Methods of treating or preventing liver diseases or conditions

Abstract

The present invention relates to compositions and methods comprising short chain fatty acids (SCFAs), such as various butyrates and acetates, in combination with antioxidants, such as vitamin E, the compositions and methods are useful for treating or preventing liver diseases or conditions, such as non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), fibrosis, and other similar diseases or conditions.

Description

[0001] Cross-references

[0002] This application claims the benefit of U.S. Provisional Application No. 63 / 383,175, filed November 10, 2022, which is incorporated herein by reference in its entirety. Background Art

[0003] Nonalcoholic steatohepatitis (NASH) is an advanced form of nonalcoholic fatty liver disease (NAFLD) characterized by fat accumulation, inflammation, hepatocellular damage, and varying degrees of fibrosis, which may progress to nonalcoholic steatohepatitis (NASH), cirrhosis, and / or hepatocellular carcinoma (HCC).

[0004] Many drug candidates have failed to show clear benefit. Most likely, none of the molecules currently under investigation are expected to provide significant improvement in NASH in even a small number of patients. This is because, given the complex pathogenesis of NASH, existing drug candidates are all intended as single-agent NASH therapies and appear unlikely to succeed due to compensatory mechanisms that may weaken the drug's effect.

[0005] Therefore, there is a need in the art for effective compositions and methods for treating or preventing liver diseases or conditions such as NAFLD, NASH, fibrosis, and other similar diseases or conditions. The present disclosure addresses this unmet need.

[0006] Incorporated by Reference

[0007] 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

[0008] Disclosed herein is a method of alleviating a condition in a subject in need thereof, wherein the method comprises 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.

[0009] Disclosed herein is a method of providing prevention of progression of a condition to fibrosis in a subject in need thereof, wherein the method comprises administering to the subject a composition comprising: (a) at least one SCFA or a pharmaceutically acceptable salt thereof; and (b) tocopherol.

[0010] Disclosed herein is a method of providing prevention of progression of NASH to fibrosis in a subject in need thereof, wherein the method comprises administering to the subject a composition comprising: (a) at least one SCFA or a pharmaceutically acceptable salt thereof; and (b) tocopherol.

[0011] Disclosed herein is 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. BRIEF DESCRIPTION OF THE DRAWINGS

[0012] Figure 1 Shown are the weights of mice from the start of treatment on day 0 until euthanasia on day 81.

[0013] Figure 2 Shown are the mean histopathology scores for mice fed high-dose SCFA, low-dose SCFA, or no drug.

[0014] Figure 3 Shown are the mean histopathology scores for mice fed high-dose SCFA, low-dose SCFA, or no drug.

[0015] Figure 4 Shown are representative H&E staining of inflammatory infiltrates characteristic of NASH in liver samples from control mice (Group 5) fed a high-fat diet and euthanized at 76 weeks of age.

[0016] Figure 5 Shown are representative H&E staining of inflammatory infiltrates characteristic of NASH in liver samples from control mice (Group 6) fed a high-fat diet and euthanized at 84 weeks of age.

[0017] Figure 6 Shown are representative H&E staining of inflammatory infiltrates characteristic of NASH in liver samples from mice fed a high dose of SCFA and euthanized at 76 weeks of age (Group 1).

[0018] Figure 7 Shown are representative H&E staining of inflammatory infiltrates characteristic of NASH in liver samples from mice fed a high dose of SCFA and euthanized at 84 weeks of age (Group 3).

[0019] Figure 8 Shown are representative Masson's trichrome staining of fibrosis in liver samples from control mice (Group 5) fed a high-fat diet and euthanized at 76 weeks of age.

[0020] Figure 9 Shown are representative Masson's trichrome staining of fibrosis in liver samples from mice fed a high dose of SCFA and euthanized at 76 weeks of age (Group 1). DETAILED DESCRIPTION

[0021] The present disclosure is based on the following unexpected results: the combination of Ca salt / Mg salt of butyric acid and tocopheryl acetate provides effective treatment for NASH with or without fibrosis. Therefore, in some aspects, the present disclosure provides a method for preventing or treating liver disease, fibrosis or inflammation using a composition comprising at least one compound selected from the following: short-chain fatty acids (SCFAs), salts of SCFAs, SCFA precursors, SCFA biosynthesis precursors, compounds comprising an SFCA portion, derivatives of SCFAs, or any combination thereof. In some embodiments, the salts of SCFAs include Ca salts of SCFAs (e.g., Ca salts of butyric acid, Ca salts of acetate, etc.), Mg salts of SCFAs (e.g., Mg salts of butyric acid, Mg salts of acetate, etc.), or any combination thereof. In some embodiments, the composition further comprises at least one antioxidant (e.g., vitamin E, tocopheryl acetate, etc.).

[0022] In one embodiment, the subject is a human. In one embodiment, the subject is a non-human animal.

[0023] Provided herein are compositions and methods for treating conditions (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 SCFA, a SCFA precursor, a SCFA biosynthetic precursor, a composition comprising an SFCA portion, a derivative of 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 administering, for example, a second pharmaceutical composition.

[0024] definition

[0025] It should be understood that the accompanying drawings and description of the present disclosure have been simplified to illustrate the elements relevant to a clear understanding of the present disclosure, while many other elements that can be found in the present disclosure have been removed for clarity. Those of ordinary skill in the art will recognize that, when implementing the present disclosure, it is desirable and / or necessary to have other elements and / or steps. However, since such elements and steps are well known in the art and since they will not be conducive to a better understanding of the present disclosure, the discussion of such elements and steps is not provided herein. Disclosure herein relates to all such variations and modifications of such elements and methods known to those skilled in the art.

[0026] 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 any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present disclosure, exemplary methods and materials are described.

[0027] As used herein, each of the following terms has the meaning associated with it in this section.

[0028] 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. For example, "an element" means one element or more than one element.

[0029] As used herein, "about" when referring to a measurable value, such as an amount, a length of time, etc., is intended to encompass deviations of ±20%, ±10%, ±5%, ±1%, or ±0.1% from the specified value, as long as such deviations are appropriate.

[0030] The term "abnormal" when used in the context of organisms, tissues, cells, or components thereof, refers to those organisms, tissues, cells, or components thereof that differ from those organisms, tissues, cells, or components thereof that exhibit the corresponding characteristic as "normal" (expected) with respect to at least one observable or detectable characteristic (e.g., age, treatment, time of day, etc.). A characteristic that is normal or expected for one cell or tissue type may be abnormal for another cell or tissue type.

[0031] 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, which may be dissolved or mixed in the same pharmaceutically acceptable carrier, for example, or administration of the first agent followed by the second agent, or administration of the second agent followed by the first agent.

[0032] The term "concomitant" as in the phrase "concomitant therapeutic treatment" includes administering an agent in the presence of a second agent. Concomitant therapeutic treatment methods include methods of administering a first agent, a second agent, a third agent, or other agents together. Concomitant therapeutic treatment methods also include methods of administering a first agent or other agent in the presence of a second agent or other agent, wherein, for example, the second agent or other agent may have been administered previously. Concomitant therapeutic treatment methods can be implemented step by step by different participants. For example, one participant can administer the first agent to the subject and a second participant can administer the second agent to the subject, and the administration steps can be implemented simultaneously, or almost simultaneously, or at very distant times, as long as the first agent (and other agents) are administered in the presence of the second agent (and other agents). The participant and the subject can be the same entity (e.g., human).

[0033] As used herein, the term "combination therapy" refers to a combination of two or more therapies, two or more therapeutic agents, or at least one therapeutic agent and at least one of the therapies such as radiation therapy, immunotherapy, and chemotherapy.

[0034] A "disease" is a health condition in an animal in which the animal is unable to maintain homeostasis and the animal's health continues to deteriorate unless the disease is ameliorated.

[0035] 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 state of health is less than it would be in the absence of the disorder. The disorder does not necessarily cause a further decline in the animal's state of health if left untreated.

[0036] A subject is "at risk for a condition" if the individual has an increased likelihood of developing the condition compared to a population (e.g., the general population, a population of similar age, a population of the same sex). The increased likelihood may be due to one factor or a combination of factors, including the presence of a particular allele / gene mutation or exposure to a particular environment.

[0037] The term "cancer," as used herein, is defined as a disease characterized by the rapid and uncontrolled growth of abnormal cells. Cancer cells can spread locally or to other parts of the body through 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, colorectal cancer, bladder cancer, kidney cancer, brain cancer, lymphoma, leukemia, and lung cancer, among others.

[0038] A disease or condition is "alleviated" if the severity of the signs or symptoms of the disease or condition, the frequency with which the patient experiences such signs or symptoms, or both, is reduced.

[0039] As used herein, the term "inhibit" means inhibiting or blocking an activity or function by at least about 10% relative to a control value. As an example, an activity is inhibited or blocked by 50%, 75% or 95% or more compared to a control value.

[0040] The terms "treatment" and "treating" and the like are generally used herein to mean obtaining a desired pharmacological and / or physiological effect. The effect may be prophylactic, in terms of completely or partially preventing a disease or condition or its symptoms, and / or therapeutic, in terms of partially or completely curing a disease or condition and / or adverse effects attributable to the disease or condition. The term "treatment" as used herein includes any treatment of a disease or condition in a subject, and includes: (a) preventing the occurrence of the disease or condition in a subject that may be susceptible to the disease or condition; (b) inhibiting the disease or condition, i.e., arresting its development; or (c) alleviating the disease or condition, i.e., causing regression of the disease or condition.

[0041] The terms "effective amount" and "pharmaceutically effective amount" refer to an amount of an agent sufficient to provide a desired biological result. The result can be a reduction and / or alleviation of the signs, symptoms or causes of a disease or condition or any other desired alteration of a biological system.

[0042] "Therapeutically effective amount" refers to an amount that provides a therapeutic effect for a given condition and dosing regimen. In particular, "therapeutically effective amount" means an amount that can effectively prevent, alleviate or improve the symptoms of a disease or condition or prolong the survival of the treated subject (which can be a human or non-human animal).

[0043] 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 administration of the compound to an organism. Various techniques for administering compounds exist in the art, including but not limited to intravenous administration, oral administration, aerosol administration, parenteral administration, ocular administration, pulmonary administration, and topical administration.

[0044] "Pharmaceutically acceptable" refers to those properties and / or materials that are acceptable to patients from a pharmacological / toxicological point of view and to pharmaceutical manufacturing chemists from a physical / chemical point of view (with respect to composition, formulation, stability, patient acceptance and bioavailability).

[0045] As used herein, the term "pharmaceutically acceptable carrier" means 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 used to carry or transport a compound useful in the compositions disclosed herein within a patient's body or to deliver the compound to a patient so that it can function as intended. Typically, such constructs are carried or transported from one organ or body part to another. Each carrier must be "acceptable" in the sense that it is compatible with the other ingredients in the formulation (including the compounds useful in the compositions disclosed herein) and is 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; powdered gum tragacanth; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; 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; ethanol; phosphate buffered saline; and other nontoxic, compatible substances used in pharmaceutical formulations. As used herein, "pharmaceutically acceptable carrier" also includes any and all coatings, antibacterial and antifungal agents, and absorption delaying agents that are compatible with the activity of the compounds useful in the compositions disclosed herein and that are physiologically acceptable to the patient. Supplementary active compounds can also be introduced into the compositions. "Pharmaceutically acceptable carrier" can further include pharmaceutically acceptable salts of the compounds useful in the compositions disclosed herein. Other additional ingredients that may be included in the pharmaceutical compositions used in the practice of the present disclosure are known in the art and are described in, for example, Remington's Pharmaceutical Sciences (Genaro, ed., Mack Publishing Co., 1985, Easton, PA), which is incorporated herein by reference.

[0046] The term "nutritional composition" may refer to a food product intended for human consumption, for example, a beverage, a drink, an energy bar, a snack, an ice cream, a dairy product such as a refrigerated dairy product or a shelf-stable dairy product, a fermented dairy product, a drink such as a milk-based drink, an infant formula, a growing-up milk, a confectionery product, a chocolate, a cereal product such as a breakfast cereal, a sauce, a soup, an instant drink, a frozen product intended for consumption after heating in a microwave or a conventional oven, a ready-to-eat product, a fast food meal or a nutritional formula.

[0047] The terms "patient," "subject," and "individual" and the like are used interchangeably herein and refer to any animal or cell thereof suitable for use in the methods described herein, whether in vitro or in situ. A patient, subject, or individual can be a human or non-human animal.

[0048] As used herein, the term "container" includes any receptacle for holding a pharmaceutical composition. For example, in one embodiment, the container is a packaging comprising a pharmaceutical composition. In other embodiments, the container is not a packaging comprising a pharmaceutical composition, that is, the container is a box or bottle or other receptacle comprising a packaged pharmaceutical composition or an unpackaged pharmaceutical composition and the instructions for use of the pharmaceutical composition. In addition, packaging technology is well known in the art. It should be understood that the instructions for use of the pharmaceutical composition may be included in the packaging comprising the pharmaceutical composition, and therefore, the instructions have formed an enhanced functional relationship with the packaged product. However, it should be understood that the instructions may include information related to the ability of the compound to perform its intended function (for example, to treat or prevent a disease in a subject).

[0049] As used herein, the term "instructional materials" includes publications, records, charts, or any other medium of expression that can be used to convey the usefulness of the components of the present disclosure in the kit for identifying or alleviating or treating the various diseases or conditions described herein. Optionally or alternatively, the instructional materials can describe one or more methods of identifying or alleviating a disease or condition in a subject's cells or tissues. The instructional materials of the kit can be, for example, affixed to a container comprising the composition or transported with a container comprising the composition.

[0050] Alternatively, the instructional material may be shipped separately from the container, with the intention that the recipient use the instructional material and the composition together.

[0051] Scope: Throughout this disclosure, various aspects of the disclosure may be presented in range format. It should be understood that the description in range format is only for convenience and brevity and should not be interpreted as a rigid limitation on the scope of the disclosure. Therefore, the description of a range should be considered to have specifically disclosed all possible sub-ranges and individual numerical values within the range. For example, the description of a range (e.g., 1 to 6) should be considered to have specifically disclosed sub-ranges (e.g., 1 to 3, 1 to 4, 1 to 5, 2 to 4, 2 to 6, 3 to 6, etc.) and individual numbers within the range (e.g., 1, 2, 2.7, 3, 4, 5, 5.3, and 6). This applies no matter how wide the range is.

[0052] describe

[0053] The present disclosure is based on the following unexpected results: the combination of Ca salt / Mg salt of butyric acid and tocopheryl acetate provides an effective treatment for NASH with or without fibrosis. Therefore, in some aspects, the present disclosure provides a method for preventing or treating liver disease, fibrosis or inflammation using a composition comprising at least one compound selected from the following: short-chain fatty acids (SCFAs), salts of SCFAs, SCFA precursors, SCFA biosynthesis precursors, compounds comprising SFCA moieties, derivatives of SCFAs, or any combination thereof. In some embodiments, the salts of SCFAs include Ca salts of SCFAs (e.g., Ca salts of butyric acid, Ca salts of acetate, etc.), Mg salts of SCFAs (e.g., Mg salts of butyric acid, Mg salts of acetate, etc.), or any combination thereof. In some embodiments, the composition further comprises at least one antioxidant (e.g., vitamin E, tocopheryl acetate, etc.).

[0054] In one embodiment, the subject is a human. In one embodiment, the subject is a non-human animal.

[0055] The present disclosure provides a method for treating or preventing liver disease, fibrosis, and / or inflammation in a subject in need thereof by administering to the subject a therapeutically effective amount of 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, or any combination thereof.

[0056] Liver disease

[0057] Liver diseases and conditions include, for example, nonalcoholic steatohepatitis (NASH). NASH is a growing public health threat worldwide because it can progress to fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). NASH is associated with chronic inflammatory conditions such as type 2 diabetes and obesity.

[0058] NAFLD / NASH currently affects hundreds of millions of people. NAFLD / NASH is a growing global epidemic, and current treatments 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 needs and attractive commercial opportunities, there are no FDA-approved therapies for NASH. Many pharmaceutical companies have tried, but unfortunately, have failed to develop drugs that can address the complexity of this disease.

[0059] The present disclosure provides methods and compositions with much higher treatment success rates than current treatment approaches. More specifically, the present disclosure provides compositions comprising a combination of butyrate and acetate in addition to antioxidants (e.g., vitamin E) that simultaneously target multiple mechanisms related to the pathogenesis of NASH, providing effective and safe treatment results. Thus, the present disclosure provides compositions for treating NASH with or without fibrosis.

[0060] In some embodiments, a composition disclosed herein is administered to a subject to prevent disease progression of a liver disease or disorder. In some embodiments, a composition disclosed herein is administered to a subject to delay disease progression of a liver disease or disorder.

[0061] In some embodiments, the compositions disclosed herein are administered to a subject for treating a liver disease or disorder. In some embodiments, the compositions disclosed herein are administered to a subject for preventing a liver disease or disorder.

[0062] In some embodiments, a composition disclosed herein is administered to a subject determined to be at risk for developing a liver disease or disorder.

[0063] 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), chronic liver disease associated with hepatitis B, dysplasia, autoimmune hepatitis, primary biliary cirrhosis (PBC), primary sclerosing cholangitis, hemochromatosis, Wilson's disease, liver failure, or any combination thereof.

[0064] In some embodiments, the compositions disclosed herein are administered to a subject for the treatment or prevention of an inflammatory condition. In some embodiments, the compositions disclosed herein are administered to a subject for the treatment or prevention of a chronic inflammatory condition. Non-limiting examples of chronic inflammatory conditions include type 2 diabetes and obesity.

[0065] Short-chain fatty acids (SCFAs)

[0066] "Short-chain fatty acids" (SCFAs) are fatty acids that generally have an aliphatic tail that is shorter than the aliphatic tail of long-chain fatty acids. Short-chain fatty acids can be derivatized to provide salts or esters thereof, for example, pharmaceutically acceptable salts and esters of fatty acids (e.g., sodium butyrate, arginine butyrate).

[0067] In some embodiments, the composition comprises from about 100 milligrams (mg) to about 100 grams (g) of at least one SCFA. In some embodiments, the composition comprises from about 100 milligrams (mg) to about 6 grams (g) of at least one SCFA. In some embodiments, the composition comprises from about 1 gram (g) to about 6 grams (g) of at least one SCFA. In some embodiments, the composition comprises from about 1 gram (g) to about 4 grams (g) of at least one SCFA. In some embodiments, the composition comprises from about 2 grams (g) to about 4 grams (g) of at least one SCFA. In some embodiments, the composition comprises from 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.

[0068] 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.

[0069] In some embodiments, a composition disclosed herein comprises 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.

[0070] In one embodiment, the composition comprises at least one SCFA, a salt thereof, or a compound containing a SCFA portion. In some embodiments, the composition disclosed herein comprises at least one SCFA. In some embodiments, the composition disclosed herein comprises at least one short-chain fatty acid (SCFA), a SCFA precursor, a SCFA biosynthetic precursor, a derivative thereof, a SCFA portion, or a combination thereof.

[0071] In some embodiments, the compositions disclosed herein comprise at least one SCFA or a compound containing a 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.

[0072] Non-limiting examples of SCFAs, salts thereof, or SCFA moieties include: acetate, butyrate (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 (and other forms of butyrate, e.g., phenylbutyrate, isobutyrate, pivaloyloxymethylbutyrate, monoacetone glucose 3-butyrate), isovaleric acid, valeric acid, isocaproic acid, hexanoic acid, lactic acid, succinic acid, pyruvic acid, octanoic acid, dodecanoic acid, (4R)-4-hydroxyvaleric acid, 2-(hydroxymethyl)butanoic acid (2-ethylhydracrylic acid). acid), 2-hydroxy-3-methylvaleric acid, 2-hydroxy-3-methylvaleric acid, 2-methylbut-2-enoic acid, 2-oxobutyric acid, 3-hydroxyvaleric acid, 3-methylbut-2-enoic acid, butenoic acid, methylbutyric acid, dimethylbutyric acid, glutadienoic acid, pentenoic acid, pivalic acid, propiolic acid, or any combination thereof.

[0073] In one embodiment, the composition comprises a salt of a SCFA or a derivative thereof. For example, in one embodiment, the salt of a SCFA comprises 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 comprises one or more of magnesium butyrate and calcium butyrate.

[0074] In some embodiments, butyrate can (1) enhance peroxisome proliferator-activated receptor (PPAR) signaling (where PPARs regulate the expression of genes involved in fatty acid β-oxidation, glucose metabolism, inflammatory responses, and are master regulators of energy homeostasis), (2) inhibit proinflammatory 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 initiation of fibrotic responses), (3) improve insulin sensitivity, (4) promote the expression of GLP-1R (where GLP-1 regulates glucose homeostasis, gastric motility, and food intake), and / or (5) inhibit the development of fibrosis (as evidenced by reduced liver 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 damage by preventing mitochondrial toxicity and blocking intrinsic apoptotic pathways. Unlike other treatments that are generally based on single-channel drugs, the present disclosure provides broad multi-channel protection.

[0075] 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 a crucial role in intestinal epithelial nutrition and maintaining immune homeostasis (Sanna et al., 2019; Van der Hee et al., 2021). SCFAs enter the liver directly via the portal vein, and there are several possible mechanisms by which SCFAs may mitigate the progression of NASH / NAFLD. For example, in the liver, SCFAs (including butyrate and acetate) induce AMP-activated protein kinase (AMPK) activation and inhibit macrophage proinflammatory activation, thereby alleviating hepatic steatosis.

[0076] In mice fed SCFAs, there is a two-fold increase in hepatic lipid oxidation, shifting hepatic lipid metabolism toward a more oxidative state. This shift is associated with increased phosphorylation and activation of AMPK, the most important regulator of energy homeostasis, and its downstream target acetyl-CoA carboxylase (ACC) (den Besten et al., 2015; Kim et al., 2016).

[0077] Butyrate and acetate also increase the transcriptional expression of adiponectin and resistin (both of which are hormones derived from adipose tissue that play a key role in preventing insulin resistance, diabetes, and obesity) in obese mice through epigenetic regulation (DNA methylation) (Dai et al., 2020); reduce the expression of lipogenic genes (via 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 effective natural HDAC inhibitor (Waldecker et al., 2008). In a mouse model, oral administration of butyrate significantly reduced hepatic steatosis and inflammation in NASH mice induced by a Western diet (Jin et al., 2015) and in NASH mice induced by a fat-fructose-cholesterol-rich diet (Baumann et al., 2020). Vinolo et al. (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).

[0078] PPARs are nuclear receptors that regulate the expression of genes involved in fatty acid β-oxidation, glucose metabolism, and inflammatory responses (acting on NF-kB and AP1 transcription factors) and are major regulators of energy homeostasis. In animal models of steatosis and steatohepatitis, PPAR activators were used to improve disease outcomes (Caligiuri et al., 2016). Butyrate prevents high-fat diet-induced obesity by a PPARγ-dependent shift 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 (FFA)) causes cellular stress and induces specific signals that trigger hepatocyte apoptosis. Strong evidence supports the key role of the proinflammatory 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 not only mediates early liver damage but also mediates the transition to more advanced liver damage (Crespo et al., 2001; Hotamisligil et al., 1993). Butyrate inhibits TNF-α (and thus inflammation), and one of the mechanisms is to promote its mRNA degradation (Fukae et al., 2005).

[0079] Other upregulated proinflammatory cytokines involved in the pathogenesis of NASH include IL-1β, IL-12, CCL2, and CCL5. The latter two recruit macrophages (and other inflammatory cells) and induce hepatic stellate cell activation, initiating a fibrotic response (Marra et al., 2014). CCR2 and CCR5 expression have been shown to be upregulated in the body and liver of obese patients with severe steatosis and NASH. Human data show that patients with NAFLD have higher serum levels of CCL2, and this is positively correlated with the patient's liver fat content (Braunersreuther et al., 2012).

[0080] In NASH patients, elevated intrahepatic CCL5 mRNA levels are associated with more severe fibrosis (Berres et al., 2010). In a HFD-induced NASH mouse model, high intrahepatic CCL5 levels were significantly reduced by butyrate (Gart et al., 2021). Clinical studies in patients with NAFLD have shown that glucagon-like peptide 1 receptor (GLP-1R) agonists reduce liver fat content. GLP-1R agonists enhance glucose-stimulated insulin secretion and inhibit glucagon secretion and are one of the few hypoglycemic agents that lead to weight loss, thereby improving hepatic steatosis. In obese mice fed a high-fat diet (HFD), butyrate stimulates 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 inhibited the development of fibrosis, as evidenced by reduced liver collagen content in liver histopathology.

[0081] 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 (via 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 disorders (Aoki et al., 2021).

[0082] A few animal studies have shown that acetate supplementation reduces hepatic lipogenesis and fatty acid absorption and protects mice from HFD-induced weight gain, steatosis, and insulin resistance (Weitkunat et al., 2017; Hernández et al., 2019). Furthermore, activation of hepatic FFAR2 by acetate may represent a promising therapeutic strategy for NAFLD / NASH (Aoki et al., 2021). In an elegant mouse study using PET-CT, it was shown that intravenously and colonically administered 11C-acetate can cross the blood-brain barrier and be absorbed in the hypothalamus. This absorption leads to reduced food intake through appetite suppression, accompanied by increased production of lactate and gamma-aminobutyric acid (Frost et al., 2014).

[0083] In addition, in humans, acetate can also cross the blood-brain barrier and be metabolized in the brain ([2-13C]acetate was administered to subjects for 2 hours and the brain was scanned using magnetic resonance spectroscopy) (Jiang et al., 2013). There are data from small human clinical studies showing the beneficial effects of acetate (Kondo et al., 2009).

[0084] In some embodiments, the salt of the SCFA comprises at least one Ca salt of the SCFA, a Mg salt of the SCFA, a 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, a Mg salt of butyric acid, a Na salt of butyric acid, a Ca salt of acetic acid, a Mg salt of acetic acid, a Na salt of acetic acid, or any combination thereof.

[0085] 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, SCFAs or SCFA moieties include compounds or structures having less than 13 carbon atoms, less than 12 carbon atoms, less than 11 carbon atoms, less than 10 carbon atoms, less than 9 carbon atoms, less than 8 carbon atoms, or less than 7 carbon atoms. In one embodiment, the SCFAs or SCFA moieties are not branched-chain fatty acids. In one embodiment, the SCFAs or SCFA moieties are branched-chain fatty acids.

[0086] In one embodiment, the composition comprises at least one compound comprising a precursor or portion thereof of a SCFA. In one embodiment, the precursor or portion thereof is selected from the group consisting of, but not limited to, plant cell wall polysaccharides, dietary non-starch polysaccharides (NSP), lactate, succinate, formate, 1,2-propanediol (1,2-propenedol), tryptamine, indole, indole-3-acetate, and combinations thereof.

[0087] In one embodiment, the composition comprises at least one compound comprising a biosynthetic precursor or portion thereof of a SCFA. In one embodiment, the biosynthetic precursor or portion thereof is selected from the group consisting of, but not limited to, an acetyl-CoA carboxylase inhibitor, an adenosine monophosphate kinase (AMPK) activator, vitamin D, and combinations thereof.

[0088] antioxidants

[0089] Vitamin E is a fat-soluble antioxidant that blocks the production of ROS formed when fat undergoes oxidation. The eight forms of vitamin E include four tocopherols (α-, β-, γ-, and δ-tocopherol) and four tocotrienols (α-, β-, γ-, and δ-tocotrienol), which have different levels of biological activity.

[0090] Tocopherols are organic compounds comprising 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-racemic α-tocopherol, dl-tocopherol, dl-tocopherol acetate, tocopherol acetate, tocopheryl acetate, α-tocopherol acetate, alpha-tocopherol acetate, dl-α-tocopherol acetate, d-α-tocopheryl acetate, α-tocopherol succinate, α-tocopherol nicotinate, α-tocopherol phosphate, tocopherol esters, tocopherol nicotinate, tocopherol linoleate, and tocopherol palmitate, gamma-tocopherol, tocopherol linoleate, beta-tocopherol, gamma-tocopherol, d-γ-tocopherol, or mixed tocopherols.

[0091] In some embodiments, vitamin E is alpha-tocopherol or alpha-tocopherol. In some embodiments, tocopherol is alpha-tocopherol or alpha-tocopherol. In some embodiments, vitamin E is d-alpha-tocopheryl acetate. In some embodiments, tocopherol is d-alpha-tocopheryl acetate. In some embodiments, vitamin E is dl-alpha-tocopherol. In some embodiments, tocopherol is dl-alpha-tocopherol.

[0092] In some embodiments, the tocopherols disclosed herein are hydrolyzed, for example, α-tocopheryl acetate is hydrolyzed to α-tocopherol and acetic acid.

[0093] 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.

[0094] Antioxidants such as tocopherol or vitamin E can prevent liver damage by preventing mitochondrial toxicity and blocking endogenous apoptosis pathways. Vitamin E can also downregulate NF-kB-dependent inflammatory pathways (Ratziu et al., 2015). However, antioxidant therapy is not always beneficial and has been shown to be associated with worsening pathology. Administration of high doses of vitamin E improves NAS within two years, but often increases insulin resistance and plasma triglyceride levels (Hackam, 2007Chalasani et al., 2012). In fact, there are concerns about the long-term safety of high doses of vitamin E, such as increasing the incidence of total mortality, hemorrhagic stroke, and even prostate cancer in men over 50 years of age (Miller et al., 2005, Ratziu et al., 2015; Hackam, 2007). In some embodiments, the high dose of vitamin E is about 800 IU.

[0095] 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 doses of vitamin E. Non-limiting examples of adverse events associated with high doses of vitamin E include: increased insulin resistance, increased plasma triglyceride levels, increased mortality, increased incidence of hemorrhagic stroke, and increased incidence of prostate cancer.

[0096] In some embodiments, a reduced amount of tocopherol in combination with at least one SCFA or a pharmaceutically acceptable salt thereof is therapeutically effective for alleviating a condition in a subject in need thereof. In some embodiments, a reduced amount of vitamin E in combination with at least one SCFA or a pharmaceutically acceptable salt thereof is therapeutically effective for alleviating a condition in a subject in need thereof.

[0097] In some embodiments, a reduced amount of tocopherol in combination with at least two SCFAs or pharmaceutically acceptable salts thereof is therapeutically effective for alleviating a condition in a subject in need thereof. In some embodiments, a reduced amount of vitamin E in combination with at least two SCFAs or pharmaceutically acceptable salts thereof is therapeutically effective for alleviating a condition in a subject in need thereof.

[0098] In some embodiments, the reduced amount of tocopherol is less than the amount of tocopherol that is effective for treating the condition in the absence of at least one SCFA or a pharmaceutically acceptable salt thereof. In some embodiments, the reduced amount of vitamin E is less than the amount of tocopherol that is effective for treating the condition in the absence of at least one SCFA or a pharmaceutically acceptable salt thereof.

[0099] In some embodiments, the reduced amount of tocopherol is less than the amount of tocopherol that is effective for treating the condition in the absence of at least two SCFAs or pharmaceutically acceptable salts thereof. In some embodiments, the reduced amount of vitamin E is less than the amount of tocopherol that is effective for treating the condition in the absence of at least two SCFAs or pharmaceutically acceptable salts thereof.

[0100] 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.

[0101] In some embodiments, the compositions disclosed herein comprise an amount of tocopherol or vitamin E that is 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 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%, about 95%, about 96%, about 97%, about 98%, about 99%, about 100%, about 101%, about 102%, about 103%, about 104%, about 105 %, 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%, about 95%, about 96%, about 97%, about 98%, about 99%.

[0102] 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.

[0103] In some embodiments, the compositions disclosed herein comprise greater than about 100 IU, greater than about 150 IU, greater than about 200 IU, greater than about 250 IU, greater than about 300 IU, greater than about 350 IU, greater than about 400 IU, greater than about 450 IU, greater than about 500 IU, greater than about 550 IU, or greater than about 600 IU of tocopherol or vitamin E.

[0104] 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.

[0105] In some embodiments, the compositions disclosed herein comprise from about 1 to about 49.9 IU of tocopherol or vitamin E. In some embodiments, the compositions disclosed herein comprise from about 1 to about 49 IU of tocopherol or vitamin E. In some embodiments, the compositions disclosed herein comprise from about 1 to about 40 IU of tocopherol or vitamin E. In some embodiments, the compositions disclosed herein comprise from about 1 to about 30 IU of tocopherol or vitamin E. In some embodiments, the compositions disclosed herein comprise from about 1 to about 20 IU of tocopherol or vitamin E. In some embodiments, the compositions disclosed herein comprise from about 1 to about 10 IU of tocopherol or vitamin E.

[0106] 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.

[0107] 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.

[0108] 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.

[0109] In some embodiments, the composition comprises 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 105 IU, about 100 IU, about 105 IU, about 100 IU, about 105 IU, about 100 IU, about 105 IU, about 100 IU, about 105 IU, about 100 IU, about 105 IU, about 100 IU, about 100 IU, about 100 IU, about 100 IU, about 100 IU, about 100 IU, about 100 IU, about 100 IU, 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, about 400 IU.

[0110] 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.

[0111] In some embodiments, the composition comprises about 1 milligram (mg) to about 100,000 milligrams (mg) of at least one antioxidant. In some embodiments, the composition comprises about 1 milligram (mg) to about 100 milligrams (mg) of at least one antioxidant. In some embodiments, the composition comprises about 1 milligram (mg) to about 90 milligrams (mg) of at least one antioxidant. In some embodiments, the composition comprises about 1 milligram (mg) to about 80 milligrams (mg) of at least one antioxidant. In some embodiments, the composition comprises about 1 milligram (mg) to about 70 milligrams (mg) of at least one antioxidant. In some embodiments, the composition comprises about 1 milligram (mg) to about 60 milligrams (mg) of at least one antioxidant. In some embodiments, the composition comprises about 1 milligram (mg) to about 50 milligrams (mg) of at least one antioxidant. In some embodiments, the composition comprises about 1 milligram (mg) to 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 from 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.

[0112] In some embodiments, the composition comprises from about 20 IU to about 300 IU of at least one antioxidant. In some embodiments, the composition comprises from about 20 IU to about 200 IU of at least one antioxidant. In some embodiments, the composition comprises from about 50 IU to about 200 IU of at least one antioxidant. In some embodiments, the composition comprises from about 200 IU to about 600 IU of at least one antioxidant.

[0113] In some embodiments, the tocopherol is tocopherol acetate. In some embodiments, the tocopherol is d-alpha-tocopherol acetate.

[0114] In some embodiments, the at least one antioxidant is vitamin E (d-alpha-tocopheryl acetate).

[0115] In some embodiments, the antioxidant comprises at least one 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 more than 300 enzymes that regulate a wide variety of biochemical reactions (including regulating blood sugar levels and detoxification, etc.). Vitamin D3 deficiency is common 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 additionally 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.

[0116] Condition

[0117] In some embodiments, diseases and conditions that can be treated, prevented, or improved by the methods of the present disclosure include, but are not limited to, inflammatory diseases and various cancers. In some embodiments, inflammatory diseases and conditions that can be treated or improved include, but are not limited to, asthma, arthritis, allergic rhinitis, psoriasis, atopic dermatitis, inflammatory bowel disease, Crohn's disease, allergic or autoimmune diseases or conditions associated with cesarean section in neonates, uveitis, and vasculitis. In some embodiments, cancers and conditions that can be treated or improved include, but are not limited to, leukemia and lymphoma.

[0118] In one embodiment, the autoimmune disease or disorder is at least one of 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), Behçet's disease, bullous pemphigoid, Castleman's disease (CD), celiac disease, Chagas disease, chronic inflammatory demyelinating polyneuropathy (CIDP), chronic relapsing multifocal osteomyelitis (CRMO), Churg-Strauss disease, cicatricial pemphigoid / benign mucous membrane pemphigoid, Cogan syndrome, cold agglutinin disease, congenital heart block, Coxsackie myocarditis (Coxsackie myocarditis), CREST syndrome, Crohn's disease, dermatitis herpetiformis, dermatomyositis, Devic's disease (neuromyelitis optica), discoid lupus, Dressler's syndrome, endometriosis, eosinophilic esophagitis (EoE), eosinophilic fasciitis, erythema nodosum, essential mixed cryoglobulinemia, Evans syndrome, fibromyalgia, fibrosing alveolitis, food allergies, gastroenteritis, giant cell arteritis (temporal arteritis), giant cell myocarditis, glomerulonephritis, Goodpasture's syndrome, granulomatosis with polyangiitis, Graves' disease, Guillain-Barré syndrome syndrome), Hashimoto's thyroiditis, hemolytic anemia, Henoch-Schonlein purpura (HSP), herpes gestationis or pemphigoid 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 syndrome, leukocytoclastic vasculitis, lichen planus, lichen sclerosus, ligneous conjunctivitis, linear IgA disease (LAD), lupus, chronic Lyme disease, Meniere's disease, microscopic polyangiitis (MPA), mixed connective tissue disease (MCTD), Mollen's ulcer, Mucha-Habermann diseasedisease), multiple sclerosis (MS), myasthenia gravis, myositis, narcolepsy, neuromyelitis optica, neutropenia, ocular cicatricial pemphigoid, optic neuritis, relapsing rheumatic disease (PR), PANDAS (pediatric autoimmune neuropsychiatric disorders associated with streptococci), paraneoplastic cerebellar degeneration (PCD), paroxysmal nocturnal hemoglobinuria (PNH), Parry-Romberg syndrome syndrome), pars planitis (peripheral uveitis), Parsonnage-Turner syndrome, pemphigus, peripheral neuropathy, perivenous encephalomyelitis, pernicious anemia (PA), POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal, gammopathy, skin changes), polyarteritis nodosa, polymyalgia rheumatica, polymyositis, post-myocardial infarction syndrome, postpericardiotomy syndrome, progesterone dermatitis, psoriasis, plaque psoriasis, guttate psoriasis, inverse psoriasis, pustular psoriasis, psoriasis vulgaris, 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, relapsing polychondritis, restless legs syndrome (RLS), retroperitoneal fibrosis, rheumatic fever, rheumatoid arthritis (RA), sarcoidosis, Schmidt's syndrome, scleritis, scleroderma, Sjögren's syndrome, sperm and testicular autoimmunity, stiff-man syndrome (SPS), subacute bacterial endocarditis (SBE), Susac's syndrome syndrome), sympathetic ophthalmia (SO), Takayasu's arteritis, temporal arteritis / giant cell arteritis, thrombocytopenic purpura (TTP), Tolosa-Hunt syndrome (THS), transverse myelitis, type 1 diabetes mellitus, ulcerative colitis (UC), undifferentiated connective tissue disease (UCTD), uveitis, vasculitis, vitiligo, and Wegener's granulomatosis (granulomatosis with polyangiitis (GPA)).

[0119] In other embodiments, diseases and conditions that can be treated, prevented, or ameliorated by the methods of the present disclosure include, but are not limited to, allergic diseases, infectious diseases, and rejection in organ transplantation, 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, spondyloarthropathy, systemic lupus erythematosus, insulin-dependent diabetes mellitus, thyroiditis, asthma, psoriasis, dermatitis scleroderma, atopic dermatitis, graft-versus-host disease, acute or chronic immune diseases associated with organ transplantation, sarcoidosis, atherosclerosis, disseminated intravascular coagulation, Kawasaki disease, Graves' disease, nephrotic syndrome, chronic fatigue syndrome, Wegener's granulomatosis, Henoch-Schoenlejn purpura, and the like. purpurea), renal microscopic vasculitis, uveitis, septic shock, toxic shock syndrome, sepsis syndrome, cachexia, acquired immunodeficiency syndrome, acute transverse myelitis, Huntington disease, Parkinson disease, Alzheimer disease, stroke, primary biliary cirrhosis, hemolytic anemia, polyglandular deficiency syndrome type I and II, Schmidt syndrome, adult (acute) respiratory distress syndrome, alopecia, alopecia areata, seronegative arthropathy, arthropathy, Reiter's disease, psoriatic arthropathy, chlamydia dia), arthropathy associated with Yersinia and Salmonella, spondyloarthropathies, atherosclerotic disease / arteriosclerosis, allergic colitis, idiopathic allergies, food allergies (e.g., peanut allergy, tree nut allergy, egg allergy, milk allergy, soy allergy, wheat allergy, seafood allergy, shellfish allergy, or sesame seed allergy), autoimmune bullous disorders, pemphigus vulgaris, pemphigus foliaceus, pemphigoid, linear IgA disease, autoimmune hemolytic anemia, Coombs-positive hemolytic anemia, acquired pernicious anemia, juvenile pernicious anemia, myalgic encephalitis / Royal Free diseaseDisease), chronic mucocutaneous candidiasis, giant cell arteritis, acquired immunodeficiency syndrome, acquired immunodeficiency-related diseases, common variable immunodeficiency (common variable hypogammaglobulinemia), dilated cardiomyopathy, fibrosing lung disease, cryptogenic fibrosing alveolitis, postinflammatory interstitial lung disease, interstitial pneumonia, interstitial lung disease associated with connective tissue disease, lung disease associated with mixed connective tissue disease, interstitial lung disease associated with systemic sclerosis, interstitial lung disease associated with rheumatoid arthritis, lung disease associated with systemic lupus erythematosus, lung disease associated with dermatomyositis / polymyositis, Sjögren's disease disease-related lung disease, ankylosing spondylitis-related lung disease, vasculitic diffuse lung disease, hemosiderosis-related lung disease, drug-induced interstitial lung disease, radiation fibrosis, bronchiolitis obliterans, chronic eosinophilic pneumonia, lymphocytic lung disease, post-infectious interstitial lung disease, gouty arthritis, autoimmune-mediated hypoglycemia, type B insulin resistance with acanthosis nigricans, hypoparathyroidism, acute immune disease associated with organ transplantation, chronic immune disease associated with organ transplantation, osteoarthritis, primary sclerosing cholangitis, idiopathic leukopenia, autoimmune neutropenia, non-idiopathic renal disease NOS), glomerulonephritis, microscopic renal vasculitis, discoid lupus, lupus erythematosus, idiopathic or nonidiopathic male infertility, 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 rheumatoid fever, rheumatoid spondylitis, Still's disease, systemic sclerosis, Takayasu's disease disease) / arteritis, autoimmune thrombocytopenia, idiopathic thrombocytopenia, autoimmune thyroid disease, hyperthyroidism, goitrous autoimmune hypothyroidism (Hashimoto's disease), atrophic autoimmune hypothyroidism, primary myxedema, lenticular uveitis, primary vasculitis, vitiligo, allergic rhinitis (pollen allergy), allergies, pet allergies, latex allergy, drug allergies, allergic rhinoconjunctivitis, eosinophilic esophagitis, hypereosinophilic syndrome, eosinophilic gastroenteritis, cutaneous lupus erythematosus, eosinophilic esophagitis, hypereosinophilic syndrome, eosinophilic gastroenteritis, and diarrhea.

[0120] Treatment

[0121] In one embodiment, the present disclosure provides methods for treating or preventing at least one disease or condition in a subject, comprising administering to the subject at least one composition comprising a SCFA or a compound containing a SCFA moiety, optionally in combination with at least one other agent or therapy.

[0122] In some embodiments, the compositions administered by the present disclosure can increase the number of disease-free days in a subject, reduce the severity of a disease or condition, reduce the risk of developing a disease or condition, reduce the risk of recurrence of a disease or condition, or a combination thereof. Compared to an untreated subject, the compositions administered by the present disclosure can increase the number of disease-free days in a subject by more than 5-60%. Compared to an untreated subject, the compositions administered by the present disclosure can reduce the severity of a disease or condition 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. The compositions administered according to the present disclosure can reduce the risk of developing a disease or condition 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 who did not receive treatment. The compositions administered according to the present disclosure can reduce the risk of recurrence of a disease or condition 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 who did not receive treatment.

[0123] In one embodiment, an exemplary method for treating or preventing a disease or condition 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 one week, at least two weeks, at least three weeks, at least one 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.

[0124] In one embodiment, the composition comprising at least one SCFA is an enteric-coated extended-release capsule.

[0125] In one embodiment, the composition comprises a derivative of a 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 yield at least one SCFA molecule and at least one PEG molecule.

[0126] In one embodiment, the composition comprises a combination of SCFAs and / or derivatives thereof. In one embodiment, the composition is prepared so that each or all of the compounds in the composition are present 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.

[0127] 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 comprise at least one SCFA attached 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.

[0128] In some cases, the SCFA of the present disclosure can be pegylated. Polyethylene glycol (PEG) has been widely used in biomaterials, biotechnology and medicine, mainly 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 have been widely used for covalent attachment to proteins (i.e., "PEGylation") to reduce immunogenicity, proteolysis and renal clearance and enhance solubility (Zalipsky, Adv. Drug Del. Rev. 16:157-82, 1995). Similarly, PEG has been connected to low molecular weight, relatively hydrophobic drugs to enhance solubility, reduce toxicity and change biodistribution. Typically, PEGylated drugs are injected as solutions. However, they can be administered orally or by other routes.

[0129] A closely related application is the synthesis of cross-linked degradable PEG networks or formulations for drug delivery, because many of the same chemical principles used in the design of degradable, soluble drug carriers can also be used for the design of degradable gels (Sawhney et al., Macromolecules 26:581-87, 1993). It is also known that macromolecular complexes can be formed by mixing solutions of two complementary polymers. Such complexes are usually stabilized by electrostatic interactions (polyanions-polycations) and / or hydrogen bonds (polyacids-polybases) 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 a solution of polyacrylic acid (PAAc) and polyethylene oxide (PEO) under appropriate conditions results in the formation of a complex primarily based on hydrogen bonds. The dissociation of these complexes under physiological conditions has been used for the delivery of free drugs (i.e., non-PEGylated drugs). In addition, complexes of complementary polymers are formed by both homopolymers and copolymers.

[0130] In one embodiment, the composition comprises a precursor of a SCFA alone or in combination with one or more SCFAs. Precursors of SCFAs include, but are not limited to, formate, lactate, succinate, 1,2-propylene glycol, tryptamine, indole, and indole-3-acetate.

[0131] In one embodiment, the composition includes a precursor of a single SCFA biosynthesis or a precursor of a SCFA biosynthesis in combination with one or more SCFAs. The precursors of SCFA biosynthesis include but are not limited to formate, lactate, succinate, acetyl-CoA carboxylase inhibitors, adenosine monophosphate kinase (AMPK) activators and vitamin D. SCFA stimulates regulatory T (Treg) cell function, which explains its partial anti-inflammatory properties. In view of the fact that inhibitors of acetyl-CoA carboxylase also promote Treg cell function, in one embodiment, the composition includes an inhibitor of a single acetyl-CoA carboxylase (including but not limited to biotin or its natural or chemically synthesized analogs (which are acetyl-CoA carboxylase inhibitors)) or an inhibitor of acetyl-CoA carboxylase in combination with one or more other SCFAs to stimulate Treg function.

[0132] In various embodiments, the compounds of the present disclosure that contain at least one SCFA or contain a SCFA moiety can be combined with one or more compounds, such as one or more other therapeutic agents, for use in a particular disease or condition. In one embodiment, the one or more SCFAs of the present disclosure can be present in the same composition as the one or more other therapeutic agents. In various embodiments, the composition can contain 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 other therapeutic agents. Exemplary other therapeutic agents and / or compounds that can be included in the compositions are discussed in detail elsewhere herein.

[0133] anti-inflammatory agents

[0134] 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 can be used in combination with the composition include, but are not limited to, nonsteroidal anti-inflammatory drugs (NSAIDs) such as diclofenac (e.g., ), diflunisal (e.g., ), etodolac (e.g., ), fenoprofen (e.g., ), ibuprofen (e.g., etc.), indomethacin (e.g. ), ketoprofen (e.g., ), ketorolac (e.g., ), fosfomycin tromethamine (e.g., ), meclofenamic acid (e.g., ), nabumetone (e.g., ), naproxen (e.g., etc.), oxaprozin (e.g., ), piroxicam (e.g., ), sulindac (e.g., ), Tolmetin (e.g., 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 one or more additional 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 and one or more additional 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.

[0135] chemotherapeutic agents

[0136] In one embodiment, the method of the present disclosure may include administering a composition in combination with one or more chemotherapeutic agents. Chemotherapeutic agents include, but are not limited to, cytarabine (ara-C), daunorubicin, cladribine (Leustatin, 2-CdA), cytotoxic agents (e.g., 5-fluorouracil, cisplatin, carboplatin, methotrexate, daunorubicin, doxorubicin, vincristine, vinblastine, doxorubicin (oxorubicin), carmustine (BCNU), lomustine (CCNU), cytarabine USP, cyclophosphamide, estramustine sodium phosphate, hexamethylmelamine, hydroxyurea, ifosfamide, procarbazine, mitomycin, busulfan, cyclophosphamide, mitoxantrone, carboplatin, cisplatin, interferon α-2a recombinant, paclitaxel, teniposide, and streptomycin. zotocin), cytotoxic alkylating agents (e.g., busulfan, chlorambucil, cyclophosphamide, melphalan, or ethionyl), alkylating agents (e.g., asaley, AZQ, BCNU, busulfan, bisulphan, carboxyplatinum, CBDCA, CCNU, CHIP, chlorambucil, chlorozotocin, cisplatin, lometasone, cyanomorpholinodoxorubicin, cyclodisone, cyclophosphamide, bisulphamide, fluorodopan, hepsulfam, hydantoin, ifosfamide, melphalan, methyl CCNU, mitomycin C, mitozolamide , nitrogen mustard, PCNU, piperazine, diketopiperazine, pipobroman, porfiromycin, spirohydantoin mustard, streptozotocin, tiroxilon, tetraplatin, thiotepa, triethylene melamine, uracil mustard, and Yoshi-864), antimitotic agents (e.g., allocolchicine, halichondrin M, colchicine, colchicine derivatives, dolastatin 10, maytansine, rhizoxin, paclitaxel derivatives, paclitaxel, thiocolchicine, tritylcysteine, vinblastine sulfate, and vincristine sulfate), plant alkaloids (e.g., actinomycin D, bleomycin, L-asparaginase, idarubicin, vinblastine sulfate, vincristine sulfate, mithramycin, mitomycin, daunomycin, VP-16- 213, VM-26, Navelbine, and Taxotere), biologics (e.g., interferon alpha, BCG, G-CSF, GM-CSF, and interleukin-2), topoisomerase I inhibitors (e.g., camptothecin, camptothecin derivatives, and morpholino doxorubicin), topoisomerase II inhibitors (e.g., mitoxantrone, amphetamine, m-AMSA, anthrapyrazole derivatives, pyrazoloacridine, bisantrene hydrochloride, daunomycin, deoxydoxorubicin, menolide, N,N-dibenzyldaunomycin, oxanthrazole, rubidazone, VM-26, and VP-16), and synthetics (e.g., hydroxyurea, procarbazine, o,p'-DDD, dacarbazine, CCNU, BCNU, cis-diamminedichloroplatinum, mitoxantrone, CBDCA, levamisole, hexamethylmelamine, all-trans retinoic acid, glitazone and porfimer sodium). In some embodiments, the composition is administered before, during or after administration of at least one antiproliferative agent for treating cancer. Antiproliferative agents are compounds that reduce the proliferation of cells. Antiproliferative agents include, but are not limited to, alkylating agents, antimetabolites, enzymes, biological response modifiers, other agents, hormones and antagonists, androgen inhibitors (e.g., flutamide and leuprolide acetate), antiestrogens (e.g., tamoxifen citrate and its analogs, toremifene, droloxifene and raloxifene). Other examples of specific antiproliferative agents include, but are not limited to, levamisole, gallium nitrate, granisetron, sargramostim, strontium-89 chloride, filgrastim, pilocarpine, dexrazoxane and ondansetron.

[0137] The composition can be administered alone or in combination with other anti-tumor agents including cytotoxic agents / antineoplastic agents and anti-angiogenic agents. Cytotoxic agents / antineoplastic agents are defined as agents that attack and kill cancer cells. Some cytotoxic agents / antineoplastic agents are alkylating agents that alkylate the genetic material in tumor cells, for example, cisplatin, cyclophosphamide, nitrogen mustard, trimethylenethiophosphoramide, carmustine, busulfan, chlorambucil, belustine, uracil, chlomaphazine and dacarbazine. Other cytotoxic agents / antineoplastic agents are antimetabolites of tumor cells, for example, cytarabine, fluorouracil, methotrexate, mercaptopurine, azathioprine and procarbazine. Other cytotoxic / antitumor forming agents are antibiotics, for example, doxorubicin, bleomycin, actinomycin, daunorubicin, mithramycin, mitomycin, mitomycin C, and daunomycin. There are many commercially available liposomal formulations of these compounds. Other cytotoxic / antitumor forming agents are mitotic inhibitors (vinca alkaloids). These include vincristine, vinblastine, and etoposide. Other cytotoxic / antitumor forming agents include taxol and its derivatives, L-asparaginase, antitumor antibodies, dacarbazine, azacytidine, amsacrine, melphalan, VM-26, ifosfamide, mitoxantrone, and vindesine.

[0138] Anti-angiogenic agents are well known to those skilled in the art. Anti-angiogenic agents suitable 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 angiogenesis inhibitors include angiostatin, endostatin, interferon, interleukin 1 (including α and β), interleukin 12, retinoic acid, and tissue inhibitors of metalloproteinases-1 and -2 (TIMP-1 and TIMP-2). Small molecules including topoisomerases such as razoxane (a topoisomerase II inhibitor with anti-angiogenic activity) can also be used.

[0139] Other anticancer agents that can be used in combination with the composition include, but are not limited to, acivicin, aclarubicin, acondazole hydrochloride, aclonine, adolesin, aldesleukin, hexamethylmelamine, amblycin, ametrine acetate, aminoglutethimide, amsacrine, anastrozole, anthramycin, asparaginase, trilin, azacitidine, azatepa, azomycin, batimastat, benzotepa, bicalutamide, bisantrene hydrochloride, binefad dimesylate, bisezole, bleomycin sulfate, brequinar sodium, bromide, busulfan, actinomycin, captestosterone, caracemide, carbetimer, carboplatin, carmustine, carrubicin hydrochloride, carzelesin, cedifingol, chlorambucil, siromycin, cisplatin, cladribine, cristal mesylate,mesylate), cyclophosphamide, cytarabine, dacarbazine, dactinomycin, daunorubicin hydrochloride, decitabine, dextromaplatin, dezaguanine, dezaguanine mesylate, diazaquinone, docetaxel, doxorubicin, doxorubicin hydrochloride, droloxifene, droloxifene citrate, drotasterone propionate, dazomib, edatrexate, eflornithine hydrochloride, elsamitrucin, enloplatin, enpromate, epiripridine, epirubicin hydrochloride, erbulazole, esorubicin hydrochloride, estramustine, estramustine sodium phosphate, etanidazole, etoposide etoposide, etoposide phosphate, etobanid, fadrozole hydrochloride, fazarabine, fenretinide, floxuridine, fludarabine phosphate, fluorouracil, flucitabine, fosquatone, fostramoxine sodium, gemcitabine, gemcitabine hydrochloride, hydroxyurea, idarubicin hydrochloride, ifosfamide, imofosine, interleukin II (including recombinant interleukin II or rIL2), interferon α-2a, interferon α-2b, interferon α-n1, interferon α-n3, interferon β-Ia, interferon γ-Ib, iproplatin, irinotecan hydrochloride Tecan, lanreotide acetate, letrozole, leuprorelin acetate, lirazole hydrochloride, lometrexol sodium, lomustine, loxantrone hydrochloride, masoprofen, maytansine, mechlorethamine hydrochloride, megestrol acetate, melengestrol acetate, melphalan, menolide, mercaptopurine, methotrexate, methotrexate sodium, metoprine, metodepa, mibutamide, mitokacin, mitoramine, mitoxantrone, mitomacin, mitomycin, mitosperm, mitotane, salt Mitoxantrone hydrochloride, mycophenolic acid, nocodazole, nogaramycin, ormaplatin, oxicolane, paclitaxel, pegaspargase, pelimycin, nemustine, pelimycin sulfate, perfosfamide, pipobroman, piposulfan, pyroxantrone hydrochloride, plicamycin, promestane, porfimer sodium, porfimer, prednimustine, procarbazine hydrochloride, puromycin, puromycin hydrochloride, pyrazofuranoside, riboadenylide, roglutimide, safinol, safinol hydrochloride, semustine, sintrazine, sparnfosate sodiumsodium), sparmycin, spironium germanium hydrochloride, spiromustine, spiroplatin, streptozocin, streptozotocin, sulfaquinoxaline, talithromycin, tecogalan sodium, tegafur, tiloxantrone hydrochloride, temoporfin, teniposide, tiroxilon, testolactone, thiabendazole, thioguanine, thiotepa, thiazofurine, tirapazamine, toremifene citrate, triptolan acetate, triciribine phosphate, trimethoprim-sulfamethoxazole, Trimethoprim, trimetrelin glucuronide, triptorelin, tobradazole hydrochloride, uramustine, uredepa, vapreotide, verteporfin, vinblastine sulfate, vincristine sulfate, vindesine, vindesine sulfate, vinpoxetine sulfate, vinsoriasis sulfate, vinorelbine tartrate, vinprodine sulfate, vinblastine sulfate, voroprelin, zeniplatin, jingsistatin, zorubicin hydrochloride. Other anticancer drugs include, but are not limited to, 20-epi-1,25-dihydroxyvitamin D3, 5-ethynyluracil, abiraterone, aclarubicin, acylfulvene, adecypenol, adolesin, aldesleukin, ALL-TK antagonists, hexamethylmelamine, amoxicillin, amidox, amifostine, aminolevulinic acid, amrubicin, amsacrine, anagrelide, anastrozole, andrographolide, angiogenesis inhibitors, antagonist D, antagonist G, antarelix, anti-dorsalizing morphogenetic protein-1, and antagonist G. protein-1), antiandrogen, prostate cancer, antiestrogen, antineoplaston, antisense oligonucleotide, glycine aphidicolin, apoptosis gene regulator, apoptosis regulator, apurinic nucleic acid, ara-CDP-DL-PTBA, arginine deaminase, asulacrine, atamestane, amustine, axinostine 1, axinostine 2, axinostine 3, azasetron, azatoxin, azatyrosine, baccatin III derivative, balanol, batimastat, BCR / ABL antagonist, benzochlorin, benzoylstaurosporine, beta-lactam derivative, beta-alethine, beta-clarithromycin B B), betulinic acid, bFGF inhibitors, bicalutamide, bisantrene, diazinon, bifenafide, bistratene A, biszelesin, breflate, bropiridone, budotitan, buthionine sulfoximine, calcipotriol, calphostin CC), camptothecin derivatives, canarypox IL-2, capecitabine, carboxamide-amino-triazole, carboxyamidotriazole, CaRest M3, CARN 700, chondroitin inhibitors, carzelesin, casein kinase inhibitors (ICOS), castanospermine, cecropin B, cetrorelix, chlorin, chloroquinoxaline sulfonamide, cicaprost, cis-porphyrin, cladribine, clomiphene analogs, clotrimazole, colimycin A, colimycin B, conpretin A4, conpretin analogs, conagenin, crambescidin 816, crisnatol, candidin 8, candidin A derivatives, curacin A A), cyclopentanthrone, cycloplatam, cypemycin, cytarabine, cytolytic factor, cytostatin, dacliximab, decitabine, dehydroepiphyseal B, deslorelin, dexamethasone, dexifosfamide, dexrazoxane, dexverapamil, diazocone, epiphyseal B, didox, diethylnorspermine, dihydro-5-azacytidine, 9-dihydropaclitaxel, dioxamycin, diphenylspiromustine, Docetaxel, docosanol, dolasetron, deoxyfluridine, droloxifene, dronabinol, duocarmycin SA, ebselen, eticomustine, edilfosine, edrecolomab, eflornithine, elemene, etifurfur, epirubicin, elesteride, estramustine analogs, estrogen agonists, estrogen antagonists, etanercept, etoposide phosphate, exemestane, fadrozole, fazarabine, fenretinide, filgrastim, finasteride, flavopiridol, fulvestrant, fusostem, fludarabine, fluorodaunorunicin hydrochloride hydrochloride), fostamik, formestane, fostramcin, fotemustine, gadolinium texaphyrin, gallium nitrate, galocitabine, ganirelix, gelatinase inhibitors, gemcitabine, glutathione inhibitors, heptylsulfonamide, heregulin, hexamethylenebisacetamide, hypericin, ibandronic acid, idarubicin, idoxifene, idemenone, imofosine, ilomastat, imidazoacridone, imiquimod, immunostimulatory peptides, insulin-like growth factor-1 receptor inhibitors, interferon agonists, interferons, interleukins, iodobenzylguanidine, iodoxorubicin, 4-ibominol, iroprax, irsogladine, isobengazole, isohomohalicondrinB), itasetron, jasplakinolide, kahalalide F, lamellarin-N triacetate, lanreotide, ranamycin, levograstim, lentinan sulfate, leptolstatin, letrozole, leukemia inhibitory factor, interferon-alpha, leuprolide + estrogen + progesterone, leuprolide, levamisole, lirazole, linear polyamine analogs, lipophilic disaccharide peptides, lipophilic platinum compounds, lissoclinamide 7, lobaplatin, lombricine, lometrexol, lonidamine, loxantrone, lovastatin, loxoribine, lutetium texaphyrin, lysofylline, lytic peptide peptides), maytansine, mannostatin A, marimastat, masorofol, maspin, matrilysin inhibitor, matrix metalloproteinase inhibitor, menolil, merbarone, meterelin, methioninase, metoclopramide, MIF inhibitor, mifepristone, miltefosine, miristem, mismatched double-stranded RNA, mitoguanidine, dibromodulcitol, mitomycin analog, mitonamin, mitotoxin fibroblast growth factor-saporin, mitoxantrone, mfarotene, moraspomicin, monoclonal antibody, human chorionic gonadotropin, monophosphoryl lipid A+ mycobacterium cell wall sk, mopidarol, multidrug resistance gene inhibitor, multiple tumor suppressor gene 1-based therapy, mustard anticancer agentagent), mycaperoxide B, mycobacterial cell wall extract, myriaporone, N-acetyldinaline, N-substituted benzamides, nafarelin, nagrestip, naloxone + pentozocin, napavin, naphterpin, nartograstim, nedaplatin, nemorubicin, neridronic acid, neutral endopeptidase, nilutamide, nisamycin n), nitric oxide modulators, nitroxide antioxidants, nitrullyn, O6-benzylguanine, octreotide, okicenone, oligonucleotides, onapristone, ondansetron, ondansetron, oracin, oral cytokine inducers, ormaplatin, oxalone, oxaliplatin, oxaunomycin, paclitaxel, paclitaxel analogs, paclitaxel derivatives, palaunamide, palmitoyl rhizoxin, pamidronate, ginsenotriol , panomifen, parabactin, pazelliptine, pegaspargase, peldesine, pentosan polysulfate sodium, pentostatin, pentrozole, perflurane, perphosphamide, perillyl alcohol, phenazinomycin, phenyl acetate, phosphatase inhibitors, picibanil, pilocarpine hydrochloride, pirarubicin, piroxine, pelestrin A, Plastin B, plasminogen activator inhibitors, platinum complexes, platinum compounds, platinum-triamine complexes, porfimer sodium, porfiromycin, prednisone, propyl diacridone, 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, pyrazoloacridine, pyridoxylated hemoglobin polyoxyethylene conjugates hemoglobin polyoxyethylene conjugate), raf antagonists, raltitrexed, ramosetron, ras farnesyl protein transferase inhibitors, ras inhibitors, ras-GAP inhibitors, demethylated retiritin, rhenium etidronate Re 186, rhizoxin, ribozyme, RII retinamide, roxithromycin, rohitukine, romotide, roquine, rubiginone B1, ruboxyl, safinol, saintopin, SarCNU, myophylline A, sargramostim, Sdi1 mimetic, semustine, senescence-derived inhibitor 1, sense oligonucleotide, signal transduction inhibitor, signal transduction regulator, single-chain antigen binding protein, sizofuran, sobuzoxane, borcarbazine sodium, sodium phenylacetate, solverol, somatomedin binding protein, sonarmin, spalfosic acid acid), spicromycin D, spiromustine, splenopentin, spongostatin 1, squalamine, stem cell inhibitor, stem cell division inhibitor, stipiamide, stromelysin inhibitor, sulfinosine, potent vasoactive intestinal peptide antagonist, suradista, suramin, swainsonine, synthetic glycosaminoglycans, tamustine, tamoxifen methyl iodide, tauromustine, tazarotene, tecogalan sodium, tegafur, tellurapyrylium, telomerase inhibitor, temoporfin, temozolomide, teniposide, tetrachlorodecyl oxide, tetrazomine, thaliblastine, sulfocoralline, thrombopoietin, thrombopoietin mimetic, thymofasin, thymopoietin receptor agonist, thymotrexone, thyroid stimulating hormone, ethylpurpurin tin

[00135] In some embodiments, the present invention includes but is not limited to: ethyletiopurpurin, tirapazamine, titanocene dichloride, topsentin, toremifene, totipotent stem cell factor, translation inhibitors, tretinoin, triacetyluridine, triciribine, trimetrexate, triptorelin, tropisetron, torosterol, tyrosine kinase inhibitors, tyrphostins, UBC inhibitors, ubenimex, urogenital sinus-derived growth inhibitory factor, urokinase receptor antagonists, vapreotide, variolin B, vector systems, erythrocyte gene therapy, vilaresol, veratramine, verdins, verteporfin, vinorelbine, vinxaltine, vitaxin, vorozole, zanoterone, zeniplatin, zilascorb, and zenastatin. In one embodiment, the anticancer drug is 5-fluorouracil, Taxol, or folinic acid.

[0140] antiviral agents

[0141] The present disclosure contemplates compositions comprising at least one SCFA or a compound containing a SCFA moiety as described herein in combination with an antiviral agent. Antiviral agents include, but are not limited to, viral uncoating inhibitors (e.g., amantadine and rimantadine), 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); antiretroviral drugs such as, for example, nucleoside analogs, reverse transcriptase inhibitors, and antiretroviral drugs. 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, atripla, boceprevirertet, cidotamivir Fosfovir, cocomitin, darunavir, delavirdine, didanosine, docosanol, edoxuridine, emtricitabine, enfuvirtide, entecavir, famciclovir, fosamprenavir, foscarnet, fosfonet, ganciclovir, ibacitabine, imunovir, idoxuridine, imiquimod, indinavir, inosine, various interferons (e.g., peginterferon alfa-2a), lopinavir, loviride, maraviroc, morphine, methisazon one), nelfinavir, nexavir, penciclovir, peramivir, praconavir, podophyllotoxin, raltegravir, ribavirin, ritonavir, pyrimidine, saquinavir, stavudine, telaprevir, tenofovir, tipranavir, trifluridine, trizivir, tromantanamide, Truvada, valacyclovir, valganciclovir, vicriviroc, vidarabine, veramidine, and zalcitabine.

[0142] Biological agents

[0143] 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 biopharmaceuticals. Exemplary biopharmaceuticals contemplated by the present disclosure include, but are not limited to, etanercept. Infliximab Apremilast and adalimumab 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 additionally one or more biopharmaceuticals. 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 biopharmaceuticals.

[0144] Other medicines

[0145] In one embodiment, the method comprises administering to a subject in need thereof a composition comprising at least one SCFA or a bioactive derivative or precursor thereof and additionally one or more other therapeutic agents. In one embodiment, the method comprises administering to a subject in need thereof a composition comprising at least one SCFA or a bioactive derivative or precursor thereof in combination with a composition comprising one or more other therapeutic agents. Other therapeutic agents contemplated for administration according to the methods of the present disclosure include, but are not limited to, rofecoxib, celecoxib, folic acid, sulfasalazine, naproxen, leflunomide, methylprednisolone acetate, parenteral gold, oral gold, indomethacin, hydroxychloroquine, hydroxychloroquine sulfate, sulindac, prednisone, enhanced betamethasone dipropionate, and acetaminophen. dipropaugmented), folate, triamcinolone acetonide, diclofenac, dimethyl sulfoxide, piroxicam, diclofenac sodium, ketoprofen, meloxicam, methylprednisolone, nabumetone, tolmetin sodium, calcipotriol, cyclosporine, diclofenac sodium / misoprostol, fluocinonide, glucosamine sulfate, gold sodium thiomalate, hydrocodone tartrate / acetaminophen, risedronate sodium, sulfadiazine, thioguanine, valdecoxib, small molecule inhibitor of KDR (ABT-123), small molecule inhibitor of Tie-2, clobetasol propionate, triamcinolone acetonide, halobetasol propionate, tazarotene, fluocinonide, enhanced betamethasone dipropionate, fluocinonide, acetonide, acitretin, tar shampoo shampoo), betamethasone valerate, mometasone furoate, ketoconazole, pramoxine / fluocinolone acetonide, hydrocortisone valerate, flurandrenolide, urea, betamethasone, clobetasol propionate / emoll, fluticasone propionate, azithromycin, hydrocortisone, moisturizing formula, folic acid, desonide, coal tar, diflorasone diacetate, folate, lactic acid, methoxsalen, methylprednisolone acetate, prednisone, sunscreen, salicylic acid, halcinonide, 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 / sodium lactate (nalact), mineral oil / peanut oil, petroleum / isopropyl myristate, psoralen, salicylic acid, soap / tribromisan, thimerosal / boric acid, celecoxib, afacept, efalizumab, tacrolimus, pimecrolimus, PUVA, UVB, sulfasalazine, alemtuzumab, dronabinol, Unimed, daclizumab, mitoxantrone, xaliproden hydrochloride, fampridine, glatiramer acetate, natalizumab, sinnabidol, α-immune factor (i , mitoxantrone), THC.CBD (cannabinoid agonist), MBP-8298, mesopromide (PDE4 inhibitor), MNA-715, anti-IL-6 receptor antibody, neurovax, pirfenidone

[00155] The present invention relates to a novel human TNF-α allotrap) 1258 (RDP-1258), sTNF-R1, CDP571 (humanized monoclonal anti-TNF-α IgG4 antibody), CDP 870 (humanized monoclonal anti-TNF-α 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). Other TNF antibodies that can be used in the present disclosure are 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-β2, tilimotide, VLA-4 antagonists (e.g., TR-14035, VLA4 Ultrahaler, Antegran-ELAN / Biogen), interferon gamma antagonists, IL-4 agonists, humanized IL-6 antibody tocilizumab, steroids (e.g., dexamethasone, prednisone, prednisolone, triamcinolone acetonide, fluorometholone, and difluprednate), rapamycin, lambalizumab, fluocinolone acetatonide, macuCLEAR eye drops, bone marrow CD34 stem cells, other stem cells, ranibizumab, brimonidine, LFG316, Exulstat hydrochloride, sirolimus, copaxone, other eye drops, AL-78898A, and eculizumab.

[0146] Application

[0147] The compositions of the present disclosure can be administered to a subject using known procedures at dosages and time periods effective for treating or preventing a disease or condition. The effective amount of the therapeutic compound required to achieve a therapeutic effect can vary depending on factors such as the state of the disease or condition in the subject, the age, sex, and weight of the subject.

[0148] The dosage regimen may affect the composition of the effective amount. In addition, the dosage of the composition can be increased or decreased in proportion as indicated by the urgency of the treatment or prevention situation. Non-limiting examples of the effective dosage range of the therapeutic compound of the present disclosure are about 1 to about 5,000 mg / kg body weight / day. The effective dose can be 1 mg to 10 mg of active ingredient / kg body weight / time, and can be 20 μg to 10 mg of component / kg body weight / time. The therapeutic compound can be administered once 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 can be 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more than 10.

[0149] One of ordinary skill in the art will be able to study the relevant factors and determine the effective amount of a therapeutic compound without undue experimentation.

[0150] Actual dosage levels of the active ingredients in the pharmaceutical compositions of the present disclosure can be varied to obtain an amount of the active ingredient that is effective to achieve the desired therapeutic response for a particular subject, composition, and mode of administration without causing toxicity to the subject. In particular, the selected dosage level will depend on a variety of factors, including the activity of the specific compound used, the time of administration, the rate of excretion of the compound, the duration of treatment, other drugs, compounds, or materials used in combination with the compound, the age, sex, weight, condition, general health, and previous medical history of the subject being treated, and similar factors well known in the medical arts.

[0151] A physician, such as a physician or veterinarian, having ordinary skill in the art can readily determine and prescribe the effective amount of the desired pharmaceutical composition. For example, the physician or veterinarian can 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.

[0152] The composition for administration can be in the range of about 1 mg to about 10,000 mg, about 20 mg to about 9,500 mg, about 40 mg to about 9,000 mg, about 75 mg to about 8,500 mg, about 150 mg to about 7,500 mg, about 200 mg to about 7,000 mg, about 3050 mg to about 6,000 mg, about 500 mg to about 5,000 mg, about 750 mg to about 4,000 mg, 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.

[0153] In some embodiments, the dose of the compounds of the present disclosure is from about 1 mg to about 2,500 mg. In some embodiments, the dose of the compounds of the present disclosure 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.

[0154] In one embodiment, the treatment regimen includes daily administration of the composition. In one embodiment, the treatment regimen includes administering the short-chain fatty acids at least once a day 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 includes administering the short-chain fatty acids three times a day 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 includes administering the composition comprising short-chain fatty acids, short-chain fatty acid precursors, short-chain fatty acid biosynthetic precursors or a combination thereof at least once a day when a disease or illness occurs.

[0155] In one embodiment, the treatment regimen includes daily oral administration of short-chain fatty acids. In an exemplary embodiment, 600mg of butyrate is administered 3 times a day (a total of 1800mg / day) for at least one week. In one embodiment, the treatment regimen includes oral administration of two butyrate capsules containing 600mg butyrate 3 times a day (a total of 3600mg / day) for at least one week. In one embodiment, the treatment regimen includes oral administration of two butyrate capsules containing 600mg butyrate 3 times a day (a total of 3600mg / day) for at least one week, followed by oral administration of 600mg butyrate capsules 3 times a day (a total of 1800mg / day) for at least one week.

[0156] As described herein, administering a composition to an individual can induce tolerance, enhance intestinal barrier integrity, and reduce inflammation in the individual. The method comprises administering a composition as described herein to the individual. In some embodiments, the composition comprises 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, enhancing intestinal barrier integrity, and reducing inflammation.

[0157] Whether the administration composition induces tolerance can be determined by using an increase or enhancement of at least one of the following as an index: the number of regulatory T cells (Treg), the ratio of Treg in the T cell population of the colon, the function of Treg or the expression of a marker of Treg. A specific method is to measure the count or percentage of Treg expressing Foxp3 in patient samples such as biopsies or blood samples, the promotion (enhancement) of IL-10 expression, the promotion (enhancement) of CTLA4 expression, the promotion (enhancement) of IDO expression or the inhibition of IL-4 expression as an index for inducing the proliferation or accumulation of regulatory T cells. Whether the administration composition enhances barrier function can be determined by using an increase in the active form TGF-β and / or tight junction-associated protein produced by intestinal epithelial cells as an index. Whether the administration composition reduces inflammation can be determined by using an increase in the production of anti-inflammatory cytokines such as IL-10 and / or TGF-β or a reduction in the production of pro-inflammatory cytokines such as IL-4 as an index.

[0158] In some embodiments, disclosed herein are regulatory cytokines. In some embodiments, the cytokine is a proinflammatory cytokine. Non-limiting examples of cytokines include: TNFα, IFNγ, IL-17A, IL-21, IL-22, IL-23, IL-27, IL-31, and MIP-3α.

[0159] 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 (β-catenin), matrix metalloproteinases 9 and 10, tissue inhibitors of metalloproteinases, nodal, and NF-κB signaling. In some embodiments, the signaling proteins regulated by SCFAs regulate biological pathways or processes, including but not limited to inflammation, immunity, proliferation, differentiation, apoptosis, tumor formation, DNA transcription, cytokine production, cell survival, angiogenesis, fibrosis, and cellular responses to stimuli such as stress, cytokines, free radicals, heavy metals, and ultraviolet radiation.

[0160] In some embodiments, the methods disclosed herein include treating or reducing the likelihood of developing a medical disease or condition 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 condition characterized by decreased levels or aberrant expression of NF-κB signaling.

[0161] The method for detecting such expression includes northern blot, RT-PCR and dot blot for detecting gene expression at the transcriptional level; ELISA, radioimmunoassay, immunoblotting, immunoprecipitation and flow cytometry for detecting gene expression at the translational level. Samples that can be used to measure such indices include tissues and body fluids obtained from individuals, such as blood, biopsy or stool samples.

[0162] Combination with other drugs

[0163] The present disclosure also relates to methods of treating or preventing the diseases or conditions described above in combination with one or more additional pharmaceutical agents.

[0164] The combination can be in a single formulation or can be separate and administered sequentially (the composition comprising at least one SCFA or a molecule containing a SCFA portion first, followed by the composition comprising the other agent, or the composition comprising the other agent first, followed by the composition comprising at least one SCFA or a molecule containing a SCFA portion). In some embodiments, the composition comprising the at least one SCFA or a molecule containing a SCFA portion can be administered to the subject 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, At least one SCFA or a molecule containing a SCFA portion is administered to a subject for 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.In other embodiments, the composition comprising at least one SCFA or a molecule containing a SCFA portion may be administered to a subject 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, 20 seconds ... The composition comprising at least one additional agent is administered to a subject for 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, or 8 weeks.

[0165] 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 for treating or preventing a disease or condition in a subject in need thereof. In one embodiment, the 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.

[0166] 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 at least one SCFA or a combination of a molecule containing a SCFA portion 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, at least about 6.5-fold, or at least about 7. fold, at least about 15.0 times, at least about 16.0 times, at least about 17.5 times, at least about 18.0 times, at least about 18.5 times, at least about 19.0 times, at least about 19.5 times, at least about 10.0 times, at least about 10.5 times, at least about 11.0 times, at least about 11.5 times, at least about 12.0 times, at least about 12.5 times, at least about 13.0 times, at least about 13.5 times, at least about 14.0 times, at least about 14.5 times, or at least about 15.0 times.

[0167] In yet other alternative embodiments, the immune response in a subject administered at least one SCFA or a molecule containing a SCFA portion in combination with a checkpoint inhibitor can 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 at least one SCFA, or a molecule containing a SCFA portion, in combination with a checkpoint inhibitor can 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%.

[0168] Immunotherapy

[0169] In one embodiment, the present disclosure provides a method for stimulating, eliciting or enhancing an immune response in an individual subject (individual), comprising administering to the subject an immunotherapeutic agent in combination with a composition comprising SCFA or a compound containing a SCFA portion. In one embodiment, the subject may be at risk for a disease, diagnosed with a disease, previously treated for a disease, or simultaneously treated for the 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 reactions associated with immunotherapy for cancer. It is expected that the therapeutic effect of treatment using a composition comprising at least one SCFA will not significantly interfere with the benefits of immunotherapy, but will treat or prevent undesirable adverse reactions associated with immunotherapy for cancer. Therefore, in one embodiment, the present disclosure relates to a composition comprising at least one SCFA, which is used as a therapeutic agent for treating or preventing adverse reactions associated with immunotherapy for cancer.

[0170] In one embodiment, the present disclosure provides a method for treating, suppressing, preventing or reducing adverse reactions associated with cancer immunotherapy by administering a composition comprising SCFA or a compound containing a SCFA portion as disclosed herein to a subject in need thereof, optionally in combination with at least one other agent or therapy. Adverse reactions 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-tumor recognition, allergic reactions, 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, suppressing, preventing or reducing diseases associated with adverse reactions associated with cancer immunotherapy, comprising administering a composition comprising at least one SCFA or a compound containing a SCFA portion as disclosed herein to a subject in need thereof. In one embodiment, adverse reactions include a combination of multiple adverse reactions.

[0171] In one embodiment, the subject who suffers an adverse effect associated with immunotherapy for cancer is a human. In one embodiment, the subject who suffers an adverse effect associated with immunotherapy for cancer is a non-human animal.

[0172] In one embodiment, to stimulate an immune response, (i) at least one SCFA or compound containing a SCFA portion and (ii) at least one immunotherapeutic agent are administered to a subject. Typically, the at least one SCFA or compound containing a SCFA portion and the immunotherapeutic agent are administered in the form of a vaccine or in a vaccine regimen. The at least one SCFA or compound containing a SCFA portion and the immunotherapeutic agent can be administered to the subject at approximately the same time, or can be administered separately and / or sequentially.

[0173] Immunotherapeutic agents that can 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 a virus associated with cancer, and anti-cancer antibodies.

[0174] Cancer antigens can be (a) cell surface antigens found on malignant cells, (b) antigens found inside malignant cells, or (c) mediators of tumor cell growth. The term "cancer antigen" refers to (i) tumor-specific antigens, (ii) tumor-associated antigens, (iii) cells expressing tumor-specific antigens, (iv) cells expressing tumor-associated antigens, (v) embryonic antigens on tumors, (vi) autologous tumor cells, (vii) tumor-specific membrane antigens, (viii) tumor-associated membrane antigens, (ix) growth factor receptors, (x) growth factor ligands, and (xi) any other type of antigen or antigen-presenting cell or substance associated with cancer.

[0175] Cancer antigens can be cells, proteins, peptides, fusion proteins, DNA encoding peptides or proteins, RNA encoding peptides or proteins, glycoproteins, lipoproteins, phosphoproteins, carbohydrates, lipopolysaccharides, lipids, a combination of two or more chemical connections, a fusion of two or more, or a mixture of two or more thereof. In another embodiment, cancer antigens are peptides 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, cancer antigens are peptides with MHC class I binding motifs or MHC class II binding motifs. In another embodiment, cancer antigens comprise peptides corresponding to one or more cytotoxic T lymphocyte (CTL) epitopes.

[0176] In one embodiment, the present disclosure provides methods of treating, inhibiting, preventing or reducing adverse effects associated with cancer immunotherapy by administering to a subject in need thereof a composition comprising SCFAs or compounds containing SCFA moieties as disclosed herein, optionally in combination with at least one immunotherapeutic agent.

[0177] In one embodiment, immunotherapy is chimeric antigen receptor T cell (CAR-T) therapy. In some embodiments, the composition is administered before, during or after the CAR-T therapy for treating cancer for the treatment of or prevention of at least one adverse reaction associated with CAR-T therapy. Specific adverse reactions that can be treated and / or prevented by the composition of the present disclosure include, but are not limited to, cytokine release syndrome (CRS), neurotoxicity, on-target / off-tumor recognition, allergic reactions, graft-versus-host disease (GVHD), off-target antigen recognition, and macrophage activation syndrome (MAS). Existing or developing treatments or preventions for these adverse reactions include pharmacological immunosuppression (i.e., IL-6R blockers, systemic corticosteroids such as dexamethasone, monoclonal antibodies, lymphocyte clearance chemotherapy using agents such as cyclophosphamide), suicide genes or clearance genes (i.e., killing CAR-T cells) and targeted activation (i.e., conditional activation of CAR-T cells with drugs or other agents). Therefore, in one embodiment, the therapeutic composition of the present disclosure is combined with at least one other strategy to reduce, prevent, treat or improve one or more adverse reactions associated with the immunotherapy of cancer. In one embodiment, the present disclosure provides a composition for treating or preventing the onset of adverse reactions associated with cancer immunotherapy. In one embodiment, the composition comprises at least one SCFA or a compound containing a SCFA portion. In one embodiment, immunotherapy includes CAR-T therapy. In another embodiment, immunotherapy includes therapy involving at least one other anti-cancer composition. In some embodiments, the composition is administered before, during, or after chemotherapy for the treatment of cancer.

[0178] In one embodiment, a composition comprising at least one SCFA is administered concurrently with chemotherapy: several days before CAR-T cell infusion (SCFAs alone) and up to several weeks after CAR-T cell infusion (SCFAs combined with reduced levels of the chemotherapeutic agent relative to subjects undergoing chemotherapy alone).

[0179] Pharmaceutical composition

[0180] The present disclosure includes pharmaceutical compositions comprising one or more compositions of the present disclosure. The formulations of the pharmaceutical compositions described herein can be prepared by any method known or hereafter developed in the field of pharmacology. Typically, such preparation methods include combining the active ingredient with a carrier or one or more other auxiliary ingredients, and then, if necessary or desired, shaping or packaging the product into a desired single dose unit or multiple dose units.

[0181] The composition may contain other medicinal agents, pharmaceutical preparations, carriers, buffers, adjuvants, dispersants, diluents, etc. according to the intended use and application.

[0182] 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., polymethacrylates), calcium carbonate, magnesium oxide, talc, or mixtures thereof.

[0183] The pharmaceutically acceptable carrier for liquid preparations is an aqueous or non-aqueous solution, suspension, emulsion or oil. Examples of non-aqueous solvents are propylene glycol, polyethylene glycol and injectable organic esters such as ethyl oleate. Examples of oils are oils of animal, plant or synthetic origin, for example, peanut oil, soybean oil, olive oil, sunflower oil, turmeric oil, cod liver oil, other marine oils or lipids from milk or eggs.

[0184] Aqueous carriers include water, alcohol / water solutions, emulsions or suspensions, including saline and buffered media such as phosphate buffered saline solutions, water, emulsions such as oil / water emulsions, various types of wetting agents, sterile solutions, etc. Compositions comprising such carriers can be prepared by well-known conventional methods. Suitable carriers can include any material that retains biological activity when combined with the bioactive 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, alcohol / water 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 solution, or fixed oils. Intravenous vehicles can include fluid and nutrient supplements and electrolyte supplements (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, etc. Additionally, the pharmaceutical compositions of the present disclosure may comprise a protein carrier, such as, for example, serum albumin or immunoglobulin.

[0185] The pharmaceutical compositions provided herein can also be administered as controlled-release compositions (i.e., compositions in which the active ingredients are released over a period of time after administration). Controlled-release or sustained-release compositions include formulations in lipophilic reservoirs (e.g., fatty acids, waxes, oils). In another embodiment, the composition is an immediate-release composition, i.e., a composition in which all active ingredients are released immediately after administration.

[0186] Furthermore, the pharmaceutical compositions according to the present disclosure and as described herein, or compositions comprising the compounds, in various embodiments, can be mixed into foods, functional foods, beverages, or medicinal foods for administration.

[0187] Although the description of the pharmaceutical compositions provided herein is primarily directed to pharmaceutical compositions suitable for ethical administration to humans, it will be understood by those skilled in the art that such compositions are generally suitable for administration to animals of all kinds. It is well known that pharmaceutical compositions suitable for administration to humans can be modified to make the compositions suitable for administration to various animals, and ordinary veterinary pharmacologists can design and perform such modifications with only ordinary experimentation (if any). It is contemplated that subjects to whom the pharmaceutical compositions are administered include, but are not limited to, humans and other primates, mammals (including commercially relevant mammals such as non-human primates, cattle, pigs, horses, sheep, cats, and dogs), non-mammals, and other veterinary applications.

[0188] The pharmaceutical compositions useful in the methods of the present disclosure can be prepared, packaged, or sold in formulations suitable for ocular, oral, rectal, vaginal, parenteral, topical, pulmonary, intranasal, buccal, intratumoral, epidural, intracerebral, intracerebroventricular, or other routes of administration. Other contemplated formulations include planned nanoparticles, liposomal formulations, resealed erythrocytes containing the active ingredient, and immune-based formulations.

[0189] Pharmaceutical compositions can be prepared, packaged, or sold in large quantities as a single unit dose or as a plurality of single unit doses. As used herein, a "unit dose" is a discrete amount of a pharmaceutical composition comprising a predetermined amount of an active ingredient. The amount of the active ingredient is generally equal to the dose of the active ingredient to be administered to a subject or a convenient fraction of such a dose, such as, for example, one-half or one-third of such a dose.

[0190] The relative amounts of the active ingredient, pharmaceutically acceptable carrier, and any other ingredients in the pharmaceutical composition will vary depending on the identity, size, and condition of the subject being treated and further on the route by which the composition is administered. For example, the composition may contain 0.1% to 100% (w / w) active ingredient.

[0191] In addition to the active ingredient, the pharmaceutical composition may further comprise one or more additional pharmaceutically active agents.

[0192] Controlled-release or sustained-release formulations of pharmaceutical compositions can be prepared using conventional techniques.

[0193] Pharmaceutical compositions also include nutraceutical compositions such as oral nutraceutical compositions for oral consumption and optionally for enteral absorption, wherein the nutraceutical composition comprises a compound of the present disclosure. Thus, in one embodiment, the present disclosure relates to a nutraceutical composition.

[0194] If the nutritional composition is formulated for oral administration, the composition can be a liquid oral nutritional supplement (e.g., an incomplete feed) or a complete feed. In this manner, the nutritional composition can be administered in any known form, including, for example, tablets, capsules, liquids, chewable tablets, soft gel capsules, sachets, powders, syrups, liquid suspensions, emulsions, infant formulas, and solutions in convenient dosage forms.

[0195] Nutritional formula encompasses any nutritionally comprehensive formula or supplemental formula (e.g., nutritional supplements). As used herein, "nutritionally comprehensive" is preferably a nutritional product that comprises sufficient types and levels of macronutrients (protein, fat, and carbohydrates) and micronutrients, sufficient to provide the sole nutritional source for the experimenter to whom it is applied. Patients can obtain 100% of their nutritional needs from this type of comprehensive nutritional composition. According to one embodiment, the nutritional formula is a supplemental formula providing nutritional supplements. A "supplemental formula" may not be nutritionally comprehensive, but preferably comprises specific nutrients that, for example, are combined with physical exercise to further support the beneficial effects of the disclosure and / or address the specific or additional needs of the experimenter.

[0196] The nutritional formula can be a generally applicable nutritional formula, such as a subject suitable for a specific age, such as a formula for children, but it can also be a formula for example for elderly patients, a formula for intensive care patients, or a specially adapted formula for patients with a specific disease. Any nutritional formula can be reconstituted, that is, for example, in a convenient drink in the form of a substantially dry form (e.g., powder form) or a liquid formula. The preparation of a pharmaceutical composition suitable for parenteral administration comprises an active ingredient in combination with a pharmaceutically acceptable carrier such as sterile water or sterile isotonic saline. Such preparations can be prepared, packaged or sold in a form suitable for push administration or continuous administration. Injectable preparations can be prepared, packaged or sold in unit dosage form (e.g., in an ampoule or in a multi-dose container containing a preservative). Preparations for parenteral administration include but are not limited to suspensions, solutions, emulsions in oily or aqueous solvents, pastes and implantable sustained release or biodegradable preparations. Such preparations may further comprise one or more additional ingredients, including but not limited to suspending agents, stabilizers or dispersants. In one embodiment of the formulation for parenteral administration, the active ingredient is provided in dry (ie, powder or granular) form for reconstitution with a suitable vehicle (eg, sterile pyrogen-free water) prior to parenteral administration of the reconstituted composition.

[0197] Pharmaceutical compositions can be prepared, packaged, or sold in the form of sterile injectable aqueous or oily suspensions or solutions. The suspensions or solutions can be formulated according to known techniques and, in addition to the active ingredient, may contain additional ingredients such as dispersants, wetting agents, or suspending agents as described herein. For example, such sterile injectable formulations can be prepared using non-toxic parenterally acceptable diluents or solvents 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 monoglycerides or diglycerides. Other useful parenteral formulations include formulations containing the active ingredient in microcrystalline form, formulations containing the active ingredient in liposomal formulations, or formulations containing the active ingredient as a component of a biodegradable polymer system. Compositions for sustained release or implantation may contain pharmaceutically acceptable polymers or hydrophobic materials such as emulsions, ion exchange resins, slightly soluble polymers, or slightly soluble salts.

[0198] The compositions of the present disclosure as described herein can be used as complete foods, components of foods, dietary supplements or portions of dietary supplements, feed additives, and can be in liquid, semisolid, or solid form. Additionally, the compositions of the present disclosure as described herein can be in the form of pharmaceutical compositions. The compositions, dietary supplements, foods, baby foods, feed additives, and / or pharmaceutical compositions of the present disclosure can advantageously be used in methods for promoting the health of an individual.

[0199] As described above, the composition can be in liquid, semi-solid or solid form. For example, the composition can be administered in the form of tablets, gel packs, capsules, gelatin capsules, flavored drinks, powders that can be reconstituted into such drinks, cooking oils, salad oils or dressings, sauces, syrups, mayonnaise or margarine, etc. In addition, the food and dietary supplements of the present disclosure may include, but are not limited to, dairy products, baby food, infant formula, beverages, energy bars, powders, food toppings, drinks, cereals, ice cream, candy, snack mixes, baked goods and fried foods. The beverages of the present disclosure include, but are not limited to, energy drinks, nutritional drinks, smoothies, sports drinks, orange juice and other fruit juice drinks. The energy bars of the present disclosure include, but are not limited to, meal replacements, nutritional bars, snack bars, energy bars and extruded bars, etc. The dairy products of the present disclosure include, but are not limited to, yogurt, yogurt drinks, cheese and milk.

[0200] Food or dietary supplements of the present disclosure may further comprise herbs, herbal extracts, fungal extracts, enzymes, fiber sources, minerals, and vitamins. Microalgae oil and microalgae biomass of the present disclosure may be used for compositions of therapeutic and non-therapeutic uses. Therefore, compositions, food, and animal feed additives of the present disclosure may be used for treatment or non-therapeutic purposes.

[0201] Compositions intended for oral administration can be prepared according to any known method for manufacturing dietary supplements or pharmaceutical preparations, and such compositions may contain at least one additive selected from the group consisting of taste-improving substances such as sweeteners or flavorings, stabilizers, emulsifiers, colorants, and preservatives to provide a dietary or pharmaceutically palatable preparation. The composition may also contain vitamins, minerals, and trace elements from any physiologically acceptable source.

[0202] The pharmaceutical compositions of the present disclosure comprise the compositions of the present disclosure in a therapeutically effective amount. The compositions may additionally comprise prescription or over-the-counter drugs. These combinations may advantageously produce one or more of the following effects: (1) additive and / or synergistic benefits; (2) reduction of side effects and / or adverse reactions associated with the use of prescription drugs in the absence of the 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 formulation.

[0203] The active agents of the present disclosure can be prepared in the form of their pharmaceutically acceptable salts. As will be understood by those skilled in the art, pharmaceutically acceptable salts are salts that retain the desired biological activity of the parent compound and do not produce undesirable toxic effects. "Pharmaceutically acceptable salts," as defined herein, include derivatives of the disclosed SCFAs or compounds containing SCFA moieties, wherein the parent compound is modified by making non-toxic salts of the carboxylate group of the parent compound, and further refer to pharmaceutically acceptable hydrates and solvates of such compounds. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of the carboxylic acid group of the SCFA. For example, conventional non-toxic acid salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, and nitric acid; and those derived from, for example, 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, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-aminobenzenesulfonic acid, 2-acetoxybenzoic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethanedisulfonic acid, oxalic acid, isethionic acid, and HOOC--(CH2) n-- Salts prepared from organic acids such as COOH (wherein n is 0-4). A list of other suitable salts can be found, for example, in Remington's Pharmaceutical Sciences, 17th edition, Mack Publishing Company, Easton, Pa., page 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 having 1 to 6 carbon atoms. For example, the SCFA can be present as an ethyl ester, a propyl ester, a butyl ester, an isopropyl ester, a tert-butyl ester, a pentyl ester, or a 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 edition, 1995). In the manufacture of pharmaceutical compositions according to the present disclosure, the active agent (including its physiologically acceptable salts) is typically mixed with, in particular, an acceptable carrier. Of course, the carrier must be acceptable from the perspective of compatibility with any other ingredients in the formulation and must be harmless to the subject. The carrier can be solid or liquid or both and can be formulated as a unit dose formulation with the activating agent, for example, a tablet containing 0.01% by weight or 0.5% by weight to 95% by weight or 99% by weight or any value of the activating agent between 0.01% by weight and 99% by weight. One or more activating agents can be introduced into the composition, which can be prepared by any known pharmaceutical technology, including mixing the components that optionally include one or more auxiliary ingredients. In addition, as mentioned above, the carrier can be preservative-free.

[0204] In some embodiments, the active agent comprises a lower range of 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 to an upper range of 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%, 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%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 100%, 101%, 102%, 103%, 104%, 105%, 106%, %, 15 wt %, 16 wt %, 17 wt %, 18 wt %, 19 wt %, 20 wt %, 21 wt %, 22 wt %, 23 wt %, 24 wt %, 25 wt %, 26 wt %, 27 wt %, 28 wt %, 29 wt %, 30 wt %, 31 wt %, 32 wt %, 33 wt %, 34 wt %, 35 wt %, 36 wt %, 37 wt %, 38 wt %, 39 wt %, 40 wt %, 41 wt %, 42 wt %, 43 wt %, 44 wt%, 45 wt%, 46 wt%, 47 wt%, 48 wt%, 49 wt%, 50 wt%, 51 wt%, 52 wt%, 53 wt%, 54 wt%, 55 wt%, 56 wt%, 56 wt%, 57 wt%, 58 wt%, 59 wt%, 60 wt%, 61 wt%, 62 wt%, 63 wt%, 64 wt%, 65 wt%, 66 wt%, 67 wt%, 68 wt%, 69 wt%, 70 wt%, 71 wt%, 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 100% by weight of the composition. In some embodiments, the active agent comprises from about 0.05% to about greater than 99% by weight of the composition.

[0205] Pharmaceutical compositions according to embodiments of the present disclosure are typically formulated for oral or topical (i.e., skin, eye, and mucosal surfaces) administration, with the most appropriate route in any given case depending on the nature and severity of the condition being treated and the nature of the specific active agent being used.

[0206] Topical preparations

[0207] Compositions of the present disclosure and pharmaceutical compositions comprising the compound can be topically applied, and therefore formulated in a form suitable for topical administration (i.e., as a pH-balanced cream formulation). An obstacle to topical drug administration is the stratum corneum of the epidermis. The stratum corneum is a highly resistant layer composed of protein, cholesterol, sphingolipids, free fatty acids, and various other lipids, and comprises corneocytes and living cells. One of the factors limiting the rate of penetration (flux) of a compound through the stratum corneum is the amount of the active substance that can be loaded or applied to the skin surface. The larger the amount of active substance applied to the skin per unit area, the larger the concentration gradient between the skin surface and the subcutaneous layer, and the larger the diffusion force of the active substance through the skin. Therefore, under all other conditions being equal, compared with preparations with less concentration, preparations comprising a larger concentration of active substance are more likely to cause the active substance to penetrate through the skin, and to penetrate at a more constant rate.

[0208] Preparations 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 or suspensions. In addition, preparations 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 and solids. Topical preparations can, for example, comprise an active ingredient of about 1% to about 10% (w / w), although the concentration of the active ingredient may be as high as the solubility limit of the active ingredient in the solvent. Preparations for topical administration can further comprise one or more additional ingredients described herein.

[0209] Penetration enhancers can be used. These substances increase the penetration rate of drugs through the skin. Typical enhancers in the art include ethanol, glyceryl monolaurate, PGML (polyethylene glycol monolaurate) and dimethyl sulfoxide (DMSO). Other enhancers include oleic acid, oleyl alcohol, ethoxydiglycol, laurocapram, alkanecarboxylic acids, dimethyl sulfoxide (DMSO), polar lipids or N-methyl-2-pyrrolidone. An acceptable solvent for topical delivery of some compositions can include liposomes. The composition of liposomes and their use are known in the art (e.g., referring to U.S. Patent No. 6,323,219).

[0210] In optional embodiment, can be with topically active pharmaceutical composition optionally with other compositions such as adjuvant, antioxidant, chelating agent, surfactant, foaming agent, wetting agent, emulsifying agent, tackifier, buffer and preservative etc.In another embodiment, penetration or penetration enhancer are included in composition, and are effective in improving active component percutaneous penetration and entering and passing through stratum corneum with respect to the composition lacking penetration enhancer.The various penetration enhancers comprising oleic acid, oleyl alcohol, ethoxydiglycol, laurocapram, alkanecarboxylic acid, dimethyl sulfoxide, polar lipid or N-methyl-2-pyrrolidone are well known by persons skilled in the art.On the other hand, composition can further comprise water-soluble solubilizing agent (hydrotropicagent), and it is used for increasing the disorder in the structure of stratum corneum, thereby makes the transport through stratum corneum increase.For example various water-soluble solubilizing agents such as isopropyl alcohol, propylene glycol or sodium xylene sulfonate are well known by persons skilled in the art.

[0211] Topically active pharmaceutical compositions should be applied in an amount effective to produce the desired change. As used herein, an "effective amount" means an amount sufficient to cover the surface area of the skin to be modified. In various embodiments, the active compound may be present in an amount of from about 0.0001% to about 15% by weight of the composition, from about 0.0005% to about 5% by weight of the composition, or from about 0.001% to about 1% by weight of the composition. Such compounds may be of synthetic or natural origin.

[0212] Oral preparations

[0213] The compositions of the present disclosure and the pharmaceutical compositions comprising the compound can be orally administered, and therefore are formulated in a form suitable for oral administration (i.e., as solid or liquid preparations). Suitable solid oral formulations include tablets, capsules, pills, granules and pellets (pellets) etc. Suitable liquid oral formulations include solutions, suspensions, dispersants, emulsions and oils etc. If formulated in the form of capsules, in addition to active compounds and inert carriers or diluents, the compositions of the present disclosure also include hard gelatin capsules. In one embodiment, the preparation for oral administration is an enteric coated time-release capsule (time release capsule).

[0214] Formulations suitable for oral administration can be present as discrete units such as capsules, cachets, lozenges or tablets, each containing a predetermined amount of the active compound; as powders or granules; as solutions or suspensions in aqueous or non-aqueous liquids; or as oil-in-water or water-in-oil emulsions. Such formulations can be prepared by any suitable pharmaceutical method comprising combining the active compound with a suitable carrier (which may contain one or more auxiliary ingredients as described above). Generally, the formulations of the present disclosure are prepared by uniformly and intimately mixing the active compound with a liquid carrier or a finely divided solid carrier or both, and then shaping the resulting mixture as desired. For example, tablets can be prepared by compressing or molding a powder or granules containing the active compound, optionally with one or more auxiliary ingredients. Compressed tablets can be prepared by compressing a free-flowing form of the compound (e.g., powder or granules), optionally mixed with a binder, lubricant, inert diluent and / or surfactant / dispersant, in a suitable machine. Molded tablets can be made by molding a powdered compound moistened with an inert liquid binder in a suitable machine.

[0215] Preparations for other routes of administration

[0216] The compositions of the present disclosure and pharmaceutical compositions containing the compounds may also be administered intranasally (ie, by inhalation) and, therefore, may be formulated in a form suitable for intranasal administration (ie, as an aerosol or liquid formulation).

[0217] The compositions of the present disclosure can also be formulated for parenteral administration. Preparations suitable for pharmaceutical compositions for parenteral administration include active ingredients in combination with pharmaceutically acceptable carriers such as sterile water or sterile isotonic saline. Such preparations can be prepared, packaged or sold in a form suitable for push administration or continuous administration. Injectable preparations can be prepared, packaged or sold in unit dosage form (e.g., in ampoules or in multi-dose containers containing preservatives). Preparations for parenteral administration include but are not limited to suspensions, solutions, emulsions in oily or aqueous solvents, pastes and implantable sustained release or biodegradable preparations. Such preparations may further include one or more additional ingredients, including but not limited to suspending agents, stabilizers or dispersants. In one embodiment of a preparation for parenteral administration, the active ingredient is provided in a dry (i.e., powder or granular) form for reconstitution with a suitable solvent (e.g., sterile pyrogen-free water) before parenteral administration of the reconstitution composition.

[0218] Pharmaceutical compositions can be prepared, packaged, or sold in the form of sterile injectable aqueous or oily suspensions or solutions. The suspensions or solutions can be formulated according to known techniques and, in addition to the active ingredient, may contain additional ingredients such as dispersants, wetting agents, or suspending agents as described herein. For example, such sterile injectable formulations can be prepared using non-toxic parenterally acceptable diluents or solvents 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 monoglycerides or diglycerides. Other useful parenteral formulations include formulations containing the active ingredient in microcrystalline form, formulations containing the active ingredient in liposomal formulations, or formulations containing the active ingredient as a component of a biodegradable polymer system. Compositions for sustained release or implantation may contain pharmaceutically acceptable polymers or hydrophobic materials such as emulsions, ion exchange resins, slightly soluble polymers, or slightly soluble salts. The formulation is prepared using a pharmaceutically acceptable "carrier" composed of materials that are considered safe and effective and can be administered to an individual without causing undesirable biological side effects or unwanted interactions. A "carrier" is all components other than the active ingredient(s) present in a pharmaceutical formulation. The term "carrier" includes, but is not limited to, diluents, binders, lubricants, disintegrants, fillers, and coating compositions.

[0219] " carrier " also comprises all components of coating composition, and it can comprise plasticizer, pigment, coloring agent, stabilizer and glidant.Delayed release preparation can be such as " Pharmaceutical dosage form tablets ", people such as Liberman compile (New York, Marcel Dekker, Inc., 1989), " Remington--The science and practice of pharmacy ", the 20th edition, Lippincott Williams&Wilkins, Baltimore, Md., 2000 and " Pharmaceutical dosage forms and drug delivery systems ", the 6th edition, people such as Ansel (Media, Pa.:Williams and Wilkins, 1995) etc. described in reference list prepare, described reference list provides about the information of carrier, material, equipment and technology for the preparation of delayed release dosage form of tablet, capsule and tablet, capsule and granule.

[0220] Examples of suitable coating materials include, but are not limited to, cellulosic 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 the like. (Roth Pharma, Westerstadt, Germany) commercially available methacrylic resins, zein, shellac, and polysaccharides.

[0221] In addition, the coating material may contain conventional carriers such as plasticizers, pigments, colorants, glidants, stabilizers, pore formers and surfactants.

[0222] The optional pharmaceutically acceptable excipient present in the tablet, bead (bead), granule or microparticle containing medicine includes but is not limited to diluent, adhesive, lubricant, disintegrating agent, coloring agent, stabilizer and surfactant.Conventionally need diluent (also referred to as " filler ") to increase the volume of solid dosage form, thus for the compression of tablet or the formation of bead and granule provide practical size.Suitable diluent includes but is 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 icing sugar.

[0223] Adhesive is used to give cohesiveness to solid preparations, thereby ensures that tablet, bead or granule remain intact after forming dosage form.Suitable adhesive materials include but are not limited to starch, pregelatinized starch, gelatin, sugar (including sucrose, glucose, dextrose, lactose and sorbitol), polyethylene glycol, wax, natural gum and synthetic gum (such as gum arabic, tragacanth gum, sodium alginate), cellulose (including hydroxypropyl methylcellulose, hydroxypropyl cellulose, ethyl cellulose and magnesium aluminum silicate (veegum)) and synthetic polymers such as acrylic acid and methacrylic acid copolymer, methacrylic acid copolymer, methyl methacrylate copolymer, methacrylic acid aminoalkyl ester copolymer, polyacrylic acid / polymethacrylic acid and polyvinyl pyrrolidone.

[0224] Lubricants are used to facilitate tablet manufacture. Examples of suitable lubricants include, but are not limited to, magnesium stearate, calcium stearate, stearic acid, glyceryl behenate, polyethylene glycol, talc, and mineral oil.

[0225] Disintegrants are used to promote 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 carboxymethyl cellulose, hydroxypropyl cellulose, pregelatinized starch, clays, celluloses, alginines, gums, or cross-linked polymers such as cross-linked PVP (Polyplasdone XL from GAF Chemical Corp).

[0226] Stabilizers are used to inhibit or retard drug decomposition reactions, including, for example, oxidation reactions.

[0227] Surfactant can be anionic surfactant, cationic surfactant, amphoteric surfactant or nonionic surfactant. Suitable anionic surfactant includes but is not limited to those comprising carboxylate ion, sulfonate ion and sulfate ion. The example of anionic surfactant includes long chain alkyl sulfonate and alkyl aryl sulfonate of sodium type, potassium type and ammonium type, such as sodium dodecylbenzenesulfonate; dialkyl sodium sulfosuccinate, such as sodium dodecylbenzenesulfonate; dialkyl sodium sulfosuccinate, such as bis-(2-ethylsulfinyl (ethylthioxyl))-sodium sulfosuccinate; and alkyl sulfate such as sodium lauryl sulfate. Cationic surfactant includes but is 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, 401, stearyl monoisopropanolamide and polyoxyethylene hydrogenated tallow amide. Examples of amphoteric surfactants include sodium N-dodecyl-β-alanine, sodium N-lauryl-β-iminodipropionate, myristoamphoacetate, lauryl betaine and lauryl sulfobetaine.

[0228] If desired, tablets, beads, granules or microparticles may also contain minor amounts of non-toxic auxiliary substances such as wetting or emulsifying agents, dyes, pH buffering agents and preservatives.

[0229] As will be understood by those skilled in the art and as described in the relevant texts and literature, many methods can be used to prepare tablets, beads, granules or microparticles containing drugs that provide a variety of drug release profiles. Such methods include, but are not limited to, coating the drug or drug-containing composition with an appropriate coating material, which is usually (but not necessarily) incorporated into a polymeric material, increasing the drug particle size, placing the drug within a matrix, and forming a complex of the drug with a suitable complexing agent.

[0230] The delayed-release dosage units can be coated with the delayed-release polymer coating using conventional techniques, for example, using conventional coating pans, airless spray techniques, or 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, Lieberman et al., eds. (New York: Marcel Dekker, Inc., 1989) and Ansel et al., Pharmaceutical Dosage Forms and Drug Delivery Systems, 6th ed. (Media, Pa.: Williams & Wilkins, 1995).

[0231] The exemplary method for preparing sustained-release tablets is to compress the blend containing the medicine, for example, the blend of particles prepared using direct compounding, wet granulation process or dry granulation process. Sustained-release tablets can also be molded (molded) rather than compressed (compressed) starting from the moistening material comprising a suitable water-soluble lubricant. However, compression rather than molding is used to manufacture tablets. The method for forming the blend containing the medicine of sustained release is to mix the drug particles directly with one or more excipients such as diluent (or filler), adhesive, disintegrant, lubricant, glidant and colorant. As an alternative to direct compounding, the blend containing the medicine can be prepared using wet granulation process or dry granulation process. The beads containing the active agent can also be prepared usually from a fluid dispersion by any of many conventional techniques. For example, a typical method for preparing drug-containing beads involves dispersing or dissolving the active agent in a coating suspension or solution containing pharmaceutically acceptable excipients such as polyvinyl pyrrolidone, methylcellulose, talc, metal stearates, silicon dioxide, or plasticizers. This mixture is used to coat bead cores such as sugar spheres (or so-called "non-pareil") having a size of about 60 to 20 mesh.

[0232] An alternative procedure for preparing drug beads is by compounding the drug with one or more pharmaceutically acceptable excipients such as microcrystalline cellulose, lactose, cellulose, polyvinyl pyrrolidone, talc, magnesium stearate, disintegrants, etc., extruding the blend, spheronizing the extrudate, drying and optionally coating to form immediate release beads.

[0233] Delayed release formulations are generated by coating the 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 the drug or a composition containing the drug with a selected coating material. The composition containing the drug can be, for example, a tablet for loading into a capsule, a tablet for use as an inner core in a "coated core" dosage form, or a plurality of drug-containing beads, microparticles, or granules for loading into a tablet or capsule. Exemplary coating materials include bioerodible polymers, gradually hydrolyzed polymers, gradually water-soluble polymers, and / or enzymatically degradable polymers, and can be conventional "enteric" polymers. As will be appreciated by those skilled in the art, enteric polymers become soluble in the higher pH environment of the lower digestive tract or slowly erode as the dosage form passes through the digestive tract, while enzymatically degradable polymers are degraded by bacterial enzymes present in the lower digestive tract (particularly the colon). Suitable coating materials for achieving delayed release include, but are not limited to, cellulosic polymers such as hydroxypropylcellulose, hydroxyethylcellulose, hydroxymethylcellulose, hydroxypropylmethylcellulose, hydroxypropylmethylcellulose acetate succinate, hydroxypropylmethylcellulose phthalate, methylcellulose, ethylcellulose, cellulose acetate, cellulose acetate phthalate, cellulose acetate trimellitate, and sodium carboxymethylcellulose; acrylic acid polymers and copolymers (e.g., formed from acrylic acid, methacrylic acid, methyl acrylate, ethyl acrylate, methyl methacrylate, and / or ethyl methacrylate), and the like commercially available cellulose acetate polymers and copolymers. Other methacrylic resins commercially available from Rohm Pharma (Westerstadt, Germany) include L30D-55 and L100-55 (soluble above pH 5.5), L-100 (soluble above pH 6.0), S (soluble above pH 7.0 due to a higher degree of esterification) and NE, RL, and RS (water-insoluble polymers with varying degrees of permeability and swellability); vinyl polymers and copolymers such as polyvinyl pyrrolidone, vinyl acetate, vinyl acetate phthalate, vinyl acetate crotonic acid copolymer, and ethylene-vinyl acetate copolymer; enzymatically degradable polymers such as azo polymers, pectin, chitosan, amylose, and guar gum; zein and shellac. Combinations of different coating materials can also be used. Multilayer coatings using different polymers can also be applied.

[0234] The coating composition can include conventional additives, such as plasticizers, pigments, colorants, stabilizers, glidants, etc. Plasticizers are usually present to reduce the brittleness of the coating, and usually will be about 10% by weight to 50% by weight of the dry weight of the polymer. The example of a typical plasticizer includes polyethylene glycol, propylene glycol, triacetin, dimethyl phthalate, diethyl phthalate, dibutyl phthalate, dibutyl sebacate, triethyl citrate, tributyl citrate, acetyl triethyl citrate, castor oil, and acetylated monoglyceride. Stabilizers are used to stabilize the microparticles in the dispersion. Typical stabilizers are nonionic emulsifiers such as sorbitan esters, polysorbate, and polyvinyl pyrrolidone. Flow aids are suggested for reducing the adhesion effect between film formation and the drying period, and usually will be about 25% by weight to 100% by weight of the polymer weight in the coating solution. An effective flow aid is talc. Other glidants such as magnesium stearate and glyceryl monostearate may also be used. Pigments such as titanium dioxide may also be used. Small amounts of defoaming agents such as silicones (e.g., simethicone) may also be added to the coating composition.

[0235] Microparticles can be prepared entirely from the therapeutic agent or from a combination of the agent and a surfactant. Microparticles 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 lightweight microparticles. Other suitable materials include, but are not limited to, gelatin, polyethylene glycol, trehalose, and dextran. Based on factors such as the microparticle material, microparticles can be designed and manufactured with degradation and release times ranging from seconds to months.

[0236] In addition to the therapeutic or diagnostic agent (or possibly other desired molecules for delivery), the microparticles may also contain excipients, such as sugars (eg, lactose), proteins (eg, albumin), and / or surfactants.

[0237] As used herein for enteric coated capsules: "gastric acid 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 that can be used for surface coating and is applied by spraying, brushing, or various industrial processes, which undergoes film formation. In most film-forming processes, a relatively low viscosity liquid coating is applied to a solid substrate and solidified into a solid, high molecular weight, polymer-based adhesive film having the properties desired by the user. For the most common applications, the thickness of the film ranges from 0.5 to 500 microns (0.0005 to 0.5 mm or 0.00002 to 0.02 inches).

[0238] As used herein, "gelling agent" refers to a substance that undergoes a high degree of crosslinking or association when hydrated and dispersed in a dispersion medium, or when dissolved in a dispersion medium. This crosslinking or association of the dispersed phase changes the viscosity of the dispersion medium. The movement of the dispersion medium is restricted by the dispersed phase, and the viscosity increases.

[0239] Gastric acid resistant film-forming compositions comprising (1) a gastric acid resistant natural polymer, (2) a film-forming natural polymer, and optionally (3) a gelling agent are described herein. Exemplary gastric acid resistant natural polymers include, but are not limited to, pectins and pectin-like polymers, which are typically composed 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 polygalacturonic acid, rhamnogalacturonic acid, and some arabinans, galactans, and arabinogalactans. These are typically classified according to the degree of esterification. In high (methyl) ester ("HM") pectins, a relatively high proportion of carboxyl groups are present as methyl esters, and the remaining carboxylic acid groups are in the form of free acids or their ammonium salts, potassium salts, calcium salts, or sodium salts.

[0240] The usable properties may vary with the degree of esterification and the degree of polymerization. Pectins in which less than 50% of the carboxylic acid units are present as methyl esters are commonly referred to as low (methyl) esters or LM-pectins. Typically, low-ester pectins are obtained by treating high-ester pectins under mild acidic or alkaline conditions. Amidated pectins are obtained from high-ester pectins when ammonia is used in an alkaline deesterification process. In this type of pectin, some of the remaining carboxylic acid groups have been converted into acid amides. The usable properties of amidated pectins may vary with the ratio of ester and amide units and the degree of polymerization. In one embodiment, the gastric acid-resistant natural polymer is pectin. The gastric acid-resistant natural polymer is present in an amount of less than about 5% (e.g., about 2% to about 4% by weight) of the composition.

[0241] 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.

[0242] The film-forming natural polymer is present in an amount from about 20% to about 40% by weight of the composition (eg, from about 25% to about 40% by weight of the composition).

[0243] The composition may optionally contain a gelling agent. Exemplary gelling agents include divalent cations such as Ca 2+ and Mg 2+ Sources of such 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 (eg, less than about 1% by weight of the composition).

[0244] One or more plasticizers can be added to the composition to promote film forming process. Suitable plasticizers include glycerine (glycerin), sorbitol, sorbitol, maltitol, glycerine (glycerol), polyethylene glycol, polyols with 3 to 6 carbon atoms, citric acid, citric acid esters, triethyl citrate and combinations thereof. The concentration of one or more plasticizers is about 8% to about 30% of a composition weight. In one embodiment, the plasticizer is glycerine and / or sorbitol.

[0245] The film-forming composition can be used to prepare soft or hard shell gelatin capsules that can encapsulate liquid or semisolid fill materials or solid tablets containing an active agent and one or more pharmaceutically acceptable excipients. Alternatively, the composition may be administered as a liquid in which the active agent is dissolved or dispersed in the composition.

[0246] The film-forming composition 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 filled formulation is fed to the encapsulation machine by gravity.

[0247] The capsule shell may comprise one or more plasticizers selected from the group consisting of glycerin, sorbitol, sorbitan, maltitol, glycerol, polyethylene glycol, polyols having 3 to 6 carbon atoms, citric acid, citric acid esters, triethyl citrate, and combinations thereof.

[0248] In addition to plasticizers, the capsule shell may contain other suitable shell additives such as opacifiers, colorants, humectants, preservatives, flavorings, and buffer salts and acids.

[0249] When the encapsulated active agent is light sensitive, an opacifier is used to render the capsule shell opaque. Suitable opacifiers include titanium dioxide, zinc oxide, calcium carbonate, and combinations thereof.

[0250] Colorants may be used for marketing and product identification / differentiation purposes. Suitable colorants include synthetic dyes, natural dyes, and combinations thereof.

[0251] Can use wetting agent to suppress the water activity of soft gel.Suitable wetting agent comprises glycerine and sorbitol that are often used as the component of plasticizer composition.Because the water activity of dry properly stored soft gel is low, therefore the biggest risk from microorganism comes from mold and yeast.For this reason, can introduce preservative into capsule shell.Suitable preservative comprises alkyl ester of p-hydroxybenzoic acid such as methyl parahydroxybenzoate, ethyl parahydroxybenzoate, propyl parahydroxybenzoate, butyl parahydroxybenzoate and heptyl parahydroxybenzoate (being collectively referred to as " parahydroxybenzoate ") or its combination.

[0252] Flavorings can be used to mask unpleasant odors and flavors in filled formulations. Suitable flavorings include both synthetic and natural flavorings. The use of flavorings can be problematic due to the presence of aldehydes, which can crosslink gelatin. Consequently, buffer salts and acids can be used with flavorings containing aldehydes to inhibit crosslinking of gelatin.

[0253] 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 whole organisms.

[0254] Filled formulations can be prepared using a pharmaceutically acceptable carrier consisting of a material that is considered safe and effective, and can be applied to an individual without causing undesirable biological side effects or unwanted interactions. A carrier is all the components present in a pharmaceutical formulation except for one or more active ingredients. As commonly used herein, a "carrier" includes but is not limited to surfactants, humectants, plasticizers, crystallization inhibitors, wetting agents, bulk fillers (bulkfilling agent), solubilizing agents, bioavailability enhancers, pH regulators, and combinations thereof.

[0255] Alternatively, the composition can be administered as a liquid in which the active agent is dissolved (eg, a solution) or dispersed (eg, a suspension) in the composition.

[0256] Suitable active agents are as described above. Solutions or suspensions 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 regulators, flavorings, adhesives, disintegrants, antisticking agents, antistatic agents, surfactants, antioxidants, coating agents, colorants, preservatives, suspending agents, emulsifiers, antimicrobials, spheronization agents, stabilizers, tension enhancers, buffers, and any combination thereof.

[0257] Mucoadhesive particles and methods of manufacture: Generally speaking, adhesion of polymers to tissue can be achieved through (i) physical or mechanical bonding, (ii) primary chemical or covalent chemical bonds, and / or (iii) secondary chemical bonds (e.g., ionic bonds). Physical or mechanical bonding can result from deposition and coating of the adhesive material within the crevices of mucus or the folds of the mucosa. Secondary chemical bonds that contribute to bioadhesive properties are composed of dispersive interactions (e.g., van der Waals interactions) and stronger specific interactions (including hydrogen bonds). The hydrophilic functional groups responsible for hydrogen bonding are hydroxyl (-OH) and carboxyl (-COOH) groups.

[0258] As described in detail below, adhesive polymer microspheres are selected based on the physical and chemical bonds that form depending on the chemical composition and physical properties (e.g., surface area). These microspheres are characterized by an adhesion force to the mucosa greater than 11 mN / cm 2 The sizes of these microspheres range from nanoparticles to millimeters in diameter. Adhesion depends on the polymer composition, biological matrix, particle morphology, particle geometry (e.g., diameter), and surface modification.

[0259] Can be used for forming the classification of the polymer of bioadhesive microsphere: can be used for forming the suitable polymer of bioadhesive microsphere and comprise soluble and insoluble, biodegradable and non-biodegradable polymer.These can be hydrogel or thermoplastic, homopolymer, copolymer or blend (natural or synthetic).Yet a key feature is, when being applied to rat intestinal mucosa surface, polymer must produce at 110N / m 2 (11mN / cm 2 ) and 100,000N / m 2 bioadhesive interactions between them.

[0260] In order for the bioadhesive particles to become embedded or entrapped in the mucus lining the gastrointestinal tract, the radius of a single particle should be the same as the thickness of the natural mucus layer. The gastric mucus layer has been shown to be typically 5 to 200 microns thick in rats and 10 to 400 microns thick in humans. However, it can sometimes reach a thickness of up to 1000 microns in humans, as described in Spiro, RG, "Glycoproteins," Annual Review of Biochemistry, 39, 599-638, 1970; Labat-Robert, J. & Decaeus, C., "Glycoproteins du Mucus Gastrique: Structure, Function, et Pathologie," Pathologie et Biologie (Paris), 24, 241, 1979; Allen, A., Hutton, DA, Pearson, JP, & Sellers, LA, "Mucus Glycoprotein Structure, Gel Formation and Gastrointestinal Mucus Function," in Mucus and Mucosa, Ciba Foundation Symposium 109 (eds. J. Nugent & M. O'Connor), p. 137 (London: Pitman, 1984). In the past, two classes of polymers appeared to exhibit useful bioadhesive properties: hydrophilic polymers and hydrogels. Among a broad 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 concentration of carboxyl groups should be the preferred materials for bioadhesion to soft tissue. Other studies have shown the most promising polymers to be sodium alginate, carboxymethyl cellulose, hydroxymethyl cellulose, and methyl cellulose. Some of these materials are water-soluble, while others are hydrogels.

[0261] Rapidly bioerodible polymers such as poly(lactide-co-glycolide), polyanhydrides, and polyorthoesters, which expose carboxyl groups on the outer surface as their smooth surfaces erode, are excellent candidates for bioadhesive drug delivery systems. Furthermore, polymers such as polyanhydrides and polyesters that contain unstable bonds are well known for their hydrolytic reactivity. Their hydrolytic degradation rates can often be altered by simple changes in the polymer backbone.

[0262] 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, acrylate and methacrylate and alginic acid polymers. Representative synthetic polymers include polyphosphazenes, poly(vinyl alcohol), polyamides, polycarbonates, polyalkylenes, polyacrylamides, polyalkylene glycols, polyalkylene oxides, polyalkylene terephthalates, polyvinyl ethers, polyvinyl esters, polyvinyl halides, polyvinyl pyrrolidone, polyglycolide, polysiloxanes, polyurethanes and copolymers thereof. Synthetic modified natural polymers include alkyl celluloses, hydroxyalkyl celluloses, cellulose ethers, cellulose esters and nitrocellulose. Other polymers of interest include, but are not limited to, methylcellulose, ethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxybutylmethylcellulose, cellulose acetate, cellulose propionate, cellulose acetate butyrate, cellulose acetate phthalate, carboxymethylcellulose, 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, polyvinyl pyrrolidone, and polyvinyl phenol. Representative bioerodible polymers include polylactide, polyglycolide and copolymers thereof, poly(ethylene terephthalate), poly(butyric acid), poly(valeric acid), poly(lactide-co-caprolactone), poly[lactide-co-glycolide], polyanhydrides, polyorthoesters, blends and copolymers thereof.

[0263] The pharmaceutically acceptable compounds of the present disclosure will typically be administered to a subject on a daily dosage regimen. For adult subjects, this may be, for example, an oral dose of between 0.1 grams and 15 grams of the at least one SCFA or compound containing a SCFA portion. In further embodiments, the oral dose of the at least one SCFA or compound containing a SCFA portion may be between 0.5 grams and 10 grams. In yet further embodiments, the oral dose of the at least one SCFA or compound containing a SCFA portion may be between 0.5 grams and 6 grams.

[0264] The pharmaceutical composition can be administered 1, 2, 3, 4 or more times per day. Thus, in certain embodiments, for example, a composition formulated for topical administration can be administered multiple times per day.

[0265] In one embodiment, a composition comprising a first SCFA and a second SCFA in a 1:1 (w / w) ratio is contemplated, wherein 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, a first SCFA and a second SCFA in a 2:1, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, 9:1, or 10:1 (w / w) ratio may be present, wherein 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 may vary from the ratios disclosed above. For example, any amount of a 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 a 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. Such amounts of either supplement can be mixed in one composition or can be in different compositions.

[0266] The pharmaceutical composition can be administered topically or systemically (e.g., by direct injection of the compound into an organ, optionally in a reservoir formulation or sustained release formulation or implant). The pharmaceutical composition can be provided in the form of a rapid release formulation, in the form of a sustained release formulation, or in the form of a moderate release formulation. Rapid release forms can provide immediate release. Sustained release formulations can provide controlled release or sustained delayed release.

[0267] In practicing the treatment or use methods provided herein, a therapeutically effective amount of a compound described herein is administered as a pharmaceutical composition to a subject suffering from the disease or condition to be treated. In some embodiments, the subject is a mammal, such as a human. The therapeutically effective amount can vary greatly depending on the severity of the disease, the age and relative health status of the subject, the efficacy of the compound used, and other factors. The compound can be used alone or in combination with one or more therapeutic agents as a component of a mixture.

[0268] Methods for preparing compositions comprising the compounds described herein include formulating the compounds with one or more inert, pharmaceutically acceptable excipients or carriers to form solid, semisolid, or liquid compositions. Solid compositions include, for example, powders, tablets, dispersible granules, capsules, and cachets. Liquid compositions include, for example, solutions in which the compound is dissolved, emulsions containing the compound, or solutions containing liposomes, micelles, or nanoparticles containing the compounds as disclosed herein. Semisolid compositions include, for example, gels, suspensions, and creams. The compositions can be liquid solutions or suspensions, solid forms suitable for dissolution or suspension in a liquid prior to use, or emulsions. These compositions may also contain small amounts of non-toxic auxiliary substances, such as wetting or emulsifying agents, pH buffers, and other pharmaceutically acceptable additives.

[0269] 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.

[0270] Compositions of the present disclosure can be, for example, quick-release forms or controlled-release formulations. Quick-release formulations can be formulated to allow the compound to act quickly. Non-limiting examples of quick-release formulations include easily soluble formulations. Controlled-release formulations can be pharmaceutical formulations that have been adjusted to allow the release rate and release profile of the active agent to match physiological and time treatment requirements, or alternatively, the pharmaceutical formulation has been formulated to achieve the release of the active agent at a programmed rate. Non-limiting examples of controlled-release formulations include granules, delayed-release granules, hydrogels (e.g., synthetic or natural origin), other gelling agents (e.g., dietary fiber forming a gel), matrix-based formulations (e.g., formulations comprising a polymeric material in which at least one active ingredient is dispersed), granules, polymer mixtures, and particulate matter within the matrix.

[0271] In some embodiments, the controlled release formulation is a delayed release form. The delayed release form can be formulated to delay the effect of the compound for an extended period of time. The delayed release form can be formulated to delay the release of one or more compounds of an effective dose for, for example, about 4 hours, about 8 hours, about 12 hours, about 16 hours, or about 24 hours.

[0272] Controlled release formulations can be sustained release forms. Sustained release forms can be formulated to allow, for example, the effects of a compound to continue for an extended period of time. Sustained release forms can be formulated to provide an effective dose of any compound described herein (e.g., to provide a physiologically effective blood profile) in about 4 hours, about 8 hours, about 12 hours, about 16 hours, or about 24 hours.

[0273] Non-limiting examples of pharmaceutically acceptable excipients can be found in, e.g., Remington: The Science and Practice of Pharmacy, 19th 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, 7th ed. (Lippincott Williams & Wilkins 1999), each of which is incorporated by reference in its entirety.

[0274] The subject can be, for example, an elderly person, an adult, a teenager, a pre-adolescent, a child, a toddler, an infant, a newborn, and a non-human animal. In some embodiments, the subject is a patient.

[0275] The methods disclosed herein involve administering the compounds disclosed herein as part of a pharmaceutical composition. In some embodiments, the compositions of the compounds disclosed herein can comprise a liquid containing the active agent in solution, in 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 that can gel in situ. In some embodiments, the composition is an aqueous solution that can gel in situ.

[0276] The pharmaceutically acceptable excipient may be present in the pharmaceutical composition at a mass level of about 0.1% to about 99% by mass of the composition. For example, a pharmaceutically acceptable excipient can be present in the pharmaceutical composition at 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% by mass of the formulation.

[0277] The pharmaceutically acceptable excipient can be present in an amount of 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 %, 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%, 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% are present.

[0278] Subject / patient population

[0279] The subject can be a human, such as an elderly person, an adult, a teenager, a pre-adolescent, a child, a toddler, an infant, a newborn, and a non-human animal, such as a mouse. In some embodiments, the subject is a patient. In some embodiments, the subject has experienced and / or exhibited at least one symptom of the disease or condition to be treated and / or the likelihood of which is to be reduced. In some embodiments, the subject has been identified or diagnosed as having a liver disease or condition, such as NASH, as described herein.

[0280] In some embodiments, the methods of treatment disclosed herein include identifying a patient population based on one or more selection criteria (e.g., biomarkers, inability to respond to primary 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 specific disease, markers associated with a poor prognosis for the disease), inability to respond to initial therapy, the patient's age, sex, health status. The screening process may include, but is not limited to, blood and / or tissue sample analysis, genetic testing, genetic screening, biopsy, drug sensitivity / resistance testing.

[0281] The methods disclosed herein involve administering the compounds disclosed herein as part of a pharmaceutical composition. In some embodiments, the pharmaceutical composition comprises a compound as described herein and a pharmaceutically acceptable excipient. In some embodiments, the composition of the compounds disclosed herein may comprise a liquid containing the active agent in solution, in 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 aqueous composition that can gel in situ. In some embodiments, the composition is an aqueous solution that can gel in situ.

[0282] Drug administration

[0283] The pharmaceutical compositions described herein can be unit dosage forms suitable for single administration of precise doses. In unit dosage forms, the preparation is divided into unit doses containing an appropriate amount of one or more compounds. The unit dose can be in the form of a package containing a discrete amount of preparation. Non-limiting examples are packaged injections, vials, or ampoules. The aqueous suspension composition can be packaged in a single dose non-re-sealable container. Multi-dose re-sealable containers can be used, for example, in combination with a preservative or in the absence of a preservative. Preparations for parenteral injection can be present in unit dosage form, for example, in ampoules or in multi-dose containers with a preservative.

[0284] The compounds described herein can be present in the composition at 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. The present invention also provides a range of about 150 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.

[0285] The compounds described herein can be administered in compositions at 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 About 180 mg, 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 are present.

[0286] 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, a compound disclosed herein is administered at 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. g, 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 of the subject.

[0287] Dosage regimen

[0288] Dosage regimen disclosed herein can be, for example, once a day, twice a day, three times a day, once a week, twice a week, or three times a week. In some embodiments, the compound disclosed herein is administered once a day. In some embodiments, the compound disclosed herein is administered once a day for 28 days (one cycle). In some embodiments, the compound disclosed herein is administered once a day in one or more 28-day cycles. In some embodiments, the compound disclosed herein is administered once a day for 3 weeks, then not administered for 1 week for a four-week cycle.

[0289] The compounds described herein can be administered before, during, or after the disease or condition occurs, and the timing of administering the composition comprising the compound can vary. For example, the compound can be used as a prophylactic and can be continuously administered to a subject susceptible to a condition or disease to reduce or lower the likelihood of the disease or condition occurring. The compounds and compositions can be administered to the subject as soon as possible during or 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 performed using any formulation described herein via any practicable route, for example, by any route described herein.

[0290] The compound can be administered as soon as possible after the onset of the disease or condition is detected or suspected and for the length of time required to treat the disease, such as, for example, from about 1 month to about 3 months. In some embodiments, the length of time the compound can be administered can be 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, about 9 months, 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, about 9 months, about 10 The length of treatment can be different for each subject.

[0291] The dosage regimen of the compounds described herein can be consistent over the duration of the dosing regimen. For example, the compound can be administered daily. Alternatively, or in addition, the dosage regimen of the compounds described herein can include a portion of the time during which administration is suspended. For example, the compound can be administered daily for 3 weeks, followed by no administration for 1 week.

[0292] The administration dosage regimen of the compound described herein may 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, the daily dose can be administered as a single dose or divided into multiple doses to be administered at intervals (e.g., twice a day or three times a day). For example, a daily dose of 100 mg can be administered, for example, once a day (100 mg), twice a day (50 mg per dose).

[0293] Multiple therapeutic agents can be used in any order or simultaneously. In some embodiments, a compound of the present disclosure is administered in combination with another therapeutic agent (for example, a medicine, such as an aromatase inhibitor), administered before being treated with the another therapeutic agent, or administered after being treated with the another therapeutic agent. In some embodiments, a compound of the present disclosure is administered at fixed intervals (such as, for example, once a day, twice a day, three times a day, etc.) and the second therapeutic agent is administered daily or intermittently or as needed. If it is simultaneous, multiple therapeutic agents can be provided in a single unified form or in multiple forms (for example, with multiple separate unit dosage forms). Medicaments can be packaged together or separately, packaged in a single package or in multiple packages. One or all therapeutic agents can be administered in multiple doses. If not simultaneously, the time between multiple dosages can vary up to about 1 month.

[0294] Reagent test kit

[0295] The disclosure also includes a kit comprising a compound useful in the methods of the disclosure and instructional materials describing, for example, methods of administering the composition as described elsewhere herein. In one embodiment, the kit comprises a composition.

[0296] Experimental example

[0297] The present invention is further described in detail by reference to the following experimental examples. These examples are provided for illustrative purposes only and, unless otherwise indicated, are not intended to be limiting. Therefore, the present invention should in no way be construed as being limited to the following examples, but rather should be construed as encompassing any and all variations that become apparent as a result of the teachings provided herein.

[0298] Without further description, it is believed that one of ordinary skill in the art can use the foregoing description and the following illustrative examples to make and use the present invention and practice the claimed methods. Therefore, the following working examples should not be construed as limiting the remainder of the disclosure in any way.

[0299] Example 1: Combination therapy for nonalcoholic steatohepatitis (NASH) and fibrosis

[0300] Given the complex pathophysiology of NASH, this study developed a novel therapy for NASH using a unique combination of short-chain fatty acids (SCFAs), butyrate and acetate (both targeting multiple mechanisms involved in the pathogenesis of NASH) and the antioxidant vitamin E (at a safer dose).

[0301] Disclosure: A unique combination of the Ca / Mg salts of butyrate (2.4 g daily) and tocopheryl acetate (a source of acetate [12 mg] vitamin E [200 IU]) was developed that provides an effective treatment for NASH with or without fibrosis.

[0302] Patients diagnosed with NAFLD are also treated with the composition to prevent progression of NAFLD to NASH and / or fibrosis.

[0303] Example 2: Treatment with short-chain fatty acids - evaluation of preventing progression of NASH to fibrosis in a preclinical model of aged mice

[0304] like Figure 1-9 As shown and described, various assays were designed and tested to assess the prevention of progression of NASH to fibrosis.

[0305] mice

[0306] All mice were fed a high fat diet (HFD) starting at 56 weeks of age until euthanasia at 76 weeks of age (Groups 1, 2, and 5) or 84 weeks of age (Groups 2, 4, and 6) (Table 1). Groups 1-4 also received 20.5 mg / kg / mouse / day of tocopherol acetate.

[0307] Mice were fed a high-fat diet (HFD) starting at 56 weeks of age. At 64 weeks of age, half of the mice were fed a high-dose SCFA, a low-dose SCFA, or no drug (day 0) for 12 weeks until euthanasia (day 84) (Table 1 and Figure 1 The other half of the mice were divided into the same groups, but fed SCFA starting at 72 weeks of age and continued for 12 weeks until euthanasia.

[0308] Table 1. Example experimental design

[0309]

[0310] weight

[0311] Body weights were measured in all C57 / BL6 male mice throughout the study period in each study ( Figure 1 No effect on body weight loss was observed in mice in groups 2 and 4 treated with low-dose SCFA ( Figure 1Although mice in groups 1 and 3 fed a high dose of SCFAs lost up to 20% of their body weight during the first few weeks of SCFA feeding ( Figure 1 ), but these mice showed no changes in food intake, body appearance, or activity, indicating no overt toxicity.

[0312] H&E staining

[0313] After euthanasia, each liver lobe from individual mice was formalin fixed and paraffin embedded. Liver sections were prepared and H&E stained to evaluate histopathology (Tables 2-3 and Figure 2-7 ), while sections from the same block were stained by trichrome staining to assess fibrosis ( Figure 8-9 ).

[0314] The histopathological score was determined independently for each of the four liver lobes from individual mice, and the data represent the average score of all four liver lobes from a single mouse (Table 2) according to the histopathological evaluation criteria (Table 3).

[0315] Table 2. Histopathological scores of individual mice

[0316]

[0317] Table 3. Exemplary histopathological evaluation criteria

[0318]

[0319] At 64 weeks of age, all mice had NASH, and at 72 weeks of age, all mice had NASH and fibrosis.

[0320] 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 Table 4-5).

[0321] Table 4. Average histopathological scores of 76-week-old mice in each group

[0322] NASH fibrosis treat Group 1 1.6 0.15 High-dose SCFA preparations Group 2 1.4 0.60 Low-dose SCFA preparations Group 5 1.4 1.3 Control (no drug)

[0323] Table 5. Average histopathological scores of 84-week-old mice in each group

[0324] NASH fibrosis treat Group 3 1.63 0.875 High-dose SCFA preparations Group 4 2.0 1.26 Low-dose SCFA preparations Group 6 1.65 1.75 Control (no drug)

[0325] Comparing the mice in groups 1 and 5 given high-dose SCFAs and those in groups 2 and 5 given low-dose SCFAs, NASH was significantly blocked at week 76 ( Figure 2Comparing Groups 3 and 6 for high-dose SCFAs and Groups 4 and 6 for low-dose SCFAs, NASH was significantly blocked at week 84 ( Figure 2 and Table 5 ).

[0326] A statistically significant reduction in the onset of fibrosis was observed in mice euthanized at week 76 ( Figure 3 Comparing mice from Groups 1 to 5, these experiments suggest that treatment with SCFAs is effective against fibrosis. A similar trend toward reduced fibrosis was observed in mice euthanized at week 84 ( Figure 3 and Table 5 ).

[0327] SCFAs attenuate the pathogenesis of NASH by blocking the development and / or progression of inflammatory lesions, thereby preventing or delaying the development of liver fibrosis.

[0328] Example 3: Treatment with Short Chain Fatty Acids - Study to Evaluate Improvement of Liver Histology in Patients with NAFLD / NASH.

[0329] Liver histology was evaluated in patients with NAFLD / NASH following administration of a composition comprising butyric acid and tocopherol acetate.

[0330] A total of 100 patients with a median age of 60 were enrolled. Patients had NAFLD / NASH and associated liver inflammation and / or cirrhosis and no contraindications to butyrate. Enrolled patients had a histological diagnosis of NASH.

[0331] Patients were given a formulation containing 600 mg of sodium butyrate and tocopheryl acetate (a source of acetic acid [12 mg] and vitamin E [200 IU]) or a placebo two to three times daily.

[0332] Evaluation of liver histology

[0333] Liver biopsy samples at baseline and after treatment (e.g., 96 weeks) were formalin-fixed, paraffin-embedded, and unstained sections were cut from the tissue blocks. The scores of the biopsies were assessed according to the NAFLD activity score (NAS) and fibrosis score, or, for example, as described in Example 1.

[0334] Laboratory analysis

[0335] Blood is collected and processed. Insulin, glucose, and the Adipo-IR index are measured. For example, the Adipo-IR index is calculated as fasting NEFA [mM] x fasting insulin [pM]. The Adipo-IR index correlates with improvements in steatosis and necroinflammation. A decrease in Adipo-IR can indicate improvement in NASH through its effects on dysfunctional adipose tissue.

[0336] Exemplary Treatments

[0337] Amount / capsule Amount / capsule Daily dose Butyric acid 600 (or 1200) mg 2400mg Acetic acid 10 (or 20) mg 40mg Vitamin E 50 (or 100) IU 200IU

[0338] In this study, drug recipients were monitored for the following outcomes: improvement in fibrosis (e.g., a decrease in fibrosis score based on liver histology in treated samples compared to baseline samples), improvement in NASH (e.g., a decrease in NASH score based on liver histology in treated samples compared to baseline samples), and / or a decrease in Adipo-IR.

[0339] Example 4: Treatment of NAFLD / NASH

[0340] Treatment of NAFLD / NASH was evaluated in subjects administered a composition comprising butyrate and tocopherol acetate.

[0341] A total of 100 patients were enrolled. Patients had NAFLD / NASH and / or associated liver inflammation and / or cirrhosis and had no contraindications to butyrate. Patients were given a formulation containing 600 mg of sodium butyrate and tocopheryl acetate (a source of acetic acid [12 mg] and vitamin E [200 IU]) two to three times daily, or a placebo.

[0342] Participants were followed for a median of 5 years. Shortly before treatment, patients were screened for: ALT / AST, GGT; liver stiffness using fibroscan; and blood levels of pro- and anti-inflammatory cytokines (e.g., TNFα, IFN-γ, IL-2, IL-4, IL-5, IL-10). Screening was repeated annually until study completion. Multivariate analysis was used to analyze the incidence of chronic liver disease (hepatitis and fibrosis), liver cancer, chronic liver disease-related death (usually due to cirrhosis), or transplantation in the treated and untreated cohorts.

[0343] Exemplary Treatments

[0344] Amount / capsule Amount / capsule Daily dose Butyric acid 600 (or 1200) mg 2400mg Acetic acid 10 (or 20) mg 40mg Vitamin E 50 (or 100) IU 200IU

[0345] In this study, the following outcomes were monitored among drug recipients: lower rates of chronic liver disease (hepatitis and fibrosis), lower rates of liver cancer, lower rates of death related to chronic liver disease (usually due to cirrhosis), and / or lower rates of transplantation in the treated cohort compared with the untreated cohort.

[0346] In the present study, decreased expression of inflammatory cytokines or mediators or inflammation was monitored in drug recipients.

[0347] The disclosures of each patent, patent application, and publication cited herein are hereby incorporated by reference in their entirety. Although the present disclosure has been disclosed with reference to specific embodiments, it is 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. The appended claims are intended to be interpreted as including all such embodiments and equivalent variations.

[0348] Implementation Plan

[0349] The following non-limiting embodiments provide illustrative examples of the invention but do not limit the scope of the invention.

[0350] Embodiment 1. A method of alleviating a condition in a subject in need thereof, wherein the method comprises 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 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.

[0351] Embodiment 2. The method according to embodiment 1, wherein the tocopherol exhibits a synergistic effect with at least one SCFA or a pharmaceutically acceptable salt thereof.

[0352] Embodiment 3. A method of providing prevention of progression of a condition to fibrosis in a subject in need thereof, wherein the method comprises administering to the subject a composition comprising: (a) at least one SCFA or a pharmaceutically acceptable salt thereof; and (b) tocopherol.

[0353] Embodiment 4. The method of any one of embodiments 1-3, wherein the condition is liver disease.

[0354] 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, autoimmune diseases or conditions, cirrhosis, liver cancer, hepatocellular carcinoma, autoimmune hepatitis, primary biliary cirrhosis (PBC), primary sclerosing cholangitis, hemochromatosis, Wilson's disease, liver failure, and any combination thereof.

[0355] Embodiment 6. The method of embodiment 4, wherein the liver disease or disorder is fatty liver disease.

[0356] Embodiment 7. The method of embodiment 4, wherein the liver disease or disorder is non-alcoholic fatty liver disease (NAFLD).

[0357] Embodiment 8. The method of embodiment 4, wherein the liver disease or disorder is non-alcoholic steatohepatitis (NASH).

[0358] Embodiment 8. The method of embodiment 4, wherein the liver disease or disorder is liver fibrosis.

[0359] Embodiment 9. The method of embodiment 4, wherein the liver disease or disorder is alcoholic liver disease.

[0360] Embodiment 10. The method of embodiment 4, wherein the liver disease or disorder is cirrhosis.

[0361] Embodiment 11. The method of embodiment 4, wherein the liver disease or disorder is liver cancer.

[0362] Embodiment 12. The method of embodiment 4, wherein the liver disease or disorder is hepatocellular carcinoma.

[0363] Embodiment 13. A method of providing prevention of progression of NASH to fibrosis in a subject in need thereof, wherein the method comprises administering to the subject a composition comprising: (a) at least one SCFA or a pharmaceutically acceptable salt thereof; and (b) tocopherol.

[0364] Embodiment 14. The method of any one of embodiments 3-13, wherein preventing comprises reducing the likelihood of progression to fibrosis.

[0365] Embodiment 15. The method of embodiment 13 or 14, wherein preventing comprises reducing the likelihood of NASH progressing to fibrosis.

[0366] Embodiment 16. The method of any one of embodiments 3-14, wherein preventing comprises delaying or slowing progression to fibrosis.

[0367] Embodiment 17. The method of any one of embodiments 13-16, wherein preventing comprises delaying or slowing the progression of NASH to fibrosis.

[0368] Embodiment 18. The method of any one of embodiments 1-17, wherein the composition comprises from about 100 milligrams (mg) to about 6 grams (g) of one of the SCFAs.

[0369] Embodiment 19. The method of embodiment 18, wherein the composition comprises about 2.4 grams (g) of one of the SCFAs.

[0370] Embodiment 20. The method of any one of embodiments 1-19, wherein the at least one SCFA or 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, hexanoic acid, lactic acid, succinic acid, pyruvic acid, octanoic acid, dodecanoic acid, (4R)-4-hydroxypentanoic acid, 2-(hydroxymethyl)butanoic acid, 2-hydroxy-3-methylvalerate, 2-hydroxy-3-methylvaleric acid, 2-methylbut-2-enoic acid, 2-oxobutanoic acid, 3-hydroxypentanoic acid, 3-methylbut-2-enoic acid, butenoic acid, methylbutyric acid, dimethylbutyric acid, glutadienoic acid, pentenoic acid, pivalic acid, propiolic acid, a pharmaceutically acceptable salt of any of the foregoing, and any combination thereof.

[0371] Embodiment 21. The method of any one of embodiments 1-20, wherein the composition comprises at least one SCFA selected from the group consisting of butyrate, propionate, and acetate, or pharmaceutically acceptable salts thereof.

[0372] Embodiment 22. The method according to any one of embodiments 1-21, 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.

[0373] Embodiment 23. The method of any one of embodiments 1-22, wherein the composition comprises at least two short chain fatty acids (SCFAs) or pharmaceutically acceptable salts thereof.

[0374] Embodiment 24. The method of embodiment 23, 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, hexanoic acid, lactic acid, succinic acid, pyruvic acid, octanoic acid, dodecanoic acid, (4R)-4-hydroxypentanoic acid, 2-(hydroxymethyl)butanoic acid, 2-hydroxy-3-methylvalerate, 2-hydroxy-3-methylvaleric acid, 2-methylbut-2-enoic acid, 2-oxobutanoic acid, 3-hydroxypentanoic acid, 3-methylbut-2-enoic acid, butenoic acid, methylbutyric acid, dimethylbutyric acid, glutadienoic acid, pentenoic acid, pivalic acid, propiolic acid, a pharmaceutically acceptable salt of any of the foregoing, and any combination thereof.

[0375] Embodiment 25. The method of any one of embodiments 1-24, wherein the composition comprises butyrate or a pharmaceutically acceptable salt thereof.

[0376] Embodiment 26. The method of any one of embodiments 1-25, 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.

[0377] Embodiment 27. The method of any one of embodiments 1-26, wherein the composition comprises acetate or a pharmaceutically acceptable salt thereof.

[0378] Embodiment 28. The method of any one of embodiments 1-27, 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.

[0379] Embodiment 29. The method of any one of embodiments 1-28, wherein the composition comprises from about 100 milligrams (mg) to about 6 grams (g) of SCFAs.

[0380] Embodiment 30. The method of embodiment 29, wherein the composition comprises about 2.4 grams (g) of SCFAs.

[0381] Embodiment 31. The method of any one of embodiments 1-30, wherein the composition comprises from about 1 IU to about 600 IU of tocopherol.

[0382] Embodiment 32. The method of any one of embodiments 1-31, wherein the composition comprises from about 1 IU to about 49.9 IU of tocopherol.

[0383] Embodiment 33. The method of any one of embodiments 1-32, wherein the composition comprises less than about 50 IU of tocopherol.

[0384] Embodiment 34. The method of any one of embodiments 1-33, wherein the composition comprises from about 100.1 IU to about 600 IU of tocopherol.

[0385] Embodiment 35. The method of any one of embodiments 1-34, wherein the composition comprises greater than about 100 IU of tocopherol.

[0386] Embodiment 36. The method of any one of embodiments 1-35, wherein the tocopherol is tocopherol acetate.

[0387] Embodiment 37. The method of embodiment 36, wherein the composition comprises from about 1 milligram (mg) to about 100 milligrams (mg) of tocopheryl acetate.

[0388] Embodiment 38. The method of embodiment 37, wherein the composition comprises about 12 milligrams (mg) of tocopheryl acetate.

[0389] Embodiment 39. The method of any one of embodiments 1-38, wherein the composition is administered orally.

[0390] Embodiment 40. The method of any one of embodiments 1-39, wherein the composition is administered with food or drink.

[0391] Embodiment 41. The method of any one of embodiments 1-39, wherein the composition is administered with food.

[0392] Embodiment 42. The method of any one of embodiments 1-41, wherein the composition is a pharmaceutical composition.

[0393] Embodiment 43. The method according to embodiment 42, wherein the pharmaceutical composition further comprises a pharmaceutically acceptable excipient.

[0394] Embodiment 44. The method of any one of embodiments 41-42, wherein the pharmaceutical composition further comprises an enteric coating.

[0395] Embodiment 45. The method of any one of embodiments 41-44, wherein the pharmaceutical composition is formulated as a tablet.

[0396] Embodiment 46. The method according to embodiments 41-45, wherein the pharmaceutical composition is formulated as a capsule.

[0397] Embodiment 47. The method of any one of embodiments 1-46, wherein the subject is a human.

[0398] 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.

[0399] 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, wherein 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.

[0400] 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 effective for treating the condition in the absence of the at least one SCFA or a pharmaceutically acceptable salt thereof.

[0401] 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.

[0402] Embodiment 52. The pharmaceutical composition of embodiment 51, wherein the amount of tocopherol is a reduced amount of tocopherol, wherein the reduced amount of tocopherol in combination with at least one SCFA or a pharmaceutically acceptable salt thereof is therapeutically effective for alleviating a condition.

[0403] Embodiment 53. The pharmaceutical composition according to 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 effective for treating the condition in the absence of the at least one SCFA or a pharmaceutically acceptable salt thereof.

[0404] Embodiment 54. The pharmaceutical composition of any one of embodiments 48-53, wherein the pharmaceutical composition comprises from about 100 milligrams (mg) to about 6 grams (g) of at least one SCFA.

[0405] Embodiment 55. The pharmaceutical composition of any one of embodiments 48-54, wherein the pharmaceutical composition comprises about 2.4 grams (g) of at least one SCFA.

[0406] Embodiment 56. The pharmaceutical composition of any one of embodiments 48-55, wherein the pharmaceutical composition comprises at least two SCFAs.

[0407] Embodiment 57. The pharmaceutical composition of any one of embodiments 48-56, wherein the pharmaceutical composition comprises butyrate or a pharmaceutically acceptable salt thereof.

[0408] Embodiment 58. The pharmaceutical composition of any one of Embodiments 48-57, wherein the pharmaceutical composition comprises the Ca salt of butyric acid.

[0409] Embodiment 59. The pharmaceutical composition of any one of embodiments 48-58, wherein the pharmaceutical composition comprises a Mg salt of butyric acid.

[0410] Embodiment 60. The pharmaceutical composition of any one of Embodiments 48-59, wherein the pharmaceutical composition comprises about 1 milligram (mg) to about 100 milligrams (mg) of at least one antioxidant.

[0411] Embodiment 61. The pharmaceutical composition of any one of Embodiments 48-60, wherein the composition comprises about 12 milligrams (mg) of at least one antioxidant.

[0412] Embodiment 62. The pharmaceutical composition of any one of embodiments 48-61, 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.

[0413] Embodiment 63. The pharmaceutical composition of any one of embodiments 48-62, wherein the antioxidant is tocopherol.

[0414] Embodiment 64. The pharmaceutical composition of any one of embodiments 48-63, wherein the composition comprises about 1 IU to about 600 IU of tocopherol.

[0415] Embodiment 65. The pharmaceutical composition of any one of embodiments 48-64, wherein the composition comprises about 1 IU to about 49.9 IU of tocopherol.

[0416] Embodiment 66. The pharmaceutical composition of any one of embodiments 48-65, wherein the composition comprises less than about 50 IU of tocopherol.

[0417] Embodiment 67. The pharmaceutical composition of any one of embodiments 48-66, wherein the composition comprises about 100.1 IU to about 600 IU of tocopherol.

[0418] Embodiment 68. The pharmaceutical composition of any one of embodiments 48-67, wherein the composition comprises greater than about 100 IU of tocopherol.

[0419] Embodiment 69. The pharmaceutical composition of any one of embodiments 48-68, wherein the antioxidant is tocopherol acetate.

[0420] Embodiment 70. The pharmaceutical composition of any one of embodiments 48-69, wherein the antioxidant is d-α-tocopheryl acetate.

[0421] Embodiment 71. The pharmaceutical composition of any one of embodiments 48-70, wherein the composition comprises about 1 milligram (mg) to about 100 milligrams (mg) of tocopherol acetate.

[0422] Embodiment 72. The pharmaceutical composition of any one of embodiments 48-71, wherein the composition comprises about 12 milligrams (mg) of tocopherol acetate.

[0423] Embodiment 73. The pharmaceutical composition of any one of embodiments 48-72, wherein the composition is administered orally.

[0424] Embodiment 74. The pharmaceutical composition of any one of embodiments 48-73, wherein the composition is administered with food or drink.

[0425] Embodiment 75. The pharmaceutical composition of any one of embodiments 48-74, wherein the composition is administered with food.

[0426] Embodiment 76. The pharmaceutical composition of any one of Embodiments 48-75, further comprising a pharmaceutically acceptable excipient.

[0427] Embodiment 77. The pharmaceutical composition of any one of embodiments 48-76, wherein the pharmaceutical composition further comprises an enteric coating.

[0428] Embodiment 78. The pharmaceutical composition of any one of Embodiments 48-77, wherein the pharmaceutical composition is formulated as a tablet.

[0429] Embodiment 79. The pharmaceutical composition according to any one of embodiments 48-78, wherein the pharmaceutical composition is formulated as a capsule.

[0430] Embodiment 80. Use of the pharmaceutical composition according to any one of embodiments 48-79 in the manufacture of a medicament.

[0431] Embodiment 81. The method of any one of embodiments 1-47, wherein administration of the composition improves liver histology in a liver biopsy sample of the subject.

[0432] Embodiment 82. The method of embodiment 81, wherein administration of the composition improves NASH score in a liver biopsy sample of the subject.

[0433] Embodiment 83. The method of embodiment 81 or 82, wherein administration of the composition improves fibrosis score in a liver biopsy sample of the subject.

[0434] Embodiment 84. The method of any one of embodiments 81-83, wherein administering the composition reduces the presence of inflammatory lesions in a liver biopsy sample of the subject.

[0435] Embodiment 85. The method of any one of embodiments 81-84, wherein administration of the composition reduces the distribution of inflammatory lesions in a liver biopsy sample of the subject.

[0436] Embodiment 86. The method of any one of embodiments 81-85, wherein administration of the composition reduces the frequency of inflammatory lesions in a liver biopsy sample of the subject.

[0437] 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.

[0438] Embodiment 88. The method of any one of embodiments 1-47 and 81-87, wherein administering the composition prevents or slows the development of liver fibrosis in the subject.

[0439] Embodiment 89. The method of any one of embodiments 1-47 and 81-88, wherein administering the composition reduces liver inflammation in the subject.

[0440] Embodiment 90. The method of any one of embodiments 1-47 and 81-89, wherein administering the composition modulates expression of an inflammatory mediator in the subject.

[0441] Embodiment 91. The method of any one of embodiments 1-47 and 81-90, wherein administering the composition reduces expression of inflammatory mediators in the subject.

[0442] Embodiment 92. A method of preventing or treating a liver disease or disorder in a subject in need thereof, wherein the method comprises 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.

[0443] Embodiment 93. The method of embodiment 92, wherein the liver disease or condition 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 condition, cirrhosis, liver cancer, hepatocellular carcinoma, autoimmune hepatitis, primary biliary cirrhosis (PBC), primary sclerosing cholangitis, hemochromatosis, Wilson's disease, liver failure, and any combination thereof.

[0444] Embodiment 94. A method of preventing or treating fibrosis in a subject in need thereof, wherein the method comprises 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.

[0445] Embodiment 95. A method of preventing or treating inflammation in a subject in need thereof, wherein the method comprises 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.

[0446] Embodiment 96. The method of any one of embodiments 92-95, wherein the composition comprises from about 100 milligrams (mg) to about 6 grams (g) of at least one SCFA.

[0447] Embodiment 97. The method of embodiment 96, wherein the composition comprises about 2.4 grams (g) of at least one SCFA.

[0448] Embodiment 98. The method of any one of embodiments 92-96, wherein the composition comprises at least SCFAs or salts thereof, wherein the SCFAs or salts thereof comprise at least one selected from the group consisting of 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 (and other forms of butyrate, such as benzyl alcohol, formic acid, benzoyl alcohol ...

[00145] Examples of the present invention include, but are not limited to, monoacetone glucose 3-butyrate, isovaleric acid, valeric acid, isocaproic acid, caproic acid, lactic acid, succinic acid, pyruvic acid, octanoic acid, dodecanoic acid, (4R)-4-hydroxypentanoic acid, 2-(hydroxymethyl)butanoic acid, 2-hydroxy-3-methylvaleric acid, 2-hydroxy-3-methylvaleric acid, 2-methylbut-2-enoic acid, 2-oxobutanoic acid, 3-hydroxypentanoic acid, 3-methylbut-2-enoic acid, butenoic acid, methylbutyric acid, dimethylbutyric acid, glutadienoic acid, pentenoic acid, pivalic acid, propiolic acid, and any combination thereof.

[0449] Embodiment 99. The method of embodiment 98, wherein the salt of the at least one SCFA comprises at least one selected from the group consisting of butyrate, propionate, and acetate.

[0450] Embodiment 100. The method of embodiment 98, wherein the at least one salt of SCFA comprises at least one selected from the group consisting of a Ca salt of a SCFA, a Mg salt of a SCFA, and any combination thereof.

[0451] 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 butyrate, a Mg salt of butyrate, a Ca salt of acetate, a Mg salt of acetate, and any combination thereof.

[0452] Embodiment 102. The method of any one of Embodiments 92-101, wherein the composition comprises from about 100 milligrams (mg) to about 6 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.

[0453] Embodiment 103. The method of embodiment 102, wherein the composition comprises about 2.4 grams (g) of the Ca salt of butyric acid, the Mg salt of butyric acid, the Ca salt of acetic acid, the Mg salt of acetic acid, or any combination thereof.

[0454] Embodiment 104. The method of any one of embodiments 92-103, wherein the composition further comprises at least one antioxidant.

[0455] 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.

[0456] Embodiment 106. The method of embodiment 105, wherein the composition comprises about 12 milligrams (mg) of at least one antioxidant.

[0457] 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.

[0458] Embodiment 108. The method of embodiment 107, wherein the antioxidant is vitamin E.

[0459] Embodiment 109. The method of embodiment 108, wherein the vitamin E comprises tocopheryl acetate.

[0460] Embodiment 110. The method of embodiment 109, wherein the composition comprises from about 1 milligram (mg) to about 100 milligrams (mg) of tocopheryl acetate.

[0461] Embodiment 111. The method of embodiment 110, wherein the composition comprises about 12 milligrams (mg) of tocopheryl acetate.

[0462] Embodiment 112. The method of any one of embodiments 92-111, wherein the composition is an enteric-coated sustained-release capsule.

[0463] Embodiment 113. The method of any one of embodiments 92-112, wherein the composition is a pharmaceutical composition.

Claims

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

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

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, 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.

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. A method of preventing progression of NASH to fibrosis in a subject in need thereof, wherein the method comprises administering to the subject a composition comprising: a. at least one SCFA or a pharmaceutically acceptable salt thereof; and b. Tocopherol.

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

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

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

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

10. The method of any one of claims 1 to 9, wherein the 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, hexanoic acid, lactic acid, succinic acid, pyruvic acid, octanoic acid, dodecanoic acid, (4R)-4-hydroxypentanoic acid, 2-(hydroxymethyl)butanoic acid, 2-hydroxy-3-methylvalerate, 2-hydroxy-3-methylvaleric acid, 2-methylbut-2-enoic acid, 2-oxobutanoic acid, 3-hydroxypentanoic acid, 3-methylbut-2-enoic acid, butenoic acid, methylbutyric acid, dimethylbutyric acid, glutadienoic acid, pentenoic acid, pivalic acid, propiolic acid, a pharmaceutically acceptable salt of any of the foregoing, and any combination thereof.

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

13. The method of any one of claims 1-12, wherein one of the SCFAs is butyrate or a pharmaceutically acceptable salt thereof. 14 . The method according to claim 13 , wherein the SCFA is a pharmaceutically acceptable salt of butyrate, and the pharmaceutically acceptable salt of butyrate is a Ca salt and a Mg salt.

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

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

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 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.

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

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

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

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

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

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

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

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