WO2024102902A1 - Methods of treating or preventing liver diseases or disorders - Google Patents
Methods of treating or preventing liver diseases or disorders Download PDFInfo
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- WO2024102902A1 WO2024102902A1 PCT/US2023/079217 US2023079217W WO2024102902A1 WO 2024102902 A1 WO2024102902 A1 WO 2024102902A1 US 2023079217 W US2023079217 W US 2023079217W WO 2024102902 A1 WO2024102902 A1 WO 2024102902A1
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- WIPO (PCT)
- Prior art keywords
- acid
- composition
- scfa
- salt
- tocopherol
- Prior art date
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Definitions
- Nonalcoholic Steatohepatitis is the advanced form of Nonalcoholic Fatty Liver Disease (NAFLD) characterized by accumulation of fat, inflammation, hepatocellular injury and different degree of fibrosis, which may progress to Nonalcoholic Steatohepatitis (NASH), cirrhosis and/or hepatocellular carcinoma (HCC).
- NASH Nonalcoholic Steatohepatitis
- HCC hepatocellular carcinoma
- Disclosed herein is a method of providing prophylaxis against 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) a tocopherol.
- the method comprises administering to the subject a composition comprising: (a) at least one SCFA or a pharmaceutically acceptable salt thereof; and (b) a tocopherol.
- FIG.1 shows weight of mice from the start of treatment at day 0 to euthanasia at day 81.
- FIG.2 shows average histopathology scores for mice fed high dose SCFA, low dose SCFA, or no drug.
- FIG.3 shows average histopathology scores for mice fed high dose SCFA, low dose SCFA, or no drug.
- FIG.4 shows representative H&E staining for inflammatory infiltrates characteristic of NASH in a liver sample of a control mouse on a high fat diet and euthanized at 76 weeks of age (group 5).
- FIG.5 shows representative H&E staining for inflammatory infiltrates characteristic of NASH in a liver sample of a control mouse on a high fat diet and euthanized at 84 weeks of age (group 6).
- FIG.6 shows representative H&E staining for inflammatory infiltrates characteristic of NASH in a liver sample of a mouse fed a high dose SCFA and euthanized at 76 weeks of age (group 1).
- FIG.7 shows representative H&E staining for inflammatory infiltrates characteristic of NASH in a liver sample of a mouse fed a high dose SCFA and euthanized at 84 weeks of age (group 3).
- FIG.8 shows representative Masson’s trichrome staining for fibrosis in a liver sample of a control mouse on a high fat diet and euthanized at 76 weeks of age (group 5).
- FIG.9 shows representative Masson’s trichrome staining for fibrosis in a liver sample of a mouse fed a high dose SCFA and euthanized at 76 weeks of age (group 1).
- the present disclosure is based on the unexpected results that a combination of Ca/Mg salts of butyric acid and tocopherol-acetate provides an effective treatment for NASH with or without fibrosis.
- the present disclosure provides a method of preventing or treating a liver disease, fibrosis, or inflammation using a composition comprising at least one compound selected from a short chain fatty acid (SCFA), salt of SCFA, SCFA precursor, SCFA biosynthesis precursor, compound comprising a SFCA moiety, derivative of SCFA, or any combination thereof.
- SCFA short chain fatty acid
- the salt of SCFA comprises a Ca salt of SCFA (e.g., Ca salt of butyric acid, Ca salt of acetic acid, etc.), Mg salt of SCFA (e.g., Mg salt of butyric acid, Mg salt of acetic acid, etc.), or any combination thereof.
- the composition further comprises at least one antioxidant (e.g., vitamin E, tocopherol-acetate, etc.).
- a subject is a human. In one embodiment, a subject is a non-human animal.
- compositions and methods for treating a condition comprising administering to a subject in need thereof a composition comprising at least one short chain fatty acid (SCFA), salt of SCFA, SCFA precursor, SCFA biosynthesis precursor, composition comprising a SFCA moiety, derivative of SCFA, or any combination thereof.
- SCFA short chain fatty acid
- a composition disclosed herein is present in a salt form.
- a method disclosed herein further comprises administering a second pharmaceutical composition, for example.
- “combination” as in the phrase “a first agent in combination with a second agent” includes co-administration of a first agent and a second agent, which for example may be dissolved or intermixed in the same pharmaceutically acceptable carrier, or administration of a first agent, followed by the second agent, or administration of the second agent, followed by the first agent.
- the term “concomitant” as in the phrase “concomitant therapeutic treatment” includes administering an agent in the presence of a second agent.
- a concomitant therapeutic treatment method includes methods in which the first, second, third, or additional agents are co- administered.
- a concomitant therapeutic treatment method also includes methods in which the first or additional agents are administered in the presence of a second or additional agents, wherein the second or additional agents, for example, may have been previously administered.
- a concomitant therapeutic treatment method may be executed step-wise by different actors. For example, one actor may administer to a subject a first agent and a second actor may administer to the subject a second agent, and the administering steps may be executed at the same time, or nearly the same time, or at distant times, so long as the first agent (and additional agents) are after administration in the presence of the second agent (and additional agents).
- the actor and the subject may be the same entity (e.g., a human).
- a “disease” is a state of health of an animal wherein the animal cannot maintain homeostasis, and wherein if the disease is not ameliorated then the animal’s health continues to deteriorate.
- a “disorder” in an animal is a state of health in which the animal is able to maintain homeostasis, but in which the animal’s state of health is less favorable than it would be in the absence of the disorder.
- a subject is “at risk for” developing a condition if there is an increased probability that the individual will develop the condition compared to a population (e.g., the general population, an age-matched population, a population of the same sex). The increased probability can be due to one or a combination of factors including the presence of specific alleles/mutations of a gene or exposure to a particular environment.
- a population e.g., the general population, an age-matched population, a population of the same sex.
- the increased probability can be due to one or a combination of factors including the presence of specific alleles/mutations of a gene or exposure to a particular environment.
- cancer as used herein is defined as disease characterized by the rapid and uncontrolled growth of aberrant cells. Cancer cells can spread locally or through the bloodstream and lymphatic system to other parts of the body.
- a disease or disorder is “alleviated” if the severity of a sign or symptom of the disease or disorder, the frequency with which such a sign or symptom is experienced by a patient, or both, is reduced.
- the term “inhibit,” as used herein, means to suppress or block an activity or function by at least about ten percent relative to a control value. As an example, the activity is suppressed or blocked by 50% compared to a control value, by 75%, or by 95% or more.
- treatment used herein to generally mean obtaining a desired pharmacological and/or physiological effect.
- the effect may be prophylactic in terms of completely or partially preventing a disease or disorder, or a symptom thereof, and/or may be therapeutic in terms of partially or completely curing a disease or disorder, and/or adverse effect attributed to the disease or disorder.
- treatment includes any treatment of a disease or disorder in a subject and includes: (a) preventing a disease or disorder from occurring in a subject which may be predisposed to the disease or disorder; (b) inhibiting the disease or disorder, i.e. arresting its development: or (c) relieving the disease or disorder, i.e.
- an effective amount and “pharmaceutically effective amount” refer to a sufficient amount of an agent to provide a desired biological result. That result can be reduction and/or alleviation of a sign, symptom, or cause of a disease or disorder, or any other desired alteration of a biological system.
- a “therapeutically effective amount” refers to that amount which provides a therapeutic effect for a given condition and administration regimen. In particular, “therapeutically effective amount” means an amount that is effective to prevent, alleviate or ameliorate symptoms of a disease or disorder, or prolong the survival of the subject being treated, which may be a human or non-human animal.
- the term “pharmaceutical composition” refers to a mixture of at least one compound of the disclosure with other chemical components and entities, such as carriers, stabilizers, diluents, dispersing agents, suspending agents, thickening agents, and/or excipients.
- the pharmaceutical composition facilitates administration of the compound to an organism. Multiple techniques of administering a compound exist in the art including, but not limited to, intravenous, oral, aerosol, parenteral, ophthalmic, pulmonary and topical administration.
- “Pharmaceutically acceptable” refers to those properties and/or substances which are acceptable to the patient from a pharmacological/toxicological point of view and to the manufacturing pharmaceutical chemist from a physical/chemical point of view regarding composition, formulation, stability, patient acceptance and bioavailability.
- the term “pharmaceutically acceptable carrier” means a pharmaceutically acceptable material, composition or carrier, such as a liquid or solid filler, stabilizer, dispersing agent, suspending agent, diluent, excipient, thickening agent, solvent, or encapsulating material, involved in carrying or transporting a compound useful within a composition disclosed herein within or to the patient such that it may perform its intended function.
- Such constructs are carried or transported from one organ, or portion of the body, to another organ, or portion of the body.
- Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation, including the compound useful within a composition disclosed herein, and not injurious to the patient.
- materials that may 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 carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients, such as cocoa butter and suppository waxes; oils, such as peanut oil, cottonseed oil, 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; buffering agents, such as magnesium hydroxide and aluminum hydroxide; surface active agents; alginic acid; pyrogen-free water; iso
- “pharmaceutically acceptable carrier” also includes any and all coatings, antibacterial and antifungal agents, and absorption delaying agents, and the like that are compatible with the activity of the compound useful withina composition disclosed herein, and are physiologically acceptable to the patient. Supplementary active compounds may also be incorporated into the compositions.
- the “pharmaceutically acceptable carrier” may further include a pharmaceutically acceptable salt of the compound useful within a composition disclosed herein.
- Other additional ingredients that may be included in the pharmaceutical compositions used in the practice of the disclosure are known in the art and described, for example in Remington's Pharmaceutical Sciences (Genaro, Ed., Mack Publishing Co., 1985, Easton, PA), which is incorporated herein by reference.
- the term “nutritional composition” may refer to a food product intended for human consumption, for example, a beverage, a drink, a bar, a snack, an ice cream, a dairy product, for example a chilled or a shelf-stable dairy product, a fermented dairy product, a drink, for example 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 oven or a conventional oven, a ready-to- eat product, a fast food or a nutritional formula.
- a food product intended for human consumption for example, a beverage, a drink, a bar, a snack, an ice cream, a dairy product, for example a chilled or a shelf-stable dairy product, a fermented dairy product, a drink, for example a milk-based drink, an infant formula, a growing-up milk
- the terms “patient,” “subject,” “individual,” and the like are used interchangeably herein, and refer to any animal, or cells thereof whether in vitro or in situ, amenable to the methods described herein.
- the patient, subject, or individual may be a human or a non-human animal.
- the term “container” includes any receptacle for holding the pharmaceutical composition.
- the container is the packaging that contains the pharmaceutical composition.
- the container is not the packaging that contains the pharmaceutical composition, i.e., the container is a receptacle, such as a box or vial that contains the packaged pharmaceutical composition or unpackaged pharmaceutical composition and the instructions for use of the pharmaceutical composition.
- packaging techniques are well known in the art. It should be understood that the instructions for use of the pharmaceutical composition may be included on the packaging containing the pharmaceutical composition, and as such the instructions form an increased functional relationship to the packaged product. However, it should be understood that the instructions may contain information pertaining to the compound’s ability to perform its intended function, e.g., treating or preventing a disease in a subject.
- “Instructional material,” as that term is used herein, includes a publication, a recording, a diagram, or any other medium of expression which can be used to communicate the usefulness of components of the disclosure in a kit for identifying or alleviating or treating the various diseases or disorders recited herein.
- the instructional material may describe one or more methods of identifying or alleviating the diseases or disorders in a cell or a tissue of a subject.
- the instructional material of the kit may, for example, be affixed to a container that contains the compositions or be shipped together with a container that contains the compositions.
- the instructional material may be shipped separately from the container with the intention that the recipient uses the instructional material and the composition cooperatively.
- Ranges throughout this disclosure, various aspects of the disclosure can be presented in a range format. It should be understood that the description in range format is merely for convenience and brevity and should not be construed as an inflexible limitation on the scope of the disclosure.
- the present disclosure provides a method of preventing or treating a liver disease, fibrosis, or inflammation using a composition comprising at least one compound selected from a short chain fatty acid (SCFA), salt of SCFA, SCFA precursor, SCFA biosynthesis precursor, compound comprising a SFCA moiety, derivative of SCFA, or any combination thereof.
- SCFA short chain fatty acid
- the salt of SCFA comprises a Ca salt of SCFA (e.g., Ca salt of butyric acid, Ca salt of acetic acid, etc.), Mg salt of SCFA (e.g., Mg salt of butyric acid, Mg salt of acetic acid, etc.), or any combination thereof.
- the composition further comprises at least one antioxidant (e.g., vitamin E, tocopherol-acetate, etc.).
- a subject is a human.
- a subject is a non-human animal.
- the present disclosure provides methods for treating or preventing a liver disease, fibrosis, and/or inflammation in a subject in need thereof by administration to said subject a therapeutically effective amount of a composition comprising at least one compound selected from a short chain fatty acid (SCFA), salt of SCFA, SCFA precursor, SCFA biosynthesis precursor, compound comprising a SFCA moiety, derivative of SCFA, or any combination thereof.
- SCFA short chain fatty acid
- Liver Disease and disorders 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).
- HCC hepatocellular carcinoma
- NASH is associated with chronic inflammatory conditions such as type 2 diabetes and obesity.
- NAFLD/NASH currently afflicts hundreds of millions of people.
- NAFLD/NASH is a growing worldwide epidemic, and current treatment approached include lifestyle adjustments, physical activity, smoking/alcohol cessation, high dose of Vitamin E (800IU, as an antioxidant), and pioglitazone (as an insulin sensitizer).
- Vitamin E 800IU
- pioglitazone as an insulin sensitizer
- the present disclosure provides methods and compositions having a much higher therapeutic success than current treatment approaches. More specifically, the present disclosure provides a composition comprising a combination of butyrate and acetate (which simultaneously target multiple mechanisms associated with the pathogenesis of NASH), in addition to an antioxidant, (e.g., Vitamin E), offer an effective and safe treatment outcome. Thus, the present disclosure provides a composition to treat NASH with or without fibrosis.
- a composition disclosed herein is administered to a subject to prevent disease progression of a liver disease or disorder.
- a composition disclosed herein is administered to a subject to delay disease progression of a liver disease or disorder. [0058] In some embodiments, a composition disclosed herein is administered to a subject for treating a liver disease or disorder. In some embodiment, a composition disclosed herein is administered to a subject for preventing a liver disease or disorder. [0059] In some embodiments, a composition disclosed herein is administered to a subject determined to be at risk for developing a liver disease or disorder.
- Non-limiting examples of a liver disease or disorder include: fatty liver disease, nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), liver fibrosis, alcoholic liver disease, autoimmune disease or disorder, cirrhosis, liver cancer, hepatocellular carcinoma (HCC), hepatitis B associated chronic liver disease, dysplasia, autoimmune hepatitis, primary biliary cirrhosis (PBC), primary sclerosing cholangitis, hemochromatosis, Wilson’s disease, liver failure, or any combination thereof.
- a composition disclosed herein is administered to a subject for treating or preventing an inflammatory condition.
- a composition disclosed herein is administered to a subject for treating or preventing a chronic inflammatory condition.
- chronic inflammatory condition includes type 2 diabetes and obesity.
- SCFA Short Chain Fatty Acid
- “Short chain fatty acids” (SCFA) are fatty acids typically with aliphatic tails shorter than aliphatic tails of long chain fatty acids. Short chain fatty can be derivatized to provide a salt or ester thereof, for example, pharmaceutically acceptable salts and esters of fatty acids (e.g., sodium butyrate, arginine butyrate).
- the composition comprises between about 100 milligrams (mg) to about 100 grams (g) of at least one SCFA.
- the composition comprises between about 100 milligrams (mg) to about 6 grams (g) of at least one SCFA. In some embodiments, the composition comprises between about 1 gram (g) to about 6 grams (g) of at least one SCFA. In some embodiments, the composition comprises between about 1 gram (g) to about 4 grams (g) of at least one SCFA. In some embodiments, the composition comprises between about 2 grams (g) to about 4 grams (g) of at least one SCFA. In some embodiments, the composition comprises between 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.
- a composition disclosed herein comprises 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 a SCFA.
- 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 a SCFA.
- the composition comprises at least one SCFA, salt thereof, or a compound comprising a SCFA moiety.
- a composition disclosed herein comprises at least one SCFA.
- a composition disclosed herein comprises at least one short chain fatty acid (SCFA), SCFA precursor, SCFA biosynthesis precursor, a derivative thereof, a SCFA moiety, or a combination thereof.
- SCFA short chain fatty acid
- a composition disclosed herein comprises at least one SCFA, or a compound comprising a SCFA moiety.
- a composition disclosed herein comprises at least two SCFAs.
- a composition disclosed herein comprises at least three SCFAs.
- Non-limiting examples of a SCFA, salt thereof, or SCFA moiety include: acetic acid, butyric acid (BA), C3-C12 fatty acids, C3-C10 fatty acids, C3-C8 fatty acids, methoxyacetic acid, valproic acid (VPA), propionic acid, 3-methoxypropionic acid, ethoxyacetic acid, formic acid, isobutyric acid, tributyrin, N-acetylbutyrate (as well as other forms of butyrate, e.g., phenylbutyrate, isobutyrate, pivaloyloxymethyl butyrate, 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- ethylhydracryl
- the composition comprises a salt of a SCFA, or a derivative thereof.
- the salt of SCFA comprises at least one butyrate, propionate, and/or acetate.
- a salt of butyric acid may be one or more of sodium butyrate, magnesium butyrate or calcium butyrate.
- the composition comprises one or more of magnesium butyrate and calcium butyrate.
- butyrate can (1) potentiate Peroxisome Proliferator-Activated Receptor (PPAR)- signaling (where PPAR regulates the expression of genes involved in fatty acid beta- oxidation, glucose metabolism, inflammation responses, and is a major regulator of energy homeostasis), (2) suppress pro-inflammatory cytokines such as Tumor Necrosis Factor (TNF)- ⁇ , CCL2/CCR2 and CCL5/CCR5 (key cytokines involved in adipocyte-related inflammation, hepatic stellate cell activation, initiating a fibrogenic response), (3) improve insulin sensitivity, (4) promote expression of GLP-1R (where GLP-1 regulates glucose homeostasis, gastric motility and food intake), and/or (5) inhibit fibrosis development (as demonstrated by decreased hepatic collagen content).
- PPAR Peroxisome Proliferator-Activated Receptor
- acetate can inhibit lipid accumulation by promoting lipolysis and fatty acid oxidation and inhibiting fatty acid synthesis.
- Vitamin E prevents liver injury by protecting against mitochondrial toxicity and blocking intrinsic apoptotic pathways. Unlike other treatments, which are generally based on single channel drugs, the present disclosure provides broad multichannel protection. [0072] Mechanisms of butyrate, acetate, and Vitamin E action in the context of NAFLD/NASH/fibrosis: SCFAs (including butyrate and acetate) are derived from bacterial fermentation of fiber and play a vital role in intestinal epithelial nutrition and maintenance of immune homeostasis (Sanna et al, 2019; Van der Hee et al, 2021).
- SCFAs directly enter the liver through the portal vein, and there are several possible mechanisms whereby SCFAs reduce the development of NASH/NAFLD.
- SCFAs including butyrate and acetate
- AMPK AMP-activated protein kinase
- SCFA-fed mice there was a two-fold increase in hepatic lipid oxidation, shifting hepatic lipid metabolism towards a more oxidative state.
- Butyrate and acetate also increased transcriptional expression of adiponectin and resistin (both are adipose tissue-derived hormones that play a crucial role in protection against insulin resistance, diabetes and obesity) through epigenetic modulation (DNA methylation) in obese mice (Dai et al, 2020); decreased the expression of lipogenic genes (via histone deacetylases [HDAC] inhibition) such as those encoding ACC, Fasn and Srebp1c (Kim et al, 2018), all of which are linked to the NASH progression. Butyrate is the most potent natural HDAC inhibitor (Waldecker et al, 2008).
- butyrate significantly decreased hepatic steatosis and inflammation in Western-style diet-induced NASH (Jin et al, 2015) and in fat-fructose-cholesterol rich diet-induced NASH mice (Baumann et al, 2020). Vinolo at al. (2012) reported that mice treated with a butyrate pro-drug, tributyrin, were protected from diet- induced obesity, insulin resistance, and hepatic steatosis. Butyrate is a PPAR agonist (Nepelska et al, 2017).
- PPARs are nuclear receptors which regulate the expression of genes involved in fatty acid beta-oxidation, glucose metabolism, inflammation responses (acting on NF-kB and AP1 transcription factors) and are major regulator of energy homeostasis.
- PPAR activators improved the disease outcome (Caligiuri et al 2016). Butyrate protected against high-fat diet-induced obesity via a PPAR ⁇ -dependent switch from lipogenesis to fat oxidation (den Besten, et al, 2015). Inflammation represents a crucial aspect in the pathogenesis of NASH.
- TNF-ct cytokine
- Other upregulated pro-inflammatory cytokines involved in the pathogenesis of NASH include IL-1 ⁇ , IL-12, CCL2 and CCL5. Latter two recruit macrophages (and other inflammatory cells) and induce hepatic stellate cell activation, initiating a fibrogenic response (Marra et al 2014). Expression of CCR2 and CCR5 has been shown to be upregulated in vivo and in the livers of obese patients with severe steatosis and NASH.
- GLP-1R agonists potentiate glucose-stimulated insulin secretion and inhibition of glucagon secretion and are one of the few glucose-lowering agents that results in weight loss, thus improvement in hepatic steatosis.
- HFD High Fat Diet
- GLP-1R Chole et al, 2020
- GLP-1 Yadav et al, 2019; Zhao et al, 2021
- Gart et al (2021) showed that butyrate inhibited fibrosis development as demonstrated by decreased hepatic collagen content in liver histopathology.
- GPR43 G-protein-coupled receptor 43
- FFAR2 free fatty acid receptor 2
- Acetate is the most selective ligand for GPR43 (Kolodziejczyk et al, 2019).
- Activation of GPR43 signaling promotes energy expenditure and inhibited 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 dysregulation (Aoki et al 2021).
- the salt of SCFA comprises at least one Ca salt of SCFA, Mg salt of SCFA, Na salt of SCFA or any combination thereof.
- the salt of SCFA comprises at least one Ca salt of butyric acid, Mg salt of butyric acid, Na salt of butyric acid, Ca salt of acetic acid, Mg salt of acetic acid, Na salt of acetic acid, or any combination thereof.
- a SCFA or SCFA moiety includes compounds or structures with 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.
- the SCFA or SCFA moiety includes compounds or structures with 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.
- the SCFA or SCFA moiety is not a branched fatty acid.
- the SCFA or SCFA moiety is a branched fatty acid.
- the composition comprises at least one compound comprising a precursor of a SCFA, or a moiety thereof.
- the precursor, or moiety thereof is selected from the group including, but not limited to, plant cell-wall polysaccharides, dietary nonstarch polysaccharides (NSP) a salt of lactate, a salt of succinate, a salt of formate, 1,2- propenedol, trypamine, indole, indole-3-acetate, and a combination thereof.
- NSP dietary nonstarch polysaccharides
- the composition comprises at least one compound comprising a biosynthesis precursor of a SCFA, or a moiety thereof.
- the biosynthesis precursor, or moiety thereof is selected from the group including, but not limited to an acetyl- CoA carboxylase inhibitor, an adenosine monophosphate kinase (AMPK) activator, vitamin D, and a combination thereof.
- AMPK adenosine monophosphate kinase
- Vitamin E is a fat-soluble antioxidant that stops the production of ROS formed when fat undergoes oxidation.
- the eight forms of Vitamin E include four tocopherols (alpha-, beta-, gamma-, and delta-tocopherol) and four tocotrienols (alpha-, beta-, gamma-, and delta- tocotrienol), that have varying levels of biological activity.
- Tocopherols are organic compounds comprising various methylated phenols, many of which have vitamin E activity.
- Non-limiting examples of a tocopherol include: alpha-tocopherol or ⁇ -tocopherol, RRR- ⁇ -tocopherol, d- ⁇ -tocopherol, ddd- ⁇ -tocopherol, RSR- ⁇ -tocopherol, all- rac- ⁇ -tocopherol, dl-tocopherol, dl- ⁇ -tocopherol, dl-tocopheryl acetate, tocopherol acetate, tocopheryl acetate, ⁇ -tocopheryl acetate, alpha-tocopherol acetate, dl- ⁇ -tocopheryl acetate, d- ⁇ - tocopherol acetate, ⁇ -tocopheryl succinate, ⁇ -tocopheryl nicotinate, ⁇ -tocopheryl phosphate, tocopheryl ester, tocopheryl
- the Vitamin E is alpha-tocopherol or ⁇ -tocopherol. In some embodiments, the tocopherol is alpha-tocopherol or ⁇ -tocopherol. In some embodiments, the Vitamin E is d- ⁇ -tocopherol acetate. In some embodiments, the tocopherol is d- ⁇ -tocopherol acetate. In some embodiments, the Vitamin E is dl- ⁇ -tocopherol. In some embodiments, the tocopherol is dl- ⁇ -tocopherol.
- a tocopherol disclosed herein is hydrolyzed, for example ⁇ - Tocopherol acetate is hydrolyzed to ⁇ -tocopherol and acetic acid.
- 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.
- Antioxidants such as tocopherol or Vitamin E
- Vitamin E may prevent liver injury by protecting against mitochondrial toxicity and blocking intrinsic apoptotic pathways.
- Vitamin E may also down-regulate NF-kB-dependent inflammatory pathways (Ratziu et al 2015).
- antioxidant therapies have not always been favorable and were shown to be associated with worsening pathology.
- Administration of high doses of Vitamin E improved NAS within two years, but often increases insulin resistance and plasma triglyceride levels (Hackam, 2007 Chalasani et al, 2012).
- a high dose of Vitamin E is about 800 IU.
- a composition disclosed herein comprises a reduced amount of the tocopherol or Vitamin E. In some embodiments, a reduced amount of the tocopherol or Vitamin E alleviates or reduces an adverse event associated with high dose Vitamin E.
- Non-limiting examples of an adverse event associated with high dose Vitamin E include: increased insulin resistance, increased plasma triglyceride levels, increased mortality, increased incidence of hemorrhagic stroke, and increased incidence of prostate cancer.
- a reduced amount of a tocopherol is therapeutically effective for alleviating a condition in a subject in need thereof in combination with at least one SCFA or the pharmaceutically acceptable salt thereof.
- a reduced amount of a Vitamin E is therapeutically effective for alleviating a condition in a subject in need thereof in combination with at least one SCFA or the pharmaceutically acceptable salt thereof.
- a reduced amount of a tocopherol is therapeutically effective for alleviating a condition in a subject in need thereof in combination with at least two SCFAs or the pharmaceutically acceptable salt thereof.
- a reduced amount of a Vitamin E is therapeutically effective for alleviating a condition in a subject in need thereof in combination with at least two SCFAs or the pharmaceutically acceptable salt thereof.
- a reduced amount of the tocopherol is less than an amount of the tocopherol that is therapeutically effective for the condition in absence of the at least one SCFA or the pharmaceutically acceptable salt thereof.
- a reduced amount of the Vitamin E is less than an amount of the tocopherol that is therapeutically effective for the condition in absence of the at least one SCFA or the pharmaceutically acceptable salt thereof.
- a reduced amount of the tocopherol is less than an amount of the tocopherol that is therapeutically effective for the condition in absence of the at least two SCFAs or the pharmaceutically acceptable salt thereof.
- a reduced amount of the Vitamin E is less than an amount of the tocopherol that is therapeutically effective for the condition in absence of the at least two SCFAs or the pharmaceutically acceptable salt thereof.
- the tocopherol exhibits synergy with the at least one SCFA or the pharmaceutically acceptable salt thereof.
- a composition disclosed herein comprises an amount of tocopherol or Vitamin E about 10%, about 11%, about 12%, about 13%, about 14% an, 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% an, about 35%, about 35%, about 36%, about 37%, about 38%, about 39%, about 40%, about 41%, about 42%, about 43%, about 44% an, about 45%, about 46%, about 47%, about 48%, about 49%, about 50%, about 51%, about 52%, about 53%, about 54% an, about 55%, about 56%, about 57%, about 58%, about 59%, about 50%, about 51%, about 52%, about 53%, about 54% an, about 55%, about 56%, about 57%, about 58%,
- a composition disclosed herein comprises 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.
- a composition disclosed herein comprises more than about 100 IU, more than about 150 IU, more than about 200 IU, more than about 250 IU, more than about 300 IU, more than about 350 IU, more than about 400 IU, more than about 450 IU, more than about 500 IU, more than about 550 IU, or more than about 600 IU of tocopherol or Vitamin E.
- a composition disclosed herein comprises about 100.1 to about 600 IU of tocopherol or Vitamin E.
- a composition disclosed herein comprises about 101 to about 600 IU of tocopherol or Vitamin E.
- a composition disclosed herein comprises about 200.1 to about 600 IU of tocopherol or Vitamin E. In some embodiments, a composition disclosed herein comprises about 201 to about 600 IU of tocopherol or Vitamin E. In some embodiments, a composition disclosed herein comprises about 300 to about 600 IU of tocopherol or Vitamin E. In some embodiments, a composition disclosed herein comprises about 400 to about 600 IU of tocopherol or Vitamin E. In some embodiments, a composition disclosed herein comprises about 500 to about 600 IU of tocopherol or Vitamin E. [0102] In some embodiments, a composition disclosed herein comprises about 1 to about 49.9 IU of tocopherol or Vitamin E.
- a composition disclosed herein comprises about 1 to about 49 IU of tocopherol or Vitamin E. In some embodiments, a composition disclosed herein comprises about 1 to about 40 IU of tocopherol or Vitamin E. In some embodiments, a composition disclosed herein comprises about 1 to about 30 IU of tocopherol or Vitamin E. In some embodiments, a composition disclosed herein comprises about 1 to about 20 IU of tocopherol or Vitamin E. In some embodiments, a composition disclosed herein comprises about 1 to about 10 IU of tocopherol or Vitamin E.
- a composition disclosed herein comprises 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.
- a composition disclosed herein comprises 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.
- a composition disclosed herein comprises 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.
- 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 105 IU, about 100 IU, about 105 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
- the composition comprises between about 1 milligram (mg) to about 100,000 milligrams (mg) of at least one antioxidant. In some embodiments, the composition comprises between about 1 milligram (mg) to about 100 milligrams (mg) of at least one antioxidant. In some embodiments, the composition comprises between about 1 milligram (mg) to about 90 milligrams (mg) of at least one antioxidant. In some embodiments, the composition comprises between about 1 milligram (mg) to about 80 milligrams (mg) of at least one antioxidant. In some embodiments, the composition comprises between about 1 milligram (mg) to about 70 milligrams (mg) of at least one antioxidant.
- the composition comprises between about 1 milligram (mg) to about 60 milligrams (mg) of at least one antioxidant. In some embodiments, the composition comprises between about 1 milligram (mg) to about 50 milligrams (mg) of at least one antioxidant. In some embodiments, the composition comprises between about 1 milligram (mg) to about 40 milligrams (mg) of at least one antioxidant. In some embodiments, the composition comprises between about 1 milligram (mg) to about 30 milligrams (mg) of at least one antioxidant. In some embodiments, the composition comprises between about 1 milligram (mg) to about 20 milligrams (mg) of at least one antioxidant.
- the composition comprises about 12 milligrams (mg) of at least one antioxidant.
- the composition comprises about 20 IU to about 300 IU of at least one antioxidant.
- the composition comprises about 20 IU to about 200 IU of at least one antioxidant.
- the composition comprises about 50 IU to about 200 IU of at least one antioxidant.
- the composition comprises about 200 IU to about 600 IU of at least one antioxidant.
- the tocopherol is tocopherol acetate.
- the tocopherol is d- ⁇ -tocopherol acetate.
- the at least one antioxidant is vitamin E (d- ⁇ -tocopherol acetate).
- the antioxidant comprises at least one vitamin C, vitamin E (d- ⁇ - tocopherol acetate), beta-carotene, carotenoid, selenium, manganese, glutathione, coenzyme Q10, lipoic acid, flavonoid, phenol, polyphenol, phytoestrogen, vitamin D3, or any combination thereof.
- Magnesium is a co-factor for more than 300 enzymes that regulate diverse biochemical reactions including regulation of blood glucose levels, detoxification, and others. Vitamin D3 deficiency is frequent in patients with immune disorders. Vitamin E has distinctive antioxidant activities.
- the method comprises administering to a subject in need thereof a composition comprising at least one SCFA, salt thereof, or a biologically-active derivative or precursor thereof, and additionally 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, 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.
- diseases and disorders that can be treated, prevented or ameliorated by the methods of the present disclosure include, but are not limited to, inflammatory diseases and various cancer diseases.
- the inflammatory diseases and disorders that can be treated or ameliorated include, but are not limited to, asthma, arthritis, allergic rhinitis, psoriasis, atopic dermatitis, inflammatory bowel diseases, Crohn’s disease, an allergic or autoimmune disease or disorder associated with C-section delivery of a neonate, uveitis, and vasculitis.
- the cancer diseases and disorders that can be treated or ameliorated include, but are not limited to, leukemias and lymphomas.
- an 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 & neuronal neuropathy (AMAN), Behcet’s disease, Bullous pemphigoid, Castleman disease (CD), Celiac disease, Chagas disease, Chronic inflammatory demyelinating polyneuropathy (CIDP), Chronic recurrent multifocal osteomyelitis (CRMO), Churg-Strauss, Cicatricial pemphigoid/benign mucosal pemphigoid, Cogan’s syndrome, Cold agglutinin disease, Congenital heart block, Coxsackie myocarditis, CREST syndrome, Cr
- diseases and disorders 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 transplantations, such as inflammatory bowel disease (IBD), ulcerative colitis, Crohn’s disease, sprue, autoimmune arthritis, rheumatoid arthritis, Type I diabetes, multiple sclerosis, graft vs.
- IBD inflammatory bowel disease
- Crohn’s disease sprue
- autoimmune arthritis rheumatoid arthritis
- Type I diabetes multiple sclerosis
- graft vs graft vs.
- the disclosure provides methods for the treatment or prevention of at least one disease or disorder in a subject, comprising administering to the subject at least one composition comprising a SCFA or a compound comprising a SCFA moiety, optionally in combination with at least one additional agent or therapy.
- the administered compositions of the present disclosure can increase the number of disease-free days, reduce the severity of a disease or disorder, reduce the risk of developing a disease or disorder, reduce the risk of recurrence of a disease or disorder, or a combination thereof in the subject.
- the administered compositions of the present disclosure can increase the number of disease-free days by 5-60% or more in the subject as compared to a subject who is not receiving treatment.
- compositions of the present disclosure can reduce the severity of a disease or disorder 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 in the subject as compared to a subject who is not receiving treatment.
- compositions of the present disclosure can reduce the risk of developing a disease or disorder 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 in the subject as compared to a subject who is not receiving treatment.
- compositions of the present disclosure can reduce the risk of recurrence of a disease or disorder 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 in the subject as compared to a subject who is not receiving treatment.
- an exemplary method for the treatment or prevention of diseases or disorder comprises administration of 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, least 4 g, at least 5 g, at least 6 g or more than 6 g of at least one SCFA at least 1 time daily, at least 2 times daily, at least 3 times daily or more than 3 times daily, 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 for more than 6 months.
- the composition comprising at least one SCFA is an enteric coated, extended-release capsule.
- the composition comprises a derivative of a SCFA.
- the derivative comprises at least one SCFA moiety linked to at least one additional moiety.
- the derivative comprises at least one SCFA moiety linked to at least one polyethylene glycol (PEG) moiety.
- PEG polyethylene glycol
- the at least one SCFA moiety linked to at least one PEG moiety hydrolyzes under a low pH condition to yield at least one SCFA molecule and at least one PEG molecule.
- the composition comprises a combination of SCFAs, and/or derivatives thereof.
- the composition is prepared at amounts of at least 10 mM, at least 20 mM, at least 30 mM, 40 mM, 50 mM, 60 mM, 70 mM, 80 mM, 90 mM, 100 mM, or more of each or all the compounds of the composition.
- SCFAs e.g., having substituents on the carbon chain such as O, S, N, methyl, ethyl, halogen, and other groups that do not interfere with the compound’s therapeutic activity may also be used to form the compositions of this disclosure.
- the compound of the disclosure comprises at least one SCFA linked to at least one additional moiety, such as O, S, N, methyl, ethyl, halogen, and other groups that do not interfere with the compound’s therapeutic activity.
- SCFA of the disclosure can be pegylated.
- Polyethylene glycol (PEG) has been widely used in biomaterials, biotechnology and medicine primarily because PEG is a biocompatible, nontoxic, nonimmunogenic and water-soluble polymer (Zhao and Harris, ACS Symposium Series 680: 458-72, 1997).
- PEG derivatives have been widely used in covalent attachment (i.e., “PEGylation”) to proteins to reduce immunogenicity, proteolysis and kidney clearance and to enhance solubility (Zalipsky, Adv. Drug Del. Rev. 16:157-82, 1995).
- PEG has been attached to low molecular weight, relatively hydrophobic drugs to enhance solubility, reduce toxicity and alter biodistribution.
- PEGylated drugs are injected as solutions. However, they may be administered orally, or by another route.
- a closely related application is synthesis of crosslinked degradable PEG networks or formulations for use in drug delivery since much of the same chemistry used in design of degradable, soluble drug carriers can also be used in design of degradable gels (Sawhney et al., Macromolecules 26: 581-87, 1993). It is also known that intermacromolecular complexes can be formed by mixing solutions of two complementary polymers. Such complexes are generally stabilized by electrostatic interactions (polyanion-polycation) and/or hydrogen bonds (polyacid- polybase) between the polymers involved, and/or by hydrophobic interactions between the polymers in an aqueous surrounding (Krupers et al., Eur.
- 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, a salt of formate, a salt of lactate, a salt of succinate, 1,2-propenedol, trypamine, indole, and indole-3- acetate.
- the composition comprises a precursor of SCFA biosynthesis alone or in combination with one or more SCFA.
- Precursors of SCFA biosynthesis include, but are not limited to, a salt of formate, a salt of lactate, a salt of succinate, acetyl-CoA carboxylase inhibitors, adenosine monophosphate kinase (AMPK) activators, and vitamin D.
- AMPK adenosine monophosphate kinase
- a composition comprises an inhibitor of acetyl-CoA carboxylase, including but not limited to, biotin or its naturally or chemically synthesized analogs (which are acetyl-CoA carboxylase inhibitors) alone or in combination with one or more other SCFAs, to stimulate Treg functions.
- a compound comprising at least one SCFA, or a compound comprising a SCFA moiety of the disclosure may be combined with one or more compounds, such as one or more additional therapeutic agent, for a particular disease or disorder.
- the one or more SCFAs of the disclosure may be in the same composition as one or more additional therapeutic agent.
- the composition may comprise at least 1, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10 or more than 10 additional therapeutic agents.
- additional therapeutic agents and/or compounds that can be included in a composition are discussed in detail elsewhere herein.
- 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 agent.
- anti-inflammatory agents that can be used in combination with the compositions include, but are not limited to nonsteroidal anti-inflammatory drugs (NSAIDs) such as diclofenac (e.g., Arthrotec ® ), diflunisal (e.g., Dolobid ® ), etodolac (e.g., Lodine ® ), fenoprofen (e.g., Nalfon ® ), ibuprofen (e.g., Advil ® , Motrin ® , and others), indomethacin (e.g., Arthrexin ® ), ketoprofen (e.g., Oruvail ® ), ketorolac (e.g., Toradol ® ), fosfomycin tromethamine (e.g., Monural ® ), meclofenamate (e.g., Meclomen ® ), nabumetone (e.g., Relafen
- Oxaprozin e.g., Daypro ®
- piroxicam e.g., Feldene ®
- sulindac e.g., Clinoril ®
- tolmetin e.g., Tolectin ® , and others
- Flavenoids e.g., luteolin, fisetin, and apigenin
- steroids e.g., antihistamines, Loratadine, Theophylline, Doxantrazole, Quercetin, 8-bromo cyclic AMP, Disodium cromoglicate
- Beclomethasone dipropionate Budesonide, Budesonide/Formoterol, Fluticasone, Fluticasone inhaled powder, Fluticasone/Salmeterol, Mometasone, Mometasone/formoterol, Cromolyn, Omalizumab, Inhaled short- or long-acting beta2-agonists, Leukotriene modifiers, and The
- 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 anti-inflammatory agent. 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 agent.
- Chemotherapeutic Agents [0133] In one embodiment, the method of the disclosure may comprise administration of the composition in combination with one or more chemotherapeutic agent.
- Chemotherapeutic agents include, but are not limited to, ara-C, daunomycin, cladribine (Leustatin, 2-CdA), cytotoxic agents (e.g., 5-fluorouracil, cisplatin, carboplatin, methotrexate, daunorubicin, doxorubicin, vincristine, vinblastine, oxorubicin, carmustine (BCNU), lomustine (CCNU), cytarabine USP, cyclophosphamide, estramucine phosphate sodium, altretamine, hydroxyurea, ifosfamide, procarbazine, mitomycin, busulfan, cyclophosphamide, mitoxantrone, carboplatin, cisplatin, interferon alfa-2a recombinant, paclitaxel, teniposide, and streptozoci), cytotoxic alkylating agents (e.g., busulfan
- a composition is administered before, during, or after administration of at least one antiproliferative agent for the treatment of cancer.
- Antiproliferative agents are compounds that decrease the proliferation of cells.
- Antiproliferative agents include, but are not limited to, alkylating agents, antimetabolites, enzymes, biological response modifiers, miscellaneous agents, hormones and antagonists, androgen inhibitors (e.g., flutamide and leuprolide acetate), antiestrogens (e.g., tamoxifen citrate and analogs thereof, toremifene, droloxifene and roloxifene), Additional examples of specific antiproliferative agents include, but are not limited to levamisole, gallium nitrate, granisetron, sargramostim strontium-89 chloride, filgrastim, pilocarpine, dexrazoxane, and ondansetron.
- compositions can be administered alone or in combination with other anti-tumor agents, including cytotoxic/antineoplastic agents and anti-angiogenic agents.
- Cytotoxic/anti- neoplastic agents are defined as agents which attack and kill cancer cells.
- Some cytotoxic/anti- neoplastic agents are alkylating agents, which alkylate the genetic material in tumor cells, e.g., cis-platin, cyclophosphamide, nitrogen mustard, trimethylene thiophosphoramide, carmustine, busulfan, chlorambucil, belustine, uracil mustard, chlomaphazin, and dacabazine.
- cytotoxic/anti-neoplastic agents are antimetabolites for tumor cells, e.g., cytosine arabinoside, fluorouracil, methotrexate, mercaptopuirine, azathioprime, and procarbazine.
- Other cytotoxic/anti-neoplastic agents are antibiotics, e.g., doxorubicin, bleomycin, dactinomycin, daunorubicin, mithramycin, mitomycin, mytomycin C, and daunomycin.
- doxorubicin e.g., doxorubicin, bleomycin, dactinomycin, daunorubicin, mithramycin, mitomycin, mytomycin C, and daunomycin.
- mitotic inhibitors (vinca alkaloids).
- cytotoxic/anti-neoplastic agents include taxol and its derivatives, L-asparaginase, anti-tumor antibodies, dacarbazine, azacytidine, amsacrine, melphalan, VM-26, ifosfamide, mitoxantrone, and vindesine.
- Anti-angiogenic agents are well known to those of skill in the art. Suitable anti-angiogenic agents for combining with the compositions of the present disclosure include anti-VEGF antibodies, including humanized and chimeric antibodies, anti-VEGF aptamers and antisense oligonucleotides.
- inhibitors of angiogenesis include angiostatin, endostatin, interferons, interleukin 1 (including alpha and beta) interleukin 12, retinoic acid, and tissue inhibitors of metalloproteinase-1 and -2. (TIMP-1 and -2).
- tissue inhibitors of metalloproteinase-1 and -2 tissue inhibitors of metalloproteinase-1 and -2.
- TIMP-1 and -2 tissue inhibitors of metalloproteinase-1 and -2.
- Small molecules including topoisomerases such as razoxane, a topoisomerase II inhibitor with anti-angiogenic activity, can also be used.
- anti-cancer agents that can be used in combination with the compositions include, but are not limited to: acivicin; aclarubicin; acodazole hydrochloride; acronine; adozelesin; aldesleukin; altretamine; ambomycin; ametantrone acetate; aminoglutethimide; amsacrine; anastrozole; anthramycin; asparaginase; asperlin; azacitidine; azetepa; azotomycin; batimastat; benzodepa; bicalutamide; bisantrene hydrochloride; bisnafide dimesylate; bizelesin; bleomycin sulfate; brequinar sodium; bropirimine; busulfan; cactinomycin; calusterone; caracemide; carbetimer; carboplatin; carmustine; carubicin hydrochloride; carzelesin
- anti- cancer drugs include, but are not limited to: 20-epi-1,25 dihydroxyvitamin D3; 5-ethynyluracil; abiraterone; aclarubicin; acylfulvene; adecypenol; adozelesin; aldesleukin; ALL-TK antagonists; altretamine; ambamustine; amidox; amifostine; aminolevulinic acid; amrubicin; amsacrine; anagrelide; anastrozole; andrographolide; angiogenesis inhibitors; antagonist D; antagonist G; antarelix; anti-dorsalizing morphogenetic protein-1; antiandrogen, prostatic carcinoma; antiestrogen; antineoplaston; antisense oligonucleotides; aphidicolin glycinate; apoptosis gene modulators; apoptosis regulators; apurinic acid; ara-CDP-DL-PTBA;
- the anti-cancer drug is 5-fluorouracil, taxol, or leucovorin.
- Anti-viral Agents [0138] The present disclosure contemplates compositions comprising at least one SCFA or compound comprising a SCFA moiety as described herein in combination with anti-viral agents.
- Anti-viral agents include, but are not limited to, inhibitors of viral uncoating (e.g., amantadine and rimantidine), reverse transcriptase inhibitors (e.g., acyclovir, zidovudine, and lamivudine), agents that target integrase; agents that block attachment of transcription factors to viral DNA; agents (e.g., antisense molecules) that impact translation (e.g., fomivirsen); agents that modulate translation/ribozyme function; protease inhibitors; viral assembly modulators (e.g., rifampicin); antiretrovirals such as, for example, nucleoside analogue reverse transcriptase inhibitors (e.g., azidothymidine (AZT), ddl, ddC, 3TC, d4T); non-nucleoside reverse transcriptase inhibitors (e.g., efavirenz, nevirapine); nucleotide ana
- 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 biologic drugs.
- biologic drugs contemplated by the present disclosure include, but are not limited to, etanercept (Enbrel ® ), infliximab (Remicade ® ), apremilast (Otezla®), and adalimumab (Humira ® ).
- 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 biologic agent.
- 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 biologic agent.
- Other Agents [0142] In one embodiment, the method comprises administering to a subject in need thereof a composition comprising at least one SCFA, or a biologically-active derivative or precursor thereof, and additionally one or more additional therapeutic agents. In one embodiment, the method comprises administering to a subject in need thereof a composition comprising at least one SCFA, or a biologically-active derivative or precursor thereof, in combination with a composition comprising one or more additional therapeutic agents.
- Additional therapeutic agents that are contemplated for administration according to the methods of the disclosureinclude, but are not limited to, rofecoxib, celecoxib, folic acid, sulfasalazine, naproxen, leflunomide, methylprednisolone acetate, parenteral gold, oral gold, indomethacin, hydroxychloroquine, hydroxychloroquine sulfate, sulindac, prednisone, betamethasone diprop augmented, folate, triamcinolone acetonide, diclofenac, dimethylsulfoxide, piroxicam, diclofenac sodium, ketoprofen, meloxicam, methylprednisolone, nabumetone, tolmetin sodium, calcipotriene, cyclosporine, diclofenac, sodium/misoprostol, fluocinonide, glucosamine sulfate, gold sodium thio
- TNF antibodies which can be used in the disclosure are described in U.S. Pat. Nos. 6,593,458; 6,498,237; 6,451,983; and 6,448,380, each of which is incorporated by reference herein, talampanel, teriflunomide, TGF-beta2, tiplimotide, VLA-4 antagonists (for example, 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, lampalizumab, fluocinolone acetaton
- Administration of the compositions of the present disclosure to a subject may be carried out using known procedures, at dosages and for periods of time effective for treating or preventing a disease or disorder in the subject.
- An effective amount of the therapeutic compound necessary to achieve a therapeutic effect may vary according to actors such as the state of the disease or disorder in the subject; the age, sex, and weight of the subject.
- the regimen of administration may affect what constitutes an effective amount. Further, the dosages of the compositions may be proportionally increased or decreased as indicated by the exigencies of the therapeutic or prophylactic situation.
- a non-limiting example of an effective dose range for a therapeutic compound of the disclosure is from about 1 to about 5,000 mg/kg of body weight/per day.
- the effective dose can be between 1mg to 10 mg active component/kg body weight/time, and can be 20 jig to 10 mg component/kg body weight/time.
- the therapeutic compound can be administered every 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, or 31 days.
- the number of doses for effective treatment can be 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more than 10.
- the active ingredients in the pharmaceutical compositions of this disclosure may be varied so as 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 being toxic to the subject.
- the selected dosage level will depend upon a variety of factors including the activity of the particular compound employed, the time of administration, the rate of excretion of the compound, the duration of the treatment, other drugs, compounds or materials used in combination with the compound, the age, sex, weight, condition, general health and prior medical history of the subject being treated, and like factors well known in the medical arts.
- a medical doctor e.g., physician or veterinarian, having ordinary skill in the art may readily determine and prescribe the effective amount of the pharmaceutical composition required.
- compositions for administration may be in the range of from 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.
- the dose of a compound of the disclosure is from about 1 mg and about 2,500 mg.
- a dose of a compound of the disclosure used in 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 there between.
- the treatment regimen comprises daily administration of a composition.
- a treatment regimen comprises administering a short chain fatty acid at least once daily for at least 1 day, at least 2 days, at least 3 days, at least 4 days, at least 5 days, at least 7 days, at least 10 days, at least 2 weeks, at least 3 weeks, at least 1 month, at least 2 months, at least 3 months, at least 6 months, at least 1 year or more than 1 year.
- a treatment regimen comprises administering a short chain fatty acid three times daily for at least 1 day, at least 2 days, at least 3 days, at least 4 days, at least 5 days, at least 7 days, at least 10 days, at least 2 weeks, at least 3 weeks, at least 1 month, at least 2 months, at least 3 months, at least 6 months, at least 1 year or more than 1 year.
- a treatment regimen comprises administering a composition comprising a short chain fatty acid, a short chain fatty acid precursor, a short chain fatty acid biosynthesis precursor, or a combination thereof at least once daily upon appearance of a disease or disorder.
- a treatment regimen comprises daily oral administration of a short chain fatty acid.
- 600 mg of butyrate is administered 3 times per day (a total of 1800 mg/day) for at least one week.
- a treatment regimen comprises oral administration of two butyrate capsules containing 600 mg of butyrate 3 times per day (a total of 3600 mg/day) for at least one week.
- a treatment regimen comprises oral administration of two butyrate capsules containing 600 mg of butyrate 3 times per day (a total of 3600 mg/day) for at least one week followed thereafter by oral administration of butyrate capsules containing 600 mg of butyrate 3 times per day (a total of 1800 mg/day) for at least one week.
- administration of a composition to an individual makes it possible to induce tolerance, strengthen gut barrier integrity, and reduce inflammation in the individual.
- the method comprises administering to an individual a composition described herein.
- the composition comprises one or more SCFAs or SCFA derivatives.
- the composition is administered to the individual in sufficient quantity to produce the desired effect of inducing tolerance, strengthening the gut barrier, and reducing inflammation.
- Whether administration of the composition induces tolerance can be determined by using, as an index, increase or reinforcement of at least one of the following: the number of regulatory T cells (Tregs), the ratio of Tregs in the T cell group of the colon, a function of Tregs, or expression of a marker of Tregs.
- a specific approach is measurement counts or percentage of Foxp3- expressing Tregs in a patient sample, such as a biopsy or a blood sample, promotion (enhancement) of IL-10 expression, promotion (enhancement) of CTLA4 expression, promotion (enhancement) of IDO expression, or suppression of IL-4 expression as the index of the induction of proliferation or accumulation of regulatory T cells.
- Whether administration of the composition strengthens barrier function can be determined by using, as an index, increase in production of active form TGF- ⁇ and/or tight junction-related proteins by intestinal epithelial cells.
- Whether administration of the composition reduces inflammation can be determined by using, as an index, increase in production of anti-inflammatory cytokines such as IL-10 and/or TGF-.beta., or decrease in production of pro-inflammatory cytokines such as IL-4.
- a disclosed herein modulates a cytokine.
- the cytokine is a pro-inflammatory cytokine.
- Non-limiting examples of cytokines include: TNF ⁇ , IFN ⁇ , IL-17A, IL-21, IL-22, IL-23, IL-27, IL-31, and MIP-3 ⁇ .
- short chain fatty acids modulate multiple cellular signaling proteins, including, but not limited to, IL-18, TLR3, IFN- ⁇ , TNF ⁇ , TGF- ⁇ , MyD88, PI3K/Akt, JAK/STAT, Smad 2/3, Smad 4, IL-10, Notch, hedgehog, Wnt (beta-catenin), matrix metalloproteinases 9 and 10, tissue inhibitor of metalloproteinases, nodal and NF- ⁇ B signaling.
- IL-18 TLR3, IFN- ⁇ , TNF ⁇ , TGF- ⁇ , MyD88, PI3K/Akt, JAK/STAT, Smad 2/3, Smad 4, IL-10, Notch, hedgehog, Wnt (beta-catenin), matrix metalloproteinases 9 and 10, tissue inhibitor of metalloproteinases, nodal and NF- ⁇ B signaling.
- the signaling proteins that are modulated by SCFAs modulate biological pathways or processes include, but are not limited to, inflammation, immunity, proliferation, differentiation, apoptosis, oncogenesis, transcription of DNA, cytokine production, cell survival, angiogenesis, fibrogenesis and cellular responses to stimuli such as stress, cytokines, free radicals, heavy metals, and ultraviolet irradiation.
- a method disclosed herein comprises treating or reducing a likelihood of developing medical diseases or disorders characterized by elevated levels or abnormal expression of at least one of IL-18, TLR3, IFN- ⁇ , TNF ⁇ , TGF- ⁇ , MyD88, PI3K/Akt, JAK/STAT, Smad 2/3, Smad 4 or IL-10 signaling.
- a method disclosed herein comprises treating or reducing a likelihood of developing medical diseases or disorders characterized by decreased levels or abnormal expression of NF- ⁇ B signaling.
- Methods for detecting such expression include northern blotting, RT-PCR, and dot blotting for detection of gene expression at the transcription level; ELISA, radioimmunoassays, immunoblotting, immunoprecipitation, and flow cytometry for detection of gene expression at the translation level.
- Samples that may be used for measuring such an index include tissues and fluids obtained from an individual, such as blood, a biopsy, or a fecal sample.
- Combination with Additional Agents [0160] The present disclosure is also directed to a method of treating or preventing a disease or disorder as described above in combination with one or more additional agents.
- the combination can be in a single formulation or can be separate and administered in sequence (either a composition comprising at least one SCFA, or a molecule comprising a SCFA moiety, first and then a composition comprising an additional agent, or a composition comprising an additional agent first and then a composition comprising at least one SCFA, or a molecule comprising a SCFA moiety).
- the at least one SCFA, or a molecule comprising a SCFA moiety 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 hours, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, 18 hours, 19 hours, 20 hours, 21 hours, 22 hours, 23 hours, 24 hours, 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 hours, 23 hours, 24 hours,
- the composition comprising at least one additional agent 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 hours, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, 18 hours, 19 hours, 20 hours, 21 hours, 22 hours, 23 hours, 24 hours, 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, 36 hours, 48 hours, 60 hours, 72 hours
- the disclosure provides a general concept for 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 disorder in a subject in need thereof.
- 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.
- 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.
- the immune response in the subject administered the combination of the at least one SCFA, or a molecule comprising a SCFA moiety, and 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, at least about 7.0-fold, at least about 7.5-fold, at least about 8.0-fold, at least about 8.5-fold, at least about 9.0-fold, at least about 9.5-fold, at least about 10.0-fold, at least about 10.5-fold, at least about 11.0-fold, at least about 11.5-fold, at least about 12.0-fold, at least about 12.5-fold, at least about 13.0-fold, at least about 13.5-fold, at least about 14.0-fold,
- the immune response in the subject administered the combination of the at least one SCFA, or a molecule comprising a SCFA moiety, and checkpoint inhibitor can be increased about 50% to about 1500%, about 50% to about 1000%, or about 50% to about 800%.
- the immune response in the subject administered the combination of the at least one SCFA, or a molecule comprising a SCFA moiety, and 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%.
- the disclosure provides a method for stimulating, eliciting or enhancing an immune response in a subject individual (individual) comprising administering to a subject an immunotherapeutic agent in combination with a composition comprising a SCFA or a compound comprising a SCFA moiety.
- the subject may be at risk for having a disease, be diagnosed as having a disease, have previously been treated for a disease, or be contemporaneously be 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 partly based upon the discovery that administration of at least one short chain fatty acid (SCFA) can be effective as a therapeutic approach for the treatment or prevention of an adverse effect associated with immunotherapy of cancer. It is expected that the therapeutic effect of treatments using compositions comprising at least one SCFA will not interfere significantly with the benefits of the immunotherapy, but will treat or prevent undesired adverse effects associated with immunotherapy of cancer. Therefore, in one embodiment, the disclosure relates to compositions comprising at least one SCFA for use as a therapeutic for the treatment or prevention of adverse effects associated with immunotherapy of cancer.
- SCFA short chain fatty acid
- the present disclosure provides methods for treatment, inhibition, prevention, or reduction of an adverse effect associated with cancer immunotherapy by administering a composition comprising a SCFA or a compound comprising a SCFA moiety, as disclosed herein, to a subject in need thereof, optionally in combination with at least one additional agent or therapy.
- Adverse effects associated with cancer immunotherapy include, but are not limited to cytokine release syndrome (CRS), neurological toxicity, on- target/off-tumor recognition, anaphylaxis, graft versus host disease (GVHD), off-target antigen recognition, and macrophage activation syndrome (MAS).
- the present disclosure provides methods for treatment, inhibition, prevention, or reduction of a disease associated with an adverse effect associated with cancer immunotherapy, comprising administering a composition comprising at least one SCFA or compound comprising a SCFA moiety, as disclosed herein, to a subject in need thereof.
- the adverse effect includes a combination of adverse effects.
- a subject suffering from adverse effects associated with immunotherapy of cancer is a human.
- a subject suffering from adverse effects associated with immunotherapy of cancer is a non-human animal.
- to stimulate an immune response the subject individual is administered (i) at least one SCFA or compound comprising a SCFA moiety, and (ii) at least one immunotherapeutic agent.
- the administration of at least one SCFA or compound comprising a SCFA moiety and the immunotherapeutic agent will be in the form of a vaccine or administered in a vaccine regimen.
- the at least one SCFA or compound comprising a SCFA moiety and the immunotherapeutic agent can be administered at about the same time to the subject individual, or can be administered separately and/or sequentially.
- Immunotherapeutic agents that may be administered according to the methods of the disclosure include, but are not limited to, one or more cancer antigens, one or more antigens derived from a virus associated with cancer, and an anti-cancer antibody.
- a cancer antigen may be (a) a cell surface antigen that can be found on a malignant cell, (b) an antigen that can be found inside a malignant cell or (c) a mediator of tumor cell growth.
- cancer antigen refers to (i) tumor-specific antigens, (ii) tumor-associated antigens, (iii) cells that express tumor-specific antigens, (iv) cells that express 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 material that is associated with a cancer.
- the cancer antigen can be a cell, a protein, a peptide, a fusion protein, DNA encoding a peptide or protein, RNA encoding a peptide or protein, a glycoprotein, a lipoprotein, a phosphoprotein, a carbohydrate, a lipopolysaccharide, a lipid, a chemically linked combination of two or more thereof, a fusion or two or more thereof, or a mixture of two or more thereof.
- the cancer antigen is a peptide comprising about 6 to about 24 amino acids; from about 8 to about 20 amino acids; from about 8 to about 12 amino acids; from about 8 to about 10 amino acids; or from about 12 to about 20 amino acids.
- the cancer antigen is a peptide having a MHC Class I binding motif or a MHC Class II binding motif.
- the cancer antigen comprises a peptide that corresponds to one or more cytotoxic T lymphocyte (CTL) epitopes.
- CTL cytotoxic T lymphocyte
- the present disclosure provides methods for treatment, inhibition, prevention, or reduction of an adverse effect associated with cancer immunotherapy by administering a composition comprising a SCFA or a compound comprising a SCFA moiety, as disclosed herein, to a subject in need thereof, optionally in combination with at least one immunotherapeutic agent.
- the immunotherapy is chimeric antigen receptor T-cell (CAR-T) therapy.
- a composition is administered before, during, or after CAR-T therapy for the treatment of cancer, for the treatment or prevention of at least one adverse effect associated with CAR-T therapy.
- Particular adverse effects treatable and/or preventable by compositions of the present disclosure include, but are not limited to: cytokine release syndrome (CRS), neurological toxicity, on-target/off-tumor recognition, anaphylaxis, graft versus host disease (GVHD), off-target antigen recognition, and macrophage activation syndrome (MAS).
- CRS cytokine release syndrome
- GVHD graft versus host disease
- MAS macrophage activation syndrome
- IL-6R blockade a systemic corticosteroids such as dexamethasone, monoclonal antibodies, lymphodepleting chemotherapy with agents such as cyclophosphamide
- suicide genes or elimination genes i.e., killing of CAR-T cells
- targeted activation i.e., conditional activation of CAR-T cells with a drug or another agent. Therefore, in one embodiment, the treatment compositions of the present disclosure are combined with at least one other strategy to reduce, prevent, treat, or ameliorate one or more adverse effects associated with immunotherapy of cancer.
- the disclosure provides a composition for treating or preventing the onset of an adverse effect associated with immunotherapy of cancer.
- the composition comprises at least one SCFA or a compound comprising a SCFA moiety.
- the immunotherapy comprises CAR-T therapy.
- the immunotherapy comprises a therapy involving at least one other anti-cancer composition.
- a composition is administered before, during, or after chemotherapy for the treatment of cancer.
- compositions comprising at least one SCFA is administered in parallel to chemotherapy: several days before CAR-T cell infusion (only SCFAs), and up to several weeks after CAR-T cell infusion (SCFAs in combination with chemotherapeutic agents at reduced levels relative to a subject undergoing chemotherapy alone).
- SCFAs in combination with chemotherapeutic agents at reduced levels relative to a subject undergoing chemotherapy alone.
- compositions comprising one or more compositions of the present disclosure.
- the formulations of the pharmaceutical compositions described herein may be prepared by any method known or hereafter developed in the art of pharmacology.
- compositions may comprise additional medicinal agents, pharmaceutical agents, carriers, buffers, adjuvants, dispersing agents, diluents, and the like depending on the intended use and application.
- suitable pharmaceutical carriers, excipients and/or diluents include: a gum, a starch (e g.
- compositions are aqueous or non-aqueous solutions, suspensions, emulsions or oils, Examples of non-aqueous solvents are propylene glycol, polyethylene glycol, and injectable organic esters such as ethyl oleate.
- oils are those of animal, vegetable, or synthetic origin, for example, peanut oil, soybean oil, olive oil, sunflower oil, turmeric oil, fish-liver oil, another marine oil, or a lipid from milk or eggs.
- Aqueous carriers include water, alcoholic/aqueous 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 formulated by well- known conventional methods. Suitable carriers may comprise any material which, when combined with the biologically active compound of the disclosure, retains the biological activity.
- Preparations for parenteral administration may include sterile aqueous or non-aqueous solutions, suspensions, and emulsions.
- non-aqueous solvents are propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate.
- Aqueous carriers include water, alcoholic/aqueous solutions, emulsions or suspensions, including saline and buffered media.
- Parenteral vehicles may include sodium chloride solution, Ringer's dextrose, dextrose and sodium chloride, lactated Ringer's, or fixed oils.
- Intravenous vehicles may include fluid and nutrient replenishes, electrolyte replenishers (such as those based on Ringer's dextrose), and the like. Preservatives and other additives may also be present including, for example, antimicrobials, anti-oxidants, chelating agents, and inert gases and the like, in addition, the pharmaceutical composition of the present disclosure might comprise proteinaceous carriers, like, e.g., serum albumin or immunoglobulin.
- the pharmaceutical compositions provided herein may also be administered as controlled- release compositions, i.e. compositions in which the active ingredient is released over a period of time after administration. Controlled- or sustained-release compositions include formulation in lipophilic depots (e.g.
- compositions are an immediate-release composition, i.e. a composition in which all the active ingredient is released immediately after administration.
- the pharmaceutical compositions according to the disclosure and as described herein in the various embodiments may or a composition comprising said compound may be administered admixed to food, functional food, drinks, medicinal food.
- pharmaceutical compositions provided herein are principally directed to pharmaceutical compositions which are suitable for ethical administration to humans, it will be understood by the skilled artisan that such compositions are generally suitable for administration to animals of all sorts.
- compositions suitable for administration to humans in order to render the compositions suitable for administration to various animals is well understood, and the ordinarily skilled veterinary pharmacologist can design and perform such modification with merely ordinary, if any, experimentation.
- Subjects to which administration of the pharmaceutical compositions are contemplated 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-mammalian animals, and other veterinary applications.
- compositions that are useful in the methods of the disclosure may be prepared, packaged, or sold in formulations suitable for ophthalmic, oral, rectal, vaginal, parenteral, topical, pulmonary, intranasal, buccal, intratumoral, epidural, intracerebral, intracerebroventricular, or another route of administration.
- Other contemplated formulations include projected nanoparticles, liposomal preparations, resealed erythrocytes containing the active ingredient, and immunologically-based formulations.
- a pharmaceutical composition may be prepared, packaged, or sold in bulk, as a single unit dose, or as a plurality of single unit doses.
- a “unit dose” is discrete amount of the pharmaceutical composition comprising a predetermined amount of the active ingredient.
- the amount of the active ingredient is generally equal to the dosage of the active ingredient which would be administered to a subject or a convenient fraction of such a dosage such as, for example, one-half or one-third of such a dosage.
- the relative amounts of the active ingredient, the pharmaceutically acceptable carrier, and any additional ingredients in a pharmaceutical composition will vary, depending upon the identity, size, and condition of the subject treated and further depending upon the route by which the composition is to be administered.
- the composition may comprise between 0.1% and 100% (w/w) active ingredient.
- a pharmaceutical composition may further comprise one or more additional pharmaceutically active agents.
- Controlled- or sustained-release formulations of a pharmaceutical composition may be made using conventional technology.
- Pharmaceutical compositions also include nutritional compositions, such as oral nutritional compositions for oral consumption and optionally for enteral adsorption, wherein the nutritional composition includes the compounds of the present disclosure. Therefore, in one embodiment, the disclosure relates to nutraceutical compositions.
- the nutritional compositions are formulated to be administered orally, the compositions may be a liquid oral nutritional supplement (e.g., incomplete feeding) or a complete feeding.
- a nutritional formula encompasses any nutritionally complete or supplementary formulation (a nutritional supplement, for example).
- nutritionally complete are preferably nutritional products that contain sufficient types and levels of macronutrients (protein, fats and carbohydrates) and micronutrients to be sufficient to be a sole source of nutrition for the subject to which it is being administered to. Patients can receive 100% of their nutritional requirements from such complete nutritional compositions.
- the nutritional formula is a supplementary formulation providing supplementary nutrition.
- a “supplementary formula” may not be nutritionally complete, but preferably contains specific nutrients that are supportive, for example in combination with physical exercise, with further of the beneficial effects of the disclosure, and/or which address specific or additional needs of the subject.
- the nutritional formula may be a generally applicable nutritional formula, for example adapted to subjects of a specific age, for example a formula for children, but it may also be a formula for elderly patients, for intensive care patients, or a specially adapted formula for patients suffering from a specific disease, for example. Any nutritional formula may be reconstitutable, that is, present in a substantially dried, for example powdered form, or ready-to- drink, in the form of liquid formulas, for example.
- Formulations of a pharmaceutical composition suitable for parenteral administration comprise the active ingredient combined with a pharmaceutically acceptable carrier, such as sterile water or sterile isotonic saline. Such formulations may be prepared, packaged, or sold in a form suitable for bolus administration or for continuous administration. Injectable formulations may be prepared, packaged, or sold in unit dosage form, such as in ampules or in multi dose containers containing a preservative. Formulations for parenteral administration include, but are not limited to, suspensions, solutions, emulsions in oily or aqueous vehicles, pastes, and implantable sustained-release or biodegradable formulations. Such formulations may further comprise one or more additional ingredients including, but not limited to, suspending, stabilizing, or dispersing agents.
- the active ingredient is provided in dry (i.e., powder or granular) form for reconstitution with a suitable vehicle (e.g., sterile pyrogen free water) prior to parenteral administration of the reconstituted composition.
- a suitable vehicle e.g., sterile pyrogen free water
- the pharmaceutical compositions may be prepared, packaged, or sold in the form of a sterile injectable aqueous or oily suspension or solution. This suspension or solution may be formulated according to the known art, and may comprise, in addition to the active ingredient, additional ingredients such as the dispersing agents, wetting agents, or suspending agents described herein.
- Such sterile injectable formulations may be prepared using a non-toxic parenterally acceptable diluent or solvent, such as water or 1,3 butane diol, for example.
- a non-toxic parenterally acceptable diluent or solvent such as water or 1,3 butane diol
- Other acceptable diluents and solvents include, but are not limited to, Ringer's solution, isotonic sodium chloride solution, and fixed oils such as synthetic mono or di-glycerides.
- Other parentally-administrable formulations which are useful include those which comprise the active ingredient in microcrystalline form, in a liposomal preparation, or as a component of a biodegradable polymer system.
- compositions for sustained release or implantation may comprise pharmaceutically acceptable polymeric or hydrophobic materials such as an emulsion, an ion exchange resin, a sparingly soluble polymer, or a sparingly soluble salt.
- pharmaceutically acceptable polymeric or hydrophobic materials such as an emulsion, an ion exchange resin, a sparingly soluble polymer, or a sparingly soluble salt.
- the compositions of the present disclosure as described herein may be used as a complete food product, as a component of a food product, as a dietary supplement or as part of a dietary supplement, as a feed additive and may be either in liquid, semisolid or solid form.
- the compositions of the present disclosure as described herein additionally may be in the form of a pharmaceutical composition.
- compositions, dietary supplements, food products, baby food products, feed additives, and/or pharmaceutical compositions of the present disclosure may advantageously be utilized in methods for promoting the health of an individual.
- the compositions may be in liquid, semisolid or solid form.
- the compositions may be administered as tablets, gel packs, capsules, gelatin capsules, flavored drinks, as a powder that can be reconstituted into such a drink, cooking oil, salad oil or dressing, sauce, syrup, mayonnaise, margarine or the like.
- the food product, dietary supplements, and the like, of the present disclosure can include, but are not limited to, dairy products, baby food, baby formula, beverages, bars, a powder, a food topping, a drink, a cereal, an ice cream, a candy, a snack mix, a baked food product and a fried food product.
- Beverages of the disclosure include but are not limited to energy drinks, nutraceutical drinks, smoothies, sports drinks, orange juice and other fruit drinks.
- a bar of the present disclosure includes, but is not limited to, a meal replacement, a nutritional bar, a snack bar and an energy bar, an extruded bar, and the like.
- Dairy products of the disclosure include, but are not limited to, including but not limited to yogurt, yogurt drinks, cheese and milk.
- the food products or dietary supplements of the present disclosure may further comprise herbals, herbal extracts, fungal extracts, enzymes, fiber sources, minerals, and vitamins.
- the microalgal oils and microalgal biomass of the present disclosure may be used in the compositions for both therapeutic and non-therapeutic uses.
- the compositions, food products and animal feed additives of the present disclosure may be used for therapeutic or non-therapeutic purposes.
- compositions intended for oral administration may be prepared according to any known method for the manufacture of dietary supplements or pharmaceutical preparations, and such compositions may include at least one additive selected from the group consisting of taste improving substances, such as sweetening agents or flavoring agents, stabilizers, emulsifiers, coloring agents and preserving agents in order to provide a dietetically or pharmaceutically palatable preparation. Vitamins, minerals and trace element from any physiologically acceptable source may also be included in the composition.
- a pharmaceutical composition of the present disclosure comprises the said compositions of the present disclosure in a therapeutically effective amount.
- the compositions may additionally comprise prescription medicines or non-prescription medicines.
- the combinations may advantageously produce one or more of the following effects: (1) additive and/or synergistic benefits; (2) reduction of the side effects and/or adverse effects associated with use of the prescription medicine in the absence of the said formulations; and/or (3) the ability to lower the dosage of the prescription medicine in comparison to the amount of prescription medicine needed in the absence of the said formulations.
- the active agents of the present disclosure can be prepared in the form of their pharmaceutically acceptable salts.
- pharmaceutically acceptable salts are salts that retain the desired biological activity of the parent compound and do not impart undesired toxicological effects.
- “Pharmaceutically acceptable salts” as defined herein include derivatives of the disclosed SCFA or compound comprising a SCFA moiety, wherein the parent compound is modified by making non-toxic salts of the carboxylate group thereof, and further refers 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.
- conventional non-toxic acid salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxylmaleic, phenylacetic, glutamic, benzoic, salicylic, mesylic, esylic, besylic, sulfanilic, 2- acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, HOOC--(CH2)n--COOH where n is 0-4, and the like.
- inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phospho
- the SCFA can be present as an ester of the SCFA's carboxylic acid with a branched or unbranched alkyl alcohol of one to 6 carbons.
- the SCFA can be present as an ethyl ester, propyl ester, butyl ester, isopropyl ester, t- butyl ester, pentyl ester, or hexyl ester.
- the active agents can be formulated for administration in accordance with known pharmacy techniques.
- the active agents (including the physiologically acceptable salts thereof) is typically admixed with, inter alia, an acceptable carrier.
- the carrier must, of course, be acceptable in the sense of being compatible with any other ingredients in the formulation and must not be deleterious to the subject.
- the carrier can be a solid or a liquid, or both, and can be formulated with the active agent as a unit-dose formulation, for example, a tablet, which can contain from 0.01% or 0.5% to 95% or 99%, or any value between 0.01% and 99%, by weight of the active agent.
- compositions which can be prepared by any of the well-known techniques of pharmacy, comprising admixing the components, optionally including one or more accessory ingredients.
- the carrier can be preservative free, as described herein above.
- the active agents comprise a lower limit ranging from about 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10% to an upper limit ranging from about 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97,
- the active agent includes from about 0.05% to about greater than 99% by weight of the composition.
- the pharmaceutical compositions according to embodiments of the present disclosure are generally formulated for oral or topical (i.e., skin, ocular and mucosal surfaces) administration, with the most suitable route in any given case depending on the nature and severity of the condition being treated and on the nature of the particular active agent which is being used.
- Topical Formulations [0204] The compositions of the present disclosure and the pharmaceutical compositions containing said compounds, may be administered topically, and thus be formulated in a form suitable for topical administration, i.e. as a pH balanced cream preparation. An obstacle for topical administration of pharmaceuticals is the stratum corneum layer of the epidermis.
- the stratum corneum is a highly resistant layer comprised of protein, cholesterol, sphingolipids, free fatty acids and various other lipids, and includes cornified and living cells.
- One of the factors that limit the penetration rate (flux) of a compound through the stratum corneum is the amount of the active substance that can be loaded or applied onto the skin surface. The greater the amount of active substance which is applied per unit of area of the skin, the greater the concentration gradient between the skin surface and the lower layers of the skin, and in turn the greater the diffusion force of the active substance through the skin.
- Formulations suitable for topical administration include, but are not limited to, liquid or semi liquid preparations such as liniments, lotions, oil in water or water in oil emulsions such as creams, ointments or pastes, and solutions or suspensions. Further, formulations suitable for topical administration can be in the form of cremes and liquids including, for example, syrups, suspensions or emulsions, inhalants, sprays, mousses, oils, gels, solids and the like.
- Topically administrable formulations may, for example, comprise from about 1% to about 10% (w/w) active ingredient, although the concentration of the active ingredient may be as high as the solubility limit of the active ingredient in the solvent.
- Formulations for topical administration may further comprise one or more of the additional ingredients described herein.
- Enhancers of permeation may be used. These materials increase the rate of penetration of drugs across the skin. Typical enhancers in the art include ethanol, glycerol monolaurate, PGML (polyethylene glycol monolaurate), dimethylsulfoxide, and the like.
- enhancers include oleic acid, oleyl alcohol, ethoxydiglycol, laurocapram, alkanecarboxylic acids, dimethylsulfoxide, polar lipids, or N-methyl-2-pyrrolidone.
- One acceptable vehicle for topical delivery of some of the compositions may contain liposomes.
- the composition of the liposomes and their use are known in the art (for example, see U.S. Patent No.6,323,219).
- the topically active pharmaceutical composition may be optionally combined with other ingredients such as adjuvants, anti-oxidants, chelating agents, surfactants, foaming agents, wetting agents, emulsifying agents, viscosifiers, buffering agents, preservatives, and the like.
- a permeation or penetration enhancer is included in the composition and is effective in improving the percutaneous penetration of the active ingredient into and through the stratum corneum with respect to a composition lacking the permeation enhancer.
- compositions may further comprise a hydrotropic agent, which functions to increase disorder in the structure of the stratum corneum, and thus allows increased transport across the stratum corneum.
- hydrotropic agents such as isopropyl alcohol, propylene glycol, or sodium xylene sulfonate, are known to those of skill in the art.
- an active compound may be present in the amount of from about 0.0001% to about 15% by weight volume of the composition, from about 0.0005% to about 5% of the composition, or from about 0.001% to about 1% of the composition. Such compounds may be synthetically-or naturally derived.
- Oral Formulations [0210] The compositions of the present disclosure and the pharmaceutical compositions containing said compounds, may be administered orally, and thus be formulated in a form suitable for oral administration, i.e. as a solid or a liquid preparation. Suitable solid oral formulations include tablets, capsules, pills, granules, pellets and the like.
- Suitable liquid oral formulations include solutions, suspensions, dispersions, emulsions, oils and the like. If formulated in form of a capsule, the compositions of the present disclosure comprise, in addition to the active compound and the inert carrier or diluent, a hard gelating capsule. In one embodiment, a formulation for oral administration is an enteric coated, time release capsule.
- Formulations suitable for oral administration can be presented in discrete units, such as capsules, cachets, lozenges, or tablets, each containing a predetemined amount of the active compound; as a powder or granules; as a solution or a suspension in an aqueous or non-aqueous liquid; or as an oil-in-water or water-in-oil emulsion.
- Such formulations can be prepared by any suitable method of pharmacy, which includes bringing into association the active compound and a suitable carrier (which can contain one or more accessory ingredients as noted above).
- the formulations of the disclosure are prepared by uniformly and intimately admixing the active compound with a liquid or finely divided solid carrier, or both, and then, if necessary, shaping the resulting mixture.
- a tablet can be prepared by compressing or molding a powder or granules containing the active compound, optionally with one or more accessory ingredients.
- Compressed tablets can be prepared by compressing, in a suitable machine, the compound in a free-flowing form, such as a powder or granules optionally mixed with a binder, lubricant, inert diluent, and/or surface active/dispersing agent(s).
- compositions of the present disclosure and the pharmaceutical compositions containing said compounds may be further administered intranasally, i.e. by inhalation and thus may be formulated in a form suitable for intranasal administration, i.e. as an aerosol or a liquid preparation.
- compositions of the present disclosure may also, for example, be formulated for parenteral administration.
- Formulations of a pharmaceutical composition suitable for parenteral administration comprise the active ingredient combined with a pharmaceutically acceptable carrier, such as sterile water or sterile isotonic saline.
- Such formulations may be prepared, packaged, or sold in a form suitable for bolus administration or for continuous administration.
- injectable formulations may be prepared, packaged, or sold in unit dosage form, such as in ampules or in multi dose containers containing a preservative.
- Formulations for parenteral administration include, but are not limited to, suspensions, solutions, emulsions in oily or aqueous vehicles, pastes, and implantable sustained-release or biodegradable formulations.
- Such formulations may further comprise one or more additional ingredients including, but not limited to, suspending, stabilizing, or dispersing agents.
- the active ingredient is provided in dry (i.e., powder or granular) form for reconstitution with a suitable vehicle (e.g., sterile pyrogen free water) prior to parenteral administration of the reconstituted composition.
- a suitable vehicle e.g., sterile pyrogen free water
- the pharmaceutical compositions may be prepared, packaged, or sold in the form of a sterile injectable aqueous or oily suspension or solution. This suspension or solution may be formulated according to the known art, and may comprise, in addition to the active ingredient, additional ingredients such as the dispersing agents, wetting agents, or suspending agents described herein.
- Such sterile injectable formulations may be prepared using a non-toxic parenterally acceptable diluent or solvent, such as water or 1,3 butane diol, for example.
- a non-toxic parenterally acceptable diluent or solvent such as water or 1,3 butane diol
- Other acceptable diluents and solvents include, but are not limited to, Ringer's solution, isotonic sodium chloride solution, and fixed oils such as synthetic mono or di-glycerides.
- Other parentally-administrable formulations which are useful include those which comprise the active ingredient in microcrystalline form, in a liposomal preparation, or as a component of a biodegradable polymer system.
- compositions for sustained release or implantation may comprise pharmaceutically acceptable polymeric or hydrophobic materials such as an emulsion, an ion exchange resin, a sparingly soluble polymer, or a sparingly soluble salt.
- Formulations are prepared using a pharmaceutically acceptable “carrier” composed of materials that are considered safe and effective and may be administered to an individual without causing undesirable biological side effects or unwanted interactions.
- the “carrier” is all components present in the pharmaceutical formulation other than the active ingredient or ingredients.
- carrier includes but is not limited to diluents, binders, lubricants, desintegrators, fillers, and coating compositions.
- Carrier also includes all components of the coating composition which may include plasticizers, pigments, colorants, stabilizing agents, and glidants.
- the delayed release dosage formulations may be prepared as described in references such as “Pharmaceutical dosage form tablets”, eds. Liberman et. al. (New York, Marcel Dekker, Inc., 1989), “Remington--The science and practice of pharmacy”, 20th ed., Lippincott Williams & Wilkins, Baltimore, Md., 2000, and “Pharmaceutical dosage forms and drug delivery systems”, 6th Edition, Ansel et.
- suitable coating materials include, but are not limited to, cellulose polymers such as cellulose acetate phthalate, hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose phthalate and hydroxypropyl methylcellulose acetate succinate; polyvinyl acetate phthalate, acrylic acid polymers and copolymers, and methacrylic resins that are commercially available under the trade name Eudragit® (Roth Pharma, Westerstadt, Germany), Zein, shellac, and polysaccharides.
- cellulose polymers such as cellulose acetate phthalate, hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose phthalate and hydroxypropyl methylcellulose acetate succinate
- polyvinyl acetate phthalate acrylic acid polymers and copolymers
- methacrylic resins that are commercially available under the trade name Eudragit® (Roth Pharma, Westerstadt, Germany), Zein, shella
- the coating material may contain conventional carriers such as plasticizers, pigments, colorants, glidants, stabilization agents, pore formers and surfactants.
- Optional pharmaceutically acceptable excipients present in the drug-containing tablets, beads, granules or particles include, but are not limited to, diluents, binders, lubricants, disintegrants, colorants, stabilizers, and surfactants. Diluents, also termed “fillers,” are typically necessary to increase the bulk of a solid dosage form so that a practical size is provided for compression of tablets or formation of beads and granules.
- Suitable diluents include, but are not limited to, dicalcium phosphate dihydrate, calcium sulfate, lactose, sucrose, mannitol, sorbitol, cellulose, microcrystalline cellulose, kaolin, sodium chloride, dry starch, hydrolyzed starches, pregelatinized starch, silicone dioxide, titanium oxide, magnesium aluminum silicate and powder sugar.
- Binders are used to impart cohesive qualities to a solid dosage formulation, and thus ensure that a tablet or bead or granule remains intact after the formation of the dosage forms.
- Suitable binder materials include, but are not limited to, starch, pregelatinized starch, gelatin, sugars (including sucrose, glucose, dextrose, lactose and sorbitol), polyethylene glycol, waxes, natural and synthetic gums such as acacia, tragacanth, sodium alginate, cellulose, including hydroxypropylmethylcellulose, hydroxypropylcellulose, ethylcellulose, and veegum, and synthetic polymers such as acrylic acid and methacrylic acid copolymers, methacrylic acid copolymers, methyl methacrylate copolymers, aminoalkyl methacrylate copolymers, polyacrylic acid/polymethacrylic acid and polyvinylpyrrolidone.
- Lubricants are used to facilitate tablet manufacture. Examples of suitable lubricants include, but are not limited to, magnesium stearate, calcium stearate, stearic acid, glycerol behenate, polyethylene glycol, talc, and mineral oil.
- Disintegrants are used to facilitate dosage form disintegration or “breakup” after administration, and generally include, but are not limited to, starch, sodium starch glycolate, sodium carboxymethyl starch, sodium carboxymethylcellulose, hydroxypropyl cellulose, pregelatinized starch, clays, cellulose, alginine, gums or cross linked polymers, such as cross- linked PVP (Polyplasdone XL from GAF Chemical Corp).
- Stabilizers are used to inhibit or retard drug decomposition reactions which include, by way of example, oxidative reactions.
- Surfactants may be anionic, cationic, amphoteric or nonionic surface active agents. Suitable anionic surfactants include, but are not limited to, those containing carboxylate, sulfonate and sulfate ions.
- anionic surfactants include sodium, potassium, ammonium of long chain alkyl sulfonates and alkyl aryl sulfonates such as sodium dodecylbenzene sulfonate; dialkyl sodium sulfosuccinates, such as sodium dodecylbenzene sulfonate; dialkyl sodium sulfosuccinates, such as sodium bis-(2-ethylthioxyl)-sulfosuccinate; and alkyl sulfates such as sodium lauryl sulfate.
- Cationic surfactants include, but are not limited to, quaternary ammonium compounds such as benzalkonium chloride, benzethonium chloride, cetrimonium bromide, stearyl dimethylbenzyl ammonium chloride, polyoxyethylene and coconut amine.
- 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, polysorbates, polyoxyethylene octylphenylether, PEG-1000 cetyl ether, polyoxyethylene tridecyl ether, polypropylene glycol butyl ether, Poloxamer® 401, stearoyl monoisopropanolamide, and polyoxyethylene hydrogenated tallow amide.
- amphoteric surfactants include sodium N-dodecyl-beta-alanine, sodium N-lauryl-beta-iminodipropionate, myristoamphoacetate, lauryl betaine and lauryl sulfobetaine.
- the tablets, beads granules or particles may also contain minor amount of nontoxic auxiliary substances such as wetting or emulsifying agents, dyes, pH buffering agents, and preservatives.
- nontoxic auxiliary substances such as wetting or emulsifying agents, dyes, pH buffering agents, and preservatives.
- Such methods include, but are not limited to, the following: coating a drug or drug-containing composition with an appropriate coating material, typically although not necessarily incorporating a polymeric material, increasing drug particle size, placing the drug within a matrix, and forming complexes of the drug with a suitable complexing agent.
- the delayed release dosage units may be coated with the delayed release polymer coating using conventional techniques, e.g., using a conventional coating pan, an airless spray technique, fluidized bed coating equipment (with or without a Wurster insert), or the like.
- An exemplary method for preparing extended release tablets is by compressing a drug- containing blend, e.g., blend of granules, prepared using a direct blend, wet-granulation, or dry- granulation process.
- Extended release tablets may also be molded rather than compressed, starting with a moist material containing a suitable water-soluble lubricant. However, tablets are manufactured using compression rather than molding.
- a method for forming extended release drug-containing blend is to mix drug particles directly with one or more excipients such as diluents (or fillers), binders, disintegrants, lubricants, glidants, and colorants.
- excipients such as diluents (or fillers), binders, disintegrants, lubricants, glidants, and colorants.
- a drug-containing blend may be prepared by using wet-granulation or dry- granulation processes. Beads containing the active agent may also be prepared by any one of a number of conventional techniques, typically starting from a fluid dispersion.
- a typical method for preparing drug-containing beads involves dispersing or dissolving the active agent in a coating suspension or solution containing pharmaceutical excipients such as polyvinylpyrrolidone, methylcellulose, talc, metallic stearates, silicone dioxide, plasticizers or the like.
- the admixture is used to coat a bead core such as a sugar sphere (or so-called “non-pareil”) having a size of approximately 60 to 20 mesh.
- An alternative procedure for preparing drug beads is by blending drug with one or more pharmaceutically acceptable excipients, such as microcrystalline cellulose, lactose, cellulose, polyvinyl pyrrolidone, talc, magnesium stearate, a disintegrant, etc., extruding the blend, spheronizing the extrudate, drying and optionally coating to form the immediate release beads.
- Delayed release formulations are created by coating a solid dosage form with a film of a polymer which is insoluble in the acid environment of the stomach, and soluble in the neutral environment of small intestines.
- the delayed release dosage units can be prepared, for example, by coating a drug or a drug-containing composition with a selected coating material.
- the drug-containing composition may be, e.g., a tablet for incorporation into a capsule, a tablet for use as an inner core in a “coated core” dosage form, or a plurality of drug-containing beads, particles or granules, for incorporation into either a tablet or capsule.
- exemplary coating materials include bioerodible, gradually hydrolyzable, gradually water-soluble, and/or enzymatically degradable polymers, and may be conventional “enteric” polymers.
- Enteric polymers become soluble in the higher pH environment of the lower gastrointestinal tract or slowly erode as the dosage form passes through the gastrointestinal tract, while enzymatically degradable polymers are degraded by bacterial enzymes present in the lower gastrointestinal tract, particularly in the colon.
- Suitable coating materials for effecting delayed release include, but are not limited to, cellulosic polymers such as hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxymethyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl methyl cellulose acetate succinate, hydroxypropylmethyl cellulose phthalate, methylcellulose, ethyl cellulose, cellulose acetate, cellulose acetate phthalate, cellulose acetate trimellitate and carboxymethylcellulose sodium; acrylic acid polymers and copolymers, e.g., formed from acrylic acid, methacrylic acid, methyl acrylate, ethyl acrylate, methyl methacrylate and/or ethyl methacrylate, and other methacrylic resins that are commercially available under the tradename Eudragit®.
- cellulosic polymers such as hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxymethyl cellulose, hydroxypropyl methyl cellulose
- Eudragit® (Rohm Pharma; Westerstadt, Germany), including Eudragit®. L30D-55 and L100-55 (soluble at pH 5.5 and above), Eudragit®. L-100 (soluble at pH 6.0 and above), Eudragit®. S (soluble at pH 7.0 and above, as a result of a higher degree of esterification), and Eudragits®.
- NE, RL and RS water-insoluble polymers having different degrees of permeability and expandability
- vinyl polymers and copolymers such as polyvinyl pyrrolidone, vinyl acetate, vinylacetate phthalate, vinylacetate 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 may also be used. Multi-layer coatings using different polymers may also be applied.
- the coating composition may include conventional additives, such as plasticizers, pigments, colorants, stabilizing agents, glidants, etc.
- a plasticizer is normally present to reduce the fragility of the coating, and will generally represent about 10 wt. % to 50 wt. % relative to the dry weight of the polymer.
- typical plasticizers include polyethylene glycol, propylene glycol, triacetin, dimethyl phthalate, diethyl phthalate, dibutyl phthalate, dibutyl sebacate, triethyl citrate, tributyl citrate, triethyl acetyl citrate, castor oil and acetylated monoglycerides.
- a stabilizing agent is used to stabilize particles in the dispersion.
- Typical stabilizing agents are nonionic emulsifiers such as sorbitan esters, polysorbates and polyvinylpyrrolidone. Glidants are recommended to reduce sticking effects during film formation and drying, and will generally represent approximately 25 wt. % to 100 wt. % of the polymer weight in the coating solution.
- One effective glidant is talc.
- Other glidants such as magnesium stearate and glycerol monostearates may also be used.
- Pigments such as titanium dioxide may also be used.
- Small quantities of an anti-foaming agent such as a silicone (e.g., simethicone), may also be added to the coating composition.
- the particles can be prepared entirely from a therapeutic agent, or from a combination of the agent and a surfactant.
- the particles can be made of a variety of materials. Both inorganic and organic materials can be used. For example, ceramics may be used. Polymeric and non- polymeric materials, such as fatty acids, may be used to form aerodynamically light particles. Other suitable materials include, but are not limited to, gelatin, polyethylene glycol, trehalose, and dextran. Particles with degradation and release times ranging from seconds to months can be designed and fabricated, based on factors such as the particle material.
- the particles can include excipients such as a sugar, such as lactose, a protein, such as albumin, and/or a surfactant.
- excipients such as a sugar, such as lactose, a protein, such as albumin, and/or a surfactant.
- Enteric Coated Capsules “Gastric resistant natural polymer,” as used herein, refers to natural polymers or mixtures of natural polymers which are insoluble in the acidic pH of the stomach. “Film-forming natural polymer,” as used herein, refers to polymers useful for surface coatings that are applied by spraying, brushing, or various industrial processes, which undergo film formation.
- a liquid coating of relatively low viscosity is applied to a solid substrate and is cured to a solid, high-molecular-weight, polymer-based adherent film possessing the properties desired by the user.
- this film has a thickness ranging from 0.5 to 500 micrometers (0.0005 to 0.5 millimeters, or 0.00002 to 0.02 inches).
- “Gelling agent,” as used herein refers to substances that undergo a high degree of cross-linking or association when hydrated and dispersed in the dispersing medium, or when dissolved in the dispersing medium. This cross-linking or association of the dispersed phase alters the viscosity of the dispersing medium.
- Gastric resistant film-forming compositions containing (1) a gastric resistant natural polymer; (2) a film-forming natural polymer; and optionally (3) a gelling agent, are described herein.
- Exemplary gastric resistant natural polymers include, but are not limited to, pectin and pectin-like polymers which typically consist mainly of galacturonic acid and galacturonic acid methyl ester units forming linear polysaccharide chains.
- these polysaccharides are rich in galacturonic acid, rhamnose, arabinose and galactose, for example the polygalacturonans, rhamnogalacturonans and some arabinans, galactans and arabinogalactans. These are normally classified according to the degree of esterification. In high (methyl) ester (“HM”) pectin, a relatively high portion of the carboxyl groups occur as methyl esters, and the remaining carboxylic acid groups are in the form of the free acid or as its ammonium, potassium, calcium or sodium salt. [0237] Useful properties may vary with the degree of esterification and with the degree of polymerization.
- Pectin in which less than 50% of the carboxyl acid units occur as the methyl ester, is normally referred to as low (methyl) ester or LM-pectin.
- low ester pectin is obtained from high ester pectin by treatment at mild acidic or alkaline conditions.
- Amidated pectin is obtained from high ester pectin when ammonia is used in the alkaline deesterification process. In this type of pectin some of the remaining carboxylic acid groups have been transformed into the acid amide.
- the useful properties of amidated pectin may vary with the proportion of ester and amide units and with the degree of polymerization.
- the gastric resistant natural polymer is pectin.
- the gastric resistant natural polymer is present in an amount less than about 5% by weight of the composition, e.g., from about 2 to about 4% by weight of the composition.
- 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. A number of other gelatin-like polymers are available commercially.
- the film-forming natural polymer is present in an amount from about 20 to about 40% by weight of the composition, e.g., from about 25 to about 40% by weight of the composition.
- the compositions can optionally contain a gelling agent. Exemplary gelling agents include divalent cations such as Ca 2+ and Mg 2+ .
- Sources of these ions include inorganic calcium and magnesium salts and calcium gelatin.
- the gelling agent is present in an amount less than about 2% by weight of the composition, e.g., less than about 1% by weight of the composition.
- One or more plasticizers can be added to the composition to facilitate the film-forming process. Suitable plasticizers include glycerin, sorbitol, sorbitans, maltitol, glycerol, polyethylene glycol, polyalcohols with 3 to 6 carbon atoms, citric acid, citric acid esters, triethyl citrate and combinations thereof. The concentration of the one or more plasticizers is from about 8% to about 30% by weight of the composition.
- the plasticizer is glycerin and/or sorbitol.
- the film-forming composition can be used to prepare soft or hard shell gelatin capsules which can encapsulate a liquid or semi-solid fill material or a solid tablet (Softlet®) containing an active agent and one or more pharmaceutically acceptable excipients. Alternatively, the composition can be administered as a liquid with an active agent dissolved or dispersed in the composition. [0243]
- 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. Fill formulations are fed into the encapsulation machine by gravity.
- the capsule shell can contain one or more plasticizers selected from the group consisting of glycerin, sorbitol, sorbitans, maltitol, glycerol, polyethylene glycol, polyalcohols with 3 to 6 carbon atoms, citric acid, citric acid esters, triethyl citrate and combinations thereof.
- the capsule shell can include other suitable shell additives such as opacifiers, colorants, humectants, preservatives, flavorings, and buffering salts and acids.
- Opacifiers are used to opacify the capsule shell when the encapsulated active agents are light sensitive.
- Suitable opacifiers include titanium dioxide, zinc oxide, calcium carbonate and combinations thereof.
- Colorants can be used to for marketing and product identification/differentiation purposes. Suitable colorants include synthetic and natural dyes and combinations thereof.
- Humectants can be used to suppress the water activity of the softgel. Suitable humectants include glycerin and sorbitol, which are often components of the plasticizer composition. Due to the low water activity of dried, properly stored softgels, the greatest risk from microorganisms comes from molds and yeasts. For this reason, preservatives can be incorporated into the capsule shell.
- Suitable preservatives include alkyl esters of p-hydroxy benzoic acid such as methyl, ethyl, propyl, butyl and heptyl (collectively known as “parabens”) or combinations thereof.
- Flavorings can be used to mask unpleasant odors and tastes of fill formulations. Suitable flavorings include synthetic and natural flavorings. The use of flavorings can be problematic due to the presence of aldehydes which can cross-link gelatin. As a result, buffering salts and acids can be used in conjunction with flavorings that contain aldehydes in order to inhibit cross-linking of the gelatin.
- Soft or hard capsules can be used to deliver a wide variety of pharmaceutically active agents.
- Suitable agents include small molecules, proteins, nucleic acid, carbohydrates, lipids, and full organisms.
- Fill formulations may be prepared using a pharmaceutically acceptable carrier composed of materials that are considered safe and effective and may be administered to an individual without causing undesirable biological side effects or unwanted interactions.
- the carrier is all components present in the pharmaceutical formulation other than the active ingredient or ingredients.
- carrier includes, but is not limited to surfactants, humectants, plasticizers, crystallization inhibitors, wetting agents, bulk filling agents, solubilizers, bioavailability enhancers, pH adjusting agents, and combinations thereof.
- the composition can be administered as a liquid with an active agent dissolved (e.g.
- Suitable active agents are described above.
- the solution or suspension may 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 filling agents, solubilizers, bioavailability enhancers, pH adjusting agents, flavorants, binding agents, disintegrating agents, anti-adherents, anti-static agents, surfactants, anti-oxidants, coating agents, coloring agents, preservatives, suspending agents, emulsifying agents, anti- microbial agents, spheronization agents, stabilizers, tonicity enhancing agents, buffers and any combination thereof
- Mucoadhesive Particles and methods of manufacturing In general terms, adhesion of polymers to tissues may be achieved by (i) physical or mechanical bonds, (ii) primary or covalent chemical bonds, and/or
- Adhesive polymeric microspheres have been selected on the basis of the physical and chemical bonds formed as a function of chemical composition and physical characteristics, such as surface area, as described in detail below. These microspheres are characterized by adhesive forces to mucosa of greater than 11 mN/cm 2 .
- Suitable polymers that can be used to form bioadhesive microspheres include soluble and insoluble, biodegradable and nonbiodegradable polymers. These can be hydrogels or thermoplastics, homopolymers, copolymers or blends, natural or synthetic.
- the polymer must produce a bioadhesive interaction between 110 N/m2 (11 mN/cm2) and 100,000 N/m2 when applied to the mucosal surface of rat intestine.
- the radius of the individual particles should be as thick as the thickness of the natural mucous layer. It has been shown that the gastric mucous layer thickness typically varies from 5 to 200.mu. in the rat and 10 to 400.mu. in man. Occasionally, however, it can reach thicknesses as great as 1000.mu. in man, as described by Spiro, R.
- hydrophilic polymers In the past, two classes of polymers have appeared to show useful bioadhesive properties: hydrophilic polymers and hydrogels.
- carboxylic groups e.g., poly[acrylic acid]
- polymers with the highest concentrations of carboxylic groups should be the materials of choice for bioadhesion on soft tissues.
- the most promising polymers were: sodium alginate, carboxymethylcellulose, hydroxymethylcellulose and methylcellulose. Some of these materials are water-soluble, while others are hydrogels.
- Rapidly bioerodible polymers such as poly[lactide-co-glycolide], polyanhydrides, and polyorthoesters, whose carboxylic groups are exposed on the external surface as their smooth surface erodes, are excellent candidates for bioadhesive drug delivery systems.
- polymers containing labile bonds such as polyanhydrides and polyesters, are well known for their hydrolytic reactivity. Their hydrolytic degradation rates can generally be altered by simple changes in the polymer backbone.
- Representative natural polymers include proteins, such as zein, modified zein, casein, gelatin, gluten, serum albumin, or collagen, and polysaccharides, such as cellulose, dextrans, polyhyaluronic acid, polymers of acrylic and methacrylic esters and alginic acid.
- proteins such as zein, modified zein, casein, gelatin, gluten, serum albumin, or collagen
- polysaccharides such as cellulose, dextrans, polyhyaluronic acid, polymers of acrylic and methacrylic esters and alginic acid.
- Representative synthetic polymers include polyphosphazines, poly(vinyl alcohols), polyamides, polycarbonates, polyalkylenes, polyacrylamides, polyalkylene glycols, polyalkylene oxides, polyalkylene terephthalates, polyvinyl ethers, polyvinyl esters, polyvinyl halides, polyvinylpyrrolidone, polyglycolides, polysiloxanes, polyurethanes and copolymers thereof.
- Synthetically modified natural polymers include alkyl celluloses, hydroxyalkyl celluloses, cellulose ethers, cellulose esters, and nitrocelluloses.
- polymers of interest include, but are not limited to, methyl cellulose, ethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxybutyl methyl cellulose, cellulose acetate, cellulose propionate, cellulose acetate butyrate, cellulose acetate phthalate, carboxymethyl cellulose, cellulose triacetate, cellulose sulfate sodium salt, poly(methyl methacrylate), poly(ethyl methacrylate), poly(butyl methacrylate), poly(isobutyl methacrylate), poly(hexyl methacrylate), poly(isodecyl methacrylate), poly(lauryl methacrylate), poly(phenyl methacrylate), poly(methyl acrylate), poly(isopropyl acrylate), poly(isobutyl acrylate), poly(octadecyl acrylate)polyethylene, polypropylene, poly(ethylene glycol), poly(ethylene oxide), poly
- bioerodible polymers include polylactides, polyglycolides and copolymers thereof, poly(ethylene terephthalate), poly(butic acid), poly(valeric acid), poly(lactide-co-caprolactone), poly[lactide- co-glycolide], polyanhydrides, polyorthoesters, blends and copolymers thereof.
- the pharmaceutically acceptable compounds of the disclosure will normally be administered to a subject in a daily dosage regimen. For an adult subject this may be, for example, an oral dose of at least one SCFA or compound comprising a SCFA moiety of between 0.1 gram and 15 grams.
- an oral dose of at least one SCFA or compound comprising a SCFA moiety can be between 0.5 gram and 10 grams. In still further embodiments, an oral dose of at least one SCFA or compound comprising a SCFA moiety can be between 0.5 grams and 6 grams.
- the pharmaceutical compositions may be administered 1, 2, 3, 4 or more times per day. Thus in particular embodiments, compositions formulated, for example, for topical administration may be administered multiple times daily.
- compositions comprising a 1:1 (w/w) ratio of a first and a second SCFA, wherein there may be 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 a first SCFA.
- there may be a 2:1, 3:1, 4:1, 5:1; 6:1, 7:1, 8:1, 9:1, or 10:1 (w/w) ratio of a first and a second SCFA wherein there may be 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 a first SCFA.
- the ratio of a first and a second SCFA administered may be varied from that disclosed herein above.
- 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 a first SCFA may 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 a second SCFA.
- Such amounts of either supplement may be admixed in one composition or may be in distinct compositions.
- a pharmaceutical composition can be administered in a local or systemic manner, for example, via injection of the compound directly into an organ, optionally in a depot or sustained release formulation or implant.
- Pharmaceutical compositions can be provided in the form of a rapid release formulation, in the form of an extended release formulation, or in the form of an intermediate release formulation.
- a rapid release form can provide an immediate release.
- An extended release formulation can provide a controlled release or a sustained delayed release.
- therapeutically-effective amounts of the compounds described herein are administered in pharmaceutical compositions to a subject having a disease or condition to be treated.
- the subject is a mammal such as a human.
- a therapeutically-effective amount can vary widely depending on the severity of the disease, the age and relative health of the subject, the potency of the compounds used, and other factors.
- the compounds can be used singly or in combination with one or more therapeutic agents as components of mixtures.
- Methods for the preparation of compositions comprising the compounds described herein include formulating the compounds with one or more inert, pharmaceutically-acceptable excipients or carriers to form a solid, semi-solid, or liquid composition.
- Solid compositions include, for example, powders, tablets, dispersible granules, capsules, and cachets.
- Liquid compositions include, for example, solutions in which a compound is dissolved, emulsions comprising a compound, or a solution containing liposomes, micelles, or nanoparticles comprising a compound as disclosed herein.
- Semi-solid compositions include, for example, gels, suspensions, and creams.
- the compositions can be in liquid solutions or suspensions, solid forms suitable for solution or suspension in a liquid prior to use, or as emulsions. These compositions can also contain minor amounts of nontoxic, auxiliary substances, such as wetting or emulsifying agents, pH buffering agents, and other pharmaceutically-acceptable additives.
- Non-limiting examples of dosage forms suitable for use in the disclosure include liquid, powder, gel, nanosuspension, nanoparticle, microgel, aqueous or oily suspensions, emulsion, and any combination thereof.
- a composition of the disclosure can be, for example, an immediate release form or a controlled release formulation.
- An immediate release formulation can be formulated to allow the compounds to act rapidly.
- Non-limiting examples of immediate release formulations include readily dissolvable formulations.
- a controlled release formulation can be a pharmaceutical formulation that has been adapted such that release rates and release profiles of the active agent can be matched to physiological and chronotherapeutic requirements or, alternatively, has been formulated to effect release of an active agent at a programmed rate.
- Non-limiting examples of controlled release formulations include granules, delayed release granules, hydrogels (e.g., of synthetic or natural origin), other gelling agents (e.g., gel-forming dietary fibers), matrix-based formulations (e.g., formulations comprising a polymeric material having at least one active ingredient dispersed through), granules within a matrix, polymeric mixtures, and granular masses.
- a controlled release formulation is a delayed release form.
- a delayed release form can be formulated to delay a compound’s action for an extended period of time.
- a delayed release form can be formulated to delay the release of an effective dose of one or more compounds, for example, for about 4, about 8, about 12, about 16, or about 24 h.
- a controlled release formulation can be a sustained release form.
- a sustained release form can be formulated to sustain, for example, the compound’s action over an extended period of time.
- a sustained release form can be formulated to provide an effective dose of any compound described herein (e.g., provide a physiologically-effective blood profile) over about 4, about 8, about 12, about 16, or about 24 h.
- Non-limiting examples of pharmaceutically-acceptable excipients can be found, for example, in Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington’s Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, H.A. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y., 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkins 1999), each of which is incorporated by reference in its entirety.
- Subjects can be, for example, elderly adults, adults, adolescents, pre-adolescents, children, toddlers, infants, neonates, and non-human animals.
- a subject is a patient.
- a method disclosed herein relates to administering the compound disclosed herein as part of a pharmaceutical composition.
- compositions of a compound disclosed herein can comprise a liquid comprising an active agent in solution, in suspension, or both.
- Liquid compositions can include gels.
- the liquid composition is aqueous.
- the composition can be an ointment.
- the composition is an in situ gellable aqueous composition.
- the composition is an in situ gellable aqueous solution.
- a pharmaceutically-acceptable excipient can be present in a pharmaceutical composition at a mass of between about 0.1% and about 99% by mass of the composition.
- a pharmaceutically-acceptable excipient can be present in a pharmaceutical composition at a mass of between about 0.1% and about 95%, between about 0.1% and about 90%, between about 0.1% and about 85%, between about 0.1% and about 80%, between about 0.1% and about 75%, between about 0.1% and about 70%, between about 0.1% and about 65%, between about 0.1% and about 60%, between about 0.1% and about 55%, between about 0.1% and about 50%, between about 0.1% and about 45%, between about 0.1% and about 40%, between about 0.1% and about 35%, between about 0.1% and about 30%, between about 0.1% and about 25%, between about 0.1% and about 20%, between about 0.1% and about 15%, between about 0.1% and about 10%, between about 0.1% and about 5%, or between about 0.1% and about
- a pharmaceutically-acceptable excipient can be present at 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
- Subjects/patient population can be, humans for example, elderly adults, adults, adolescents, pre-adolescents, children, toddlers, infants, neonates, and non-human animals, e.g., a mouse.
- a subject is a patient.
- a subject has experienced and/or exhibited at least one symptom of the disease or disorder to be treated and/or reduced in likelihood to occur.
- the subject has been identified or diagnosed as having a liver disease or disorder described herein, e.g., NASH.
- a method of treatment disclosed herein comprises, identification of a patient population based on one or more selection criteria, e.g., biomarkers, failure to respond to a primary therapy and administering a compound disclosed herein, e.g., Compound 1 to treat the patient.
- the patient population selection criteria can include but are not limited to, presence of a biomarker, e.g., marker associate with a particular disease, a marker associated with poor prognosis of a disease, failure to respond to an initial therapy, age, gender, health of the patient.
- the screening procedure may include but are not limited to blood and/or tissue sample analysis, genetic tests, genetic screening, biopsy, drug sensitivity/resistance test.
- compositions of a compound disclosed herein can comprise a liquid comprising an active agent in solution, in suspension, or both.
- Liquid compositions can include gels.
- the liquid composition is aqueous.
- the composition is an ointment.
- the composition is an in situ gellable aqueous composition.
- the composition is an in situ gellable aqueous solution.
- compositions described herein can be in unit dosage forms suitable for single administration of precise dosages.
- the formulation is divided into unit doses containing appropriate quantities of one or more compounds.
- the unit dosage can be in the form of a package containing discrete quantities of the formulation.
- Non-limiting examples are packaged injectables, vials, or ampoules.
- Aqueous suspension compositions can be packaged in single-dose non-reclosable containers. Multiple-dose reclosable containers can be used, for example, in combination with or without a preservative.
- Formulations for parenteral injection can be presented in unit dosage form, for example, in ampoules, or in multi-dose containers with a preservative.
- a compound described herein can be present in a composition in a range of from about 1 mg to about 5 mg, from about 5 mg to about 10 mg, from about 10 mg to about 15 mg, from about 15 mg to about 20 mg, from about 20 mg to about 25 mg, from about 25 mg to about 30 mg, from about 30 mg to about 35 mg, from about 35 mg to about 40 mg, from about 40 mg to about 45 mg, from about 45 mg to about 50 mg, from about 50 mg to about 55 mg, from about 55 mg to about 60 mg, from about 60 mg to about 65 mg, from about 65 mg to about 70 mg, from about 70 mg to about 75 mg, from about 75 mg to about 80 mg, from about 80 mg to about 85 mg, from about 85 mg to about 90 mg, from about 90 mg to about 95 mg, from about 95 mg to about 100 mg, from about 100 mg to about 125 mg, from about 125 mg to about 150 mg, from about 150 mg to about 175 mg, from about 175 mg to about 200 mg, from about 200 mg to about 225 mg, from about 225
- a compound described herein can be present in a composition in an amount of about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 120 mg, about 140 mg, about 160 mg, about 180 mg, 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.
- a compound 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.
- the compound disclosed herein is administered to a subject in an amount of about 1 mg/kg, about 2 mg/kg, about 3 mg/kg, about 4 mg/kg, about 5 mg/kg, about 6 mg/kg, about 7 mg/kg, about 8 mg/kg, about 9 mg/kg, about 10 mg/kg, about 11 mg/kg, about 12 mg/kg, about 13 mg/kg, about 14 mg/kg, about 15 mg/kg, about 16 mg/kg, about 17 mg/kg, about 18 mg/kg, about 19 mg/kg, about 20 mg/kg, about 25 mg/kg, about 30 mg/kg, about 35 mg/kg, about 40 mg/kg, about 45 mg/kg, 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
- a dosing regimen disclosed herein can be, for example, once a day, twice a day, thrice a day, once a week, twice a week, or thrice a week.
- a compound disclosed herein is administered once daily.
- a compound disclosed herein is administered once daily for 28 days (one cycle).
- a compound disclosed herein is administered once daily in one or more 28 day cycles.
- a compound disclosed herein is administered in a four-week cycle of consecutive once daily administration for three weeks, followed by one week with no administrations.
- a compound described herein can be administered before, during, or after the occurrence of a disease or condition, and the timing of administering the composition containing a compound can vary.
- a compound can be used as a prophylactic and can be administered continuously to subjects with a propensity to conditions or diseases to lessen or reduce a likelihood of the occurrence of the disease or condition.
- a compound and composition can be administered to a subject during or as soon as possible after the onset of the symptoms. The administration of a compound can be initiated within the first 48 hours of the onset of the symptoms, within the first 24 hours of the onset of the symptoms, within the first 6 hours of the onset of the symptoms, or within 3 hours of the onset of the symptoms.
- the initial administration can be via any route practical, such as by any route described herein using any formulation described herein.
- a compound can be administered as soon as is practical after the onset of a disease or condition is detected or suspected, and for a length of time necessary for the treatment of the disease, such as, for example, from about 1 month to about 3 months.
- the length of time a 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 months, about 11 months, about 1 year, about 13 months, about 14 months, about 15 months, about 16 months, about 17 months, about 18 months, about 19 months, about 20 months, about 21 months, about 22 months about 23 months, about 2 years, about 2.5 years, about 3 years, about 3.5 years, about 4 years, about 4.5 years, about
- a dosing schedule for administration of a compound described herein can be consistent for the length of the dosing regimen.
- a compound can be administered daily.
- a dosing schedule for administration of a compound described herein can include portions of time where dosing is paused. For example, a compound can be administered every day for 3 weeks and then not be administered for one week.
- a dosing schedule for administration of a compound described herein can include once daily (QD), twice daily (BID), three times daily (TID), four times daily (QID), once weekly, twice weekly, three times weekly, once monthly, twice monthly, and once every other month.
- a daily dose can be given in a single dose or divided into multiple doses to be administered in intervals, e.g., twice daily or three times daily.
- a daily dose of 100 mg can be given, for example, once daily (100 mg), twice daily (50 mg per dose).
- Multiple therapeutic agents can be administered in any order or simultaneously.
- a compound of the disclosure is administered in combination with, before, or after treatment with another therapeutic agent, e.g., a drug, such as an aromatase inhibitor.
- a compound of the disclosure is administered at regular intervals, such as, for example, once daily, twice daily, thrice daily, etc. and the second therapeutic agent is administered daily or intermittently or on an as-needed basis.
- kits comprising compounds useful within the methods of the disclosure and an instructional material that describes, for instance, the method of administering compositions as described elsewhere herein.
- the kit comprises a composition.
- Example 1 Combination Treatment for Nonalcoholic Steatohepatitis (NASH) and Fibrosis
- NASH Nonalcoholic Steatohepatitis
- SCFAs Short-Chain Fatty Acids
- butyrate and acetate both of which target multiple mechanisms associated with the pathogenesis of NASH, and anti-oxidant Vitamin E (at safer doses).
- mice [0296] Patients diagnosed with NAFLD are also treated with this composition to prevent the progression of NAFLD to NASH and/or fibrosis.
- EXAMPLE 2 Treatment with Short Chain Fatty Acids – assessment of arresting the progression of NASH to fibrosis in a preclinical model of aged mice [0297] Various assays to assessment of arresting the progression of NASH to fibrosis were designed and tested as shown and described for FIGs.1-9. [0298] Mice [0299] All mice were fed a high fat diet (HFD) starting at 56 weeks of age until euthanasia at 76 weeks (groups 1, 2 and 5) or 84 weeks (groups 2, 4 and 6) of age (TABLE.1).
- HFD high fat diet
- Groups 1-4 inclusive also received 20.5 mg/kg/mouse/day tocopherol acetate.
- Mice were fed a high fat diet (HFD) starting at 56-weeks of age. At 64 weeks of age, half the mice were fed either a high dose of SCFA, a low dose of SCFA, nor no drug (day 0), for 12 weeks until euthanasia (day 84) (TABLE.1 and FIG.1). Mice in the other half of the colony were divided into the same groups, except that feeding of SCFA started at 72 weeks of age for 12 weeks until euthanasia.
- HFD high fat diet
- Body weight was determined in all C57/BL6 male mice over the whole period of each study (FIG.1). No effect on body weight loss was observed in mice of groups 2 and 4 treated with low dose of SCFA (FIG.1). Although mice of groups 1 and 3 fed with a high dose of SCFA lost up to 20% of their body weight within the first few weeks of SCFA feeding (FIG.1), food intake of these mice was unaltered, and physical appearance and activity did not change, suggesting no overt toxicity.
- H&E staining [0303] Upon euthanasia, each liver lobe from individual mice were formalin fixed and paraffin embedded. Liver sections were prepared, and H&E stained to evaluate histopathology (Tables 2-3 and FIGs.2-7), while slides from the same blocks were stain by trichrome to assess fibrosis (FIGs.8-9). [0304] Histopathology scores were independently determined by each of 4 lobes from individual mice, and the data represents the average score from all 4 lobes of single mouse (Table 2) according to histopathology evaluation criteria (Table 3). [0305] Table 2. Histopathology Score for Individual mice
- EXAMPLE 3 Treatment with Short Chain Fatty Acids – Study evaluating improvement of liver histology in patients with NAFLD/NASH.
- Liver histology in patients having NAFLD/NASH is assessed following administration of a composition comprising butyric acid and tocopherol acetate.
- a total of 100 patients with a median age of 60 are recruited. The patients have NAFLD/NASH and associated liver inflammation and/or cirrhosis and no contraindication for butyrate. Patients enrolled have a histological diagnosis of NASH.
- liver histology Baseline and treated (e.g., 96-week) liver biopsy specimens are formalin-fixed, paraffin- embedded, and unstained slides are cut from tissue blocks. Scoring of biopsies are assessed according to NAFLD activity score (NAS) and fibrosis score, or for example as described in Example 1.
- NAS NAFLD activity score
- fibrosis score or for example as described in Example 1.
- Adipo-IR index is calculated, for example, as fasting NEFA [mM] x fasting insulin [pM].
- Adipo-IR index is associated with an improvement in steatosis and necroinflammation. A decrease in Adipo-IR can indicate improvement of NASH through its effect on dysfunctional adipose tissue.
- exemplary Treatment In the study, drug recipients are monitored for the following outcomes: an improvement in fibrosis (e.g., a reduced fibrosis score according to liver histology in a treated sample compared to baseline sample), an improvement in NASH (e.g., a reduced NASH score according to liver histology in a treated sample compared to baseline sample), and/or a decrease in Adipo- IR.
- EXAMPLE 4 Treatment of NAFLD/NASH
- Treatment of NAFLD/NASH is assessed in a subject administered a composition comprising butyric acid and tocopherol acetate. [0324] A total of 100 patients are recruited.
- the patients have NAFLD/NASH and/or associated liver inflammation and/or cirrhosis and no contraindication for butyrate.
- the patients are dosed with a formulation comprising 600 mg sodium butyrate and tocopherol acetate (source of acetic acid [12 mg] and Vitamin E [200 IU]) two to three times daily or given placebo. [0325]
- the subjects are followed for a median of 5 years. Just prior to treatment, patients are screened for ALT/AST, GGT; liver stiffness by fibroscan; pro-inflammatory and anti- inflammatory cytokines in blood (e.g., TNF ⁇ , IFN- ⁇ , IL-2, IL-4, IL5- IL-10). The screenings are repeated yearly until completion of the study.
- Patients are analyzed by multivariate analysis for incidence of chronic liver disease (hepatitis and fibrosis), liver cancer, chronic liver disease related death (usually from cirrhosis), or transplantation in the treated and untreated cohorts.
- Exemplary Treatment [0327] In the study, drug recipients are monitored for the following outcomes: lower incidence of chronic liver disease (hepatitis and fibrosis), lower incidence of liver cancer, lower incidence of chronic lower incidence of liver disease related death (usually from cirrhosis), and/or lower incidence of transplantation in the treated cohort compared to the untreated cohort. [0328] In the study, drug recipients are monitored for a decreased expression of an inflammatory cytokine or a mediator or inflammation.
- a method of alleviating a condition in a subject in need thereof 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 a tocopherol, wherein the reduced amount of the tocopherol is therapeutically effective for alleviating the condition in combination with the at least one SCFA or the pharmaceutically acceptable salt thereof, and wherein the reduced amount of the tocopherol is less than an amount of the tocopherol that is therapeutically effective for the condition in absence of the at least one SCFA or the pharmaceutically acceptable salt thereof.
- SCFA short chain fatty acid
- Embodiment 2 Embodiment 2.
- Embodiment 3 A method of providing prophylaxis against 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) a tocopherol.
- Embodiment 4 The method of any one of embodiments 1-3, wherein the condition is a liver disease.
- liver disease is selected from the group consisting of a fatty liver disease, nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), liver fibrosis, alcoholic liver disease, 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.
- NAFLD nonalcoholic fatty liver disease
- NASH nonalcoholic steatohepatitis
- liver fibrosis alcoholic liver disease
- autoimmune disease or disorder cirrhosis
- liver cancer hepatocellular carcinoma
- autoimmune hepatitis hepatocellular carcinoma
- autoimmune hepatitis primary biliary cirrhosis
- PBC primary sclerosing cholangitis
- hemochromatosis Wilson’s disease, liver failure, and any combination thereof
- liver disease or disorder is nonalcoholic fatty liver disease (NAFLD).
- Embodiment 8 The method of embodiment 4, wherein the liver disease or disorder is nonalcoholic steatohepatitis (NASH).
- NASH nonalcoholic steatohepatitis
- Embodiment 8. The method of embodiment 4, wherein the liver disease or disorder is liver fibrosis.
- Embodiment 9. The method of embodiment 4, wherein the liver disease or disorder is alcoholic liver disease.
- Embodiment 10 The method of embodiment 4, wherein the liver disease or disorder is cirrhosis.
- Embodiment 11 The method of embodiment 4, wherein the liver disease or disorder is liver cancer.
- Embodiment 13 A method of providing prophylaxis against 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) a tocopherol.
- Embodiment 14 The method of any one of embodiments 3-13, wherein the prophylaxis comprises reducing a likelihood of progression to fibrosis.
- Embodiment 15 The method of embodiment 13 or 14, wherein the prophylaxis comprises reducing a likelihood of progression of NASH to fibrosis.
- Embodiment 17 The method of any one of embodiments 13-16, wherein the prophylaxis comprises delaying or slowing progression of NASH to fibrosis.
- Embodiment 18 The method of any one of embodiments 1-17, wherein the composition comprises between about 100 milligrams (mg) to about 6 grams (g) of one of the SCFAs.
- Embodiment 19 The method of embodiment 18, wherein the composition comprises about 2.4 grams (g) of one of the SCFAs.
- Embodiment 20 Embodiment 20.
- 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, caproic acid, lactic acid, succinic acid, pyruvic acid, octanoic acid, dodecanoic acid, (4R)-4-hydroxypentanoic acid, 2- ethylhydracrylic acid, 2-hydroxy-3-methylpentanoate, 2-hydroxy-3-methylpentanoic acid, 2- methylbut-2-enoic acid, 2-oxobutanoic acid, 3-hydroxypentanoic acid, 3-methylbut-2
- 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 a pharmaceutically acceptable salt thereof.
- Embodiment 22 The method of 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.
- Embodiment 23 The method of any one of embodiments 1-22, wherein the composition comprises at least two short chain fatty acids (SCFA) or a pharmaceutically acceptable salt thereof.
- Embodiment 24 Embodiment 24.
- SCFA or pharmaceutically acceptable salt thereof are selected from the group consisting of: acetic acid, butyric acid (BA), methoxyacetic acid, valproic acid (VPA), propionic acid, 3-methoxypropionic acid, ethoxyacetic acid, formic acid, isobutyric acid, tributyrin, butyrate, propionate, N- acetylbutyrate, isovaleric acid, valeric acid, isocaproic acid, caproic acid, lactic acid, succinic acid, pyruvic acid, octanoic acid, dodecanoic acid, (4R)-4-hydroxypentanoic acid, 2-ethylhydracrylic acid, 2-hydroxy-3-methylpentanoate, 2-hydroxy-3-methylpentanoic acid, 2-methylbut-2-enoic acid, 2 - oxobutanoic acid, 3-hydroxypentanoic acid, 3-methylbut-2-enoic
- Embodiment 25 The method of any one of embodiments 1-24, wherein the composition comprises butyrate or a pharmaceutically acceptable salt thereof.
- Embodiment 26 The method of any one of embodiments 1-25, wherein the composition comprises the pharmaceutically acceptable salt of butyrate, and the pharmaceutically acceptable salt of butyrate is a Ca salt, a Mg salt, or a Na salt.
- Embodiment 27 The method of any one of embodiments 1-26, wherein the composition comprises acetate or a pharmaceutically acceptable salt thereof.
- Embodiment 28 Embodiment 28.
- Embodiment 29 The method of any one of embodiments 1-28, wherein the composition comprises between about 100 milligrams (mg) to about 6 grams (g) of the SCFAs.
- Embodiment 30 The method of embodiment 29, wherein the composition comprises about 2.4 grams (g) of the SCFAs.
- Embodiment 31 The method of any one of embodiments 1-30, wherein the composition comprises between about 1 IU to about 600 IU of the tocopherol.
- Embodiment 32 Embodiment 32.
- Embodiment 33 The method of any one of embodiments 1-31, wherein the composition comprises between about 1 IU to about 49.9 IU of the tocopherol.
- Embodiment 34 The method of any one of embodiments 1-33, wherein the composition comprises between about 100.1 IU to about 600 IU of the tocopherol.
- Embodiment 35 The method of any one of embodiments 1-34, wherein the composition comprises more than about 100 IU of the tocopherol.
- Embodiment 36 Embodiment 36.
- Embodiment 37 The method of embodiment 36, wherein the composition comprises between about 1 milligram (mg) to about 100 milligrams (mg) of tocopherol-acetate.
- Embodiment 38 The method of embodiment 37, wherein the composition comprises about 12 milligrams (mg) of tocopherol-acetate.
- Embodiment 39 The method of any one of embodiments 1-38, wherein the composition is administered orally.
- Embodiment 40 The method of any one of embodiments 1-39, wherein the composition is administered with food or drink.
- Embodiment 42 The method of any one of embodiments 1-41, wherein the composition is a pharmaceutical composition.
- Embodiment 43 The method of embodiments 42, wherein the pharmaceutical composition further comprises a pharmaceutically acceptable excipient.
- Embodiment 44 The method of any one of embodiments 41-42, wherein the pharmaceutical composition further comprises an enteric coating.
- Embodiment 45 The method of any one of embodiments 41-44, wherein the pharmaceutical composition is formulated as a tablet.
- Embodiment 46 The method of embodiments 41-45, wherein the pharmaceutical composition is formulated as a capsule.
- Embodiment 47 The method of any one of embodiments 1-46, wherein the subject is s human.
- Embodiment 48 A pharmaceutical composition comprising in a unit dosage form active ingredients, wherein the active ingredients comprise (a) a therapeutically effective amount of at least one SCFA or a pharmaceutically-acceptable salt thereof; and (b) at least one antioxidant.
- 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 at least one antioxidant is therapeutically effective for alleviating a condition in combination with the at least one SCFA or the pharmaceutically acceptable salt thereof.
- Embodiment 50 Embodiment 50.
- Embodiment 51 A pharmaceutical composition comprising in a unit dosage form active ingredients, wherein the active ingredients comprise (a) a therapeutically effective amount of at least one SCFA or a pharmaceutically-acceptable salt thereof; and (b) a tocopherol.
- Embodiment 52 A pharmaceutical composition comprising in a unit dosage form active ingredients, wherein the active ingredients comprise (a) a therapeutically effective amount of at least one SCFA or a pharmaceutically-acceptable salt thereof; and (b) a tocopherol.
- Embodiment 53 The pharmaceutical composition of embodiment 51 or 52, wherein the amount of the tocopherol is a reduced amount of the tocopherol, wherein the reduced amount of tocopherol is less than an amount of the tocopherol that is therapeutically effective for a condition in absence of the at least one SCFA or the pharmaceutically acceptable salt thereof.
- Embodiment 54 Embodiment 54.
- Embodiment 55 The pharmaceutical composition of any one of embodiments 48-54, wherein the pharmaceutical composition comprises about 2.4 grams (g) of the at least one SCFA.
- Embodiment 56 The pharmaceutical composition of any one of embodiments 48-55, wherein the pharmaceutical composition comprises at least two SCFAs.
- Embodiment 57 The pharmaceutical composition of any one of embodiments 48-56, wherein the pharmaceutical composition comprises a butyrate or a pharmaceutically acceptable sale thereof.
- Embodiment 58 Embodiment 58.
- Embodiment 62 The pharmaceutical composition of any one of embodiments 48-57, wherein the pharmaceutical composition comprises a Ca salt of butyric acid.
- Embodiment 59 The pharmaceutical composition of any one of embodiments 48-58, wherein the pharmaceutical composition comprises a Mg salt of butyric acid.
- Embodiment 60 The pharmaceutical composition of any one of embodiments 48-59, wherein the pharmaceutical composition comprises between about 1 milligram (mg) to about 100 milligrams (mg) of the at least one antioxidant.
- Embodiment 61 The pharmaceutical composition of any one of embodiments 48-60, wherein the composition comprises about 12 milligrams (mg) of the at least one antioxidant.
- Embodiment 62 The pharmaceutical composition of any one of embodiments 48-60, wherein the composition comprises about 12 milligrams (mg) of the at least one antioxidant.
- Embodiment 63 The pharmaceutical composition of any one of embodiments 48-62, wherein the antioxidant is a tocopherol.
- Embodiment 64 The pharmaceutical composition of any one of embodiments 48-63, wherein the composition comprises between about 1 IU to about 600 IU of the tocopherol.
- Embodiment 65 Embodiment 65.
- Embodiment 66 The pharmaceutical composition of any one of embodiments 48-65, wherein the composition comprises less than about 50 IU of the tocopherol.
- Embodiment 67 The pharmaceutical composition of any one of embodiments 48-66, wherein the composition comprises between about 100.1 IU to about 600 IU of the tocopherol.
- Embodiment 68 The pharmaceutical composition of any one of embodiments 48-67, wherein the composition comprises more than about 100 IU of the tocopherol.
- Embodiment 69 Embodiment 69.
- Embodiment 70 The pharmaceutical composition of any one of embodiments 48-68, wherein the antioxidant is tocopherol acetate.
- Embodiment 70 The pharmaceutical composition of any one of embodiments 48-69, wherein the antioxidant is a d-alpha-tocopherol acetate.
- Embodiment 71 The pharmaceutical composition of any one of embodiments 48-70, wherein the composition comprises between about 1 milligram (mg) to about 100 milligrams (mg) of tocopherol-acetate.
- Embodiment 72 The pharmaceutical composition of any one of embodiments 48-71, wherein the composition comprises about 12 milligrams (mg) of tocopherol-acetate.
- Embodiment 73 Embodiment 73.
- Embodiment 74 The pharmaceutical composition of any one of embodiments 48-73, wherein the composition is adm4inistered with food or drink.
- Embodiment 75 The pharmaceutical composition of any one of embodiments 48-74, wherein the composition is administered with food.
- Embodiment 76 The pharmaceutical composition of any one of embodiments 48-75, further comprising a pharmaceutically acceptable excipient.
- Embodiment 77 The pharmaceutical composition of any one of embodiments 48-76, wherein the pharmaceutical composition further comprises an enteric coating.
- Embodiment 78 The pharmaceutical composition of any one of embodiments 48-72, wherein the composition is administered orally.
- Embodiment 81 The method of any one of embodiments 1-47, wherein administering the composition improves liver histology in a liver biopsy sample of the subject.
- Embodiment 82 The method of embodiment 81, wherein administering the composition improves NASH score in the liver biopsy sample of the subject.
- Embodiment 83 The method of embodiment 81, wherein administering the composition improves NASH score in the liver biopsy sample of the subject.
- Embodiment 84 The method of any one of embodiments 81-83, wherein administering the composition reduces the presence of inflammatory foci in the liver biopsy sample of the subject.
- Embodiment 85 The method of any one of embodiments 81-84, wherein administering the composition reduces the distribution of inflammatory foci in the liver biopsy sample of the subject.
- Embodiment 86 The method of any one of embodiments 81-85, wherein administering the composition reduces the frequency of inflammatory foci in the liver biopsy sample of the subject.
- Embodiment 87 Embodiment 87.
- Embodiment 91 The method of any one of embodiments 1-47 and 81-86, wherein administering the composition attenuated the pathogenesis of NASH in the subject.
- Embodiment 88 The method of any one of embodiments 1-47 and 81-87, wherein administering the composition prevents or delays the development of liver fibrosis in the subject.
- Embodiment 89 The method of any one of embodiments 1-47 and 81-88, wherein administering the composition decreases liver inflammation in the subject.
- Embodiment 90 The method of any one of embodiments 1-47 and 81-89, wherein administering the composition modulates expression of a mediator of inflammation in the subject.
- Embodiment 91 Embodiment 91.
- 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: a short chain fatty acid (SCFA), salt of SCFA, SCFA precursor, SCFA biosynthesis precursor, compound comprising a SFCA moiety, derivative of SCFA, and any combination thereof.
- SCFA short chain fatty acid
- Embodiment 93 Embodiment 93.
- liver disease or disorder is selected from the group consisting of a fatty liver disease, nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), liver fibrosis, alcoholic liver disease, 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.
- NAFLD nonalcoholic fatty liver disease
- NASH nonalcoholic steatohepatitis
- liver fibrosis alcoholic liver disease
- autoimmune disease or disorder cirrhosis
- liver cancer hepatocellular carcinoma
- autoimmune hepatitis hepatocellular carcinoma
- autoimmune hepatitis primary biliary cirrhosis (PBC), primary sclerosing cholangitis, hemochromatosis, Wilson’s disease, liver failure, and any
- a method of preventing or treating a fibrosis in a subject in need thereof comprising administering to the subject a composition comprising at least one compound selected from the group consisting of: a short chain fatty acid (SCFA), salt of SCFA, SCFA precursor, SCFA biosynthesis precursor, compound comprising a SFCA moiety, derivative of SCFA, and any combination thereof.
- SCFA short chain fatty acid
- SCFA biosynthesis precursor compound comprising a SFCA moiety, derivative of SCFA, and any combination thereof.
- a method of preventing or treating an inflammation in a subject in need thereof comprises administering to the subject a composition comprising at least one compound selected from the group consisting of: a short chain fatty acid (SCFA), salt of SCFA, SCFA precursor, SCFA biosynthesis precursor, compound comprising a SFCA moiety, derivative of SCFA, and any combination thereof.
- SCFA short chain fatty acid
- Embodiment 96 The method of any one of embodiments 92-95, wherein the composition comprises between about 100 milligrams (mg) to about 6 grams (g) of at least one SCFA.
- Embodiment 97 The method of embodiment 96, wherein the composition comprises about 2.4 grams (g) of at least one SCFA.
- Embodiment 98 The method of any one of embodiments 92-96, wherein the composition comprises at least SCFA or salt thereof comprising 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 (as well as other forms of butyrate, e.g., phenylbutyrate, isobutyrate, pivaloyloxymethyl butyrate, monoacetone glucose 3-butyrate), isovaleric acid, valeric acid, isocaproic acid, caproic acid, lactic acid, succinic acid, pyruvic acid, octa
- Embodiment 99 The method of embodiment 98, wherein the at least one salt of SCFA comprises at least one selected from the group consisting of: butyrate, propionate, and acetate.
- 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 SCFA, Mg salt of SCFA, and any combination thereof.
- Embodiment 101 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 butyric acid, Mg salt of butyric acid, Ca salt of acetic acid, Mg salt of acetic acid, and any combination thereof.
- Embodiment 102 The method of any one of embodiments 92-101, wherein the composition comprises between about 100 milligrams (mg) to about 6 grams (g) of Ca salt of butyric acid, Mg salt of butyric acid, Ca salt of acetic acid, Mg salt of acetic acid, or any combination thereof.
- Embodiment 103 The method of embodiment 102, wherein the composition comprises about 2.4 grams (g) of Ca salt of butyric acid, Mg salt of butyric acid, Ca salt of acetic acid, Mg salt of acetic acid, or any combination thereof.
- Embodiment 104 The method of any one of embodiments 92-103, wherein the composition further comprises at least one antioxidant.
- Embodiment 105 The method of embodiment 104, wherein the composition comprises between about 1 milligram (mg) to about 100 milligrams (mg) of at least one antioxidant.
- Embodiment 106 The method of embodiment 105, wherein the composition comprises about 12 milligrams (mg) of at least one antioxidant.
- 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, carotenoid, selenium, manganese, glutathione, coenzyme Q10, lipoic acid, flavonoid, phenol, polyphenol, phytoestrogen, and any combination thereof.
- Embodiment 108 The method of embodiment 107, wherein the antioxidant is a vitamin E.
- Embodiment 109 The method of embodiment 108, wherein the vitamin E comprises tocopherol-acetate.
- Embodiment 110 The method of embodiment 109, wherein the composition comprises between about 1 milligram (mg) to about 100 milligrams (mg) of tocopherol-acetate.
- Embodiment 111 The method of embodiment 110, wherein the composition comprises about 12 milligrams (mg) of tocopherol-acetate.
- Embodiment 112. The method of any one of embodiments 92-111, wherein the composition is an enteric coated extended-release capsule.
- Embodiment 113 The method of any one of embodiments 92-112, wherein the composition is a pharmaceutical composition.
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Abstract
The invention relates to compositions and methods that include short chain fatty acids (SCFAs), such as various butyrate and acetate, in combination with an antioxidant, such as Vitamin E, for the treatment or prevention of liver diseases or disorders, such as a nonalcoholic fatty liver disease (NAFLD), nonalcoholic sieatohepatitis (NASH), fibrosis, and other similar diseases or disorders.
Description
METHODS OF TREATING OR PREVENTING LIVER DISEASES OR DISORDERS CROSS-REFERENCE [0001] This application claims the benefit of U.S. Provisional Application No.63/383,175 filed on November 10, 2022, which is incorporated herein by reference in its entirety. BACKGROUND OF THE DISCLOSURE [0002] Nonalcoholic Steatohepatitis (NASH) is the advanced form of Nonalcoholic Fatty Liver Disease (NAFLD) characterized by accumulation of fat, inflammation, hepatocellular injury and different degree of fibrosis, which may progress to Nonalcoholic Steatohepatitis (NASH), cirrhosis and/or hepatocellular carcinoma (HCC). [0003] Numerous drug candidates failed to demonstrate clear benefits. Most likely, none of the molecules under current investigation are expected to provide significant improvement of NASH in more than a minority of patients. This is because, given the complex pathogenesis of NASH, existing drug candidates are for a single-drug NASH therapy and seem to be challenging to succeed as compensatory mechanisms can attenuate drug’s effect. [0004] Thus, there is a need in the art for effective compositions and methods of treating or preventing liver diseases or disorders, such as a NAFLD, NASH, fibrosis, and other similar diseases or disorders. The present disclosure addresses this unmet need. INCORPORATION BY REFERENCE [0005] 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 [0006] 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 a pharmaceutically acceptable salt thereof; and (b) a reduced amount of a tocopherol, wherein the reduced amount of the tocopherol is therapeutically effective for alleviating the condition in combination with the at least two SCFA or the
pharmaceutically acceptable salt thereof, and wherein the reduced amount of the tocopherol is less than an amount of the tocopherol that is therapeutically effective for the condition in absence of the at least two SCFA or the pharmaceutically acceptable salt thereof. [0007] Disclosed herein is a method of providing prophylaxis against 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) a tocopherol. [0008] Disclosed herein is a method of providing prophylaxis against 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) a tocopherol. [0009] Disclosed herein is a pharmaceutical composition comprising in a unit dosage form active ingredients, wherein the active ingredients comprise (a) a therapeutically effective amount of at least one SCFA or a pharmaceutically-acceptable salt thereof; and (b) a tocopherol. BRIEF DESCRIPTION OF THE DRAWINGS [0010] FIG.1 shows weight of mice from the start of treatment at day 0 to euthanasia at day 81. [0011] FIG.2 shows average histopathology scores for mice fed high dose SCFA, low dose SCFA, or no drug. [0012] FIG.3 shows average histopathology scores for mice fed high dose SCFA, low dose SCFA, or no drug. [0013] FIG.4 shows representative H&E staining for inflammatory infiltrates characteristic of NASH in a liver sample of a control mouse on a high fat diet and euthanized at 76 weeks of age (group 5). [0014] FIG.5 shows representative H&E staining for inflammatory infiltrates characteristic of NASH in a liver sample of a control mouse on a high fat diet and euthanized at 84 weeks of age (group 6). [0015] FIG.6 shows representative H&E staining for inflammatory infiltrates characteristic of NASH in a liver sample of a mouse fed a high dose SCFA and euthanized at 76 weeks of age (group 1). [0016] FIG.7 shows representative H&E staining for inflammatory infiltrates characteristic of
NASH in a liver sample of a mouse fed a high dose SCFA and euthanized at 84 weeks of age (group 3). [0017] FIG.8 shows representative Masson’s trichrome staining for fibrosis in a liver sample of a control mouse on a high fat diet and euthanized at 76 weeks of age (group 5). [0018] FIG.9 shows representative Masson’s trichrome staining for fibrosis in a liver sample of a mouse fed a high dose SCFA and euthanized at 76 weeks of age (group 1). DETAILED DESCRIPTION [0019] The present disclosure is based on the unexpected results that a combination of Ca/Mg salts of butyric acid and tocopherol-acetate provides an effective treatment for NASH with or without fibrosis. Thus, in some aspects, the present disclosure provides a method of preventing or treating a liver disease, fibrosis, or inflammation using a composition comprising at least one compound selected from a short chain fatty acid (SCFA), salt of SCFA, SCFA precursor, SCFA biosynthesis precursor, compound comprising a SFCA moiety, derivative of SCFA, or any combination thereof. In some embodiments, the salt of SCFA comprises a Ca salt of SCFA (e.g., Ca salt of butyric acid, Ca salt of acetic acid, etc.), Mg salt of SCFA (e.g., Mg salt of butyric acid, Mg salt of acetic acid, etc.), or any combination thereof. In some embodiments, the composition further comprises at least one antioxidant (e.g., vitamin E, tocopherol-acetate, etc.). [0020] In one embodiment, a subject is a human. In one embodiment, a subject is a non-human animal. [0021] Provided herein are compositions and methods for treating a condition (e.g., liver disease, fibrosis, or inflammation) comprising administering to a subject in need thereof a composition comprising at least one short chain fatty acid (SCFA), salt of SCFA, SCFA precursor, SCFA biosynthesis precursor, composition comprising a SFCA moiety, derivative of SCFA, or any combination thereof. In some embodiments, a composition disclosed herein is present in a salt form. In some embodiments, a method disclosed herein further comprises administering a second pharmaceutical composition, for example. Definitions [0022] It is to be understood that the figures and descriptions of the present disclosure have been simplified to illustrate elements that are relevant for a clear understanding of the present
disclosure, while eliminating, for the purpose of clarity, many other elements found in the disclosure. Those of ordinary skill in the art may recognize that other elements and/or steps are desirable and/or required in implementing the present disclosure. However, because such elements and steps are well known in the art, and because they do not facilitate a better understanding of the present disclosure, a discussion of such elements and steps is not provided herein. The disclosure herein is directed to all such variations and modifications to such elements and methods known to those skilled in the art. [0023] Unless defined elsewhere, 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. [0024] As used herein, each of the following terms has the meaning associated with it in this section. [0025] The articles “a” and “an” are used herein to refer to one or to more than one (i.e., to at least one) of the grammatical object of the article. By way of example, “an element” means one element or more than one element. [0026] “About” as used herein when referring to a measurable value such as an amount, a temporal duration, and the like, is meant to encompass variations of ±20%, ±10%, ±5%, ±1%, or ±0.1% from the specified value, as such variations are appropriate. [0027] The term “abnormal” when used in the context of organisms, tissues, cells or components thereof, refers to those organisms, tissues, cells or components there that differ in at least one observable or detectable characteristic (e.g., age, treatment, time of day, etc.) from those organisms, tissues, cells or components thereof that display the “normal” (expected) respective characteristic. Characteristics which are normal or expected for one cell or tissue type, might be abnormal for a different cell or tissue type. [0028] As used herein, “combination” as in the phrase “a first agent in combination with a second agent” includes co-administration of a first agent and a second agent, which for example may be dissolved or intermixed in the same pharmaceutically acceptable carrier, or administration of a first agent, followed by the second agent, or administration of the second agent, followed by the first agent.
[0029] The term “concomitant” as in the phrase “concomitant therapeutic treatment” includes administering an agent in the presence of a second agent. A concomitant therapeutic treatment method includes methods in which the first, second, third, or additional agents are co- administered. A concomitant therapeutic treatment method also includes methods in which the first or additional agents are administered in the presence of a second or additional agents, wherein the second or additional agents, for example, may have been previously administered. A concomitant therapeutic treatment method may be executed step-wise by different actors. For example, one actor may administer to a subject a first agent and a second actor may administer to the subject a second agent, and the administering steps may be executed at the same time, or nearly the same time, or at distant times, so long as the first agent (and additional agents) are after administration in the presence of the second agent (and additional agents). The actor and the subject may be the same entity (e.g., a human). [0030] The term “combination therapy”, as used herein, refers to the administration of two or more therapies, two or more therapeutic agents, or a combination of at least one therapeutic agent and at least one method of therapy, such as radiation, immunotherapy, and chemotherapy. [0031] A “disease” is a state of health of an animal wherein the animal cannot maintain homeostasis, and wherein if the disease is not ameliorated then the animal’s health continues to deteriorate. [0032] In contrast, a “disorder” in an animal is a state of health in which the animal is able to maintain homeostasis, but in which the animal’s state of health is less favorable than it would be in the absence of the disorder. Left untreated, a disorder does not necessarily cause a further decrease in the animal’s state of health. [0033] A subject is “at risk for” developing a condition if there is an increased probability that the individual will develop the condition compared to a population (e.g., the general population, an age-matched population, a population of the same sex). The increased probability can be due to one or a combination of factors including the presence of specific alleles/mutations of a gene or exposure to a particular environment. [0034] The term “cancer” as used herein is defined as disease characterized by the rapid and uncontrolled growth of aberrant cells. Cancer cells can spread locally or through the bloodstream and lymphatic system to other parts of the body. 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, renal cancer, brain cancer, lymphoma, leukemia, lung cancer and the like. [0035] A disease or disorder is “alleviated” if the severity of a sign or symptom of the disease or disorder, the frequency with which such a sign or symptom is experienced by a patient, or both, is reduced. [0036] The term “inhibit,” as used herein, means to suppress or block an activity or function by at least about ten percent relative to a control value. As an example, the activity is suppressed or blocked by 50% compared to a control value, by 75%, or by 95% or more. [0037] The terms “treatment”, “treating” and the like are used herein to generally mean obtaining a desired pharmacological and/or physiological effect. The effect may be prophylactic in terms of completely or partially preventing a disease or disorder, or a symptom thereof, and/or may be therapeutic in terms of partially or completely curing a disease or disorder, and/or adverse effect attributed to the disease or disorder. The term “treatment” as used herein includes any treatment of a disease or disorder in a subject and includes: (a) preventing a disease or disorder from occurring in a subject which may be predisposed to the disease or disorder; (b) inhibiting the disease or disorder, i.e. arresting its development: or (c) relieving the disease or disorder, i.e. causing regression of the disease or disorder. [0038] The terms “effective amount” and “pharmaceutically effective amount” refer to a sufficient amount of an agent to provide a desired biological result. That result can be reduction and/or alleviation of a sign, symptom, or cause of a disease or disorder, or any other desired alteration of a biological system. [0039] A “therapeutically effective amount” refers to that amount which provides a therapeutic effect for a given condition and administration regimen. In particular, “therapeutically effective amount” means an amount that is effective to prevent, alleviate or ameliorate symptoms of a disease or disorder, or prolong the survival of the subject being treated, which may be a human or non-human animal. [0040] As used herein, the term “pharmaceutical composition” refers to a mixture of at least one compound of the disclosure with other chemical components and entities, such as carriers, stabilizers, diluents, dispersing agents, suspending agents, thickening agents, and/or excipients. The pharmaceutical composition facilitates administration of the compound to an organism. Multiple techniques of administering a compound exist in the art including, but not limited to,
intravenous, oral, aerosol, parenteral, ophthalmic, pulmonary and topical administration. [0041] “Pharmaceutically acceptable” refers to those properties and/or substances which are acceptable to the patient from a pharmacological/toxicological point of view and to the manufacturing pharmaceutical chemist from a physical/chemical point of view regarding composition, formulation, stability, patient acceptance and bioavailability. [0042] As used herein, the term “pharmaceutically acceptable carrier” means a pharmaceutically acceptable material, composition or carrier, such as a liquid or solid filler, stabilizer, dispersing agent, suspending agent, diluent, excipient, thickening agent, solvent, or encapsulating material, involved in carrying or transporting a compound useful within a composition disclosed herein within or to the patient such that it may perform its intended function. Typically, such constructs are carried or transported from one organ, or portion of the body, to another organ, or portion of the body. Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation, including the compound useful within a composition disclosed herein, and not injurious to the patient. Some examples of materials that may 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 carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients, such as cocoa butter and suppository waxes; oils, such as peanut oil, cottonseed oil, 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; buffering agents, such as magnesium hydroxide and aluminum hydroxide; surface active agents; alginic acid; pyrogen-free water; isotonic saline; Ringer’s solution; ethyl alcohol; phosphate buffer solutions; and other non-toxic compatible substances employed in pharmaceutical formulations. As used herein, “pharmaceutically acceptable carrier” also includes any and all coatings, antibacterial and antifungal agents, and absorption delaying agents, and the like that are compatible with the activity of the compound useful withina composition disclosed herein, and are physiologically acceptable to the patient. Supplementary active compounds may also be incorporated into the compositions. The “pharmaceutically acceptable carrier” may further include a pharmaceutically acceptable salt of the compound useful within a composition disclosed herein. Other additional ingredients that may be included in the pharmaceutical compositions used in the practice of the
disclosure are known in the art and described, for example in Remington's Pharmaceutical Sciences (Genaro, Ed., Mack Publishing Co., 1985, Easton, PA), which is incorporated herein by reference. [0043] The term “nutritional composition” may refer to a food product intended for human consumption, for example, a beverage, a drink, a bar, a snack, an ice cream, a dairy product, for example a chilled or a shelf-stable dairy product, a fermented dairy product, a drink, for example 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 oven or a conventional oven, a ready-to- eat product, a fast food or a nutritional formula. [0044] The terms “patient,” “subject,” “individual,” and the like are used interchangeably herein, and refer to any animal, or cells thereof whether in vitro or in situ, amenable to the methods described herein. The patient, subject, or individual may be a human or a non-human animal. [0045] As used herein, the term “container” includes any receptacle for holding the pharmaceutical composition. For example, in one embodiment, the container is the packaging that contains the pharmaceutical composition. In other embodiments, the container is not the packaging that contains the pharmaceutical composition, i.e., the container is a receptacle, such as a box or vial that contains the packaged pharmaceutical composition or unpackaged pharmaceutical composition and the instructions for use of the pharmaceutical composition. Moreover, packaging techniques are well known in the art. It should be understood that the instructions for use of the pharmaceutical composition may be included on the packaging containing the pharmaceutical composition, and as such the instructions form an increased functional relationship to the packaged product. However, it should be understood that the instructions may contain information pertaining to the compound’s ability to perform its intended function, e.g., treating or preventing a disease in a subject. [0046] “Instructional material,” as that term is used herein, includes a publication, a recording, a diagram, or any other medium of expression which can be used to communicate the usefulness of components of the disclosure in a kit for identifying or alleviating or treating the various diseases or disorders recited herein. Optionally, or alternately, the instructional material may describe one or more methods of identifying or alleviating the diseases or disorders in a cell or a tissue of a subject. The instructional material of the kit may, for example, be affixed to a container that
contains the compositions or be shipped together with a container that contains the compositions. [0047] Alternatively, the instructional material may be shipped separately from the container with the intention that the recipient uses the instructional material and the composition cooperatively. [0048] Ranges: throughout this disclosure, various aspects of the disclosure can be presented in a range format. It should be understood that the description in range format is merely for convenience and brevity and should not be construed as an inflexible limitation on the scope of the disclosure. Accordingly, the description of a range should be considered to have specifically disclosed all the possible subranges as well as individual numerical values within that range. For example, description of a range such as from 1 to 6 should be considered to have specifically disclosed subranges such as from 1 to 3, from 1 to 4, from 1 to 5, from 2 to 4, from 2 to 6, from 3 to 6 etc., as well as individual numbers within that range, for example, 1, 2, 2.7, 3, 4, 5, 5.3, and 6. This applies regardless of the breadth of the range. [0049] Description [0050] The present disclosure is based on the unexpected results that a combination of Ca/Mg salts of butyric acid and tocopherol-acetate provides an effective treatment for NASH with or without fibrosis. Thus, in some aspects, the present disclosure provides a method of preventing or treating a liver disease, fibrosis, or inflammation using a composition comprising at least one compound selected from a short chain fatty acid (SCFA), salt of SCFA, SCFA precursor, SCFA biosynthesis precursor, compound comprising a SFCA moiety, derivative of SCFA, or any combination thereof. In some embodiments, the salt of SCFA comprises a Ca salt of SCFA (e.g., Ca salt of butyric acid, Ca salt of acetic acid, etc.), Mg salt of SCFA (e.g., Mg salt of butyric acid, Mg salt of acetic acid, etc.), or any combination thereof. In some embodiments, the composition further comprises at least one antioxidant (e.g., vitamin E, tocopherol-acetate, etc.). [0051] In one embodiment, a subject is a human. In one embodiment, a subject is a non-human animal. [0052] The present disclosure provides methods for treating or preventing a liver disease, fibrosis, and/or inflammation in a subject in need thereof by administration to said subject a therapeutically effective amount of a composition comprising at least one compound selected from a short chain fatty acid (SCFA), salt of SCFA, SCFA precursor, SCFA biosynthesis precursor, compound comprising a SFCA moiety, derivative of SCFA, or any combination
thereof. [0053] Liver Disease [0054] Liver disease and disorders 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. [0055] NAFLD/NASH currently afflicts hundreds of millions of people. NAFLD/NASH is a growing worldwide epidemic, and current treatment approached include lifestyle adjustments, physical activity, smoking/alcohol cessation, high dose of Vitamin E (800IU, as an antioxidant), and pioglitazone (as an insulin sensitizer). Despite the urgent clinical need and attractive commercial opportunity, there are no FDA-approved therapies for NASH. Many pharmaceutical companies have tried and unfortunately failed to develop a drug capable of unraveling the complexities of this disease. [0056] The present disclosure provides methods and compositions having a much higher therapeutic success than current treatment approaches. More specifically, the present disclosure provides a composition comprising a combination of butyrate and acetate (which simultaneously target multiple mechanisms associated with the pathogenesis of NASH), in addition to an antioxidant, (e.g., Vitamin E), offer an effective and safe treatment outcome. Thus, the present disclosure provides a composition to treat NASH with or without fibrosis. [0057] 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. [0058] In some embodiments, a composition disclosed herein is administered to a subject for treating a liver disease or disorder. In some embodiment, a composition disclosed herein is administered to a subject for preventing a liver disease or disorder. [0059] In some embodiments, a composition disclosed herein is administered to a subject determined to be at risk for developing a liver disease or disorder. [0060] Non-limiting examples of a liver disease or disorder include: fatty liver disease, nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), liver fibrosis, alcoholic liver disease, autoimmune disease or disorder, cirrhosis, liver cancer, hepatocellular
carcinoma (HCC), hepatitis B associated chronic liver disease, dysplasia, autoimmune hepatitis, primary biliary cirrhosis (PBC), primary sclerosing cholangitis, hemochromatosis, Wilson’s disease, liver failure, or any combination thereof. [0061] In some embodiments, a composition disclosed herein is administered to a subject for treating or preventing an inflammatory condition. In some embodiments, a composition disclosed herein is administered to a subject for treating or preventing a chronic inflammatory condition. Non-limiting examples of chronic inflammatory condition includes type 2 diabetes and obesity. [0062] Short Chain Fatty Acid (SCFA) [0063] “Short chain fatty acids” (SCFA) are fatty acids typically with aliphatic tails shorter than aliphatic tails of long chain fatty acids. Short chain fatty can be derivatized to provide a salt or ester thereof, for example, pharmaceutically acceptable salts and esters of fatty acids (e.g., sodium butyrate, arginine butyrate). [0064] In some embodiments, the composition comprises between about 100 milligrams (mg) to about 100 grams (g) of at least one SCFA. In some embodiments, the composition comprises between about 100 milligrams (mg) to about 6 grams (g) of at least one SCFA. In some embodiments, the composition comprises between about 1 gram (g) to about 6 grams (g) of at least one SCFA. In some embodiments, the composition comprises between about 1 gram (g) to about 4 grams (g) of at least one SCFA. In some embodiments, the composition comprises between about 2 grams (g) to about 4 grams (g) of at least one SCFA. In some embodiments, the composition comprises between about 2 grams (g) to about 3 grams (g) of at least one SCFA. For example, in one embodiment, the composition comprises about 2.4 grams (g) of at least one SCFA. [0065] In some embodiments, a composition disclosed herein comprises 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 a SCFA. [0066] 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 a SCFA. [0067] In one embodiment, the composition comprises at least one SCFA, salt thereof, or a compound comprising a SCFA moiety. In some embodiments, a composition disclosed herein comprises at least one SCFA. In some embodiments, a composition disclosed herein comprises at least one short chain fatty acid (SCFA), SCFA precursor, SCFA biosynthesis precursor, a derivative thereof, a SCFA moiety, or a combination thereof. [0068] In some embodiments, a composition disclosed herein comprises at least one SCFA, or a compound comprising a SCFA moiety. In some embodiments, a composition disclosed herein comprises at least two SCFAs. In some embodiments, a composition disclosed herein comprises at least three SCFAs. [0069] Non-limiting examples of a SCFA, salt thereof, or SCFA moiety include: acetic acid, butyric acid (BA), C3-C12 fatty acids, C3-C10 fatty acids, C3-C8 fatty acids, methoxyacetic acid, valproic acid (VPA), propionic acid, 3-methoxypropionic acid, ethoxyacetic acid, formic acid, isobutyric acid, tributyrin, N-acetylbutyrate (as well as other forms of butyrate, e.g., phenylbutyrate, isobutyrate, pivaloyloxymethyl butyrate, 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- ethylhydracrylic acid, 2- hydroxy-3-methylpentanoate, 2-hydroxy-3-methylpentanoic acid, 2-methylbut-2-enoic acid, 2- oxobutanoic acid, 3-hydroxypentanoic acid, 3-methylbut-2-enoic acid, butenoic acid, methylbutyric acid, dimethylbutyric acid, pentadienoic acid, pentenoic acid, pivalic acid, propynoic acid, or any combination thereof. [0070] In one embodiment, the composition comprises a salt of a SCFA, or a derivative thereof. For example, in one embodiment, the salt of SCFA comprises at least one butyrate, propionate, and/or acetate. A salt of butyric acid may 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. [0071] In some embodiments, butyrate can (1) potentiate Peroxisome Proliferator-Activated Receptor (PPAR)- signaling (where PPAR regulates the expression of genes involved in fatty
acid beta- oxidation, glucose metabolism, inflammation responses, and is a major regulator of energy homeostasis), (2) suppress pro-inflammatory cytokines such as Tumor Necrosis Factor (TNF)-α, CCL2/CCR2 and CCL5/CCR5 (key cytokines involved in adipocyte-related inflammation, hepatic stellate cell activation, initiating a fibrogenic response), (3) improve insulin sensitivity, (4) promote expression of GLP-1R (where GLP-1 regulates glucose homeostasis, gastric motility and food intake), and/or (5) inhibit fibrosis development (as demonstrated by decreased hepatic collagen content). In some embodiments, acetate can inhibit lipid accumulation by promoting lipolysis and fatty acid oxidation and inhibiting fatty acid synthesis. In some embodiments, Vitamin E prevents liver injury by protecting against mitochondrial toxicity and blocking intrinsic apoptotic pathways. Unlike other treatments, which are generally based on single channel drugs, the present disclosure provides broad multichannel protection. [0072] Mechanisms of butyrate, acetate, and Vitamin E action in the context of NAFLD/NASH/fibrosis: SCFAs (including butyrate and acetate) are derived from bacterial fermentation of fiber and play a vital role in intestinal epithelial nutrition and maintenance of immune homeostasis (Sanna et al, 2019; Van der Hee et al, 2021). SCFAs directly enter the liver through the portal vein, and there are several possible mechanisms whereby SCFAs reduce the development of NASH/NAFLD. For example, in the liver, SCFAs (including butyrate and acetate) induces AMP-activated protein kinase (AMPK) activation and suppress macrophage pro- inflammatory activation, thus alleviating hepatic steatosis. [0073] In the SCFA-fed mice, there was a two-fold increase in hepatic lipid oxidation, shifting hepatic lipid metabolism towards a more oxidative state. This shift was associated with increased phosphorylation and activation of AMPK (a central regulator of energy homeostasis) and its downstream target, acetyl-CoA carboxylase (ACC) (den Besten et al, 2015; Kim et al, 2016). [0074] Butyrate and acetate also increased transcriptional expression of adiponectin and resistin (both are adipose tissue-derived hormones that play a crucial role in protection against insulin resistance, diabetes and obesity) through epigenetic modulation (DNA methylation) in obese mice (Dai et al, 2020); decreased the expression of lipogenic genes (via histone deacetylases [HDAC] inhibition) such as those encoding ACC, Fasn and Srebp1c (Kim et al, 2018), all of which are linked to the NASH progression. Butyrate is the most potent natural HDAC inhibitor (Waldecker et al, 2008). In murine models, oral administration of butyrate significantly decreased
hepatic steatosis and inflammation in Western-style diet-induced NASH (Jin et al, 2015) and in fat-fructose-cholesterol rich diet-induced NASH mice (Baumann et al, 2020). Vinolo at al. (2012) reported that mice treated with a butyrate pro-drug, tributyrin, were protected from diet- induced obesity, insulin resistance, and hepatic steatosis. Butyrate is a PPAR agonist (Nepelska et al, 2017). [0075] PPARs are nuclear receptors which regulate the expression of genes involved in fatty acid beta-oxidation, glucose metabolism, inflammation responses (acting on NF-kB and AP1 transcription factors) and are major regulator of energy homeostasis. In animal models of steatosis and steatohepatitis, the use of PPAR activators improved the disease outcome (Caligiuri et al 2016). Butyrate protected against high-fat diet-induced obesity via a PPARγ-dependent switch from lipogenesis to fat oxidation (den Besten, et al, 2015). Inflammation represents a crucial aspect in the pathogenesis of NASH. Overload of toxic lipids, mainly Free Fatty Acids (FFA), causes cellular stress and induces specific signals that trigger hepatocyte apoptosis. Strong evidence supports a key role of pro-inflammatory cytokine TNF-ct in the pathogenesis of NASH (Day et al, 1998). In the liver, TNF-ct is secreted directly by hepatocytes and Kupffer cells or indirectly by abdominal fat. Data from animal and clinical studies indicate that TNF-α mediates not only the early, but also transition to more advanced, stages of liver damage (Crespo et al, 2001; Hotamisligil et al,1993). Butyrate suppresses TNF-ct (thus inflammation), and one of the mechanisms is facilitating its mRNA degradation (Fukae et al, 2005). [0076] Other upregulated pro-inflammatory cytokines involved in the pathogenesis of NASH include IL-1β, IL-12, CCL2 and CCL5. Latter two recruit macrophages (and other inflammatory cells) and induce hepatic stellate cell activation, initiating a fibrogenic response (Marra et al 2014). Expression of CCR2 and CCR5 has been shown to be upregulated in vivo and in the livers of obese patients with severe steatosis and NASH. There is human data showing that patients with NAFLD had higher serum levels of CCL2, and this positively correlated with liver fat content in patients (Braunersreuther et al, 2012). [0077] In NASH patients, increased levels of intrahepatic mRNA of CCL5 were associated with more severe fibrosis (Berres et al, 2010). In the HFD-induced NASH murine model, high levels of intrahepatic CCL5 were significantly decreased by butyrate (Gart et al 2021). Clinical studies with NAFLD patients showed that Glucagon-like Peptide 1 receptor (GLP-1R) agonists decreased hepatic fat content. GLP-1R agonists potentiate glucose-stimulated insulin secretion and
inhibition of glucagon secretion and are one of the few glucose-lowering agents that results in weight loss, thus improvement in hepatic steatosis. In High Fat Diet (HFD)-fed obese mice, butyrate stimulated 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 fibrosis development as demonstrated by decreased hepatic collagen content in liver histopathology. [0078] One of the mechanisms by which SCFAs affect fat accumulation both in the liver and adipose tissue is regulation of insulin sensitivity via G-protein-coupled receptor 43 (GPR43), also called 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 inhibited 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 dysregulation (Aoki et al 2021). [0079] Few animal studies showed that acetate supplementation reduced hepatic lipogenesis and fatty acid uptake, and protected mice from HFD-induced weight gain, steatosis and insulin resistance (Weitkunat et al, 2017; Hernández et al, 2019). Moreover, the activation of hepatic FFAR2 by acetate can 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 taken up in the hypothalamus. This uptake resulted in decreased food intake through appetite suppression accompanied by increased production of lactate and γ-aminobutyric acid (Frost et al, 2014). [0080] Furthermore, in humans, acetate can also cross the blood–brain barrier and be metabolized in the brain (the subjects were administered [2-13C] acetate for 2 hours and brain was scanned with magnetic resonance spectroscopy) (Jiang et al 2013). There is data from small human clinical studies showing beneficial effect of acetate (Kondo et al, 2009). [0081] In some embodiment, the salt of SCFA comprises at least one Ca salt of SCFA, Mg salt of SCFA, Na salt of SCFA or any combination thereof. For example, in some embodiments, the salt of SCFA comprises at least one Ca salt of butyric acid, Mg salt of butyric acid, Na salt of butyric acid, Ca salt of acetic acid, Mg salt of acetic acid, Na salt of acetic acid, or any combination thereof. [0082] Non-limiting examples of a SCFA or SCFA moiety includes compounds or structures with at least 12 carbon atoms, at least 11 carbon atoms, at least 10 carbon atoms, at least 9 carbon
atoms, at least 8 carbon atoms, at least 7 carbon atoms, at least 6 carbon atoms, at least 5 carbon atoms, at least 4 carbon atoms, at least 3 carbon atoms, and at least 2 carbon atoms. In one embodiment, the SCFA or SCFA moiety includes compounds or structures with 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 SCFA or SCFA moiety is not a branched fatty acid. In one embodiment, the SCFA or SCFA moiety is a branched fatty acid. [0083] In one embodiment, the composition comprises at least one compound comprising a precursor of a SCFA, or a moiety thereof. In one embodiment, the precursor, or moiety thereof, is selected from the group including, but not limited to, plant cell-wall polysaccharides, dietary nonstarch polysaccharides (NSP) a salt of lactate, a salt of succinate, a salt of formate, 1,2- propenedol, trypamine, indole, indole-3-acetate, and a combination thereof. [0084] In one embodiment, the composition comprises at least one compound comprising a biosynthesis precursor of a SCFA, or a moiety thereof. In one embodiment, the biosynthesis precursor, or moiety thereof, is selected from the group including, but not limited to an acetyl- CoA carboxylase inhibitor, an adenosine monophosphate kinase (AMPK) activator, vitamin D, and a combination thereof. [0085] Antioxidant [0086] Vitamin E is a fat-soluble antioxidant that stops the production of ROS formed when fat undergoes oxidation. The eight forms of Vitamin E include four tocopherols (alpha-, beta-, gamma-, and delta-tocopherol) and four tocotrienols (alpha-, beta-, gamma-, and delta- tocotrienol), that have varying levels of biological activity. [0087] Tocopherols are organic compounds comprising various methylated phenols, many of which have vitamin E activity. Non-limiting examples of a tocopherol include: alpha-tocopherol or α-tocopherol, RRR-α-tocopherol, d-α-tocopherol, ddd-α-tocopherol, RSR-α-tocopherol, all- rac-α-tocopherol, dl-tocopherol, dl-α-tocopherol, dl-tocopheryl acetate, tocopherol acetate, tocopheryl acetate, α-tocopheryl acetate, alpha-tocopherol acetate, dl-α-tocopheryl acetate, d-α- tocopherol acetate, α-tocopheryl succinate, α-tocopheryl nicotinate, α-tocopheryl phosphate, tocopheryl ester, tocopheryl nicotinate, tocopheryl linolate, and tocopheryl palmitate, γ- tocopherol, tocopheryl linoleate, β-tocopherol, γ-tocophero, d-γ-tocopherol, or mixed tocopherol.
[0088] In some embodiments, the Vitamin E is alpha-tocopherol or α-tocopherol. In some embodiments, the tocopherol is alpha-tocopherol or α-tocopherol. In some embodiments, the Vitamin E is d-α-tocopherol acetate. In some embodiments, the tocopherol is d-α-tocopherol acetate. In some embodiments, the Vitamin E is dl-α-tocopherol. In some embodiments, the tocopherol is dl-α-tocopherol. [0089] In some embodiments, a tocopherol disclosed herein is hydrolyzed, for example α- Tocopherol acetate is hydrolyzed to α-tocopherol and acetic acid. [0090] In some embodiments, the tocopherol is synthetic. In some embodiments, the tocopherol is fully synthetic. In some embodiments, the tocopherol is semi-synthetic. In some embodiments, the tocopherol is natural. In some embodiments, the tocopherol is fractionated. In some embodiments, the tocopherol is highly fractionated. In some embodiments, the tocopherol is less fractionated. [0091] Antioxidants, such as tocopherol or Vitamin E, may prevent liver injury by protecting against mitochondrial toxicity and blocking intrinsic apoptotic pathways. Vitamin E may also down-regulate NF-kB-dependent inflammatory pathways (Ratziu et al 2015). However, antioxidant therapies have not always been favorable and were shown to be associated with worsening pathology. Administration of high doses of Vitamin E improved NAS within two years, but often increases insulin resistance and plasma triglyceride levels (Hackam, 2007 Chalasani et al, 2012). Indeed, concerns about long-term safety of high-dose Vitamin E exist, such as an increase in overall mortality, the incidence of hemorrhagic stroke, and even prostate cancer in males older than 50 years (Miller et al, 2005, Ratziu et al 2015; Hackam, 2007). In some embodiments, a high dose of Vitamin E is about 800 IU. [0092] In some embodiments, a composition disclosed herein comprises a reduced amount of the tocopherol or Vitamin E. In some embodiments, a reduced amount of the tocopherol or Vitamin E alleviates or reduces an adverse event associated with high dose Vitamin E. Non-limiting examples of an adverse event associated with high dose Vitamin E include: increased insulin resistance, increased plasma triglyceride levels, increased mortality, increased incidence of hemorrhagic stroke, and increased incidence of prostate cancer. [0093] In some embodiments, a reduced amount of a tocopherol is therapeutically effective for alleviating a condition in a subject in need thereof in combination with at least one SCFA or the pharmaceutically acceptable salt thereof. In some embodiments, a reduced amount of a Vitamin E is
therapeutically effective for alleviating a condition in a subject in need thereof in combination with at least one SCFA or the pharmaceutically acceptable salt thereof. [0094] In some embodiments, a reduced amount of a tocopherol is therapeutically effective for alleviating a condition in a subject in need thereof in combination with at least two SCFAs or the pharmaceutically acceptable salt thereof. In some embodiments, a reduced amount of a Vitamin E is therapeutically effective for alleviating a condition in a subject in need thereof in combination with at least two SCFAs or the pharmaceutically acceptable salt thereof. [0095] In some embodiments, a reduced amount of the tocopherol is less than an amount of the tocopherol that is therapeutically effective for the condition in absence of the at least one SCFA or the pharmaceutically acceptable salt thereof. In some embodiments, a reduced amount of the Vitamin E is less than an amount of the tocopherol that is therapeutically effective for the condition in absence of the at least one SCFA or the pharmaceutically acceptable salt thereof. [0096] In some embodiments, a reduced amount of the tocopherol is less than an amount of the tocopherol that is therapeutically effective for the condition in absence of the at least two SCFAs or the pharmaceutically acceptable salt thereof. In some embodiments, a reduced amount of the Vitamin E is less than an amount of the tocopherol that is therapeutically effective for the condition in absence of the at least two SCFAs or the pharmaceutically acceptable salt thereof. [0097] In some embodiments, the tocopherol exhibits synergy with the at least one SCFA or the pharmaceutically acceptable salt thereof. In some embodiments, the Vitamin E exhibits synergy with the at least one SCFA or the pharmaceutically acceptable salt thereof. [0098] In some embodiments, a composition disclosed herein comprises an amount of tocopherol or Vitamin E about 10%, about 11%, about 12%, about 13%, about 14% an, 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% an, about 35%, about 35%, about 36%, about 37%, about 38%, about 39%, about 40%, about 41%, about 42%, about 43%, about 44% an, about 45%, about 46%, about 47%, about 48%, about 49%, about 50%, about 51%, about 52%, about 53%, about 54% an, about 55%, about 56%, about 57%, about 58%, about 59%, about 60%, about 61%, about 62%, about 63%, about 64% an, about 65%, about 66%, about 67%, about 68%, about 69%, about 70%, about 71%, about 72%, about 73%, about 74% an, about 75%, about 76%, about 77%, about 78%, about 79%, about 80%, about 81%, about 82%, about 83%, about 84% an, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about
91%, about 92%, about 93%, about 94% an, about 95%, about 96%, about 97%, about 98%, about 99% less than a an amount of tocopherol or Vitamin E that is therapeutically effective for the condition in absence of the at least one SCFA or the pharmaceutically acceptable salt thereof. [0099] In some embodiments, a composition disclosed herein comprises less than about 600 IU, less than about 550 IU, less than about 500 IU, less than about 450 IU, less than about 400 IU, less than about 350 IU, less than about 300 IU, less than about 250 IU, less than about 200 IU. , less than about 150 IU, less than about 100 IU, less than about 50 IU, less than about 40 IU, less than about 30 IU, less than about 20 IU, or less than about 10 IU of tocopherol or Vitamin E. [0100] In some embodiments, a composition disclosed herein comprises more than about 100 IU, more than about 150 IU, more than about 200 IU, more than about 250 IU, more than about 300 IU, more than about 350 IU, more than about 400 IU, more than about 450 IU, more than about 500 IU, more than about 550 IU, or more than about 600 IU of tocopherol or Vitamin E. [0101] In some embodiments, a composition disclosed herein comprises about 100.1 to about 600 IU of tocopherol or Vitamin E. In some embodiments, a composition disclosed herein comprises about 101 to about 600 IU of tocopherol or Vitamin E. In some embodiments, a composition disclosed herein comprises about 200.1 to about 600 IU of tocopherol or Vitamin E. In some embodiments, a composition disclosed herein comprises about 201 to about 600 IU of tocopherol or Vitamin E. In some embodiments, a composition disclosed herein comprises about 300 to about 600 IU of tocopherol or Vitamin E. In some embodiments, a composition disclosed herein comprises about 400 to about 600 IU of tocopherol or Vitamin E. In some embodiments, a composition disclosed herein comprises about 500 to about 600 IU of tocopherol or Vitamin E. [0102] In some embodiments, a composition disclosed herein comprises about 1 to about 49.9 IU of tocopherol or Vitamin E. In some embodiments, a composition disclosed herein comprises about 1 to about 49 IU of tocopherol or Vitamin E. In some embodiments, a composition disclosed herein comprises about 1 to about 40 IU of tocopherol or Vitamin E. In some embodiments, a composition disclosed herein comprises about 1 to about 30 IU of tocopherol or Vitamin E. In some embodiments, a composition disclosed herein comprises about 1 to about 20 IU of tocopherol or Vitamin E. In some embodiments, a composition disclosed herein comprises about 1 to about 10 IU of tocopherol or Vitamin E. [0103] In some embodiments, a composition disclosed herein comprises about 100.1 IU, about 100.2 IU, about 100.3 IU, about 100.4 IU, about 100.5 IU, about 100.6 IU, about 100.7 IU, about
100.8 IU, about 100.9 IU, about 101.0 IU, about 101.1 IU, about 101.2 IU, about 101.3 IU, about 101.4 IU, about 101.5 IU, about 101.6 IU, about 101.7, about 101.8 IU, about 101.9 IU, or about 102.0 IU of tocopherol or Vitamin E. [0104] In some embodiments, a composition disclosed herein comprises about 200.1 IU, about 200.2 IU, about 200.3 IU, about 200.4 IU, about 200.5 IU, about 200.6 IU, about 200.7 IU, about 200.8 IU, about 200.9 IU, about 201.0 IU, about 201.1 IU, about 201.2 IU, about 201.3 IU, about 201.4 IU, about 201.5 IU, about 201.6 IU, about 201.7, about 201.8 IU, about 201.9 IU, or about 202.0 IU of tocopherol or Vitamin E. [0105] In some embodiments, a composition disclosed herein comprises about 49.9 IU, about 49.8 IU, about 49.7 IU, about 49.6 IU, about 49.5 IU, about 49.4 IU, about 49.3 IU, about 49.2 IU, about 49.1 IU, about 49.0 IU, about 48.9 IU, about 48.8 IU, about 48.7 IU, about 48.6 IU, about 48.5 IU, about 48.4 IU, about 48.3 IU, about 48.2 IU, about 48.1 IU, or about 48.0 IU of tocopherol or Vitamin E. [0106] In some embodiments, the composition 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 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 of [0107] In various embodiments, the method of the present disclosure comprises administering to a subject in need thereof a composition disclosed herein further comprising at least one antioxidant. [0108] In some embodiments, the composition comprises between about 1 milligram (mg) to about 100,000 milligrams (mg) of at least one antioxidant. In some embodiments, the composition comprises between about 1 milligram (mg) to about 100 milligrams (mg) of at least one antioxidant. In some embodiments, the composition comprises between about 1 milligram (mg) to about 90 milligrams (mg) of at least one antioxidant. In some embodiments, the composition comprises between about 1 milligram (mg) to about 80 milligrams (mg) of at least one
antioxidant. In some embodiments, the composition comprises between about 1 milligram (mg) to about 70 milligrams (mg) of at least one antioxidant. In some embodiments, the composition comprises between about 1 milligram (mg) to about 60 milligrams (mg) of at least one antioxidant. In some embodiments, the composition comprises between about 1 milligram (mg) to about 50 milligrams (mg) of at least one antioxidant. In some embodiments, the composition comprises between about 1 milligram (mg) to about 40 milligrams (mg) of at least one antioxidant. In some embodiments, the composition comprises between about 1 milligram (mg) to about 30 milligrams (mg) of at least one antioxidant. In some embodiments, the composition comprises between about 1 milligram (mg) to about 20 milligrams (mg) of at least one antioxidant. For example, in some embodiments, the composition comprises about 12 milligrams (mg) of at least one antioxidant. [0109] In some embodiments, the composition comprises about 20 IU to about 300 IU of at least one antioxidant. In some embodiments, the composition comprises about 20 IU to about 200 IU of at least one antioxidant. In some embodiments, the composition comprises about 50 IU to about 200 IU of at least one antioxidant. In some embodiments, the composition comprises about 200 IU to about 600 IU of at least one antioxidant. [0110] In some embodiments, the tocopherol is tocopherol acetate. In some embodiments, the tocopherol is d-α-tocopherol acetate. [0111] In some embodiments, the at least one antioxidant is vitamin E (d-α-tocopherol acetate). [0112] In some embodiments, the antioxidant comprises at least one vitamin C, vitamin E (d-α- tocopherol acetate), beta-carotene, carotenoid, selenium, manganese, glutathione, coenzyme Q10, lipoic acid, flavonoid, phenol, polyphenol, phytoestrogen, vitamin D3, or any combination thereof. Magnesium is a co-factor for more than 300 enzymes that regulate diverse biochemical reactions including regulation of blood glucose levels, detoxification, and others. Vitamin D3 deficiency is frequent in patients with immune disorders. Vitamin E has distinctive antioxidant activities. In one embodiment, the method comprises administering to a subject in need thereof a composition comprising at least one SCFA, salt thereof, or a biologically-active derivative or precursor thereof, and additionally 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, salt thereof, or a biologically-active derivative or precursor thereof, in combination with a composition comprising one or more of magnesium, vitamin D3,
and vitamin E. [0113] Conditions [0114] In some embodiments, diseases and disorders that can be treated, prevented or ameliorated by the methods of the present disclosure include, but are not limited to, inflammatory diseases and various cancer diseases. In some embodiments, the inflammatory diseases and disorders that can be treated or ameliorated include, but are not limited to, asthma, arthritis, allergic rhinitis, psoriasis, atopic dermatitis, inflammatory bowel diseases, Crohn’s disease, an allergic or autoimmune disease or disorder associated with C-section delivery of a neonate, uveitis, and vasculitis. In some embodiments, the cancer diseases and disorders that can be treated or ameliorated include, but are not limited to, leukemias and lymphomas. [0115] In one embodiment, an 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 & neuronal neuropathy (AMAN), Behcet’s disease, Bullous pemphigoid, Castleman disease (CD), Celiac disease, Chagas disease, Chronic inflammatory demyelinating polyneuropathy (CIDP), Chronic recurrent multifocal osteomyelitis (CRMO), Churg-Strauss, Cicatricial pemphigoid/benign mucosal pemphigoid, Cogan’s syndrome, Cold agglutinin disease, Congenital heart block, Coxsackie myocarditis, CREST syndrome, Crohn’s disease, Dermatitis herpetiformis, Dermatomyositis, Devic’s disease (neuromyelitis optica), Discoid lupus, Dressler’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-Barre syndrome, Hashimoto’s thyroiditis, Hemolytic anemia, Henoch-Schonlein purpura (HSP), Herpes gestationis or pemphigoid gestationis (PG), Hypogammalglobulinemia, IgA Nephropathy, IgG4-related sclerosing disease, Inclusion body myositis (IBM), Inflammatory bowel disease, Interstitial cystitis (IC), Juvenile arthritis, Juvenile rheumatoid arthritis, Juvenile diabetes (Type 1 diabetes), Juvenile myositis (JM), Kawasaki disease, Lambert-Eaton syndrome, Leukocytoclastic vasculitis, Lichen planus, Lichen sclerosus, Ligneous conjunctivitis, Linear IgA disease (LAD), Lupus, Lyme disease chronic, Meniere’s disease, Microscopic polyangiitis (MPA), Mixed
connective tissue disease (MCTD), Mooren’s ulcer, Mucha-Habermann disease, Multiple sclerosis (MS), Myasthenia gravis, Myositis, Narcolepsy, Neuromyelitis optica, Neutropenia, Ocular cicatricial pemphigoid, Optic neuritis, Palindromic rheumatism (PR), PANDAS (Pediatric Autoimmune Neuropsychiatric Disorders Associated, with, Streptococcus), Paraneoplastic cerebellar degeneration (PCD), Paroxysmal nocturnal hemoglobinuria (PNH), Parry Romberg 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, Postmyocardial 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 syndrome, Scleritis, Scleroderma, Sjogren’s syndrome, Sperm & testicular autoimmunity, Stiff person syndrome (SPS), Subacute bacterial endocarditis (SBE), Susac’s syndrome, Sympathetic ophthalmia (SO), Takayasu’s arteritis, Temporal arteritis/Giant cell arteritis, Thrombocytopenic purpura (TTP), Tolosa-Hunt syndrome (THS), Transverse myelitis, Type 1 diabetes, Ulcerative colitis (UC), Undifferentiated connective tissue disease (UCTD), Uveitis, Vasculitis, Vitiligo, and Wegener’s granulomatosis (Granulomatosis with Polyangiitis (GPA)). [0116] In other embodiments, diseases and disorders that 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 transplantations, such as inflammatory bowel disease (IBD), ulcerative colitis, Crohn’s disease, sprue, autoimmune arthritis, rheumatoid arthritis, Type I diabetes, multiple sclerosis, graft vs. host disease following bone marrow transplantation, osteoarthritis, juvenile chronic arthritis, Lyme arthritis, psoriatic arthritis, reactive arthritis, spondy loarthropathy, systemic lupus erythematosus, insulin dependent diabetes mellitus, thyroiditis, asthma, psoriasis, dermatitis scleroderma, atopic dermatitis, graft versus host disease, acute or chronic immune disease associated with organ transplantation, sarcoidosis, atherosclerosis, disseminated intravascular coagulation, Kawasaki's disease, Grave's disease,
nephrotic syndrome, chronic fatigue syndrome, Wegener's granulomatosis, Henoch-Schoenlejn purpurea, microscopic vasculitis of the kidneys, uveitis, septic shock, toxic shock syndrome, sepsis syndrome, cachexia, acquired immunodeficiency syndrome, acute transverse myelitis, Huntington's chorea, Parkinson's disease, Alzheimer's disease, stroke, primary biliary cirrhosis, hemolytic anemia, polyglandular deficiency type I syndrome and polyglandular deficiency type II syndrome, Schmidt's syndrome, adult (acute) respiratory distress syndrome, alopecia, alopecia areata, seronegative arthopathy, arthropathy, Reiter's disease, psoriatic arthropathy, chlamydia, yersinia and salmonella associated arthropathy, spondyloarhopathy, atheromatous disease/arteriosclerosis, allergic colitis, atopic allergy, food allergies such as peanut allergy, tree nut allergy, egg allergy, milk allergy, soy allergy, wheat allergy, seafood allergy, shellfish allergy, or sesame seed allergy, autoimmune bullous disease, pemphigus vulgaris, pemphigus foliaceus, pemphigoid, linear IgA disease, autoimmune haemolytic anaemia, Coombs positive haemolytic anaemia, acquired pernicious anaemia, juvenile pernicious anaemia, myalgic encephalitis/Royal Free Disease, chronic mucocutaneous candidiasis, giant cell arteritis, Acquired Immunodeficiency Disease Syndrome, Acquired Immunodeficiency Related Diseases, common varied immunodeficiency (common variable hypogammaglobulinaemia), dilated cardiomyopathy, fibrotic lung disease, cryptogenic fibrosing alveolitis, postinflammatory interstitial lung disease, interstitial pneumonitis, connective tissue disease associated interstitial lung disease, mixed connective tissue disease associated lung disease, systemic sclerosis associated interstitial lung disease, rheumatoid arthritis associated interstitial lung disease, systemic lupus erythematosus associated lung disease, dermatomyositis/polymyositis associated lung disease, Sjogren's disease associated lung disease, ankylosing spondylitis associated lung disease, vasculitic diffuse lung disease, haemosiderosis associated lung disease, drug-induced interstitial lung disease, radiation fibrosis, bronchiolitis obliterans, chronic eosinophilic pneumonia, lymphocytic infiltrative lung disease, postinfectious 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, osteoarthrosis, primary sclerosing cholangitis, idiopathic leucopenia, autoimmune neutropenia, renal disease NOS, glomerulonephritides, microscopic vasulitis of the kidneys, discoid lupus, erythematosus, male infertility idiopathic or NOS, sperm autoimmunity, multiple sclerosis (all subtypes), insulin
dependent diabetes mellitus, sympathetic ophthalmia, pulmonary hypertension secondary to connective tissue disease, Goodpasture's syndrome, pulmonary manifestation of polyarteritis nodosa, acute rheumatoid fever, rheumatoid spondylitis, Still's disease, systemic sclerosis, Takayasu's disease/arteritis, autoimmune thrombocytopenia, idiopathic thrombocytopenia, autoimmune thyroid disease, hyperthyroidism, goitrous autoimmune hypothyroidism (Hashimoto's disease), atrophic autoimmune hypothyroidism, primary myxoedema, phacogenic uveitis, primary vasculitis, vitiligo, allergic rhinitis (pollen allergies), anaphylaxis, pet allergies, latex allergies, drug allergies, allergic rhinoconjuctivitis, eosinophilic esophagitis, hypereosinophilic syndrome, eosinophilic gastroenteritis cutaneous lupus erythematosus, eosinophilic esophagitis, hypereosinophilic syndrome, and eosinophilic gastroenteritis, and diarrhea. [0117] Method of Treatment [0118] In one embodiment, the disclosure provides methods for the treatment or prevention of at least one disease or disorder in a subject, comprising administering to the subject at least one composition comprising a SCFA or a compound comprising a SCFA moiety, optionally in combination with at least one additional agent or therapy. [0119] In some embodiments, the administered compositions of the present disclosure can increase the number of disease-free days, reduce the severity of a disease or disorder, reduce the risk of developing a disease or disorder, reduce the risk of recurrence of a disease or disorder, or a combination thereof in the subject. The administered compositions of the present disclosure can increase the number of disease-free days by 5-60% or more in the subject as compared to a subject who is not receiving treatment. The administered compositions of the present disclosure can reduce the severity of a disease or disorder 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 in the subject as compared to a subject who is not receiving treatment. The administered compositions of the present disclosure can reduce the risk of developing a disease or disorder 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 in the subject as compared to a subject who is not receiving treatment. The administered compositions of the present disclosure can reduce the risk of recurrence of a disease or disorder 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 in the subject as compared to a subject who is not receiving treatment. [0120] In one embodiment, an exemplary method for the treatment or prevention of diseases or disorder comprises administration of 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, least 4 g, at least 5 g, at least 6 g or more than 6 g of at least one SCFA at least 1 time daily, at least 2 times daily, at least 3 times daily or more than 3 times daily, 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 for more than 6 months. [0121] In one embodiment, the composition comprising at least one SCFA is an enteric coated, extended-release capsule. [0122] In one embodiment, the composition comprises a derivative of 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 hydrolyzes under a low pH condition to yield at least one SCFA molecule and at least one PEG molecule. [0123] In one embodiment, the composition comprises a combination of SCFAs, and/or derivatives thereof. In one embodiment, the composition is prepared at amounts of at least 10 mM, at least 20 mM, at least 30 mM, 40 mM, 50 mM, 60 mM, 70 mM, 80 mM, 90 mM, 100 mM, or more of each or all the compounds of the composition. [0124] Derivatives of SCFAs, e.g., having substituents on the carbon chain such as O, S, N, methyl, ethyl, halogen, and other groups that do not interfere with the compound’s therapeutic activity may also be used to form the compositions of this disclosure. In one embodiment, the compound of the disclosure comprises at least one SCFA linked to at least one additional moiety, such as O, S, N, methyl, ethyl, halogen, and other groups that do not interfere with the compound’s therapeutic activity. [0125] In some instances, the SCFA of the disclosure can be pegylated. Polyethylene glycol
(PEG) has been widely used in biomaterials, biotechnology and medicine primarily because PEG is a biocompatible, nontoxic, nonimmunogenic and water-soluble polymer (Zhao and Harris, ACS Symposium Series 680: 458-72, 1997). In the area of drug delivery, PEG derivatives have been widely used in covalent attachment (i.e., “PEGylation”) to proteins to reduce immunogenicity, proteolysis and kidney clearance and to enhance solubility (Zalipsky, Adv. Drug Del. Rev. 16:157-82, 1995). Similarly, PEG has been attached to low molecular weight, relatively hydrophobic drugs to enhance solubility, reduce toxicity and alter biodistribution. Typically, PEGylated drugs are injected as solutions. However, they may be administered orally, or by another route. [0126] A closely related application is synthesis of crosslinked degradable PEG networks or formulations for use in drug delivery since much of the same chemistry used in design of degradable, soluble drug carriers can also be used in design of degradable gels (Sawhney et al., Macromolecules 26: 581-87, 1993). It is also known that intermacromolecular complexes can be formed by mixing solutions of two complementary polymers. Such complexes are generally stabilized by electrostatic interactions (polyanion-polycation) and/or hydrogen bonds (polyacid- polybase) between the polymers involved, and/or by hydrophobic interactions between the polymers in an aqueous surrounding (Krupers et al., Eur. Polym J.32:785-790, 1996). For example, mixing solutions of polyacrylic acid (PAAc) and polyethylene oxide (PEO) under the proper conditions results in the formation of complexes based mostly on hydrogen bonding. Dissociation of these complexes at physiologic conditions has been used for delivery of free drugs (i.e., non-PEGylated). In addition, complexes of complementary polymers have been formed from both homopolymers and copolymers. [0127] 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, a salt of formate, a salt of lactate, a salt of succinate, 1,2-propenedol, trypamine, indole, and indole-3- acetate. [0128] In one embodiment, the composition comprises a precursor of SCFA biosynthesis alone or in combination with one or more SCFA. Precursors of SCFA biosynthesis include, but are not limited to, a salt of formate, a salt of lactate, a salt of succinate, acetyl-CoA carboxylase inhibitors, adenosine monophosphate kinase (AMPK) activators, and vitamin D. SCFAs stimulate T regulatory (Treg) cell function, which accounts for some of their anti-inflammatory
properties. Given that inhibitors of acetyl-CoA carboxylase also promote Treg cell function, in one embodiment, a composition comprises an inhibitor of acetyl-CoA carboxylase, including but not limited to, biotin or its naturally or chemically synthesized analogs (which are acetyl-CoA carboxylase inhibitors) alone or in combination with one or more other SCFAs, to stimulate Treg functions. [0129] In various embodiments, a compound comprising at least one SCFA, or a compound comprising a SCFA moiety of the disclosure may be combined with one or more compounds, such as one or more additional therapeutic agent, for a particular disease or disorder. In one embodiment, the one or more SCFAs of the disclosure may be in the same composition as one or more additional therapeutic agent. In various embodiments the composition may comprise at least 1, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10 or more than 10 additional therapeutic agents. Exemplary additional therapeutic agents and/or compounds that can be included in a composition are discussed in detail elsewhere herein. [0130] Anti-Inflammatory Agents [0131] In one embodiment, the method comprises administering to a subject in need thereof a composition comprising at least one SCFA, or a biologically-active derivative or precursor thereof, in combination with one or more anti-inflammatory agent. Exemplary anti-inflammatory agents that can be used in combination with the compositions include, but are not limited to nonsteroidal anti-inflammatory drugs (NSAIDs) such as diclofenac (e.g., Arthrotec®), diflunisal (e.g., Dolobid®), etodolac (e.g., Lodine®), fenoprofen (e.g., Nalfon®), ibuprofen (e.g., Advil®, Motrin®, and others), indomethacin (e.g., Arthrexin®), ketoprofen (e.g., Oruvail®), ketorolac (e.g., Toradol®), fosfomycin tromethamine (e.g., Monural®), meclofenamate (e.g., Meclomen®), nabumetone (e.g., Relafen®), naproxen (e.g., Anaprox®, and others). Oxaprozin (e.g., Daypro®), piroxicam (e.g., Feldene®), sulindac (e.g., Clinoril®), tolmetin (e.g., Tolectin®, and others), Flavenoids (e.g., luteolin, fisetin, and apigenin), steroids, antihistamines, Loratadine, Theophylline, Doxantrazole, Quercetin, 8-bromo cyclic AMP, Disodium cromoglicate, Beclomethasone dipropionate, Budesonide, Budesonide/Formoterol, Fluticasone, Fluticasone inhaled powder, Fluticasone/Salmeterol, Mometasone, Mometasone/formoterol, Cromolyn, Omalizumab, Inhaled short- or long-acting beta2-agonists, Leukotriene modifiers, and Theophylline. 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 anti-inflammatory agent. 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 agent. [0132] Chemotherapeutic Agents [0133] In one embodiment, the method of the disclosure may comprise administration of the composition in combination with one or more chemotherapeutic agent. Chemotherapeutic agents include, but are not limited to, ara-C, daunomycin, cladribine (Leustatin, 2-CdA), cytotoxic agents (e.g., 5-fluorouracil, cisplatin, carboplatin, methotrexate, daunorubicin, doxorubicin, vincristine, vinblastine, oxorubicin, carmustine (BCNU), lomustine (CCNU), cytarabine USP, cyclophosphamide, estramucine phosphate sodium, altretamine, hydroxyurea, ifosfamide, procarbazine, mitomycin, busulfan, cyclophosphamide, mitoxantrone, carboplatin, cisplatin, interferon alfa-2a recombinant, paclitaxel, teniposide, and streptozoci), cytotoxic alkylating agents (e.g., busulfan, chlorambucil, cyclophosphamide, melphalan, or ethylesulfonic acid), alkylating agents (e.g., asaley, AZQ, BCNU, busulfan, bisulphan, carboxyphthalatoplatinum, CBDCA, CCNU, CHIP, chlorambucil, chlorozotocin, cis-platinum, clomesone, cyanomorpholinodoxorubicin, cyclodisone, cyclophosphamide, dianhydrogalactitol, fluorodopan, hepsulfam, hycanthone, iphosphamide, melphalan, methyl CCNU, mitomycin C, mitozolamide, nitrogen mustard, PCNU, piperazine, piperazinedione, pipobroman, porfiromycin, spirohydantoin mustard, streptozotocin, teroxirone, tetraplatin, thiotepa, triethylenemelamine, uracil nitrogen mustard, and Yoshi-864), antimitotic agents (e.g., allocolchicine, Halichondrin M, colchicine, colchicine derivatives, dolastatin 10, maytansine, rhizoxin, paclitaxel derivatives, paclitaxel, thiocolchicine, trityl cysteine, vinblastine sulfate, and vincristine sulfate), plant alkaloids (e.g., actinomycin D, bleomycin, L-asparaginase, idarubicin, vinblastine sulfate, vincristine sulfate, mitramycin, mitomycin, daunorubicin, VP-16-213, VM-26, navelbine and taxotere), biologicals (e.g., alpha interferon, BCG, G-CSF, GM-CSF, and interleukin-2), topoisomerase I inhibitors (e.g., camptothecin, camptothecin derivatives, and morpholinodoxorubicin), topoisomerase II inhibitors (e.g., mitoxantron, amonafide, m-AMSA, anthrapyrazole derivatives, pyrazoloacridine, bisantrene HCL, daunorubicin, deoxydoxorubicin, menogaril, N,N-dibenzyl daunomycin, oxanthrazole, rubidazone, VM-26 and VP-16), and synthetics (e.g., hydroxyurea, procarbazine, o,p'-DDD, dacarbazine, CCNU, BCNU, cis-
diamminedichloroplatimun, mitoxantrone, CBDCA, levamisole, hexamethylmelamine, all-trans retinoic acid, gliadel and porfimer sodium). In some embodiments, a composition is administered before, during, or after administration of at least one antiproliferative agent for the treatment of cancer. Antiproliferative agents are compounds that decrease the proliferation of cells. Antiproliferative agents include, but are not limited to, alkylating agents, antimetabolites, enzymes, biological response modifiers, miscellaneous agents, hormones and antagonists, androgen inhibitors (e.g., flutamide and leuprolide acetate), antiestrogens (e.g., tamoxifen citrate and analogs thereof, toremifene, droloxifene and roloxifene), Additional examples of specific antiproliferative agents include, but are not limited to levamisole, gallium nitrate, granisetron, sargramostim strontium-89 chloride, filgrastim, pilocarpine, dexrazoxane, and ondansetron. [0134] The compositions can be administered alone or in combination with other anti-tumor agents, including cytotoxic/antineoplastic agents and anti-angiogenic agents. Cytotoxic/anti- neoplastic agents are defined as agents which attack and kill cancer cells. Some cytotoxic/anti- neoplastic agents are alkylating agents, which alkylate the genetic material in tumor cells, e.g., cis-platin, cyclophosphamide, nitrogen mustard, trimethylene thiophosphoramide, carmustine, busulfan, chlorambucil, belustine, uracil mustard, chlomaphazin, and dacabazine. Other cytotoxic/anti-neoplastic agents are antimetabolites for tumor cells, e.g., cytosine arabinoside, fluorouracil, methotrexate, mercaptopuirine, azathioprime, and procarbazine. Other cytotoxic/anti-neoplastic agents are antibiotics, e.g., doxorubicin, bleomycin, dactinomycin, daunorubicin, mithramycin, mitomycin, mytomycin C, and daunomycin. There are numerous liposomal formulations commercially available for these compounds. Still other cytotoxic/anti- neoplastic agents are mitotic inhibitors (vinca alkaloids). These include vincristine, vinblastine and etoposide. Miscellaneous cytotoxic/anti-neoplastic agents include taxol and its derivatives, L-asparaginase, anti-tumor antibodies, dacarbazine, azacytidine, amsacrine, melphalan, VM-26, ifosfamide, mitoxantrone, and vindesine. [0135] Anti-angiogenic agents are well known to those of skill in the art. Suitable anti-angiogenic agents for combining with the compositions of the present disclosure include anti-VEGF antibodies, including humanized and chimeric antibodies, anti-VEGF aptamers and antisense oligonucleotides. Other known inhibitors of angiogenesis include angiostatin, endostatin, interferons, interleukin 1 (including alpha and beta) interleukin 12, retinoic acid, and tissue inhibitors of metalloproteinase-1 and -2. (TIMP-1 and -2). Small molecules, including
topoisomerases such as razoxane, a topoisomerase II inhibitor with anti-angiogenic activity, can also be used. [0136] Other anti-cancer agents that can be used in combination with the compositions include, but are not limited to: acivicin; aclarubicin; acodazole hydrochloride; acronine; adozelesin; aldesleukin; altretamine; ambomycin; ametantrone acetate; aminoglutethimide; amsacrine; anastrozole; anthramycin; asparaginase; asperlin; azacitidine; azetepa; azotomycin; batimastat; benzodepa; bicalutamide; bisantrene hydrochloride; bisnafide dimesylate; bizelesin; bleomycin sulfate; brequinar sodium; bropirimine; busulfan; cactinomycin; calusterone; caracemide; carbetimer; carboplatin; carmustine; carubicin hydrochloride; carzelesin; cedefingol; chlorambucil; cirolemycin; cisplatin; cladribine; crisnatol mesylate; cyclophosphamide; cytarabine; dacarbazine; dactinomycin; daunorubicin hydrochloride; decitabine; dexormaplatin; dezaguanine; dezaguanine mesylate; diaziquone; docetaxel; doxorubicin; doxorubicin hydrochloride; droloxifene; droloxifene citrate; dromostanolone propionate; duazomycin; edatrexate; eflornithine hydrochloride; elsamitrucin; enloplatin; enpromate; epipropidine; epirubicin hydrochloride; erbulozole; esorubicin hydrochloride; estramustine; estramustine phosphate sodium; etanidazole; etoposide; etoposide phosphate; etoprine; fadrozole hydrochloride; fazarabine; fenretinide; floxuridine; fludarabine phosphate; fluorouracil; fluorocitabine; fosquidone; fostriecin sodium; gemcitabine; gemcitabine hydrochloride; hydroxyurea; idarubicin hydrochloride; ifosfamide; ilmofosine; interleukin II (including recombinant interleukin II, or rIL2), interferon alfa-2a; interferon alfa-2b; interferon alfa-n1; interferon alfa-n3; interferon beta-I a; interferon gamma-I b; iproplatin; irinotecan hydrochloride; lanreotide acetate; letrozole; leuprolide acetate; liarozole hydrochloride; lometrexol sodium; lomustine; losoxantrone hydrochloride; masoprocol; maytansine; mechlorethamine hydrochloride; megestrol acetate; melengestrol acetate; melphalan; menogaril; mercaptopurine; methotrexate; methotrexate sodium; metoprine; meturedepa; mitindomide; mitocarcin; mitocromin; mitogillin; mitomalcin; mitomycin; mitosper; mitotane; mitoxantrone hydrochloride; mycophenolic acid; nocodazole; nogalamycin; ormaplatin; oxisuran; paclitaxel; pegaspargase; peliomycin; pentamustine; peplomycin sulfate; perfosfamide; pipobroman; piposulfan; piroxantrone hydrochloride; plicamycin; plomestane; porfimer sodium; porfiromycin; prednimustine; procarbazine hydrochloride; puromycin; puromycin hydrochloride; pyrazofurin; riboprine; rogletimide; safingol; safingol hydrochloride; semustine; simtrazene; sparfosate sodium;
sparsomycin; spirogermanium hydrochloride; spiromustine; spiroplatin; streptonigrin; streptozocin; sulofenur; talisomycin; tecogalan sodium; tegafur; teloxantrone hydrochloride; temoporfin; teniposide; teroxirone; testolactone; thiamiprine; thioguanine; thiotepa; tiazofurin; tirapazamine; toremifene citrate; trestolone acetate; triciribine phosphate; trimetrexate; trimetrexate glucuronate; triptorelin; tubulozole hydrochloride; uracil mustard; uredepa; vapreotide; verteporfin; vinblastine sulfate; vincristine sulfate; vindesine; vindesine sulfate; vinepidine sulfate; vinglycinate sulfate; vinleurosine sulfate; vinorelbine tartrate; vinrosidine sulfate; vinzolidine sulfate; vorozole; zeniplatin; zinostatin; zorubicin hydrochloride. Other anti- cancer drugs include, but are not limited to: 20-epi-1,25 dihydroxyvitamin D3; 5-ethynyluracil; abiraterone; aclarubicin; acylfulvene; adecypenol; adozelesin; aldesleukin; ALL-TK antagonists; altretamine; ambamustine; amidox; amifostine; aminolevulinic acid; amrubicin; amsacrine; anagrelide; anastrozole; andrographolide; angiogenesis inhibitors; antagonist D; antagonist G; antarelix; anti-dorsalizing morphogenetic protein-1; antiandrogen, prostatic carcinoma; antiestrogen; antineoplaston; antisense oligonucleotides; aphidicolin glycinate; apoptosis gene modulators; apoptosis regulators; apurinic acid; ara-CDP-DL-PTBA; arginine deaminase; asulacrine; atamestane; atrimustine; axinastatin 1; axinastatin 2; axinastatin 3; azasetron; azatoxin; azatyrosine; baccatin III derivatives; balanol; batimastat; BCR/ABL antagonists; benzochlorins; benzoylstaurosporine; beta lactam derivatives; beta-alethine; betaclamycin B; betulinic acid; bFGF inhibitor; bicalutamide; bisantrene; bisaziridinylspermine; bisnafide; bistratene A; bizelesin; breflate; bropirimine; budotitane; buthionine sulfoximine; calcipotriol; calphostin C; camptothecin derivatives; canarypox IL-2; capecitabine; carboxamide-amino- triazole; carboxyamidotriazole; CaRest M3; CARN 700; cartilage derived inhibitor; carzelesin; casein kinase inhibitors (ICOS); castanospermine; cecropin B; cetrorelix; chlorins; chloroquinoxaline sulfonamide; cicaprost; cis-porphyrin; cladribine; clomifene analogues; clotrimazole; collismycin A; collismycin B; combretastatin A4; combretastatin analogue; conagenin; crambescidin 816; crisnatol; cryptophycin 8; cryptophycin A derivatives; curacin A; cyclopentanthraquinones; cycloplatam; cypemycin; cytarabine ocfosfate; cytolytic factor; cytostatin; dacliximab; decitabine; dehydrodidemnin B; deslorelin; dexamethasone; dexifosfamide; dexrazoxane; dexverapamil; diaziquone; didemnin B; didox; diethylnorspermine; dihydro-5- azacytidine; dihydrotaxol, 9-; dioxamycin; diphenyl spiromustine; docetaxel; docosanol; dolasetron; doxifluridine; droloxifene; dronabinol; duocarmycin SA; ebselen;
ecomustine; edelfosine; edrecolomab; eflornithine; elemene; emitefur; epirubicin; epristeride; estramustine analogue; estrogen agonists; estrogen antagonists; etanidazole; etoposide phosphate; exemestane; fadrozole; fazarabine; fenretinide; filgrastim; finasteride; flavopiridol; flezelastine; fluasterone; fludarabine; fluorodaunorunicin hydrochloride; forfenimex; formestane; fostriecin; fotemustine; gadolinium texaphyrin; gallium nitrate; galocitabine; ganirelix; gelatinase inhibitors; gemcitabine; glutathione inhibitors; hepsulfam; heregulin; hexamethylene bisacetamide; hypericin; ibandronic acid; idarubicin; idoxifene; idramantone; ilmofosine; ilomastat; imidazoacridones; imiquimod; immunostimulant peptides; insulin-like growth factor-1 receptor inhibitor; interferon agonists; interferons; interleukins; iobenguane; iododoxorubicin; ipomeanol, 4; iroplact; irsogladine; isobengazole; isohomohalicondrin B; itasetron; jasplakinolide; kahalalide F; lamellarin-N triacetate; lanreotide; leinamycin; lenograstim; lentinan sulfate; leptolstatin; letrozole; leukemia inhibiting factor; leukocyte alpha interferon; leuprolide+estrogen+progesterone; leuprorelin; levamisole; liarozole; linear polyamine analogue; lipophilic disaccharide peptide; lipophilic platinum compounds; lissoclinamide 7; lobaplatin; lombricine; lometrexol; lonidamine; losoxantrone; lovastatin; loxoribine; lurtotecan; lutetium texaphyrin; lysofylline; lytic peptides; maitansine; mannostatin A; marimastat; masoprocol; maspin; matrilysin inhibitors; matrix metalloproteinase inhibitors; menogaril; merbarone; meterelin; methioninase; metoclopramide; MIF inhibitor; mifepristone; miltefosine; mirimostim; mismatched double stranded RNA; mitoguazone; mitolactol; mitomycin analogues; mitonafide; mitotoxin fibroblast growth factor-saporin; mitoxantrone; mofarotene; molgramostim; monoclonal antibody, human chorionic gonadotrophin; monophosphoryl lipid A+myobacterium cell wall sk; mopidamol; multiple drug resistance gene inhibitor; multiple tumor suppressor 1- based therapy; mustard anticancer agent; mycaperoxide B; mycobacterial cell wall extract; myriaporone; N-acetyldinaline; N-substituted benzamides; nafarelin; nagrestip; naloxone+pentazocine; napavin; naphterpin; nartograstim; nedaplatin; nemorubicin; neridronic acid; neutral endopeptidase; nilutamide; nisamycin; nitric oxide modulators; nitroxide antioxidant; nitrullyn; O6-benzylguanine; octreotide; okicenone; oligonucleotides; onapristone; ondansetron; ondansetron; oracin; oral cytokine inducer; ormaplatin; osaterone; oxaliplatin; oxaunomycin; paclitaxel; paclitaxel analogues; paclitaxel derivatives; palauamine; palmitoylrhizoxin; pamidronic acid; panaxytriol; panomifene; parabactin; pazelliptine; pegaspargase; peldesine; pentosan polysulfate sodium; pentostatin; pentrozole; perflubron;
perfosfamide; perillyl alcohol; phenazinomycin; phenylacetate; phosphatase inhibitors; picibanil; pilocarpine hydrochloride; pirarubicin; piritrexim; placetin A; placetin B; plasminogen activator inhibitor; platinum complex; platinum compounds; platinum-triamine complex; porfimer sodium; porfiromycin; prednisone; propyl bis-acridone; prostaglandin J2; proteasome inhibitors; protein A-based immune modulator; protein kinase C inhibitor; protein kinase C inhibitors, microalgal; protein tyrosine phosphatase inhibitors; purine nucleoside phosphorylase inhibitors; purpurins; pyrazoloacridine; pyridoxylated hemoglobin polyoxyethylene conjugate; raf antagonists; raltitrexed; ramosetron; ras farnesyl protein transferase inhibitors; ras inhibitors; ras-GAP inhibitor; retelliptine demethylated; rhenium Re 186 etidronate; rhizoxin; ribozymes; RII retinamide; rogletimide; rohitukine; romurtide; roquinimex; rubiginone B1; ruboxyl; safingol; saintopin; SarCNU; sarcophytol A; sargramostim; Sdi 1 mimetics; semustine; senescence derived inhibitor 1; sense oligonucleotides; signal transduction inhibitors; signal transduction modulators; single chain antigen binding protein; sizofuran; sobuzoxane; sodium borocaptate; sodium phenylacetate; solverol; somatomedin binding protein; sonermin; sparfosic acid; spicamycin D; spiromustine; splenopentin; spongistatin 1; squalamine; stem cell inhibitor; stem- cell division inhibitors; stipiamide; stromelysin inhibitors; sulfinosine; superactive vasoactive intestinal peptide antagonist; suradista; suramin; swainsonine; synthetic glycosaminoglycans; tallimustine; tamoxifen methiodide; tauromustine; tazarotene; tecogalan sodium; tegafur; tellurapyrylium; telomerase inhibitors; temoporfin; temozolomide; teniposide; tetrachlorodecaoxide; tetrazomine; thaliblastine; thiocoraline; thrombopoietin; thrombopoietin mimetic; thymalfasin; thymopoietin receptor agonist; thymotrinan; thyroid stimulating hormone; tin ethyl etiopurpurin; tirapazamine; titanocene bichloride; topsentin; toremifene; totipotent stem cell factor; translation inhibitors; tretinoin; triacetyluridine; triciribine; trimetrexate; triptorelin; tropisetron; turosteride; tyrosine kinase inhibitors; tyrphostins; UBC inhibitors; ubenimex; urogenital sinus-derived growth inhibitory factor; urokinase receptor antagonists; vapreotide; variolin B; vector system, erythrocyte gene therapy; velaresol; veramine; verdins; verteporfin; vinorelbine; vinxaltine; vitaxin; vorozole; zanoterone; zeniplatin; zilascorb; and zinostatin stimalamer. In one embodiment, the anti-cancer drug is 5-fluorouracil, taxol, or leucovorin. [0137] Anti-viral Agents [0138] The present disclosure contemplates compositions comprising at least one SCFA or compound comprising a SCFA moiety as described herein in combination with anti-viral agents.
Anti-viral agents include, but are not limited to, inhibitors of viral uncoating (e.g., amantadine and rimantidine), reverse transcriptase inhibitors (e.g., acyclovir, zidovudine, and lamivudine), agents that target integrase; agents that block attachment of transcription factors to viral DNA; agents (e.g., antisense molecules) that impact translation (e.g., fomivirsen); agents that modulate translation/ribozyme function; protease inhibitors; viral assembly modulators (e.g., rifampicin); antiretrovirals such as, for example, nucleoside analogue reverse transcriptase inhibitors (e.g., azidothymidine (AZT), ddl, ddC, 3TC, d4T); non-nucleoside reverse transcriptase inhibitors (e.g., efavirenz, nevirapine); nucleotide analogue reverse transcriptase inhibitors; and agents that prevent release of viral particles (e.g., zanamivir and oseltamivir), abacavir, adefovir, amantadine, amprenavir, ampligen, arbidol, atazanavir, atripla, boceprevirertet, cidofovir, combivir, darunavir, delavirdine, didanosine, docosanol, edoxudine, emtricitabine, enfuvirtide, entecavir, famciclovir, fosamprenavir, foscarnet, fosfonet, ganciclovir, ibacitabine, imunovir, idoxuridine, imiquimod, indinavir, inosine, various interferons (e.g., peginterferon alfa-2a), lopinavir, loviride, maraviroc, moroxydine, methisazone, nelfinavir, nexavir, penciclovir, peramivir, pleconaril, podophyllotoxin, raltegravir, ribavirin, ritonavir, pyramidine, saquinavir, stavudine, telaprevir, tenofovir, tipranavir, trifluridine, trizivir, tromantadine, truvada, valaciclovir, valganciclovir, vicriviroc, vidarabine, viramidine, and zalcitabine. [0139] Biologic Agents [0140] In one embodiment, the method comprises administering to a subject in need thereof a composition comprising at least one SCFA, or a biologically-active derivative or precursor thereof, in combination with one or more biologic drugs. Exemplary biologic drugs contemplated by the present disclosure include, but are not limited to, etanercept (Enbrel®), infliximab (Remicade®), apremilast (Otezla®), and adalimumab (Humira®). In one embodiment, the method comprises administering to a subject in need thereof a composition comprising at least one SCFA, or a biologically- active derivative or precursor thereof, and additionally one or more biologic agent. 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 biologic agent. [0141] Other Agents [0142] In one embodiment, the method comprises administering to a subject in need thereof a composition comprising at least one SCFA, or a biologically-active derivative or precursor
thereof, and additionally one or more additional therapeutic agents. In one embodiment, the method comprises administering to a subject in need thereof a composition comprising at least one SCFA, or a biologically-active derivative or precursor thereof, in combination with a composition comprising one or more additional therapeutic agents. Additional therapeutic agents that are contemplated for administration according to the methods of the disclosureinclude, but are not limited to, rofecoxib, celecoxib, folic acid, sulfasalazine, naproxen, leflunomide, methylprednisolone acetate, parenteral gold, oral gold, indomethacin, hydroxychloroquine, hydroxychloroquine sulfate, sulindac, prednisone, betamethasone diprop augmented, folate, triamcinolone acetonide, diclofenac, dimethylsulfoxide, piroxicam, diclofenac sodium, ketoprofen, meloxicam, methylprednisolone, nabumetone, tolmetin sodium, calcipotriene, cyclosporine, diclofenac, sodium/misoprostol, fluocinonide, glucosamine sulfate, gold sodium thiomalate, hydrocodone bitartrate/apap, risedronate sodium, sulfadiazine, thioguanine, valdecoxib, small molecule inhibitor of KDR (ABT-123), small molecule inhibitor of Tie-2, clobetasol propionate, triamcinolone acetonide, halobetasol propionate, tazarotene, fluocinonide, betamethasone diprop augmented, fluocinolone, acetonide, acitretin, tar shampoo, betamethasone valerate, mometasone furoate, ketoconazole, pramoxine/fluocinolone, 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, emollient, pimecrolimus emollient, fluocinonide/emollient, mineral oil/castor oil/na lact, mineral oil/peanut oil, petroleum/isopropyl myristate, psoralen, salicylic acid, soap/tribromsalan, thimerosal/boric acid, celecoxib, alefacept, efalizumab, tacrolimus, pimecrolimus, PUVA, UVB, sulfasalazine, alemtuzumab, dronabinol, Unimed, daclizumab, mitoxantrone, xaliproden hydrochloride, fampridine, glatiramer acetate, natalizumab, sinnabidol, a-immunokine NNSO3, ABR-215062, AnergiX.MS, chemokine receptor antagonists, BBR-2778, calagualine, CPI-1189, LEM (liposome encapsulated mitoxantrone), THC.CBD (cannabinoid agonist) MBP-8298, mesopram (PDE4 inhibitor), MNA-715, anti-IL-6 receptor antibody, neurovax, pirfenidone allotrap 1258 (RDP-1258), sTNF-R1, CDP571 (a humanized monoclonal anti-TNF-alpha IgG4 antibody), CDP 870 (a humanized monoclonal anti-TNF-alpha antibody fragment), an 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 in U.S. Pat. No.6,090,382 as D2E7). Additional TNF antibodies which can be used in the disclosure are described in U.S. Pat. Nos. 6,593,458; 6,498,237; 6,451,983; and 6,448,380, each of which is incorporated by reference herein, talampanel, teriflunomide, TGF-beta2, tiplimotide, VLA-4 antagonists (for example, 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, lampalizumab, fluocinolone acetatonide, macuCLEAR eyedrops, bone marrow CD34 stem cells, other stem cells, ranibizumab, brimonidine, LFG316, ORACEA®, emixustat hydrochloride, sirolimus, copaxone, othera eye drops, AL-78898A, and eculizumab. [0143] Administration [0144] Administration of the compositions of the present disclosure to a subject may be carried out using known procedures, at dosages and for periods of time effective for treating or preventing a disease or disorder in the subject. An effective amount of the therapeutic compound necessary to achieve a therapeutic effect may vary according to actors such as the state of the disease or disorder in the subject; the age, sex, and weight of the subject. [0145] The regimen of administration may affect what constitutes an effective amount. Further, the dosages of the compositions may be proportionally increased or decreased as indicated by the exigencies of the therapeutic or prophylactic situation. A non-limiting example of an effective dose range for a therapeutic compound of the disclosure is from about 1 to about 5,000 mg/kg of body weight/per day. The effective dose can be between 1mg to 10 mg active component/kg body weight/time, and can be 20 jig to 10 mg component/kg body weight/time. The therapeutic compound can be administered every 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, or 31 days. The number of doses for effective treatment can be 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more than 10. [0146] One of ordinary skill in the art would be able to study the relevant factors and make the determination regarding the effective amount of the therapeutic compound without undue experimentation. [0147] Actual dosage levels of the active ingredients in the pharmaceutical compositions of this disclosure may be varied so as 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 being toxic to the subject. In particular, the selected dosage level will depend upon a variety of factors including the activity of the particular compound employed, the time of administration, the rate of excretion of the compound, the duration of the treatment, other drugs, compounds or materials used in combination with the compound, the age, sex, weight, condition, general health and prior medical history of the subject being treated, and like factors well known in the medical arts. [0148] A medical doctor, e.g., physician or veterinarian, having ordinary skill in the art may readily determine and prescribe the effective amount of the pharmaceutical composition required. For example, the physician or veterinarian could start doses of the compounds of the disclosure employed in the pharmaceutical composition at levels lower than that required in order to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved. [0149] Compositions for administration may be in the range of from 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. [0150] In some embodiments, the dose of a compound of the disclosure is from about 1 mg and about 2,500 mg. In some embodiments, a dose of a compound of the disclosure used in 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 there between. [0151] In one embodiment, the treatment regimen comprises daily administration of a
composition. In one embodiment, a treatment regimen comprises administering a short chain fatty acid at least once daily for at least 1 day, at least 2 days, at least 3 days, at least 4 days, at least 5 days, at least 7 days, at least 10 days, at least 2 weeks, at least 3 weeks, at least 1 month, at least 2 months, at least 3 months, at least 6 months, at least 1 year or more than 1 year. In one embodiment, a treatment regimen comprises administering a short chain fatty acid three times daily for at least 1 day, at least 2 days, at least 3 days, at least 4 days, at least 5 days, at least 7 days, at least 10 days, at least 2 weeks, at least 3 weeks, at least 1 month, at least 2 months, at least 3 months, at least 6 months, at least 1 year or more than 1 year. In one embodiment, a treatment regimen comprises administering a composition comprising a short chain fatty acid, a short chain fatty acid precursor, a short chain fatty acid biosynthesis precursor, or a combination thereof at least once daily upon appearance of a disease or disorder. [0152] In one embodiment, a treatment regimen comprises daily oral administration of a short chain fatty acid. In one exemplary embodiment, 600 mg of butyrate is administered 3 times per day (a total of 1800 mg/day) for at least one week. In one embodiment, a treatment regimen comprises oral administration of two butyrate capsules containing 600 mg of butyrate 3 times per day (a total of 3600 mg/day) for at least one week. In one embodiment, a treatment regimen comprises oral administration of two butyrate capsules containing 600 mg of butyrate 3 times per day (a total of 3600 mg/day) for at least one week followed thereafter by oral administration of butyrate capsules containing 600 mg of butyrate 3 times per day (a total of 1800 mg/day) for at least one week. [0153] As described herein, administration of a composition to an individual makes it possible to induce tolerance, strengthen gut barrier integrity, and reduce inflammation in the individual. The method comprises administering to an individual a composition described herein. In some embodiments, the composition comprises one or more SCFAs or SCFA derivatives. The composition is administered to the individual in sufficient quantity to produce the desired effect of inducing tolerance, strengthening the gut barrier, and reducing inflammation. [0154] Whether administration of the composition induces tolerance can be determined by using, as an index, increase or reinforcement of at least one of the following: the number of regulatory T cells (Tregs), the ratio of Tregs in the T cell group of the colon, a function of Tregs, or expression of a marker of Tregs. A specific approach is measurement counts or percentage of Foxp3- expressing Tregs in a patient sample, such as a biopsy or a blood sample, promotion
(enhancement) of IL-10 expression, promotion (enhancement) of CTLA4 expression, promotion (enhancement) of IDO expression, or suppression of IL-4 expression as the index of the induction of proliferation or accumulation of regulatory T cells. Whether administration of the composition strengthens barrier function can be determined by using, as an index, increase in production of active form TGF-β and/or tight junction-related proteins by intestinal epithelial cells. Whether administration of the composition reduces inflammation can be determined by using, as an index, increase in production of anti-inflammatory cytokines such as IL-10 and/or TGF-.beta., or decrease in production of pro-inflammatory cytokines such as IL-4. [0155] In some embodiments, a disclosed herein modulates a cytokine. In some embodiments, the cytokine is a pro-inflammatory cytokine. Non-limiting examples of cytokines include: TNFα, IFNγ, IL-17A, IL-21, IL-22, IL-23, IL-27, IL-31, and MIP-3α. [0156] In some embodiments, short chain fatty acids (SCFAs) modulate multiple cellular signaling proteins, including, but not limited to, IL-18, TLR3, IFN-γ, TNFα, TGF-β, MyD88, PI3K/Akt, JAK/STAT, Smad 2/3, Smad 4, IL-10, Notch, hedgehog, Wnt (beta-catenin), matrix metalloproteinases 9 and 10, tissue inhibitor of metalloproteinases, nodal and NF-κB signaling. In some embodiments, the signaling proteins that are modulated by SCFAs modulate biological pathways or processes include, but are not limited to, inflammation, immunity, proliferation, differentiation, apoptosis, oncogenesis, transcription of DNA, cytokine production, cell survival, angiogenesis, fibrogenesis and cellular responses to stimuli such as stress, cytokines, free radicals, heavy metals, and ultraviolet irradiation. [0157] In some embodiments, a method disclosed herein comprises treating or reducing a likelihood of developing medical diseases or disorders characterized by elevated levels or abnormal 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, a method disclosed herein comprises treating or reducing a likelihood of developing medical diseases or disorders characterized by decreased levels or abnormal expression of NF-κB signaling. [0158] Methods for detecting such expression include northern blotting, RT-PCR, and dot blotting for detection of gene expression at the transcription level; ELISA, radioimmunoassays, immunoblotting, immunoprecipitation, and flow cytometry for detection of gene expression at the translation level. Samples that may be used for measuring such an index include tissues and
fluids obtained from an individual, such as blood, a biopsy, or a fecal sample. [0159] Combination with Additional Agents [0160] The present disclosure is also directed to a method of treating or preventing a disease or disorder as described above in combination with one or more additional agents. [0161] The combination can be in a single formulation or can be separate and administered in sequence (either a composition comprising at least one SCFA, or a molecule comprising a SCFA moiety, first and then a composition comprising an additional agent, or a composition comprising an additional agent first and then a composition comprising at least one SCFA, or a molecule comprising a SCFA moiety). In some embodiments, the at least one SCFA, or a molecule comprising a SCFA moiety, 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 hours, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, 18 hours, 19 hours, 20 hours, 21 hours, 22 hours, 23 hours, 24 hours, 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 before the composition comprising at least one additional agent is administered to the subject. In other embodiments, the composition comprising at least one additional agent 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 hours, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, 18 hours, 19 hours, 20 hours, 21 hours, 22 hours, 23 hours, 24 hours, 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 before the composition comprising at least one SCFA, or a molecule comprising a SCFA moiety, is administered to the
subject. [0162] In one embodiment, the disclosure provides a general concept for 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 disorder 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. [0163] In some embodiments, the immune response can be increased by about 0.5-fold to about 15-fold, about 0.5-fold to about 10-fold, or about 0.5-fold to about 8- fold. Alternatively, the immune response in the subject administered the combination of the at least one SCFA, or a molecule comprising a SCFA moiety, and 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, at least about 7.0-fold, at least about 7.5-fold, at least about 8.0-fold, at least about 8.5-fold, at least about 9.0-fold, at least about 9.5-fold, at least about 10.0-fold, at least about 10.5-fold, at least about 11.0-fold, at least about 11.5-fold, at least about 12.0-fold, at least about 12.5-fold, at least about 13.0-fold, at least about 13.5-fold, at least about 14.0-fold, at least about 14.5-fold, or at least about 15.0-fold. [0164] In still other alternative embodiments, the immune response in the subject administered the combination of the at least one SCFA, or a molecule comprising a SCFA moiety, and checkpoint inhibitor can be increased about 50% to about 1500%, about 50% to about 1000%, or about 50% to about 800%. In other embodiments, the immune response in the subject administered the combination of the at least one SCFA, or a molecule comprising a SCFA moiety, and 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%.
[0165] Immunotherapy [0166] In one embodiment, the disclosure provides a method for stimulating, eliciting or enhancing an immune response in a subject individual (individual) comprising administering to a subject an immunotherapeutic agent in combination with a composition comprising a SCFA or a compound comprising a SCFA moiety. In one embodiment, the subject may be at risk for having a disease, be diagnosed as having a disease, have previously been treated for a disease, or be contemporaneously be 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 partly based upon the discovery that administration of at least one short chain fatty acid (SCFA) can be effective as a therapeutic approach for the treatment or prevention of an adverse effect associated with immunotherapy of cancer. It is expected that the therapeutic effect of treatments using compositions comprising at least one SCFA will not interfere significantly with the benefits of the immunotherapy, but will treat or prevent undesired adverse effects associated with immunotherapy of cancer. Therefore, in one embodiment, the disclosure relates to compositions comprising at least one SCFA for use as a therapeutic for the treatment or prevention of adverse effects associated with immunotherapy of cancer. [0167] In one embodiment, the present disclosure provides methods for treatment, inhibition, prevention, or reduction of an adverse effect associated with cancer immunotherapy by administering a composition comprising a SCFA or a compound comprising a SCFA moiety, as disclosed herein, to a subject in need thereof, optionally in combination with at least one additional agent or therapy. Adverse effects associated with cancer immunotherapy that may be treated using the methods of the disclosure include, but are not limited to cytokine release syndrome (CRS), neurological toxicity, on- target/off-tumor recognition, anaphylaxis, graft versus host disease (GVHD), off-target antigen recognition, and macrophage activation syndrome (MAS). In one embodiment, the present disclosure provides methods for treatment, inhibition, prevention, or reduction of a disease associated with an adverse effect associated with cancer immunotherapy, comprising administering a composition comprising at least one SCFA or compound comprising a SCFA moiety, as disclosed herein, to a subject in need thereof. In one embodiment, the adverse effect includes a combination of adverse effects. [0168] In one embodiment, a subject suffering from adverse effects associated with immunotherapy of cancer is a human. In one embodiment, a subject suffering from adverse effects
associated with immunotherapy of cancer is a non-human animal. [0169] In one embodiment, to stimulate an immune response, the subject individual is administered (i) at least one SCFA or compound comprising a SCFA moiety, and (ii) at least one immunotherapeutic agent. Typically, the administration of at least one SCFA or compound comprising a SCFA moiety and the immunotherapeutic agent will be in the form of a vaccine or administered in a vaccine regimen. The at least one SCFA or compound comprising a SCFA moiety and the immunotherapeutic agent can be administered at about the same time to the subject individual, or can be administered separately and/or sequentially. [0170] Immunotherapeutic agents that may be administered according to the methods of the disclosure include, but are not limited to, one or more cancer antigens, one or more antigens derived from a virus associated with cancer, and an anti-cancer antibody. [0171] A cancer antigen may be (a) a cell surface antigen that can be found on a malignant cell, (b) an antigen that can be found inside a malignant cell or (c) a mediator of tumor cell growth. The term “cancer antigen” refers to (i) tumor-specific antigens, (ii) tumor-associated antigens, (iii) cells that express tumor-specific antigens, (iv) cells that express 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 material that is associated with a cancer. [0172] The cancer antigen can be a cell, a protein, a peptide, a fusion protein, DNA encoding a peptide or protein, RNA encoding a peptide or protein, a glycoprotein, a lipoprotein, a phosphoprotein, a carbohydrate, a lipopolysaccharide, a lipid, a chemically linked combination of two or more thereof, a fusion or two or more thereof, or a mixture of two or more thereof. In another embodiment, the cancer antigen is a peptide comprising about 6 to about 24 amino acids; from about 8 to about 20 amino acids; from about 8 to about 12 amino acids; from about 8 to about 10 amino acids; or from about 12 to about 20 amino acids. In one embodiment, the cancer antigen is a peptide having a MHC Class I binding motif or a MHC Class II binding motif. In another embodiment, the cancer antigen comprises a peptide that corresponds to one or more cytotoxic T lymphocyte (CTL) epitopes. [0173] In one embodiment, the present disclosure provides methods for treatment, inhibition, prevention, or reduction of an adverse effect associated with cancer immunotherapy by
administering a composition comprising a SCFA or a compound comprising a SCFA moiety, as disclosed herein, to a subject in need thereof, optionally in combination with at least one immunotherapeutic agent. [0174] In one embodiment, the immunotherapy is chimeric antigen receptor T-cell (CAR-T) therapy. In some embodiments, a composition is administered before, during, or after CAR-T therapy for the treatment of cancer, for the treatment or prevention of at least one adverse effect associated with CAR-T therapy. Particular adverse effects treatable and/or preventable by compositions of the present disclosure include, but are not limited to: cytokine release syndrome (CRS), neurological toxicity, on-target/off-tumor recognition, anaphylaxis, graft versus host disease (GVHD), off-target antigen recognition, and macrophage activation syndrome (MAS). Existing or developing treatment or prevention of these adverse effects include pharmacological immunosuppression (i.e., IL-6R blockade, systemic corticosteroids such as dexamethasone, monoclonal antibodies, lymphodepleting chemotherapy with agents such as cyclophosphamide), suicide genes or elimination genes (i.e., killing of CAR-T cells), and targeted activation (i.e., conditional activation of CAR-T cells with a drug or another agent). Therefore, in one embodiment, the treatment compositions of the present disclosure are combined with at least one other strategy to reduce, prevent, treat, or ameliorate one or more adverse effects associated with immunotherapy of cancer. In one embodiment, the disclosure provides a composition for treating or preventing the onset of an adverse effect associated with immunotherapy of cancer. In one embodiment, the composition comprises at least one SCFA or a compound comprising a SCFA moiety. In one embodiment, the immunotherapy comprises CAR-T therapy. In another embodiment, the immunotherapy comprises a therapy involving at least one other anti-cancer composition. In some embodiments, a composition is administered before, during, or after chemotherapy for the treatment of cancer. [0175] In one embodiment, the composition comprising at least one SCFA is administered in parallel to chemotherapy: several days before CAR-T cell infusion (only SCFAs), and up to several weeks after CAR-T cell infusion (SCFAs in combination with chemotherapeutic agents at reduced levels relative to a subject undergoing chemotherapy alone). [0176] Pharmaceutical Compositions [0177] The present disclosure includes pharmaceutical compositions comprising one or more compositions of the present disclosure. The formulations of the pharmaceutical compositions
described herein may be prepared by any method known or hereafter developed in the art of pharmacology. In general, such preparatory methods include the step of bringing the active ingredient into association with a carrier or one or more other accessory ingredients, and then, if necessary or desirable, shaping or packaging the product into a desired single- or multi-dose unit. [0178] Said compositions may comprise additional medicinal agents, pharmaceutical agents, carriers, buffers, adjuvants, dispersing agents, diluents, and the like depending on the intended use and application. [0179] Non-limiting examples of suitable pharmaceutical carriers, excipients and/or diluents include: a gum, a starch (e g. corn starch, pre-gelatinized starch), a sugar (e.g., lactose, mannitol, sucrose, dextrose), a cellulosic material (e.g. microcrystalline cellulose), an acrylate (e.g. polymethylacrylate), calcium carbonate, magnesium oxide, talc, or mixtures thereof. [0180] Pharmaceutically acceptable carriers for liquid formulations are aqueous or non-aqueous solutions, suspensions, emulsions or oils, Examples of non-aqueous solvents are propylene glycol, polyethylene glycol, and injectable organic esters such as ethyl oleate. Examples of oils are those of animal, vegetable, or synthetic origin, for example, peanut oil, soybean oil, olive oil, sunflower oil, turmeric oil, fish-liver oil, another marine oil, or a lipid from milk or eggs. [0181] Aqueous carriers include water, alcoholic/aqueous 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 formulated by well- known conventional methods. Suitable carriers may comprise any material which, when combined with the biologically active compound of the disclosure, retains the biological activity. Preparations for parenteral administration may include sterile aqueous or non-aqueous solutions, suspensions, and emulsions. Examples of non-aqueous solvents are propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate. Aqueous carriers include water, alcoholic/aqueous solutions, emulsions or suspensions, including saline and buffered media. Parenteral vehicles may include sodium chloride solution, Ringer's dextrose, dextrose and sodium chloride, lactated Ringer's, or fixed oils. Intravenous vehicles may include fluid and nutrient replenishes, electrolyte replenishers (such as those based on Ringer's dextrose), and the like. Preservatives and other additives may also be present including, for example, antimicrobials, anti-oxidants, chelating agents, and inert gases and the like, in addition, the
pharmaceutical composition of the present disclosure might comprise proteinaceous carriers, like, e.g., serum albumin or immunoglobulin. [0182] The pharmaceutical compositions provided herein may also be administered as controlled- release compositions, i.e. compositions in which the active ingredient is released over a period of time after administration. Controlled- or sustained-release compositions include formulation in lipophilic depots (e.g. fatty acids, waxes, oils). In another embodiment, the composition is an immediate-release composition, i.e. a composition in which all the active ingredient is released immediately after administration. [0183] Further, the pharmaceutical compositions according to the disclosure and as described herein in the various embodiments may or a composition comprising said compound may be administered admixed to food, functional food, drinks, medicinal food. [0184] Although the description of pharmaceutical compositions provided herein are principally directed to pharmaceutical compositions which are suitable for ethical administration to humans, it will be understood by the skilled artisan that such compositions are generally suitable for administration to animals of all sorts. Modification of pharmaceutical compositions suitable for administration to humans in order to render the compositions suitable for administration to various animals is well understood, and the ordinarily skilled veterinary pharmacologist can design and perform such modification with merely ordinary, if any, experimentation. Subjects to which administration of the pharmaceutical compositions are contemplated 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-mammalian animals, and other veterinary applications. [0185] Pharmaceutical compositions that are useful in the methods of the disclosure may be prepared, packaged, or sold in formulations suitable for ophthalmic, oral, rectal, vaginal, parenteral, topical, pulmonary, intranasal, buccal, intratumoral, epidural, intracerebral, intracerebroventricular, or another route of administration. Other contemplated formulations include projected nanoparticles, liposomal preparations, resealed erythrocytes containing the active ingredient, and immunologically-based formulations. [0186] A pharmaceutical composition may be prepared, packaged, or sold in bulk, as a single unit dose, or as a plurality of single unit doses. As used herein, a “unit dose” is discrete amount of the pharmaceutical composition comprising a predetermined amount of the active ingredient. The
amount of the active ingredient is generally equal to the dosage of the active ingredient which would be administered to a subject or a convenient fraction of such a dosage such as, for example, one-half or one-third of such a dosage. [0187] The relative amounts of the active ingredient, the pharmaceutically acceptable carrier, and any additional ingredients in a pharmaceutical composition will vary, depending upon the identity, size, and condition of the subject treated and further depending upon the route by which the composition is to be administered. By way of example, the composition may comprise between 0.1% and 100% (w/w) active ingredient. [0188] In addition to the active ingredient, a pharmaceutical composition may further comprise one or more additional pharmaceutically active agents. [0189] Controlled- or sustained-release formulations of a pharmaceutical composition may be made using conventional technology. [0190] Pharmaceutical compositions also include nutritional compositions, such as oral nutritional compositions for oral consumption and optionally for enteral adsorption, wherein the nutritional composition includes the compounds of the present disclosure. Therefore, in one embodiment, the disclosure relates to nutraceutical compositions. [0191] If the nutritional compositions are formulated to be administered orally, the compositions may be a liquid oral nutritional supplement (e.g., incomplete feeding) or a complete feeding. In this manner, the nutritional compositions may be administered in any known form including, for example, tablets, capsules, liquids, chewables, soft gels, sachets, powders, syrups, liquid suspensions, emulsions, infant formulas and solutions in convenient dosage forms. [0192] A nutritional formula encompasses any nutritionally complete or supplementary formulation (a nutritional supplement, for example). As used herein, “nutritionally complete” are preferably nutritional products that contain sufficient types and levels of macronutrients (protein, fats and carbohydrates) and micronutrients to be sufficient to be a sole source of nutrition for the subject to which it is being administered to. Patients can receive 100% of their nutritional requirements from such complete nutritional compositions. According to one embodiment, the nutritional formula is a supplementary formulation providing supplementary nutrition. A “supplementary formula” may not be nutritionally complete, but preferably contains specific nutrients that are supportive, for example in combination with physical exercise, with further of the beneficial effects of the disclosure, and/or which address specific or additional needs of the
subject. [0193] The nutritional formula may be a generally applicable nutritional formula, for example adapted to subjects of a specific age, for example a formula for children, but it may also be a formula for elderly patients, for intensive care patients, or a specially adapted formula for patients suffering from a specific disease, for example. Any nutritional formula may be reconstitutable, that is, present in a substantially dried, for example powdered form, or ready-to- drink, in the form of liquid formulas, for example. Formulations of a pharmaceutical composition suitable for parenteral administration comprise the active ingredient combined with a pharmaceutically acceptable carrier, such as sterile water or sterile isotonic saline. Such formulations may be prepared, packaged, or sold in a form suitable for bolus administration or for continuous administration. Injectable formulations may be prepared, packaged, or sold in unit dosage form, such as in ampules or in multi dose containers containing a preservative. Formulations for parenteral administration include, but are not limited to, suspensions, solutions, emulsions in oily or aqueous vehicles, pastes, and implantable sustained-release or biodegradable formulations. Such formulations may further comprise one or more additional ingredients including, but not limited to, suspending, stabilizing, or dispersing agents. In one embodiment of a formulation for parenteral administration, the active ingredient is provided in dry (i.e., powder or granular) form for reconstitution with a suitable vehicle (e.g., sterile pyrogen free water) prior to parenteral administration of the reconstituted composition. [0194] The pharmaceutical compositions may be prepared, packaged, or sold in the form of a sterile injectable aqueous or oily suspension or solution. This suspension or solution may be formulated according to the known art, and may comprise, in addition to the active ingredient, additional ingredients such as the dispersing agents, wetting agents, or suspending agents described herein. Such sterile injectable formulations may be prepared using a non-toxic parenterally acceptable diluent or solvent, such as water or 1,3 butane diol, for example. Other acceptable diluents and solvents include, but are not limited to, Ringer's solution, isotonic sodium chloride solution, and fixed oils such as synthetic mono or di-glycerides. Other parentally-administrable formulations which are useful include those which comprise the active ingredient in microcrystalline form, in a liposomal preparation, or as a component of a biodegradable polymer system. Compositions for sustained release or implantation may comprise pharmaceutically acceptable polymeric or hydrophobic materials such as an emulsion,
an ion exchange resin, a sparingly soluble polymer, or a sparingly soluble salt. [0195] The compositions of the present disclosure as described herein may be used as a complete food product, as a component of a food product, as a dietary supplement or as part of a dietary supplement, as a feed additive and may be either in liquid, semisolid or solid form. The compositions of the present disclosure as described herein additionally may be in the form of a pharmaceutical composition. The compositions, dietary supplements, food products, baby food products, feed additives, and/or pharmaceutical compositions of the present disclosure may advantageously be utilized in methods for promoting the health of an individual. [0196] As indicated above, the compositions may be in liquid, semisolid or solid form. For example, the compositions may be administered as tablets, gel packs, capsules, gelatin capsules, flavored drinks, as a powder that can be reconstituted into such a drink, cooking oil, salad oil or dressing, sauce, syrup, mayonnaise, margarine or the like. Furthermore, the food product, dietary supplements, and the like, of the present disclosure can include, but are not limited to, dairy products, baby food, baby formula, beverages, bars, a powder, a food topping, a drink, a cereal, an ice cream, a candy, a snack mix, a baked food product and a fried food product. Beverages of the disclosure include but are not limited to energy drinks, nutraceutical drinks, smoothies, sports drinks, orange juice and other fruit drinks. A bar of the present disclosure includes, but is not limited to, a meal replacement, a nutritional bar, a snack bar and an energy bar, an extruded bar, and the like. Dairy products of the disclosure include, but are not limited to, including but not limited to yogurt, yogurt drinks, cheese and milk. [0197] The food products or dietary supplements of the present disclosure may further comprise herbals, herbal extracts, fungal extracts, enzymes, fiber sources, minerals, and vitamins. The microalgal oils and microalgal biomass of the present disclosure may be used in the compositions for both therapeutic and non-therapeutic uses. Thus, the compositions, food products and animal feed additives of the present disclosure may be used for therapeutic or non-therapeutic purposes. [0198] Compositions intended for oral administration may be prepared according to any known method for the manufacture of dietary supplements or pharmaceutical preparations, and such compositions may include at least one additive selected from the group consisting of taste improving substances, such as sweetening agents or flavoring agents, stabilizers, emulsifiers, coloring agents and preserving agents in order to provide a dietetically or pharmaceutically palatable preparation. Vitamins, minerals and trace element from any physiologically acceptable
source may also be included in the composition. [0199] A pharmaceutical composition of the present disclosure comprises the said compositions of the present disclosure in a therapeutically effective amount. The compositions may additionally comprise prescription medicines or non-prescription medicines. The combinations may advantageously produce one or more of the following effects: (1) additive and/or synergistic benefits; (2) reduction of the side effects and/or adverse effects associated with use of the prescription medicine in the absence of the said formulations; and/or (3) the ability to lower the dosage of the prescription medicine in comparison to the amount of prescription medicine needed in the absence of the said formulations. [0200] The active agents of the present disclosure can be prepared in the form of their pharmaceutically acceptable salts. As understood by one of skill in the art, pharmaceutically acceptable salts are salts that retain the desired biological activity of the parent compound and do not impart undesired toxicological effects. “Pharmaceutically acceptable salts” as defined herein include derivatives of the disclosed SCFA or compound comprising a SCFA moiety, wherein the parent compound is modified by making non-toxic salts of the carboxylate group thereof, and further refers 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, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxylmaleic, phenylacetic, glutamic, benzoic, salicylic, mesylic, esylic, besylic, sulfanilic, 2- acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, HOOC--(CH2)n--COOH where n is 0-4, and the like. Lists of additional suitable salts may be found, e.g., in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., p.1418 (1985). In some embodiments the SCFA can be present as an ester of the SCFA's carboxylic acid with a branched or unbranched alkyl alcohol of one to 6 carbons. For example, the SCFA can be present as an ethyl ester, propyl ester, butyl ester, isopropyl ester, t- butyl ester, pentyl ester, or hexyl ester. The active agents can be formulated for administration in accordance with known pharmacy techniques. See, e.g., Remington, The Science And Practice of Pharmacy (9th Ed.1995). In the manufacture of a pharmaceutical composition according to the
present disclosure, the active agents (including the physiologically acceptable salts thereof) is typically admixed with, inter alia, an acceptable carrier. The carrier must, of course, be acceptable in the sense of being compatible with any other ingredients in the formulation and must not be deleterious to the subject. The carrier can be a solid or a liquid, or both, and can be formulated with the active agent as a unit-dose formulation, for example, a tablet, which can contain from 0.01% or 0.5% to 95% or 99%, or any value between 0.01% and 99%, by weight of the active agent. One or more active agents can be incorporated in the compositions, which can be prepared by any of the well-known techniques of pharmacy, comprising admixing the components, optionally including one or more accessory ingredients. Moreover, the carrier can be preservative free, as described herein above. [0201] In some embodiments, the active agents comprise a lower limit ranging from about 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10% to an upper limit ranging from about 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99 and 100% by weight of the composition. In some embodiments, the active agent includes from about 0.05% to about greater than 99% by weight of the composition. [0202] The pharmaceutical compositions according to embodiments of the present disclosure are generally formulated for oral or topical (i.e., skin, ocular and mucosal surfaces) administration, with the most suitable route in any given case depending on the nature and severity of the condition being treated and on the nature of the particular active agent which is being used. [0203] Topical Formulations [0204] The compositions of the present disclosure and the pharmaceutical compositions containing said compounds, may be administered topically, and thus be formulated in a form suitable for topical administration, i.e. as a pH balanced cream preparation. An obstacle for topical administration of pharmaceuticals is the stratum corneum layer of the epidermis. The stratum corneum is a highly resistant layer comprised of protein, cholesterol, sphingolipids, free fatty acids and various other lipids, and includes cornified and living cells. One of the factors that limit the penetration rate (flux) of a compound through the stratum corneum is the amount of the active substance that can be loaded or applied onto the skin surface. The greater the amount of
active substance which is applied per unit of area of the skin, the greater the concentration gradient between the skin surface and the lower layers of the skin, and in turn the greater the diffusion force of the active substance through the skin. Therefore, a formulation containing a greater concentration of the active substance is more likely to result in penetration of the active substance through the skin, and more of it, and at a more consistent rate, than a formulation having a lesser concentration, all other things being equal. [0205] Formulations suitable for topical administration include, but are not limited to, liquid or semi liquid preparations such as liniments, lotions, oil in water or water in oil emulsions such as creams, ointments or pastes, and solutions or suspensions. Further, formulations suitable for topical administration can be in the form of cremes and liquids including, for example, syrups, suspensions or emulsions, inhalants, sprays, mousses, oils, gels, solids and the like. Topically administrable formulations may, for example, comprise from about 1% to about 10% (w/w) active ingredient, although the concentration of the active ingredient may be as high as the solubility limit of the active ingredient in the solvent. Formulations for topical administration may further comprise one or more of the additional ingredients described herein. [0206] Enhancers of permeation may be used. These materials increase the rate of penetration of drugs across the skin. Typical enhancers in the art include ethanol, glycerol monolaurate, PGML (polyethylene glycol monolaurate), dimethylsulfoxide, and the like. Other enhancers include oleic acid, oleyl alcohol, ethoxydiglycol, laurocapram, alkanecarboxylic acids, dimethylsulfoxide, polar lipids, or N-methyl-2-pyrrolidone. One acceptable vehicle for topical delivery of some of the compositions may contain liposomes. The composition of the liposomes and their use are known in the art (for example, see U.S. Patent No.6,323,219). [0207] In alternative embodiments, the topically active pharmaceutical composition may be optionally combined with other ingredients such as adjuvants, anti-oxidants, chelating agents, surfactants, foaming agents, wetting agents, emulsifying agents, viscosifiers, buffering agents, preservatives, and the like. In another embodiment, a permeation or penetration enhancer is included in the composition and is effective in improving the percutaneous penetration of the active ingredient into and through the stratum corneum with respect to a composition lacking the permeation enhancer. Various permeation enhancers, including oleic acid, oleyl alcohol, ethoxydiglycol, laurocapram, alkanecarboxylic acids, dimethylsulfoxide, polar lipids, or N- methyl-2-pyrrolidone, are known to those of skill in the art. In another aspect, the composition
may further comprise a hydrotropic agent, which functions to increase disorder in the structure of the stratum corneum, and thus allows increased transport across the stratum corneum. Various hydrotropic agents, such as isopropyl alcohol, propylene glycol, or sodium xylene sulfonate, are known to those of skill in the art. [0208] The topically active pharmaceutical composition should be applied in an amount effective to affect desired changes. As used herein “amount effective” shall mean an amount sufficient to cover the region of skin surface where a change is desired. In various embodiments, an active compound may be present in the amount of from about 0.0001% to about 15% by weight volume of the composition, from about 0.0005% to about 5% of the composition, or from about 0.001% to about 1% of the composition. Such compounds may be synthetically-or naturally derived. [0209] Oral Formulations [0210] The compositions of the present disclosure and the pharmaceutical compositions containing said compounds, may be administered orally, and thus be formulated in a form suitable for oral administration, i.e. as a solid or a liquid preparation. Suitable solid oral formulations include tablets, capsules, pills, granules, pellets and the like. Suitable liquid oral formulations include solutions, suspensions, dispersions, emulsions, oils and the like. If formulated in form of a capsule, the compositions of the present disclosure comprise, in addition to the active compound and the inert carrier or diluent, a hard gelating capsule. In one embodiment, a formulation for oral administration is an enteric coated, time release capsule. [0211] Formulations suitable for oral administration can be presented in discrete units, such as capsules, cachets, lozenges, or tablets, each containing a predetemined amount of the active compound; as a powder or granules; as a solution or a suspension in an aqueous or non-aqueous liquid; or as an oil-in-water or water-in-oil emulsion. Such formulations can be prepared by any suitable method of pharmacy, which includes bringing into association the active compound and a suitable carrier (which can contain one or more accessory ingredients as noted above). In general, the formulations of the disclosure are prepared by uniformly and intimately admixing the active compound with a liquid or finely divided solid carrier, or both, and then, if necessary, shaping the resulting mixture. For example, a tablet can be prepared by compressing or molding a powder or granules containing the active compound, optionally with one or more accessory ingredients. Compressed tablets can be prepared by compressing, in a suitable machine, the compound in a free-flowing form, such as a powder or granules optionally mixed with a binder,
lubricant, inert diluent, and/or surface active/dispersing agent(s). Molded tablets can be made by molding, in a suitable machine, the powdered compound moistened with an inert liquid binder. [0212] Formulations for Other Routes of Administration [0213] The compositions of the present disclosure and the pharmaceutical compositions containing said compounds may be further administered intranasally, i.e. by inhalation and thus may be formulated in a form suitable for intranasal administration, i.e. as an aerosol or a liquid preparation. [0214] The compositions of the present disclosure may also, for example, be formulated for parenteral administration. Formulations of a pharmaceutical composition suitable for parenteral administration comprise the active ingredient combined with a pharmaceutically acceptable carrier, such as sterile water or sterile isotonic saline. Such formulations may be prepared, packaged, or sold in a form suitable for bolus administration or for continuous administration. Injectable formulations may be prepared, packaged, or sold in unit dosage form, such as in ampules or in multi dose containers containing a preservative. Formulations for parenteral administration include, but are not limited to, suspensions, solutions, emulsions in oily or aqueous vehicles, pastes, and implantable sustained-release or biodegradable formulations. Such formulations may further comprise one or more additional ingredients including, but not limited to, suspending, stabilizing, or dispersing agents. In one embodiment of a formulation for parenteral administration, the active ingredient is provided in dry (i.e., powder or granular) form for reconstitution with a suitable vehicle (e.g., sterile pyrogen free water) prior to parenteral administration of the reconstituted composition. [0215] The pharmaceutical compositions may be prepared, packaged, or sold in the form of a sterile injectable aqueous or oily suspension or solution. This suspension or solution may be formulated according to the known art, and may comprise, in addition to the active ingredient, additional ingredients such as the dispersing agents, wetting agents, or suspending agents described herein. Such sterile injectable formulations may be prepared using a non-toxic parenterally acceptable diluent or solvent, such as water or 1,3 butane diol, for example. Other acceptable diluents and solvents include, but are not limited to, Ringer's solution, isotonic sodium chloride solution, and fixed oils such as synthetic mono or di-glycerides. Other parentally-administrable formulations which are useful include those which comprise the active ingredient in microcrystalline form, in a liposomal preparation, or as a component of a
biodegradable polymer system. Compositions for sustained release or implantation may comprise pharmaceutically acceptable polymeric or hydrophobic materials such as an emulsion, an ion exchange resin, a sparingly soluble polymer, or a sparingly soluble salt. Formulations are prepared using a pharmaceutically acceptable “carrier” composed of materials that are considered safe and effective and may be administered to an individual without causing undesirable biological side effects or unwanted interactions. The “carrier” is all components present in the pharmaceutical formulation other than the active ingredient or ingredients. The term “carrier” includes but is not limited to diluents, binders, lubricants, desintegrators, fillers, and coating compositions. [0216] “Carrier” also includes all components of the coating composition which may include plasticizers, pigments, colorants, stabilizing agents, and glidants. The delayed release dosage formulations may be prepared as described in references such as “Pharmaceutical dosage form tablets”, eds. Liberman et. al. (New York, Marcel Dekker, Inc., 1989), “Remington--The science and practice of pharmacy”, 20th ed., Lippincott Williams & Wilkins, Baltimore, Md., 2000, and “Pharmaceutical dosage forms and drug delivery systems”, 6th Edition, Ansel et. al., (Media, Pa.: Williams and Wilkins, 1995) which provides information on carriers, materials, equipment and process for preparing tablets and capsules and delayed release dosage forms of tablets, capsules, and granules. [0217] Examples of suitable coating materials include, but are not limited to, cellulose polymers such as cellulose acetate phthalate, hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose phthalate and hydroxypropyl methylcellulose acetate succinate; polyvinyl acetate phthalate, acrylic acid polymers and copolymers, and methacrylic resins that are commercially available under the trade name Eudragit® (Roth Pharma, Westerstadt, Germany), Zein, shellac, and polysaccharides. [0218] Additionally, the coating material may contain conventional carriers such as plasticizers, pigments, colorants, glidants, stabilization agents, pore formers and surfactants. [0219] Optional pharmaceutically acceptable excipients present in the drug-containing tablets, beads, granules or particles include, but are not limited to, diluents, binders, lubricants, disintegrants, colorants, stabilizers, and surfactants. Diluents, also termed “fillers,” are typically necessary to increase the bulk of a solid dosage form so that a practical size is provided for compression of tablets or formation of beads and granules. Suitable diluents include, but are not
limited to, dicalcium phosphate dihydrate, calcium sulfate, lactose, sucrose, mannitol, sorbitol, cellulose, microcrystalline cellulose, kaolin, sodium chloride, dry starch, hydrolyzed starches, pregelatinized starch, silicone dioxide, titanium oxide, magnesium aluminum silicate and powder sugar. [0220] Binders are used to impart cohesive qualities to a solid dosage formulation, and thus ensure that a tablet or bead or granule remains intact after the formation of the dosage forms. Suitable binder materials include, but are not limited to, starch, pregelatinized starch, gelatin, sugars (including sucrose, glucose, dextrose, lactose and sorbitol), polyethylene glycol, waxes, natural and synthetic gums such as acacia, tragacanth, sodium alginate, cellulose, including hydroxypropylmethylcellulose, hydroxypropylcellulose, ethylcellulose, and veegum, and synthetic polymers such as acrylic acid and methacrylic acid copolymers, methacrylic acid copolymers, methyl methacrylate copolymers, aminoalkyl methacrylate copolymers, polyacrylic acid/polymethacrylic acid and polyvinylpyrrolidone. [0221] Lubricants are used to facilitate tablet manufacture. Examples of suitable lubricants include, but are not limited to, magnesium stearate, calcium stearate, stearic acid, glycerol behenate, polyethylene glycol, talc, and mineral oil. [0222] Disintegrants are used to facilitate dosage form disintegration or “breakup” after administration, and generally include, but are not limited to, starch, sodium starch glycolate, sodium carboxymethyl starch, sodium carboxymethylcellulose, hydroxypropyl cellulose, pregelatinized starch, clays, cellulose, alginine, gums or cross linked polymers, such as cross- linked PVP (Polyplasdone XL from GAF Chemical Corp). [0223] Stabilizers are used to inhibit or retard drug decomposition reactions which include, by way of example, oxidative reactions. [0224] Surfactants may be anionic, cationic, amphoteric or nonionic surface active agents. Suitable anionic surfactants include, but are not limited to, those containing carboxylate, sulfonate and sulfate ions. Examples of anionic surfactants include sodium, potassium, ammonium of long chain alkyl sulfonates and alkyl aryl sulfonates such as sodium dodecylbenzene sulfonate; dialkyl sodium sulfosuccinates, such as sodium dodecylbenzene sulfonate; dialkyl sodium sulfosuccinates, such as sodium bis-(2-ethylthioxyl)-sulfosuccinate; and alkyl sulfates such as sodium lauryl sulfate. Cationic surfactants include, but are not limited to, quaternary ammonium compounds such as benzalkonium chloride, benzethonium chloride,
cetrimonium bromide, stearyl dimethylbenzyl 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, polysorbates, polyoxyethylene octylphenylether, PEG-1000 cetyl ether, polyoxyethylene tridecyl ether, polypropylene glycol butyl ether, Poloxamer® 401, stearoyl monoisopropanolamide, and polyoxyethylene hydrogenated tallow amide. Examples of amphoteric surfactants include sodium N-dodecyl-beta-alanine, sodium N-lauryl-beta-iminodipropionate, myristoamphoacetate, lauryl betaine and lauryl sulfobetaine. [0225] If desired, the tablets, beads granules or particles may also contain minor amount of nontoxic auxiliary substances such as wetting or emulsifying agents, dyes, pH buffering agents, and preservatives. [0226] As will be appreciated by those skilled in the art and as described in the pertinent texts and literature, a number of methods are available for preparing drug- containing tablets, beads, granules or particles that provide a variety of drug release profiles. Such methods include, but are not limited to, the following: coating a drug or drug-containing composition with an appropriate coating material, typically although not necessarily incorporating a polymeric material, increasing drug particle size, placing the drug within a matrix, and forming complexes of the drug with a suitable complexing agent. [0227] The delayed release dosage units may be coated with the delayed release polymer coating using conventional techniques, e.g., using a conventional coating pan, an airless spray technique, fluidized bed coating equipment (with or without a Wurster insert), or the like. For detailed information concerning materials, equipment and processes for preparing tablets and delayed release dosage forms, see Pharmaceutical Dosage Forms: Tablets, eds. Lieberman et al. (New York: Marcel Dekker, Inc., 1989), and Ansel et al., Pharmaceutical Dosage Forms and Drug Delivery Systems, 6th Ed. (Media, Pa.: Williams & Wilkins, 1995). [0228] An exemplary method for preparing extended release tablets is by compressing a drug- containing blend, e.g., blend of granules, prepared using a direct blend, wet-granulation, or dry- granulation process. Extended release tablets may also be molded rather than compressed, starting with a moist material containing a suitable water-soluble lubricant. However, tablets are manufactured using compression rather than molding. A method for forming extended release
drug-containing blend is to mix drug particles directly with one or more excipients such as diluents (or fillers), binders, disintegrants, lubricants, glidants, and colorants. As an alternative to direct blending, a drug-containing blend may be prepared by using wet-granulation or dry- granulation processes. Beads containing the active agent may also be prepared by any one of a number of conventional techniques, typically starting from a fluid dispersion. For example, a typical method for preparing drug-containing beads involves dispersing or dissolving the active agent in a coating suspension or solution containing pharmaceutical excipients such as polyvinylpyrrolidone, methylcellulose, talc, metallic stearates, silicone dioxide, plasticizers or the like. The admixture is used to coat a bead core such as a sugar sphere (or so-called “non-pareil”) having a size of approximately 60 to 20 mesh. [0229] An alternative procedure for preparing drug beads is by blending drug with one or more pharmaceutically acceptable excipients, such as microcrystalline cellulose, lactose, cellulose, polyvinyl pyrrolidone, talc, magnesium stearate, a disintegrant, etc., extruding the blend, spheronizing the extrudate, drying and optionally coating to form the immediate release beads. [0230] Delayed release formulations are created by coating a solid dosage form with a film of a polymer which is insoluble in the acid environment of the stomach, and soluble in the neutral environment of small intestines. The delayed release dosage units can be prepared, for example, by coating a drug or a drug-containing composition with a selected coating material. The drug-containing composition may be, e.g., a tablet for incorporation into a capsule, a tablet for use as an inner core in a “coated core” dosage form, or a plurality of drug-containing beads, particles or granules, for incorporation into either a tablet or capsule. Exemplary coating materials include bioerodible, gradually hydrolyzable, gradually water-soluble, and/or enzymatically degradable polymers, and may be conventional “enteric” polymers. Enteric polymers, as will be appreciated by those skilled in the art, become soluble in the higher pH environment of the lower gastrointestinal tract or slowly erode as the dosage form passes through the gastrointestinal tract, while enzymatically degradable polymers are degraded by bacterial enzymes present in the lower gastrointestinal tract, particularly in the colon. Suitable coating materials for effecting delayed release include, but are not limited to, cellulosic polymers such as hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxymethyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl methyl cellulose acetate succinate, hydroxypropylmethyl cellulose
phthalate, methylcellulose, ethyl cellulose, cellulose acetate, cellulose acetate phthalate, cellulose acetate trimellitate and carboxymethylcellulose sodium; acrylic acid polymers and copolymers, e.g., formed from acrylic acid, methacrylic acid, methyl acrylate, ethyl acrylate, methyl methacrylate and/or ethyl methacrylate, and other methacrylic resins that are commercially available under the tradename Eudragit®. (Rohm Pharma; Westerstadt, Germany), including Eudragit®. L30D-55 and L100-55 (soluble at pH 5.5 and above), Eudragit®. L-100 (soluble at pH 6.0 and above), Eudragit®. S (soluble at pH 7.0 and above, as a result of a higher degree of esterification), and Eudragits®. NE, RL and RS (water-insoluble polymers having different degrees of permeability and expandability); vinyl polymers and copolymers such as polyvinyl pyrrolidone, vinyl acetate, vinylacetate phthalate, vinylacetate 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 may also be used. Multi-layer coatings using different polymers may also be applied. [0231] The coating composition may include conventional additives, such as plasticizers, pigments, colorants, stabilizing agents, glidants, etc. A plasticizer is normally present to reduce the fragility of the coating, and will generally represent about 10 wt. % to 50 wt. % relative to the dry weight of the polymer. Examples of typical plasticizers include polyethylene glycol, propylene glycol, triacetin, dimethyl phthalate, diethyl phthalate, dibutyl phthalate, dibutyl sebacate, triethyl citrate, tributyl citrate, triethyl acetyl citrate, castor oil and acetylated monoglycerides. A stabilizing agent is used to stabilize particles in the dispersion. Typical stabilizing agents are nonionic emulsifiers such as sorbitan esters, polysorbates and polyvinylpyrrolidone. Glidants are recommended to reduce sticking effects during film formation and drying, and will generally represent approximately 25 wt. % to 100 wt. % of the polymer weight in the coating solution. One effective glidant is talc. Other glidants such as magnesium stearate and glycerol monostearates may also be used. Pigments such as titanium dioxide may also be used. Small quantities of an anti-foaming agent, such as a silicone (e.g., simethicone), may also be added to the coating composition. [0232] The particles can be prepared entirely from a therapeutic agent, or from a combination of the agent and a surfactant. The particles can be made of a variety of materials. Both inorganic and organic materials can be used. For example, ceramics may be used. Polymeric and non- polymeric materials, such as fatty acids, may be used to form aerodynamically light particles.
Other suitable materials include, but are not limited to, gelatin, polyethylene glycol, trehalose, and dextran. Particles with degradation and release times ranging from seconds to months can be designed and fabricated, based on factors such as the particle material. [0233] In addition to a therapeutic or diagnostic agent (or possibly other desired molecules for delivery), the particles can include excipients such as a sugar, such as lactose, a protein, such as albumin, and/or a surfactant. [0234] Enteric Coated Capsules: “Gastric resistant natural polymer,” as used herein, refers to natural polymers or mixtures of natural polymers which are insoluble in the acidic pH of the stomach. “Film-forming natural polymer,” as used herein, refers to polymers useful for surface coatings that are applied by spraying, brushing, or various industrial processes, which undergo film formation. In most film-formation processes, a liquid coating of relatively low viscosity is applied to a solid substrate and is cured to a solid, high-molecular-weight, polymer-based adherent film possessing the properties desired by the user. For most common applications, this film has a thickness ranging from 0.5 to 500 micrometers (0.0005 to 0.5 millimeters, or 0.00002 to 0.02 inches). [0235] “Gelling agent,” as used herein, refers to substances that undergo a high degree of cross-linking or association when hydrated and dispersed in the dispersing medium, or when dissolved in the dispersing medium. This cross-linking or association of the dispersed phase alters the viscosity of the dispersing medium. The movement of the dispersing medium is restricted by the dispersed phase, and the viscosity is increased. [0236] Gastric resistant film-forming compositions containing (1) a gastric resistant natural polymer; (2) a film-forming natural polymer; and optionally (3) a gelling agent, are described herein. Exemplary gastric resistant natural polymers include, but are not limited to, pectin and pectin-like polymers which typically consist mainly 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, for example the polygalacturonans, rhamnogalacturonans and some arabinans, galactans and arabinogalactans. These are normally classified according to the degree of esterification. In high (methyl) ester (“HM”) pectin, a relatively high portion of the carboxyl groups occur as methyl esters, and the remaining carboxylic acid groups are in the form of the free acid or as its ammonium, potassium, calcium or sodium salt.
[0237] Useful properties may vary with the degree of esterification and with the degree of polymerization. Pectin, in which less than 50% of the carboxyl acid units occur as the methyl ester, is normally referred to as low (methyl) ester or LM-pectin. In general, low ester pectin is obtained from high ester pectin by treatment at mild acidic or alkaline conditions. Amidated pectin is obtained from high ester pectin when ammonia is used in the alkaline deesterification process. In this type of pectin some of the remaining carboxylic acid groups have been transformed into the acid amide. The useful properties of amidated pectin may vary with the proportion of ester and amide units and with the degree of polymerization. In one embodiment, the gastric resistant natural polymer is pectin. The gastric resistant natural polymer is present in an amount less than about 5% by weight of the composition, e.g., from about 2 to about 4% by weight of the composition. [0238] Exemplary film-forming natural polymers include, but are not limited to, gelatin and gelatin-like polymers. In an exemplary embodiment, the film-forming natural polymer is gelatin. A number of other gelatin-like polymers are available commercially. [0239] The film-forming natural polymer is present in an amount from about 20 to about 40% by weight of the composition, e.g., from about 25 to about 40% by weight of the composition. [0240] The compositions can optionally contain a gelling agent. Exemplary gelling agents include divalent cations such as Ca2+ and Mg2+. Sources of these ions include inorganic calcium and magnesium salts and calcium gelatin. The gelling agent is present in an amount less than about 2% by weight of the composition, e.g., less than about 1% by weight of the composition. [0241] One or more plasticizers can be added to the composition to facilitate the film-forming process. Suitable plasticizers include glycerin, sorbitol, sorbitans, maltitol, glycerol, polyethylene glycol, polyalcohols with 3 to 6 carbon atoms, citric acid, citric acid esters, triethyl citrate and combinations thereof. The concentration of the one or more plasticizers is from about 8% to about 30% by weight of the composition. In one embodiment, the plasticizer is glycerin and/or sorbitol. [0242] The film-forming composition can be used to prepare soft or hard shell gelatin capsules which can encapsulate a liquid or semi-solid fill material or a solid tablet (Softlet®) containing an active agent and one or more pharmaceutically acceptable excipients. Alternatively, the composition can be administered as a liquid with an active agent dissolved or dispersed in the composition.
[0243] 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. Fill formulations are fed into the encapsulation machine by gravity. [0244] The capsule shell can contain one or more plasticizers selected from the group consisting of glycerin, sorbitol, sorbitans, maltitol, glycerol, polyethylene glycol, polyalcohols with 3 to 6 carbon atoms, citric acid, citric acid esters, triethyl citrate and combinations thereof. [0245] In addition to the plasticizer(s), the capsule shell can include other suitable shell additives such as opacifiers, colorants, humectants, preservatives, flavorings, and buffering salts and acids. [0246] Opacifiers are used to opacify the capsule shell when the encapsulated active agents are light sensitive. Suitable opacifiers include titanium dioxide, zinc oxide, calcium carbonate and combinations thereof. [0247] Colorants can be used to for marketing and product identification/differentiation purposes. Suitable colorants include synthetic and natural dyes and combinations thereof. [0248] Humectants can be used to suppress the water activity of the softgel. Suitable humectants include glycerin and sorbitol, which are often components of the plasticizer composition. Due to the low water activity of dried, properly stored softgels, the greatest risk from microorganisms comes from molds and yeasts. For this reason, preservatives can be incorporated into the capsule shell. Suitable preservatives include alkyl esters of p-hydroxy benzoic acid such as methyl, ethyl, propyl, butyl and heptyl (collectively known as “parabens”) or combinations thereof. [0249] Flavorings can be used to mask unpleasant odors and tastes of fill formulations. Suitable flavorings include synthetic and natural flavorings. The use of flavorings can be problematic due to the presence of aldehydes which can cross-link gelatin. As a result, buffering salts and acids can be used in conjunction with flavorings that contain aldehydes in order to inhibit cross-linking of the gelatin. [0250] Soft or hard capsules can be used to deliver a wide variety of pharmaceutically active agents. Suitable agents include small molecules, proteins, nucleic acid, carbohydrates, lipids, and full organisms. [0251] Fill formulations may be prepared using a pharmaceutically acceptable carrier composed of materials that are considered safe and effective and may be administered to an individual without causing undesirable biological side effects or unwanted interactions. The carrier is all
components present in the pharmaceutical formulation other than the active ingredient or ingredients. As generally used herein “carrier” includes, but is not limited to surfactants, humectants, plasticizers, crystallization inhibitors, wetting agents, bulk filling agents, solubilizers, bioavailability enhancers, pH adjusting agents, and combinations thereof. [0252] Alternatively, the composition can be administered as a liquid with an active agent dissolved (e.g. solution) or dispersed (e.g., suspension) in the composition. [0253] Suitable active agents are described above. The solution or suspension may 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 filling agents, solubilizers, bioavailability enhancers, pH adjusting agents, flavorants, binding agents, disintegrating agents, anti-adherents, anti-static agents, surfactants, anti-oxidants, coating agents, coloring agents, preservatives, suspending agents, emulsifying agents, anti- microbial agents, spheronization agents, stabilizers, tonicity enhancing agents, buffers and any combination thereof [0254] Mucoadhesive Particles and methods of manufacturing: In general terms, adhesion of polymers to tissues may be achieved by (i) physical or mechanical bonds, (ii) primary or covalent chemical bonds, and/or (iii) secondary chemical bonds (e.g., ionic). Physical or mechanical bonds can result from deposition and inclusion of the adhesive material in the crevices of the mucus or the folds of the mucosa. Secondary chemical bonds, contributing to bioadhesive properties, consist of dispersive interactions (e.g., Van der Waals interactions) and stronger specific interactions, which include hydrogen bonds. The hydrophilic functional groups responsible for forming hydrogen bonds are the hydroxyl (--OH) and the carboxylic groups (--COOH). [0255] Adhesive polymeric microspheres have been selected on the basis of the physical and chemical bonds formed as a function of chemical composition and physical characteristics, such as surface area, as described in detail below. These microspheres are characterized by adhesive forces to mucosa of greater than 11 mN/cm2. The size of these microspheres range from between a nanoparticle to a millimeter in diameter. The adhesive force is a function of polymer composition, biological substrate, particle morphology, particle geometry (e.g., diameter) and surface modification. [0256] Classes of Polymers Useful in Forming Bioadhesive Microspheres: Suitable polymers that can be used to form bioadhesive microspheres include soluble and insoluble, biodegradable and
nonbiodegradable polymers. These can be hydrogels or thermoplastics, homopolymers, copolymers or blends, natural or synthetic. A key feature, however, is that the polymer must produce a bioadhesive interaction between 110 N/m2 (11 mN/cm2) and 100,000 N/m2 when applied to the mucosal surface of rat intestine. [0257] In order for bioadhesive particles to embed themselves or become engulfed in the mucus lining the GI tract, the radius of the individual particles should be as thick as the thickness of the natural mucous layer. It has been shown that the gastric mucous layer thickness typically varies from 5 to 200.mu. in the rat and 10 to 400.mu. in man. Occasionally, however, it can reach thicknesses as great as 1000.mu. in man, as described by Spiro, R. G., “Glycoproteins,” Annual Review of Biochemistry, 39, 599638, 1970; Labat-Robert, J. & Decaeus, C., “Glycoproteins du Mucus Gastrique: Structure, Fonction, et Pathologie,” Pathologie et Biologie (Paris), 24, 241, 1979; Allen, A., Hutton, D. A., Pearson, J. P., & Sellers, L. A., “Mucus Glycoprotein Structure, Gel Formation and Gastrointestinal Mucus Function” in Mucus and Mucosa, Ciba Foundation Symposium 109 (eds. J. Nugent & M. O'Connor), pp.137 (London: Pitman, 1984). In the past, two classes of polymers have appeared to show useful bioadhesive properties: hydrophilic polymers and hydrogels. In the large class of hydrophilic polymers, those containing carboxylic groups (e.g., poly[acrylic acid]) exhibit the best bioadhesive properties. One could infer that polymers with the highest concentrations of carboxylic groups should be the materials of choice for bioadhesion on soft tissues. In other studies, the most promising polymers were: sodium alginate, carboxymethylcellulose, hydroxymethylcellulose and methylcellulose. Some of these materials are water-soluble, while others are hydrogels. [0258] Rapidly bioerodible polymers such as poly[lactide-co-glycolide], polyanhydrides, and polyorthoesters, whose carboxylic groups are exposed on the external surface as their smooth surface erodes, are excellent candidates for bioadhesive drug delivery systems. In addition, polymers containing labile bonds, such as polyanhydrides and polyesters, are well known for their hydrolytic reactivity. Their hydrolytic degradation rates can generally be altered by simple changes in the polymer backbone. [0259] Representative natural polymers include proteins, such as zein, modified zein, casein, gelatin, gluten, serum albumin, or collagen, and polysaccharides, such as cellulose, dextrans, polyhyaluronic acid, polymers of acrylic and methacrylic esters and alginic acid. Representative synthetic polymers include polyphosphazines, poly(vinyl alcohols), polyamides, polycarbonates,
polyalkylenes, polyacrylamides, polyalkylene glycols, polyalkylene oxides, polyalkylene terephthalates, polyvinyl ethers, polyvinyl esters, polyvinyl halides, polyvinylpyrrolidone, polyglycolides, polysiloxanes, polyurethanes and copolymers thereof. Synthetically modified natural polymers include alkyl celluloses, hydroxyalkyl celluloses, cellulose ethers, cellulose esters, and nitrocelluloses. Other polymers of interest include, but are not limited to, methyl cellulose, ethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxybutyl methyl cellulose, cellulose acetate, cellulose propionate, cellulose acetate butyrate, cellulose acetate phthalate, carboxymethyl cellulose, cellulose triacetate, cellulose sulfate sodium salt, poly(methyl methacrylate), poly(ethyl methacrylate), poly(butyl methacrylate), poly(isobutyl methacrylate), poly(hexyl methacrylate), poly(isodecyl methacrylate), poly(lauryl methacrylate), poly(phenyl methacrylate), poly(methyl acrylate), poly(isopropyl acrylate), poly(isobutyl acrylate), poly(octadecyl acrylate)polyethylene, polypropylene, poly(ethylene glycol), poly(ethylene oxide), poly(ethylene terephthalate), poly(vinyl acetate), polyvinyl chloride, polystyrene, polyvinyl pyrrolidone, and polyvinylphenol. Representative bioerodible polymers include polylactides, polyglycolides and copolymers thereof, poly(ethylene terephthalate), poly(butic acid), poly(valeric acid), poly(lactide-co-caprolactone), poly[lactide- co-glycolide], polyanhydrides, polyorthoesters, blends and copolymers thereof. [0260] The pharmaceutically acceptable compounds of the disclosure will normally be administered to a subject in a daily dosage regimen. For an adult subject this may be, for example, an oral dose of at least one SCFA or compound comprising a SCFA moiety of between 0.1 gram and 15 grams. In further embodiments, an oral dose of at least one SCFA or compound comprising a SCFA moiety can be between 0.5 gram and 10 grams. In still further embodiments, an oral dose of at least one SCFA or compound comprising a SCFA moiety can be between 0.5 grams and 6 grams. [0261] The pharmaceutical compositions may be administered 1, 2, 3, 4 or more times per day. Thus in particular embodiments, compositions formulated, for example, for topical administration may be administered multiple times daily. [0262] In one embodiment, compositions are contemplated comprising a 1:1 (w/w) ratio of a first and a second SCFA, wherein there may be 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 a first SCFA. In other embodiments there may be a 2:1, 3:1, 4:1, 5:1; 6:1, 7:1, 8:1, 9:1, or 10:1 (w/w) ratio of a first and a second SCFA, wherein there may be 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 a first SCFA. Of course, the ratio of a first and a second SCFA administered may be varied from that disclosed herein 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 a first SCFA may 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 a second SCFA. Such amounts of either supplement may be admixed in one composition or may be in distinct compositions. [0263] A pharmaceutical composition can be administered in a local or systemic manner, for example, via injection of the compound directly into an organ, optionally in a depot or sustained release formulation or implant. Pharmaceutical compositions can be provided in the form of a rapid release formulation, in the form of an extended release formulation, or in the form of an intermediate release formulation. A rapid release form can provide an immediate release. An extended release formulation can provide a controlled release or a sustained delayed release. [0264] In practicing the methods of treatment or use provided herein, therapeutically-effective amounts of the compounds described herein are administered in pharmaceutical compositions to a subject having a disease or condition to be treated. In some embodiments, the subject is a mammal such as a human. A therapeutically-effective amount can vary widely depending on the severity of the disease, the age and relative health of the subject, the potency of the compounds used, and other factors. The compounds can be used singly or in combination with one or more therapeutic agents as components of mixtures. [0265] Methods for the preparation of compositions comprising the compounds described herein include formulating the compounds with one or more inert, pharmaceutically-acceptable excipients or carriers to form a solid, semi-solid, or liquid composition. Solid compositions include, for example, powders, tablets, dispersible granules, capsules, and cachets. Liquid compositions include, for example, solutions in which a compound is dissolved, emulsions comprising a compound, or a solution containing liposomes, micelles, or nanoparticles comprising a compound as disclosed herein. Semi-solid compositions include, for example, gels, suspensions, and creams. The compositions can be in liquid solutions or suspensions, solid forms suitable for solution or suspension in a liquid prior to use, or as emulsions. These compositions can also contain minor amounts of nontoxic, auxiliary substances, such as wetting or emulsifying agents, pH buffering agents, and other pharmaceutically-acceptable additives.
[0266] Non-limiting examples of dosage forms suitable for use in the disclosure include liquid, powder, gel, nanosuspension, nanoparticle, microgel, aqueous or oily suspensions, emulsion, and any combination thereof. [0267] A composition of the disclosure can be, for example, an immediate release form or a controlled release formulation. An immediate release formulation can be formulated to allow the compounds to act rapidly. Non-limiting examples of immediate release formulations include readily dissolvable formulations. A controlled release formulation can be a pharmaceutical formulation that has been adapted such that release rates and release profiles of the active agent can be matched to physiological and chronotherapeutic requirements or, alternatively, has been formulated to effect release of an active agent at a programmed rate. Non-limiting examples of controlled release formulations include granules, delayed release granules, hydrogels (e.g., of synthetic or natural origin), other gelling agents (e.g., gel-forming dietary fibers), matrix-based formulations (e.g., formulations comprising a polymeric material having at least one active ingredient dispersed through), granules within a matrix, polymeric mixtures, and granular masses. [0268] In some embodiments, a controlled release formulation is a delayed release form. A delayed release form can be formulated to delay a compound’s action for an extended period of time. A delayed release form can be formulated to delay the release of an effective dose of one or more compounds, for example, for about 4, about 8, about 12, about 16, or about 24 h. [0269] A controlled release formulation can be a sustained release form. A sustained release form can be formulated to sustain, for example, the compound’s action over an extended period of time. A sustained release form can be formulated to provide an effective dose of any compound described herein (e.g., provide a physiologically-effective blood profile) over about 4, about 8, about 12, about 16, or about 24 h. [0270] Non-limiting examples of pharmaceutically-acceptable excipients can be found, for example, in Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington’s Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, H.A. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y., 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkins 1999), each of which is incorporated by reference in its entirety.
[0271] Subjects can be, for example, elderly adults, adults, adolescents, pre-adolescents, children, toddlers, infants, neonates, and non-human animals. In some embodiments, a subject is a patient. [0272] A method disclosed herein relates to administering the compound disclosed herein as part of a pharmaceutical composition. In some embodiments, compositions of a compound disclosed herein can comprise a liquid comprising an active agent in solution, in suspension, or both. Liquid compositions can include gels. In some embodiments, the liquid composition is aqueous. Alternatively, the composition can be an ointment. In some embodiments, the composition is an in situ gellable aqueous composition. In some embodiments, the composition is an in situ gellable aqueous solution. [0273] A pharmaceutically-acceptable excipient can be present in a pharmaceutical composition at a mass of between about 0.1% and about 99% by mass of the composition. For example, a pharmaceutically-acceptable excipient can be present in a pharmaceutical composition at a mass of between about 0.1% and about 95%, between about 0.1% and about 90%, between about 0.1% and about 85%, between about 0.1% and about 80%, between about 0.1% and about 75%, between about 0.1% and about 70%, between about 0.1% and about 65%, between about 0.1% and about 60%, between about 0.1% and about 55%, between about 0.1% and about 50%, between about 0.1% and about 45%, between about 0.1% and about 40%, between about 0.1% and about 35%, between about 0.1% and about 30%, between about 0.1% and about 25%, between about 0.1% and about 20%, between about 0.1% and about 15%, between about 0.1% and about 10%, between about 0.1% and about 5%, or between about 0.1% and about 1%, by mass of the formulation. [0274] A pharmaceutically-acceptable excipient can be present at about 0.1%, about 0.2%, about 0.3%, about 0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9%, about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, about 21%, about 22%, about 23%, about 24%, about 25%, about 26%, about 27%, about 28%, about 29%, about 30%, about 31%, about 32%, about 33%, about 34%, about 35%, about 36%, about 37%, about 38%, about 39%, about 40%, about 41%, about 42%, about 43%, about 44%, about 45%, about 46%, about 47%, about 48%, about 49%, about 50%, about 51%, about 52%, about 53%, about 54%, about 55%, about 56%, about 57%, about 58%,
about 59%, about 60%, about 61%, about 62%, about 63%, about 64%, about 65%, about 66%, about 67%, about 68%, about 69%, about 70%, about 71%, about 72%, about 73%, about 74%, about 75%, about 76%, about 77%, about 78%, about 79%, about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, about 99.1%, about 99.2%, about 99.3%, about 99.4%, about 99.5%, about 99.6%, about 99.7%, about 99.8%, or about 99.9% by mass of the formulation. Subjects/patient population [0275] Subjects can be, humans for example, elderly adults, adults, adolescents, pre-adolescents, children, toddlers, infants, neonates, and non-human animals, e.g., a mouse. In some embodiments, a subject is a patient. In some embodiments, a subject has experienced and/or exhibited at least one symptom of the disease or disorder to be treated and/or reduced in likelihood to occur. In some embodiments, the subject has been identified or diagnosed as having a liver disease or disorder described herein, e.g., NASH. [0276] In some embodiments, a method of treatment disclosed herein comprises, identification of a patient population based on one or more selection criteria, e.g., biomarkers, failure to respond to a primary therapy and administering a compound disclosed herein, e.g., Compound 1 to treat the patient. The patient population selection criteria can include but are not limited to, presence of a biomarker, e.g., marker associate with a particular disease, a marker associated with poor prognosis of a disease, failure to respond to an initial therapy, age, gender, health of the patient. The screening procedure may include but are not limited to blood and/or tissue sample analysis, genetic tests, genetic screening, biopsy, drug sensitivity/resistance test. [0277] A method disclosed herein relates to administering the compound disclosed herein as part of a pharmaceutical composition. In some embodiments, a pharmaceutical composition comprises a compound described herein and a pharmaceutically-acceptable excipient. In some embodiments, compositions of a compound disclosed herein can comprise a liquid comprising an active agent in solution, in suspension, or both. Liquid compositions can include gels. In some embodiments, the liquid composition is aqueous. In some embodiments, the composition is an ointment. In some embodiments, the composition is an in situ gellable aqueous composition. In some embodiments, the composition is an in situ gellable aqueous solution. Dosing
[0278] Pharmaceutical compositions described herein can be in unit dosage forms suitable for single administration of precise dosages. In unit dosage form, the formulation is divided into unit doses containing appropriate quantities of one or more compounds. The unit dosage can be in the form of a package containing discrete quantities of the formulation. Non-limiting examples are packaged injectables, vials, or ampoules. Aqueous suspension compositions can be packaged in single-dose non-reclosable containers. Multiple-dose reclosable containers can be used, for example, in combination with or without a preservative. Formulations for parenteral injection can be presented in unit dosage form, for example, in ampoules, or in multi-dose containers with a preservative. [0279] A compound described herein can be present in a composition in a range of from about 1 mg to about 5 mg, from about 5 mg to about 10 mg, from about 10 mg to about 15 mg, from about 15 mg to about 20 mg, from about 20 mg to about 25 mg, from about 25 mg to about 30 mg, from about 30 mg to about 35 mg, from about 35 mg to about 40 mg, from about 40 mg to about 45 mg, from about 45 mg to about 50 mg, from about 50 mg to about 55 mg, from about 55 mg to about 60 mg, from about 60 mg to about 65 mg, from about 65 mg to about 70 mg, from about 70 mg to about 75 mg, from about 75 mg to about 80 mg, from about 80 mg to about 85 mg, from about 85 mg to about 90 mg, from about 90 mg to about 95 mg, from about 95 mg to about 100 mg, from about 100 mg to about 125 mg, from about 125 mg to about 150 mg, from about 150 mg to about 175 mg, from about 175 mg to about 200 mg, from about 200 mg to about 225 mg, from about 225 mg to about 250 mg, or from about 250 mg to about 300 mg. [0280] A compound described herein can be present in a composition in an amount of about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 120 mg, about 140 mg, about 160 mg, about 180 mg, about 200 mg, about 220 mg, about 240 mg, about 260 mg, about 280 mg, about 300 mg, about 320 mg, about 340 mg, about 360 mg, about 380 mg, about 400 mg, about 420 mg, about 440 mg, about 460 mg, about 480 mg, about 500 mg, about 520 mg, about 540 mg, about 560 mg, about 580 mg, or about 600 mg. [0281] A compound described herein can be administered to a subject in an amount of about 0.1 mg/kg to about 500 mg/kg, about 1 mg/kg to about 500 mg/kg, about 0.1 mg/kg to about 300 mg/kg, about 1 mg/kg to about 300 mg/kg, or about 0.1 mg/kg to about 30 mg/kg. In some
embodiments, the compound disclosed herein is administered to a subject in an amount of about 1 mg/kg, about 2 mg/kg, about 3 mg/kg, about 4 mg/kg, about 5 mg/kg, about 6 mg/kg, about 7 mg/kg, about 8 mg/kg, about 9 mg/kg, about 10 mg/kg, about 11 mg/kg, about 12 mg/kg, about 13 mg/kg, about 14 mg/kg, about 15 mg/kg, about 16 mg/kg, about 17 mg/kg, about 18 mg/kg, about 19 mg/kg, about 20 mg/kg, about 25 mg/kg, about 30 mg/kg, about 35 mg/kg, about 40 mg/kg, about 45 mg/kg, 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. Dosing Regimens [0282] A dosing regimen disclosed herein can be, for example, once a day, twice a day, thrice a day, once a week, twice a week, or thrice a week. In some embodiments, a compound disclosed herein is administered once daily. In some embodiments, a compound disclosed herein is administered once daily for 28 days (one cycle). In some embodiments, a compound disclosed herein is administered once daily in one or more 28 day cycles. In some embodiments, a compound disclosed herein is administered in a four-week cycle of consecutive once daily administration for three weeks, followed by one week with no administrations. [0283] A compound described herein can be administered before, during, or after the occurrence of a disease or condition, and the timing of administering the composition containing a compound can vary. For example, a compound can be used as a prophylactic and can be administered continuously to subjects with a propensity to conditions or diseases to lessen or reduce a likelihood of the occurrence of the disease or condition. A compound and composition can be administered to a subject during or as soon as possible after the onset of the symptoms. The administration of a compound can be initiated within the first 48 hours of the onset of the symptoms, within the first 24 hours of the onset of the symptoms, within the first 6 hours of the onset of the symptoms, or within 3 hours of the onset of the symptoms. The initial administration can be via any route practical, such as by any route described herein using any formulation described herein. [0284] A compound can be administered as soon as is practical after the onset of a disease or condition is detected or suspected, and for a length of time necessary for the treatment of the
disease, such as, for example, from about 1 month to about 3 months. In some embodiments, the length of time a 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 months, about 11 months, about 1 year, about 13 months, about 14 months, about 15 months, about 16 months, about 17 months, about 18 months, about 19 months, about 20 months, about 21 months, about 22 months about 23 months, about 2 years, about 2.5 years, about 3 years, about 3.5 years, about 4 years, about 4.5 years, about 5 years, about 6 years, about 7 years, about 8 years, about 9 years, about 10 years, about 11 years, about 12 years, about 13 years, about 14 years, about 15 years, about 16 years, about 17 years, about 18 years, about 19 years, about 20 years, about 21 years, about 22 years, about 23 years, about 24 years, or about 25 years. The length of treatment can vary for each subject. [0285] A dosing schedule for administration of a compound described herein can be consistent for the length of the dosing regimen. For example, a compound can be administered daily. Alternatively, or in addition to, a dosing schedule for administration of a compound described herein can include portions of time where dosing is paused. For example, a compound can be administered every day for 3 weeks and then not be administered for one week. [0286] A dosing schedule for administration of a compound described herein can include once daily (QD), twice daily (BID), three times daily (TID), four times daily (QID), once weekly, twice weekly, three times weekly, once monthly, twice monthly, and once every other month. For example, a daily dose can be given in a single dose or divided into multiple doses to be administered in intervals, e.g., twice daily or three times daily. For example, a daily dose of 100 mg can be given, for example, once daily (100 mg), twice daily (50 mg per dose). [0287] Multiple therapeutic agents can be administered in any order or simultaneously. In some embodiments, a compound of the disclosure is administered in combination with, before, or after treatment with another therapeutic agent, e.g., a drug, such as an aromatase inhibitor. In some embodiments, a compound of the disclosure is administered at regular intervals, such as, for
example, once daily, twice daily, thrice daily, etc. and the second therapeutic agent is administered daily or intermittently or on an as-needed basis. If simultaneously, the multiple therapeutic agents can be provided in a single, unified form, or in multiple forms, for example, as multiple separate unit dosage forms. The agents can be packed together or separately, in a single package or in a plurality of packages. One or all the therapeutic agents can be given in multiple doses. If not simultaneous, the timing between the multiple doses can vary to as much as about a month. [0288] Kits [0289] The disclosure also includes a kit comprising compounds useful within the methods of the disclosure and an instructional material that describes, for instance, the method of administering compositions as described elsewhere herein. In one embodiment, the kit comprises a composition. [0290] EXPERIMENTAL EXAMPLES [0291] The invention is further described in detail by reference to the following experimental examples. These examples are provided for purposes of illustration only, and are not intended to be limiting unless otherwise specified. Thus, the invention should in no way be construed as being limited to the following examples, but rather should be construed to encompass any and all variations which become evident as a result of the teaching provided herein. [0292] Without further description, it is believed that one of ordinary skill in the art can, using the preceding description and the following illustrative examples, make and utilize the present invention and practice the claimed methods. The following working examples therefore are not to be construed as limiting in any way the remainder of the disclosure. [0293] Example 1: Combination Treatment for Nonalcoholic Steatohepatitis (NASH) and Fibrosis [0294] Given the complex pathophysiology of NASH, the present studies develop a novel treatment for NASH with unique combination of Short-Chain Fatty Acids (SCFAs), butyrate and acetate, both of which target multiple mechanisms associated with the pathogenesis of NASH, and anti-oxidant Vitamin E (at safer doses).
[0295] disclosureA unique combination of Ca/Mg salts of butyric acid (2.4 g daily) and tocopherol-acetate (source of acetic acid [12 mg] Vitamin E [200IU]) is developed that provides an effective treatment for NASH with or without fibrosis. [0296] Patients diagnosed with NAFLD are also treated with this composition to prevent the progression of NAFLD to NASH and/or fibrosis. EXAMPLE 2: Treatment with Short Chain Fatty Acids – assessment of arresting the progression of NASH to fibrosis in a preclinical model of aged mice [0297] Various assays to assessment of arresting the progression of NASH to fibrosis were designed and tested as shown and described for FIGs.1-9. [0298] Mice [0299] All mice were fed a high fat diet (HFD) starting at 56 weeks of age until euthanasia at 76 weeks (groups 1, 2 and 5) or 84 weeks (groups 2, 4 and 6) of age (TABLE.1). Groups 1-4 inclusive also received 20.5 mg/kg/mouse/day tocopherol acetate. Mice were fed a high fat diet (HFD) starting at 56-weeks of age. At 64 weeks of age, half the mice were fed either a high dose of SCFA, a low dose of SCFA, nor no drug (day 0), for 12 weeks until euthanasia (day 84) (TABLE.1 and FIG.1). Mice in the other half of the colony were divided into the same groups, except that feeding of SCFA started at 72 weeks of age for 12 weeks until euthanasia.
ng i s e D l a t n emi r e p x E y r a l pme x E . 1 e l b a T
[0300] Body weight [0301] Body weight was determined in all C57/BL6 male mice over the whole period of each study (FIG.1). No effect on body weight loss was observed in mice of groups 2 and 4 treated with low dose of SCFA (FIG.1). Although mice of groups 1 and 3 fed with a high dose of SCFA lost up to 20% of their body weight within the first few weeks of SCFA feeding (FIG.1), food intake of these mice was unaltered, and physical appearance and activity did not change, suggesting no overt toxicity. [0302] H&E staining [0303] Upon euthanasia, each liver lobe from individual mice were formalin fixed and paraffin embedded. Liver sections were prepared, and H&E stained to evaluate histopathology (Tables 2-3 and FIGs.2-7), while slides from the same blocks were stain by trichrome to assess fibrosis (FIGs.8-9). [0304] Histopathology scores were independently determined by each of 4 lobes from individual mice, and the data represents the average score from all 4 lobes of single mouse (Table 2) according to histopathology evaluation criteria (Table 3). [0305] Table 2. Histopathology Score for Individual mice
[0306] Table 3. Exemplary Histopathology evaluation criteria
[0307] At 64 weeks of age, all mice had NASH. At 72 weeks of age, all mice had NASH and fibrosis.
[0308] The presence, frequency and distribution of NASH and fibrosis were assessed in SCFA treated mice compared to control animals at weeks 76 and 84 (FIG.2 and Tables 4-5). [0309] Table 4. Average histopathology scores for groups of mice at 76 weeks of age
[0310] Table 5. Average histopathology scores for groups of mice at 84 weeks of age
[0311] Comparing groups 1 and 5 given high dose of SCFA, and groups 2 and 5 in mice give given low dose of SCFA, NASH was significantly blocked at week 76. (FIG.2 and Table 4). Comparing groups 3 and 6 for high dose SCFA and groups 4 and 6 for low dose SCFA, NASH was significantly blocked at week 84. (FIG.2 and Table 5). [0312] A statistically significant decrease in fibrosis onset was observed in mice euthanized at week 76 (FIG.3 and Table 4). Comparing mice from group 1 to group 5, these experiments demonstrated that treatment with SCFA is effective against fibrosis. A similar trend of decreased fibrosis was observed in mice euthanized at week 84 (FIG.3 and Table 5). [0313] SCFAs attenuated the pathogenesis of NASH by blocking the development and/or progression of inflammatory foci to prevent or delay the development of liver fibrosis. EXAMPLE 3: Treatment with Short Chain Fatty Acids – Study evaluating improvement of liver histology in patients with NAFLD/NASH. [0314] Liver histology in patients having NAFLD/NASH is assessed following administration of a composition comprising butyric acid and tocopherol acetate.
[0315] A total of 100 patients with a median age of 60 are recruited. The patients have NAFLD/NASH and associated liver inflammation and/or cirrhosis and no contraindication for butyrate. Patients enrolled have a histological diagnosis of NASH. [0316] The patients are dosed with a formulation comprising 600 mg sodium butyrate and tocopherol acetate (source of acetic acid [12 mg] and Vitamin E [200 IU]) two to three times daily or given placebo. [0317] Evaluation of liver histology [0318] Baseline and treated (e.g., 96-week) liver biopsy specimens are formalin-fixed, paraffin- embedded, and unstained slides are cut from tissue blocks. Scoring of biopsies are assessed according to NAFLD activity score (NAS) and fibrosis score, or for example as described in Example 1. [0319] Laboratory Analyses [0320] Blood is collected and samples are processed. Measurements of insulin, glucose, and Adipo-IR index are measured. Adipo-IR index is calculated, for example, as fasting NEFA [mM] x fasting insulin [pM]. Adipo-IR index is associated with an improvement in steatosis and necroinflammation. A decrease in Adipo-IR can indicate improvement of NASH through its effect on dysfunctional adipose tissue. [0321] Exemplary Treatment
[0322] In the study, drug recipients are monitored for the following outcomes: an improvement in fibrosis (e.g., a reduced fibrosis score according to liver histology in a treated sample compared to baseline sample), an improvement in NASH (e.g., a reduced NASH score according to liver histology in a treated sample compared to baseline sample), and/or a decrease in Adipo- IR.
EXAMPLE 4: Treatment of NAFLD/NASH [0323] Treatment of NAFLD/NASH is assessed in a subject administered a composition comprising butyric acid and tocopherol acetate. [0324] A total of 100 patients are recruited. The patients have NAFLD/NASH and/or associated liver inflammation and/or cirrhosis and no contraindication for butyrate. The patients are dosed with a formulation comprising 600 mg sodium butyrate and tocopherol acetate (source of acetic acid [12 mg] and Vitamin E [200 IU]) two to three times daily or given placebo. [0325] The subjects are followed for a median of 5 years. Just prior to treatment, patients are screened for ALT/AST, GGT; liver stiffness by fibroscan; pro-inflammatory and anti- inflammatory cytokines in blood (e.g., TNF α, IFN-γ, IL-2, IL-4, IL5- IL-10). The screenings are repeated yearly until completion of the study. Patients are analyzed by multivariate analysis for incidence of chronic liver disease (hepatitis and fibrosis), liver cancer, chronic liver disease related death (usually from cirrhosis), or transplantation in the treated and untreated cohorts. [0326] Exemplary Treatment
[0327] In the study, drug recipients are monitored for the following outcomes: lower incidence of chronic liver disease (hepatitis and fibrosis), lower incidence of liver cancer, lower incidence of chronic lower incidence of liver disease related death (usually from cirrhosis), and/or lower incidence of transplantation in the treated cohort compared to the untreated cohort. [0328] In the study, drug recipients are monitored for a decreased expression of an inflammatory cytokine or a mediator or inflammation. [0329] The disclosures of each and every patent, patent application, and publication cited herein are hereby incorporated herein by reference in their entirety. While this disclosure has been disclosed with reference to specific embodiments, it is apparent that other embodiments and variations of this disclosure may be devised by others skilled in the art without departing from the true spirit and scope of the disclosure. The appended claims are intended to be construed to include all such embodiments and equivalent variations.
EMBODIMENTS [0330] The following non-limiting embodiments provide illustrative examples of the invention, but do not limit the scope of the invention. [0331] Embodiment 1. A method of alleviating a condition in a subject in need thereof, 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 a tocopherol, wherein the reduced amount of the tocopherol is therapeutically effective for alleviating the condition in combination with the at least one SCFA or the pharmaceutically acceptable salt thereof, and wherein the reduced amount of the tocopherol is less than an amount of the tocopherol that is therapeutically effective for the condition in absence of the at least one SCFA or the pharmaceutically acceptable salt thereof. [0332] Embodiment 2. The method of embodiment 1, wherein the tocopherol exhibits synergy with the at least one SCFA or the pharmaceutically acceptable salt thereof. [0333] Embodiment 3. A method of providing prophylaxis against 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) a tocopherol. [0334] Embodiment 4. The method of any one of embodiments 1-3, wherein the condition is a liver disease. [0335] Embodiment 5. The method of embodiment 4, wherein the liver disease is selected from the group consisting of a fatty liver disease, nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), liver fibrosis, alcoholic liver disease, autoimmune disease or disorder, cirrhosis, liver cancer, hepatocellular carcinoma, autoimmune hepatitis, primary biliary cirrhosis (PBC), primary sclerosing cholangitis, hemochromatosis, Wilson’s disease, liver failure, and any combination thereof. [0336] Embodiment 6. The method of embodiment 4, wherein the liver disease or disorder is a fatty liver disease. [0337] Embodiment 7. The method of embodiment 4, wherein the liver disease or disorder is nonalcoholic fatty liver disease (NAFLD). [0338] Embodiment 8. The method of embodiment 4, wherein the liver disease or disorder is nonalcoholic steatohepatitis (NASH). [0339] Embodiment 8. The method of embodiment 4, wherein the liver disease or disorder is liver
fibrosis. [0340] Embodiment 9. The method of embodiment 4, wherein the liver disease or disorder is alcoholic liver disease. [0341] Embodiment 10. The method of embodiment 4, wherein the liver disease or disorder is cirrhosis. [0342] Embodiment 11. The method of embodiment 4, wherein the liver disease or disorder is liver cancer. [0343] Embodiment 12. The method of embodiment 4, wherein the liver disease or disorder is hepatocellular carcinoma. [0344] Embodiment 13. A method of providing prophylaxis against 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) a tocopherol. [0345] Embodiment 14. The method of any one of embodiments 3-13, wherein the prophylaxis comprises reducing a likelihood of progression to fibrosis. [0346] Embodiment 15. The method of embodiment 13 or 14, wherein the prophylaxis comprises reducing a likelihood of progression of NASH to fibrosis. [0347] Embodiment 16. The method of any one of embodiments 3-14, wherein the prophylaxis comprises delaying or slowing progression to fibrosis. [0348] Embodiment 17. The method of any one of embodiments 13-16, wherein the prophylaxis comprises delaying or slowing progression of NASH to fibrosis. [0349] Embodiment 18. The method of any one of embodiments 1-17, wherein the composition comprises between about 100 milligrams (mg) to about 6 grams (g) of one of the SCFAs. [0350] Embodiment 19. The method of embodiment 18, wherein the composition comprises about 2.4 grams (g) of one of the SCFAs. [0351] Embodiment 20. The method of 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, caproic acid, lactic acid, succinic acid, pyruvic acid, octanoic acid, dodecanoic acid, (4R)-4-hydroxypentanoic acid, 2- ethylhydracrylic acid, 2-hydroxy-3-methylpentanoate, 2-hydroxy-3-methylpentanoic acid, 2- methylbut-2-enoic acid, 2-oxobutanoic acid, 3-hydroxypentanoic acid, 3-methylbut-2-enoic acid,
butenoic acid, methylbutyric acid, dimethylbutyric acid, pentadienoic acid, pentenoic acid, pivalic acid, propynoic acid, a pharmaceutically acceptable salt of any of the foregoing, and any combination thereof. [0352] 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 a pharmaceutically acceptable salt thereof. [0353] Embodiment 22. The method of 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. [0354] Embodiment 23. The method of any one of embodiments 1-22, wherein the composition comprises at least two short chain fatty acids (SCFA) or a pharmaceutically acceptable salt thereof. [0355] Embodiment 24. The method of embodiment 23, wherein the at least two SCFA or pharmaceutically acceptable salt thereof are selected from the group consisting of: acetic acid, butyric acid (BA), methoxyacetic acid, valproic acid (VPA), propionic acid, 3-methoxypropionic acid, ethoxyacetic acid, formic acid, isobutyric acid, tributyrin, butyrate, propionate, N- acetylbutyrate, isovaleric acid, valeric acid, isocaproic acid, caproic acid, lactic acid, succinic acid, pyruvic acid, octanoic acid, dodecanoic acid, (4R)-4-hydroxypentanoic acid, 2-ethylhydracrylic acid, 2-hydroxy-3-methylpentanoate, 2-hydroxy-3-methylpentanoic acid, 2-methylbut-2-enoic acid, 2
- oxobutanoic acid, 3-hydroxypentanoic acid, 3-methylbut-2-enoic acid, butenoic acid, methylbutyric acid, dimethylbutyric acid, pentadienoic acid, pentenoic acid, pivalic acid, propynoic acid, a pharmaceutically acceptable salt of any of the foregoing, and any combination thereof. [0356] Embodiment 25. The method of any one of embodiments 1-24, wherein the composition comprises butyrate or a pharmaceutically acceptable salt thereof. [0357] Embodiment 26. The method of any one of embodiments 1-25, wherein the composition comprises the pharmaceutically acceptable salt of butyrate, and the pharmaceutically acceptable salt of butyrate is a Ca salt, a Mg salt, or a Na salt. [0358] Embodiment 27. The method of any one of embodiments 1-26, wherein the composition comprises acetate or a pharmaceutically acceptable salt thereof. [0359] Embodiment 28. The method of any one of embodiments 1-27, wherein the composition comprises the pharmaceutically acceptable salt of acetate, and the pharmaceutically acceptable salt of acetate is a Ca salt, a Mg salt, or a Na salt. [0360] Embodiment 29. The method of any one of embodiments 1-28, wherein the composition comprises between about 100 milligrams (mg) to about 6 grams (g) of the SCFAs.
[0361] Embodiment 30. The method of embodiment 29, wherein the composition comprises about 2.4 grams (g) of the SCFAs. [0362] Embodiment 31. The method of any one of embodiments 1-30, wherein the composition comprises between about 1 IU to about 600 IU of the tocopherol. [0363] Embodiment 32. The method of any one of embodiments 1-31, wherein the composition comprises between about 1 IU to about 49.9 IU of the tocopherol. [0364] Embodiment 33. The method of any one of embodiments 1-32, wherein the composition comprises less than about 50 IU of the tocopherol. [0365] Embodiment 34. The method of any one of embodiments 1-33, wherein the composition comprises between about 100.1 IU to about 600 IU of the tocopherol. [0366] Embodiment 35. The method of any one of embodiments 1-34, wherein the composition comprises more than about 100 IU of the tocopherol. [0367] Embodiment 36. The method of any one of embodiments 1-35, wherein the tocopherol is tocopherol-acetate. [0368] Embodiment 37. The method of embodiment 36, wherein the composition comprises between about 1 milligram (mg) to about 100 milligrams (mg) of tocopherol-acetate. [0369] Embodiment 38. The method of embodiment 37, wherein the composition comprises about 12 milligrams (mg) of tocopherol-acetate. [0370] Embodiment 39. The method of any one of embodiments 1-38, wherein the composition is administered orally. [0371] Embodiment 40. The method of any one of embodiments 1-39, wherein the composition is administered with food or drink. [0372] Embodiment 41. The method of any one of embodiments 1-39, wherein the composition is administered with food. [0373] Embodiment 42. The method of any one of embodiments 1-41, wherein the composition is a pharmaceutical composition. [0374] Embodiment 43. The method of embodiments 42, wherein the pharmaceutical composition further comprises a pharmaceutically acceptable excipient. [0375] Embodiment 44. The method of any one of embodiments 41-42, wherein the pharmaceutical composition further comprises an enteric coating. [0376] Embodiment 45. The method of any one of embodiments 41-44, wherein the pharmaceutical composition is formulated as a tablet. [0377] Embodiment 46. The method of embodiments 41-45, wherein the pharmaceutical
composition is formulated as a capsule. [0378] Embodiment 47. The method of any one of embodiments 1-46, wherein the subject is s human. [0379] Embodiment 48. A pharmaceutical composition comprising in a unit dosage form active ingredients, wherein the active ingredients comprise (a) a therapeutically effective amount of at least one SCFA or a pharmaceutically-acceptable salt thereof; and (b) at least one antioxidant. [0380] Embodiment 49. The pharmaceutical composition of embodiment 49, wherein the amount of the at least one antioxidant is a reduced amount of the at least one antioxidant, wherein the reduced amount of at least one antioxidant is therapeutically effective for alleviating a condition in combination with the at least one SCFA or the pharmaceutically acceptable salt thereof. [0381] Embodiment 50. The pharmaceutical composition of embodiment 48 or 49, wherein the amount of the at least one antioxidant is a reduced amount of the at least one antioxidant, wherein the reduced amount of at least one antioxidant is less than an amount of the at least one antioxidant that is therapeutically effective for a condition in absence of the at least one SCFA or the pharmaceutically acceptable salt thereof. [0382] Embodiment 51. A pharmaceutical composition comprising in a unit dosage form active ingredients, wherein the active ingredients comprise (a) a therapeutically effective amount of at least one SCFA or a pharmaceutically-acceptable salt thereof; and (b) a tocopherol. [0383] Embodiment 52. The pharmaceutical composition of embodiment 51, wherein the amount of the tocopherol is a reduced amount of the tocopherol, wherein the reduced amount of tocopherol is therapeutically effective for alleviating a condition in combination with the at least one SCFA or the pharmaceutically acceptable salt thereof. [0384] Embodiment 53. The pharmaceutical composition of embodiment 51 or 52, wherein the amount of the tocopherol is a reduced amount of the tocopherol, wherein the reduced amount of tocopherol is less than an amount of the tocopherol that is therapeutically effective for a condition in absence of the at least one SCFA or the pharmaceutically acceptable salt thereof. [0385] Embodiment 54. The pharmaceutical composition of any one of embodiments 48-53, wherein the pharmaceutical composition comprises between about 100 milligrams (mg) to about 6 grams (g) of the at least one SCFA. [0386] Embodiment 55. The pharmaceutical composition of any one of embodiments 48-54, wherein the pharmaceutical composition comprises about 2.4 grams (g) of the at least one SCFA. [0387] Embodiment 56. The pharmaceutical composition of any one of embodiments 48-55, wherein the pharmaceutical composition comprises at least two SCFAs.
[0388] Embodiment 57. The pharmaceutical composition of any one of embodiments 48-56, wherein the pharmaceutical composition comprises a butyrate or a pharmaceutically acceptable sale thereof. [0389] Embodiment 58. The pharmaceutical composition of any one of embodiments 48-57, wherein the pharmaceutical composition comprises a Ca salt of butyric acid. [0390] Embodiment 59. The pharmaceutical composition of any one of embodiments 48-58, wherein the pharmaceutical composition comprises a Mg salt of butyric acid. [0391] Embodiment 60. The pharmaceutical composition of any one of embodiments 48-59, wherein the pharmaceutical composition comprises between about 1 milligram (mg) to about 100 milligrams (mg) of the at least one antioxidant. [0392] Embodiment 61. The pharmaceutical composition of any one of embodiments 48-60, wherein the composition comprises about 12 milligrams (mg) of the at least one antioxidant. [0393] 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, carotenoid, selenium, manganese, glutathione, coenzyme Q10, lipoic acid, flavonoid, phenol, polyphenol, phytoestrogen, and any combination thereof. [0394] Embodiment 63. The pharmaceutical composition of any one of embodiments 48-62, wherein the antioxidant is a tocopherol. [0395] Embodiment 64. The pharmaceutical composition of any one of embodiments 48-63, wherein the composition comprises between about 1 IU to about 600 IU of the tocopherol. [0396] Embodiment 65. The pharmaceutical composition of any one of embodiments 48-64, wherein the composition comprises between about 1 IU to about 49.9 IU of the tocopherol. [0397] Embodiment 66. The pharmaceutical composition of any one of embodiments 48-65, wherein the composition comprises less than about 50 IU of the tocopherol. [0398] Embodiment 67. The pharmaceutical composition of any one of embodiments 48-66, wherein the composition comprises between about 100.1 IU to about 600 IU of the tocopherol. [0399] Embodiment 68. The pharmaceutical composition of any one of embodiments 48-67, wherein the composition comprises more than about 100 IU of the tocopherol. [0400] Embodiment 69. The pharmaceutical composition of any one of embodiments 48-68, wherein the antioxidant is tocopherol acetate. [0401] Embodiment 70. The pharmaceutical composition of any one of embodiments 48-69, wherein the antioxidant is a d-alpha-tocopherol acetate.
[0402] Embodiment 71. The pharmaceutical composition of any one of embodiments 48-70, wherein the composition comprises between about 1 milligram (mg) to about 100 milligrams (mg) of tocopherol-acetate. [0403] Embodiment 72. The pharmaceutical composition of any one of embodiments 48-71, wherein the composition comprises about 12 milligrams (mg) of tocopherol-acetate. [0404] Embodiment 73. The pharmaceutical composition of any one of embodiments 48-72, wherein the composition is administered orally. [0405] Embodiment 74. The pharmaceutical composition of any one of embodiments 48-73, wherein the composition is adm4inistered with food or drink. [0406] Embodiment 75. The pharmaceutical composition of any one of embodiments 48-74, wherein the composition is administered with food. [0407] Embodiment 76. The pharmaceutical composition of any one of embodiments 48-75, further comprising a pharmaceutically acceptable excipient. [0408] Embodiment 77. The pharmaceutical composition of any one of embodiments 48-76, wherein the pharmaceutical composition further comprises an enteric coating. [0409] Embodiment 78. The pharmaceutical composition of any one of embodiments 48-77, wherein the pharmaceutical composition is formulated as a tablet. [0410] Embodiment 79. The pharmaceutical composition of embodiments 48-78, wherein the pharmaceutical composition is formulated as a capsule. [0411] Embodiment 80. Use of the pharmaceutical composition of any one of embodiments 48-79 in the manufacture of a medicament. [0412] Embodiment 81. The method of any one of embodiments 1-47, wherein administering the composition improves liver histology in a liver biopsy sample of the subject. [0413] Embodiment 82. The method of embodiment 81, wherein administering the composition improves NASH score in the liver biopsy sample of the subject. [0414] Embodiment 83. The method of embodiment 81 or 82, wherein administering the composition improves fibrosis score in the liver biopsy sample of the subject. [0415] Embodiment 84. The method of any one of embodiments 81-83, wherein administering the composition reduces the presence of inflammatory foci in the liver biopsy sample of the subject. [0416] Embodiment 85. The method of any one of embodiments 81-84, wherein administering the composition reduces the distribution of inflammatory foci in the liver biopsy sample of the subject. [0417] Embodiment 86. The method of any one of embodiments 81-85, wherein administering the composition reduces the frequency of inflammatory foci in the liver biopsy sample of the subject.
[0418] Embodiment 87. The method of any one of embodiments 1-47 and 81-86, wherein administering the composition attenuated the pathogenesis of NASH in the subject. [0419] Embodiment 88. The method of any one of embodiments 1-47 and 81-87, wherein administering the composition prevents or delays the development of liver fibrosis in the subject. [0420] Embodiment 89. The method of any one of embodiments 1-47 and 81-88, wherein administering the composition decreases liver inflammation in the subject. [0421] Embodiment 90. The method of any one of embodiments 1-47 and 81-89, wherein administering the composition modulates expression of a mediator of inflammation in the subject. [0422] Embodiment 91. The method of any one of embodiments 1-47 and 81-90, wherein administering the composition decreases expression of a mediator of inflammation in the subject. [0423] Embodiment 92. A method of preventing or treating a liver disease or disorder in a subject in need thereof, wherein the method comprises administering to the subject a composition comprising at least one compound selected from the group consisting of: a short chain fatty acid (SCFA), salt of SCFA, SCFA precursor, SCFA biosynthesis precursor, compound comprising a SFCA moiety, derivative of SCFA, and any combination thereof. [0424] Embodiment 93. The method of embodiment 92, wherein the liver disease or disorder is selected from the group consisting of a fatty liver disease, nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), liver fibrosis, alcoholic liver disease, autoimmune disease or disorder, cirrhosis, liver cancer, hepatocellular carcinoma, autoimmune hepatitis, primary biliary cirrhosis (PBC), primary sclerosing cholangitis, hemochromatosis, Wilson’s disease, liver failure, and any combination thereof. [0425] Embodiment 94. A method of preventing or treating a 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: a short chain fatty acid (SCFA), salt of SCFA, SCFA precursor, SCFA biosynthesis precursor, compound comprising a SFCA moiety, derivative of SCFA, and any combination thereof. [0426] Embodiment 95. A method of preventing or treating an 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: a short chain fatty acid (SCFA), salt of SCFA, SCFA precursor, SCFA biosynthesis precursor, compound comprising a SFCA moiety, derivative of SCFA, and any combination thereof. [0427] Embodiment 96. The method of any one of embodiments 92-95, wherein the composition comprises between about 100 milligrams (mg) to about 6 grams (g) of at least one SCFA.
[0428] Embodiment 97. The method of embodiment 96, wherein the composition comprises about 2.4 grams (g) of at least one SCFA. [0429] Embodiment 98. The method of any one of embodiments 92-96, wherein the composition comprises at least SCFA or salt thereof comprising 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 (as well as other forms of butyrate, e.g., phenylbutyrate, isobutyrate, pivaloyloxymethyl butyrate, 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-ethylhydracrylic acid, 2-hydroxy-3-methylpentanoate, 2-hydroxy-3-methylpentanoic acid, 2-methylbut-2-enoic acid, 2-oxobutanoic acid, 3-hydroxypentanoic acid, 3-methylbut-2-enoic acid, butenoic acid, methylbutyric acid, dimethylbutyric acid, pentadienoic acid, pentenoic acid, pivalic acid, propynoic acid, and any combination thereof. [0430] Embodiment 99. The method of embodiment 98, wherein the at least one salt of SCFA comprises at least one selected from the group consisting of: butyrate, propionate, and acetate. [0431] Embodiment 100. The method of embodiment 98, wherein the at least one salt of SCFA comprises at least one selected from the group consisting of a Ca salt of SCFA, Mg salt of SCFA, and any combination thereof. [0432] Embodiment 101. 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 butyric acid, Mg salt of butyric acid, Ca salt of acetic acid, Mg salt of acetic acid, and any combination thereof. [0433] Embodiment 102. The method of any one of embodiments 92-101, wherein the composition comprises between about 100 milligrams (mg) to about 6 grams (g) of Ca salt of butyric acid, Mg salt of butyric acid, Ca salt of acetic acid, Mg salt of acetic acid, or any combination thereof. [0434] Embodiment 103. The method of embodiment 102, wherein the composition comprises about 2.4 grams (g) of Ca salt of butyric acid, Mg salt of butyric acid, Ca salt of acetic acid, Mg salt of acetic acid, or any combination thereof. [0435] Embodiment 104. The method of any one of embodiments 92-103, wherein the composition further comprises at least one antioxidant. [0436] Embodiment 105. The method of embodiment 104, wherein the composition comprises between about 1 milligram (mg) to about 100 milligrams (mg) of at least one antioxidant.
[0437] Embodiment 106. The method of embodiment 105, wherein the composition comprises about 12 milligrams (mg) of at least one antioxidant. [0438] Embodiment 107. The method of embodiment 106, wherein the antioxidant comprises at least one selected from the group consisting of vitamin C, vitamin E, beta-carotene, carotenoid, selenium, manganese, glutathione, coenzyme Q10, lipoic acid, flavonoid, phenol, polyphenol, phytoestrogen, and any combination thereof. [0439] Embodiment 108. The method of embodiment 107, wherein the antioxidant is a vitamin E. [0440] Embodiment 109. The method of embodiment 108, wherein the vitamin E comprises tocopherol-acetate. [0441] Embodiment 110. The method of embodiment 109, wherein the composition comprises between about 1 milligram (mg) to about 100 milligrams (mg) of tocopherol-acetate. [0442] Embodiment 111. The method of embodiment 110, wherein the composition comprises about 12 milligrams (mg) of tocopherol-acetate. [0443] Embodiment 112. The method of any one of embodiments 92-111, wherein the composition is an enteric coated extended-release capsule. [0444] Embodiment 113. The method of any one of embodiments 92-112, wherein the composition is a pharmaceutical composition.
Claims
CLAIMS WHAT IS CLAIMED IS: 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 (SCFAs) or a pharmaceutically acceptable salt thereof; and b. a reduced amount of a tocopherol, wherein the reduced amount of the tocopherol is therapeutically effective for alleviating the condition in combination with the at least two SCFAs or the pharmaceutically acceptable salt thereof, and wherein the reduced amount of the tocopherol is less than an amount of the tocopherol that is therapeutically effective for the condition in absence of the at least two SCFAs or the pharmaceutically acceptable salt thereof.
2. The method of claim 1, wherein the condition is a liver disease.
3. The method of claim 2, wherein the liver disease is selected from the group consisting of a fatty liver disease, nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), liver fibrosis, alcoholic liver disease, 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 of any one of claims 1-3, wherein the tocopherol exhibits synergy with the at least two SCFAs or the pharmaceutically acceptable salt thereof.
5. A method of providing prophylaxis against 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. a tocopherol.
6. The method of claim 5, wherein the prophylaxis comprises reducing a likelihood of progression of NASH to fibrosis.
7. The method of claim 5 or 6, wherein the prophylaxis comprises delaying or slowing progression of NASH to fibrosis.
8. The method of any one of claims 1-7, wherein the composition comprises between 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 1-9, wherein the two SCFAs 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, caproic acid, lactic acid, succinic acid, pyruvic acid, octanoic acid, dodecanoic acid, (4R)-4-hydroxypentanoic acid, 2- ethylhydracrylic acid, 2-hydroxy-3-methylpentanoate, 2-hydroxy-3-methylpentanoic acid, 2- methylbut-2-enoic acid, 2-oxobutanoic acid, 3-hydroxypentanoic acid, 3-methylbut-2-enoic acid, butenoic acid, methylbutyric acid, dimethylbutyric acid, pentadienoic acid, pentenoic acid, pivalic acid, propynoic acid, a pharmaceutically-acceptable salt of any of the foregoing, and any combination thereof.
11. The method of any one of claims 1-10, wherein at least one of the SCFAs is a pharmaceutically-acceptable salt selected from the group consisting of: butyrate, propionate, and acetate salt.
12. The method of any one of claims 1-11, wherein the at least one of the SCFAs is a pharmaceutically-acceptable salt selected from the group consisting of: a Ca salt, Mg salt, a
Na salt, 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 of claim 13, wherein the SCFA is the 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 the 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 between about 100 milligrams (mg) to about 6 grams (g) of Ca salt of butyric acid, Mg salt of butyric acid, Ca salt of acetic acid, 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 Ca salt of butyric acid, Mg salt of butyric acid, Ca salt of acetic acid, Mg salt of acetic acid, or any combination thereof.
19. The method of any one of claims 1-18, wherein the composition comprises between 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 between about 1 milligram (mg) to about 600 milligrams (mg) of tocopherol-acetate.
22. The method of claim 20 or 21, wherein the composition comprises between about 1
milligram (mg) to about 100 milligrams (mg) of tocopherol-acetate.
23. The method of any one of claims 20-22, wherein the composition comprises about 12 milligrams (mg) of tocopherol-acetate.
24. The method of any one of claims 1-23, wherein the composition is an enteric coated extended-release capsule.
25. The method of any one of claims 1-24, wherein the composition is a pharmaceutical composition.
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US202263383175P | 2022-11-10 | 2022-11-10 | |
US63/383,175 | 2022-11-10 |
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WO2024102902A1 true WO2024102902A1 (en) | 2024-05-16 |
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PCT/US2023/079217 WO2024102902A1 (en) | 2022-11-10 | 2023-11-09 | Methods of treating or preventing liver diseases or disorders |
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