFAs.

10. The two SCFA or pharmaceutically acceptable salts thereof are acetic acid, butyric acid (BA), methoxyacetic acid, valproic acid (VPA), propionic acid, 3-methoxypropionic acid, ethoxyacetic acid, formic acid, isobutyric acid, tributyrin, butyrate, propionate, N-acetylbutyrate, isovaleric acid, valeric acid, isocaproic acid, caproic acid, lactic acid, succinic acid, pyruvic acid, octanoic acid, dodecanoic acid, (4R)-4-hydroxypentanoic acid, 2-ethylhydracrylic acid 10. The method of any one of claims 1 to 9, wherein the hydroxybenzoate is selected from the group consisting of 2-hydroxy-3-methylpentanoate, 2-hydroxy-3-methylpentanoic acid, 2-methylbut-2-enoic acid, 2-oxobutanoic acid, 3-hydroxypentanoic acid, 3-methylbut-2-enoic acid, butenoic acid, methylbutyric acid, dimethylbutyric acid, pentadienoic acid, pentenoic acid, pivalic acid, propynoic acid, a pharmaceutically acceptable salt of any of these, and any combination thereof.

11. 11. The method of any one of claims 1 to 10, wherein at least one of the SCFAs is a pharmaceutically acceptable salt selected from the group consisting of butyrate, propionate, and acetate.

12. 12. The method of any one of claims 1 to 11, wherein at least one of the SCFAs is a pharmaceutically acceptable salt selected from the group consisting of a Ca salt, a Mg salt, a Na salt, and any combination thereof.

13. 13. The method of any one of claims 1 to 12, wherein one of the SCFAs is butyrate or a pharmaceutically acceptable salt thereof.

14. 14. The method of claim 13, wherein the SCFA is a pharmaceutically acceptable salt of butyrate, and the pharmaceutically acceptable salt of butyrate is a Ca salt and an Mg salt.

15. The method of any one of claims 1 to 14, wherein the composition comprises acetate or a pharmaceutically acceptable salt thereof.

16. 16. The method of claim 15, wherein the composition comprises a pharmaceutically acceptable salt of acetate, wherein the pharmaceutically acceptable salt of acetate is a Ca salt or an Mg salt.

17. 17. The method of any one of claims 1-16, wherein the composition comprises about 100 milligrams (mg) to about 6 grams (g) of a Ca butyric acid salt, a Mg butyric acid salt, a Ca acetic acid salt, a Mg acetic acid salt, or any combination thereof.

18. 18. The method of claim 17, wherein the composition comprises about 2.4 grams (g) of a Ca salt of butyric acid, a Mg salt of butyric acid, a Ca salt of acetic acid, a Mg salt of acetic acid, or any combination thereof.

19. 19. The method of any one of claims 1 to 18, wherein the composition comprises from about 1 IU to about 600 IU of the tocopherol.

20. 20. The method of any one of claims 1 to 19, wherein the tocopherol is tocopherol acetate.

21. 21. The method of claim 20, wherein the composition comprises from about 1 milligram (mg) to about 600 milligrams (mg) of tocopherol acetate.

22. 22. The method of claim 20 or 21, wherein the composition comprises about 1 milligram (mg) to about 100 milligrams (mg) of tocopherol acetate.

23. 23. The method of any one of claims 20-22, wherein the composition comprises about 12 milligrams (mg) of tocopherol acetate.

24. 24. The method of any one of claims 1 to 23, wherein the composition is an enteric coated sustained release capsule.

25. The method of any one of claims 1 to 24, wherein the composition is a pharmaceutical composition.

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