Compositions and use thereof in treatment of metabolic syndrome

Abstract

The current invention is directed to a method for ameliorating or treating a metabolic syndrome-related disease or disorder in a subject in need thereof, including administering to the subject a therapeutically effective amount of a composition including L-arginine and sodium butyrate.

Description

COMPOSITIONS AND USE THEREOF IN TREATMENT OF METABOLIC SYNDROMECROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of priority of U.S. Provisional Patent Application No. 63 / 614,721, titled “COMPOSITIONS AND USE THEREOF IN TREATMENT OF METABOLIC SYNDROME” filed 26 December 2023, the contents of which is incorporated herein by reference in its entirety.FIELD OF THE INVENTION

[0002] The invention relates generally to the field of, inter alia, combination therapy, such as including L-arginine and Sodium butyrate, for treating a metabolic syndrome related disease or disorder, e.g., obesity.BACKGROUND

[0003] Obesity is a major health concern globally, leading to increased morbidity and mortality rates. Various diets have been proposed to address obesity, with studies showing that high-protein and high-fiber diets can increase satiety and enhance weight loss. Two dietary components individually, L-arginine and sodium butyrate, have been researched for their effect on obesity and satiety.

[0004] L-arginine, an amino acid, has been found to increase the secretion of anorectic gut hormones, including GLP-1, a hormone that plays a significant role in regulating insulin secretion, glucose metabolism, and satiety. Studies have revealed that the supplementation of L-arginine can improve glucose metabolism and increase satiety in individuals with obesity.

[0005] Sodium butyrate, a short-chain fatty acid produced by gut bacteria, has also been found to improve glucose tolerance and reduce body weight gain in animal and human studies. It was suggested that these effects are mediated by affecting the secretion of guthormones, increasing GLP1 secretion in both animal and human subjects and promoting satiety.

[0006] However, no studies have investigated the effect of combining both L-arginine and sodium butyrate. Thus, there remains a need for new therapeutic combinations, such that includes L-arginine and sodium butyrate for treatment of a metabolic syndrome related disease or condition, or ameliorating a symptom thereof.SUMMARY

[0007] According to the first aspect, there is provided a method for ameliorating or treating a metabolic syndrome-related disease or disorder in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a composition comprising L-arginine and sodium butyrate, thereby ameliorating or treating a metabolic syndrome related disease or disorder in the subject.

[0008] According to another aspect, there is provided a composition comprising L- arginine and sodium butyrate, for use in amelioration or treatment of a metabolic syndrome- related disease or disorder in a subject in need thereof.

[0009] According to another aspect, there is provided a composition comprising a carrier and an active ingredient, wherein the active ingredient consists essentially of L-arginine and sodium butyrate.

[0010] In some embodiments, the metabolic syndrome-related disease or disorder comprises obesity, type 2 diabetes, or both.

[0011] In some embodiments, the subject is characterized by body mass index (BMI) of 30.0 or more.

[0012] In some embodiments, the treating comprises: increasing blood level of glucagon- like peptide-1 (GLP-1), reducing blood glucose level, or both, in the subject.

[0013] In some embodiments, the L-arginine and sodium butyrate are present in a mole per mole (m:m) ratio ranging between 5:9 and 50:9 in the composition.

[0014] In some embodiments, the L-arginine is a mixture of L-arginine in a free form and arginine hydrochloride.

[0015] In some embodiments, the mixture comprises L-arginine in a free form and arginine hydrochloride in a w / w ranging between 1:1 (w / w) to 1:4 (w / w).

[0016] In some embodiments, the administering comprises multiple administrations.

[0017] In some embodiments, the administering is orally administering.

[0018] In some embodiments, the composition is an oral composition.

[0019] In some embodiments, the composition is formulated for oral administration.

[0020] In some embodiments, the composition is an edible composition.

[0021] In some embodiments, the edible composition comprises a foodstuff.

[0022] Unless otherwise defined, all technical and / or scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the invention pertains. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of embodiments of the invention, exemplary methods and / or materials are described below. In case of conflict, the patent specification, including definitions, will control. In addition, the materials, methods, and examples are illustrative only and are not intended to be necessarily limiting.

[0023] Further embodiments and the full scope of applicability of the present invention will become apparent from the detailed description given hereinafter. However, it should be understood that the detailed description and specific examples, while indicating preferred embodiments of the invention, are given by way of illustration only, since various changes and modifications within the spirit and scope of the invention will become apparent to those skilled in the art from this detailed description.BRIEF DESCRIPTION OF THE FIGURES

[0024] Some embodiments of the invention are herein described, by way of example only, with reference to the accompanying figures.

[0025] With specific reference now to the figures in detail, it is stressed that the particulars shown are by way of example and for purposes of illustrative discussion of embodiments of the invention. In this regard, the description together with the drawings makes apparent tothose skilled in the art, how embodiments of the invention may be practiced. Dimensions of components and features shown in the figures are generally chosen for convenience and clarity of presentation and are not necessarily shown to scale. The figures are listed below.

[0026] Figs. 1A-1B includes graphs showing the effects of L-arginine and sodium butyrate on GLP-1 release in obese subjects following a standard meal (Ensure® 250 m ). Results for no intervention (null), 3 g of L-arginine, and 3 g of L-arginine with 1 g of sodium butyrate (n=7) on AUCGLP-I (pmol / Lxmin). Data are expressed as means ± SEM. (1A) A graph showing the pharmacokinetics of the study; (IB) A graph showing calculated area under the curve (AUC) of 1A.

[0027] Fig. 2 includes a graph showing graphs showing the effects of L-arginine and sodium butyrate on plasma glucose levels in obese subjects following a standard meal (Ensure® 250 mL). Results for no intervention (null), 3 g of L-arginine, and 3 g of L-arginine with 1 g of sodium butyrate (n=7) on AUCGLP-I (pmol / Lxmin). Data are expressed as means ± SEM. Different letters (a, b) represent statistically significant difference between the controls (null and 3 g L-arginine) and the experimental group (3 g L-arginine with 1 g sodium butyrate).

[0028] Figs. 3A-3B includes graphs showing the effects of L-arginine and sodium butyrate on hunger visual analogue scales (VAS; 3A) and fullness VAS (3B) in obese subjects following a standard meal (Ensure® 250 mL). Results for no intervention (null), 3 g of L- arginine, and 3 g of L-arginine with 1 g of sodium butyrate (n=7) on AUCGLP-I (pmol / Lxmin). Data are expressed as means ± SEM.DETAILED DESCRIPTION OF THE INVENTION

[0029] According to the first aspect, there is provided a method for ameliorating or treating a metabolic syndrome-related disease or disorder in a subject in need thereof.

[0030] In some embodiments, the method comprises administering to the subject a therapeutically effective amount of a composition comprising L-arginine and sodium butyrate, thereby ameliorating or treating a metabolic syndrome related disease or disorder in the subject.

[0031] As used herein, the term "metabolic syndrome, disease, disorder, or condition" refers to any disease or disorder characterized by excess abdominal fat, hypertension, abnormal fasting plasma glucose level or insulin resistance, high triglyceride levels, low high-density lipoprotein (HDL) cholesterol level, and any combination thereof. In some embodiments, the metabolic syndrome disorders which can be treated according to the present invention are diverse and will be easily understood by the skilled artisan. Without any limitation mentioned are obesity, pre-diabetes, diabetes, hyperglycemia, diabetic dyslipidemia, hyperlipidemia, hypertriglyceridemia, hyper-fattyacidemia, hypercholesterolemia, hyperinsulinemia, insulin-resistance or insulin-resistance related. High risks of metabolic syndrome disease include, but are not limited to, obstructive sleep apnea, nonalcoholic steatohepatitis, chronic kidney disease, polycystic ovary syndrome and low plasma testosterone, erectile dysfunction, or both.

[0032] In some embodiments, the metabolic syndrome-related disease or disorder comprises: obesity, type 2 diabetes, or both.

[0033] In some embodiments, the subject is characterized by body mass index (BMI) of 30.0 or more. In some embodiments, the subject is characterized by a BMI of at least 30.0, 31.0, 32.0, or 35.0, or any value and range therebetween. Each possibility represents a separate embodiment of the invention. In some embodiments, the subject is characterized by a BMI of 30.0-40.0, 30.0-34.9, or 35.0-40. Each possibility represents a separate embodiment of the invention.

[0034] Methods and means for determining and / or calculating BMI of a subject are common and would be apparent to one of ordinary skill in the art.

[0035] In some embodiments, treating comprises: increasing blood level of glucagon-like peptide- 1 (GLP-1), reducing blood glucose level, or both, in the subject.

[0036] Methods and means for determining and / or calculating blood levels of GLP-1, glucose, or both, are common and would be apparent to a person of ordinary skill in the art. Non-limiting examples of such methods include, but are not limited to, western blot, mass spectrometry, dot blot, enzyme linked immunosorbent assay (ELISA), glucose tolerance test (GTT), glucose uptake test such as using 2-[3H]-deoxyglucose (2DOG), or any conventional methods known to a person of skill in the art for the afore-mentioned determination purposes.

[0037] In some embodiments, L-arginine and sodium butyrate are present in a mole per mole (m:m) ratio ranging between 5:9 and 50:9, 10:9 and 50:9, 15:9 and 50:9, 20:9 and 50:9, 25:9 and 50:9, 30:9 and 50:9, 35:9 and 50:9, 40:9 and 50:9, or 45:9 and 50:9 in the composition. Each possibility represents a separate embodiment of the invention.

[0038] In some embodiments, the L-arginine is a mixture of L-arginine in a free form and arginine hydrochloride.

[0039] As used herein, the term “free form arginine” refers to L-arginine that is not bound to other molecules or compounds, such as salts or esters, and / or is in its pure, unmodified form.

[0040] In some embodiments, the mixture comprises L-arginine in a free form and arginine hydrochloride in a w / w ranging between 1 :1 (w / w) to 1:4 (w / w), 1:1 (w / w) to 1 :3 (w / w), or 1: 1 (w / w) to 1 :2 (w / w). In some embodiments, the mixture comprises L-arginine in a free form and arginine hydrochloride in a w / w of at least 1 : 1 (w / w), at least 1:2 (w / w), at least 1:3 (w / w), at least 1:4 (w / w), or any value and range therebetween. Each possibility represents a separate embodiment of the invention.

[0041] In some embodiments, the composition comprises L-arginine, sodium butyrate, or both, in an amount of millimole (mmole). In some embodiments, mole per mole ratio (m:m) comprises mmole per mmole ratio.

[0042] In some embodiments, administering comprises multiple administrations.

[0043] In some embodiments, multiple administering comprises administering once a day, once every other day, twice a week, or 3 times a week. In some embodiments, multiple administering comprises administering at least once a day. In some embodiments, multiple administering comprises administering multiple times a day.

[0044] In some embodiments, administering comprises postprandial administering.

[0045] In some embodiments, administering comprises orally administering.

[0046] In some embodiments, the composition is an oral composition. In some embodiments, the composition is formulated for oral administration. In some embodiments, the composition is an edible composition. In some embodiments, the edible composition comprises a foodstuff or an ingredient thereof.

[0047] According to another aspect, there is provided a composition comprising L- arginine and sodium butyrate, for use in amelioration or treatment of a metabolic syndrome- related disease or disorder, or at least one symptom associated therewith, in a subject in need thereof.

[0048] According to another aspect, there is provided a composition comprising a carrier and an active ingredient, wherein the active ingredient consists essentially of L-arginine and sodium butyrate.

[0049] As used herein, the term “consists essentially of’ denotes that a given compound or substance constitutes the vast majority of the active ingredient’s portion or fraction of the composition.

[0050] In some embodiments, consists essentially of means that: (a) a carotenoid mixture comprising phytoene, phytofluene, zeta carotene, or any combination thereof; and (b) a ceramide, constitutes at least 95%, at least 98%, at least 99%, or at least 99.9% by weight, of the active ingredient(s) of the composition, or any value and range therebetween. Each possibility represents a separate embodiment of the invention.

[0051] The present invention also contemplates pharmaceutical compositions for human medical and veterinary use, which comprise at least one mixture of L-arginine and sodium butyrate of this invention.

[0052] The pharmaceutical compositions of the invention can be formulated in the form of a pharmaceutically acceptable salt comprising L-arginine and sodium butyrate, or analogs thereof. “Pharmaceutically acceptable salts” include those salts formed with free amino groups such as salts derived from non-toxic inorganic or organic acids such as hydrochloric, phosphoric, acetic, oxalic, tartaric acids, and the like, and those salts formed with free carboxyl groups of a fatty acid such as salts derived from non-toxic inorganic or organic bases such as sodium, potassium, ammonium, calcium, ferric hydroxides, isopropylamine, triethylamine, 2-ethylamino ethanol, histidine, procaine, and the like. In one embodiment, pharmaceutical compositions of the present invention are manufactured by processes well known in the art, e.g., by means of conventional mixing, dissolving, granulating, drageemaking, levigating, emulsifying, encapsulating, entrapping or lyophilizing processes.

[0053] The term "pharmaceutically acceptable" means suitable for administration to a subject, e.g., a human or animal. For example, the term "pharmaceutically acceptable" can mean approved by a regulatory agency of the Federal or a state government or listed in the U. S. Pharmacopeia or other generally recognized pharmacopeia for use in animals, and more particularly in humans.

[0054] The term "carrier" refers to a diluent, adjuvant, excipient, or vehicle with which the therapeutic compound is administered. Such pharmaceutical carriers can be sterile liquids, such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like, polyethylene glycols, glycerin, propylene glycol or other synthetic solvents. Water is a preferred carrier when the pharmaceutical composition is administered intravenously. Saline solutions and aqueous dextrose and glycerol solutions can also be employed as liquid carriers, particularly for injectable solutions. Suitable pharmaceutical excipients include starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene glycol, water, ethanol and the like. The composition, if desired, can also contain minor amounts of wetting or emulsifying agents, or pH buffering agents such as acetates, citrates or phosphates. Antibacterial agents such as benzyl alcohol or methyl parabens; antioxidants such as ascorbic acid or sodium bisulfite; and agents for the adjustment of tonicity such as sodium chloride or dextrose are also envisioned. The carrier may constitute, in total, from about 0.1% to about 99.99999% by weight of the pharmaceutical compositions presented herein.

[0055] An embodiment of the invention relates to a composition, presented in unit dosage form and, is prepared by any of the methods well known in the art of pharmacy and pharmacology. In an embodiment of the invention, the unit dosage form is in the form of a tablet, capsule, lozenge, wafer, patch, ampoule, vial or pre-filled syringe. In addition, in vitro assays may optionally be employed to help identify optimal dosage ranges. The precise dose to be employed in the formulation will also depend on the route of administration, and the nature of the disease or disorder, and should be decided according to the judgment of the practitioner and each patient's circumstances. Effective doses can be extrapolated from doseresponse curves derived from in-vitro or in-vivo animal model test bioassays or systems.

[0056] The compositions may comprise preservatives, such as benzalkonium chloride and thimerosal and the like; chelating agents, such as EDTA sodium and others; buffers such as phosphate, citrate and acetate; tonicity agents such as sodium chloride, potassium chloride, glycerin, mannitol and others; antioxidants such as ascorbic acid, acetylcystine, sodium metabisulfote and others; aromatic agents; viscosity adjustors, such as polymers, including cellulose and derivatives thereof; and polyvinyl alcohol and acid and bases to adjust the pH of these aqueous compositions as needed. The compositions may also comprise local anesthetics or other actives.

[0057] In addition, the compositions may further comprise binders (e.g. acacia, cornstarch, gelatin, carbomer, ethyl cellulose, guar gum, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, povidone), disintegrating agents (e.g. cornstarch, potato starch, alginic acid, silicon dioxide, croscarmellose sodium, crospovidone, guar gum, sodium starch glycolate), buffers (e.g., Tris-HCI., acetate, phosphate) of various pH and ionic strength, additives such as albumin or gelatin to prevent absorption to surfaces, detergents (e.g., Tween 20, Tween 80, Pluronic F68, bile acid salts), protease inhibitors, surfactants (e.g. sodium lauryl sulfate), permeation enhancers, solubilizing agents (e.g., glycerol, polyethylene glycerol), anti-oxidants (e.g., ascorbic acid, sodium metabisulfite, butylated hydroxyanisole), stabilizers (e.g. hydroxypropyl cellulose, hydroxypropylmethyl cellulose), viscosity increasing agents (e.g. carbomer, colloidal silicon dioxide, ethyl cellulose, guar gum), sweeteners (e.g. aspartame, citric acid), preservatives (e.g., Thimerosal, benzyl alcohol, parabens), lubricants (e.g. stearic acid, magnesium stearate, polyethylene glycol, sodium lauryl sulfate), flow-aids (e.g. colloidal silicon dioxide), plasticizers (e.g. diethyl phthalate, triethyl citrate), emulsifiers (e.g. carbomer, hydroxypropyl cellulose, sodium lauryl sulfate), polymer coatings (e.g., poloxamers or poloxamines), coating and film forming agents (e.g. ethyl cellulose, acrylates, polymethacrylates) and / or adjuvants.

[0058] In one embodiment, compositions of the present invention are presented in a pack or dispenser device, such as an FDA approved kit, which contains one or more unit dosage forms containing the active ingredient. In one embodiment, the pack or dispenser device is accompanied by instructions for administration.

[0059] In some embodiments, the composition is in the form of, but not limited to, a liquid, gel, solid or biofumigant. In some embodiments, the composition comprises a surfactant to be used for the purpose of emulsification, dispersion, wetting, spreading, integration, disintegration control, stabilization of active ingredients, and improvement of fluidity or rust inhibition.

[0060] Pharmaceutical compositions of the invention are formulated in a conventional manner, using one or more pharmaceutically acceptable inactive ingredients that facilitate processing of the active compounds into preparations that are used pharmaceutically. A formulation depends upon the route of administration chosen. A summary of pharmaceutical compositions described herein is 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, Pa. 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), herein incorporated by reference for such disclosure.

[0061] In another embodiment, a composition according to the invention comprises a mixture of L-arginine and sodium butyrate, and at least one additional active ingredient. In another embodiment, a pharmaceutical composition comprises inactive ingredients, such as carriers, excipients, binders, filling agents, suspending agents, flavoring agents, sweetening agents, disintegrating agents, dispersing agents, surfactants, lubricants, colorants, diluents, solubilizers, moistening agents, plasticizers, stabilizers, penetration enhancers, wetting agents, anti-foaming agents, antioxidants, preservatives, or one or more combination thereof. The pharmaceutical composition, in some embodiments, facilitates administration of the active agent / ingredient, e.g., L-arginine and sodium butyrate, to a subject, such as a mammal subject, e.g., a human subject.

[0062] In another embodiment, compositions described herein include, but are not limited to, aqueous liquid dispersions, self-emulsifying dispersions, solid solutions, liposomal dispersions, aerosols, solid dosage forms, powders, immediate release formulations, controlled release formulations, fast melt formulations, tablets, capsules, pills, delayedrelease formulations, extended release formulations, enteric coated formulations, pulsatile release formulations, multiparticulate formulations, and mixed immediate and controlled release formulations.

[0063] In another embodiment, the composition of the invention is administered orally. All formulations for oral administration are in dosages suitable for such administration. In another embodiment, the solid dosage forms disclosed herein are in the form of a tablet, a pill, a powder, a capsule, solid dispersion, solid solution, bioerodible dosage form, controlled release formulations, pulsatile release dosage forms, multiparticulate dosage forms, beads, pellets, granules. In other embodiments, the pharmaceutical formulation is in the form of a powder. In another embodiment, the pharmaceutical formulation is in the form of a tablet. In another embodiment, the pharmaceutical formulation is in the form of a suspension tablet, a fast-melt tablet, a bite-disintegration tablet, a rapid-disintegration tablet, an effervescent tablet, or a caplet. In another embodiment, pharmaceutical formulation is in the form of a capsule.

[0064] In another embodiment, the pharmaceutical solid oral dosage forms are formulated to provide a controlled release of the active compound. Controlled release profiles include, for example, sustained release, prolonged release, pulsatile release, and delayed release profiles.

[0065] In another embodiment, liquid formulation dosage forms for oral administration are in the form of aqueous suspensions selected from the group including, but not limited to, pharmaceutically acceptable aqueous oral dispersions, emulsions, solutions, elixirs, gels, and syrups. See, e.g., Singh et al., Encyclopedia of Pharmaceutical Technology, 2nd Ed., pp. 754-757 (2002).

[0066] In another embodiment, there is provided use of composition comprising L- arginine and sodium butyrate, in the manufacture of a medicament or a product for prevention or treatment of a disease, disorder or conditions, as disclosed herein.

[0067] In another embodiment, the composition is formulated in a pharmaceutically acceptable composition which refers to a material, such as a carrier or diluent, which does not abrogate the biological activity or properties of the compound, and is relatively nontoxic, i.e., the material is administered to an individual without causing undesirable biologicaleffects or interacting in a deleterious manner with any of the components of the composition in which it is contained.

[0068] In some embodiments, increasing comprises at least 5%, 25%, 50%, 75%, 100%, 250%, 500%, 750%, or 1,000% increase, or any value and range therebetween. Each possibility represents a separate embodiment of the invention.

[0069] In some embodiments, increasing comprises 5-100%, 25-250%, 50-450%, 75- 650%, 100-900%, or 250-1,250% increase. Each possibility represents a separate embodiment of the invention.

[0070] In some embodiments, reducing comprises at least 5%, 20%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 99%, or 100% reducing, or any value and range therebetween. Each possibility represents a separate embodiment of the invention.

[0071] In some embodiments, reducing comprises 5-10%, 5-40%, 20-50%, 45-80%, 10- 90%, or 25-100% reducing. Each possibility represents a separate embodiment of the invention.

[0072] In some embodiments, the subject is a mammal subject. In some embodiments, the subject is a human subject.

[0073] The terms “reducing” or “reduce” and “inhibiting” or “inhibit” are interchangeable.

[0074] A “therapeutically effective amount” depends on the severity and course of the disease or condition, previous therapy, the patient's health status, weight, and response to the drugs, and the judgment of the treating physician. Therapeutically effective amounts are optionally determined by methods including, but not limited to, a dose escalation clinical trial. Therapeutically effective amounts include the administration of the pharmaceutical composition described herein for prophylactic purposes.General

[0075] As used herein the term “about” refers to ± 10 %.

[0076] The terms "comprises", "comprising", "includes", "including", “having” and their conjugates mean "including but not limited to". The term “consisting of’ means “including and limited to”. The term "consisting essentially of' means that the composition, method orstructure may include additional ingredients, steps and / or parts, but only if the additional ingredients, steps and / or parts do not materially alter the basic and novel characteristics of the claimed composition, method or structure.

[0077] The word “exemplary” is used herein to mean “serving as an example, instance or illustration”. Any embodiment described as “exemplary” is not necessarily to be construed as preferred or advantageous over other embodiments and / or to exclude the incorporation of features from other embodiments.

[0078] The word “optionally” is used herein to mean “is provided in some embodiments and not provided in other embodiments”. Any particular embodiment of the invention may include a plurality of “optional” features unless such features conflict.

[0079] As used herein, the singular form "a", "an" and "the" include plural references unless the context clearly dictates otherwise. For example, the term "a compound" or "at least one compound" may include a plurality of compounds, including mixtures thereof.

[0080] Throughout this application, various embodiments of this invention may be presented in a range format. It should be understood that the description in range format is merely for convenience and brevity and should not be construed as an inflexible limitation on the scope of the invention. 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, 3, 4, 5, and 6. This applies regardless of the breadth of the range.

[0081] Whenever a numerical range is indicated herein, it is meant to include any cited numeral (fractional or integral) within the indicated range. The phrases “ranging / ranges between” a first indicate number and a second indicate number and “ranging / ranges from” a first indicate number “to” a second indicate number are used herein interchangeably and are meant to include the first and second indicated numbers and all the fractional and integral numerals therebetween.

[0082] As used herein the term "method" refers to manners, means, techniques and procedures for accomplishing a given task including, but not limited to, those manners, means, techniques and procedures either known to, or readily developed from known manners, means, techniques and procedures by practitioners of the chemical, pharmacological, biological, biochemical and medical arts.

[0083] As used herein, the term “treating” includes abrogating, substantially inhibiting, slowing or reversing the progression of a condition, substantially ameliorating clinical or aesthetical symptoms of a condition or substantially preventing the appearance of clinical or aesthetical symptoms of a condition. Further, treat, treatment, treating, as used herein, means any of the following: the reduction in severity of a metabolic syndrome disorder; the prophylaxis of one or more symptoms associated with a metabolic syndrome disorder; the reduction in the duration of a disease course of a metabolic syndrome disorder; the amelioration of one or more symptoms associated with a metabolic syndrome disorder; without necessarily curing the metabolic syndrome disorder.

[0084] As used herein, the terms “preventing” or “prevention” of a disease, disorder, or condition encompasses the delay, prevention, suppression, or inhibition of the onset of a disease, disorder, or condition. As used in accordance with the presently described subject matter, the term "prevention" relates to a process of prophylaxis in which a subject is exposed to the presently described compositions or composition prior to the induction or onset of the disease / disorder process. This could be done where an individual has a genetic pedigree indicating a predisposition toward occurrence of the disease / disorder to be prevented. For example, this might be true of an individual whose ancestors show a predisposition toward certain types of, for example, inflammatory disorders. The term "suppression" is used to describe a condition wherein the disease / disorder process has already begun but obvious symptoms of the condition have yet to be realized. Thus, the cells of an individual may have the disease / disorder, but no outside signs of the disease / disorder have yet been clinically recognized. In either case, the term prophylaxis can be applied to encompass both prevention and suppression. Conversely, the term "treatment" refers to the clinical application of active agents to combat an already existing condition whose clinical presentation has already been realized in a patient.

[0085] As used herein, "treating" comprises ameliorating and / or preventing.

[0086] In those instances where a convention analogous to "at least one of A, B, and C, etc." is used, in general such a construction is intended in the sense one having skill in the art would understand the convention (e.g., "a system having at least one of A, B, and C" would include but not be limited to systems that have A alone, B alone, C alone, A and B together, A and C together, B and C together, and / or A, B, and C together, etc.). It will be further understood by those within the art that virtually any disjunctive word and / or phrase presenting two or more alternative terms, whether in the description, claims, or drawings, should be understood to contemplate the possibilities of including one of the terms, either of the terms, or both terms. For example, the phrase "A or B" will be understood to include the possibilities of "A" or "B" or "A and B."

[0087] It is appreciated that certain features of the invention, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention, which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable subcombination or as suitable in any other described embodiment of the invention. Certain features described in the context of various embodiments are not to be considered essential features of those embodiments unless the embodiment is inoperative without those elements.

[0088] Additional objects, advantages, and novel features of the present invention will become apparent to one ordinarily skilled in the art upon examination of the following examples, which are not intended to be limiting. Additionally, each of the various embodiments and aspects of the present invention as delineated hereinabove and as claimed in the claims section below finds experimental support in the following examples.

[0089] Various embodiments and aspects of the present invention as delineated hereinabove and as claimed in the claims section below find experimental support in the following examples.EXAMPLES

[0090] Generally, the nomenclature used herein and the laboratory procedures utilized in the present invention include chemical, molecular, biochemical, and cell biology techniques. Such techniques are thoroughly explained in the literature. See, for example, "Molecular Cloning: A laboratory Manual" Sambrook et al., (1989); "Current Protocols in Molecular Biology" Volumes I-III Ausubel, R. M., ed. (1994); "Cell Biology: A Laboratory Handbook", Volumes I-III Cellis, J. E., ed. (1994); The Organic Chemistry of Biological Pathways by John McMurry and Tadhg Begley (Roberts and Company, 2005); Organic Chemistry of Enzyme-Catalyzed Reactions by Richard Silverman (Academic Press, 2002); Organic Chemistry (6th Edition) by Leroy "Skip" G Wade; Organic Chemistry by T. W. Graham Solomons and, Craig Fryhle.Methods

[0091] This study was conducted at Rambam Health Care Campus (RHCC), a tertiary hospital in Northern Israel. Ethical approval was obtained from the RHCC institutional review board and ethics committee, and all participants provided written informed consent before participating in the study.

[0092] Eligible participants were adults with obesity (body mass index (BMI) > 30 kg / cm2). Those with conditions related to malabsorption, a history of type 1 or type 2 diabetes, chronic renal failure with an estimated glomerular filtration rate (eGFR) < 60 mL / min / 1.73 m2, chronic liver disease, active cancer, prior or planned surgical treatment for obesity, use of any medication intended to promote weight loss within 90 days before screening, and pregnancy were excluded. The study protocol is described in detail in Table 1 below.Table 1. Study protocol

[0093] The screening visit involved anthropometric measurements, complete blood count, and biochemistry tests.

[0094] Eligible patients attended three visits at two- week intervals. Participants fasted for eight hours before each visit. During the control visit (visit 2), they received an isocaloric intake of Ensure® (250 mL) at time t = 60 minutes without any prior intervention. At visit 3, they received oral L- Arginine (3 g) at t = 0 minutes, followed by Ensure® intake (250 mL) at t = 60 minutes. During visit 4, they received oral L-Arginine (3 g) and sodium butyrate (1 g) in combination at t = 0 minutes, followed by Ensure® intake (250 mL) at t = 60 minutes.

[0095] During each visit, blood tests were conducted at 15-minute intervals, starting 15 minutes before the ingestion of study supplementation (i.e., 75 minutes before Ensure® intake), to measure plasma GLP-1 and glucose levels. Participants were also asked to complete visual analogue scales (VAS) at each time-point, assessing subjective feelings of hunger and fullness (Table 2).Table 2. Schedule of interventions and assessments (V2-V4)

[0096] For the study, Abbott's Ensure® (250 mL) was used as a meal replacement, while L-arginine and sodium butyrate were produced by West Bengal Chemical Industries, India. The dosage of L-arginine (3 g) and sodium butyrate (1 g in 5 mL) was based on previous research.

[0097] Laboratory tests were conducted by the Hematology and Biochemical Laboratories at RHCC, and GLP-l was measured using the Enzyme Immunoassay (EIA) Kit, a quantitative in vitro assay produced by Sigma- Aldrich, St. Louis, Missouri, USA. The intraassay coefficient of variation for GLP-l was 6%.Statistical analysis

[0098] The descriptive data were reported as means ± standard deviations (SD) unless otherwise stated. To compare plasma GLP-l and glucose levels, GLP-l area under the curve (AUC), and satiety VAS scores across intervention groups, repeated measures ANOVA was used. This was followed by a post-hoc Bonferroni correction to account for multiple comparisons, resulting in a corrected significance level (a) of 0.01667. Statistically significant differences were considered if p-values were below this threshold.

[0099] The total AUC was calculated using the trapezoid rule. As per a prior study, a 30% rise in plasma GLP-l levels was deemed significant after consuming the supplement. To ensure accuracy, seven patients were enrolled with a 5% alpha level (95% two-sided confidence interval) and 80% power (beta). All statistical analyses were performed using STATA version 17 (Stata Corp., Texas, USA).Results

[0100] The inventors recruited seven adults with obesity, including five women and two men, between May 2022 and November 2022. The participants had an average age of 40.2 ± 11.9 years and an average BMI of 34.5 ± 3.8 kg / m2. Table 3 provides the baseline characteristics of the participants.Table 3. Baseline characteristics for participantsransferase; AST, aspartate lasma glucose; HDL, high-

[0101] The simultaneous administration of L-arginine and sodium butyrate before the Ensure® (250 mL) meal significantly increased the mean AUC of plasma GLP-1 (AUCGLP- i) compared to ‘no treatment’ control (8,564.3 ± 4,200.9 vs. 7,082.5 ± 4,136.6 pmol / (L min), respectively; p = 0.015). There was a trend towards high levels of GLP-1 following the oral ingestion of L-arginine alone, but this effect was not statistically significant (Fig- 1)

[0102] At t=l 50 minutes, a significantly lower mean glucose level of 107.3 ± 38.4 mg / dL was observed in the combined L-arginine and sodium butyrate treatment. This is in comparison to 120.1 ± 33.2 mg / dL or 122. 15 ± 36.6 after treatment with L-arginine alone, or with no intervention, respectively (Fig, 2).

[0103] The oral administration of L-arginine, either alone or in combination with sodium butyrate, was well-tolerated and did not result in any self-reported adverse effects. The VAS scores for nausea did not show any significant changes.

[0104] A slight trend towards reduced hunger following the combined administration of L-arginine and sodium butyrate between t=120 and t=l 50 minutes was observed. The mean VAS hunger score was 6.3 ± 2.7 compared to 7.7 ± 2.8 with no intervention at t=l 50 minutes (Fig. 3).

[0105] The current study demonstrated that combined administration of L-arginine and sodium butyrate before a meal can increase postprandial circulating GLP-1 levels in individuals with obesity. The combination of these components has been deemed safe and weil-toierated. Hunger levels were found to decrease slightly between 120 and 150 minutes after this intervention. Furthermore, 90 minutes after an Ensure® (250 mL) meal (t=150), the combination of L-arginine and sodium butyrate resulted in lower glucose levels compared to L-arginine alone or no intervention. These findings suggest that combining these two components could have an additive effect on GLP-1 secretion, appetite, and regulation of blood glucose levels.

[0106] Further to the above, the inventors conducted various experiments to develop both solid and liquid formulations aimed at addressing two main challenges: (1) Masking the bitter and salty taste of L-arginine; and (2) Eliminating the off-putting smell of sodium butyrate in the final selected blend.

[0107] The chosen blend composition included 1 gram of sodium butyrate and 3 grams of L-arginine, where part of the arginine was in a free form and the other part was as arginine hydrochloride in specific molar ratios to neutralize the butyrate. Sodium butyrate has a molecular weight of 110.088 g / mol, so 1 gram equals 9 mmol. To balance it, the inventors measured 9 mmol of arginine hydrochloride with a molecular weight of 210.66 g / mol, which equals 1.9 grams. Additionally, the inventors added 1.1 grams of free L-arginine to the mixture. This resulted in a pH-balanced blend containing 1 gram of sodium butyrate and 3 grams of arginine. This solid mixture underwent several processes, including: Drygranulation; and Wet granulation using water or alcohol.

[0108] Additionally, the inventors explored combinations with various available oils, such as lecithin oil derived from sunflowers combined with alpha-lipoic acid (9 parts + 1 part), and soy-derived lecithin oil. From these, the inventors developed solid formulations by incorporating commonly used emulsifiers in the food industry7, such as cocoa butter, or suspensions within an aqueous medium by heating the tv / o phases to form dispersed liposomes.

[0109] For both types of preparations (solid and liquid), the inventors added standard flavoring and aromatic agents used in the food and dietary supplement industries to enhance palatability.

[0110] These formulations were evaluated for taste and smell and were found to be acceptable. Additional tests such as stability and particle size analysis are conducted.

[0111] Although the invention has been described in conjunction with specific embodiments thereof, it is evident that many alternatives, modifications, and variations will be apparent to those skilled in the art. Accordingly, it is intended to embrace all such alternatives, modifications and variations that fall within the spirit and broad scope of the appended claims.

Claims

CLAIMSWhat is claimed is:

1. A method for ameliorating or treating a metabolic syndrome-related disease or disorder in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a composition comprising L-arginine and sodium butyrate, thereby ameliorating or treating a metabolic syndrome related disease or disorder in the subject.

2. The method of claim 1, wherein said metabolic syndrome-related disease or disorder comprises obesity, type 2 diabetes, or both.

3. The method of claim 2, wherein said subject is characterized by body mass index (BMI) of 30.0 or more.

4. The method of any one of claims 1 to 3, wherein said treating comprises: increasing blood level of glucagon-like peptide-1 (GLP-1), reducing blood glucose level, or both, in said subject.

5. The method of any one of claims 1 to 4, wherein said L-arginine and sodium butyrate are present in a mole per mole (m:m) ratio ranging between 5:9 and 50:9 in said composition.

6. The method of any one of claims 1 to 5, wherein said L-arginine is a mixture of L- arginine in a free form and arginine hydrochloride.

7. The method of claim 6, wherein said mixture comprises L-arginine in a free form and arginine hydrochloride in a weight per weight ratio (w / w) ranging between 1 : 1 (w / w) to 1:4 (w / w).

8. The method of any one of claims 1 to 7, wherein said administering comprises multiple administrations.

9. The method of any one of claims 1 to 8, wherein said administering is orally administering.

10. The method of any one of claims 1 to 9, wherein said composition is an oral composition.

11. The method of any one of claims 1 to 10, wherein said composition is formulated for oral administration.

12. The method of any one of claims 1 to 11, wherein said composition is an edible composition.

13. The method of claim 12, wherein said edible composition comprises a foodstuff.

14. A composition comprising L-arginine and sodium butyrate, for use in amelioration or treatment of a metabolic syndrome-related disease or disorder in a subject in need thereof.

15. The composition for use according to claim 14, wherein said metabolic syndrome- related disease or disorder comprises obesity, type 2 diabetes, or both.

16. The composition for use according to claim 14 or 15, wherein said L-arginine and sodium butyrate are present in a m:m ratio ranging between 5:9 to 50:9 in said composition.

17. The composition for use according to any one of claims 14 to 16, wherein said L- arginine is a mixture of L-arginine in a free form and arginine hydrochloride.

18. The composition for use according to claim 17, wherein said mixture comprises L- arginine in a free form and arginine hydrochloride in a w / w ranging between 1 : 1 (w / w) to 1:4 (w / w).

19. The composition for use according to any one of claims 14 to 18, wherein said composition is an oral composition.

20. The composition for use according to any one of claims 14 to 19, wherein said composition is formulated for oral administration.

21. The composition for use according to any one of claims 14 to 20, wherein said composition is an edible composition.

22. The composition for use according to claim 21, wherein said edible composition comprises a foodstuff.

23. A composition comprising a carrier and an active ingredient, wherein said active ingredient consists essentially of L-arginine and sodium butyrate.

24. The composition of claim 23, wherein said L-arginine and sodium butyrate are present in a nrmole ratio ranging between 5:9 and 50:9 in said composition.

25. The composition of claim 23 or 24, wherein said L-arginine is a mixture of L-arginine in a free form and arginine hydrochloride.

26. The composition of claim 25, wherein said mixture comprises L-arginine in a free form and arginine hydrochloride in a w / w ranging between 1 : 1 (w / w) to 1 :4 (w / w).

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