Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K33/00—Medicinal preparations containing inorganic active ingredients
  • A61K33/06—Aluminium, calcium or magnesium; Compounds thereof, e.g. clay
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
  • A61K9/0095—Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches
• • A—HUMAN NECESSITIES
  • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
  • A23L—FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES, NOT OTHERWISE PROVIDED FOR; PREPARATION OR TREATMENT THEREOF
  • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
  • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
  • A61K31/205—Amine addition salts of organic acids; Inner quaternary ammonium salts, e.g. betaine, carnitine
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
  • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
  • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K33/00—Medicinal preparations containing inorganic active ingredients
  • A61K33/14—Alkali metal chlorides; Alkaline earth metal chlorides
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
  • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
  • A61K47/22—Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/0012—Galenical forms characterised by the site of application
  • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/08—Solutions
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
  • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
  • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
  • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics

Definitions

• the present invention in some embodiments thereof, relates to nutrition and, more particularly, to magnesium and L-Carnitine containing formulations which enhance the effect of exercise on fat metabolism, and which are useful, for example, in the treatment of liver conditions, such as fatty liver disease, chronic liver disease, non alcoholic fatty liver disease (NAFLD), alcoholic liver disease (ALD), hepatitis, fibrosis, cirrhosis and non-alcoholic steatohepatitis (NASH).
• liver conditions such as fatty liver disease, chronic liver disease, non alcoholic fatty liver disease (NAFLD), alcoholic liver disease (ALD), hepatitis, fibrosis, cirrhosis and non-alcoholic steatohepatitis (NASH).
• Magnesium is a natural element widely diffused in living organisms, especially in mammals, wherein the largest concentration thereof occurs in bones.
• a magnesium deficiency, or hypomagnesaemia, is often associated with increased incidence of diabetes mellitus, metabolic syndrome, and mortality rate from coronary artery disease (CAD).
• CAD coronary artery disease
• Magnesium deficiency in a living organism has also been associated with abnormal muscle excitability as well as convulsions, psychiatric disturbances, and calcium and/or potassium abnormalities.
• the current daily Recommended Dietary Allowances for magnesium is 420 mg/day for males and 320 mg/day for females above 31 years, with an additional 300 mg/day during pregnancy or physical growth. Surveys show that a substantial number of adults in the United States fail to consume recommended daily amounts of magnesium.
• Carnitine (vitamin Bt; 3-hydroxy-4-trimethylammonio-butanoate) is a quaternary ammonium compound biosynthesized from the amino acids lysine and methionine. In living cells, it is required for the transport of fatty acids from the cytosol into the mitochondria during the breakdown of lipids for the generation of metabolic energy.
• Carnitine exists in two stereoisomers.
• the biologically active form is L- carnitine, whilst its enantiomer, D-carnitine, is biologically inactive.
• L-carnitine is for humans an essential co-factor for the transport of long-chain fatty acids across the inner mitochondrial membrane into the matrix, where they are broken down for energy production (b-oxidation).
• L-carnitine-L-tartrate is the salt of L-carnitine base with tartaric acid with the formula (C 7 H 16 N0 3 ) 2 .C 4 H 4 0 6 . It is a crystalline powder, with a melting point of 169- l75°C, consisting of approximately 68 % L-carnitine and 32 % L-tartaric acid. It has a molecular weight of 472.5 g/mol and CAS Registry Number 36687-82-8. Its chemical name is: 3-carboxy-2-hydroxy-N,N,N-trimethyl-(2R)-l-propanaminium, 2:1 salt with (2R,3R)-2,3-dihydroxybutanedioic acid.
• L-carnitine-containing products have been reported as improving exercise performance. These reports concern studies which demonstrated that L-carnitine plays an essential role in the body for producing energy from fat; ensuring athletic endurance; promoting recovery after exercise; providing the heart and immune cells with energy; and preventing early onset of fatigue during exercise.
• Fatty liver disease is a reversible condition where large vacuoles of triglyceride fat accumulate in liver cells.
• the disease has multiple causes, but is associated primarily with excessive intake of alcohol or another drug or toxin, with obesity and insulin resistance, and with other conditions that influence fat metabolism.
• Non-alcoholic fatty liver disease is one of the types of fatty liver disease, which occurs when fat is deposited (steatosis) in the liver due to causes other than excessive alcohol use.
• NASH Non-alcoholic steatohepatitis
• Alcoholic liver disease encompasses liver manifestations related to alcohol overconsumption, including fatty liver, alcoholic hepatitis and chronic hepatitis with liver fibrosis and cirrhosis.
• Hepatitis includes the inflammation of liver tissue
• fibrosis includes the formation of excess fibrosis connective tissue in an organ, e.g., the liver
• cirrhosis is a condition in which the liver does not function properly due to long term damage characterized by the replacement of normal liver tissue by scar tissue.
• a formulation containing a source of magnesium, a source of L-carnitine and a physiologically acceptable carrier containing a source of magnesium, a source of L-carnitine and a physiologically acceptable carrier.
• a formulation containing a source of magnesium, a source of L-carnitine, dihydroquercetin (DHQ) and a physiologically acceptable carrier.
• DHQ dihydroquercetin
• a formulation comprising magnesium lactate, L-carnitine-L-tartrate and an aqueous solution.
• kits comprising packaging material and a source of magnesium, a source of L-carnitine and a physiologically acceptable carrier packaged within the packaging material, the kit indicated for the treatment liver conditions, such as fatty liver disease, chronic liver disease, non-alcoholic fatty liver disease (NAFLD), alcoholic liver disease (ALD), hepatitis, fibrosis, cirrhosis and non-alcoholic steatohepatitis (NASH).
• liver conditions such as fatty liver disease, chronic liver disease, non-alcoholic fatty liver disease (NAFLD), alcoholic liver disease (ALD), hepatitis, fibrosis, cirrhosis and non-alcoholic steatohepatitis (NASH).
• kits comprising a packaging material and a formulation described herein packaged within the packaging material, the kit indicated for the treatment of liver conditions, such as fatty liver disease, chronic liver disease, non-alcoholic fatty liver disease (NAFLD), alcoholic liver disease (ALD), hepatitis, fibrosis, cirrhosis and non alcoholic steatohepatitis (NASH).
• liver conditions such as fatty liver disease, chronic liver disease, non-alcoholic fatty liver disease (NAFLD), alcoholic liver disease (ALD), hepatitis, fibrosis, cirrhosis and non alcoholic steatohepatitis (NASH).
• a nutrition supplement comprising a formulation described herein.
• a use of a formulation described herein in the manufacture of a nutrition supplement is provided.
• the formulation further comprises an antioxidant.
• the antioxidant is dihydroquercetin (DHQ).
• the source of magnesium comprises magnesium lactate.
• the source of L-carnitine comprises L- carnitine tartrate.
• the formulation is in a liquid form.
• the carrier is an aqueous solution.
• the formulation is formulated for oral administration.
• the formulation is indicated for use in combination with exercise.
• the formulation is administered from about 10 minutes to about 3 hours prior to performing exercise.
• the formulation is administered about one hour prior to performing exercise.
• the formulation is administered once a day.
• the formulation is administered for a time period that ranges from about 10 days to about 200 days.
• the source of magnesium and the source of L-carnitine are packaged individually within the packaging material.
• each of the source of magnesium, the source of L-carnitine and the carrier are packaged individually within the packaging material.
• the source of magnesium and the carrier are packaged together within the packaging material, and the kit further comprises instruction to mix the source of L-carnitine with the source of magnesium and the carrier. According to some embodiments, the kit further comprises an antioxidant packaged within the packaging material.
• the antioxidant is dihydroquercetin (DHQ).
• the kit is indicated for use in combination with exercise.
• the kit is indicated for treating liver conditions, such as fatty liver disease, chronic liver disease, non-alcoholic fatty liver disease (NAFLD), alcoholic liver disease (ALD), hepatitis, fibrosis, cirrhosis and non alcoholic steatohepatitis (NASH).
• liver conditions such as fatty liver disease, chronic liver disease, non-alcoholic fatty liver disease (NAFLD), alcoholic liver disease (ALD), hepatitis, fibrosis, cirrhosis and non alcoholic steatohepatitis (NASH).
• the nutrition supplement is indicated for use in combination with exercise.
• the nutrition supplement is indicated for the treatment of liver conditions, such as fatty liver disease, chronic liver disease, non alcoholic fatty liver disease (NAFLD), alcoholic liver disease (ALD), hepatitis, fibrosis, cirrhosis and non-alcoholic steatohepatitis (NASH).
• liver conditions such as fatty liver disease, chronic liver disease, non alcoholic fatty liver disease (NAFLD), alcoholic liver disease (ALD), hepatitis, fibrosis, cirrhosis and non-alcoholic steatohepatitis (NASH).
• Some embodiments of the invention are directed to a method of treating or reducing the severity of the chronic liver disease, fatty liver disease, non alcoholic fatty liver disease (NAFLD), alcoholic liver disease (ALD), hepatitis, fibrosis, cirrhosis or NASH comprising administering the formulation of the invention to a subject in need thereof.
• the formulation is administered prior to exercising.
• the present invention in some embodiments thereof, relates to nutrition and, more particularly, but not exclusively, to magnesium and L-carnitine containing formulations, which are useful, for example, for treating liver conditions, such as fatty liver disease, chronic liver disease, non-alcoholic fatty liver disease (NAFLD), alcoholic liver disease (ALD), hepatitis, fibrosis, cirrhosis and non-alcoholic steatohepatitis (NASH).
• liver conditions such as fatty liver disease, chronic liver disease, non-alcoholic fatty liver disease (NAFLD), alcoholic liver disease (ALD), hepatitis, fibrosis, cirrhosis and non-alcoholic steatohepatitis (NASH).
• a formulation containing a source or magnesium, a source of L-carnitine, and a physiologically acceptable carrier a formulation containing a source or magnesium, a source of L-carnitine, and a physiologically acceptable carrier.
• magnesium refers to the magnesium ion Mg 2+ , except where indicated otherwise.
• physiologically acceptable carrier refers to a carrier or a diluent that does not cause significant irritation to an organism and does not abrogate the biological activity and properties of the administered compound.
• carriers are: propylene glycol, saline, emulsions and mixtures of organic solvents with water, as well as solid (e.g., powdered) and gaseous carriers.
• the formulation further comprises an antioxidant.
• the antioxidant comprises a flavonoid.
• the flavonoid comprises a flavanonol, that is, a flavonoid comprising a 2,3-dihydroflavonol backbone.
• antioxidant flavanonols include, for example, dihydroquercetin (DHQ) and dihydrokaempferol. DHQ is an exemplary antioxidant.
• the antioxidant may be a chiral or achiral compound.
• an antioxidant chiral (e.g., DHQ)
• the compound may comprise any of the chiral forms of the compound, or any mixture thereof (e.g., a racemate).
• DHQ may comprise (2R,3R)-DHQ, (2S,3S)-DHQ, (2R,3S)-DHQ, and/or (2S,3R)- DHQ.
• the DHQ is (2R,3R)-DHQ.
• a formulation containing a source or magnesium, a source of L-carnitine, an antioxidant and a physiologically acceptable carrier.
• a formulation containing a source or magnesium, a source of L-carnitine, a flavanonol antioxidant and a physiologically acceptable carrier containing a source or magnesium, a source of L-carnitine, a flavanonol antioxidant and a physiologically acceptable carrier.
• a formulation containing a source of magnesium, a source of L-carnitine, dihydroquercetin (DHQ) (e.g., (2R,3R)-DHQ) and a physiologically acceptable carrier e.g., (2R,3R)-DHQ
• DHQ dihydroquercetin
• source of magnesium encompasses compounds, salts, complexes and compositions that generate magnesium (e.g., magnesium ions) in a physical medium and include, for example, salts and complexes of magnesium and mixtures (e.g., solutions, suspensions) comprising magnesium (e.g., magnesium ions).
• the source of magnesium is a pharmaceutically acceptable salt of magnesium.
• the phrase“pharmaceutically acceptable salt” refers to a charged species of the parent compound (e.g., Mg 2+ , L-carnitine) and its counter ion(s).
• the counter ion(s) is typically selected to modify the solubility characteristics of the parent compound and/or to reduce any significant irritation to an organism by the salt, while not abrogating the biological activity and properties of the administered compound.
• a counter ion e.g., anion
• a cation e.g., magnesium, L-carnitine
• a pharmaceutically acceptable salt examples include ammonium, sodium and potassium.
• a counter ion for a divalent ion such as magnesium (Mg 2+ ) may comprise, for example, one or more univalent anions, which may be combined with magnesium at a 2:1 anion:magnesium molar ratio; one or more divalent anions, which may be combined with magnesium at a 1 : 1 aniommagnesium molar ratio; and a trivalent anion, which may be combined with magnesium at a 2:3 aniommagnesium molar ratio.
• univalent, divalent and trivalent anions may be used.
• the counter ion for magnesium consists of a univalent anion (one or more univalent anions) and/or a divalent anion (one or more divalent anions).
• the counter ion for magnesium is a univalent anion (one or more univalent anions).
• a magnesium salt with anions characterized by a relatively low valence i.e., divalent and univalent anions
• univalent anions will facilitate dissolution of the magnesium, and thereby enhance, for example, bioavailability of the magnesium, ease of formulation, and/or ease of administration of the formulation.
• the salt of magnesium comprises magnesium lactate. In some embodiments, the lactate comprises L-lactate. In some embodiments, the lactate comprises D-lactate. In some embodiments, the lactate comprises racemic lactate.
• magnesium lactate is a highly suitable source of magnesium, because it is a highly water-soluble salt, and because the lactate can further serve as a significant source of energy to the body when administered prior to performing exercise.
• the formulation comprises magnesium lactate (e.g., magnesium ions and lactic acid) as a source of magnesium.
• magnesium lactate e.g., magnesium ions and lactic acid
• the phrase“source of L-carnitine” encompasses pure L-carnitine, as well as salts, complexes, compounds or compositions that generate L-carnitine in a physiological medium, and mixtures (e.g., solutions, suspensions) comprising L- carnitine.
• the source of L-camitine comprises zwitterionic L- carnitine, that is, L-carnitine comprising a positive charge (e.g., an ammonium cation) and an equal negative charge (e.g., carboxylate anion).
• L-carnitine comprising a positive charge (e.g., an ammonium cation) and an equal negative charge (e.g., carboxylate anion).
• the source comprises pure (e.g., zwitterionic) L- carnitine.
• the source comprises a pharmaceutically acceptable salt of L-carnitine.
• the pharmaceutically acceptable salt of L-carnitine comprises zwitterionic L-carnitine, a positively charged counter ion (e.g., cations described herein), and a negatively charged counter ion (e.g., anions described herein).
• the pharmaceutically acceptable salt of L-carnitine comprises positively charged L-carnitine (e.g., comprising a cationic ammonium group and a neutral carboxylic acid group) and one or more negatively charged counter ions (e.g., anions described herein).
• positively charged L-carnitine e.g., comprising a cationic ammonium group and a neutral carboxylic acid group
• negatively charged counter ions e.g., anions described herein.
• a counter ion for positively charged L-carnitine may comprise, for example, one or more univalent anions, which may be combined with L-carnitine at a 1 :1 aniomL-carnitine molar ratio; one or more divalent anions, which may be combined with L-carnitine at a 1 :2 anion :L-carnitine molar ratio; and one or more trivalent anions, which may be combined with L-carnitine at a 1 :3 aniomL-carnitine molar ratio.
• univalent anions which may be combined with L-carnitine at a 1 :1 aniomL-carnitine molar ratio
• divalent anions which may be combined with L-carnitine at a 1 :2 anion :L-carnitine molar ratio
• trivalent anions which may be combined with L-carnitine at a 1 :3 aniomL-carnitine molar ratio.
• the counter ion for L-carnitine consists of a univalent anion (one or more univalent anions) and/or a divalent anion (one or more divalent anions).
• Tartrate is an exemplary divalent anion.
• the tartrate comprises D-tartrate. In some embodiments, the tartrate comprises meso-tartrate. In some embodiments, the tartrate comprises racemic tartrate (L-tartrate and D-tartrate). In exemplary embodiments, the tartrate comprises L-tartrate.
• the counter ion for L-carnitine is a univalent anion (one or more univalent anions).
• an L-carnitine salt with anions characterized by a relatively low valence may help to avoid interfering with dissolution of magnesium, when the L- carnitine salt is contacted with the magnesium.
• the counter ions of magnesium and/or L-carnitine may be chiral or achiral.
• a compound or ion when a compound or ion is chiral (e.g., lactate, tartrate), the compound may comprise any of the chiral forms of the compound or ion, or any mixture thereof (e.g., a racemate).
• the formulation is in liquid form, for example, a formulation wherein the physiologically acceptable carrier is a liquid.
• the physiologically acceptable carrier is an aqueous solution.
• aqueous solution encompasses pure water (to which the sources of magnesium and L-carnitine are added) as well as water with solutes (e.g., solutes other than magnesium and L-camitine).
• an aqueous solution contains both the carrier (e.g., water) and at least one other component of the formulation (e.g., magnesium, L- carnitine, or antioxidant).
• the aqueous solution may be the source of magnesium or source of L-carnitine described herein.
• magnesium-enriched water which may optionally serve as both carrier and source of magnesium.
• Magnesium-enriched water suitable for use in the formulation may be prepared, for example, as described in International Patent Application PCT/IL2010/000843 (published as WO 2011/045795).
• a concentration of magnesium in a formulation in liquid form is in a range of from about 120 mg/1 to about 3000 mg/1. In some embodiments, the concentration of magnesium is in a range of from about 200 mg/1 to about 2000 mg/1. In some embodiments, the concentration of magnesium is in a range of from about 300 mg/1 to about 1200 mg/1. In some embodiments, the concentration of magnesium is in a range of from about 400 mg/1 to 800 mg/1. In exemplary embodiments, the concentration of magnesium is about 600 mg/1. In some embodiments, the concentration of magnesium is in a range of from about 120 mg/1 to about 300 mg/1. In some embodiments, the concentration of magnesium is in a range of from about 300 mg/1 to about 600 mg/1.
• the concentration of magnesium is in a range of from about 600 mg/1 to about 900 mg/1. In some embodiments, the concentration of magnesium is in a range of from about 900 mg/1 to about 1200 mg/1. In some embodiments, the concentration of magnesium is in a range of from about 1200 mg/1 to about 1500 mg/1. In some embodiments, the concentration of magnesium is in a range of from about 1500 mg/1 to about 1800 mg/1. In some embodiments, the concentration of magnesium is in a range of from about 1800 mg/1 to about 2000 mg/1. In some embodiments, a concentration of L-carnitine in a formulation in liquid form (e.g., as described herein) is in a range of from about 1360 mg/l to about 10880 mg/l.
• the concentration of L-carnitine is in a range of from about 2720 mg/l to about 10880 mg/l. In some embodiments, the concentration of L- carnitine is in a range of from about 2720 mg/l to about 8160 mg/l. In some embodiments, the concentration of L-carnitine is in a range of from about 4080 mg/l to about 6800 mg/l. In exemplary embodiments, the concentration of L-carnitine is about 5440 mg/l. In some embodiments, the concentration of L-carnitine is in a range of from about 1360 mg/l to about 2720 mg/l.
• the concentration of L-carnitine is in a range of from about 2720 mg/l to about 4080 mg/l. In some embodiments, the concentration of L-carnitine is in a range of from about 4080 mg/l to about 5440 mg/l. In some embodiments, the concentration of L-carnitine is in a range of from about 5440 mg/l to about 6800 mg/l. In some embodiments, the concentration of L-carnitine is in a range of from about 6800 mg/l to about 8160 mg/l. In some embodiments, the concentration of L-carnitine is in a range of from about 8160 mg/l to about 9520 mg/l. In some embodiments, the concentration of L-carnitine is in a range of from about 9520 mg/l to about 10880 mg/l.
• a concentration of L-carnitine-L-tartrate in a formulation in liquid form is in a range of from about 2000 mg/l to about 16000 mg/l. In some embodiments, the concentration of L-carnitine-L- tartrate is in a range of from about 4000 mg/l to about 16000 mg/l. In some embodiments, the concentration of L-carnitine-L-tartrate is in a range of from about 4000 mg/l to about 12000 mg/l. In some embodiments, the concentration of L- carnitine-L-tartrate is in a range of from about 6000 mg/l to about 10000 mg/l.
• the concentration of L-carnitine-L-tartrate is about 8000 mg/l. In some embodiments, the concentration of L-carnitine-L-tartrate is in a range of from about 2000 mg/l to about 4000 mg/l. In some embodiments, the concentration of L-carnitine-L-tartrate is in a range of from about 4000 mg/l to about 6000 mg/l. In some embodiments, the concentration of L-carnitine-L-tartrate is in a range of from about 6000 mg/l to about 8000 mg/l. In some embodiments, the concentration of L- carnitine-L-tartrate is in a range of from about 8000 mg/l to about 10000 mg/l. In some embodiments, the concentration of L-carnitine-L-tartrate is in a range of from about 10000 mg/l to about 12000 mg/l.
• the source of magnesium in the formulation comprises about 150mg/l magnesium. According to some embodiments, the source of magnesium in the formulation comprises about 100-110mg/l of magnesium. According to some embodiments, the source of magnesium in the formulation comprises about 110-120mg/l of magnesium. According to some embodiments, the source of magnesium in the formulation comprises about 120-130mg/l of magnesium. According to some embodiments, the source of magnesium in the formulation comprises about 130-140mg/l of magnesium. According to some embodiments, the source of magnesium in the formulation comprises about 140-150mg/l of magnesium. According to some embodiments, the source of magnesium in the formulation comprises about 150-160mg/l of magnesium.
• the source of magnesium in the formulation comprises about 160-170mg/l of magnesium. According to some embodiments, the source of magnesium in the formulation comprises about 170-180mg/l of magnesium. According to some embodiments, the source of magnesium in the formulation comprises about 180-190mg/l of magnesium. According to some embodiments, the source of magnesium in the formulation comprises about 190-200mg/l of magnesium.
• about 10%w/w of the magnesium source is magnesium. According to some embodiments, between about 5-15%w/w of the magnesium source is magnesium.
• the magnesium source is magnesium lactate or magnesium citrate.
• the amount of the magnesium source per dose of formulation is about 1500mg. According to some embodiments, the amount of the magnesium source per dose of formulation is between about 1000-1250mg. According to some embodiments, the amount of the magnesium source per dose of formulation is between about 1250-1500mg. According to some embodiments, the amount of the magnesium source per dose of formulation is between about 1500- l750mg. According to some embodiments, the amount of the magnesium source per dose of formulation is between about l750-2000mg.
• the amount of the magnesium source per dose of formulation is between about 3-l500mg. According to some embodiments, the amount of the magnesium source per dose of formulation is between about 3-l0mg. According to some embodiments, the amount of the magnesium source per dose of formulation is between about l0-50mg. According to some embodiments, the amount of the magnesium source per dose of formulation is between about 50-l00mg. According to some embodiments, the amount of the magnesium source per dose of formulation is between about l00-200mg. According to some embodiments, the amount of the magnesium source per dose of formulation is between about 200- 300mg. According to some embodiments, the amount of the magnesium source per dose of formulation is between about 300-400mg.
• the amount of the magnesium source per dose of formulation is between about 400- 500mg. According to some embodiments, the amount of the magnesium source per dose of formulation is between about 500-600mg. According to some embodiments, the amount of the magnesium source per dose of formulation is between about 600- 700mg. According to some embodiments, the amount of the magnesium source per dose of formulation is between about 700-800mg. According to some embodiments, the amount of the magnesium source per dose of formulation is between about 800- 900mg. According to some embodiments, the amount of the magnesium source per dose of formulation is between about 900-l000mg. According to some embodiments, the amount of the magnesium source per dose of formulation is between about 1000- l lOOmg.
• the amount of the magnesium source per dose of formulation is between about H00-l200mg. According to some embodiments, the amount of the magnesium source per dose of formulation is between about 1200- l300mg. According to some embodiments, the amount of the magnesium source per dose of formulation is between about l300-l400mg. According to some embodiments, the amount of the magnesium source per dose of formulation is between about 1400- l500mg. According to some embodiments, the amount of the L-carnitine source per dose of formulation is between about l00-2500mg. According to some embodiments, the amount of the L-carnitine source per dose of formulation is between about 100- 200mg.
• the amount of the L-carnitine source per dose of formulation is between about 200-300mg. According to some embodiments, the amount of the L-carnitine source per dose of formulation is between about 300- 400mg. According to some embodiments, the amount of the L-carnitine source per dose of formulation is between about 400-500mg. According to some embodiments, the amount of the L-carnitine source per dose of formulation is between about 500- 750mg. According to some embodiments, the amount of the L-carnitine source per dose of formulation is between about 750-l000mg. According to some embodiments, the amount of the L-carnitine source per dose of formulation is between about 1000- l250mg.
• the amount of the L-carnitine source per dose of formulation is between about 1250-1500mg. According to some embodiments, the amount of the L-carnitine source per dose of formulation is between about 1500- l750mg. According to some embodiments, the amount of the L-carnitine source per dose of formulation is between about l750-2000mg. According to some embodiments, the amount of the L-carnitine source per dose of formulation is between about 2000- 2250mg. According to some embodiments, the amount of the L-carnitine source per dose of formulation is between about 2250-2500mg.
• the amount of the magnesium source per dose of formulation is about l500mg and the amount of free magnesium per dose of formulation is about l50mg. According to some embodiments, the amount of the magnesium source per dose of formulation is between about l000-l250mg and the amount of the free magnesium is per dose of formulation between about l00-l25mg. According to some embodiments, the amount of the magnesium source per dose of formulation is between about l250-l500mg and the amount of the free magnesium per dose of formulation is between about l25-l50mg. According to some embodiments, the amount of the magnesium source per dose of formulation is between about 1500- l750mg and the amount of the free magnesium per dose of formulation is between about !50-l75mg. According to some embodiments, the amount of the magnesium source per dose of formulation is between about l750-2000mg and the amount of the free magnesium per dose of formulation is between about l75-200mg.
• the amount of the magnesium source in the formulation is about l500mg
• the amount of free magnesium is about l50mg
• the amount of the L-carnitine source is between about l500-2000mg.
• a concentration of DHQ in a formulation in liquid form is in a range of from about 20 mg/l to about 600 mg/l. In some embodiments, the concentration of DHQ is in a range of from about 40 mg/l to about 300 mg/l. In some embodiments, the concentration of DHQ is in a range of from about 60 mg/l to about 200 mg/l. In exemplary embodiments, the concentration of DHQ is about 60 mg/l. In some embodiments, the concentration of DHQ is in a range of from about 20 mg/l to about 40 mg/l. In some embodiments, the concentration of DHQ is in a range of from about 40 mg/l to about 60 mg/l.
• the concentration of DHQ is in a range of from about 60 mg/l to about 80 mg/l. In some embodiments, the concentration of DHQ is in a range of from about 80 mg/l to about 100 mg/l. In some embodiments, the concentration of DHQ is in a range of from about 100 mg/l to about 120 mg/l. In some embodiments, the concentration of DHQ is in a range of from about 120 mg/l to about 140 mg/l. In some embodiments, the concentration of DHQ is in a range of from about 140 mg/l to about 160 mg/l. In some embodiments, the concentration of DHQ is in a range of from about 160 mg/l to about 180 mg/l.
• the concentration of DHQ is in a range of from about 180 mg/l to about 200 mg/l. In some embodiments, the concentration of DHQ is in a range of from about 200 mg/l to about 220 mg/l. In some embodiments, the concentration of DHQ is in a range of from about 220 mg/l to about 240 mg/l. In some embodiments, the concentration of DHQ is in a range of from about 240 mg/l to about 260 mg/l. In some embodiments, the concentration of DHQ is in a range of from about 260 mg/l to about 280 mg/l. In some embodiments, the concentration of DHQ is in a range of from about 280 mg/l to about 300 mg/l.
• Example 1 An exemplary formulation according to some embodiments of the present invention is presented in Example 1 hereinafter.
• a general formulation comprises a source of magnesium, e.g., releasing about 150 mg magnesium, a source of L-carnitine, e.g., containing about 2,000 mg of the source of L-carnitine, water, and optionally dihydroquercetin (DHQ), e.g., at an amount of 15-50 mg.
• a source of magnesium e.g., releasing about 150 mg magnesium
• a source of L-carnitine e.g., containing about 2,000 mg of the source of L-carnitine
• water e.g., water
• DHQ dihydroquercetin
• An exemplary formulation contains 1 ,500 mg magnesium lactate (approximately 150 mg magnesium and 1,350 mg lactic acid); 2000 mg L-carnitine-L- tartrate (approximately 1360 mg L-carnitine); 15 mg DHQ, and water to complete a 250 ml formulation.
• a general formulation comprises a source of magnesium, e.g., releasing about 150 mg magnesium, a source of L-carnitine, e.g., containing about 1500-2000 mg of the source of L- carnitine, water, and optionally dihydroquercetin (DHQ), e.g., at an amount of 15-50 mg.
• a source of magnesium e.g., releasing about 150 mg magnesium
• a source of L-carnitine e.g., containing about 1500-2000 mg of the source of L- carnitine
• water optionally dihydroquercetin (DHQ), e.g., at an amount of 15-50 mg.
• DHQ dihydroquercetin
• Other formulations may contain other sources of magnesium (e.g., in a form of magnesium-enriched water); other sources of L-carnitine (e.g., as a pure crystalline form of free base L-carnitine, a HC1 salt of L-carnitine; and more); other amounts of the source of magnesium; other amounts of a source of L-carnitine; other anti oxidants; and other amounts, including absence, of DHQ or any other antioxidant.
• sources of magnesium e.g., in a form of magnesium-enriched water
• sources of L-carnitine e.g., as a pure crystalline form of free base L-carnitine, a HC1 salt of L-carnitine; and more
• other amounts of the source of magnesium e.g., other amounts of a source of L-carnitine; other anti oxidants; and other amounts, including absence, of DHQ or any other antioxidant.
• the formulation described herein may be provided for use in a form of a nutrition supplement.
• the formulation described herein in the manufacture of a nutrition supplement.
• the nutrition supplement is for use in combination with exercise (e.g., as described herein).
• a nutrition supplement which comprises a formulation as described herein.
• the nutrition supplement is for use in combination with exercise (e.g., as described herein).
• the nutrition supplement includes one or more additional nutrients, in addition to the magnesium, L-carnitine and optional antioxidant as described herein.
• suitable nutrients include, without limitation, essential minerals (e.g., calcium, iron, potassium, sodium), vitamins (e.g., vitamins A, Bi, B 2 , B3, B ⁇ , Bi2, C, D, E and/or K), and amino acids (e.g., any of the 20 standard amino acids, any of the 9 essential amino acids).
• the nutrition supplement comprises additional additives and/or active ingredients which may provide a beneficial effect. Examples of such additives include, but are not limited to, caffeine, L-arginine, ornithine, guarana, ginseng, and ginkgo balboa.
• any of the formulations and nutrition supplements described herein are useful for the treatment of liver conditions, as detailed herein, in a subject, upon exercising.
• the method is for treating liver conditions, such as fatty liver disease, chronic liver disease, non-alcoholic fatty liver disease (NAFLD), alcoholic liver disease (ALD), hepatitis, fibrosis, cirrhosis and non-alcoholic steatohepatitis (NASH)in a subject upon exercising.
• liver conditions such as fatty liver disease, chronic liver disease, non-alcoholic fatty liver disease (NAFLD), alcoholic liver disease (ALD), hepatitis, fibrosis, cirrhosis and non-alcoholic steatohepatitis (NASH)in a subject upon exercising.
• the method comprises administering the formulation and/or nutrition supplement as described herein to the subject prior to exercising.
• Fatty liver disease encompasses both non-alcoholic fatty liver disease and fatty liver disease associated with alcoholic liver disease.
• the fatty liver disease is non-alcoholic fatty liver disease.
• the fatty liver disease is associated with alcoholic liver disease.
• Fatty liver disease may be determined in accordance with known criteria used in the art of medicine, including for example, imaging of the liver (e.g., by ultrasonography, computed tomography, magnetic resonance imaging) and/or by tests for biomarkers (e.g., elevated liver enzymes).
• imaging of the liver e.g., by ultrasonography, computed tomography, magnetic resonance imaging
• biomarkers e.g., elevated liver enzymes
• suitable non-invasive tests for fatty liver disease include, without limitation, the FibroTest and the SteatoTest.
• formulation and/or nutrition supplement is optionally administered prior to beginning to perform exercise.
• the administration of the formulation and/or nutrition supplement is performed up to about 3 hours prior to exercising. In some embodiments, the administration of the formulation and/or nutrition supplement is performed from about 10 minutes to about 3 hours prior to exercising.
• the administration of the formulation and/or nutrition supplement is performed up to about 2 hours prior to exercising. In some embodiments, the administration of the formulation and/or nutrition supplement is performed from about 10 minutes to about 2 hours prior to exercising.
• the administration of the formulation and/or nutrition supplement is performed up to about 1.5 hours prior to exercising. In some embodiments, the administration of the formulation is performed from about 10 minutes to about 1.5 hours prior to exercising.
• the administration of the formulation and/or nutrition supplement is performed at least about 10 minutes prior to exercising. In some embodiments, the administration of the formulation and/or nutrition supplement is performed at least about 20 minutes prior to exercising. In some embodiments, the administration of the formulation and/or nutrition supplement is performed at least about 30 minutes prior to exercising. In some embodiments, the administration of the formulation and/or nutrition supplement is performed at least about 40 minutes prior to exercising. In some embodiments, the administration of the formulation and/or nutrition supplement is performed at least about one hour prior to exercising.
• the administration of the formulation and/or nutrition supplement is performed from about 20 minutes to about 2 hours prior to exercising. In some embodiments, the administration of the formulation and/or nutrition supplement is performed from about 30 minutes to about 1.5 hours prior to exercising. In some embodiments, the administration of the formulation and/or nutrition supplement is performed about one hour prior to exercising.
• the administration of the formulation and/or nutrition supplement is performed once a day.
• a daily exercise may be performed shortly thereafter, for example, within about three hours or less after administration of the formulation, e.g., as described herein.
• the daily exercise may be performed as a single exercise session or as a series of relatively short exercise sessions.
• a daily exercise is completed within about 3 hours or less after the administration of the formulation and/or nutrition supplement.
• the administration of the formulation and/or nutrition supplement (and in some embodiments, the accompanying exercise) is performed over a time period of at least about 10 days.
• the time period is at least about 14 days.
• the time period is at least about 20 days.
• the time period is at least about 28 days.
• the time period is at least about one month.
• the time period is at least about two months.
• the time period is at least about 3 months.
• the time period is at least exercising 4 months.
• the time period is at least exercising 5 months.
• the time period is at least exercising 6 months.
• the administration of the formulation and/or nutrition supplement (and in some embodiments, the accompanying exercise) is performed over a time period of up to about 365 days.
• the time period is up to about 200 days.
• the time period is up to about 150 days.
• the time period is up to about 100 days.
• the time period is up to about 60 days.
• the time period is up to about 30 days.
• the administration of the formulation and/or nutrition supplement (and in some embodiments, the accompanying exercise) is performed over a time period of from about 10 days to about 365 days.
• the time period is from about 10 days to about 200 days.
• the time period is from about 14 days to about 150 days.
• the time period is from about 20 days to about 100 days.
• the time period is from about 28 days to about 60 days.
• the time period is from about one day to about 200 days.
• the time period is from about one to 10 days.
• the time period is from about 10 to 20 days. In some embodiments, the time period is from about 20 to 50 days.
• the time period is from about 50 to 100 days. In some embodiments, the time period is from about 100 to 150 days. In some embodiments, the time period is from about 150 to 200 days. In some embodiments, the time period is from about 200 to 250 days. In some embodiments, the time period is from about 250 to 300 days. In some embodiments, the time period is from about 300 to 365 days.
• the administration of the formulation and/or nutrition supplement is performed over a time period of about 28 days. It is believed that due to the efficacy of the formulation described herein, a regimen comprising the administration of the formulation and exercising will be more effective in treating liver conditions, such as fatty liver disease, chronic liver disease, non-alcoholic fatty liver disease (NAFLD), alcoholic liver disease (ALD), hepatitis, fibrosis, cirrhosis and non-alcoholic steatohepatitis (NASH), than a corresponding regimen of exercise alone or a corresponding regimen of exercise and the administration of L-carnitine.
• A“corresponding regimen” refers to a regimen with an equivalent amount of exercise and/or L-carnitine (e.g., in dose and time).
• Characterization of the effect of a combination of exercise and a formulation and/or nutrition supplement described herein may be performed by studying a group of subjects and averaging the results, as commonly performed in the art. Similarly, comparisons between the effects of a combination of exercise and a formulation described herein and exercise, alone or a combination of exercise and L-carnitine (as described herein), may be characterized by comparing average results for groups of subjects.
• each group comprises at least 4 subjects. In some embodiments, each group comprises at least 5 subjects. In some embodiments, each group comprises at least 6 subjects. In some embodiments, each group comprises at least 8 subjects. In some embodiments, each group comprises at least 10 subjects. In some embodiments, each group comprises at least 15 subjects. In some embodiments, each group comprises at least 20 subjects.
• the amount of magnesium in the formulation to be administered in per dose is in a range of from about 30 mg to about 750 mg. In some embodiments, the amount of magnesium is in a range of from about 50 mg to about 500 mg. In some embodiments, the amount of magnesium is in a range of from about 75 mg to about 300 mg. In some embodiments, the amount of magnesium is in a range of from about 100 mg to about 200 mg. In exemplary embodiments, the amount of magnesium is about 150 mg. In some embodiments, the amount of magnesium is in a range of from about 30 mg to about 50 mg. In some embodiments, the amount of magnesium is in a range of from about 50 mg to about 75 mg.
• the amount of magnesium is in a range of from about 75 mg to about 100 mg. In some embodiments, the amount of magnesium is in a range of from about 100 mg to about 125 mg. In some embodiments, the amount of magnesium is in a range of from about 125 mg to about 150 mg. In some embodiments, the amount of magnesium is in a range of from about 150 mg to about 175 mg. In some embodiments, the amount of magnesium is in a range of from about 175 mg to about 200 mg. In some embodiments, the amount of magnesium is in a range of from about 200 mg to about 250 mg. In some embodiments, the amount of magnesium is in a range of from about 250 mg to about 300 mg.
• the amount of magnesium is in a range of from about 300 mg to about 350 mg. In some embodiments, the amount of magnesium is in a range of from about 350 mg to about 400 mg. In some embodiments, the amount of magnesium is in a range of from about 400 mg to about 450 mg. In some embodiments, the amount of magnesium is in a range of from about 450 mg to about 500 mg.
• the amount of L- carnitine in the formulation to be administered per dose(e.g., a daily administration) is in a range of from about 340 mg to about 2720 mg. In some embodiments, the amount of L-carnitine is in a range of from about 680 mg to about 2720 mg. In some embodiments, the amount of L-carnitine is in a range of from about 680 mg to about 2040 mg. In some embodiments, the amount of L-carnitine is in a range of from about 1020 mg to about 1700 mg. In exemplary embodiments, the amount of L- carnitine is about 1360 mg.
• the amount of L-carnitine is in a range of from about 340 mg to about 680 mg. In some embodiments, the amount of L- carnitine is in a range of from about 680 mg to about 1020 mg. In some embodiments, the amount of L-carnitine is in a range of from about 1020 mg to about 1360 mg. In some embodiments, the amount of L-carnitine is in a range of from about 1360 mg to about 1700 mg. In some embodiments, the amount of L-carnitine is in a range of from about 1700 mg to about 2040 mg. In some embodiments, the amount of L-carnitine is in a range of from about 2040 mg to about 2380 mg. In some embodiments, the amount of L-carnitine is in a range of from about 2380 mg to about 2720 mg.
• the L-carnitine is in the form of L-carnitine-L-tartarte, and the amount of L-carnitine-L-tartrate in the formulation to be administered per dose (e.g., a daily administration) is in a range of from about 500 mg to about 4000 mg.
• the amount of L- carnitine-L-tartrate is in a range of from about 1000 mg to about 4000 mg.
• the amount of L-camitine-L- tartrate is in a range of from about 1000 mg to about 3000 mg.
• the amount of L-carnitine-L-tartrate is in a range of from about 1500 mg to about 2500 mg.
• the amount of L-carnitine-L-tartrate is about 2000 mg. In some embodiments, the amount of L-carnitine-L-tartrate is in a range of from about 500 mg to about 750 mg. In some embodiments, the amount of L-carnitine-L-tartrate is in a range of from about 750 mg to about 1000 mg. In some embodiments, the amount of L-carnitine-L-tartrate is in a range of from about 1000 mg to about 1250 mg. In some embodiments, the amount of L-carnitine-L-tartrate is in a range of from about 1250 mg to about 1500 mg.
• the amount of L-carnitine-L-tartrate is in a range of from about 1500 mg to about 1750 mg. In some embodiments, the amount of L-carnitine-L- tartrate is in a range of from about 1750 mg to about 2000 mg. In some embodiments, the amount of L-carnitine-L-tartrate is in a range of from about 2000 mg to about 2250 mg. In some embodiments, the amount of L-carnitine-L-tartrate is in a range of from about 2250 mg to about 2500 mg. In some embodiments, the amount of L-carnitine- L-tartrate is in a range of from about 2500 mg to about 2750 mg. In some embodiments, the amount of L-camitine-L- tartrate is in a range of from about 2750 mg to about 3000 mg.
• the amount of DHQ in the formulation to be administered per dose is in a range of from about 5 mg to about 150 mg. In some embodiments, the amount of DHQ is in a range of from about 10 mg to about 75 mg. In some embodiments, the amount of DHQ is in a range of from about 15 mg to about 50 mg. In exemplary embodiments, the amount of DHQ is about 15 mg. In some embodiments, the amount of DHQ is in a range of from about 10 mg to about 20 mg. In some embodiments, the amount of DHQ is in a range of from about 20 mg to about 30 mg.
• the amount of DHQ is in a range of from about 30 mg to about 40 mg. In some embodiments, the amount of DHQ is in a range of from about 40 mg to about 50 mg. In some embodiments, the amount of DHQ is in a range of from about 50 mg to about 60 mg. In some embodiments, the amount of DHQ is in a range of from about 60 mg to about 70 mg. In some embodiments, the amount of DHQ is in a range of from about 70 mg to about 80 mg. In some embodiments, the amount of DHQ is in a range of from about 80 mg to about 90 mg. In some embodiments, the amount of DHQ is in a range of from about 90 mg to about 100 mg.
• the amount of DHQ is in a range of from about 100 mg to about 110 mg. In some embodiments, the amount of DHQ is in a range of from about 110 mg to about 120 mg. In some embodiments, the amount of DHQ is in a range of from about 120 mg to about 130 mg. In some embodiments, the amount of DHQ is in a range of from about 130 mg to about 140 mg. In some embodiments, the amount of DHQ is in a range of from about 140 mg to about 150 mg.
• An aqueous carrier may be beneficial prior to exercise by providing water required by the body during exercise.
• the volume of a liquid formulation based on an aqueous solution as described herein which is to be administered in a single administration (e.g., a daily administration containing suitable amounts of magnesium and L-carnitine, and optionally DHQ, as described herein), contains a substantial amount of water, such that the liquid formulation has a substantial volume, for example, at least about 0.2 ml.
• the volume of the formulation is in a range of from about 0.2 ml to about 1.0 ml. In some embodiments, the volume of the formulation is in a range of from about 1.0 ml to about lOml.
• the volume of the formulation is in a range of from about 10 ml to about 25 ml. In some embodiments, the volume of the formulation is in a range of from about 25 ml to about 50 ml. In some embodiments, the volume of the formulation is in a range of from about 50 ml to about 100 ml. In some embodiments, the volume of the formulation is in a range of from about 50 ml to about 500 ml. In some embodiments, the volume is in a range of from about 100 ml to about 500 ml. In some embodiments, the volume is in a range of from about 150 ml to about 400 ml.
• the volume is in a range of from about 200 ml to about 300 ml. In some embodiments, the volume is about 250 ml. In some embodiments, the volume is in a range of from about 50 ml to about 100 ml. In some embodiments, the volume is in a range of from about 100 ml to about 150 ml. In some embodiments, the volume is in a range of from about 150 ml to about 200 ml. In some embodiments, the volume is in a range of from about 200 ml to about 250 ml. In some embodiments, the volume is in a range of from about 250 ml to about 300 ml.
• the volume is in a range of from about 300 ml to about 350 ml. In some embodiments, the volume is in a range of from about 350 ml to about 400 ml. In some embodiments, the volume is in a range of from about 400 ml to about 450 ml. In some embodiments, the volume is in a range of from about 450 ml to about 500 ml.
• the formulation of the invention comprising palatinose, citric acid, carnitine L, magnesium citrate, flavorings, such as wild berry flavoring and cranberry flavoring, ascorbic acid, sucralose, potassium sorbate and water.
• the formulation comprises about 1 gr/per dose palatinose, about 0.2 gr/per dose citric acid, about 1.5 gr/per dose carnitine L, about 1.5 gr/per dose magnesium citrate, about 0.1 gr/per dose wild berry flavoring, about 0.05 gr/per dose cranberry flavoring, about 0.01 gr/per dose ascorbic acid, about 0.012 gr/per dose sucralose, about 0.0225 gr/per dose potassium sorbate and about 10.6055 gr/per dose water, wherein the dose is of about 15ml.
• Formulations of embodiments the present invention may be manufactured by processes well known in the art, e.g., by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or lyophilizing processes.
• Formulations in accordance with embodiments of the present invention thus may be formulated in conventional manner using one or more physiologically acceptable carriers comprising excipients and auxiliaries, which facilitate processing of the sources of magnesium and F-carnitine into preparations which can be used pharmaceutically. Proper formulation is dependent upon the route of administration chosen.
• the formulation is formulated for oral administration.
• the magnesium and L-carnitine of embodiments the invention can be formulated readily by combining the sources of magnesium and L- carnitine with physiologically acceptable carriers well known in the art.
• physiologically acceptable carriers well known in the art.
• Such carriers enable the magnesium and L-carnitine to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions, and the like, for oral ingestion by a subject.
• the formulation or nutrition supplement is formulated as a beverage, that is, a liquid which can be drunk by a typical subject in relatively large amounts (e.g., at least 50 ml) with no significant discomfort or adverse effects.
• Formulation of a beverage will generally include water or an aqueous solution as the carrier.
• the beverage may optionally include further ingredients known in the art for enhancing palatability of beverages, e.g., flavoring agents, sweeteners, coloring agents, and the like.
• Formulations and nutrition supplements for oral use can be made using a solid excipient, optionally grinding the resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries if desired, to obtain tablets or dragee cores.
• Suitable excipients include, in particular, fillers such as sugars, including lactose, sucrose, mannitol and/or sorbitol; cellulose preparations such as, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methylcellulose, hydroxypropylmethyl-cellulose, and/or sodium carboxymethylcellulose; and/or physiologically acceptable polymers such as polyvinylpyrrolidone (PVP).
• disintegrating agents may be added, such as cross-linked polyvinylpyrrolidone, agar, and/or alginic acid or a salt thereof such as sodium alginate.
• Dragee cores may be provided with suitable coatings.
• suitable coatings For this purpose, concentrated sugar solutions may be used which may optionally contain gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol, titanium dioxide, lacquer solutions and suitable organic solvents or solvent mixtures.
• Dyestuffs or pigments may be added to the tablets or dragee coatings for identification or to characterize different combinations of active magnesium and/or L-carnitine doses.
• Formulations and nutrition supplements which can be used orally further include push-fit capsules prepared from gelatin, as well as soft, sealed capsules prepared from gelatin and a plasticizer, such as glycerol or sorbitol.
• the push-fit capsules may contain the active ingredients in admixture with fillers, such as lactose, binders, such as starches, lubricants, such as talc or magnesium stearate, and optionally stabilizers.
• the magnesium and L-carnitine may be dissolved or suspended in suitable liquids, such as water, aqueous solutions, fatty oils, liquid paraffin, or liquid polyethylene glycols.
• stabilizers may be added.
• All formulations for oral administration should be in dosages suitable for the chosen route of administration.
• the magnesium and L-carnitine of embodiments of the invention may be formulated in aqueous solutions, such as physiologically compatible buffers such as Hank’s solution, Ringer’s solution, or physiological saline buffer with or without organic solvents such as propylene glycol, polyethylene glycol.
• physiologically compatible buffers such as Hank’s solution, Ringer’s solution
• physiological saline buffer with or without organic solvents such as propylene glycol, polyethylene glycol.
• penetrants may be used in the formulation.
• compositions may take the form of tablets or lozenges formulated in conventional manner.
• the magnesium and L-carnitine for use according to the present invention may be delivered in the form of an aerosol spray presentation (which typically includes powdered, liquefied and/or gaseous carriers) from a pressurized pack or a nebulizer, with the use of a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane or carbon dioxide.
• a suitable propellant e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane or carbon dioxide.
• the dosage unit may be determined by providing a valve to deliver a metered amount.
• Capsules and cartridges of, e.g., gelatin for use in an inhaler or insufflator may be formulated containing a powder mix of the sources of magnesium and L-carnitine and a suitable powder base such as, but not limited to, lactose or starch.
• the sources of magnesium and L-carnitine described herein may be formulated for parenteral administration, e.g., by bolus injection or continuous infusion.
• Formulations for injection may be presented in unit dosage form, e.g., in ampoules or in multidose containers with optionally, an added preservative.
• the compositions may be suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents.
• Formulations for parenteral administration include aqueous solutions of the sources of magnesium and L-carnitine in water-soluble form.
• suspensions of the sources of magnesium and L-carnitine may be prepared as appropriate oily injection suspensions and emulsions (e.g., water- in-oil, oil- in- water or water-in-oil in oil emulsions).
• Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acids esters such as ethyl oleate, triglycerides or liposomes.
• Aqueous injection suspensions may contain substances, which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol or dextran.
• the suspension may also contain suitable stabilizers or agents, which increase the solubility of the magnesium and L-carnitine to allow for the preparation of highly concentrated solutions.
• the sources of magnesium and L-carnitine may be in powder form for constitution with a suitable vehicle, e.g., water, before use.
• the sources of magnesium and L-carnitine described herein may also be formulated in rectal compositions such as suppositories or retention enemas, using, e.g., conventional suppository bases such as cocoa butter or other glycerides.
• formulations and nutrition supplements described herein may also comprise suitable solid or gel phase carriers or excipients.
• suitable solid or gel phase carriers or excipients include, but are not limited to, calcium carbonate, calcium phosphate, various sugars, starches, cellulose derivatives, gelatin and polymers, such as polyethylene glycols.
• the formulation or nutrition supplement is in a unit dosage form.
• unit dosage form describes physically discrete units, each unit containing a predetermined quantity of active ingredients (e.g., magnesium and L-carnitine) calculated to produce the desired effect, in association with at least one physiologically acceptable carrier, diluent, excipient, or combination thereof.
• active ingredients e.g., magnesium and L-carnitine
• the unit dosage form comprises an amount of magnesium and L-carnitine (and optionally also an antioxidant such as DHQ) suitable for a formulation to be administered per dose (e.g., a daily administration), as described herein (e.g., from 30 mg to 750 mg magnesium, from 340 mg to 2720 mg L-carnitine (e.g., from 500 mg to 4000 mg L-carnitine-L-tartrate), e.g., from 5 mg to 150 mg DHQ).
• a formulation to be administered per dose e.g., a daily administration
• Composition unit dosage forms for oral administration include sachets, pills, caplets, capsules, tablets, or discrete (e.g., separately packaged) units of powder, granules, or suspensions or solutions in aqueous or non-aqueous media.
• the unit dosage form comprises the formulation in a liquid form (e.g., suspension or solution), for example, a beverage (e.g., as described herein).
• a liquid form e.g., suspension or solution
• a beverage e.g., as described herein.
• the liquid of the unit dosage form may be packaged in a suitable packaging, for example, a bottle or a can.
• the volume of liquid formulation (or nutrition supplement) in a unit dosage form is at least about 50 ml. In some embodiments, the volume is in a range of from about 50 ml to about 500 ml. In some embodiments, the volume is in a range of from about 100 ml to about 500 ml. In some embodiments, the volume is in a range of from about 150 ml to about 400 ml. In some embodiments, the volume is in a range of from about 200 ml to about 300 ml. In some embodiments, the volume is about 250 ml.
• the unit dosage form is in a form of a solid (e.g., sachets, pills, caplets, capsules, tablets, or discrete units of powder, granules) or concentrated liquid (e.g., a syrup) and is prepared for use by mixing with a volume of water to form a suspension or solution.
• the volume of water may be determined so as to result in a liquid formulation described herein (e.g., having a volume of from about 50 ml to about 500 ml).
• kits comprising a packaging material, a source of magnesium (e.g., as described herein), a source of L-carnitine (e.g., as described herein) and a physiologically acceptable carrier (e.g., as described herein).
• a source of magnesium e.g., as described herein
• a source of L-carnitine e.g., as described herein
• a physiologically acceptable carrier e.g., as described herein
• the kit comprises two or more individually packaged components of a formulation described herein which may be combined by a user to form the formulation.
• the source of magnesium and the source of L-carnitine described herein are packaged individually (e.g., as separate components within the kit). In some embodiments, at least one of the aforementioned sources is packaged as a powder.
• a carrier as described herein is packaged individually (e.g., as a third component within the kit).
• the carrier is packaged in combination with another component, such as the source of magnesium or the source of L-carnitine, for example, in a form of a solution or suspension of the source of magnesium or source of L-carnitine.
• the source of magnesium and carrier are packaged in combination, for example, as a solution containing magnesium (e.g., magnesium- enriched water).
• the L-carnitine is packaged separately as a solid (e.g., powder) which may be added to the carrier in combination with magnesium.
• magnesium is an element and thus resistant to degradation
• L-carnitine and many antioxidants e.g., DHQ
• DHQ antioxidants
• a liquid carrier is packaged in combination with the source of magnesium, and organic compounds in the kit (e.g., L-carnitine, DHQ) are packaged individually in solid form (which is generally less susceptible than liquid forms to degradation), for example, as a powder.
• organic compounds in the kit e.g., L-carnitine, DHQ
• the organic compounds are packaged individually.
• the organic compounds are packaged in combination, e.g., as a powder mixture.
• the active ingredients may, if desired, be presented in a pack or dispenser device, such as an FDA (the U.S. Food and Drug Administration) approved kit, which may contain one or more unit dosage forms containing the active ingredients.
• the pack may, for example, comprise metal or plastic foil, such as, but not limited to, a blister pack or a pressurized container (for inhalation).
• the pack or dispenser device may be accompanied by instructions for administration.
• the pack or dispenser may also be accompanied by a notice associated with the container in a form prescribed by a governmental agency regulating the manufacture, use or sale of pharmaceuticals, which notice is reflective of approval by the agency of the form of the compositions for human or veterinary administration.
• a notice associated with the container in a form prescribed by a governmental agency regulating the manufacture, use or sale of pharmaceuticals, which notice is reflective of approval by the agency of the form of the compositions for human or veterinary administration.
• Such notice for example, may be of labeling approved by the U.S. Food and Drug Administration for prescription drugs or of an approved product insert.
• Compositions comprising formulations described herein may also be prepared, placed in an appropriate container, and labeled for the treatment of an indicated condition, as is detailed herein.
• the formulations, kits or nutrition supplements described herein are packaged in a packaging material and identified in print, in or on the packaging material, for any of the uses as described herein, including for use in the treatment of a condition selected from the group consisting of excess weight, fatty liver disease and chronic fatigue syndrome (as described herein).
• the formulation, kit, or nutrition supplement is indicated for use in combination with exercise (e.g., as described herein).
• the term“about” refers to ⁇ 10 %
• the terms "comprises”, “comprising”, “includes”, “including”,“having” and their conjugates mean “including but not limited to”.
• compositions, method or structure 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.
• a compound or “at least one compound” may include a plurality of compounds, including mixtures thereof.
• a numerical range is indicated herein, it is meant to include any numeral value (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.
• 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.
• 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.
• a general formulation comprises a source of magnesium, e.g., releasing about 150 mg magnesium, a source of L-carnitine, e.g., containing about 2,000 mg of the source of L-carnitine, water, and optionally dihydroquercetin (DHQ), e.g., at an amount of 15-50 mg.
• a source of magnesium e.g., releasing about 150 mg magnesium
• a source of L-carnitine e.g., containing about 2,000 mg of the source of L-carnitine
• water e.g., containing about 2,000 mg of the source of L-carnitine
• DHQ dihydroquercetin
• An exemplary formulation contains 1 ,500 mg magnesium lactate
• formulations may contain other sources of magnesium (e.g., in a form of magnesium-enriched water); other sources of L-carnitine (e.g., as a pure crystalline form of free base L-carnitine, a HC1 salt of L-carnitine; and more); other amounts of the source of magnesium; other amounts of a source of L-carnitine; other anti-oxidants; and other amounts, including absence, of DHQ or any other antioxidant.
• liver conditions such as fatty liver disease, chronic liver disease, non-alcoholic fatty liver disease (NAFLD), alcoholic liver disease (ALD), hepatitis, fibrosis, cirrhosis and non-alcoholic steatohepatitis (NASH), at an age of from 20 to 70, will be recruited for the study.
• NAFLD non-alcoholic fatty liver disease
• ALD alcoholic liver disease
• hepatitis hepatitis
• fibrosis fibrosis
• cirrhosis non-alcoholic steatohepatitis
• Each volunteer will be instructed to consume a 250 ml formulation about an hour before exercising, and to perform a one -hour exercise on a treadmill (walking at a speed of 6.5 kilometers per hour).
• L-carnitine group receiving a formulation containing two grams of L- carnitine
• Test group receiving the abovementioned exemplary formulation containing a source of magnesium, a source of L-carnitine, and DHQ.
• the treatment regimen (diet, exercise and formulations) will be applied for 4 weeks.
• Patients with fatty liver disease will be divided into two groups (e.g., of 20 patients each). Patients in one group will be administered the formulation described in Example 1 (e.g., for 3 months), whereas patients in the other group will receive a placebo during the same time period. Administration of the formulation and placebo will be performed in conjunction with a suitable exercise regimen (e.g., as described in Example 1).
• a suitable exercise regimen e.g., as described in Example 1).
• the effect of the treatment on the liver (relative to the placebo) will be assessed using a SteatoTest, which estimates steatosis, and will be performed in Rambam Laboratories in Jerusalem, Israel.
• OBJECTIVES To evaluate the effectiveness of the combination of a formulation comprising amino acid L-carnitine and magnesium together with exercise, when treating patients with NAFLD.
• MATERIALS & METHODS A Phase 3, randomized, double blind, placebo- controlled, NAFLD clinical trial was performed between 10/2017 and 5/2018, at the Liver Diseases Unit at Haemek Medical Center, Afula, Israel. Patients were randomly assigned and double blinded to two groups: The group was the“research group” which received a test formulation as detailed in Table 1 below for 16 weeks. The group was the“control group” which received a placebo (mineral water) for 8 weeks followed by an additional 8 weeks of the test formulation. Steatosis and liver fibrosis were assessed according to shear-wave elastography sonographic measurements using the supersonic sonographic unit (Trance) at the beginning and end of the study.
• RESULTS A total of 22 patients were recruited. The research group and the control group consisted of 11 patients each. In the research group, the aspartate aminotransferase (AST), alanine aminotransferase (ALT) and c-reactive protein (CRP) levels decreased significantly during the 16 weeks of treatment; however, the lipid profile and the insulin levels did not change significantly. In the control group there were no significant changes in AST, ALT and CRP levels and/or in the lipid profile or the insulin levels. Shear wave elastography failed to demonstrate a statistically significant difference between the two groups in terms of fibrosis.
• AST aspartate aminotransferase
• ALT alanine aminotransferase
• CRP c-reactive protein

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